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LIBRARY
Michigan State
University

 

 

 

This is to certify that the
dissertation entitled

ROLE OF TITANIUM IMIDO IN C—N BOND
FORMATIONIMECHANISM AND SYNTHESIS OF
PYRROLES AND SECONDARY ALLYLIC AMINES

presented by
BALA RAMANATHAN

has been accepted towards fulfillment
of the requirements for the

Ph. D degree in CHEMISTRY

Major Professor’s Signature
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Date

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ROLE OF TITANIUM IMIDO IN C—N BOND FORMATION: MECHANISM AND
SYNTHESIS OF PYRROLES AND SECONDARY ALLYLIC AMINES

By
BALA RAMANATHAN

A DISSERTATION
Submitted to
Michigan State University
in partial fulfillment Of the requirements
for the degree of

DOCTOR OF PHILOSOPHY
Department of Chemistry
2007

PIT

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ABSTRACT

ROLE OF TITANIUM IMIDO IN C—N BOND FORMATION: MECHANISM AND
SYNTHEIS OF PYRROLES AND SECONDARY ALLYLIC AMINES

By
BALA RAMANATHAN

The initial part of the thesis will focus on a new methodology for the synthesis of
pyrroles via hydroamination of diynes, catalyzed by titanium. The diynes include
terminal and internal diynes. The catalysts used for this were pyrrole—based chelating
dipyrrolyl ligands based on N, N ’-di(pyrrolyl-0t-methyl)-N-methylamine (dpma) and 5,5—
dimethylpyrrolylmethane (dmpm) catalysts. Attempts have been made to synthesize
vinylpyrroles as an extension of the work on hydroamination chemistry. The Diels-Alder
chemistry of these vinylpyrroles was also investigated.

Another aspect of titanium imido chemistry that this thesis will focus on, in the latter
stages, is the synthesis of secondary allylic amines starting from primary allyl alcohols
and primary aromatic amines. A library of compounds was synthesized showing the
versatility of this methodology. An unusual reaction with homoallylic alcohol will also be
presented. Trace amount of product formation in the reaction of 2-methyl-2-propen-l-ol
with Ti(NMe2)4 combined with the kinetic data suggests a [2+2]-cycloaddition/retro-
[2+2]-cycloaddition transition state for the. Kinetic isotope effects were probed and

compared to data obtained fi'om DFT (Density Functional Theory) calculations.

Dedicated to my family and my fiance, Medha

iii

ACKNOWLEDGEMENTS

I would like to thank Michigan State University for their generous support. The
writer gratefully appreciates the support of the Department of Chemistry for a Brubaker
Fellowship, as well as the use of instruments and laboratory space. A special mention to
my Mom, Dad and my sisters without them I would not have landed in USA for graduate
school. To my fiance, Medha who was always there for me and I look forward to
spending the rest of my life.

I have so many people to thank during my stay in Michigan State University.
Thanks to Bob Rasico, Melissa Parsons, and Bill Flick for taking care of the request and
helping me take care of the lab. Special thanks to Dan Holmes for allowing me use the
NMR for long blockage time and with the kinetic measurements. Also I would like to
mention Glenn Wesley and Tom Bartlett in the Machine shop; Scot Sanderson and Dave
Cedarstaff in the Electronics sh0p; Tom Geissenger in Stores; Karen Maki, Beth McGaw
and Cindy Sanford in the Business Office; Nan Murray; Wendy Tsuji, Steve Poulios;
Debbie Roper and Lisa Dillingham for her crucial help when it was desperately needed.

Last but not the least, a special thanks to Aaron, for his understanding, patience
and constant support throughout my research and also helping with the thesis. He has
always been there to help me whenever I needed it, especially during my initial years.
Thanks to Milton Smith III and Babak Borhan for serving in my committee for and
listening and putting things into perspective. A special mention to Robert Maleczka for
being on this committee and his generous donation of Formula One tickets over the years.
Even though we disagree in the support to our teams during the race, we agree in our

passion for racing.

iv

 

 

 

 

To my labmates Sanjukta, Supriyo, Doug, Steve, Eyal and Kapil for putting up
with me. The group will always be special and the fun time will be sorely missed. A
special thanks to Eyal for helping me with my thesis. Thanks to all the exceptionally
good undergraduates whom I have worked with especially Adam Keith, Karthik, P and
Kevin Gipson. There have been so many people whose names have not been mentioned,

without their help this PhD would not have been possible, and to them I apologize.

 

 

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TABLE OF CONTENTS

LIST OF SCHEMES ........................................................................................................ viii
LIST OF FIGURES ........................................................................................................... xi
LIST OF TABLES ........................................................................................................... xiv
LIST OF ABBREVIATIONS ........................................................................................... xv
1. INTRODUCTION TO HYDROAMINATION .......................................................... 1
1.1 Introduction ............................................................................................................... 1
1.2. Hydroamination using mercury ............................................................................... 4
1.3 Hydroamination using lanthanides and actinides ..................................................... 5
1.4 Hydroamination using ruthenium and rhodium ........................................................ 6
1.5 Hydroamination using Group(IV) complexes .......................................................... 7
1.5.1 Zirconium ........................................................................................................... 7
1.5.2 Titanium ............................................................................................................. 8

1.6 Research in the Odom group ................................................................................... 11
1.7 Conclusion .............................................................................................................. 16
1.8 References ............................................................................................................... 17

2. HYDROAMINATION OF DIYNES ....................................................................... 19
2.1 Introduction ............................................................................................................. 19
2.2 Aim of the project ................................................................................................... 20
2.3 Baldwin Rules for Ring Closure ............................................................................. 22
2.4 Synthesis and hydroamination of 1,4-diynes .......................................................... 23
2.4.1 Synthesis .......................................................................................................... 23
2.4.2 Hydroamination of 1,4-Diynes ............................................................................ 24
2.5 Synthesis and hydroamination 1,5—diynes .............................................................. 27
2.5.1 Synthesis of 1,5-diynes .................................................................................... 27
2.5.2 Hydroamination of 1,5-diynes ......................................................................... 28

2.6 Mechanism of diyne hydroamination ..................................................................... 28
2.6.1 Cyclization of 1,4-diynes ................................................................................. 28
2.6.2 Cyclization of 1,5-diynes ..................................................................................... 31
2.7 Three component couplings with diynes ................................................................ 31
2.8 Vinylpyrroles .......................................................................................................... 32
2.8.1 Proposed route ................................................................................................. 32
2.8.2 Synthesis and hydroamination of of enediyne ..................................................... 33
2.8.3 Hydroamination of enediynes .............................................................................. 33
2.9 Summary ................................................................................................................. 33
2.10 General Procedures ............................................................................................... 37
2.11 Experimental Section ............................................................................................ 38
2.12 References ............................................................................................................. 49

vi

 

 

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3.

ALLYLIC AMINE: SYNTHESIS & MECHANISM INVESTIGATION .............. 53
3.1 Introduction to allylic amines ................................................................................. 53
3.2 Conclusion .............................................................................................................. 66
3.3 References ............................................................................................................... 67

SYNTHESIS OF ALLYLIC AMINES .................................................................... 70
4.1 Introduction ............................................................................................................. 70
4.2 Synthesis of library of allylic amines ...................................................................... 71

4.2.1 Reaction with allyl alcohol (44) ....................................................................... 71

4.2.2 Reaction with 2-methyl-3-buten-2-ol (74) ....................................................... 72

4.2.3 Reaction with E:Z-2-buten-1-ol (78) ............................................................... 73

4.2.4 Reaction with 3-buten-2-ol (81) ....................................................................... 73

4.2.5 Reaction with 2-phenyl-3-buten-2-ol (84) ....................................................... 74

4.2.6 Reaction with 2-phenyl-2-propen-1-ol (87) ..................................................... 75

4.2.7 Reaction with 3-phenyl-2-propen-1-ol (90) ..................................................... 75

4.2.8a Reaction with 3-methyl-2-buten-1-ol (92) ..................................................... 75

4.2.8b Reaction with 2-methyl-2-propen-1-ol (93) ................................................... 76
4.3 Discussion of mechanism for reaction of allyl alcohol to allylic amine ................. 77
4.4 Reaction with homoallylic alcohol ......................................................................... 79
4.5 Mechanism for conversion of homoallylic alcohol (97) to 1-azaspiro-[5.5]-
undecane (98) ................................................................................................................ 81
4.6 Explanation for alkyl migration in homoallylic alcohol ......................................... 83
4.7 Evidence against alkyl migration in homoallylic alcohol ....................................... 84
4.8 Reaction with n-butanol .......................................................................................... 87
4.9 Reaction with TiCl4 (108) ....................................................................................... 87
4.10 General Methods ................................................................................................... 89
4.11 Experimental Section ............................................................................................ 91
4. 12. References .......................................................................................................... l 19

KINETIC ISOTOPE EFFECT ................................................................................ 121
5.1 Introduction ..................................................... 121
5.2 Kinetic Isotope Effect (KIE) ................................................................................. 122

5.2.1 Introduction to KIE ........................................................................................ 122

5.2.2 KIE in Cope and Claisen rearrangement ....................................................... 126
5.3 Computational studies ........................................................................................... 131

5.3.1 Bigeleisen Equation ....................................................................................... 131

5.3.2 Initial studies .................................................................................................. 132

5.3.3 Initial KIE experimental results ..................................................................... 133
5.4 Computational studies in the rhenium case .......................................................... 135
5.5 Need for a model titanium imido system .............................................................. 139
5.6 Ti-imido alkoxide complex-SKIE results ............................................................. 139
5.7 Comparison to vanadium imido complex ............................................................. 146
5.8 Summary ............................................................................................................... 149
5.9 General Methods ................................................................................................... 150
5.10 Experimental Section .......................................................................................... 152
5.11 References ........................................................................................................... 170

vii

LIST OF SCHEMES

Scheme 1.1. Alkyne hydroamination .................................................................................. 1
Scheme 1.2. Thermodynamic data comparing hydroamination of ethylene by ammonia or
ethylamine. .......................................................................................................................... 2
Scheme 1.3. Hydroamination of a terminal alkyne with Hg salt. ....................................... 4
Scheme 1.4. Intra- and intermolecular hydroamination of alkynes catalyzed by
lanthanides. ......................................................................................................................... 5
Scheme 1.5. Bergman’s mechanism for hydroamination of alkynes .................................. 8

Scheme 1.6. First example of an attempted hydroamination of 3-hexyne with titanium-

imido complex. ................................................................................................................... 9
Scheme 1.7. Synthesis of (i)-monomorine via a [2+2]-cycloaddition pathway. ............. 10
Scheme 1.8. Group(IV) metals with amidate ligand ......................................................... 11
Scheme 1.9. Synthesis of Ti(dpma)(NMe2)2 (6). .............................................................. 13
Scheme 1.10. Synthesis of Ti(dmpm)(NMe2)2 (10) .......................................................... 14
Scheme 1.11. Proposed three-component coupling mechanism ....................................... 16
Scheme 2.1. Proposed scheme for hydroamination of 1,4- and 1,5-diynes. ..................... 21
Scheme 2.2. Baldwin’s rules for ring closure in 3- to 7-membered rings. ....................... 23
Scheme 2.3. Synthesis of 1,4-diynes. ............................................................................... 24
Scheme 2.4. Hydroamination of 1,4-pentadiyne (16) by aniline (2) and benzylarnine (Z).
........................................................................................................................................... 4
Scheme 2.5. Hydroamination of 1-phenyl-l,4-hexadiyne (23) by 2, 7, and 24 ................ 27
Scheme 2.6. Gevorgyan’s cyclization of 1-imino-2-alkynes catalyzed by copper. .......... 29

Scheme 2.7. Synthesis of 26 using Pd-catalyzed procedure from methyl vinyl ketone. .. 34

viii

Scheme 3.1. Overman’s procedure for converting allyliv alcohols to allylic amines via

1,3-allylic transposition ..................................................................................................... 54
Scheme 3.2. Graselli’s radical pathway mechanism ......................................................... 55
Scheme 3.3. Proposed pathway for Chan’s rearrangement. ............................................. 56

Scheme 3.4. Osbom’s molybdenum catalyst and a [3,3]-sigmatropic rearrangement. 59

Scheme 3.5. Proposed mechanism for the use of vanadium oxo catalyst in isomerisation

of allyl alcohol. ................................................................................................................. 60
Scheme 3.6. Use of 59 to convert 46 into 60 and 61 via allylic transposition .................. 61
Scheme 3.7. Osbom’s rhenium catalyst (62) for 1,3-allylic transposition. ...................... 62

Scheme 3.8. Conversion of tertiary to primary allylic alcohols using 64 and BSA. ........ 63

Scheme 3.9. Reaction of zirconium imido complex (68) to give allylic amines via 8N2,
allylic substitution. ............................................................................................................ 65

Scheme 4.1. Proposed methodology for allylic amination of 44 by 2 mediated by 1. ..... 70

Scheme 4.2. Possible route for rearrangement via [3,3]-sigmatropic and [2+2]-

cycloaddition/retro-[2+2]-cycloaddition pathway. ........................................................... 77
Scheme 4.3. Proposed [2+2]-cycloaddition/retro-[2+2]-cycloaddition pathway for the
titanium chemistry through transition state 96 .................................................................. 78
Scheme 4.4. Replacing methyl by phenyl in 93 enhances reactivity. ............................... 79
Scheme 4.5. Literature procedure for synthesis for 1-azaspiro-[5.5]undecane. ............... 82
Scheme 4.6. One possible mechanism for the formation of 100. ..................................... 82

Scheme 4.7. Mechanistic explanation for the formation of 80 in the reaction between 78
and 2 by 1. ......................................................................................................................... 85

Scheme 5.1. Proposed [3,3]-sigmatropic transition state for a Claisen rearrangement. . 126
Scheme 5.2. Preparation of deuterated allyl alcohols 111, 112 and 113 for SKIE .......... 133

Scheme 5.3. Comparison of SKIE from reaction between 1, deuterated alcohol 111 and 2
with reaction of 1, alcohol 74 and 2 ................................................................................ 134

ix

 

 

 

Scheme 5.4. Comparison of SKIE from reaction between 1, deuterated alcohol 112 and 2

with reaction of 1, alcohol 74 and 2. ............................................................................... 134
Scheme 5.5. Comparison of SKIE from reacion between 1, deuterated alcohol 113 and 2
with reaction of 1, alcohol 74 and 2 ................................................................................ 135
Scheme 5.6. Osborn’s catalyst favors the [3,3]-sigmatropic transition state. ................. 138
Scheme 5.7. Planned synthesus of titanium system for SKIE studies. ........................... 140
Scheme 5.8. Proposed scheme for the synthesis of titanium-imido complex ................. 141
Scheme 5.9. SKIE of 0.5 for deuteration in the two position of allyl alcohol. ............... 146
Scheme 5 .10. Proposed synthesis of vanadium complex 128. ....................................... 147

Scheme 5.11. Reaction of thallium derivative of dipyrrin with vanadium complex 128.
......................................................................................................................................... 148

LIST OF FIGURES

Figure 1.1 Yttrium diamidoamine, ATI and Scandium catalyst. ........................................ 6
Figure 2.1. Pyrrole core structure in NSAIDs and natural products. ................................ 21
Figure 2.2. Structure of Vinylpyrroles 39 and 40. ............................................................. 33
Figure 2.3. Structure of 1—phenyl-2-butyl-5-methylpyrrole (l9) ...................................... 38
Figure 2.4. Structure of 1-benzyl-2-butyl-5-methylpyrrrole (20) ..................................... 39
Figure 2.5. Structure of 1-phenyl-2-benzyl-5-methylpyrrole (25) .................................... 40
Figure 2.6. Structure of 1,2-dibenzyl-5-methylpyrrole (26) ............................................. 42
Figure 2.7. Structure of 1-(4-methoxybenzyl)-2-benzyl-5-methylpyrrole (27) ................ 43
Figure 2.8. Structure of 1-phenyl-2,5-dimethylpyrrole (30) ............................................. 44
Figure 2.9. Structure of 1-benzyl-2,5-dimethylpyrrole (31) ............................................. 45
Figure 2.10. Structure of 1-phenyl-2,5-dibenzylpyrrole (32) ........................................... 46
Figure 2.11. Structure of l-cyclohexenyl-l ,4-pentadiyne (42) ......................................... 47
Figure 3.1. Structure of Terbinafine, Naftidine, Haouamine and Narciclasine. ............... 53
Figure 4.1. 3-methyl-2-buten-1-ol (92) ............................................................................. 76
Figure 4.2. 2-methyl-2-propen-1-ol (93). ......................................................................... 76
Figure 4.3. Structure of (-)-Histrionicotoxin .............................................. ' ....................... 80
Figure 4.4. Example of a 4-membered transition state with titanium ............................... 82
Figure 4.5.Structure of N-phenylallylamine (71) .............................................................. 91
Figure 4.6 Structure of N-benzhydryl-N—allylamine (72). ................................................ 92
Figure 4.7. NMR spectra for compound (72). .................................................................. 93
Figure 4.8. Structure of N-cyclohexyl-N—allylarnine (73). ................................................ 94

xi

 

 

 

 

Figure 4.9. Structure of N-(3-methylbut—2-enyl)aniline (75). ........................................... 95

Figure 4.10.Structure of N-(3-methylbut-2-enyl)-N-benzhydrylamine (76) ..................... 96
Figure 4.11. NMR spectra for compound 76. ................................................................... 97
Figure 4.12. Structure of N—(3-methylbut-2-enyl)-N-cyclohexylamine (77). ................... 98
Figure 4.13. Structure of N—(but-3-en-2-yl)aniline (79) .................................................... 99
Figure 4.14. NMR spectra for compound 79. ................................................................. 101
Figure 4.15. Structure of N-(but-2-enyl)aniline (81). ..................................................... 102
Figure 4.16. NMR spectra for compound 81. ................................................................. 104
Figure 4.17. Carbon spectra for compound 81. .............................................................. 105
Figure 4.18.Structure of N-(but-2-enyl)-N-cyclohexylamine (83). ................................ 106
Figure 4.19. Structure of N—(3-phenyl-2-butenyl)aniline (85). ....................................... 107
Figure 4.20. Structure of N-(3-phenyl-2-butenyl)-N-benzhydrylamine (86). ................. 109
Figure 4.21. Structure ofN-(2-methyla11yl)aniline (88). ................................................ 111
Figure 4.22. Structure of N-(2-methylallyl)cyclohexylamine (89). ................................ 112
Figure 4.23. Structure of N—(l-phenylallyl)aniline (90) .................................................. 113
Figure 4.24. NMR spectra for compound 90. ................................................................. 114
Figure 4.25. Structure of 1-azaspiro[5.5]-undecane (96). ............................................... 115
Figure 4.26. Structure of 1-azaspiro-2,2-2H-[5.5]-undecane (97). ................................. 116
Figure 4.27. Structure of N-phenyl-3,3-2H-allylamine (so). .......................................... 117
Figure 4.28. Structure of N-(2-methyl-2-propen-3,3-2H)aniline (95) ............................. 118
Figure 5.1. Vibrational energy levels and transitions for a diatomic molecule. ............. 124
Figure 5.2. Streitwieser hybridization model for bending motion. ................................. 125
Figure 5.3. More 0’ Ferrall-Jencks diagram for Claisen rearrangement of AVE. ......... 127

xii

Figure 5.4. More O’Ferrall-Jencks diagram for Cope rearrangement substitution pattern.

......................................................................................................................................... 129
Figure 5.5. Energy diagram comparing transition state for BCH and 1,5-hexadiene..... 130
Figure 5.6. SKIE values for rhenium system. ................................................................. 136
Figure 5.7. Kinetics with titanium imido alkoxide 116. ................................................. 143
Figure 5.8. Proof of 1St order kinetics, plot of lnlY - Yind versus time ............................ 144
Figure 5.9. Structure of 2-methyl(O,4,4-2H)but-3-en-2-ol (111) .................................... 152
Figure 5.10. Structure of 2-methyl(O,3,4,4-2H)but-3-en-2-ol (112) ............................... 153
Figure 5.11. Structure of 2-methyl(3-2H)but-3-en-2-ol (113). ....................................... 154
Figure 5.12. Structure of (2-methylbut-3-en-2-olate) thallium (I) (120). ....................... 155
Figure 5.13. Structure of (2,3-dimethylbut-3-en-2-olate) thallium (I) (124). ................. 155
Figure 5.14. Structure of bis(2-methyl-3-buten-2-alkoxide)(phenylimido)titanium (IV)
(116). ............................................................................................................................... 157
Figure 5.15. Structure of bis(2,3-dimethyl-3-buten-2-alkoxide)(phenylimido)titanium
(IV) (125). ....................................................................................................................... 158
Figure 5.16. Structure of bis(2-methyl-3-buten-3-2H-2-alkoxide)(phenylimido)titanium
(IV) (126). ....................................................................................................................... 159
Figure 5.17. Run 1 for comound 116. ............................................................................. 163
Figure 5.18. Run2 for comound 116. .............................................................................. 164
Figure 5.19. Run 3 for comound 116. ............................................................................. 165
Figure 5.20. Run 1 for comound 126. ............................................................................. 166
Figure 5.21. Run 2 for comound 126. ............................................................................. 167
Figure 5.22. Run 3 for comound 126. ............................................................................. 168
Figure 5.23. Run 1 for comound 125. ............................................................................. 169

xiii

 

 

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LIST OF TABLES

Table 2.1. Results for hydroamination of 1,4- and 1,5-diynes with aromatic amines ...... 36

Table 3.1. Comparison of some early transition metal catalysts for 1,3 allylic

transposition. ..................................................................................................................... 64
Table 4.1. Library of allylic amines synthesized using our methodology ........................ 86
Table 4.2. Reaction of titanium substrates with n-butanol (105) ...................................... 87
Table 5.1. Comparison of computational KIE and experimental KIE ............................ 135
Table 5.2. DF T calculations on rhenium allyl and 2-methyl allyl case. ......................... 137

Table 5.3. Comparison of SKIE in 3-methyl-1,5-hexadiene via experiments and
calculations (restricted Hartree-Fock) ............................................................................. 138

xiv

NMP

dpma

dppm
dap
PMB
NSAID
COX
DMP
DMSO
DMAD

AVE

ATI
Ind
SOHIO
BCH
DF T

HMDS

LIST OF ABBREVIATIONS

N-methyl pyrrolidine
Di(pyrrolyl—or-methyl)methylamine
5,5-Dimethylpyrrolylmethane
5,5-Di-n-propyldipyrrolylmethane
(x-(Dimethylaminomethyl)pyrrole
p-Methoxybenzylamine
Non-steoridal anti-inflammatory drugs
cyclooxygenase

Dess-Martin Periodinane
Dimethylsulfoxide
Dimethylacetylenedicarboxylate
Allyl vinyl ether

ns-MesCs

nS-MertCs

Aminotroponiminate

Indenyl

Standard Oil of Ohio
Bicyclohexane

Density Functional Theory

Hexamethyldisiloxane

XV

 

 

 

 

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1. INTRODUCTION TO HYDROAMINATION

1.1 Introduction

Hydroamination is the formal direct addition of an N—H bond across a C—C multiple
bond. Hydroamination of alkynes is a desirable transformation in organic chemistry from
a synthetic point of view as the products are important bulk chemicals, fine chemicals,
and building blocks in organic chemistry. This reaction is of potential industrial
importance because every year several million tons of various amines are produced
worldwide, and 90% of pharmaceutical products have C—N bonds (Scheme 1.1).1 The
hydroamination reaction is atom economical with 100% atom efficient; therefore,
efficient hydroamination processes offer significant economical and environmental
benefits compared to classical methods2 for the synthesis of the mentioned target
compounds. From a thermodynamic point of View, addition of amines or ammonia across
alkynes and olefins is possible since the corresponding reactions are often exothermic to
therrnoneutral. In this thesis, we will be concerned with primary amine addition to
alkyne, which yields enamines or imines.

One could obtain imines by the addition of primary amines to ketones, but in cases
where ordinary Schiff base condensation is not possible, hydroamination is advantageous.

R3

’R3 N'R4
R1-——: R2 + H"N\ _ Enamine

R4 R1 R2

R1 R2

 

 

for
R4 = H
NR3

 

Imine

Scheme 1.1. Alkyne hydroamination.

 

 

 

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To illustrate this fact, two representative sets of thermodynamic data for the reactions
of ammonia and ethylamine with ethylene are presented in Scheme 1.2.3 Comparison
between thermodynamics of amine addition to alkynes versus that to alkenes is not
possible. However, addition of ammonia to acetylene is estimated (AMI-semiemperical
calculations) to be ~63 kJ mol'1 more exothermic than that to ethylene.1 By regarding this
estimation, the hydroamination of alkynes should be thermodynamically more favorable

than the corresponding hydroamination of alkenes.

AG° = - 14.7 kJ mor1

NH2 AH° = - 52.7 kJ mol-1
= + NH3 —*~—— —/ As°=-127.3Jmor1K-1
NHEt
= + EtNH2_“~—-

AG° = - 33.4 kJ mol-1
AH° = - 78.7 kJ mol"
AS° = - 152.2 J mol‘1 K"

Scheme 1.2. Thermodynamic data comparing hydroamination of ethylene by ammonia or
ethylamine.4

A high activation barrier exists for the direct addition of amines across C—C multiple
bonds, which arises from electrostatic repulsion between the lone pair at the nitrogen
atom and the electron rich n-bond of the alkyne or alkene. However, one cannot achieve
uncatalyzed hydroamination by increasing the temperature because of the negative
reaction entropy, AS° of the amine addition; the equilibrium of the reaction shifts back to
the reactants with increasing temperature.4

In contrast to the hydroamination of alkenes, which yields amines, the hydroamination

of alkynes gives enamines and imines. These imines and enamines can be reduced by

 

 

 

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q
l

 

standard organic procedures to give amines, if those are the desired products. Alkenes are
inexpensive compared to alkynes but the hydroamination of unactivated alkenes is a
challenging and largely unsolved problem. Great progress, however, has been achieved in
developing hydroamination procedures for unactivated alkynes in the last two decades.
Since the above mentioned thermodynamic data suggest that hydroamination of alkynes
is easier than that of alkenes, it is reasonable to develop efficient catalytic
hydroamination protocols for alkynes first and subsequently apply the obtained
knowledge to the related procedures for alkenes. In this context, one could say that
hydroamination of alkynes can be seen as a basis for future hydroamination of alkenes.
Some of the preliminary investigations in this field are highlighted and will be discussed
before moving on to Group(IV) hydroamination chemistry.

Howk discovered one of the earliest examples of hydroamination reactions in 1954,
wherein ammonia and primary amines add to alkenes in the presence of alkali metals or
their hydrides, but the reaction typically requires harsh conditions (175-200 °C, 800-1000
atm).5 The yields were poor and the reaction oflen contained a mixture of mono and
multiple hydroaminated products. Pez reported several alkali metal-amide catalyzed
addition of diethylarnine and ammonia to ethylene and propylene at 101 °C.6 Although
only 1 mol% of the catalyst was required, over 100 atm of pressure was employed
limiting the use of this methodology. One of the earliest protocols for hydroamination of
alkynes comes from the Kruse group, wherein ammonia adds across acetylene at 300-350
°C in the presence of silica or alumina catalysts.7

Hydroamination of alkynes can either be an intramolecular or intermolecular reaction,

the latter one being the more difficult of the two. This is due to a net entropy decrease for

the intermolecular process relative to an intramolecular one even though both processes
involve a decrease in entropy.3
There are a number of different transition and main group metals used for

hydroamination including mercury,8 alkali metals,9 lanthanides, actinides,‘°"2

8 21

ruthenium,l7 rhodium,i zirconium, palladium,‘9 gold,20 and titanium.23 To place
titanium-catalyzed reactions in context, a brief discussion of representative
hydroamination catalysts is provided.
1.2. Hydroamination using mercury

Mercury complexes catalyze reactions involving terminal alkynes. Hudrlik, reported a

low yield of the hydroamination product; an aziridine enamine, from the reaction of 1-

octyne and aziridine in presence of mercuric acetate as the catalyst (Scheme 1.3).8

N
N I
\ 00
W + HT) 10 m0|/ Hg(OAC)2> M + N

 

 

\L benzene. 020 1

Scheme 1.3. Hydroamination of a terminal alkyne with Hg salt.
1.3 Hydroamination using lanthanides and actinides

Markslo provided the first example of an intramolecular hydroamination of amino
alkynes catalyzed by the organolanthanides Cp'anCH(SiMe3)2 (Ln = La, Nd, Sm, Lu;

Cp' = ns—MesCs) and MeZSiCp"2LnCH(SiMe3)2 (Ln = Nd, Sm; Cp" = 05—Me4C5). This

offers a new route to heterocycles and natural product skeletons. The catalysts also
perform intermolecular hydroamination of internal alkynes with primary amines
producing imines in high yields (Scheme 1.4). The temperature for the reactions ranged

from 20-60 °c.”

R

 

 

 

HzN ) 10 mol% Cp'anCH(SiMe3)L Kiri)
) m r
R : C6H6 m
__ 10% Cp'anCH(SiMe3)L R/Y
R — + /\/NH2 7 N
C6H6 \/\
R: ms, Ph. Me 85-90%

Scheme 1.4. Intra- and intermolecular hydroamination of alkynes catalyzed by
lanthanides.

Roesky“2 reported the synthesis of mono- and bis(N-iso-propyl)-2-(iso-propylamino
troponiminato)yttrium amides, [(‘Pr)2ATI]Y[1\I(SiMe3)2]2 and [(‘Pr)2ATI]2Y[N(SiMe3)2]
(ATI = Aminotroponiminate) catalysts for the intramolecular hydroamination of or,a)-
amino alkyne. An yttrium-based catalyst for the intramolecular hydroamination of
alkenes and alkynes has been developed by Hultzch.l3 A scandium-based cationic
catalyst, used by Schafer, has also found application in the intramolecular
hydroamination of alkynes.l4 The structure of these catalysts is shown in Figure 1.1

Some aspects of catalyzed actinide hydroamination were introduced by Eisen,
providing the first example of catalytic intermolecular hydroamination of terminal

alkynes with aliphatic amines using actinides, i.e. thorium and uranium.15

 

 

 

tn

LL?

  
  

Ar

N~ Y’N(SIM83)2
N/ \N(S|Me3)2 (C (22“)Y N(SiMe3)2 '---N\ CH3B(C6F5)3
' S

Y

/N \Ar [if
N _ A =
CN - .:NH2 r

Yttrium catalyst with ATI Scandium catalyst

I

‘---N CH3

Mes THF

MesN
(\N’ , -N(SiHMe2)2

<41.

Me
Hultzsch's diamidoamine yttrium catalyst

Figure 1.1 Yttrium diamidoamine, ATI and Scandium catalyst.
1.4 Hydroamination using ruthenium and rhodium

Uchimaru showed that phenylacetylene reacts with N-methylaniline in the presence of
Ru3(CO)12 to afford N-methyl-N-(or-styryl)aniline in high yields. ‘6 Wakatsuki showed that
hydroamination of phenylacetylene with aromatic amines catalyzed by Ru3(CO)12 gave
imines in the presence of additives like NH4PF6 and HBF4.l7

An example of a cationic version of the rhodium catalyst comes from the Beller group,
where hydroamination of terminal alkynes with substituted anilines is carried out in the
presence of rhodium(l) catalyst, [Rh(COD)2][BF4] under very mild conditions to yield up

to 99% of the corresponding imines.18

1.5 Hydroamination using Group(IV) complexes

1.5.1 Zirconium

An early example of a isolated zirconium—imido complex came from Wolczanski and
Bergman groups.19 In 1992, Bergman reported that the zirconium bis(amide) complex
Cer(NHR)2 catalyze the intermolecular hydroamination of internal alkynes with

sterically hindered primary amines to give enamines or their tautomeric imines (Equation

 

 

1.1).20
3mo|°/ c rNHAr HAr
Ph 2 Ph + ArNH2 ° p22 ( )2= F8 (1-1)
06H6,120°C
Ar = 2,6—dimethylphenyl Ph Ph
60%

A transient imido-complex, CpZZr=NAr is obtained by thermolysis of the bis(amide)
complex, which then undergoes a reversible [2+2]-cycloaddition with the internal alkyne
to provide an azametallacyclobutene (Scheme 1.5). Further, the metallacyclobutene reacts
with the amine to form the enamine and Cp2Zr=NAr, beginning the catalytic cycle again.
The metallacyclobutene was isolated and characterized. Reaction of unsymmetrical
alkynes with CpZZFNAr occurs regioselectively to give a metallacycle, with the larger
alkyne substituent located a to the metal center. Hydrolysis of the metallacycle then
gives enamines and imines, which are the net result of anti-Markovnikov addition to the

alkyne.

