Alkoxy-directed radical reductions of ketones using trichlorosilane

Full text of DOI:10.1021/jo981763w

2
610
J . Org. Chem. 1999, 64, 2610-2611
Alk oxy-Dir ected Ra d ica l Red u ction s of
Keton es Usin g Tr ich lor osila n e
Sch em e 1
Eric J . Enholm* and J ames P. Schulte II
Department of Chemistry, University of Florida,
Gainesville, Florida 32611
Ta ble 1. Sila n e Ra d ica l Red u ction s of
Received August 28, 1998 (Revised Manuscript Received February
4
-t-Bu tylcycloh exa n on e
2
6, 1999 )
The reduction of ketones with hydride reagents is a well-
established two-electron transformation that has been used
1
extensively in organic synthesis. The related free-radical
reduction of ketones remains a potentially valuable one-
electron alternative to this reaction. Reagents used in this
capacity include nBu3SnH,2 SmI2,3 and silanes; however,
this reaction is not nearly as well-developed as hydride
reductions. If a silane bears substituents that can react with
an alcohol, an R-hydroxy ketone can be an excellent stereo-
chemical scaffold for a free-radical ketone reduction. In this
scenario, the siloxy function behaves as a steric bias for a
stereoselective hydrogen atom abstraction in a one-electron
reduction. Although R-alkoxy-directed reactions of ketones
are now well-established with nucleophiles and hydride
reagents, the related free-radical reductions have not been
examined.5
reducing agent
Me3Si)3SiH
Cl3SiH
Ph3SiH
Et3SiH
time (h)
condns
yield (%)
4
(
10.5
16
9
hν
hν
66
82
50
13
110 °C, toluene
36
hν
expensive than both tributyltin hydride and tris(trimethyl-
silyl)silane (TTMSS).9
The reduction of a simple ketone, 4-tert-butylcyclohex-
anone (4), was first examined using several silanes as shown
in Table 1. The attachment of trimethylsilyl, halogen, and
phenyl functions to the silane have been previously used to
stabilize the silicon free radical that subsequently reacts
In this paper, the reduction of simple ketones with silanes
led to a new highly diastereoselective reduction of R-hydroxy
ketones to anti-1,2-diols under neutral free radical condi-
tions. Using the inexpensive and convenient reagent tri-
chlorosilane, the alkoxy-directed reduction of 1 gave dia-
stereomeric ratios up to 134:1, favoring the anti-1,2-diol 2,
4,6,10
with the ketone presumably via O-silyl ketyl 5.
Although
the equatorial hydroxyl predominated in the trans-4-tert-
butylcyclohexanol (6) product, a small amount of the cis
isomer (5-20%) formed in each reaction and was included
4c
in the yield for each experiment.
6
as shown in Scheme 1. When other one-electron reagents
The most interesting conclusion from these data was that
the yield for trichlorosilane was higher than any other silane
tested. Except for triphenylsilane, the silane reducing agents
were used as solvents. Most silanes except TTMSS reacted
very sluggishly, and triphenylsilane did not react at all
under photolytic conditions and required forcing thermal
conditions at 110 °C.
were examined, much lower diastereomeric ratios or none
of the desired products were obtained. Moreover, trichloro-
silane was more stereoselective than established alcohol-
directed two-electron hydride reagents such as sodium
borohydride and lithium aluminum hydride, which favored
2
in lower ratios ranging from 5:1 to 20:1. A mechanistic
test confirmed the free-radical nature of the reaction, which
likely involves a preliminary reaction with the hydroxyl
function prior to ketone reduction.
The reduction of R-hydroxy ketone 7a , R ) cyclohexyl, was
studied next, comparing the diastereoselectivity of several
silanes and nBu3SnH as free-radical reductants.11 This is
Trichlorosilane also has two additional useful benefits for
the organic chemist. First, silanes in general are an appeal-
ing alternative to tin analogues, due to the environmentally
shown in Table 2. For comparison purposes, the diastereo-
selectivities for the common two-electron hydride reductants,
NaBH4 and LiAlH4, were also obtained. Adequate separation
of the diastereomeric product diols could not be achieved by
capillary GC, so conversion to the acetonides was adapted,
as shown in Scheme 2. This was achieved by reacting the
diastereomeric diol mixture with 2,2-dimethoxypropane,
acetone, and a catalytic amount of p-TsOH. The syn-8 and
anti-8 diols produced the anti-9 and syn-9 ketals, respec-
tively, by rotation about the carbon-carbon bond between
the hydroxyl functions to accommodate the acetonide ring.
