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Chapter 27. Reactions of Interest in Medicinal Chemistry
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Section VI Topics in Chemistry Editor: R. E. Counsell, University of Michigan, Ann Arbor, Michigan Chapter 27. Reactions of Interest in Medicinal Chemistry David M. Spatz, Dow Chemical U.S.A., Pharmaceutical R&D, Midland, MI Useful reference books published recently include: Annual Reports in Organic Synthesis-1975, by R. B. Miller and L. G. Wade, Jr.; Transition Metal Organometallics in Organic Synthesis, edited by H. Alper; Survey of Organic Syntheses, Volume 2 , by C. A. Buehler and D. E. Pearson; Organic Synthesis, Volume 55, edited by S. Masamune; Organic Reactions, Volumes 23 and 2 4 , edited by W. G. Dauben; Advances in Heterocyclic Chemistry, Volume 19, edited by A. R. Katritzky and A. J. Boulton; Synthetic Methods, Volume 30, edited by W. Theilheimer; Reagents for Organic Synthesis, Volume 5 by M. Fieser and L. M. Fieser; Special Topics in Heterocyclic Chemistry, Volume 30, edited by A. Weissberger and E. C. Taylor; Advances in Organometallic Chemistry, Volume 1 4 , edited by F. G. Stone and R. West. Reviews - Acyl anion equivalents, crown ethers in synthesis, intramolecular 1,3-dipolar additions, oxazolines in synthesis, oxidation-reduction condensations, oxythallation, transition metals in synthesis, and ynamines in synthesis. Also reviewed are syntheses of pyridines , pyrroles, and indolizines. Other reviews are in specific sections. The Institute f o r Scientific Information now publishes Index to Scientific Reviews semi-annually.
'
C-C Bond Formations reviewed."
-
Organoboranes for C-C bond formation have been
Trimethylsilyl enol ethers continue to be useful synthons for various aldol and Michael"," reactions. Their utility in part is due to their ease of regiospecific preparation, ease of cleavage and high reactivity. Danishefsky and coworkers have shown that silyl enol ethers react with dimethyl(methy1ene)ammonium iodide yielding Mannich bases. Otherwise inaccessible Mannich bases are accessible via the series below.
'
Nitro-olefins react with trimethylsilyl enol ethers under Lewis acid catalysis in a regiospecific manner yielding 1,4-diketones.2 o
a-Halo-a,B-unsaturated carbonyl compounds are conveniently prepared by addition of a dihalo carbene to silyl enol ethers.21 Further uses of trimethylsilyl enol ethers are discussed in later sections.
Chap. 27
Chemical Reactions
Spatz
2.62
Substitution in the a-position of an a,B-unsaturated ketone can be achieved by addition of an alkyl or aryl Grignard reagent to an a,$-epoxy N,N-dimethyl hydrazone.22-2 ,CH 3
1. RMgx > 2. H+, H20 a-Seleno carbanions added to the appropriate electrophile yield an aseleno carbonyl compound, which upon oxidation produces a,$-unsaturated ketones.24 1. g-BuLi seb 2. R3COC1 RiCp @SeH> RICHP ,c=o ‘C’ 3 . Oxidize R2 R < ‘se0
,
Corey and coworkers have outlined the wide usefulness of N,N-dimethyl hydrazones (DMH) in synthesis.25-9 The parent carbonyl compounds can be regenerated by oxidative hydrolysis via periodate at pH 7 or with the very mild cupric acetate in water-THF. Metallation of these hydrazones selectively occurs at the less alkylated carbon. Alkylation occurred axially in the cyclohexane derivatives studied. Quenching of the metallated DMH’s
with carbonyl compounds or epoxides yields $-hydroxycarbonyl compounds or y-hydroxycarbonyl compounds, respectively. The metallated DMH’s add 1,2to a,B-unsaturated carbonyl compounds; however, cuprate derivatives can be formed which add 1 , 4 and afford a path to 1,5-diketones. Silyl aldehyde DMH’s produce a,@-unsaturated aldehydes. 1. LDA CHO / 2. (CH3) BSiC1, R2\ c-c, RiCH2CH=N-N(CH3) 2 3 . LDA :R Ri 4 . RgCOR? (LDA = Lithium Diisopropylamide) Another interesting a-functionalization of the metallated DMH’s is achieved by addition of dimethyl disulfide. Again, the new group is added axially. Hydrolysis produces 2-thiomethylketones. Alternatively, an axial acetoxy or methoxy group is introduced by mercuric chloride catalyzed solvolysis in acetic acid or methanol.
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Enantioselective alkylation of cyclohexanones can be accomplished via a chiral lithio-chelated enamine. Doubly lithiated nitroalkanes react rapidly with electrophiles providing an improved method for C-C bond formation from nitroalkanes.3’ Doubly lithiated methanol can be prepared to give a nucleophilic hydroxymethylation reagent.32 OH I 0CHO + LiCHlOLi BCH-CHzOH
-----+
’
The bis(pheny1thio)carbanion can be condensed with a ketone yielding an intermediate bis (pheny1thio)alcohol. Trifluoroacetic acid catalyzed hydrolysis generates an alkylated carbonyl compound without the utilization of an alkyl halide.
Olofson and coworkers have published improved syntheses of cyclopropanols. 3‘-6 These make use of the high selectivity of lithium 2,2,6,6tetramethylpiperidide (LITME’, H+arpoon) in generation of alkoxy carbenes from various chloromethyl ethers. ClCHzCH20CH2C1
LiTMp>
[ClCH2CH20CH:]
>’
0
mOCHzCH2Cl
Cyclopropanes can be synthesized from many organic gem-dihalides using copper and a trace of iodine as catalysts.37 This procedure is comparable to the Simmons-Smith reaction in yields and is more convenient because of a wider range of substrates available. Br2CHC02CH3
+
( --+
>COzCH3
Several improved titanium-derived catalysts have been reported for the reductive coupling of carbonyls to diols and olefins, activated halides to alkanes and %-dihalides to olefins.
’-‘
Allenes are cleanly formed by addition of C-rignard reagents to propargyl chlorides with ferric chloride catalyst. “ Formation of a functionalized C-C bond in an allylic position can be carried out with methyl cyanodithioformate via a sequence of an ene reaction followed by a [ 2,3]-sigmatropic rearrangement.”
