Regio- and diastereoselective reduction of nonenolizable α-diketones to acyloins mediated by indium metal

Article abstract of DOI:10.1021/ol025593s

(equation presented) α-Diketones are efficiently reduced with indium metal in methanol-water in the presence of NH₄Cl, LiCl, or NaCl to give regio-and diastereoselectively the corresponding acyloins in good to excellent yield. The cleavage of the acyloins under Pb(OAc)₄MeOH-PhH condition provides a convenient and regioselective access to highly functionalized cyclopentane carboxaldehydes, potential building blocks in organic syntheses.

Full text of DOI:10.1021/ol025593s

ORGANIC
LETTERS
2002
Vol. 4, No. 6
1015-1018
Regio- and Diastereoselective Reduction
of Nonenolizable r-Diketones to
Acyloins Mediated by Indium Metal
Faiz Ahmed Khan,* Jyotirmayee Dash, Nilam Sahu, and Sharad Gupta
Department of Chemistry, Indian Institute of Technology, Kanpur-208 016, India
faiz@iitk.ac.in
Received January 21, 2002
ABSTRACT
r-Diketones are efficiently reduced with indium metal in methanol−water in the presence of NH Cl, LiCl, or NaCl to give regio- and
4
diastereoselectively the corresponding acyloins in good to excellent yield. The cleavage of the acyloins under Pb(OAc)4/MeOH−PhH condition
provides a convenient and regioselective access to highly functionalized cyclopentane carboxaldehydes, potential building blocks in organic
syntheses.
It is well-known that the acyloin (R-hydroxyketone) func-
tional group plays an important role in organic synthesis and
is widespread in compounds of natural origin as well as in
advanced intermediates en route to several target molecules.1
Conventionally, R-hydroxyketones are prepared by acyloin
condensation reaction,2 oxidation of enolates,3 and reduction
of R-diketones.4 However, the problems of over-reduction
to a diol5 or to an R-methylene ketone6 that are associated
with reduction of R-diketones make this procedure less
attractive. Thallium(III)-promoted R-oxidation of ketones to
R-acetoxy ketones is the most recent entry7 to the growing
list. Indium-mediated reactions have gained considerable
importance in the recent past due to their mild nature,
functional group tolerance, high stereoselectivity, ease of
handling, and versatility of the reagent for a number of useful
transformations that could be carried out even in water as
solvent, without a need to rigorously exclude air.8 However,
there are limited number of reports in the literature on
indium-mediated reductions.9 In continuation of our work
on indium-mediated reactions,10 we report herein a mild,
efficient, and stereoselective route to acyloins mediated by
indium metal in MeOH and water in the presence of NH4-
Cl, LiCl, or NaCl.
(1) (a) Kido, F.; Kitahara, H.; Yoshikoshi, A. J. Org. Chem. 1986, 51,
1478. (b) Murahashi, S.-I.; Saito, T.; Hanaoka, H.; Murakami, Y.; Naota,
T.; Kumobayashi, H.; Akutagawa, S. J. Org. Chem. 1993, 58, 2929. (c)
Piers E.; Renaud, J. J. Org. Chem. 1993, 58, 11. (d) Money, T. Studies in
Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier: New York,
1989, Vol. 4, p 625.
(2) (a) Schra¨pler, U.; Ru¨hlmann, K. Chem. Ber. 1964, 97, 1383. (b) Mori,
T.; Nakahara, T.; Nozaki, H. Can. J. Chem. 1969, 47, 3266.
(3) (a) Bailey, E. J.; Barton, D. H. R.; Elks, J.; Templeton, J. F. J. Chem.
Soc. 1962, 1578. (b) Adam, W.; Mu¨ller, M.; Prechtl, F. J. Org. Chem. 1994,
59, 2358.
The requisite R-diketones 1a-26a were prepared ef-
ficiently in excellent yields from the readily available Diels-
Alder adducts11 following a methodology developed recently
(7) Lee, J. C.; Jin, Y. S.; Choi, J.-H. Chem. Commun. 2001, 956.
(8) (a) Cintas, P. Synlett 1995, 1087. (b) Chan, T.-H.; Isaac, M. B. Pure
Appl. Chem. 1996, 68, 919. (c) Marshall, J. A. Chemtracts 1997, 10, 481.
(d) Hashmi, A. S. K. J. Pract. Chem. 1998, 340, 84. (e) Li, C.-J.; Chan,
T.-H. Tetrahedron 1999, 55, 11149.
(4) Hayakawa, R.; Sahara, T.; Shimizu, M. Tetrahedron Lett. 2000, 41,
7939 and references therein.
(5) (a) Clerici, A.; Porta, O. J. Org. Chem. 1985, 50, 76. (b) Yamada,
M.; Horie, T.; Kawai, M.; Yamamura, H.; Araki, S. Tetrahedron 1997, 53,
15685.
(9) (a) Pittas, M. R.; Harrison, J. R.; Moody, C. J. J. Chem. Soc., Perkin
Trans. 1 2001, 955 and references therein; (b) Ranu, B. C.; Dutta, J.;
Guchhait, S. K. Org. Lett. 2001, 3, 2603 and references therein.
(10) Khan, F. A.; Prabhudas, B. Tetrahedron 2000, 56, 7595.
(11) Khan, F. A.; Prabhudas, B.; Dash, J. J. Prakt. Chem. 2000, 342,
512.
(6) Reusch, W.; Lemahieu, R. J. Am. Chem. Soc. 1964, 86, 3068.
10.1021/ol025593s CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/28/2002

