A solution of borane in tetrahydrofuran. A stereoselective reducing agent for reduction of cyclic ketones to thermodynamically more stable alcohols

Full text of DOI:10.1021/jo010401c

7514
J . Org. Chem. 2001, 66, 7514-7515
Ta ble 1. Ster eoselective Red u ction of Cyclic Keton es
A Solu tion of Bor a n e in Tetr a h yd r ofu r a n .
w ith a Solu tion of Bor a n e in Tetr a h yd r ofu r a n
A Ster eoselective Red u cin g Agen t for
Red u ction of Cyclic Keton es to
Th er m od yn a m ica lly Mor e Sta ble Alcoh ols
(BH3-THF )a
ratio of more
yields of
alcohol (%)
time (d) 0 °C 25 °C reflux under refluxb
stable isomerb (%)
reaction
ketone
J in Soon Cha,* Suk J oung Moon, and J ae Hyung Park
2-methylcyclo-
hexanone
0.25
3
5
0.25
64
64
68
68
70
92
81
88
100 (81)
81
Department of Chemistry and Institute of Natural Sciences,
Yeungnam University, Gyongsan 712-749, Republic of Korea
68 >99.5
82
83
3-methylcyclo-
hexanone
80
80
83
85
jscha@yu.ac.kr
3
96
5
0.25
3
5
0.25
1
5
7
0.25
3
7
14
0.25
1
7
0.25
84 >99.5
100
85
99
Received April 17, 2001
4-methylcyclo-
hexanone
79
79
80
82
82
85
Recent developments in the area of stereoselective
reduction of cyclic ketones have been exceptionally
promising. The reagents developed for conversion of cyclic
ketones to the thermodynamically less stable alcohols are
extraordinary.1 Moreover, the newly devised methods for
conversion of cyclic ketones to the thermodynamically
more stable alcohols are encouraging.2
A solution of borane in THF (BH3-THF) represents a
valuable reducing agent3 and has been widely used in
organic synthesis. Nevertheless, the reagent has not
attracted much attention in the stereoselective reduction
of cyclic ketones because the stereoselectivity achieved
by the reagent at 0 °C is poor.4 However, in the course of
reexamining the reducing characteristics of BH3-THF,
we have found that the reagent reveals an unexpectedly
high stereoselectivity in such cyclic ketone reductions at
higher temperatures in THF to provide the corresponding
to thermodynamically more stable alcohols. This report
describes such stereoselective reduction.
82 >99.5
100 (82)
4-tert-butylcyclo-
hexanone
84
83
85
86
85
37
37
89
90
91
45
90
92
99
100
74
82
87
3,3,5-trimethylcyclo-
hexanone
27
28
38 >99.5
>99.5
100
norcamphor
camphor
4
4
5
5
6
7
89
99
38
39
38
1
5
7
40
41
42
45
49
89
97
98
64
75
92
99
10
a
b
A 1:3.3 ratio for reagent to ketone was utilized. Analyzed by
GC with tridecane as an internal standard. The numbers in
parentheses are isolated yields.
reaction temperature (i.e., 0 °C, 25 °C and reflux), and
the reactivity and the isomeric ratios obtained of the
product mixture are summarized in Table 1.
Resu lts a n d Discu ssion
The reduction of representative cyclic ketones (10%
The most characteristic feature of the Table 1 is that
the stereochemistry of reduction under reflux is depend-
ent on the reaction time, while the reactions at 0 and 25
°C show no such a time dependence. Thus, under reflux,
the stereoselectivity increases consistently with increase
of the reaction time to afford the thermodynamically
more stable isomer alcohols exclusively (eq 1), with the
exception of norcamphor.5
excess) with BH3-THF has been studied at different
(1) (a) Brown, H. C.; Krishnamurthy, S. J . Am. Chem. Soc. 1972,
94, 7159. (b) Krishnamurthy, S.; Brown, H. C. J . Am. Chem. Soc. 1976,
98, 3383. (c) Brown, H. C.; Krishnamurthy, S. J . Organomet. Chem.
1978, 156, 111. (d) Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979,
35, 567. (e) Brown, H. C.; Cha, J . S.; Nazer, B. J . Org. Chem. 1984,
49, 2073. (f) Cha, J . S.; Yoon, M. S.; Kim, Y. S.; Lee, K. W. Tetrahedron
Lett. 1988, 29, 1069. (g) Cha, J . S.; Yoon, M. S.; Lee, K. W.; Lee, J . C.
