(”A _\_x '—I I _cn4>.c> T..- ("gage 1'13“ijunnxuwum $61 h “g,- “8‘381fi‘3 Ll&;§V@?3‘H“$ l #J This is to certify that the dissertation entitled nsmr LIBRARIES \\| \\ \\\\\ Chapter I The Synthesis and Reactions of Sterically Hindered Silyl Enol Ethers Chapter II The Reactions of a-Azido Esters with Base Chapter III The Phenylation of Ketone Enolates with Diphenyliodonium Salts presented by Paul A. Manis has been accepted towards fulfillment of the requirements for Ph . D . degree in Chemistry Major professor Date February 25, 1982 MS U is an Affirmative Action/Equal Opportunity Institution / \ _ ’ . ,-' y . 1 ' fi/yf/l .fi ‘/ . / .. H" (y 0-12771 MSU LIBRARIES “ BEIURNING MATERIAL§z Place in book drop to remove this checkout from your record. FINES will be charged if book is returned after the date stamped below. CHAPTER I THE SYNTHESIS AND REACTIONS OF STERICALLY HINDERED SILYL ENOL ETHERS CHAPTER II THE REACTIONS OF G~AZIDO ESTERS WITH BASE CHAPTER III THE PHENYLATION OF KETONE ENOLATES WITH DIPHENYLIODONIUM SALTS By Paul A. Manis A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1982 ABSTRACT CHAPTER I THE SYNTHESIS AND REACTIONS OF STERICALLY HINDERED SILYL ENOL ETHERS CHAPTER II THE REACTIONS Oth—AZIDO ESTERS WITH BASE CHAPTER III THE PHENYLATION 0F KETONE ENOLATES WITH DIPHENYLIODONIUM SALTS By Paul A. Manis I, A new class of highly hindered silylating agents for ketones has been developed and utilized in the synthesis of silyl enol ethers. Applications of these sterically hindered silyl enol ethers in synthe- sis and their stability relative to standard silyl enol ethers have been explored. }_I_. The reactions of a-azido esters with various bases have been explored. These a-azido esters are found to react with catalytic amounts of lithium ethoxide to form biologically interesting dehydro- amino esters, and, after hydrolysis, ‘32 L = Leaving Group 1 R the reagents that have been used to perform this reaction include chlorotrimethylsilane with base“), trimethylsilyl iodide with base”, Br Br? ‘;_v RCHO TiCl OH Figure 1. VI 0 Ph C+BF CH 01 OTMS TiC CHZC OH ArCO H 3CCl 1n 12 -73° + 1) CHZ-N Me 2) CHBI,[§ 1 ) A80Ac I2 CH2C12 2) Et3NHF 2 o ' OAc Some Reactions of TMS Enol Ethers hexamethyldisilazane with imidazole12, trimethylsilyl triflate13, big- trimethylsilyl acetamidem, N,N-dimethylamino trimethylsilane15, and ethyl trimethylsilyl acetatejé. ‘This diversity of reagents provides easy access to TMS enol ethers; unfortunately, TMS enol ethers are very susceptible to hydrolysisna’b , and this limits their usefulness. The stability of silyl enol ethers to hydrolysis may be improved by synthe- sis of the tert-butyldimethylsilyl derivatives £77 (eq 2); these more 0 H 0,31Me2'g-Bu R R + _t-BuSiMe2C1 431-) R ‘2 RB a 1,3 hindered silyl enol ethers are hydrolysed much more slowly than the TMS derivatives17a’b. However, the requisite ‘tggtebutyldimethylsilyl (TBDS) chloride is considerably more expensive than the corresponding trimethylsilylating reagent18. We therefore desired to develop a hindered silylating agent which would give enol ether derivatives with a hydrolytic stability similar to TBDS derivatives, but at a more reason- able cost. TBDS chloride is prepared by the reaction of .t_e_r:_t_-butyllithium with dichlorodimethylsilane19 (eq 3). The necessity for using the alkyllithium reagent to form the carbon-silicon bond is the major reason (CH3)231012 + (CH3)3CLi ———> (CH3)3031(CH3)201 (3) for the high cost of TBDS chloride. It has been known for some time that the silicon-chlorine bond is easily replaced by a silicon-oxygen bond through reaction with alco- hols20 (eq u). Since there are many commercially available inexpensive 31m“ + nROH —> SiCl(u_n)(OR)n (u) alcohols, the reaction of an apprOpriate hindered alcohol with a silyl chloride would appear to be an alternative to the use of alkyllithium reagents. In addition, replacement of an Si-C bond with an 81-0 bond might alter the properties of silyl enol ethers due to overlap of oxygen lone pairs with the empty silicon d-orbitals. We proposed to react a hindered, inexpensive alcohol with a silyl chloride to obtain a silyl- ating agent for ketones. RESULTS AND DISCUSSION 2,6-Di-tert-butylphenol is a commercially available and inexpen- sive alcoh0121. Reaction of this phenol with dichlorodimethylsilane and triethylamine in refluxing acetonitrile gave a 75% yield of the desired (2,6-di-tert-butylphenoxy)dimethylsilyl chloride (DPS chlor- ide, 3, eq 5). It was our hope that the hindrance afforded by the large 0/Si(CHB)201 Et3N + (CH3)231C12 W (5) A 5 di-tert-butylphenoxy substituent would allow the synthesis of hindered, hence more stable, silyl enol ethers. The white, crystalline DPS chloride was reacted with cyclohexanone according to the procedure of 11 Duboudin in an attempt to synthesize the silyl enol ether 3 (eq 6). Si(CH3 )2\ O NaI E i + CHBCN ‘-‘ This procedure, which has been used to synthesize trimethylsilyl enol ethers, is thought to generate a complex silylating reagent 2 more ... [CHBCNSiRB] I 5 potent than the silyl chloridezz. After 3 hours, a mixture of the desired 3 and cyclohexanone was observed by GLC in approximately equal amounts. An increase in the reaction time to 6 hours resulted in complete reaction, and after aqueous workup, 3 was isolated in 87% yield. We then compared the rate of acid induced hydrolysis of 3 with the corresponding TBDS enol ether (eq 7). The DPS enol ether proved to be more resistant to acid hydrolysis than the TBDS derivative. OR CH3COZH/THF/H2 O (7) 3: 1:1 TBDS 1 h 90% DPS 1 h 10% In order to replace the use of TMS enol ethers, DPS enol ethers must undergo the same reactions in comparable yields. We decided to 23 of silyl enol ethers to see investigate the tert-butylation reaction if'fl underwent reaction in a.manner comparable to the TMS enol ether (eq 8). The results were disappointing, only 151 of the desired uptert- butylcyclohexanone was observed; the remainder of the material was TiClu.q fl) (8) CH2012 5_ + (CH3)3CC1 recovered as cyclohexanone. These results were not improved by varying the Lewis acid employed, reaction temperature or time. We considered that the poor yields might be due to competing tert-butylation of the aromatic ring (eq 9). The acid thus generated could hydrolyze enol /Si(CH3 )\ /Si(CH3)2\ TiClu (CH3)3001 Si(CH ) 0/ 3 2\O -H A 7 ether 3, accounting for the large amount of recovered ketone. If this was indeed the case, an obvious solution would be to replace the 2,6- disubstituted phenol with a 2,”,6-trisubstituted phenol. The reaction of 2,”,6-trietggt-butylphenol, also a commercially available and inex- pensive alcoholzu, with dichlorodimethylsilane provided (2,“,6-tri- M—butylphenoxy)dimethylsilyl chloride (TPS chloride, g) in 93% yield (eq 10), as a white crystalline solid (mp 79-8000). Silyl chloride Q o’ 31(CH3 )2 