:: . Rel n... A. .c! .0. “w L: E 4i meuytbfin. 2. y 3.5% ‘THESIS Z, RSIRITYLB RARIES WWii\||\WWliliiimiliiii L N 31293 015 i This is to certify that the dissertation entitled A STUDY OF ENOLATE FORMATION USING DIORGANOPHOSPHIDE ANIONS presented by Shau-Lin Lyu has been accepted towards fulfillment of the requirements for Ph . D . _ Chemistry degree in WaMuu/éw Major professor Date 2-26-96 MSU is an Affirmative Action/Equal Opportunity Institution 0-12771 LIBRARY Michigan State University PLACE IN RETURN BOX to romovo this chockout from your record. TO AVOID FINES rotum on or baton doto duo. DATE DUE DATE DUE DATE DUE EL % e j L? fim MSU loAn Afflnnotivo Action/Emu Opportunity Inotltuion 7 mm: A STUDY OF ENOLATE FORMATION USING DIORGANOPHOSPHIDE ANIONS By Shau-Lin Lyu A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1996 ABSTRACT A STUDY OF ENOLATE FORMATION USING DIORGANOPHOSPHIDE ANIONS By Shau-Lin Lyu The metal diorganophosphides were prepared by a direct metallation method. Diphenylphosphide ions of magnesium, lithium, and potassium were obtained using phenylmagnesium bromide, n- butyl lithium, and potassium as metallation agents, respectively. The preparation of alkali metal di-t-butylphosphides were achieved using n-butyl alkali reagents, in the presence of THF. Lithium diphenylphosphide reacts with simple enolizable ketones to generate enolates. Enolate formation was determined by phosphorus-31 NMR measurement of the diphenylphosphine produced and proton NMR measurement of the silyl enol ether obtained after chlorotrimethylsilane quenching. Enolates of ester and tertiary amide were prepared by using the stronger base, lithium di— t-butylphosphide. The enolates react with benzyl bromide to give excellent yields of alkylation products. Either enolate regioisomer of an unsymmetrical ketone can be selectively generated by using lithium diorganophosphides, under kinetic controlled conditions. Only the more substituted enolate was produced when lithium diphenylphosphide reacted with 2- methylcyclohexanone. The less substituted enolate was selectively generated in the reaction of 2-heptanone with lithium di—t- butylphosphide. The reactions of alkali metal diorganophosphides with 3- pentanone furnished the Z enolate stereoisomer as the major product, regardless of the base used. The higher aggregation state of lithium diphenylphosphide, in benzene, is responsible for the higher ratio of E enolate stereoisomer production in the reaction with 2',4',6'- trimethylpropiophenone. Alkylation, acylation, and aldol reactions were performed to study the reactivities of enolates (obtained by diorganophosphide anions). ACKNOWLEDGMENTS The author wishes to express his appreciation to Dr. Michael W. Rathke for his guidance throughout the course of this investigation. Thanks is given to Dr. William H. Reusch for his many helpful suggestions in the preparation of this thesis. Thanks is also extended to Dr. Harry A. Eick for his interest in this work. The financial support provided by Michigan State University is gratefully acknowledged. Finally, I wish to thank my family, without their love and support this thesis would have been impossible. iv TABLE OF CONTENTS Page INTRODUCTION ............................................................................................... 1 RESULTS AND DISCUSSIONS ..................................................................... 14 (i) THE PREPARATION OF METAL DIORGANOPHOSPHIDES ..... 1 4 (ii) THE REACTIONS OF METAL DIORGANOPHOSPHIDES WITH KETONES .................................................................................... 2 1 (iii) THE REACTIONS OF METAL DIORGANOPHOSPHIDES WITH ESTERS AND TERTIARY AMIDE ....................................... 3 1 (iv) REGIOSELECTIVE ENOLATES FORMATION USING METAL DIORGANOPHOSPHIDES AS BASES ............................................... 4 2 (v) STEREOSELECTIVE ENOLATES FORMATION USING METAL DIORGANOPHOSPHIDES AS BASES .............................. 5 5 (vi) THE REACTIONS OF KETONE ENOLATES ..................................... 6 2 EXPERIMENTAL ............................................................................................... 71 REFERENCES ....................................................................................................... 95 Table II III IV VI VII VIII IX LIST OF TABLES The preparation of metal diorganophosphides ..................... Phosphorus-31 NMR studies for the reactions of metal diorganophosphides with ketones .............................................. The reactions of ketone enolates with TMSCl ........................ Phosphorus-31 NMR studies for the reactions of metal diorganophosphides with esters and tertiary amide .......... The reactions of ester and tertiary amide enolates with benzylbromide ..................................................................................... Regioselective enolate formation of 2- methylcyclohexanone ....................................................................... Regioselective enolate formation of 2- methylcyclopentanone ..................................................................... Regioselective enolate formation of 2-heptanone ................ Regioselective enolate formation of phenylacetone ............ The effects of base / ketone ratio on regioselective enolate formation of 2-heptanone .............................................. vi page 20 29 3O 34 35 43 44 45 46 49 XI Enolate of 2-methylcyclopentanone equilibrium in the presence of additives ........................................................................ 5 1 XII Comparison of regioselective enolate formation of 2- methylcyclohexanone ....................................................................... 5 2 X111 Comparison of regioselective enolate formation of 2- heptanone .............................................................................................. 54 XIV Stereoselective enolate formation of ethyl ketones ............ 6O XV Comparison of stereoselective enolate formation of 3- pentanone .............................................................................................. 61 XVI The reactions of ketone enolates with electrophiles ........... 7O vii LIST OF FIGURES Figure page 1 Common bases used for enolates preparation .................... 3 2 Potential bases could be used for enolates preparation. 4 3 Lithium diphenylphosphide aggregation in ether and inTI-IF ................................................................................................... 8 4 The reactions of alkali metal di-t-butylphosphides with tin (II) chloride ...................................................................... 1 1 5 Nucleophilic addition of BngPth to ketone carbonyl. 27 6 Schematic diagram of 31P NMR chemical shifts of metal diphenylphosphides .......................................................... 2 8 7 Stereoselective enolate formation using LiP(t-Bu)2 ,,,,,,,,, 57 8 Solvent effects on enolate formation ...................................... 59 9 Enolate of isobutylphenone aggregations in dioxane and in DME ......................................................................................... 6 3 1 O Enolate of phenylacetone ............................................................. 6 3 II Lithium enolate of isobutylphenone and LiCl mix aggregation ......................................................................................... 6 4 viii Scheme II III IV LIST OF SCHEMES page Alkylation of dioxanone using P4 base ............................... 3 The reaction of metal diorganophosphide with ketone ................................................................................................ 26 The reaction of lithium diphenylphosphide with ethyl acetate .................................................................................. 4 0 Kinetic vs thermodynamic enolate formation of 2 heptanone ........................................................................................ 4g ix INTRODUCTION Enolate anions are important intermediates in organic synthesis. The preparation of enolate anions is most commonly accomplished by deprotonation of an enolizable carbonyl compound by using the sterically hindered, nonnucleophilic, lithium diisopropylamide (LDA) as a basel’ 2 (eq. 1). O O'Li+ /“\/R' + /LNJ\ ___.. JVR' + ANk R Li R H (1) LDA enolate Such enolate preparations may be illustrated with three representative cases. 2-Methylcyclohexanone was deprotonated with LDA to generate the ketone enolate. The enolate was then reacted with chlorotrimethylsilane (TMSCl) to obtain a 99 /1 ratio of regioisomers and a 74 % total yield of silyl enol ether3 (eq. 2). O OSiMea OSiM93 . 3’ LDA C ____... + b) TMSCI ‘ (2) 99% 1% 74% yield Ireland4 used LDA to prepare the ester enolate of methyl propionate, obtaining a 90% yield of E / Z stereoisomers in a 95 / 5 ratio (eq. 3). O a) LDA OTBS OTBS \JLONG b) TBSCI / avg + [)wa (3) z E 91% 9% 90% yield The enolate from N, N-dimethylacetamide was obtained previously in this laboratory5 by using LDA as a base (eq. 4). 0 LDA i: /u\N(CH3)2 (CH3)2 >99% yield (4) It is important to choose a proper base for the deprotonation of certain enolizable carbonyl compounds. Bases that have been used for the generation of enolates include : lithium bis(trimethylsi1yl)amide (LHMDS)6 (Figure l), lithium 2,2,6,6- tetramethylpiperidide (LITMP)7, and lithium isopropylcyclohexylamide (LICA)3. 4,: >0< AT, LITMP LICA LHMDS Figure 1 Common bases used for enolates preparation The recently discovered P4 base shows unique react1v1ty toward dioxanones. The highly reactive enolates of dIOxanones can be prepared and alkylated If P4 base is used, whereas LDA is Ineffective for this reaction9 (Scheme 1) P4 base / BnBr 830/0 d5 MD —_J ‘0’” = LDA / BnBr (no reaction) I O (5) NM92 Ifil Wag l MezN—P =N— P —N= P—NM62 I I ' t-Bu-P4 base NM92 N NMe2 ll MOZN— $‘NM62 pKBH+ (CH30N) I 42.6 NMGZ Scheme I Alkylation of dioxanone usmg P4 base The base strength of a compound is reflected by the pKa of its conjugate acid. In this respect, the conjugate bases of secondary phosphines such as diphenylphosphine (pKa 22)10 (Figure 2), dicyclohexylphosphine (pKa 36), and di-t-butylphosphine (pKa 37) appear to be sufficiently high for enolate preparation. Since no attempt has been made thus far to prepare enolates by using phosphide bases, we decided to study the reactivities of various phosphide anions toward enolizable carbonyl compounds. ”3 ”a 932 M: Mg, Li, Na, K Figure 2. Potential bases could be used for enolates preparation. Several methods are available for the preparation of metal diorganophosphides. Alkali diphenylphosphides can be prepared by reacting an alkali metal with diphenylphosphine“. Sodium and potassium diphenylphosphide were Obtained in quantitative yield, and in high purity, from reactions of diphenylphosphine with sodium and potassium metal, respectively. However, lithium diphenylphosphide can only be obtained in a 50% yield by this method (eq. 5). HPPh2 + M ——-- MPPh2 + H; yield (5) M=Li 50% Na 100% K 100% Metallation of diorganophosphines with alkali metal compounds also provides a convinent procedure for the preparation of many alkali diorganophosphides. Thus, diphenylphosphine can be metallated with n-BuLi11 (eq. 6), NaNH212 (eq. 7) and t-BuOK11 (eq. 8) to furnish the corresponding alkali diphenylphosphides. HPth + n-BuLi —> UPth + butane (6) prh2 + NaNH2 __» NaPPh2 + NH3 (7) HPth + t-BuOK —> KPPh2 + t-BuOH (8) Alkali diphenylphosphides have also been prepared by the reductive cleavage of triphenylphosphine”. The reaction of triphenylphosphine with lithium in a tetrahydrofuran (THF) solution at room temperature for 4 hours afforded lithium diphenylphosphide in quantitative yield. This yield was determined from the diphenylphosphine obtained after hydrolysis. In the same manner, sodium and potassium diphenylphosphides can be generated14 (eq. 9). The ease of handling triphenylphosphine offered an advantage to this methodology. The unwanted phenyl alkali bases can be selectively eliminated by the addition of t-butylchloride15. t-BuCl PPh3 + M —-> MPPh2 + MPh ——>MPPh2 M= Li, Na, K (9) Another useful method for the preparation of alkali diphenylphosphides involves the reduction of chlorodiphenylphosphine by alkali metals. When chlorodiphenylphosphine is reacted with sodium, the initial product is tetraphenylbiphosphine (eq. 10). Sodium diphenylphosphide is then produced by reduction with additional sodium metal16 (eq. 11). However, formation of lithium diphenylphosphide by the same procedure required more rigorous conditions”. 