It is noteworthy that only two of the silane reagents gave
diol products. Trichlorosilane gave an excellent (93%) yield
of syn-9a with a ratio of 63:1. A GC trace of the crude
reaction mixture shows syn-9a is 97% pure. The hydride
7
and physiologically less toxic qualities of the reagents. The
reagent is volatile and can be pumped away under reduced
pressure; alternatively, after workup with dilute aqueous
saturated NaHCO3, trichlorosilane and its byproducts are
converted to much less-harmful hydroxysilanes. Second,
Cl3SiH is a commercial and abundant byproduct of the
industrial Rochow process.8 It is also considerably less
(
1) For a review, see: Cary, F. A.; Sundberg, R. J . Advanced Organic
Chemistry, 3rd ed.; Plenum Press: New York, 1990; Part B, p 232-244.
2) Pereyre, M.; Quintard, J . P.; Rahm A. Tin in Organic Synthesis;
Butterworths: Boston, 1987.
(
(
3) Molander, G. A. Chem. Rev. 1992, 92, 29-68.
(
4) (a) Alberti, A.; Chatgilialoglu, C. Tetrahedron 1990, 46, 3963-3972.
(
b) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188-194. (c) Kulicke, K. J .;
Giese, B. Synlett 1990, 91-92. (d) Giese, B. Damm, W.; Dickhaut, J .;
(9) The 1998-99 Aldrich Chemical Co. catalog lists 500 g of Cl
3
SiH for
SnH for $71.70.
Wetterich, F.; Sun, S.; Curran, D. P. Tetrahedron Lett. 1991, 32, 6097-
$41.60, 25 g of TTMSS for $143.50, and 50 g of nBu
3
6
100.
(10) (a) Sano, H.; Takeda, T.; Migita, T. Chem. Lett. 1988, 119-122. (b)
Barton, D. H. R.; J ang, D. O.; J aszberenyi, J . Cs. Tetrahedron Lett. 1992,
33, 6629-6632. (c) Giese, B.; Kopping, B. Tetrahedron Lett. 1989, 30, 681-
684.
(
5) For a review, see: Smith, M. B. Organic Synthesis; McGraw-Hill: New
York, 1994; p 403.
6) For earlier work with Cl
Lett. 1990, 31, 5265-5268.
7) Crich, D.; Sun S. J . Org. Chem. 1996, 61, 7200-7201 and references
therein.
(
3
SiH, see: Kraus, G. A.; Liras, S. Tetrahedron
(11) Ketone 7a was prepared by the reaction of cyclohexanecarboxalde-
(
hyde with the Grignard reagent of R-bromostyrene in THF at 0 °C.
Ozonolysis of the product in dichloromethane at -78 °C, followed by
dimethyl sulfide quench, gave 7a in 85% yield for the two-step synthetic
sequence.
(
8) Sun, D. H.; Bent, B. E.; Wright, A. P.; Naasz, B. M. J . Mol. Catal.
1
998, 131, 169-83.
1
0.1021/jo981763w CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/26/1999

Communications
J . Org. Chem., Vol. 64, No. 8, 1999 2611
Ta ble 2. Dia ster eoselective Sila n e Ra d ica l Red u ction s
Sch em e 3
of r-Hyd r oxy Keton e 7a
reducing
agent
time
(h)
syn-9/ yield
equiv
1.2
condns
110 °C
hν
110 °C, toluene
110 °C
EtOH
anti-9
(%)
(
Me3Si)3SiH
16
16
72
16
1.5
2.0
40
1:1
63:1
47c
93
e
d
a,b
Cl3SiH
Ph3SiH
Et3SiH
NaBH4
LiAlH4
Bu3SnH
4.0
2.0
4.0
d
e
1.1
1.1
2.4
20:1
17:1
3:1
Et2O
110 °C
d
72c
Sch em e 4
a
Two step yield. b Crude GC shows product is 97% pure. c Yield
d
reflects intermediate diol isolated and purified. Used as solvent.
