:5: .2... “a " r314 so... It... a r rixa... 3;: 1L! .6. r E. . . a... 1 .. n. ,E . .. ,fimnfiwmnwm .. .. g :.y 596.... E. , . .15 .15}. . . Jest: : .i .c 39? :1 light! :4.- - ‘2 .9. , b:- ufh 5 at; .I: Q 3 1...: 7. .t .2. .3... {.13 a .3 b w: 1... .r I :sfi...hfi.3§rnnvo_!fi3‘5... . T‘gv-l a: .v x . .9127... 6 E‘slnrlil’ A}. (it 4‘... i113!!! .1- 5-1.? is. 33:33.}... 5.011;!!! I. 6.1!... LIBRARY MIC“? ‘34.“; -- "gun I U‘ale UniversiLj This is to certify that the dissertation entitled SYNTHESIS OF HETEROCYCLES USING GROUP-4 METAL CATALYZED C—N BOND FORMATION presented by Supriyo Majumder has been accepted towards fulfillment of the requirements for the PhD degree in Chemistry / - 441‘. K LI” Major Professor’s Signature MSU is an Affirmative Action/Equal Opportunity Employer PLACE IN RETURN BOX to remove this checkout from your record. TO AVOID FINES return on or before date due. MAY BE RECALLED with earlier due date if requested. DATE DUE DATE DUE DATE DUE 5/08 KzlPrqlAcc&Pres/ClRC/DateDue Indd SYNTHESIS OF HETEROCYCLES USING GROUP-4 METAL CATALYZEDC-N BOND FORMATION By Supriyo Majumder A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chemistry 2009 ABSTRACT SYNTHESIS OF HETEROCYCLES USING GROUP-4 METAL CATALYZED C—N BOND FORMATION By Supriyo Majumder Group-4 metal-catalyzed C—N bond formation has been utilized in synthesizing a variety of heterocycles and natural products. The research has been primarily focused on two major aspects. The first part of the thesis discusses the catalytic application of titanium and zirconium complexes bearing the 5,5-dimethyldipyrrolylmethane ancillary ligand in intramolecular hydroamination of alkenes. The zirconium precatalyst was found catalyze the hydroamination of both primary and secondary aminoalkenes. The mechanisms of the transformations have also been addressed. The second part of the thesis talks about the extention of hydroamination into multi-oomponent coupling reactions. Titanium-catalyzed 3-component coupling of an alkyne, isonitrile, and amine can be used to generate tautomers of 1,3-diimines. These diimines produced in situ undergo cyclization with hydrazine and amidine derivatives in a one-pot procedure to provide pyrazoles and pyrimidines respectively. The acid mediated cyclizations of diimines have also been investigated and a variety of quinolines, benzoquinolines and other heterocyclic compounds were prepared in one-pot procedures. This new one-pot multicomponent coupling reactions have been applied for the synthesis of natural products such as withasomnine and angustureine. A model study towards the synthesis of bis-indolyl pyrimidines has been investigated. Dedicated to my parents and my wife iv ACKNOWLEDGEMENTS First and foremost I would like to thank my advisor, Professor Aaron Odom, for all his support and guidance during my stay at Michigan State. He has always been there to help me whenever I needed it, especially during first few years when my chemistry was not working well. I would like to thank Michigan State University for their support. I also appreciate the support of the Department of Chemistry for the Brubaker Fellowship. I would also like to acknowledge all my past and present group members: Bala, Kapil, Sanjukta, Sam, Doug, Eyal, Steve, Troy, Kavin, Nick, Amila, and Rami. Doug deserves special thanks for being such a wonderful friend and colleague for last 5 years. I would also like to have a special “Thank You” for Bala for his generous help inside and outside the lab. Also, I am very fortunate to work with a few dedicated undergraduate students. I I would like to acknowledge Professor Bill Wulff, Professor Greg Baker, and Professor Jim McCusker for serving on my committee, for their guidance, and teaching me a degree of professionalism in presenting my research. Thanks to Professor Tepe for some helpful suggestions. Much thanks goes to Dr. Richard J. Staples and Dr. Daniel Holmes for their help in solving crystal structures and running various NMR experiments. I would like to thank Aman Desai and Konstantinos Rampalakos from the Wulff group for their help in doing some asymmetric catalysis. Words are not enough to express my gratitude towords my friends Prantik, Sabuj, Tapas, Partha, Santanu, Sudip, Bubai and Babua. The chain of gratitude would be incomplete if I forget to thank my teachers (Anup Samanta and Dilip Dutta) of my early days. Their efforts not only motivated me to pursue a career in science but also taught me to stand strong for my principles. Also, I would like to have a special gratitude to my “chorda” without whom I would ever be able to pursue a career in organic chemistry. Lastly, I would like to express my deepest sense of gratitude to my father, my mother and my wife for all their sacrifice, love, support and faith they put on me which helped me to succeed in every aspects of life. TABLE OF CONTENTS List of Tables ................................................................................................... ix List of Figures .................................................................................................. xi List of Abbreviations ........................................................................................ xii List of Schemes ............................................................................................... xiii 1. lntroductlon to Group-4 metal medlated C—N bond formation and Its appllcatlon to the synthesls of heterocycles and natural products... 1 1.1 Hydroamination ............................................................................................ 1 1.2 Zirconium-catalyzed alkyne hydroamination ......................................... 3 1.3 Titanium-catalyzed alkyne hydroamination ........................................... 5 1.4 Alkyne Hydroamination in the Odom group ........................................... 9 1.5 lntramolecular hydroamination of olefins ............................................... 15 1.6 Applications of hydroamination in heterocycle synthesis ...................... 18 1.7 Hydroamination based natural product synthesis .................................. 23 1.8 Conclusion ............................................................................................ 25 1.9 References ............................................................................................ 26 . Group-4 dlpyrrolylmethane complexes In lntramolecular olefln hydroamlnatlon ......................................................................................... 29 2.1 Introduction ........................................................................................... 29 2.2 Pyrrolyl ancillary ligands in hydroamination ........................................... 32 2.3 Synthesis and hydroamination of aminoalkenes ................................... 35 2.4 Results and discussion .......................................................................... 38 2.5 Conclusion ............................................................................................ 49 2.6 Experimental ......................................................................................... 50 2.7 References ............................................................................................ 59 . Pyrazole synthesls uslng a tltanlum-catalyzed multlcomponent coupling reactlon and synthesls of wlthasomnlne ................................................ 62 3.1 Introduction ........................................................................................... 62 3.2 Results and discussion .......................................................................... 65 3.3 Conclusion ............................................................................................ 79 3.4 Experimental ......................................................................................... 80 3.5 References ............................................................................................ 99 4. Tltanlum-catalyzed one-pot multlcomponent coupllng reactlon for direct access to pyrlmldlnes and model studles toward the synthesls of l-lyrtlnadlne A ............................................................................................. 104 4.1 Introduction ........................................................................................... 104 4.2 Results and discussion .......................................................................... 106 4.3 Conclusion ............................................................................................ 123 4.4 Experimental ......................................................................................... 125 4.5 References ............................................................................................ 151 5. A multlcomponent coupllng sequence for dlrect access to substltuted qulnollnes and related heterocycles ....................................................... 153 5.1 Introduction ........................................................................................... 153 5.2 Results and discussion .......................................................................... 154 5.3 Conclusion ............................................................................................ 168 5.4 Experimental ......................................................................................... 169 5.5 References ............................................................................................ 190 6. Appendlx .................................................................................................... 192 Crystal data and structure refinement for Compound 13 (chapter 4) ........... 193 Crystal data and structure refinement for Compound 12 (chapter 4) ........... .208 Crystal data and structure refinement for [Zr(dpm)(NMe2)2]2. ..................... .223 viii Table 1 .1 Table 1.2 Table 2.1 Table 3.1 Table 3.2 Table 4.1 Table 4.2 Table 5.1 Table 5.2 Table 5.3 Table 5.4 Table A.1 Table A2 Table A.3 Table A.4 Table A.5 Table 8.1 LIST OF TABLES Alkyne hydroamination with 5 mol% Ti(dpm)(NMe2)2 ................ 13 Hydroamination of enynes with 10 mol% Ti(dap)2(NMe2)2. ....... 15 Catalytic intramolecular hydroamination reactions with zirconium catalysts ..................................................................................... 44 Examples of pyrazole (3) syntheses using phenylacetylene and a variety of hydrazines. ................................................................. 72 Examples of pyrazole (3) syntheses using phenylhydrazine with other alkynes. ............................................................................ 74 Examples of pyrimidine (3) syntheses using benzamidine hydrochloride. ............................................................................ 1 1 1 Examples of pyrimidine (4) syntheses using different amidines. 115 Examples of quinoline syntheses ............................................... 156 Examples of benzoquinoline syntheses ..................................... 159 Examples of products prepared from amino-heterocycles ......... 163 Organocatalytic asymmetric reduction of 2-pentquuinoline ....... 167 Atomic coordinates and equivalent isotropic displacement parameters for Compound 13 .................................................... 194 Bond lengths and angles for Compound 13 ............................... 196 Anisotropic displacement parameters for Compound 13 ........... 202 Hydrogen coordinates and isotropic displacement parameters for Compound 13 ............................................................................ 204 Torsion angles for Compound 13 ............................................... 205 Atomic coordinates and equivalent isotropic displacement parameters for Compound 12 .................................................... 209 Table 8.2 Table 8.3 Table 8.4 Table 8.5 Table 0.1 Table 0.2 Table C.3 Table 0.4 Bond lengths and angles for Compound 12 ............................... 211 Anisotropic displacement parameters for Compound 12 ........... 217 Hydrogen coordinates and isotropic displacement parameters for Compound 12 ............................................................................ 219 Torsion angles for Compound 12 ............................................... 220 Atomic coordinates and equivalent isotropic displacement for [Zr(dpm)(NMe2)2]2 .................................................................... 224 Bond lengths and angles for [Zr(dpm)(NMe2)2]2 ....................... 225 Anisotropic displacement parameters for [Zr(dpm)(NMe2)2]2 230 Hydrogen coordinates and isotropic displacement parameters for [Zr (dpm)(NM92)2]2 .................................................................... 231 LIST OF FIGURES Flgure 1.1 Structure of Ti(dpma)(NMe2)2 .................................................... 10 Flgure1.2 Indene-based olefin hydroamination precatalysts ...................... 17 Flgure 2.1 Lanthanide and Group-4 metal-based intramolecular hydroamination precatalysts ...................................................... 30 Flgure 2.2 Structure of [Zr(dpm)(NMe2)2]2 (2) by X-ray diffraction .............. 40 Flgure 4.1 Regioselectivity in alkyne addition ............................................. 114 Flgure 4.2 Bis-indole alkaloid Hyrtinadine A ............................................... 117 Flgure 4.3 Model compound 2,5-bis(indolyl)pyrimidine (5) ......................... 117 Flgure 4.4 Structure of 2,4-bis(indolyl)pyrimidine 13 (top) and 2,5- bis(indolyl)pyrimidine 12 (bottom) by X-ray diffraction. .............. 122 Flgure 5.1 Natural products based on tetrahydroquinolines ........................ 164 Flgure 5.2 Chiral catalysts used for asymmetric reductions ........................ 166 Dap me dpma GC/FID THF DME TFA RT EtOAc 3CC Bn DMF NMR DMSO-de M.p. LIST OF ABBREVIATIONS 2-((dimethyamino)methyl)pyrrolyl 5,5-dimethyldipyrrolylmethane N,N-di(pyrrolyI-a-methyl)-N-methylamine Gas Chromatography Flame Ionization Detector tetrahydrofuran 1 ,2-dimethoxyethane trifluoroacetic acid room temperature ethyl acetate three-component coupling benzyl N,N-dimethyl formamide nuclear magnetic resonance deuterated dimethyl sulfoxide melting point LIST OF SCHEMES Scheme 1.1 Zirconium-catalyzed intermolecular hydroamination .................. 3 Scheme 1.2 Proposed mechanism for the catalytic hydroamination .............. 4 Scheme 1.3 Zirconium-catalyzed hydroamination of allene ........................... 5 Scheme 1.4 Titanium-catalyzed intramolecular hydroamination of aminoalkynes ................................................................................................... 6 Scheme 1.5 Cp2TiMe2-catalyzed intermolecular hydroamination of alkynes. 6 Scheme 1.6 lnd2TiMe2 catalyzed hydroamination of alkynes ........................ 8 Scheme 1.7 Synthesis of prm and Ti(NMe2)2(dpm) .................................. 12 Scheme 1.8 Synthesis and application of (NPS)Zr(NMe2)2 in aminoalkene hydroamination .......................................................................... 1 7 Scheme 1.9 Pyrrole synthesis via hydroamination of 1,4- and 1,5-diynes ..... 18 Scheme1.10Dihydropyridine synthesis using hydroamination/C—H insertion tandem catalysis ........................................................................ 19 Scheme 1.11 Pyrroles from hydroamination of chloroenynes ........................ 20 Scheme 1.12 One-pot indole synthesis via hydroamination ........................... 20 Scheme 1.13 Benzo[b]furan synthesis using anti-Markivnikov hydroamination ................................................................................................... 21 Scheme 1.14 Hydroamination based synthesis of tricyclic benzo[a]quinolizine ................................................................................................... 22 Scheme 1.15 Pyrrolizidine from hydroamination/cross-coupling .................... 22 Scheme 1.16 Synthesis of (S‘)-(+)-Laudanosine and (.S‘)-(-)-Xylopinine based on intramolecurar hydroamination of alkynes ................................. 23 Scheme 1 .17 Synthesis of ( :1: ) Monomorine .................................................. 24 Scheme 2.1 [2 + 2]-cycloaddition mechanism of Bergman (left) and the 1,2- insertion mechanism of Marks (right) ......................................... 31 Scheme 2.2 Mechanism of olefin metathesis (left) and the Bergman mechanism of alkyne hydroamination ........................................................... 33 Scheme 2.3 Synthesis of H2dpm and Ti(NMe2)2(dpm) (1) ............................ 34 Scheme 2.4 Synthesis of gem-substituted aminoalkenes .............................. 35 Scheme 2.5 Synthesis of 4,5-disubstituted aminoalkene ............................... 36 Scheme 2.6 Synthesis of unsubstituted aminoalkene .................................... 36 Scheme 2.7 o-allylaniline via Aza-Claisen rearrangement ............................. 37 Scheme 2.8 Preparation of secondary aminoalkene 37 Scheme 2.9 Gem-dialkyl effect, a combination of Thorpe-Ingold (top) and reactive rotamer effects (bottom) ............................................... 42 Scheme 2.10 Possible route to the product distribution observed when IV- methyl-2,2-diphenylpent-4-en-1-amine is reacted with 2 ,,,,,,,,,,,,,,,,,,,, 47 Scheme 3.1 Palladium-catalyzed 3-component coupling for pyrazole synthesis ................................................................................................... 63 Scheme 3.2 One-pot palladium catalyzed 4-component synthesis of pyrazole ................................................................................................... 63 Scheme 3.3 Titanium catalyzed 3-component iminoamination of alkynes ..... 65 Scheme 3.4 Proposed mechanism for titanium-catalyzed iminoamination of alkynes ...................................................................................... 66 Scheme 3.5 Synthesis of szpma, H2dpm, Ti(NMe2)2(dpma) (1), and Ti(NMe2)2(dpm) (2) .................................................................... 67 Scheme 3.6 Effect of catalysts on regioselectivity ......................................... 68 Scheme 3.7 Multicomponent coupling using enynes ..................................... 69 xiv Scheme 3.8 One-pot synthesis of pyrazoles (3) ............................................ 70 Scheme 3.9 Regioselectivity of pyrazole formation using 1-hexyne as the substrate and catalyst 1 and 2 ................................................... 75 Scheme 3.10 Synthesis of withasomnine ....................................................... 77 Scheme 4.1 One-pot synthesis of pyrimidines (3) ......................................... 106 Scheme 4.2 Synthesis of 2-ethynylthiophene and 2-ethynylfuran ................. 108 Scheme 4.3 Synthesis of N,N-diethyl-5-phenylpent-4-yn-1-amine ................ 108 Scheme 4.4 Retrosynthetic analysis of 2,5—bis-indolyl pyrimidine (5) ............ 118 Scheme 4.5 Synthesis of the indole-alkyne 6 ................................................ 119 Scheme 4.6 Synthesis of the amidine 7 ......................................................... 120 Scheme 4.7 One-pot synthesis of bis-indolyl pyrimidine 12 and 13 ............... 121 Scheme 5.1 Quinoline synthesis using titanium-catalyzed multicomponent coupling ..................................................................................... 155 Scheme 5.2 Proposed mechanism for quinoline synthesis ............................ 157 Scheme 5.3 Synthesis of benzo[b]thiophen-3-amine ..................................... 160 Scheme 5.4 3 step synthesis of 1-aminopyrrole from phthalimide ................. 161 Scheme 5.5 Synthesis of racemic Angustureine (5) ...................................... 165 CHAPTER 1 Introduction to Group-4 metal mediated C—N bond formation and its application to the synthesis of heterocycles and natural products 1.1 Hydroamlnatlon Organic molecules containing nitrogen atoms are undoubtedly one of the most important class of compounds due to their wide range of applications in pharmaceuticals and agrochemicals as well as in commodity and fine chemicals. Therefore, synthetic methods aiming incorporation of nitrogen atoms in organic molecules should be highly desirable, and hence, numerous C—N bond-forming strategies have been developed in recent years. “Hydroamination” is the addition of an amine N—H functionality to an unsaturated carbon—carbon bond either in an intermolecular (Equation 1.1) or intramolecular fashion (Equation 1.2).1 The reaction is 100% atom economical and generates amine products from alkenes or imine products from alkynes. .81 H N-R2 - + HN L > < n2 H “'1’ WE t HHS W) The direct addition of amines to alkenes is generally thermodynamically feasible. However, this simple addition reaction doesn’t occur without the presence of a catalyst. This is due to the higher activation barrier caused by the electrostatic repulsion between the electron pair of the nitrogen and the n- electron cloud on the olefin. Due to the negative reaction entropy. higher temperature actually shifts the equilibrium towards the starting materials.2 Also, a [2+2]-cycloaddition of the N—H with the olefin is not favorable due to the high- energy difference between It (C=C) and o (N-H). Therefore, uncatalyzed simple addition of amines to alkenes is only observed for activated, electron deficient olefins.3 To date a variety of metal catalysts have been developed to overcome the high-energy barrier of this seemingly simple transformation. These transformations can be placed in two different categories: alkyne or alkene activation or N—H activation. Alkyne or alkene activation has been accomplished by their coordination with the lewis acidic metal catalyst, which includes gold,4 platinum,5 palladium,6 and silver7 based systems. However, the more common N-H activation has been carried out in four different ways. The two most attractive, efficient, and general approaches involve lanthanide8 as well as actinide9 catalyzed formation of very reactive M—N (amido) intermediates, which undergo insertion of the carbon-carbon multiple bond. Alternatively, group-410 & 511 complexes generate M=N (imido) intermediates, which undergo [2+2]- cycloaddition with a carbon-carbon unsaturation. In other approaches, nucleophilic amide species are generated in presence of alkali metals12 or direct oxidative addition-insertion pathways can be present in low-valent late transition 3 metals like ruthenium1 or iridium.14 This chapter will mostly focus on group-4 metal catalyzed hydroamination and related reactions. 1.2 Zirconium-catalyzed alkyne hydroamination Pioneering work by Bergman and co-workers in 1992 provided the first example of zirconium-catalyzed intermolecular hydroamination of alkynes (Scheme 1.1).15 However, the reaction was found to work only with sterically hindered amines. Cp22r(NHAr)2 (3 mol%) HN-Ar Ph—Z—Ph + ArNH2 > /=( benzene-d6, 120 °C Ph Ph Scheme 1.1. Zirconium-catalyzed intermolecular hydroamination. The proposed mechanism for the above catalytic hydroamination is shown in Scheme 1.2. The bis-amido precatalyst (A) can undergo a-elimination to form zirconium imido (8) intermediate. An azazirconacyclobutene (C) is formed via reversible [2+2]-cycloaddition of imido (B) with diphenylacetylene. Protonolysls of the metallacycle (C) is believed to form the intermediate D, which is converted back the imido (B) with release of the hydroamination product. Cp22r(NHAr)2 A Ph HN-Ar % /==< Cp22r=NAr \Ph Ph Ph B A “Ni: ,q , \ Ph ’ Ph szzr. H 0922' / AN“ Ph c r o ArNH2 Scheme 1.2. Proposed mechanism for the catalytic hydroamination. The attempted hydroamination of unactivated alkenes with a bis(amido) zirconium precatalyst was unsuccessfull, but the more reactive double bond of allene was hydroaminated catalytically by the bisamide A (Scheme 1.3). The anti-Markovnikov addition product, the 2,6-dimethylphenylimine of acetone, was isolated in 83% yield. CpZZr(NHAr)2 (2.7 mol%) N‘Ar H20:C:CH2 + ATNHQ V l 90 °C, 6 d Me/kMe Scheme 1.3. Zirconium-catalyzed hydroamination of allene. More recently, Schafer and coworkers have reported bis(amidate) zirconium complexes (Equation 1.3) as effective precatalysts for both intra- and intermolecular hydroamination of alkynes.16 O toluene N NEt2 + Zr NEt > z' ' 2 RJLnJ< ( 2)“ A.14 h (R_ i-PerEt (40 mol%) flvph H2N THF, 25 °C. 30 min 7 N 94% _ Cp'|”IC|3 (20 mol%) Ph—_;> i-PerEt (40 mol%) _ 0V toluene, 80 °C, 30 m? N’ P“ H2N 88% Scheme 1.4. Titanium-catalyzed lntramolecular hydroamination of amino alkynes. In 1999, the Doye group introduced a versatile Cp-based hydroamination precatalyst, CpZTiMez. This precatalyst was very efficient for the hydroamination internal and terminal alkynes with a variety of aryl as well as alkyl amines. The hydroamination products, imines, were isolated either as the ketones after passing through silica or reduced to amines with LiAlH4 (Scheme 1.5).18 o 1) 3 mol% Cp2TiMe2 P“ 2 P“ 1) 3 mol% szTileez NHR A toluene, 100 °C + toluene, 100 C: Ph Ph 2) SiOz R-NH2 2) LiAlH4, THF, 65 °C P“ P“ Scheme 1.5. szTiMez-catalyzed intermolecular hydroamination of alkynes. Although hydroamination with Cp2TiMe2 was quite successful with aryl as well as sterically demanding sec- and tart-alkyl amines, relatively poor yields were obtained with n-alkyl and benzyl amines. Interestingly, a slightly modified Cp-based titanium catalyst, Cp2*TiMe2 (Cp* = Me5C5-) was found to be more successful with less sterically hindered amines.19 More recently the same group found that among the class of titanocene catalysts, commercially available lndQTiMez (Ind = indenyl) proved to be a highly active and general catalyst for the intermolecular hydroamination of alkynes. With this catalyst, primary aryl-, tert- alkyl-, sec-alkyl-, and n-alkyl amines can be reacted with internal and terminal alkynes. Subsequent reduction of the initially formed imines with Na8H30N in the presence of ZnCI2 gives access to secondary amines in good to excellent yields (Scheme 1.6).20 Me 1) 5 mol% lnd2TiMe2 0 Me 105 °C, 24 h HN Ph—Z—Ph + O > H2N 2) NaBH30N,ZnCI2 Ph\)\ph 98% OMe HN n-C H 1) 5 mol% lnd2TiMe2 6 ‘3\/l 1 Me 1 o ’ 1 h . 950/ ”CSH13—:——_H + O 05 C = + - ° H2N 2) NaBH3CN, anl2 "'06H13YM9 4 ”“0 Me Scheme 1.6. lndzTiMez catalyzed hydroamination of alkynes. In 2002, the Beller group introduced an aryloxo—based titanium precatalyst for chemo- and regioselective intermolecular hydroamination of internal and terminal alkynes with aliphatic and aromatic amines (Equation 1.4).21 The reaction was clean and formed imine products in good yields. They observed that the regioselectivity of the amine addtion can also be reversed by changing the substituent on the aryloxo ligand.22 NMe2 0 Ti Cat NMez R H 2 ‘ 1.4 Alkyne Hydroamlnatlon In the Odom group Research in our group was focused on using pyrrolyl-based ancillary ligands for hydroamination of alkynes. However, we were the first group to report Ti(NMe2)4 as a catalyst for intermolecular hydroamination of alkynes with primary amines (Equation 1.5).23 The reaction was surprisingly fast with many substrates and often selective for the Markovnikov product with terminal alkynes. R. /H st_NH catTi(NMe2)4_ I}: + R1,\(,N‘R 15 81/ + 2 ' R‘ Me H ' major minor (Markovnikov) (anti-Markovnikov) Although commercially available Ti(NMez)4 was found to be an effective catalyst for alkyne hydroamination with aryl amines, it failed when alkyl amines were employed. Hence, ongoing research in the group revealed that titanium complexes bearing pyrrolyl ancillary ligands were very efficient catalysts for intermolecular hydroamination of alkynes. Pyrroles are less n-donating compared to amines and alkoxides because the loan-pair on nitrogen is directly involved in maintaining the aromaticity. Therefore, metal-centers containing pyrrolyl ancillary ligands are often electron deficient and Lewis acidic. A pyrrolyl-based ancillary ligand, H2dpma24 (dpma = IV,N-di(pyrrolyl-a-methyl)-N-methylamine) was synthesized in a single step by Mannich condensation of pyrrole, formaldehyde, and methylamine hydrochloride in ethanol/water. The actual precatalyst, Ti(dpma)(NMe2)2 (Figure 1.1)25 was made by reacting H2dpma with Ti(NMez)4. TI(NMe2)2(dpma) Figure 1 .1 Structure of Ti(dpma)(NMe2)2. This new pyrrolyl-based catalyst was very efficient for alkyne hydroamination.26 Both internal and terminal alkynes were hydroaminated with aryl as well as alkyl amines; however, the hydroamination of terminal alkynes was most effective. Compared to Ti(NM82)4. Ti(dpma)(NMe2)2 was more selective for Markovnikov products. For example, hydroamination of 1-hexyne with aniline gave 50:1 selectivity towards Markovnikov product when Ti(dpma)(NMe2)2 was employed, but the same reaction gave only 3:1 selectivity with Ti(NMe2)4. The dpma ligand architecture bears pyrrolyl ligands with an 111,111- coordination in the solid state and in solution when bound to titanium. To date, this is the only bonding hapticity observed for the dpma ligand. Even though 10 Ti(NMe2)2(dpma) was a relatively good hydroamination catalyst, modifications in the structure to create a more Lewis acidic metal were explored. The most logical modification to the dpma ligand was removal of the donor amine in the dpma backbone, which leads to the use of dipyrrolylmethanes as ligands. The most commonly employed catalyst in this reaction is Ti(NMe2)2(dpm);27i szpm is available from condensation of pyrrole and acetone (Scheme 1.7) in the presence of trifluoroacetic acid (TFA).28 The solid state structure of Ti(NMe2)2(dpm) has the pyrrolyls 111,115-bound; however, in solution the 1H NMR spectrum shows equivalent pyrrolyls, indicative of fast pyrrolyl exchange on the NMR timescale. Using line shape analysis and spin saturation transfer experiments our group has been able to place a barrier for pyrrolyl exchange at ~10 kcal/mol.29 11 H H N o 10mol% TFA \ N 20 '1) + Y ’ \ I / NH / 50% szpm ether, RT Ti(NMe2)4 3h 91% Ti(dpm)(NMe2)2 Scheme 1.7. Synthesis of szpm and Ti(dpm)(NMe2)2. The hydroamination of terminal alkynes in presence of catalytic amounts of Ti(dpm)(NMe2)2 formed products in 5 minutes at room temperature in moderate to high yields. Internal alkynes such as 1-phenylpropyne or diphenylacetylene reacted slowly and hence they required up to a day for completion at elevated temperature. The hydroamination also works well with alkyl amines to produce imine products in high yields; however, elevated temperatures and prolonged reaction times can be necessary for complete conversion. Table 1.1 shows some examples of alkyne hydroamination with 5 mol% Ti(dpm)(NMez)2 as catalyst. 