Al-Isopropoxydiisobutylalane. a Stereoselective Reducing Agent for Reduction of cyclic Ketones to Thermodynamically More Stable Alcohols

Full text of DOI:10.1021/jo970083a

J . Org. Chem. 1997, 62, 3019-3020
3019
Ta ble 1. Ster eoselective Red u ction of Cyclic Keton es
Al-Isop r op oxyd iisobu tyla la n e. A
Ster eoselective Red u cin g Agen t for
Red u ction of Cyclic Keton es to
w ith Al-Isop r op oxyd iisobu tyla la n e (DIBAOiP r ) in Eth yl
Eth er a t 25 °Ca
ratio of
Th er m od yn a m ica lly Mor e Sta ble Alcoh ols
reaction more stable
yield of
ketone
time (h) isomer (%)b alcohol (%)b
J in Soon Cha* and Oh Oun Kwon
2-methylcyclohexanone
3
6
49
67
85
91
94
95
96
89
91
93
93
94
95
89
92
94
97
>99.9
91
95
95
97
98
97
98
>99.9
>99.9
85
90
92
93
95
97
31
51
71
92
98
99
>99.9
100 (82)
94
98
99
Department of Chemistry, Yeungnam University,
Kyongsan 712-749, Republic of Korea
24
72
96
120
168
3
Received J anuary 15, 1997
In recent years, new developments in the area of
stereoselective reduction of cyclic ketones have been
exceptionally encouraging. Especially, the reagents de-
veloped for conversion of cyclic ketones to the thermo-
dynamically less stable alcohols are extraordinary.1
However, although several useful reagents have been
devised for converting cyclic ketones to the thermody-
namically more stable alcohols,2 generally acceptable
synthetic methods for this conversion have still been
lacking. In the course of a systematic study of the
reducing characteristics of Al-alkoxydiisobutylalane, we
have found that Al-isopropoxydiisobutylalane, one of
these derivatives, reveals an excellent stereoselectivity
in such cyclic ketone reductions to provide the corre-
sponding thermodynamically more stable alcohols. This
paper describes this stereoselective reduction.
3-methylcyclohexanone
6
24
72
96
120
3
24
72
96
120
6
24
48
72
96
12
24
72
96
6
24
48
72
96
120
24
120
168
>99.9
100
100
98
4-methylcyclohexanone
99
>99.9
100
100
98
>99.9
100
100
100 (84)
89
94
99
100
43
76
4-tert-butylcyclohexanone
3,3,5-trimethylcyclohexanone
norcamphor
Resu lts a n d Discu ssion
Al-isopropoxydiisobutylalane (DIBAOiPr) is readily
prepared by a simple reaction between diisobutylalumi-
num hydride (DIBAH) and isopropyl alcohol in ethyl
ether(eq 1). The reactivity of this reagent in a stoichio-
89
96
>99.9
100
7
camphor
36
37
14
23
a
b
A 1:1 ratio for reagent to ketone was utilized. Analyzed by
GC. The numbers in parentheses are isolated yields.
tions. This seems to be a phenomenon that must rise
metric amount toward representative cyclic ketones at
25 °C and the isomeric ratio of the product mixture are
summarized in Table 1.
The most striking feature of the Table 1 is that the
stereochemistry of reduction with DIBAOiPr is appar-
ently dependent on the reaction time. The stereoselec-
tivity increases consistently with increase of reaction time
to afford the thermodynamically more stable isomer
alcohols exclusively (eq 2), with the exception of camphor
which is resistant to reduction under the reaction condi-
where the thermodynamically less stable alcohol isomer,
one of the two isomer produced by reduction with
DIBAOiPr, is converted to the more stable one by
thermodynamically controlled isomer equilibration via a
Meerwein-Ponndorf-Verley type reduction.3
(1) (a) Brown, H. C.; Krishnamurthy, S. J . Am. Chem. Soc. 1972,
94, 7159. (b) Krishnamurthy, S. Aldrichim. Acta 1974, 7, 55. (c)
Krishnamurthy, S.; Brown, H. C. J . Am. Chem. Soc. 1976, 98, 3383.
(d) Brown, C. A.; Krishnamurthy, S. J . Organomet. Chem. 1978, 156,
111. (e) Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979, 35, 567.
(f) Brown, H. C.; Cha, J . S.; Nazer, B. J . Org. Chem. 1984, 49, 2073.
(g) Yoon, N. M.; Kim, K. E.; Kang, J . J . Org. Chem. 1986, 51, 226. (h)
Cha, J . S.; Yoon, M. S.; Kim, Y. S.; Lee, K. W. Tetrahedron Lett. 1988,
29, 1069.
Exp er im en ta l Section 4
P r ep a r a tion of Al-Isop r op oxyd iisobu tyla la n e (DIBAO-
iP r ) in Eth yl Eth er . The following procedure served for the
preparation of the reagent. An oven-dried, 200-mL, round-
(2) (a) Eliel, E. L.; Rerick, M. J . Am. Chem. Soc. 1960, 82, 1367.
(b) Eliel, E. L.; Martin, R. J . L.; Nasipuri, D. Organic Syntheses;
Wiley: New York, 1973; Coll. Vol. 5, p 175. (c) Abramovitch, R. A.;
Marsh, W. C.; Saha, J . G. Can. J . Chem. 1965, 43, 2631. (d) Mestroni,
G.; Zassinovich, G.; Camus, A.; Martinelli, F. J . Organomet. Chem.
1980, 198, 87. (e) Toros, S.; Kollar, L.; Heil, B.; Marko, L. J .
Organomet. Chem. 1983, 255, 377. (f) Spogliarich, R.; Mestroni, G.;
Graziani, M. J . Mol. Catal. 1984, 22, 309. (g) Maruoka, K.; Sakurai,
M.; Yamamoto, H. Tetrahedron Lett. 1985, 26, 3853. (h) Sarkar, A.;
Rao, B. R.; Ram, B. Synth. Commun. 1993, 23, 291. (i) Fisher, G. B.;
Fuller, J . C.; Harrison, J .; Alvarez, S. G.; Burkhardt, E. R.; Goralski,
C. T.; Singaram, B. J . Org. Chem. 1994, 59, 6378. (j) Fort, Y.
Tetrahedron Lett. 1995, 36, 6051.
(3) (a) A similar time dependence was reported by Haubenstock and
Davidson (J . Org. Chem. 1963, 28, 2772) as observed in the reduction
of excess 3,3,5-trimethylcyclohexanone with triisobutylaluminum (TIBA).
(b) Heinsohn, G. E.; Ashby, E. C. J . Org. Chem. 1973, 38, 4232.
(4) All reactions were performed under a dry N2 atmosphere. All
chemicals used were commercial products of the highest purity
available; ethyl ether was dried over 4-Å molecular sieves and distilled
from sodium-benzophenone ketyl prior to use. 27Al NMR spectra were
recorded on a Bruker AMX 300 spectrometer, and the chemical shifts
3+
are reported in parts per million with reference to Al(H2O)6
chromatographic analyses were carried out with
chromatograph using a 50 m HP 20 M capillary column.
. Gas
a
Varian 3300
S0022-3263(97)00083-2 CCC: $14.00 © 1997 American Chemical Society