 

 

 

n\u

ll;

1“ _

 

CpZZr(NHAr)2 ——- [Cp22r=(NAr)] + ArNH2

I": _ NHAr Ph———: H
Ph H

Ar\

H \
N N
0923/1 CpZZr// H
\ Ph
NHAr
Ph
ArNHz

Scheme 1.5. Bergman’s mechanism for hydroamination of alkynes.

Drawbacks of this reaction include slow rate and limitation to disubstituted alkyne
substrates. Additionally, attempts to hydroarninate olefins such as ethylene, allylbenzene
and norbomene with Cp22r(NHR)2 and corresponding amines at higher temperatures
were unsuccessful. In 1993, hydroamination of terminal alkynes with Cp22r(NHR)2,

which, predominantly gave the anti-Markovnikov product was published by Bergman. 2'

1.5.2 Titanium

Titanium is the second most abundant transition metal in the earth’s crust after iron
and ninth overall.22 The earliest example of a titanium-catalyzed hydroamination was
provided by Rothwell, wherein bis(phenylarnido) titanium (IV) complex hydroaminated
3-hexyne by aniline.23 The titanium imido complex does not show any evidence of
hydroamination with 3-hexyne even after heating at 110 °C for days (Scheme 1.6). This

is the also the first example of an isolated terminal titanium imido complex.

 

 

 

 

 

‘ (/.‘
r

\\ ';-

 

"ArOz,, ,Ph 2NH2Ph > "ArOz., _/NHPh

 

 

T1 T
.. I \ I
NO P“ "Aro’ \NHPh
Ar" = i-Pr2C6H3
2W
liY'
/ \ "Aroln’lo.. .—
._ I—NHPh
py'
py‘
__ "A o ...,,, heat
L: . "Aio"'l‘:”“"“ = NR
py'

Scheme 1.6. First example of an attempted hydroamination of 3-hexyne with titanium-
irnido complex.

Livinghouse provided other examples of a titanium-catalyzed hydroamination,
wherein CpTiCl; catalyzed the intramolecular hydroamination of y—aminoalkyne (Scheme
1.7).24 This intramolecular hydroamination results in an imidotitanium-alkyne [2+2]-
cycloaddition, which is used in the synthesis of the indolizidine alkaloid (:1:)-
monomorine. A pyrrolidine alkaloid, (+)-preussin, was also synthesized using the

imidotitanium—alkyne [2+2]-cycloaddition methodology described above.25

 

 

 

 

 

 

 

””2 . TL
JZO mFoI°/':>J CpTiC|3 (:t)-monomorine
/—\ t3
" 13 steps
_ HN ,
o "0 '=
\
IDIBAL-H. THF
I
' N
o "O

 

 

 

Scheme 1.7. Synthesis of (:lz)-monomorine via a [2+2]-cycloaddition pathway.

In 1999 Doye published an intermolecular hydroamination of alkynes and aromatic
amines with commercially available szTiMez to give amines, obtained by reduction of
enamines and imines, in relatively good yield of 65-80%.26 The mechanism for this
hydroamination follows Bergman’s mechanistic pathway. Doye also reported an
intramolecular hydroamination followed by cyclization of aminoalkynes to give five- and
six-membered cyclic imines using szTiMez as a catalyst. 27 The imines can subsequently
be reduced with sodium borohydride and zinc chloride at room temperature to give
amines in 70-85% yield. A highly active IndzTiMez catalyst for the intermolecular

hydroamination of terminal and internal alkyne was reported recently (Ind = Indenyl).28

10

 

 

 

 

{/7
r—.

 

 

The major product of hydroamination of terminal arylalkynes is always the anti-
Markovnikov product, whereas alkylalkynes react with arylamines to give the
Markovnikov product. In 2002 Richeson developed a Ti(IV) terminal imido complex
possessing guanidinate ancillary ligands, which catalyzes the intermolecular

hydroamination of alkynes.29

 

 

Ackermann published a catalytic intermolecular hydroamination of internal alkynes by

TiCl4.3° This methodology is tolerant to halide substituent on the aromatic ring of the

 

aniline, allowing expansion of this process in a one-pot synthesis of substituted indoles. .
Schafer reported the preparation and characterization of amidate complexes of both J

titanium and zirconium and their application as catalysts for the intramolecular

hydroamination of alkynes.3 I The catalysts were prepared from reacting amide proligands

with Ti(NMe2)4 and Zr(NMe2)4 (Scheme 1.8).

 

i toluene, heat, 14 h _ xNRZ
J< "' MINRZN T R ’\ M\NR
R Pi 2

M=Ti, Zr
R = Et, Me

Scheme 1.8. Group(IV) metals with amidate ligand.

1.6 Research in the Odom group
Early research in our lab was aimed towards the use of non-cyclopentadienyl system
for hydroamination of alkynes. We were the first group to report the use of Ti(NMe2)4 (l)

as a catalyst for hydroamination of alkynes with primary amines such as aniline (2).32

11

 

 

A

v...

The hydroamination reaction predominantly gave the Markovnikov addition product,

which is in contrast to MezTisz (Equation 1.2).

10% Ti(NMezl4 (1L xN-A' if” (1 2)
. - + ,/K,R '
toluene, 75 C R' R R

R, R' = (Bun. H): (EL 51): (Ph. H); (Ph- Ph) For R' = H : Markovnikov anti-Markovnikov

 

 

R : R' + 3ArNH2

The ratio of Markovnikovzanti-Markovnikov products varied from 3:1 to >50:1 with
the different substrates examined. The hydroamination is fast and proceeds to completion
two hours for 1-hexyne (3). For internal alkynes like 3-hexyne (4), reaction times are
longer.

We examined the possibility of a use of pyrrole-based ligand on titanium. The
aromatic stabilization energy (ASE) of pyrrole ~23kca1/mol is lesser compared to
benzene at ~35 kcal/mol, which results in the stabilization of the pyrrole molecule. The
lone pair of electrons on the nitrogen atom is delocalized to complete the aromaticity of
pyrrole and hence making the titanium metal center more Lewis acidic}3 Pyrrole ligands
by themselves have been found to be inefficient as ligands on titanium. The pyrrole
ligands can also undergo substitution reaction like Mannich reaction between pyrrole,
formaldehyde and methylamine hydrochloride to yield szpma (5) in high yield [dpma =
di(pyrrolyl-or-methyl)methylamine].34 A new catalyst Ti(dpma)(NMe2)2 (6), was

synthesized from the reaction between 1 and 5 in near quantitative yield (Scheme 1.9).

12

 

 

 

 

 

A.”
.1.
1
L
m

 

 

Z\ 221:

H
H
0 i + MeNH HCI EtOH/HZO N N
2 + 2 H H 2' 55°C,4h \l \
szpma (5) 88% yield on 179 scales
Ti(NMe2)4 (1)

Ether, RT, 2 h
68%

NM82
/ Nfii—l—NMGZ
’- ||||N\

Me
(6)

Scheme 1.9. Synthesis of Ti(dpma)(NMe2)2 (6).

Hydroamination of alkynes using 6 gave imines in yields up to 90% for some substrates.
Some of the reactions took longer time for completion at 75 °C, giving low product
conversions after several days. In general, hydroaminations involving internal alkynes were
slow with alkyl amines. By raising the temperature to 130 °C, product yields increased after
reasonable reaction times. The hydroamination of 1-phenylpropyne has the nitrogen
attachment ,8 to the phenyl group. The selectivity for the formation of the Markovnikov
product is greater than 1, when 6 is used as the catalyst. Hydroamination using amines such
as benzylamine (7) and benzhydrylamine (8) is also possible with 6, but reaction times are
longer and product yields are ~70-90%. Amine 8 showed poor regioselectivity, with the
Markovnikov product being favored by only 3:1, whereas 7 gave high Markovnikov
selectivity. These results are in marked contrast to catalysis with 1, where hydroamination
of 3 by 7, and 8 displayed poor yields and selectivities under the same conditions.

As an extension, a new catalyst was obtained by reacting 1 with 5,5-
dimethylpyrrolylmethane (szmpm)35 (9) to give Ti(dmpm)(NMe2)2 (10). Catalyst 10
was developed in an attempt to decrease steric constraint, increase the Lewis acidity of

13

 

 

 

 

 

 

U. i -’ «KL?
‘

Irilrllvy . .
c

 

the metal center and to decrease the coordination number. In solution, 10 has both

pyrroles connected in a 77' fashion to the titanium metal center (Scheme 1.10).

H H H
N i catTFA : N N
25 U T Me Me neat,5 min. \ I I /

53%, 59 scale 9

Q n Ether, RT,3h
+ T' NM :
\ I I / 'I 62)“ 68%
1

 

 

 

Scheme 1.10. Synthesis of Ti(dmpm)(NMe2)2 (10).

Because of poor solubility of 10 in some common organic solvents, Ti(dppm)(NMe2)2
(11) (szppm = 5,5-di-n-propyldipyrrolylmethane) was prepared from szppm (12) and
1. The solid state structure of both 10 and 11 has one nS-pyrrolyl ligand, and an 77‘-
pyrrole. The hydroamination reaction of terminal alkynes with 10 as a catalyst yields the
product in 5 minutes at room temperature in moderate to high yields of 50-80%. Internal
alkynes like 4 and l-phenylpropyne (l3) react slower, requiring a day for completion.
The Markovnikov product was selectively obtained for most of the cases, with greater
than 40:1 regioselectivity.

A titanium-catalyzed three-component coupling between amines, alkynes, and
isonitriles to generate or,,B-unsaturated ,B-iminoamines in moderate to high yields was
also developed (Equation 1.3).36 Experimental evidence provided by Martins” reveals the
insertion of an isonitriles in a Ti—C bond is favorable and exothermic for zirconium and

titanium. The empirical data is also supported by DFT calculations.

14

_ 2 _ 10mol%64 R?
_ H + HZNR + C=N"R3 N NHR3 (1.3)

24 moo 0c 7 I
"BU/Ky

 

 

"Bu
3 R2 = Ph (2), Cy (14)
R3 = tert-butyl, 1.1.3.3-tetramethybutane

Different combinations of isonitriles along with terminal and internal alkynes were
surveyed for three-component couplings with aniline and cyclohexylamine. The catalyst
used for the three-component coupling was 6. Aryl and alkyl amines as well as terminal
and internal alkynes can be functionalized using this methodology. Regioselectivities in
the three-component coupling reactions using 6 as catalyst were similar to
hydroamination. Hydroamination of 3 by cyclohexylamine (14) results in a 1.621 mixture
of Markovnikov:anti-Markovnikov products. Three-component coupling between 3, l4,
and tert-butylisonitrile (15) results in a 12:1 mixture of separable isomers. The
mechanism for the three-component coupling is shown below (Scheme 1.11). The
catalysis involves the reaction of isonitrile with the azatitanocyclobutene formed during
hydroamination (See Scheme 1.5). The titanium imido complex can react reversibly with
an alkyne to form a azatitanocyclobutene. Consequently, 1,1-insertion of an isonitrile into
a Ti—C bond, which is usually favorable and reversible, generates a new C—C bond and
an iminoacyl complex followed by protonolysis by amine to generate the observed three-

component coupling product.

15

""1

 

NR1

R
Rz/U\[ 3

i
NHR4 hi
IT

 

 

major
I]
R1-NH2
RUN
R2 R1\ R2
Rh NEE protonolysis_ )|\/R3
N \ .l 7 R2
,1 R3 rn]
[Tl] R3
\N V
I
R4 V
RfNC
R1 - Ph. CY
R2 = H, M8
R3 = "BU, Ph
R4 = t3". CsH1a

Scheme 1.11. Proposed three-component coupling mechanism.
1.7 Conclusion

A plethora of metal complexes are available as catalysts for hydroamination of
alkynes and amines. Titanium catalysts offer high yields for the hydroamination of
alkynes with primary amines and tolerate a variety of substituents. The reaction offers
high regioselectivity for product formation. Titanium catalyst 1 is cheap and readily
available and can also be synthesized in bulk quantity. The pyrrole framework offer a
wide range of ligands which can be modified and easily prepared by simple organic
reactions. Titanium and the organic ligands have lower toxicity compared to some that
have been used for hydroamination like mercury. These versatile catalysts will be used in
hydroamination of diynes by primary amines to give pyrroles in a one-pot reaction,

presented in Chapter 2.

l6

1.8 References
1) Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104.

2) Heilen, G.; Mercker, J. H.; Frank, D.; Reck, A. R.; Jackh, R. In Ullman's
Encyclopedia of Industrial Chemistry. 1985, A2, p36.

3) Steinbom, D.; Taube, R. Z. Chem, 1986, 26, 349.

4) Straub, T.; Haskel, A.; Neyroud, G.T.; Kapon, M.; Botoshansky M.; Eisen, M. S.
Organometallics 2001, 20, 5017.

5) Howk, B. W.; Little, E. L.; Scott, S. L.; Whitman, G. M. J. Am. Chem. Soc. 1954, 76,
1899.

6) Pez, G. P.; Galle, J. E. Pure Appl. Chem. 1985, 12, 1917.

7a) Kruse, C. W.; Kleinschmidt, R. F. J. Am. Chem. Soc. 1961, 83, 213. b) Kruse, C. W.;
Kleinschmidt, R. F. J. Am. Chem. Soc. 1961, 83, 216.

8) Hudrlik, F. P.; Hudrlik, M. A. J. Org. Chem. 1973, 38, 4254.

9) Tzalis, D.; Koradin, C.; Knochel. P. Tetrahedron Lett. 1999, 40, 6193.

10) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 1757.

11) Li, Y.; Marks, T. J. Organometallics 1996, 15, 3770.

12) Roesky, W. P.; Berberich, H.; Burgstein, R. M. Organometallics 1998, 17, 1452.
13) Hampel, F.; Wagner, T. Hultzsch, C. K Organometallics 2004, 23, 2601.

14) Lauterwasser, F.; Hayes, G. P.; Brase, S.; Piers, E. W.; Schafer, L. L Organometallics
2004, 23, 2234.

15) Askel, A.; Straub, T.; Eisen, M. S. Organometallics 1996, I5, 3776.

16) Uchimaru, Y. Chem. Commun. 1999, 1133.

17) Tokunaga, M.; Eckert, M.; Wakatsuki, Y. Angew. Chem. Int. Ed. 1999, 38, 3222.

18) Hartung, G. C.; Tillack, A.; Trauthwein, H.; Beller, M.; J. Org. Chem. 2001, 66,6339.

19a) Walsh, P. J.; Hollander, F. J.; Bergman, R. G. J. Am. Chem. Soc. 1988, 110, 8729.
(b) Cummins, C. C.; Baxter, S. M.; Wolczanski, P. T. J. Am. Chem. Soc. 1988, 110,

17

 

l.‘ Ji-I l-I .

Jim -

 

. u... (k.

8731. (c) Carney, M. J.; Walsh, P. J.; Hollander, R. G.; Bergman, R. G. J. Am. Chem.
Soc. 1989, 111, 8751.

20) Walsh, J. P.; Baranger, M. A.; Bergman, G. R. J. Am. Chem. Soc. 1992, 114, 1708.
21) Baranger, M. A.; Walsh, J. P.; Bergman, G. R. J. Am. Chem. Soc. 1993, 115, 2753.

22) Greenwood, N. N. Chemistry of the elements; Eamshaw, A. Pergamon Press: New
York, 1984.

23) Hill, E. J.; Profilet, D. R.; Fanwick, E. P.; Rothwell, P. I. Angew. Chem. Int. Ed.
1990, 29, 664.

24) McGrane, L. P.; Livinghouse, T. J. Org. Chem. 1992, 57, 1323.

25) McGrane, L. P.; Livinghouse, T. J. Am. Chem. Soc. 1993, 115, 11485.

26) Haak, E.; Bytschkov, 1.; Doye, S. Angew. Chem. Int. Ed. 1999, 38, 3389.
27) Bytschkov, 1.; Doye, S. Tetrahedron Lett. 2002, 43, 3715.

28) Heutling, A.; Pohlki, F .; Doye, S. Chem. Eur. J. 2004, 10, 3059.

29) Ong, G. T.; Yap, A. P. G.; Richeson, S. D. Organometallics 2002, 21, 2839.
30) Ackermann, L.; Loy, N. R.; Bergman, G. R. Org. Lett. 2004, 6, 2519.

31) Li, C.; Thomson, K. R; Gillon, B.; Patrick, 0. B.; Schafer, L. L. Chem. Commun.
2003, 2462.

32) Shi, Y.; Ciszewski, J. T.; Odom, A. L. Organometallics 2001, 20, 5011.
33) March, J. Advanced Organic Chemistry. 4th ed; John Wiley and Sons: New York, 1992.

34a) Li, Y.; Turnas, A.; Ciszewski, J.; Odom, A. L. Inorg. Chem. 2002, 41, 6298. (b) Harris,
S. A.; Ciszewski, J. T.; Odom, A. L. Inorg. Chem. 2001, 40, 1987.

35) Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem. Commun. 2003, 586.
36) Cao, C.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2003, 125, 2880.

37) Martins, A. M.; Ascenso, J. R.; De Azevedo, C, G.; Dias, A. R.; Duarte, M. T.; Da
Silva, J. F .; Veiros, L. F .; Rodrigues, S. S. Organometallics 2003, 22, 4218.

18

 

'12.; Li
L

 

 

2. HYDROAMINATION OF DIYNES

2.1 Introduction
Hydroamination of alkynes was discussed in the previous chapter along with some recent
advances in the field by the Odom group using titanium-based catalysts. In this chapter,
hydroamination of diynes will be presented which will result in a one-pot synthesis of
pyrroles. Pyrroles are important biologically as they are present in many naturally
occurring alkaloids and some NSAIDS (non-steroidal anti-inflammatory drugs).1 The
early impetus for the study of pyrroles came from degradative work relating to the
structure of two pigments central to life processes: the blood respiratory pigment (heme)
and, the green photosynthetic pigment of plants (chlorophyll).2 Pyrroles are also
important components in material sciences.3

NSAIDS are one of the most widely used groups of drugs in the history of medicine.
Worldwide, it is estimated more than 30 million people take NSAIDS daily.4 Global sales
of NSAIDS in 1999 and 2000 reached 10 billion 8 with the United States accounting for 5
billion 3.5 NSAIDS can be classified into salicylates, arylalkanoic acids, 2-aryl propionic
acids, N-arylanthranilic acids, pyrazolidine derivatives, oxicams, and COX-2 inhibitors
(cyclooxygenase-2). The NSAIDS work by inhibition of the enzyme cyclooxygenase
responsible for the formation of prostaglandins and thromboxane from archidonic acid.
Prostaglandins in turn are responsible for the actual process of inflammation.6

Some of the NSAIDS that have a pyrrole in their core structure are, Tolmetin Sodium®

(T olectin)7 and Ketorolac Tromethamine® (Toradol).8 A few natural products that include

the pyrrole core are Polycitone A and B,9 Lamellarin O,'0 and Lukianol A10 (Figure 2.1).

19

HO
HZN km
OH
Ketorolac Tromethamine

H
Ph / \ O
o N OH
R:
Br
0 O

N OH

R \ / R

R ONa 2H20 R R

 

 

Br
Pol atone A
OMNR\§| e Tolectin Sodium y
MeOZC OR)kS-—Z/U\RRB=I‘ Br
HO\O /O O\ NO Polycitone B
OH HO OH
Lamellarin O Lukianol A

Figure 2.1. Pyrrole core structure in NSAIDS and natural products.
2.2 Aim of the project

Hydroamination of 1,4-diynes and 1,5-diynes with primary amines was used to
generate 4-iminoalkynes that can undergo cyclization. In the case of 1,5-diynes a 5-ex0
dig cyclization would be possible to yield the pyrrole (Scheme 2.1). H For 1,4-diyne 5-

endo dig cyclization is expected.

20

Mltm'z' 3‘;

 

 

 

 

 

R,
N
catal st
+ RNHZ y *7 M

lS-endo dig

<
\\

'3
Me N
U

 

 

 

Rt
_ N
: + RNHz ' M
%
I"
5-exo dig #9
Me

'3
N
Um

Scheme 2.1. Proposed scheme for hydroamination of 1,4-and 1,5-diynes.
Pyrroles are traditionally synthesized via the Paal-Knorr synthesis,l2 which involves

condensation of 1,4-diketone with amine (Equation 2.1).

M RNHZ =/[—\>\ (2.1)
-2H20 N

o I
R

 

A classic procedure for the synthesis of 1,4-dicarbonyls is the Stetter reaction,13 which
is a 1,4-addition (conjugate addition) of an aldehyde to an a, ,B—unsaturated compound,

catalyzed by cyanide or a thiazolium salt (Scheme 2.2).

21

“in!

r - “11.x

 

 

descr
react
mm?
mm?
mulIf;
the b.
The h}.
for 5;
bOId I i

liuf

Piui.

 

 

 

fl + /\n/ mtaIYst >j\/Y (22)
R H O

O
2.3 Baldwin Rules for Ring Closure
Before explaining the synthesis of pyrroles via hydroamination of diynes, a brief
description of Baldwin rules is presented. Baldwin studied several types of cyclization
reactions and categorized them.l4 Baldwin’s rules are for certain ring closings of 3- to 7-
membered rings. These rules distinguish two types of ring closure, called exo, if one
member of the multiple bond is outside the ring and endo, if both members of the
multiple bonds are enclosed in the ring. For a tet atom the em and endo rule pertains to
the bond being broken is present in or out of the ring. The reaction is also categorized by
the hybridization of the atom involved in the ring closure: tet for sp3, trig for sp2, and dig
for sp. The rules that apply for the cyclizations of 1,4- and 1,5-diynes are highlighted in
bold (Scheme 2.2).
Rule 1. Tetrahedral systems
(a) 3 to 7-exo-tet are favored
(b) 5 to 6- endo-re! are disfavored
Rule 2. Trigonal systems
(a) 3 to 7-exo-trig are favored
(b) 3 to 5-endo-trig are disfavored
(c) 6 to 7-endo-trig are favored
Rule 3. Digonal systems
(a) 3 to 4-exo-dig are disfavored

(b) 5 to 7- exo-dig are favored

22

but“? .- . “sq

.1

awn—w I-

 

 

(I?
(‘J
:3"
r?)

"[l
diiiic.
Trost'
getter;

CPCIiZ.

2.4 s}.

3.4.] g

)8er

hfxaih

Nu.

 

(c) 3 to 7- endo-dig are favored

CR AQ
-, Y
@er-

X'

Scheme 2.2. Baldwin’s rules for ring closure in 3- to 7-membered rings.

“Disfavored” does not mean cyclization is impossible; it just means that it is more
difficult than “Favored”. Some exceptions to this rule, have been individually reported by
Trostls and Auvray.“ From the Baldwin rules, we conclude cyclization of imino alkynes
generated from 1,4— and 1,5-diynes should be facile since both S-endo dig and S-exo dig

cyclizations respectively are Favored.

2.4 Synthesis and hydroamination of 1,4-diynes

2.4.1 Synthesis

The substrates for the hydroamination, i.e. the diynes, were synthesized using
Verkruijsse’s procedure.17 The unsymmetrical internal-1,4-diyne and 1-phenyl-1,4-

hexadiyne was synthesized by the same procedure (Scheme 2.3).

23

 

 

Ar
anilir.
reacti
H}‘dr.

ptodu.

 

 

1) EtMgBr R

 

 

 

 

R : H 2) CUBT ; \\ //
3):—-——\
OTs R _ H n .
60-70% - (16),Ph(21), Bu (18), SIMe3(22)
1) EtMgBr
_ 2)CuBr _ ph
Ph — H _ V \\ //
60% ms internal diyne (23)

Scheme 2.3. Synthesis of 1,4-diynes.
2.4.2 Hydroamination of 1,4-Diynes

An attempt was made to hydroaminate 1,4-pentadiyne (16) with 1 equivalent of
aniline (2) using Ti(dpma)(NMe2)2 (6) as the catalyst. The major product obtained in the
reaction had a mass consistent with double hydroamination of 16 (Scheme 2.4).
Hydroamination of diynes attempted with Ti(NMe2)4 (l) as a catalyst showed low

product conversions to pyrrole.

\ / 10 l°/6
V + IanNI-I2 ——'—"3—9——> NR

100 °C, 24 h
16 7
Ph. .Ph
N HN
2 ---—-—-—-> / major
40°C, 24 h M
16 2 17

Scheme 2.4. Hydroamination of 1,4-pentadiyne (16) by aniline (2) and benzylamine (7).
Data for the dihydroamination product (17), obtained from the hydroamination of 16
by 2, matched an authentic sample of 2,4-bis(phenylimino)pentane synthesized by the
condensation of 2,4-pentanedione and 2 using catalytic p-toluenesulfonic acid.18 This
suggests that second hydroamination is faster than both monohydroamination and S-endo
dig cyclization. Other catalysts like Ti(dmpm)(NMe2)2 (10) were screened, but 6 gave the

highest product conversion. Increasing the temperature led to oligomerization of the

24

 

 

dim
baht
film

COPS

dam

With it
fleetr.

Where

 

 

 

 

 

diyne, and lowering the temperature led to dihydroamination. There is some reason to
believe that 16 is unstable at room temperature and also when stored in a freezer inside a

glove—box since precipitate formation is seen in less than a week. This result was

confirmed from the company GFS,® which markets 16 as a trimethylsilyl-protected

derivative.

Hydroamination of 1,4-nonadiyne (18) by amines 2 and 7 at 100 °C with 6 as catalyst
led to the corresponding pyrroles in moderate yields (Equation 2.3). Hydroamination of
18 by 2 gave 1-phenyl—2-butyl-5-methylpyrrole (19) in 55% isolated yield.
Hydroamination with 7 required longer reaction time and gave a yield of 35% of 1-
benzyl-2-butyl-5-methylpyrrole (20). The pyrrole product obtained from imine
cyclization is preferentially derived from Markovnikov addition to the terminal alkyne.
When the above result is compared to hydroamination of l-hexyne (3) by amines 2 or 7,
the product observed is derived from Markovnikov addition to the alkyne preferentially,
with 6 as the catalyst.19 Considering the terminal diynes used here are not sterically or
electronically different from l-hexyne (3), the major product expected in all the cases

where a terminal diyne is present is an imine resulting from Markovnikov addition.

 

ii
"Bu \ N
/ 10 mol% 6
V + RNHZ > Una“ (2.3)
18 100 °c
_ 19 Ph (2) 19, 56%, 24 h
R ‘ P“ (2" 3“”) 20 Bn (2) 19. 35%, 48 h

Hydroamination of l-phenyl-l ,4-pentadiyne (21) by either aryl or alkyl amines did not
yield the desired pyrrole with 1, 6, or 10 as catalyst (Equation 2.4). The lack of pyrrole
formation could be a result of diyne oligomerization. Hydroamination of 21 by 2 did

yield a product, but it could not be characterized.

25

 

 

the a.’
alkyl
relati:
demo:
math.

by

’9

1
—

 

Ph

H T'catal st
\\ // + HzN-R I y = NR (2.4)
(no reaction)

 

2‘ R= Ph (2),-CH2Ph (7)
Hydroamination of l-tn'methylsilyl-l,4-pentadiyne (22) by amines 2 and 7 employed
did not yield the pyrrole product. Several titanium catalysts were screened but no pyrrole
product was seen. Deprotection of trimethylsilyl group was often observed in the reaction

and confirmed by GC-MS spectroscopy (Equation 2.5).

 

22 R: Ph (2),-CH2Ph (7)

Hydroamination reactions by titanium have been shown to be sensitive to the size of
the alkyne substrate.20 Hence, replacing hydrogen on the terminal position of the diyne by
alkyl or aryl groups should significantly slow down the second hydroamination reaction
relative to the 5-endo dig cyclization as seen in the case of 16. We successfully
demonstrated this by hydroaminating 1-phenyl-1,4-hexadiyne (23) by 2, 7, and p-
methoxybenzylamine (24) using 10 as the catalyst (Equation 2.6). Hydroamination of 23
by 2 gave l-phenyl-Z-benzyl—S-methyl pyrrole (25) in 62% isolated yield.
Hydroamination of 23 by 7 gave 1,2—dibenzyl-5-methylpyrrole (26) in 53% yield, while
with 24 (PMB-NHZ), l-(4-methoxy-benzyl)-2-benzyl-5-methyl pyrrole (27) was obtained
(Scheme 2.5). This result, a selective hydroamination of phenyl-bearing alkyne, can be
explained in terms of hydroamination of alkynes explained in Chapter 1. Hydroamination
of l-phenylpropyne (13) occurs with amination ,6 to the phenyl group, which is consistent
with the observed regioselectivity for the diyne substrate, 23. Also hydroamination of 13

is generally more facile than dialkyl substituted alkynes, e. g. 3-hexyne (4). Consequently,

26

' _ ‘kL
a

 

.. :. vw-‘t—rf’_wr"" - - r

 

 

4

his

toti

Sch:

///

 

it is likely that regioselectivity for this substrate is due to kinetically favored amination ,6

to the phenyl group of 23.

1) 1o mol%10 )3"

Ph
Me 100°C,24h N h
\\ // + PhNHz f l/
2) 30 mol% Cul, NEt3, 110 c

 

23 2 62% 25
ph 7‘
\\ // Me __1_O_mQL%_1_O_. N Ph
+ RNH2 |
100 °C, 24 h /
23 R = Ph (2). PMB (24) 26

26 R = Ph (2) 53%
27 R = PMB (24) 30%

Scheme 2.5. Hydroamination of l-phenyl-l,4-hexadiyne (23) by 2, 7, and 24.

The cyclization for 25 was incomplete during thermal cyclization and to complete the
cyclization, Gevorgyan’s procedure using 30 mol% of CuI in the presence of Et3N at 110
°C was employed prior to work-up.21 Interestingly, the addition of copper for the
cyclization was only required for the aniline substrate, whose mechanism will be
discussed subsequently.

2.5 Synthesis and hydroamination 1,5-diynes

2.5.1 Synthesis of 1,5-diynes

The 1,5-diynes used were 1,5-hexadiyne (28), which is commercially available and

1,6-diphenyl-1,5-hexadiyne (29), synthesized by the literature procedure22 (Equation 2.6).

 

- 32‘°'%Io/°i‘:'dpp — O
:___/—=+2©-I '."'°°‘h$iO-—- (2.6)
'PI'ZNH,THF
28 29

27

 

 

!'-’
' I!

if!

benz}

 

2.5.2 Hydroamination of 1,5-diynes

Hydroamination of 28 proceeds smoothly by 2 with 6 as the catalyst, at 75 °C in 6 h to
give 1-phenyl-2,S-dimethylpyrrole (30) (Equation 2.7). Hydroamination of 28 by 7 takes
a longer time for completion and gives 1-benzyl-2,5-dimethylpyrrole (31) with 6 as the
catalyst. The yields vary from 68% for hydroamination by 2 to 34% by 7. The reactions

are clean and do not yield any dihydroamination product, as is the case with 16.