Chap. 27
Chemical Reactions
1. Z-BuLi
S
+
QCH2
/c\It CN
2. CHjI
CH3S
27 1 -
Spatz
/cB CN
CH3S
'Q GSCH CH3S
3
Interesting new 1,3-dienes €or the Diels-Alder reaction include (Z)-1phenylthio-2-methoxy-ly3-butadiene, 2-methoxy-3-phenylthio-ly3-butadine,4 4 and N-acyl-1-amino-1 ,3-butadiene.
'
Aromatic Substitution - Phenols can be oxidized directly to ortho-quinones with diphenylseleninic anhydride. " Blocking of the para-position is unnecessary and yields are good. A trifluoromethylthio group can be introduced into an aromatic ring by coupling of trifluoromethylthio copper (I) and an aryl bromide or iodide.4 Aryl chlorides are inert. Nucleophilic displacement of the nitro group of nitrobenzenes substituted with a variety of electron-withdrawing groups is readily possible at 25OC with HMPA as solvent.48 Carbon, oxygen, and sulfur nucleophiles have been used with excellent yields reported.
doCH3
Regiospecific quinone isoprenylation can be effected by the following 49 scheme used in the synthesis of vitamin K 2 (5) ' 0
2. R 1. r M g * ,(CH3)
0
CH 3
BrMgO
A sequence of anodic oxidation followed by metallation provides quinone carbanions which allow specific electrophilic substitution of quinones OOCH3 CH3O OCH3 CH30 OCH3 CHJOH o B r 1. G-BuLi, I Pt anode 2 . 0COCl CHBO OCH3 CH,O OCH, OCH3
.'
6"'
,
@rO
Heterocycles - Aromatic substitution via N-oxides has been reviewed." Palladium catalyzed intramolecular addition of amines to olefins has resulted in new syntheses of in dole^'^-^ and isoquinuclidines.5 3 An interesting reaction for 5-amidomethylation of indoles unblocked in the 3-position has been reported. The conditions are N-hydroxymethylphthalimide in room temperature and excellent yields are obtained.
''
272
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-
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Counsell, Ed.
A general synthesis of 2-alkyl-3-acylpyridines is achieved from 2substituted pyridines via a [2,3]-sigmatropic rearrangement of an intermediate a-cyanoamine.
n
Halogenations - An improved procedure €or the regiospecific preparation of a-bromocarbonyl compounds uses the reqyisite trimethylsilyl enol ether and either bromine or N-bromosuccinimide. Direct fluorination at saturated carbon is possible with either elemental fluorine or CFBOF and a radical inhibitor. 5 7 - 8 The transformation is an electrophilic fluorination, regiospecific by virtue of the highly polar transition state sensitive to the inductive effects of nearby or remote polar substituents. Substitution occurs almost exclusively at tertiary positions with monosubstitution predominating. With various substituents, selective fluorination at positions 9, 14, or 17 of the steroid nucleus was reported.
AcO
50%
AcO
Primary unbranched amines have been converted to geminal dihalides by the combination of alkyl nitrites and anhydrous copper (11) halides.5 9 CuBr 2 ~CHZCH~CH~NH~ t-MONO’ -
dCHzCH2CHBr2
Alkyl halides can be prepared from selenides and selenoxides. Oxidations
-
Active manganese dioxide oxidations have been reviewed.
Several new procedures for the selective oxidation of secondary alcohols in the presence of primary alcohols have appeared. Distannoxanebromine, a neutral reagent, efficiently oxidizes secondary or benzylic alcohols to ketones in the presence of primary alochols.62 Trialkyltin alkoxides and bromine oxidize both primary and secondary alcohols. Woelm W-200, neutral, dehydrated alumina oxidizes secondary alcohols to ketones in the presence of primary alcohols with trichloroacetaldehyde as the hydride acceptor. The reverse reduction process had previously been reported. Oxidation of triphenylmethyl ethers of primary, secondary diols with triphenyl carbenium salts proceeds only at the secondary positions. Dimethylsulfoxide trifluoroacetic anhydride at low temperature is a mild reagent for the oxidation of hindered alcohols.
“-’
y-Hydroxylation of a,b-unsaturated esters is possible via a-thiomethylation, oxidation and [2,3]-sigmatropic rearrangement.6a
Chap. 27
Chemical Reactions
Spatz
273
a-Diketones are prepared in excellent yield from ketones by singlet oxygen oxidation of an intermediate enamino ketone.
Regiospecific preparation of a-benzoyloxy carbonyl compounds by lead tetrabenzoate (LTB) oxidation of the trimethylsilyl enol ethers is possible. 7 0 Similarly, a-thiolated ketones can be prepared from a disulfi.de. 7 1 Sulfoxides can be obtained from sulfides without sulfone formation by either acyl nitrates (0COCl + HNOB or Ac20 + HN03)72 or sulfuryl chloride and wet silica Both methods are clean, mild and rapid. Sharpless and coworkers have reported a new series of reagents for allylic amination of olefins, 4-5 vicinal oxyamination of olefins, and 1,2-diamination of 1,3-dienes.7 7
6
TsN=Se=NTs 0"
Chloramine-T Cat. Osot,, t-BuOH, 60"' Reduction - An excellent review of diborane reductions has appeared.7 8 Lithium and potassium tri-E-butylborohydride (L- and K-Selectride selectively reduce the olefin of many a,B-unsaturated carbonyl compounds.2 9 The intermediate enolate anions may also be trapped by electrophiles, providing a regiospecific reductive alkylation of a,B-unsaturated carbonyl compounds. Sodium cyanoborohydride in acidic methanol reduces a,B-unsaturated esters, nitriles, and nitro compounds to their saturated derivatives. The olefinic bond of a,B-unsaturated carbonyl compounds can also be reduced by two transition metal hydrides , NaHFe2 (CO) and NaHCrp (CO) 1 0 . 82 Neither reagent reduces nitriles, ketones, aldehydes or non-conjugated carbon-carbon double bonds. Sodium bis[2-methoxy~thoxy]aluminum hydride (SMEAH) can be modified to selectively and rapidly reduce lactones to lactols or esters to aldehydes.
274
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S M W leq C11,CH20H, 0' CH2 CH3O-@H=CHCOzCH3 -
COZCH,
CH, SMEAH n > leq HN 0, 0'
C02CH,
CH~O+H=CH-CHO -
Lf
Lithium trisiamylborohydride (LTSBH) shows unique stereoselectivity in the reduction of unhindered ketones.8 4 Ketones such as 4-~-butylcyclohexanone undergo exclusive equatorial attack yielding the cis-carbinol. The reagent is superior to LTMBH and L-Selectride.
