Highly chemoselective reduction of carbonyl groups in the presence of aldehydes

Article abstract of DOI:10.1021/ol300188e

The exquisite ability of diethylaluminum benzenethiolate to efficiently discriminate between aldehydes and other carbonyl functions enables the chemoselective in situ reduction of ketones and methyl esters in the presence of aldehydes. This potent strateg

Full text of DOI:10.1021/ol300188e

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1306–1309
Highly Chemoselective Reduction of Carbonyl
Groups in the Presence of Aldehydes
ꢀ ꢀ
Gulluzar Bastug, Steve Dierick, Frederic Lebreux, and Istvan E. Marko*
ꢀ
ꢀ
ꢀ
^
Universite Catholique de Louvain, Laboratory of Organic and Medicinal Chemistry, Batiment
Lavoisier, Place Louis Pasteur 1 bte L4.01.02., B-1348 Louvain-la-Neuve, Belgium
istvan.marko@uclouvain.be
Received January 23, 2012
ABSTRACT
The exquisite ability of diethylaluminum benzenethiolate to efficiently discriminate between aldehydes and other carbonyl functions enables the
chemoselective in situ reduction of ketones and methyl esters in the presence of aldehydes. This potent strategy avoids the usual drawbacks of
traditional protecting group methodologies and could be extended to various other transformations.
Functional Group Interconversions (FGIs) form a cen-
tral theme in organic chemistry.1 Among them, modifying
the oxidation state of carbonyl groups is of crucial
importance.1,2 The chemoselective reduction of aldehydes
in the presence of less reactive carbonyl functions can be
easily achieved using specially designed reagents.3 How-
ever, the opposite transformation, i.e. the reduction of a
carbonyl group, such as a ketone or an ester, in the
presence of an aldehyde remains elusive.
Although specific protecting groups for aldehydes have
been introduced,4 several drawbacks still persist. In parti-
cular, their use in polyfunctional molecules is sometimes
difficult and unselective. Moreover, this protecting group
methodology requires a three-step process: protection,
reaction, and deprotection. Accordingly, it is hardly sur-
prising that modern synthetic endeavors, aimed at effi-
ciency and convergency, will try to avoid such practice by
attempting to minimize the number of steps, decreasing the
amount of byproduct and saving time.5
A more elegant strategy can solve most of these short-
comings. Indeed, the aldehyde can be reversibly trans-
formed in situ in an unreactive derivative, leaving other
untouched carbonyl groups to react. This principle has
been successfully applied by Reetz and Yamamoto for the
chemoselective alkylation of ketones in the presence of
aldehydes.6 In his pioneering work, Luche used lantha-
noids for the hemiacetalization of aldehydes, enabling the
selective reduction of ketones.7 Unfortunately, this aque-
ous system displays moderate selectivities and is limited to
aliphatic substrates. In a one-pot procedure, Paradisi
preferentially converted aldehydes into imines before re-
ducing ketones with an alumino-hydride reagent, even-
tually releasing the unreacted aldehydes.8 However, the
intermediate imine is too reactive to extend this methodol-
ogy to other transformations.
As part of an ongoing research program, aimed at the
efficient assembly of R-methylene-γ-butyrolactones, we
have recently reported a novel tandem Claisenꢀene rear-
rangement (Scheme 1).9 In the course of this process,
(1) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis;
Wiley: New-York, 1995.
(2) (a) Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis;
VCH: Weinheim, 1996. (b) Hudlickꢀy, T.; Reed, J. W. The Way of Synthesis;
Wiley-VCH: Weinheim, 2007.
(3) Burke, S. D.; Danheiser, R. L. Handbook of Reagents for Organic
Synthesis. Oxidizing and Reducing Agents; Wiley: Chichester, 1999.
(6) (a) Reetz, M. T.; Wenderoth, B.; Peter, R. J. Chem. Soc., Chem.
Commun. 1983, 406. (b) Maruoka, K.; Araki, Y.; Yamamoto, H.
Tetrahedron Lett. 1988, 3101.
(7) (a) Gemal, A. L.; Luche, J.-L. J. Org. Chem. 1979, 44, 4187. (b)
Luche, J.-L.; Gemal, A. L. J. Am. Chem. Soc. 1979, 101, 5848.
(8) Paradisi, M. P.; Zecchini, G. P.; Ortar, G. Tetrahedron Lett. 1980,
21, 5085.
ꢀ
(4) (a) Kocienski, P. J. Protecting Groups, 3th ed.; Thieme: Stuttgart,
2004. (b) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in
Organic Synthesis, 4th ed.; Wiley: Hoboken, NJ, 2007.
(5) (a) Hendrickson, J. B. J. Am. Chem. Soc. 1975, 97, 5784. (b)
Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404. (c)
Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38,
3010. (d) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193.
ꢀ
(9) Leclercq, C.; Marko, I. E. Tetrahedron Lett. 2005, 46, 7229.
r
10.1021/ol300188e
Published on Web 02/17/2012
2012 American Chemical Society