c1 Et 3N W (10) when reacted with cyclohexanone in the presence of triethylamine gave (CH3)281C12 + the silyl enol ether la in 91% yield (eq 11). Compound 1a, reacts with O OTPS Et3N 6 + NaI 5 (11) CHBCN A E tert-butyl chloride to give the corresponding a-tert-butyl ketone in 831 yield (eq 12). This marked improvement in yield would appear to support the hypothesis outlined in equation 9. TiClu E + (CH3)3CC1 W (‘2) -78° 83% Next, the hydrolytic stability offlZa was compared to the correspon- ding TMS and TBDS enol ether derivatives under a wide variety of conditions. The results are summarized in Table I. It can be seen that the TPS enol ether is markedly more resistant to acid hydrolysis than the TMS enol ether. In fact, hydrolysis conditions B demonstrate that the TPS enol ether is even more resistant to acid hydrolysis than the TBDS derivative. These results demonstrate the potential of the TPS enol ethers as a protecting group for ketones. The last entry in Table I demonstrates that KF on Celite in acetonitrile is capable of removing the TPS group to regenerate the ketone quantitatively. The TPS group can thus be introduced and removed efficiently. The general nature of the synthesis of TPS enol ethers was demon- strated by the reaction of TPS chloride with several ketones. These results are summarized in Table II. TPS enol ethers are obtained in good to excellent yields. As expected, mixtures of stereoisomers were obtained where such mixtures are possible (of. If, 1h). The regiochemi- cal aspects of this reaction were not examined. Where a single isomer is obtained, the product is a.white, crystalline solid which can be stored, apparently indefinitely, without special protection from moisture or air. In this respect, TPS enol ethers are a distinct improvement over TMS enol ethers. An extension of the tert-butylation reaction (eq 12) Table I. Cleavage of Silyl Enol Ethers Cleavage Reaction Silyl Enol Ether Conditionsa Time (h) 1 Ketoneb A 6 100 B 0.25 100 C 1 5 A 1 B 0.25 80 B 1 100 C 1 O A 1 OTPS A 6 B 0.25 10 B 1 70 B 2 100 1 O 12 c D 1 100 aA: HOAc/THF/H o, 1:10:1; B: THF/1 M HCl (aq), 20:1; c: THE/1 M NaOH (aq), 20:1; : KF on Celite 1:1, 2 M in CHBCN. Reactions mixtures with solutions A, B, and C are homogeneous. bDetermined by GLC using an internal standard (see experimental). 10 Table II. Formation of TPS Enol Ethers Reaction 0 b Ketone Timea, h Product mp c 1 Yield 0 1 OTPS 66-68 88 ..2 1 [OTPS 69.5-70.5 91 Illill llill .3 o 8 OTPS 87.5-88.5 81 V f .9 o 1.5 OTPS 51-52 92 11g f 2 ,OTPS 65.6-67 91 Table II (cont'd) W W WA Ph \)\, OTPS 7N-75 ‘\\ 15 OTPS oil ' .732 OTPS ///L§§s Ph 71 OTPS ~\\ 85-86 Ph 11 73 95 86° 87 a b Reaction times are not optimized. Yield of isolated product after purification. 0Mixture of E and Z isomers. 12 to some of the enol ethers described in Table II, resulted in the synthesis of severalat-tert-butyl ketones (Table III). The results are comparable to those obtained for TMS enol ethers23. Finally, we investigated the trityl tetrafluoroborate oxidation of silyl enol ethers to the corresponding enones3a (eq 13). A major 0R O “x + Ph3C+BFu' CH2C12 ' (13) H problem with this reaction sequence is recovery of unoxidized ketone. While the source of the ketone has not been determined, it appears to arise from fluoride cleavage of the Si-O bondzs. Use of the TPS enol ethers appears to offer improved results over the TMS derivatives (Table IV, reference 3a) These reactions demonstrate that TPS chloride is a valuable hin- dered silylating agent for ketones, and that TPS enol ethers are a viable alternative to TMS and TBDS enol ethers in t-butylation and oxidation reactions. Finally, there are a number of very inexpensive hindered phenols such as butylated hydroxy toluene (BHT, g) and butyla- ted hydroxy anisole (BRA, 19), that are currently used in foods as antioxidants, which could be expected to provide silylating reagents with similar properties to TPS chloride at an even lower cost. OH OH 9 1O ' —' -— OCH 13 Table III. ‘teButylation of TPS Enol Ethers Silyl Enol Ether Product Yield ($) 0 £22 0 §2 O _8_c O J_q 79 g o 1“ Table IV. Oxidation of TPS Enol Ethers Yield (i) Silyl Enol Ether Enone Ketone 0B R = ms3a 50 15 R = TPS 55 10 OR = ms3a 6:: 3a 33 R = TBDS 35 5 R : TPS 91 6 OH R = ms3a 60 18 R = TPS 75 10 aYield determined by GLC (see experimental). 1 5 EXPERIMENTAL Acetonitrile, triethylamine, and all ketones were distilled from calcium hydride before use and stored under argon. _t_e_r_~t-Butyl chloride, titanium tetrachloride, and dichlorodimethylsilane were distilled be- fore use and stored under argon. Sodium iodide was flame-dried under vacuum imediately before use. Acetonitrile, triethylamine, aceto- phenone, and sodium iodide were obtained from Fisher Chemical. 3- Pentanone and 2,6-dimethyl-ll-heptanone were obtained from Matheson Coleman and Bell. Titanium tetrachloride was purchased from Alfa- Ventron. All other ketones, 2,6-di-tggt—butylphenol, 2,1},6-tri-_t_e_r_t_- butylphenol, Belt-butyl chloride, chlorotrimethylsilane, and dichloro- dimethylsilane were obtained from Aldrich Chemical Co.. M-Butyldi- methylsilyl chloride was prepared by the method of Corey19. TMS and TBDS enol ethers were prepared by the method of Duboudin“. Trityl tetrafluoroborate was prepared according to the procedure of Dauben26. All reactions were carried out under an argon atmosphere. Gas chromato- graphic analyses were performed on a Varian 920 chromatograph equipped with a ll ft x 0.25 in column packed with 15% 88-30 on acid-washed Chromsorb P (except where noted). 1H NMR spectra were recorded on Bruker WM-ZSO and Varian T-60 spectrometers at 250 MHz and 60 MHz respectively with CDCl3 as the solvent and are reported in parts per million in the 6 scale relative to internal MeuSi. Infrared spectra were recorded on a Perkin-Elmer 237 B spectrometer as solutions with CHCl3 as the solvent and a polystyrene standard. Low resolution electron impact mass spectra were obtained with a Finnegan l4000 GC/MS at 70 eV. High resolution mass spectra were obtained with a Varian CH-S 16 double-focusing mass spectrometer at the Michigan State University Department of Biochemistry Mass Spectrometry Faciltiy. Elemental anal- yses were performed by the Spang Microanalytical Laboratory, Eagle Harbor, MI. Melting points were taken on a Thomas-Hoover capillary melting point apparatus and are uncorrected. Boiling points are uncorrected. Preparation of DPS Chloride (31 Triethylamine (38.5 mL, 275 mmol), 2,6-di-t_erl-butylphenol (51.6 g, 250 mol) and dichlorodimethylsilane (311.1 mL, 275 mmol) were dissolved in 300 mL of acetonitrile then heated under reflux for 21 h. The solution was cooled, filtered, and the filter cake washed with 100 mL of ether. The solution was concentrated E 11922 and combined with the ether wash. The combined solutions were filtered, then concentrated in w. The crude yellow solid obtained was recrystallized from heptane, affording 55.8 g (75%) of DPS chloride as white prisms: mp 1 95.5-96°C; H NMR (60 MHz) 6.62-7.23 (m, 3H), 1.u2 (s, 18H), 0.70 (s, 6H); EI-MS m/e 298 (M‘), 283. 