Protecting Groups - Detonation has been reported for compounds where oxidaIt aption of tetrahydropyranyl (THP) ether derivatives was performed. pears that the THP-protecting group forms sensitive organic peroxides when treated with peroxy reagents. Normal precautions in the work-up of such reactions were insufficient in destruction of the sensitive compounds. THF, dioxolane, and methoxymethyl ether groups should also be presumed to form explosive derivatives upon contact with peroxy reagents.
''
Aldrich now offers 2-~-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON) as a non-explosive replacement for the thermally unstable and shock-sensitive - B O C azide. 8 6 The 8-methoxyethoxymethyl (MEM) group has been introduced as a new general protecting group for the hydroxyl function.87 The MEM group is rapidly introduced under either aprotic basic or aprotic neutral conditions. The MEM group may be selectively cleaved with ZnBrp or TIC14 with no interference from esters or benzyl, allyl, THP, TBDMS, trichloroethyl, or MTM ethers. Conversely, these groups may be removed in the presence of MEM ethers. MEM ethers are stable to strong bases, reducing agents, organometallic reagents, many oxidizing agents, and mild acids. Further extensions of the use of the methylthiomethyl (MTM) protecting group for alcohols have been reported.
"-'
Methyl ethers can be cleaved in minutes at room temperature with diiodomethyl methyl ether. g Methylenation of catechols is greatly im roved with potassium or cesium fluoride in DMF and CHzC12 or CH2Br2. 9 7 The S-2-methoxybenzyl and S-t-butyl protectin groups for cysteine are rapidly cleaved with mercury (11) trifluoroacetate.i 2
Chap. 27
Chemical Reactions
Spat2
275
2-Acyloxymethylbenzoic acids can be used to protect amines. 9 3 The amides so derived can be cleaved with mild acid or base due to neighboring group participation of the generated alcohol. 0
0
The trimethylsilyloxy group of allylic or benzylic alcohols is readily displaced by nucleophiles (malonate anion, alkyl Grignard reagents, hydride This limitation as a protecting group should be noted. (AlC13-LfilH1,)). Miscellaneous - Chiral and achiral thiiranes can be prepared from carbonyl compounds and 2- (alkylthio)-2-oxazolines. 9 5 6-Ketoesters are mildly decarboxylated in refluxing 1.5% aqueous dioxane using alumina (Merck, type T, basic) as catalyst.9 6 References
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.
20. 21. 22. 23. 24. 25. 26. 27. 28.
H. Stetter, Angew. Chem. Int. Ed. Engl., l5, 639 (1976). 0. W. Lever, Jr., Tetrahedron, 32, 1943 (1976). G. W. Gokel and H. D. Durst, Synthesis, 168 (1976). A. Padwa, Angew. Chem. Int. Ed. Engl., l5, 123 (1976). , 2, 270 (1976). A. J. Meyers and E. E. Mihelich, T. Mukaiyama, l5, 94 (1976). A. McKillop and E. C. Taylor, Endeavour, 125, 88 (1976). A. P. Kozikowski and H. F . Wetter, Synthesis, 561 (1976). J. Schwartz and J. A. Labinger, Angew. Chem. Int. Ed. Engl., 15,333 (1976). J. Ficini, Tetrahedron, 32, 1449 (1976). F. Krohnke, Synthesis, 1 (1976). J. M. Patterson, 281 (1976). T. Uchida and K. Matsumoto, M., 209 (1976). J. Weill-Raynal, 633 (1976). T. Mukaiyama, K. Saigo, and 0. Takazawa, Chem. Lett., 1033 (1976). K. Banno, Bull. Chem. SOC. Jap., 49, 2284 (1976). 2,779 (1976) K. Narasaka, K. Soai, Y. Aikawa, and T. Mukaiyama, K. Saigo, M. Osaki, and T. Mukaiyama, Chem. Lett., 163 (1976). S . Danishefsky, T. Kitahara, R. McKee, and P. F. Schuda, J. Amer. Chem. SOC. , 98, 6715 (1976). M. Miyashita, T. Yanami, and A. Yoshikoshi, 98, 4679 (1976). P. Amice, L. Blanco, and J. M. Conia, Synthesis, 196 (1976). G. Stork and A. A. Ponaras, J. Org. Chem., 41, 2937 (1976). P. L. Fuchs, 41, 2935 (1976). J. N. Denis, W. Dumont, and A. Krief, Tetrahedron Lett., 453 (1976). E. J. Corey and D. Enders, w.,3 (1976). E. J. Corey, D. Enders, and M. G. Bock, w.,7 (1976). E. J. Corey and D. Enders, 11 (1976). E. J. Corey and S. Knapp, 3667 (1976).
u.,
m.
u., m.,
w.,
m.,
u.,
m.,
w.,
276 -
Sect. VI
-
Topics in Chemistry
Counsell, Ed.