in our laboratory.12 We first examined monosubstituted
generally high except in case of substrates 4a, 9a, and 10a
(entries 7, 14, and 16). However, the yields in these cases
could be considerably improved (entries 8, 15, and 17), albeit
at the expense of diminished regioselectivity, by changing
the solvent system to THF-H2O (4:1). This solvent system
also gave satisfactory results in the case of ester derivatives
6a, 12a, 13a, and 16a, which reacted sluggishly in aqueous
methanolic medium. The two solvent systems appear to play
an important role with respect to the yield and regioselectivity
of the products. In MeOH-H2O, the regioselectivity is high
compared to aqueous THF, but for sensitive substrates the
latter gives better results in terms of yield.
derivatives (Table 1).13 The substrates 1a-12a were sub-
Table 1. Indium-Mediated Reduction of Monosubstituted
R-Diketones to Acyloinsa
The derivatives 13a and 14a follow the same trend as the
monosubstituted cases (Scheme 1), demonstrating that an
time yield
entry substrate
R
products
(h)
(%)b ratio b:c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1a
Ph
1b,c
12
13
12
9
97
100:0
100:0
100:0
80:20
93:7
Scheme 1
95c
95d
99
2a
3a
CH2OMe
CH2OAc
2b,c
3b,c
4
84
96e
68
90e,f
100
76e
96
52
91e
34
68e
40
85e,f
15
12
16
12
6
7
4
16
12
5
64:36
100:0
70:30
71:29
65:35
81:19
100:0
100:0
85:15
85:15
100:0
80:20
81:19
68:32
4a
OAc
4b,c
5a
6a
7a
8a
OEt
5b,c
6b,c
7b,c
8b,c
CO2Me
SiMe3
Ph
9a
CH2OAc
OAc
9b,c
additional exo substituent placed either on the vicinal carbon
or on the same carbon that bears the endo substituent has
no influence on the regio- and diastereoselectivity (compare
entries 1 and 10, Table 1).
10a
10b,c
6
6
9
10
11a
12a
OEt
CO2Me
11b,c
12b,c
83
68e
a All reactions were run using 2 equiv of indium metal, and NH4Cl was
used, unless otherwise specified. b Isolated yields of analytically pure b+c.
c MeOH:10% HCl (4:1) without MCl. d NaCl was used. e THF:H2O (4:1).
f LiCl was used.
The structural assignments in case of the products derived
from the monosubstituted derivatives 1a-14a were made
1
from their H and 13C NMR spectra. It is known that in
bicyclo [2.2.1] systems the presence of an endo oxygen
substituent at C2 has a remarkable deshielding effect on the
endo-H6. The exo-H6 also experiences a shielding effect. The
comparison of 1H NMR (400 MHz) values of exo- and endo-
H6 of acyloins with those of the parent R-diketone unam-
biguously confirms the stereochemical assignments.15 In
compounds 1b-14b the endo-H6 clearly showed a consis-
tent deshielding effect ranging from 0.2 to 0.5 ppm
while the exo-H6 is shielded by 0.2 to 0.4 ppm. Further proof
came from the W-coupling between the carbinol exo-H2
and the exo-H6 (0.7-2.4 Hz). In 13C NMR spectrum, C6
is consistently shielded by 3-4 ppm due to endo-OH
at C2.
In case of disubstituted derivatives 17a-26a, indium-
mediated reduction proceeds stereoselectively to furnish the
acyloins 17b-26b (Table 2).13 The diester derivatives 15a
(X ) H) and 16a gave the corresponding lactones 15c and
16c. The products 25d and 26d formed via over-reduction
of 25a and 26a were characterized on the basis of the
coupling shown by the bridgehead proton with the exo-H5
jected to indium-mediated reductions in MeOH:H2O (4:1)
at reflux temperature in the presence of NH4Cl, LiCl, or
NaCl.14 Both chloro and bromo derivatives underwent
smooth transformation to the acyloins in a regio- and
stereoselective manner to furnish 1b-12b as the major
isomer and 2c-7c, 9c-12c as the minor isomer, probably
via the protonation of the common acyloinate intermediate
(Table 1). The substrates 1a and 8a furnished essentially a
single regioisomer, 1b and 8b, respectively. The yields were
(12) (a) Khan, F. A.; Prabhudas, B.; Dash, J.; Sahu, N. J. Am. Chem.
Soc. 2000, 122, 9558. The full details of the preparation of some new
diketones reported in the present paper will be published in a full account
in the near future.
(13) All new compounds gave satisfactory analytical and spectral data.
(14) General procedure for the indium-mediated reduction of r-dike-
tones: A mixture of R-diketone (0.3 mmol), indium metal (0.6 mmol, cut
into small pieces), and NH4Cl (0.9 mmol) in MeOH (4 mL) and water (1
mL) was refluxed for the specified time (Tables 1 and 2 and Scheme 1).
After completion of the reaction, as monitored by TLC, the reaction mixture
was quenched with 3 mL of 5% HCl and extracted with ethyl acetate. The
combined organic layer was washed once with brine and dried over
anhydrous Na2SO4. Concentration followed by silica gel column chroma-
tography gave the acyloins in the specified yields.
(15) A deatailed comparison in tabular form is presented in the Supporting
Information.
1016
Org. Lett., Vol. 4, No. 6, 2002