diethylaluminum benzenethiolate (Et2AlSPh),10 which
was used as a mild Lewis acid to catalyze the initial Claisen
rearrangement, added to the in situ generated aldehyde as
soon as it was formed. The resulting O,S-aluminum acetal
2 proved to be surprisingly robust, and the aldehyde 3,
needed for the subsequent ene reaction, had to be un-
masked by the addition of phenylsulfenyl chloride.11
is, as expected, crucial; the lower the temperature, the
better the selectivity and the higher the yield (entries
2ꢀ5). Another important parameter to control proved to
be the quantity of diethylaluminum benzenethiolate. In-
deed, if a near-stoichiometric quantity of this reagent is
employed, the selectivity drops to 78% (entry 6). On the
other hand, the use of 1.4 equiv of this Lewis acid provides
the highest levels of chemoselectivity albeit at the expense
of the conversion (entry 7).14 The best compromise be-
tween high selectivity and good yield involves the use 1.1
equiv of Et2AlSPh. Furthermore, the temperature of re-
duction also has some influence on the selectivity and
should be at ꢀ78 °C or below. Finally, replacing toluene
with dichloromethane or tetrahydrofuran does not im-
prove the yield but decreases the selectivity (entries 8, 9).
Scheme 1. Tandem ClaisenꢀEne Rearrangement
Table 1. Optimization of the Chemoselective Reduction of
Hydrocinnamaldehyde (6) in the Presence of Benzylacetone (7)
Attracted by this unexpected reactivity, we investigated
the behavior of this particular Lewis acid toward various
aldehydes and ketones. In the event, hydrocinnamalde-
hyde (6) and benzylacetone (7) were reacted individually,
at ꢀ78 °C, with diethylaluminum benzenethiolate in hex-
ane giving the corresponding O,S-aluminum acetals 8 and
9, respectively (Figure 1). According to the 13C NMR
analyses of the crude reaction mixtures measured at 25 °C,
we were pleased to notice that (i) aldehyde 6 was completely
transformed into the acetal 8 and did not undergo a
Tishchenko reaction (spectrum A)12,13 and (ii) ketone 7
reacted partially to give ketal 9(spectrum B). In a competitive
experiment, hydrocinnamaldehyde (6) and benzylacetone
(7) were treated with 1 equiv of Et2AlSPh. Gratifyingly,
aldehyde 6 was smoothly converted into the acetal 8 while
the ketone 7 remained unaltered (spectrum C).
entry
temp
Et2AlSPh
selectivitya
yieldb
1c
2
3d
4
ꢀ
0 equiv
1.1 equiv
1.1 equiv
1.1 equiv
1.1 equiv
1.02 equiv
1.4 equiv
1.1 equiv
1.1 equiv
0%
42%
48%
66%
98%
78%
99%
88%
85%
50%
65%
68%
77%
89%
81%
72%
86%
89%
rt
ꢀ15 °C
ꢀ15 °C
ꢀ78 °C
ꢀ78 °C
ꢀ78 °C
ꢀ78 °C
ꢀ78 °C
5
6
7
8e
9f
Encouraged by these preliminary observations, we de-
signed a protocol for the selective reduction of benzylace-
tone (7) in the presence of an equimolar amount of
hydrocinnamaldehyde (6). Some relevant results are pre-
sented in Table 1. It transpires, from this optimization
study, that the temperature for the formation of the acetal
a Selectivity is defined as (secondary alcohol ꢀ primary alcohol)/
(secondary alcohol þ primary alcohol) and determined by GC.
b GC yields measured with dodecane (1 equiv) as an internal standard.
c 1.0 equiv of DIBALH was used. d Reduction was performed at
ꢀ15 °C. e Toluene was replaced by CH2Cl2. f Toluene was replaced by
THF.
Figure 1. Partial 13C NMR spectra of the aluminum adducts.
Org. Lett., Vol. 14, No. 5, 2012
1307