29. E. J. Corey and S. Knapp, Tetrahedron Lett., 4687 (1976). 30. A. I. Meyers, D. R. Williams and M. Druelinger, J. Amer. Chem. SOC., 98, 3032 (1976). 31. D. Seebach and F. Lehr, Angew. Chem. Int. Ed. Engl., 15, 505 (1976). 2, 438 (1976). 32. D. Seebach and N. Meyer, 33. P. Blatcher, J. I. Grayson and S. Warren, Chem. Commun., 547 (1976). 34. G. N. Barber and R. A. Olofson, Tetrahedron Lett., 3783 (1976). 35. R. A. Olofson, K. D. Lotts, and G. N. Barber, G.,3779 (1976). 3381 (1976). 36. R. A. Olofson, K. D. Lotts, and G. N. Barber, 37. N. Kawabata, M. Naka, and S. Yamashita, J. Amer. Chem. SOC., 98, 2676 (1976). 38. J. E. McMurry and M. P. Fleming, J. Org. Chem., 41,896 (1976). 41,260 39. E. J. Corey, R. L. Danheiser, and S. Chandrasekaran, (1976). 40. G. A. Olah and G. K. S. Prakash, Synthesis, 607 (1976). 41. D. J. Pasto, G. F. Hennion, R. H. Shults, A. Waterhouse and S.-K. Chou, J. Org. Chem., 41,3496 (1976). 42. B. B. Snider, N. J. Hrib, and L. Fuzesi, J. h e r . Chem. SOC., 98, 7115 (1976). 43. T. Cohen, A. J. Mura, Jr., D. W. Shull, E. R. Fogel, R. J. Ruffner, and J. R. Falck, J. Org. Chem., 41, 3218 (1976). 44. B. M. Trost and A. J. Bridges, J. h e r . Chem. SOC., 98, 5017 (1976). 45. L. E. Overman, G. F. Taylor, and P. J. Jessup, Tetrahedron Lett., 3089 (1976). 46. D. H. R. Barton, A. G. Brewster, S. V. Ley, and M. N. Rosenfeld, Chem. Commun., 985 (1976). 47. D. C. Remy, K. E. Rittle, C. A. Hunt, and M. B. Freedman, J. Org. Chem., 41, 1644 (1976). 48. N. Kornblum, L. Cheng, R. C. Kerber, M. M. Kestner, B. N. Newton, H. W. Pinnick, R. G. Smith, and P. A. Wade, 41,1560 (1976). 49. D. A. Evans and J. W. Hoffman, J. Amer. Chem. SOC., 98, 1983 (1976). 50. M. J. Manning, R. W. Raynolds, and J. S. Swenton, 98, 5008 (1976). 51. R. A. Abramovitch and I. Shinkai, Accts. Chem. Res., 9, 192 (1976). 52. L. S. Hegedus, G. F. Allen, and E. L. Waterman, J. Amer. Chem. SOC., 98, 2674 (1976). 98, 8516 (1976). 53. B. M. Trost and J. P. Genet, 54. K. Freter, F. Hess, and K. Grozinger, Ann. Chem., 241 (1976). 55. E. B. Sanders, H. V. Secor, and J. I. Seeman, J. Org. Chem., 41,2658 (1976). 56. L. Blanco, P. Amice, and J. M. Conia, Synthesis, 194 (1976). 57. D. H. R. Barton, R. H. Hesse, R. E. Markwell, M. M. Pechet, and H. T. Toh, J. her. Chem. SOC., 98,3034 (1976). 58. D. H. R. Barton, R. H. Hesse, R. E. Markwell, M. M. Pechet, and S. Rozen, w.,98, 3036 (1976). 59. M. P. Doyle and B. Siegfried, Chem. Commun., 433 (1976). 60. M. Sevrin, W. Dumont, L. Hevesi, and A. Krief, Tetrahedron Lett., 2647 (1976). 61. A. J. Fatiadi, Synthesis, 65, 133 (1976). 62. Y. Ueno and M. Okawara, Tetrahedron Lett., 4597 (1976).
=.,
w.,
m.,
w., w.,
u.,
Chap. 27
Chemical Reactions
Spatz
277
63. K. Saigo, A. Morikawa, and T. Mukaiyama, Bull. Chem. SOC. Jap., 2, 1656 (1976). 64. G. H. Posher, R. B. Perfetti, and A. W. Runquist, Tetrahedron Lett., 3499 (1976). 65. M. E. Jung and L. M. Speltz, J. Amer. Chem. SOC., 98, 7882 (1976). 66. K. Omura, A . K. Sharma, and D. Swern, J. Org. Chem. , 41, 957 (1976). 4 l , 3329 (1976). 67. S. L. Huang, K. Omura, and D. Swern, 68. P. R. Ortiz de Montellano and C. K. Hsu, Tetrahedron Lett., 4215 (1976). 69. H. H. Wasserman and J. L. Ives, J. Amer. Chem. SOC., 98, 7868 (1976). 70. G. M. Rubottom, J. M. Gruber, and G. M. Mong, J. Org. Chem., 41, 1673 (1976). 71. D. Seebach and M. Teschner, Chem. Ber., 109, 1601 (1976). 72. R. Louw, H. P. W. Vermeeren, J. J. A . van Asten, and W. J. Ultee, Chem. Commun., 496 (1976). 73. M. Hojo and R. Masuda, Tetrahedron Lett., 613 (1976). 74. K. B. Sharpless, T. Hori, L. K. Truesdale, and C. 0. Dietrich, J. Amer. Chem. Soc., 98, 269 (1976). 75. K. B. Sharpless and T. Hori, J. Org. Chem., 41, 176 (1976). 41, 177 (1976). 76. K. B. Sharpless, A. 0. Chong, and K. Oshima, 41, 2504 (1976). 77. K. B. Sharpless and S. P. Singer, 78. C. F. Lane, Chem. Rev., 76, 773 (1976). 79. J. M. Fortunato and B. Ganem, J. Org. Chem., 41,2194 (1976). 80. R. 0. Hutchins, D. Rotstein, N. Natale, J. Fanelli, and D. Dimmel, --, ibid 41, 3328 (1976). 81. J. P . Collman, R. G. Finke, P. L. Matlock, R. Wahren, and J. I. Brauman, J. Amer. Chem. SOC., 98, 4685 (1976). 82. G. P. Boldrini and A. Umani-Ronchi, Synthesis, 596 (1976). 526 (1976). 83. R. Kanazawa and T. Tokoroyama, 84. S. Krishnamurthy and H. C. Brown, J. Amer. Chem. Soc., 98, 3383 (1976). 85. A . I. Meyers, S. Schwartzman, G. L. Olson, and H.-C. Cheung, Tetrahedror Lett., 2417 (1976). 4393 (1975). 86. M. Itoh, D. Hagiwara, and T. Kamiya, 809 (1976). 87. E. J. Corey, J.-L. Gras, and P. Ulrich, 88. P. M. Pojer and S. J. Angyal, 3067 (1976). 65 (1976). 89. K. Yamada, K. Kato, H. Nagase, and Y. Hirata, 90. C. A. Smith and J. B. Grutzner, J. Org. Chem., 41, 367 (1976). 91. J. H. Clark, H. L. Holland, and J. M. Miller, Tetrahedron Lett., 3361 (1976). 92. M. Fujino and 0. Nishimura, Chem. Commun., 998 (1976). 93. B. F. Cain, J. Org. Chem., 41, 2029 (1976). 94. J. M. Midgley, J. S . Millership, and W. B. Whalley, J. Chem. SOC. Perkin I, 1384 (1976). 95. A. I. Meyers and M. E. Ford, J. Org. Chem., 41, 1735 (1976). 96. A. E. Greene, A. Cruz, and P. Crabbe, Tetrahedron Lett., 2707 (1976).