12 Table 1.1. Alkyne hydroamination with 5 mol% Ti(dpm)(NMe2)2 Amine Alkyne % catalyst, conditions °/o yield Selectivity Ph-NH2 Bu : H 5 mol%, 25 °C, 5 min 57 4o ; 1 Ph—z H 5 mol%, 25 °C, 5 min 41 3.6 : 1 Ph : Me 5 mol%, 50 °C, 6 h 83 50 : 1 Et—E—Et 5 mol%, 50 °C, 24 h 94 Ph—Z—Ph 5 mol%, 75 °C, 24 h 34 Cy-NHZ PhéH 5 mol%, 25 °C, 10 min 54 1.6 I 1 Ph—Z—Me 5 mol%, 75 °C, 24 h 93 11 ; 1 Et 2 Et 10 mol%, 75 °C, 48 h 73 Ph—Z—Ph 10 mol%, 100 °C, 48 h 72 The alkyne hydroamination was expanded to enyne substrates resulting in ants-unsaturated imines,30 which can be difficult to synthesize by the reaction of an (1.8-unsaturated ketone or aldehyde with a primary amine due to competing Michael addition}31 The Ti(dpm)(NMe2)2 catalyst can conveniently hydroaminate internal enynes in 5 h at 100 °C (Equation 1.6). Me Cy. / 10 mol% Ti(d m)(NMe ) N / p 2 2 | + O NH ‘ > Me 73% 13 Although Ti(dpm)(NMe2)2 was a very active catalyst for the hydroamination of enynes having an internal alkyne, it was a relatively poor catalyst for enynes cantaining terminal alkynes. For those highly reactive and polymerization-sensitive enynes, e.g. where the alkyne is terminal, the catalyst Ti(dap)2(NMez)2. where clap is IV,N-dimethylaminomethylpyrrolyl, was often optimal (Table 1.2). Ti(dap)2(NMe2)2 was synthesized in one-step by reacting Hdap with Ti(NMe2)4 (Equation 1.7).32 \ NMez \ NI,.._|L/NMe2 N Nil/192+ TINMG : I\ 1.7 V ( 2)4 95% N/lil NM92 MGR / Tl(dap)2(NMe2)2 14 Table 1.2. Hydroamination of enynes with 10 mol% Ti(dap)2(NMez)2. Amine 1,3-enyne conditions Pl'OdUCt % yield NPh Ph-NH2 0—: 50 °C, 16 h 0-K 88 NPh >—: 50 °C, 44 h .<\—( 64 Ph NPh >—E—Ph 130 °C, 19 h H 70 NPh NCy >-E 50 °C, 43 h H 73 1.5 lntramolecular hydroamination of olefins The intramolecular hydroamination of alkenes offers a direct one-step method for the synthesis of azacycles. Though the hydroamination of alkynes are well documented with group-4 metal catalysts, the hydroamination of alkenes using group-4 metals remain a significant challenge with the only reported examples of early transition metals being used for this transformation requiring the highly strained norbornene olefin with selective aniline derivatives. In 2005, Schafer and coworkers disclosed the first example of a neutral group-4 metal catalyst for intramolecular hydroamination of alkenes.34 They 15 33 found that commercially available Ti(NMez)4 can catalyze the cyclohydroamination of alkenes to form pyrrolidine products in high yields (Equation 1.8). Ph Ph toluene, 110 °C R = H, Ph 24 h Ph upto 92% yield . H HZNWR 5 mol% TI(NM62)': QAR 1 8 Ph Later in the same year the Livinghouse group reported a neutral zirconium based catalyst for this cyclization reaction.35 The precatalyst was synthesized by reacting chelating “NPS” ligand with Zr(NMe2)4. The NPS-Zr cpmplex was found to be a competent precatalyst for the cyclization of representative primary aminoalkenes (Scheme 1.8) 16 4.. 42.} 1358 NH 0 D .25 °C NE / ”Me? >C + ZI'(NM62)4 6 6 ” ><:/Z zr/r N.” 10min N./ \S NMe2 spas .P’Sj "NPS" (NPS)Zr(NMe2)2 5 mol% (NPS)Zr(NMe2)2 / NH > 2 de-Toluene, N 150 °C, 2 5 h H 98% Scheme 1.8. Synthesis and application of (NPS)Zr(NMe2)2 in aminoalkene hydroamination. A recent report from the Doye group revealed that indenyl based group-4 matal catalysts (Figure 1.2) are quite active for intramolecular cyclization.36 Both five-and six-membered amine products can be obtained in good yields; however, attempts to make 7-membered rings were unsuccessful. C \ ...CH3 mm M = Ti, Zr, Hf Figure 1.2. lndene-based olefin hydroamination precatalysts. 17 1.6 Applications of hydroamination In heterocycle synthesis The group-4 metal catalyzed hydroamination reaction has been used for the synthesis of various heterocyclic cores. In 2004, our group developed a novel synthesis of pyrroles via the hydroamination of 1,4-(equation 1.9) and 1,5-diynes (equation 1 .10).37 R3 R1 R2 Titanium catalyst R1 N \\ // + NH2R3 > U12 1.9 R R3 R1—:——\_ Titanium catalyst R1 N Z: R2 + NHZR3 +7 V 1.10 R2 Using a 1,4-diyne, monohydroamination with Markovnikov selectivity would yield the 4—iminoalkyne, which could undergo 5-endo dig cyclization to the pyrrole. Similarly, Markovnikov addition of a primary amine to a 1,5-diyne would generate a 5-iminoalkyne, which could undergo 5-exo dr'g cyclization (Scheme 1.9). R. . B \\ // + NHZR Catalyst : ilk/é 5-endo dig: Mew Me R 1; + NH2R aays ; | = UMe Me Scheme 1.9. Pyrrole synthesis via hydroamination of 1,4- and 1,5-diynes. l8 We also have applied enyne hydroamination in the synthesis of heterocyclic compounds. The titanium-catalyzed enyne hydroamination leads to (LB-unsaturated imines, which can be further functionalized using a rhodium- catalyzed C,H-activation/alkyne insertion process to generate dihydropyridines after electrocyclic ring closure (Scheme 1.10).38 / / 10 mol% Tl da NMe N‘Ph (j/ + PhNH2 ( p)2( 2): O_<, toluene, 50 °C, 16 h Me not isolated 1) 50 mol% H20 2)5 equivEt : Et 2 mOlo/o RhCl(PPh3)3 toluene, 150 °C, 16 h V Et Et ’ Et Et ‘ electrocyclization and — N-Ph olefin isomerization N-ph _ ‘ I Me Me 66% _ _ Scheme 1.10. Dihydropyridine synthesis using hydroamination/C-H insertion tandem catalysis. Very recently Ackermann and coworkers reported another elegant synthesis of pyrroles from chloroenynes or a-haloalkynols using two titanium- catalyzed reaction sequences. Titanium-catalyzed intermolecular hydroamination of (ElZ)-chloroenynes followed by cyclization produced pyrrole products in moderate to good yields (Scheme 1.11)?9 19 R3 4 OH/ / R “”2 2 3 R2 / R2 / - R R cat. TlCl \ 1/ -H o I 4 T m R1 2 t-Bu-NH2 Cl R4 R1 ml R2 17,}... Scheme 1.11. Pyrroles from hydroamination of chloroenynes. The same group also developed one-pot titanium-catalyzed hydroamination followed by palladium-mediated coupling sequence for the synthesis of substituted indoles (Scheme 1.12).40 ph cat. TiCI4 cat. [Pd] Ph (>01 + II Hail—NHL CEO/[P KOt-Bu > ma NH2 PhMe, 105 °C N Et PhMe. 105 0C {2" Et Scheme 1.12. One-pot indole synthesis via hydroamination. They also reported an indirect synthesis of benzo[b]furans using the anti- Markovnikov hydration of unsymmetrically substituted terminal and internal alkynes based on TiCl4-catalyzed hydroamination reactions (Scheme 1.13).41 20 R2 / R“ \ / 1)cat.TiCl4,R3NH2‘ R1 wR ' / x 2) H20 ’ / X0 2 X = 8r, Cl cat [Cu] / 0 Scheme 1.13. Benzo[b]furan synthesis using anti-Markivnikov hydroamination. Schafer and coworkers reported a tetrahydroquinoline synthesis via hydroamination of alkynes. The anti-Markovnikov hydroamination of terminal alkynes has been exploited in an alternative route for the efficient one-pot synthesis of 1-substituted tetrahydroisoquinolines via intermolecular hydroamination of phenylethylamines with terminal alkynes, followed by trifluoracetic acid-catalyzed Pictet-Spengler cyclization.42 The potential of this reaction sequence was further expanded to the highly atom-economical synthesis of the tricyclic benzo[alquinolizine derivative in 72% overall yield (Scheme 1 .14).43 21 mo°o I-caa S MeO NH2 y NH 06H... 65 °C, 24 h MeO + 2) TFA, A,12h ' HO XOM o O MeO N O ‘_ MeO xylene 140 °C, 12 h 72% (3steps) Scheme 1.14. Hydroamination-based synthesis of tricyclic benzo[ajquinolizine. The Doye group reported intramolecular hydroamination of ortho-halide- substituted aminoalkyl(phenyl)alkynes. After reduction ,B-arylethylamines can be readily cyclized via palladium-catalyzed cross-coupling to pyrrolizidines (Scheme 1.15).44 // NH2 R__,_\ 5 mol% Ti-cat ‘ ._\ \ ' / X toluene,110°C, 671 ' / X N NaBHacN an|2 II 5 mol% szdbaa Ru. \ KOBut R m l < l / N dioxane, 110 °C / )2“ Scheme 1.15. Pyrrolizidine from hydroamination/cross-coupling. 22 1.7 Hydroamlnatlon based natural product synthesis MBOIIVN‘H’CFa 1) PPh3,HN’Pr2, M60 I 0 16h, 25 C = + 2) KOH, MeOH/HZO % OMe OMe 16h, 25°C pi. If M60 0 I hu/ / Ii Ph‘" N’ CI MeO NH < I"2 92%, 93% ee HCOOH. EtaN OMe OM 10 mol% szTiMez toluene, 100 °C, 16 h e CHZO HCOOH ’ .. CH20, NaBH4 ”20'9” 0'2“ MeOH,H20 25 °C, 16 h II “”0 0 «9’2" Q OMe o O OMe 92% OMe 99/0 OMe (S)-(-)-xylopinine (S)-(+)-laudanosine Scheme 1.16. Synthesis of (S)-(+)-Laudanosine and (S)-(-)-Xylopinine based on intramolecurar hydroamination of alkynes. 23 A few natural products were synthesized based on the intramolecular hydroamination of alkynes. The Doye group reported the total synthesis of (S)- (+)-Laudanosine and (S)-(-)-Xyloplnine based on intramolecurar hydroamination of alkynes (Scheme 1.16).45 Highly regioselective titanium-catalyzed hydroamination/cyclization of the aminoalkyne led to the 3,4-dihydroisoquinoline, which was converted into the natural products in few steps. In 1992, Livinghouse and coworkers utilized the lntramolecular hydroamination of y-aminoalkyne as the key step in the total synthesis of indolizidine alkaloid (:i:) Monomorine (Scheme 1.17).46 They also employed similar strategy for the synthesis of pyrrolidine alkaloid (+)-preussin.47 r 1 20 mol% CpTiCI3 l 40 mol% Et3N N .3 THF, 25 °c ’ DUO ' 93% Me 7 (5:) Monomorine L A I Scheme 1.17. Synthesis of (:t) Monomorine. 24 1.8 Conclusion Hydroamination has been found to be an attractive methodology for direct incorporation of nitrogen into organic substrates. A wide range of metal catalysts covering all the areas of periodic table have been developed to carry out this seemingly simple transformation. However, as of now there is no general catalyst for hydroamination. Group-4 metal based catalyst can be used for both intra- and intermolecular hydroamination reaction. This methodology has been successfully used not only in the synthesis of various heterocyclic core structures, but also for various natural products. We are actively involved in hydroamination research and CHAPTER 2 will talk about the development of a new hydroamination catalyst and its application in intramolecular olefin hydroamination. CHAPTER 3,4, and 5 will discuss the extension of the hydroamination reaction into multi-component couplings and its application in one-pot synthesis of various heterocyclic compounds as well as natural products. 25 1.9 References 10. ll. 12. l3. 14. 15. 16. For reviews on hydroamination see: a) Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. b) Severin, R.; Doye, 8. Chem. Soc. Rev. 2007, 36, 1407. c) Odom, A. L. Dalton Trans. 2005, 225. d) Miiller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675. Hultzsch, K. C. on. Synth. Catal. 2005, 347, 367. Roundhill, D. M. Chem. Rev. 1992, 92, 1. Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem. 2006, 4555. Wang, W.; Widenhoefer, R. A. Organometa/lics. 2004, 23, 1649. Muller, T. E.; Grosche, M.; Herdtweck, E.; Pleier, A.-K.; Walter, E.; Yan, Y. K. Organometallics. 2000, 19, 170. a) Robinson, R. 8.; Dovey, M. C.; Gravestock, D. Tetrahedron Lett. 2004, 45, 6787. b) Carney, J. M.; Donoghue, P. J.; Wuest, W. M.; Wiest. O.; Helquist, P. Org. Lett. 2008, 10, 3903. Marks, T. J.; Hong, S. Acc. Chem. Res. 2004,37, 673. a) Stubbert, B. D.; Marks, T. J. J. Am. Chem. Soc. 2007, 129, 4253. b) Haskel, A.; Straub, T.; Eisen, M. S. Organometa/lics. 1996, 15, 3773. Pohiki, F.; Doye, S. Angew. Chem, Int. Ed. 2001, 40, 2305. Anderson, L.; Arnold, J; Bergman, R. G. Org. Lett. 2004, 6, 2519. Ates, A.; Quinet, C. Eur. J. Org. Chem. 2003, 1623. Tokunaga, M.; Eckert, M.; Wakatsuki, Y. Angew. Chem. Int. Ed. 1999, 38, 3222. Beller, M.; Trauthwein, H.; Eichberger, M.; Breindi, C.; Muller, T. E. Eur. J. Inorg. Chem. 1999, 1121. Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114, 1708. Li, C.; Thomson, R. K.; Gillon, 8.; Patrick, 8. O.; Schafer, L. L. Chem. Commun. 2003, 2462. 26 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. McGrane, P. L.; Jensen, M.; Livinghouse, T. J. Am. Chem. Soc. 1992, 114, 5459. Haak, E.; Bytschkov, l.; Doye, S. Angew. Chem. Int. Ed. 1999, 38, 3389. Heutling, A.; Doye, S. J. Org. Chem. 2002, 67, 1961. Heutling, A. ; Pohlki, F.; Doye, 3. Chem. Eur. J. 2004, 10, 3059. Khedkar, V.; Tillack, A.; Beller, M. Org. Left. 2003, 5, 4767. Tillack, A.; Khedkar, V.;Beller, M. Tetrahedeon. Left. 2004, 45, 8875. Shi, Y.; Ciszewski, J. T.; Odom, A. L. Organometallics. 2001, 20, 3967. Li, Y.; Turnas, A.; Ciszewski, J. T.; Odom, A. L. Inorg. Chem. 2002, 41, 6298. Harris, S. A.; Ciszewski, J. T.; Odom, A. L. Inorg. Chem. 2001, 40, 1987. Cao, C.; Ciszewski, J. T.; Odom, A. L. Organometallics. 2001, 20, 5011. (a) Shi, Y.; Hall, 0.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem. Commun. 2003, 586. (b) Novak, A.; Blake, A. J.; Wilson, G; Love J. 8. Chem. Commun. 2002, 2796. Littler, B. J.; Miller, M. A.; Hung, C.-H.; Wagner, R. W.; O’Shea, D. F.; Boyle, P. D.; Lindsey, J. S. J. Org. Chem. 1999, 64, 1391. Shi, Y.; Hall, 0.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem. Commun. 2003, 586. Cao, C.; Li, Y.; Shi, Y.; Odom, A. L. Chem. Commun. 2004, 2002. For a few examples of Michael addition to (LB-unsaturated ketones see Stocking, E. M.; Sanz-Cervera, J. F.; Williams, R. M. J. Am. Chem. Soc. 2000, 122, 1675. The condensation to generate imines can be run successfully in some cases. Greenlee, W. J. J. Org. Chem. 1984, 49, 2632. Dechambre, C.; Chezal, J. M.; Moreau, E.; Estour, F.; Combourieu, 8.; Grassy, G.; Gueiffier, A.; Enguehard, C.; Gaumet, V.; Chavignon, O.; Teulade, J. C. Tetrahedron Lett. 2002, 43, 9119. Cao, C.; Shi, Y.; Odom, A. L. Org. Left. 2002, 4, 2853. (a) Ackermann, L.; Kaspar, L. T.; Gschrei, C. J. Org. Lett. 2004, 6, 27 34. 35. 36. 37. 38. 39. 40. 41. 42. 45. 45. 46. 47. 2515. (b) Anderson, L. L.; Arnold, J.; Bergman, R. G. Org. Left. 2004, 6, 2519. Bexrud, J. A.; Beard, D. J.; Leitch, D. C.; Schafer, L. L. Org. Left. 2005, 7, 1959 Kim, H.; Lee, P. H.; Livinghouse, T. Chem. Commun. 2005, 5205. a) Miiller, C.; Loos, C.; Schulenberg, N.; Doye, S. Eur. J. Org. Chem. 2006, 2499. b) Miiller, C.; Saak, W.; Doye, S. Eur. J. Org. Chem. 2008, 2731. Ramanathan, 8.; Keith, A. J.; Armstrong, 0.; Odom, A. L. Org. Left. 2004, 6, 2957. Cao, C.; Li, Y.; Shi, Y.; Odom, A. L. Chem. Commun. 2004, 2002. Ackermann, L.; Sandmann, R.; Kaspar, L. T. Org. Left. 2009, 11, 2031. a) Ackermann, L.; Kaspar, L. T.; Gschrei, C. J. Chem. Commun. 2004, 2824. b) Ackermann, L.; Sandmann, R.; Villar, A.; Kaspar, L. T. Tetrahedron 2008, 64, 769. Ackermann, L.; Kaspar, L. T. J. Org. Chem. 2007, 72, 6149. Zhang, 2.; Schafer, L. L. Org. Left. 2003, 5, 4733. Zhang, Z.; Leitch, D. C.; Lu, M.; Patrick, 8. O.; Schafer, L. L. Chem. Eur. J. 2007, 13, 2012. Bytschkov, l.; Siebeneicher, H.; Doye, S. Eur. J. Org. Chem. 2003, 2888. Mujahidin, D.; Doye, S. Eur. J. Org. Chem. 2005, 2689. McGrane, P. L.; Livinghouse, T. J. Org. Chem. 1992, 57, 1323. McGrane, P. L.; Livinghouse, T. J. Am. Chem. Soc. 1993, 115, 11485. 28 CHAPTER 2 Group-4 dipyrrolylmethane complexes in intramolecular olefin hydroamination 2.1 Introduction lntramolecular hydroamination1 of olefins is a reaction of great potential utility in the formation of N—heterocycles. Over the last few years the intramolecular hydroamination of aminoalkenes (lHA) has become an attractive area of research as it is a highly desirable, atom economical route for the synthesis of amines in a single step. A plethora of complexes, many involving group-3 elements, Ianthanides,2'3 and group-44 metals (Figure 2.1) have been explored as catalysts for this reaction. 29 % .TMs 1.... . L N ' Ln = Nd, LU Marks, 1999 'N(SlHMeg)2 Q Hultzsch, 2003 //, P>S\ Ti(NMe2)4 Schafer, 2005 ><:l::zr >IS/NMe2 d ’z 58’ ’NMe .\CH3 2 “'CH3 Doye, 2006 Livinghouse, 2005 Figure 2.1. Lanthanide and Group-4 metal based intramolecular hydroamination precatalysts. Marks and co-workers have developed both metallocene and non- metallocene based complexes of Group-3 metals as active catalysts for this important class of cyclization reaction. Many of the known catalysts for intramolecular hydroamination are believed to use either a [2 + 2]-cycloaddition5 or 1,2-insertion6’1c route; these are illustrated in Scheme 2.1. 30 MINM62I2X2 M(NM62)2X2 RR RR "m m RZ‘R‘L R“ RR ~M° 21,, “R e H N \ [2+2] N [Illa Ncloaddmon H [M1,NH \ 12 l l insertion Marks' H R Z 3 Bergman's R R N Me Mechanism 1? RR N R 1 / V M] v.“ [M] H H Scheme 2.1. [2 + 2]-cycloaddition mechanism of Bergman (left) and the 1,2- Mechanism insertion mechanism of Marks (right). 31 2.2 Pyrrolyl ancillary ligands In hydroamination Schrock and co-workers7 have studied the ancillary ligand effects in the olefin metathesis reaction, which is known to proceed through the Chauvin Mechanism. The mechanism involves initial [2+2]-cycloadditon to form a four membered metallacyle followed by retro [2+2]-cycloaddition. One of the results in Schrock’s studies is that reactivity of the catalyst increases with increasing Lewis acidity of the (10 metal center. This increase in reactivity is possibly due to better coordination of the olefin with the metal center prior to the [2+2]-cycloaddition_ reaction. There are several similarities between the Schrock metathesis (Chauvin mechanism) and Bergman hydroamination systems: dO metal centers, metal- ligand multiple bond intermediates, and [2 + 2]-cycloaddition reactions with unsaturated substrates to form four-membered metallacycles (Scheme 2.2). So, it may be possible to enhance the catalytic activity in IHA by making the metal center more electron deficient in analogy to olefin metathesis. 32 9H2 R /= M —R 1 2 "I —__" + = R — R H NR . . 2 —> .18 R R R M R1 R2 1 / R, R R [El/l N | 8' -NHR M 2 ”VJ M R H2NR Olefin Metathesls Group-4 Hydroamlnatlon (Chauvin Mechanism) (Bergman Mechanism) Scheme 2.2. Mechanism of olefin metathesis (left) and the Bergman mechanism of alkyne hydroamination. Our group has extensively studied pyrrolyl-based ancillary ligands181 in hydroamination reactions. Pyrrolyl based ancillary ligands posses several advantages over other classes of ancillary ligands. First of all, pyrrole, unlike many alkoxide and amide ligands, is not strongly rt-donating because the -1)Ia alTOmatic stabilization energy of pyrrole (~21 kcal mol directly competes with TI ~donation to the metal center. Secondly, various multidentate pyrrolyl ligands can be accessed easily using well-known condensation chemistry of pyrroles. Moreover, multidentate ancillary ligands often increase the stability of calatytic 33 species in a variety of reactions. Hence, we thought to make stable as well as Lewis acidic metal centers using pyrrolyl-based ancillary ligands in titanium- catalyzed hydroamination. It has been found that dipyrrolylmethane ligands on titanium provide catalysts capable of extremely fast hydroamination of alkynes with primary amines.8 One of the most commonly employed dipyrrolylmethane ligand is 5,5- dimethyldipyrrolylmethane (szpm). This ligand can be prepared in a single step by the condensation of pyrrole with acetone in presence of an acid catalyst. H2dpm can be placed on titanium in near quantitative yield by reaction with commercially available Ti(NMe2)4 (Scheme 2.3).9 H H HN \ 20 N o 10% TFA _ N .— U + A 5min,RT' I/ 53% szpm Ti(NMe2)4 90% ether II / N /TI(NM62)2 Ti(NM92I2(de) Scheme 2.3. Synthesis of szpm and Ti(NMe2)2(dpm) (1). 34 2.3 Synthesis and hydroamination of aminoalkenes Gem-disubstituted aminoalkenes were synthesized according to literature procedures10'4h by treating the appropriate nitrile with an allyl halide in the presence of a strong base like lithium diisopropylamide (LDA) to generate an alkene-nitrile compound (Scheme 2.4). The alkene-nitriles were then reduced to the desired amino alkenes with LiAlH4 in excellent to moderate yields. 1. LDA, -78 °C 91,22 F1352 1h, THF _ UA'H4 g NC H 2. WBr Ncfl 15120. Timer m 2 \ 0°C—>RT 3 h, THF, RT % Yield R1 82 Time Step I Step II Ph Ph 5 h 89 84 Ph H Overnight 33 81 —(CH2)5- Overnight 47 75 Scheme 2.4. Synthesis of gem-substituted aminoalkenes. The 4,5-disubstituted aminoalkene4h was synthesized by refluxing d"IDhenylacetonitrile in the presence of lithiumbis(trimethylsilyl)amide followed by 35 the addition of cinnamylbromide in refluxing THF. The crude product was reduced with LiAlH4 (Scheme 2.5). 1. LiN(SiM63)2, THF, reflux Ph Ph 45min Ph Ph LiAlH4 Ph Ph NCXH . . T NC T 2.Clnnamylbrom.1de, \ Ph [£120,080, RT, NH2 \ ph reflux, 45 mln overnjght 60% 42% Scheme 2.5. Synthesis of 4,5-disubstituted aminoalkene. The unsubstituted aminoalkene11 was achieved by reducing the amide of 4-pentenoic acid, which was prepared from the corresponding acid according to the literature procedure (Scheme 2.6). 0 (cool)2 _ on m Neat, RT ' Cl \ 3 h aq. NH3 RT, 1 h 40% (over 2 steps) q LiA11-I4 0Y1 ””2 \ E120, 0 °C, RT, ””2 \ 20 h 30 °/o Scheme 2.6. Synthesis of unsubstituted aminoalkene. 36 Aza-Claisen rearrangement of N-allylaniline in presence of BF3.EtZO produced o-allylaniline12 in moderate yield (Scheme 2.7). HN NH2 W BF3 . EtZO _ / dry Xylene, ' 3 d, reflux 65% Scheme 2.7. o-allylaniline via Aza-Claisen rearrangement. The secondary aminoalkene was made from the primary aminoalkene in a two-step protocol via formylation with ethylformate followed by reduction with LiAIH4 (Scheme 2.8).13 Ph Ph 0 Ph Ph Ph Ph d HJLOEt d LiAlH4 NH2 \ neat, reflux ' OYNH \ EtZO, RT ',NH \ 81% H 90% Scheme 2.8. Preparation of secondary aminoalkene. 37 2.4 Results and dlscusslon It was mentioned earlier that our group has explored the use of pyrrolyl- based ancillary ligands in intermolecular alkyne hydroamination. While this reaction is also of great potential utility, it was thought that catalyst development for intermolecular hydroamination of alkynes may provide clues as to catalyst development for intermolecular olefin hydroamination of unactivated olefins, a reaction for which there are as yet no general catalysts. Here, we report the results of intramolecular olefin hydroamination studies using a very rapid alkyne hydroamination precatalyst, n 5, 1) 1-(5,5- dimethyldipyrrolylmethane)bis(dimethylamido)titanium(IV) or Ti(dpm)(NMe2)2 (1). in addition, we report the synthesis, structure, and catalytic reactivity of its zirconium derivative.14 Reaction of 2,2-diphenylpent—4-en-1-amine with 5 mol% 1 in toluene was carried out at temperatures up to 100 °C (Equation 2.1). This complex, which can catalyze the hydroamination of many alkynes and primary amines rapidly even at '00"! temperature, reacted quite slowly with this alkene substrate reaching 40% Conversion after 24 h 38 N 24 h Me H 40% conversion The low reactivity of the titanium complex led us to prepare the zirconium derivative, reasoning its larger ionic radius would perhaps led to increased activity with these olefin substrates. The zirconium derivative (2) was prepared according to Equation 2.2. Zr(N M92)4 + toluene, 1 h> [Zr(dpm)(2NMez)2]2 (2-2) \ / 84% (l \ NH HN / X-ray diffraction on a sample of the complex revealed the compound to be an unusual dimer in the solid state. The structure for 2 is shown in Figure 2.2.15 The two n 5-pyrrole ligands are on one zirconium with two dimethylamido ligands, creating a structure similar to a Group-4 metallocene. The other zirconium center is Coordinated to two dimethylamidos, two n1-pyrroleS. and the tWO nitrogens 0f the n 5-pyrrole ligands facially bound to its cohabitant zirconium. Consequently, one of the zirconium atoms in the complex is pseudo-octahedral, and there is an approximate two-fold axis along the Zr-Zr vector (Figure 2.2). The structure in solution, as judged by NMR spectroscopy, is consistent with the solid-state 39 structure. However, considering the titanium derivative 1 has an n1,n5-dpm in the solid state and solution, the ( n 1, 7) 5-5,5- dimethyldipyrrolylmethane)bis(dimethylamido)zirconium(IV) monomer and the dimeric structure observed in the solid-state may be difficult to distinguish by NMR alone. ' 1m ‘ ‘~ Flgure 2.2. Structure of [Zr(dpm)(NMe2)2]2 (2) by X-ray diffraction. Selected distances (A): Zr(1)-N(13) 2.049(4), Zr(2)-N(23) 2.060(4), Zr(1)-N(11) 2.515(3), Zr(2)-N(11) 2.404(3), Zr(2)-N(21) 2.232(4). 2r(1)-C(111) 21515(4)- Selected angles (°): N(14)-Zr(1)-N(13) 94.9(2), N(23)-Zr(2)-N(24) 101.9(2). N(23)-zr(2)-N(12) 97.4(1), N(12)-Zr(2)-N(22) 80.0(1), N(12)-2r(2)-N(11) 73.0(1), Nb 1 )-Zr(2)-N(22) 81 .0(1). 40 There is some evidence that this dimer is relatively easy to convert to the two monomers. An El MS experiment on the solid complex resulted in the monomer being the highest molecular weight observed. The solution molecular weight of the complex, determined cryogenically in benzene, was consistently between monomer and dimer favoring the monomer. Initial experiments focused on the intramolecular hydroamination of 2,2- diphenylpent—4-en-1-amine with 2.5 mol% [Zr(dpm)(NMe2)2]2 (2) at 100 °C in toluene. In presence of the zirconium derivative, the starting aminoalkene undergoes 100% conversion to the product in 1 hour at the same temperature (Equation 2.3). Pb 2.5 mol% Ph ph Toluene, 100 °C / H2N 1 h Me ”I 100% conversion The zirconium derivative is significantly more active in intramolecular olefin hydroamination than the titanium complex, and the results with several sUbstrates are shown in Table 2.1. It is well documented that the rate of intramolecular cyclization can be enr'lt‘atnced by geminal disubstitution between the two reaction termini. In case of N" intramolecular hydroamination of aminoalkenes, increased rate of cyclization was observed when the 2-position was substituted with two phenyl (Entry 1 and 4). cyclohexyl (Entry 2) or phenyl-allyl (Entry 3) moieties and decreased with 41 monosubstitution (Entry 6). Moreover, attempts to convert unsubstituted pent-4- en-1-amine to 2-methylpyrrolidine resulted in no reaction (Entry 8). This phenomenon, i.e., increased rate of cyclization with geminal disubstitution is known as the gem-dialkyl effect,16 which is a combination of the Thorpe — lngold and the reactive rotamer effects (Scheme 2.9). Thorpe-lngold Effect increased sterics A Ph Ph NH2 \ J decreased bond angles / Reactlve Rotamer Effect H2N Ph H H P“ NH2 H Phk} PW ._ FRI/s . PW H H H anti gauche Hydroamination product Scheme 2.9. Gem-dialkyl effect, a combination of Thorpe-lngold (top) and reactive rotamer effects (bottom). 42 Catalytic reactions involving 2 to form 6-membered rings (Entry 4) were slower compared to 5-membered rings. The cyclization reaction of trans- disubstituted olefin (Entry 5) required longer reaction time (96 h) and slightly elevated temperature (110 °C) to obtain 55% conversion to the desired cyclized product. In the case of Entry 3 and Entry 6, pyrrolidine products were obtained as a mixture of two inseparable diastereomers; however, the diastereoselectivities were found to be ~ 1:1 in both examples. Interestingly, 2-allylaniline can be hydroaminated to the 2-methylindoline product in 73% isolated yield at an elevated temperature. 43 Table 2.1. Catalytic intramolecular hydroamination reactions with zirconium catalystsa Zr(N'Mez)4 . [Zr(dpm)(NMe ) Entry Aminoalkenes Products Time Temperature (0/0 Conv)/ 2 212 (°/° COHV)/ h (°C) %1 l t d ( ) % isolated maidb 3°36 )neidb m 1 100 (100)/ 92 (92) NH2 \ 2 3 100 (100)/ 86 (100) NH2 \ It)" Ph 2‘) 3 100 (100)/ 96 (100) 3 "'II NH2 \ N N H 1:1 H Ph Ph Ph Ph 4 U 15 100 (100) (tom/83° NH2 / n P" Ph Ph Ph 5 h, 55 100/87 hm N ph 96 110 ( ) ( ) Ph H Ph Ph Ph 6 d m 2 5...,120 150 (93)/57 (97) NH2 \ u 1 .1 n 7 / av m 96 150 (92)/ 73 --d NH2 {1 e a a a) 25 \ a 2- 5 mol% [Zr(dpm)(NMez)2]2 (2) or 5 mol% Zr(NMe2)4 in toluene. b % conversion by GC/FID and % isolated yield. ° Reaction time was 3 l1.d Some product observed but not a clean reactien.e Hydroamination product not observed. 