297, 191, 175, 131, 93, 75, 57. Preparation of_§yclohexanone DPS Enol Ether (u) Triethylamine (21 mL, 150 mmol), cyclohexanone (10.4 mL, 100 mmol), and DPS chloride (30 g, 100 mmol) were added to a suspension of sodium iodide (15 g, 100 mmol) in 100 mL of dry acetonitrile. The mixture was stirred for 6 h at room temperature, then diluted with 250 ml of ether and washed with water (2 x 100 ml). The ether solution was dried with MgSOu, then concentrated Q V3029 The residue was distilled (Kugelrohr) affording a clear, colorless, highly viscous oil: bp 1600 17 (0.05 torr); 1H NMR (60 MHz) 6.56-7.23 (m, 3H), “.78 (m, 1H), 1.20-2.20 (m, an), 1.38 (s, 188), 0.35 (s, 6H); CI-MS (0H,) m/e 801 (M+u1), 389 (1929). 361 (M + 1), 3‘15. 333, 305, 252. 2‘17. Hydrolysis Studies: Cyclohexanone DPS Enol Ether H vs. TBDS Enol Ether 5 mmol of each silyl enol ether was dissolved in 5 mL of a 3:1:1 solution of acetic acid/water/THF. After 1 h, a decane standard was added, the solution was extracted with 10 mL of ether, and analyzed for cyclohexanone by GLC. The DPS enol ether was less than 10% hydrolyzed while the TBDS enol ether was nearly completely (> 90%) hydrolyzed. .tert-Butylation of Cyclohexanone DPS Enol Ether u 23b This procedure was adopted from the work of Chan, gt El- . tert- Butyl chloride (0.60 mL, 5.5 mmol) was dissolved in 5 mL CHZClZ and cooled to -78°C. Titanium tetrachloride (0.60 mL, 5.5 mmol) was added. To this mixture was added dropwise asolution of cyclohexanone DPS enol ether (1.80 g, 5.0 mmol) in 3 mL of “’2“? 1 h at -78°C,then quenched with 10 mL of water. The organic layer was The solution was stirred for washed with 2 x 10 mL water, dried with MgSOu, and analyzed by GLC after addition of standard. a-Egt—Butylcyclohexanone was present in 13% yield, while cyclohexanone was present in #01 yield. These results were virtually unchanged by longer reaction time, higher temperatures (-fl0°, 0°, 25°), changes in concentration, or use of excess Eggt-butyl chloride or titanium tetrachloride. 18 Preparation of (2,u,6-Tri-tert-butylphenoxy)dimethylsilyl Chloride 2,“,6-Trigtggtebutylphenol (131 g, 0.5 mol), triethylamine (8“ mL, 0.6 mol) and dichlorodimethylsilane (67 mL, 0.55 mol) were dissolved in 500 mL of acetonitrile and refluxed overnight. The reaction was then allowed to cool to ambient temperature, and concentrated in 13229. The residue was dissolved in 500 mL of pentane, and washed (3 x 100 mL) with water. The solution was dried with MgSOu, decolorized with Norit-A, and filtered through Celite. The clear, lightly colored solution was concentrated, giving 165 s (931) of.3 as white crystals: mp 79-8100; 1H NMR (250 MHz) 7.28 (s, 2H), 1.hu (s, 18H), 1.30 (8,9H), 0.73 (s, 6H); 1 IR 29115, 11120, 1260, 1200, 1120 cm. ; EI-MS m/e 3511 (14”). 339. 303. The crystals may be recrystallized from heptane giving white needles melting at 80-81°C. He found that this last step was unnecessary for subsequent use of 3 to prepare silyl enol ethers. Anal. Calcd for C20H3SOSiC1: C, 67.77; H, 9.9“; 0, ”.51; Cl, 9.99; m/e 35M.2186. Found: C, 67.68; H, 10.05; 0, ”.38; Cl, 9.85; m/e 358.2152. General Procedure for Preparation of TPS Enol Ethers (7) TPS Enol Ether of Acetophenone (7i) Acetophenone (2.92 mL, 25 mmol), triethylamine (6.3 mL, 37.5 mol), sodium iodide (11.95 g, 27 mmol), and TPS chloride (8.9 g, 25 mmol) were dissolved in 25 mL of acetonitrile and refluxed for 3 h. After cooling to ambient tempera- ture, the mixture was diluted with 50 mL of pentane, and washed 2 x 25 mL with water. The organic layer was dried (MgSOu) and concentrated in ‘33329. The residue was purified by either bulb-to-bulb distillation or recrystallization13 from hexanes giving 9.9 g (86.1) of ii as white 19 1 crystals: mp 96-96.5°c; H NMR (250 MHz) 7.05-7.67 (m, 7H), 8.90 (d, 1H, J=2.5 Hz), 8.85 (d, 1H, J=2.5 Hz), 1.83 (s, 18H), 1.28 (s, 9H), 0.83 (s, 18 GB); IR 1665 cm“ (0:0); CI-MS m/e 879 (M+81), 867 (M+29), 839 (M + 1), 823, 383. Anal. Calcd for C 0231: C, 76.66; H, 9.65; 0, 72.9; 28333 Si, 6.80; m/e (M-57) 381.2250. Found: C, 76.56; H, 9.71; 0, 7.02; Si, 6.86; m/e (M-57) 381.2237. Using the same procedure, the following TPS enol ethers were prepared: TPS Enol Ether of Cyclohexanone (7a) 9.5 g (91%), white crystals: 1H NMR (250 MHz) 7.25 (s, 2H), 8.88 (m, 1H), 1.2-2.1 (m, .mp 69.5-70.5°c; 8H), 1.83 (s, 18H), 1.29 (s, 9H), 0.37 (s, 6H); IR 1665 cm“ (0:0); EI- MS m/e 816 (14*), 801, 360, 385, 303, 155, 75, 57. Anal. Calcd for 0268,“,0231: 0, 78.98; H, 10.68; 0, 7.68; 31, 6.73; m/e 816.3111. Found: C, 75.08; H, 10.69; 0, 7.79; Si, 6.88; m/e 816.3181. TPS Enol Ether of Cyclopentanone (7b) 8.8 g (881), white crystals: mp 66-68°C; 1H NMR (250 MHz) 7.25 (s, 2H), 8.68 (m, 1H), 1.2-2.8 (m, 6H), 1.88 (s, 18H), 1.29 (s, 9H), 0.39 (s, 6H); IR 1685 cm-1 (0:0); EI- MS m/e 802 (11*), 387, 331, 303, 287, 75, 57; mass spectrum, calcd 802.2958, obsd 802.2959. TPS Enol Ether of 2,6-Dimeth11cyclohexanone (70) 9.0 g (81%), white crystals: mp 87.5-88.50C; 1 H NMR (250 MHz) 7.26 (s, 2H), 1.2-2.2 (m, 7H), 1.57 (s, 3H), 1.85 (s, 18H), 1.30 (s, 9H), 1.06 (d, 3H,.J=:6.8 Hz), 0.36 (s, 3H), 0.28 (s, 3H); IR 1680 cm“ (0:0), EI-MS m/e 888 (11*), 387. 303, 75, 57. Anal. Calcd for 028H880231‘ c, 75.51; H, 10.33; 0, 7.19; Si, 6.31; m/e 888.3828. Found: C, 75.81; H, 10.78; 0, 7.18; Si, 6.38; m/e 888.3821. 20 TPS Enol Ether of Cycloheptanone (7d) 9.9 g (92%). white crystals: 1 mp 51-52°c; H NMR (250 MHz) 7.25 (s, 2H), 5.01 (t, 1H, J=6.7 Hz), 1.2- 2.3 (m, 10 H), 1.83 (s, 188), 1.29 (s, 98), 0.36 (s, 6H); IR 1650 cm"1 (0:0); EI-MS m/e 830 (8*), 815, 373. 303, 169, 75, 57; mass spectrum, calcd 830.3267, obsd 830.3278. TPS Enol Ether of Cyclooctanone (7e) 10.1 g (911), white crystals: mp 65.5-67°C, ‘ H NMR (250 MHZ) 7.25 (s, 2H), 8.77 (t, 1H, J=8.8 Hz), 1.2-2.3 (m, 128), 1.88 (s, 18H), 1.29 (s, 9H), 0.36 (s, 6H); IR 1660 cm"1 (C:C); EIAMS m/e 888 (M*), 829, 387, 336, 321; mass spectrum, calcd 888.3828, obsd 888.3861. TPS Enol Ether of 3-Pentanone (7r) 7.8 g (73%), oil consisting of E and z isomers; bp 120°C (0.2 torr); 1H’NMR (60 MHz) (partial) 8.63 (q, J=6 Hz) and 8.55 (q, J=6 Hz) E and Z vinyl H; IR 1670 cm-1 (C=C); EI-MS m/e 808 (M+), 389, 387, 319, 303, 183, 75, 57; mass spectrum, calcd 808.3111, obsd 808.3110. TPS Enol Ether of 2,8-Dimethy1-3-pentanone (7g) 10.3 g (95%), white crystals: mp 78-750C; 1 H NMR (250 MHz) 7.26 (s, 2H), 2.87 (m, 1H, J=6.6 Hz), 1.68 (8, 3H), 1.65(8, 3H), 1.88 (8 18H), 1.30 (8, 9H), 0.93 (d, 6H, J=6.6 Hz), 0.30 (s, 6H); IR 1670 cm”1 (C=C); EI-MS m/e 832 (M), 817, 376, 319, 303, 263, 75; mass spectrum, calcd 832.3828, obsd 832.3808. TPS Enol Ether of 2,6-Dimethyl-8-heptanone (7h) 9.9 8 (86%), oil consisting of E and Z isomers; bp 160°C (0.2 torr); 1 H NMR (60 MHz) (partial) 8.53 (d, J=9.9 Hz) and 8.31 (d, J=9.8 Hz) E and 2 vinyl H; EI- MS m/e 860 (M7), 885, 803, 321, 303, 287, 75, 57; mass spectrum, calcd 860.3737. obsd 860.3783. 