A. Clerici, N. Pastori, O. Porta
FULL PAPER
mer, and the axial alcohols of all other cycloalkanones of Table
1 to the cis isomer.
It must be empasised that NH4Cl is formed in situ when
ammonia is used to neutralize the aqueous acidic TiCl3 solu-
tion. NH4Cl is usually used to destroy organometallic species
before workup.
20.1 (CH3), 36.2 (C-3), 45.6 (C-2), 75.0 (C-1), 123.2 (C-5), 123.6
(C-7), 126.7 (C-6), 128.0 (C-8), 145.0 (C-9), 147.3 (C-4).
[15]
[16]
Acknowledgments
We gratefully acknowledge the financial support for this work from
E. Hayon, M. Simic, Acc. Chem. Res. 1974, 7, 114Ϫ121.
[17] [17a]
`
V. Rautenstrauch, B. Willhaln, W. Thommen, U. Burger,
Ministero dell’Universita e della Ricerca Scientifica e Tecnologica
[17b]
Helv. Chim. Acta 1981, 64, 2109Ϫ2137. Ϫ
V. Rauten-
(Cofin. 1998).
strauch, J. Chem. Soc., Chem. Commun. 1986, 1558Ϫ1560. Ϫ
[17c]
V. Rautenstrauch, Tetrahedron 1988, 44, 1613Ϫ1618.
[1] [1a]
[18]
[19]
J. W. Huffman, Comprehensive Organic Synthesis, B. M.
R. V. Lloyd, G. Causey, J. Chem. Soc., Perkin Trans. 2 1981,
1143Ϫ1147.
Trost, Ed., Pergamon: New York, 1991, vol. 8, p. 107Ϫ127. Ϫ
[1b] P. Girad, J. L. Namy, H. B. Kagan, J. Am. Chem. Soc. 1980,
Accordingly, Pradhan (ref.[2c]) suggested that the stereoselectiv-
ity observed for dissolving metal reductions of cyclohexanones
in alcoholic solvents (see ref.[2e]) is determined by the ketyl Aeq
↔ Aax equilibrium of Scheme 1 and ab initio calculations (see
ref.[3]) confirmed that the equatorial preference of Aeq (98.3:1.7,
barrier inversion 2.4 kcal molϪ1) is about the same as that ex-
perimentally found for the equatorial alcohol (98:2), ref.[2e]
Whereas the calculated equatorial preference of Beq is too low
(80:20) and that of anion Ceq is too high (ഠ 100%) to account
for the observed stereoselectivity.
[1c]
102, 2693Ϫ2698. Ϫ
H. B. Kagan, J. L. Namy, P. Girad,
Tetrahedron Suppl. n°1, 1981, 37, 175Ϫ180. Ϫ [1d] Y. Kamochi,
T. Kudo, Tetrahedron Lett. 1991, 32, 3511Ϫ3514. Ϫ
[1e]
J. M.
Khurana, A. Sehgal, A. Gogia, A. Manian, G. C. Maikap, J.
Chem. Soc., Perkin Trans. 1 1996, 2213Ϫ2216.
[2] [2a]
D. H. R. Barton, C. H. Robinson, J. Chem. Soc. 1954,
[2b]
3045Ϫ3051. Ϫ
H. O. House, Modern Synthetic Reactions,
[2c]
2nd edn., W. A. Benjamin: New York, 1972, p.150Ϫ172. Ϫ
[2d]
S. K. Pradhan, Tetrahedron 1986, 42, 6351Ϫ6388. Ϫ
J. W.
Huffman, Acc. Chem. Res. 1983, 16, 399Ϫ405. Ϫ [2e] J. W. Huff-
man, J. T. Charles, J. Am. Chem. Soc. 1968, 90, 6486Ϫ6491.
J-D. Wu, K. N. Houk, J. Am. Chem. Soc. 1992, 114,
1656Ϫ1661 and references therein.
[20]
Hydroxy or alkoxy substituents at a carbanionic center signific-
antly increase the anion inversion barrier and evidence for pro-
tonation of organometallic compounds with retention of con-
figuration is very strong: J. S. Sawyer, T. L. Macdonald, G.
J. Mc Garvey, J. Am. Chem. Soc. 1984, 106, 3376Ϫ3377. See
also ref.[2c]
11 and 10 are conformationally labile: J. March, Advanced Or-
ganic Chemistry, 3rd edn., Wiley Interscience: New York, 1985,
p. 126.
A. M. Wilson, N. L. Allinger, J. Am. Chem. Soc. 1961, 83,
1999Ϫ2001. According to these authors, the axial conformer
of 2-Cl-cyclohexanone is the most easily reduced form.
B. C. Gilbert, M. Trenwith, J. Chem. Soc., Perkin Trans. 2 1975,
10, 1083Ϫ1090.
[3]
[4] [4a]
A. Clerici, O. Porta, M. Riva, Tetrahedron Lett. 1981, 22,
[4b]
1043Ϫ1046. Ϫ
A. Clerici, O. Porta, Tetrahedron 1982, 38,
1293Ϫ1297. Ϫ [4c] A. Clerici, O. Porta, J. Org. Chem. 1982, 47,
[21]
[22]
[23]
[4d]
2852Ϫ2856. Ϫ
A. Clerici, O. Porta, Tetrahedron 1983, 39,
1239Ϫ1246. Ϫ [4e] A. Clerici, O. Porta, J. Org. Chem. 1983, 48,
[4f]
1690Ϫ1694. Ϫ
A. Clerici, O. Porta, P. Zago, Tetrahedron
1986, 42, 561Ϫ572.