44 In general Zr(NMe2)4 was a comparable catalyst to the pyrrolyl complex 2 and only modest improvements are seen in any case, e.g., Entry 7. This is, again, in contrast to the titanium alkyne catalysis chemistry where Ti(NMe2)2(dpm) (1) is noticeably faster than Ti(NMe2)4.17 The catalytic reactions involving Zr(NMe2)4 to form 6-membered rings (Entry 4) and reactions with trans- disubstituted olefins (Entry 5) were faster in comparison with compared to catalyst 2. From the above results, a possible mechanistic pathway is expected to involve a Zr(lV) imido complex, which can then undergo a [2+2]-cycloaddition reaction with the alkene to form an azazirconacyclobutene intermediate. Protonolysls with aminoalkenes can regenarate the Zr(lV) imido complex along with the formation of the pyrrolidine products (Scheme 2.1). Most neutral zirconium complexes are believed to use the [2 + 2]- cycloaddition mechanism (Scheme 2.1).18 However, reaction of N-methyl-2,2- diphenylpent-4-en-1-amine with 5 mol% [Zr(dpm)(NMe2)2]2 (2) results in formation of compounds consistent with hydroamination. Since it is highly unlikely that an imido-based mechanism could be operative in equation 2.4 a 1,2- insertion route is favored. The reaction is significantly slower than in the related primary amine ring closure (Entry 1, Table 21)- 45 pr. Ph Ph Ph Ph Ph 21 5 mol% [Zr(dpm)(NM92)2]2 h + UM (2-4) > e ,NH \ Toluene, 5 d N Me N 150 °C Me Me 35% 34% A reaction under similar conditions utilizing the secondary amine substrate in Equation 2.4 and Zr(NMe2)4 resulted in production of the hydroamination product with full conversion after 12 h. The dehydrogenated product was not observed. This secondary amine does not undergo cyclization with added Ti(NMe2)4 under these conditions, and starting material is recovered. Several control experiments were run on the reaction in Equation 2.4. No reaction was observed in the absence of catalyst. Addition of bases to the reaction, to rule out proton involvement, was also investigated. The reaction was run under the same conditions with either 2,6-di-tertbutyl-4-methylpyridine or tris(n—octyl)amine (1 equiv with respect to amine substrate). Neither base had a noticeable effect on the yield or selectivity of the reaction. A possible route for generating these products would involve formation of a Zr(lV) amido complex A, which can undergo olefin insertion into the Zr—N bond to form an intermediate C. Protonolysis of the intermediate C would result the desired hydroaminated product D. Alternatively, B-hydride elimination of the alkyl Zirconium intermediate (C) would generate the enamine product E (Scheme 2- 1 0)- The enamine product was observed by 1H NMR and GC/MS; however, it 46 was not isolable as a pure compound from the pyrrolidine.19 Consequently, the yield given for the enamine is approximate and based on the GC-FID, the response of the isolable pyrrolidine. [Zr(dpm)(NMea)2]2 Me. / N M? N Me HNMe2 Ph Ph D Me Ph [Zr]—N Ph IA MeeN/W H ph ph Marks' Mechanism Me. Ph Me Ph [Zr] N P“ 12ri;;:'§‘~ C _ V B " Me ' Me By isomerization 5:], Ph ph Ph ph E Ph Scheme 2.10. Possible route to the product distribution observed when N- r"iethyl-2,2-diphenylpent-4-en-1-amine is reacted with 2. 47 These results suggest that [Zr(dpm)(NMe2)2]2 (2) uses 1,2-insertion either exclusively or in concert with the [2 + 2]-cyc|oaddition pathway. However, the neutral zirconium complexes reported to use this mechanism by Marks did not seem to have significantly different activity with primary and secondary amines as seen for 2.18 Whether this indicates that 2 can access both mechanisms with the [2 + 2]-cycloaddition route being lower in energy will require further study. Currently, there are several intriguing mechanistic possibilities, including differing routes for the monomer and dimer in solution. 48 2.5 Conclusion Titanium and zirconium complexes bearing the 5,5- dimethyldipyrrolylmethane (dpm) ancillary ligand were tested for their activity in intramolecular hydroamination of olefins. The titanium precatalyst Ti(NMe2)2(dpm), despite being an excellent catalyst for intermolecular alkyne hydroamination, was a relatively poor catalyst for intramolecular olefin hydroamination. The zirconium derivative was significantly more active. A variety of aminoalkene substrates can be hydroaminated into pyrrolidines in very good yields. With a secondary amine, [Zr(NMe2)2(dpm)]2 did catalyze the hydroamination reaction, albeit slowly. Consequently, the mechanism of the reaction with zirconium may use a 1.2-insertion into a Zr—N amido bond as the key mechanistic step, or the complex may be able to access both the [2 + 2]- Cycloaddition and 1,2-insertion mechanisms. The zirconium precatalyst was structurally characterized by X-ray diffraction and is a dimer in the solid state, but solution molecular weight determination gave results closer to the monomer in benzene. 49 2.6 Experlmental General Considerations: All manipulations of air sensitive compounds were carried out in an MBraun drybox under a purified nitrogen atmosphere. Toluene was purified by sparging with dry N2, then water was removed by running through activated alumina systems purchased from Solv-Tek. Deuterated solvents were dried over purple sodium benzophenone ketyl (C606) or phosphoric anhydride (CDCI3) and distilled under a nitrogen atmosphere. Deuterated toluene was dried by passing through two columns of neutral alumina. 1H and 13C spectra were recorded on VXR-5OO spectrometers. Zr(NMe2)42° was made according to the literature procedure and recrystallized from ether-pentane. szpm21 was previously reported. The compounds 2,2-diphenyl-4-pentenylamine,22 2,2- 23 23,24 diphenyl-S-hexenylamine, 2,2,5-triphenyl-4-pentenylamine, 2-phenyI-4- 26 23.25 on -alIylcyclohexyl)-methylamine. 2- 2 pentenylamine, o-allylaniline,1 11,12 phenyl-2-(2-propenyl)-4-pentenenitrile,27 1-amino-4epentene, and N-methyl- 3 2,2-diphenyI-4-pentenylamine1 were made according to previously reported procedures and purified either by distillation or by column chromatography. Synthesls of [Zr(dpm)(NMe2)2]2: Under an atmosphere of dry nitrogen (glove 50 box), a 20 mL scintillation vial was loaded with Zr(NMez)4 (0.267 g, 1.0 mmol) in ~3 mL of toluene. A separate vial was loaded with szpm (0.172 g, 1.0 mmol) in ~3 mL of toluene. Both vials were placed in a liquid nitrogen cooled cold well for 15 min or until frozen. The szpm was then added dropwise to the vial containing the slightly above freezing solution of Zr(NMe2)4. The solution was allowed to stir at room temperature for 1 h. Removal of the solvent in vacuo, followed by washing with dry ether provided the desired compound as a yellow powder in 84% yield (0.294 g). 1H NMR (0606, 500 MHz): 1.36 (8 H, s), 1.58 (8 H, s), 2.42 (6 H, s), 3.16 (6 H, s), 4.44 (1 H, t, J: 1.5 Hz), 6.08 (1 H, dd, J: 3 and 1.5 Hz), 6.24 (1 H, dd, J: 3.5 and 2.0 Hz), 6.42 (1 H, dd, J: 3.0 and 2.5 Hz), 7.89 (1 H, dd, J = 2.5 and 1.5 Hz). 130(1H} NMR (0606, 125 MHz): 26.04, 35.64, 39.06, 43.46, 48.94, 104.93, 108.14, 109.24, 121.39, 126.99, 128.18, 131.54, 143.58, 156.56. MS(E|): m/z 350.3 (M+). Elemental Analysis; Found (Expected): %C, 50.89 (51.24); %H, 6.70 (6.88); %N, 15.68 (15.93). Ph b /e d c b NH \ a2d e 2—Phenyl—2-(2-propenyl)-1-amlno-4-pentene: To a stirred suspension of LiAIH4 (2.32 g, 60.8 mmol) in dry ether (75 mL) at 0 °C under nitrogen was slowly added a sOll..ltion of 2-phenyl-2-(2-propenyl)-4-pentenenitrile (6.0 g, 30.4 mmol) in 25 mL 51 dry ether over 10 min. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was cooled to 0 °C, diluted with 100 mL of ether, and quenched sequentially with water (5 mL), 15% NaOH (5 mL), and water (5 mL). The mixture was stirred at room temperature for 30 min and filtered. The filtrate was dried over NaZSO4 and concentrated under vaccum. The crude product was purified by column chromatography to obtain 73% yield (7.6 g). 1H NMR (CDCI3, 500 MHz): 1.00 (2 H, br s, a), 2.45 (4 H, m, b), 2.89 (2 H, s, c), 5.00 (4 H, dd, e), 5.55-5.64 (2 H, m, d), 7.20 (1 H, tt, Ar-H), 7.30-7.34 (4 H, m, Ar-H). 13ci‘H) NMR (CDCI3, 125 MHz): 89.97, 45.88, 49.18, 117.85, 126.26, 1 27.11, 128.61, 184.68, 144.59, MS(E|): m/z201 (M+). General procedure for lntramolecular,hydroamlnatlon of aminoalkenes: In a N2 filled glove box, a 50 mL pressure tube, equipped with a magnetic stirbar was loaded with aminoalkene (1 mmol), [Zr(dpm)(NMe2)2]2 (2) (0.025 mmol) and 500 ML of dry toluene. The pressure tube was sealed with a Teflon screw cap, taken out of the dry box, and heated to the appropriate temperature for the desired time with stirring. After completion of the reaction, the pressure tube was removed from the oil bath and cooled to room temperature. The solution in the pressure tube was diluted with 1:1 mixture of dichloromethanezethanol and filtered through a p'ug of silica. The solution was concentrated under reduced pressure, and the crude product was purified either by column chromatography or converted to the 52 N-naphthoyl derivative following the literature procedure. 09 d N CH3 H C 2-Methyl-44dlphenyl—pyrrolldlne: The product was purified by flash column chromatography using silica gel and 1:1 ethyl acetatezhexanes to remove free szpm. Then the eluent was changed to 88:10:2 dichloromethanezmethanol:tert- butylamine. The product was isolated in 92% yield. 1H NMR (CDCI3, 500 MHz), 500 MHz): 1.22 (3 H, d, J: 6 Hz, a), 1.92 (1 H, br s, c), 2.05 (1 H, dd, J: 9.0 and 13.0 Hz, b), 2.76 (1 H, dd, J: 12.5 and 6.5 Hz, b), 3.40 (1 H, rn, e), 3.50 (1 H, d, J: 11 Hz, d), 3.70 (1 H, d, J: 11.5 Hz, d), 7.17-7.20 (2 H, m, Ar-H), 7.25- 7.31 (8 H, m, Ar-H). 130(1H} NMR (CDCI3, 125 MHz): 22.68, 47.40, 53.34, 57.58, 58.24, 126.22, 127.31, 128.58, 147.41, 148.11. MS(E|): m/2237 (M"). h 9 f b 6 a d CH3 N H c 3-Methyl-2-aza-splro[4.5]decane: The product was purified by flash column chromatography using silica gel and 1:1 ethylacetatezhexanes to remove free szpm. Then the eluent was changed to 88:10:2 dichloromethanezmethanol:tert- 53 butylamine. The product was isolated in 86% yield. 1H NMR (CDCI3, 500 MHz), 500 MHz): 1.3-1.5 (14 H, a,b,f,g,h), 1.92 (1 H, dd, J: 12.5 and 6.5 Hz, b), 2.86 (1 H, d, J= 11.5 Hz, d), 2.99 (1 H, d, J: 11.5 Hz, d), 3.57 (1 H, m, e), 7.0 (1 H, br s, c). 13C{‘H} NMR (00013, 125 MHz): 19.26, 28.48, 28.97, 25.92, 36.73, 37.98, 43.31, 45.71, 54.77, 56.42. MS(E|): m/z 158 (M+). 2-Methyl-5,5-dlphenyl-plperldlne: The product was purified by flash column chromatography using silica gel with 88:10:2 dichloromethanezmethanol:terr- butylamine as eluent. The purified product was isolated in 83% yield. 1H NMR (CDCI3, 500 MHz), 500 MHz): 1.00 (2 H, d, J: 6 Hz, a), 1.10-1.20 (1 H, m, b), 1 £04.65 (2 H, m, f and c), 2.20 (1 H, app td, J: 15.0 and 5.0 Hz, b), 2.67-2.70 (1 H, m, r), 2.77 (1 H, m, e), 3.10(1 H, d, J: 14 Hz, d), 8.90 (1 H, dd, J: 14 and 3 Hz, d), 7.09-7.41 (10 H, m, Ar-H). 1"‘C(‘H} NMR (CDCI3, 125 MHz): 22.62, 31.58, 35.64, 45.50, 52.60, 55.98, 126.04, 126.68, 128.46, 128.88, 144.93, 1 49.01. MS(E|): m/z 252 (M+H+). 54 2-BenzyI-4,4-dIphenyl-pyrrolldlne: The product was purified by flash column chromatography using silica gel and 88:10:2 dlchloromethane:methanol:tert- butylamine and was isolated in 87% yield. 1H NMR (CDCI3, 500 MHz): 2.0 (1 H, br s, c), 2.03 (1 H, dd, J: 9.0 and 12.5 Hz, b), 2.58 (2 H, m, a and b), 2.72 (1 H, dd, J: 7.5 and 13.5 Hz, a), 3.34-3.44 (2 H, m, d and e), 3.56 (1 H, d, J: 11.0 Hz, d), 7.0-7.15 (15 H, m, Ar-H). 1SC{1H}NMR(CDCI3, 125 MHz): 43.85, 45.18, 56.88, 57.96, 59.45, 126.33, 126.35, 126.48, 127.25, 127.38, 128.63, 128.7, 1 28.72, 129.39, 140.17, 147.1, 147.99. MS(E|): m/z 313 (M*). f 9 b a hflCHa N d HC 2-Methyl-lndollne: The product was purified by column chromatography using alumina and hexane to 5% EtOAc in hexane and was isolated in 73% yield. 1H NMR (00013, 500 MHz): 1.27 (3 H, d, J: 6 Hz, a), 2.68 (1 H, dd, J: 15.0 and 7.5 Hz, b), 3.12 (1 H, dd, J: 15.5 and 8.5 Hz, b), 3.78 (1 H, br s, c), 8.97 (1 H, 55 m, e), 6.59 (1 H, d, J: 7.5 Hz, 9), 6.68 (1 H, app t, J: 6.5 Hz, f), 6.99 (1 H, app t, J: 7.0 Hz, h), 7.06 (1 H, d, J: 7.0 Hz, d). 13C{‘H} NMR (CDCI3, 125 MHz): 22.52, 38.0, 55.44, 109.39, 118.75, 124.94, 127.46, 129.11, 151.19. MS(E|): m/z 133 (M+). 1,2-Dlmethyl-4,4-dlphenyI-pyrrolldlne: The product was purified by column chromatography using alumina and hexane and was isolated in 35% GO yield. (GC-FID, using dodecane as standard). 1H NMR (CDCI3, 500 MHz): 1.12 (3 H, d, J = 6.5 Hz, a), 2.19 (1 H, dd, J = 13.0 and 9.0 HZ, b), 2.35 (3 H, s, c), 2.44-2.52 (1 H, m, e), 2.85 (2 H, dd, J: 13.0 and 7.5 Hz, d), 3.79 (1 H, d, J: 10 Hz, b), 7.1-7.28 (10 H, m, Ar-H). 1306 H} NMR (CDCI3, 125 MHz): 19.16, 40.71, 48.74, 52.89, 62.13, 70.58, 125.73, 126, 127.33,127.66, 128.26, 128.43, 149.25, 150.9; MS(E|): m/z 252 (M+H+). 56 Ph ”‘2le \ a d N CH3 CH3 C 1,5-dlmethyl-3,3-dlphenyl-2,3-dlhydro-1H-pyrrole: The product was isolated by column chromatography using alumina using hexane then 1:1 ethyl acetatezhexane then dichloromethane. The product was the slowest moving compound on the column. The compound apparently decomposes on the column over time. Attempts to use silica gel did not provide any compound; apparently, it could not be removed from the column with any solvents applied. The yield in the crude reaction mixture was 34% from GC-FID using dodecane as standard calibrated for closely related 1,2-dimethyl—4,4-diphenyl-pyrrolidine. 1H NMR (CDCI3, 500 MHz): 1.82 (3 H, s, a ), 2.60 (3 H, s, c), 3.66 (2 H, s, d), 5.05 (1 H, s, b), 727.4 (10 H, m, Ar-H). “’06 H} NMR (00013, 125 MHz): 13.49, 37.92, 57.23, 69.68, 107.3, 126.07, 127.25, 128.39, 148.04, 149.03. MS(E|): m/z 249 (M+). Ph N CH3 H 4-Allyl-2-methyl-4nphenyl-pyrrolIdIne: The products were purified by flash 57 column chromatography using silica gel and 1:1 ethyl acetatezhexanes to remove free szpm. Then the eluent was changed to 88:10:2 dichloromethanezmethanol:tert-butylamine. A 1:1 mixture of two diastereomers was isolated in 96% yield. The ratio of the two diastereomers was determined by GC-FID. 1H NMR (00013, 500 MHz) of the mixture: 1.16 (3 H, d, J: 6.5 Hz), 1.21 (3 H, d, J: 6.5 Hz), 1.53 (1 H, dd, J: 13 and 8H2), 1.60 (1 H, dd, J: 12.5 and 9.5 Hz), 2.01 (2 H, bs), 2.27 (1 H, dd, J: 12.5 and 6.5 Hz), 2.33-2.48 (5 H, m), 8.18-8.25 (4 H, m), 8.42-3.47 (1 H, m), 4.90-4.98 (4 H, m), 5.89-5.49 (2 H, m), 7.14-7.82 (10 H, m). 13C{1H} NMR (CDCI3, 125 MHz): 22.8, 22.5, 45.5, 45.9, 46.0, 47.5, 52.2, 53.4, 54.3, 57.3, 58.2, 117.50, 117.57, 126.0, 126.1, 127.0, 128.8, 128.88, 185.2, 185.4, 147.2, 147.5. MS(E|): m/z 201 (M*). 58 2.7 References 1. For hydroamination reviews see: (a) Odom, A. L. Dalton Trans 2005, 225. (b) Hultzsch, K. C. Adv. Synth. Catal. 2005, 347, 367. (c) Hong, 8.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673. (d) Mueller, T. E.; Beller, M. Chem. Rev. 1998, 98,675. 2. For some recent examples of intramolecular hydroamination with Group-3 and lanthanide catalysts see: (a) Lauterwasser, F.; Hayes, P. G.; Brass, H. G.; Piers, W. E.; Schafer, L. L. Organometallics 2004, 23, 2234-7. (b) Kim, J. Y.; Livinghouse, T. Org. Lett. 2005, 7, 4391-4393. (c) Rlegert, D.; Collic, J.; Daran, J.-C.; Fillebeen, T.; Schulz, E.; Lyubov, D.; Fukin, G.; Trifonov, A. Eur. J. Inorg. Chem. 2007, 1159-68. (d) O’Shaughnessy, P. N.; Scott, P. Tetrahedron: Asymmetry 2003, 14, 1979-83. (6) Yu, X.; Marks, T. J. Organometallics. 2007, 26, 365-376. (8) Kim, Y. K.; Livinghouse, T.; Bercaw, J. E. Tetrahedron Lett. 2001, 42, 2933-5. 3. Kim, H.; Kim Y. K.; Shim, J. H.; Kim, M.; Han, M.; Livinghouse, T.; Lee, P. H. Adv. Synth. Catal. 2006, 348, 2609-18. 4. For some recent examples of intramolecular hydroamination with Group-4 catalysts see: (a) Gott, A. L.; Clarke, A. J.; Clarkson, G. J.; Scott, P. Organometallics 2007, 26, 1729-37. (b) Knight, P. D.; Munslow, l.; O’Shaughnessy, P. M; Scott, P. Chem. Comm. 2004, 894-5. (0) Muller, C.; Loos, C.; Schulenberg, N.; Doye, S. Eur. J. Org. Chem. 2006, 2499-2503. (d) Wood, M. C.; Leitch, D. C.; Yeung, C. S.; Kozak, J. A.; Schafer, L. L. Angew. Chem. Int. Ed. 2006, 46, 354-8. (e) Ackermann, L.; Bergman, R. G.; Loy, R. N. J. Am. Chem. Soc. 2003, 125, 11956-63. (f) Ackermann, L.; Bergman, R. G. Org. Lett. 2002, 4, 1475-8. (9) Watson, D. A.; Chieu, M.; Bergman, R. G. Organometallics 2006, 25, 4731-3. (h) Bexrud, J. A.; Beard, J. D.; Leitch, D. C.; Schafer, L. L. Org. Lett. 2005, 7, 1959-62. (i) Kim, H.; Lee, P. H.; Livinghouse, T. Chem. Comm. 2005, 5205-7. (j) Thomson, R. K.; Bexrud, J. A.; Schafer, L. L. Organometallics 2006, 25, 4069. 5. (a) Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114, 5459. (b) Baranger, A. M.; Walsh, P. J.; Bergman, R. G. J. Am. Chem. Soc. 1993, 115, 2753. 6. Ryu, J.-S.; Marks, T. J.; McDonald, F. E. J. Org. Chem. 2004, 69, 1038. 59 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. Schrock, R.R.; Murdzek, J.S.; Bazan G.C.; Robbins, J.; DiMare, M.; O’Reagan, M. J. Am. Chem. Soc. 1990, 112, 3875. Y. Shi, C. Hall, J. T. Ciszewski, C. Cao and A. L. Odom, Chem. Commun., 2003, 586. (a) Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem. Commun. 2003, 586. (b) Novak, A.; Blake, A. J.; Wilson, 0.; Love, J. B. Chem. Commun. 2002, 23, 2796. Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127, 1070. Yang, 0.; Wolfe, J. P. Org. Lett. 2005, 7, 2575. Gange, M. R.; Charlotte, L. 8.; Marks, T. J. J. Am. Chem. Soc. 1992, 114, 275. Knight, P. D.; Munslow, I.; O'Shaughnessy, P. M; Scott, P. Chem. Comm. 2004, 894. Majumder, S.; Odom. A.L. Organometallics, 2008, 27, 1174. Monoclinic P2(1)/n; a = 10.892(3) A, b = 16.012(4) A, c = 18.471(5) A, b = 100.392°; Reflections total/unique = 26880l4578 [R(int) = 0.0492] for 362 parameters; Goodness-of-fit = 1.045; R1 [l > 25] = 0.0349, wR2 [I > 2s] = 0.0905; R1 [all data] = 0.0437, wR2 [all data] = 0.0947. (a) Jung, J.E; Piizzi, G. Chem. Rev. 2005, 105, 1735. (b) Bexrud, J. A. PhD Thesis, 2008, The University of British Columbia. Swartz, D. L.; Odom, A. L. Organometallics 2006, 25, 6125. It has been reported recently that neutral zirconium “constrained- geometry" catalysts use the 1,2-insertion pathway. Stubbert, B. D.; Marks, T. J. J. Am. Chem. Soc. 2007, 129, 6149-67. The zirconium complex here, if a monomer in the active species, may be quite similar in overall structure to the Marks catalyst, especially if retaining the n 5,1) 1-geometry for the dipyrrolylmethane. A report of a closely related enamine suggests it may be unstable under typical work-up conditions. Pugin, B.; Venanzi, L. M. J. Am. Chem. Soc. 1983, 105, 6877. 20. 21. 22. 23. 24. 25. 26. 27. (a) Bradley, D. C.; Thomas, I. M. Proc. Chem. Soc. 1959, 225. (b) Bradley, D. C.; Thomas, I. M. J. Chem. Soc. 1960, 3857. Littler, B. J.; Miller, M. A.; Hung, C.-H.; Wagner, R. W.; O’Shea, D. F.; Boyle, P. D.; Lindsey, J. S. J. Org. Chem. 1999, 64, 1391. Hong, S.; Tian, S.; Metz, M. V.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 14768. Kondo, T.; Okada, T.; Mitsudo, T. A. J. Am. Chem. Soc. 2002, 124, 186. Black, D. St. 0.; Doyle, J. E. Australian J. of Chem. 1978, 31, 2247. Michael, F. E.; Cochran, B. M. J. Am. Chem. Soc. 2006, 128, 4246. Bender, C. F., Widenhoefer, R. A. J. Am. Chem. Soc. 2007, 127, 1070. Ciganek, E. J. Org. Chem. 1995, 60, 5803. 61 CHAPTER 3 Pyrazole synthesis using a titanium-catalyzed multicomponent coupling reaction and synthesis of Withasomnine 3.1 lntroductlon Catalyzed multicomponent coupling reactions offer the opportunity to generate important classes of molecules, such as heterocycles, in a small number oflsteps. The main advantages of this type of scheme are the time saved by the researcher in the preparation of the compounds, the variety of compounds that can be made using these protocols by varying substituents in the starting materials, and the availability of catalysts that can be tuned to provide regio-, . 1 stereo-, or even chemoselectlve control from one set of substrates. Pyrazoles and related structures are important heterocycles for their applications to pharmaceuticals such as celecoxib (Celebrex®), sildenafil (Viagra®), and rimonabant (Acomplia®); they are also one of the most common cores found in herbicides, fungicides, and insecticides.2 Pyrazoles are also found in a few natural products such as withasomnine. Withasomnine is a popular compound in alternative medicine found in several plant species with alleged applications to a variety of ailments. It has been shown to be a mild analgesic and a central nervous system depressant.3 In recent years, several research groups have pursed transition metal- catalyzed multicomponent coupling reactions for direct access to substituted pyrazole compopunds. In 2008, Muller and co-workers4 as well as Jiang and co- workers5 independently reported palladium-catalyzed 3- component coupling of acid chloride, alkyne, and hydrazine to generate pyrazole compounds in good yields (Scheme 3.1). PdC|2(PPh3)2 I CUI R1 i // B3” ’ \ + 2 = N. 2 R‘ C' R RNHNH2 N R » R Scheme 3.1. Palladium-catalyzed 3-component coupling for pyrazole synthesis. A novel synthesis of pyrazoles using palladium-mediated 4-component coupling of alkyne, hydrazine, and aryl halide in presence of carbon monoxide was reported independently by Mori group6 and more recently by the Stonehouse group (Scheme 3.2).7 Ar PdCl PPh Ar’l + // + RNHNH2 2‘ 3"" 2 n. R1 N R CO (gas) (5; Scheme 3.2. One-pot palladium catalyzed 4-component synthesis of pyrazole. 63 In this study, we demonstrate that a variety of pyrazoles can be prepared in a one-pot 4-component fashion. The methodology uses a titanium-catalyzed 3- component coupling8 of an alkyne, isonitrile, and primary amine to generate unsymmetrical 1,3-diimine tautomers.9 Pyrazoles result from simply removing the volatiles from the multicomponent coupling reaction and treating the crude product with commercially available hydrazines.10 Finally, we present a new, concise synthesis of the natural product withasomnine using this multicomponent coupling methodology. 64 3.2 Results and Dlscusslon The multicomponent coupling reaction utilized here is a formal alkyne iminoamination, addition of an iminyl and amine across the triple bond (Scheme 3.3).4'1 ‘ R4N titanium catalyst RLNH \ H2NR‘ + R2 : R3+ CEN-R4 = — R2 R3 Scheme 3.3. Titanium catalyzed 3-component iminoamination of alkynes. The proposed mechanism for the reaction is shown in Scheme 3.4. Titanium was added as dimethylamido-containing precatalysts, which are easily synthesized from commercially available Ti(NMez)4.12 The dimethylamido ligands are protolytically removed by the primary amine substrate13 to generate titanium imido complexes that undergo [2 + 2]-cycloaddition with alkynes.14 The resulting azatitanacyclobutenes undergo 1,1-insertion of isonitriles to generate 5- membered metallacycles.15 The 5-membered metallacycles are protolytically converted back to imidos by primary amines with concomitant release of the iminoamination products. 65 [Til(NMez)2 precatalyst H2NR11— 2 HNM82 RLN \>.__/? R1 I H NR [Ti] 2 R1 . .r'1 ”if N / R3 54%. C\\\N fimli: Scheme 3.4. Proposed mechanism for titanium-catalyzed iminoamination of alkynes. For this study, we employed two different pyrrole-based catalysts. Both catalysts use ligand architectures synthesized in a single step from pyrrole, and both ancillary ligands can be placed on titanium in near quantitative yields by reaction with commercially available Ti(NM82)4 (Scheme 3.5). The first catalyst described for this 3-component coupling reaction was Ti(NMe2)2(dpma),16 where dpma17 = N, N-di(pyrrolyl-a-methyl)-N-methylamine. More recently, we have found that Ti(NMez)2(dpm),18 where dpml9 = 5,5-dipyrrolylmethane, is a quite active catalyst for alkyne iminoamination. 66 H H N +2HCHO \ N N 2 U +MeNH3Cl EtOH T mMm / H20 szpma 55°C 88% ether, RT Ti(NMe2)4 1 h 97% Ti(NMez)2(dpma) (1) H H N O 10 mol% CF COOH \ N 20 3 U + Y 50% T \ N” l / H2dpm ether, RT 11(NM82)4 8 h 91% Ti(dpm)(NMe2)2 (2) Scheme 3.5. Synthesis of H2dpma, szpm, T1(NM82)2(dpma) (1), and 67 In some cases, Ti(NMez)2(dpm) (2) is a preferred catalyst over Ti(NMez)2(dpma) (1). For example, 3CC of 1-hexyne, cyclohexyl amine and tert- butylisonitrile in presence of 10 mol% Ti(NMe2)2(dpma) resulted formation of two regioisomeric 300 products in 121.2 ratio, however, changing the catalyst to Ti(NMe2)2(dpm) not only reversed the regioselectivity but also increased the selectivity to 20:1 (Scheme 3.6). 10 mol% QN\ +QN\SBU“ Tl(NMez)2(dme toluene, 100 °C n Bun—E- 24h N B“ N\\ . 7i 7f NH2 > 20 I 1 1' 10 mol% Q >rrr-C TI(NM92)2(dea)_ HN , HN Bu” toluene, 100 °C 7 n 24h ”x B” X 1.2 Scheme 3.6. Effect of catalysts on regioselectivity. Ti(NM82)2(dpm) is also a preferred catalyst for 3CC reaction using enynes. Changing the catalyst to Ti(NMez)2(dpma) resulted poor yields of the 3CC product. An example is shown in scheme 3.7. 68 Q C : + G + NaC 10 mol% catalyst> HN X toluene, 100 °C l0 24h N\ 7( Tl(NMe2)2(dpm) : 58% Tl(NMe2)2(dpma) : 28% Scheme 3.7. Multicomponent coupling using enynes. The multicomponent coupling reaction can be facile using both terminal and internal alkynes with a variety of amines. Because the substituent on the isonitrile does not end up in the final pyrazole product, tert-butylisonitrile was employed exclusively here because of its general applicability in this reaction. Ease of access is also an advantage for t-BuNC, which is both commercially available and readily prepared from tart-butylamine and chloroform in the 20 presence of base. Barluenga and coworkers published a large series of notable papers in “1- azabutadiene” chemistry where the intermediates were obtained by reaction of saturated nitriles with Schiff bases using AlCI3.21 These 1-azabutadienes are close derivatives of the iminoamination products used here; however, the available substitution patterns are quite different. In addition, the iminoamination procedure produces useful intermediates in a one-step 3-component coupling procedure, and catalyst variations can be used to control regioselectivity giving different products from the same substrates. We explored the reactions of in situ generated iminoamination products with hydrazines in the presence of base.22 69 The reactions can be carried out with an isolated iminoamination product (Equation 3.1) or more conveniently in a one-pot procedure generating the pyrazoles directly from alkyne, amine, isonitrile, and hydrazine (Scheme 3.8). Q .. > FN (3-1) N" PhNHNH2 :/>—Ph . . N' HN Pyridine, 150 °C Ph 24 h 7) -70). 2 — 8 _ R j R 94mm 10 mol% Catalyst R‘N | RLNHZ o : R3 toluene, 100 C 2 R + _ _ 4. : R N‘C R5-NHNH2 pyridine, 150 °C Scheme 3.8. One-pot synthesis of pyrazoles (3). The general procedure involved the addition of amine (1 mmol), catalyst (10 mol%), alkyne (1 mmol), isonitrile (1-1.5 mmol), and 2 mL of toluene to a 40 mL pressure tube under nitrogen, which was sealed and heated at 100 °C with stirring. Once the multicomponent coupling reaction was complete as judged by 70 GC-FID, the volatiles were removed in vacuo and 3 mL of pyridine along with hydrazine or hydrazine hydrochloride was added to the crude residue. After additional heating,23 the product pyrazole (3) was purified by chromatography or crystallization. Some applications of the methodology are shown in Tables 3.1 and 3.2. For this initial study, we chose to look at the multicomponent coupling product of phenylacetylene, tert-butylisonitrile, and cyclohexylamine with a variety of different hydrazines, which generated pyrazoles 3a-I. Since all hydrazines tested seemed equally successful in the second step of the reaction, a large variety of N-substituted and N-H pyrazoles can likely be prepared in comparable yields. 71 Table 3.1. Examples of pyrazole (3) syntheses using phenylacetylene and a variety of hydrazines. Hydrazlne Product (3) G0 or NMR (Isolated) Ylelda 3 Ph Z—i) Ph D Ph NH2NH2 H20 H' 51 (43) 0 Ph T1. N. C6"‘11r‘l(H)'\IHZ : 52 (45) d Pl'l Ti. ButN(H)NH2 gut 68 (5°) / \ MeN(H)NH2 $.11 (35) Me f thj / \N BnN(H)NH2 ,1, 45 (45) Bn 9 Ph 4-MeOCeH4N(H)NH2 © 6° (45) OMG '1 Ph 4-CNCGH4N(H)NH2 © 53 (41) ON I Ph INEN 4-COzMeCSH4N(H)NH2 Q 46 (39) COzMe a) 10 mol% 1 used as catalyst. 72 In the second stage of the study (Table 3.2), a selection of different internal and terminal alkynes was used with phenylhydrazine, which generated pyrazoles 3j-q. Terminal alkynes and 1-phenylpropyne reactions could be done with the milder catalyst 1. More difficult substrates like diphenylacetylene and 3- hexyne required 2 as catalyst, sometimes with increased catalyst loadings or longer reaction times. In one case (3]), the product was structurally characterized by X-ray diffraction to help ensure proper assignment of the regiochemistry as the 1,4,5- trisubstituted pyrazole. 73 Table 3.2. Examples of pyrazole (3) syntheses using phenylhydrazine with other alkynes. Alkyne Product (3) GO or NMR (Isolateg)Yleld Ph I /Ph Me I \N / N' M" for. 45 (40)?"d k é In)" in 89 (87)ID I Ph 1311/ Ph Ph’Z/F‘N c r'an 84 (24) / \ ///©/ 1):“ 50 (41)a Ph n Bu" l'l //Bu 2,3” b Ph 35 (28) o Ph Ph | "N & N. b M32 Ph (81) NEtg p M90 0% \ M60 IN-" 45 (88)b Ph q | ‘,N 2 N. C ,, , OTBS 44 (85) ores a) 10 mol% 1. b) 10 mol% 2. c) 20 mol% 2. d) See Equation 1 and text for regioselectivity discussion. 