w.,
w.,
w.,
w.,
m., u., u.,
w.,
Section VI Topics in Chemistry Editor: R. E. Counsell, University of Michigan, Ann Arbor, Michigan Chapter 27. Reactions of Interest in Medicinal Chemistry David M. Spatz, Dow Chemical U.S.A., Pharmaceutical R&D, Midland, MI Useful reference books published recently include: Annual Reports in Organic Synthesis-1975, by R. B. Miller and L. G. Wade, Jr.; Transition Metal Organometallics in Organic Synthesis, edited by H. Alper; Survey of Organic Syntheses, Volume 2 , by C. A. Buehler and D. E. Pearson; Organic Synthesis, Volume 55, edited by S. Masamune; Organic Reactions, Volumes 23 and 2 4 , edited by W. G. Dauben; Advances in Heterocyclic Chemistry, Volume 19, edited by A. R. Katritzky and A. J. Boulton; Synthetic Methods, Volume 30, edited by W. Theilheimer; Reagents for Organic Synthesis, Volume 5 by M. Fieser and L. M. Fieser; Special Topics in Heterocyclic Chemistry, Volume 30, edited by A. Weissberger and E. C. Taylor; Advances in Organometallic Chemistry, Volume 1 4 , edited by F. G. Stone and R. West. Reviews - Acyl anion equivalents, crown ethers in synthesis, intramolecular 1,3-dipolar additions, oxazolines in synthesis, oxidation-reduction condensations, oxythallation, transition metals in synthesis, and ynamines in synthesis. Also reviewed are syntheses of pyridines , pyrroles, and indolizines. Other reviews are in specific sections. The Institute f o r Scientific Information now publishes Index to Scientific Reviews semi-annually.
'
C-C Bond Formations reviewed."
-
Organoboranes for C-C bond formation have been
Trimethylsilyl enol ethers continue to be useful synthons for various aldol and Michael"," reactions. Their utility in part is due to their ease of regiospecific preparation, ease of cleavage and high reactivity. Danishefsky and coworkers have shown that silyl enol ethers react with dimethyl(methy1ene)ammonium iodide yielding Mannich bases. Otherwise inaccessible Mannich bases are accessible via the series below.
'
Nitro-olefins react with trimethylsilyl enol ethers under Lewis acid catalysis in a regiospecific manner yielding 1,4-diketones.2 o
a-Halo-a,B-unsaturated carbonyl compounds are conveniently prepared by addition of a dihalo carbene to silyl enol ethers.21 Further uses of trimethylsilyl enol ethers are discussed in later sections.
Chap. 27
Chemical Reactions
Spatz
2.62
Substitution in the a-position of an a,B-unsaturated ketone can be achieved by addition of an alkyl or aryl Grignard reagent to an a,$-epoxy N,N-dimethyl hydrazone.22-2 ,CH 3
1. RMgx > 2. H+, H20 a-Seleno carbanions added to the appropriate electrophile yield an aseleno carbonyl compound, which upon oxidation produces a,$-unsaturated ketones.24 1. g-BuLi seb 2. R3COC1 RiCp @SeH> RICHP ,c=o ‘C’ 3 . Oxidize R2 R < ‘se0
,
Corey and coworkers have outlined the wide usefulness of N,N-dimethyl hydrazones (DMH) in synthesis.25-9 The parent carbonyl compounds can be regenerated by oxidative hydrolysis via periodate at pH 7 or with the very mild cupric acetate in water-THF. Metallation of these hydrazones selectively occurs at the less alkylated carbon. Alkylation occurred axially in the cyclohexane derivatives studied. Quenching of the metallated DMH’s
with carbonyl compounds or epoxides yields $-hydroxycarbonyl compounds or y-hydroxycarbonyl compounds, respectively. The metallated DMH’s add 1,2to a,B-unsaturated carbonyl compounds; however, cuprate derivatives can be formed which add 1 , 4 and afford a path to 1,5-diketones. Silyl aldehyde DMH’s produce a,@-unsaturated aldehydes. 1. LDA CHO / 2. (CH3) BSiC1, R2\ c-c, RiCH2CH=N-N(CH3) 2 3 . LDA :R Ri 4 . RgCOR? (LDA = Lithium Diisopropylamide) Another interesting a-functionalization of the metallated DMH’s is achieved by addition of dimethyl disulfide. Again, the new group is added axially. Hydrolysis produces 2-thiomethylketones. Alternatively, an axial acetoxy or methoxy group is introduced by mercuric chloride catalyzed solvolysis in acetic acid or methanol.
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- Topics in Chemistry
Counsell, Ed.
Enantioselective alkylation of cyclohexanones can be accomplished via a chiral lithio-chelated enamine. Doubly lithiated nitroalkanes react rapidly with electrophiles providing an improved method for C-C bond formation from nitroalkanes.3’ Doubly lithiated methanol can be prepared to give a nucleophilic hydroxymethylation reagent.32 OH I 0CHO + LiCHlOLi BCH-CHzOH
-----+
’
The bis(pheny1thio)carbanion can be condensed with a ketone yielding an intermediate bis (pheny1thio)alcohol. Trifluoroacetic acid catalyzed hydrolysis generates an alkylated carbonyl compound without the utilization of an alkyl halide.
Olofson and coworkers have published improved syntheses of cyclopropanols. 3‘-6 These make use of the high selectivity of lithium 2,2,6,6tetramethylpiperidide (LITME’, H+arpoon) in generation of alkoxy carbenes from various chloromethyl ethers. ClCHzCH20CH2C1
LiTMp>
[ClCH2CH20CH:]
>’
0
mOCHzCH2Cl
Cyclopropanes can be synthesized from many organic gem-dihalides using copper and a trace of iodine as catalysts.37 This procedure is comparable to the Simmons-Smith reaction in yields and is more convenient because of a wider range of substrates available. Br2CHC02CH3
+
( --+
>COzCH3
Several improved titanium-derived catalysts have been reported for the reductive coupling of carbonyls to diols and olefins, activated halides to alkanes and %-dihalides to olefins.
’-‘
Allenes are cleanly formed by addition of C-rignard reagents to propargyl chlorides with ferric chloride catalyst. “ Formation of a functionalized C-C bond in an allylic position can be carried out with methyl cyanodithioformate via a sequence of an ene reaction followed by a [ 2,3]-sigmatropic rearrangement.”