Heterocycles 1988, 27, 1455. (h) Cha, J . S.; Min, S. J .; Kim, J . M.; Kwon,
O. O.; J eoung, M. K. Org. Prep. Proced. Int. 1993, 25, 444.
(2) (a) Mestroni, G.; Zassinovich, G.; Camus, A.; Martinelli, F. J .
Organomet. Chem. 1980, 198, 87. (b) Toros, S.; Kollar, L.; Heil, B.;
Marko, L. J . Organomet. Chem. 1983, 255, 377. (c) Spogliarich, R.;
Mestroni, G.; Graziani, M. J . Mol. Catal. 1984, 22, 309. (d) Maruoka,
K.; Sakurai, M.; Yamamoto, H. Tetrahedron. Lett. 1985, 26, 3853. (e)
Sarkar, A.; Rao, B. R.; Ram, B. Synth. Commun. 1993, 23, 291. (f)
Fisher, G. B.; Fullerm J . C.; Harrison, J .; Alvarez, S. G.; Burkhardt,
E. R.; Goralski, C. T.; Singaram, B. J . Org. Chem. 1994, 59, 6378. (g)
Fort, Y. Tetrahedron Lett. 1995, 36, 6051. (h) Cha, J . S.; Kwon, O. O.
J . Org. Chem. 1997, 62, 3019. (i) Cha, J . S.; Kwon. O. O.; Kim. J . M.;
Cho, S. D. Synlett 1997, 1465. (j) Cha, J . S.; Kwon, O. O.; Bull. Korean
Chem. Soc. 1997, 18, 689. (k) Cha, J . S.; Moon, S. J .; Kwon, O. O.;
Lee, Y. R. Bull. Korean Chem Soc. 2000, 21, 128. (l) Kwon, O. O.; Cha,
J . S. Bull. Korean Chem. Soc. 2000, 21, 659.
(3) (a) Brown, H. C.; Yoon, N. M. J . Am. Chem. Soc. 1968, 90, 2686.
(b) Brown, H. C.; Yoon, N. M. Chem. Commun. 1968, 1549. (c) Brown,
H. C.; Hein, P.; Yoon, N. M. J . Am. Soc. 1970, 92, 1637. (d) Yoon, N.
M.; Park, C. S.; Brown, H. C.; Krishnamurthy, S.; Stoky, T. P. J . Org.
Chem. 1973, 38, 2786. (e) Yoon, N. M.; Cha, J . S. J . Korean Chem.
Soc. 1977, 21, 108. (f) Brown, H. C.; Krishnamurthy, S. Tetrahedron
1979, 35, 567. (g) Yoon, N. M.; Cho, B. T. Tetrahedron. Lett. 1982, 23,
2475. (h) Cha, J . S.; Park, J . H.; Lee, D. Y. Bull. Korean Chem. Soc.
2001, 22, 325.
This appears to be a situation that must rise where
the thermodynamically less stable alcohol isomer, one of
the two isomers produced by reduction with BH3-THF,
is converted to the more stable one by thermodynamically
controlled isomer equilibration via a Meerwein-Ponndorf-
Verley (MPV) type reduction (eq 2).6
(5) Fortunately, the reaction of alane derivatives2h-l is favorable for
norcamphor. Consequently, the two procedures complement each other.
(6) Evidence for the MPV-type reaction of boron alkoxides is
provided by the preliminary experiments that triisopropoxyboron
readily reacts with simple ketones at room temperature or in refluxing
THF under a stream of nitrogen to give the corresponding alcohols in
high yields. For example, the reduction of 3 equiv of 2-heptanone yields
97% of 2-heptanol for 3 d at room temperature and for 1 d under reflux.
