A convenient methodology for the chemoselective reduction of a wide variety of functionalized alkenes

Article abstract of DOI:10.1016/j.tetlet.2009.11.061

An efficient method to effect chemoselective reduction of alkenes (including trisubstituted olefins) possessing various sensitive and/or reducible groups such as acetals, allylic alcohols, benzyl ethers, epoxides, esters, halides, nitriles, and sulfones is reported. The reduction is facile at 0 °C in aqueous N,N-dimethylacetamide containing sodium borohydride in the presence of 15 mol % ruthenium(III) chloride. Regioselective reduction of dienes is also feasible if the double bonds are sufficiently different in their structural environment.

Full text of DOI:10.1016/j.tetlet.2009.11.061

Tetrahedron Letters 51 (2010) 439–441
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Tetrahedron Letters
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A convenient methodology for the chemoselective reduction
of a wide variety of functionalized alkenes
*
James H. Babler , Nicholas A. White
Department of Chemistry, Loyola University Chicago, Chicago, IL 60660, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method to effect chemoselective reduction of alkenes (including trisubstituted olefins) pos-
sessing various sensitive and/or reducible groups such as acetals, allylic alcohols, benzyl ethers, epoxides,
esters, halides, nitriles, and sulfones is reported. The reduction is facile at 0 °C in aqueous N,N-dimethyl-
acetamide containing sodium borohydride in the presence of 15 mol % ruthenium(III) chloride. Regiose-
lective reduction of dienes is also feasible if the double bonds are sufficiently different in their structural
environment.
Received 3 September 2009
Revised 13 November 2009
Accepted 13 November 2009
Available online 1 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
It has been nearly 50 years since Brown and Brown reported1
that certain platinum metal salts catalyzed the hydrolysis of so-
dium borohydride, thereby generating hydrogen for in situ reduc-
tion of carbon–carbon double bonds. In the decades that ensued,
the combination of sodium borohydride with cobalt(II), nickel(II),
copper(II), and rhodium(III) halides was employed to reduce other
functional groups (e.g., nitriles and amides) which are inert to so-
dium borohydride alone.2 This type of transformation continues to
be of interest as evidenced by a recent communication3 that re-
ported the selective hydrogenation of mono- and disubstituted ole-
fins by use of sodium borohydride in aqueous tetrahydrofuran
(THF) in combination with a catalytic amount of ruthenium(III)
chloride hydrate.
a-pinene, 1-methylcyclohexene, and cholesterol) were inert to
such conditions.
Unexpectedly, we found that Sharma’s methodology3 when ap-
plied to (À)-carveol (1) led to a rather slow reduction; and a signif-
icant amount of hydrogenation of the trisubstituted olefin occurred
once the isopropenyl moiety had been reduced by 50%. In an effort
to minimize over-reduction by altering the solvent mixture, we
discovered unexpected behavior4 of the reductant in aqueous
N,N-dimethylacetamide (DMA). The present Letter presents the re-
sults of this investigation of NaBH4/cat. RuCl3 in aqueous DMA for
the reduction of functionalized alkenes.
5
Previous studies of the transition metal-catalyzed (CoCl2 and
RuCl33) hydrolysis of NaBH4 in aqueous THF have shown such a
procedure to be ineffective in the hydrogenation of trisubstituted
olefins. In sharp contrast, we have found that NaBH4/cat. RuCl3 in
aqueous DMA is considerably more robust, being capable of
As part of an on-going research project we required an efficient
method for the regioselective hydrogenation of (À)-carveol (1) to
obtain allylic alcohol 3.
The method of Sharma et al.3 utilizing NaBH4/cat. RuCl3 in
aqueous THF seemed to be an attractive choice for effecting the
desired transformation (1?3) since trisubstituted olefins (e.g.,
reducing a variety of trisubstituted olefins (entries 1, 3, 7, 8, 10,
13, and 14 in Table 1). Despite the more reactive nature of this mix-
ture, its use in small-scale hydrogenations is easier to control than
in the related methods since the evolution of hydrogen is rather
slow and pressure equipment is not required. An additional feature
(in contrast with the use of NaBH4/RuCl3 in aqueous THF,3 which
* Corresponding author.
E-mail address: jbabler@luc.edu (J.H. Babler).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.061