21 TPS Enol Ether of Isobutyrophenone (73) 9.5 g (81%). white crystals: mp 85-86°c; 18 NMR (250 MHz) 7.2-7.8 (m, 78), 1.77 (s, 38), 1.67 (s, 3H), 1.85 (s, 18H), 1.29 (s, 9H), 0.086 (s, 6H); IR 1660 cm"1 (0:0); EI-Ms m/e 866 (8*), 851, 809, 353. 303, 205, 131, 75. 57; mass spectrum, calcd 866.3267, obsd 866.3271. Hydrolysis Studies These studies were conducted on the TPS, TMS, and TBDS enol ethers of cyclohexanone by dissolving 1 mmol of silyl enol ether in 2.5 mL of solution A, B, C, or D. After the indicated time, the standard, decane, was added and 10 mL of ether was used to extract the solution (except for solution D, which was anlayzed directly), the solution was washed with 1 x 5 mL of H 0, dried with MgSOu, and analyzed 2 by GLC. General Procedure for the Preparation of a-tert-Butylketones 823b a-tert-Butylcyclohexanone (8b) Cyclohexanone TPS enol ether (2.08 g, 5.0 mmol) and Eggt-butyl chloride (0.60 mL, 5.5 mmol) were dissolved in 5 mL of CH2C12 and cooled to -78°C. Titanium tetrachloride (0.60 mL, 5.5 mmol) was added dropwise and the solution stirred for 2 h at -78°C. The reaction was quenched with 5 mL of water and warmed to room temperature. The organic layer was dried with.MgSOu and analyzed by GLC relative to a hexadecane standard, indicating the presence of 975232- butylcyclohexanone in 83% Yield. 01 -tert-Butylcyclopentanone (8a) This compound was prepared as above. GLC analysis showed'afitgrt-butylcyclopentanone in 71! yield. <1-tert-Butyl-2,6-dimethylcyclohexanone (80) This compound was pre- pared as above. GLC analysis showed 89 in 76% yield. a-tert-Butylcycloheptanone (8d) This compound was prepared as above. GLC analysis showed 8g in 79% yield. 22 a-tert-Butylcyclooctanone (8e) This compound was prepared as above. GLC anlaysis showed 8_e in 83% yield. General Procedure for the Trityl Tetrafluoroborate Oxidation of TPS Enol Ethers38 Trityl Tetrafluoroborate Oxidation of 7a A solution of fl (2.08 g, 5 mol) in 2.5 mL of CH Cl was added dropwise to a suspension of trityl 2 2 tetrafluoroborate (1.80 g, 5.5 mmol) in 2.5 mL of CH Cl over 1 min at 2 2 25°C. After 10 min the reaction was quenched with 10 mL of water. The 01-12012 layer was dried (MgSOu) and the internal standard, n—hexadecane, was added. GLC analysis (8 ft x 0.25 in column packed with 15% Carbowax 20 M terephthalate on Chromsorb W) showed cyclohexenone (91%) and cyclohexanone (6%). Oxidation of 7b Cyclopentanone TPS enol ether was reacted as above. GLC analysis (as above) indicated the presence of cyclopentenone (751) and cyclopentanone (15$). Oxidation of 7c 2,6-Dimethylcyclohexanone TPS enol ether was reacted as above. GLC analysis (as above) showed 2,6-dimethyl-2— cyclohexenone (821) and 2,6-dimethylcyclohexanone (131). CHAPTER II THE REACTIONS OF G-AZIDO ESTERS WITH BASE INTRODUCTION a-Keto esters 11a and acids 1113 are molecules of biological lkyl 27 significance. They are the biological precursors to amino acids , and have also been isolated as steroid metabolitesza. In addition, these compounds have been employed as synthons for the construction of side chains of biologically active B-lactamszg, and in the synthesis of dipeptidesBO. However, methodology for the synthesis of this important functionality is somewhat limited in its utility and generality. Class- ically, a -keto acids have been prepared by the hydrolysis of acyl cyanides31 (eq 18), the hydrolysis of oxime esters32 (eq 15), the O O RgBr + CuCN-4> RgCN H30+ RgCO H 8 A a 2 (1) 60-87% 75% 23 28 g- on 1 HCOZH a R1 RgCO H R- -C02R 8030208 R0002 -—————-—e> 2 (15) 0-90 Z hydrolysis of oxalo acid esters33 (eq 16) and by reaction of Grignard N" 11 EtOCCOEt + R0820028 £993) EtOCCCHRCO H H2808 2 =. _1_3_b_ (16) 8-98 Z reagents with diethyl oxamatesBu (eq 17). In addition, various Specific 00 00 00 nu "8 "H H 0* 11b (17) RM x EtOCCOEt + HNEtz-Z-eK EtOCCNEt2 «———5—-5> RCCNEt2 3 a -——- 60$ syntheses have been developed32’35 36, and the dimethyl sulfoxide oxidation of an , including the permanganate oxida- tion of an u-hydroxy acid a-bromo ester37. The generality of these particular reactions has not been explored. Some more recent developments include the selenium 38 and methyl ketones39, the oxida- dioxide oxidation of ArCCOZH (18) 2 1’ N ... I 27-95% 25 ' 1 13131 ROCCOR + R ng———> R 00R (19) 65-93% 82 83a alkyl a-oxo-1 H-imidazole-1-acetates (eq 20). Both Seebach and ROgfl—f 1 88 + R ng -—-——€> RCCOR (20) / 22-771 'Eliell'3b have used metallated dithianes derived from ethyl glyoxalate as an acyl anion equivalent in the synthesis ofcx-keto esters and acids (eq 21). This method would clearly be unsuitable for R = aromatic, as O 1) Base f//~\\] N—Bromo \. l E;;:;;L Ej—§§‘_" S Succinimide " RLCOZEt (21) S H CO Et :>‘<; 2 R C028t well as cases where competing elimination of HX becomes a factor (20 & 3° Rx). Neef and Eder report the use of the anion from 0,0-dimethyoxy methylacetate in aldol condensations with ketonesuu (eq 22). Dehydra- tion, reduction, and deketalization completes the synthesis of a-keto O OH (0M9)2 1) H 0+ 0 - 1 a (Me0)20002083 + RULRZ-w RR0—00028e 37%» R1R2CC02Me (22) 26 esters but the authors report that these are not trivial reactions, and yields are often poor. A potentially useful synthesis of a-keto esters involves the osmium tetroxide oxidation of alkynyl ethersu5 (eq 23). 0 .. 1 0“’08 1' 1 R 0 ..-. 0—0R '—_9K010u R0002R ( 23) 80% However, osmium tetroxide is extremely toxicué, and the utility of catalytic quantities of’osmium in this sequence has yet to be demonstra- ted. Of all the previously mentioned syntheses, only the dimethylsulf- oxide oxidation of a-bromo esters37 involves manipulation at the 01- carbon of an ester containing all of the carbon atoms present in the target a-keto ester. This procedure has only been applied successfully in the reaction of ethyl a-bromo (or chloro) acetate and propionate; there is a report that it fails for more complicated moleculesu7. We decided that a desirable procedure for the synthesis of a—keto esters would involve performing chemistry at the a-carbon of a readily avail— able ester precursor. M.O. Foster extensively investigated the chemistry of a—azido esters 2 almost seventyfive years ago“. He observed that careful hydrolysis of 12 allowed isolation of the corresponding carboxylates 13, and ultimately, the a-azido acids (eq 28). Further treatment with N 13 I3 ’ 50H a excess RCHCOZH H20 R HCOZK -7aif4> Né + ? (28) 12 13 27 base resulted in evolution of nitrogen, although a full equivalent was not obtained. He suspected the intermediacy of an a-imino acid 18, and for