74 Not only do the two catalysts differ in their reactivity, but the regioselectivity of reactions with 1 and 2 was often different as well. In general, dipyrrolylmethane 2 favored 4-substitutlon in the pyrazole products when terminal alkynes were employed. The trldentate ligand 1 favored 4-substitution for aromatic groups and 3-substitution (or 5-substitution - vide infra) for alkyl- containing alkynes. For example, reactions with 1-hexyne as substrate and catalysts 1 and 2 were carried out under similar conditions (Scheme 3.9).24 Catalyst 1 provides 3- butylpyrazole (3r) as the major isomer, while catalyst 2 generates 4-butylpyrazole (33) as the major product.25 1) 10% Ti(dpma)(NMe2)2 (1) R = Ph, toluene 100 °C, 24 h n 2) NH2NH2, pyridine Bun Bu 150 °C, 12 h 7 (1 Z‘“ ’ / ,N + / ,N : Bun 53°/o 1:1 {III + 3r : 38 R-NH 1) 10% Ti(dpm)(NM82)2 (2) 6 : 1 2 R = cyclohexyl, toluene + 100 °C, 24 n n n i 2) NH2NH2, pyridine 3” 3“ ONE“ 150 °C, 12h (fl \ / ( ' ’ ,N + ,N 27% N N H H 3r : 3s 1 : 12 Scheme 3.9. Regioselectivity of pyrazole formation using 1-hexyne as the substrate and catalyst 1 and 2. 75 If an alkyl or aryl hydrazine is employed with an unsymmetrical 3- component coupling product, mixtures could potentially result due to different regioisomers from the hydrazine addition (Equation 3.1). Even so, one isomer can often be strongly favored. For example, the 3-component coupling product“ derived from 1-phenylpropyne reacts with phenylhydrazine to give 1-phenyl-4- phenyl-S-methylpyrazole (3]) with 9:1 selectivity over the alternative isomer 1- phenyl-3-methyl-4-phenylpyrazole26 (Equation 3.2). Methods for controlling the regioselectivity further in this step are under investigation. Ph N\ Me PhNHNH2 hp (3. 2) Bu‘HN / o T Me N + ph Pyridine, 150 C NN’ 24h 1h 31h 9 : 1 As might be expected, several of the compounds in Table 3.1 have been prepared previously. In general, the route here often compares favorably with previously reported syntheses in number of steps, overall yield, or both. For example, one can examine 4-phenylpyrazole (3b), which we prepare in 43% yield in a single step from phenylacetylene. In this case, the product precipitates from the reaction mixture and is collected by filtration and recrystallized. There are . . 27 . . several distinct routes to the same compound. For example, Vllsmeler formylation of phenylacetaldehyde diethylacetal followed by hydrazine affords 4- 76 phenylpyrazole in 36% yield in two steps.28 The pyrazole was prepared in 8% yield by Suzuki coupling of 5-B(OH)2-pyrazole and PhCI.29 Kumada coupling of 1-trityl-4-bromopyrazole and PhMgBr catalyzed by PdCI2(dppf) is high yielding but requires 4 steps from pyrazole.3O We also applied this methodology to the synthesis of the natural product withasomnine, which has been prepared using a diverse array of routes.31 The advantages of the multicomponent coupling strategy presented here are the inexpensive and readily available reagents used in a straightforward synthesis (Scheme 3.10) of the natural product. flc’“ n WW... // + t3 ' // 4 > 2)TBS-Cl, lmidazole ph DMF Ph' PhNHz, Bu‘NC 96% (2 steps) 1)10 mol% Ti(dpm)(NMe2)2 (2) 35% (2 steps) 110 °C, 48 h, toluene 2, .NHzNHz pyrIdIne, 150 °C v 24 h BBI'3 Ph 1) CHZCIZ, FlT P“ \ , \N ‘ 24 h / .N N' 2) NaOEt, EtOH N reflux, 20 h H 6 o T WIthasomnlne 71 A (2 steps) C; BS 24% overall yield Scheme 3.10. Synthesis of withasomnine. 77 High yielding Sonogoshira coupling of iodobenzene and 4-pentyn-1-ol followed by protection of the alcohol by tent-butyl(dimethyl)silation provided alkyne 4.32 lminoamination using 10 mol% 2, aniline, and tert-butylisonitrile followed by addition of hydrazine hydrate gave the desired pyrazole 5 with the desired regioselectivity. The TBDMS protection was removed and converted to the alkyl bromide with BBr3. Some of the natural product 6 was formed during the reaction with tribromoborane, and ring-closure was completed with the addition of NaOEt/EtOH to provide withasomnine in 71% yield from 5. The overall yield was 24% from the 4-pentyn-1-ol. This is comparable in yield to the recently reported synthesis by Allin et al.,33 which used 4-bromopyrazole as the starting material with an interesting radical cyclization to close the aliphatic ring. 78 3.3 Conclusion Titanium-catalyzed 3-component coupling of primary amine, alkyne, and isonitrile followed by treatment with hydrazines provides pyrazoles in a one-pot procedure. This new procedure has significant flexibility in the types pyrazoles that can be accessed. The yields are generally modest, but the products are readily isolated using either column chromatography or crystallization. Reactions with terminal alkynes are more facile and can be accomplished with the milder Ti(dpma)(NMe2)2 (1) as catalyst. The more active dipyrrolylmethane catalyst Ti(dpm)(NMe2)2 (2) was used for internal alkynes. The reaction has several points to allow optimization for a specific target of interest. For example, the type of substituent on the isonitrile can potentially be varied in this reaction to improve regioselectivities or yields. The catalyst architectures themselves are also quite flexible and could be optimized for specific products. In fact, it was found that some regiochemical control is possible using simple catalysts 1 and 2 with alkyl-substituted terminal alkynes, and either 3-butyl- or 4-butylpyrazole can be synthesized from the same substrates preferentially depending on the catalyst employed (Scheme 3.7). The 3-component coupling followed by hydrazine treatment strategy was also applied to the synthesis of the natural product withasomnine (6) from commercially available 4-pentyn-1-ol in 24% overall yield. 79 3.4 Experimental General Conslderatlons: All manipulations of air sensitive compounds were carried out in an MBraun dry box under a purified nitrogen atmosphere. Toluene was purified by purging with dry N2, then water was removed by running through activated alumina systems purchased from Solv-Tek. Deuterated solvents were dried over purple sodium benzophenone ketyl (0606) or phosphoric anhydride (CDCI3) and distilled under a nitrogen atmosphere. Deuterated toluene was degassed then dried by passing through two columns of neutral alumina. 1H and 130 spectra were recorded on VXR-SOO spectrometers. Melting points were measured on a Mel-Temp ll apparatus with a mercury thermometer and are uncalibrated. Ti(dpm)(NMe2)2 (2)18 and Ti(dpma)(NMe2)2 (1)16 were made following the literature procedures. Alkynes were purchased either from Sigma- Aldrich Co. or from GFS chemicals and dried from CaO under dry nitrogen. Amines were purchased from Sigma-Aldrich Co., dried over KOH, and distilled under dry nitrogen. terIf-Butylisonitrile20 was made from CHCI3 and tert- butylamine according to the reported procedure and purified by distillation under nitrogen. Phenylhydrazine was purchased from Sigma-Aldrich Co. and dried from KOH. Hydrazine hydrate was purchased from Spectrum Chemicals and used as received. All other hydrazines were purchased from Sigma-Aldrich Co. as 80 hydrochloride salts and used as received. Pyridine was dried over KOH and distilled under nitrogen. The alkynes 5-(tert-butyldimethylsilyloxy)—1 -phenylpent-1- yne and 5-phenylpent-4-yn-1-ol were made according to the literature 31 procedures. The GC yields in Table 3.1and 3.2 are from crude reaction mixtures relative to internal octane added after reaction completion and are calibrated versus pure product/octane standards. Pyrazole(3) Syntheses General Procedure for Pyrazole Syntheses: In an N2 filled glove box, a 40 mL pressure tube equipped with a magnetic stirbar was loaded with amine (1 mmol), catalyst (10-20 mol%), alkyne (1 mmol), isonitrile (1-1.5 mmol), and dry toluene (2 mL). The pressure tube was sealed with a Teflon screw cap, taken out of the dry box, and heated to the appropriate temperature for the desired time with vigorous stirring. After completion of the reaction, the pressure tube was cooled to room temperature, and volatiles were removed under reduced pressure. Then the tube was charged with hydrazine or hydrazine hydrochloride (1.5 mmol) in pyridine (3 mL) and heated to 150 °C for 24 h. After completion of the reaction, pyridine was removed under reduced pressure. The crude product was dissolved in CHZCIZ and washed with water. The organic layer was dried over NaZSO4 and concentrated on a rotary evaporator. The crude product was purified either by column chromatography or by crystallization from a suitable solvent. 81 SR 1,4-dlphenylpyrazole (3a): A reaction using the general conditions was carried out with tert-butylisonitrile (171 ”L, 1.5 mmol), cyclohexylamine (99 mg, 1 mmol), phenylacetylene (102 mg, 1 mmol), and Ti(NMe2)2(dpma) (1, 32.3 mg, 0.1 mmol) in toluene (2 mL) and was heated for 24 h at 100 °C. Volatiles were removed, and phenylhydrazine (162 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyl acetate 9:1, which afforded the desired compound (106 mg, 48%) as a pale yellow solid. M.p.: 95-96 °C (Lit34 Mp. 97 °C). 1H NMR (coc13, 500 MHz): 7.28-7.34 (2 H, m, Ar-H), 7.42 (2 H, t, J: 7.5 Hz, Ar-H), 7.49 (2 H, t, J: 8 Hz, Ar-H), 7.57-7.59 (2 H, m, Ar-H), 7.75-7.77 (2 H, m, Ar-H), 8.03 (1 H, d, J = 0.5 Hz, 3-CH-pyrazole), 8.17 (1 H, d, J: 1 Hz, 5-CH-pyrazole). 130011} NMR (CDCI3, 125 MHz): 119.0, 123.3, 124.9, 125.7, 126.5, 126.8, 128.9, 129.4, 132.0, 138.8, 140.0. MS(E|): m/z 220 (M+). High resolution MS: m/z Calc. for c15H13N2”: 221.1079; Found 221.1065. 4-phenylpyrazole (3b): A reaction using the general conditions was carried outwith tert-butylisonitrile (855 pL, 7.5 mmol), cyclohexylamine (495 mg, 5 mmol), phenylacetylene (510 mg, 5 mmol), and Ti(NMe2)2(dpma) (1, 162 mg, 0.5 mmol) in toluene (10 mL) and was heated for 24 h at 100 °C. Volatiles were 82 removed, and hydrazine hydrate (375 mg, 7.5 mmol) in dry pyridine (15 mL) was added. The mixture was heated to 150 °C for 24 h. Pyridine was removed under vacuum, and the crude product was recrystallized from methanol/ethyl acetate to yield the desired product (310 mg, 43%) as a white solid. M.p.: 233-234 °C (Lit27 M.p. 235-236 °C). 1H NMR (DMSO-de, 500 MHz): 7.15 (1 H, t, J: 7.5 Hz, Ar-H), 7.32 (2 H, t, J: 7.5 Hz, Ar-H), 7.57 (2 H, dd, J: 7.5 and 1.5 Hz, Ar-H), 7.89 (1 H, br s, 3-CH pyrazole), 8.15 (1 H, br s, 5-CH pyrazole), 12.90 (1 H, br s, NH). 13c:{‘H} NMR (DMSO-de, 125 MHz): 121.1, 125.1, 125.3, 125.8, 128.7, 132.9, 136.1. MS(E|): m/z 144 (M+). 1cyclohexyl-4»phenylpyrazole (3c): A reaction using the general conditions was carried out with tert-butylisonitrile (171 (1L, 1.5 mmol), cyclohexylamine (99 mg, 1 mmol), phenylacetylene (102 mg, 1 mmol), and Ti(NMe2)2(dpma) (1, 32.3 mg, 0.1 mmol) in toluene (2 mL) and was heated for 24 h at 100 °C. Volatiles were removed, and cyclohexylhydrazine hydrochloride (226 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyl acetate 9:1, which afforded the desired compound (102 mg, 45%) as a yellow solid. M.p.: 69-70 °C. 1H NMR (CDCI3, 500 MHz): 1.22-1.30 (1 H, m, cyclohexyl), 1.38-1.48 (2 H, m, cyclohexyl), 1.70-1.78 (3 83 H, m, cyclohexyl), 1.88-1.91 (2 H, m, cyclohexyl), 217-22 (2 H, m, cyclohexyl), 4.08-4.14 (1 H, m, 1-cyclohexyl), 7.17-7.20 (1 H, m, Ar-H), 7.31-7.34 (2 H, m, Ar- H), 7.44-7.46 (2 H, m, Ar-H), 7.64 (1 H, d, J= 0.5 Hz, 3-CH—pyrazole), 7.75 (1 H, d, J: 0.5 Hz, 5-CH-pyrazole). 130{1H}NMR(CDCI3, 125 MHz): 25.4, 33.6, 61.4, 122.3, 123.5, 125.4, 126.2, 128.8, 132.9, 136.0. Two of the resonances, assigned as being due to the 3- and 4-carbons of the cyclohexyl, are coincident in the 130 NMR spectrum at 25.39 ppm. MS(E|): m/z 226 (M+). High resolution MS: m/z Calc. for C15H19N2+z 227.1548; Found 227.1552. 1-tert-butyI-4-phenylpyrazole (3d): A reaction using the general conditions was carried out with tert-butylisonitrile (171 pL, 1.5 mmol), cyclohexylamine (99 mg, 1 mmol), phenylacetylene (102 mg, 1 mmol), and Ti(NMe2)2(dpma) (1, 32.3 mg, 0.1 mmol) in toluene (2 mL) and was heated for 24 h at 100 °C. Volatiles were removed, and tert-butylhydrazine hydrochloride (187 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyl acetate 9:1, which afforded the desired compound (100 mg, 50%) as a yellow liquid. 1H NMR (CDCI3, 500 MHz): 1.61 (9 H, s, CH3), 7.18 (1 H, tt, J: 7.5 and 1 Hz, 4-H-Ph), 7.33 (2 H, t, J: 8 Hz, Ar-H), 7.46-7.48 (2 H, m, Ar-H), 7.74 (1 H, d, J: 1 Hz, 3-CH-pyrazole), 7.78 (1 H, s, 5- 84 CH-pyrazole). 1300 H} NMR (CDCI3, 125 MHz): 29.8, 58.5, 122.2, 122.6, 125.4, 126.1, 128.8, 133.0, 136.1. MS(E|): m/z 200 (M+). High resolution MS: m/z Calc. for C13H17N2+z 201.1392; Found 201.1393. 1-methyl-4-phenylpyrazole (3e): A reaction using the general conditions was carried out with tert-butylisonitrile (855 (1L, 7.5 mmol), cyclohexylamine (495 mg, 5 mmol), phenylacetylene (510 mg, 5 mmol), and Ti(NMe2)2(dpma) (323 mg, 1 mmol) in toluene (10 mL) and was heated for 24 h at 100 °C. Volatiles were removed, and methylhydrazine (345 mg, 7.5 mmol) in dry pyridine (15 mL) was added. The mixture was heated to 140 °C for 24 h. After completion of the reaction, pyridine was removed under reduced pressure and crude product was dissolved in EtOAc and washed with water. The organic layer was dried over Na2304 and concentrated on a rotary evaporator. The crude product was purified by column chromatography using 20% ethyl acetate/hexanes on neutral alumina. Yield: 280 mg (35%). M.p.: 98-99 °C (Lit35 Mp. 100-1 °C). 1H NMR (00013, 500 MHz): 3.92 (3 H, s, CH3). 7.20 (1 H, tt, .1: 7.5 and 1 Hz, Ar—H), 7.34 (2 H, t, J: 8 Hz, Ar-H), 7.44-7.46 (2 H, m, Ar-H), 7.58 (1 H, s, 3-CH-pyrazole), 7.74 (1 H, d, J = 0.5 Hz, 5-CH—pyrazole). 1"C{‘H) NMFI (c003, 125 MHz): 39.1, 123.2, 125.5, 126.3, 126.8, 128.8, 132.6, 136.7. MS (EI): m/z 158 (MP‘). High resolution MS: m/z Calc. for C10H11N2+z 159.0922; Found 159.0909. 85 was MHZ 8H2 (1H Wt 1-benzyl-4-phenylpyrazole (31‘): A reaction using the general conditions was carried out with ten-butylisonitrile (171 pL, 1.5 mmol), cyclohexylamine (99 mg, 1 mmol), phenylacetylene (102 mg, 1 mmol), and Ti(NMe2)2(dpma) (1, 32.3 mg, 0.1 mmol) in toluene (2 mL) and was heated for 24 h at 100 °C. Volatiles were removed, and benzylhydrazine (183 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was 15% ethyl acetate/hexanes, which afforded the desired compound (105 mg, 45%) as a white solid. M.p.: 92-94 °c (Lit36 Mp. 95-96 °C). 1H NMR (coc13, 500 MHz): 5.35 (2 H, s, N-CHZ), 7.25 (1 H, t, J: 7.5 Hz, Ar-H), 7.27-7.29 (2 H, d, J: 8 Hz, Ar-H), 7.35-7.40 (5 H, m, Ar-H), 7.50 (2 H, dd, J: 8.5 and 1 Hz, Ar-H), 7.64 (1 H, s, 3-CH-pyrazole), 7.85 (1 H, s, 5-CH-pyrazole). 1306 H} NMR (CDCI3, 125 MHz): 56.2, 123.6, 125.5, 126.5, 126.4,127.8, 128.2, 128.8, 128.9, 132.5, 136.4, 137.0. MS(E|): m/z 234 (MP‘). High resolution MS: m/z Calc. for C16H15N2+2 235.1235; Found 235.1238. 1-(4-methoxyphenyl)-4-phenylpyrazole (39): A reaction using the general conditions was carried out with tert-butylisonitrile (171 pL, 1.5 mmol), cyclohexylamine (99 mg, 1 mmol), phenylacetylene (102 mg, 1 mmol), and Ti(NMe2)2(dpma) (1, 32.3 mg, 0.1 mmol) in toluene (2 mL) and was heated for 24 86 h at 100 °C. Volatiles were removed, and 4-methoxyphenylhydrazine hydrochloride (261 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was 15% ethyl acetate/hexanes, which afforded the desired compound (110 mg, 44%) as a white solid. M.p.: 124- 125 °C. 1H NMR (CDCI3, 500 MHz): 3.87 (3 H, s, OMe), 7.0-7.02 (2 H, m, Ar-H), 7.28 (1 H, tt, J: 7.5 and 1 Hz, Ar-H), 7.41 (2 H, t, J: 8 Hz, Ar-H), 7.57 (2 H, dd, J: 8 and 1 Hz, Ar-H), 7.64-7.66 (2 H, m, Ar-H), 7.98 (1 H, d, J = 0.5 Hz, 3-CH- pyrazole), 8.08 (1 H, d, J = 0.5 Hz, 5-CH-pyrazole). 13C{‘H)NMR (CDCI3, 125 MHz): 55.5, 114.5, 120.7, 123.4, 124.5,1256, 126.7, 128.9, 132.2, 1339,1383, 158.3. MS(E|): m/z 250 (M+). High resolution MS: m/z Calc. for C16H15N20+2 251.1184; Found 251.1169 1-(4-cyanophenyl)—4—phenylpyrazole (3h): A reaction using the general conditions was carried out with tert-butylisonitrile (171 uL, 1.5 mmol), cyclohexylamine (99 mg, 1 mmol), phenylacetylene (102 mg, 1 mmol), and Ti(NMe2)2(dpma) (32.3 mg, 0.1 mmol) in toluene (2 mL) and was heated for 24 h at 100 °C. Volatiles were removed, and 4—cyanophenylhydrazine hydrochloride (255 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyl acetate 4:1, which afforded the desired compound (100 mg, 41%) as a white solid. M.p.: 166-167 °c. 1H NMFI 87 (CDCI3, 500 MHz): 7.27—7.31 (1 H, m, Ar-H), 7.40 (2 H, t, J: 8 Hz, Ar-H), 7.53- 7.54 (2 H, m, Ar-H), 7.74-7.76 (2 H, m, Ar-H), 7.85-7.87 (2 H, m, Ar-H), 8.02 (1 H, s, 3-CH pyrazole), 8.18 (1 H, d, J = 0.5 Hz, 5-CH pyrazole). ‘30{‘H} NMFl (C0013, 125 MHz): 109.6, 118.3, 118.7, 123.0, 125.8, 126.2, 127.4, 129.0, 131.2, 133.6, 140.2, 142.8 MS (El): m/z 245 (M+). High resolution MS: m/z Calc. for C16H12N3+z 246.1031; Found: 246.1040. 1-(4-methylcarboxylphenyl)—4-phenylpyrazole (3|): A reaction using the general conditions was carried out with ten-butylisonitrile (171 pL, 1.5 mmol), cyclohexylamine (99 mg, 1 mmol), phenylacetylene (102 mg, 1 mmol), and Ti(NMe2)2(dpma) (32.3 mg, 0.1 mmol) in toluene (2 mL) and was heated for 24 h at 100 °C. Volatiles were removed, and methyl 4-hydrazinylbenzoate hydrochloride (303 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyl acetate 4:1 , which afforded the desired compound (108 mg, 39%) as a white solid. M.p.: 179- 180 °C. 1H NMR (CDCI3, 500 MHz): 3.92 (3 H, s, OCH3). 7.26-7.29 (1 H, m, Ar- H), 7.39 (2 H, t, J: 8 Hz, Ar-H), 7.53-7.55 (2 H, m, Ar-H), 7.80-7.82 (2 H, m, Ar- H), 8.13-8.15 (2 H, m, Ar-H), 8.01 (1 H, s, 3-CH pyrazole), 8.21 (1 H, d, J: 0.5 Hz, 5-CH pyrazole). ‘30( 1H) NMR (CDCI3, 125 MHz): 52.2, 118.1, 123.2, 125.7, 88 125.8. 11'). 279.11 0003‘. as ICE 7.4- %ndlt 125.8, 127.2, 127.9, 129.0, 131.2, 131.6, 139.7, 143.1, 166.3. MS (El): m/z 278 (M+). High resolution MS: m/z Calc. for C17H15N202+2 279.1134; Found: 279.1131. 1,4-dlphenyl-5-methylpyrazole (3]): A reaction using the general conditions was carried outwith tert-butylisonitrile (136 uL, 1.2 mmol), aniline (92 mg, 1 mmol), 1-phenylpropyne (116 mg, 1 mmol), and Ti(NMe2)2(dpma) (1, 32.3 mg, 0.1 mmol) in toluene (2 mL) and was heated for 48 h at 100 °C. Volatiles were removed, and phenylhydrazine (162 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was 10- 15% ethyl acetate/hexanes, which afforded the desired compound (95 mg, 40%) as a pale yellow solid. M.p.: 150-152 °c (Lit37 Mp. 159—160 °C). 1H NMR (CDCI3, 500 MHz): 2.42 (3 H, s, Me), 7.28 (1 H, tt, J = 7 and 2 Hz, Ar-H), 7.37- 7.44 (5 H, m, Ar-H), 7.49 (4 H, d, J: 4.5 Hz, Ar-H), 7.77 (1 H, s, 3-CH-pyrazole). 13C{1H}NMF1 (CDCI3, 125 MHZ): 12.0, 122.0, 125.1, 126.4, 127.8, 127.8, 128.7, 129.1, 133.5, 135.3, 139.2, 139.9. MS(E|): m/z 234 (M*). 4,5-dlethyl-1-phenylpyrazole (3k): A reaction using the general conditions was carried out with tert-butylisonitrile (171 11L, 1.5 mmol), aniline (92 89 mg, 1 mmol), 3-hexyne (82 mg, 1 mmol), and Ti(NMe2)2(dpm) (2, 30.8 mg, 0.1 mmol) in toluene (2 mL) and was heated for 48 h at 110 °C. Volatiles were removed, and phenylhydrazine (162 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexanes:ethyl acetate 9:1, which afforded the desired compound (74 mg, 37%) as a yellow-red liquid. ‘H NMR (CDCI3, 500 MHz): 1.03 (3 H, t, .1 = 7.5 Hz, 4- CHZCHa), 1.23 (3 H, t, J = 7.5 Hz, 5-CHZCHa), 2.47 (2 H, q, J = 7.5 Hz, 4- CHZCHa), 2.64 (2 H, q, .1: 7.5 Hz, 5-01120H3) 7.34-7.45 (5 H, m, Ar-H), 7.46 (1 H, s, 3-CH—pyrazole). 130(‘H} NMFl (CDCI3, 125 MHz): 13.8, 15.2, 17.1, 17.6, 121.0, 125.3, 127.6, 129.0, 139.2, 140.4, 140.9. MS(E|): m/z 200 (M+). High resolution MS: m/z Calc. for C13H17N2+z 201.1392; Found 201.1395. 1,4,5-trlphenylpyrazole (3|): A reaction using the general conditions was carried out with tert-butylisonitrile (171 (1L, 1.5 mmol), aniline (92 mg, 1 mmol), diphenylacetylene (174 mg, 1 mmol), and Ti(NMe2)2(dpm) (2, 61.6 mg, 0.2 mmol) in toluene (2 mL) and was heated for 48 h at 140 °C. Volatiles were removed, and phenylhydrazine (162 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was 90 hexaneszethyl acetate 9:1, which afforded the desired compound (71 mg, 24%) as a pale pink solid. M.p.: 202-203 °C (Lit38 M.p. 197-198 °C). 1H NMR (CDCI3, 500 MHz): 7.16-7.35 (15 H, m, Ar-H), 7.94 (1 H, s, 3-CH pyrazole). ‘3C(1 H} NMR (CDCI3, 125 MHz): 122.4, 125.1, 126.4, 127.2, 128.0, 128.4, 128.4, 128.6, 128.7, 130.2, 130.4, 132.8, 139.2, 139.7, 139.9. MS(E|): m/z 296 (M+). High resolution MS: m/z Calc. for C2,H,7N2+: 297.1392; Found 297.1388. 1-phenyI-4-(p-tolyl)pyrazole (3m): A reaction using the general conditions was carried out with tert-butylisonitrile (171 (1L, 1.5 mmol), cyclohexylamine (99 mg, 1 mmol), p-tolylacetylene (116 mg, 1 mmol), and Ti(NMe2)2(dpma) (1, 32.3 mg, 0.1 mmol) in toluene (2 mL) and was heated for 24 h at 100 °C. Volatiles were removed, and phenylhydrazine (162 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyl acetate 9:1, which afforded the desired compound (96 mg, 41%) as a pale yellow solid. M.p.: 120-121 °C (Lit39 Mp. 127-128 °C). 1H NMR(CDCI3, 500 MHz): 2.36 (3 H, s, CH3). 7.20 (2 H, d, .1: 8 Hz, Ar-H), 7.28 (1 H, 11, J: 7.5 and 1 Hz, 4-H-Ph), 7.43-7.47 (4 H, m, Ar-H), 7.71-7.73 (2 H, m, Ar-H), 7.97 (1 H, d, J: 0.5 Hz, 3-CH-pyrazole), 8.11 (1 H, d, J: 0.5 Hz, 5-CH- pyrazole). 1"C(‘H) NMR (CDCI3, 125 MHz): 21.1, 118.9, 123.0, 124.9, 125.6, 91 126.4, 129.1, 129.4, 129.6, 136.5, 138.7, 140.1. MS(E|): m/z 234 (MP‘). High resolution MS: m/z Calc. for C16H1 5N2”? 235.1235; Found 235.1242. 1-phenyl-4-butylpyrazole (3n): A reaction using the general conditions was carried out with tert-butylisonitrile (171 uL, 1.5 mmol), cyclohexylamine (99 mg, 1 mmol), 1-hexyne (82 mg, 1 mmol), and Ti(NM62)2(dpm) (2, 30.8 mg, 0.1 mmol) in toluene (2 mL) and was heated for 24 h at 100 °C. Volatiles were removed, and phenylhydrazine (162 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyl acetate 9:1, which afforded the desired compound (56 mg, 28%) as a yellow-red liquid. 1H NMR (CDCI3, 500 MHz): 0.96 (3 H, t, .1 : 7.5 Hz, CH2CHZCH2CH3). 1.39-1.46 (2 H, m, CHZCHZCHZCHa). 1.58-1.65 (2 H, m, CHZCHZCHZCHsl. 2.55 (2 H, t, .1: 7.5 Hz, 01-120H2CH20H3). 7.26 (1 H, tt, .1 : 7.5 and 1 Hz, Ar-H), 7.4-4 (2 H, tt, J= 7.5 and 0.5 Hz, Ar-H), 7.56 (1 H, S, 3-CH- pyrazole), 7.67-7.69 (2 H, m, Ar-H), 7.72 (1 H, d, J = 1 Hz, 5-CH-pyrazole). 13C(‘H} NMR (CDCI3, 125 MHz): 13.8, 22.3, 23.8, 32.9, 118.7, 124.0, 124.6, 125.9, 129.3, 140.3, 140.9. MS(E|): m/z 200 (M+). 92 131' 32'): 181 l 2 t I Wt 11': ii:- Ai- leg 1,4—dlphenyl-5-(3-N,N-dIethylamlno-n-propyl)pyrazole (3o): A reaction using the general conditions was carried out with tert-butylisonitrile (85 (1L, 0.75 mmol), aniline (46 (1L, 0.5 mmol), N,N-diethyl-5-phenylpent-4-yn-1-amine (107.5 mg, 0.5 mmol), and Ti(NMe2)2(dpm) (2, 15.4 mg, 0.05 mmol) in toluene (1 mL) and was heated for 48 h at 110 °C. Volatiles were removed, and phenylhydrazine (81 mg, 0.75 mmol) in dry pyridine (1.5 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyl acetateztriethylamine 74:25:1, which afforded the compound (52 mg, 31%) as a red liquid. 1H NMR (CDCI3, 500 MHz): 0.87 (6 H, t, .1 : 7 Hz, CHZCH3), 1.48-1.54 (2 H, m, CHZCH2CH2NEt2), 2.24 (2 H, t, .1: 7 Hz, CH2CH2CH2NEt2), 2.31 (4 H, q, .1: 7 Hz, CHZCHS), 2.87 (2 H, t, .1: 8 Hz, CH2CH2C1-12NEt2), 7.29-7.33 (1 H, m, Ar-H), 7.43-7.48 (5 H, m, Ar-H), 7.49-7.51 (4 H, m, Ar-H), 7.76 (1 H, s, 3-CH pyrazole). 13C(‘H} NMR (CDCI3, 125 MHz): 11.4, 22.6, 26.1, 46.5, 52.1, 121.5, 125.8, 126.4, 127.9, 128.1, 128.6, 129.0, 133.7, 139.4, 139.9, 140.1. MS (El): mlz 333 (M+). High resolution MS: m/z Calc. for 022H28N3“: 334.2283; Found: 334.2291. 1-phenyl-4-(4-methoxyphenyl)pyrazole (3p): A reaction using the general conditions was carried out with ten-butylisonitrile (171 uL, 1.5 mmol), 93 cyclohexylamine (99 mg, 1 mmol), 4-methoxyphenylacetylene (132 mg, 1 mmol), and Ti(NMe2)2(dpm) (2, 30.8 mg, 0.1 mmol) in toluene (2 mL) and was heated for 24 h at 100 °C. Volatiles were removed, and phenylhydrazine (162 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyl acetate 9:1, which afforded the desired compound (94 mg, 38%) as a white solid. M.p.: 136-138 °C (l.it40 Mp. 138-140 °C). 1H NMR (CDCI3, 500 MHz): 3.82 (3 H, s, OCH3), 6.92-6.94 (2 H, m, Ar-H), 7.26-7.29 (1 H, m, Ar-H), 7.43747 (4 H, m, Ar-H), 7.70-7.72 (2 H, m, Ar-H), 7.92 (1 H, s, 3-CH pyrazole), 8.06 (1 H, d, .1 : 1 Hz, 5-CH pyrazole). 130(1H}NMR (CDCI3, 125 MHz): 55.2, 114.3, 118.9, 122.6, 124.56, 124.58, 126.3, 126.8, 129.3, 138.4, 139.9, 158.6. MS (El): m/z 250 (M+). High resolution MS: m/z Calc. for C16H15N20+z 251.1184; Found: 251.1185. 1-phenyl-5-(3-(tert-butyldlmethylslloxy)propyl)-pyrazole (3q): A reaction using the general conditions was carried outwith tert-butylisonitrile (171 (1L, 1.5 mmol), aniline (93 mg, 1 mmol), tert-butyldimethyl(pent-4-ynyloxy)silane (198 mg, 1 mmol), and Ti(NMe2)2(dpma) (1, 32.3 mg, 0.1 mmol) in toluene (2 mL) and was heated for 24 h at 100 °C. Volatiles were removed, and phenylhydrazine (162 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The 94 mixture was heated to 150 °C for 24 h which afforded two isomer in 6.6:1 ratio. Purification of the major isomer was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyl acetate 9:1, which afforded the major isomer (110 mg, 35%) as a yellow-red liquid. 1H NMR (CDCI3, 500 MHz): Major isomer 0.015 (6 H, s, Si-CH3). 0.86 (9 H, s, Si-CMeZCHg), 1.79-1.84 (2 H, m, CH2CH2CH20TBS), 2.77 (2 H, t, .1: 7.5 Hz, CHZCHZCHZOTBS), 3.62 (2 H, t, J = 6 Hz, CHZCHZCHZOTBS), 6.23 (1 H, d, J = 2 Hz, 4-CH pyrazole), 7.37-7.40 (1 H, m, Ar-H), 7.44-7.48 (4 H, m, Ar-H), 7.60 (1 H, d, J = 1.5 Hz, 3-Cprrazole). 13C>{1H}NMF1 (CDCI3, 125 MHz): —5.4, 18.1, 22.5, 25.8, 31.8, 61.8, 105.3, 125.2, 127.6, 128.9, 139.7, 139.9, 143.1. MS (El): m/z 317 (M* + H). High resolution MS: m/z Calc. for C13H29N208i+z 317.2049; Found: 317.2055. 3-butylpyrazole (3r): A reaction using the general conditions was carried out with tert-butylisonitrile (565 11L, 5 mmol), aniline (456 p.L, 5 mmol), 1-hexyne (575 (11L, 5 mmol), and Ti(NMe2)2(dpma) (1, 162 mg, 0.5 mmol) in toluene (10 mL) and was heated for 24 h at 100 °C. Volatiles were removed, and hydrazine hydrate (375 mg, 7.5 mmol) in dry pyridine (15 mL) was added. The mixture was heated to 150 °C for 12 h. Purification was accomplished by Kugelrohr distillation, which afforded the desired compound (328 mg, 53%) as a mixture of two isomers in a 6:1 ratio as a pale yellow liquid. Data for the major isomer: 1H NMR41 95 (CDCI3, 500 MHz): 0.91 (3 H, t, .1: 7.5 Hz, CHZCHchZCI-Ia), 1.34-1.38 (2 H, m, CHZCHZCHZCHs), 1.59-1.65 (2 H, m, CHZCHZCHQCHa), 2.66 (2 H, t, .1: 8.0 Hz, CHZCHZCHZCH3), 6.06 (1 H, d, J: 2 Hz, 4-CH- pyrazole), 7.47 (1 H, d, J= 2 Hz, 5-CH-pyrazole). 13C(‘H) NMR (CDCI3, 125 MHz): 13.8, 22.3, 26.4, 31.5, 103.4, 121.3. MS (El): m/z 124 (MP). 4-butylpyrazole (3s): A reaction using the general conditions was carried out with tert-butylisonitrile (855 (1L, 7.5 mmol), cyclohexylamine (570 (1L, 5 mmol), 1-hexyne (575 11L, 5 mmol), and Ti(NMe2)2(dpm) (2, 154 mg, 0.5 mmol) in toluene (10 mL) and was heated for 24 h at 100 °C. Volatiles were removed, and hydrazine hydrate (375 mg, 7.5 mmol) in dry pyridine (15 mL) was added. The mixture was heated to 150 °C for 12 h. Purification was accomplished by Kugelrohr distillation, which afforded the desired compound (167 mg, 27%) as a pale yellow liquid.27 1H NMR (CDCI3, 500 MHz): 0.90 (3 H, t, .1 : 7.5 Hz, CHZCHZCHZCHa), 1.30-1.37 (2 H, m, CH2CH2CH2CH3), 1.50-1.56 (2 H, m, CHZCHZCHZCHa), 2.47 (2 H, t, .1: 7.0 Hz, CH2CHZCH2CH3), 7.37 (2 H, s, CH- pyrazole), 9.43 (1 H, br s, NH). 13C{1 H} NMR (CDCI3, 125 MHz): 13.8, 22.3, 23.6, 33.1, 121.4, 132.6. MS (El): m/z 124 (M*). 96 WIthasomnlne(6) Synthesls 5-[3-(tert-butyldImethylsllyloxy)propyI]-4-phenyl-1H-pyrazole (5): A reaction using the general conditions was carried out with tert-butylisonitrile (1.29 mL, 7.5 mmol), aniline (465 mg, 5 mmol), 5-(tert-butyldimethylsilyloxy)-1- phenylpent-t-yne23 (1.37 g, 5 mmol), and Ti(NMe2)2(dpm) (2, 154 mg, 0.5 mmol) in toluene (5 mL) and was heated for 48 h at 110 °C. Volatiles were removed, and hydrazine hydrate (375 mg, 7.5 mmol) in pyridine (15 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was initially hexaneszethyl acetate 1:1 followed by 5% methanol in ethyl acetate, which afforded the desired compound (552 mg, 35%) as a viscous dark red oiI. 1H NMR (CDCI3, 500 MHz): 0.055 (6 H, s, Si-CH3), 0.89 (9 H, s, Si-CCHa), 1.85-1.91 (2 H, m, CHZCHZCHZOTBDMS), 2.91 (2 H, t, .1: 7.5 Hz, CHZCHZCHZOTBDMS), 3.69 (2 H, t, .1: 6 Hz, CHZCHZCHZOTBDMS), 7.23-7.26 (2 H, m, Ar-H, NH), 7.36-7.39 (4 H, m, Ar-H), 7.64 (1 H, s, 3-CH-pyrazole). 13C(1 H} NMR (CDCI3, 125 MHz): -5.4, 18.3, 22.2, 25.9, 31.4, 62.6, 119.6, 126.2, 127.7, 128.2, 128.6, 131.5, 133.6. MS (El): m/z 316 (M+). High resolution MS: m/z Calc. for C18H29N20Si+z 317.2049; Found 317.2041. 97 Withasomnine (6): Under nitrogen 5 (140 mg, 0.443 mmol) in 5 mL CHZCIQ was treated with BBr3 (1.1 mL, 1 M soln in CHZCIZ, 1.1 mmol). The reaction was stirred at room temperature for 48 h and then quenched with saturated NaHCO3. The organic layer was separated, dried over Na2804, and concentrated under rotary evaporation. The crude product was dissolved in absolute EtOH (10 mL) and treated with sodium ethoxide (240 mg, 3.53 mmol). The mixture was heated to reflux for 20 h and then cooled to room temperature. The volatiles were removed under rotary evaporation. The crude mixture was dissolved in CH2C|2, washed with water, dried over NaZSO4, and concentrated under rotary evaporation. The product was purified by column chromatography on alumina using ethyl acetatezhexanes 1:1 with gradient to methanolzethyl acetate 1:4 to obtain withasomnine (58 mg) in 71% yield. M.p.: 113-115 °C (Lit3d M.p. 117—1 18 °C). 1H NMR (CDCI3, 500 MHz): 2.64-2.70 (2 H, m, N-CHZCHZCHz). 