2Ph2PCI + 2Na ._—.. PhZP-Pth + 2NaC| (10) 11 thP-Pth + 2Na ——> 2Ph2PNa ( ) By using phenyl lithium for the cleavage of tetraphenylbiphosphine, an alternative preparation of lithium diphenylphosphide from tetraphenylbiphosphine is achieved18 (eq. 12). thP-Pth + PhLi —- thPI—i + PPhe (12) Despite the variety of procedures that are available for the preparation of aryl substituted alkali metal diorganophosphides, we have found that the preparation of heavier alkali metal dialkylphosphides remains a challenge. Synthesis of KP(i-Pr)2 can only be achieved in 25% yield from the reaction of KH and HP(i-Pr)2 after twenty hours in a refluxing THF solution19 (eq. 13). HP(i-Pr)2 +KH _. KP(i-Pr)2 +H2 (13) 25% yield In addition, the cleavage of tetramethylbiphosphine with K only produced a 36% yield of KP(Me)2 after ten hours in refluxing TI-IF19 (eq. 14). MezP-PMez +K _. KPMez (14) 36% yield Generally, organophosphides are very sensitive to water and protic solvents. They are also inflamable on contact with air. Alkali diphenylphosphides readily dissolve in THF giving a deep red color in solution. Lithium diphenylphosphide has been identified as a dimeric aggregation in diethylether at -30°C20. In THF, the 31P and 13C NMR data has shown that lithium diphenylphosphide is a tetrameric structure21 (Figure 3). R S S /\3—Li/ Ph.‘ /L\ xph \LI—E— F-/R| ~. ~' -Li- --P (P\ /P\P Ii, |/\R P - h —L' LI R/P |E dimer tetramer Figure 3. Lithium diphenylphosphide aggregation in ether and in THF. In the past, alkali metal diorganophosphides have been used as potent nucleophiles. The reaction of dialkyl or diaryl phosphides with alkyl halides leads to substitution products in excellent yield22 (eq. 15). KPth + Br-[CH2]4-Br ——> thP-[CH2]4-Br + KBr (15) LiPPh2 is often used as a transition metal ligand23. Reaction of LiPth with an organocupper(l) reagent, BuCu, gives Bu(PPh2)CuLi. This can be reacted with benzoyl chloride, resulting in a 99% yield of the corresponding ketone, at 0°C (eq. 16). This methodology offers the advantage of conserving the R group of homocuprates, R2CuLi, for reactions where R is valuable. The reactivities of organocopper reagents are also changed by the presence of the PPh2 group. For example, Bu(PPh2)CuLi is thermally more stable than the commonly used Bu(SPh)CuLi. 0 Cl BuCu(PPh2);_i Bu 3 (16) 99% yield LiPPh2 has also been used to invert olefin stereochemistry, through an epoxide intermediate“. An 8N2 epoxide ring opening of cis-stilbene oxide by LiPth. The crude product was then reacted with methyl iodide leading to a phosphorus betaine (I), which then fragments into trans-stilbene and methyldiphenylphosphine oxide. The overall result is the conversion of cis- to trans-stilbene in a 95% yield with >99% isomeric purity (eq. 17). p Ph 0 Li Ph b”'o. 0 .~\‘\\ LiPth w .s“\H CH3| ’ Ph“ ""'—” Pth — 95% yield Ph (17) (I) A similar Wittig-type fragmentation of methyldiphenylphosphine oxide was observed for the reaction of benzoin with 2 equivalents of LiPPh225. It was proposed that an initial deprotonation of the a- 10 hydroxyl group is performed by the first equivalent of LiPth, followed by addition of a second equivalent of LiPPh2 to the ketone carbonyl. The resulting dianion was quenched with methyl iodide to give phosphorus betaine (II) which underwent elimination leading to desoxylbenzoin in 76% yield (eq. 18). This methodology demonstrates the facile dehydroxylation of a a-hydroxy ketone using LiPth. 0 HO Ph LiO ph Ph LiPPh ph_}_< __0"__a_.' +_< OH P“ 2P 0U thfa. (DU 043 x/ Ph ACOH /”\/ Ph Ph —’ Ph 760/0 yield (18) A synthetic procedure using LiPth for the facile demethylation of methyl aryl ether was recommended by Ireland25. The reaction is specific for methyl ethers and may be carried out in the presence of ethyl ethers. 4-Ethoxy-3-hydroxybenzaldehyde was prepared in 98% yield from its methyl ether counterpart (eq. 19). CH30 LiPPh HO HC 2 = O + (06H5)2PCH3 CHaCH20 ' CH3Ci-120 98% yield (19) 11 The reactivity of metal diorganophosphides can be manipulated with different organic substituents on phosphorus. Thus, LiPth underwent direct substitution with chloroethyl acetate (eq. 20), while an ester cleavage reaction was observed using lithium diethylphosphide27 (eq. 21). CICHZCOZEt + LiPPh2 —> thPCHZCOzEt + LiCl (20) CICH2002Et + LiP(Et)2 ——> CICH2002Li + P(Et)3 (21) The cationic moiety of metal diorganophosphides also has a significant effect on the outcome of reactions. The reaction of two equivalents of KP(t-Bu)2 with SnC12 in a toluene solution produced the disubstitution product Sn[P(t-Bu)2]2. The monosubstitution product was obtained using LiP(t-Bu)2 under comparable conditions28 (Figure 4). But ‘ But But \ /BU But P BU \ / \ \ / \ P —Sn Li-THF P —Sn Sn —- P / \ / / \ / t Bu‘ P But P\ BU i \ t But But BU BU 2 KP(t-Bu)2 + SnClz 3 LiP(t—Bu)2 + SnClz Figure 4. The reactions of alkali metal di-t-butylphosphides with tin (II) chloride. 12 The strong basicity of diorganophosphides has been demonstrated by deprotonation of acetonitrile with KPth, resulting in the formation of HPPh2 and the self-condensation product of acetonitrile29 (eq. 23). CH3-CN + KPPh2 —> CH3-C(NH)-CHZCN + HPPh2 (23) The reaction of LiP(t-Bu)2 with p-fluorotoluene produced a mixture of p- and m-tolyldi—t-butylphosphine (eq. 24)”. An elimination-addition mechanism involving a tolyne intermediate was proposed. Tolyne formation was most likely due to the strong basicity of LiP(t-Bu)2. F P(t-BU)2 / - O LiP(t-Bu)2 :‘ I “BUM: 0 O > ——> 4- CH3 CH3 CH3 CH3 (24) The goal of this study was to evaluate the reactivities of alkali metal diorganophosphides with enolizable carbonyl compounds. It was hoped that secondary phosphide ions could be used for the generation of enolates, while simultaneously achieving a new level of selectivity with these bases. Diphenylphosphine was used throughout this investigation 13 because it is readily available and the metal salts are easily synthesized. Metal diphenylphosphides were used to screen reactivities toward enolizable carbonyl compounds. 14 RESULTS AND DISCUSSIONS (i) THE PREPARATION OF METAL DIORGANOPHOSPHIDES We began our studies with the preparation of metal diorganophosphides. Among the many methods for the preparation of alkali metal diorganophosphides, the direct metallation of a secondary phosphine with alkali metal reagents provided a simple laboratory operation. LiPth was the first compound selected because the starting material, HPth, can be easily Obtained in 0.1 mole quantity by hydrolysis of the reaction mixture from PPh3 and Li13 (eq. 24, 25). PPh3 + Li —> LiPth + PhLi (24) LiPth + H20 -———> HPPh2 (2 5) 90% yield LiPPh2 was generated by adding n-BuLi to a solution of HPth in THF at 0°C (eq. 26), the solution instantly changed from colorless to a deep red color. Phosphorus-31 NMR analysis of the LiPPh2 solution displayed a singlet at -20 ppm“. It was therefore determined that LiPPh2 formation was quantitative, and the reaction was complete in 10 minutes, as the solution warmed from 0°C to room temperature. LiPPh2 is readily soluble in THF and Et20. LiPth can also be obtained in benzene and hexane, and it deposits as a yellow powder in heterogeneous solutions. 15 HPth + n-BuLi —> LiPth + Butane (26) 5 -40 8 -20 >99% yield Previously, BngPth was generated by the reaction of LiPth and MgBr231. We prepared BngPth from the convinent reaction of HPPh2 and BngPh in a THF solution (eq. 27). Phosphorus-31 NMR analysis displayed a singlet at -46 ppm. HPth +PhMgBr __—> BngPPh2 +Benzene (27) 8-40 8-46 >99% yield To prepare the potassium diorganophosphides, HPPh2 was added dropwise to a THF solution containing potassium sand (eq. 28); this reaction mixture was stirred for a period of 8 hours at -78°C. The KPth solution thus obtained showed a singlet phosphorus-31 NMR signal at -10 ppm“. HPth + K ——> KPPh2 + H2 (28) 5-40 5-10 >99% yield Di-t-butylphosphide ions are among the strongest bases as well as the most hindered of the dialkylphosphides. Di-t-Butylphosphine was prepared from the reaction of 4 equivalents of t-BuMgCl with 1 16 equivalent of PC13 in a THF solution (eq. 29), the chloride was then reduced with 1 equivalent of LiAlH4, and HP(t-Bu)2 was isolated in 77% yield32 (eq. 30). t-BuMgCl +PCl3 _. ClP(t-Bu)2 +MgC12 (29) ClP(t-Bu)2 +LiAlH4 _. HP(t-Bu)2 (30) 77% yield Metallation of HP(t-Bu)2 with BuLi in either hexane or ether did not result in LiP(t-Bu)2. However, in a THF solution, HP(t-Bu)2 was lithiated quantitatively in less than 10 minutes (eq. 31). The phosphorus-31 NMR resonance of HP(t-Bu)2 at 19 ppm completely disappeared and was replaced by a resonance of LiP(t-Bu)2 at 38 HP(t-Bu)2 + n-BuLi —... LiP(t-Bu)2 + Butane (31) 8 19 8 38 >99% yield In an attempt to prepare NaP(t-Bu)2, HP(t-Bu)2 was added to a suspension of PhNa in a hexane solution, which was obtained from the reaction of PhBr with Na in hexane solution. HP(t-Bu)2 remained unchanged after 12 hours at room temperature, as determined from a phosphorus-31 NMR measurement. Addition of THF to the above mixture resulted in a severe exothermic reaction and a gel like product. Similar results were obtained when the reaction was conducted at -78°C. Using n-BuNa (prepared from n-BuBr and Na) 17 did not induce any metallation of HP(t-Bu)2, However, a clear yellow solution was obtained after the addition of THF to a suspended mixture of HP(t-Bu)2 and n-BuNa (The n-BuNa was prepared by addition of n-BuLi to a t-BuONa suspension in hexane at 0°C”). Phosphorus-31 NMR analysis gave only one singlet at 53 ppm, indicating quantitative formation of NaP(t-Bu)2 (eq. 32), HP(t-Bu)2 +n-BuNa ——> NaP(t-Bu)2 +Butane (32) 819 853 >99% yield Preparation of KP(t-Bu)2 was effected by a procedure similar to that used for NaP(t-Bu)2, except n-BuK was used instead of n-BuNa (eq. 33). n-BuK was obtained from the slow addition of n-BuLi to t- amyl-OK in hexane at 0°C34. A summary of metal diorganophosphides preparations is shown in Table I. HP(t—Bu)2 + n-BuK KP(t-Bu)2 +Butane (33) 8 19 8 63 >99% yield It was observed that HP(t-Bu)2 can be lithiated with n-BuLi in a THF solution but not in hexane or ether solutions. We believe the aggregation state of n-BuLi is responsible for this phenomenon. Since THF is a better cation solvating agent, n—BuLi aggregation is dissociated in the presence of THF which results in a more reactive n-BuLi species. The aggregation state of n-BuLi influences the rate of 18 metallation of the bulky HP(t-Bu)2. By using solid n—BuNa, a highly pure form of NaP(t-Bu)2 was Obtained in quantitative yield. To the best of our knowledge, this is the first example of NaP(t-Bu)2 preparation. Owing to its high acidity, HPth can be metallated using t-BuOK in DMSO solution (eq. 34). Methods for the preparation of a highly pure form of KPth have also been described in a recent report“. HPth + t-BuOK KPth +t-BuOH (34) 98% yield The generation of potassium dialkylphosphides is more difficult. No report regarding either the characterization or efficient formation of KP(t-Bu)2 has been published. In an earlier report of its reaction with SnC1235, KP(t-Bu)2 was prepared by the potassium cleavage of (t-Bu)2P-P(t-Bu)2; however, the experimental details were not stated. It is well documented that (t-Bu)2P-P(t-Bu)2 can be obtained in 50% yield from the reduction of ClP(t-Bu)2 with potassium (eq. 35). It is expected that