440
J. H. Babler, N. A. White / Tetrahedron Letters 51 (2010) 439–441
Table 1
Ru+3-catalyzed reduction of functionalized alkenes using NaBH4 in aqueous DMAa
_________________________________________
NaBH 4/cat. RuCl3
Solvent
x
Method
RuCl3 H2O
NaBH4
(mmol)
C
H
C
H
C
C
(CH3)2NC(=O)CH3, H2O, 0 °C
(mmol)
_________________________________________
0.034
0.24
0.75 mL of
2:1 (v/v) DMA:H2O
A
B
C
0.24
1.00 mL of
3:1 (v/v) DMA:H2O
0.034
0.019
0.106
0.60 mL of
5:1 (v/v) DMA:H2O
Entry Substrateb
Method Product(s)c
Recovery
Isolated yield of
[product(s) + unreacted reduction product(s)
substrate] (%)
85
(%)
85
1
2
(À)-Carveold (1)
A
C
9:1 Mixture of 2d: 3d
(À)-Carveold (1)
3d,e
86
47
OH
3
4
A
A
3,7-Dimethyloctan-1-olf
83
83
Geraniol
O
O
O
O
71
71
O
O
O
O
Diethyl maleate
1,2-Epoxy-9-decene
1-Nonen-4-ol
Diethyl succinate
5
6
B
A
1,2-Epoxydecaneg
Nonan-4-ol
79
83
79
82
OH
7
A
3,7-Dimethyloctan-1-ol
92
79
Citronellol
8
9
B
B
50h
13
65
a
-Pinene
cis-Pinane
10-Bromodec-1-ene
1-Bromodecane
65h
1:1 Mixture of 1-isopropyl-4-
10
B
methylcyclohexaned and 4-isopropyl-1-
methylcyclohexene
65h
62
(R)-(+)-Limonene
Ph
Ph
11
12
A
A
75
77
15
58
CN
CN
Cinnamonitrile
3-Phenylpropanenitrile
Ethyl cinnamate [ethyl 3-phenyl-(2E)-
Ethyl 3-phenylpropanoate
propenoate]