3.08 (2 H, t, .1: 7.5 Hz, N-CHZCHZCHz). 4.16 (2 H, t, .1: 7.5 Hz, N-CHZCHZCHZ), 7.16 (1 H, 11, .1: 7 and 1 Hz, Ar-H), 7.33 (2 H, d, .1: 7.5 Hz, Ar-H), 7.42-7.44 (2 H, m, Ar-H), 7.79 (1 H, s, 3-CH—pyrazole). 13C(1 H} NMR (CDCI3, 125 MHz): 23.8, 26.4, 47.6, 115.3, 125.0, 125.6, 128.8, 133.4, 140.9, 142.6. MS (EI): m/z 184 (M+). 98 3.5 References 1. For selected recent examples of catalyzed multicomponent couplings to generate heterocycles see a) Krenske, E. H.; Houk, K. N.; Arndtsen, B. A.; Cyr, D. J. St. J. Am. Chem. Soc. 2008, 130, 10052; b) Lu, Y.; Arndtsen, B. A. Angew. Chem. Int. Ed. 2008, 47, 5430; c) Black, D. A.; Beveridge, R. E.; Arndtsen, B. A. J. Org. Chem. 2008, 73, 1906; d) Kalisiak, J.; Sharpless, K. B.; Fokin, V. V. Org. Lett. 2008, 10, 3171; e) Isambert, N.; Lavilla, R. Chem. Eur. J. 2008, 14, 8444; f) Church, T. L.; Byrne, C. M.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2007, 129, 8156; g) D’Souza, D. M.; Miiller, T. J. Chem. Soc. Rev. 2007, 36, 1095; h) Dhawan, R.; Dghaym, R. D.; Cyr, D. J. St.; Arndtsen, B. A. Org. Lett. 2006, 8, 3927; i) Siamaki, A. R.; Arndtsen, B. A. J. Am. Chem. Soc. 2006, 128, 6050; j) Mitsudo, K.; Thansandote, P.; Wilhelm, T.; Mariampillai, B.; Lautens, M. Org. Lett. 2006, 8, 3939; k) Zhu, J.; Bienayme, H. eds. Multicomponent Reactions, Wiley-VCH: Weinheim, 2005; I) Balme, G. Angew. Chem. Int. Ed. 2004, 43, 6238; m) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Org. Chem. 2004, 69, 2386; n) Kamijo, S.; Jin, T.; Yamamoto, Y. Tetrahedron Lett. 2004, 45, 689; o) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 7786; p) Bossharth, E.; Desbordes, P.; Monteiro, N.; Balme, G.; Org. Lett. 2003, 5, 2441. 2. Lamberth, C. Heterocycles 2007, 71, 1467. 3. For papers on withasomnine’s isolation from natural sources and biological studies see (a) Adesanya, S. A.; Nia, R.; Fontaine, C.; Pais, M. Phytochemistry1994, 35, 1053. (b) Wube, A. A.; Wenzig, E.-M.; Gibbons, S.; Asres, K.; Bauer, R.; Bucar, F. Phytochemistry 2008, 69, 982. (c) Houghton, P. J.; Pandey, R.; Hawkes, J. E. Phytochemistry 1994, 35, 1602. (d) Schroter, H.-B.; Neumann, D.; Katritzky, A. R.; Swinbourne, R. J. Tetrahedron 1966, 2895. (e) Ravikanth, V.; Ramesh, P.; Diwan, P. V.; Venkateswarlu, Y. Biochemical Systematics and Ecology 2001, 29, 753. 4. Willy, B.; Mi'lller, T. J. J. Eur. J. Org. Chem. 2008, 4157. 5. Liu, H.-L.; Jiang, H.-F.; Zhang, M.; Yao, W.-J.; Zhu, Q.-H.; Tang, 2. Tetrahedron Lett 2008, 49, 3805. 6. Ahmed, M. S. M.; Kobayashi, K.; Mori, A. Org. Lett. 2005, 7, 4487. 99 10. 11. 12. 13. 14. 15. 16. 17. 18. Stonehouse, J. P.; Chekmarev, D. S.; lvanova, N. V.; Lang, 8.; Pairaudeau, G.; Smith, M; Stocks, M. J.; Sviridov, S. l.; Utkinab, L. M. Syn/ett 2008, 100. Cao, C.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2003, 125, 2880. For a review on azadienes in synthesis see (a) Jayakumar, S.; lshar, M. P. S.; Mahajan, M. P. Tetrahedron 2002, 58, 379. See also (b) Calvo, L. A.; Gonzalez-Nogal, A. M.; Gonzalez-Ortega, A.; Safiudo, M. C. Tevahedron Lett. 2001, 42, 8981 for related silyl isoxazole chemistry. (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th Ed., Blackwell Publishing, 2000. (b) Makino, K.; Kim, H. S.; Kurasawa, Y. J. Heterocyclic Chem. 1999, 36, 321; (c) Halcrow, M. A. Dalton Trans. 2009,2059. Odom, A. L. Dalton Trans. 2005, 25. Bradley, D. C.; Thomas, I. M. J. Chem. Soc. 1960, 3859. Li, Y.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2004, 126, 1794. (a) Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114, 1708. (b) Baranger, A. M.; Walsh, P. J.; Bergman, R. G. J. Am. Chem. Soc. 1993, 115, 2753. (c) McGrane, P. L.; Jenson, M.; Livinghouse, T. J. Am. Chem. Soc. 1992, 114, 5459. (d) Zi, G.; Blosch, L. L.; Jia, L.; Andersen, R. A. Organometallics 2005, 24, 4602. (e) Poise, J. L.; Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc. 1998, 120, 13405. (f) Duncan, A. P.; Bergman, R. G. Chem. Rec. 2002, 2, 431. (g) Severin, R.; Doye, S. Chem. Soc. Rev. 2007, 36, 1407. A derivative of this metallacycle has recently been isolated and structurally characterized. Vujkovic, N.; Fillol, J. L.; Ward, B. D.; Wadepohl, H.; Mountford, P.; Gade, L. H. Organometallics 2008, 27, 2518. Cao, C.; Ciszewski, J. T.; Odom, A. L. Organometallics 2001, 20, 5011. Li, Y.; Turnas, A.; Ciszewski, J. T.; Odom, A. L. Inorg. Chem. 2002, 41, 6298. (a) Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem. Commun. 2003, 586. (b) Novak, A.; Blake, A. J.; Wilson, 0.; Love, J. B. Chem. Commun. 2002, 23, 2796. 100 19. 20. 21. 22. 23. 24. 25. 26. Littler, B. J.; Miller, M. A.; Hung, C.-H.; Wagner, R. W.; O’Shea, D. F.; Boyle, P. D.; Lindsey, J. S. J. Org. Chem. 1999, 64, 1391. Gokel, G. W.; Widera, R. P.; Weber, W. P. Org. Synth. 1976, 55, 96. For reviews on the extensive work of Barluenga and coworkers on applications of 1.3-diimines to organic synthesis see (a) Barluenga, J.; Tomas, M. Adv. Heterocyclic Chem. 1993, 57, 1. (b) Barluenga, J. Bull. Soc. Chim. Belg. 1988, 97, 545. For some references related more specifically to 1.3-diimines reactions related to those here see (c) Barluenga, J.; Rubio, E.; Rubio, V.; Muniz, L.; lglesias, M. J.; Gotor, V. J. Chem. Res. (8) 1985, 124. (d) Barluenga, J.; lglesias, M. J.; Gotor, V. Synthesis 1987, 662. (e) Gotor, V.; Brieva, R.; Aguirre, A.; Garcia-Granda, S.; Gomez-Beltran, F. Heterocycles 1989, 29, 1695. (f) Barluenga, J.; L0pez—Ortiz, J. F.; Tomas, M.; Gotor, V. J. Chem. Soc. Perkin Trans. I 1981, 1891. (g) Barluenga, J.; Jardon, J.; Rubio, V.; Gotor, V. J. Org. Chem. 1983, 48, 1379. A similar condensation reactions with hydrazines were reported by Barluenga and coworkers (Barluenga, J.; Rubio, E.; Rubio, V.; Muniz, L.; lglesias, M.; Gotor, V. J. Chem. Res, Synop, 1985, 4, 124), however the substitution patterns were different. Moreover, the pyrazole were made in 4 steps fom commercially available materials, whereas we made pyrazoles in a one-pot 2 step protocol starting form inexpensive commercially available materials without isolating the intermediates. None of the reaction times have been fully optimized. Reactions were generally run for about 24 h. Different amines were used for the two reactions in this scheme due to complications. Aniline seems to give superior yields for the multicomponent coupling reactions with 1. With catalyst 2, when aniline is used as the substrate in these reactions a different product due to a 4- component coupling reaction is a significant by-product. The 4-CC product is being reported separately: Barnea, E.; Majumder, S.; Staples, R. J.; Odom, A. L. Organometallics 2009, 28, 3876. At room temperature the proton migration between pyrazole nitrogens is often rapid on the NMR timescale. Claramunt, R. M.; Lopez. 0.; Santa Maria, M. D.; Sanz, E.; Elguero, J. Prog. Nucl. Mag. Reson. Spectr. 2006, 49, 169. This compound was not isolated in pure form but was observed by 1H NMR. The ratio given is from NMR integration. 101 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. For some additional references to syntheses of 4-phenylpyrazole not discussed explicitly see (a) Cativiela, C.; Diaz de Villegas, M. D.; Gainza, M. P. Synthetic Commun. 1987, 17, 165. (b) Neunhoeffer, H.; Clausen, M.; Voetter, H. D.; Ohl, H.; Krueger, C.; Angermund, K. Liebigs Ann. Chem. 1985, 1732. (C) Escribano, F. C.; Alcantara, M. P. D.; Gomez-Sanchez, A. Tetrahedron Lett. 1988, 29, 6001. For a very nice synthesis applicable to a few 4-(alkyl)pyrazoles involving Vilsmeier formylation see Reger, D. L.; Gardinier, J.R.; Grattan, T. C.; Smith, M. R.; Smith, M. D. New J. Chem. 2003, 27, 1670. Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem, Int. Ed. 2006, 45, 1282. Protection of the pyrazole NH leads to much higher yields for the coupling but adds additional steps. lchikawa, H.; Ohno, Y.; Usami, Y.; Arimoto, M. Heterocycles 2006, 68, 2247. (a) Allin, S. M.; Barton, W. R. S.; Bowman, W. R.; Mclnally, T. Tetrahedron Lett. 2002, 43, 4191. (b) Kulinkovich, 0.; Masalov, N.; Tyvorskii, V.; Kimpe, N. De.; Keppens, M. Tetrahedron Lett. 1996, 37, 1095. (c) Ranganathan, D.; Bamezai, S. Synthetic Commun. 1985, 15, 259. (d) Guzman-Perez, A.; Maldonado, L. A. Synthetic Commun. 1991, 21, 1667. (e) Morimoto, A.; Noda, K.; Watanabe, T.; Takasugi, H. Tetrahedron Lett. 1968, 9, 5707. (f) Takano, S.; lmamura, Y.; Ogasawara, K. Heterocycles 1982, 19, 1223. (g) Allin, S. M.; Barton, W. R. S.; Bowman, W. R.; Bridge, E.; Elsegood, M. R. J.; Mclnally, T.; McKee, V. Tetrahedron 2008, 64, 7745. a) Six, Y. Eur. J. Org. Chem. 2003, 1157. b) Zheng, T.; Narayan, T. S.; Schomaker, J. M.; Borhan, B. J. Am. Chem. Soc. 2005, 127, 6946. See reference 20a. Their overall yield was 27% in 6 steps if one includes the synthesis of l(CH2)3SnPh, which doesn’t seem to be commercially available. Baldwin, J. E.; Adlington, R. M.; Robertson, J. Tetrahedron 1989, 45, 909. Their starting material is 4-bromopyrazole, which is commercially available. Rupe, H.; Knup, E. He/v. Chim. Acta. 1927, 10, 299. Pavlik, J. W.; Kebede, N. J. Org. Chem. 1997, 62, 8325. Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem. Int. Edn. 2004, 43, 1871. 102 37. 38. 39. 40. 41. House, H. 0.; Reif, D. J. J. Am. Chem. Soc. 1955, 77, 6525. Olivera, R.; SanMartin, R.; Dominguez, E. J. Org. Chem. 2000, 65, 7010. Kano, S.; Yuasa, Y.; Shibuya, S.; Hibino, S. Heterocycles 1982, 19, 1079. Razler, T. M.; Hsiao, Y.; Qian, F.; Fu, R.; Khan, R. K.; Doubleday, W. J. Org. Chem. 2009, 74, 1381. Huisgen, R.; Koszinowski, J.; Ohta, A.; Schiffer, R. Angew.Chem. Int. Edn. 1980, 19,202. 103 CHAPTER 4 Titanium-catalyzed one-pot multicomponent coupling reaction for direct access to pyrimidines and model studies toward the synthesis of Hyrtinadine A 4.1 lntroductlon Heterocycles containing the pyrimidine core have been found in a wide range of natural products and bioactive molecules.1 Over the past several years pyrimidyl structural motifs 'have appeared in a variety of synthetic pharmacophores having antibacterial,2 antimicrobial, antifungal,3 and antimycotic4 activities, even in the drug zidovudine (Retrovir®), the first drug approved for the treatment of AIDS and HIV infection.5 Some diaminopyrimidines such as pyrimethamine (Daraprim®) or trimeth0prim (Proloprim®) are powerful antimalarial drugs.‘5 Due to the ubiquity of the pyrimidine substructure in natural products and pharmaceuticals, a plethora of synthetic routes have been developed, however a majority of these synthetic protocols involve direct condensation of amidines or amidinium salts with 1,3-dicarbonyl compounds. In recent years, development in cross-coupling chemistry has advanced the synthesis of various substituted 104 pyrimidines from halo precursors.7 In all of the above methods the practical disadvantage is the difficulty in synthesizing unsymmetrical pyrimidine compounds due to the multistep synthesis of the unsymmetrical diketone precursors or the appropriately substituted halo pyrimidines. To this end, transition metal catalyzed multicomponent coupling reaction should be a viable alternative for direct access to unsymmetrical 1,3-dicarbonyl precursors. Herein we report a new, one-pot titanium-catalyzed multicomponent coupling, followed by a condensation sequence for direct access to substituted pyrimidines. 4.2 Results and Dlscusslon In previous multicomponent coupling research in our group, we discovered a novel titanium catalyzed 3-component (3CC) coupling8 of an alkyne, isonitrile, and primary amine to generate unsymmetrical 1,3-diimine tautomers.9 The proposed catalytic cycle for the formation of a 3CC product is based on the mechanism of catalytic alkyne hydroamination10 discussed in the previous chapter. In this work, we reacted in situ generated 1,3—diimine tautomers with a variety of amidine derivatives and developed a new one-pot, 4-component coupling strategy for direct access to substituted pyrimidine compounds (Scheme. 4.1). This study mainly used two different pyrrolyl-based titanium catalysts, Ti(dpma)(NMe2)211 (1) and Ti(dpm)(NMe2)212 (2). R3 : R2 ,_ R2 + 10% Ti-Catalyst RIN’ “3 R‘-NH2 > I toluene, 100 °C R4HN + — R4-NEC R5 Py, 150 °C & H2N NH R5 1*": KKKRZ R3 Scheme 4.1. One-pot synthesis of pyrimidines (3). 106 The multicomponent coupling reactions can be facile using both terminal and internal alkynes with a variety of aliphatic and aromatic amines. Since the substituent on the isonitrile does not end up in the final pyrimidine product, tert- butylisonitrile was employed exclusively here because of its general applicability in this reaction. Ease of access is also an advantage for t-BuNC, which is both commercially available and readily prepared from ten-butylamine and chloroform in the presence of base (Equation 4.1).13 Similarly, in the case of amine, we focused on inexpensive and readily available cyclohexyl amine and aniline; as the amine is lost in the second step (condensation reaction) of the one-pot synthesis. CHCI3, 3NaOH [EthCHzPhr Cl- H20, CHZCl2 A ’Bu-NH2 : 'Bu-NC (4.1) Most alkynes employed in this study are commercially available; however, 2-ethynylthiophene14 was synthesized via Sonogashira coupling and 2- ethynylfuran15 using the Corey-Fuchs method (Scheme 4.2). 107 EE—TMS 1- Pd(PPh3)2C|2, CUI / \ Et3N,THF ’ / \ S ' 2, TBAF,THF S // 0}: // Br PPh3,CBr MeLi UCHO 4* W Br = O DCM Scheme 4.2. Synthesis of 2-ethynylthiophene and 2-ethynylfuran. N, N-diethyl-5-phenylpent-4-yn-1 -amine was prepared from 4-pentyne-1-ol as shown in Scheme 4.3. PM OH Pd(PPh3)4, Cul / OH W > / Et3N, THF Ph Ts-CI, Et3N DCM v OTs /\/\NEt2 EtzNH /\/\ // ‘ / K Ph CO 2 3: Ph THF Scheme 4.3. Synthesis of IV,N-diethyI-5-phenylpent-4-yn-1-amine. Barluenga and co-workers published a series of notable papers in “1- azabutadiene” chemistry where the intermediates were obtained by reaction of saturated nitriles with Schiff bases using AICI3.16 Gupton and co-workers reported syntheses of pyrimidines from vinylogous iminium salts which were 108 prepared in a few steps starting from a,,19-unsaturated fi-aminoketones.17 These “1-azabutadienes” and vinylogous iminium salts are close derivatives of the iminoamination products used here; however, the available substitution patterns are quite different. In addition, the iminoamination procedure produces these useful intermediates in a one-step, 3-component coupling process, in which catalyst variations can be used to control regioselectivity giving different products from the same substrates. Initial studies were focused on the condensation reaction of the isolated 3CC products with benzamidine hydrochloride, where the pyrimidine compounds were isolated in 60-70% yields under the optimal reaction conditions (Equation 4.2). With the optimal conditions in hand, the multicomponent coupling was carried out with phenylacetylene, cyclohexylamine and tert-butylisonitrile followed by condensation with benzamidine hydrochloride. From a one-pot procedure the final diphenyl pyrimidine was isolated in 51% yield. Q 1“ Ph HN / tert-amyl alcohol, V 7‘ 150 °C, 24 1') P11 60-70% Isolated 3CC product The general procedure involved the addition of amine (1 mmol), catalyst (10 mol%), alkyne (1 mmol), isonitrile (1-1.5 mmol), and 2 mL of toluene to a 40 mL pressure tube under nitrogen, which was sealed and heated at 100 °C while stirring. Once the multicomponent coupling reaction was complete as judged by 109 GC-FID, the volatiles were removed in vacuo and 2 mL of tert-amyl alcohol along with amidine or amidine hydrochloride was added to the crude residue. After additional heating,18 the product pyrimidine was purified by column chromatography or crystallization. 110 Table b.1010: Table 4.1. Examples of pyrimidine (3) syntheses using benzamidine hydrochloride. R3 2 R2 + )10 mol% Ti-Ca’tcazlyst Ah R1-NH2 to uene, 100 ’ NI N Ph V‘RZ + [g 3 t _ 2) H2N NHPHCI R BU 'N=C tert-amyl alcohol 150 °C Entry Alk ne C t I t Pmduct % Yielda y a a ys (GC) N Ph a Ph/// 1 37 \‘N 51 (59) P“ N Ph é ’ 7‘11 1 x 40 (45) b Me N~ I (43) + HN’Q I\KkMe V‘Me t- = Ph Bu NC A . 1 Ph 2 , 3.5 ) “2'“ H HCl t-amyl alcohol, 150 °C 24h 50% 116 As already mentioned, wide ranges of bioactive molecules contain the pyrimidine core structure. Recently, a novel bis-indole alkaloid with a pyrimidine core, Hyrtinadine A (Figure 4.2) was isolated from an Okinawan marine sponge of the Hyrtios genus.19 This compound exhibits in vitro cytotoxic activity against murine leukemia L1210 cells (le0 1 719/ mL) and human epidermoid carcinoma KB cells (I050 3 pg/mL). OH HO O..- O HN/ \N/ \NH Hyrtinadine A L J Figure 4.2. Bis-indole alkaloid Hyrtinadine A It was envisioned that the removal of the two hydroxy groups from the actual natural product might increase the activity of the molecule because the 5- position of indole is the metabolic site. Hence, a model study towards the synthesis of 2,5-bis-indolyl pyrimidine (5) (Figure 4.3) was undertaken. O _..O HN/ \N \NH Figure 4.3. Model compound 2,5-bis(indolyl)pyrimidine (5). We sought to utilize our multicomponent coupling reaction followed by condensation with amidine for the construction of the pyrimidine ring. Therefore 117 the retrosynthetic analysis of 5 results in an indole-alkyne (6) and the indole- amidine (7). Interestingly, both of these fragments (6 and 7) can be generated from a common 3-iodoindole (8) precursor (Scheme 4.4). NH / // H2N N ‘N :1) CH NH | \ + / N N\ \ Bn Bn NH 6 7 5 Scheme 4.4. Retrosynthetic analysis of 2,5-bis-indolyl pyrimidine (5). lodinatlon of indole using l2 in DMF formed 3-iodoindole in quantitative yield.20 This compound was found to decompose over time; hence, it was immediately converted to 8 by treating with benzyl bromide in the presence of KO’Bu. Sonogashira coupling of 8 with TMS-acetylene resulted in compound 9 in moderate yield. The TMS deprotection can be done using either TBAF or KZCO3 in MeOH; however, the latter gave a higher yield of the desired alkyne 6 (Scheme 4.5). 118 the SO 1) l2, KOH ' Co - m H 2) KOBu‘, BnBr N THF 8 Bn 83% (2 steps) :.———TMS Pd(PPha)4 64% CUI, EtaN THF y TMS // // K2003 \ < \ N MeOH N 8” 84°/o én 6 9 Scheme 4.5. Synthesis of the indole-alkyne 6. We found that compound 8 cleanly converts to the cyano-indole (10) with CuCN in refluxing DMF. The amidate 11 was made by passing HCI gas through the methanolic solution of 10. The final amidine (7) was isolated as a buff colored solid by passing anhydrous NH3 through a methanolic solution of compound 11 (Scheme 4.6). Both 11 and 7 were obtained as hydrochloride salts. 119 m CuCN _ ©f§ N DMF, 150 PC' N Bn 12h ' 8 30% 10 B" HCI (9) 80% MeOH H N V 2 NFI lMeC) [NH C((PHCI< dry NH3 \ -HCl N MeOH N 3" 92% Bn 7 11 Scheme 4.6. Synthesis of the amidine 7. lminoamination of indole-alkyne (6) using 10 mol% Ti(dpm)(NMeZ)2 (2), aniline, and tert-butylisonitrile followed by condensation with amidine hydrochloride (7) in pyridine produced compound 12 as a single regioisomer (2,5- disubstituted pyrimidine). interestingly, under similar conditions, two different regioisomeric compounds (12 and 13) were formed in 122.66 ratio when Ti(dpma)(NMe2)2 (1) was employed (Scheme 4.7), however, the 2,4-disubstituted pyrimidine (13) was found to be the major one. Both 12 and 13 have been characterized by X-ray crystallography (Figure 4.4). 120 // Q1 + kPh Ph-NH2 —>—NEC 10% Ti(dpm)(NMez)2 1) toluene, 100 °C 24 h H2N NH 2) CngCI N \‘Ph Py, 150 °C 24 h k —" 10% Ti(dpma)(NMez)2 1) toluene, 100 °C 24h H2N NH 2) ©j§HCl N LPh Py, 150 °C 24 h .0 v3 N / N ‘N I / \ 30% N> P11 12 Ph Ph > < ZEN / N \N N \N I / WQ \ \ N N> 1 : 2.66 p), Z v 12 13 Scheme 4.7. One-pot synthesis of bis-indolyl pyrimidine 12 and 13. Surprisingly, this same catalyst (1) gave a ~ 1:1 mixture of 12 and 13 when aniline was replaced with cyclohexyl amine, although a higher yield was obtained (Equation 4.4). J N> NH )10% Ti(dpm)(NMe ) / : N\://+ 0’ 2 toluene, 24:100 °C 2 2 N ‘N )/ > ' / NI :N (4.4) hN->—=C NH \ \ N 2) ©f§ HCI N 1 :1 ) N ) Ph kPh Ph Py, 150 °C 12 13 24 h p J 121 r\ ‘1’ (1"! \ .; Nl3l \‘. \l 4 D Figure 4.4. Structure of 2,4-bis(indolyl)pyrimidine 13 (top) and 2,5- bis(indolyl)pyrimidine 12 (bottom) by X-ray diffraction. 122 8 Va 31: 81 US 51 Die dill 4.3 Conclusion Titanium-catalyzed 3-component coupling of a primary amine, alkyne, and isonitrile followed by condensation with amidine hydrochloride provides pyrimidines in a one-pot procedure. This new methodology has significant flexibility in the types of pyrimidines that can be accessed. The yields are typically modest, but the products are readily isolated using either column chromatography or crystallization. Reactions with terminal alkynes are more facile and can be accomplished with the milder Ti(dpma)(NMe2)2 (1) as a catalyst. The more active dipyrrolylmethane catalyst Ti(dpm)(NMe2)2 (2) was used for internal alkynes. The reaction has several points to allow optimization for a specific target of interest. For example, the type of substituent on the isonitrile Can potentially be varied in this reaction to improve regioselectivities or yields. The catalyst architectures themselves are also quite flexible and could be optimized for specific products. In fact, it was found that some regiochemical control is possible using simple catalysts 1 and 2 with alkyl-substituted terminal alkynes, and either 5-butyl- or 4-butylpyrimidine can be synthesized from the same substrates preferentially depending on the catalyst employed. Moreover, a variety of different heteroatom substituted amidines work equally well to produce 2- heteroatom substituted pyrimidines. This one-pot pyrimidine synthesis 123 methodology has been successfully applied towards a model study for the synthesis of bis(indolyl) pyrimidines. Interestingly, modifications of the catalyst architectures were found to give different regioisomeric products. 124 4.4 Experimental General Considerations: All manipulations of air sensitive compounds were carried out in an MBraun drybox under a purified nitrogen atmosphere. Toluene was purified by parging with dry N2 and removing water by running through activated alumina systems purchased from SoIv-Tek. Deuterated solvents were dried over purple sodium benzophenone ketyl (0606) or phosphoric anhydride (CDCI3) and distilled under a nitrogen atmosphere. Deuterated toluene was dried passing through two columns of neutral alumina. 1H and 130 spectra were recorded on VXR-500 spectrometers. Ti(dpm)(NMe2)212 and Ti(dpma)(NMe2)2ll were made following the known procedures. Alkynes were purchased either from Aldrich or from GFS chemicals and dried from CaO under dry nitrogen. Amines were purchased from Aldrich, dried from KOH and distilled under dry nitrogen. tert-Butylisonitrilel3 was made according to the reported procedure and purified by distillation under nitrogen. 2-ethynylthiophenel4 and 2-ethynyifuran15 were made according to the literature procedures. Amidines were purchased either from Alfa Aesar or from TCI, however, 2-aminobenzimidazole was purchased from Aldrich. 125 General procedure for Pyrlmldlne Synthesis: in a N2 filled glove box, a 40 mL pressure tube, equipped with a magnetic stirbar was loaded with amine (5 mmol), catalyst (10-20 mol%), alkyne (5 mmol), isonitrile (7.5 mmol), and 10 mL of dry toluene. The pressure tube was sealed with a Teflon screw cap, taken out of the dry box, and heated to the appropriate temperature for the desired time with vigorous stirring. After completion of the reaction, the pressure tube was cooled to room temperature and volatiles were removed under reduced pressure. Then the same pressure tube was charged with amidine hydrochloride (7.5 mmol) in tert-amylalcohol (10 mL) and heated to 145-150 °C for 24 h. After completion of the reaction, tert-amyl alcohol was removed under reduced pressure and crude product was dissolved in CHZCIZ and washed with water. The organic layer was dried over NaZSO4 and concentrated on a rotary evaporator. The crude product was purified either by column chromatography or by crystallization from a suitable solvent. 126 Preparation and Characterization of Compounds In Table 4.1 2, 5-dipheny/pyrimidine: The general procedure was followed. The reaction was carried outwith tert-butylisonitrile (855 pL, 7.5 mmol), cyclohexylamine (495 mg, 5 mmol), phenylacetylene (510 mg, 5 mmol), and Ti(NMe2)2(dpma) (162 mg, 0.5 mmol) in toluene (10 mL) and was heated for 24 h at 100 °C. Volatiles were removed and benzamidine hydrochloride (1.17 g, 7.5 mmol) in dry tert-amyl alcohol (10 mL) was added. The mixture was heated to 145-150 °C for 24 h. Purification was accomplished by column chromatography on silica. The eluent was hexaneszethyl acetate 4:1, which afforded the desired compound (588 mg, 51%) as a pale yellow solid. M.p.: 179-180 PC (Lit21 M.p.: 180-182). 1H NMR (CDCI3, 500 MHz): 7.43-7.46 (1 H, m, Ar-H), 7.48-7.53 (5 H, m, Ar-H), 7.61-7.63 (2 H, m, Ar-H), 8.46-8.48 (2 H, m, Ar-H), 9.01 (2 H, s, 4-CH pyrimidine). 13C{1H} NMR (CDCI3, 125 MHz): 126.8,128.1, 128.6, 128.7, 129.4, 130.8,131.7, 134.5, 137.2, 155.2, 163.4. MS(E|): m/z 232 (M+). High resolution MS: m/z Calc. for C16H13N2“: 233.1079; Found: 233.1075. 127 2-phenyI-5-p-to/ylpyrimidine: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (855 11L, 7.5 mmol), cyclohexylamine (495 mg, 5 mmol), p-tolyl acetylene (580 mg, 5 mmol), and Ti(NMe2)2(dpma) (162 mg, 0.5 mmol) in toluene (10 mL) and was heated for 24 h at 100 °C. Volatiles were removed and benzamidine hydrochloride (1.17 g, 7.5 mmol) in dry tert-amyl alcohol (10 mL) was added. The mixture was heated to 145-150 °C for 24 h. Purification was accomplished by column chromatography on silica. The eluent was hexaneszethyl acetate 4:1, which afforded .the desired compound (500 mg, 40%) as a white solid. M.p.: 150-151 °C. 1H NMR (CDCI3, 500 MHz): 2.42 (3H, s, CH3). 7.32 (2 H, d, .1: 8 Hz, Ar-H), 7.49-7.52 (5 H, m, Ar-H), 8.47-8.49 (2 H, m, Ar-H), 9.01 (2 H, s, 4-CH pyrimidine). 13C{‘H) NMR (CDCI3, 125 MHz): 21.2, 126.6, 128.1, 128.7, 130.1, 130.9, 131.3, 131.7, 136.8, 139.0, 154.9, 162.7. MS(E|): m/z 246 (M+). High resolution MS: m/z Calc. for C17H15N2+z 247.1235; Found: 247.1236. ,‘\< (an "Bu 128 5-butyI-2-phenylpyrimidine: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (855 11L, 7.5 mmol), cyclohexylamine (495 mg, 5 mmol), 1-hexyne (575 11L, 5 mmol), and Ti(NMe2)2(dpm) (154 mg, 0.5 mmol) in toluene (10 mL) and was heated for 24 h at 100 °C. Volatiles were removed and benzamidine hydrochloride (1.17 g, 7.5 mmol) in dry tert-amyl alcohol (10 mL) was added. The mixture was heated to 140 °C for 36 h. Purification was accomplished by column chromatography on silica. The eluent was hexaneszethyl acetate 4:1, which afforded the desired compound (457 mg, 43%) as a yellow-red liquid. 1H NMR (CDCI3, 500 MHz): 0.95 (3 H, t, .1: 7.5 Hz, CH2CH2CH2C1-13), 1.37-1.42 (2 H, m, CHZCHZCHcha), 1.61-1.68 (2 H, m, CHZCHZCHZCH3), 2.66 (2 H, t, .1: 7.5 Hz, CHZCHZCHZCHa), 7.49-7.50 (3 H, m, Ar-H), 8.45-8.47 (2 H, m, Ar-H), 8.70 (2 H, s, 4-CH pyrimidine). 13C{1H} NMR (CDCI3, 125 MHz): 13.7, 22.1, 29.9, 32.8, 127.8, 128.5, 130.3, 132.9, 137.6, 157.0, 162.6. MS(E|): m/z 212 (M+). High resolution MS: m/z Calc. for C14H17N2“: 213.1392; Found: 213.1395. P 4-butyI-2-phenylpyrimidine: The general procedure was followed. The reaction h was carried out with tert-butylisonitrile (570 IL, 5 mmol), aniline (460 pL, 5 129 mmol), 1-hexyne (575 11L, 5 mmol), and Ti(NMe2)2(dpma) (162 mg, 0.5 mmol) in toluene (10 mL) and was heated for 24 h at 100 °C. Volatiles were removed and benzamidine hydrochloride (1.17 g, 7.5 mmol) in dry tert-amyl alcohol (10 mL) was added. The mixture was heated to 140 °C for 24 h. Purification was accomplished by column chromatography on silica. The eluent was hexaneszethyl acetate 3:1, which afforded the desired compound (540 mg, 51%) as a yellow-red liquid (~10% of the other was also formed in the reaction). 1H NMR (CDCI3, 500 MHz): 0.95 (3 H, t, .1: 7.5 Hz, CHZCHZCHZCHa). 1.37-1.43 (2 H, m, CHZCHZCHZCHsl. 1.74-1.80 (2 H, m, CHZCH20H2CH3). 2.80 (2 H, t, .1: 7.5 Hz, CHZCHZCHZCHa). 7.01 (1 H, d, J: 5 Hz, 5-CH pyrimidine), 7.45-7.47 (3 H, m, Ar-H), 8.42844 (2 H, m, Ar-H), 8.64 (1 H, d, J = 5 Hz, 4-CH pyrimidine). ‘3C{‘H} NMR (CDCI3, 125 MHz): 13.9, 22.4, 30.7, 37.7, 117.9, 128.4, 128.5, 130.4, 137.9, 156.8, 164.3, 171.0. MS(E|): m/z 212 (MP). High resolution MS: m/z Calc. for C14H17N2+z 213.1392; Found: 213.1388. Ph Me 4-methyI-2,5-diphenylpyrimidine: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (680 pL, 5.5 mmol), aniline (460 pL, 5 mmol), 1-phenylpropyne (625 11L, 5 mmol), and Ti(NMe2)2(dpma) (162 mg, 130 0.5 mmol) in toluene (10 mL) and was heated for 48 h at 100 °C. Volatiles were removed and benzamidine hydrochloride (1.17 g, 7.5 mmol) in dry tert-amyl alcohol (10 mL) was added. The mixture was heated to 145-150 °C for 24 h. Purification was accomplished by column chromatography on silica. The eluent was hexaneszethyl acetate 4:1, which afforded the desired compound (428 mg, 35%) as a white solid. M.p.: 83-84 °C. 1H NMR (CDCI3, 500 MHz): 2.57 (3H, s, 01-1,),7.35-7.37(2 H, m, Ar-H), 7.40-7.44 (1 H, m, Ar-H), 7.46-7.51 (5 H, m, Ar- H), 846-848 (2 H, m, Ar-H), 8.59 (1 H, s, 4-CH pyrimidine). 