Importantly, these pathways typically proceed with
exquisite control of structure and stereochemistry and
provide bond disconnections which are impossible to
achieve with other reagents.4 However, despite extensive
use of SmI2 in synthesis, a general methodfor the reduction
of unactivated carboxylic acids using the reagent has not
been reported (Figure 1).
electron transfer reduction of carboxylic acids with SmI2
(Figure 2).9
Our interest in new strategies for synthesis involving
atypical intermediates accessed using SmI2 and protic
additives led us to introduce SmI2ÀH2O as the first
SmI2-based reagent capable of the selective reduction of
unactivated lactones and cyclic 1,3-diesters.5,6 Further-
more, we demonstrated that radical anions formed in
SmI2ÀH2O-mediated reductions can be utilized in reduc-
tive couplings with alkenes and cascade processes to
afford complex molecular architectures.5,6 Recently,
we found that addition of amines to the SmI2ÀH2O
complex results in the formation of an even more
thermodynamically powerful reductant and reported the
first examples of the reduction of unactivated esters with
SmI2.7 On the basis of these results, we hypothesized that a
SmI2ÀH2O complex could be fine-tuned to allow direct
electron transfer to unactivated carboxylic acids. Impor-
tantly, we recognized the 2-fold value of this process: (1) as
a welcome addition to the synthetic toolbox for acces-
sing primary alcohols from bench stable, commercially
available precursors under conditions orthogonal to
the use of hydride reagents;8 (2) as a method of gen-
erating atypical ketyl-type radical intermediates from
widely available carboxylic acid feedstocks for future exploi-
tation in CÀC bond formation.1aÀf,3À6 Herein, we disclose
a robust protocol employing SmI2ÀH2O for the first general
Figure 2. Electron transfer reduction of unactivated carboxylic
acids and the proposed intermediate in the reduction.
We began with the optimization of the reduction of
hydrocinnamic acid (Table 1). We were pleased to find that
a combination of SmI2ÀH2O10 and Et3N11 promoted the
fourÀelectron reduction in excellent yield (entry 4). Both
an amine and a proton source were required for the
reaction (entries 1À4).
Table 1. Effect of Additives on the Reduction of Unactivated
Carboxylic Acids with SmI2ÀH2O
proton
proton
source
amine
time
(h) conva(%)
entry source
amine (equiv) (equiv)
1
Et3N
18
18
18
18
2
<5
<5
<5
99
15
11
45
86
97
96
98
95
51
28
78
2
3
4
5
6
7
8
9
H2O
18
800
18
18
18
9
(5) (a) Duffy, L. A.; Matsubara, H.; Procter, D. J. J. Am. Chem. Soc.
2008, 130, 1136. (b) Parmar, D.; Duffy, L. A.; Sadasivam, D. V.;
Matsubara, H.; Bradley, P. A.; Flowers, R. A., II; Procter, D. J.
J. Am. Chem. Soc. 2009, 131, 15467. (c) Guazzelli, G.; De Grazia, S.;
Collins, K. D.; Matsubara, H.; Spain, M.; Procter, D. J. J. Am. Chem.
Soc. 2009, 131, 7214. (d) Collins, K. D.; Oliveira, J. M.; Guazzelli, G.;
Sautier, B.; De Grazia, S.; Matsubara, H.; Helliwell, M.; Procter, D. J.
Chem.;Eur. J. 2010, 16, 10240.
(6) (a) Parmar, D.; Price, K.; Spain, M.; Matsubara, H.; Bradley,
P. A.; Procter, D. J. J. Am. Chem. Soc. 2011, 133, 2418. (b) Sautier, B.;
Lyons, S. E.; Webb, M. E.; Procter, D. J. Org. Lett. 2012, 14, 146.
(7) Szostak, M.; Spain, M.; Procter, D. J. Chem. Commun. 2011, 47,
10254.
(8) (a) Hudlicky, M. Reductions in Organic Chemistry; Ellis Horwood:
Chichester, 1984. (b) Seyden-Penne, J. Reductions by Alumino and Boro-
hydrides in Organic Synthesis; Wiley: New York, 1997.
(9) Kamochi and Kudo have described the reduction of aryl car-
boxylic acid derivatives and some aliphatic carboxylic acids using SmI2,
however the latter process is low yielding and limited in scope. (a)
Kamochi, Y.; Kudo, T. Chem. Lett. 1993, 1495. (b) Kamochi, Y.; Kudo,
T. Chem. Lett. 1991, 893. (c) Kamochi, Y.; Kudo, T. Bull. Chem. Soc.
Jpn. 1992, 65, 3049.
H2O
H2O
Et3N
Et3N
Et3N
18
18
18
18
18
18
18
18
18
18
6
MeOH
t-BuOH
18
18
18
2
(HOCH2)2 Et3N
H2O
H2O
n-BuNH2
i-Pr2NH
18
18
2
10 H2O
11 H2O
12 H2O
13 H2O
14 H2O
15 H2O
pyrrolidine 18
morpholine 18
2
2
piperidine
Et3N
18
6
2
18
18
18
Et3N
18
12
Et3N
12
a Determined by 1H NMR or GC, see Supporting Information.
(10) For a review on the SmI2-H2O system, see: Szostak, M.; Spain,
M.; Parmar, D.; Procter, D. J. Chem. Commun. 2012, 48, 330.
(11) For selected studies with SmI2-H2O-amine systems, see: (a)
Other protic additives known to strongly coordinate to
SmI2 did not promote the reaction,12 highlighting the key
role of water as an additive for SmI2.10
By contrast, other amines could be used in place of
Et3N with only a minor impact on reaction efficiency
(entries 8À12). The determined ratios of SmI2ÀH2OÀ
ꢀ
ꢀ
Dahlen, A.; Hilmersson, G. Chem.;Eur. J. 2003, 9, 1123. (b) Dahlen,
A.; Sundgren, A.; Lahmann, M.; Oscarson, S.; Hilmersson, G. Org. Lett.
ꢀ
2003, 5, 4085. (c) Dahlen, A.; Hilmersson, G. Tetrahedron Lett. 2003, 44,
ꢀ
2661. (d) Dahlen, A.; Hilmersson, G.; Knettle, B. W.; Flowers, R. A.
II J. Org. Chem. 2003, 68, 4870. (e) Davis, T. A.; Chopade, P.;
ꢀ
Hilmersson, G.; Flowers, R. A., II Org. Lett. 2005, 7, 119. (f) Dahlen,
ꢀ
A.; Hilmersson, G. J. Am. Chem. Soc. 2005, 127, 8340. (g) Dahlen, A.;
Nilsson, A.; Hilmersson, G. J. Org. Chem. 2006, 71, 1576. (h) Ankner, T.;
Hilmersson, G. Tetrahedron 2009, 65, 10856. (i) Ankner, T.; Hilmersson, G.
Org. Lett. 2009, 11, 503.
(12) (a) Teprovich, J. A., Jr.; Balili, M. N.; Pintauer, T.; Flowers,
R. A., II Angew. Chem., Int. Ed. 2007, 46, 8160. (b) Upadhyay, S. K.;
Hoz, S. J. Org. Chem. 2011, 76, 1355. (c) See, also ref 10.
Org. Lett., Vol. 14, No. 3, 2012
841