R
—- Ph // I
=_/—:— 10 mol°/ 6 g ‘N 59x0 di N
_ + RNHZ , ° , U ——fl—»\||:/)—_ (27)
Me

28
R=Ph (2). 3'10) 30R=Ph(2)68%,75°C,6h
31 R = Bn (7) 34%, 100 °C, 14h

 

Hydroamination of 29 by 2 at 150 °C using 6 as catalyst yields, 1-phenyl-2,5-di-

benzylpyrrole (32) in 90% yield after 26 h (Equation 2.8).

 

[Ph
Bn
_ ph 10 mol% 10 g N
__—_/_ + PnNH , (2.8)
Pb — 2 150°C, 26h l / B"
29 2 90% 32

Reaction of 29 by 7 gave a trace amount of product having a mass consistent with the
expected pyrrole using 10 as the catalyst. The slow reactivity with 7 probably represents
a limitation to the activity of our current catalysts rather than an inherent problem with
the substrate combination.

2.6 Mechanism of diyne hydroamination

2.6.1 Cyclization of 1,4-diynes

Experimentally it was shown by Gevorgyan that l-imino-Z-alkynes require copper
catalysis to be cyclized. This probably occurs through an allene intermediate (Scheme
26).”

28

 

 

33
HIE re

 

“15m-

 

 

R3\ CU' R2

 

Scheme 2.6. Gevorgyan’s cyclization of l-imino-Z-alkynes catalyzed by copper.

A key unsolved puzzle is the role titanium plays in cyclization of iminoalkynes in
diyne hydroamination. The question unanswered is whether the cyclization occurs
thermally in the absence of titanium or is titanium needed for cyclization to pyrrole.
Consequently, we sought to generate an imino alkyne in the absence of the transition
metal compound to observe the cyclization, if it happens.

The goal was to synthesize 4-nonyn-2-ol23 (33) from propylene oxide, oxidize it to 4-

24a

 

 

 

nonyn-2-one (34) and perform a Schiff base reaction with aniline to give the imino-
alkyne (Equation 2.9).
. : n H "BU 0 DB
22:“ a": a .. M
THF/HMPA
80% 33 34

,I/.

33 was synthesized and oxidation was attempted using various oxidation conditions.
The reaction failed as 34 could not be isolated due to isomerisation to the allene product.
Alternate oxidations like Swem and Jones oxidation did not work either. Attempts to

protect the alkyne with C02(CO)3 and deprotect it afier condensation with 2 failed. The

29

I ,'
-m'

 

 

dep

“hi

beer
Itith

pres.

pflfr

amQLL
SP'SC’:
lmim,
“lib ti

/ 4!

Fri;

‘he C\

 

 

deprotection step involves addition of an aqueous solution of ceric ammonium nitrate,
which was not desired since we have a hydrolyzable imine in our case.25
While numerous attempts to isolate the iminoalkyne were unsuccessful, they have
been observed in the reactions. During 1,4-diyne hydroamination two peaks are observed
with the mass of the product confirmed by GC/MS. One of the peaks is transient,
presumably the iminoalkyne, which converts to the pyrrole of the same mass.
An alternate oxidation by Dess-Martin Periodinane (DMP) was successful in

performing the oxidation to 34 (Equation 2.10).24b

DMP

n "Bu
H é BU [O] 97 M (210)

33 80%
34

 

The oxidized compound 34 was reacted with aniline and refluxed, which resulted in
allene (36) formation. An alternate route of reacting 34 with 2 in the presence of
molecular sieves was also tried to avoid heat, but the result was similar with formation of
36. The allene was reacted with 6 to observe any cyclization to pyrrole 20. Only a trace
amount of pyrrole 20 was observed after heating at 100 °C confirmed by mass
spectrometry. No pyrrole was seen when 34 and 2 were reacted together. With no
iminoalkyne being isolated a proposed mechanism for the cyclization is shown below

with three possible intermediates (Equation 2.11).

V + H2NPh__——>1om0|%6 P/K/Bu" P/'\/B °' Pym] (211)

19 2

”Bu

3 possible intermediates
From the above scheme, one can argue that 36 would not be the likely intermediate in

the cyclization, as it would constitute a 5-ena'o-trig cyclization, which is a disfavored

30

 

.. I- « ‘3. .——. . _..—

 

pro

(501'.

 

Til, .

fJ
\J
-—i

.3.’

Smil.

t J
H
‘JJ

H‘df'

 

 

process by Baldwin rules. Isomer 35 is likely to be more stable than 37 since a
conjugation of the double bond and triple bond is possible in 35, which is not possible in
structure 37. It is likely the proposed scheme involves reaction of isomer 35 with
Ti(dpma)(NMe2)2 (6), where titanium is coordinated to enamine nitrogen, helping in the
cyclization.
2.6.2 Cyclization of 1,5-diynes

Even though the imine product was not observed in the hydroamination of 1,5-
hexadiyne (28), it is still likely that an imine or enamine is an intermediate. The relevant
ketone derivative of this intermediate, hex-5-yn-2-one (38) was prepared according to the
literature procedure.26 Reaction of 38 by 2 (Equation 2.12) in the absence of titanium

leads to a product that is spectroscopically identical to 30.

reflux,
benzene /Ph
\\+ HZNPh ———’ | (2.12)

38 2

2.7 Three component couplings with diynes
Another application attempted, was a multi-cornponent reaction with diynes in a

similar vein as previously shown with monoalkynes, isonitriles, and amines (Equation

 

2.13).27
h
"B“ 10 mol%6 n IF
\\ // + H2NPh+ CEN—‘Bu = Bum (2.13)
/
t
19 2 15 NHBu

The reaction did not afford the expected product with any of the 1,5-diynes attempted.
1,4-diyne did react with 2 and tert-butyl isocyanide (15), but the product could not be

characterized.

31

w; “‘4
i

 

 

fl .
-.L

 

stud.

fan:

III).
S.
MUCH.

 

 

2.8 Vinylpyrroles

2.8.1 Proposed route

As an extension of hydroamination of alkynes, a one-pot synthesis of substituted

Vinylpyrroles using a titanium-based catalyst was proposed (Equation 2.14).

R
I
\\ //H + RNH2 —-°——°——5->1 m V" @Q/Mdzm

R = Ph (2), Bn (7)
C-Vinylpyrroles having the structure 39 and 40 (Figure 2.2)28 have been extensively
studied as building blocks for the synthesis of various representatives of the pyrrole

family, especially condensed heterocycles related to pyrrole.29

/\ )5
i‘\ I
39 40

Figure 2.2. Structure of Vinylpyrroles 39 and 40.

2-Vinylpyrrole (structure 39) is found in molecules of vital natural compounds
(porphyrins, chlorophylls, vitamin BIZ, etc). 3-Vinylpyrrole structural elements 40
compose molecules of chlorophylls a, b, c and haemoglobin. C-Vinylpyrroles bearing
functional groups on the double bond (or those without them) are highly reactive starting
compounds for the targeted synthesis of conjugated and fused heterocycles similar to
natural pyrrole assemblies. Over the past few years, functionalized C-vinylpyrroles

started attracting attention as molecular optical switches, in particular, as ultra fast ones,

32

 

 

fin

Ienq»

One 0

aCCeSS

flan]?

It,“

 

for design of photo- and electroconducting materials, nanodevices30 and also as ligands

for new photocatalysts and biologically active complexes.31

2.8.2 Synthesis and hydroamination of of enediyne
l-ethynylcyclohex-l-ene (41) was synthesized using a literature procedure.32 41 was

reacted with EtMgBr and CuBr followed by propargyl tosylate in a similar procedure to

the synthesis of 1,4-diynes (Equation 2.15).

1) EtMgBr

< >——: QCUB' = H 2.15
3)E—\ \\ // ( )

41 OTs

 

42
2.8.3 Hydroamination of enediynes
Hydroamination of l-cyclohexenyl-l,4-pentadiyne (42) by amines 2 and 7 using 6 as
the catalyst did not yield any 2-vinylpyrrole. Changing the conditions by increasing the

temperature and switching to 10 as the catalyst did not yield any products either.

2.9 Summary

Applications of this new pyrrole synthesis based on alkyne hydroamination are currently
under investigation. It is hoped that this new pyrrole synthesis will complement existing
procedures such as the Paal-Knorr synthesis, at least in circumstances where
unsymmetrical pyrroles are desired. Many unsymmetrical 1,4-diynes can be prepared in
one or two steps from commercially available compounds and may be as or more
accessible than the corresponding unsymmetrical 1,4-diones in some cases. The titanium-
based pyrrole synthesis of 1,2-dibenzyl-5-methylpyrrole (26) provides an interesting
example for comparison with current and progressing ketone-based methodologies, e. g.,

Paal-Knorr synthesis. Generally, unsymmetrical 1,4-diketones are relatively difficult to
33

 

 

dior

 

 

access in a short synthetic sequence. However, the diketone needed for the synthesis of
26 by Paal-Knorr synthesis and its reaction with benzylamine were recently reported
(Scheme 2.7).33 The diketone was prepared using a novel Pd-catalyzed procedure from
methyl vinyl ketone and benzylzinc chloride a procedure specific for benzyl containing
diones. Overall, 26 was available in 54% yield over two steps. Using the procedure of
Verkruijsse to generate the diyne and titanium hydroamination, we prepared the
unsymmetrical pyrrole 26 in the comparable yield of 41% in two steps. It is safe to
assume that for hydroamination of terminal diynes catalyst 6 is the choice, whereas for
internal diynes, catalyst 10 is more efficient. This may be attributed to higher reactivity of

10 compared to 6 and also slower reactivity of internal diynes compared to terminal ones.

0

 

Pd PPh3)4 (1.5 mol°/)
ZnCl + 1.5 N + CO ( o:
O (1 atrn) TMSCI (3.5 eq) 0
LiCl (5 eq)
BnNHz (7),
reflux, CsHa

Ph

54% over two steps
26

Scheme 2.7. Synthesis of 26 using Pd-catalyzed procedure from methyl vinyl ketone.33
In addition, we investigated the use of this new methodology in synthesis of pyrroles

where application of the Paal-Knorr synthesis may lead to unwanted side reactions. An

attempt was made to extend the syntheses of pyrroles to 2-vinylpyrroles. We have had

limited success as far as this goal was concerned, compounded by the fact that these

34

 

5‘st

 

183

iss

 

reactions are low yielding. Probably, there is a need for some variation in the catalysts
that are currently employed for hydroamination. A tabular version of pyrroles synthesized

is shown below.

35

Table 2.1. Results for hydroamination of 1,4- and 1,5-diynes with aromatic amines

 

 

 

 

 

 

 

 

 

 

 

diyne amine Conditions 100 °C product
R-NHZ catalyst, time
R = Ph (2) (% yield)
R = -CH2Ph (7)
"Bu Ph
\\ // 2 6, 24 h I;
(56) I "Bu
18 / 19
18 7 6, 48 h P")
(35) N
l / ”Bu 20
Ph Ph
\\ // Me 10,30 h /
23 2 (62) Wt]
25
Ph
10, 30 h )
23 7 (53) W11
/ 26
PMB
24 10, 26 h I
23 (30) W“
/ 27
i311
I 6, 75 °C,
=_/———— 2 6 h, (68) EN)»
28 / 30
Ph
7 6, 14 h )
28 (34) \EN)‘
/ 31
fh
:Ph 2 10150°C26h
Ph—E—r— ’ ’ B" N
(90) U
/ Bn
29 32

 

 

 

 

6 = Ti(dpma)(NMe2)2 and 10 = Ti(dmpm)(NMe2)2

36

 

 

 

11nd

510

WC‘l'

 

 

2.10 General Procedures

Unless otherwise stated, all manipulations were performed in an MBraun drybox
under an atmosphere of purified nitrogen. 2, 7 and 24 were distilled prior to use and
stored in the glove-box. All solvents were stored in the glove-box. Catalysts 6 and 10
were prepared and stored in glove box. 1H NMR (300 MHz) and '3 C NMR (75 MHz)
spectra were recorded on a Varian Inova 300 spectrometer at room temperature unless
otherwise stated. 1H and '3 C NMR chemical shifts are reported with respect to internal
solvent (7.24 ppm and 77.0 ppm respectively for CDCl3). Oxidation of 33 to 34 was
followed by 1H NMR and IR spectroscopy. IR was recorded on a Nicolet 42
spectrometer. GC-FID and GC-MS were recorded on an Agilent 6890-GC and Agilent
5973 N inert spectrometer respectively. CAUTION: The starting materials for 1,4-diynes
are propargyl tosylates. Explosions have resulted from purifying propargyl tosylate and

its derivatives by vacuum distillation. Diynes 18, 21, 22 and 23 were synthesized using

the literature procedure.l7 1,5-Hexadiyne (28) was bought from GFS,® distilled and stored

in the glove box prior to hydroamination. 1,6-Diphenyl-l,5-hexadiyne (29) was
synthesized by the literature procedure (Scheme 10).22 l-Ethynyl-cyclohex-l-ene (41)
was synthesized using a literature procedure. CAUTION: Explosion occurred while
distilling 41 and care should be taken to avoid rapid heating. Compound 42 was

synthesized in a similar manner to diyne 18.

37

2.11 Experimental Section

 

Figure 2.3. Structure of l-phenyl-2-butyl-5-methylpyrrole (19).

C15H19N Preparation of 1-phenyl-2-butyl-5-methylpyrrole (19): Under an atmosphere
of dry nitrogen, a threaded-top pressure tube was loaded with toluene (0.416 mL),
Ti(dpma)(NMe2)2 (6) (0.269 g, 0.832 mmol), aniline (2) (757 uL, 8.32 mmol), and 1,4-
nonadiyne (18) (1.00 g, 8.32 mmol). The tube was sealed with a Teflon cap, and the
reaction mixture was heated in an oil bath at 100 °C for 22 h. The volatiles were removed
from the reaction mixture in vacuo, and the residue was subjected to column
chromatography using 300 g of alumina with 7:1 pentane:ether as the eluent. The product
eluted in the first fractions in 55% yield (0.98 g, 4.56 mmol). The compound is a yellow
viscous oil. 1H NMR (300 MHz, CDC13): 8 = 7.44-7.54 (m, 3 H), 7.24-7.30 (m, 2 PD,
5.98 (app 8, 2 H, fand g), 2.38 (t, 2 H, J= 7.0 Hz, b), 2.06 (s, 3 H, a), 1.44-1.54 (m, 2 H,
c), 1.24-1.34 (m, 2 H, d), 0.84 (t, 3 H, J= 7.3 Hz, e). '3C{‘H} NMR (CDC13): 5 = 139.3
(j), 134.1, 128.5, 128.8, 127.7, 122.8, 105.6 (for g), 104.6 (for g), 31.2 (b), 26.8 (c or d),

22.4 (c or d), 13.0 (a), 13.9 (e). MS (EI) m/z = 213 (Mi).

38

 

Figure 2.4. Structure of l-benzy1-2-butyl-5-methylpyrrole (20).

C16H21N Preparation of 1-benzyl-2-butyl-S-methylpyrrole (20): Under an atmosphere
of dry nitrogen, a threaded-top pressure tube was loaded with toluene (0.416 mL),
Ti(dpma)(NMe2)2 (6) (0.269 g, 0.832 mmol), benzylamine (7) (933 1.1L, 8.32 mmol), and
1,4-nonadiyne (19) (1.00 g, 8.32 mmol). The tube was sealed with a Teflon cap, and the
reaction mixture was heated at 100 °C in an oil bath for 46 h. The volatiles were removed
from the reaction mixture in vacuo, and the residue was subjected to column
chromatography using 300 g of alumina with 7:1 pentane:ether as the eluent. The product
eluted in the first fractions in 35% yield (0.66 g, 2.91 mmol). The compound is yellow
viscous oil. 1H NMR” (300 MHz, c0013): 8 = 7.22-7.30 (m, 3 H), 6.85—6.90 (m, 2 H),
5.92 (app s, 2 H, 1' and g), 5.06 (s, 2 H, n), 2.48 (t, 2 H, J = 7.5 Hz, b), 2.16 (s, 3 H, a),
1.52-1.64 (m, 2 H, c or d), 1.30-1.42 (m, 2H, c or d), 0.84 (t, 3 H, J= 7.4 Hz, 8). '3C{'H}
NMR34 (CDC13): 8 = 138.8 (0), 133.1, 128.7, 128.0, 126.4, 121.6, 105.5 (f or g), 104.4 (f
or g), 46.6 (n), 31.1 (b), 26.5 (c or d), 22.6 (c or d), 14.0 (e), 12.5 (a). MS (EI) m/z = 227
(M).

39

 

Figure 2.5. Structure of l-phenyl-2-benzyI-5-methyh7yrrole (25).

ClanN Preparation of 1phenyl-2-benzyl-5-methylpyrrole (25): Under an
atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with chlorobenzene
(0.324 mL), Ti(dmpm)(NMe2)2 (10) (0.20 g, 0.648 mmol), aniline (2) (590.0 uL, 6.48
mmol), and 1-phenylhexa-1,4-diyne (23) (1.00 g, 6.48 mmol). The tube was sealed with a
Teflon cap, and the reaction mixture was heated at 100 °C for in an oil bath 30 h. The
volatiles were removed from the reaction mixture in vacuo, and the residue was subjected
to cyclization with CuI (0.370 g, 1.945 mmol), followed by addition of anhydrous N,N-
dimethylacetamide (28 mL) and EN (14 mL). The mixture was stirred for 110 °C with
protection from light for 7 h in an oil bath. The mixture was cooled to room temperature
and poured into water (100 mL). After shaking with pentane (50 mL), a 3-1ayer system
was formed. The lower (water) phase and upper (organic) phase was thoroughly
separated from the middle layer, which contained an emulsion of copper complexes. The
emulsion and water phases were separately extracted with pentane (3 x 30 mL and 1 x 30
mL respectively). The combined pentane extracts were collected and dried over
anhydrous Na2804. The solvent was evaporated under reduced pressure, and the residue
was subjected to column chromatography using 300 g of alumina with 7:1 pentane:ether
as the eluent. The product eluted in the first fractions and was distilled at 200 °C (0.8

torr) to give yellow oil in 35% isolated yield (0.56 g, 2.27 mmol). 1H NMR (300 MHz,

40

CDCl3): 8 = 7.38-7.32 (m, 4 H), 7.16-7.04 (m, 4 H), 6.94 (d, 2 H, J= 7.0 Hz), 5.93 (d, 1
H, J= 3.3 Hz, for g), 5.89 (d, J= 3.2 Hz, 1 H, for g) 3.71 (8,2 H, b), 1.99 (s, 3 H, a).
'3C{'H} NMR (CDC13): 8 = 140.2 (C or j), 139.0 (c or j), 132.4, 129.7, 129.1, 128.8,

128.3, 128.0, 126.8, 126.0, 107.0 (for g), 106.0 (for g), 33.8 (b), 13.1 (a). MS (EI) m/z =
247 (M).

41

 

Figure 2.6. Structure of 1,2-dibenzyl-S-methylpyrrole (26).

C19H19N Preparation of 1,2-dibenzyl-5-methylpyrrole (26): Under an atmosphere of
dry nitrogen, a threaded-top pressure tube was loaded with chlorobenzene (0.325 mL),
Ti(dmpm)(NMe2)2 (10) (0.20 g, 0.65 mmol), benzylamine (7) (708 11L, 6.49 mmol), and
l-phenylhexa-l ,4-diyne (23) (1.00 g, 6.49 mmol). The tube was sealed with a Teflon cap,
and the reaction mixture was heated at 100 °C in an oil bath for 30 h. The volatiles were
removed from the reaction mixture in vacuo, and the residue was subjected to column
chromatography using 300 g of alumina with 7:1 pentane:ether as the eluent. The product
eluted in the first fractions to give a yellow oil in 53% (0.90 g, 3.45 mmol) isolated yield.
1H NMR35 (300 MHz, CDC13): 8 = 7.28-7.40 (m, 6 H), 7.11 (d, 2H, J = 7.0 Hz), 6.81 (d,
2 H, J= 6.9 Hz) 5.90 (d, 1 H, J= 3.0 Hz, for g), 5.85 (d, 1 H, J= 3.3 Hz, for g), 4.90
(s, 2 H, n), 3.79 (s, 2 H, b), 2.12 (s, 3 H, a). ‘3C{‘H} NMR35 (CDCl3): 8 = 139.7 (c or j),
138.5 (c or j), 130.9, 128.8, 128.7, 128.6, 128.4, 127.0, 126.1, 125.6, 107.0 (for g), 105.6

(for g), 46.8 (n), 33.3 (b), 12.5 (a). MS (EI) m/z = 261 (1W).

42

 

Figure 2.7. Structure of 1-(4-methoxybenzyl)-2-benzyl-5-methyl pyrrole (27).

ConleO Preparation of 1-(4-methoxybenzyl)-2-benzyl-5-methyl pyrrole (27): Under
an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with
chlorobenzene (0.162 mL), Ti(dmpm)(NMe2)2 (10) (0.10 g, 0.32 mol), 4-
methoxybenzylamine (24) (424 uL, 3.24 mmol), and 1-phenylhexa-l,4-diyne (23) (0.50
g, 3.24 mmol). The tube was sealed with a Teflon cap, and the reaction mixture was
heated at 100 °C in an oil bath for 26 h. The volatiles were removed from the reaction
mixture in vacuo, and the residue was subjected to column chromatography using 300 g
of alumina with 7:1 pentane:ether as the eluent. The product eluted in the first fractions to
give a yellow oil in 35% (0.33 g, 1.14 mmol) isolated yield. 1H NMR (300 MHz, CDCl3):
6 = 7.30-7.20 (m, 3 H), 7.18-7.12 (m, 2H), 6.86-6.76 (m, 4 H), 5.92 (d, l H, J= 3.5 Hz, 1'
or g), 5.87 (d, l H, J= 3.3 Hz, for g), 4.87 (s, 2 H, n), 3.83 (s, 2 H, b), 3.80 (s, 3 H, m),
2.16 (s, 3 H, a). ‘3C{‘H} NMR (CDC13): 8 = 158.6, 139.8, 130.9, 130.6, 128.8, 128.6,
128.4, 126.8, 126.1, 114.1, 107.0 (for g), 105.6 (for g), 55.3 (m), 46.3 (n), 33.3 (b), 12.5

(a). MS (EI) m/z = 291 (M*).

43

e

d
bN

3W

C

Figure 2.8. Structure of 1-phenyl-2,5-dimethylpyrrole (30).

C12H13N Preparation of 1-phenyl-2,5-dimethylpyrrole (30): Under an atmosphere of
dry nitrogen, a threaded-top pressure tube was loaded with toluene (640 uL),
Ti(dpma)(NMe2)2 (6) (0.415 g, 1.28 mmol), aniline (2) (1.7 mL, 12.8 mmol), and 1,5-
hexadiyne (28) (1.00 g, 12.8 mmol). The tube was sealed with a Teflon cap, and the
reaction mixture was heated at 75 °C in an oil bath for 6 h. The volatiles were removed
from the reaction mixture in vacuo, and the residue was subjected to column
chromatography using 300 g of alumina and diethyl ether as the eluent. The product
eluted in the first fractions in 68% isolated yield (1.50 g, 8.76 mmol). When solvent was
removed, a colorless liquid was obtained, which solidified on standing. mp. 45-46 °C, lH
NMR35 (300 MHz, CDC13): 8 = 7.2-7.6 (m, 5 H), 5.93 (s, 2 H, c), 2.07 (s, 6 H, a).
l3C{'H} NMR36 (300 MHz, CDC13): 8 = 139.3 ((1), 129.3, 129.0, 128.5, 127.9, 105.9 (c),

13.2 (a). MS (EI) m/z = 171 (M‘).

44

Figure 2.9. Structure of 1-benzyl-2,5-dimethylpyrrole (31).

C13H15N Preparation of I-benzyl-Z,5-dimethylpyrrole (31): Under an atmosphere of
dry nitrogen, a threaded-top pressure tube was loaded with toluene (640 uL),
Ti(dpma)(NMe2)2 (6) (0.415 g, 1.28 mmol), benzylamine (7) (1.4 mL, 12.7 mmol), 1,5-
hexadiyne (28) (1.00 g, 12.8 mmol). The tube was sealed with a Teflon cap and heated at
100 °C in an oil bath for 14 h. The volatiles were removed from the reaction mixture in
vacuo, and the residue was subjected to column chromatography using 317 g of alumina
with pentane, then ether as eluents. The product was isolated in 34 % yield (0.80 g, 4.32
mmol) as a colorless liquid that solidified on standing. mp. 41-42 °C. 1H NMR” (300
MHz, CDCl3): 8 = 7.40-7.32 (m, 3 H), 7.12-7.07 (m, 2 H), 6.03 (s, 2 H, c), 5.16 (s, 2 H,
d), 2.30 (s, 6 H, a). '3C{‘H} NMR36 (300 MHz, CDC13): 8 = 138.7 (e), 128.9, 128.1,

127.2, 125.8, 105.6 (c), 46.8 (d), 12.6 (a). MS (EI) m/z = 185 (M‘).

45

i O ‘ ’ O
b
Figure 2.10. Structure of 1-phenyl-2,5-dibenzylpyrrole (32).

C24H21N Preparation of I-phenyl-Z,5-dibenzylpyrrole (32): Under an atmosphere of
dry nitrogen, a threaded-top pressure tube was loaded with chlorobenzene (1.10 mL),
Ti(dmpm)(NMe2)2 (10) (0.13 g, 0.43 mmol), aniline (2) (600 uL, 6.58 mmol), and 1,6-
diphenyl-l,5-hexadiyne (29) (1.00 g, 4.34 mmol). The tube was sealed with a Teflon cap,
and the reaction mixture was heated at 150 °C for 26 h. The volatiles were removed from
the reaction mixture in vacuo, and the residue was subjected to column chromatography
using 300 g of alumina with 1:1 pentane:ether as the eluent. The product was recovered
in 90% (1.26 g, 3.90 mmol) isolated yield as a pale yellow oil. 1H NMR (300 MHz,
CDCl3): 8 = 7-6-7.0 (m, 12 H), 6.80-6.70 (m, 3 H), 5.92 (s, 2 H, b), 3.70 (s, 4 H, c).
‘3C{‘H} NMR (CDC13): 8 = 158.6 (h or (1), 139.8 (h or d), 133.0, 129.1, 128.9, 128.3,

128.1, 126.0, 114.1, 107.0 (b), 33.7 (c). MS (EI) m/z = 323 (M).

46

Figure 2.11. Structure of 1—Cyclohexenyl-1,4-pentadiyne (42).

Cl 1H12 Preparation of 1 -CycIohexenyl-1, 4-pentadiyne (42)

In a 1 L, 3-necked flask with a stir bar, reflux condenser and dropping funnel under
nitrogen atmosphere were placed l-ethynyl-l-cyclohexene (50.0 g, 0.472 mol) and THF
(300mL). With cooling in an ice bath, ethyl magnesium bromide (236 ml, 0.472 mol, 2M
solution in THF) was added via a canula for 1 h. The solution was refluxed for l h. The
reaction mixture was cooled in an ice bath. To this solution, copper (I) bromide (2.73 g)
was added. 30 minutes after this addition. 1-tosyloxy-2-butyne17 (105.73 g, 0.472 mol) in
150 mL THF was added with vigorous stirring over a period of 30 minutes at 0 °C.
During this addition, the temperature of the reaction mixture was kept between 0 °C and
+5 °C. The bath was then removed, and the reaction was stirred overnight at room
temperature. The reaction was quenched with a solution made from 1 L of water and 100
g of ammonium chloride, and 10 g sodium cyanide. The mixture was stirred over a period
10 minutes. The organic phase was separated and aqueous phase was extracted with (4 x
50 mL) pentane. The combined organic phase was dried over MgSO4, and the solvent
was removed under reduced pressure. The crude product was purified by distillation at 78
°C (760 mm) to yield a pure oil in 67% isolated yield (45.54 g, 316.2 mmol). 1H NMR

(300 MHz, CDCl3): 8 = 6.00 (s, 1 H, 11), 3.20 (s, 2 H, a), 1.60-2.10 (m, 8 H), 2.03 (s, 1 H,

47

d). l3C{'H} NMR (CDC13): 8 = 10.3 (a), 21.7, 22.5, 25.8, 29.3, 68.8, 78.6, 80.0, 82.9,

120.5, 135.0.

48

2.12 References

1a) Kalgutkar, S. A.; Marnett, B. A.; Crews, C. B.; Remmel, P. R.; Marnett, L. J. Med.
Chem. 2000, 43, 2860. (b) DeWitt, D. L.; Smith, W. L. Proc. Natl. Acad. Sci. USA.
1988, 85, 1412. (c) Yokoyama, C.; Tanabe, T. Biochem. Biophys. Res. Commun. 1989,
I65, 888. (d)H1a, T.; Neilson, K. Proc. Natl. Acad. Sci. USA. 1992, 89, 73 84.

2) Rodd, E. H. The pyrrole pigments. In Chemistry of Carbon Compounds; Elsevier
Science Ltd: 1977; pp 239.

3) For a recent review on conjugated polymers incorporating the pyrrole unit, see: (a)
Higgins, S. Chem. Soc. Rev. 1997, 26, 247. For some recent examples on the use of
pyrrole derivatives in material science, see: (b) Ogawa, K.; Rasmussen, R. C. J. Org.
Chem. 2003, 68, 2921 (c) Naji, A.; Cretin, M.; Persin, M.; Sarrazin, J. J. Membr. Sci.
2003, 212, 1 ((1) Chen, J.; Too, C. 0.; Wallace, G. G.; Swiegers, G. F.; Skelton, B. W.;
White, A. H. Electrochim. Acta 2002, 47, 4227 (e) Zotti, G.; Zecchin, S.; Schiavon, G.;
Berlin, A. Chem. Mater. 2002, I4, 3607 (t) Glidle, A.; Swann, M. J.; Hadyoon, C. S.;
Cui, L.; Davis, J .; Ryder, K. S.; Cooper, J. M. J. Electron. Spectrosc. 2001, 121, 131 (g)
Pleus, S.; Schulte, B. J. Solid State Electrochem. 2001, 5, 522 (h) Korri-Youssoufi, H.;
Makrouf, B.; Yassar, A. Mater. Sci. Eng, C 2001, I5, 265 (i) Gale, P. A.; Bleasdale, E.
R.; Chen, G. Z. Supramol. Chem. 2001, I3, 557 (j) Costello, B. P. J. D.; Evans, P.;
Guernion, N.; Ratcliffe, N. M.; Sivanand, P. S.; Teare, G. C. Synth. Met. 2001, 118, 199
(k) Chou, S. S. P.; Yeh, Y. H. Tetrahedron Lett. 2001, 42, 1309 (l) Tietze, L. P.;
Kettschau, G.; Heuschert, U.; Nordmann, G. Chem. Eur. J. 2001, 7, 368.

4) Baum, C.; Kennedy, D. L.; Forbes, M. B. Arthritis. Rheum. 1985, 28, 686.

5) Laine L. Gastroenterology 2001, 120, 594.

6a) Lewis, A. J .; Furst, D. E. Introduction. In Non-Steroidal Anti-Inflammatory Drugs,
Marcel Dekker Inc: New York, 1987; pp 1-29 (b) Smith, C. J.; Zhang, Y.; Koboldt, C.
M.; Muhammad, J .; Zweifel, B. S.; Shaffer, A.; Talley, J. J .; Masferrer, J. L.; Seibert, K.;
Isakson, P. C. Proc. Natl. Acad. Sci. USA. 1998, 95, 13313.