reductive cleavage of (t-Bu)2P-P(t-Bu)2 with potassium would require even more rigorous conditions (eq. 36). toluene ClP(t-Bu)2 +K reflux 14 h: (t-Bu)2P—P(t-Bu)2 (35) 50% yield (t-Bu)2P-P(t-Bu)2 +K _L__. KP(t-Bu)2 (36) 19 We have achieved the preparation of highly pure KP(t-Bu)2 by the deprotonation of HP(t-Bu)2 with n—BuK. Metal aggregation is an important factor in this reaction, and as a result, n-BuK must be prepared in a crystalline form. Using n—BuK obtained from the reaction of n-BuBr and K did not result in deprotonation of HP(t-Bu)2; the addition of a cation complexing agent did not improve metallation. We reason that n-BuK, obtained from n-BuBr and K, is a mixture aggregate of n-BuK and KBr. In the reaction with bulky HP(t- Bu)2, KBr is more tightly associated with n-BuK than with bulky KP(t- Bu)2 (eq. 37), Addition of THF apparently caused the n-BuK.KBr aggregate to disperse rather than to dissociate. A reactive form of the potassium metallation agent, n-BuK, can be prepared from the transmetallation of t-amyl-OK and n-BuLi34. HP(t-Bu)2 +n-BuK.KBr _. KBr.KP(t-Bu)2 +Butane (37) 0% yield 20 Table I. The preparation of metal diorganophosphides HPR2 + R'M MPRz + R'H HPRz R'M solvent % MPR2a 1 HPth PhMgBr THF >99 2 HP(t-Bu)2 n-BuLi hexane 0 3 ether 0 4 THF >99 5 HP(t-Bu)2 n-BuNa+NaBrb hexane 0 6 n-BuNaC THF >99 7 HP(t-Bu)2 n-BuK+KBrd hexane 0 8 n-BuKe THF >99 9 HP(Chx)2 n-BuLi THF >99 1 0 HP(Mes)2 n-BuLi THF 5 5 a) Yields determined by 31P NMR. The only signal observed in b) C) d) e) 31P NMR was the phosphide ion. n-BuNa+NaBr obtained by the reaction of n-BuBr and Na. n-BuNa obtained by the reaction of t-BuONa and n-BuLi. n-BuK+KBr obtained by the reaction of n-BuBr and K. n-BuK obtained by the reaction of t-amleK and n-BuLi. 21 (ii) THE REACTIONS OF METAL DIORGANOPHOSPHIDES WI I H KETONES Simple enolizable ketones were reacted with metal diorganophosphides. Acetophenone was added dropwise to the deep red solution of LiPth (previously prepared). A fading of the color, similar to that of a titration, was observed. Phosphorus-31 NMR analysis indicated complete deprotonation of acetophenone, a resonance signal for HPth, at -40 ppm, was the only absorption detected. This suggests that the enolate of acetophenone was formed in quantitative yield (eq. 38). To confirm this finding, excess TMSCI was added to the reaction flask; a white precipitate (LiCl) was formed immediately. After one hour at room temperature, the solvent was evaporated and CDC13 was injected. The reaction mixture was transfered to a test tube. The LiCl precipitate was separated by a centrifuge, and the supernatant was transfered to a NMR tube for proton NMR analysis. It was found that trimethylsiloxystyrene, a silyl enol ether derivative of acetophenone enolate, was the sole ketone derived solute (eq. 39). The yield was determined by proton NMR integration of the vinyl hydrogens by using the aryl hydrogens as a reference. Integration of two vinylic hydrogens of trimethylsiloxystyrene (two doublets at 4.3 ppm and 4.86 ppm36) with respect to integration of fifteen hydrogens (sum of HPth and trimethylsiloxystyrene ) in the aryl region. 22 0 O'Li+ LiPth . Pin/L __. HPth + [ah/K (38) 5-20 5-40 >99% yield O-Li+ OTMS TMSCl + [ah/K —» Ph/K +LiCl (39) 8 4.3 (d, 1H) 8 4.86 (d, 1H) >99% yield Under similar conditions, enolates of cyclohexanone, 3-pentanone, pinacolone, and 2,4-dimethyl-3-pentanone were generated in quantitative yield (Table 11, entries 4, 6, 8, 10). The yields of the corresponding silyl enol ether derivatives varied (Table III). The reaction of BngPth with acetophenone proved to take a different course from the reaction with LiPth. Acetophenone was added to a THF solution of BngPth, at room temperature. A broad resonance at 20 ppm was observed in the phosphorus-31 NMR spectrum, suggesting that an addition reaction had occurred (eq. 40). O OMgBr BngPth 5, Ph/lk kPth (40) 8 -46 8 20 _,Ph >99% yield 23 Similar results were obtained with cyclohexanone and 3- pentanone (Table 11, entries 3 and 5). However, BngPth deprotonated pinacolone in quantitative yield (eq. 41). The enolate intermediate generated from this ketone was confirmed by its silyl enol ether derivative (eq. 42). BngPPh2 also effected deprotonation of 2,4-dimethyl-3-pentanone (Table 11, entry 9), and its silyl enol ether derivative could be obtained after TMSCI quenching (Table 111, entry 7). O OMgBr BngPth + >,/lk __.. HPth + XK (41) 6 -46 5 -40 >99% yield OMgBr OTMS TMSC1+ >'/K __.. MgBrCl + >(K (42) 5 3.93 (d, 1H) 84.08 (d, 1H) 65% yield The 0t,B-unsaturated ketones, cyclohexenone and mesityl oxide, were also reacted with metal diorganophosphides. It was determined that a conjugate addition adduct was Obtained from the reaction of LiP(t-Bu)2 with cyclohexenone (eq. 43). This was deduced from a signal at 49 ppm in the phosphorus-31 NMR. The most likely product is a 1,4-addition product since a separate experiment, reacting HPth 24 with cyclohexenone, gave an identical absorption at 49 ppm. With bulky metal diorganophosphides, such as LiP(Mes)2 and LiP(t-Bu)2, no deprotonation of either cyclohexenone or mesityl oxide was observed (Table 11, entries 12, 13, 14). O O —~ 0 LiP(t-Bu)2+ P(t-BU)2 8 38 8 49 >99% yield The preparation of ketone enolates is often complicated by the problems of enolate self-condensation, addition of the bases to the ketone carbonyl function, and ketone reduction. For example, t-BuOK in t-BuOH solution only converted 15-25% of 2-methylcyclohexanone to its enolate anion37 (eq. 44). The enolate anion may react with coexisting free ketone, resulting in self condensation products. O OK“ OK" 0 t-BuOK o o + O + o (44) 15% 85% 25 Competition between deprotonation and addition has been noted for other organometallic bases. For example, PhLi reacted with acetophenone giving 96% addition to the carbonyl function and only producing 4% of the enolate anion?)8 (eq. 45). 0 O'LI+ O'Li“ LiPh + Ph/u\ ——> Ph/‘99 0 2 LiPPh2 0 >99 3 BngPPh2 cyclohexanone >99 0 4 LiPPh2 0 >99 5 BngPth 3-pentanone >99 0 6 LiPth 0 >99 7 BngPth pinacolone 0 >99 8 LiPPh2 0 >99 9 BngPPhg 2,4-dimethyl- 0 >99 3-pentanone 1 0 LiPth 0 >99 1 1 LiPth cyclohexenone >99 0 12 LiP(Mes)2 >99 0 13 LiP(t-Bu)2 >99 0 14 mesityl oxide >99 0 (1) Reactions performed in NMR tubes, ketones were added to MPR2 in THF solution, at 0°C. b) Addition (tertiary phosphine) and deprotonation (secondary phosphine) products were determined by 31P NMR. 30 Table III. The reactions of ketone enolates with TMSCI“ O OTMS vak . 24» Rvk . R b) TMSCI R MPR2 ketones % yieldb 1 LiPPh2 acetophenone >99 2 cyclohexanone >99 3 3-pentanone 64 4 pinacolone 3 1 5 BngPth 60 . 3:222:29:- .. 7 BngPPh2 7 5 8 LiPth acetophenone SC 9 KPth acetophenone >996 a) Kctone (1 mmole) was added dropwise to a 0.5 M THF solution of MPRz (1.1 mmole), at room tcmterature. After 15 min, excess TMSCI was added. Solution was kept stirring for an additional 60 min. CDCI3 was injected after evaporation of THF. Precipitate was removed by a centrifuge. Supernatant was analysis by proton NMR. b) Yields determined by 1H NMR integration. c) Reactions conducted at -78°C. 31 (iii) THE REACTIONS OF IVTETAL DIORGANOPHOSPHIDES WITH ESTERS AND TERTIARY AMIDE To expand the application of metal diorganophosphides as bases, enolizable esters and tertiary amide were reacted with metal diorganophosphides, hoping that enolates of these compounds could be prepared in high concentration. Methyl phenylacetate was added to LiPth in THF solution at 0°C. A sample was submitted for phosphorus-31 NMR analysis. Two resonances, one at -40 ppm which corresponds to the deprotonation product of HPth and another at 3 ppm which corresponds to an addition product of the phosphine, were observed. The extent of deprotonation and addition was determined by the relative integration value of each individual component. It was found that LiPPh2 deprotonated methyl phenylacetate in 85% yield, and underwent addition to methylphenylacetate in 15% yield (eq. 47). Excess TMSCI was then added to the solution, and the corresponding ketene acetal was obtained in 72% yield (eq. 48). The total yield of ketene acetal was determined by the proton NMR integration of one vinyl hydrogen at 5.5 ppm by using fifteen aryl hydrogens at 7-8 ppm as a reference. 32 O O LiPPh2+ Ph\/”\Ove —. HPPh2+ Ph\/u\PPh2 (47) 8-40 83 85% 15% O‘Li” OTMS TMSC1+ Ph\2\OMe _. LiCl+ Ph\/kGVe (48) 85.5(S,1H) 72% yield Ethyl acetate was also subjected to a reaction with LiPth. It was determined from 3”P NMR that 58% of the LiPth added to the carbonyl group and 42% of the LiPth performed deprotonation on ethyl acetate (Table IV, entry 1). Esters with different steric factors such as t-butylacetate and t-butylpropionate were also reacted with LiPth; the extent of deprotonation never exceed 55% (Table IV, entries 7, 9). Since we were interested in enolate formation, a more reactive base, KPth, was used to direct the reaction to deprotonation. The extent of deprotonation was indeed enhanced by the reaction of KPth with ethyl acetate (TableIV, entry 2). Finally, complete deprotonation was achieved by using LiP(t-Bu)2 as the base. LiP(t-Bu)2 was reacted with ethyl acetate, and HP(t-Bu)2 was the only product detected by phosphorus-31 NMR (eq. 49), indicating quantitative deprotonation of ethyl acetate by LiP(t-Bu)2. The general utility of LiP(t-Bu)2 in the deprotonation of enolizable 33 esters was tested by using several representive esters, such as ethyl isobutyrate, ethyl hexanoate, t-butylacetate, and t-butylpropionate. All of the esters were quantitatively deprotonated by LiP(t-Bu)2 (Table IV, entries 4, 5, 6, 8, 10), The enolate of t-butylacetate was reacted with benzylbromide and afforded excellent yields of alkylation product (eq. 50). Enolates of ethyl isobutyrate and t- butylpropionate were also reacted with benzylbromide and generated excellent yields of alkylation product (Table V, entries 3,4). 0 O'Li“ LiP(t-Bu)2 + kOEt HP(t-Bu)2 + A03 (50) 8 38 8 19 >99% yield O O Jko LiP(t—Bu)2 Mk0 t-Bu Bn Br P t-Bu (52) 34 Table IV. Phosphorus-31 NMR studies for the reactions of metal diorganophosphides with esters and tertiary amide O - + - + R\JJ\ fl R\j)99 2 t-butylacetate 9 8 3 ethyl isobutyrate 9 2 4 t-butylpropionate 92 5 N,N-dimethylacetamide >99 a) Ester (1 mmole) was added dropwise to a 0.5 M THF solution of LiP(t-Bu)2 (1.1 mmole), at -78°C. After 60 min, BnBr (2 mmole) was added. b) Yields determined by 1H NMR integration. 36 Ester enolization is a more difficult task than ketone enolization. This is in part because esters are weaker carbon acids compared to ketones. In addition, ester enolates are prone to decomposition at room temperature. For example, the enolate of t-butyl bis(trimethylsilyl)acetate was prepared by adding t-butyl bis(trimethylsilyl)acetate to a THF solution of LDA at -78°C. When the enolate solution was warmed to room temperature, the decomposition product, bis(trimethylsilyl)ketene, was obtained in 85% yield40 (eq. 51). SI(CH3)3 Si(CH3)3 O LDA 25 C CH0020(CH3)3 —>o Li\CHCOZC(CH3)3 ——-» THF, -78 C / 30 min. SI(CH3)3 SI(CH3)3 SIICHSIS LIOC(CH3)3 + Si(CH3)3 (51) 85% yield The preparation of ester enolates demands a stronger non- nucleophilic base for the deprotonation to be both rapid and quantitative, at low temperatures. This is necessary to avoid possible equilibration and decomposition. There are a limited number of bases that can be used for ester enolate preparation. LHMDS was the first reagent used to generate a stable ester enolate. The lithium enolate of ethyl acetate was prepared from the reaction of LHMDS and ethyl acetate at low temperatures“). Subsequent aldol condensation with cinnamaldehyde yielded the 37 hydroxyester(eq. 52). This methodology was specific for ethyl acetate, other esters do not react with LHMDS to provide the desired ester enolates. When ethyl hexanoate was treated with LHMDS, the self condensation product was a serious side reaction. CH3COZCZH5 M LiCH2C02C2H5 + O CH=CHCHO OH _, | 94% yield (5 2) However, in a later experiment, Ireland41 prepared the ester enolate of ethyl propionate in 90% yield using LHMDS in the presence of hexamethylphosphoramide (HMPA) (eq. 53). HMPA is necessary for the LHMDS deprotonation of the ester at low temperatures. A parallel result was obtained using KHMDS as the base. O ores 0TBS \JL n... VL O/\ = > / O/\ / O/\ THF / 23%HM PA Z E 91% 9% total yield : 90% (53) 38 Rathke8 described a useful method for alkylating esters in near quantitative yield (eq. 54). I LICA . THF DM . R LiCCOzR + RX I so: RCCOZR + LiX I I (54) Sullivan42 isolated lithio-t-butylacetate from the reaction of t- butylacetate and LDA. Since the product is a white solid that is stable in air at room temperature, it has simplified many organic transformations (eq. 55). Today, LDA is probably the most popular base for ester deprotonation. O'Li+ 0 LDA amine free lithium salt )ko A stable in air at RT t-Bu I'BU (55) A boron reagent was recently suggested for ester enolate preparation“. t-Butylacetate was enolized by using a combination of a chiral boron reagent and diisopropylethylamine. The resulting ester enolate was reacted with an aldehyde providing the hydroxyester with excellent enantioselectivity (eq. 56). 