Electron transfer reduction of unactivated esters using SmI 2-H2O

Article abstract of DOI:10.1039/c1cc14014k

The reduction of unactivated esters using samarium diiodide is reported for the first time. The optimised protocol allows for the reduction of primary, secondary and tertiary alkyl esters in excellent yields and is competitive with reductions mediated by metal hydrides and alkali metals.

Full text of DOI:10.1039/c1cc14014k

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COMMUNICATION
Electron transfer reduction of unactivated esters using SmI –H Ow
2
2
Michal Szostak, Malcolm Spain and David J. Procter*
Received 5th July 2011, Accepted 2nd August 2011
DOI: 10.1039/c1cc14014k
The reduction of unactivated esters using samarium diiodide is
reported for the first time. The optimised protocol allows for the
reduction of primary, secondary and tertiary alkyl esters in
excellent yields and is competitive with reductions mediated by
metal hydrides and alkali metals.
conditions using a non-pyrophoric, commercial reagent would be
a welcome addition to the synthetic toolbox. In this communi-
cation we disclose the first reduction of unactivated aliphatic
esters using SmI . This reaction provides a protocol competitive
2
to the reduction of esters using metal hydrides and alkali metals.
Furthermore, ester reduction with SmI
utilise simple esters as precursors to acyl radical equivalents
in C–C bond-forming processes mediated by SmI
Although H O has been used as an additive in SmI
reactions, recently, we reported that the addition of excess
O to SmI results in the formation of a thermodynamically
2
opens the door to
Since its introduction in 1977 by Kagan, samarium diiodide
(
SmI , Kagan’s reagent) has become one of the most popular
2
2
.
1,2
reducing agents available in the laboratory. Arguably the most
attractive feature of SmI is its versatility and applications
2
2
3
k
2
range from the reduction of functional groups to the initiation
of powerful reductive cascades that construct complex molecular
3
architectures. In particular, the electron transfer reduction of
H
2
2
stronger Sm(II) reductant capable of reducing cyclic 1,3-diesters
6
and six-membered lactones with unprecedented selectivity.
ketones and aldehydes provides straightforward access to ketyl
Furthermore, we demonstrated that radical anions formed in
radicals, which can be exploited in a variety of useful post-
SmI -H O-mediated reductions can be utilised in reductive
2 2
2
reductive transformations (Fig. 1). Despite the extensive use
,3
6
intramolecular couplings with alkenes. Our studies have been
extended to include cascade cyclisation processes that afford
7
complex azulene motifs in a one-pot reaction. The presence of
of SmI in organic synthesis over the last 30 years, the reduction
2
of unactivated esters with SmI has not been reported.
2
H
2
O and the cyclic nature of substrates were essential for these
reactions. Prior to these studies it was thought that aliphatic
8
ester carbonyl groups could not be reduced by SmI
2
.
We hypothesised that the activating effect of H O on SmI
2
2
could be extended to allow the reduction of unactivated
aliphatic esters, a transformation without precedent in the
1
–3
rich history of Kagan’s reagent. After screening a range of
conditions, we were pleased to find that the addition of triethyl-
amine to SmI
SmI -based reductant capable of reducing unactivated acyclic
esters (Table 1).
2 2
–H O resulted in the formation of a powerful
2
9
,10
We determined that triethylamine could be
2
Fig. 1 Classical and unknown SmI -mediated reductive transformations.
replaced by a variety of amines, however, the conditions described
for the reduction of hydrocinnamic methyl ester (Table 1,
The development of new methods for the reduction of
common functional groups is a major goal of modern organic
1
0
entry 1) were found to be optimal for other substrates. Other
proton donors could be used instead of water, however the
reaction was found to be much less efficient, emphasising the
4
synthesis. In particular, the reduction of esters is a practical
strategy for accessing primary alcohols. This transformation
has been typically performed with metal hydrides and alkali
metals, however, mainly because of hazards associated with
the handling of pyrophoric reagents, alternative methods have
1
1
unique role of water as an additive for use with SmI
.
No
2
reaction was observed when either amine or water was excluded
from this protocol. Interestingly, the use of a large excess of
water in the absence of amine, our optimal conditions for the
5
been extensively investigated. As such, a general protocol
6,7
based on an electron transfer reduction of esters under mild
2
efficient reduction of lactones and cyclic 1,3-esters with SmI ,
did not promote the reduction of aliphatic acyclic esters (Table 1,
entry 3).
School of Chemistry, University of Manchester, Oxford Road,
Manchester, M13 9PL, United Kingdom.
E-mail: david.j.procter@manchester.ac.uk;
Next, we investigated the influence of the ester group using a
range of esters of hydrocinnamic acid (Table 2). Ethyl, isopropyl,
tert-butyl, phenyl and benzyl esters were all reduced in high
yields. Remarkably, sterically-demanding esters were reduced
smoothly with a slightly longer reaction time (entries 3–4).
Web: http://people.man.ac.uk/Bmbdssdp2/;
Fax: +44 (0)161 2754939; Tel: +44 (0)161 2751425
w Electronic supplementary information (ESI) available: Experimental
details and characterisation data. See DOI: 10.1039/c1cc14014k
1
0254 Chem. Commun., 2011, 47, 10254–10256
This journal is c The Royal Society of Chemistry 2011