7) Batsila, C.; Gogonas, E. P.; Kostakis, G.; Hadjiarapoglou, L. P. Org. Lett. 2003, 5,
1511.

8) Gilpin, R. K.; Pachla, L. A. Anal. Chem. 1999, 71, 217.
9) Kreipl, A. T.; Reid, C.; Steglich, W. Org. Lett. 2002, 4, 3287.

10) Boger, D. L.; Boyce, C. W.; Labroli, M. A., Sehon, C. A.; Qing. J. J. Am. Chem. Soc.
1999, 121, 54.

11) For recent examples of pyrrole syntheses from imino alkynes see a) Cossy, J.;
Poitevin, C.; Sallé, L.; Pardo, D. G. Tetrahedron Lett. 1996, 37, 6709 (b) Tarasova, O.

49

A.; Nedolya, N. A.; Vvedensky, V. Y.; Brandsma, L.; Trofimov, B. A. Tetrahedron Lett.
1997, 38, 7241 (c) McDonald, F. E.; Chatterjee, A. K. Tetrahedron Lett. 1997, 38, 7687
(d) Arcadi, A.; Anacardio, R.; D’Anniballe, G.; Gentile, M. Synlett 1997, 1315 (e)
Knight, D. W.; Redfem, A. L.; Gilmore, J. Chem. Commun. 1998, 2207 (1) Le, C.-F;
Yang, L.-M.; ku, T.-Y.; Feng, A.-S.; Tseng, J.-C.; Luh, T.-Y. J. Am. Chem. Soc. 2000,
122, 4992 (g) Kim, J. T.; Gevorgyan, V. Org. Lett. 2002, 4, 4697 (h) Gabriele, B.;
Salerno, G.; Fazio, A.; Bossio, M. R. Tetrahedron Lett. 2001, 42, 1339.

Similar cyclizations have been explored in indole synthesis. For examples see: (a)
Fujiwara, J.; Fukutani, Y.; Sano, H.; Maruoka, K.; Yamamoto, H. J. Am. Chem. Soc.
1983, 105, 7177 (b) Rudisill, D. E.; Stille, J. K. J. Org. Chem. 1989, 54, 5856 (c) Larock,
R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689 (d) Kuyper, L. F .; Baccanari, D. P.;
Jones, M. L.; Hunter, R. H.; Tansik, R. L.; Joyner, S. S.; Boytos, C. M.; Rudolph, S. K.;
Knick, V.; Wilson, H. R.; Caddell, J. M.; Friedman, H. S.; Comley, J. C. W.; Stables, J.
N. J. Med. Chem. 1996, 39, 892 (e) Larock, R. C.; Yarn, B. K.; Refvik, M. D. J. Org.
Chem. 1998, 63, 7652 (f) Xu, L.; Lewis, I. R.; Davidsen, S. K.; Summers, J. B.
Tetrahedron Lett. 1998, 39, 5159 (g) Yasuhara, A.; Kanamori, Y.; Kaneko, M.; Numata,
A.; Kondo, Y.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1. 1999, 529 (h) Rodriguez, A.
L. Koradin, C.; Dohle, W.; Knochel, P. Angew. Chem. Int. Ed. 2000, 39, 2488 (i) Hiroya,
K.; Itoh, S.; Ozawa, M.; Kanamori, Y.; Sakamoto, T. Tetrahedron Lett. 2002, 43, 1277 (j)
Battistuzzi, G.; Cacchi, S.; Fabrizi, G.; Marinelli, F .; Parisi, L. M. Org. Lett. 2002, 4,
1355 (k) Kamijo, S.; Jin, T.; Yamamoto, Y. Angew. Chem. Int. Ed. 2002, 41, 1780 (l)
Barluenga, J .; Trincado, M.; Rubio, 13.; Gonzalez, J. M. Angew. Chem. Int. Ed. 2003, 42,
2406 (m) van Esseveldt, B. C. J.; van Delft, F. L.; de Gelder, R.; Rutjes, F. P. J. T. Org.
Lett. 2003, 5, 1717.

12) Bishop, W. S. J. Am. Chem. Soc. 1945, 67, 2261.

13a) Stetter, H.; Kuhlmann, H. In Organic Reactions; Paquette, L. A., Ed.; Wiley: New
York, 1991; Vol. 40, pp 407 (b) Enders, D.; Breuer, K.; Runsink, J .; Teles, J. H. Helv.
Chim. Acta 1996, 79, 1899 (c) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem.
Soc. 2002, 124, 10298 ((1) Kerr, M. S.; Rovis, T. Synlett 2003, 1934 (e) Kerr, M. S.;
Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876 (t) Pesch, J .; Harms, K.; Bach, T. Eur. J.
Org. Chem. 2004, 2025 (g) Mennen, 8.; Blank, J.; Tran-Dube, M. B.; Imbriglio, J. E.;
Miller, S. J. Chem. Commun. 2005, 195. For examples of the Stetter reaction with acyl
silanes, see: (h) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc.
2004, 126, 2314.

14) Baldwin, J. E.; Lusch, M. J. Tetrahedron 1982, 38, 2939.
15) Trost, B. M; Bonk, P. J. J. Am. Chem. Soc. 1985, 107, 1778.
16) Auvray, P.; Knochel, P.; Normant, J. F. Tetrahedron Lett. 1985, 26, 4455.

17a) Verkruijsse, H.D.; Hasselaar, M. Synthesis 1979, 292 (b) Hurley, A. L.; Welker, M.
E.; Day, C. S. Organometallics 1998, 17, 2832.

50

 

 

to)
(.1

18) McAdams, A.; Leonard, A.; Kim, W.; Guzei, I. A.; Rheingold, A.; Theopold, K. H.
Organometallics 2002, 21, 952.

19) Cao, C.; Ciszewski, J. T.; Odom, A. L. Organometallics 2001, 20, 5011.

20) Cao, C.; Shi, Y.; Odom, A. L. Org. Lett. 2003, 4, 2853.

21) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074.

22) Lucht, B. L.; Mao, S. S. H.; Tilley, T. D. J. Am. Chem. Soc. 1998, 120, 4354.

23) Mukhopadhay, T.; Seebach, D. Helv. Chim. Acta. 1982, 65, 385.

24a) For the original procedure of oxidation of 4-nonyn-2-ol to 4-nonyn-2-one see,
Brandsma, L.; Verkruij sse, H.D. In Synthesis of Acetlyene, Allenes and Cumulenes;
Elsevier: Amsterdam, 1981.

The compound was prepared from oxidation of 4-nonyn-2-ol, but using Dess-Martin
Periodinane oxidation reported by Dembinski. (b) Sniady, A.; Wheeler, K. A. Dembinski,
R. Org. Lett. 2005, 7, 1769.

25) Tang, P. C.; McCallum, S. J.; Wulff, D. W. J. Am. Chem. Soc. 1981, 103, 7677.

26) Davis, L. B.; Greenberg, S. G.; Sammes, P. G. J. Chem. Soc, Perkin Trans. 1 1981,
1909.

27) Cao, C.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2003, 125, 2880.

28a) Flitsch, W.; Heidhues, R. Chem. Ber. 1968, 101, 3343 (b) Foumari, P.; Tironflef. J.
Bull. Soc. Chim. Fr. 1963, 486 (c) Remers, A. W.; Meiss. J. M. J. Am. Chem. Soc. 1965,
87, 5762 (d) Remers, A. W.; Roth, H. R.; Gibs, J. G.; Weiss, J. M. J. Org. Chem. 1971,
36, 1232.

29) Brown, D.; Griffiths, D.; Rider, E. M.; Smith, C. R. J. Chem. Soc. Perkin Trans. 1,
1986, 455.

30) Jones, R. A.; Mariott, P. T. M.; Rosentahl, W. P.; Sepulveda, J. J. Org. Chem. 1980,
45, 4515.

31) Fischer, H.; Orth, H. In Die Chemie Des Pyrroles; Vol 1, Akad. Verlags; Leipzig,
1934; pp 224.

32) Brandsma, L. In Preparaive Acetylenic Chemistry; Elseim Publishers: Amsterdarn-
London-New York, 1971; pp 137.

33) Yuguchi, M.; Tokuda, M.; Orito, K. J. Org. Chem. 2004, 69, 908.

51

«\J

3)

3)

51..

 

 

A1. I

“\A ‘I-.'

 

34) Von Daacke, A.; Ahlbrecht, H. Synthesis 1984, 610.
35) Davies, A. G.; Julia, L.; Yazdi, S. N. J. Chem. Soc. Perkin Trans. 11 1989, 239.

36) Katritzky, A. R.; Yousaf, T, 1.; Chen, B. C.; Guang-Zhi, Z. Tetrahedron 1986, 42,
623.

37) Ranu, B. C.; Hajra, A. Tetrahedron 2001, 5 7, 4767.

52

. nuns

 

 

Fit

3. ALLYLIC AMINE: SYNTHESIS & MECHANISM INVESTIGATION

3.1 Introduction to allylic amines

Allylic amines are important building blocks in organic chemistry and have been used as
starting materials for the synthesis of numerous compounds such as a- and ,6-amino
acids, various alkaloids, and carbohydrate derivatives.l From a pharmaceutical
prespective, allylamines are present in important antifungal drugs, like Terbinafine

(Lamisil‘m)2a and Naftidine.2b Natural products such as Narciclasinezc and Haouamine2d

also have allylic amine functionality in their core structure (Figure 3.1).

 

NWPh
0" Naftidine
. 9H
' OH
.. , o
. OH
HaouamIne <0 0 NH
I o
N \ é
Narciclasine

00

Terbinafine (Lamisil®)

Figure 3.1. Structure of Terbinafine, Nafiidine, Haouamine and Narciclasine.
A protocol for allylic amine synthesis starting from allyl alcohols was shown by

Overman, which involves a [3,3]-sigmatropic rearrangement of trichloroacetimidates. 3

53

 

 

 

ca

C01

the

011”

1631

the

 

/ 1CCI3CN m 3MNaOH_ /
/ OH 214o°c \ 25°C \

HN HzN

YO
0
CI3C 55 /0 overall

Scheme 3.1. Overman’s procedure for converting allylic alcohols to allylic amines via
1,3-allylic transposition.2

This chapter will not dwell on synthesis of allylic amines catalyzed by a specific
transition metal and will restrict its focus on mechanistic relevance to the titanium
chemistry since there are plethora of articles on allylic amine synthesis mediated or
catalyzed by metals like Cu,4 Ir,5 Rh,6 Ru,7 Au,8 and Pd.9

The [3,3]-sigmatropic rearrangement is a critical reaction in organic chemistry as
highlighted by the classic Claisen and Cope rearrangements.” C—N bond formation is of
fundamental importance to the pharmaceutical industry as more than 90% of the drugs
contain the N-functional group present in the core structure.

The [3,3]-sigmatropic rearrangement is also reported as the mechanistic pathway in
the SOHIO (Standard Oil of Ohio) process. The SOHIO process for ammoxidation of
propylene generates acrylonitrile,ll a vital intermediate in chemical industry. The the key

C—N bond formation step supposedly involves a [3,3]-sigmatropic rearrangement of an

alkoxide and a terminal imido ligand (Equation 3.1). ‘2

300450°c /\
+ 3/202 + NH = // \ + 3H0 (3.1)
2 3 “0003/3le3 N 2

 

Several studies have been carried out investigating the mechanism.13 Since the
reaction is heterogeneous, it is difficult to study compared to a homogeneous one. One of

the proposed steps in the pathway is rate-limiting hydrogen abstraction from propylene to

54

form a symmetric allyl radical. The radical pathway suggested by Grasellil4 involves the
cleavage of a methyl C-H bond of the propylene, by an oxygen atom attached to bismuth
affording an allyl species, which has radical character (Scheme 3). The allyl radical is
trapped by a Mo center to yield a rr-allyl complex followed by subsequent migration of
either end of the allyl group to the Mo=NH bond leading to the formation of allylamido

linkage, which ultimately yields acrylonitrile.

 

H
—\= A o ,0~ /NH
/ ‘ I
,0. .05 loNH 81 ,Mo:
BI Mos ‘—— O NH
/0 (K NH /O \ NH3
{‘91 IMo’i-O
7fi§§ /£>R
011MO<NH 'H20I I: H\
’ /°. , \9
Bi ,Mo
/ / /
OH ’5 /OH :(/ If NV
_,0\ H’N" /°\ N H P.” D\ kai-I

7' Mo\ l MO\
K03» NH\TH jog/Mo ___, /(§)R \0

Scheme 3.2. Graselli’s radical pathway mechanism.l4

An alternate pathway to the above radical mechanism was postulated by Osborn,
wherein; after a formation of Mo-allyloxo species, [3,3]-sigmatropic rearrangement takes
place with a transfer of the allyl group from O to N giving an allyl amido species

(Equation 3.2).”

55

 

The C—N bond formation step has also been examined by Chan.16 A tungsten complex
bearing two tert-butylimido and one tert—butylamido ligands, (W[N‘Bu]2[NH‘Bu]2), (43)
was reacted with a series of allylic alcohols at 110-150 °C .

44

 

K \

Bu'N\\ oNtBU 2 W0” Bu‘NnO [3.3] ButN. ’0
I #7 ’ —_. NV]
Bu’HN NH'Bu Bu'HNIW\ Bum" \
.3 Q 45 \

Scheme 3.3. Proposed pathway for Chan’s rearrangement.16

Heating a 1:1 mixture of W(N’Bu)2(NH’Bu)2 (43) and two equivalents of allylic
alcohol (44) resulted in a bis(imido)bis(allylalkoxide)tungsten(V I) (45) complex with
liberation of tert-butylamine. The allyl group migrates to the imido nitrogen via a [3,3]-
sigmatropic mechanism to form an allyl-tert—butylamido complex, which on hydrolysis
yields the corresponding amine (Scheme 4). Linalool (46) when reacted with 43 at 110
°C for 68 h gave a mixture of rearranged geranyl (47) and neryl amine (48) in 90% yield

on hydrolysis (Equation 3.3).

r t
t x \ t HO
Bu HN NH Bu
100 °C
HZNM + HZNJ—_<—/_<
47 43
geranyl amine neryl amine

56

An interesting result is the experiment performed with allyl alcohol-1,1-d2 (49) under
the same reaction conditions. The reaction afforded a mixture of 22% 1,1- (50) and 78%
3,3-(51) dideuterated allyl-tert-butylamines (Equation 3.4). We will compare this result

with the titanium mediated allylic amines synthesis in Chapter 4.

W<N‘Bu>2<N’Bu>2 + =>(—0H
D D

43 49
1) toluene, 145 °C
68 h

 

V

.. o
->(—NH'Bu + >=\_

t
D D 0 NH Bu

50 22:78 mixture 51

The radical aspect of Graselli’s mechanism for the SOHIO process was also
investigated using Group(VI) metals, Cr and Mo. Benzyl radical was chosen over allyl
radical as stability of benzyl radicals are greater than the allyl ones. Oxidation both

17

benzyl and allyl radicals exhibit similar behavior. Reaction of chromium and

molybdenum bis(imido)bis(trimethylsiloxy) complexes with benzyl radical followed by
hydrolysis yielded benzylidene-tert-butylamine in 52% isolated yield. This experiment
proves benzyl radical can be trapped by bis(imido)bis(trimethylsiloxy) complexes of Mo
(52) and Cr (53) at the imido nitrogen (Equation 3.5)

‘BuN\

Bu‘N

\\ ,NCHzPh

Bu'N\\ ,/N'Bu

+ PhCHz. . / \ 3-5
Me3SiO/ \OSiMea M6330 OSiMes ( )
I +
M = M0 (52), Cr (53) i 'H
PhHC=NtBu

57

Matta18 also studied the behavior and reactivity of Group(VI) metals, viz Mo and W,
for their role in the SOHIO process and potential intermediates in catalytic oxidation of
allylamine into acrylonitrile.19 A tungsten(VI) (54) complex shown in equation 3.6, was
converted to W(IV) allylideneamido complex (55) by treatment with a base like tert-

butyllithium via a fl-hydrogen abstraction.

W(CI)4(THF) iwCDSUHFh
t .
~ __B“_L'__. “I (,6,
\ I
54 55

A Mo(V) complex, Mo(=NCH2CH=CH2)Cl3(PPh3)2 was also synthesized,20 but no
reactivity details were reported.

Osborn through the synthesis of molybdenum complexes viz.
MoOz(OCMe2CH=CH2)2L2 (56) and MoONR(OCMe2CH=CH2)2L2 (57) (L = '/2
bipyridine, CH3CN, or pyridine, R = ’Bu and Ph) studied the 1,3-transposition of allylic
alcohols and also a possible intermediate in the SOHIO process.12 Mo bis(oxo)
complexes catalyze isomerisation of allylic alcohols faster than the corresponding imido
complexes. The isomerisation takes place at room temperature and a [3,3]-sigmatropic

pathway has been postulated as the probable mechanism (Scheme 3.4).

58

 

CH3 CN -10 °C

MoO(Y)C|2 2% jOY 0,:if-llo- >L\\ = Kiggfijo- -o>L\\

Y = O (56), NR (57) L = 1/2 bipyridyl, CH30N. Pyridine

Scheme 3.4. Osbom’s molybdenum catalyst and a [3,3]-sigmatropic rearrangement.12

 

Fun
A detailed study of allyl migration from allyloxo and allylimido to Mo=O or Mo=NR
in the molybdenum-based complexes and their relative rates of transfer were performed.
i
The study concluded with the order of migration in the molybdenum case heavily ;

favoring the 0— based ligand (0 to 0 > 0 to N > N to N). The results also prove the
assumption that migration of allyl groups from an oxo to an imido nitrogen is possible,
and this could indeed play a pivotal role in the C—N bond formation step in the SOHIO
process.

The allylic isomerisation is also utilized in the fragrance industry; wherein, linalool
(46), a key intermediate in making a number of fragrance alcohols, is isomerized by

vanadium oxo complex (Scheme 3.5). 2'

59

i? .
RO/Y\OR )fiMe A R' Me
56 OR W ROecP I Q’ W
R. RO’V§O R0; $2
Me ROH R0 0
ml

R'JE
R' 6
HO \

. l
. RO’V\

R Me R0 0
Hofi

Scheme 3.5. Proposed mechanism for the use of vanadium oxo catalyst in isomerisation
of allyl alcohol.2

Chabardes has extensively reviewed the use of vanadium oxo tris(alkoxy) and siloxy-
based catalysts [VO(OR)3] (58), for their role in 1,3-allylic transposition. He also
reported the use of a tungsten-based catalyst, [WO(OSiPh)3]4 (59), to convert 46 to
geraniol (60) and nerol (61) with 74% selectivity at 200 °c (Scheme 3.6.).22 In both the
above cases a [3,3]-sigmatropic rearrangement has been postulated as the potential
transition state in the mechanism. A superior timgsten based catalyst was reported by
Fujita, which is apparently several times more active than 58 with 93% selectivity and

uses a lower catalyst loading. 23

60

I III“ .3."

 

W catalyst001mol% W

200 °C
linalsool geraniol
catalyst RO\fi/OR
200°C cat= /w\ 59 R=OSi(Ph)3
0 r1; OR
H / I
_ _ \
61
nerol

Scheme 3.6. Use of 59 to convert 46 into 60 and 61 via allylic transposition.22
The first rhenium-oxo catalyzed reaction was demonstrated by Narasaka; wherein,
under acidic conditions tetra-n-butylammonium perrhenate (N Bu4)(ReO4) (62)

isomerized allylic alcohols (Equation 3.7).24

\

 

Me 20 mol% TsOH
CHZCIZ 23 °c 24 h
6-phenyihex-3-en-2-ol 400/ 1-phenylhex4-en-3wl
O

Matsubara demonstrated that bis(acetoacetate)vanadium(IV) [O=V(acac)2] (63) in
combination with a catalytic amount of bis(trimethylsilyl)peroxide (TMSOOTMS)
isomerizes allyl alcohols at room temperature.25 The group also demonstrated the first
example of a chirality transfer with a metal oxo complex to give an enantioenriched
alcohol (Equation 3.8).

H H
9 10 mol% OV(awc)2 (63) 9

30 mol% msooms
> ,.\OH + (3-3)
CHzclz, 23 °C, 5 h Me

 

Me
40% ee 33:; See“ 3?; y.ieeld starting material

61

An efficient catalyst for the 1,3-isomerization of allylic alcohols is O3ReOSiPh326
(64), which is prepared by the reaction of Re207 and Ph3SiOH. It was reported that 1,3-
allylic transpositions of allylic alcohols attained equilibrium within 5 min at 0 °C.27
Calculations performed on this reaction predict a [3,3]-sigmatropic mechanistic pathway
via a chair-like transition state involving an anionic perrehenate moiety and a cationic
allyl moiety (Scheme 3.7). The calculations on the transition state will be discussed in
depth in Chapter 5.

(54)
2 ReO3(OSiPh3) R
1 >

 

 

Scheme 3.7. Osbom’s rhenium catalyst (62) for 1,3 allylic transposition.27

Espenson used a rhenium catalyst, CH3ReO3 (65) to catalyze the 1,3-tranposition of
allylic alcohols.28 A series of allylic alcohols were examined, and isolated yields were
reasonable for most of the products obtained (63-98%) (Equation 3.9). The reaction

works well for aliphatic as well as aromatic substituents on the allyl alcohol.

”3

H CH3ReO3 (65) HO—FisoH
\XR O” —> UR + ('19:: -0 (3.9)
\

64 has also been utilized to selectively isomerize allylic alcohols in a catalytic process

 

reported by Grubbs, to yield the E-isomer preferentially.27 The reactions are high yielding

and are complete in less than 30 min at room temperature. Electron-rich allyl substrates

62

readily isomerize at -50 °C, but exhibit a side product at elevated temperatures. A general
procedure to selectively convert tertiary allylic alcohols to primary allylic alcohols was

also reported with the addition of N,0—bis(trimethylsilyl)acetamide (BSA) (Scheme 3.8).

.. 05 5;,0 _
\ OH ReO3OSiPh3(64) ,Ree‘ j
Me ' ’ ,7 i HO / Me

1.2 BSA ~ ' M
+ e

5 Ph3SiOH (64) [5:2
99:1

 

 

 

Scheme 3.8. Conversion of tertiary to primary allylic alcohols using 64 and BSA.27

A comparison of early transition metal catalysts versus rhenium oxo complex
catalyzed shown below.27 From the table one can clearly see that rhenium is the most
efficient transition metal that can be used for allylic transposition. The reaction with 64

along with BSA and TMSA catalyzes the allylic transposition of 66 to 67 in 30 min at 23

°C.

63

Table 3.1. Comparison of some early transition metal catalysts for 1,3 allylic
transposition.

 

 

 

H Me
Me LnM=O l
‘ - Me / OH
Me / \
Me
Me . _
3,7-d'methylocta-1 ,6—dien-3-ol (66) 3.7-dlmethylocta-2.6-dlen-1-o| (67)
temp time ratio

entry catalyst (mol%) solvent (0C) (11) (66367)
1 OW(OSiPh3)4 (0.003) neat 200 3 70:30

2 OW(OSiPh3)4 (0.007) neat 160 1.5 69:31
3 OW(OMe)4-pyridine (0.01) neat 200 3 61 :39
4 OV(O’Bu)4 (0.054) neat 200 2.5 62:38
5 OV(acac)2-(TMSO)2 (10) CH2C'2 23 12 82: 18
6 O3ReOSiPh3 (2) 5,20 23 0.5 62:38
7 O3ReOSiPh3/BSA/TMSA 5120 23 0.5 11:39

An interesting Group(IV) imido complex was reported by Bergman, which undergoes
rearrangement via a SN2’ substitution from allylic ethers to yield allylic amines.29 A
zirconocene imido complex (68) (Scheme 18) reacts with allylic ethers at 70 °C followed
by the addition of Cszl (Cbz = PhCHzOCO-) to give substituted allylic amines in 90%

yield. The reaction also shows preference for Z substituted allylic ethers (Equation 3.10).

 

NHCbz
R _ 1 c o , 16h 70°C
v + szzlr—NTBS ) 6 6 a M (3.10)
Me3SiCH20 THF 2) Cszl, THF R
K co .23 °C
63 2 3 R= C3H7, C5H9,C3HGOC6H5,

C3HBCI,CZH4SZC4H7
The substitution reaction tolerates a variety of functional groups including terminal

alkenes, phenyl ethers, and 1,3-dithianes. The mechanism is though to proceed via the

64

formation of an imido complex, that makes an adduct with THF (solvent). The active
species is formed by the loss of THF, and then reacts with the silyl ether via an SN2’
mechanism to give the allylic amine. The proposed transition state for the reaction,

keeping in mind the regiospecific nature of this reaction is chair-shaped structure

(Scheme 3.9).

 

THF + Cp22r=NTBS

 

Cpgfir=NTBS
THF 68
“[8

S
R1 R2 N \ R
—_—> I 1
Cp22r=NTBs + ROMRB cpzcz):R 13R?

' H R2 ‘

Ci/k

R """"" I R
1 I’ v’zr I 3
v’ “\N

\

b —

 

 

Scheme 3.9. Reaction of zirconium imido complex (68) to give allylic amines via SN2’
allylic substitution.29

65

3.2 Conclusion

A review of allyic amines in this Chapter point towards their importance as vital
intermediates in pharmaceutical and chemical industries. Several transition metals are
used to catalyze the formation of allylic amines. A [3,3]-sigmatropic rearrangement has
been proposed as the transition state in the mechanistic pathway for reactions like 1,3-

transposition of allylic alcohols and the SOHIO process for synthesis of acrylonitrile.

66

3.3 References

la) For review see: Johannsen, M.; Jorgensen, K. A. Chem. Rev. 1998, 98, 1689 (b)
Catviela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517 (c)
Petranyi, G.; Ryder, N. S.; Stutz, A. Science 1984, 224, 1239 ((1) Johnson, T. A.; Curtis,
M. D.; Beak, P. J. Am. Chem. Soc. 2001, 123, 1004.

2a) Gupta, A. K., and Shear, N. H. J. Am. Acad. Dermatol. 1997, 37, 979 (b) Parish, C.
L.; Uitto, J. J. Int. J. Dermatol. 1991, 30, 73 (c) Hudlicky, T.; Rinner, U.; Gonzalez, D.;
Akgun, H.; Schilling, S.; Siengalewicz, P.; Martinot, T. A.; Pettit, G. R. J. Org. Chem.
2002, 6 7, 8726 (d) Baran, P. 8.; Burns, N. Z. J. Am. Chem. Soc. 2006, 128, 3908.

3a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597 (b) Overman, L. E. J. Am. Chem.
Soc. 1976, 98, 2901 (c) Overman, L. E.; Kakimoto, M. J. Org. Chem. 1978, 43, 4564 (d)
Overman, L. E. Acc. Chem. Res. 1980, 13, 218.

4a) Germon, C.; Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1980, 21, 3763. (b)
Baruah, J. B.; Samuelson, A. G. Tetrahedron 1991, 4 7, 9449.

5a) Shekhar, S.; Trantow, B.; Leitner, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
11770. (b) Hu, C.; Leitner, A.; Hartwig, J. F. Angew. Chem. Int. Ed. 2004, 43, 4797. (c)
Defeiber, C.; Ariger, M. A.; Moriel, P.; Carriera, E. M. Angew. Chem. Int. Ed. 2007, 46,
3139. (d) Weihofen, R.; Tverskoy, O.; Helmchen, G. Angew. Chem. Int. Ed. 2006, 45,
5546.

6a) Hayashi, T.; Ishigedani, M. Tetrahedron 2001, 5 7, 2589. (b) Evans, P. A.; Robinson,
J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121, 6761.

7) Ragaini, F.; Cenini, S.; Turra, F.; Caselli, A. Tetrahedron 2004, 60, 4989.

8) Guo, 8.; Song, F.; Liu, Y. Synlett 2007, 964.

9) Lee, E. E.; Batey, R. A. Angew. Chem. Int. Ed. 2004, 43, 1865 (b) Lee, E. E.; Batey,
R. A. J. Am. Chem. Soc. 2005, 127, 14887 (c) Chen. 3.; Mapp, A. K. J. Am. Chem. Soc.
2004, 126, 5364; J. Am. Chem. Soc. 2005, 127, 6712 (d) Ferguson, M. L.; Senecal, T. D.;
Groendyke, T. M.; Mapp, A. K. J. Am. Chem. Soc. 2006, 126, 4576 (e) Besson, L.; Gore,
J .; Cases, B. Tetrahedron Lett. 1995, 36, 3857 (f) Tamaru, Y.; Bando, T.; Kawamura, Y.;
Okamura, K.; Yoshida, Z.; Shiro, M. Chem. Commun. 1992, 20, 1498.

10a) Claisen, L. Ber. 1912, 45, 3157 (b) Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc.
1940, 62, 441.

11) Graselli, R. K. Catalysis Today 2005, 99, 23.

67

 

12a) Belgacem, J.; Kress, J.; Osborn, J. A. J. Am. Chem. Soc. 1992, 114, 1501 (b)
Belgacem, J.; Kress, J .; Osborn, J. A. J. Mol. Cat. 1994, 86, 267 (c) Bellemin—Laponnaz,
S.; Gisie, H.; Le Ny, J. P.; Osborn, J. A. Angew. Chem. Int. Ed. Engl. 1997, 36, 976.

13a) Keulks, G. W. J. Catal. 1970, 19, 232 (b) Keulks, G. W.; Krenzke, D. L. In Proc.
Int. Cong. Catal. 6th: 1976 (c) Wragg, R.D.; Ashmore, P. G.; Hockey, J. A. J. Catal.
1971, 22, 49 (d) Peacock, J. M.; Parker, A. J.; Ashmore, P. G.; Hockey, J. A. J. Catal.
1969, 15, 398 (e) Adams, C. R.; Voge, H. H.; Morgan, C. 2.; Armstrong, W. E. J. Catal.
1964, 3, 379 (t) Trifiro, F .; Pasquon, I. J. Catal. 1968, 12, 412 (g) Rossi, S. D.; LoJacono,
M.; Porta, P.; Valigi, M.; Gazzoli, D.; Minelli, G.; Anichini, A. J. Catal. 1986, 100, 95
(h) Voge, H. H.; Wagner, C. D.; Stevenson, D. P. J. Catal. 1963, 2, 58 (i) McCain, C. C.;
Gough, G.; Godin, G. W. Nature 1963, 198, 989.

14a) Adams, C. R.; Jennings, T. J. Catal. 1963, 2, 63; 1964, 3, 549. (c) Burrington, J. D.;
Kartisek, C. T.; Graselli, R. K. J. Org. Chem. 1981, 46, 1877.

15) Belgacem, J .; Kress, J, Osborn, J. A. J. Mol. Cat. 1994, 86, 267.
16) Chan, D. M. —T.; Nugent, W. A. Inorg. Chem. 1985, 24, 1424.

17) Sheldon, R. A.; Kochi, J. K. In Metal Catalyzed Oxidations of Organic Compounds,
Academic Press: New York, 1981; pp 324.

18) Matta, E. A.; Du, Y. J. Am. Chem. Soc. 1988, 110, 8249.
19) Schuit, G. C. A.; Gates, B. C. CHEMTECH 1983, 13, 693.
20) Matta, E.A.; Du, Y.; Rheingold, A. L. J. Chem. Soc., Chem. Commun. 1990, 756.

21) Parshall, G. W. Ittel, S. D. Homogeneous Catalysis, 2nd ed; Wiley Interscience: New
York, 1992; pp 19.

22) Chabardes, P.; Kuntz, E.; Varagnat, J. Tetrahedron 1977, 33, 1775.
23) Hosogai, T.; Fujita, Y.; Ninagawa, Y.; Nishida, T. Chem. Lett. 1982, 357.