39 O I- H O 1 (8,8) OBR 2 .. . ’ PhCHO t-Bu diisopropylethylamme ——> Ph 5 t-Bu t-Bu ph Ph '5: .9 73‘7 ield CF’ }—\’ F3 80% Ze -R‘z = p‘ SOZ—TK /N"’ 802 c. 5* CF. Br 1 (S, S) (56) Brown44 has advanced this methodology for ester enolization. Dicyclohexyliodoborane and triethylamine were used to enolize ethylpropionate, and the boron enolate was obtained in quantitative yield, under mild conditions (eq. 57). \j: Chx28| 030““ 98% yield In this study, we found that enolates of esters can be generated with diorganophosphide bases. The enolate of methyl phenylacetate can be generated by using LiPth as the base. The acidity of the ester was enhanced by a (It-phenyl substitution. However, complications arose when alkyl esters were treated LiPth. Ester enolate equilibration and decomposition contributed to the observation of the B ketoester (III) in the proton NMR. The tertiary phosphine (IV) observed in 31P NMR was due to a competing 40 addition reaction (Scheme 111). Despite the fact that KPth improved the deprotonation process, the potassium enolates equilibrate much faster than their lithium analogs, resulting in B-ketoester products. O'Li+ O O O 0 A + k0 + HDPP LiPPh2 Et Et —" Et ' I III )kOEt O I I )kPth (IV) Scheme III. The reaction of lithium diphenylphosphide with ethyl acetate. Dialkylphosphide ions are more reactive than diphenylphosphide ions. This is because the negative charge on diarylphosphide ion is distributed through the whole phosphide anion, stemming from the mesomeric effect of the phenyl group. LiP(t-Bu)2 is an effective base for the formation of a variety of ester enolates. The enolates themselves were then reacted with an active alkylating agent to furnish alkylation products in near quantitative yield. t-Butylacetate was benzylated in 98% yield by using LiP(t-Bu)2 as base. When tertiary amides, which are normally less acidic than esters, were reacted with metal diorganophosphides, we found that there was no reaction when either LiPPh2 or KPPh2 was reacted with N,N- dimethylacetamide (Table IV, entries 12, 13). N,N- Dimethylacetamide was quantitatively deprotonated by LiP(t-Bu)2 (eq. 58), and the enolate of N,N-dimethylacetamide was alkylated 41 with benzylbromide, in quantitative yield (eq. 59). 0 O'Li” LiP(t-Bu)2 + /“\NMe2 5 38 8 19 >99% yield HP(I-BU)2 + M62 0 , 0 AN a) LlP(t-BU)2 MN M92 b) BnBr P M92 (58) (59) The enolate of N,N-dimethylacetamide has been prepared from strong bases, such as n-BuLi and LDA46. We found LiP(t-Bu)2 is also an effective base for N,N-dimethylacetamide enolate formation, and the enolate itself can be benzylated in quantitative yield (Table V. entry 5). 42 (iv) REGIOSELECT IVE ENOLATES FORMATION USING METAL DIORGANOPHOSPPHDES AS BASES As mentioned earlier (11), enolates of symmetric ketones or ketones that can enolized in only one direction were obtained in quantitative yield by using metal diorganophosphides as bases. The enolates themselves were then sucessfully isolated as silyl enol ether derivatives, by adding an excess of TMSCI. These results encouraged us to study the regioselectivity of metal diorganophosphide bases toward unsymmetrical ketones. 2-Methylcyclohexanone was added dropwise to a slight excess of LiPPh2 in THF solution ( the excess was indicated by the persistant red color of LiPth ) at 0°C. After 5 minutes, excess TMSCI was added, and a white precipitate of LiCl formed immediately. The reaction mixture was allowed to continue stirring for one hour at room temperature. The solvent was evaporated and CDC13 was injected. The LiCl precipitate was separated by centrifuge, and the supernatant was transfered to a NMR tube for proton NMR analysis. This reaction was expected to produce two regioisomers having structures 1A and 1B from 2-methylcyclohexanone (eq. 60). To identify compounds 1A and IE, literature values3' 36 were compared to ours. A broad Singlet at 1.55 ppm corresponging to methyl group of 18, and the characteristic vinyl hydrogen of 1A at 4.65 ppm were used to determine the enolates compositions. Since 1A was not observed in this reaction, the total yield was solely determined based on the relative integration value of methyl group at 1.55 ppm with respect to 1.1 equivalent of aryl hydrogens from the nonvolatile 43 HPPh2 present (HPPh2 was generated during the deprotonation process). For the reaction of 2-methylcyclohexanone with LiPth, the isomer ratio of 1A / 18 was 1 / 99 and total yield was 75% (Table VI, entry 1). Using a bulkier LiP(MeS)2 base increased the production of isomer 1A (Table VI, entry 2). O OSiMe3 OSiMe3 MFR 61) 2 : + (60) b)TMSCl 1A 18 84.65 (t, 1H) 8 1.55 (br, 3H) Table VI. Regioselective enolate formation of 2-methylcyclohexanone MPRZ %1A %lB % yield 1 LiPPh2 1 9 9 7 5 2 LiP(Mes)2 7 6 2 4 8 8 a) Kctone (1 mmole) was added dropwise to a 0.5 M THF solution of MPR2 (1.2 mmole). 19) Yields determined by 1H NMR integration. In a similar manner, 2-methylcyclopentanone was reacted with various diorganophosphide bases (Table VII), (eq. 61). Proton NMR analysis shown that LiPth generated only one regioisomer, 2A (Table VII, entry 1), while LiP(t-Bu)2 generated isomers of 2A and 2B in a ratio of 43 / 57 (Table VII, entry 2). 44 O OSIMe3 OSIMe3 MPR 8') 2: + \ (61) b) TMSCI 2A 213 5 4.43 (t, 1H) 5 1.48 (br, 3H) Table VII. Regioselective enolate formation of 2-methylcyclopentanone MPRz %2A %213 % yield 1 LiPPh2 1 9 9 8 1 2 LiP(t-Bu); 4 3 5 7 8 4 a) Kctone (1 mmole) was added dropwise to a 0.5 M THF solution of MPR2 (1.2 mmole), b) Yields determined by 1H NMR integration. The regioselectivity of the diorganophosphide bases toward acyclic ketones was examined. 2-Heptanone reacted with diorganophosphide bases, and its enolate anion was trapped as the silyl enol ether derivative for proton NMR analysis (Table VIII), (eq. 62). Isomers 3A and 33 were obtained in a 58 / 42 ratio by using LiPPh2 as base (Table VIII, entry. 1). When LiP(t-Bu)2 was used, enolate 3A was selectively generated. (Table VIII, entry 2) 45 O a) MPR2 OTMS + (62) ”'BU\/"\———> b) TMSCI n BU\/K n-Buv:ims 8 4.0 (s, 2H) 8 4.36 (t, 1H) 5 4.53 (t, 1H) Table VIII. Regioselective enolate formation of 2-heptanone MPRz %3A %3B % yield 1 LiPPh2 5 8 4 2 9 2 2 LiP(t-Bu); 9 9 1 9 9 a) Kctone (1 mmole) was added dropwise to a 0.5 M THF solution of MPR2(1.2 mmole), b) Yields determined by 1H NMR integration. The cation effect on the regioselectivity of metal diorganophosphides was studied by using phenylacetone. The characteristic vinyl hydrogens of silyl enol ether derivatives of phenylacetone, obtained from the reactions of diorganophosphide and phenylacetone and TMSCI, were used for product analysis (eq. 63). The regioisomer ratio was determined by the relative integration values. It can be summarized from the results in Table IX that enolate 4B was the only isomer observed in the reaction of phenylacetone with several metal diorganophosphides, and the cation of the diorganophosphide ion has little effect on its 46 regioselectivity. LiP(t-Bu)2 deprotonated the more acidic proton Of phenylacetone to afford enolate 4B exclusively (Table IX, entry 1). An attempt to generate enolate 4A, using either a more reactive KP(t-Bu)2 base (TableIX, entry 3) or a less steric hindered LiP(Chx)2 base (TableIX, entry 4) was unsuccessful. O a) MPRZ; OTMS Ph\/Ik b) TMSCI Ph\/K Pinks (63) 85.31 (s, 1H) 8 5.73 (s, 1H) Table IX. Regioselective enolate formation of phenylacetone base %4A %4B (2 / E) % yield 1 LiP(t-Bu)2 0 100 (87 / 13) 85 2 NaP(t-Bu)2 0 100 (87 / 13) 88 3 KP(t-Bu)2 0 100 (86 / 14) 91 4 LiP(Chx)2 0 100 (90 / 10) 72 a) Kctone (1 mmole) was added dropwise to a 0.5 M THF solution of MPRZ (1.2 mmole), b) Yields determined by 1H NMR integration. 47 A survey of the regioselectivity of enolate generation using metal diorganophosphides, with unsymmetric ketones, showed that LiPth displayed excellect regioselectivity toward cyclic ketones, and favored the more substituted enolates (Table VI, entry 1; Table VII, entry 1). LiP(t-Bu)2 exhibited excellent regioselectivity toward acyclic ketones (Table VIII, entry 2). The less substituted enolate of 2-heptanone was generated selectively, and in excellent yield. For the reaction of LiPPh2 with 2-heptanone, two regioisomers 3A and 3B were produced, in proportions of 58% and 42% upon deprotonation with LiPth. These products ratios may either reflect that the deprotonation process is irreversible, which means the formation of these two regioisomers is controlled by their relative deprotonation rates (kinetic control conditions). Or, the deprotonation process is reversible, which means the formation of isomers is controlled by their relative stabilities (thermodynamic control conditions). 48 0 O'Li+ O'l.i+ n-Budk + LIPRZ ——’n-Bu\/K + n-BumA 3A 3B O'Li“ k n-B VK + HPR 0 /a' ” 2 n-Bu\/“\ + LIPR2 - ,. k\- OL' + HPR2 b n'BUV‘A R = t-Bu, kinetic controlled conditions, 3A / 3B = 99 / l CyLi+ n-BUVK + HPRz O n-Bu\/II\ + LIPR2 V\‘ OII+ n-BUV‘A R = Ph, thermodynamic controlled conditions, 3A / 38 = 42 / 58 Scheme IV. Kinetic vs. thermodynamic enolate formation of 2-heptanone 49 We decided to study the process of metal diorganophosphide bases deprotonation of ketones. Is it a thermodynamic or a kinetically controlled process for the LiPPh2 deprotonation of 2-heptanone? To answer this question, 2-heptanone was added to 4 equivalents of LiPth. Product analysis gave a 78 : 22 isomer ratio of 3A : 38 (Table X, entry 1). We reasoned that an irreversible process was ensured by the presence of excess of LiPth, the enolate isomers thus generated reflected the true kinetic ratio for LiPth deprotonation, in comparison with isomer ratio obtained with 1 equivalent of LiPth (Table X, entry 2), and with 0.7 equivalent of LiPth (Table X, entry 3). We concluded that the deprotonation of 2- heptanone with LiPth was a thermodynamically controlled process. The enolate isomers underwent fast equilibrium by a reversible process. However, the deprotonation Of 2-heptanone with LiP(t-Bu)2 was a kinetically controlled process. Table X. The effects of base / ketone ratio on regioselective enolate formation of 2-heptanone O a) LiPPh2_ OTMS + OTMS n-Bu\/II\ b) TMSCIV n'BUVK n-BuvL/k ketone LiPth / ketone 3A : 3B 2-heptanone 4 78 : 22 1.2 58 : 42 0.7 42 : 58 50 Apparently, a 99 / 1 regio isomer ratio of 2A / ZB for the reaction of LiPPh2 with 2-methylcyclopentanone was a result of enolate fast equlibrium (thermodynamic control product). The fast equilibration may either come from the proton source of HPth, generated in the system, or by the ketone itself. To determine the factor which induced enolate equilibrium, a known enolate composition of 2-methylcyclopentanone was generated using LHMDS as base. A 80 : 20 ratio of less