R = Ph was able to isolate benzoyl formic acid (E, R = Ph, eq 25). NH + O KOH “ H3O L3 —-5 RC COZK ———b RCCOZH (25) R = Ph 18 15 It appears that hydroxide is a strong enough base to remove the a- proton from the 0- azido carboxylate to provide an intermediate car- banion which can evolve nitrogen, leading to a species such as 18 which is hydrolyzed to E (eq 26). Although Forster did not attempt to investigate these reactions in detail, it occured to us that by the choice of appropriate reaction conditions, we might achieve a general synthesis of a-keto esters from a—azido esters. .. . _ f! 11—112 N n— N=N NH 1 -111 11 R— 0-0028 Laf’é— 0028 _z_> 800021 R-c HCOZEt (27) 16 'found, however, that the use of N,N-dimethylformamide as the solvent allowed shorter reaction times and also facilitated the isolation of 16. The a-bromo esters are available from the esters by a variety of meansso; therefore, the a-azido esters were quite accessible. We envisioned a sequence such as that described in equation 26, where the base utilized would be chosen such that it would not hydrolyze the ester. We reasoned that the esters would be easier to isolate and handle than the corresponding acids, which could suffer decarboxyla- tion32. Treatment of ethyl-Z-azidopropionate‘11_with triethylamine did not result in evolution of nitrogen even at reflux temperatures (eq 28). N I 3 c a CH3CHCOZEt + Et3N THF No Reaction (28 ) 17 29 The reaction of 11 with one equivalent of sodium hydroxide in aqueous tetrahydrofuran (THF) resulted in hydrolysis of the ester, but no evolution of nitrogen (eq 29). We concluded from these results that a N H 0 I3 _1_7_ + NaOH —3——>THF CH3CHC02Na (29) non-aqueous base system‘was needed, and that simple amine bases were not powerful enough to deprotonate a-azido esters such 33.11: Treatment of 11_wdth lithium diisopropylamide (LDA) in THF at Dry Ice temperature resulted in the evolution of approximately one-half the expected volume of nitrogen. Aqueous workup of the reaction mixture afforded an intractable tar. We concluded that the problem was the instability of the proposed intermediate 1_8_ under the reaction conditions, N I O CH3CCOZR 2 CHBCCOZR (3 ) Under aqueous reaction conditions, 18 should be rapidly protonated (eq 30). With anhydrous LDA/THF, however, this anion would not be proton- ated, and could be expected to react further to give polymeric products. As a result of this reasoning, we concluded that the base used had to be sufficiently powerful so as to remove the a—hydrogen from an a-azido ester and had to provide a conjugate acid capable of protonating the intermediate imine anion 18, We decided initially to investigate sodium 3O ethoxide in ethanol as a base/solvent system. The reaction of _11 with sodium ethoxide in ethanol resulted in slow (8 h) and quantitative evolution of nitrogen. Hydrolysis of the reaction mixture gave a 10% yield of ethyl pyruvate (eq 31). An examination of equation 31 reveals H -NZ N 1_7 + NaOEt———) CH3ECOZEt + EtOH -——>CH31ZCOZEt , (31) H 0* 8 + no“ —5-—> CH 000 Et 3 2 that it should be possible to use a catalytic amount of ethoxide. We also reasoned that the rate of reaction should be increased by the use of a non-protic solvent. This would eliminate the hydrogen bonding present between the base (sodium ethoxide) and solvent, allowing the base to act more effectively. Finally, we switched from sodium to lithium ethoxide because we found it to be very convenient to generate the latter from ethanol and n—butyllithium. Ultimately, we found that treatment of E with 0.1 equivalents of lithium ethoxide in THF resulted in rapid (15 min) and complete evolution of nitrogen. Workup with aqueous acid gave a 50% yield of ethyl pyruvate (eq 32). Several 01— azido esters were treated in this fashion, and a-keto esters were NH 4- I, H 0 17 + 0.1 equivalent LiOEt 333—9 CH 000 Et —-3——> -— 15 min 3 2 17 (32) CH 800 E 3 2 t 50% 31 obtained in good yields (Table V). This procedure appears to be applicable to the synthesis of a variety of a-keto esters. We next turned our attention to the intermediate imino esters (i.e. 12). These compounds are of considerable interest51, because of their 52 postulated intermediacy in amino acid synthesis and their presence in microbial peptidesSB. The methodology for the synthesis of imino (and their tautomers, enamino) esters has been limited to the reaction ofc1- keto esters with Wittig-type reagentssu (eq 33) or elimination of RX 0 NPh NHPh 1| 108000 Et + PhN=PPh —b RR1 1 II | CHCCO Et ‘——, RR 0:000 Et (3 3) RR 2 3 2 2 from appropriately substituted a-amino estersss-57 (eqs 38-36). It has CH SCH Ph CH 2 2 u 2 t-Boc NHCHCOzMe -£L€>.t-Boc NHCCOZMe (38) NH-t-Boc Cl-N-t-Boc R8108-(128 — 1311300131; 1 (1m DBU R1'11gigBoc COzMe NaOMe RR CH- CO2Me -—-—-4> R C C 02Me (35) 1 I-flf-t—Boc 1 RR C=CC02Me 9 OAc 10:88.2 1 R 000281; £3.11.) R108:00022t (36) 880R2 8 O 32 Table V. Formation of a—Keto Esters from a-Azido Esters N3 0 1 LiOEt HCl " RCHCO 2E1; m F269 RCCOZEt .19 _1a reac ion 1 b R time, min yield CH3 15 50 CH3CH2 20 86 (CH3)2CH 3O 98 Ph 2 91 PhCH 85 98c 2 a bTime fer complete evolution of nitrogen at 25°C. GLC yields, determined with internal standard, unless otherwise note . In all cases, removal of solvent left a residue of essentially pure ( H NMR analysis) a-keto ester. cYield of distilled product. 33 also been reported Os-nitro-a,8-unsaturated esters can be reduced di- rectly to the imino esters by treatment with aluminum amalgam in 58 (eq 37). We thought that synthesis of these a - refluxing ether dehydroamino esters from 01 -azido esters would be a general and useful method nicely complementing currently available techniques. N0 NH NH 1 12 1——-*1'Hg 1 '2 4- 1 11 837) RR C: COZE‘C Ether RR C=CC02313 _7 RR CHCCOZEt It seemed to us that omission of the aqueous workup from our a-keto ester synthesis would allow isolation of the dehydroamino esters. Attempts to isolate ethyl 2-iminopropanoate (12) by distillation of unhydrolyzed reaction mixtures were unsuccessful. The pot contents turned dark on heating and eventually formed a nonvolatile tar. How- ever, carefill evaporation of solvent at 25°C from freshly prepared reaction mixtures gave a residue of essentially pure _12 as judged by 1H NMR analysis (the only apparent impurity being lithium ethoxide). Alternatively, addition of triethylamine and acetyl chloride to the unhydrolyzed reaction mixture gave a 601 isolated yield of the corres- ponding N-acetyl derivative _2_Q (eq 38). 