(4) (a) Klein, J .; Dunkelblum, E. Isr. J . Chem. 1967, 5, 181. (b) Klein,
J .; Dunkelblum, E. Tetrahedron 1967, 23, 205. (c) Brown, H. C.; Varma,
V. J . Org. Chem. 1974, 39, 1631.
10.1021/jo010401c CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/09/2001

Notes
J . Org. Chem., Vol. 66, No. 22, 2001 7515
Ta ble 2. Ster eoselective Red u ction of Cyclic Keton es
w ith a Solu tion of BH3-SMe2 (BMS) in Tetr a h yd r ofu r a n
u n d er Reflu xa
reaction
time (d)
ratio of more
ketone
stable isomerb (%)
2-methylcyclohexanone
7
14
7
14
7
14
3
7
14
3
7
14
3
59
59
82
81
79
80
76
76
76
44
53
81
7
3-methylcyclohexanone
4-methylcyclohexanone
4-tert-buthylcyclohexanone
Support for the above explanation is provided by the
fact that the reaction of trialkoxyboron, formed from 3
equiv of cis-2-methylcyclohexanol (a 99% isomeric purity)
and BH3-THF, in the presence of 0.3 equiv of 2-meth-
ylcyclohexanone for 5 days under reflux, gives trans-2-
methylcyclohexanol in 99.5% isomeric purity upon hy-
drolysis (eq 3).7 This is an interesting example which
shows a possibility for isomer conversion from the
thermodynamically less stable alcohols to the more stable
ones. We are examining this possibility in detail.
3,3,5-trimethylcyclohexanone
norcamphor
7
14
3
7
14
7
7
44
45
51
camphor
a
b
A 1:3.3 ratio for reagent to ketone was utilized. Analyzed by
GC.
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 is listed in Tables 1 and 2.
Isola tion of Alcoh ols. The following procedure is for larger
scale reactions. In the assembly previously described was placed
20 mL of 1.0 M BH3-THF solution (20 mmol). Into the solution
was injected 7.4 g of 2-methylcyclohexanone (66 mmol). The
reaction was brought to gentle reflux, and the reaction mixture
was stirred for 5 d. The mixture was then hydrolyzed with 20
mL of 3 N HCl and saturated with NaCl. The separated organic
layer was dried over anhydrous K2CO3. All the volatile materials
were evaporated under reduced pressure and fractional distil-
lation gave 5.5 g (81% yield) of essentially pure 2-methylcyclo-
hexanol, bp 165-167 °C (759 mm). GC examination revealed
the presence of a trace amount of cis- and >99.5% trans-2-
methylcyclohexanol.
Rea ction of Tr is(2-m eth ylcycloh exyloxy)bor on in th e
P r esen ce of 2-Meth ylcycloh exa n on e. The following proce-
dure served for conversion of the thermodynamically less stable
isomer alcohol to the more stable one. In a 50-mL flask was
placed 5.0 mL of a 1.0 M solution of BH3-THF (5.0 mmol). To
this, 1.71 g of cis-2-methylcyclohexanol (a 99% isomeric purity,
15 mmol) was injected dropwise with stirring at room temper-
ature. After the complete addition, the reaction mixture was
allowed to stir for an additional 1 h at that temperature, and
then 0.17 g of 2-methylcyclohexanone (1.5 mmol) was added.
After being stirred for 5 d under reflux, the mixture was
quenched by addition of 3 N HCl. The aqueous layer was
saturated with MgSO4, and the organic layer was dried over
anhydrous K2CO3. GC analysis indicated the presence of trans-
2-methylcyclohexanol in a purity of higher than 99.5%.
The same reactions with a solution of borane-dimethyl
sulfide (BMS) in THF under reflux were also carried out
for comparison, and the isomeric ratios of the product
mixture are summarized in Table 2. The stereoselectivity,
however, shows no dependence on the reaction time.
Exp er im en ta l Section 8
Red u ction of Cyclic Keton es. The following procedure was
used to explore the stereoselectivity of the reagent.9 An oven-
dried, 50-mL, round-bottomed flask, equipped with a sidearm,
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 10.0 mL of the 1.0 M solution of the reagent in THF
(10.0 mmol) and 3.70 g of 2-methylcyclohexanone (33 mmol).
Tridecane was added as an internal standard.
The reaction was brought to gentle reflux. After the appropri-
ate time intervals, the reaction aliquots were withdrawn and
then quenched by addition of 3 N HCl. The aqueous layer was
(7) In the case of the reaction without added 2-methylcyclohexanone
under reflux, the cis-alcohol was recovered without change of isomeric
purity.
(8) All reactions were performed under a dry N2 atmosphere. All
chemicals used were commercial products of the highest purity
available; THF was dried over 4-Å molecular sieves and distilled from
sodium-benzophenone ketyl prior to use. Gas chromatographic analy-
ses were carried out with a Varian CP-3380 chromatograph using a
30 m DB-WAX capillary column.
Ack n ow led gm en t. This work was supported by a
Korea Research Foundation Grant (KRF-2000-015-
DPO269) and Yeungnam University research grants in
2000.
(9) A solution of BH3-THF was prepared from NaBH4 and Me2SO4
in THF; BMS was purchased from Aldrich Chemical Co.
J O010401C