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Table 1 Reduction of hydrocinnamic acid methyl ester with SmI –H
2
2
O
2 2
Table 3 Reduction of unactivated esters with SmI –H O
a
Entry
Et
3
N (equiv)
H
2
O (equiv)
Time
Conversion (%)
1
2
3
4
12
—
—
12
18
18
800
—
5 min
72 h
24 h
24 h
>95
o5
o5
5–7
a
1
Determined by GC or H NMR.
2 2
Table 2 Reduction of hydrocinnamic esters with SmI –H O
Entry
Ester
R
Amine
Time (h)
Yield (%)
1
2
3
4
5
6
1
3
4
5
6
7
Me
Et
i-Pr
t-Bu
Ph
Et
Et
Et
3
3
3
N
N
N
2
2
5
5
2
2
97
99
88
83
94
97
pyrrolidine
2
suggesting that anions are generated and protonated by H O
6,11
Et
Et
3
N
N
during a series of single electron transfers.
A primary
Bn
3
kinetic isotope effect k /kD of 1.4 Æ 0.1 determined for
H
isopropyl 3-phenylpropanoate (4) indicates that the proton
The use of pyrrolidine as an amine was found to be optimal for
the reduction of the tert-butyl ester (entry 4, see ESI for
additional details).
transfer is not involved in the rate limiting step and is
6
consistent with the proposed mechanism.
,9
Following our initial studies, we examined the scope of this
novel SmI -mediated protocol. As illustrated in Table 3, a
2
broad range of esters readily participated in the reaction.
Primary, secondary and tertiary alkyl esters provided the
corresponding alcohols in excellent yields. Examination of
acetic and hydrocinnamic acid derivatives revealed that sub-
stituents on the aromatic ring and at the a-position were
tolerated very well. Importantly, sterically-demanding substi-
tuents were accommodated with a minimal impact on the
yield. Diesters were also efficiently reduced to the correspond-
ing diols. As expected, the protocol could be used to reduce
lactones, aromatic esters, coumarins and heterocyclic esters.
Notably, the reduction of simple lactones with SmI –H O and
2 2
Scheme 1 Proposed mechanism for reduction of esters with SmI –H O.
In summary, we have developed a straightforward method
for the reduction of esters to primary alcohols using a
2
2
amine demonstrated considerably higher reaction rates com-
pared to our previously reported protocols with SmI and
2 2 2 2
SmI –H O reagent system. Activation of SmI with H O
2
creates a thermodynamically stronger reductant, permitting
the first reduction of unactivated esters using Kagan’s reagent.
A broad range of ester substrates was reduced in excellent yield
under mild reaction conditions and preliminary observations
regarding the mechanism of the reduction have been made.
6
2
excess H O.
A possible mechanism for the transformation is presented in
Scheme 1 and mirrors the previously reported reduction of
6
,12
cyclic 1,3-diesters and lactones with SmI
2
–H
2
O.
Activation
–H O and
of the ester carbonyl by coordination to SmI
2
2
As SmI is commercially available, or convenient to prepare,
2
electron transfer generates radical anion 23a which is then
protonated. A second electron and proton transfer yield the
intermediate 23d, which collapses to the corresponding alde-
hyde 23e. The aldehyde is then reduced by a third electron
transfer from Sm(II) to give a ketyl radical anion 23f. A final
electron transfer from Sm(II) gives an organosamarium that is
easy to handle, operates at ambient temperature, and does not
require toxic co-solvents or additives, this protocol offers an
attractive alternative to pyrophoric metal hydrides and alkali
metals that are typically used for ester reduction. Crucially,
ester reduction with SmI
used as precursors to acyl radical equivalents for a plethora of
C–C bond-forming processes mediated by SmI that are
analogous to those involving aldehydes and ketones. Further
applications of the SmI –H O system will be described shortly.
2
suggests that simple esters can be
protonated by H
to elucidate the mechanism of the ester reduction (see ESI for
details). The reduction of 1 with SmI –D O gave 2-D,D,
2
O. We have carried out preliminary studies
2
2
2
2
2
This journal is c The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10254–10256 10255