9 I O HNCCH CH |(1C1 CH 8C0 at (38) 3 a 38 Mere simply, verification of 9li-dehydroamino ester formation was obtained by reaction of 16 with lithium ethoxide in carbon tetrachloride solution. Direct 1H NMR analysis of the reaction mixtures indicated quantitative formation of 9l-dehydroamlno esters 2_1, R = Me, Et(a mixture of imino and enamino esters was formed), and Ph . In view of the fact that «pazido esters are readily available in two steps from the corresponding ester, this methodology59 appears to offer significant advantages over previously published procedures for the synthesis of both dehydroamino esters and a—keto esters. EXPERIMENTAL THF was distilled from a sodium-benzophenone ketyl still under argon. Other solvents were distilled before use. Acetyl chloride, ethyl 2-bromobutanoate, and 2-bromo-2-phenylacetic acid were obtained from Aldrich Chemical. Ethyl 2-bromo-3-methylbutanoate was prepared by the method of Rathkesoa. 2-Bromo-3-phenylpropanoic acid was prepared by the method of Marvelsob and esterified by standard procedures. All reactions were conducted under argon atmosphere. Gas chromatographic data were obtained on a Varian 920 chromatograph equipped with a 8 ft x 0.25 in column packed with 10% Carbowax 20 M terephthalate on Chromsorb 0.1 H NMR spectra were recorded on a Varian T-60 spectrometer at 60 MHz using CDCl3 as the solvent (except where noted) and are reported in parts per million in the scale relative to internal MeuSi. Infrared 35 spectra were taken on a Perkin-Elmer 237 B spectrometer, using poly- styrene as a reference. Electron impact-mass spectra were obtained at 70 eV with a Finnegan 8000 GC/MS. lMelting points and boiling points are uncorrected. Yields of the azides are not maximized and ranged from 50- 85%. General Procedure for Preparation of Azides (16) Ethyl 2-Azidopropanoateuga (16L_R = Me) Ethyl 2-bromopropanoate (65 mL, 0.50 mol) was added to a suspension of sodium azide (89 g, 0.76 mol) in 50 mL of dimethylfonmamide at 25°C and stirred for 2.5 h. .After addition of 200 mL of water, the solution was extracted with two 50-mL portions of CH2C12. of water, dried (11380"), and concentrated in 29312. Distillation The combined organic layers were washed with 200 mL afforded 51.01 g (72%) of 16 (R = Me) as a clear, colorless oil: bp 36- 80°C (0.5 torr); 18 NMR 8.18 (q, J : 7 Hz, 28), 3.90 (q, J : 7 Hz, 1H), 1.82 (d, J = 7 Hz), and 1.28 (t, J = 7 Hz) (total 6H); IR (neat) 2100 (s, 1 CN3), 1785 (s, 0:0) cm” ; EI-MS m/e 183 (8*), 73, 70, 56, 82. Ethyl 2-Azidobutanoate (16, R = Et) ‘This compound was prepared as above: bp 38-80°C (0.15 torr); 1H NMR 8.20 (0. J : 7 Hz, 2H), 3.73 (t, J = 6 Hz, 1H), 1.82 (m, 2H), 1.30 (t, J = 7 Hz) and 1.00 (t, J = 7 Hz) 1 (total 6H); IR (neat) 2100 (s CNB)’ 1785 (s, C=O) cm. ; EI-MS m/e 157 (8*). 88. 73. 69. 56. Ethyl 01-Azidoisovalerate119b (16, R = (CH ) CH) This compound was 3._2— prepared as above: bp 85-85.5°C (0.35 torr); 1H NMR 8.13 (Q. J = 7 Hz, 28), 3.57 (d, J : 6 Hz, 1H), 2.08 (m, 1H), 1.27 (t, J : 7 Hz) and 1.00 (dd, J : 7 Hz) (total 98); IR (neat) 2090 (s, 083), 1730 (s, 0:0) om'1; EI-MS m/e 171 (8*), 102, 70, 83. 36 89c Ethyl 2-Azidophenylacetate (164 R = Ph) This compound was prepared as above: bp 85-88°C (0.05 torr); 1H NMR 7.28 (s, 5H), 8.87 (s, 1H), 8.08 (q, J = 7 Hz, 2H), 1.10 (t, J = 7 Hz, 3H); IR (neat) 2100 1; EI-MS m/e 205 (8*), 163, 132, 108, 77, 51. 89d (3, 0N3) 1735 (s, C=O) cm- Ethyl 2-Azido-3-phenylpropanoate (16, R = PhCHal' This compound was prepared as above: bp 107-107.5°C (0.05 torr); 1HZNMR 7.10 (s, 5H), 3.8-8.3 (m, 3H), 2.85-3.10 (m, 2H), 1.15 (t, J = 7 Hz, 3H); IR (neat) 2100 (s, CN3), 1700 (s, 0:0) cm'1; EI-MS m/e 219 (8*), 191, 176, 91. General Procedure for Preparation of Dehydroamino Esters (21) Ethyl 2-Iminopropanoate (21, R = Me) Ethanol (0.05 mL, 0.8 mmol) was added to n-butyllithium (1.6 M, 0.32 mL, 0.5 mmol) in hexane. The mixture was dissolved in 5 mL of CClu at 25°C. Ethyl 2-azidopropanoate (16, R : Me) was added dropwise and stirred at 25°C until 125 mL (5 mmol) of Hz was evolved (20 min). Benzene (0.22 mL, 2.5 mmol) was added, and the yield was determined by 1H NMR60 analysis: yield 100%; 1H NMR (CClu) 10.91 (br s, 1H), 8.28 (q, J = 7 Hz, 2H), 2.29 (s, 3H), 1.81 (t, J = 7 Hz, 3H). Ethyl 2-Iminobutanoate (21, R = Et) This solution was prepared as above: yield 100%60 (mixture of imine and enamine); partial 1H NMR 1 (CClu) for imine, 2.68 (q, J = 8 Hz, 2H); partial H NMR (CClu) for enamine, 5.58 (q, 1H, J = 7 Hz), 1.70 (d, 3H, J = 7 Hz). Ethyl 2-Iminophenylacetate (21, R = Ph) This solution was prepared 1 as above: yield 100160; H NMR (CClu) 10.5 (s, 1H), 7.3-8.0 (m, 5H), 8.20 (0, J = 7 Hz, 2H), 0.85 (t, J = 7 Hz, 3H). 37 N-Acetyl-Z,3-dehydroalanine (20) Imine 21 (R = Me) was prepared as above. Triethylamine (0.77 mL, 5.5 mmol) was added and the solution cooled to 0°C. Acetyl chloride (0.58 mL, 5.5 mmol) was added dropwise. The mixture was filtered, concentrated _i_n m9, and the residue purified by bulb-to-bulb distillation, giving 0.82 g (58%) of pale yellow oil; 18 NMR 8.20 (br s, 1H), 6.58 (s, 1H), 5.90 (br s, 18), 8.80 (q, J = 7 Hz, 2H), 2.27 (s, 1H), 1.86 (t, J = 7 Hz, 3H). General Procedure for Preparation of a-Keto Esters (11a) Ethyl 2-Oxobutanoate(11a, R = Et, R' = Et) Ethanol (0.05 mL, 0.8 mmol) was added to n—butyllithium (1.6 M, 0.32 mL, 0.5 mmol) in hexane. The mixture was dissolved in 5 mL of THF and stirred at 25°C. Ethyl 2- azidobutanoate (0.76 mL, 5.0 mmol) was added dropwise. After 20 min at 25°C, 125 mL (5 mmol) of N had evolved, and the reaction was quenched 2 with 2 ml. of 3 N HCl. The solution was extracted with two 10 mL portions of ether. The combined organic layers were dried (KZCOB) and concentra- 1 tedlig vacuo. The yield was 861 as determined by GLC: H NMR 8.13 (Q. J = 7 Hz, 2H), 2.70 (q, J = 7 Hz, 2H), 1.23 (t, J = 7 Hz, 3H), 1.00 (t, J = 7 Hz, 3H); 2,8-DNP, mp 139-180.5°c (lit.61 mp 181-182°0); EI-MS m/e 310 (8*). Ethyl Pyruvate (1181 R = Me, R' = Et) This compound was prepared as above: yield 501; 1H NMR 8.31 (q, J = 7 Hz, 2H), 2.85 (s, 3H), 1.50 62 mp 158.5-155°c); EI- (t, J : 7 Hz, 3H); 2,8-DNP, mp 158.5-155°0 (lit. MS m/e 296 (8*). Ethyl a-Oxoisovalerate (11a, R = (033220”: R' = Et) This compound was prepared as above: yield 981; 1H NMR 8.25 (q, J = 7 Hz, 2H), 3.20 (m, 1H), 1.35 (t, J = 7 Hz, 3H), 1.17 (d, J = 7 Hz, 6H); 2,8-DNP, mp 38 63 172.5-173.5°0 (lit. mp 171.5-172°0); EI-MS m/e 328 (8*). Ethyl Phenylglyoxlate(11a, R = Ph, R' = Et) This compound was prepared as above: Yield 91%; 1H NMR 7.20-8.00 (m, 5H), 8.37 (9. J = 7 68 Hz, 2H), 1.23 (t, J : 7 Hz, 3H); 2,8-DNP, mp 161-162.5°0 (lit. up 162- 163.5°0); EI-MS m/e 358 (8*). Ethyl Phenylpyruvate (11a, R = PhCH,u R' = Et) This compound was prepared as above. The residue was purified by bulb-to—bulb distilla- tion, affording a 981 yield of clear, light yellow oil identified as the 65, 1 keto ester containing a small amount of enol H NMR of keto form, 7.25 (s, 5H), 8.30 (q, J = 7 Hz, 2H), 8.15 (s, 2H), 1.80 (t, J = 7 Hz, 66 3H); 2,8-DNP, mp 132.5-133°0 (lit. mp 132.5-133°0); EI-MS m/e 372 (8*). CHAPTER III THE PHENYLATION OF KETONE ENOLATES WITH DIPHENYLIODONIUM SALTS INTRODUCTION 1 The introduction of an aryl group