Chap. 27
Chemical Reactions
1. Z-BuLi
S
+
QCH2
/c\It CN
2. CHjI
CH3S
27 1 -
Spatz
/cB CN
CH3S
'Q GSCH CH3S
3
Interesting new 1,3-dienes €or the Diels-Alder reaction include (Z)-1phenylthio-2-methoxy-ly3-butadiene, 2-methoxy-3-phenylthio-ly3-butadine,4 4 and N-acyl-1-amino-1 ,3-butadiene.
'
Aromatic Substitution - Phenols can be oxidized directly to ortho-quinones with diphenylseleninic anhydride. " Blocking of the para-position is unnecessary and yields are good. A trifluoromethylthio group can be introduced into an aromatic ring by coupling of trifluoromethylthio copper (I) and an aryl bromide or iodide.4 Aryl chlorides are inert. Nucleophilic displacement of the nitro group of nitrobenzenes substituted with a variety of electron-withdrawing groups is readily possible at 25OC with HMPA as solvent.48 Carbon, oxygen, and sulfur nucleophiles have been used with excellent yields reported.
doCH3
Regiospecific quinone isoprenylation can be effected by the following 49 scheme used in the synthesis of vitamin K 2 (5) ' 0
2. R 1. r M g * ,(CH3)
0
CH 3
BrMgO
A sequence of anodic oxidation followed by metallation provides quinone carbanions which allow specific electrophilic substitution of quinones OOCH3 CH3O OCH3 CH30 OCH3 CHJOH o B r 1. G-BuLi, I Pt anode 2 . 0COCl CHBO OCH3 CH,O OCH, OCH3
.'
6"'
,
@rO
Heterocycles - Aromatic substitution via N-oxides has been reviewed." Palladium catalyzed intramolecular addition of amines to olefins has resulted in new syntheses of in dole^'^-^ and isoquinuclidines.5 3 An interesting reaction for 5-amidomethylation of indoles unblocked in the 3-position has been reported. The conditions are N-hydroxymethylphthalimide in room temperature and excellent yields are obtained.
''
272
Sect. VI
-
Topics in Chemistry
Counsell, Ed.
A general synthesis of 2-alkyl-3-acylpyridines is achieved from 2substituted pyridines via a [2,3]-sigmatropic rearrangement of an intermediate a-cyanoamine.
n
Halogenations - An improved procedure €or the regiospecific preparation of a-bromocarbonyl compounds uses the reqyisite trimethylsilyl enol ether and either bromine or N-bromosuccinimide. Direct fluorination at saturated carbon is possible with either elemental fluorine or CFBOF and a radical inhibitor. 5 7 - 8 The transformation is an electrophilic fluorination, regiospecific by virtue of the highly polar transition state sensitive to the inductive effects of nearby or remote polar substituents. Substitution occurs almost exclusively at tertiary positions with monosubstitution predominating. With various substituents, selective fluorination at positions 9, 14, or 17 of the steroid nucleus was reported.
AcO
50%
AcO
Primary unbranched amines have been converted to geminal dihalides by the combination of alkyl nitrites and anhydrous copper (11) halides.5 9 CuBr 2 ~CHZCH~CH~NH~ t-MONO’ -
dCHzCH2CHBr2
Alkyl halides can be prepared from selenides and selenoxides. Oxidations
-
Active manganese dioxide oxidations have been reviewed.
Several new procedures for the selective oxidation of secondary alcohols in the presence of primary alcohols have appeared. Distannoxanebromine, a neutral reagent, efficiently oxidizes secondary or benzylic alcohols to ketones in the presence of primary alochols.62 Trialkyltin alkoxides and bromine oxidize both primary and secondary alcohols. Woelm W-200, neutral, dehydrated alumina oxidizes secondary alcohols to ketones in the presence of primary alcohols with trichloroacetaldehyde as the hydride acceptor. The reverse reduction process had previously been reported. Oxidation of triphenylmethyl ethers of primary, secondary diols with triphenyl carbenium salts proceeds only at the secondary positions. Dimethylsulfoxide trifluoroacetic anhydride at low temperature is a mild reagent for the oxidation of hindered alcohols.
“-’
y-Hydroxylation of a,b-unsaturated esters is possible via a-thiomethylation, oxidation and [2,3]-sigmatropic rearrangement.6a
Chap. 27
Chemical Reactions
Spatz
273
a-Diketones are prepared in excellent yield from ketones by singlet oxygen oxidation of an intermediate enamino ketone.
Regiospecific preparation of a-benzoyloxy carbonyl compounds by lead tetrabenzoate (LTB) oxidation of the trimethylsilyl enol ethers is possible. 7 0 Similarly, a-thiolated ketones can be prepared from a disulfi.de. 7 1 Sulfoxides can be obtained from sulfides without sulfone formation by either acyl nitrates (0COCl + HNOB or Ac20 + HN03)72 or sulfuryl chloride and wet silica Both methods are clean, mild and rapid. Sharpless and coworkers have reported a new series of reagents for allylic amination of olefins, 4-5 vicinal oxyamination of olefins, and 1,2-diamination of 1,3-dienes.7 7
6
TsN=Se=NTs 0"
Chloramine-T Cat. Osot,, t-BuOH, 60"' Reduction - An excellent review of diborane reductions has appeared.7 8 Lithium and potassium tri-E-butylborohydride (L- and K-Selectride selectively reduce the olefin of many a,B-unsaturated carbonyl compounds.2 9 The intermediate enolate anions may also be trapped by electrophiles, providing a regiospecific reductive alkylation of a,B-unsaturated carbonyl compounds. Sodium cyanoborohydride in acidic methanol reduces a,B-unsaturated esters, nitriles, and nitro compounds to their saturated derivatives. The olefinic bond of a,B-unsaturated carbonyl compounds can also be reduced by two transition metal hydrides , NaHFe2 (CO) and NaHCrp (CO) 1 0 . 82 Neither reagent reduces nitriles, ketones, aldehydes or non-conjugated carbon-carbon double bonds. Sodium bis[2-methoxy~thoxy]aluminum hydride (SMEAH) can be modified to selectively and rapidly reduce lactones to lactols or esters to aldehydes.
274
Sect. VI
-
Topics in Chemistry
Counsell, Ed.
S M W leq C11,CH20H, 0' CH2 CH3O-@H=CHCOzCH3 -
COZCH,
CH, SMEAH n > leq HN 0, 0'
C02CH,
CH~O+H=CH-CHO -
Lf
Lithium trisiamylborohydride (LTSBH) shows unique stereoselectivity in the reduction of unhindered ketones.8 4 Ketones such as 4-~-butylcyclohexanone undergo exclusive equatorial attack yielding the cis-carbinol. The reagent is superior to LTMBH and L-Selectride.