13C(‘H} NMR (CDCI3, 125 MHz): 23.1, 128.1, 128.5, 128.7, 129.0, 130.5, 132.3, 136.1, 137.5, 156.6, 162.9, 164.6. MS(E|): m/z 246 (MP‘). High resolution MS: m/z Calc. for C17H15N2+z 247.1235; Found: 247.1238. Ph Ph 2,4,5-triphenylpyrimidine: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (513 pL, 4.5 mmol), aniline (276 pL, 3 mmol), diphenylacetylene (534 mg, 3 mmol), and Ti(NMez)2(dpm) (93 mg, 0.3 mmol) in toluene (6 mL) and was heated for 48 h at 125 °C. Volatiles were removed and benzamidine hydrochloride (0.702 g, 4.5 mmol) in dry tert-amyl alcohol (6 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was 131 accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyi acetate 9:1, which afforded the desired compound (156 mg, 17%) as a yellow-orange solid. M.p.: 108-110 °C. 1H NMR (CDCI3, 500 MHz): 7.26- 7.28 (2 H, m, Ar-H), 7.30-7.33 (2 H, m, Ar-H), 7.36-7.39 (4 H, m, Ar-H), 7.51-7.54 (3 H, m, Ar-H), 7.57-7.58 (2 H, m, Ar-H), 8.58-8.60 (2 H, m, Ar-H), 8.81 (1 H, s, 4- CH pyrimidine). 13C(1H} NMR (CDCI3, 125 MHz): 127.9, 128.0, 128.2, 128.5, 128.7, 129.3, 130.0, 130.6, 130.8, 136.6, 137.5, 137.9, 158.6, 163.2, 163.3. MS(E|): m/z 308 (M+). High resolution MS: m/z Calc. for C22H17N2+z 309.1392; Found: 309.1399. E1 E1 4, 5-diethyl-2-phany/pyrimidine: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (855 11L, 7.5 mmol), aniline (460 11L, 5 mmol), 3-hexyne (410 mg, 5 mmol), and Ti(NMe2)2(dpm) (154 mg, 0.5 mmol) in toluene (10 mL) and was heated for 24 h at 100 °C. Volatiles were removed and benzamidine hydrochloride (1.17 g, 7.5 mmol) in dry tert-amyl alcohol (10 mL) was added. The mixture was heated to 140 °C for 24 h. Purification was accomplished by column chromatography on silica. The eluent was hexaneszethyl acetate 3:1, which afforded the desired compound (265 mg, 25%) as a red liquid. 1H NMR (CDCI3, 500 MHZ): 1.29 (3 H, t, J = 7.5 Hz, 5- 132 CHZCHg). 1.41 (3 H, t, .1 : 7.5 Hz, 4-CHZCHs). 2.69 (2 H, q, J : 7.5 Hz, 5- CI-I2CH3). 2.88 (2 H, q, .1 : 7.5 Hz, 4-CHZCH3) 7.46-7.50 (3 H, m, Ar-H), 8.46- 848 (2 H, m, Ar-H), 8.51 (1 H, s, 4-CH pyrimidine). 13C(‘H} NMR (CDCI3, 125 MHz): 12.2, 14.4, 22.4, 27.3, 127.8, 128.4, 130.0, 131.6, 138.1, 156.1, 162.1, 169.1. MS(E|): m/z 212 (M+). High resolution MS: m/z Calc. for C14H17N2+2 213.1392; Found: 213.1396. 5-cyclohexenyl-2-phany/pyrimidine: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (855 pL, 7.5 mmol), cyclohexylamine (495 mg, 5 mmol), cyclohexenylacetylene (530 mg, 5 mmol), and Ti(NMe2)2(dpm) (154 mg, 0.5 mmol) in toluene (10 mL) and was heated for 24 h at 100 °C. Volatiles were removed and benzamidine hydrochloride (1.17 g, 7.5 mmol) in dry tert-amyl alcohol (10 mL) was added. The mixture was heated to 145-150 °C for 24 h. Purification was accomplished by column chromatography on silica. The eluent was hexaneszethyl acetate 4:1, which afforded the desired compound (352 mg, 31%) as a pale yellow solid. M.p.: 97-98 °C. 1H NMR (CDCI3, 500 MHz): 1.66-1.70 (2 H, m, CH2), 1.78-1.83 (2 H, m, CH2), 2.23-2.25 133 R3 N“ C. re IBI alt PL Th (2 H, m, CH2), 2.40-2.41 (2 H, m, CH2), 6.25-6.26 (1 H, m, CH), 7.45-7.47 (3 H, m, Ar-H), 8.41 (2 H, d, .1: 8 Hz, Ar-H), 8.77 (2 H, s, 4-CH pyrimidine). 13C(‘H} NMR (CDCI3, 125 MHz): 21.7, 22.5, 25.9, 26.5, 127.8, 127.9, 128.6, 130.4, 131.1, 132.6, 137.4, 153.4, 162.6. MS(E|): m/z 236 (M+). High resolution MS: m/z Calc. for C,6H,7N2*: 237.1392; Found: 237.1384. 2-phenyl-5-(thiophen-2-yl)pyrimidine: The general procedure was followed. The reaction was carried outwith tert-butylisonitrile (374 mg, 4.5 mmol), aniline (279 mg, 3 mmol), 2-ethynylthiophene (324 mg, 3 mmol), and Ti(NMe2)2(dpm) (93 mg, 0.3 mmol) in toluene (6 mL) and was heated for 24 h at 100 °C. Volatiles were removed and benzamidine hydrochloride (0.515 g, 3.3 mmol) in dry tert-amyl alcohol (6 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyl acetate 9:1, which afforded the desired compound (185 mg, 27%) as a yellow solid. M.p.: 118-119 °C. 1H NMR (CDCI3, 500 MHz): 7.16 (1 H, dd, .1: 9 and 5 Hz, Ar-H), 7.42-7.43 (2 H, m, Ar-H), 7.47-7.50 (3 H, m, Ar-H), 8.44-8.46 (2 H, m, Ar-H), 9.00 (2 H, s, 4-CH pyrimidine). 13C(‘H} NMR 134 (CDCI3, 125 MHz): 124.8, 126.1, 1268,1280, 1285,1286, 130.8, 136.8, 137.0, 153.7, 163.1. MS(E|): m/z 238 (M+). High resolution MS: m/z Calc. for C14H,,N2s*: 239.0643; Found: 239.0642. 5-(furan-2-yl)-2-phenylpyrimidine: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (375 mg, 4.5 mmol), aniline (279 mg, 3 mmol), 2-ethynylfuran (276 mg, 3 mmol), and Ti(NMe2)2(dpm) (93 mg, 0.3 mmol) in toluene (6 mL) and was heated for 24 h at 100 °C. Volatiles were removed and benzamidine hydrochloride (0.515 g, 3.3 mmol) in dry pyridine (6 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyl acetate 9:1, which afforded the desired compound (160 mg, 24%) as a yellow solid. M.p.: 151-152 PC (Lit22 M.p.: 153-154). 1H NMR (CDCI3, 500 MHz): 6.56 (1 H, dd, J: 3.5 and 1.5 Hz, Ar-H), 6.87 (1 H, d, J = 3.5 hz, Ar-H), 7.50-7.52 (3 H, m, Ar-H), 7.59 (1 H, d, .1: 1.5 Hz, Ar-H), 8.49-8.51 (2 H, m, Ar- H), 9.11 (2 H, s, 4-CH pyrimidine). 13C(‘H} NMR (CDCI3, 125 MHz): 107.3, 112.0,122.6, 128.1, 128.6, 130.7, 137.2, 143.7, 148.6, 152.1, 162.8. MS(E|): m/z 222 (M*). High resolution MS: m/z Calc. for C14H11N20+: 223.0865; Found: 135 22 223.0871 . MeO 5—(4-methoxyphenyl)-2-phenylpyrim1dine: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (513 1.1L, 4.5 mmol), cyclohexylamine (297 mg, 3 mmol), p-rnethoxyphenylacetylene (396 mg, 3 mmol), and Ti(NMe2)2(dpm) (93 mg, 0.3 mmol) in toluene (6 mL) and was heated for 24 h at 100 °C. Volatiles were removed and benzamidine hydrochloride (0.702 g, 4.5 mmol) in dry tert-amyl alcohol (6 mL) was added. The mixture was heated to 145-150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyl acetate 85:15, which afforded the desired compound (245 mg, 31%) as a white solid. M.p.: 170-172 PC (0123 M.p.: 174-175). 1H NMR (CDCI3, 500 MHz): 3.86 (3H, s, CCH,), 7.03-7.04 (2 H, m, Ar-H), 7.48-7.50 (3 H, m, Ar-H), 7.54-7.56 (2 H, m, Ar- H), 8.45-8.47 (2 H, m, Ar-H), 8.97 (2 H, s, 4-CH pyrimidine). 13C(1H} NMR (CDCI3, 125 MHz): 55.4, 114.9, 126.8, 127.9, 128.0, 128.6, 130.6, 131.3, 137.3, 154.7, 160.3, 162.8. MS(E|): m/z 262 (M+). High resolution MS: m/z Calc. for C17H150N2+1 263.1184; Found: 263.1183. 136 Et2N 3-(2,5-diphenylpyrimidin-4-yI)-N,N-diethylpropan-1-amine: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (85 11L, 0.75 mmol), aniline (46 pL, 0.5 mmol), N,N-diethyl-5-phenylpent-4-yn-1-amine (107.5 mg, 0.5 mmol), and Ti(NMe2)2(dpm) (15.4 mg, 0.05 mmol) in toluene (1 mL) and was heated for 36 h at 125 °C. Volatiles were removed and benzamidine hydrochloride (118 mg, 0.75 mmol) in dry tert-amyl alcohol (1 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyi acetateztriethylamine 78:20:2, which afforded the desired compound (66 mg, 38%) as a red oil. 1H NMR (CDCi3, 500 MHz): 0.93 (6 H, t, .1: 7 Hz, CHZCH3), 1.91-1.97 (2 H, m, CHchchzNEtz), 2.41'2.47 (6 H, m, CHQCHchzNEtZ & CHZCHa). 2.81 (2 H, t, .1 : 8 Hz, CHQCHZCHZNEtzl. 7.34-7.50 (8 H, m, Ar-H), 8.49-8.51 (2 H, m, Ar-H), 8.56 (1 H, s, 4-CH pyrimidine) . 13C(1H} NMR (CDCI3, 125 MHz): 11.7, 25.6, 32.9, 46.7, 52.4, 128.0, 128.1, 128.4, 128.6, 129.1, 130.4, 132.2, 136.2, 137.7, 156.8, 162.9, 167.6. MS (El): m/z 345 (M+). High resolution 137 MS: mlz Calc. for 023H28N3“: 346.2283; Found: 346.2278. Preparation and Characterization of Compounds in Table 4.2 37” \N 5-phenylpyrimidine: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (855 pL, 7.5 mmol), cyclohexylamine (495 mg, 5 mmol), phenylacetylene (510 mg, 5 mmol), and Ti(NMe2)2(dpma) (162 mg, 0.5 mmol) in toluene (10 mL) and was heated for 24 h at 100 °C. Volatiles were removed and formamidine acetate (0.780 g, 7.5 mmol) in dry tert-amyl alcohol (10 mL) was added. The mixture was heated to 140 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was initially hexaneszethy lacetate 7:3 and increased to 1:19 methanolzethylacetate which afforded the desired compound in 43% (337 mg) yield (5% of the other isomer could not be separated). Major isomer 1H NMR (CDCI3, 500 MHz): 7.42- 7.46 (1 H, m, Ar-H), 7.47-7.51 (2 H, m, Ar-H), 754-756 (2 H, m, Ar-H), 8.92 (1 H, s, 4-CH pyrimidine), 9.18 (1 H, s, 2-CH pyrimidine). 13C{1 H} NMR (CDCI3, 125 MHz): 126.9, 129.0, 129.4, 134.2, 134.3, 154.9, 157.5. MS (El): mlz 156 (M+). High resolution MS: mlz Calc. for C10H9N2+2 157.0666; Found: 157.0666. 138 2-memyl-S-phenylpyrimidine: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (855 11L, 7.5 mmol), cyclohexylamine (495 mg, 5 mmol), phenylacetylene (510 mg, 5 mmol), and Ti(NMe2)2(dpma) (162 mg, 0.5 mmol) in toluene (10 mL) and was heated for 24 h at 100 °C. Volatiles were removed and acetamidine hydrochloride (0.709 g, 7.5 mmol) in dry tert-amyl alcohol (10 mL) was added. The mixture was heated to 140 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyl acetate 4:1 which afforded the desired compound (321 mg, 38%) as a pale yellow solid. M.p.: 57-58 °C. 1H NMR (CDCI3, 500 MHz): 2.79 (3H, s, CHa). 741-745 (1 H, m, Ar-H), 7.47-7.51 (2 H, m, Ar-H), 7.53- 7.55 (2 H, m, Ar-H), 8.85 (2 H, s, 4-CH pyrimidine). 13C{1 H} NMR (CDCI3, 125 MHz): 25.4, 126.8, 128.7, 129.3, 131.2, 134.2, 154.9, 166.5. MS(E|): m/z 170 (M+). High resolution MS: m/z Calc. forC11H11N2+z 171.0922; Found: 171.0918. 5-phenylpyrimidin-2-amine: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (855 ,uL, 7.5 mmol), cyclohexylamine (495 139 mg, 5 mmol), phenylacetylene (510 mg, 5 mmol), and Ti(NMez)2(dpma) (162 mg, 0.5 mmol) in toluene (10 mL) and was heated for 24 h at 100 °C. Volatiles were removed and guanidine hydrochloride (0.528 g, 7.5 mmol) in dry pyridine (10 mL) was added. The mixture was heated to 140 °C for 24 h. The crude product was purified by recrystalization from ethanol, which afforded the desired compound (282 mg, 33%) as a pale brown solid. M.p.: 158-159 PC (Lit24 M.p.: 161-163). 1H NMR (CDCI3, 500 MHz): 5.23 (2H, bs, NH,), 7.33-7.36 (1 H, m, Ar-H), 741-747 (4 H, m, Ar-H), 8.52 (2 H, s, 4-CH pyrimidine). ”CC H} NMR (CDCI3, 125 MHz): 125.0, 126.0, 127.6, 129.2, 135.1, 156.4, 161.9. MS(E|): m/z 171 (M+). High resolution MS: mlz Calc. for C10H10N3+2 172.0875; Found: 172.0873. SEt H (SN Ph 2-(ethy/thio)-5-phenylpyrimidine: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (855 11L, 7.5 mmol), cyclohexylamine (495 mg, 5 mmol), phenylacetylene (510 mg, 5 mmol), and Ti(NMe2)2(dpma) (162 mg, 0.5 mmol) in toluene (10 mL) and was heated for 24 h at 100 °C. Volatiles were removed and S-ethylisothiourea hydrobromide (1.39 g, 7.5 mmol) in dry tert-amyl alcohol (10 mL) was added. The mixture was heated to 140 145-150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyl acetate 85:15 which afforded the desired compound (350 mg, 35%) as white solid. M.p.: 70-71 °C. 1H NMR (CDCI3, 500 MHz): 1.41 (3 H, t, .1 : 7 Hz, CHZCH3), 3.19 (2 H, q, .1 : 7.5 Hz, CHZCHS), 7.38-7.42 (1 H, m, Ar-H), 7.45-7.48 (2' H, m, Ar-H), 7.50-7.52 (2 H, m, Ar-H), 8.71 (2 H, s, 4-CH pyrimidine). ‘3C(‘H) NMR (CDCI3, 125 MHz): 14.4, 25.3, 126.5, 128.4, 129.3, 134.4, 155.2, 171.1. MS(E|): mlz 216 (M+). High resolution MS: mlz Calc. for C12H1ZSN2+z 217.0799; Found: 217.0802. 4-methyI-3-phenylpyrimidol1,2—a]-benzimidazole: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (136 uL, 1.2 mmol), aniline (92 pL, 1 mmol), 1-phenylpropyne (116 mg, 1 mmol), and Ti(NMe2)2(dpma) (32.3 mg, 0.1 mmol) in toluene (2 mL) and was heated for 48 h at 100 °C. Volatiles were removed and 2-aminobenzimidazole (200 mg, 1.5 mmol) in dry tert-amyl alcohol (3 mL) was added. The mixture was heated to 145- 150 °C for 24 h. Purification was accomplished by column chromatography on 141 silica. The eluent was Et3Nzethyl acetate 3:97, which afforded the desired compound (131 mg, 50%) as a mixture of two isomers in 3.5:1 ratio (the ratio of the two isomers was confirmed from the crude product mixture before purification). Major isomer, 1H NMR (CDCI3, 500 MHz) : 3.01 (3H, s, CH3), 7.38- 7.39 (3 H, m, Ar-H), 7.46-7.48 (1 H, m, Ar-H), 7.50-7.53 (2 H, m, Ar-H), 7.56-7.59 (1 H, m, Ar-H), 8.05 (1 H, d, J: 8.5 Hz, Ar-H), 8.10 (1 H, d, J: 8.5 Hz, Ar-H), 3.70 (1 H, s, 4-CH pyrimidine). 13C(‘Hj NMR (CDCI3, 125 MHz): (Could not assign the major isomer in 13C) 18.4, 25.9, 110.4, 115.2, 120.4, 120.6, 121.4, 121.7, 126.0, 126.3, 128.4, 123.6, 123.9, 129.0, 129.6, 130.1, 130.9, 134.7, 145.0, 145.4, 150.9, 156.5. MS(E|): mlz 259 (M+). High resolution MS: mlz Calc. for C17H14N3": 260.1188; Found: 260.1186 Preparation and Characterization of Compounds for the Model Study Oi.) \ Bn 7-benzyl-3-iodoindole: To a solution of 3-iodoindole (10.8 g, 44.4 mmol) in dry TH F (200 mL) was added t-BuOK (6.05 g, 54 mmol) at 0 PC under N2. The so'l-ltion was stirred for 1.5 h and then benzyl bromide (11.2 g, 65.5 mmol) was 142 added dropwise over 15 min at 0 °C. The reaction was then warmed to room temperature and stirred for overnight. After the completion of the reaction, water (150 mL) was added and the mixture was extracted with ethyl acetate (3 x 100). The organic layer was dried over NaZSO4 and concentrated under rotary evaporator. The crude yellow-red liquid was recrystalized from ethyl acetate- hexanes to give 12.3 g (83 %) of the pure compound as a white solid. M.p.: 75-77 °C. 1H NMR (CDCI3, 500 MHz): 5.32 (2 H, s, CH2). 7.16-7.18 (2 H, m, Ar-H), 7.23 (1 H, s, 2CH), 7.25-7.37 (6 H, m, Ar-H), 7.53755 (1 H, m, Ar-H). 13C(‘Hj NMR (CDCl3, 125 MHz): 50.3, 55.9, 109.3, 120.4, 121.4, 122.3, 126.9, 127.3, 123.3, 130.6, 132.0, 136.3, 136.7. (El): mlz 333 (M+) 1-benzyl-indole-3-carbonitri/e: A 100 mL Schlenk tube was loaded with 1-benzyl- 3-iodo-indole (5 g, 15 mmol), CuCN (1.47 g, 16.5 mmol) and 10 mL DMF. The mixture was heated to 165 °C for 12 h. After the completion of the reaction (checked by GC—FID) and solvent was removed under reduced pressure. The crude product was dissolved in CHZCIZ, washed with water, dried over NaZSO4 and concentrated under reduced pressure. The crude dark red oil was purified by column chromatography on silica using 40% ethyl acetate/hexanes. The product 143 was isolated as a yellow-orange solid in 80% (2.78 g) isolated yield. M.p.: 63-65 °C. 1H NMR (CDCI3, 500 MHz): 5.35 (2 H, s, CH2), 7.16-7.18 (2 H, m, Ar-H), 7.31-7.40 (6 H, m, Ar-H), 7.61 (1 H, s, 2CH), 7.79-7.31 (1 H, m, Ar-H). 13C(‘H} NMR (CDCI3, 125 MHz): 50.3, 36.2, 110.8, 115.7, 119.9, 122.2, 123.9, 127.0, 127.9, 128.3, 129.0, 134.9, 135.1, 135.5. (El): mlz 232 (MP‘). High resolution MS: mlz Calc. for C16H13N2+: 233.1079; Found: 233.1039. SIM63 // \ N \ Bn 1-benzyI-3-((trimethy/silyl)ethyny/)-indole: Under N2 an oven dried round bottom Schlenk flask was charged with 1-benzyl-3-iodo-indole (3.67 g, 11 mmol), Pd(PPh3)4 (635 mg, 5 mol%), Cul (210 mg, 10 mol%), 60 mL Et3N and 5 mL THF. The mixture was stirred at room temperature for 30 min after which trimethylsilyl acetylene (1.79 g, 18 mmol) was added. Then the mixture was stirred at room temperature for another 36 h. After the completion of the reaction (checked by GC-FID and GC-MS), another 30 mL Et3N was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and 144 the crude product was purified by silica gel column chromatography using 25% ethylacetate/hexanes. The product was isolated as a yellow solid in 64% (2.1 g) isolated yield. M.p.: 103-105 PC. 1H NMR (CDCI3, 500 MHz): 0.34 (9 H, s, CH3), 5.28 (2 H, s, CH2), 7.13-7.15 (2 H, m, Ar-H), 7.24-7.26 (2 H, m, Ar-H), 729-733 (4 H, m, Ar-H), 7.37 (1 H, s, 2CH), 780-782 (1 H, m, Ar-H). 13C(‘H} NMR (CDCI3, 125 MHz): 0.30, 50.2, 95.3, 97.7, 98.6, 109.9, 120.3, 120.5, 122.3, 126.9, 127.8, 123.8, 129.5, 132.2, 135.6, 136.5. (El): mlz 303 (M+). High resolution MS: mlz Calc. for CZOHZZNSF: 304.1522; Found: 304.1543. // \ N. Bn 1-benzyI-3-ethynyI-indole: Under the atmosphere of N2, dry K2003 (150 mg) was added to a mixture containing 1-benzyl-3-((trimethylsiiyl)ethynyl)-indole (5 g, 16.5 mmol) in 100 mL dry methanol. The mixture was stirred at room temperature for overnight after which it was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 25% ethylacetate/hexanes. The product was isolated as a yellow-orange solid in 84% (3.2 g) isolated yield. M.p.: 60-62 °C. 1H NMR (CDCI3, 500 MHz): 3.25 (1 H, s, 145 CCH), 5.30 (2 H, s, CH2), 7.14-7.16 (2 H, m, Ar-H), 7.22-7.27 (2 H, m, Ar-H), 729-735 (4 H, m, Ar-H), 7.40 (1 H, s, 2CH), 7.79-7.81 (1 H, m, Ar-H). 13C(‘H} NMR (CDCI3, 125 MHz): 50.3, 77.4, 78.8, 96.5, 110.0, 120.1, 120.6, 122.9, 126.9, 127.9, 128.8, 129.5, 132.5, 135.6, 136.4. (El): m/z 231 (MP‘). High resolution MS: m/z Calc. for C17H14N+z 232.1126; Found: 232.1127. HN OMe \ H N .01 Bn Methyl 1-benzyl-indole-3-carbimidate hydrochloride: 1-benzyl-indoIe-3- carbonitrile (1.7 g) was dissolved in dry MeOH (50 mL) and anhydrous hydrogen chloride was bubbled through the solution for 2 h and then the solution was allowed to stand to room temperature for 24 h. The precipitate formed was filtered and washed with methanol. The product was isolated as a white solid in 30% (1.75 g) yield. M.p.: 158-160 °C. 1H NMR (DMSO—ds, 500 MHz): 4.31 (3 H, s, OCH3), 5.58 (2 H, s, CH2), 729-737 (7 H, m, Ar-H), 7.72 (1 H, d, J= 7.5 Hz, Ar-H), 7.95 (1 H, dd, J: 7.5 and 1.5 Hz, Ar-H), 9.16 (1 H, s, 2CH), 10.60 (1 H, bs, NH), 11.60 (1 H, bs, H"). 13C(‘H} NMR (DMSO-ds, 125 MHz): 51.0, 59.6, 102.3, 112.8, 121.7, 123.8, 124.5, 125.7, 128.2, 128.7, 129.5, 136.8, 137.2, 146 138.7, 169.7. (El): m/z 264 (M+-HCI). High resolution MS: mlz Calc. for C,7H,7N20+ [(M+H)—HCI]: 265.1341; Found: 265.1344. HN NH2 \ HCI N . Bn 1 -benzyI-indole-3-carboximidamide hydrochloride: Methyl 1-benzyl-indole-3- carbimidate hydrochloride (1.7 g) was dissolved in dry MeOH (50 mL) and anhydrous ammonia was bubbled through the solution for ~2 h and then the solution was allowed to stand to room temperature for 24 h. The solvent was removed under reduced pressure for obtain the amidine product as a buff-colored solid in 92% yield (1.47 g). M.p.: 224-226 °C. 1H NMR (DMSO-ds, 500 MHz): 5.55 (2 H, s, CH2), 7.25-7.33 (7 H, m, Ar-H), 7.63 (1 H, dd, J: 8.5 and 2 Hz, Ar- H), 7.86 (1 H, dd, J= 7.5 and 1.5 Hz, Ar-H), 8.52 (1 H, s, 2CH), 8.92 (2 H, bs, NH2), 3.97 (2 H, bs, NH, H“). 13C(1 H} NMR (DMSO—de, 125 MHz): 49.3, 103.0, 111.6, 120.0, 121.9, 123.2, 124.3, 127.4, 127.8, 128.6, 135.0, 136.3, 136.5, 161.0. (El): mlz 249 (M*-HCI). High resolution MS: mlz Calc. for C16H16N3+ [(M+H)-HCl]: 250.1344; Found: 250.1343. 147 3.311 press 0.43 (100 10109 dry 0 the r Were Charg mmo leaCl dlSSo 3,3’-(pyrimidine-2,5-diyl)bis(1-benzy/-indole): In a N2 filled glove box, a 20 mL pressure tube, equipped with a magnetic stirbar was loaded with aniline (41 mg, 0.43 mmol), Ti(NMe2)2(dpm) (14 mg, 0.043 mmol), 1-benzyl-3-ethynyl indole (100 mg, 0.43 mmol), tert-butylisonitrile (55 mg, 0.66 mmol) and 2 mL of dry toluene. The pressure tube was sealed with a Teflon screw cap, taken out of the dry box, and heated for 24 h at 100 °C with vigorous stirring. After completion of the reaction, the pressure tube was cooled to room temperature and volatiles were removed under reduced pressure. Then the same pressure tube was charged with 1-benzyl indole-3-carboximidamide hydrochloride (123 mg, 0.43 mmol) in pyridine (3 mL) and heated to 150 °C for 24 h. After completion of the reaction, pyridine was removed under reduced pressure and crude product was dissolved in CHZCIZ and washed with water. The organic layer was dried over NaZSO4 and concentrated on a rotary evaporator. The crude product was purified by column chromatography on neutral alumina. The eluent was hexaneszethyiacetate 3:1, which afforded the desired compound (64 mg, 30%) as 148 a pale yellow solid. M.p.: 208-210 °C. 1H NMR (CDCI3, 500 MHz): 5.41-5.42 (4 H, two overlapping singlets, two-CHz) 7.21-7.40 (17 H, m, Ar-H), 7.96 (1 H, d, J= 7.5 Hz, Ar-H), 8.17 (1 H, s, Ar-H), 8.79 (1 H, d, J= 8 Hz, Ar-H), 9.05 (2 H, s, 4- CH pyrimidine). 13C(1 H} NMR (CDCI3, 125 MHz): 50.3, 50.6, 110.0, 110.3, 111.0, 115.6, 119.6, 120.7, 121.2, 122.5, 122.7, 122.8, 124.3, 125.8, 126.1, 126.8, 126.9, 127.0, 127.8, 127.9, 128.8, 128.9, 131.4, 136.6, 136.7, 137.1, 137.5, 154.7, 161.4. MS(E|): m/z 490 (M"). High resolution MS: mlz Calc. for C34H27N4*: 491.2236; Found: 491.2223. Ph > N / N \N W l N > 3,3’-(pyrim1dine-2, 4-diyl)bis(1-benzyI-indo/e): In a N2 filled glove box, a 20 mL pressure tube, equipped with a magnetic stirbar was loaded with aniline (93 mg, 1.0 mmol), Ti(NMe2)2(dpma) (32.3 mg, 0.1 mmol), 1-benzyl-3-ethynyl indole (231 mg, 1 mmol), tert-butylisonitrile (171 pL, 1.5 mmol) and ~ 3 mL of dry toluene. The pressure tube was sealed with a Teflon screw cap, taken out of the dry box, and heated for 24 h at 100 °C with vigorous stirring. After completion of the 149 reaction, the pressure tube was cooled to room temperature and volatiles were removed under reduced pressure. Then the same pressure tube was charged with 1-benzyl-indoIe-3-carboximidamide hydrochloride (300 mg, 1.1 mmol) in pyridine (3 mL) and heated to 150 °C for 24 h. After completion of the reaction, pyridine was removed under reduced pressure and crude product was dissolved in CHZCIZ and washed with water. The organic layer was dried over Na2804 and concentrated on a rotary evaporator. The crude product was purified by column chromatography on basic alumina. The eluent was initially hexaneszethylacetate 3:1 to remove the 2,5-isomer, then the eluent was changed to EtOAc which afforded the desired compound (103 mg, 21%) as a pale yellow solid. M.p.: 206- 203 PC. 1H NMR (CDCI3, 500 MHz):: 5.42-5.43 (4 H, two overlapping singlets, two-CH2) 722-740 (17 H, m, Ar-H), 3.01(1 H, s, Ar-H), 3.24(1 H, s, Ar-H), 3.53 (1 H, d, .1: 7.5 Hz, Ar-H), 3.65 (1 H, d, .1: 5 Hz, Ar-H), 3.33 (1 H, d, .1: 7.5 Hz, Ar-H). 130(1H} NMR (CDCI3, 125 MHz): 50.5, 109.9, 110.3, 112.2, 115.0, 116.2, 121.1, 121.4, 121.8, 122.3, 122.7, 122.9, 126.3, 127.00, 127.04, 127.7, 127.9, 128.8, 128.9, 130.5, 131.8, 136.3, 136.7, 137.4, 137.6, 156.4, 161.1, 163.7. MS(E|): m/z 490 (M+). High resolution MS: mlz Calc. for 034H27N4+: 491.2236; Found: 491.2233. 150 13 4.5 References 1. Lagoja, l. M. Chem. Biodiversity. 2005, 2, 1. 2. Ahiuwalia, V. K.; Kaila, N.; Bala, S. Indian J. Chem, Sect. 81987, 268, 700. 3. El-Hashash, M. A.; Mahmoud, M. R.; Madboli, S. A. Indian J. Chem, Sect. 8 1 993, 323, 449. 4. Keutzberger, A.; Gillessen, J. Arch. Pharm. (Weinheim, Ger.) 1985, 318, 370. 5. Fischl, M. A.; Richman, D. D.; Grieco, M. H.; Gottlieb, M. S.; Volberding, P. A.; Laskin, O. L.; Leedom, J. M.; Groopman, J. E.; Mildvan, D.; Schooley, R. T. N. Eng/J. Med. 1987, 317. 185. 6- Joffe, A. M.; Farley, J. 0.; Linden, D.; Goldsand, G. Am. J. Med. 1989, 87, 332. 7- For reviews see : (a) Chinchilla, R.; Najera, C.; Yus, M. Chem. Rev. 2004, 104, 2667. (b) Turck, A.; Plé, N.; Mongin, F.; Quéguiner, G. Tetrahedron 2001, 57, 4489. 8- C. Cao, v. Shi, A. L. Odom, .1. Am. Chem. Soc. 2003, 125, 2380. 9- For a review on azadienes in synthesis see (a) S. Jayakumar, M. P. S. I shar, M. P. Mahajan, Tetrahedron 2002, 58, 379. See also (b) L. A. Calvo, A. M. Gonzalez-Nogal, A. Gonzalez-Ortega, M. C. Sanudo, Tetrahedron Lett. 2001, 42, 8981 for related silyl isoxazole chemistry. 10- For a recent review on hydroamination see Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. 1 1 - Harris, S. A.; Ciszewski, J. T.; Odom, A. L. Inorg. Chem. 2001. 40. 1937- ‘2- (a) Shi, Y.; Hall, 0; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem. Commun. 2003, 586. (b) Novak, A.; Blake, A. J.; Wilson, 0.; Love J. B. Chem. Commun. 2002, 2796. ‘ G. W. Gokel, F1. P. Widera, W. P. Weber, Org. Synth. 1976, 55, 96. ’ Rosiak, A.; Frey, W.; Christoffers, J. Eur. J. Org. Chem. 2006, 17, 4044. 151 ll 15. 16. 17. 18. 19. 20. 21. 22. 23. 24 Carpita, A.; Rossi, R.; Veracini, C. A. Tetrahedron. 1985, 41, 1919. For reviews on the extensive work of Barluenga and coworkers on applications of 1,3-diimines to organic synthesis see (a) J. Barluenga, M. Tomas, Adv. Heterocyclic Chem. 1993, 57, 1. (b) J. Barluenga, Bull. Soc. Chim. Belg. 1988, 97, 545. For some references related more specifically to 1.3-diimines reactions related to those here see (c) J. Barluenga, E. Rubio, V. Rubio, L. Muniz, M. J. lglesias, V. Gotor, J. Chem. Res. (S) 1985, 124. (d) J. Barluenga, M. J. lglesias, V. Gotor, Synthesis 1987, 662. (e) V. Gotor R. Brieva, A. Aguirre, S. Garcia-Granda, F. Gomez-Beltran, Heterocycles 1989, 29, 1695. (f) J. Barluenga, J. F. Lopez-Ortiz, M. Tomas, V. Gotor, J. Chem. Soc. Perkin Trans. I 1981, 1891. (9) J. Barluenga, J. Jardon, V. Rubio, V. Gotor, J. Org. Chem. 1983, 48, 1379. Gupton, J. T.; Petrich, S. A.; Hicks, F. A.; Wilkinson, D. R.; Vargas, M.; Hosein, K. N.; Sikorski, J. A. Heterocycles1998, 47, 689. None of the reaction times have been fully optimized. Reactions were generally run for about 24 h. Endo, T.; Tsuda, M.; Fromont, J.; Kobayashi, J. J. Nat. Prod. 2007, 70, 423. Witulski, B.; Buschmann, N.; Bergstrasser, U. Tetrahedron. 2000, 56, 8473. lbrahim, Y. B.; Al-Awadi, N. A.; lbrahim, M. R. Tetrahedron. 2004, 60, 9121. Promel, R.; Cardon, A.; Daniel, M.; Jacques, G.; Vandersmissen, A. Tetrahedron. Lett, 1968, 26, 3067. Mosquera, A.; Riveiros, R.; Sestelo, J. P.; Sarandeses, L. A. Org. Lett, 2008, 10, 3745. Protopopova, T. V.; Klimko, V. T.; Skoldinov, A. P. Khimicheskaya Naukai Promysh/ennost, 1959, 4, 805. 152 CHAPTER 5 A multicomponent coupling sequence for direct access to substituted quinolines and related heterocycles 5.1 Introduction New synthetic protocols1 for quinolines, due to the ubiquity of these heterocycles, are of great interest as these heterocycles have utility in diverse areas such as pharmaceuticals,2 photonic materials,3 and redox switches.4 Several heterocyclic compounds containing the quinoline core are often reported to have antimalarial, antifungal and antimicrobial activities.5 Classical quinoline syntheses, e.g., Skraup, Friedlénder and Doebner-Miller reactions, often involve condensation of aniline with ketone/aldehyde compounds6 to access a variety of quinoline compounds. However, in recent years some attention has been paid to direct access to quinolines from alkynes and anilines using transition metal-catalyzed reactions.7 153 5.2 Results and Discussions We have been investigating a titanium-catalyzed 3-component coupling (SCC) reaction that generates tautomers of 1.3-diimines.8 Here we report that these 3CC products, when prepared using aromatic amines, can be used as direct precursors for quinolines and related heterocycles in a one-pot procedure simply by adding acetic acid to the multicomponent coupling product (Scheme 5.1). I \ R—r / ButHN NH2 R W1 + a? Tlcatalyst N = \ 2 % toluene |\ \1 R R1 / R HOAC "HQNBUt ii 1 / N\ R Fi— l \ / Scheme 5.1. Quinoline synthesis using titanium-catalyzed multicomponent coupling. The proposed catalytic cycle involved in the synthesis of the 300 product (discussed in chapter 3) is based on the mechanism for catalytic hydroamination.9 154 This new quinoline synthesis can be viewed as an alternative to some well-known quinoline syntheses that use anilines and 1,3-dicarbonyls or related compounds, such as the Combes synthesis.lo These reactions are very effective but require somewhat difficult to access unsymmetrical 1,3-dicarbonyls if their quinolines are to be produced.11 One of the advantages of this class of transformations is that it takes advantage of the large number of commercially available aniline derivatives. Two titanium catalysts Ti(dpm)(NMe2)2 (1);12 and Ti(dpma)(NMe2)2 (2).13 were employed for these study. They can be prepared (refer to chapter 3) in a single step by reacting the protio ancillary ligands with commertially available Tl(NM62)4. The results for 300 of some aryl amines with a few different alkynes are shown in Table 5.1. The yields for the quinoline compounds are modest, but the reactions are readily run on multigram scales and provide products from a single pot. A variety of different aniline derivatives have been used in the multicomponent coupling reaction, and in general the quinoline synthesis works better for electron rich anilines. 1) 10 mol% Ti cat. \NH2 toluene 100 °C R/R + CNBu ’ e / 2) HOAC, 150 °C 155 Table 5.1. Examples of quinoline syntheses. Amine Alkyne NH2 Ph // NH2 C H [:1 // 5 11 NH2 Ph ii / Me NH2 Ph 11 / Ph NH2 E1 é Q Et/ NH2 Ph CL / OMe Me NH2 Ph / Me M82 N NH2 l Ph / Me NH2 ©/ Catalyst Product é IE2 2\ IEZ O V Z :i 3 ° g o é :2 3 5 Z a Mo N Ph \ \ 1;; 3' Z to 3 (D E} 152 m m Me 3 3 Z g Q NMe \ Z 13 z 8 3 N M g I: 1, 3 Z to 30 <0 \/2 Z 0‘” % Yield“ 55 30 71 36 25 8Most reactions carried outwith arylamine, alkyne, and tert-butyl isonitrile in a 1:1:1.5 ratio with 10 mol% catalyst at 100 °C for 24-48 h. Once the 300 is complete, product was heated at 150 °C in HOAc. bUsed 20 mol% Ti(dpm)(NM82)2(1) at 140 °C. 156 The cyclizations of the 30C product involve Bronsted acid-catalyzedl4 intramolecular attack on the pendant aromatic ring (Scheme 5.2). Then, tert-butyl amine is lost in the aromatization of the nitrogen heterocycle in a step reminescent of the Povarov reaction. But R2 But “2 HNyYH‘ l H“ N ———-> ' \ P-CF / HN/ R‘ \l W (qu age 611 electrocyclic cyclization _ t 2 But R2 B” R N at HNQ \ R‘ \ \ H+ v \ NH , \ N / Scheme 5.2. Proposed mechanism for quinoline synthesis. Using this methodology, the 4-position of the quinoline product will be unsubstituted. In addition, the route takes advantage of the abundance of aryl amines available commercially to make substituted quinolines. The regioselectivity of the reaction would be 'set by the [2 + 2]- cycloaddition reaction in conjunction with the relative trapping rates by isonitrile under this scheme. It has been proposed that the regioselectivity of the addition is electronically controlled when an arene is found in the alkyne by stabilization of 157 a partial anionic charge adjacent to the metal in the azametallacyclobutene intermediate. This results in 3-substitution being electronically favored for aryl- substituted alkynes. For 1-hexyne, the favored product was generally the 2- substituted quinoline derivative. 