to more substituted enolate isomers of 2-methylcyclopentanone was prepared from LHMDS and 2-methylcyclopentanone, at 0°C (Table XI, entry 1). Enolate composition did not change during a period of one hour. To this solution was added HPth, after 30 minutes, TMSCI quenching produced a 32 : 68 ratio of 2A : 23 (Table XI, entry 2). In a separate experiment, 0.3 equivalent of 2—methylcyclopentanone was used as an additive, and a 1 : 99 ratio of 2A : 28 was observed in less than 5 minutes (Table XI, entry 3). From these experiments, we concluded that the ketone itself contributed to the fast equilibrium in the LiPth deprotonation of an unsymmetric ketone. The reaction rate of enolate equilibrium was faster than the ketone deprotonation, by LiPth. As a result, enolates 1B, 28, and 33 were exclusively produced when LiPth was used as the base. 51 Table XI. Enolate of 2-methylcyclopentanone equilibrium in the presence of additives O'Li* O'Li+ additives -——> \ <——— TMSCI OSIMeg OSIM93 \ ZB 2A additives equivalent time (min.) 2A : 2B HMDS l 60 80 : 20 diphenylphosphine 1 30 32 : 68 2-methylcyclopentanone 0.3 6 1 : 99 We found that either regioisomer can be selectively generated by chosing the proper diorganophosphide base. LiPPh2 exhibited excellent regioselectivity toward cyclic ketones. The preparation of the thermodynamic enolate isomer of 2-methylcyclohexanone was essentially accomplished under kinetically controlled conditions (ketone added slowly to excess base, in an aprotic solvent). A similar process was observed by Holton and Kraft45 using bromomagnesium diisopropylamide (BMDA) as base (eq. 64). However, the typical reaction time for BMDA deprotonation of 2-methylcyclohexanone 52 required 12 hours. Furthermore, treatment Of BMDA with a less hindered ketone, such as cyclooctanone, resulted in extensive self condensation. LiPth deprotonated 2-methylcyclohexanone in 15 minutes, and the reaction with 2-heptanone (a ketone that tends to undergo self condensation upon deprotonation) produced 92% of the enolate anion. A summary of literature values for regioselective enolate formation of 2-methylcyclohexanone is present in Table XII. O OSiMe3 OSiMe3 a) BMDA, 12hr. > + (64) b) TMSCI 3% 97% Table XII. Comparison of regioselective enolate formation of 2-methylcyclohexanone O OSiMe3 OSiM63 . a) base + s b) TMSCI 1A 1B base time (min.) 1A / 18 ref. LDA <1 99 / 1 (3) Ph(Bu)NMnBr 3O 99 / 1 (46) KH 5 67 / 33 (47) BMDA 720 4 / 96 (45) LiPPh2 10 1 / 99 this work 53 Previously, several efforts have been made to selectively generate the less substituted enolate, 3A, of 2-heptanone3’ 47. 43. One of the most successful examples was by Corey and Gross“; they introduced a bulky lithium t-octyl-t-butylamide (LOBA) base utilizing an internal quench technique to achieve a 97.5 / 2.5 selectivity of 3A / 3B (eq. 65). In their experiments, 2-heptanone was added to a solution of LOBA and TMSCI to avoid the self condensation problem. O a) LOBA OTMS n-BuV‘k—T mmscn n BUVK WEB/EMS ‘6” 2.5% 97.5% We recognized that LiP(t-Bu)2 was an effective base for the selective preparation of the less substituted enolate, of acyclic ketones. 2-Heptanone was selectively deprotonated by LiP(t-Bu)2 under kinetically controlled conditions. Enolate isomers 3A and 33 were generated in 99 / 1 ratio in a two step procedure. A summary of literature values for regioselective enolate formation of 2- heptanone is presented in Table XIII. 54 Table XIII. Comparison of regioselective enolate formation of 2-heptanone O a) base OTMS OTMS _, ,+ b) TMSCI n-BUVK n-BUvL/k 3A 38 base %3A %3B % yield ref. 1 KH 4 6 5 4 9 0 (47) 2 LDA (two step) 84 16 65 (3) 3 LDA (internal quench) 95 5 >99 (48) 4 LOBA (internal quench) 97.5 2.5 >99 (48) 5 LiP(t-Bu); (two step) 99 1 >99 this work 55 (v) STEREOSELECTIVE EN OLATES FORMATION USING METAL DIORGANOPHOSPHIDES AS BASES Stereoselectivity of metal diorganophosphides is one of the subjects of our studies. Stereoselectivity is an important aspect in the aldol condensation of metal enolates49. Consideration of facile proton NMR identification of stereoisomers allowed us to use ethyl ketones, which can produce vinylic hydrogens that can be distinquished by proton NMR, of silyl enol ether derivatives. These included 3- pentanone, propiophenone and 2',4',6'-trimethyl-propiophenone50. Ireland4 reported that an E / Z enolate isomer ratio of 77 / 23 was obtained using LDA with 3-pentanone in a THF solution. An inverted stereoselectivity of 5 / 95 was Observed when HMPA was used as a co-solvent (eq. 66). O a) LDA OTMS OTMS ————> + b TMSCI \/I\/ I \ VS (66) Z E THF 23% 77% THF / HMPA 95% 5% The selectiveE enolate generation of 3-pentanone was improved by Corey and Gross“; they obtained a E/ Z enolate isomer ratio of 98 / 2 by using the bulky LOBA base, under kinetic conditions (eq. 67). 56 O a) LOBA OTMS OTMS + b TMSCI Vk/ 2% 98% A comparableE Stereoselectivity was observed by Collum51 using LiTMP-LiBr mixed aggregation species (eq. 68). A summary of literature values for stereoselective enolate formation of 3— pentanone is presented in Table XV. O a) LiTMP-LiBr OTMS OTMS . + I \ \/I\| (68) 2% 98% In our experiment, 3-pentanone was added dropwise to a 1.1 equivalent of LiPPh2 in a THF solution, excess TMSCI was then added. After the usual work-up procedure previously described, the proton NMR data showed a quartet at 4.45 ppm, which was assigned to the vinylic hydrogen of Z-3-trimethylsiloxy-Z-pentene (eq. 69). The vinylic hydrogen of E-3-trimethylsiloxy-2-pentene, a quartet at 4.57 ppm, was not observed in this reaction. It was determined that Z enolate was Obtained exclusively from the reaction of LiPth with 3- pentan one. 0 a) MPRZ OTMS OTMS + 8 4.45 (q, 1H) 8 4.57 (q, 1H) 57 For the reaction of LiP(t-Bu)2 and 3-pentanone, at room temperature the enolate of 3-pentanone wich geometry was predominate (Table XIV, entry 3). In consideration of the strong basicity of LiP(t-Bu)2, which can quantitatively deprotonate HMDS and form an equilibrium with diisopropylamine after one hour at room temperature, we would expect that the deprotonation of 3- pentanone by LiP(t-Bu)2 would produce the E stereoisomer as the major product. To our surprise, the products generated favored the Z stereoisomer. We reason that the production of the major Z isomer is not a reflection of the steric congestion between the t-Bu group of LiP(t- Bu)2 and the Me group of 3-pentanone in the transition state. It is most likely due to the greater ionic character between P and Li of LiP(t-Bu); caused by the concomitant formation of HP(t-Bu)2, A deprotonation process went through a transition state similar to that earlier proposed by Ireland4 (Figure 7), using HMPA as a complexing agent. O Et . 1‘ II'I OSIM93 0 LiP(t-Bu)2 CH Li; TMSCI Up = , .. ——» . t-Bu—li|>"’ t-Bu Figure 7. Stereoselective enolate formation using LiP(t-Bu)2 58 In an attempt to increase the E isomer production, LiP(t-Bu)2 was added to a mixture of 3-pentanone and excess of T MSCI, an "in situ"procedure, and no silyl enol ether was isolated (Table XIV, entry 4). LiP(t-Bu)2 underwent substitution of TMSCI much faster than deprotonation of 3-pentanone. In all the cases studied (Table XIV), the major product was the Z stereoisomer, even when efforts were made to use a more ionic KP(t-Bu)2 base (Table XIV, entry 5), and a less steric hindered LiP(Chx)2 base (Table XIV, entry 6), The enolates of several ethyl ketones can be quantitatively generated with LiPPh2 (Table XIV, entries 1, 7, 8). The effects of the LiPPh2 aggregation state on stereoselectivity was briefly examined by using 2',4',6'-trimethylpropiophenone (Table XIV, entries 8, 9, 10). The enolate of 2',4',6'-trimethylpropiophenone was generated by adding a ketone to a LiPPh2 solution, at 0°C. The enolate isomer ratio and a total yield were determined by the integration of proton NMR data. The silyl enol ether derivative, with Z geometry, has a characteristic signal at 5.07 ppm, while the E isomer has a signal at 5.62 ppm (eq. 70). O O'IMS OTMS a) MPR2 : \ + \ b) TMSCI 8 5.62 (q, 1H) 8 5.07 (q, 1H) (70) 59 A trend of increasing E isomer generation was observed as the solvent was changed from THF to ether to benzene (Table XIV, entries 8, 9, 10). This result was rationalized from the aggregation states of LiPth in THF and in benzene by considering steric factors. LiPPh2 tends to be highly associated and bulky in benzene, thus the deprotonation process is favored by transition state (A), which leads to the E isomer. On the other hand, LiPPh2 tends to be dissociated and small in THF and the deprotonation process is favored by transition state (B), which leads to the Z isomer (Figure 6). 0-- ' Mes OSM . CH ' 93 0 LiPPh2 H L.. 3 TMSCI I I : ———> \ 4' Me Me benzene Ph—l=|’"'H Ph E A Q... , Mes . CH 1 ’H OSIM63 0 LiPPh2 Li : TMSCI > ’I A -_—.’ \ Me THF ph—ilau Mes Ph Z B Figure 8. Solvent effects on enolate formation 60 Table XIV. Stereoselective enolate formation of ethyl ketones O OSiM93 OSiMe3 R )J\/ —’ R N + R /lfi Z E R base %Z %E total yield 1 Et LiPPh2 1 00 0 6 5 2 LiP(Mes)2 100 0 6 3 3 LiP(t-Buz) 7 4 2 6 6 8 4 LiP(t-Buz) 0 0 0 5 LiP(Chx)2 7 6 2 4 7 1 6 KP(t-Buz) 100 0 8 2 7 Ph LiPPh2 l 00 0 >99 8 Mes 7 5 2 5 >99 9 6 2 3 8 >99 1 0 4 3 5 7 >99 a) Ketone (1 mmole) was added dropwise to a 0.5 M THF solution of MPR2 (1.2 mmole)_ b) Yields determined by 1H NMR integration. 61 Table XV. Comparison of stereoselective enolate formation of 3-pentanone O a) base ¥ OTMS + OTMS \Uk/ b) TMSCT VK/ \/I\l Z E base solvent E / Z ref LDA THF 77 / 23 (41) THF-HMPA 5 / 95 (41) LOBA THF 98 / 2 (48) THF-HMPA 37 / 63 (48) LiTMP THF 86 / 14 (52) THF-HMPA 8 /92 (52) LiTMP-LiBr THF 98 / 2 (51) LHMDS THF 34 / 66 (50) LICA THF 65 / 35 (50) LiPPh2 THF 1 / 99 this work 62 (vi) THE REACTIONS OF KETONE ENOLATES The reactivity of the lithium enolate, of a ketone, is very sensitive to its aggregation state. One of the remarkable features of lithium enolates is that they display a wide spectrum of reactivities through the presence or absence of solvents, complexing agents, lithium salts and secondary amines53. Jackman54 studied the effects of the lithium enolate aggregation states on alkylation reactions in dioxane and in DME solutions. It was reported that the lithium enolate of isobutylphenone in dioxane primarily exists as a tetramer and reacts with dimethylsulfate producing the methyl enol ether (O-alkylation) and pivalophenone (C-alkylation) in a C / 0 ratio of 1.56 (eq. 71). A C / 0 ratio of 1.22 was obtained in DME solution, and the enolate was characterized as a dimer in DME. Jackman indicated that the differences in the C / 0 ratio was a reflection of the changing enolate aggregation state in different solvents (Figure 8). CU OCH3 O O \ O \ O O'aIKYIaIIon C'aIKYIation (71) 63 R S ‘;k}—-Lf/S | R I \flJ-é—CIRI [:Ck~ EMT/0w 6586/86 R/}>-"'LKS I R tetramer dimer in dioxane in DME C/O=1.56 C/O=1.22 Figure 9. Enolate of isobutylphenone aggregations in dioxane and in DME The nature of enolate aggregation can be modified by the addition of a cation complexing agent. House55 observed a significant upfield shift of the or carbon of the lithium enolate of phenylacetone in the presence of 4 equivalents of HMPA in an ether solution (Figure 9). H I //CH3 (‘r—=C \( ‘\ Me (72) temp. °C 1/ u yield % without LiCl 0 4 : 1 73 with LiCl -7O 99 : 1 87 The secondary amine generated from the reaction of a metal amide and a ketone also formed a mix aggregation of an enolate. As a result, the lithium enolate of t—butylacetate becomes totally soluble in hexane that is in the presence of one equivalent of 65 diisopropylamine. The complications caused by the secondary amine, in lithium enolate alkylation53, acylation59 and coupling reactions“, may be eliminated simply by using an amine-free enolate. In this study, a new class of lithium enolate was obtained from the reaction of diorganophosphides with enolizable carbonyl compounds. Alkylation, acylation and the aldol reaction were used as a probe to define the nature of enolates. Excess methyliodide was added to a THF solution containing the enolate of acetophenone, prepared from LiPth and acetophenone. The reaction mixture was kept stirring for one hour at room temperature. Then, dilute hydrochloric acid was added to remove Lil and HPth. The aqueous solution was extracted with ether, and evaporation of the ether gave 80% propiophenone, 15% isobutylphenone and 5% recovered acetophenone (eq. 73). The yield of each component was determined by the proton NMR integration value of each characteristic resonance, relative to the internal standard (aryl region hydrogens). A control reaction that used LHMDS for the formation of the enolate was performed under comparable conditions, and it produced 50% propiophenone, 35% isobutylphenone and 15% acetophenone. 