Protecting Groups - Detonation has been reported for compounds where oxidaIt aption of tetrahydropyranyl (THP) ether derivatives was performed. pears that the THP-protecting group forms sensitive organic peroxides when treated with peroxy reagents. Normal precautions in the work-up of such reactions were insufficient in destruction of the sensitive compounds. THF, dioxolane, and methoxymethyl ether groups should also be presumed to form explosive derivatives upon contact with peroxy reagents.
''
Aldrich now offers 2-~-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON) as a non-explosive replacement for the thermally unstable and shock-sensitive - B O C azide. 8 6 The 8-methoxyethoxymethyl (MEM) group has been introduced as a new general protecting group for the hydroxyl function.87 The MEM group is rapidly introduced under either aprotic basic or aprotic neutral conditions. The MEM group may be selectively cleaved with ZnBrp or TIC14 with no interference from esters or benzyl, allyl, THP, TBDMS, trichloroethyl, or MTM ethers. Conversely, these groups may be removed in the presence of MEM ethers. MEM ethers are stable to strong bases, reducing agents, organometallic reagents, many oxidizing agents, and mild acids. Further extensions of the use of the methylthiomethyl (MTM) protecting group for alcohols have been reported.
"-'
Methyl ethers can be cleaved in minutes at room temperature with diiodomethyl methyl ether. g Methylenation of catechols is greatly im roved with potassium or cesium fluoride in DMF and CHzC12 or CH2Br2. 9 7 The S-2-methoxybenzyl and S-t-butyl protectin groups for cysteine are rapidly cleaved with mercury (11) trifluoroacetate.i 2
Chap. 27
Chemical Reactions
Spat2
275
2-Acyloxymethylbenzoic acids can be used to protect amines. 9 3 The amides so derived can be cleaved with mild acid or base due to neighboring group participation of the generated alcohol. 0
0
The trimethylsilyloxy group of allylic or benzylic alcohols is readily displaced by nucleophiles (malonate anion, alkyl Grignard reagents, hydride This limitation as a protecting group should be noted. (AlC13-LfilH1,)). Miscellaneous - Chiral and achiral thiiranes can be prepared from carbonyl compounds and 2- (alkylthio)-2-oxazolines. 9 5 6-Ketoesters are mildly decarboxylated in refluxing 1.5% aqueous dioxane using alumina (Merck, type T, basic) as catalyst.9 6 References
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.
20. 21. 22. 23. 24. 25. 26. 27. 28.
H. Stetter, Angew. Chem. Int. Ed. Engl., l5, 639 (1976). 0. W. Lever, Jr., Tetrahedron, 32, 1943 (1976). G. W. Gokel and H. D. Durst, Synthesis, 168 (1976). A. Padwa, Angew. Chem. Int. Ed. Engl., l5, 123 (1976). , 2, 270 (1976). A. J. Meyers and E. E. Mihelich, T. Mukaiyama, l5, 94 (1976). A. McKillop and E. C. Taylor, Endeavour, 125, 88 (1976). A. P. Kozikowski and H. F . Wetter, Synthesis, 561 (1976). J. Schwartz and J. A. Labinger, Angew. Chem. Int. Ed. Engl., 15,333 (1976). J. Ficini, Tetrahedron, 32, 1449 (1976). F. Krohnke, Synthesis, 1 (1976). J. M. Patterson, 281 (1976). T. Uchida and K. Matsumoto, M., 209 (1976). J. Weill-Raynal, 633 (1976). T. Mukaiyama, K. Saigo, and 0. Takazawa, Chem. Lett., 1033 (1976). K. Banno, Bull. Chem. SOC. Jap., 49, 2284 (1976). 2,779 (1976) K. Narasaka, K. Soai, Y. Aikawa, and T. Mukaiyama, K. Saigo, M. Osaki, and T. Mukaiyama, Chem. Lett., 163 (1976). S . Danishefsky, T. Kitahara, R. McKee, and P. F. Schuda, J. Amer. Chem. SOC. , 98, 6715 (1976). M. Miyashita, T. Yanami, and A. Yoshikoshi, 98, 4679 (1976). P. Amice, L. Blanco, and J. M. Conia, Synthesis, 196 (1976). G. Stork and A. A. Ponaras, J. Org. Chem., 41, 2937 (1976). P. L. Fuchs, 41, 2935 (1976). J. N. Denis, W. Dumont, and A. Krief, Tetrahedron Lett., 453 (1976). E. J. Corey and D. Enders, w.,3 (1976). E. J. Corey, D. Enders, and M. G. Bock, w.,7 (1976). E. J. Corey and D. Enders, 11 (1976). E. J. Corey and S. Knapp, 3667 (1976).
u.,
m.
u., m.,
w.,
m.,
u.,
m.,
w.,
276 -
Sect. VI
-
Topics in Chemistry
Counsell, Ed.