[5]
[6]
A. Clerici, O. Porta, Tetrahedron Lett. 1982, 23, 3517Ϫ3520; In
this work the reaction was made alkaline by the addition of
NaOH instead of NH3 solution.
The reducing power of the TiIV/TiIII system is strongly pH de-
pendent. The equation E ϭ 0.029 Ϫ 0.236 pH Ϫ 0.059 log
TiIII is valid in basic medium where insoluble TiO2 is formed:
[24] [24a]
J. Gloux, M. Guglielmi, H. Lemaire, Mol. Phys. 1970, 19,
[24b]
833Ϫ840. Ϫ
See ref.[2c], p. 6355.
[25] [25a]
J. B. Umland, B. W. Williams, J. Org. Chem. 1956, 21,
`
`
Pourbaix, N. Atlas d’Equilibres Electrochimiques, Goutier-
Villars: Paris, 1963; p. 213.
[25b]
1302Ϫ1304. Ϫ
Soc. 1956, 78, 2788Ϫ2790. Ϫ
J. B. Umland, M. I. Jefraim, J. Am. Chem.
[25c]
See ref.[8b], p. 118Ϫ119.
[7]
A. Clerici; L. Clerici, O. Porta, Tetrahedron Lett. 1996, 37,
3035Ϫ3038.
[26]
According to Barton’s generalisation, ‘‘when a distinction has
to be made between two alternatives, it is logical that the pre-
ferred conformation places the larger substituent in the equat-
orial position avoiding steric congestion’’: D. H. R. Barton, J.
Chem. Soc. 1953, 1027Ϫ1040. In our case, the kinetically fa-
voured C may well be the intermediate of ‘‘minimum energy’’
and, hence, its formation would not only be faster, but also less
reversible (Scheme 1).
NaBH4 reduction of ketone 17 afforded a trans to cis ratio of
70: 30. B. Caro, G. Jaouen, Tetrahedron Lett. 1974, 14,
1229Ϫ1231.
P. T. Lansbury, R. E. MacLeay, J. Org. Chem. 1963, 28,
1940Ϫ1241.
[8] [8a]
[8b]
See ref.[2b], p. 60Ϫ70. Ϫ
J. D. Morrison, H. S. Mosher,
Asymmetric Organic Reactions, Prentice-Hall Inc.: New Jersey,
[8c]
1971, p. 116Ϫ132. Ϫ
E. C. Ashby, J. R. Boone, J. Org.
Chem. 1976, 41, 2890Ϫ2897. Ϫ [8d] K. S. Ravikumar, S. Chand-
rasekaran, J. Org. Chem. 1996, 61, 826Ϫ830 and references
[8e]
therein. Ϫ
M. C. Barden, J. Schwartz, J. Org. Chem. 1995,
60, 5963Ϫ5965.
[27]
[9]
D. C. Wigfield, J. Canad. Chem. 1977, 646Ϫ649.
H. Handel, G. L. Pierre, Tetrahedron Lett. 1976, 24,
2029Ϫ2032.
[10]
[28]
[29]
TiIV salts catalyse acetal formation in basic medium of either
aliphatic and aromatic aldehydes or cyclic aliphatic ketones: A.
Clerici, N. Pastori, O. Porta, Tetrahedron 1998, 54,
15679Ϫ15690; A. Clerici, N. Pastori, O. Porta, Tetrahedron
2001, 57, 217Ϫ225.
[11]
G. Buono, G. Triantaphylides, G. Peiffer, Synthesis 1982,
1030Ϫ1033.
H. Mimoun, J. Org. Chem. 1999, 64, 2582Ϫ2589.
[30]
[31]
[12] [12a]
J. A. Dean, Handbook of Organic Chemistry, Mc Graw-
Alcohols from ketones 1؊6, 12؊16, 19, 21؊23 are commercial
products, supplied by Aldrich. The relevant references of the
others alcohols are given in succession. cis and trans-1-phenyl-
cyclohexan-4-ol from ketone 7: P. A. England, D. A. Rouch,
A. C. G. Westlake, S. G. Bell, D. P. Nickerson, M. Webberley,
S. L. Flitsch, L-L. Wong, Chem. Commun. 1996, 357Ϫ358; cis
and trans -3,3,5-trimethylcyclohexanol from ketone 8: R. H.
Crabtree, M. W. Davis, J. Org. Chem. 1986, 51, 2655Ϫ2661;
cis and trans-4-hydroxy-2,2,6-trimethylcyclohexan-1-one from
ketone 9: H. G. W. Leuenberger, W. Boguth, E. Widmer, R.
Zell, Helv. Chim. Acta 1976, 59, 1832Ϫ1849; trans-2-methoxy-
cyclohexanol from ketone 11: D. D. Roberts, J. Org. Chem.
Hill: New York, 1987, p. 8Ϫ76. Ϫ [12b] L. Meites, Polarographic
Techniques, 2nd edn., Wiley-Interscience: New York, 1965, p.
671Ϫ711. Ϫ [12c] α-Halocarbonyls are usually reduced at signi-
ficantly less negative potentials than those required for the cor-
responding ketones. For example the reduction potential of
cyclohexanone and 2-chlorocyclohexanone are Ϫ2.45 and
Ϫ0.98 V (vs. SCE), respectively, ref.[12b]
G. A. Molander, G. Hahn, J. Org. Chem. 1986, 51, 1135Ϫ1138
and references therein.
The axial alcohol of ketones 3, 8 and 9 correspond to the trans
isomer, the axial alcohol of norchamphor 19 to the endo iso-
[13]
[14]
2242
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