3W Qir 8 2.6 (s, 3H) 8 2.4 (q, 2H) 8 3.1(sep, 1H) (73) 66 The enolate of acetophenone was acylated with Ac20 by adding excess Aczo to a THF solution containing the enolate of acetophenone (prepared from LiPPh2 and acetophenone). The ambiguous nature of the enolate intermediate resulted in O-acylated and C-acylated products (eq. 74). The products ratio can be determined by relative integration values of the singlet at 6.12 ppm61 (C-acylated) and the two doublets at 4.9 ppm and at 5.35 ppm (O-acylated). 0 OAc O O a) LiPPh2 : + (74) O m O 8 4.9 (d, 1H) 8 6.12 (s, 1H) 8 5.35 (d, 1H) We compared the two enolates generated from LiPth and LHMDS and found that the enolate generated with LiPth produced less polyalkylation products (Table XVI, entries 1, 2). The acetic anhydride acylation of the enolate, generated from LiPth, produced more C-acylated product (C / 0 ratio was 26 / 74) than that with LHMDS (C / 0 ratio was 9 / 91) (Table XVI, entries 3, 4). Based on these observations we reasoned that the lithium enolate prepared with LiPPh2 has more contact ion pair character (lithium enolate is more aggregated), which results in lower reactivity. Also, as a result of this reduced reactivity, it is responsible for enhancing monoalkylation product formation and allowing more enolate equilibration during the acetic anhydride acylation. 67 Methylation of cyclohexanone has been the subject of extensive study62. House reported63 that the methylation of the enolate produced from LDA and cyclohexanone affords 74% 2- methylcyclohexanone and 26% polyalkylation products. The polyalkylation problem can be reduced by some extent by employing higher concentrations, shorter reaction times and excess alkyl electrophile. Another useful method used to enhance monoalkylation is to coordinate the lithium enolate with a complexing agent so that the reaction can take place under milder conditions. Introduction of triethylaluminum64, triethylborane65, or triethanolamineborate65 into the system dramatically reduced the amount of polyalkylation products. On the other hand, the addition of HMPA facilitated the equilibriation process of the lithium enolate. For example, the benzylation of cyclohexanone produced 40% polyalkylation products and 10% enol ether (O-alkylation). Methylation of the enolate prepared from cyclohexanone and LiPPhg produced 98% yield of 2-methylcyclohexanone (eq. 75). The yield was determined by using proton NMR integration of the doublet at 1 ppm (methyl group of 2-methylcyclohexanone) by using the aryl hydrogens as a reference. 0 O a) LiPPh2_ o .M. , o 98% yield 68 For an unsymmetrical ketone it is necessary to direct the alkylation to either the less or the more substituted position for a synthetic operation. Benzylation at the less substituted side of 2- methylcyclohexanone was accomplished by House using LDA, under kinetic conditions. The problem of enolate equilibrium can not be totally avoided because the enolate equilibrium rate is faster than the alkylation rate. In addition, the more substituted enolate is more reactive than the less substituted one. House concluded that the benzylation at the less substituted position of 2-heptanone, using LDA, would not result in a clean reaction. However, the benzylation at the less substituted position of 2—heptanone was achieved under kinetically controlled conditions, the enolate was activated by the addition of HMPA“. In the presence of excess ketone, thermodynamic control conditions, benzylation at the more substituted position did not give satisfactory results. It was necessary to take extra measures in order to obtain a good yield in the benzylation at the more substituted position of 2-methylcyclohexanone. Thus, the more substituted enolate derivatives of enol esters and silyl enol ethers were prepared and benzylation was carried out by the MeLi cleavage of the enol ester and silyl enol ether. Benzylation of 2-methylcyclohexanone by using LiPPh2 as a base resulted in 72% yield of 2-methyl-2-benzylcyclohexanone (eq. 76). Yields were determined by proton NMR integration of the singlet at 3.8 ppm (benzyl group of 2-methyl-2-phenylcyclohexanone) by using the aryl hydrogens as a reference. 69 O O 4.1, s, 2H 72% yield An aldol reaction was performed, at -78°C, by adding benzaldehyde to the lithium enolate of 3-pentanone (prepared from LiP(t-Bu)2 and 3-pentanone). After the usual work up procedure, one pair of diastereomers was obtained (eq. 77). Their relative ratios were determined by the proton NMR integration of the doublet, with coupling constant 3 Hz, at 4.8 ppm (syn product) and integration of the doublet, with coupling constant 8 Hz, at 4.48 ppm (anti product). The aldol reaction was also performed with KP(t-Bu)2 as base (Table XVI, entry 10). 0 III 0 :1: O IIIIO :1: Ph Ph 4% O a) LiP(t-Bn)2 \/u\/ b) PhCHO Me File (77) 8 4.8 (d, 1H) 8 4.48 (d, 1H) 70 Table XVI. The reactions of ketone enolates with electrophiles O O de MPR2 ' R E R ' R <-> R R E base ketone electrophile total yield 1 LiPth acetophenone Mel 100 (80/15/5)“ 2 LHMDS MeI 100 (50/35/15) 3 LiPth AczO 88 (26/74)b 4 LHMDS Ac20 91 (9/91) 5 LiPPh2 i-PrBr 0 6 n-BuBr 0 7 cyclohexanone Mel 98 8 2-methylcyclo- BnBr 72 hexanone 9 LiP(t-Bu)2 3-pentanone PhCHO 90 (77/23)C 1 0 KP(t-Bu)2 67 (36/74) a) (isobutylphenone/propiophenone/acetophenone) b) (C-acylation/O-acylation) c) (syn/anti) d) Yields determined by 1H NMR integration 71 EXPERIMENTAL (i) General procedure All glassware used for the experiments was thoroughly dried in an oven, cooled and assembled under a stream of nitrogen. All reactions were carried out under nitrogen, and all solutions were transferred by syringe techiques. KPth solution was standardized in a 50 ml three-neck round bottom flask equipped with septum inlet, magnetic stirrer and mercury bubbler. A 1 ml aliquot of the phosphide solution was quenched with 10 ml of distilled water, under nitrogen, and titrated to a phenolphthalein endpoint, with a standardized HCl solution. NMR Spectroscopy Proton NMR spectra were recorded on a Gemini-300 MHz instrument. All proton NMR spectra were measured in CDCl3 with tetramethylsilane (TMS) as an internal standard and the chemical shifts expressed in ppm. Multiplicities are given as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). Coupling constants are in hertz. Phosphorus-31 NMR spectra were recorded on a Varian VXR-300 MHz instrument operating at 121.42 MHz, using H3PO4 as an external standard, with resonances deshielded from the standard being reported as negative value. For a 0.5 M solution, 40 transients gave an excellent signal to noise ratio and the spectrometer was unlocked during acquisition. 72 (ii) Materials Reagent-grade tetrahydrofuran (THF) was distilled immediately before use under nitrogen from a deep-blue solution of sodium benzophenone ketyl. A 1.6M butyllithium in hexane solution and phosphorus trichloride were purchased from Aldrich and used as recieved. Triphenylphosphine was Obtained from J. T. Baker chemical Co. Commercial samples of acetophenone, cyclohexanone, 2,4- dimethyl-3-pentanone, pinacolone, cyclohexenone, mesityl oxide, 2- methylcyclohexanone, 2-methylcyclopentanone, 2-heptanone, ethyl acetate, and chlorotrimethylsilane were distilled over CaHz before use. 2',4',6'-Trimethylpropiophenone was prepared from mesitylene and propionyl chloride according to Heathcock's procedure50. Phenylacetone was prepared from benzyl cyanide and ethyl acetate following a procedure in Org. Syn. 18, 54. t-Butylacetate was prepared from t-butanol and acetic anhydride following a procedure in Org. Syn. III, 141. t-Butylpropionate was prepared from propionyl chloride and t-butanol in pyridine. Methyl phenylacetate and ethyl isobutyrate were prepared by azeotropic removal of water from the corresponding carboxylic acid and excess alcohol in the presence of toluenesulfonic acid. N,N-Dimethylacetamide was obtained by distillation of a mixture of 30% aqueous solution of dimethylamine with 2 equivalents of acetic anhydride. Sodium t-butoxide was obtained by refluxing t-butanol and sodium in hexane solution overnight. Potassium -t-amylate was obtained by refluxing t-amyl alcohol and potassium in hexane solution overnight. 73 n-Butyl sodium and sodium bromide mix aggregate To a hexane solution (40 ml) containing sodium sand (0.92g, 40 mmole) was added n—BuBr (2.1 ml, 20 mmole). The reaction mixture was stirred at room temperature for 4 hours to obtain n-BuNa and NaBr mix aggregate precipitate. n-Butyl sodium crystalline To a suspension of sodium t-butoxide (4.8g, 0.05mole) , in hexane (50 ml), was added n-BuLi (1.6 M hexane solution, 63 ml, 0.1 mole), with stirring, at 0°C. The reaction mixture was warmed to room temperature and stirred at room temperature for 30 minutes. The powdery n-BuNa was transfered to a 30 ml centrifuge tube via a 1mm diameter cannula. n-BuNa was separated from excess of n-BuLi by centrifugation. n-BuNa was washed twice with hexane (15 ml x 2), and suspended in hexane (20 ml). n-Butyl potassium and potassium bromide mix aggregate T o a hexane solution (40 ml) containing potassium sand (1.6g, 40 mmole) was added n-BuBr (2.1 ml, 20 mmole). The reaction mixture was stirred at room temperature for 4 hours to obtain a n-BuK and KBr mix aggregate precipitate. 74 n-Butyl potassium crystalline To a suspension of potassium t-amylate (6.3g, 0.05 mole), in hexane (50 ml), was added n-BuLi (1.6 M hexane solution, 63 ml, 0.1 mole), with stirring, at —78°C. The reaction mixture was slowly warmed to 0°C and stirred at 0°C for 1 hour. The powdery n-BuK was transfered to a 30 ml centrifuge tube via a 1mm diameter cannula. n-BuK was then separated from the excess n-BuLi by centrifugation. n—BuK was washed twice with hexane (15 ml x 2), and suspended in hexane (20 ml). Diphenylphosphine A 250 ml round bottom flask equipped with septum inlet, magnetic stirrer and mercury bubbler was charged with lithium pieces (1.4g, 0.2 mmol), (prepared from cutting lithium wire into 1 mm pieces with scissors and washed twice with 10 ml of hexane) and THF (100 ml). To this solution was added PPh3 (26.2g, 0.1 mmol) via a powder funnel under a stream of argon. The reaction mixture was stirred at room temperature for 4 hours until all the lithium pieces were dissolved. The reaction flask was placed in an ice-bath and ether (50 ml), saturated with deoxygenated water, was added followed by deoxygenated water to hydrolyze the deep-red LiPth solution, The product was extracted with ether (30 ml x 2), dried over sodium sulfate and concentrated and then distilled under reduced pressure to obtain 16.7g (90%, bp 188-190°C / 15 torr) of HPth, 1H NMR (CDC13) 5.25 (d, l H, J p-H =218 Hz), 7.23-7.48 (m, 10 75 H); 31P NMR (CDCI3) 8 -40. Dimesitylphosphine A 100 ml round bottom flask equipped with septum inlet, magnetic stirrer and addition funnel was charged with Mg turnings (0.5g, 20 mmol) and THF (20 ml). A solution of 2-bromomesitylene (4g, 20 mmol) in THF (10 ml) was added at such a rate as to keep the reaction mixture at a gentle reflux. The mixture was allowed to reflux for 1 hour upon completion of the addition. A separate 250 ml round bottom flask equipped with septum inlet, magnetic stirrer and addition funnel was charged with PCl3 (1.4g, 10 mmol) and THF (20 ml). The flask was placed in a dry-ice bath, and the Grignard reagent was added drOpwise via an addition funnel over a period of 1 hour. The reaction mixture was stirred at room temperature overnight. The flask was recooled in a dry-ice bath. To this solution, a slurry of LiAlH4 (0.4g, 10 mmol) in THF (10 ml) was added dropwise, with pipet, under a stream of nitrogen. The reaction mixture was stirred overnight, at room temperature. The solvent was removed under reduced pressure, and the product was extracted with hexane (30 ml x2). Evaporation of the hexane gave the desired product (2g, 75%). 