alpha to a carbonyl is an important chemical reaction. Molecules containing the a-aryl ketone moiety, such as cephalotaxinone 22, are important intermediates for the 67. As a synthesis of a number of biologically interesting molecules result, there are many examples in the literature of attempts to a- arylate ketones. Many a-aryl ketone syntheses involve phenylation of the correspon— ding ketone enolate or equivalent. The reaction of'ketone enolates with benzyne generated from halobenzenes results in moderate yields (28-757) of a-phenylated product68 (eq 39). Enol ethers and acetates react with 11" 7' ONa (x 1 X 0 ' ‘ 1 1 + Rama-91 ‘2‘: H 0+‘ 4 Ph * (39) 3 35% 1— .... diazonium salts in the presence of CuI to givecl-phenyl ketones in fair yield69 (eq 80,81). Heck has reported70 that enol esters react with in 39 80 008 N *Cl' Cl 3 2 0 + Cu2C12 --——* 20% 01 (81) situ generated aryl palladium compounds to give phenylated products (eq 82). However, the aryl palladium compounds are synthesized from toxic 1’ ‘éPh AngCl + ,z’ II 9 h (82) Ph C“ Ph 80% aryl mercury compounds. Beringer has extensively investigated the reactions of iodonium salts with various nucleophiles71. Reaction of these iodonium salts with simple ketone enolates gives mixed results72 (eq 83,88). This reaction is postulated to proceed E a radical coupling mechanism73. 3 2821*01' g u PhCCH(CH3)2 3>203i7 ph C(CH3)2Ph ( 3) CH3CH2C(CH 81% CH3CH2C(CH3)20K 81 S PhZI+ 01 8 211008208(083)2 CH3::2 C(CH3 ) 203> PhCCHPhCH(CH3)2 (88) CH3C “C(CH ) :OK 23% Bunnett has done much work in the area of the aromatic (SRN1) reaction7u. He has found that phenyl radicals generated either photoly- tically or chemically will react with enolates in a radical chain process to give 9t-phenyl ketones75 (eq 85). Semmelhack has used this Br OM O 2 R 2 . R1 ’1 _8_or_ny_, R Ph (85) NH3(1) 3 R3 R M = K or Na 0-95% (procedure in a key bond forming step as part of a cephalotaxine synthesis76 (eq 86). Senlnelhack77 has also attempted the same reaction using bis(1,5-cyclooctadiene)nickel(0) ENi(COD)é] to arylate the eno- late Q (eq 87). <’ " Haw 82 23 Ni(COD)2 g (87) \/ 30% Finally, Semmelhack76 has also attempted the benzyne approach (eq 78 has 39). This reaction converts 23 to 22 in only 15% yield. Fuchs taken a different route. Instead of reacting a ketonic nucleophile with an arylating agent, he generates an "enolate cation" and phenylates with phenylcopper. His "enolate cation" is generated from a a-bromo tosylhydrazone, which in turn arises from the corresponding a-bromoke- tone (eq 88). This sequence works for cyclic and acyclic ketones, and various substituted aryl copper reagents were used effectively. N;;NTS NNHTs ‘ Ph '———> 2) BF3- Eta Brown79 has developed a potentially useful synthesis of a-aryl ketones by reaction of aryl boranes with a-bromoketones (eq 89). The PhB::I>+ R”:L‘\”B+ (89) -t-Bu 90% R 76% Ph 931 83 aryl boranes are readily prepared from 9-borabicyclo 6.3.1] nonane and the appropriate aryllithium8o (eq 50), thus making this route very H ArLi + 1430 ———-—->\B@ MeSOH ArB® (50) Ar,/_ 3 ———> Li* attractive. Several other procedures involving the arylation of B-keto esters have also been developed81. 72 (eq We were particularly intrigued by the Beringer procedure 83,88). A major disadvantage of this route, aside from the variability in yields, is that the particular base/solvent system will generate thermodynamic enolate mixtures 82; thus, unsymetrical ketones with 01- and a'-hydrogens will lead to mixture of products. We proposed to investigate the reaction of enolates generated by strong bases in aprotic solvents with diphenyliodonium salts. RESULTS AND DISCUSSION Our studies began by first attempting to use Beringer's proce- 72 dure with cyclohexanone (eq 51) as our test ketone. We observed CHBCHZC ( CH3) OH —> ' h ... _ 1 + Ph2I Cl CH3CH2C( CH3 ) 20K (51 ) O 0 15% 88 formation of 151 of a-phenyl cyclohexanone and 50% recovered cyclohex- anone. This is consistent with Beringer's observation that isovalero- phenone is phenylated in only 23$ Yield (eq 88) and may be explained in terms of radical stability: the expected intermediate for both cyclo- hexanone and isovalerophenone is a.2° radical, which is less stable than the radical generated from isobutyrophenone (3°). It is not clear whether the difficulty lies in formation of the radical or in the subsequent reaction. We then turned our attention to strong base/aprotic solvent sys- tems. Lithium diisopropylamide (LDA) is a strong base that completely converts ketones to enolates under aprotic conditions°2. 'We used LDA in a variety of solvents, including tetrahydrofuran (THF), dimethylsulf- oxide (DMSO), N,N-dimethylformamide (DMF), and 1,2-dimethyoxyethane (glyme). The enolate of cyclohexanone, generated with LDA in THF, was reacted with PhZI+Cl- (eq 52). No a-phenyl cyclohexanone was observed. LDA + (52) We attempted this reaction in a variety of solvents and at several temperatures. The enolate was generated with LDA in THF, concentrated _i_n vacuo and dissolved in the apprOpriate solvent. The results, summarized in Table VI, reveal that this reaction does not work well. 85 We decided to examine a system similar to one where Beringer's reaction worked well, (i.e. 3° a-carbon) and so looked at reactions of diiSOpro- pyl ketone 25. When 23 was reacted according to Beringer's procedure”, a small amount of 2-phenyl-2,8-dimethyl-3-pentanone 2§_was observed (eq 53, Table VII). When we varied the metal cation, the solvent, or the 0 P112 1* Cl- CH CH2 (CH ) 20H Ph + PhI + 28 (53) CH3 CH: (CH3 ) :ONa 22 9% temperature, only small variations in the yield of 222 were observed (Table VII). In all cases, a full equivalent of iodobenzene was observed by GLC, and 2fl_was also present in 85-60$. It is possible that the phenyl radicals that are generated abstract a hydride from the solvent, although this seems unlikely as the yield is not improved by using excess iodonium salt (Table VII). The next variable we changed was the iodonium.saltu Diphenyliodon- 83 ium tetrafluoroborate was reacted with the lithium enolate offi2fl under a variety of conditions (eq 58, Table VIII). The results vary, but are M + 9821838,,“ —> _2_§ (58) better than reaction with diphenyliodonium chloride. Finally, we synthesized diphenyliodonium hexafluorOphosphate. This salt was reacted with metal enolates of 23 under a variety of 46 Table VI. Reaction of the Lithium Enolate of Cyclohexanone with ‘ Diphenyliodonium Chloridea OLi 0 Ph + ph21*c1' >> Solvent Temp. 0C Yield (%) THF 0° 0 DMF 25° 2 DMSO 25° 0 O CH3CH2C(CH3)20H o 15 aThese reactions were conducted with amine-free enolate. ‘47 Table VII. Reaction of the Enolate of Diisopropyl Ketone with Diphenyliodonium Chloridea GM 0 ‘\\ Ph + thI+Cl- *€> Metal (M) Solvent Temp. °c Yield (x) Li CH3CH2C(CH3)20H 0° 18 O Na CHBCH2C(CH3)20H 0 9 Li CH3CH2C(CH3)20H 1n Na CH3CH2C(CH3)20H 13 K CHBCHZC(CH3)20H o 9 Li DMSO 0 10 Na DMSO 0° 0 Li THF 0° 13 Na THF 0° 5 Li Glyme 15 K Glyme 15 8These reactions were conducted with amine-free enolate. 