158 Both a- and B-aminonapthalenes were also explored, which provide various benzoquinolines (Table 5.2). From this sampling, the reaction appears equally amenable to having the amine in either of these two positions. Table 5.2. Examples of benzoquinoline syntheses. Amine Alkyne Catalyst Product Yield“ 0 / 1 0 Ph NH 2 Bun 2 47° 0 / D H 60d Bun W H2N Ph N / I ca ”9% ‘ co 6’ aMost reactions carried out with arylamine, alkyne, and tent-butyl isonitrile in a 1:1:1.5 ratio with 10mol% catalyst at 100 °C for 24-48 h. bUsed 20 mol% Ti(dpm)(NMe2)2(1) at 140 °C. cTotal yield for two regioisomers; isomer shown favored 10:1. dTotal yield for two regioisomers; isomer shown favored 2.521. 159 The reaction can also be generalized to include various amine-substituted heterocycles. A variety of amino heterocycles can be synthesized in few steps following the literature procedures. 3-Aminothiophene was achieved via the saponification of methyl 3- aminothiophene-2-carboxylate (Equation 5.1).15 NH2 NaOH ””2 m .. (j/ \ (5.1) 002Me reflux S S The reaction of methyl thioglycolate with 2-cyano nitrobenzene produced methyl 3-aminobenzo[b]thiophene-2-carboxylate, which upon base mediated hydrolysis followed my decarboxylation generated benzo[b]thiophen-a-amine in good yields (Scheme 5.3).16 NH ’ ‘ NH ON A 2 HN NH 2 002Me KOH. DMF s NMP 8 N02 130 °c Scheme 5.3. Synthesis of benzo[b]thiophen-3-amine. Phthalimide was converted to the 1-aminopyrrole in 3 steps following the literature procedure (Scheme 54)." 160 O O OMe MeO 0 dioxane N H O (/ \> 2 4 \ < N‘N N MeOH (>1 :2 NH2 0 Scheme 5.4. 3 step synthesis of 1-aminopyrrole from phthalimide. 3-Methylindole was directly converted to 1-amino-3-methylindole in a single step, however the yield was very low (Equation 5.2).18 Me NH20803H Me Q13 > Q1 (5.2) u KOH 1y NH2 DMF,1 h RT 20% Finally, 1-benzyl-5-amino indole was made in two steps from 5-nitro indole via N-benzylation followed by reduction with stannic chloride (Equation 5.3).19 H2N 1) PhCHzBr Q1 K2003 , Q_\> (5.3) N H 2) SUCIQ 3n 161 The multicomponent coupling of these heterocyclic amine substrates offer access to some unique heterocyclic structures, which could be difficult to access using traditional synthetic chemistry. The results of a short study using 1- phenylpropyne are shown in Table 5.3, which illustrate the variety of heterocyclic frameworks available. Using 2-aminothiophene as a substrate generated a thienopyridine (Entry 1). In addition, 3-aminobenzothiophene provided the benzothienopyridine (Entry 2). The methodology is also applicable to pyrrolo- and indolopyridazines. 162 ll 9 Table 5.3. Examples of products prepared from amino-heterocycles. Amlne s D NH2 | S MD Alkyne Ph / Ph / Me Ph / Me Product Ylelda S b I / \ Ph 43 N‘ Me Ph / s \ 45 Me N M Ph 9 / \N 37 N l / 31 En I N 56 \ ,N Ph Me a Most reactions carried out with arylamine, alkyne, and tert-butyl isonitrile in a 1:1:1.5 ratio with 10 mol% catalyst at 100 °C for 24-48 h. b Converts directly to quinoline without external acid. The quinoline heterocyclic core is very common in a large number of natural products, and a variety of natural products can be derived from quinolines. Figure 5.1 shows some examples for natural products, which can be synthesized from quinolines. W WOMG Me Me O OMe Angustureine Cuspareine O O N 0 N OH I r O > I 0 Me 0 Me OMe Galipinine Galipeine Flgure 5.1. Natural products based on tetrahydroquinolines. We also applied this one-pot multicomponent coupling methodology to the synthesis of the natural product Angustureine, which has been prepared using a diverse array of routes.7 The advantages of the multicomponent coupling strategy presented here are the inexpensive and readily available reagents used in a straightforward synthesis (Scheme 5.5) of the natural product. 164 Dr: 515 \E 1) 10 mol% Ti(dpma)(NMez)2 o \ NH2 4. toluene, 100 C > W %NC 2) HOAc 3 150 °C 300/ 5 mol% (PhO)2P(0)0H | | Me N Me H benzene, 60 °C y 12 h W Mel, K2003 W N t . EtOH, reflux N Me 20 h H 4 Angustureine(5) 3 steps from aniline Scheme 5.5. Synthesis of racemic Angustureine (5). Three-component coupling of 1-heptyne, aniline, and tert-butylisonitrile followed by treatment with acetic acid resulted in 2-pentquuinoline (3) in 30% yields. The quinoline (3) was reduced to the tetrahydroquinoline (4) in presence of a Hanstz ester and acid catalyst. N-rnethylation was done by methyl iodide in Presence of a base to yield the final natural product Angustureine (5) in 3 steps starting from aniline. In collaboration with the Wulff group organocatalytic asymmetric reductions of 2-pentquuinoline (3) to 2-pentyltetrahydroquinoline (4) have Studied. For the initial study, a variety of chiral Bronsted acid catalysts (Figure 5-2) have been used to carry out the asymmetric reductions. 165 Flgure 5.2. Chiral catalysts used for asymmetric reductions 166 we \ Catalyst me n ’ Bu" N U EtOZC C02Et N 2.4 equiv. H H Me N Me H benzene, time, temperature Table 5.4. Organocatalytic asymmetric reduction of 2-pentquuinoline. Entry Catalyst Loading Time Temperature Conversion Yield ee (mol%) (h) (°C) (%) (%) (%) 1 A 20 1o 60 100 >99 _ 2 (FD-B 5 1o 60 100 >99 63 3 (FD-C 1o 12 60 100 >99 37 4 (8)-D 1O 12 60 100 >99 50 5 (SHE 10 12 60 100 >99 31 (3)-F 10 31 6O 6 6 70 ~90 88 17 7 (FD-G 1o 12 60 100 >99 72 (3 runs) 8 (8)-G 10 12 60 100 ND 79 9 (8)-H 1o 12 60 100 88 2o 1 0 (SH 10 12 60 100 ND 9 1 1 n 39 60 - 80 0 ( )-J 20 14 7O incomplete 1 2 (8)-K 20 (133 $8 incomplete 78 0 Table 5.4 shows the results of the asymmetric reductions of 2- pentquuinoline in presence of different catalysts. Modest enantioselectivities Were obtained when (Fi)-7 and (8)-7 were used. 167 is: l8 as US 1111 va he till all C0 5.3 Conclusion Titanium-catalyzed 3-component coupling of primary amine, alkyne, and isonitrile followed by treatment with acetic acid provides quinolines in a one-pot procedure. This new procedure has significant flexibility in the types of quinolines that can be accessed. The yields are generally modest, but the products are readily isolated using either column chromatography or crystallization. Reactions with terminal alkynes can be accomplished with the milder Ti(dpma)(NMe2)2 (2) as catalyst. The more active dipyrrolylmethane catalyst Ti(dpm)(NMe2)2 (1) was used for internal alkynes. The reaction has several points to allow optimization for a specific target of interest. For example, the type of substituent on the isonitrile can potentially be varied in this reaction to improve regioselectivities or yields. The methodology has been extended in synthesizing other class of heterocycles using a variety of different heterocyclic anime substrates The 3-component coUpling followed by acid treatment strategy was also applied to the synthesis of the natural product Angustureine (5) from commercially available aniline in 3 steps. 168 5.4 Experimental General Conslderatlons: All manipulations of air sensitive compounds were carried out in an MBraun drybox under a purified nitrogen atmosphere. Toluene was purified by sparging with dry N2 and removing water by running through activated alumina systems purchased from Solv-Tek. Deuterated solvents were dried over purple sodium benzophenone ketyl (0606) or phosphoric anhydride (CDCI3) and distilled under a nitrogen atmosphere. Deuterated toluene was dried passing through two columns of neutral alumina. 1H and 130 spectra were recorded on VXR-500 spectrometers Ti(dpm)(NMe2)212 and Ti(dpma)(NMe2)213 were made following the known procedures. Alkynes were purchased either from Aldrich or from GFS chemicals and dried from CaO under dry nitrogen. Amines were purchased from Aldrich, dried from KOH and distilled under dry nitrogen. tert-Butylisonitrile was made according to the reported procedure and purified by distillation under nitrogen.1-Aminonaphthalene was purchased from Aldrich and used without any further purification. 2-aminonaphthalene was isolated as a side product in the synthesis of 2,2-diamino-1,1-binaphthalene. 3-aminothiophene,15 3—aminobenzothiophene,16 N-aminopyrrole," N-amino-3-methylindole18 and 1- 19 benzyl-1H-indoI-5-amine were made following the literature procedures. 169 General procedure for Qulnollne Synthesls: In a N2filled glove box, a 40 mL pressure tube, equipped with a magnetic stirbar was loaded with amine (1 mmol), catalyst (10-20 mol%), alkyne (1 mmol), isonitrile (1-1.5 mmol) and 2 mL of dry toluene. The pressure tube was sealed with a Teflon screw cap, taken out of the dry box, and heated to the appropriate temperature for the desired time with stirring. After completion of the reaction (checked by GC—FID), the pressure tube was cooled to room temperature and volatiles were removed under reduced pressure. Then the same pressure tube was charged with glacial acetic acid (2 mL) and heated to 150 °C for 24 h. After completion, the reaction mixture was cooled to room temperature, diluted with CHZCIZ and neutralized with saturated NaHCO3 solution. The organic layer was washed with water, dried over Na2804 and concentrated on a rotary evaporator. The crude product was purified by column chromatography as described. Preparation and Characterlzatlon of Compounds In Table 5.1 N Me Gil / Ph 2-memyI-3-phenquuino/ine: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (171 pL, 1.5 mmol), aniline (92 mg, 1 mmol), 1-phenylpropyne (116 mg, 1 mmol), and Ti(NMe2)2(dpm) (30.8 mg, 0.1 mmol) in toluene (2 mL) and was heated for 48 h at 100 °C. Volatiles were 170 removed and glacial acetic acid (2 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethyl acetate 9:1, which afforded the desired compound (120 mg, 55%) as a yellow-red liquid. 1H NMR (CDCI3, 500 MHz): 2.57 (3 H, s, CH3), 7.28-7.32 (3 H, m, Ar-H), 735-740 (3 H, m, Ar-H), 7.56-7.60 (1 H, m, Ar-H), 7.66 (1 H, d, ‘J=8 Hz, Ar-H), 7.84 (1 H, s, 4CH), 7.97 (1 H, d, J: 8.5 Hz, Ar-H). 13C(‘H) NMR (CDCI3, 125 MHz): 24.5, 125.9, 126.7, 127.3, 127.5, 128.35, 128.37, 129.1, 1292,1358, 135.9, 139.8, 147, 157.2. MS (El): mlz 219 (M+). High resolution MS: mlz Calc. for C16H14N+z 220.1126; Found: 220.1119. Elemental Analysis: Found (Expected): %C, 86.92 (87.41); %H, 6.86 (8.93); %N, 5.54 (5.66). W N/ 2-penlquuino/ine: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (855 pL, 7.5 mmol), aniline (460 (1L, 5 mmol), 1- heptyne (480 mg, 5 mmol), and Ti(NMe2)2(dpma) (323 mg, 1 mmol) in toluene (10 mL) and was heated for 24 h at 100 °C. Volatiles were removed and glacial acetic acid (10 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was 540% ethyl acetate/hexanes, which afforded the desired 171 compound (300 mg, 30%) as a pale yellow liquid. 1H NMR (CDCI3, 500 MHz): 0.88 (3 H, t, J 7 H2, CH20H20H20H20%)i 1H33‘139 (4 H, m, CH20H2CH20HQCH3)1 1.76'1.82 (2 H, m, CH20H20H2CI'I20H3), 295 (2 H, t, J: 7.5 Hz, CHZCHZCHZCHZCHa). 7.27 (1 H, d, J = 8.5 Hz, Ar-H), 7.43-7.47 ((1 H, m, Ar-H), 7.64-7.67 (1 H, m, Ar-H), 7.74 (1 H, d, J: 8 Hz, Ar-H), 8.01-8.04 (2 H, m, Ar-H). 13C{‘H} NMR (CDCI3, 125 MHz): 13.9, 22.5, 29.7, 31.7, 39.3, 121.3, 125.5, 126.6, 127.4, 128.8, 129.2, 136.1, 147.8, 183.1. (El): mlz 199 (M+). High resolution MS: mlz Calc. for C14H18N": 200.1439; Found: 200.1443. Me N Me \ Me 2,5, 7-trimemyI-S-pheny/quinoline.' The general procedure was followed. The reaction was carried out with tert-butylisonitrile (171 pL, 1.5 mmol), 3,5- dimethylaniline (121 mg, 1 mmol), 1-phenylpropyne (116 mg, 1 mmol), and Ti(NMez)2(dpm) (30.8 mg, 0.1 mmol) in toluene (2 mL) and was heated for 48 h at 100 °C. Volatiles were removed and glacial acetic acid (2 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexaneszethylacetate 9:1, which afforded the desired compound (175 mg, 71%) as a pale yellow solid. M.p.: 172 79-80 °c. 1H NMR (CDCI3, 500 MHz): 2.50 (3 H, s, CH3). 2.60 (3 H, s, CH3). 2.63 (3 H, s, ZCH3), 7.16 (1 H, s, 6CH), 7.39-7.41 (3 H, m, Ar-I-o, 7.44-7.47 (2 H, m, Ar-H), 7.69 (1 H, s, 80H), 8.02 (1 H, s, 40H). 130(1H} NMR (00013, 125 MHz): 18.4, 21.8, 24.3, 124.1, 125.7, 127.4, 128.3, 128.8, 129.3, 132.5, 133.9, 134.3, 139.1, 140.4, 147.6, 156.5. MS (El): m/z 247 (M+). High resolution Ms: m/z Calc. for c18H18N“: 248.1439; Found: 248.1432. Me N Ph \ Me 5, 7-dimethyI-2,3-dlphenquuinoline: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (171 pL, 1.5 mmol), 3,5- dimethylaniline (121 mg, 1 mmol), diphenylacetylene (178 mg, 1 mmol), and Ti(NMe2)2(dpm) (61.6 mg, 0.2 mmol) in toluene (2 mL) and was heated for 48 h at 140 °C. Volatiles were removed and glacial acetic acid (2 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexanes:ethylacetate 9:1, which afforded the desired compound (93 mg, 30%) as a light yellow-red solid. M.p.: 136-138 °C. 1H NMR (000,, 500 MHz): 2.55 (3 H, s, CH3), 2.70 (3 H, s, CH3). 7.25-7.31 (9 H, m, Ar-H), 7.44-7.46 (2 H, m, Ar-H), 7.86 (1 H, s, Ar-H), 8.27 173 (1 H, s, 40H). 1306 H} NMR (C00,, 125 MHz): 18.5, 21.8, 124.6, 126.7, 127.0, 127.83, 127.86, 128.2, 129.5, 129.8, 130.0, 133.2, 133.9, 134.0, 139.5, 140.60, 147.9, 157.7. MS (El): m/z 309 (M+). High resolution MS: m/z Calc. for c23H20N+: 310.1596; Found: 310.1604. Me N\ Et (EL/1.. Mo 2, 3—diethyI-5, 7-dimethquuinoline: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (171 pL, 1.5 mmol), 3,5- dimethylaniline (121 mg, 1 mmol), 3-hexyne (82 mg, 1 mmol), and Ti(NMe2)2(dpm) (30.8 mg, 0.1 mmol) in toluene (2 mL) and was heated for 48 h at 110 °C. Volatiles were removed and glacial acetic acid (2 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexanes:ethylacetate 9:1, which afforded the desired compound (77 mg, 36%) as a yellow solid. M.p.: 41- 42 °C. 1H NMR (00013, 500 MHz): 1.31 (3 H, t, J: 7.5 Hz, SCHZCHg). 1.34 (3 H, t. .1: 7.5 Hz, ZCHZCHg). 2.45 (3 H, s, CH3). 2.59 (3 H, s, CH3). 2.81 (2 H, q, J: 7-5 Hz, 3CH2CH3), 2.97 (2 H, q, J: 7.5 Hz, ZCH20H3). 7.09 (1 H, s, 60H), 7.64 (1 H, s, 80H), 7.92 (1 H, s, 4CH). 13C{1H}NMR(CDCI3, 125 MHz): 13.6, 14.8, 174 18.4, 21.7, 25.4, 28.6, 124.6, 125.8, 128.3, 130.3, 133.2, 133.8, 137.9, 147, 182.2. MS (El): mlz 213 (M+). High resolution MS: mlz Calc. for C15H20N+z 214.1596; Found: 214.1594. “Mme / Ph 7-methoxy-2-methyI-3-phenquuinoline: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (171 pL, 1.5 mmol), 3- methoxyaniline (123 mg, 1 mmol), 1-phenylpropyne (116 mg, 1 mmol), and Ti(NM62)2(dpm) (30.8 mg, 0.1 mmol) in toluene (2 mL) and was heated for 48h at 100 °C. Volatiles were removed and glacial acetic acid (2 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexanes:ethylacetate 9:1, which afforded the desired compound (135 mg, 54%) as a light red solid. M.p.: 82-84 °c. ‘H NMR (000,, 500 MHz): 2.82 (3 H, s, 20H3), 3.94 (3 H, s, OCH3), 7.14 (1 H, dd, J: 6 and 2.5 Hz, Ar-H), 7.36-7.39 (4 H, m, Ar-H), 7.42-7.45 (2 H, m, Ar-H), 7.84 (1 H, d, .1: 9 Hz, Ar-H), 7.88 (1 H, s, 4CH). 130(1H} NMR (CDCl3, 125 MHz): 24.4, 55.5, 108.5, 119.2, 121.9, 127.3, 128.32, 128.37, 128.4, 129.3, 133.5, 135.9, 140, 157.4, 180.7. MS (El): mlz 249 (M+). High resolution MS: m/z Calc. for c,7H,6No*: 250.1232; Found: 250.1232. 175 N Me 011 MezN / Ph N,N,2-trimethyI-3-phenquuino/in-6-amine: The general procedure was followed. The reaction was carried out with fert-butylisonitrile (171 pL, 1.5 mmol), 4- (dimethylamino)aniline (136 mg, 1 mmol), 1-phenylpropyne (116 mg, 1 mmol), and Ti(NMe2)2(dpm) (30.8 mg, 0.1 mmol) in toluene (2 mL) and was heated for 24 h at 100 °C. Volatiles were removed and glacial acetic acid (2 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was 74% hexanes, 25% ethyl acetate, and 1% EtaN, which afforded the desired compound (131 mg, 50%) as a red oil. 1H NMR (CDCI3, 500 MHz): 2.47 (3 H, s, cha), 2.90 (8 H, s, NCH3), 8.57 (1 H, d, J: 3 Hz, Ar-H), 7.20 (1 H, dd, J: 9 and 3 Hz, Ar-H), 724-726 (3 H, m, Ar-H), 7.29-732 (2H, m, Ar-H), 7.83 (1 H, s, 4CH), 7.80 (1 H, d, J: 9 Hz, Ar- H). 13o{‘H} NMR (CDCI3, 125 MHz): 24.0, 40.8, 105.0, 119.2, 127.2, 128.10, 128.16, 128.8, 129.1, 134.3, 135.7, 140.4, 141.1, 148.2, 152.6. MS (El): mlz 262 (M+). High resolution MS: mlz Calc. for C18H19N2+2 263.1548; Found: 263.1555. N Me 00: l / Ph 6-I'Odo-2-methyI-3-phenquuinoline.' The general procedure was followed. The 176 reaction was carried out with tert-butylisonitrile (171 pL, 1.5 mmol), 4»iodoaniline (219 mg, 1 mmol), 1-phenylpropyne (116 mg, 1 mmol), and Ti(NMe2)2(dpm) (30.8 mg, 0.1 mmol) in toluene (2 mL) and was heated for 24 h at 100 °C. Volatiles were removed and glacial acetic acid (2 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexanes:ethyl acetate 9:1, which afforded the desired compound (86 mg, 25%) as a pale yellow viscous oil. 1H NMR (000,, 500 MHz): 2.81 (3 H, s, CH3). 7.34-7.36 (2 H, m, Ar-h), 7.38- 7.41 (1 H, m, Ar-I-o, 7.43-7.46 (2 H, m, Ar-H), 7.75 (1 H, d, J = 8.5 Hz, Ar-H), 7.78 (1 H, s, 4CH), 7.87 (1 H, dd, J: 9 and 2 Hz, Ar-H), 8.12 (1 H, d, J: 2 Hz, Ar-H). 130{1H} NMR (00013, 125 MHz): 24.8, 91.2, 127.7, 128.4, 128.5, 129, 130.1, 134.8, 138, 136.4, 137.9, 139.3, 145.9, 158.1. Ms (El): mlz 345 (M+). High resolution MS: mlz Calc. for C16H13Nl+z 346.0093; Found: 346.0107. .. o O\ / Me N Me 3-cyclohexenyI-2, 5, 7-trimethy/quino/ine: The general procedure was followed. The reaction was carried out with ten-butylisonitrile (171 pL, 1.5 mmol), 3,5- dimethylaniline (121 mg, 1 mmol), 1-(prop-1-ynyl)cyclohex-1-ene (120 mg, 1 mmol), and Ti(NMe2)2(dpm) (38.8 mg, 0.1 mmol) in toluene (2 mL) and was 177 heated for 24h at 100 °C. Volatiles were removed and glacial acetic acid (2 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexanes:ethyl acetate 9:1, which afforded the desired compound (100 mg, 40%) as a bright red viscous liquid. 1H NMR (CDCI3, 500 MHz): 1.68-1.73 (2 H, m, CH2). 1.76-1.81 (2 H, m, CH2). 2.18-2.21 (2 H, m, CH2). 2.23-2.26 (2 H, m, CH2), 2.45 (3 H, s, CH3). 2.57 (3 H, s, CH3). 2.64 (3 H, s, CH3). 5.66 (1 H, m, CH), 7.08 (1 H, s, Ar-H), 7.61(1 H, s, Ar-H), 7.83 (1 H, s, 4CH),. 136(1 H} NMR (CDCI3, 125 MHz): 18.4, 21.7, 22.0, 22.9, 23.5, 25.4, 30.2, 124.1, 125.8, 127.2, 128.4, 130.7, 133.6, 136.8, 137.7, 138.3, 147.2, 156.8. MS (El): mlz 251 (M*). High resolution MS: mlz Calc. for c18H22N”: 252.1752; Found: 252.1758. 178 Preparation and Characterizatlon of Compounds In Table 5.2 Ph N, Ph I 00 2,3diphenylbenzolhjquinoline: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (171 uL, 1.5 mmol), 1- aminonaphthalene (143 mg, 1 mmol), diphenylacetylene (178 mg, 1 mmol), and Ti(NMe2)2(dpm) (61.6 mg, 0.2 mmol) in toluene (2 mL) and was heated for 48 h at 140 °C. Volatiles were removed and glacial acetic acid (2 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexanes:ethyl acetate 19:1, which afforded the desired compound (143 mg, 44%) as a white solid. M.p.: 141- 143 °C (Lit2° M.p. 144 °C). 1H NMR (CDCI3, 500 MHz): 7.29-730 (8 H, m, Ar-H), 7.58-7.60 (2 H, m, Ar-H), 7.66-7.73 (3 H, m, Ar-H), 7.82 (1 H, d, J: 9 Hz, Ar-H), 7.90 (1 H, d, J: 7.5 Hz, Ar-H), 8.17 (1 H, s, 4CH), 9.41 (1 H, d, J: 7.5 Hz, Ar-H). 13o{‘H) NMFi (00013, 125 MHz): 124.8, 124.9, 125.0, 126.9, 127.1, 127.7, 127.8, 127.9, 128.1, 128.3, 129.7, 130.5, 131.5, 133.7, 134.7, 137.7, 140.2, 140.5, 145.2, 156.1. (El): mlz 331 (M+). Elemental Analysis: Found (Expected): %C, 90.30 (90.60); %H, 5.24 (5.17); %N, 4.23 (4.23). High resolution MS: m/z Calc. for 025H18N+z 332.1439; Found: 332.1442. 179 3-bulylbenzolquuinoline: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (171 pL, 1.5 mmol), 2-aminonaphthalene (143 mg, 1 mmol), 1-hexyne (82 mg, 1 mmol), and Ti(NMe2)2(dpma) (32.3 mg, 0.1 mmol) in toluene (2 mL) and was heated for 24 h at 100 °C. Volatiles were removed and glacial acetic acid (2 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was 5-10% ethyl acetate/hexanes, which afforded the mixture of two isomeric compounds (110 mg, 47%) in 10:1 ratio. M.p.: 40-42 °c. Major isomer 1H NMR (CDCI3, 500 MHz): 0.96 (3 H, t, .1 = 7.5 Hz, CHZCHZCHZCHa). 1.41-1.48 (2 H, m, CHZCHZCHchg). 1.79-1.85 (2 H, m, CHZCHQCHZCHs). 3.00 (2 H, t, J: 8 Hz, CHZCHZCHZCHa). 7.43 (1 H, d, J: 8.5 Hz, Ar-H), 7.58-7.61 ((1 H, m, Ar-H), 7.64-7.67 (1 H, m, Ar-H), 7.79 (1 H, d, J: 7.5 Hz, Ar-H), 7.98 (2 H, s, Ar-H), 8.57 (1 H, d, J: 8 Hz, Ar-H), 8.84 (1 H, d, J: 8 Hz, Ar-H). ‘3C(‘H) NMR (000,, 125 MHz): 14.2, 22.9, 32.5, 38.9, 121.4, 122.6, 123.6, 127.0, 127.1, 128.3, 128.8, 129.9, 130.8, 131.1, 131.6, 148.0, 162.8. (El): mlz 235 (M+). High resolution MS: mlz Calc. for C17H18N+: 236.1439; 180 Found: 236.1432. 2-butylbenzo[h]quinoline: The general procedure was followed. The reaction was carried out with fert-butylisonitrile (171 pL, 1.5 mmol), 1-aminonaphthalene (143 mg, 1 mmol), 1-hexyne (82 mg, 1 mmol), and Ti(NMez)2(dpma) (32.3 mg, 0.1 mmol) in toluene (2 mL) and was heated for 24 h at 100 °C. Volatiles were removed and glacial acetic acid (2 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was 5% ethyl acetate/hexanes, which afforded the mixture of two isomeric compounds (140 mg, 60%) in 2.521 ratio as red oil. (See attached NMR spectra). High resolution MS: m/z Calc. for C17H18N+2 236.1439; Found: 236.1444. 2-melhyl-3-phenylbenzo[h]quinoline: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (171 pL, 1.5 mmol), 1- 181 aminonaphthalene (143 mg, 1 mmol), 1-phenylpropyne (116 mg, 1 mmol), and Ti(NMe2)2(dpm) (30.8 mg, 0.1 mmol) in toluene (2 mL) and was heated for 48 h at 100 °C. Volatiles were removed and glacial acetic acid (2 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexanes:ethyl acetate 19:1, which afforded the desired compound (180 mg, 67%) as a pale yellow solid. M.p.: 51-52 °C. 1H NMR (00013, 500 MHz): 2.78 (3 H, s, CH3), 7.39-7.48 (5 H, m, Ar- H), 7.63-7.76 (4 H, m, Ar-H), 7.88 (1 H, d, J: 7 Hz, Ar-H), 8.96 (1 H, s, 4CH), 9.34 (1 H, d, J = 8 Hz, Ar-H). ‘%{‘H} NMR (CDCI3, 125 MHz): 24.8, 124.6, 125.3, 127.1, 127.3, 127.7, 128.0, 128.1, 128.6, 129.5, 129.7, 131.4, 133.9, 138.2, 136.3, 140.4, 145.2, 155.9. (El): m/z 289 (M+). High resolution Ms: m/z Calc. for 020H16N”: 270.1283; Found: 270.1271. 182 Preparation and Characterlzatlon of Compounds In Table 5.3 N Me / I \ 3 / Ph 5-methyI-6-phenylfllienol3,2-b]pyridine: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (64 pL, 0.56 mmol), 3- aminothiophene (37 mg, 0.373 mmol), 1-phenylpropyne (43 mg, 0.373 mmol), and Ti(NMe2)2(dpm) (11.5 mg, 0.037 mmol) in toluene (2 mL) and was heated for 48 h at 110 °C. Volatiles were removed and the crude product was purified by column chromatography on neutral alumina. The eluent was hexanes:ethyl acetate 4:1, which afforded the desired compound (37 mg, 43%) as a pale yellow-red liquid. 1H NMR (c0013, 500 MHz): 2.82 (3 H, s, CH3), 7.37-7.39 (3 H, m, Ar-H), 7.45-7.48 (2 H, m, Ar-H), 7.54 (1 H, dd, J: 5.5 and 1 Hz, SCHCH), 7.72 (1 H, d, J: 5.5 Hz, SChCH), 8.01 (1 H, s, 4CH). 13C{1H}NMR(CDCI3, 125 MHz): 23.8, 124.8, 127.4, 128.4, 1292,1304, 130.7, 131.0, 133.0, 140.1, 154.0, 154.8. MS (El): mlz 225 (M+). High resolution MS: mlz Calc. for C14H12NS+: 226.0690; Found: 226.0696. M6 N\ s 2-memyl-3-phenyl-benzo[4,51thieno[3,2-b]pyndine: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (148 pL, 1.3mmol), 183 3-aminobenzothiophene (130 mg, 0.872 mmol), 1-phenylpropyne (102 mg, 0.872 mmol), and Ti(NMe2)2(dpm) (26.8 mg, 0.0872 mmol) in toluene (1.5 mL) and was heated for 36 h at 100 °C. Volatiles were removed and glacial acetic acid (2 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexanes:ethyl acetate 9:1, which afforded the desired compound (108 mg, 45%) as a red viscous liquid. 1H NMR (CDCl3, 500 MHz): 2.55 (3 H, s, CH3), 724-728 (3 H, m, Ar-H), 731-734 (2 H, m, Ar-H), 7.38—7.41 (2 H, m, Ar-h), 7.69-7.71 (1 H, m, Ar-H), 7.81 (1 H, s, 4CH), 8.40-8.42 (1 H, m, Ar-H). “‘06 H} NMR (CDCI3, 125 MHZ): 23.75, 122.85, 122.88, 124.7, 127.4, 128.0, 128.3, 129.1, 131.06, 131.08, 134.5, 134.9, 139.9, 140.0, 150.5, 153.3. MS (EI): mlz 275 (M+). High resolution MS: mlz Calc. for c,8H,4Ns*: 278.0847; Found: 278.0831. 2-melhyI-3-phenylpyrrolo[1,2-b]pyridazine .' The general procedure was followed. The reaction was carried out with tert-butylisonitrile (171 pL, 1.5 mmol), N- aminopyrrole (82 mg, 1 mmol), 1-phenylpropyne (116 mg, 1 mmol), and Ti(NMe2)2(dpm) (30.8 mg, 0.1 mmol) in toluene (2 mL) and was heated for 48 h 184 at 100 °C. Volatiles were removed and glacial acetic acid (2 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexanes:ethyl acetate 19:1, which afforded the desired compound (76 mg, 37%) as a dark red viscous liquid. 1H NMR (CDCI3, 500 MHz): 2.41 (3 H, s, CH3). 8.49 (1 H, dd, J: 5 and 1.5 Hz, pyrrole-CH), 6.83 (1 H, dd, J = 4.5 and 2.5 Hz, pyrrole-CH), 736-738 (2 H, m, Ar-H), 7.39-7.42 (1 H, m, Ar-H), 745-748 (2 H, m, Ar-H), 7.57 (1 H, s, 4CH), 7.72-7.73 (1 H, m, pyrrole-CH). 13C(‘H} NMR (CDCI3, 125 MHz): 21.3, 99.3, 112.4, 116.1, 125.4, 125.8, 128.3, 127.4, 128.4, 129.0, 138.8, 149.1. Ms (El): m/z 208 (M+). High resolution MS: m/z Calc. for C14H13N2+z 209.1079; Found: 209.1082. 2, 5-dimethyl-3-phenylpyridazinol1, 6-a]indole: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (171 pL, 1.5 mmol), N-amino-3-methylindole (146 mg, 1 mmol), 1-phenylpropyne (116 mg, 1 mmol), and Ti(NMe2)2(dpm) (30.8 mg, 0.1 mmol) in toluene (2 mL) and was heated for 185 48 h at 100 °C. Volatiles were removed and glacial acetic acid (2 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was hexanes:ethyl acetate 19:1, which afforded the desired compound (85 mg, 31%) as 8 orange solid. M.p.: 88-89 °C. 1H NMR (CDCI3, 500 MHz): 2.42 (3 H, s, CH3), 2.51 (3 H, s, CH3), 735-748 (7 H, m, Ar-H), 7.59 (1 H, s, 4CH), 7.78-7.78 (1 H, m, Ar-H), 8.15-8.17 (1 H, m, Ar-H). 1"’C(‘H) NMR (CDCI3, 125 MHz): 7.9, 21.5, 98.9, 111.2, 118.7, 121.2, 122.1, 124.8, 126.9, 127.0, 127.7, 128.4, 128.8, 128.9, 130.7, 138.9, 148.1. Ms (El): mlz 272 (M+). High resolution MS: m/z Calc. for c,9H,7N2*: 273.1392; Found: 273.1382. Ph: TA’ ‘ :N‘Bn \ O Me N 3-benzyl-7-methyl-8-phenyl-3H-pyrrolo[3,2—f]quinoline: The general procedure was followed. The reaction was carried out with tert-butylisonitrile (171 pL, 1.5 mmol), N-benzyl-S-aminolindole (222 mg, 1 mmol), 1-phenylpropyne (116 mg, 1 mmol), and Ti(NMe2)2(dpm) (30.8 mg, 0.1 mmol) in toluene (2 mL) and was heated for 48 h at 100 °C. Volatiles were removed and glacial acetic acid (2 mL) was added. The mixture was heated to 150 °C for 24 h. Purification was accomplished by column chromatography on neutral alumina. The eluent was 186 hexanes:ethyl acetate 7:3, which afforded the desired compound (195 mg, 56%) as a pale yellow solid. M.p.: 108-110 °c. 1H NMR (CDCIS, 500 MHz): 2.71 (3 H, s, CH3), 5.44 (2H, s, NCHZ), 7.04 (1 H, d, J: 3 Hz, Ar-H), 7.13 (2 H, d, J: 8 Hz, Ar-H), 7.25-7.34 (4 H, m, Ar-H), 7.43-7.53 (5 H, m, Ar-H), 7.67 (1 H, d, J: 8.5 Hz, pyrrole-CH), 7.83 (1 H, d, J: 9 Hz, pyrrole-CH), 8.38 (1 H, s, 4CH). ‘3C(‘H) NMR (CDCI3, 125 MHZ): 24.2, 50.4, 101.0, 114.5, 121.5, 122.9, 123.0, 126.6, 127.33, 127.37, 127.7, 128.3, 128.8, 129.3, 131.6, 132.3, 134.9, 137.2, 140.6, 143.9, 153.5. MS (El): m/z 348 (M+). High resolution MS: m/z Calc. for 025H21N2“: 349.1705; Found: 349.1703. H 2-pentyl- 1,2,3, 4-tetrahydroquinoline (4): A 20 mL pressure tube was loaded with 2-pentquuinoline (100 mg, 0.5 mmol), Hanstz ester (308 mg, 1.2 mmol) and diphenylphosphate (8 mg, 5 mol%) in 4 mL benzene and the mixture was heated to 60 °C for 20 h. After the completion of the reaction the solvent was evaporated and after the usual work-up the crude product was purified by column chromatography on neutral alumina. The eluent was hexanes:ethyl acetate 9:1, which afforded the desired compound (91 mg, 90%) as a pale yellow liquid. 1H 187 NMR (CDCI3, 500 MHZ): 0.9 (3 H, t, J: 6.5 HZ), 1.30-1.40 (6 H, m), 1.45-1.50 (2 H, m), 1.51-1.63 (1 H, m), 1.92-1.96 (1 H, m), 2.69-2.83 (2 H, m), 3.19-3.24 (1 H, m), 3.76 (1 H, bs), 6.46 (1 H, d, J: 8 Hz), 6.58 (1 H, t, J: 7.5 HZ), 692-695 (2 H, m). ‘3C(‘ H} NMR (CDCI3, 125 MHz): 14.0, 22.6, 25.3, 26.4, 28.0, 31.9, 36.6, 51.5, 113.9, 116.8, 121.3, 128.8, 129.2, 144.7. MS (El): mlz 203 (M‘). Ma (:2) Angustureine (5): A 50 mL round-bottom flask fitted with a reflux condenser was charged with 2-pentyl-1,2,3,4-tetrahydroquinoline (4) (60 mg, 0.3 mmol), methyl iodide (255 mg, 1.8 mmol) and K2003 (42 mg, 0.3 mmol) in 15 ml THF and the mixture was refluxed for 18 h. After the completion of the reaction the solvent was removed in rotary evaporator and the crude product was purified by flash column chromatography on neutral alumina. The product was obtained as a yellow liquid in 81% (52 mg) isolated yield. 1H NMR (CDCI3, 500 MHZ): 0.9 (3 H, t, J: 7.0 Hz), 1.25-1.41 (7 H, m), 1.56-1.59 (1 H, m), 1851.90 (2 H, m), 2.84 (1 H, td, J: 8.0 and 4 Hz), 2.78-2.83 (1 H, m), 2.91 (3 H, s) 3.20-3.24 (1 H, m), 6.51 (1 H, d, J: 8 Hz), 6.57 (1 H, t, J: 7.5 Hz), 6.96 (1 H, d, J: 7.5 Hz), 7.07 (1 H, t, 188 J: 75 Hz). 13C(‘ H} NMR (CDCI3, 125 MHz): 14.0, 22.6, 23.5, 24.4, 25.7, 31.2, 32.0, 37.9, 58.9, 110.3, 115.1, 121.8, 127.0, 128.6, 145.4. MS (El): mlz 217 (M+). 