3020 J . Org. Chem., Vol. 62, No. 9, 1997
Notes
bottomed flask, equipped with a side arm, a condenser, and an
adaptor connected to a mercury bubbler, was cooled to room
temperature under a stream of nitrogen and maintained under
a static pressure of nitrogen. To this flask was added 14.22 g
of i-Bu2AlH (100 mmol) and 25 mL of ethyl ether, and the flask
was cooled to 0 °C in an ice-water bath. A 6.31 g amount of
isopropyl alcohol (105 mmol) was added to the solution of
i-Bu2AlH dropwise with vigorous stirring at 0 °C. After the
complete evolution of hydrogen, the reagent solution was brought
to room temperature. The solution was then diluted with ethyl
ether to make a total volume of 100 mL to be 2 M. 27Al NMR of
the solution showed a broad singlet centered at δ 160.
Red u ction of Cyclic Keton es. The following procedure was
used to explore the stereoselectivity of this reagent. In a 50-
mL, round-bottomed flask was placed 5.0 mL of the 2.0 M
solution of the reagent in ethyl ether (10.0 mmol). The flask
was maintained at 25 °C by immersion in a water bath. To the
flask was added 10 mL of 2-methylcyclohexanone solution in
ethyl ether (1.0 M in ketone), and the reaction mixture was
stirred at 25 °C. After the appropriate time intervals, the
reaction aliquot was withdrawn and then quenched by addition
of 3 N HCl. The aqueous layer was saturated with MgSO4, and
the organic layer was dried over anhydrous K2CO3. The isomeric
ratio of alcohol product analyzed by GC using a capillary column
are listed in Table 1.
Isola tion of Alcoh ols. The following procedure is for the
larger scale reaction. In the assembly previously described was
placed 25 mL of 2.0 M reagent solution (50 mmol). Into the
solution was injected 25 mL of a 2.0 M solution of 2-methylcy-
clohexanone (5.6 g, 50 mmol) in ethyl ether, and the reaction
mixture was stirred for 7 days at room temperature. The
mixture was then hydrolyzed with 50 mL of 3 N HCl, until the
gelatinous precipitate was dissolved, and saturated with NaCl.
The separated organic layer was washed three times with 3 N
NaOH (3 × 20 mL) and dried over anhydrous K2CO3. All the
volatile materials were evaporated under reduced pressure to
yield almost pure 2-methylcyclohexanol (>98% purity). Frac-
tional distillation gave 4.7 g (82% yield) of essentially pure
2-methylcyclohexanol, bp 166-168 °C (754 mm). GC examina-
tion revealed the presence of 4% cis- and 96% trans-2-methyl-
cyclohexanol.
Ack n ow led gm en t. This research was supported by
Ministry of Education (BSRI-96-3420) and Organic
Chemistry Research Center-KOSEF, Republic of Korea.
J O970083A