After successfully developing the methodology for the
regioselective reduction of diketones, it occurred to us that
the cleavage of acyloin, particularly for monosubstituted
norbornyl derivatives, could be highly fruitful in achieving
stereoselective transformation and may lead to derivatives
that are not easily accessible otherwise. For example, the
attempted selective reduction of 1f (obtained from 1a)12 using
1 equiv of DIBAL-H at -78 °C furnished a mixture, thus
disqualifying this as a useful route to aldehyde 1e. On the
other hand, treatment of acyloin 1b, obtained via indium
reduction of 1a, furnished the aldehyde 1e in good yield upon
treatment with Pb(OAc)4 in MeOH-PhH (3:1),17 thus
constituting an efficient and stereoselective route to highly
functionalized cyclopentane carboxaldehydes (Scheme 2).
Table 2. Indium-Mediated Reduction of Disubstituted
R-Diketones to Acyloinsa
time
yield
(%)b
entry substrate
R
product
(h)
1
2
3
4
5
15a
16a
17a
18a
19a
20a
CO2Me
CO2Me
CH2OAc
-CH2OCH2OCH2- 18b
-(CH2)3-
-(CH2)4-
15c
16c
17b
15
23
14
6
8
7
71
83c
88d
94
Scheme 2
19b
20b
100
6
100
100e
100
95
67c,d
72c,d
7
5
8
9
10
11
12
13
21a
22a
23a
24a
25a
26a
-(CH2)6-
-CH2OCH2-
CH2OAc
-CH2OCH2OCH2- 24b
-(CH2)4-
21b
22b
23b
7
11
6
7
6
25b,d
26b,d
72, 13c
22, 44d
-CH2OCH2-
8
a All reactions were run using 2 equiv of indium metal ,and NH4Cl was
used, unless otherwise specified. b Isolated yields of analytically pure
sample. c THF:H2O (4:1). d LiCl was used. e NaCl was used.
and W-coupling between the carbinol exo-H2 and the exo-
H6. The characteristic signals for a bromine-bearing bridge-
head and carbinol carbon at 67.2, 83.2 ppm for 25d and at
63.0 and 83.0 for 26d in 13C NMR spectrum unambiguously
confirmed the structural assignment.
Further, the method was successfully employed for the
smooth reduction of benzil to benzoin 27 in high yield. The
reduction of camphorquinone also proceeded efficiently in
quantitative yield in MeOH-H2O, giving rise to a 1:1
mixture of regioisomers 28 and 29 (Figure 1). The structural
assignments in this case were based on the literature report.16
The procedure was efficiently extended to other derivatives
4b, 5b, 7b, and 11b to obtain the corresponding cyclopentane
carboxaldehydes in good yield.
In summary, we have described a novel, efficient, and
regio- as well as diastereoselective conversion of non-
enolizable bicyclic R-diketones into synthetically useful
acyloins mediated by indium metal, tolerable to a variety of
sensitive substituents such as acetate, ester, and bridgehead
halogens. Further, the methodology is extended to the
synthesis of highly functionalized cyclopentane carboxalde-
hydes, potential building blocks in organic syntheses, via
(16) Rubin, M. B.; Ben-Bassat, J. M. Tetrahedron Lett. 1971,
3403.
(17) General procedure for the cleavage of acyloins: To a stirred
solution of the acyloins (0.2 mmol) in MeOH (3 mL) and benzene
(1 mL) was added Pb(OAc)4 (0.5 mmol) in portions over a period of 15
min at room temperature. After stirring for the required time (moni-
tored by TLC, Scheme 2), 3 mL of water was added and the reaction mix-
ture extracted with ethyl acetate. The combined organic layer was washed
with water, once with a dilute NaHCO3 solution, and once with brine
and dried over anhydrous Na2SO4. Concentration followed by silica
gel chromatography of the crude yielded the pure cyclopentane carboxal-
dehydes.
Figure 1.
Org. Lett., Vol. 4, No. 6, 2002
1017

cleavage of the acyloins under Pb(OAc)4/MeOH-PhH
conditions.
Supporting Information Available: Spectral and ana-
lytical data for all acyloins and cyclopentane carboxalde-
hydes. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We thank the Department of Science
and Technology, New Delhi for financial assistance. J.D.
thanks CSIR-India for a fellowship.
OL025593S
1018
Org. Lett., Vol. 4, No. 6, 2002