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We thank the EPSRC and GSK for support. We thank
Dr Emmanuel Demont (GSK, Stevenage) for useful discussions.
M. Spain and D. J. Procter, J. Am. Chem. Soc., 2009, 131, 7214;
(
d) K. D. Collins, J. M. Oliveira, G. Guazzelli, B. Sautier, S. De
Grazia, H. Matsubara, M. Helliwell and D. J. Procter, Chem.–Eur.
J., 2010, 16, 10240.
Notes and references
7
D. Parmar, K. Price, M. Spain, H. Matsubara, P. A. Bradley and
D. J. Procter, J. Am. Chem. Soc., 2011, 133, 2418.
1
2
3
(a) J. L. Namy, P. Girard and H. B. Kagan, Nouv. J. Chim., 1977,
, 5; (b) P. Girard, J. L. Namy and H. B. Kagan, J. Am. Chem.
Soc., 1980, 102, 2693.
D. J. Procter, R. A. Flowers, II and T. Skrydstrup, Organic Synthesis
using Samarium Diiodide: A Practical Guide, RSC Publishing,
Cambridge, 2009.
1
8 Kamochi and Kudo have described the reduction of aryl car-
boxylic acid derivatives using SmI (a) Y. Kamochi and
T. Kudo, Chem. Lett., 1993, 1495; (b) Y. Kamochi and T. Kudo,
Chem. Lett., 1991, 893. Marko has described the SmI -mediated
reduction of aryl esters in procedures for deoxygenation and
protecting group removal: (c) K. Lam and I. Marko, Org. Lett.,
2008, 10, 2773; (d) K. Lam and I. Marko, Org. Lett., 2009,
11, 2752; (e) K. Lam and I. Marko, Tetrahedron, 2009, 65, 10930.
9 For seminal work on the addition of amines to SmI -H O, see:
(a) W. Cabri, I. Candiani, M. Colombo, L. Franzoi and
A. Bedeschi, Tetrahedron Lett., 1995, 36, 949; (b) A. Dahlen and
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127, 8340; (g) A. Dahle
2
:
´
2
For general reviews on SmI
2
, see: (a) H. B. Kagan, Tetrahedron,
003, 59, 10351; (b) G. A. Molander and C. R. Harris, Chem. Rev.,
´
2
1
9
´
996, 96, 307; (c) A. Krief and A. M. Laval, Chem. Rev., 1999,
9, 745; (d) P. G. Steel, J. Chem. Soc., Perkin Trans. 1, 2001, 2727;
´
2
2
(e) D. J. Edmonds, D. Johnston and D. J. Procter, Chem. Rev.,
2004, 104, 3371; (f) K. C. Nicolaou, S. P. Ellery and J. S. Chen,
´
Angew. Chem., Int. Ed., 2009, 48, 7140; (g) M. Szostak and
D. J. Procter, Angew. Chem., Int. Ed., 2011, DOI: 10.1002/
´
anie.201103128; (h) A. Dahle
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SmI -H O, see: M. Szostak, M. Spain, D. Parmar and
´
n and G. Hilmersson, Eur. J. Inorg.
´
(
4
´
´
˚
´
n, A. Nilsson and G. Hilmersson, J. Org.
2
2
D. J. Procter, Chem. Commun., DOI: 10.1039/C1CC14252F.
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4
5
(c) P. G. Andersson and I. J. Munslow, Modern Reduction Methods,
10 The Electronic Supplementary Information (ESI) contains detailed
information regarding the optimisation of the reduction of unactivated
Wiley-VCH, Weinheim, 2008; (d) D. Addis, S. Das, K. Junge and
M. Beller, Angew. Chem., Int. Ed., 2011, 50, 6004.
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2 2
esters with SmI –H O.
11 (a) P. R. Chopade, E. Prasad and R. A. Flowers, II, J. Am. Chem.
Soc., 2004, 126, 44; (b) E. Prasad and R. A. Flowers, II, J. Am. Chem.
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(
¨
d) S. Das, K. Moller, K. Junge and M. Beller, Chem.–Eur. J.,
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2
H. Nagashima, J. Am. Chem. Soc., 2009, 131, 15032. For a recent
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2 2
12 As we believe that SmI –H O is coordinatively unsaturated and
that the reductions are likely to involve inner-sphere electron
transfer, alternative mechanisms involving H-bond activation of
the ester by H O polarised by coordination to Lewis acidic Sm(II)/
2
Sm(III) appear less likely. For a leading review on combined acid
catalysis, see: H. Yamamoto and K. Futatsugi, Angew. Chem., Int.
Ed., 2005, 44, 1924.
6
(c) G. Guazzelli, S. De Grazia, K. D. Collins, H. Matsubara,
1
0256 Chem. Commun., 2011, 47, 10254–10256
This journal is c The Royal Society of Chemistry 2011