24a) Naraska, K.; Kusama, H.; Hayashi, Y. Tetrahedron 1992, 48, 2059 (b) Naraska, K.;
Kusama, H.; Hayashi, Y. Chem. Lett. 1991, 1413.

25a) Matsubara, S.; Okazoe, T.; Oshima, K.; Takai, K.; Nozaki, H. Bull. Chem. Soc. Jpn.
1985, 58, 844 (b) Matsubara, S.; Takai, K.; Nozaki, H. Tetrahedron Lett. 1983, 24, 3741.

26) Schoop, T.; Roesky, H. W.; Noltemeyer, M.; Schmidt, H.-G. Organometallics 1993,
12, 571.

27) Morrill, C.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 12 7, 2842.

68

28) Jacob, J.; Espenson, J. H.; Jensen, J. H.; Gordon, M. S. Organometallics 1998, 17,
1835.

29) Lalic, G.; Blum, S. A.; Bergman, R. G. J. Am. Chem. Soc. 2005, 127, 16790.

69

4. SYNTHESIS OF ALLYLIC AMINES

4.1 Introduction
In Chapter 3 we saw an example of a stoichiometric reaction between a Group(IV)
zirconium-imido complex and an allylic ether to make an allylic amine. We also came

across examples of Group(V) and -(V I) metals as catalysts for allylic transposition.

 

it

Currently ReSiOPh3 is the fastest catalyst available for 1,3-allylic transposition of allylic 1"

alcohols. We intended to develop titanium-mediated conversions of allylic alcohols to ;.
allylic amines.

Our efforts towards the synthesis of allylic amines involve the use of stoichometric E

amounts of Ti(NMe2)4 (l) as shown in Scheme 4.1. One can envision the formation of
tris(dimethylamido)allylalkoxide titanium (IV) (69), when one equivalent of allyl alcohol
(44) reacts with one equivalent of 1. We propose that, with addition of
aniline (2) to 69, a titanium imido complex (70) is formed that can potentially undergo a
[3,3]-sigmatropic rearrangement to give a titanium oxo complex, which would ultimately

yield N-phenyl allylamine (71) after an aqueous quench.

NH;
I'Dh
v?
_ _ 2 /Ti)\
Ti(NMe2)4 ,‘XOH —> Ti(NMe2)3(Ox_ )—> NMez o
1 44 69 7O
1 [3,3]-sigmatropic
rearrangement
Ph /
H20 til/\/
H 71 NMez/ °O

Scheme 4.1. Proposed methodology for allylic amination of 44 by 2 mediated by l.

70

Reactions carried out with one equivalent of 2 did not show good product conversion.
Experiments were then performed with varying amounts of 44 and 2. The reaction
showed higher product conversion with larger amounts of amine. Ultimately, the
optimized conditions involved addition of three equivalents of 2 (Equation 4.1). The
optimization also includes initial reaction of 1 with 44 in toluene at room temperature
with stirring for a few minutes followed by the addition of 2 and heating the reaction at

160 °C (Equation 4.1).

 

. =4 3 PhNHz (22 _ ph. V
TKNMeZh + OH toluene, 160 °C H (4.1)
1 44 24 h 71
78%(51%)
GC(isoIated)

Several allylic alcohols were examined with a series of amines, and a library of
secondary allylic amines was synthesized. The next part in this chapter will discuss the
preparation of allylic amines, synthesized with varying substituents on the allylic alcohols
screened with a series of amines.

4.2 Synthesis of library of allylic amines

4.2.1 Reaction with allyl alcohol (44)

With the optimized conditions in hand, N-allylaniline (71) was synthesized using 44
and 1 stoichiometrically along with three equivalents of 2, yielding 51% of the isolated
product after 24 h. Replacing 2 with benzhydrylamine (8) yielded N-(benzhydryl)—N-
allylamine (72) in 50% isolated yield after 18 h. Product 72 contained trace amounts of
impurities associated with benzhydrylamine decomposition. For more information see
General Methods (pp 88-89). Cyclohexylamine (14), on reaction with 1 and 44, gave N-

cyclohexyl-N—allylamine (73) after 24 h at 160 °C in 30% isolated yield (Equation 4.2).

71

 

3RNHi _ RtN/V
toluene, 160 °C H

1 44 GC(isoIated) time
71 R = Ph (2), 78%(51%), 24 h
72 R = PhZCH- (a) 72%(50%), 18 h
73 R = CyNHz (14) 63%(30%), 24 h

Ti(NMe2)4 + =LOH (4.2)

In light of the experimental data, a deuterium labeling experiment was carried out

with 1,1-dideuteroallyl alcohol1 (49), 2, and 1 (Equation 4.3).

 

3 PhNHz (2) ph J
Ti NMe + _ —" ; ‘ (4-3)
( 2)‘ >V0H toluene, 160 °C {‘1 D
o o 24 h

1 49 50

N-phenyl-3,3-2H-allylamine (50) was the product isolated from the reaction proving
the reaction is regioselective for 1,3-allylic transposition. By comparison, a similar
experiment conducted by Nugent and Chan,2 resulted in a 22:78 mixture of labeled
products (see Chapter 3 equation 3.4). This reaction will be further discussed later in this

Chapter.

4.2.2 Reaction with 2-methyl-3-buten-2-ol (74)

Reaction of 1 with one equivalent of 2-methyl-3-buten—2-ol (74) and three equivalents
of 2 yielded N-(3-methyl-2-butenyl)-N-aniline (75) in 74% yield after 10 h. Replacing 2
with 8 gave N—(3-methyl-2—butenyl)-N-benzhydrylamine (76) after 16 h in 72% yield.
Product 76 contained trace amounts of impurities associated with benzhydrylamine

decomposition. For more information see General Methods (pp 88-89). With 14 as the

72

 

amine, N—(3-methyl-2-butenyl)-N-cyclohexylamine (77) was obtained in 69% yield after

16 h (Equation 4.4).

 

— 3RNH2 R, /\2\
Ti NMe + —* > N 4.4
( 2)‘ 9‘0“ toluene, 160 °c H ( )
1 74 GC(isoIated) time

75 R = Ph (2), 97%(74%), 10 h
76 R = PhZCH- (8) (72%), 16 h T
77 R = CyNH2 (14) (69%), 16 h

4.2.3 Reaction with EsZ-2-buten-l-ol (78)

Reaction of l with three equivalents of 2 and one equivalent of EsZ-2-buten-l-ol (78)

 

yielded (:l:)-N-(3~buten-2-yl)aniline (79) after 8 h in 31% isolated yield. No product was r
isolated when 14 and 8 were reacted with 78 (Equation 4.5). The product 79 contains a
small amount of N—(2-butenyl)aniline (80), confirmed by NMR spectroscopy and MS(EI).
Compound 80 was inseparable from 79. Formation of 80 is possible due to multiple

transfers instead of allylic transposition. This result will be discussed in depth in Section

 

 

4.7.
NH2
3 (2)
. _ _ : Phx JV
Tl(NMeZ)4 + ROH r toluene 160°C {ti (45)
8h
1 73 79
57%(31%)
GC(isoIated)

4.2.4 Reaction with 3-buten-2-ol (81)

Reaction of 1 with three equivalents of 2 and one equivalent of 3-buten-2-ol (81) gave
(E:Z)-N-(2-butenyl)aniline (80) in 80% yield after 10 h. The ratio of E:Z was 2:1, and

consistent with GC-FID. The product contains a small amount of (i)-N-(3-buten-2-

73

yl)aniline (79) confirmed by NMR spectroscopy and MS(EI). Compound 79 was
inseparable from 80. This result will be discussed in depth in Section 4.7. Replacing
aniline by 8 gave (E:Z)-N—(2-butenyl)benzhydrylamine (82) after 8 h. Compound 82
could not be isolated as a pure compound even after column chromatography and
distillation. The presence of compound 82 was detected by 1H NMR, and the GC yield is
87%. The ratio of E:Z was 1:2. Reacting l, 80, and three equivalents of 14 gave (E:Z)-N-

(2-butenyl)cyclohexylamine (83) in 30% isolated yield after 10 h at 160 °C. The ratio of

E:Z was 1:2 (Equation 4.6).

‘ ¥
7 7'

toluene, 160 °c H
1 80 GC(isoIated) time

81 R = Ph (2), (80%), 10 h E:Z 2:1
82 R = PhZCH- (8) 87%. 8h E:Z 1:2
33 R = CyNH2 (14) 61 %(30%), 10 h E:Z1:2

(4.6)

. —" 3RNH \ A;
Ti(NMez)4 + ‘>—OH 2 R N

4.2.5 Reaction with 2-phenyl-3 -buten—2-ol (84)

Reaction of 1 with three equivalents of 2 and one equivalent of 2-phenyl-3-buten—2-ol
(84) after 36 h, gave (E:Z)-N-(3-phenyl-2-buteny1)aniline (85) in 57% yield. The ratio of
E:Z was 1:2. Replacing 2 with 8 gave (E:Z)-N-(3-phenyl-2-butenyl)benzhydrylamine (86)
in 54% isolated yield with an E:Z ratio of 5:1 (Equation 4.7). Product 86 contained trace
amounts of impurities associated with benzhydrylamine decomposition. For more
information see General Methods (pp 88-89). Cyclohexylamine did react under these

conditions, but the product could not be isolated as a pure compound.

74

Ph

Ti(NMe2)4 + _>YOH 3RNH2 A? R‘N/j‘m" (4.7)

Pb toluene, 160 °C H

 

GC(isoIated) time
85 R = Ph (2), 69%(57%), 36 h
86 R = PhZCH- (8) 68%(54%). 36 h

1 84

4.2.6 Reaction with 2-phenyl-2-propen-l-ol (87)

Reaction of 1 with three equivalents of 2 and one equivalent of 2-phenyl-2-propen-1-

_._._ c.-. u_ 1',"

01 (87) after 15 h, gave N-(2-phenylallyl)aniline (88) in 31% yield. The benzhydrylamine

derivative could not be isolated, but the cyclohexylamine derivative, N-(2-

 

phenylallyl)cyclohexylamine (89) was isolated after 15 h in 45% isolated yield (Equation L
4.8).

Ph 3 RNH2

‘ R‘
T. NM + =< > V Y 4.8
'( e2)4 OH toluene, 160 °C H Ph ( )

1 87 GC(isoIated) time

88 R = Ph (2), 40%(31%), 15 h
89 R = Cy (8) 58%(45%), 36 h

 

4.2.7 Reaction with 3-phenyl-2-propen-1-ol (90)

Reaction of 1 with three equivalents of 2 and one equivalent of 3-phenyl-2-propen-1-

01 (90) gave N-(2-phenylallyl)aniline (91) in 20% yield after 40 h (Equation 4.9).

 

_ 3 PhNHz (2) _ n
T'mMeZ)‘ + phr\—QH toluene, 160 °C A ‘Ph (4.9)
40 h Ph
1 90 37%(20%) 91
GC(isoIated)

4.2.8a Reaction with 3-methy1-2-buten-1-ol (92)

Interestingly, no product formation was seen in the reaction between 3-methyl-2-

buten-l-ol (92) with 1 and using 2, 8, and 14 (Figure 4.1). The lack of reactivity of 92 can

75

be explained on the basis of sterics, since having two methyl groups in the terminal

position may inhibit the reaction.

Ho.

92

Figure 4.1 . 3-methyl-2-buten— 1 -01 (92).

4.2.8b Reaction with 2-methyl-2-propen-l-ol (93)
A trace amount of product is seen in the reaction between 2-methyl-2-propen-l-ol (93)

and 1 with amines 2, 8 and 14 afier 7 (1 (Figure 4.2) at 180 °C (~15% by GC yield).

=9...

93
Figure 4.2. 2-methyl-2-propen-l-ol (93).

It is startling to see only a trace amount of product formation when 1 reacts with 93,
since having a methyl in the ,B-position of the allyl alcohol (44) should not hamper the
reactivity in any way. A deuterium labeled reaction was carried out with 2-methyl-2-
propen-1,1-2H-1-ol3 (94) with 2 and l. The reaction was heated at 180 °C for 7 d, and
10% of the product, N—(2-methyl-2-propen-3,3-H2)-aniline (95), was isolated by column
chromatography. As in the case of reaction with allyl alcohol 50, the 1,3—transposition

product 95 is the only one observed (Equation 4.10).

=<, 3 PhNHz (2) Ph /
Ti NMe + _'"" t \ (4-10)
( 2” 0“ toluene, 180 °C H D

D D 168 h
1 94 95

 

76

4.3 Discussion of mechanism for reaction of allyl alcohol to allylic amine

In light of the experiment with allyl alcohol 93, there is good reason to believe that
[3,3]-sigmatropic rearrangement may not be involved in the reaction. An alternate
mechanism would be the [2+2]-cycloaddition/retro-[2+2]-cycloaddition pathway that has
received little attention in literature.4 An example from Casey’s group involves formation
of 1-p-toyl-3-buten-1-one via a pseudo-Claisen rearrangement of a tungsten allyloxy
carbene complex that can either undergo a [3,3]-sigmatropic pathway or a [2+2]-
cycloaddition/retro-[2+2]-cycloaddition pathway followed by reductive elimination to

give the product (Scheme 4.2).

filftla/Ai.

F
(CO)5W:()
R

 

L [m

 

 

 

R

/
Dian;

Scheme 4.2. Possible route for rearrangement via [3,3]-sigmatropic and [2+2]-
cycloaddition/retro-[2+2]-cycloaddition pathway.

We saw in Chapter 1 that 1 reacts with 2 to form a titanium-imido complex (Chapter
1, Scheme 1.12). We propose a [2+2]-cycloaddition/retro-[2+2]-cycloaddition pathway
for the titanium case; wherein, afier the addition of allyl alcohol (44) to 1 followed by the
addition of aniline (2), a titanium-imido alkoxide (70) is formed (Scheme 4.1). This can

undergo a [2+2]-Cycloaddition reaction to give two fused 4-membered rings

77

 

(oxazatitanobicyclo[2.2.0]hexane 96), which can undergo a retro-[2+2]-cycloaddition to

give the allylic amine (Scheme 4.3).

 

   

 

 

44
1 _
Ti(NMe2)4 2 = “if” __. (WI
l .
1 3.3"“”“:éolc ‘° m...
uene,
24h 7° [2+2]
lcycloadditio
- -1 retro-[2+2]-
Ph~N cycloaddition
I
[W1
0
96

Scheme 4.3. Proposed [2+2]-cycloaddition/retro-[2+2]-cycloaddition pathway for the
titanium chemistry through transition state 96.

Replacing the methyl in the ,B-position of 93 by a phenyl group shows some reactivity
(see Section 4.2.6) which supports an idea of some partial electronic component to this
reaction. After the formation of the transition state 96, the carbon adjacent to the titanium
would have a partial negative charge and the electropositive titanium a partial positive
charge. The partial negative charge on the carbon is stabilized by a phenyl group, where

the charge is delocalized compared to the electron-donating methyl group (Scheme 4.4).

78

 

 

h
1) < OH 37 Ph H Ph.
. N
Ti(NMe2)4 : ”mph 5+ 1 Igp
2) 3PhNH2(2) [“1
1 88 o

 

 

3) tolm‘flgvh160 C 40% isolated

' "I

1) =<_ 93 CH3 H Ph.
, OH N
Tu<NMe2>4 = AN»: and 9H3
1 2) 3PhNH2(2) l
o 15% product observed 0
3) ‘°'“e"e' 16° C by GC-FID after168h

at 180 °C _ J

 

 

 

Scheme 4.4. Replacing methyl by phenyl in 93 enhances reactivity.
4.4 Reaction with homoallylic alcohol

An attempt was made to isolate [2+2]-cycloaddition intermediate by using a
homoallylic alcohol like 3-buten-1-ol (97). Initial experiments performed with 97 and 2
showed a trace amount of the product with a mass expected for transfer of the homoallyl
fragment to 2 by GC/MS (m/z = 147). Alcohol 97 reacts with 8, but the product could not
be isolated due to impurities present. The product was inseparable from diphenylmethane
[MS(EI) m/z =168 (M+)], benzhydrylamine [MS(EI) m/z = 183 (M4)], and an unidentified
compound [probably N—(diphenylmethylene)-l,l-diphenylmethanamine with MS(EI) m/z
= 347 (W)]. For more information see General Methods (pp 88-89). Reaction of 1 with
one equivalent of 3-buten-1-ol (97) with 14 for 60 h, at 180 °C gave l-azaspiro-[5.5]-
undecane (98) in 35% isolated yield. There was no N-(3-butenyl)cyclohexylamine

observed in the reaction (Equation 4.11).

79

ZI

 

. — 3 CYNHz (14)
Ti(NMe2)4 + —\_\ = (4.11)
toluene, 180 °C

OH
60 h
1 93
97 63% (35%)

GC(isoIated)
The core structure of the natural product Histrionicotoxin contains a spiro structure
similar to the product obtained by the reaction of CyNHz (14) with 97. Histrionicotoxin is
isolated from the neotropical poison arrow frog Dendrobates Histrionicus in quantities of

less than 20 mg per frog5 and is found to be potent inhibitor of the acetylcholine receptor

/
/ /§
|_ OH
H

Figure 4.3. Structure of (-)-Histrionicotoxin.

channel (Figure 4.3).

The successful total syntheses of (-)-histrionicotoxin were demonstrated by Kishi,6
Stork,7 and more recently by Fuchs.8 The parent spiro compound 98 has been synthesized

previously in seven steps in 6% overall yield (Scheme 4.5).9

80

 

0 NO NO
N02 W 2 2
O/ OEt > CH20H2COOEt CHZCHZCOOH

NH2 N02 Mo2

Pd- C
©0H20H2CH2COOEt ‘—2/——H OCHchfiHzCOOEt ‘—-—-— OCHZCHZCOC'

lheat
EtOl-l

d5 0’9

Scheme 4.5. Literature procedure for synthesis for 1-azaspiro-[5.5]undecane.9
4.5 Mechanism for conversion of homoallylic alcohol (97) to l—azaspiro-[5.5]-undecane
(98)

In an attempt to get evidence for how product 98 is formed a homoallylic alcohol (99)
with deuterium atoms next to the carbon was synthesized using the literature procedure,'0
and a reaction was performed using alcohol 99, l, and 14 at 180 °C. Surprisingly, the

deuterium atom ends up on the carbon adjacent to the nitrogen atom in the product (100)

(Equation 4.12).

 

H
N D
Ti(NMe2)4 + — D 3CyNHZ(14) > (4.12)
3% toluene,h180 °C D
1 99 60 100

The proposed mechanism for this transformation is shown below and involves a

migration of a homoallyl fragment from an alkoxide to the imido nitrogen (Scheme 4.6).

81

 

 

 

£3

Scheme 4.6. One possible mechanism for the formation of 100.

A scheme for the formation of spiro compound involves a four-membered transition
state (101), and an alkyl migration takes place where the homoallyl fragment transfers to
the imido nitrogen. A fl-hydride elimination follows the alkyl migration step, which takes
place from the tertiary carbon of the cyclohexylamine followed by a nucleophilic attack
of carbon adjacent to titanium on the quaternary carbon to give a spiro structure.

One example of a transition state similar to 101 reported in literature11 is the four-
membered transition state of (Silox)2Ti=NSi'Bu3 (Silox = -OSi’Bu3) apparently involved

in C—H activation (Figure 4.4).

 

 

Figure 4.4. Example of a 4-membered transition state with titanium.ll

82

A brief description of precedent for alkyl, aryl and hydride migration to terminal
oxo complexes is described as migration to terminal oxo complexes are more common.
4.6 Explanation for alkyl migration in homoallylic alcohol

There are few examples of an alkyl migration to an imido nitrogen or a terminal oxo
position on a transition metal. An aryl to imido nitrogen migration was suggested by
Chan for his observation with a tungsten complex (43) (Chapter 3, Scheme 4). Examples
of migration of an alkyl group attached to an alkoxide to give a metal oxo complex are
described below. The migration of alkyl or hydride to a terminal oxo has been proposed
as a method of oxidation of an organic fragement.12 Migration of an alkyl or hydride
from an alkoxide to a metal center to yield a terminal oxo complex also has been seen in

a handful of cases (Equation 4.13).

R
0 ?/
II
MQR—> M(n-2)+ (4.13)
metal oxo metal akoxide

Migration of an alkyl group in alkoxide to metal center takes place in Cp'zTaOCH3
(Cp' = qS-CsMes), which rearranges to the isomeric metal oxo methyl complex,
Cp‘zTa(O)CH3.l3. An example of a hydride migration occurs in tris(3-hexyne)hydroxy
rhenium(I) to the corresponding bis(3-hexyne)(oxo)hydrido rhenium(III) in benzene as
seen in Equation 4.14.l4

Et‘ t j: Et IL;\
\\<‘& Z awajlfi H (4.14)

Et Et Et'— '3

 

83

An example of aryl migration to a terminal oxo is the rearrangement of the phenyl
complex, (HBp23)ReO(Ph)Cl (HBpZ3 = hydrotris(1-pyrazolyl)borate), via a
photochemical pathway to give (HBpZ3)Re(OPh)(Cl)py as seen in Equation 4.15.l5

,Ph
8,0 M 943'

N'Re‘Ph ————> N'. 8W (4.15)
RU. "Y “F1

C606

N
(Q) =Hydrotris(1-pyrazolyl)borate
N

py= pyridine

An alkyl migration has also been observed in (HBpZ3)ReO(C2H5)Cl to give
(HBpZ3)Re(OC2H5)(Cl)py using UV photolyis in benzene. Both migrations (alkyl and
aryl) described above do not rearrange under thermal conditions even at 160 °C.

4.7 Evidence against alkyl migration in homoallylic alcohol

In section 4.4 we saw the reaction of homoallylic alcohol 97 with 14 mediated by 1
yielded the spiro compound 98. The deuterium labeling studies carried out places the
deuterium atoms in the product 100 adjacent to the nitrogen atom suggesting an alkyl
migration in homoallylic alcohol compared to 1,3-allylic transposition in the case of
allylic alcohols (See Section 4.2.1). The homoallylic alcohol reaction requires longer
reaction times and higher temperature compared to allylic alcohol reaction. This suggests
that alkyl migration is slower than allylic transposition. Reaction of deuterated allyl
alcohol 49 with 2 mediated by 1 yields one single allylic amine product 50 (Equation

4.3). A similar deuterium labeling carried out with deuterated 2-methyl-2-propen-l-ol 94,

84

yields the 1,3-allylic transposition product 95 in 10% yield after 7 d at 180 °C. This data
suggests that alkyl migration may not be possible in the case of allylic alcohols.

In the case of formation of minor allylic amine products N-(2-butenyl)aniline (80) in
the reaction of (E:Z)-2-buten-l-ol (78) and (i)-N-(3-buten-2-yl)aniline (79) in the
reaction involving 3-buten-2-ol (81), multiple transfers may be possible. In the case of
reaction of 78 with Ti(NMe2)4 (1), after the formation of product 79 there exists a
possibility of 79 coordinating with titanium imido complex to give 102 (Scheme 4.6).
The titanium imido complex is formed by the reaction of (l) and aniline (2). Intermediate
102 can then undergo a retro-[2+2]-cycloaddition to give the minor allylic amine product

80. A similar argument can be made in the reaction of allyl alcohol 81.

Ti(NM82)4 4. Pthk/ PthJ\/

H [2+2]- I ,
cycloaddition T'(NW‘eah
1 79

 

PhNI-I2 (2)

F — I /\}
Ph. /
P”‘~— l J
Ph. /
l N

 

 

 

 

 

. [Ti]
ml—l retro-[2f2_]- | H20 H
N—i cycloaddition ,NH
/ \ Ph so
i- Ph _
102

Scheme 4.7. Mechanistic explanation for the formation of 80 in the reaction between 78
and 2 by 1.

85

Table 4.1. Library of allylic amines synthesized using our methodology

 

 

Entry

l

10

ll

12

l3

14

15

 

Amine
2

8

l4

l4

I4

14

 

Alcohol

WOH
44

3,...

74

78

90

 

Product
ll
A; ‘Ph 71
WN‘CHPhZ 72
H
N.
A Can 73
, H
h" 75
Ph
,, H
N, 76
CHth
h“
06”" 77
H
dN‘ph 79
H

WN‘Ph 31

H
/ \
wN CHPhg 82

H

W CGHH 83

/ H
hN. 35
Ph
RH
N\
CH P112 35

Ph
H
a. ..

Ph
Ph

Ph P“
H
N\ 39
06““
/ H
WN‘ 91
Ph Ph

 

GC%(isolated%)

78(51)
72(50)

63(30)

9704)

(72)

(69)

57(31)

(80)

(87)

(6l)30

69(57)

68(54)

40(31)

58(45)

37(20)

 

 

4.8 Reaction with n-butanol

To verify the transfer of alkyl group to a titanium-imido complex, a series of reactions
were attempted with n—butanol (105) and titanium compounds (Equation 4.16).

Table 4.2. Reaction of titanium substrates with n-butanol (105).

 

 

 

 

 

 

 

 

 

 

 

 

Entry Titanium substrate (eqv) Amine RI Yield(GC)% Time h
l TiCl(NMe2)3 (103) (3) Aniline (2) 12 72
2 Ti(NMez)4 (l) (3) Ph3SiNH2 (104) >90 24
3 Ti(NMe2)4 (l) (1.1) Ph3SiNH2 (104) 85% 24
1
Ti substrate + MOH > R NHZ : MNHR‘ (4'16)
105 1) toluene, 160 °C

R= Ph3Si- (107)
No reaction was seen with secondary alcohol (sec-butanol), tertiary alcohol (tert—butanol)
and aryl alcohol (phenol).

4.9 Reaction with TiCl4 (108)

Reactions were also perorfmed with TiCl4 (108), one equivalent of base, 44 and 2.
(Equation 4.17). A series of different bases were used and the results are shown in
Equation 4.17. The reaction does show some reactivity with piperidine as the base. These
are some preliminary data and one could further explore the use of other bases to perform

the reaction.

87

TiCI4 + base + =\—OH

108

44

3RNH2

toluene, 160 °C

88

\ /
Ph N/\/ (4.17)
H
72
base 60
piperidine 20—30%
Et3N <15%
EtzNH <10%
tBuNH2 -

4.10 General Methods

All reactions, unless otherwise specified, were performed under an inert atmosphere of
nitrogen. All chemicals were purchased commercially, were purified prior to use, and
stored in a MBraun glove-box. Distilled solvents were transferred under vacuum into
vacuum-tight glass vessels and stored in glove-box. Lithium aluminum hydride and
lithium alumintun deuteride were purified before use.'6 Ti(NMe2)4 was synthesized using
the literature procedure.l7 Allyl-1,1-d2-alcohol,l 3-buten-l-ol-I,1-alg-alcohol,10 2-phenyl-
3-buten-2-ol18 and 2-phenyl-2-propen-1-ol19 were synthesized according to the literature
procedures. All other allyl alcohols were bought commercial sources, purified before use
by distillation from magnesium, and stored in the glove box. Thin layer chromatography
was performed on 0.20 mm thick aluminum-backed silica gel plates. Components were
visualized with ultraviolet light (x = 254 nm). 'H, 13c: were recorded in CDC13 and 2H
NMR spectra in CHCl3. NMR were recorded at 25 °C in 5 mm NMR tubes on a 500 MHz
Varian Inova spectrometer. Chemical shifts are reported in parts per million (ppm)
relative to the tetramethylsilane (TMS) internal standard at 0 ppm for deuterated
chloroform. The experiments were heated in a constant oil bath maintained at 160 °C,
using Barnstead Electrothermal Set-Temp apparatus. The deuteration for allyl-1 -d2-
alcohol and 3-buten-l-ol-1,1-d2 were more than 99.5% for the indicated positions. GC-
F ID chromatograms were recorded on an Agilent 6890 GC system. GC-MS
chromatograms were recorded on a 5973 inert mass spectrometer. Reactions carried out
with benzhydrylamine contained trace amounts of diphenylmethane [MS(EI) m/z =168
(M+)], benzhydrylamine [MS(EI) m/z = 183 (M+)], and an unidentified compound
[probably N-(diphenylmethylene)-1,l-diphenylmethanamine MS(EI) m/z = 347 (M)].

89

This was confirmed by heating benzhydrylamine 160 °C for 24 h and the decomposition

products were analyzed by GC-MS.

90

4.1 1 Experimental Section

He
f l
b“ 1

Figure 4.5. Structure of N-phenylallylamine (71).

Preparation of N-phenylallylamine (71) C9H11N

Under an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with
toluene (2.0 mL), Ti(NMe2)4 (0.50 g, 2.23 mmol), and allyl alcohol (152.0 uL, 2.23
mmol). The reaction mixture was stirred for 20 min, and aniline (609 11L, 6.69 mmol)
was added. The tube was sealed with a Teflon cap, and the reaction mixture was heated at
160 °C for 24 h. The solution was acidified with 5% HCl, and a saturated solution of
NaHCO3 was added to the reaction mixture. The solution was extracted with ether (4 x
20 mL) and dried over NaZSO4. The volatiles were removed from the reaction mixture in
vacuo, and the residue was subjected to column chromatography using 300 g of silica gel
and 1:1 hexanes—ethyl acetate as the eluent. The product eluted in the first fractions in
51% isolated yield as yellow oil (152 mg, 1.14 mmol). 1H NMR20 (500 MHz, CDClg): 5 =
7.30 (app t, 2 H, J = 7.9 Hz), 6.84 (tt, 1 H, J= 7.4 and 1.04 Hz), 6.72 (dd, 2 H, J= 8.6
and 1.06 Hz), 6.0-6.10 (m, 1 H, d), 5.40 (app dq, 1 H, J = 17.3 and 1.7 Hz, b), 5.28 (app
dq, 1 H, c, J = 10.2 and 1.5 Hz), 3.85 (app dt, 2 H, a, J = 5.3 and 1.7 Hz). 13(:{'H}
NMR20 (500 MHz, coon): 5 = 148.2 (g), 135.6, 129.3, 117.6, 116.3 (f), 113.1, 46.6 (a).
MS(EI) m/z = 133 (M+). Peak f was assigned with the help of a deuterium labeling

experiment (See page 117).

91

 

 

 

Figure 4.6. Structure of N-benzhydryl-N-allylamine (72).

Preparation of N-benzhydryl—N-allylamine (72) C16H17N: Under an atmosphere of dry
nitrogen, a threaded-top pressure tube was loaded with toluene (2.0 mL), Ti(NMez)4 (0.50
g, 2.23 mmol), and allyl alcohol ( 152.0 11L, 2.23 mmol). The reaction mixture was stirred
for 20 min, and benzhydrylamine (1.1 mL, 6.69 mmol) was added. The tube was sealed
with a Teflon cap, and the reaction mixture was heated at 160 °C for 16 h. The solution
was acidified with 5% HCl, and a saturated solution of NaHCO3 was added to the
reaction mixture. The solution was extracted with ether (4 x 20 mL) and dried over
Na2804. The volatiles were removed from the reaction mixture in vacuo, and the residue
was subjected to column chromatography using 300 g of silica gel and 1:9 hexanes—ethyl
acetate as the eluent. The product eluted in the first fractions in 42% yield as yellow oil
(210 mg, 0.90 mmol). lH NMR2| (500 MHz, CDClg): 5 = 7.42 (d, 4 H, J= 8.1 Hz), 7.30
(t, 4 H, J= 7.7 Hz), 7.22 (d, 2 H, J= 7.4 Hz), 5.95 (m, 1 1H, d), 5.19 (app dq, 1 H, b, J=
17.2 and 1.8 Hz), 5.11 (app dq, 1 H, c, J= 10.47 and 1.9 Hz), 4.78 (s, 1 H, k), 3.22 (app
dt, 2 H, a, J= 5.90 and 1.4 Hz), 1.65 (s, 1 H, e). ‘3C{'H} NMR2| (500 MHz, cock): 8 =
145.0 9 (g), 128.4, 127.6, 123.8, 124.2 (d or f), 114.7 (d or f), 67.8 (k), 47.1 (a). MS(EI)
m/z = 233 (IVE). The product was inseparable from diphenylmethane [MS(EI) m/z =168
(MW, benzhydrylamine [MS(EI) m/z = 183 (M+)], and an unidentified compound

[probably N-(diphenylmethylene)-1 ,1 -diphenylmethanamine MS(EI) m/z = 347 (MW.