Only diketone observed.
e
Sch em e 2
An experiment shown in Scheme 3 was next adopted to
determine whether trichlorosilane is reacting as a free-
radical reducing agent (10 f 11 f 12) or as a hydride donor
(10 f 13) toward a ketone under the same conditions of our
reactions. The reaction of cyclopropyl-4-methoxyphenyl ke-
tone (10) with trichlorosilane should distinguish between the
one- and two-electron reduction by the production of 12 or
1
3, respectively. Under photochemical conditions, ketone 12
was formed in 87% yield, with no trace of alcohol 13 observed
by GC.13
We propose the mechanism shown in Scheme 4 to account
for the high diastereoselectivity seen in the radical reduc-
tions of 7a -d . Although a chelation-controlled mechanism
is possible, the higher diastereoselectivies are more consist-
Ta ble 3. Dia ster eoselective Red u ction s of
r-Hyd r oxyk eton es 7a -d w ith C3SiH
ent with the covalent bonded R-silyl ether ketone intermedi-
Cl3SiH
(equiv)
time
(h)
syn-9/
anti-9
yielda
(%)
ate 14.1
4,15
Due to the remaining chlorine substituents, the
b
substrate
hydrogen atom abstraction forms an electrophilic silyl radi-
cal 15. This facilitates the formation of the cyclic bis-silyl
ether 16 by silyl radical attack at the electron-rich oxygen
of the ketone. The five-membered ring incorporating the
O-silyl ketyl radical provides a steric bias for stereoselective
H-atom abstraction to produce 17. Workup gave the anti-
7
7
7
7
a , R ) cyclohexyl
b, R ) phenyl
4
2
2
2
16
5 d
48
4
63:1 (20:1)
38:1
134:1 (7:1)
21:1 (5:1)
93
80
64
75
c, R ) 1-naphthyl
d , R ) CH2CH(CH)2
a
Two-step yield. b Ratios in parentheses are for conversion with
NaBH4.
8
a diol and subsequent acetonide formation leads to the syn-
reagents, NaBH4 and LiAlH4, gave reasonable ratios of 20:1
and 17:1, respectively, likely because of chelation-controlled
delivery of the hydride via the alcohol.12 Tributyltin hydride
and TTMSS produced low distereoselectivities of 3:1 and 1:1,
respectively. Triphenyl- and triethylsilane did not produce
any diol products by crude H NMR, and interestingly, we
observed (<25%) the diketone of 7a in each case, along with
numerous byproducts.
Several other R-hydroxy ketones 7a -d were cleanly
reduced to their corresponding vicinal diols 8a -d by em-
ploying 2-4 equiv of Cl3SiH, as shown in Table 3. In each
case, the crude mixture of diol products was converted to
the respective acetonide derivatives syn-9 and anti-9. The
overall ratios in these examples were excellent, and in the
case of 9c, R ) 1-naphthyl, the ratio was found to be as high
as 134:1, demonstrating that the syn-9c acetonide derivative
is highly favored via the erythro-diol (anti-8c). In three
examples, we compared the lower chelation-controlled ratio
from NaBH4. This observation was useful in our mechanistic
interpretation below.
9a isopropylidine derivative.
In summary, a method to reduce R-hydroxy ketones to 1,2-
diols using trichlorosilane was investigated. High dia-
stereoselectivities of 134:1 favor the anti-1,2-diol via a
mechanism that appears to first involve the reaction of
trichlorosilane with the R-hydroxyl, followed by ketyl forma-
tion with the adjacent ketone. This reduction provides a
stereoselective, mild, one-electron alternative to the estab-
lished two-electron methods that use hydride reagents.
1
Ack n ow led gm en t. We gratefully acknowledge support
by the National Science Foundation (Grant CHE-9708139)
for this work.
Su p p or tin g In for m a tion Ava ila ble: A general procedure
and spectral data for compounds 7-9.
J O981763W
(13) For a similar mechanistic analysis using TTMSS, see ref 4c.
(14) (a) Allen, A. D.; Charlton, J . C.; Eaborn, C.; Modena, G. J . Chem.
Soc. 1957, 3668-3670. (b) Allen, A. D.; Modena, G. J . Chem. Soc. 1957,
3
671-3678.
(
12) Nakata, T.; Tanaka, T.; Oishi, T. Tetrahedron Lett. 1983, 24, 2653-
(15) Havill, M. E.; J offe, I.; Post, H. W. J . Org. Chem. 1948, 13, 280-
2
656.
283.