1H NMR (CDC13) 2.24 (s, 6H), 2.25 (s, 12H), 5.25 (d, 1H, JP-“ =232 Hz), 6.83 (s, 4H); 31P NMR (CDCI3) 8 -91.3. 76 Di-t-Butylphosphine A 500 ml round bottom flask equipped with septum inlet, magnetic stirrer and addition funnel was charged with Mg turning (10.7g, 0.44 mol) and THF (150 ml). To this solution was added I- Butylchloride (43.5m1, 0.4 mol) in THF (100 m1), at such a rate as to keep the reaction mixture at a gentle reflux. The mixture was allowed to reflux for 1 hour upon completion of the addition. A separate 1000 ml round bottom flask equipped with septum inlet, magnetic stirrer, and addition funnel was charged with PCl3 (8.7ml, 0.1 mol) in T HF (100 ml). The solution was stirred and equilibrated to -78°C, and the Gringard reagent was added dropwise via an addition funnel over a period of 1 hour. The reaction mixture was stirred at room temperature overnight. The flask was recooled in a dry-ice bath. To this solution, a slurry of LiAlH4 (3.8g, 0.1mol) in THF (50 ml) was added dropwise, with pipet, under a stream of nitrogen. The reaction mixture was stirred overnight at room temperature. The mixture was filtered through a sintered-glass pad under a positive nitrogen pressure, and the inorganic precipitate was washed twice with fresh distilled THF (100 ml x 2). The solvent was removed by fractional distillation on an one foot vigreux column, and the resulting clear liquid was distilled under reduced pressure to obtain 11.3g (77%, bp 88-95°C / 15 torr) of HP(t-Bu)2. 1H NMR (CDCI3) 1.10 (s, 9H), 1.15 (s, 9H), 3.05 (d, 1H,] p-1-1 =210 Hz) ; 31P NMR (CDCI3) 8 19 77 Dicyclohexylphosphine A 250 ml round bottom flask equipped with septum inlet, magnetic stirrer and addition funnel was charged with Mg turnings (3.4g, 0.14 mol) and THF (50 ml). To the solution was added cyclohexyl chloride (11.9 ml, 0.1 mol) in THF (30 ml), at such a rate as to keep the reaction mixture at a gentle reflux. The mixture was allowed to reflux for 1 hour upon completion of the addition. A separate 500 ml round bottom flask equipped with septum inlet, magnetic stirrer, and addition funnel was charged with PC13 (4.35 ml, 0.05 mol) in THF (100 ml). The solution was stirred and equilibrated to -78°C, and the Gringard reagent was added dropwise via an addition funnel over a period of 1 hour. The reaction mixture was stirred at room temperature overnight. The flask was recooled in a dry-ice bath. To this solution was added dropwise a slurry of LiA1H4 (1.9g, 0.05 mol) in THF (100 ml), with pipet, under a stream of nitrogen. The reaction mixture was stirred overnight at room temperature. The mixture was filtered through a sintered-glass pad under a positive nitrogen pressure, and the inorganic precipitate was washed twice with fresh distilled THF (100 ml x 2). The solvent was removed by fractional distillation on an one foot vigreux column, and the resulting clear liquid was distilled under reduced pressure to obtain 4.6g (46%, bp 124-130°C / 15 torr) of HP(Chx)2. 31P NMR (CDCI3)811 78 Lithium diphenylphosphide A 50 ml round bottom flask equipped with septum inlet, magnetic stirrer and mercury bubbler was charged with HPth (2.79g, 15 mmol) and THF (15 ml). The solution was stirred and equilibrated to 0°C. To the solution was added n-BuLi (1.6 M hexane solution, 10.3 ml 16.5 mmole) dropwise by means of a syringe. The resulting solution was allowed to react for additional 30 minutes at 0°C upon completion of addition. The LiPth solution thus prepared was quantitative. 31P NMR (THF) 8 -20. Potassium diphenylphosphide(l6) A 50 ml round bottom flask equipped with septum inlet, magnetic stirrer and mercury bubbler was charged with potassium sand (0.39g, 10 mmol) (prepared from heating potassium in mineral oil to 80°C with intensive stirring for 15 minutes and then washed twice with hexane), and THF (18 ml). The solution was stirred and equilibrated to -78°C. To this solution was added HPth (1.86g, 10 mmole) dropwise by means of a syringe. The resulting solution was allowed to react for additional 8 hours at -78°C upon completion of the addition. The KPth solution thus prepared was determined as a 0.5 M solution (100%). 31 P NMR (THF) 8 -10; The solution was sealed and stored in a refrigerator. 79 Magnesium bromide diphenylphosphide A 50 ml round bottom flask equipped with septum inlet, magnetic stirrer and mercury bubbler was charged with PhMgBr (1 M, 15 ml) in THF solution. To this solution was added HPth (2.79g, 15 mmol) dropwise by means of a syringe. The resulting solution was allowed to react for additional 2 hours at room temperature upon completion of the addition. The BngPPh2 solution thus prepared was determined as a 0.5 M solution (100%). 31 P NMR (THF) 8 ~46 Lithium di-t—butylphosphide A 50 ml round bottom flask equipped with septum inlet, magnetic stirrer and mercury bubbler was charged with HP(t-Bu)2 (2.79g, 15 mmole) and THF (15 ml). The solution was stirred and equilibrated to 0°C. To this solution was added n-BuLi (1.6 M hexane solution, 10.3 ml 16.5 mmole) dropwise by means of a syringe. The resulting solution was allowed to react for additional 30 minutes at 0°C upon completion of addition. The LiP(t-Bu)2 solution thus prepared was quantitative. 31 P NMR (THF) 8 38 Sodium di-t-Butylphosphide A 10 ml round bottom flask equipped with septum inlet, magnetic stirrer and mercury bubbler was charged with n-BuNa crystalline (10% suspension in hexane, 2 mmole). The solution was stirred and equilibrated to -78°C, and HP(t-Bu)2 (0.19 ml, 1 mmole) was added. 80 To this solution was added T HF (1 ml) dropwise by means of a syringe. The resulting solution was allowed to warm up to room temperature. The NaP(t-Bu)2 solution thus prepared was quantitative. 31P NMR (THF) 8 53. Potassium di-t-Butylphosphide A 10 ml round bottom flask equipped with septum inlet, magnetic stirrer and mercury bubbler was charged with n-BuK crystalline (10% suspension in hexane, 3 mmole). The solution was stirred and equilibrated to -78°C, and HP(t-Bu)2 (0.19 ml, 1 mmole) was added. To this solution was added THF (1 ml) dropwise by means of a syringe. The resulting solution was allowed to warm up to room temperature. The KP(t-Bu)2 solution thus prepared was quantitative. 31P NMR (THF) 8 63. (A) Phosphorus-31 NMR studies for the reaction of LiPPh2 with ketones 1. LiPPh2/ Acetophenone To a 5 mm NMR tube, with rubber septum secured by teflon tape, (prior to use the NMR tube was purged several times with nitrogen by using a needle connected to nitrogen and water aspirator), was added HPth (0.087ml, 0.5 mmole) and THF (1 ml). The solution was stirred and equilibrated to 0°C, and n-BuLi (1.6 M hexane solution, 0.34 ml, 0.5 mmole) was added and mixed well by inverting the tube occasionally. After 15 min at 0°C, acetophenone (0.06ml, 0.5 mmole) '81 was added to the deep-red solution. The resulting solution was allowed to react for an additional 15 minutes at 0°C upon completion of the addition, and submitted for 31P NMR analysis. HPPh2 (8 -40) was the only product observed (>99% deprotonation). 2. LiPth / Cyclohexanone Using the procedure described above the combination of cyclohexanone and LiPth resulted in HPth as the only product (>99% deprotonation). 3. LiPPh2 / 3-Pentanone Using the procedure described above the combination of cyclohexanone and LiPth resulted in HPth as the only product (>99% deprotonation). 4. LiPth/ Pinacolone Using the procedure described above the combination of pinacolone and LiPth resulted in HPPh2 as the only product (>99% deprotonation). 5. LiPPh2 / 2,4-Dimethyl-3-pentanone Using the procedure described above the combination of cyclohexanone and LiPth resulted in HPth as the only product (>99% deprotonation). 82 6. LiPth / cyclohexenone Using the procedure described above the combination of cyclohexenone and LiPPh2 resulted in tertiary phosphine as the only product (>99% addition)(eq. 43). 7. LiPth/mesityl oxide Using procedure described above the combination of mesityl oxide and LiPth resulted in tertiary phosphine as the only product (>99% addition)(Table II. 14). (B) Phosphorus—31 NMR studies for the reaction of BngPth with ketones 1. BngPPh2/ Acetophenone To a 5 mm NMR tube, equipped with a rubber septum secured by teflon tape, (which was purged several times with nitrogen by using a needle connected to nitrogen and a water aspirator), the BngPPh2 (0.5 M, 1 ml) THF solution was added. The solution was stirred and equilibrated to 0°C, and acetophenone (0.06ml, 0.5 mmole) was added and mixed well by inverting the tube occasionally. The resulting solution was allowed to react for an additional 1 hour upon completion of the addition, and submitted for 31P NMR analysis. The NMR data show a broad absorption at 0 ppm, which suggested a tertiary phosphine (>99% addition). 83 2. BngPPh2 / Cyclohexanone Using the procedure described above the combination of cyclohexanone and BngPth resulted in the tertiary phosphine as the only product (>99% addition). 3. BngPth / 3-Pentanone Using the procedure described above the combination of cyclohexanone and BngPth resulted in the tertiary phosphine as the only product (>99% addition). 4. BngPPh2/ Pinacolone Using the procedure described above the combination Of pinacolone and LiPPh2 resulted in HPPh2 as the only product (>99% deprotonation). 5. BngPPh2 / 2,4—Dimethyl-3-pentanone Using the procedure described above the combination of 2,4- Dimethyl-3-pentanone and BngPth resulted in HPth as the only product (>99% deprotonation). (C) General procedure for the silylation of ketone enolate 1. LiPPh2/ Acetophenone / TMSCI A 10 ml round bottom flask equipped with septum inlet, magnetic stirrer and mercury bubbler was charged with HPth (0.21ml, 1.2 mmole) and THF (2 ml). The solution was stirred and equilibrated to 0°C. To the solution was added n-BuLi (1.6 M hexane solution, 0.75 84 ml, 1.2 mmole) dropwise by means of a syringe. After 15 min at 0°C with stirring, acetophenone (0.12ml, 1 mmole) was added. The resulting solution was allowed to react for an additional 30 minutes at 0°C, then allowed to warm to room temperature. The resulting solution was quenched with TMSCI (0.38ml, 3 mmole) and stirred for an additional 1 hour. The solvent was removed under reduced pressure, CDC13 (2 ml) was added, and the solution was transferred to a centrifuge tube. Centrifugation resulted in the separation of the silyl enol ether solution from LiCl, which was transferred to an NMR tube for 1H NMR analysis. 1H NMR (CDCI3) : 0.2 (s, 9H) ; 4.3 (d, 1H, J=1.5 Hz) ; 4.86 (d, 1H, J=1.5 Hz) ; 7.1-7.4 (m, 3H) ; 7.4-7.7 (m, 2H) 2. LiPPh2/Cyclohexanone / TMSCI Using the procedure described above the combination of cyclohexanone, LiPth, and TMSCI at room temperture produced silyl enol ether derivative. 1H NMR (CDCI3) : 0.15 (s, 9H) ; 1.3-2.2 (m, 8H) ; 4.75 (m, 1H). 3. LiPth / 3-Pentanone / TMSCI Using the procedure described above the combination of cyclohexanone, LiPth, and T MSCl at room temperature produced silyl enol ether derivative. 1H NMR (CDCI3) : 0.15 (s, 9H) ; 1.0 (t, 3H, =7.2 Hz) ; 1.6 (d, 3H, J=6.5 Hz) ; 2.0 (q, 2H, J=7.2 Hz) ; 4.37 (q, 1H, J=6.5 Hz). 4. LiPthl Pinacolone / TMSCI Using the procedure described above the combination of 85 pinacolone, LiPth, and TMSCI at room temperature produced silyl enol ether derivative. 