92

1 / _

 

I“ 41.1' All-

 

1

Figure 4.7. NMR spectra for compound (72).

 

 

 

 

 

 

 

 

m
_
3
3
0
It gut Du wing- II
2H0. i0. 31w
IOHQOIR. 0003'
3
9
_r-r P) 1hr
— d d1 1 — 1 4 r— 1! d — d d d —r J 4 — d 1
I Q a m U u u. to ‘6'
It It}, .1 r1. { r}. .1 ... r1
0 no 0.0-.Ou .uu p.00 .00
0.0..Ow 0.3 O-.. 0.9. u...

He
CHWNfi .
f 1
H .
b 1

Figure 4.8. Structure of N—cyclohexyl-N-allylamine (73).

Preparation of N-cyclohexyl-N-allylamine (73) C9H17N

Under an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with
toluene (2.0 mL), Ti(NMe2)4 (0.50 g, 2.23 mmol), and allyl alcohol (152.0 11L, 2.23
mmol). The reaction mixture was stirred for 20 min, and cyclohexylamine (766 11L, 6.69
mmol) was added. The tube was sealed with a Teflon cap, and the reaction mixture was
heated at 160 °C for 24 h. The solution was acidified with 5% HCl, and a saturated
solution of NaHCO3 was added to the reaction mixture. The solution was extracted with
ether (4 x 20 mL) and was dried over Na2804. The volatiles were removed from the
reaction mixture in vacuo, and the residue was subjected to column chromatography
using 300 g of silica gel and 05:95 hexanes—ethyl acetate as the eluent. The product
eluted in the first fractions in 30% isolated yield as yellow oil (93 mg, 0.67 mmol). 1H
NMR22 (500 MHz, CDC13): 5 = 5.82-5.86 (m, 1 H, d), 5.10 (app dq, 1 H, b, J= 17.3 and
1.5 Hz), 5.00 (app dq, 1 H, c, J= 10.2 and 1.30 Hz), 3.21 (app dt, 2 H, a, J= 6.0 and 1.3
Hz), 2.39 (m, 1 H, g), 1.4-1.8 (m, 5 H), 0.8-1.2 (rn, 6 H). ‘3C{‘H) NMR22 (500 MHz,
CDC13): 8 = 137.3 (d or 1‘), 115.5 (d or f), 56.2 (a), 49.5 (g), 33.6, 26.2, 25.1. MS(EI) m/z

= 139 (M*).

94

H::Cf

Figure 4.9. Structure of N-(3-methylbut-2-enyl)aniline (75).

Preparation of N-(3-methylbut—2-enyl)aniline (75) C1 1H15N

Under an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with
toluene (2.0 mL), Ti(NMe2)4 (0.50 g, 2.23 mmol), and 2-methyl-3-buten-2-ol (233.0 uL,
2.23 mmol). The reaction mixture was stirred for 20 min, and aniline (609 11L, 6.69
mmol) was added. The tube was sealed with a Teflon cap, and the reaction mixture was
heated at 160 °C for 10 h. The solution was acidified with 5% HCl, and a saturated
solution of NaHCO3 was added to the reaction mixture. The solution was extracted with
ether (4 x 20 mL) and was dried over Na2804. The volatiles were removed from the
reaction mixture in vacuo, and the residue was subjected to column chromatography
using 300 g of silica gel with 7:1 hexanes—ethyl acetate as the eluent. The product eluted
in the first fractions in 74% isolated yield as yellow oil (251 mg, 1.56 mmol). 1H NMR23
(500 MHz, CDCl3): 8 = 7.20 (d, 2 H, J = 8.0 Hz), 6.72 (tt, 1 H, J = 7.2 and 1.2 Hz), 6.62
(d, 2 H, J= 8.0 Hz), 5.36 (tt, 1 1H, d, J= 6.9 and 1.4 Hz,) 3.70 (d, 2 H, a, J= 6.9 Hz), 3.60
(br s, 1 H, e), 1.76 (s, 3 H, b or c), 1.72 (s, 3 H, b or c). ‘3C{‘H) NMR23 (500 MHz,
CDC13): 6 = 148.7 (g), 135.8 (f or d), 129.5, 122.0, 117.6, 113.2, 42.3 (a), 26.0 (b or c),

18.3 (b or c). MS(EI) m/z = 161 (M+).

95

'13ch k
CH3 3
. 0

Figure 4.10. Structure of N-(3-methylbut-2-enyl)-N—benzyhydrylamine (76).

Preparation of N-(3-methylbut-2-enyl)-N-benzhydrylamine (76) C|3H21N

Under an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with
toluene (2.0 mL), Ti(NMe2)4 (0.50 g, 2.23 mmol), and 2-methyl-3-buten-2-ol (233.0 uL,
2.23 mmol). The reaction mixture was stirred for 20 min, and benzhydrylamine (1.1 mL,
6.69 mmol) was added. The tube was sealed with a Teflon cap, and the reaction mixture
was heated at 160 °C for 10 h. The solution was acidified with 5% HCl, and a saturated
solution of NaHCO3 was added to the reaction mixture. The solution was extracted with
ether (4 x 20 mL) and dried over NaZSO4. The volatiles were removed from the reaction
mixture in vacuo, and the residue was subjected to column chromatography using 300 g
of silica gel with 7:1 hexanes—ethyl acetate as the eluent. The product eluted in the first
fractions in 72% isolated yield as yellow oil (400 mg, 1.59 mmol). 1H NMR (500 MHz,
CDC13): 6 = 7.25 (d, 4 H, J = 8.0 Hz), 6.9-7.1 (m, 5 H), 6.97-7.03 (t, 2 H, J = 6.5 Hz),
5.18 (t, 1 H, J= 7.0 Hz, d), 4.68 (s, 1 H, k) 3.20 (d, 2 H, a, J= 7.2 Hz), 1.56 (s, 3 H, b or
c), 1.36 (s, 3 H, b or c). '3C{‘H} NMR (500 MHz, CDCl3): 5 = 144.7, 134.8, 128.9,
127.8, 127.4, 123.6, 67.4 (k), 46.] (a), 26.3 (b or c), 18.4 (b or c). MS(EI) m/z = 251
(M+).The product was inseparable from diphenylmethane [MS(EI) m/z =168 (M+)],
benzhydrylamine [MS(EI) m/z = 183 (M+)], and an unidentified compound [probably N-

(diphenylmethylene)-l,l -diphenylmethanamine MS(EI) m/z = 347 (M+)].

96

Figure 4.11. NMR spectra for compound 76.

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97

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Figure 4.12. Structure of N—(3-methy1but-2-eny1)-N—cyclohexlamine (77).

Preparation of N-(3-methylbut-2-enyl)-N-cyclohexylamine (77) C) 1H21N

Under an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with
toluene (2.0 mL), Ti(NMe2)4 (0.50 g, 2.23 mmol), and 2-methyl-3-buten-2-ol (233.0 uL,
2.23 mmol). The reaction mixture was stirred for 20 min, and cyclohexylamine (765 uL,
6.69 mmol) was added. The tube was sealed with a Teflon cap, and the reaction mixture
was heated at 160 °C for 24 h. The solution was acidified with 5% HCl, and a saturated
solution of NaHCO3 was added to the reaction mixture. The solution was extracted with
ether (4 x 20 mL) and dried over NaZSO4. The volatiles were removed from the reaction
mixture in vacuo, and the residue was subjected to column chromatography using 100 g
of Florisil® with 95:05 hexanes—ethyl acetate as the eluent. The product eluted in the
first fractions in 69% isolated yield as brown oil (192 mg, 1.15 mmol). ]H NMR23 (500
MHz, CDC13): 6 = 5.16 (tt, 1 H, d, J= 6.9 and 1.5 Hz), 3.12 (d, 2 H, a, J= 6.8 Hz), 2.32-
2.36 (m, l H, g), 1.58 (s, 3 H, b or c), 1.52 (s, 3 H, b or c), 1.74-1.84 (m, 2 H), 1.50-1.68
(m, 3 H), 0.9-1.2 (m, 5 H), 0.8 (br s, 1 H, e). l3C{‘H} NMR23 (500 MHz, CDC13): 133.8
(f or d), 123.7 ( for d), 56.2 (a), 44.3 (g), 33.8, 26.3, 25.6, 25.0, 17.8. MS(EI) m/z = 167

(NF).

98

d

1 @“W”

i?“ *1
Figure 4.13. Structure of N-(but-3-en—2-yl)aniline (79).
Preparation of (i)—N-(but-3-en-2-yl)aniline (79) CIOHBN
Under an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with
toluene (2.0- mL), Ti(NMe2)4 (0.50 g, 2.23 mmol), and 2-buten-1-ol (191.0 “L, 2.23
mmol). The reaction mixture was stirred for 20 min, and aniline (609 uL, 6.69 mmol)
was then added. The tube was sealed with a Teflon cap, and the reaction mixture was
heated at 160 °C for 8 h. The solution was acidified with 5% HCl, and a saturated
solution of NaHCO; was added to the reaction mixture. The solution was extracted with
ether (4 x 20 mL) and dried over Na2S04. The volatiles were removed from the reaction
mixture in vacuo, and the residue was subjected to column chromatography using 300 g
of silica gel with 1:9 hexanes—ethyl acetate as the eluent. The product eluted in the first
fractions in 31% isolated yield as brown oil (110 mg, 0.75 mmol). lH NMR24 (500 MHz,
CDCl3): 5 = 6.94-7.02 (m, 2 H), 6.51 (tt, 1 H, J= 7.3 and 1.3 Hz), 6.42 (d, 2 H, J= 8.8
Hz), 5.62-5.66 (m, 1 H, d), 5.04 (dt, 1 H, c, J= 17.3 and 1.5 Hz), 4.90 (dt, 1 H, b, J =
10.3 and 1.3 Hz), 3.78-3.82 (m, l H, a), 3.42 (br s, 1 H, e), 1.56 (d, 3 H, k, J= 6.1 Hz).
'3C{'H} NMR24 (500 MHz, CDC13): 147.5 (g), 141.3, 129.2, 117.3, 114.2, 113.5, 51.1,
21.7. MS(EI) m/z = 147 (M+).The product contains ~20% of N—(but-2-enyl)aniline,
confirmed by NMR spectroscopy and MS(EI). The presence was also confirmed by

comparing the fragmentation pattern with the product obtained from the reaction of 3-

99

buten-2-ol by aniline and the GC-FID retention time. The allylic amine, N-(but-2-

enyl)ani1ine was inseparable from N-(but-3-en-2-yl)aniline (See Section 4.7).

100

Figure 4.14. NMR spectra for compound 79.

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101

Figure 4.15. Structure of N-(but-2-enyl)aniline (81).

Preparation of (E:Z)-N-(but-2-enyl)aniline (81) C10H13N

Under an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with
toluene (2.0 mL), Ti(NMe2)4 (0.50 g, 2.23 mmol), and (i)-3-buten-2-ol (80) (193.0 11L,
2.23 mmol). The reaction mixture was stirred for 20 min, and aniline (609 uL, 6.69
mmol) was added. The tube was sealed with a Teflon cap, and the reaction mixture was
heated at 160 °C for 10 h. The solution was acidified with 5% HCl, and a saturated
solution of NaHCO; was added to the reaction mixture. The solution was extracted with
ether (4 x 20 mL) and dried over Na2804. The volatiles were removed from the reaction
mixture in vacuo, and the residue was subjected to column chromatography using 300 g
of silica gel with 2:1 hexanes—ethyl acetate as the eluent. The product eluted in the first
fractions in 80% isolated yield as brown oil (262 mg, 1.78 mmol). 1H NMR25 (500 MHz,
CDC13): 8 = 7.22-7.32 (m, 2 H), 6.8-6.9 (m, l H), 6.68-6.76 (m, 2 H), 5.62-5.82 (m, 2 H),
3.86 (d, 2 H, a or m, J= 5.6 Hz), 3.80 (br s, 1 H, e), 3.75 (d, 2 H, a or m, J= 5.8 Hz)
1.60 (d, 3 H, c or k, J: 6.1 Hz), 1.20 (d, 3 H, c or R, J: 6.7 Hz). '3C{'H} NMR25 (500
MHz, CDCl3): 148.2, 129.3, 128.1, 128.0, 127.7, 127.3, 117.7, 117.6, 113.2, 46.2, 41.1,
17.9, 13.5. MS(EI) m/z = 147 (W. The E:Z ratio was 2:1. The product contains a small
amount (~6%) of (i)-N-(but-3-en-2-yl)aniline by NMR spectroscopy. The presence was
also confirmed by comparing the fragmentation pattern with the product obtained from

the reaction of 2-buten-1-ol by aniline and the GC-FID retention time. N—(but-3-en-2-

102

yl)aniline was inseparable from N—(but-2-enyl)aniline (See Section 4.7). The scale gets
distorted by 0.2 ppm when the graphs are made to fit on a page. The values above are

from the actual data obtained on the NMR spectrophotometer.

103

Figure 4.16. NMR spectra for compound 81.

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104

Figure 4.17. Carbon spectra for compound 81.

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Figure 4.18. Structure of N-but-2-eny1)-N-cyclohexylamine (83).

Preparation of (E:Z) N—(but-Z-enyl)-N-cyclohexylamine (83) CloHtoN
Under an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with

toluene (2.0 mL), Ti(NMe2)4 (0.50 g, 2.23 mmol), and 3-buten-2-ol (193.0 11L, 2.23

mmol). The reaction mixture was stirred for 20 min, and cyclohexylamine (766 11L, 6.69
mmol) was added. The tube was sealed with a Teflon cap, and the reaction mixture was
heated at 160 °C for 10 h. The solution was acidified with 5% HCl, and a saturated
solution of NaI-ICO3 was added to the reaction mixture. The solution was extracted with
ether (4 x 20 mL) and dried over Na2SO4. The volatiles were removed from the reaction
mixture in vacuo, and the residue was subjected to column chromatography using 300 g
of silica gel with 95:05 hexanes—ethyl acetate as the eluent. The product eluted in the
first fractions in 30% isolated yield as yellow oil (100 mg, 0.65 mmol). The E:Z ratio was
1:2 and determined by NMR spectroscopy. It was consistent with the results from GC-
FID. The spectrum will be reported for both the compounds together since it is not
possible to individually assign the aromatic region. 1H NMR26 (500 MHz, CDCl3): 8 =
5.44-5.60 (m, 2 H), 3.26 (d, 2 H, m or a, J= 5.8 Hz), 3.14 (d, 2 H, m or a, J= 4.9 Hz),
2.38-2.42 (m, 1 H), 1.80-1.90 (m, 2 H), 1.58-1.70 (m, 7 H), 1.0-1.2 (m, 7 H). l3C{1H}
NMR26 (500 MHz, CDC13): 130.0, 129.4, 126.9, 125.7, 56.4, 56.2, 48.8, 43.1, 33.6, 26.2,

25.1, 17.8, 13.5. MS(EI) m/z =153(M+).

106

 

 

d H k u
H3Cb/ Nbl V t
C a n S p H . w
9 m q / N J x
1) CH3 ° y
i r

Figure 4.19. Structure of N-(3-phenyl-2-butenyl)aniline (85).

Preparation of (E.'Z)-N-(3-phenyI-2-butenyl)aniline (85) C16H17N

Under an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with
toluene (2.0mL), Ti(NMe2)4 (0.50 g, 2.23 mmol), and 2-phenyl-3-buten-2-ol (84b) (331.0
mg, 2.23 mmol). The reaction mixture was stirred for 20 min and, aniline (609 uL, 6.69
mmol) was added. The tube was sealed with a Teflon cap, and the reaction mixture was
heated at 160 °C for 36 h. The solution was acidified with 5% HCl, and a saturated
solution of NaHCO3 was added to the reaction mixture. The solution was then extracted
with ether (4 x 20 mL) and was dried over Na2S04. The volatiles were removed fi'om the
reaction mixture in vacuo, and the residue was subjected to column chromatography
using 300 g of silica gel with 7 :1 hexanes—ethyl acetate as the eluent. The product eluted
in the first fractions in 57% isolated yield as yellow oil (281 mg, 1.26 mmol). The E:Z .
ratio was 1:2 and determined by NMR spectroscopy. It was consistent with the results
from GC-FID. The spectrum reported is for both the isomers since it is not possible to
individually assign the peaks. IH NMR (500 MHz, CDCl:,): 8 = 7.20-7.50 (m, 16 H),
6.66-6.84 (m, 4 H), 6.57 (d, J= 8.6 Hz, 2 H), 5.96 (tq, 1 H, p or d, J= 6.7 and 1.4 Hz),
5.68 (tq, 1 H, p or d, J= 6.9 and 1.6 Hz), 3.96 (dd, 2 H, 0 or a, J= 6.8 and 0.9 Hz), 3.72
(dd, 2 H, 0 or a, J= 6.8 and 1.2 Hz), 2.18 (app dd, 3 H, r or b, J= 7.0 and 0.9 Hz), 2.15

(app dd, 3 H, r or b, J = 6.8 and 1.2 Hz). '3C{'H} NMR (500 MHz, CDC13): 148.0,

107

 

147.9, 142.8, 140.9, 139.5, 137.4, 129.1, 129.0, 128.14, 128.10, 127.6, 127.0, 126.9,

125.6, 125.2, 124.3, 117.4, 117.2, 112.82, 112.80, 42.6, 42.5, 25.3, 16.0. MS(EI) m/z =

223 (M+).

108

   

Figure 4.20. Structure of N-(3-phenylbut-2-enyl)-N-benzhydrylamine (86).

Preparation of (E:Z) N-(3-phenylbut—2-enyl)-N-benzhydrylamine (86) C23H23N

Under an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with
toluene (2.0 mL), Ti(NMe2)4 (0.50 g, 2.23 mmol), and 2-methyl-3-buten-2-ol (233.0 11L,
2.23 mmol). The reaction mixture was stirred for 20 min, and benzhydrylamine (1.1 mL,
6.69 mmol) was added. The tube was sealed with a Teflon cap, and the reaction mixture
was heated at 160 °C for 36 h. The solution was acidified with 5% HCl, and a saturated
solution of NaHCO3 was added to the reaction mixture. The solution was extracted with
ether (4 x 20 mL) and dried over NaZSO4. The volatiles were removed from the reaction
mixture in vacuo, and the residue was subjected to column chromatography using 300 g
of silica gel with 9:1 hexanes—ethyl acetate as the eluent, followed by 8:2 pentane—ether.
The product eluted in the first fractions in 54% isolated yield as yellow oil (376 mg, 1.20
mmol). The E :Z ratio is 1:5 and determined by NMR spectroscopy. It was consistent with
the results from GC-F ID. The spectrum reported is for both the isomers since it is not
possible to individually assign the peaks. 1H NMR (500 MHz, CDC13): 8 = 7.10-7.50 (m,
20 H), 5.95 (t, 1 H, J= 7.2 Hz, p or d), 5.70 (t, 1 H, J= 7.1 Hz, p or d), 4.94 (s, 1 H, u or
t), 4.78 (s, 1 H, u or t), 3.42 (d, 2 H, 0 or a, J= 7.0 Hz), 3.16 (d, 2 H, 0 or a, J= 7.0 Hz),
2.08 (s, 3 H, b or r), 1.92 (s, 3 H, b or r), 1.72 (br s, 2 H, e). '3C{'H) NMR (500 MHz,

CDC13): 5 = 144.2, 143.6, 137.3, 128.8, 128.7, 128.5, 128.3, 128.0, 127.7, 127.0, 127.6,

109

127.5, 127.3, 127.2, 126.7, 126.0, 67.1, 67.2, 46.7, 46.4, 25.8, 16.3. MS(EI) m/z = 313
(M+). The product contained a trace amount of diphenylmethane [MS(EI) rn/z =168
(M+)], benzhydrylamine [MS(EI) m/z = 183 (M+)] and an unidentified compound

[probably N-(diphenylmethylene)-1,1-diphenylmethanamine MS(EI) m/z = 347 (M+)].

110

 

Figure 4.21. Structure of N-(2-methy1allyl)aniline (88).

Preparation of N-(2-methylallyl)aniline (88) C15H15N

Under an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with
toluene (2.0 mL), Ti(NMe2)4 (0.50 g, 2.23 mmol), and 2-phenyl-2-propen-1-ol (299.0
mg, 2.23 mmol). The reaction mixture was stirred for 20 min, and aniline (609 1.1L, 6.69
mmol) was added. The tube was sealed with a Teflon cap, and the reaction mixture was
heated at 160 °C for 15 h. The solution was acidified with 5% HCl, and a saturated
solution of NaHC03 was added to the reaction mixture. The solution was extracted with
ether (4 x 20 mL) and dried over Na2804. The volatiles were removed from the reaction
mixture in vacuo, and the residue was subjected to column chromatography using 300 g
of silica gel with 1:1 hexanes—ethyl acetate as the eluent. The product eluted in the first
fractions in 31% isolated yield as yellow oil (142 mg, 0.68 mmol). 1H NMR27 (500 MHz,
CDC13): 5 = 7.36 (d, 2 H, J = 8.4 Hz), 7.18-7.22 (m, 3 H), 7.06 (t, 2 H, J = 8.3 Hz), 6.60
(t, 1 H, J= 7.5 Hz), 6.52 (d, 2 H, J= 8.4 Hz), 5.36 (s, 1 H, b or c), 5.22 (s, 1 H, b or c),
4.04 (s, 2 H, a), 3.88 (br s, l H, e). '3C{‘H} NMR27 (500 MHz, CDC13): 5 = 147.9 (j or
k), 144.6 (j or k), 139.2, 129.1, 128.4, 127.8, 126.0, 117.4, 113.5, 112.8, 47.9 (a). MS(EI)

m/z = 209M).

111

 

Figure 4.22. Structure of N-(2-methylal1yl)cyclohexylamine (89).

Preparation of N-(Z-methylallyl)cyclohexylamine (89) C15H21N

Under an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with
toluene (2.0 mL), Ti(NMe2)4 (0.50 g, 2.23 mmol), and 2-phenyl-2-propen-1-ol (299.0
mg, 2.23 mmol). The reaction mixture was stirred for 20 min, and cyclohexylamine (765
uL, 6.69 mmol) was added. The tube was sealed with a Teflon cap, and the reaction
mixture was heated at 160 °C for 16 h. The solution was acidified with 5% HCl, and a
saturated solution of NaHCO3 was added to the reaction mixture. The solution was
extracted with ether (4 x 20 mL) and dried over Na2S04. The volatiles were removed
from the reaction mixture in vacuo, and the residue was subjected to column
chromatography using 300 g of silica gel with 1:2 hexanes—ethyl acetate as the eluent.
The product eluted in the first fractions in 45% isolated yield as yellow oil (215 mg, 51.0
mmol). 1H NMR (500 MHz, CDCl3): 5 = 7.1-7.4 (m, 5 H), 5.30 (s, 1 H, b or c), 5.12 (s, l
H, b or c), 3.58 (s, 2 H, a), 2.34-2.38 (m, 1 H, j), 1.5-1.8 (m, 5 H), 0.9-1.2 (m, 6 H).
'3C{'H} NMR (500 MHz, CDC13): 6 = 146.7 (k), 139.9, 128.2, 127.4, 126.0, 112.7, 55.9

(a), 50.4 (j), 33.5, 26.0, 24.8. MS(EI) m/z = 215 (M+).

112

b daHe
M if:
f l
H l i
c
m

n
Figure 4.23. Structure of N-(l-phenylallyl)aniline (90).

Preparation of (1)-N-(1 -phenylallyl)aniline (90) C15H15N

Under an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with
toluene (2.0 mL), Ti(NMe2)4 (0.50 g, 2.23 mmol), and 3-phenyl-2-propen-1-ol (300 mg,
2.23 mmol). The reaction mixture was stirred for 20 min, and aniline (609 11L, 6.69
mmol) was added. The tube was sealed with a Teflon cap, and the reaction mixture was
heated at 160 °C for 40 h. The solution was acidified with 5% HCl, and a saturated
solution of NaHC03 was added to the reaction mixture. The solution was extracted with
ether (4 x 20 mL) and dried over NaZSO4. The volatiles were removed from the reaction
mixture in vacuo, and the residue was subjected to column chromatography using 300 g
of silica gel with 10:1 hexanes—ethyl acetate as the eluent. The product eluted in the first
fractions in 20% isolated yield as yellow oil (95 mg, 0.45 mmol). 1H NMR28 (500 MHz,
CDC13): 5 = 7.32-7.46 (m, 5 H), 7.19-7.22 (m, 2 H), 6.78 (t, l H, i, J = 7.4 Hz), 6.64-6.70
(m, 2 H), 6.06-6.22 (m, 1 H, d), 5.28-5.38 (m, 2 H, b and c), 5.04 (d, 1 H, a, J = 6.5 Hz),
4.01 (br s, 1 H, e). '3C{'H} NMR28 (500 MHz, CDC13): 5 = 147.5 (k or j), 139.4 (k or j),
129.4, 129.1, 128.8, 127.8, 127.5, 118.0, 116.4, 113.9, 61.2 (a). MS(EI) m/z = 209 (M+).
The reaction did contain small amount of unidentified impurity. (See attached 1H NMR

spectrum below).

113

Figure 4.24. NMR spectra for compound 90.

 

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114

Figure 4.25. Structure of 1-azaspiro-[5.5]-undecane (96).

Preparation of 1 -azaspiro-[ 5. 5 ]-undecane (96) ClongN

Under an atmosphere of dry nitrogen, a Schlenk tube was loaded with chlorobenzene (7.0
mL), Ti(NMe2)4 (0.50 g, 2.23 mmol), and 3-buten-1-ol (192 11L, 2.23 mmol). The
reaction mixture was stirred for 20 min, and cyclohexylamine (765 1.1L, 6.69 mmol) was
added. The tube was sealed with a Teflon cap, and the reaction mixture was heated at 180
°C for 60 h. The solution was acidified with 15% HCl, and a 6 N solution of NaOH was
added to the reaction mixture. The solution was extracted with ether (6 x 20 mL) and
dried over Na2804. The volatiles were removed from the reaction mixture in vacuo, and
the residue was subjected to column chromatography using 100 g of Florisil® with ethyl
acetate as the eluent. The isolated yield obtained was 35% as yellow oil (110 mg, 0.72
mmol). ‘H NMR29 (500 MHz, CDC13): 5 = 2.71 (t, 2 H, a, J= 5.8 Hz), 1.2-1.6 (m, 17 H).
'3C{'H} NMR29 (500 MHz, cock): 5 = 50.6, 40.8 (a), 36.7, 36.3, 27.3, 26.6, 21.9, 20.4.
MS(EI) m/z = 153 (M). The GC yield is 63% with toluene as the solvent. The low
isolated yield of the 1-azaspiro-[5.5]-undecane is due to the thick viscous emulsion that
results afier the addition of 6 N NaOH solution, which makes the extraction with ether

harder than usual.

115

 

Figure 4.26. Structure of 1-azaspiro-2,2-2H-[5.5]-undecane (97).

Preparation of 1 -azaspiro-2, 2-2H-[ 5. 5 ]-undecane (97)

Under an atmosphere of dry nitrogen, a Schlenk tube was loaded with chlorobenzene (9.0
mL), Ti(NMe2)4 (1.00 g, 4.46 mmol), and 3-buten-1-ol-1,I-d2 (331 mg, 4.46 mmol). The
reaction mixture was stirred for 20 min, and cyclohexylamine (1.5 mL, 13.4 mmol) was
then added. The tube was sealed with a Teflon cap, and reaction mixture was heated at
180 °C for 60 h. The solution was acidified with 15% HCl, and a 6 N solution of NaOH
was added to the reaction mixture. The solution was extracted with ether (6 x 20 mL) and
dried over NaZSO4. The volatiles were removed from the reaction mixture in vacuo, and
the residue was subjected to column chromatography using 100 g of Florisil® with ethyl
acetate as the eluent. The isolated yield obtained was 36% (215 mg, 1.39 mmol). lH
NMR (500 MHz, CDClg): 5 = 1.2-1.6 (m, 17 H). l3C{‘H} NMR (500 MHz, CDCl;): 5 =
50.6, 39.5 (quintet, a), 36.7, 36.3, 27.3, 26.6, 21.9, 20.4. MS(EI) m/z = 155 (M+). 2H

NMR (76.7 MHz, CHC13): 5 = 2.6 (s, 1 D).

116

o d “a
/ .
NM |
D 1'

Figure 4.27. Structure of N-phenyl 3, 3-2H-allylamine (50).

Preparation ofN-phenyl 3, 3-2H-allylamine (50) CoHoDzN

Under an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with
toluene (2.0 mL), Ti(NMe2)4 (0.50 g, 2.23 mmol), and allyl-1,1-d2-alcohol (154.0 uL,
2.23 mmol). The reaction mixture was stirred for 20 min, and aniline (609 uL, 6.69
mmol) was added. The tube was sealed with a Teflon cap, and the reaction mixture was
heated at 160 °C for 24 h. The solution was acidified with 5% HCl, and a saturated
solution of NaHCO3 was added to the reaction mixture. The solution was extracted with
ether (4 x 20 mL) and was dried over NaZSO4. The volatiles were removed from the
reaction mixture in vacuo, and the residue was subjected to column chromatography
using 300 g of silica gel with 1:1 hexanes—ethyl acetate as the eluent. 1H NMR (500
MHz, CDCl;): 5 = 7.30 (app t, 2 H), 6.84 (t, 1 H, J = 7.4 Hz), 6.72 (dd, 2 H, J = 7.8 and
1.2 Hz, b), 5.88 (s, 1 H, d), 3.85 (d, 2 H, a, J = 5.3 Hz). '3C{‘H} NMR (500 MHz,
CDCl3): 5 = 148.2, 135.6, 129.3, 117.6, 116.3 (quintet, 1’), 113.1, 46.6 (a). 2H NMR (76.7

MHz, CHC13): 5 = 5.1 (s, 1 D), 4.8 (s, 1 D) MS(EI) m/z = 135 (W).

117

Figure 4.28. Structure of N-(2-methyl-2-propen-3,3-2H)aniline (95).

Preparation of N-(Z-methyI-Z-propen-3,3-2H)aniline (95) CloHl (DzN

Under an atmosphere of dry nitrogen, a threaded-top pressure tube was loaded with
chlorobenzene (3.0 mL), Ti(NMe2)4 (1 .00 g, 4.50 mmol), and 2-methyl-2-propen-l,l-2H-
l-ol (331.0 mg, 4.50 mmol). The reaction mixture was stirred for 20 min, and aniline
(1.14 mL, 13.5 mmol) was added. The tube was sealed with a Teflon cap, and the
reaction mixture was heated at 180 °C for 168 h. The solution was acidified with 5%
HCl, and a saturated solution of NaHCO3 was added to the reaction mixture. The solution
was extracted with ether (4 x 20 mL) and was dried over Na2S04. The volatiles were
removed from the reaction mixture in vacuo, and the residue was subjected to column
chromatography using 300 g of silica gel with 2:1 hexanes—ethyl acetate as the eluent.
The isolated yield was 10% (67 mg, 0.45 mmol). lH NMR (500 MHz, CDC13): 5 = 7.10
(t, 2 H, J= 7.8 Hz), 6.62 (t, 1 H, J= 7.4 Hz), 6.50 (d, 2 H, J= 8.0 Hz), 3.60 (s, 2 H, a),
1.70 (s, 3 H, k). '3C{'H} NMR (500 MHz, CDCl3): 147.2, 141.5, 128.8, 128.1, 115.1,
116.2 (quintet, 1), 111.7, 48.8 (a), 19.3 (k). 2H NMR (76.7 MHz, CHC13): 5 = 5.1 (s, 1

D), 4.8 (s, 1 D). MS(EI) m/z = 149 (M+).