29. E. J. Corey and S. Knapp, Tetrahedron Lett., 4687 (1976). 30. A. I. Meyers, D. R. Williams and M. Druelinger, J. Amer. Chem. SOC., 98, 3032 (1976). 31. D. Seebach and F. Lehr, Angew. Chem. Int. Ed. Engl., 15, 505 (1976). 2, 438 (1976). 32. D. Seebach and N. Meyer, 33. P. Blatcher, J. I. Grayson and S. Warren, Chem. Commun., 547 (1976). 34. G. N. Barber and R. A. Olofson, Tetrahedron Lett., 3783 (1976). 35. R. A. Olofson, K. D. Lotts, and G. N. Barber, G.,3779 (1976). 3381 (1976). 36. R. A. Olofson, K. D. Lotts, and G. N. Barber, 37. N. Kawabata, M. Naka, and S. Yamashita, J. Amer. Chem. SOC., 98, 2676 (1976). 38. J. E. McMurry and M. P. Fleming, J. Org. Chem., 41,896 (1976). 41,260 39. E. J. Corey, R. L. Danheiser, and S. Chandrasekaran, (1976). 40. G. A. Olah and G. K. S. Prakash, Synthesis, 607 (1976). 41. D. J. Pasto, G. F. Hennion, R. H. Shults, A. Waterhouse and S.-K. Chou, J. Org. Chem., 41,3496 (1976). 42. B. B. Snider, N. J. Hrib, and L. Fuzesi, J. h e r . Chem. SOC., 98, 7115 (1976). 43. T. Cohen, A. J. Mura, Jr., D. W. Shull, E. R. Fogel, R. J. Ruffner, and J. R. Falck, J. Org. Chem., 41, 3218 (1976). 44. B. M. Trost and A. J. Bridges, J. h e r . Chem. SOC., 98, 5017 (1976). 45. L. E. Overman, G. F. Taylor, and P. J. Jessup, Tetrahedron Lett., 3089 (1976). 46. D. H. R. Barton, A. G. Brewster, S. V. Ley, and M. N. Rosenfeld, Chem. Commun., 985 (1976). 47. D. C. Remy, K. E. Rittle, C. A. Hunt, and M. B. Freedman, J. Org. Chem., 41, 1644 (1976). 48. N. Kornblum, L. Cheng, R. C. Kerber, M. M. Kestner, B. N. Newton, H. W. Pinnick, R. G. Smith, and P. A. Wade, 41,1560 (1976). 49. D. A. Evans and J. W. Hoffman, J. Amer. Chem. SOC., 98, 1983 (1976). 50. M. J. Manning, R. W. Raynolds, and J. S. Swenton, 98, 5008 (1976). 51. R. A. Abramovitch and I. Shinkai, Accts. Chem. Res., 9, 192 (1976). 52. L. S. Hegedus, G. F. Allen, and E. L. Waterman, J. Amer. Chem. SOC., 98, 2674 (1976). 98, 8516 (1976). 53. B. M. Trost and J. P. Genet, 54. K. Freter, F. Hess, and K. Grozinger, Ann. Chem., 241 (1976). 55. E. B. Sanders, H. V. Secor, and J. I. Seeman, J. Org. Chem., 41,2658 (1976). 56. L. Blanco, P. Amice, and J. M. Conia, Synthesis, 194 (1976). 57. D. H. R. Barton, R. H. Hesse, R. E. Markwell, M. M. Pechet, and H. T. Toh, J. her. Chem. SOC., 98,3034 (1976). 58. D. H. R. Barton, R. H. Hesse, R. E. Markwell, M. M. Pechet, and S. Rozen, w.,98, 3036 (1976). 59. M. P. Doyle and B. Siegfried, Chem. Commun., 433 (1976). 60. M. Sevrin, W. Dumont, L. Hevesi, and A. Krief, Tetrahedron Lett., 2647 (1976). 61. A. J. Fatiadi, Synthesis, 65, 133 (1976). 62. Y. Ueno and M. Okawara, Tetrahedron Lett., 4597 (1976).
=.,
w.,
m.,
w., w.,
u.,
Chap. 27
Chemical Reactions
Spatz
277
63. K. Saigo, A. Morikawa, and T. Mukaiyama, Bull. Chem. SOC. Jap., 2, 1656 (1976). 64. G. H. Posher, R. B. Perfetti, and A. W. Runquist, Tetrahedron Lett., 3499 (1976). 65. M. E. Jung and L. M. Speltz, J. Amer. Chem. SOC., 98, 7882 (1976). 66. K. Omura, A . K. Sharma, and D. Swern, J. Org. Chem. , 41, 957 (1976). 4 l , 3329 (1976). 67. S. L. Huang, K. Omura, and D. Swern, 68. P. R. Ortiz de Montellano and C. K. Hsu, Tetrahedron Lett., 4215 (1976). 69. H. H. Wasserman and J. L. Ives, J. Amer. Chem. SOC., 98, 7868 (1976). 70. G. M. Rubottom, J. M. Gruber, and G. M. Mong, J. Org. Chem., 41, 1673 (1976). 71. D. Seebach and M. Teschner, Chem. Ber., 109, 1601 (1976). 72. R. Louw, H. P. W. Vermeeren, J. J. A . van Asten, and W. J. Ultee, Chem. Commun., 496 (1976). 73. M. Hojo and R. Masuda, Tetrahedron Lett., 613 (1976). 74. K. B. Sharpless, T. Hori, L. K. Truesdale, and C. 0. Dietrich, J. Amer. Chem. Soc., 98, 269 (1976). 75. K. B. Sharpless and T. Hori, J. Org. Chem., 41, 176 (1976). 41, 177 (1976). 76. K. B. Sharpless, A. 0. Chong, and K. Oshima, 41, 2504 (1976). 77. K. B. Sharpless and S. P. Singer, 78. C. F. Lane, Chem. Rev., 76, 773 (1976). 79. J. M. Fortunato and B. Ganem, J. Org. Chem., 41,2194 (1976). 80. R. 0. Hutchins, D. Rotstein, N. Natale, J. Fanelli, and D. Dimmel, --, ibid 41, 3328 (1976). 81. J. P . Collman, R. G. Finke, P. L. Matlock, R. Wahren, and J. I. Brauman, J. Amer. Chem. SOC., 98, 4685 (1976). 82. G. P. Boldrini and A. Umani-Ronchi, Synthesis, 596 (1976). 526 (1976). 83. R. Kanazawa and T. Tokoroyama, 84. S. Krishnamurthy and H. C. Brown, J. Amer. Chem. Soc., 98, 3383 (1976). 85. A . I. Meyers, S. Schwartzman, G. L. Olson, and H.-C. Cheung, Tetrahedror Lett., 2417 (1976). 4393 (1975). 86. M. Itoh, D. Hagiwara, and T. Kamiya, 809 (1976). 87. E. J. Corey, J.-L. Gras, and P. Ulrich, 88. P. M. Pojer and S. J. Angyal, 3067 (1976). 65 (1976). 89. K. Yamada, K. Kato, H. Nagase, and Y. Hirata, 90. C. A. Smith and J. B. Grutzner, J. Org. Chem., 41, 367 (1976). 91. J. H. Clark, H. L. Holland, and J. M. Miller, Tetrahedron Lett., 3361 (1976). 92. M. Fujino and 0. Nishimura, Chem. Commun., 998 (1976). 93. B. F. Cain, J. Org. Chem., 41, 2029 (1976). 94. J. M. Midgley, J. S . Millership, and W. B. Whalley, J. Chem. SOC. Perkin I, 1384 (1976). 95. A. I. Meyers and M. E. Ford, J. Org. Chem., 41, 1735 (1976). 96. A. E. Greene, A. Cruz, and P. Crabbe, Tetrahedron Lett., 2707 (1976).
w.,
w.,
w.,
w.,
m., u., u.,
w.,