189 5.5 Refrences 10. 11. For some recent developments and examples see (a) Li, L.; Jones, W. D. J. Am. Chem. Soc. 2007, 129, 10707. (b) Zhang, 2. H.; Tan, J. J.; Wang, Z. Y. Org. Lett. 2008, 10, 173. (c) Kouznetsov, V. V.; Romero Bohérquiez, A. R.; Stashenko, E. E. Tetrahedron Lett. 2007, 48, 8855. For a review see Michael, J. P. Nat. Prod. Reports 2008, 25, 166. Other papers: (a) Markees, D. G.; Dewey, V. C.; Kidder, G. W. J. Med. Chem. 1 970, 13, 324; (b) Alhaider, A. A.; Abdelkader, M. A.; Lien, E. J. J. Med. Chem. 1985, 28, 1398; (c) Campbell, S. F.; Hardstone, J. D.; Palmer, M. J. J. Med. Chem. 1988, 31, 1031. Zhang, X.; Shetty, A. S.; Jeneckhe, S. A. Macromolecules 1999, 32, 7422. Das, D.; Dai, 2.; Holmes, A.; Canary J. W. Chirality 2008, 20, 585. (a) Musiol, R.; Jampilek, J.; Kralova, K.; Richardson, D. R.; Kalinowski, D.; Podeszwa, B.; Finster, J.; Niedbala, H.; Palka, A.; Polanski, J. Bioorg. Med. Chem. 2007, 15, 1280. (b) Michael, J. P. Nat. Prod. Rep. 2007, 24, 223. Kouznetsov, V. V.; Mendez, L. V.; GOmez, C. M. M. Curr. Org. Chem. 2005, 9, 141. (a) Zhang, X.; Campo, M. A.; Larock, R. C. Org. Lett. 2005, 7, 763. (c) Gabriele, B.; Mancuso, R.; Salerno, G.; Ruffolo, G.; Plastina, P. J. Org. Chem. 2007, 72, 6873—6877. (d) Amii, H.; Kishikawa, Y.; Uneyama, K. Org. Lett. 2001, 3, 1109. 080, C.; Shi, Y. Odom, A. L. J. Am. Chem. Soc. 2003, 125, 2880. For a recent review on hydroamination see Milller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108.3795. Kouznetsov, V. V.; Vargas Mendez, L. Y.; Melendez GOmez, C. M. Curr. Org. Chem. 2005, 9, 141. For a recent quinoline synthesis involving rhodium catalysis see Horn, J.; Marsden, S. R; Nelson, A.; House, D.; Weingarten, G. G. Org. Lett. 2008, 10, 4117. 190 12. 13. 14. 15. 16. 17. 18. 19. 20. (a) Shi, Y.; Hall, 0.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem. Commun. 2003, 586. (b) Novak, A.; Blake, A. J.; Wilson, 0.; Love J. B. Chem. Commun. 2002, 2796. Harris, S. A.; Ciszewski, J. T.; Odom, A. L. Inorg. Chem. 2001, 40, 1987. A related acid-catalyzed cyclization of 1,3-diimine tautomers has been used previously to generate quinolines in a multistep synthesis. Their 1,3- diimine tautomers were prepared from enolizable arylimine condensation with nitriles. The cyclization was accomplished by addition of the Lewis acid AlCla. Barluenga, J.; Cuervo, H.; Fustero, S.; Gotor, V. Synthesis 1 987, 82. Attempts to use AICl3 with the derivatives listed here resulted in very low yields. Barker, J. M.; Huddleston, P. R.; Wood, M. L. Synth. Commun. 1995, 25, 3729. Salvati, M. E.; Balog, J. A.; Shari, W.; Giese. S. US. Pat. Appl. Publ. 2003, 18pp. Dey, S. K.; Lightner, D. A. J. Org. Chem. 2007, 72, 9395. Somei, M.; Natsume, M. Tetrahedron. Lett. 1974, 5, 461. Benod, C.; Subra, G.; Nahoum, V.; Mallavialle, A.; Guichou, J. F.; Mihau, J.; Robles, S.; Bourguet, W.; Pascussi, J. M.; Balaguer, P.; Chavanieu, A. Bioorg. Med. Chem. 2008, 16, 3537. Borsche, W.; Wagner, R. M.; Weber, W. P. J. Liebs. Ann. Chemie 1940, 544, 272. 191 Appendix (Crystal structure data) 192 Crystal data and structure refinement for Cpmpound 13 (chapter 4). Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection Indexranges Reflections collected Independent reflections Completeness to theta = 25.00° Absorption correction Max. and min. transmission Refinement method Data Irestraints I parameters Goodness-of-fit on F2 Final R indices [l>25igma(l)] R indices (all data) Largest diff. peak and hole alo108m 034 H26 N4 490.59 173(2) K 0.71073 A Monoclinic P 21/n a = 14.903(3) A a: 90°. b = 5.8088(13) A b: 91 .169(3)°. c = 28.404(6) A g = 90°. 2458.3(9) A3 4 1.326 Mg/m3 0.079 mm-1 1032 0.40 x 0.20 x 0.10 mm3 1.53 to 25.00°. -17<=h<=17, -6<=k<=6, -33<=|<=33 21309 4311 [R(int) = 0.0576] 99.9 % Semi-empirical from equivalents 0.9921 and 0.9691 Full-matrix least-squares on F2 4311 /0 /444 1.080 R1 = 0.0783, wnz = 0.2138 R1 = 0.1087, wR2 = 0.2351 0.419 and -0.275 e.A'3 193 Table A1. Atomic coordinates and equivalent isotropic displacement parameters for Compound 13 x y z U(eq) N(1 ) 8978(2) 5410(6) 2336(1 ) 23(1 ) N(2A) 8845(3) 21 82(8) 2844(2) 36(1 ) C(3A) 81 75(3) 2105(7) 2056(2) 33(1 ) C(38) 8845(3) 2182(8) 2844(2) 36(1) N(ZB) 8175(3) 2105(7) 2056(2) 33(1) N(3) 8502(2) 8094(7) 985(1 ) 29(1 ) N(4) 1 0690(2) 8237(7) 3361 (1 ) 28(1 ) C(1 ) 9147(3) 4326(8) 2751 (2) 25(1 ) 0(2) 8366(4) 1083(9) 2482(2) 45(1) 0(4) 8493(3) 4284(8) 2006(2) 24(1 ) 0(5) 8321(3) 5477(8) 1561(1) 24(1) C(6) 8775(3) 7425(8) 1428(2) 26(1) 0(7) 7855(3) 6576(8) 820(2) 26( 1 ) C(8) 7718(3) 4896(8) 1 176(2) 25(1) 0(9) 7077(3) 3175(9) 1093(2) 31 (1 ) C(10) 6606(3) 31 58(9) 664(2) 35(1 ) C(1 1 ) 6768(3) 481 1 (9) 320(2) 34(1) C(1 2) 7388(3) 6530(9) 388(2) 31 (1 ) C(13) 8927(3) 9953(9) 720(2) 33(1 ) C(14) 9926(3) 9495(8) 661 (1 ) 26(1 ) C(1 5) 10207(3) 7459(9) 461 (2) 34(1 ) C(16) 1 1 125(4) 7053(10) 406(2) 44(1) C(17) 1 1745(4) 8683(1 1) 553(2) 45(1) C(18) 11458(4) 10712(11) 750(2) 43(1) C(19) 10543(3) 11121 (1 0) 805(2) 36(1) C(20) 971 5(3) 5545(8) 3088(1 ) 24(1 ) C(21) 10179(3) 7516(9) 2983(2) 28(1) C(22) 10581 (3) 6683(8) 3722(2) 26(1 ) 194 C(23) C(24) C(25) C(28) C(27) C(28) C(29) C(30) C(31 ) C(32) C(33) C(34) 9968(3) 9728(3) 1 01 28(3) 1 0738(3) 10975(3) 1 1388(3) 1 2288(3) 1 2440(3) 1 3292(3) 1401 7(3) 13878(3) 1 3028(3) 4977(8) 3235(9) 3245(9) 4960(10) 6709(9) 10044(8) 9171 (8) 7060(9) 6365(9) 7810(10) 9913(10) 10611(9) Table A1 Continued.... 3572(2) 3890(2) 4339(2) 4477(2) 4173(2) 3348(2) 3232(1) 3027(2) 2904(2) 2989(2) 3195(2) 3322(2) 27(1) 29(1) 34(1) 36(1) 32(1) 28(1) 27(1) 29(1) 34(1) 41(1) 41(1) 37(1) 195 Table A 2. Bond lengths and angles for Compound 13. N(1)-C(4) N(1)-C(1) N(2A)-C(1 ) N(2A)-0(2) C(3A)-C(4) C(3A)-C(2) C(3A)-H(3A) N(3)-C(6) N(3)-C(7) N(3)-C(13) N(4)-C(21 ) N(4)-C(22) N(4)-C(28) C(1)-C(20) C(2)-H(2) C(4)-C(5) C(5)-C(6) C(5)-C(8) C(8)-H(8) C(7)-C(12) C(7)°C(8) C(8)-0(9) C(9)-C(10) C(9)-H(9) C(10)-C(1 1) C(10)-H(10) C(1 1)-C(12) C(1 1)-H(1 1) C(12)-H(12) C(13)-C(14) C(13)-H(13A) C(13)-H(138) C(14)-C(19) C(14)-C(15) 1 341(5) 1 355(5) 1 352(7) 1 395(8) 1 .381 (8) 1 .371 (7) 0.9500 1 372(8) 1 382(8) 1 .467(6) 1 369(8) 1 379(8) 1 .456(6) 1 .451 (6) 1 .02(8) 1 .461 (6) 1 374(8) 1 .441 (6) 1 .04(5) 1 399(6) 1 .423(6) 1 399(6) 1 394(7) 097(5) 1 394(7) 094(5) 1 371(7) 099(5) 095(6) 1 525(7) 1 .04(6) 097(8) 1 375(7) 1 .381 (7) 196 C(15)-C(16) C(15)-H(15) C(16)-C(17) C(16)-H(16) C(17)-C(18) C(17)-H(17) C(18)-C(19) C(18)-H(18) C(19)-H(19) C(20)-C(21) C(20)-C(23) C(21)-H(21) C(22)-C(27) C(22)-C(23) C(23)-C(24) C(24)-C(25) C(24)-H(24) C(25)-C(28) C(25)-H(25) C(28)-C(27) C(28)-H(28) C(27)-H(27) C(28)-C(29) C(28)-H(28A) C(28)-H(28B) C(29)-C(30) C(29)-C(34) C(30)-C(31 ) C(30)-H(30) C(31 )-C(32) C(31 )-H(31 ) C(32)-C(33) C(32)-H(32) C(33)-C(34) C(33)-H(33) Table A 2 continued.... 1 400(7) 1 05(5) 1 .381 (8) 1 09(7) 1 377(8) 1 .03(6) 1 398(7) 1 .06(6) 093(8) 1 .374(6) 1 .455(6) 094(5) 1 398(6) 1 409(8) 1 .407(6) 1 398(7) 093(5) 1 .400(7) 1 03(8) 1 383(7) 094(5) 1 .01 (8) 1 .503(6) 1 00(5) 096(5) 1 379(7) 1 405(7) 1 385(7) 098(5) 1 385(7) 1 .04(5) 1 372(8) 099(5) 1 385(7) 097(7) 197 C(34)-H(34) C(4)-N(1)-C(1) C(1)-N(2A)-C(2) C(4)-C(3A)-C(2) C(4)-C(3A)-H(3A) C(2)-C(3A)-H(3A) C(8)-N(3)-C(7) C(8)-N(3)-C(13) C(7)-N(3)-C(13) C(21 )-N(4)-C(22) C(21)-N(4)-C(28) C(22)-N(4)-C(28) N(2A)-C(1)-N(1) N(2A)-C(1)-C(20) N(1)-C(1)-C(20) C(3A)-C(2)-N(2A) C(3A)-C(2)-H(2) N(2A)-C(2)-H(2) N(1)-C(4)-C(3A) N(1)-C(4)-C(5) C(3A)-C(4)-C(5) C(6)-C(5)-C(8) C(8)-C(5)-C(4) C(8)-C(5)-C(4) N(3)-C(6)-C(5) N(3)-C(6)-H(8) C(5)-C(6)-H(6) N(3)-C(7)-C(12) N(3)-C(7)-C(8) C(12)-C(7)-C(8) C(9)-C(8)-C(7) C(9)-C(8)-C(5) C(7)-C(8)-C(5) Table A 2 contlnued.... 1 .00(6) 1 179(4) 1 16.4(4) 1 153(4) 122.3 122.3 108.8(4) 123.8(4) 126.9(4) 108.2(4) 124.9(4) 125.8(4) 122.8(4) 120.8(4) 1 16.4(4) 123.1 (5) 120(3) 1 17(3) 124.4(4) 1 17.1 (4) 1 18.4(4) 106.8(4) 123.3(4) 129.9(4) 1 103(4) 121(3) 129(3) 129.9(4) 107.8(4) 1 223(4) 1 18.6(4) 135.1(4) 1 08.4(4) 198 Table A 2 continued.... C(10)-C(9)-C(8) 1 18.8(5) C(10)-C(9)-H(9) 125(3) C(8)-C(9)-H(9) 1 18(3) C(9)-C(10)-C(11) 121.1(5) C(9)-C(10)-H(10) 121(3) C(11)-C(10)-H(10) 118(3) C(12)-C(11)-C(10) 122.0(5) C(12)-C(11)-H(11) 118(3) C(10)-C(11)-H(11) 120(3) C(11)-C(12)-C(7) 117.3(5) C(11)-C(12)-H(12) 120(3) C(7)-C(12)-H(12) 122(3) N(3)-C(13)-C(14) 111.1(4) N(3)-C(13)-H(13A) 105(3) C(14)-C(13)-H(13A) 112(3) N(3)-C(13)-H(138) 108(3) C(14)-C(13)-H(13B) 110(3) H(13A)-C(13)-H(138) 110(5) C(19)-C(14)-C(15) 120.2(5) C(19)-C(14)-C(13) 119.8(4) C(15)-C(14)-C(13) 120.0(4) C(14)-C(15)-C(16) 119.7(5) C(14)-C(15)-H(15) 121(3) C(16)-C(15)-H(15) 119(3) C(17)-C(16)-C(15) 120.0(5) C(17)-C(16)-H(16) 117(4) C(15)-C(18)-H(18) 123(4) C(18)-C(17)-C(16) 119.9(5) C(18)-C(17)-H(17) 121(3) C(16)-C(17)-H(17) 119(3) C(17)-C(18)-C(19) 120.2(5) C(17)-C(18)-H(18) 125(3) C(19)-C(18)-H(18) 115(3) C(14)-C(19)-C(18) 120.0(5) 199 C(14)-C(19)-H(19) C(18)-C(19)-H(19) C(21)-C(20)-C(1) C(21)-C(20)-C(23) C(1)-C(20)-C(23) N(4)-C(21)-C(20) N(4)-C(21)-H(21) C(20)-C(21)-H(21 ) N(4)-C(22)-C(27) N(4)-C(22)-C(23) C(27)-C(22)-C(23) C(24)-C(23)-C(22) C(24)-C(23)-C(20) C(22)-C(23)-C(20) C(25)-C(24)-C(23) C(25)-C(24)-H(24) C(23)-C(24)-H(24) C(24)-C(25)-C(26) C(24)-C(25)-H(25) C(26)-C(25)-H(25) C(27)-C(26)-C(25) C(27)-C(28)-H(28) C(25)-C(26)-H(28) C(28)-C(27)-C(22) C(28)-C(27)-H(27) C(22)-C(27)-H(27) N(4)-C(28)-C(29) N(4)-C(28)-H(28A) C(29)-C(28)-H(28A) N(4)-C(28)-H(28B) C(29)-C(28)-H(288) H(28A)-C(28)-H(28B) C(30)-C(29)-C(34) C(30)-C(29)-C(28) Table A 2 continued.... 1 14(4) 128(3) 123.5(4) 105.9(4) 130.5(4) 1 11 0(4) 125(3) 124(3) 128.4(4) 108.7(4) 122.9(4) 1 189(4) 134.7(4) 106.3(4) 1 18.1 (5) 121 (3) 120(3) 121 .5(5) 1 19(3) 1 19(3) 121 .4(5) 120(3) 1 19(3) 1 17.1 (5) 1 17(3) 126(3) 1 13.5(4) 107(3) 1 12(3) 107(3) 1 12(3) 104(4) 1 18.0(4) 123.4(4) 200 C(34)-C(29)-C(28) C(29)-C(30)—C(31) C(29)-C(30)-H(30) C(31)-C(30)-H(30) C(30)-C(31)-C(32) C(30)-C(31)-H(31) C(32)-C(31)-H(31) C(33)-C(32)-C(31) C(33)-C(32)-H(32) C(31)-C(32)-H(32) C(32)-C(33)-C(34) C(32)-C(33)-H(33) C(34)-C(33)-H(33) C(33)-C(34)-C(29) C(33)-C(34)-H(34) C(29)-C(34)-H(34) Table A 2 contlnued.... 1 18.6(4) 121 .8(5) 125(3) 1 13(3) 1 19.7(5) 1 17(3) 124(3) 1 19.4(5) 123(3) 1 18(3) 121 2(5) 124(4) 1 15(4) 120.0(5) 121 (3) 1 19(3) Symmetry transformations used to generate equivalent atoms: 201 Table A 3. Anisotropic displacement parameters Compound 13. [J11 u22 u33 u23 u13 ”12 N(1) 21(2) 24(2) 24(2) 1 (2) 1 (1 ) 3(2) N(2A) 37(3) 31 (3) 41 (3) 9(2) 15(2) 9(2) C(3A) 28(2) 25(2) 46(3) -2(2) 5(2) -2(2) C(33) 37(3) 31(3) 41(3) 9(2) 15(2) 9(2) N(2B) 28(2) 25(2) 46(3) -2(2) 5(2) -2(2) N(3) 28(2) 28(2) 29(2) 2(2) 0(2) -1(2) N(4) 28(2) 30(2) 26(2) 2(2) -1(2) 2(2) C(1 ) 20(2) 30(3) 25(2) 3(2) 9(2) 7(2) C(2) 38(3) 23(3) 75(4) 1 (3) 28(3) 1 (2) C(4) 1 8(2) 25(2) 30(2) 0(2) 6(2) 0(2) C(5) 21(2) 25(2) 24(2) -3(2) 3(2) 2(2) C(6) 24(2) 25(2) 29(2) -2(2) -6(2) 2(2) C(7) 20(2) 29(3) 29(2) -3(2) 1 (2) 2(2) C(8) 21 (2) 26(2) 27(2) -6(2) 4(2) 4(2) C(9) 29(2) 30(3) 33(3) -4(2) 4(2) -4(2) C(10) 30(3) 40(3) 35(3) -9(2) -1 (2) -5(2) C(1 1) 33(3) 41(3) 28(2) -6(2) -3(2) -1(2) C(12) 27(2) 36(3) 29(2) -1(2) -3(2) 3(2) C(13) 34(3) 24(3) 41(3) 7(2) -3(2) -3(2) C(14) 32(2) 27(2) 20(2) 5(2) -2(2) -4(2) C(15) 39(3) 28(3) 36(3) 0(2) 1 (2) -1(2) C(16) 43(3) 45(3) 44(3) 3(3) 12(2) 4(3) C(17) 29(3) 63(4) 43(3) 14(3) 7(2) -2(3) C(1 8) 39(3) 50(4) 41 (3) 6(3) -3(2) -1 1 (3) C(19) 36(3) 37(3) 35(3) -4(2) -3(2) -1 1 (2) C(20) 22(2) 27(2) 21 (2) 4(2) 4(2) 7(2) C(21) 27(2) 34(3) 23(2) 5(2) 2(2) 5(2) C(22) 21(2) 35(3) 22(2) 2(2) 4(2) 6(2) C(23) 23(2) 32(3) 26(2) 4(2) 6(2) 8(2) C(24) 26(2) 30(3) 31 (3) 8(2) 5(2) 5(2) 202 C(25) C(26) C(27) C(28) C(29) C(30) C(31 ) C(32) C(33) C(34) 34(3) 32(3) 27(2) 35(3) 31(2) 23(2) 33(3) 30(3) 29(3) 40(3) 41 (3) 52(3) 44(3) 22(2) 31 (3) 32(3) 35(3) 50(4) 47(3) 32(3) 23(3) 25(2) 25(2) 23(2) 17(2) 27(2) 29(3) 43(3) 43(3) 37(3) Table A 3 Continued... 12(2) 5(2) -2(2) -2(2) 3(2) -4(2) 0(2) 9(3) 5(3) 1 (2) 9(2) 2(2) 3(2) 1 (2) -1 (2) -1 (2) 6(2) 5(2) -7(2) -5(2) 10(2) 10(2) 7(2) 0(2) -3(2) -4(2) 1 (2) 0(3) -14(3) -7(2) 203 Table A 4. Hydrogen coordinates and isotropic displacement parameters Compound 13. x y 2 WW) H(3A) 7343 1344 1313 49 H(33) 3953 1463 3140 55 H(2) 8160(40) -560(1 10) 2540(20) 64(18) H(6) 9230(30) 8410(90) 1622(17) 36(13) H(9) 7000(30) 2070(90) 1344(1 8) 39(14) H(10) 6200(30) 1 970(80) 587(1 5) 23(1 2) H(1 1 ) 6430(30) 4760(80) 17(17) 35(13) H(1 2) 7430(40) 7740(1 00) 1 70(20) 53(1 7) H(1 3A) 8580(40) 9990(1 00) 400(20) 58(1 7) H(138) 8840(40) 1 1380(1 10) 890(20) 57(17) H(15) 9750(30) 6130(90) 382(16) 36(13) H(16) 1 1380(40) 5450(130) 260(20) 80(20) H(17) 1 2420(40) 8320(100) 530(20) 61 (18) H(18) 1 1880(40) 12040(1 10) 880(20) 61 (18) H(19) 10300(40) 12380(100) 957(19) 49(16) H(21 ) 10130(30) 8280(80) 2690(18) 34(13) H (24) 9360(30) 2020(90) 3788(16) 28(1 3) H(25) 9930(40) 1930(100) 4570(20) 52(16) H(26) 1 1 000(30) 4890(80) 4782(17) 30(1 3) H(27) 1 1330(40) 7950(100) 4303(19) 54(17) H(28A) 1 1360(30) 1 0870(90) 3654(17) 32(13) H(28B) 1 1 160(30) 1 1 190(90) 31 24(16) 29(1 2) H(30) 1 1 980(30) 5910(80) 2957(1 5) 28(1 2) H(31 ) 13350(30) 4720(90) 2764(16) 31 (12) H(32) 14620(40) 7260(90) 2904(13) 45(15) H(33) 14360(40) 1 0970(1 20) 3280(20) 70(20) H(34) 1 2920(40) 12210(1 10) 3440(20) 58(17) 204 Table A 5. Torsion angles Compound 13. C(2)-N(2A)-C(1)-N(1) C(2)-N(2A)-C(1)-C(20) C(4)-N(1)-C(1)-N(2A) C(4)-N(1)—C(1)-C(20) C(4)—C(3A)-C(2)-N(2A) C(1)-N(2A)-C(2)-C(3A) C(1)-N(1)-C(4)-C(3A) C(1)-N(1)-C(4)-C(5) C(2)-C(3A)-C(4)-N(1) C(2)-C(3A)-C(4)-C(5) N(1)-C(4)-C(5)-C(6) C(3A)-C(4)-C(5)-C(6) N(1)-C(4)-C(5)-C(8) C(3A)-C(4)-C(5)-C(8) C(7)-N(3)-C(6)-C(5) C(13)-N(3)-C(6)-C(5) C(8)-C(5)-C(6)-N(3) C(4)-C(5)-C(6)-N(3) C(6)-N(3)-C(7)-C(12) C(13)-N(3)-C(7)-C(12) C(6)-N(3)-C(7)-C(3) C(13)-N(3)-C(7)-C(8) N(3)-C(7)-C(8)—C(9) C(12)-C(7)-C(3)-C(9) N(3)-C(7)-C(8)-C(5) C(12)-C(7)-C(8)-C(5) C(6)-C(5)-C(8)-C(9) C(4)-C(5)-C(8)-C(9) C(6)-C(5)-C(8)-C(7) C(4)-C(5)—C(8)-C(7) C(7)-C(8)-C(9)-C(10) C(5)-C(8)—C(9)-C(10) C(8)-C(9)-C(10)-C(1 1) C(9)-C(10)-C(1 1 )-C(12) 205 2.0(6) -174.9(4) -0.3(6) 176.7(4) 0.6(7) 21(7) -1 .4(6) -179.3(4) 1 .3(6) 179.6(4) 14.1(6) -164.4(4) -169.0(4) 12.6(7) 0.2(5) -172.9(4) -0.5(5) 177.1 (4) -179.2(5) -6.3(3) 0.1(5) 172.9(4) 179.0(4) -1 .6(6) 04(5) 173.9(4) -173.7(5) 3.9(3) 0.6(5) ~176.8(4) 0.8(6) 130.0(5) 0.2(7) -0.5(3) C(10)-C(11)-C(12)-C(7) N(3)-C(7)-C(12)-C(1 1) C(8)-C(7)-C(12)-C(1 1) C(6)-N(3)-C(13)-C(14) C(7)-N(3)-C(13)-C(14) N(3)-C(13)-C(14)-C(19) N(3)-C(13)-C(14)-C(15) C(19)-C(14)-C(15)-C(16) C(13)-C(14)—C(15)-C(16) C(14)-C(15)—C(16)-C(17) C(15)-C(16)-C(17)-C(18) C(16)-C(17)-C(18)-C(19) C(15)-C(14)-C(19)-C(18) C(13)-C(14)-C(19)-C(18) C(17)-C(18)-C(19)-C(14) N(2A)-C(1)-C(20)-C(21) N(1)-C(1)-C(20)-C(21) N(2A)-C(1)-C(20)-C(23) N(1)-C(1)-C(20)-C(23) C(22)-N(4)-C(21)-C(20) C(28)-N(4)-C(21)-C(20) C(1)-C(20)-C(21)-N(4) C(23)-C(20)-C(21)-N(4) C(21)-N(4)-C(22)-C(27) C(23)-N(4)-C(22)-C(27) C(21)-N(4)-C(22)-C(23) C(28)-N(4)-C(22)-C(23) N(4)-C(22)-C(23)-C(24) C(27)-C(22)-C(23)-C(24) N(4)-C(22)-C(23)-C(20) C(27)-C(22)-C(23)-C(20) C(21)-C(20)-C(23)-C(24) C(1)-C(20)-C(23)-C(24) C(21)-C(20)-C(23)-C(22) C(1)-C(20)-C(23)-C(22) Table A 5 Continued... -0.3(7) -179.4(5) 1.4(7) 57.1 (6) -114.7(5) -125.3(5) 55.3(6) 0.4(7) 179.3(4) 0.0(8) -0.3(8) 0.3(8) -0.4(7) -179.3(4) 0.0(8) 167.3(4) -9.8(6) -3.4(7) 174.5(4) 1.5(5) 169.8(4) -177.4(4) -0.8(5) 179.5(4) 1 1 .4(7) -1.7(5) -169.8(4) -177.3(4) 1.0(6) 1.2(5) -1 799(4) 173.5(5) -5.2(8) -0.3(5) 176.0(4) 206 C(22)-C(23)-C(24)-C(25) C(20)-C(23)-C(24)-C(25) C(23)-C(24)-C(25)-C(26) C(24)-C(25)-C(26)-C(27) C(25)-C(26)-C(27)-C(22) N(4)-C(22)-C(27)-C(26) C(23)-C(22)-C(27)-C(26) C(21)-N(4)-C(28)-C(29) C(22)-N(4)-C(28)-C(29) N(4)-C(28)-C(29)-C(30) N(4)-C(28)-C(29)-C(34) C(34)-C(29)-C(30)-C(31) C(23)-C(29)-C(30)-C(31 ) C(29)-C(30)-C(31)-C(32) C(30)-C(31)-C(32)-C(33) C(31)-C(32)-C(33)-C(34) C(32)-C(33)-C(34)-C(29) C(30)-C(29)-C(34)-C(33) C(28)-C(29)-C(34)-C(33) Table A 5 Continued... -1 .7(6) 179.6(5) 1 5(7) -0.6(7) -0.1(7) 173.6(4) -0.1(7) -39.6(5) 76.6(5) 13.3(6) -164.4(4) -0.9(7) 176.5(4) 0.2(7) 0.1(3) 0.4(3) -1 .0(3) 1 3(7) -176.2(5) Symmetry transformations used to generate equivalent atoms: 207 Crystal data and structure refinement for Compound 12 (chapter 4). Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection Indexranges Reflections collected Independent reflections Completeness to theta = 25.00° Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [l>2sigma(l)] R indices (all data) Largest diff. peak and hole al0208m C34 H26 N4 490.59 173(2) K 0.71073 A Monoclinic 02/0 3 = 47.431 (13) A a: 90°. b = 5.943(2) A b: 112.393(4)°. c = 19.219(7) A g = 90°. 5019(3) A3 8 1.299 Mg/m3 0.077 mm"1 2064 0.45 x 0.05 x 0.05 mm3 1.86 to 28.19°. -61<=h<=62, -7<=k<=7, -25<=|<=24 24438 5666 [R(int) = 0.0830] 99.9 % Semi-empirical from equivalents 0.9961 and 0.9660 Full-matrix least-squares on F2 5666 /0 I447 1.055 R1: 0.0601, wR2 = 0.1181 R1 = 0.1271, wR2 = 0.1387 0.304 and -0.257 e.A‘3 208 Table B 1. Atomic coordinates and equivalent isotropic displacement parameters for Compound 1 2. x y 2 WW) N(1) 1 156(1 ) 4209(3) 2004(1 ) 26(1 ) N(2) 1203(1) 7499(3) 1349(1) 27(1) N(3) 1652(1) 9494(3) 4657(1 ) 25(1 ) N(4) 643(1) 1752(3) -174(1) 24(1) C(1) 1114(1) 5384(4) 1370(1) 23(1) C(2) 1343(1) 8543(4) 2014(1) 27(1) C(3) 1396(1) 7510(4) 2703(1) 22(1 ) C(4) 1 299(1 ) 5284(4) 2652(1 ) 25(1 ) C(5) 1 537( 1 ) 8644(4) 3430(1 ) 23(1 ) C(6) 1493(1) 3079(4) 4075(1) 24(1) C(7) 1303(1) 11041(4) 4395(1) 23(1) C(8) 1743(1) 10543(4) 3631(1) 24(1) C(9) 1333(1) 1 1343(4) 3244(1) 27(1) C(10) 2073(1) 13594(4) 3619(1) 31 (1) C(11) 2128(1) 14063(4) 4374(1) 32(1) C(12) 1998(1) 12805(4) 4771(1) 29(1) C(13) 1670(1) 9293(4) 5431(1) 25(1) C(14) 1912(1) 7689(4) 5908(1) 24(1) C(15) 2212(1) 7823(4) 5958(1) 28(1) C(1 6) 2431 (1 ) 6322(4) 6396(1 ) 32(1 ) C(17) 2356(1) 4636(4) 6306(1) 33(1) C(13) 2060(1) 4541(5) 6770(1) 36(1) C(19) 1340(1) 6034(4) 6322(1) 31(1) C(20) 953(1 ) 4243(4) 656(1 ) 22(1 ) C(21) 787(1) 2303(4) 571(1) 25(1) C(22) 725(1) 3343(4) -596(1) 23(1) C(23) 919(1) 4931(4) -92(1) 22(1) C(24) 1034(1) 6711(4) -386(1) 26(1) C(25) 949(1) 6373(4) -1156(1) 29(1) C(26) 753(1) 5275(4) -1643(1) 32(1) 209 C(27) C(23) C(29) C(30) C(31 ) C(32) C(33) C(34) 637(1) 436(1) 1 10(1) -36(1) 337(1) -497(1) 305(1) -3(1) 3499(4) -106(4) 632(4) -760(5) -143(5) 1344(5) 3243(5) 2654(5) Table B 1 Continued.... -1374(1) -473(1 ) -900(1 ) -1449(2) -1330(2) -1672(2) -1 135(2) -749(1) 30(1) 29(1) 25(1) 33(1) 47(1) 40(1) 41(1) 36(1) 210 Table B 2. Bond lengths and angles for Compound 12. N(1)-C(4) N(1)-C(1) N(2)-C(1 ) N(2)-C(2) N(3)-C(6) N(3)-C(7) N(3)-C(13) N(4)-C(21) N(4)-C(22) N(4)-C(28) C(1 )—C(20) C(2)—C(3) C(2)-H(2) C(3)-C(4) C(3)-C(5) C(4)-H(4) C(5)-C(6) C(5)-C(8) C(6)-H(6) C(7)-C(12) C(7)-C(8) C(3)-C(9) C(9)-C(10) C(9)-H(9) C(10)-C(1 1) C(10)-H(10) C(1 1)-C(12) C(1 1)-H(1 1) C(12)-H(12) C(13)-C(14) C(13)-H(13A) C(13)-H(133) C(14)-C(19) C(14)—C(15) 1 334(3) 1 352(3) 1 .341 (3) 1 344(3) 1 375(3) 1 339(3) 1 463(3) 1 363(3) 1 333(3) 1 460(3) 1 459(3) 1 393(3) 1 02(2) 1 394(3) 1 464(3) 099(2) 1 374(3) 1 447(3) 097(2) 1 393(3) 1 413(3) 1 407(3) 1 334(3) 093(2) 1 400(3) 1 03(3) 1 373(3) 099(2) 096(3) 1 507(3) 099(2) 1 .02(2) 1 336(3) 1 394(3) 211 C(15)-C(16) C(15)-H(15) C(16)-C(17) C(16)-H(16) C(17)-C(13) C(17)-H(17) C(13)-C(19) C(13)-H(13) C(19)-H(19) C(20)-C(21) C(20)-C(23) C(21)-H(21) C(22)-C(27) C(22)-C(23) C(23)-C(24) C(24)-C(25) C(24)-H(24) C(25)-C(26) C(25)-H(25) C(26)-C(27) C(26)-H(26) C(27)-H(27) C(28)-C(29) C(28)-H(28A) C(28)-H(288) C(29)-C(30) C(29)-C(34) C(30)-C(31 ) C(30)-H(30) C(31 )-C(32) C(31 )-H(31 ) C(32)-C(33) C(32)-H(32) C(33)-C(34) C(33)-H(33) Table B 2 Continued... 1 .386(3) 1 01(2) 1 330(3) 099(2) 1 336(3) 1 00(2) 1 339(3) 094(3) 096(3) 1 .371 (3) 1 444(3) 097(2) 1 393(3) 1 414(3) 1 405(3) 1 331(3) 1 .01 (2) 1 407(3) 096(2) 1 331(3) 093(2) 093(2) 1 512(3) 1 01(2) 1 02(2) 1 334(3) 1 .391 (3) 1 .386(4) 099(3) 1 374(4) 091(3) 1 370(4) 094(2) 1 337(3) 1 03(3) 212 C(34)-H(34) C(4)-N(1i-C(1) C(1)-N(2)-C(2) C(6)-N(3)-C(7) C(6)-N(3)-C(13) C(7)-N(3)-C(13) C(21)-N(4)-C(22) C(21)-N(4)-C(28) C(22)-N(4)-C(23) N(2)-C(1)-N(1) N(2)-C(1)-C(20) N(1)—C(1)-C(20) N(2)-C(2)-C(3) N(2)-C(2)-H(2) C(3)-C(2)-H(2) C(2)-C(3)-C(4) C(2)-C(3)-C(5) C(4)-C(3)-C(5) N(1)-C(4)-C(3) N(1)-C(4)-H(4) C(3)-C(4)-H(4) C(6)-C(5)-C(8) C(6)-C(5)-C(3) C(8)-C(5)-C(3) C(5)-C(6)-N(3) C(5)-C(6)-H(6) N(3)-C(6)-H(6) N(3)-C(7)-C(12) N(3)-C(7)-C(8) C(12)-C(7)-C(8) C(9)-C(8)-C(7) C(9)-C(8)-C(5) C(7)-C(8)-C(5) Table B 2 Continued... 099(3) 1 16.2(2) 1 16.62(19) 103.23(13) 125.5(2) 126.14(19) 103.74(13) 125.7(2) 125.42(19) 125.15(19) 1 13.01 (19) 1 16.8(2) 123.3(2) 1 14.5(13) 122.2(13) 1 14.7(2) 123.3(2) 121 5(2) 123.9(2) 1 15.7(13) 120.3(13) 105.70(19) 125.3(2) 129.0(2) 1 1 1.0(2) 127.7(12) 121.2(12) 129.7(2) 107.65(19) 122.6(2) 1 133(2) 134.3(2) 10732(19) 213 C(10)-C(9)-C(8) 1 190(2) C(10)-C(9)-H(9) 1 19.6(12) C(8)-C(9)-H(9) 121.4(12) C(9)-C(10)-C(11) 121.1(2) C(9)-C(10)-H(10) 113.3(14) C(11)-C(10)-H(10) 120.1 (14) C(12)-C(11)-C(10) 121.5(2) C(12)-C(11)-H(11) 117.5(14) C(10)-C(11)-H(11) 121.0(14) C(1 1)-C(12)-C(7) 1 17.5(2) C(11)-C(12)-H(12) 123.4(16) C(7)-C(12)—H(12) 119.0(16) N(3)-C(13)-C(14) 113.30(13) N(3)-C(13)-H(13A) 104.7(13) C(14)-C(13)-H(13A) 113.6(14) N(3)-C(13)-H(133) 107.7(12) C(14)-C(13)-H(13B) 112.9(12) H(13A)-C(13)-H(138) 103.2(13) C(19)-C(14)-C(15) 117.9(2) C(19)-C(14)-C(13) 120.2(2) C(15)-C(14)-C(13) 121.9(2) C(16)-C(15)—C(14) 121.0(2) C(16)-C(15)-H(15) 121.9(12) C(14)-C(15)-H(15) 117.1(12) C(17)-C(16)-C(15) 120.3(2) C(17)-C(16)-H(16) 119.9(14) C(15)-C(16)-H(16) 119.7(14) C(16)-C(17)-C(13) 119.5(2) C(16)-C(17)-H(17) 119.4(13) C(18)-C(17)-H(17) 121.1(13) C(17)-C(18)-C(19) 119.9(2) C(17)—C(18)-H(18) 115.0(16) C(19)-C(18)-H(18) 125.1(16) C(14)-C(19)-C(18) 121.4(2) Table B 2 Continued... 214 C(14)-C(19)-H(19) C(18)—C(19)-H(19) C(21)-C(20)-C(23) C(21)-C(20)—C(1) C(23)-C(20)-C(1) N(4)-C(21)-C(20) N(4)-C(21)-H(21) C(20)-C(21)-H(21) N(4)-C(22)-C(27) N(4)-C(22)-C(23) C(27)-C(22)-C(23) C(24)-C(23)—C(22) C(24)-C(23)-C(20) C(22)-C(23)-C(20) C(25)-C(24)-C(23) C(25)-C(24)-H(24) C(23)-C(24)-H(24) C(24)-C(25)-C(26) C(24)-C(25)-H(25) C(26)-C(25)-H(25) C(27)-C(26)-C(25) C(27)-C(26)-H(26) C(25)-C(26)-H(26) C(26)-C(27)-C(22) C(26)-C(27)-H(27) C(22)-C(27)-H(27) N(4)-C(28)-C(29) N(4)-C(28)-H(28A) C(29)-C(23)-H(23A) N(4)-C(28)-H(28B) C(29)-C(23)-H(23B) H(28A)-C(28)-H(28B) C(30)-C(29)-C(34) C(30)-C(29)-C(28) Table B 2 Continued... 1 15.4(15) 123.1(16) 106.22(19) 125.1(2) 123.6(2) 1 106(2) 1 17.2(13) 132.2(13) 129.5(2) 107.64(13) 122.9(2) 1 13.6(2) 134.6(2) 106.30(19) 1 19.0(2) 121.3(12) 1 19.7(12) 120.9(2) 1 19.9(14) 1 19.2(14) 121.3(2) 1 13.2(14) 120.0(14) 1 16.9(2) 120.7(14) 122.4(14) 1 13.3(2) 109.1 (12) 103.2(12) 1 10.1 (13) 106.9(13) 103.6(13) 1 134(2) 1 19.2(2) 215 C(34)-C(29)-C(28) C(29)-C(30)—C(31 ) C(29)-C(30)-H(30) C(31)-C(30)-H(30) C(32)-C(31 )-C (30) C(32)-C(31 )-H(31 ) C(30)-C(31)-H(31) C(33)-C(32)-C(31) C(33)-C(32)-H(32) C(31)-C(32)-H(32) C(32)-C(33)-C (34) C(32)-C(33)-H(33) C(34)-C(33)—H(33) C(33)-C(34)-C(29) C(33)-C(34)-H(34) C(29)-C(34)-H(34) Table B 2 Continued... 122.4(2) 120.3(3) 1 13.0(15) 121 .7(15) 120.3(3) 122.6(13) 1 16.5(18) 1 19.5(3) 122.4(15) 1 13.1 (15) 120.3(3) 121.7(14) 1 13.0(14) 120.7(2) 120.7(15) 1 13.6(15) Symmetry transformations used to generate equivalent atoms: 216 Table B 3. Anisotropic displacement parameters for Compound 12. 217 (J11 u22 (J33 (J23 u13 u12 N(1) 27(1) 25(1) 25(1) 0(1) 10(1) 2(1) N(2) 30(1) 24(1) 25(1) -1(1) 9(1) -1(1) N(3) 25(1) 29(1) 20(1) -1(1) 6(1) -2(1) N(4) 21(1) 24(1) 25(1) -1(1) 6(1) -2(1) C(1) 21(1) 23(1) 24(1) 0(1) 10(1) 5(1) C(2) 29(1) 25(1) 25(1) -1(1) 8(1) 1(1) C(3) 19(1) 25(1) 23(1) 0(1) 8(1) 2(1) C(4) 24(1) 27(1) 24(1) 2(1) 9(1) 4(1) C(5) 19(1) 24(1) 24(1) 1(1) 6(1) 5(1) C(6) 21(1) 26(1) 25(1) -2(1) 7(1) -3(1) C(7) 20(1) 25(1) 23(1) 1(1) 7(1) 4(1) C(8) 23(1) 26(1) 21(1) 3(1) 7(1) 5(1) C(9) 25(1) 32(2) 24(1) 1 (1 ) 10(1) 3(1) C(10) 32(1) 30(2) 33(1) 3(1) 14(1) -3(1) C(11) 31(1) 29(2) 35(2) -5(1) 10(1) -7(1) C(12) 29(1) 30(2) 26(1) -2(1) 8(1) 0(1) C(13) 26(1) 30(2) 23(1) -2(1) 13(1) 0(1) C(14) 26(1) 26(1) 20(1) -7(1) 8(1) -4(1) C(15) 27(1) 28(1) 28(1) 1(1) 10(1) -2(1) C(16) 26(1) 34(2) 34(1) -2(1) 9(1) -1(1) C(17) 37(2) 33(2) 24(1) 1 (1 ) 7(1) 5(1) C(18) 50(2) 32(2) 29(1) 5(1) 19(1) -2(1) C(19) 30(1) 37(2) 29(1) 1(1) 15(1) -4(1) C(20) 17(1) 21(1) 26(1) 1(1) 7(1) 3(1) C(21) 21(1) 29(1) 23(1) 1(1) 6(1) 2(1) C(22) 21(1) 22(1) 27(1) -2(1) 9(1) 0(1) C(23) 20(1) 23(1) 24(1) -1(1) 8(1) 5(1) C(24) 25(1) 26(1) 29(1) -3(1) 10(1) 2(1) C(25) 35(1) 26(1) 31(1) 5(1) 18(1) 3(1) C(26) 37(1) 37(2) 25(1) 3(1) 15(1) 7(1) C(27) C(28) C(29) C(30) C(31 ) C(32) C(33) C(34) 29(1 ) 26(1 ) 26(1 ) 36(2) 37(2) 26(1 ) 32(2) 34(1 ) 35(2) 25(1) 24(1) 30(2) 47(2) 48(2) 43(2) 37(2) 21 (1 ) 34(2) 26(1 ) 41 (2) 44(2) 43(2) 49(2) 36(2) Table B 3 Continued... -6(1) -3(1) 0(1) -9(1) -3(2) 14(1) -2(1) -10(1) 6(1) 8(1) 12(1) 6(1) 1(1) 10(1) 19(1) 13(1) 0(1) -4(1) -3(1) -5(1) -1 2(2) 6(1) 6(1) -2(1) 218 Table B 4. Hydrogen coordinates and isotropic displacement parameters for Compound 12. x y 2 WW) H(2) 1401(5) 10170(40) 1976(12) 37(7) H(4) 1334(5) 4400(40) 31 16(12) 27(6) H(6) 1362(5) 6900(40) 4137(1 1 ) 27(6) H(9) 1349(4) 1 1550(30) 2717(1 1) 17(5) H(10) 21 80(5) 14530(40) 3337(1 3) 49(7) H(1 1 ) 2263(5) 15310(40) 4641 (13) 37(7) H(1 2) 2038(6) 13040(40) 5295(1 5) 55(8) H(13A) 1461 (6) 8870(40) 5382(1 2) 39(7) H(13B) 1695(5) 10870(40) 5653(12) 28(6) H(1 5) 2260(5) 9020(40) 5649(1 2) 26(6) H(1 6) 2642(5) 6420(40) 6414(1 2) 37(7) H(17) 251 8(5) 3650(40) 7133(1 2) 32(6) H(1 8) 2024(6) 3390(40) 7058(14) 49(8) H(1 9) 1 631 (6) 5960(40) 6260(13) 49(8) H(21 ) 745(5) 1350(40) 929(1 2) 31 (6) H(24) 1 176(5) 7840(40) -35(1 1) 24(6) H(25) 1 027(5) 8080(40) -1365(13) 36(7) H(26) 690(5) 5440(40) -21 88(14) 33(6) H(27) 507(5) 2370(40) -1 71 9(13) 36(7) H(28A) 441(5) -1120(40) -51(12) 27(6) H(283) 498(5) -1 020(40) -845(1 3) 37(7) H(30) -1 (6) -2160(50) -1575(14) 49(8) H(31) -503(6) -1090(50) -2201 (16) 61(9) H(32) -703(5) 2190(40) -1941 (1 2) 30(6) H(33) -380(6) 4740(50) -993(14) 51 (8) H(34) 1 39(6) 3680(40) -369(1 5) 53(8) 219 Table B 5. Torsion angles for Compound 12. C(2)-N(2)-C(1)-N(1) C(2)-N(2)-C(1)-C(20) C(4)-N(1)-C(1)-N(2) C(4)-N(1)-C(1)-C(20) 0(1)-N(2)-C(2)-C(3) N(2)-C(2)-C(3)-C(4) N(2)-C(2)-C(3)-C(5) 0(1)-N(1)-C(4)-C(3) C(2)-C(3)-C(4)-N(1) C(5)-C(3)-C(4)-N(1) C(2)-C(3)-C(5)-C(6) C(4)-C(3)-C(5)-C(6) C(2)-C(3)-C(5)-C(8) C(4)-C(3)-C(5)-C(8) C(8)-C(5)-C(6)-N(3) C(3)-C(5)-C(6)-N(3) C(7)-N(3)-C(6)-C(5) C(13)-N(3)—C(6)-C(5) C(6)-N(3)-C(7)-C(12) C(13)-N(3)-C(7)-C(12) C(6)-N(3)-C(7)-C(8) C(13)-N(3)-C(7)-C(8) N(3)-C(7)-C(8)-C(9) C(12)-C(7)-C(8)-C(9) N(3)-C(7)-C(8)-C(5) C(12)-C(7)-C(8)-C(5) C(6)-C(5)-C(8)-C(9) C(3)-C(5)-C(8)-C(9) C(6)-C(5)-C(8)-C(7) C(3)-C(5)—C(8)-C(7) C(7)-C(8)-C(9)-C(10) C(5)-C(8)-C(9)-C(10) C(8)-C(9)-C(10)-C(1 1) C(9)-C(10)-C(1 1)-C(12) -30(3) 176.99(19) 1 0(3) -173.94(19) 2.2(3) 02(3) -173.6(2) 1 3(3) -24(3) 176.5(2) 153.3(2) 240(3) 256(3) 155.6(2) 03(2) -173.73(19) -02(2) -176.5(2) 179.3(2) 39(4) 05(2) 175.3(2) -177.99(19) 1 3(3) 09(2) -179.3(2) 177.6(2) 23(4) -1 .1 (2) 173.5(2) -1 5(3) 130.0(2) 04(3) 05(4) 220 (x10){x11)(x12)rx7) hu3)23igma(I)] R1 = 0.0349, wR2 = 0.0905 R indices (all data) R1 = 0.0437, wR2 = 0.0947 Extinction coefficient 0.0007806) Largest diff. peak and hole 0.601 and —0.562 e.A"-3 223 Table C 1. Atomic coordinates and equivalent isotropic displacement for [Zr(dpm)(NM32)2]2. y z U(eq) Zr(l) 2158(1) 3659(1) 1645(1) 17(1) 21(2) 3267(1) 2189(1) 112(1) 18(1) N(1 1) 3148(3) 3609(2) 516(2) 18(1) N(12) 2370(3) 2153(2) 1227(2) 19(1) N(13) 3016(3) 4138(2) 2636(2) 26(1) N(14) 482(3) 4240(2) 1653(2) 27(1) N(Zl) 5010(3) 2253(2) 957(2) 23(1) N(22) 1254(3) 2449(2) -367(2) 22(1) N(23) 3210(3) 924(2) -93(2) 27(1) N(24) 4021(3) 2643(2) -756(2) 27(1) C(1) 5366(4) 3794(3) 1222(2) 24(1) C(2) 85(4) 2006(3) 634(2) 22(1) C(11) 5982(4) 3958(3) 542(3) 31(1) C(12) 6013(4) 4343(3) 1862(3) 33(1) C(21) -1 191(4) 2164(3) 852(3) 33(1) C(22) 172(4) 1062(3) 456(3) 29(1) C(1 1 1) 4021(4) 4065(3) 998(2) 19(1) C(112) 3501(4) 4837(3) 1129(2) 22(1) C(1 13) 2285(4) 4864(3) 709(2) 21(1) C(114) 2099(4) 41 13(3) 336(2) 19(1) C(121) 1109(4) 2191(2) 1283(2) 19(1) C(122) 1010(4) 2303(3) 2015(2) 22(1) C(123) 2230(4) 2306(3) 2434(2) 22(1) C(124) 3039(4) 2207(2) 1937(2) 20(1) C(131) 2893(5) 5036(3) 2744(3) 40(1) C(132) 3902(5) 3807(3) 3254(3) 40(1) C(141) -27(5) 4240(4) 2328(3) 53(2) C(142) 471(4) 4554(3) 1056(3) 35(1) C(211) 5541(4) 2880(3) 1425(2) 23(1) C(212) 6328(4) 2538(3) 2020(3) 29(1) C(213) 6291(4) 1668(3) 1924(3) 32(1) C(214) 5501(4) 1515(3) 1279(3) 28(1) C(221) 200(4) 2502(3) -52(2) 21(1) C(222) -704(4) 2973(3) 490(2) 26(1) C(223) 201(4) 3224(3) -1 108(2) 28(1) C(224) 975(4) 2894(3) 4018(2) 26(1) C(231) 2787(5) 692(3) -868(3) 46(1) C(232) 3323(5) 172(3) 359(3) 38(1) C(241) 5024(6) 2148(4) -980(3) 51(2) C(242) 3898(5) 3428(3) -1 148(3) 36(1) 224 Table C 2. Bond lengths and angles for [Zr(dpm)(NMe2)2]2. Zr(1)-N(l3) Zr(l)-N(l4) Zr(l)-C(l 14) Zr(l)-N(1 1) 21(1)-c024) Zr(l)-N(12) Zr(l)-C(123) Zr(l)-C(l 13) Zr(l)-C(lll) Zr(l)-C(121) Zr(l)-C(122) 21(1)-C(1 12) Zr(2)-N(23) Zr(2)-N(24) Zr(2)-N(21) Zr(2)-N(22) Zr(2)-N(l 1) Zr(2)-N(12) N(ll)-C(l 1 1) N(1 1)-C(1 14) N(12)-C(124) N(12)—C(121) N(l3)-C(l32) N(l3)-C(l3l) N(l4)-C(l4l) N(14)-C(l42) N(21)-C(21 1) N(21)—C(214) N(22)—C(221) N(22)—C(224) N(23)-C(232) N(23)-C(23l) N(24)—C(242) N(24)-C(24l) C(1)