118

 

4. 12. References

1) Schuetz, R. D.; Millard, W. F.; Volker, S. J. Org. Chem. 1959, 24, 297.

2) Nugent, W. A.; Chan, D. M. Inorg. Chem. 1985, 24, 1422.

3a) Orfanopoulos, M.; Smonou, I.; Foote, C. S. J. Am. Chem. Soc. 1990, 112, 3607 (b)
Jorgenson, M. J. Tetrahedron Lett. 1962, 3, 569 (c) Brown, H. C.; Hess, H. M. J. Org.
Chem. 1969, 34, 2206.

4) Shusterman, A. J .; Casey, C. P. Organometallics 1985, 4, 736.

5a) Daly, J. W.; Karle, I.;Myers, C.W.; Tokuyama, T.; Waters, J. A.; Witkop, B.; Proc.
Natl. Acad. Sci. USA, 1971, 68, 1870. (b) Gessner, W.; Takahashi, K.; Witkop, B.;
Brossi, B.; Maleque, M. A.; Albuquerque, E. X, Helv. Chim. Acta 1985, 65, 252.

6) Care, S. C.; Aratani, M, Kishi, Y Tetrahedron 1985, 26, 5887.

7) Kang, Z.; Stork, G. J. Am. Chem. Soc. 1990, 112, 5875.

8) Karatholuvhu, M. S.; Sinclair, A.; Newton, A. F .; Alcaraz, M-Lyne.; Stockman, R. A.;
Fuchs, P. L. J. Am. Chem. Soc. 2006, 128, 12656.

9a) Mimura, M.; Hayashida, M.; Nomiyama, K.; Ikegami, S.; Iida, Y.; Tamura, M.;
Hiyama, Y.; Ohishi, Y. Chem. Pharm. Bull. 1993, 41, 1971. (b) See also: Hodjat, H.;
Lattes, A.; Laval, J. P.; Moulines, J.; Perie, J. J. Heterocycl. Chem. 1972, 9, 1081.

10) Negishi, E.; Boardman, L. D.; Sawada, H.; Bagheri, V.; Stoll, A. T.; Tour, J. M.;
Rand, C. L. J. Am. Chem. Soc. 1988, 110, 5383.

11a) Sharpless, K. B.; Teranishi, A. Y.; Backvall, J .-E. J. Am. Chem. Soc. 1977, 99, 3120
(b) Hentges, S. G.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 4263 (c) Gobel, T.;
Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1993, 32, 1329. (d) Gable, K. P.; Phan, T.
N. J. Am. Chem. Soc. 1994, 116, 833 (e) Jorgensen, K. A,; Schiott, B. Chem. Rev. 1990,
90, 1483.

12a) van Asselt, A.; Burger, B. J.; Gibson, V. C.; Bercaw, J. E.; J. Am. Chem. Soc. 1986,
108, 5347 (b) Parkin, G.; Bunel, E.; Burger, B. J. J. Mol. Catal. 1987, 41, 21 (0) Nelson,
J.E.; Parkin, G.; Bercaw, J. E. Organometallics 1992, 11, 2181.

13) Tahmassebi, S. K.; Conry, R. R.; Mayer, J. M. J. Am. Chem. Soc. 1993, 115, 7553.
14) Mayer, J. M.; Brown, S. N. Organometallics 1995, 14, 2951.

15) Slaughter, L. M.; Wolczanski, P. T.; Klinckrnan, T. R.; Cundari, T. R. J. Am. Chem.
Soc. 2000, 122, 7953.

119

16) Buchwald, S. L.; LaMaire, S. J.; Nielsen, R. B.; Watson, B. T.; King, S. M.
Tetrahedron. Lett. 1987, 28, 3895.

17) Bradley, D. C.; Thomas, I. M. J. Chem. Soc. 1960, 3859.

18) Morill, C.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 12 7, 2842.

19) Dubodin, J. G.; Jousseaume, B. Synth. Commun. 1979, 9, 53.

20) Kinoshita, H.; Shinokubo, H.; Oshima, K. Org. Lett. 2004, 6, 4085.
21) Hellion, G. F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993, 58, 6109.

22) Yadav, J. S.; Madhuri, C.; Reddy, B. V. S.; Reddy, G. S. Kumar, K.; Sabitha, G.
Synth. Commun. 2002, 32, 2771.

23) Shea, G. R.; Fitzner, N. J.; Fankhauser, E. J.; Spaltenstein, A.; Carpino, A. P.;
Peevey, M. R.; Pratt, V. D.; Tenge, J. B.; Hopkins, B. P. J. Org. Chem. 1986, 51, 5243.

24) Jolidon, S.; Hansen, H. J. Helv. Chim. Acta 1977, 60, 978.

25) Ozawa, F.; Okamoto, H.; Kawagishi, S.; Yamamoto, S.; Minami, T.; Yoshifuji, M. J.
Am. Chem. Soc. 2002, 124, 10968.

26) Castro, B.; Selve, C. Bull. Soc. Chim. Fr. 1971, 4368.
27) Srivastava, S. R.; Khan, A. M.; Nicholas, K. M. J. Am. Chem. Soc. 2005, 12 7, 7278.

28) Leitner, A.; Shekhar, S.; Pouy, M. J.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127,
15506.

29) Mimura, M.; Hayashida, M.; Nomiyama, K.; Ikegami, S.; Iida, Y.; Tamura, M.;
Hiyama, Y.; Ohishi, Y. Chem. Pharm. Bull. 1993, 41 , 1971.

120

5. KINETIC ISOTOPE EFFECT

5.1 Introduction

The previous Chapter dealt with development of new methodology to convert primary
allylic alcohols to secondary allylic amines selectively. In this Chapter efforts to establish
the mechanism for the C—N bond formation reaction and comparison with organic
reactions like the Claisen and Cope rearrangements via kinetic isotope effects (KIE) will
be discussed. A discreet titanium-imido complex was also synthesized and kinetics were
performed to identify the value of KIE.

In Chapter 4 we saw the failure of 2-methyl-2-propen-1-ol (93) to react with
Ti(NMe2)4 with amines l, 8 and 14 and based on this result a scheme involving [2+2]-
cycloaddition/retro-[2+2]-cycloaddition (transition state 96) was proposed instead of a
[3,3]-sigmatropic transition state (See Section 4.3). One of the ways to investigate further
into the mechanism of synthesis of secondary allylic amines is a comparison of kinetic
isotope effect (KIE) value. This is obtained by replacing the hydrogen atom with a
deuterium atom in the reaction system, since KIE have been used to determine the nature
of the transition state in the rate-determining step of the reaction.1 In order to investigate
the KIE a deuterium labeled allyl alcohol was synthesized, which would yield a
secondary kinetic isotope effect (SKIE) for the titanium system as seen in Equation 5 .1.

A brief introduction to KIE will be presented in the next section.

 

 

 

" ‘ I
PhP/H HID
. DI HID 3 PhNH2 (2) g N HID
”we?“ + _ toluene 150 °c' [Ti] ‘51)
D/H OH 2411
1 o
k... lkD = SKIE

121

5.2 Kinetic Isotope Effect (KIE)

5.2.1 Introduction to KIE

A primary KIE occurs when a rate change due to an isotopic substitution occurs at a
site of bond-breaking or bond-making in the rate-determining step of a mechanism. A
secondary KIE (SKIE) occurs when rate change is due to an isotopic substitution adjacent
to a site of bond-breaking or bond-making in the rate-determining step of the mechanism.
The kinetic isotope effect is referred to as a normal KIE, when kH/kD > 1 and inverse KIE
when kH/kD < 1. A normal KIE occurs when the degree of hybridization of the reaction
center in the transition state is less than that of the starting materials for instance, when
the hybridization is converted from sp3 to SP2 or from sz to Sp. An inverse KIE occurs
when the degree of hybridization of the reaction center in the transition state is higher
than that of the starting materials, for instance when the hybridization is converted from
sp‘? to sp3 or from sp to spz. This will be explained in detail in the following pages using
Streitwieser’s hybridization model.2 SKIE depends on change of hybridization and
hyperconjugation. To understand KIE further a brief description of the origin of isotope
effects, which is linked to changes in vibrational force constant, will be presented.

Consider a case when two atoms combine together to form a stable molecule. The two
atoms will settle at a distance (internuclear distance) where the repulsive and attractive
forces are at a minimum. The repulsive forces arise from the repulsion between the
electrons of the two atoms (or the repulsion between the two positively charged nuclei),
and the attractive forces arise due to the attraction between the positively charged nucleus
of one atom and the electrons of the other atom. The vibrational energy that a molecule

possesses in the ground state is known as the zero-point energy, E; (ZPE), and forms the

122

basis for the rise of KIE. If the molecule undergoes an oscillation, the frequency v is
calculated as shown below (Equation 5.1), where c is the velocity of light in cm s", k is
the force constant and ,u is the reduced mass given by mrmz/m1+m2, where m; and m2 are

the molecular weight of the two atoms involved.

1 k

o=— —
27“, ,u (5.1)

Vibrational energies, like other molecular energies, are quantized and the allowed
energy for the system may be calculated from the Schrtidinger equation, which is E =
(n+1)h u, where h is Planck’s constant. At ZPE, n = 0, and hence E0 is ha. The number of
vibrational modes available for the molecule is 3N - 6 normal modes and includes
translational, rotational, and vibrational motion for a nonlinear molecule. To understand
this more consider a potential-energy curve for an anharmonic oscillator (Figure 5.1). The
dissociation energy required to break a bond is the difference between the zero-point
energy (E0) and the energy at infinite distance r between the atoms where the bond is
broken. The ZPE is lower for an isotopically substituted deuterium atom, since the ZPE

decreases with increasing reduced mass, ,u of the two atoms.

123

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 5.1. Vibrational energy levels and transitions for a diatomic molecule.

In the case of SKIE, the normal or inverse SKIE arises due to change in hybridization.
A rule to determine normal or inverse kinetic isotope effect is as shown by Streitwieser’s
rehybridization model (Figure 5.2).2 Consider a C—H bond which undergoes
hybridization change from tip3 to spz. The vibrational modes that would undergo changes
are the bending modes, including in-plane and out-of-plane modes and stretching modes.
In the stretching mode the C—H bond stretch increases in the order from sp3 to Sp atom
(sp3<sp2<sp), and hence force constants also follow the same trend. This trend is
followed in IR stretching frequencies, where there is a change in force constant when an
atom undergoes rehybridization leading to a SKIE. The change in force constant for a
stretching frequency (undergoing hybridization change) is not big enough to contribute
significantly when compared to a huge change in force constant that occurs in a primary

KIE. Hence stretching frequencies do not contribute significantly to SKIE.

124

Consider the same C—H bond undergoing bending motions in an Sp3 and sz atom. The
in-plane bending has the same frequency in Sp3 and sz atom indicating no change in
force constant for these motions.

ln-plane-bend Out-of-plane-bend

I

1350 cm-1 1350 cm"
4) {{X
1350 cm" 300 cm"

Figure 5.2. Streitwieser hybridization model for bending motion.2

However the in-plane bending is a much tougher task to perform in an spz carbon than
out-of-plane bending motion due to less steric interactions in an out-of-plane bending for
a sz hybridized carbon atom. This large difference in the force constant for the out-of-
plane bending motion of an Sp3 versus sz atom implies significant changes in ZPE
between C—H and C—D bond undergoing hybridization and hence a greater contribution
to SKIE from the bending modes. A similar analogy can be made when comparing an sz
versus Sp atom. In summary, the energy difference between the out-of-plane bending
modes gives rise to SKIE and since bending modes are of relatively low energy the
associated SKIE is small.

SKIE can also be caused by hyperconjugation, which is the ability of ,B-hydrogen to
stabilize an adjacent carbocation. Usually these SKIE are normal and can be as large as

SKIE’s arising from rehybridization. Equilibrium isotope effect (EIE) arises due to

125

isotopic substitution, but is a thermodynamic effect. EIE depends on the difference in

AZPE for the deuterated and protonated molecule.

5.2.2 KIE in Cope and Claisen rearrangement

Cope3 and Claisen4 rearrangements apparently takes place via the [3,3]-sigmatropic
mechanism, the nature of whose transition state have been a point of contention for
decades. For the aliphatic Claisen rearrangement three different transition states have

been proposed by Gajewskisa (Scheme 5.1).

1A4WI MsNWI
2 . I 2
C—WO 1“ <1“ ——-°©
az’ ~ ,,' ~.-,' ~\\
‘v V
4 6 . 4 6
ammmm

Scheme 5.1. Proposed [3,3]-sigmatropic transition state for a Claisen rearrangement.
With the help of a More O’Ferrall-Jencks diagram,5b’c the transition states have been
explained using SKIE. The diagrams show projection of the reaction on the x-and y-axes,
which represent individual reaction coordinates. The reactant and product are plotted on
diagonal ends of the square. The two remaining ends (diagonal) represent the two
transition states that might be possible for a [3,3]-sigmatropic reaction. There are a
number of key assumptions in these diagrams. First, the EIE (equilibrium isotope effect)
for the individual bond-making and bond-breaking process are assumed to be the
maximum possible and the SKIE for the reaction would be some fraction of EIE. Second,
the SKIE is assumed to be directly related to the change in a-bond ordering proceeding

from the ground state to the transition state. The SKIE is derived from the experiment and

126

 

the EIE from fractionation factors, which are equilibrium isotope effect for the partioning
of deuterium between the sites involved in equilibrium.

The effects of energy changes in the transition state in a More O’Ferrall-Jencks diagram
can be summarized as follows:

1) Along the reaction coordinate the transition state structure shifts toward the end that is
raised, away from the end that is lowered.

2) Perpendicular to the reaction coordinate the transition state structure shifts toward the
side that is lowered, away from the side that is raised.

Gajewski’s calculation5d of SKIE at C4 in allyl vinyl ether (AVE) calculated was 1.092
and EIE at C4 was 1.27, while the SKIE at C.; was 1.03 and the corresponding EIE was
1.16. The ratio of SKIE/EIE at the bond breaking site is 1.092-1/1.27-1, which is 0.33,
while the ratio of SKIE/EIE at the bond making site is 1.025-1/1.16-1.0, which calculates

out to a value of 0.19 (Figure 5.3).

o’/’;\~ 0/
\:/’ I, \

 

Bond-Breaking /

0.33 """

\
-----—

 

 

/\ 0.19 Bond-M aklng 10
0.0
/

 

Figure 5.3. More 0’ F errall-Jencks diagram for Claisen rearrangement of AVE.

127

For AVE along the diagonal the transition state appears to be “early” due to the
exothermic nature of the reaction. From the diagram it can be concluded that a large
amount of bond-breaking occurs than bond-making for AVE. The authors also suggest
that the presence of a radical stabilizing substituent in C1, C4 and C6 stabilizes the
transition state to a greater extent than substituent at C2 and C5.

The substituent effect in a Cope rearrangement was also investigated since it is
believed to follow the [3,3]-sigmatropic pathway.68 The More O’Ferrall-Jencks diagram
whose structural x-axes are C1 and C6 for bond-making and the y-axes corresponds to C3
and C4 for bond-breaking. The effect of substituent on 1,5-hexadiene is as shown below.
The bond-making kinetic isotope effect (BMKIE) for 3-methyl-2-phenyl-1,5-hexadiene
was found to be 1.129i0.018 and the bond breaking kinetic isotope effect (BBKIE) was
found to be 1.07:1:0.025, which gives a BMKIE-1.0/BBKIE-1.0 ratio of 1.85:1:1.0. For 2,5-
diphenyl-l,1,6,6-tetradeuteratedhexadiene the BMKIE is 1573:0035 and the BBKIE is
107250.024, which gives a BMKIE-1.0/BBKIE-l.0 ratio of 8.1i2.0. From the above
values one could argue that SKIE in a [3,3]-sigmatropic shift varies over a large range as

a function of substitution (Figure 5.4).

128

)

\
O)
\l

I
(o

(

C

 

 

 

 

‘ ’ Ph
I, ‘l
P11
C15

0

Figure 5.4. More O’Ferrall-Jencks diagram for Cope rearrangement substitution pattern.

A comparison was made between the thermal isomerisation of bicycle[2.2.0]hexane

(BCH) and 1,5-hexadiene by Gajewski’s group.‘5b The low energy concept aromatic

pathway (Figure 5.5) in a [3,3]-sigmatropic transition state was found to be 12 kcal/mol

lower in energy compared to the cyclohexane-1,4-diyl pathway in BCH, but the authors

do not completely rule out the 1,4-diyl pathway. They found that the rate of exo-endo

isomerisation of 2,3,5,6-teraduterio-BCH has the same rate as cleavage to 1,5-hexadiene.

If one closely examines Figure 5.5 we can assume that BCH can possibly be a transition

state in the thermal isomerisation of BCH of 1,5-hexadiene. It is also comparable to the

two, four membered ring transition state 96 (oxazatitanobicyclo[2.2.0]hexane) proposed

for the titanium case originally proposed in Chapter 4. One thing to keep in mind is the

BCH transition state, which could exist in the Cope rearrangement of 1,5-hexadiene,

would be a symmetry forbidden transition state as it involves a [2+2]-cycloaddition.

129

 

cleavage of 1.4-diyl

Q 53 kcal/mol

 

41 kcal/mol

18 kwl/mol

Ener
gy \5\[2+2}-symmetry forbidden

C 3

Reaction co-ordinate

 

0 kcal/mol

 

 

 

Figure 5.5. Energy diagram comparing transition state for BCH and 1,5-hexadiene.

From the above scheme one can conclude that indeed, the two isolated radical
fragment transition state would not be an energetically favored structure. Subsequent
investigation by Doering7 into the cyclohexane-l,4-diyl pathway provided evidence for a
four-centered “chair” transition state and subsequent theoretical calculations performed
ruled out the diyl pathway. Results from Houk’s group,8 later confirmed the calculations
performed by Doering and reaffinned the result that there was more bond-breaking
present than bond-making in the concerted [3,3]-sigmatropic transition state.

In the above section an insight into the [3,3]-sigmatropic mechanism was presented
with the help of SKIE experiments performed on the Claisen and Cope rearrangement.
The structure of the transition has been a point of contention for years and support can be
found for both the concerted as well as non-concerted nature. A majority of the studies do

point towards a concerted nature of transition state over the isolated 1,4-diy1 species and

130

there is a general agreement over the concerted nature of [3,3]-sigmatropic transition
state.9

5.3 Computational studies

5.3.1 Bigeleisen Equation

Our initial approach began with an initial computational study on the reaction between
Ti(NMe2)4 (l), allyl alcohol (44) and aniline (2) using the Bigeleisen equationlo to
calculate the SKIE. The Bigeleisen equation has been extensively used to calculate
theoretical isotope effects from force constants. The geometry of each structure is
optimized using DFT (Density Functional Theory), subjected to a complete vibrational
analysis and the resulting molecular geometry is used in the DFT function (basis set) to
compute the vibrational frequencies for the ground state and transition state as shown
below (Equation 5.2).

KIE = kH/kD = MMI x VIB (5.2a)

I), 12, 13 are the principal moments of inertia, M is the total mass of the system, u,- = hv/

kT where vi is the vibrational frequency of the ith normal mode, h is Planck’s constant

and k is Boltzmann’s constant.

 

 

VIB =
i=1 avian/2 _ eui-imyz i=1 eui(H)/2 _ euro/m (5.25)

MiM 372 111*111 I 1 ”2
MM=[ H D] [ H1 H2 H3 D1 02 D3] (53)

MEMH IElI£21£3IHIIH21H3

131

The Bigeleisen equation was further modified by incorporation of the Redlich-Teller
product rule11 to give the equation shown below, where the first factor is a ratio of

imaginary frequencies in the transition state.

VH 31fi7 V119 3111116 VD'
KIE = T -—I- —-I- X VIB
VD i=1 Vi),- i=1 VH) (5'4)

 

r
5.3.2 Initial studies
Computational studies were performed by Odom (unpublished results) and a simple
model (Equation 5.5) that would allow mechanistic exploration of the reaction was 'L

chosen, Ti[(=NPh)(OCMezCH=CH2)(NH2)(NH3)](109). The model reaction involves
rearranging of complex 109 to the terminal titanium-oxo complex,

Ti[N(Ph)CMe2CH=CH2](=O)(NH2)(NH3) (110).

PthJL<ge
HaN'T . 5:} ——> HaN'T'is (5-5)
' HZN’ 0

110

The calculations were performed using Gaussian03M12 by DFT using the 6-31G**
basis set. Two different hybrid functionals were used to test the agreement, B3PW91 and
MPWlPW9l.l3 Attempts to locate a [3,3]-sigmatropic transition state were unsuccessful
and instead the calculations pointed towards the [2+2]-cycloaddition transition state

(oxazatitanobicyclo[2.2.0]hexane 96) as shown in Equation 5.6.

132

ph Ph. Ph /|</
I N \N

N \ .. H N l .. .
+ I 3 ’ - + I . .
H3N' +1Lj< [2 2]-cyc oaddltlon> Hszw'i retrojg gl-cyc oaddltIOfl; H3NrTIeO (5.6)

 

 

O H2N
(109) (110)

5.3.3 Initial KIE experimental results

To get more substantial information, deuterium labeling experiments were performed
with deuterated allyl alcohols 2-methyl-(O,4,4-2H)-but-3-en-2-ol (111), 2-methyl-
(O,3,4,4-2H)-but-3-en-2-ol (112) and 2-methyl-(O,3-2H)-but-3-en—2-ol (113). The

deuterated allyl alcohols compounds were synthesized as shown below (Scheme 5.2). ’4

H—:——<— 351M 3' D——_-"—-<— 2LiAlH4: D
0H DZO/DCI on 020 D>—>§oo

 

2 LiAIDa 2 LiAID4 111
H20 D20
D D
i014 DiOH
113 112

Scheme 5.2. Preparation of deuterated allyl alcohols 11], 112 and 113 for SKIE.

The reactions were performed in NMR tubes sealed under vacuum followed by
heating at 160 °C. NMR spectra were recorded at regular time intervals. The KIE with
alcohol 111 was experimentally determined using the standard conditions with Ti(NMe2)4
(l). The experimental rate for protonated 2-methyl-3-buten-2-ol (74) was (2.23 :I: 0.4) X
10‘ 4 s4 on six independent runs (99% confidence limit). Kinetics performed with 1,
alcohol 111 and 2 resulted in a rate of (5.22 d: 1.24) X 10'4 s'1 from six runs, which gave a
large inverse SKIE (kn/k0) of 0.44 (Scheme 5.3). This number is strikingly different

when compared to organic reactions like Cope and Claisen rearrangements involving

133

[3,3]-sigmatropic transition state, which generally provide much smaller effects ofien
between ~0.80 to ~10 for SKIE. A kH/kD value of 0.84 is calculated from the DFT

(B3PW91) calculations.

 

D/H D/H>KH/3\
Phx /
Tl(NM82)4 + _ > 3 PhNHZ (2) > N
D/H OD

toluene, 160 °C ['Ti]:O

1 74/111 kH/ko = 0.44

PhP’H HID
N

[Tii
o

 

 

Scheme 5.3. Comparison of SKIE from reaction between 1, deuterated alcohol 111 and 2
with reaction of 1, alcohol 74 and 2.

On deuteration of all three vinyl protons, alcohol 112, there is a large change observed
in the SKIE from the dideuterated example (Scheme 5.4). The kH/kD value of 0.91 is
calculated from the DFT (B3PW91) calculations. The experimental kD calculated was

(2.58 i 0.54) X 10", which gave an experimental SKIE of 0.88 in agreement with the

 

DFT calculated value.
D/H ID D/H HID
Ti(NMe2)4 + >=§< : 3 PM”? : Ph\N>S/k
D/H OH H
1 74,112 toluegz, h160 °C HID
kH/ko = 0.88
\ I
PhP’H H/D /
'1‘ mo
{Ti}
0

Scheme 5.4. Comparison of SKIE from reaction between 1, deuterated alcohol 112 and 2
with reaction of 1, alcohol 74 and 2.

134

On deuteration of the two position, alcohol 113, the experimental kD was (2.52 :1: 0.16)
x 104, which gives an experimental SKIE of 0.90. The kH/kD value of 1.03 is calculated

from the DF T (B3PW91) calculations (Scheme 5.5).

 

HID Phx
Ti(NMe2)4 + 4 3 PhNHZ (2)¢ I}; /
0H toluene, 160 °C [Ti] \ HID
‘0
1 74/113 kH/kD = 0.90

I
\ Ph, /
'fl H/D
[Ti]
0

Scheme 5.5. Comparison of SKIE from reaction between 1, deuterated alcohol 113 and 2
with reaction of 1, alcohol 74 and 2.

An alternate function, MPWIPW91, was also used and the results are compared to
B3PW91 and the experimental SKIE in Table 5.1.
Table 5.1. Comparison of computational KIE and experimental KIE.

MPWlPW9l B3PW91 Experimental

Dideuterated (1 1 1) 0.89 0.84 0.43:1:0. 1 3
Trideuterated (112) 1.02 0.91 0.88:1:O.30
Monodeuterated (1 13) 1.04 1.03 0.90i0.17

5.4 Computational studies in the rhenium case
For comparison SKIE for the model system ReO3(OCH2CH=CH2) (114), where the
[3,3]-sigmatropic transition state can be found,15 was calculated (Figure 5.6). The

frequencies were determined by DFT/B3LYP/LANL2DZ calculations, and the labeling

was done as in the titanium case. The kH/kD value calculated was 0.75 for d2— and 0.67 for

135

 

d3-allyl, different from those found in the [2+2]/retro-[2+2] transition state and with a

relatively small difference between d2- and d3-labeled reactions.

   

 

 

 

 

 

r.

— SKIE=0.75 _ _ SKIE=0.67 -

Figure 5.6. SKIE values for rhenium system.
The calculations suggest the mechanism for the rhenium case passes through a [3,3]- E

sigmatropic transition state, which is evident from the DF T calculations performed on
114 and ReO3(O-2-methylallyl) (115) case using B3LYP, B3PW91, MPWIPW91, MP2,
PBElPBE basis set. The take home message from these calculations is that there is no
difference (AAGI values are comparative in allyl and 2-methyl case) between the 2-
methyl case and allyl alcohol case, i.e. both involve a [3,3]-sigmatropic transition state
(Table 5.2). A similar investigation carried out (B3PW91/LANL2DZ) to locate the [3,3]-
sigmatropic transition state in the titanium case resulted in structure 96. The 2-
methylallyl alcohol case in titanium resulted in neither the [2+2]-cycloaddition transition
state nor the [3,3]-sigmatropic route converging, indicating the [2+2]-cycloaddition

pathway is significantly destabilized by a methyl in the 2-position.

136

Table 5.2. DFT calculations on rhenium ally] and 2-methy1 allyl case.

 

Re03 Re03(2-Me 2-Me allyllrtGZ-Me- AAG’
Function allyl TS 1410 allyl

(OaIIyl) allyl) TS allyl (kcal/mol)
B3LYP -0.316 -0.290 16.349 -0.603 -0.577 16.788 0.438
B3PW9I -0.183 -0.156 16.951 -0.458 _0,432 16.415 -0.536
MPWIPW9I -0.l97 -0.l69 17.157 -0.476 -0.448 17.945 0.788
MP2(all c) -0.309 ~0.278 19.969 ~O.400 -0.371 18.140 -1.829
PBElPBE -496.809 496.782 16.932 636.049 -536.021 17.433 0.500

 

 

 

 

 

 

 

 

 

 

A similar comparison can be found in mechanistic studies performed by Osborn16 on
the isomerisation of 1-hex-en-3-ol by Re03OSiPh3 (64) (Scheme 5.6). Osborn suggests a
[3,3]-sigmatropic transition state and kinetic studies demonstrate the reaction is first order
in catalyst and allylic alcohol. Thermodynamics of the reaction reveals a large negative
activation entropy for the formation of E isomer, consistent with a [3,3]—sigmatropic

rearrangement through a highly-ordered chair transition state as shown below.

137

 

 

H Re03(OSiPh3) (64) R603
/ = /
AS: = 44.8 CU V: 24.9 CU

 

 

 

R63030
I
IlReh ”’* ‘stl’ r
O \‘ 8", ‘ n-C3H7
O
n-03H7 — .-

 

 

/\jH n-C3H7 \ '
\ IL
n-C3H

7 E HO
Z
Scheme 5.6. Osborn’s catalyst favors the [3,3]-sigmatropic transition state.
Shown below are experimental and restricted Hartree-Fock calculated SKIE values for a
typical [3,3]-sigmatropic rearrangement (Table 5.3). The values are in the range of
0.8~l.3 for all the positions.

Table 5.3. Comparison of SKIE in 3-methyl-1,5-hexadiene via experiments and
calculations (restricted Hartree-Fock).

 

. 3-Methyl-1,5—hexadiene
ReaCtant 3-Methyl-1.5-hexadlene RHF/6-31G.

Experimental (RHF/6-31G.)

\(02) 0.8910018 0.90(o.37)
/ (Dz)

\C 0.9510019 095(0'9“)
/ (Dz)

“(92) 10710025 1 .05(1.07)
\IADz)

 

138

5.5 Need for a model titanium imido system

The initial kinetics described above was performed in NMR tubes sealed under
vacuum and heated in an oil bath at 160 °C. The reaction was removed from the oil bath
at regular time intervals and immersed in a beaker with ice to quench the reaction and
NMR spectra were then recorded. Since the kinetics involved mixing of l, 44 and 2, there
was no accurate method of identifying the proposed titanium-imido species and its co-
ordination number. Hence a model system to investigate SKIE with the reactant and
product characterized was planned where the kinetics could actually be performed inside
the NMR spectrophotometer. This would eliminate experimental inconsistencies like
improper sealing of NMR tubes, inconsistent oil bath heating, NMR instrument error, in
situ generation of the titanium-imido complex, and a complex reaction.
5.6 Ti-imido alkoxide complex-SKIE results

The idea started of with the synthesis of a discrete titanium imido complex, bis(2-
methylbut—3-en-2-yloxy)(imido)titanium(IV) (116), followed by kinetic studies of the
rearrangement to the titanium oxo complex (117) (Scheme 5.7). The titanium starting
material initially selected was Ti(N’Bu)(Py)3(Cl)2 (118), synthesized by Mountford‘7 by
the reaction of TiCl4 (108) and tert-butylamine in excess pyridine. The compound was
selected keeping in mind the phenyl derivative, Ti(NPh)(Py)3(Cl)2 (119), was readily
available by a simple reaction of 118 with 2 at room temperature. The next step was a
simple substitution of the chloride ligands by (2-methylbut-3-en-2-olate)thallium(l)

(120).

139

 

9 M. 912

 

N/," N ‘\\\C| ; N/’,".”.“\\\O
2m; + 2 / /T'\ /
N Cl N O
M=K,Li, Na or Tl "5

N
C =4,4'-di-tert-butyl-2,2'bipyridine
N

 

1
Ph\ V\

(Natal/p

N /TI\O /
117

Scheme 5.7. Planned synthesis of titanium system for SKIE studies.