48 Table VIII. Reaction of the Lithium Enolate of Diisopropyl Ketone with Diphenyliodonium Tetrafluoroborate OLi 0 Ph + thI+BFu' —-> T Equivalents Ph I+BF ‘ Solvent Temp. °c Yield (1) 2 u THF -78° 12 2 THF -78° 11 0.5 THF -78° 9° 0.1 THF -78° 50° 1 THF -780 "0 1 THF 0° 5 1 DMSO -78° 23 1 mmo 0° 10 b o 1 THF -78 32 8These reactions were conducted with amine-free enolate. bEnolate and Ph I+BF ' concentrations were 0.2 M for this reaction. All other concentrations are 1 M. cheld based on amount of Ph21+BFu . #9 conditions (Table IX). PhZI+PF6- is highly soluble in THF as compared to Ph21+Cl-, and hence was added as a solution in THF to THF solutions of the enolate. The best results were obtained when a 2M solution of PhZfPFG' in THF was added to a 1M solution of enolate in THF at -78° (eq 55). OLi \ THF + - ———> + PhZI PF6 -78° _22 (55) 15 min 40% The lithium enolate of cyclohexanone was reacted with PhZI+PF6 under a variety of conditions (Table X). As with 25, the best results are obtained when the lithium enolate of cyclohexanone is reacted with thI+PF6- in THF at -78°c (eq 56). Curiously, the best yield is on 0 Ph . - THF 4- Ph I+PF > 5 2 6 -78° (5 ) 15 min ”2% virtually identical to that of the diisOpropyl ketone reaction. Under these reaction conditions, it appears that radical stability is not an important factor. Finally, isobuterphenone was reacted under the same conditions (eq 57). Again, the yield is the same as for both cyclohex- anone and diisopropyl ketone. L1 0 \ . P“ + thfppé' _1’550—9 ”MP“ (57) '78 m 15 min 50 .oonfloeo eoaeoaa oo memou no .oonfloeo eaaeoafi oo omaz do coapaoum >9 owumnonmuo coauwuom an omumsocoo .Aamucoawaoaxm oomv <94 scam ocaamHzaoLaomHHnm o z N 2 P oz P om»: coo mm 2 N 2 F oz P om»: naz pm 2 N x F mm» P om»: H4 mm 2 N 2 F oz N can: «4 NF 2 N 2 P oz P 00 H4 0 z N 2 P oz P om»: M on 2 N 2 F oz F ooh: H4 mm 2 P 2 P oz P own: «a Any odes» +Hmaa oonaoem nocaa< Any uses no .oaoa sz Hood: ems -oaa+Hmea + so 40, so .mzh ca mumnanongocosammxoz asacouofiazcmsafio coax ocouoz HzQOLaomHHn mo oumaocm on» no COfiaomom .xH manna 51 Table X. Reaction of the Enolate of Cyclohexanone with Diphenyliodonium Hexafluorophosphate. 0M 0 Ph 4. .— + thl PF6 a: Metal (M) Solvent Temp. 0C Yield (1) Na CH3CH2C(CH3)20H 0° 0 Li Glyme -78° M2 Li Glyme 0o 15 Li DMSO 25° 0 Li THF -78° u2 52 Although the yields are moderate, it appears that diphenyliodonium hexafluorophosphate is a good phenylating agent for ketone enolates 81 generated under kinetic conditions , thus nicely complementing Beringer's72 procedure. EXPERIMENTAL THF was distilled from a sodium-benzophenone ketyl still. All other solvents were distilled from calcium hydride before use. Cyclo- hexanone, diisopropyl ketone, and isobuterphenone were obtained from the Aldrich Chemical Co. and distilled from calcium hydride before use. Diphenyliodonium salts were prepared by the procedure of Beringer83. Gas chromatographic data were obtained on a Varian 920 chromatograph equipped with a 11 ft x 0.25 in column packed with 2.5% SE-3O on Chromsorb W. 1H NMR spectra were recorded on a.Varian T-60 Spectrometer at 60 MHz using CDCl3 as the solvent and are reported in parts per million in the 6 scale relative to internal MeuSi. Preparation of Potassium Hexamethyldisilazide Potassium hydride (5 M, 20 ml, 100 mmol) in oil was washed 3 x 20 mL with pentane, the solvent being carefully removed :23 syringe. After the final wash, the residue was concentrated 29:12922, then dissolved in 20 mL of THF. Hexamethyldisilazane (2“ mL, 115 mmol) was added, and the reaction was stirred for 1 h. The majority of the solvent was removed .123 syringe, and the residue concentrated 29.33329 affording 15 g (75%) of potassium hexamethyldisilazide as an off-white solid which was stored under argon. 53 Generation of Lithium Enolates Lithium Enolate of Diisopropyl Ketone n-Butylithium (2.UM, 2.08 mL, 5.0 mmol) was dissolved in 2.5 mL of pentane at 0°C. Diisopropyl- amine (0.71 mL, 5.0 mmol) was added dropwise. The solution was stirred for 15 min at 0°C, then concentrated ég‘xgggg. The white residue was dissolved in 5 mL of THF and cooled to 0°C. DiisOpropyl ketone (0.70 mL, 5.0 mmol) was added drOpwise at 0°C, and the solution was stirred for 15 min. At this point, if amine free enolate was desired, the solution was concentrated 22.32329, then redissolved in the appropriate solvent. Lithium Enolates of Cyclohexane and Isobuterphenone These enol- ates were prepared as above. Generation of Sodium Enolates Sodium Enolate of Cyclohexanone Sodium (0.12 g, 5.0 mmol) was dissolved in 25 mL of E-amyl alcohol. Cyclohexanone (0.52 mL, 5.0 mmol) was added and the solution was cooled to 0°C. Sodium Enolate of Diisopropyl Ketone This enolate was prepared as above. Generation of Potassium Enolate Potassium Enolate of DiisoprOpyl Ketone Hexamethyldisilazane (0.61 g, 3.0 mmol) was dissolved in 5 mL of THF. Diisopropyl ketone (0.“2 mL, 3.0 mmol) was added dr0pwise. The solution was stirred for 1 h, then concentrated _ig £992. The enolate was redissolved in the appropriate solvent. 5H Phenylations of Enolates Phenylation of Cyclohexanone Lithium Enolate The lithium enolate of cyclohexanoner(5 mmol) was prepared as above and dissolved in 5 mL of THF. The reaction was cooled to -78°C. Diphenyliodonium hexafluoro- phosphate (2.13 g, 5.0 mmol) was dissolved in 2.5 mL of THF and added dropwise to the enolate. The reaction was stirred for 15 min at -78°C, then allowed to warm to room temperature and quenched with 10 mL of 1 M HCl. The solution was extracted with 10 mL of ether, dried with MgSOu, and analyzed by GLC which showed a ”2% yield of 2-phenylcyclohexanone: NMR 6.90-7.20 (m, 5H), 3.20-3.85 (m, 1H), 1.50-2.80 (m, 8H). Phenylation of Diisopropyl Ketone Lithium Enolate This reaction was conducted as above, affording a H11 yield of 2-phenyl-2,u-dimethyl- 3-pentanone: NMR 7.08 (s, 5H), 2.h-2.9 (m, J = 6 Hz, 1H), 1.15 (s, 6H), 1.90 (d, J = 6 Hz, 6H). Phenylation of Isobutyrophenone Lithium Enolate This reaction was conducted as above, affording a 41% yield of<1-phenylisobutyrophenone: NMR 6.80-7.45 (m, 10H), 1.55 (s, 6H). Other reactions were conducted in analagous fashion by dissolving the desired enolate in the appropriate solvent, and adding iodonium salt. Diphenyliodonium chloride was added neat. (See Tables VI-X for specific combination of reagents). REFERENCES 5a. 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Benjamin:Menlo Park, 1972; Chapter 9; and references cited therein. Beringer, F.M.; Geering, E.J.; Kuntz, 1.; Mausner, M. J. ths. Chem. 1956, 69, 1H1. HICHIGRN STATE UNIV. LIBRQRIES 1|ll"1|”I11111111111"1|WIHIIIWWIIHHHI 31293015914629