J. H. Babler, N. A. White / Tetrahedron Letters 51 (2010) 439–441
441
Table 1 (continued)
Entry Substrateb
Method Product(s)c
Recovery
Isolated yield of
[product(s) + unreacted reduction product(s)
substrate] (%)
75
(%)
75
13
14
6-Methyl-5-hepten-2-one
A
6:1 Mixture of 6-methylheptan-2-ol and 6-
methyl-5-hepten-2-ol
O
O
O
O
A
68j
34
2-Methyl-2-(4-methylpent-3-enyl)-1,3-
dioxolanei
2-Methyl-2-(4-methylpentyl)-1,3-dioxolanei
a
All reactions were conducted by addition of NaBH4 to an aqueous DMA solution of substrate (0.18–0.20 mmol) and ruthenium(III) chloride hydrate at 0 °C and by stirring
the mixture at 0 °C for 60 min. An extended reaction time did not result in an increase in the isolated yield of the reduction product for entries 8, 11, and 14—an indication
that the catalyst had been deactivated during the course of the reaction. See Ref. 6 for the general procedure (Method A).
b
All substrates, except entry 14, are commercially available from Sigma–Aldrich (Milwaukee, WI, USA).
Structural assignments and product ratios were based on analysis of 1H NMR spectral data (300 MHz) and on comparison with that exhibited by authentic samples of
c
these known products and substrates. See Ref. 7 for most of these spectra.
d
Mixture of stereoisomers.
Contaminated with a trace amount (<2%) of 2.
>97% reduction of both double bonds.
No cleavage of the epoxide was detected.
The losses upon isolation are due to the volatility of the substrate/product.
For a previous synthesis of this compound, see Ref. 8.
No cleavage of the acetal was detected.
e
f
g
h
i
j
2. Heinzman, S. W.; Ganem, B. J. Am. Chem. Soc. 1982, 104, 6801–6802. and
references cited therein.
3. Sharma, P. K.; Kumar, S.; Kumar, P.; Nielsen, P. Tetrahedron Lett. 2007, 48, 8704–
required 2 M equiv of NaBH4 for each double bond) is a more effi-
cient use of hydride (e.g., entry 3 in Table 1).
In regard to the regioselective hydrogenation of (À)-carveol
8708. and references cited therein.
4. Consistent with the observations of Sharma et al.,3 the addition of NaBH4 to a
(1?3), enhanced selectivity for reduction of the disubstituted dou-
dark-colored solution of RuCl3 and alkene substrate in aqueous THF at 0 °C
resulted in a rapid evolution of H2, precipitation of a flocculent black powder
ble bond was observed (Table 1, entry 2) by the use of less reduc-
tant and, more importantly, by decreasing the water content of the
mixture. No effort was made to optimize the conditions for mono-
hydrogenation of sterically differentiated dienes such as (À)-carve-
ol (1) since we were able to effect that transformation (1?3) by
use of molar excesses of both cobalt(II) chloride and NaBH4 in eth-
anol,9 using a method reported by Chung.10 Instead, our efforts fo-
cused on the chemoselective reduction of the carbon–carbon
double bond in various alkenes possessing sensitive and/or reduc-
ible functional groups. In addition to the substrates listed in Table
1, benzyl ether and phenyl propyl sulfone were inert to NaBH4/cat.
RuCl3 in aqueous DMA (Method A); and o-nitrotoluene was moder-
ately stable11 using the conditions of Method C.
In conclusion, a robust (yet experimentally convenient) process
has been developed for small-scale hydrogenation of alkenes
(including trisubstituted olefins) that avoids the use of a hydrogen
cylinder and pressure equipment. It uses the readily available so-
dium borohydride as the reducing agent in the presence of a cata-
lytic amount of a halide salt of ruthenium, which is neither
poisonous nor explosive.3 Despite the robust nature of the process,
various sensitive and/or reducible functionalities are inert to the
reaction conditions, making this process an attractive method for
chemoselective reduction of carbon–carbon double bonds.
after several minutes, and loss of color in the liquid phase. In sharp contrast, a
similar reaction in aqueous DMA at 0 °C resulted in the slow ‘controlled release’
of H2 and the appearance of a long-lasting (>20 min) dark-blue/green color in
the liquid phase.
5. Satyanarayana, N.; Periasamy, M. Tetrahedron Lett. 1984, 25, 2501–2504.
6. General procedure for alkene reduction (Method A): To a 15-mL 1-neck reaction
flask fitted with a glass stopper [Note: A larger-scale reaction may require the
use of a pressure vessel and/or addition of NaBH4 in small portions.] were
added a small spin bar, 0.18–0.20 mmol of substrate, 0.50 mL of DMA (HPLC-
grade), 0.25 mL of H2O, and 7.0 mg (0.034 mmol) of ruthenium(III) chloride
hydrate (Sigma–Aldrich Catalog No. 206229). After cooling the latter mixture
to 0 °C (external ice-H2O bath), 9.0 mg (0.24 mmol) of NaBH4 powder was
added in one portion; and the mixture was subsequently stirred at 0 °C for
60 min. The product was isolated by dilution of the reaction mixture with
10 mL of 4:1 (v/v) pentane/dichloromethane; and solid material was removed
by filtration through a small pad of Hyflo Super-CelÒ filtering aid. Removal of
DMA was accomplished by washing the organic filtrate with 15% (w/v) aqueous
NaCl (4 Â 10 mL portions). The organic layer was subsequently dried over
anhydrous MgSO4, filtered, and the volatile organic solvents were removed by
evaporation at reduced pressure.
7. The proton NMR spectral data of nearly all substrates and products are
freely accessible via the Spectral Data Base System (SDBS) maintained by
the Japanese National Institute of Advanced Industrial Science and
Technology at: http://riodb01.ibase.aist.go.jp/sdbs/cgi-bin/cre_index.cgi?
lang=eng.
8. Mousseron-Canet, M.; Mousseron, M.; Levallois, C. Bull. Soc. Chim. Fr. 1963,
376–378.
9. Treatment of 38 mg (0.25 mmol) of (À)-carveol with 102 mg (0.43 mmol)
of cobalt(II) chloride hexahydrate and 39 mg (1.03 mmol) of NaBH4 in
1.00 mL of ethanol at 20 °C for 14 h afforded 31 mg (82% yield) of a 7:1
mixture of allylic alcohol 3: unreacted carveol, with only a trace (<2%) of
over-reduction.
References and notes
10. Chung, S.-K. J. Org. Chem. 1979, 44, 1014–1016.
11. The isolated product was a 7:1 mixture of o-nitrotoluene/o-toluidine.
1. (a) Brown, H. C.; Brown, C. A. J. Am. Chem. Soc. 1962, 84, 1495; (b) Brown, C. A.;
Brown, H. C. J. Org. Chem. 1966, 31, 3989–3995.