Screening different metal alkoxides led to the use of thallium allylalkoxide 120, which
gave the best results. An advantage of using compound 120 is the insolubility of thallium
chloride that precipitates out of the reaction mixture in organic solvents. Reaction of one
equivalent of 120 led to a product mixture of mono- and di-substituted products and
hence two equivalents of complex 120 was reacted with 118 (Scheme 5.8). The problem
was also compounded by difficulties in purification encountered while recrystallizing

119, which contained trace amounts of tert—butyl ammonium salt and could not be

completely separated from the reaction mixture.

140

 

4 I i f“ t"
N PhNH2(2) ll
Tic:4 + (5'30th2 -——-—> Ti(pyla(C|)2 "' ' Ti(DY)3(C')2
103
113 119

I)”.

not a clean reaction due to
purification problems of 119

=K,Li. Na or Tl

Scheme 5.8. Proposed scheme for the synthesis of titanium-imido complex.
An alternate titanium imido compound (121) was synthesized by the reaction of 1, 2

and slow addition of trimethyl silyl chloride at 80 °C for 14 h (Equation 5.7).18

 

P11
1) PhNH2(2)
Ti(NMez)4 mamasic' = MezNHSjI'r‘aNHMeZ (5.7)
1 >90% 121

With compound 121 in hand the next (step was an addition of 4,4-di-tert-butyl-2,2’-
bipyridine (122) at room temperature in pyridine followed by the addition of two
equivalents of 120 to yield the titanium complex, 116 (Equation 5.8). The addition of 122

would prevent any possible dimerization of the titanium(IV) center.

'i" 2_—Tl__>lo::l/ ' 0%
120 N’" N “‘0 (58)
MeZNH—y'r—NHMe2+ .
N/

TI /
01’ Cl N/\

116
>90%

With complex 116 in hand, an attempt was made to establish the rearrangement
reaction to the corresponding titanium oxo complex (117) at 130 °C. Secondary allylic
amine, N-(3-methyl-2-butenyl)aniline (75), was obtained after an aqueous quench. The

141

 

 

rearrangement takes place at 130 °C with more than 60% conversion after 24 h to give

complex 117 (Equation 5.9).

Q )9 FNMA

Nn,~..l|]|-..~\“O 130 °C Nh"'1|-.//O (5 9)
l / '\ / .
N/ \O N/ O

 

1 16 1 17

Rate constant for the rearrangement reaction was obtained by investigating the
rearrangement in the NMR instrument with the probe temperature set to 100 °C (This is
currently the maximum limit that one can attain with the instruments in the department).
The fits are plotted to the exponential growth of the product using the scientific graphing
program Origin.® The exact expression used to fit the data used is Y, = Yinf+ (Yo — Yinf)
exp(-kobst), where Yt equals formation of product at time t.19 The following graph shows
typical first order kinetics with time in the x-axes plotted against the combined methyl
peak integration for the product in y-axes (Figure 5.7). A first-order reaction is

characterized by a linear plot of lnlY - Yind versus time (Figure 5.8).

142

 

.J

 

20-

 

 

  

 

 

 

 

 

 

i
18 a
c 16 -
.9
‘66 - Data: Data1_B
‘5, Model: Bala
9 14 d Weighting:
.E 40 mg
~05 .
6 Chi"2/DoF = 0.0721
9 12 - R"2 = 0.98949
0.
1 yO 9.463 10
yinf 19.9433 i0.17007
10 - k 0.00408 10.00015
8 l ' l ' l ‘ I I ' l I 1
0 100 200 300 400 500 600
time in mine

Figure 5.7. Kinetics with titanium imido alkoxide 116.

143

 

 

 

 

 

 

 

2.7 - Data: Data1_B
Model: Line
' Equation: y = A + B'x
2.6 - Weighting:
y No weighting
2 5 q Chi‘2/DOF = 0.00045
' R"2 = 0.99257

2 4 _ A 2.65886 $001253
c ' B -0.00127 10.00004
c .
3; 2.3 - .
Z, .
C I
_ 2.2 "' \

J

2.1 .9 I

2.0 -

1 .9 l U I I l I l U l I l I I

0 100 200 300 400 500 600
time in mins

Figure 5.8. 1St order kinetics, plot of ln|Y - Yinfl versus time.

The rate (k) for rearrangement of titanium compound 116 is (4.01 :t 0.64) X 10'3 s“1
with 99% confidence limit on three independent runs. The appearance of product methyl
peaks (integrated methyl peaks-y axes) in the rearranged compound were measured and
plotted versus time (x-axes). An important case is the effect on the rate when a
substitution is made in the two position of allyl alcohol (93). A trace amount of product is
seen in the reaction between 1 alcohol 93 and 2. The required alcohol, 2,3-dimethyl-3-
buten-2-ol (123) was synthesized using a modified established procedure.20 The complex,

bis(2-methylbut—3-en-2—yloxy)(imido)titanium(IV) (125), was synthesized along the same

144

 

lines as complex 116 (Equation 5.10). Surprisingly the reaction time for formation of

complex 125 was found to be longer than for compound 116.

TIO
'i" zlim: Q OJ?
NI” N...“
MezNH C—I’TF—‘NHMez N/ N/Ti‘\125\O-J<((5 10)

40°C (48 h)
> 90%

 

The kinetics performed on 125 reveals some interesting results. First, the
rearrangement indeed occurs for complex 125, with a single peak observed for the
product N-(2,3-dimethyl-2-butenyl)aniline in the GC-MS, with m/z =175. The presence
of titanium-imido in the complex was also confirmed via the GC-MS for aniline (m/z =
93) and 1,2-diphenyldiazaene (m/z = 182) respectively. Second, complex 125 has a much
slower rate of rearrangement than complex 116, which rearranges in 24 h at 100 °C.
Third, the NMR kinetics was performed in the NMR probe initially for 12 h at 100 °C
and then in a constant temperature oil-bath at 100 °C. Attempts were made to determine
the rate constant for the reaction, which was found to be ~7% complete after 11 days of
heating at 100 °C in a constant temperature oil-bath.

The rate (k) for the kinetics for the titanium complex (126) synthesized using mono
deuterated allyl alcohol 113, was (7.98 i 3.2) X 10‘3 s"1 with 99% confidence limit on
three independent runs. The SKIE obtained was 0.52 :I: 0.2, which is indeed inverse for
the position indicated (Scheme 5.14) but also a significantly large one (Graphs plotted for
the appearance of product methylene peak versus time gave a value of 0.38 (kn/kD)-refer

experimental section).

145

 

Q or.
NM,” 9‘ \‘0 Ph”: v1 ——"
[Tl‘]\\0 H/D

. - H/D [Ti];
N/Tl\
o lo [2+2]-
cycloaddition
118/128 ”’0 '9 “42”}
~ Ph 7 I cycloaddition

'i‘ H/D
'[i
o kH/kD = 0.5

Scheme 5.9. SKIE of 0.5 for deuteration in the two position of allyl alcohol.

 

 

5.7 Comparison to vanadium imido complex

The above results do point towards a [2+2]-cycloaddition/retro-[2+2]-cycloaddition
transition state for titanium chemistry in contrast to rhenium chemistry of 1,3-allylic
transposition, which is believed to proceed through a [3,3]-sigmatropic transition state.
We believe there is a shift in the mechanistic pathway as one moves across from left to
right in the periodic table, from titanium to molybdenum. As a validation to our above
statement our efforts were focused on comparing similar isotopic effect values in
vanadium, since vanadium oxo complexes isomerize allylic alcohols in a 1,3-manner and
is also believed to involve a [3,3]-sigmatropic transition state.

An attempt was made to synthesize a vanadium analogue to the titanium imido
alkoxide (116) by the reaction of a trichlorophenylimidovanadium(V) V(=NPh)Cl3, 127
and three equivalents of lithium alkoxide of 2-propen-2-methyl-1-ol (74). This route
could not be pursued as the product could never be completely purified. An alternative
route developed was through an anionic charged ligand viz. S-mesityldipyrrin, which was

lithiated and substituted for a chloride ligand on reacting with complex 127 to yield

146

 

complex 128. The reaction failed to work and reduction at the metal center was seen,

evident from the paramagnetic nature of the lH NMR (Scheme 5.10).

  
 
 

 

r|=h
Eh {N01, ”MCI
m/jl'wcr -LiC| : /V\C|
Cl -7800 an
127 128
DDQ L

 

 

H
N
‘\

\ZI

Scheme 5.10. Proposed synthesis of vanadium complex 128.

The S-mesityldipyrrin is synthesized using standard oxidation from 5-
mesityldipyrrolylmethane, which in turn is synthesized from pyrrole, mesitylaldehyde,
and MgBrz.21 An alternate route to make the vanadium analogue of complex 116 would
be to replace all the chloride ligands with NEtz since the vanadium imido-

tris(diethylamide)phenylimidovanadium(V), V=NPh(NEt2)3 (129) was known and can

possibly help in preventing reduction to vanadium(IV) as seen in the Equation 5.11.22
F?“ F?“
W, -31Jcn
Cl/lv ””CI 4' 3 LiNEt2 —_’ EtzN/IVWHNEtZ (5.11)
CI EfizN
127 129

147

The reaction of 129 with lithiated S-mesityldipyrrin was unsuccessful and cleavage of
dipyrrin was seen along with reduction at the vanadium center. Another route was the
reaction of thallium derivative of 5-mesityldipyrrin with 127 to afford complex 128

(Scheme 5.11).

 

 

Ph
ii
Cl/V'HHCI + 'TICI >
1 -78 °C
Cl
127

128

 

Scheme 5.11. Reaction of thallium derivative of dipyrrin with vanadium complex 128.
We have confirmation that the thallium route was successful, but do not have

characterization on compound 128.

148

5.8 Summary

As the kinetics was performed in the NMR spectrophotometer for 10 h at 100 °C only
20% of product conversion was seen. This is a disadvantage over the earlier route where
the kinetics were performed in an oil-bath at 160 °C, since the kinetics is faster at
elevated temperatures. One possible explanation for the low conversion could be the
product inhibiting further conversion as the reaction is homogeneous at 100 °C and also
no product titanium dimers or oligomers precipitate out of the reaction. A solution to this
problem would be performing kinetics with complex 116 at higher temperature in an oil-
bath. The SKIE obtained for compound 116/126 indicate a value of 0.5 with the
deuterium in the two position, which is a large SKIE compared to values of O.8~1.0 for
Claisen and Cope reactions. At this point of time it is not clear if the SKIE value for
deuteration in the two position is an accurate representation as only 20% product
conversion was achieved during the kinetic runs. Even though one could argue about the
validity of the actual SKIE value itself, unfortunately it is the only one that we have been
able to obtain so far. Experimental and theoretical calculations performed indicate the
[3,3]-sigmatropic transition state is unlikely for titanium chemistry. Experiments also
indicate a considerable amount of deceleration in the rate, when the 2-position in the allyl
alcohol is substituted. The theoretical calculations performed on the rhenium case do
show a tilt towards the [3,3]-sigmatropic transition state. Calculations also indicate no

change in the mechanism when a substitution is made in the 2-position of allyl alcohol.

149

5.9 General Methods

All reactions, unless otherwise specified, were performed under an inert atmosphere of
nitrogen. All chemicals were purchased commercially, were purified prior to use, and
were stored in a MBraun glove-box. Distilled solvents were transferred under vacuum
into vacuum-tight glass vessels and were stored in the glove box. Deuterated toluene was
distilled over sodium benzophenone and distilled under nitrogen. Pyridine was refluxed
and distilled over calcium hydride. Thallium ethoxide was purchased commercially and
purified by filtration to remove residual metallic thallium. Lithium aluminum hydride and
lithium aluminum deuteride was purified before use.23 Ti(NMe2)4 was synthesized using
the literature procedure.24 1H and '3 C NMR were recorded in CDC13 and 2H NMR spectra
in CHC13. NMR spectra were recorded at 25 °C in 5 mm NMR tubes on a 500 MHz and
a 300 MHz Varian Inova spectrometer. Chemical shifts are reported in parts per million
(ppm) relative to the trimethylsilane (TMS) internal standard at 0 ppm for deuterated
chloroform. GC-FID chromatograms were recorded on an Agilent 6890 GC system. GC-
MS chromatograms were recorded on an Agilent 5973 inert mass spectrometer. The
initial kinetics with Ti(NMe2)4 were performed in a sealed Wilmad NMR tube under
vacuum and heated in a constant oil bath maintained at 160 °C. Barnstead Electrothermal
Set-Temp apparatus was used to maintain the temperature constant at 160 °C. Kinetics
with the discrete titanium-imido complexes were performed in a J-Young tube fitted with
a Teflon cap. Samples were accurately weighed out to 40 mg and dissolved in deuterated
toluene solution, measuring 0.77 mL. The tube was removed from the drybox and heated
at 100 °C in a 500 MHz Varian Inova spectrometer. The kinetic experiments were

performed in the NMR instrument programmed to record spectra every 10 min for

150

 

duration of 10 h. Hexamethyldisiloxane (HMDS) was used as an internal standard. The
relative appearance of the dimethyl peaks in the product versus HMDS concentration was
monitored as a fimction of time. The graphs were plotted using the scientific graphing
program Origin. The exact expression used to fit the data was Y, = Y... + (Y0 - Y.o )exp-
kobst where Y, = formation of product at time t.'9 The variables Yw, Y0, and kobs were

optimized in the fits.

151

 

5.10 Experimental Section

D

Figure 5.9. Structure of 2-methyl(0, 4,4-2H)but-3-en-2-ol (111).

Preparation 0f2-methyl(0, 4, 4-2H)but-3-en-2-ol (111)

A solution of LiAlH4 (1.76 g, 46.4 mmol) in dry ether (150 mL) was stirred under a
nitrogen atmosphere and cooled to 5-10 °C. A solution of 2-methyl (O, 4-2H) but-3-yn-2-
0125 (2.0 g, 23.2 mmol) in 20 mL Et20 was added dropwise to the solution in 10 min; the
solution was then allowed to warm to room temperature and refluxed at 50 °C for 60 h.
The mixture was cooled to 0 °C and deuterium oxide (6 mL) was added dropwise over a
10 min period. The solution was stirred for 12 h before 15% aqueous NaOH (6 mL) and
then H20 (7 mL) were added. The precipitated inorganic solids were removed by
filtration and washed well with ether. The combined filtrate was dried (MgSO4), filtered,
and distilled (bp 92-97 °C under N2) to afford 2-methyl (O, 4, 4-2H) but-3-en-2-ol (0.9 g,
10.1 mmol, 43% yield). lH NMR (500 MHz, CDCl3) 8 = 5.94 (s, 1 H), 1.34 (s, 6 H). 2H
NMR (76.7 MHz, CHC13) 6 = 5.22 (s, l D), 5.04 (s, 1 D), 0.8 (br, 1 D). The deuteration

was more than 99.5% for the positions indicated.

152

 

0&0

D

Figure 5.10. Structure of 2-methyl(O, 3,4,4-2H)but-3-en-2-ol (112).

Preparation of 2-methyl(0, 3, 4, 4-2H)but-3-en-2-ol (112)

A solution of LiAlD4 (1.56 g, 46.4 mmol) in dry ether (150 mL) was stirred under a
nitrogen atmosphere and cooled to 5-10 °C. A solution of 2-Methyl (O, 4-2H) but-3-yn-2-
0125 (2.0 g, 23.2 mmol) in 20 mL Et20 was added dropwise to the solution in 10 min; the
solution was then allowed to warm to room temperature and was refluxed at 50 °C for 60
h. The mixture was cooled to 0 °C and deuterium oxide (6 mL) was added dropwise over
a 10-min period. The solution was stirred for 12 h before 15 % aqueous NaOH (6 mL)
and then water (7 mL) were added. The precipitated inorganic solids were removed by
filtration and washed well with ether. The combined filtrate was dried (MgSO4), filtered,
and distilled (bp 92-97 °C) to afford 2-methyl(0, 3,4,4-2H)but-3-en-2-ol (1.0 g, 11.1
mmol, 48% yield). lH NMR (300 MHz, CDC13) 5 = 1.34 (s, 6 H). 2H NMR (76.7 MHz,

CHC13) 5 = 5.94 (s, 1 D), 5.22 (s, 1 D), 5.04 (s, 1 D), 0.8 (br, 1 D).

153

 

A?“

Figure 5.11. Structure of 2-methyl(3-2H)but-3-en-2-ol (113).

Preparation of 2-methyl (3-2H)but-3 -en-2-ol (113)

A solution of LiAlD4 (1.56 g, 46.4 mmol) in dry ether (150 mL) was stir under a nitrogen
atmosphere and cooled to 5-10 °C. A solution of 2-methyl (O, 43H) but-3-yn-2-ol (2.0 g,
23.2 mmol)25 in 20 mL 320 was added dropwise to the solution in 10 min; the solution
was then allowed to warm to room temperature and was refluxed at 50 °C for 120 h. The
mixture was cooled to 0 °C and water (6 mL) was added dropwise over a 10-min period.
The solution was stirred for 12 h before 15% aqueous NaOH (6 mL) was added. The
precipitated inorganic solids were removed by filtration and washed well with ether. The
combined filtrate was dried (MgSO4), filtered, and distilled (bp 92-97 °C under N2) to
afford 2-methyl (3-2H) but-3-en-2-ol (0.3 g, 3.44 mmol, 15% yield). 1H NMR (300 MHz,
CDC13) 8 = 5.22 (d, 1 H), 5.04 (d, 1 H), 1.34 (s, 6 H), 0.8 (br, 1 H). 2H NMR (76.7 MHz,
CHCl;;) 6 = 5.94 (s, 1 D). 13C NMR (500 MHz, CDC13): 145.4, 108.7, 70.3, 28.5. The

deuteration was more than 99.5% for the position indicated.

154

 

Preparation of thallium(I) triflate (129)

To a cold solution of TlOCsz (4.24 g, 16.96 mmol) in DME (3 mL), was added TfOH
(2.54 g, 16.96 mmol) in DME (3 mL). The reaction was warmed to room temperature and
allowed to stir for a period 16 h. The solvents were removed in vacuo and the dark
solution extracted with pentane to give a white solid, with 90% yield. The compound is
insoluble in benzene, reacts with chloroform and decomposes slowly in acetone.

e):

TIO

Figure 5.12. Structure of (2-methylbut-3-en-2-olate)thallium(l) (120).

Preparation of (2-methylbut-3-en-2-olate)thallium(I) (120)

To a cold solution of TlOCsz (3.2 g, 12.77 mmol) in THF (3 mL) was added 2-
methylbut-B-en-2-ol (3 g, 34.8 mmol) and was then allowed to warm to room temperature
and stirred for a period 16 h. The solvents were removed in vacuo and the solution was
filtered. The filtered solution was kept in the freezer and the product crystallizes out as
white crystals in 90% yield. The compound is insoluble in benzene, reacts with

chloroform and decomposes slowly in acetone. mp = 180 °C.

TIO

Figure 5.13. Structure of (2,3-dimethylbut-3-en-2-olate)thallium(I) (124).
Preparation of (2, 3-dimethylbut—3-en-2-olate)thallium(I) (124)
To a cold solution of TlOCsz (2.25 g, 9.0 mmol) in THF (3 mL) was added 2,3-

dimethylbut—3-en-2-ol (3 g, 30.0 mmol) and was then allowed to warm to room

155

 

gag

 

temperature and stirred for a period 16 h. The solvents were removed in vacuo and the
solution was filtered. The filtered solution was kept in the freezer and the product
crystallizes out as white crystals in 90% yield. The compound is insoluble in benzene,

reacts with chloroform and decomposes slowly in acetone. mp = 195 °C.

 

 

156

 

Figure 5.14. Structure of bis(2-methyl-3-buten—2-alkoxide)(phenylimido)titanjum(IV)
(116).

C34H47N302Ti Preparation of bis(2-methyl-3 -buten-2-alkoxide) (phenylimido)titanium(l V)
(116). To a solution of 121 (180 mg, 0.6 mmol) in pyridine (3 mL), was added 4,4'-di-
tert-butyl-2,2'-bipyridine (161 mg, 0.6 mmol) in pyridine (2 mL) and allowed to stir for
15 min. The solution was cooled and a cold solution of thallium(I) 2-methylbut-3-en-2-
olate (347 mg, 1.2 mmol) was added and allowed to stir at room temperature for 16 h.
Rapid formation of thallium(I) chloride is seen and the wine red solution is filtered
through celite. The solvent was evaporated to give the product in 90% isolated yield (310
mg, 0.54 mmol). Melting point of the compound could not be recorded due to the viscous
nature of the solid (semi-solid compound). The compound shows a peculiar behavior in
1H and has unusually long relaxation time (T1) = 25 s. IH NMR (500 MHz, CDC13) 8 =
8.6 (dd, 2H, J= 5.3 and 0.76 Hz), 8.4 (dd, 2H, J= 2.0 and 0.75 Hz), 7.3 (dd, 2H, J= 5.1,
2.0 Hz), 7.1-7.2 (m, 2 H), 6.7-6.8 (t, 1 H, J = 7.5 Hz), 6.667 (d, 2 H, J = 7.8 Hz), 5.9 (m,
2H, c), 5.2 (dd, 2H, p or d, J= 17.4 and 1.5 Hz), 4.9 (dd, 2H, p or d, J: 10.6 and 1.5
Hz), 1.4 (s, 18 H, j), 1.3 (s, 12 H, b). 13C NMR (500 MHz, CDC13) 160.9, 156.5, 149.8,
149.0, 146.4, 136.0, 129.7, 129.3, 120.7, 118.2, 109.9, 82.3, 34.9, 30.8, 30.6. Elemental

analysis (Cale), C: 70.63 (70.72). H: 8.70 (8.15). N: 7.30 (7.23).

157

 

 

 

Figure 5.15. Structure of (phenylimido)bis(2,3-dimethy1-3-buten-2-alkoxide)
titanium(IV) (125).

C36H51N302Ti Preparation of @henylimido)bis(2,3-dimethyI-3-buten-2-alkoxide)
titanium(IIO (125). To a solution of 121 (180 mg, 0.6 mmol) in pyridine (3 mL), was
added 4,4'-di-tert-butyl-2,2'-bipyridine (161 mg, 0.6 mmol) in pyridine (2 mL) and
allowed to stir for 15 min. The solution was cooled and a cold solution of (2,3-dimethyl-
3-buten-2-olate)thallium(I) (375 mg, 1.2 mmol) was added. The solution was allowed to
stir at room temperature for 48 h and heated at 40 °C for 24 h. Formation of thallium(I)
chloride is seen and the wine red solution is filtered through celite. The solvent was
evaporated to give the product in 90% isolated yield (315 mg 0.52 mmol). Melting point
of the compound could not be recorded due to the viscous nature of the solid (semi-solid
compound). The compound shows a peculiar behavior in 1H and has unusually long
relaxation time (T1) = 25 s. 1H NMR (500 MHz, CDC13) 5 = 8.6 (dd, 2H, J = 5.3 and
0.76 Hz), 8.4 (dd, 2H, J= 1.9 and 0.75 Hz), 7.3 (dd, 2H, J= 5.5 and 2.0 Hz), 7.1-7.2 (m,
2 H), 6.7-6.8 (t, 1 H, J = 7.5 Hz), 6.6-6.7 (d, 2 H, J = 7.8 Hz), 5.2 (s, 2H, p or d), 4.9 (s,
2H, p or d), 1.7 (s, 6 H, r), 1.4 (s, 18 H, j), 1.3 (s, 12 H, b). 13C NMR (500 MHz, CDC13)
160.9, 157.5, 151.9, 150.1, 149.1, 136.0, 129.5, 129.0, 120.7, 118.0, 107.9, 84.5, 34.9,
30.4, 30.2, 19.2. Elemental analysis (Ca1c.), C: 70.83 (71.41). H: 7.80 (8.40). N: 7.13

(6.94).

158

' Wi";-“-°.‘1J

 

 

 

Figure 5.16. Structure of (phenylimido)bis-(2-methyl-3-buten-3-2H-2-alkoxide)titanium
(IV) (126).

C34H45D2N302Ti Preparation of (phenylimido)bis-(2-methyl-3-buten-3-2H-2-
alkoxide)titanium (110 (126). To a solution of 121 (77 mg, 0.26 mmol) in pyridine (3
mL), was added 4,4’-di-tert-butyl-2,2'-bipyridine (69 mg, 0.26 mmol) in pyridine (2 mL)
and the solution was allowed to stir for 15 min. The solution was cooled and a cold
solution of (2-methyl-3-2H-but-3-en-2-olate)thallium(l) (0.150 mg, 0.51 mmol) was
added and allowed to stir at room temperature for 16 h. Rapid formation of thallium(I)
chloride is seen, and the wine red solution is filtered through celite. The solvent was
evaporated to give the product in 97% isolated yield (145 mg, 0.25 mmol). Melting point
of the compound could not be recorded due to the viscous nature of the solid (semi-solid
compound). The compound shows a peculiar behavior in lH and has unusually long
relaxation time (T1) = 25 s. 1H NMR (500 MHz, CDC13) 5 = 8.6 (dd, 2H, J = 5.3 and
0.76 Hz), 8.4 (dd, 2H, J = 1.9 and 0.75 Hz), 7.3 (dd, 2H, J = 5.5 and 2.0 Hz), 7.1-7.2 (m,
2 H), 6.7-6.8 (t, 1 H, J = 7.5 Hz), 6.6—6.7 (d, 2 H, J = 7.8 Hz), 5.2 (m, 2H, p or d), 4.9 (m,
2H, p or d), 1.4 (s, 18 H, j), 1.3 (s, 12 H, b). 13C NMR (500 MHz, CDC13) 161.3, 159.1,
156.6, 149.4, 146.5 (quintet, c), 136.0, 129.4, 129.2, 121.1, 118.4, 110.1, 82.5, 35.2, 30.8,

30.5. 2H NMR (76.7 MHz, CHC13): 8 = 6.0 (s, 1 D).

159

 

 

Kinetic data

99% confidence limit values for compound 116
Run 1 k = 0.00404

Run 2 k = 0.00388

Run 3 k = 0.00401

S 1 N — i
S = _ X—X 2
m N ,/N(N—1)[.Z=1:( ' ):l

1
[(0.00408 — 0.00401)2 + (0.003 88 - 0.00401)2 + (0.00406 — 0.0401)2 :12

1
— ,/3(3 - 1)

1

J30)

1
_ 2.4495

 

l
[5x10'°+17x10'9+3x10'9]2

I
[25x109]2

 

Sm = 0.000064549

A = 9.92x0.000064549

= i0.00064033

= 0.00465 to 0.00337

S = standard deviation

N = number of observation

Sm = 99.5% confidence limit

A = deviation permitted for 99.5% value,

t = student’s t value i.e. 9.92 for 3 readings

99% confidence limit values for compound 126

Run 1 k = 0.00832

160

 

 

f“
Hm:
uni—'0:

Run 2 k = 0.00733

Run 3 k = 0.00829

1

S l " — -
= X— 2
Jfi JNrN—1)l§( ' ml

 

1
1 ) [(000832 _ 0.00798)2 + (0.00733 — 0.00798)2 + (0.00829 — 0.0079102]2

= ,/3(3—1

I
=—1-[116x10'9 +423x10'9 +96x10'9]2
J30)

 

1 ,, l
=— 635x10 2
£[ 1

1
= — 0.000796869
JE[ ]

Sm = 0.000325319

A = 9.92 x 0.000325319

= :t 0.003227

=0.01121 to 0.004753

S = standard deviation

N = number of observation

Sm = 99.5% confidence limit

A = deviation permitted for 99.5% value

t = student’s t value i.e. 9.92 for 3 readings

SKIE for deuterium in the 2-position

SKIE = 0.00401 / 0.00798 = 0.502

161

Error in SKIE value for deuterium in the 2-position

 

 

 

0.0032272 2 0.00064033 2
a,=0.5 —— +
0.00798 0.00401

6, = 0.5J0.1636 + 0.0255

 

a, = 0.5x0.435 = 30.22

03, = propagation of error

x= value whose error is being calculated

p = mean value of kD

q = mean value of kg

0;, = deviation from value in kg for 99.5% calculation

0., = deviation from value in kH for 99.5% calculation

The graphs plotted below represent the appearance of product methyl peaks.

Y=Yin(+(Yo-Yinf)exp(-kt)

162

 

201

18- f

 

16 . /f

 

 

 

 

 

 

C
.9
E ‘ Chi"2/DOF =0.0721
E 14- R02 = 0.98949
C
‘9 yo 9.463 .0
g 12- ' yinf 19.9433 10.17007
9 k 0.00408 .0.00015
10-
8 l ' l ' l r l ' l j l ' I
0 100 200 300 400 500 600
time in mins

Figure 5.17. Run 1 for compound 116

163

 

 

 

 

 

 

 

25-
I
4 {If/fr
20- /./i
c I
g .
g1..- _ Chi"2/D0F =0.50407
jg R"2 = 0.98506
‘9
g 10- yO 3.98.0
a .1- yinf 24.86375 10.66186
k 0.00388 .0.00026
5- J
0 l r l v I v [ ' l ' I ' I fl
0 100 200 300 400 500 600

time in mins

Figure 5.18. Run 2 for compound 116

164

 

24-

 

 

 

 

 

 

22- f
20.1 is
/K
C 18'- . I
.g Chm/D61: =0.09954
9 R"2 = 0.98881
3 18-
5 yo 11.38 .0
14.. yinf 23079231020157
k 0.00406 .0.00015
12-
10 I ' I ' I I ' I T T ' I
0 1 00 200 300 400 500 600
time in mins

Figure 5.19. Run 3 for compound 116

165

 

Kinetics for compound 126 plotted for appearance of product methyl peak

20-

18‘

161

 

  

 

 

 

  

 

 

 

c ChiA2/D0F =0.10985
,9; 14- R"2 = 0.98493
8) c1
9:312- y0 7.8035 .0
7' yinf 18584631007572
10_ k 0.00832 90.0002
8" l/
I
6 1 ' 1 ' I r I I ' I ' I
0 100 200 300 400 500 600
time(mins)

Figure 5.20. Run 1 for compound 126

166

1
700

 

 

  
 

   

 

 

 

 

 

20-
9‘—
18d
16-
5,5 Chi"2/DoF =0.1763
g 14- R"2 = 0.98989
0)
3.: yo 9.07797 to
12- yinf 18852181010709
_ k 0.00733 90.00029
10- /
/
i
8

r ' 1 ' r
0 100 200

Figure 5.21. Run 2 for compound 126

I ' I ' I ' I
300 400 500 600
time in mins

167

I
700

 

 

 

 

 

 

 

 

 

22-
20- /”’#—f
18-
g ' Chi"2/DOF =0.37417
=3; 16- _- R42 = 0.93983
‘61
.9 ' -'
.5 14_ _ y0 10.42466 .0
_ yinf 20882281014017
‘ / k 0.00829 .0.00043
12- l/
/
I/
10-
l r l ' l ' I ' l ' l ' l ' 1
0 100 200 300 400 500 600 700

time in mins

Figure 5.22. Run 3 for compound 126

168

13-

 

 

 

 

 

 

 

- a“ Chi"2/DoF =0.05843
12- R02 = 0.98785
. .\ yO 13.13285 .0378
x 11- \s yinf -5.67675.23.74368
8 k 0.00003 .0.00004
0. \I a.
a» i
E 10-
o -
U \\.\\
9-
I \ ~.\
81 \\I
0 1 20.00 t 4600 T 6000 ' 8000 I 10000 U 12000 '

time(mins)

Figure 5.23. Run 1 for compound 125
Rate = (3 3. 4) x 10'5

Only a single run was performed for complex 125 due to the duration of the
experiment. The error is indeed large for the run performed, but this is just a comparison
(kH) with complex 116 and it represents the effect of substitution in the 2-position of allyl

alcohol 44.

169

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11111311111911

6