1H NMR (CDCI3) : 0.2 (s, 9H) ; 1.05 (s, 9H) ; 3.93 (d, 1H, 1:2 Hz) ; 4.08 (d, 1H, 122 Hz). 5. LiPPh2/2,4-Dimethyl-3-pentanone / TMSCI Using the procedure described above the combination of 2,4- Dimethyl-3-pentanone and LiPth and TMSCI at room temperature produced silyl enol ether derivative. 1H NMR (CDCI3) : 0.2 (s, 9H) ; 0.93 (d, 6H, J=7 Hz) ; 1.53 (s, 3H) ; 1.60 (s, 3H) ; 2.76 (sept, 1H, J=7 Hz). 6. LiPPh2/2-methylcyclohexanone / TMSCI Using the procedure described above the combination of 2- methylcyclohexanone and LiPPh2 and TMSCI at room temperature produced silyl enol ether derivatives. 1H NMR (CDCI3) 1A : 0.15 (s, 9H) ; 0.98 (d, 3H, J=6.5 Hz) ; 1.3-2.2 (m, 7H) ; 4.65 (t, 1H, J=3.3 Hz). 1B : 0.16 (s, 9H) ; 1.55 (s, broad, 3H) ; 1.3-2.2 (m, 8H). 7. LiPth/2-methylcyclopentanone / TMSCI Using the procedure described above the combination of 2- methylcyclopentanone and LiPPh2 and TMSCI at room temperature produced silyl enol ether derivatives. 1H NMR (CDCI3) 2A : 0.15 (s, 9H) ; 0.96 (d, 3H, J=6.5 Hz) ; 1.3-2.2 (m, 5H) ; 4.43 (t, 1H, J=3.3 Hz). 2B : 0.16 (s, 9H) ; 1.48 (s(broad), 3H) ; 1.3-2.2 (m, 6H). 8. LiPPh2/2-heptanone / TMSCI Using the procedure described above the combination of 2- 86 heptanone and LiPPh2 and TMSCI at room temperature produced silyl enol ether derivatives. 1H NMR (CDC13) 3A : 0.2 (s, 9H) ; 0.9 (m, 3H) ; 1.34 (m, 6H) ; 2.0 (m, 2H) ; 4.0 (s, 2H). 33 : Z 0.16 (s, 9H) ; 0.9 (m, 3H) ; 1.34 (m, 6H) ; 1.68 (s, broad, 3H) ; 4.53 (t, 1H, J=7.3 Hz). E 0.16 (s, 9H) ; 0.9 (m, 3H) ; 1.34 (m, 6H) ; 1.73 (s, broad, 3H) ; 4.36 (t, 1H, J=6.8 Hz). 9. LiPth/phenylacetone / TMSCI Using the procedure described above the combination of 2,4- Dimethyl-3-pentanone and LiPth and TMSCI at room temperature produced silyl enol ether derivatives. 1H NMR (CDCI3) 48 :Z 0.08 (s, 9H) ; 1.8 (d, 3H, J=0.8 Hz) ; 5.31 (s, broad, 1H) ; 7.03 (m, 5H). E 0.08 (s, 9H) ; 1.8 (d, 3H, J=0.8 Hz) ; 5.73 (s, broad, 1H) ; 7.03 (m, 5H). 10. BngPth/ Pinacolone / TMSCI A 10 ml round bottom flask equipped with septum inlet, magnetic stirrer and mercury bubbler was charged with BngPPh2 (0.5 M, 2.4 ml, 1.2 mmole) THF solution. To this solution was added acetophenone (0.12ml, 1 mmole). After 15 min at room temperature. TMSCI (0.38ml, 3 mmole) was added and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and CDC13 (2 ml) was added, the resulting solution was transferred to a centrifuge tube. Centrifugation resulted in the separation of the silyl enol ether solution from LiCl, which was transferred to an NMR tube for 1H NMR analysis. 87 11. BngPth/2,4-Dimethyl-3-pentanone / TMSCI Using the procedure described above the combination of 2,4- Dimethyl—3—pentanone, BngPth, and TMSCI at room temperature produced silyl enol ether derivative. 12. LiP(t-Bu)2/ 2-methylcyclopentanone / TMSCI A 10 ml round bottom flask equipped with septum inlet, magnetic stirrer and mercury bubbler was charged with HP(t-Bu)2 (0.22 ml, 1.2 mmole) and THF (2 ml). The solution was stirred and equilibrated to 0°C. To the solution was added n-BuLi (1.6 M hexane solution, 0.75 ml, 1.2 mmole) dropwise by means of a syringe. The resulting solution was allowed to react for an additional 30 minutes, and then allowed to warm up to room temperature. To the solution was added 2-methylcyclopentanone (0.12ml, l mmole). The reaction mixture was kept stirring for an additional 15 minutes, TMSCI (0.38ml, 3 mmole) was added and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and CDCl3 (2 ml) was added; the resulting solution was transferred to a centrifuge tube. Centrifugation resulted in the separation of the silyl enol ether solution from LiCl, which was transferred to an NMR tube for 1H NMR analysis. 13. LiP(t-Bu)2/2-heptanone / TMSCI Using the procedure described above the combination of 2- heptanone, LiP(t-Bu)2, and TMSCI at room temperature produced silyl enol ether derivative. 88 14. LiP(t-Bu)2/phenylacetone / TMSCI Using the procedure described above the combination of phenylacetone, LiP(t-Bu)2, and TMSCI at room temperature produced silyl enol ether derivative. (D) Phosphorus-31 NMR studies for the reaction of LiP(t-Bu)2 with CSICI’S 1. LiP(t-Bu)2/ ethyl acetate To a 5 mm NMR tube, with rubber septum secured by teflon tape (which was purged several times with nitrogen by using a needle ‘ connected to nitrogen and a water aspirator), was added HP(t-Bu)2 (0.093ml, 0.5 mmole) and THF (1 ml). The solution was stirred and equilibrated to 0°C, and n-BuLi (1.6 M hexane solution, 0.34 ml, 0.5 mmole) was added and mixed well by inverting the tube occasionally. After 15 min at 0°C, ethyl acetate (0.06ml, 0.5 mmole) was added. The reaction mixture was allowed to react for additional 15 minutes at 0°C, and submitted for 31P NMR analysis. HP(t-Bu)2 (8 38) was the only product observed (deprotonation). 2. LiP(t-Bu)2/ethyl isobutyrate Using the procedure described above the combination of ethyl isobutyrate and LiP(t-Bu)2 at 0°C resulted in HP(t-Bu)2 as the only product. 3. LiP(t-Bu)2/t-butyl acetate Using the procedure described above the combination of t-butyl 89 acetate and LiP(t—Bu)2 at 0°C resulted in HP(t-Bu)2 as the only product. 4. LiP(t-Bu)2/t-butyl propionate Using the procedure described above the combination of t-butyl propionate and LiP(t-Bu)2 at 0°C resulted in HP(t-Bu)2 as the only product. 5. LiP(t-Bu)2 /methyl phenylacetate Using the procedure described above the combination of methyl phenylacetate and LiP(t-Bu)2 at 0°C resulted in HP(t-Bu)2 as the only product. (E) Phosphorus-31 NMR studies for the reaction of LiP(t-Bu)2 with N,N-dimethylacetamide LiP(t-Bu)2/ N,N-dimethylacetamide To a 5 mm NMR tube, with rubber septum secured by teflon tape (which was purged several times with nitrogen by using a needle connected to nitrogen and a water aspirator), was added HP(t—Bu)2 (0.093ml, 0.5 mmole) and THF (1 ml). The solution was stirred and equilibrated to 0°C, and n-BuLi (1.6 M hexane solution, 0.34 ml, 0.5 mmole) was added and mixed well by inverting the tube occasionally. After 15 min at 0°C, ethyl acetate (0.049ml, 0.5 mmole) was added. The reaction mixture was allowed to react for an additional 15 minutes at 0°C, then submitted for 31P NMR analysis. HP(t-Bu)2 (8 38) was the only product observed (deprotonation). 90 (F) General procedure for alkylation of ester enolates 1. LiP(t-Bu)2/ ethyl acetate / BnBr A 10 ml round bottom flask equipped with septum inlet, magnetic stirrer and mercury bubbler was charged with HP(t—Bu)2 (0.22 ml, 1.2 mmole) and THF (2 ml). The solution was stirred and equilibrated to 0°C, and n-BuLi (1.6 M hexane solution, 0.75 ml, 1.2 mmole) was added dropwise by means of a syringe. After 15 min at 0°C with stirring, the reaction mixture was allowed to warm up to room temperature. The flask was placed in a dry-ice bath. To the above solution was added ethylacetate (0.1 ml, 1 mmole) and stirred at -78°C for 1 hour, BnBr (0.24 ml, 2 mmole) was then added and slowly warmed up to room temperature. The reaction mixture was hydrolyzed with 10 ml of water and extracted with ether, dried over Na2S04. Ether was removed under reduced pressure. 1H NMR analysis gave alkylation product. 2. LiP(t-Bu)2/t-butyl acetate / BnBr Using procedure described above the combination of t-butyl acetate and LiP(t-Bu)2 and BnBr at -78°C gave alkylation product. 3. LiP(t-Bu)2/ethyl isobutyrate / BnBr Using the procedure described above the combination of ethyl isobutyrate and LiP(t-Bu)2 and BnBr at -78°C gave alkylation product. 91 (G) Alkylation of N,N-dimethylacetamide enolates LiP(t-Bu)2/ N,N-dimethylacetamide / BnBr A 10 ml round bottom flask equipped with septum inlet, magnetic stirrer and mercury bubbler was charged with HP(t-Bu)2 (0.22 ml, 1.2 mmole) and THF (2 ml). The solution was stirred and equilibrated to 0°C, and n-BuLi (1.6 M hexane solution, 0.75 ml, 1.2 mmole) was added dropwise by means of a syringe. After 15 min at 0°C with stirring, the reaction mixture was allowed to warm up to room temperature. The flask was placed in a dry-ice bath, N,N- dimethylacetamide (0.093 ml, 1 mmole) was added and stirred at -78°C for 1 hour. BnBr (0.24 ml, 2 mmole) was then added and slowly warmed up to room temperature. The reaction mixture was hydrolyzed with 10 ml of water and extracted with ether, dried over NazSO4. Ether was removed under reduced pressure. 1H NMR analysis gave alkylation product. 1H NMR (CDCI3) 2.4 (t, 2H), 2.8 (t, 2H), 2.8 (s, 6H), 7.3 (s, 5H). (H) General procedure for alkylation of ketone enolates 1. LiPth / acetophenone / Mel A 10 ml round bottom flask equipped with septum inlet, magnetic stirrer and mercury bubbler was charged with HPth (0.21 ml, 1.2 mmole) and THF (2 ml). The solution was stirred and equilibrated to 0°C, and n-BuLi (1.6 M hexane solution, 0.75 ml, 1.2 mmole) was added dropwise by means of a syringe. After 15 min at 0°C with stirring, the reaction mixture was allowed to warm up to room 92 temperature. To the solution was added 2-methylcyclohexanone (0.12 ml, 1 mmole), and stirred for additional 20 minutes. To the resulting solution was added Mel (5 mmole), and the reaction mixture was allowed to react for 1 hour at room temperature. The solvent was removed under reduced pressure, and CDCI3 (2 ml) was added. The reaction mixture was transferred to a centrifuge tube via syringe. Centrifugation resulted in the separation of the silyl enol ether solution from LiCl, which was transferred to an NMR tube for analysis. 2. LiPth/cyclohexanone / Mel Using the procedure described above the combination of cyclohexanone and LiPth and Mel at room temperature gave alkylation product. 1H NMR (CDCI3) : 0.2 (s, 9H) ; 4.3 (d, 1H, J=1.5 Hz) ; 4.86 (d, 1H, J=1.5 Hz) ; 7.1-7.4 (m, 3H) ; 7.4-7.7 (m, 2H) 3. LiPth/2-methylcyclohexanone / BnBr Using the procedure described above the combination of 2- methylcyclohexanone and LiPth and BnBr at room temperature gave alkylation product. 1H NMR (CDCI3) : 0.95 (s, 3H) ; 1.4-2.0 (m, 6H) ; 2.2-2.6 (m, 2H) ; 2.78 (s, 2H) ; 6.9-7.3 (m, 5H). (1) Acylation of ketone enolate A 10 ml round bottom flask equipped with septum inlet, magnetic stirrer and mercury bubbler was charged with HPPh2 (0.21 ml, 1 2 mmole) and THF (2 ml). The solution was stirred and equilibrated to 0°C, and n-BuLi (1.6 M hexane solution, 0.75 ml, 1.2 mmole) was 93 added dropwise by means of a syringe. After 15 min at 0°C with stirring, the reaction mixture was allowed to warm up to room temperature. Acetophenone (0.12 ml, 1 mmole) was added and stirred for 20 minutes. To the resulting solution was added acetic anhydride (0.47 ml, 5 mmolee), and the reaction mixture was allowed to react for 1 hour at room temperature. The reaction mixture was hydrolyzed with 10 ml of water and extracted with ether, dried over Na2SO4. Ether was removed under reduced pressure. The crude product was submitted for 1H NMR analysis. 1H NMR (CDCI3) : O-alkylation 2.2 (s, 3H), 4.9 (d, 1H), 5.35 (d, 1H), 7.1-7.5 (m, 5H). C-alkylation 2.13 and 2.24 (both 3, 3H), 4.03 (s, 1H), 6.12 (s, 1H), 7.2-7.5 (m, 3H), 7.65 (m, 2H). (J) Aldol reaction of ketone enolate A 10 ml round bottom flask equipped with septum inlet, magnetic stirrer and mercury bubbler was charged with HP(t-Bu)2 (0.22 ml, 1.2 mmole) and THF (2 ml). The flask was placed in an ice bath, and n-BuLi (1.6 M hexane solution, 0.75ml, 1.2 mmole) was added slowly by syringe. After 15 min at 0°C with stirring, the reaction mixture was allowed to warm up to room temperature, and then recooled in a dry-ice bath. To the solution was added 3-pentanone (0.1 ml, 1 mmole), and the reaction mixture was allowed to react for 1 hour at -78°C. To the resulting solution was added benzaldehyde (0.1 ml, 1 mmole), and the solution was stirred at -78°C for 1 hour. The reaction mixture was allowed to warm up slowly to room temperature. The reaction mixture was hydrolyzed with 10 ml of water and extracted with ether, dried over NazSO4. 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