Table 2. Chemoselective Reduction of Ketones
a Selectivity is defined as (secondary alcohol ꢀ primary alcohol)/(secondary alcohol þ primary alcohol) and determined by GC for intermolecular
reaction and by 1H NMR for intramolecular reaction. b GC yields measured with dodecane (1 equiv) as an internal standard. c No trace of
neopentylalcohol was detected in the crude mixture by GC. d Isolated yields after column chromatography on silica gel. e Performed in the presence
of 1-octyne (1 equiv). f Isolated as the acetate derivative.15
With the optimization study completed, the scope and
limitations of this novel, chemoselective reduction metho-
dology were investigated next (Table 2). In the aliphatic
series, increasing the steric hindrance around the ketone
function has little effect on the selectivity and yield. Both
remain excellent (entries 1ꢀ3). The aromatic substrates
give slightly lower yields and selectivities (entries 4ꢀ6). It is
worth noting that, in these cases, an important influ-
ence of steric hindrance is operating, with the isopropyl
group significantly raising the selectivity. An impress-
ive result arises from the reduction of benzylacetone in
the presence of pivalaldehyde. In this case, no trace of
neopentyl alcohol could be detected (entry 7). Thus, a
quaternary center R to the aldehyde group does not
prevent the formation of the corresponding O,S-acetal.
Moreover, functionalities sensitive to diisobutylalumi-
num hydride, such as alkynes and nitriles, are well
tolerated under these conditions (entries 8, 9). Finally,
the synthetically useful intramolecular version of our
protocol proceeds smoothly to give outstanding selec-
tivities and good yields (entries 10, 11).15
(10) (a) Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. Bull. Chem. Soc.
Jpn. 1984, 57, 446. (b) Mori, I.; Takai, K.; Oshima, K.; Nozaki, H.
Tetrahedron 1984, 40, 4013. (c) Takai, K.; Mori, I.; Oshima, K.; Nozaki,
H. Tetrahedron Lett. 1981, 22, 3985.
(11) The addition of PhSCl to the O,S-aluminum acetal 2 afforded
not only inert (PhS)2 but also Et2AlCl, the Lewis acid required for the
ene reaction, thereby increasing further the efficiency of the overall
process.
(12) The presence of several signals around 83 ppm in the 13C NMR
spectrum of 8 suggests that this species might exist in a dimeric form or
even as an oligomeric assembly. Studies are currently underway to
establish the aggregation state of 8 in solution.
(13) Cronin, L.; Manoni, F.; O’ Connor, C. J.; Connon, S. J. Angew.
Chem., Int. Ed. 2010, 49, 3045.
(14) Using a large excessof diethylaluminum benzenethiolate leads to
the partial ketalization of the ketone which could not be reduced further.
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Org. Lett., Vol. 14, No. 5, 2012

Table 3. Chemoselective Reduction of Methyl Esters
a Selectivity is defined as (alcohol from ester ꢀ alcohol from aldehyde)/(alcohol from ester þ alcohol from aldehyde) and determined by GC for
intermolecular reaction and by 1H NMR for intramolecular reaction. b Isolated yields after column chromatography on silica gel. c No trace of
hydrocinnamic alcohol was detected in the crude mixture by GC. d Isolated as the acetate derivative.15
Having successfully demonstrated the synthetic poten-
tial of our methodology, we turned our attention to the
more challenging reduction of methyl esters in the presence
of aldehydes. Some of our results are collected in Table 3.
In these cases, 2 equiv of diisobutylaluminum hydride have
been used in the reduction step which was performed at
0 °C. Pleasantly, the reduction of both aromatic and
aliphatic methyl esters could be accomplished in good
yields and with excellent levels of chemoselectivity in the
presence of an aliphatic aldehyde (entries 1, 2). An intra-
molecular version of this process gave remarkable selectiv-
ity, though the yield was slightly lower (entry 3).15
increasing steric hindrance around both carbonyl groups.
Moreover, all the reagents employed in this reaction are
commercially available and cheap.16 Further studies on
extending this methodology to various nucleophilic addi-
tions on differentially activated carbonyl functions are
actively being pursued in our laboratory. The results of
our progress will be reported in due course.
Acknowledgment. Financial support of this work by the
ꢁ
F.R.I.A. (Fond pour la Formation a la Recherche dans
l0Industrie et l0Agriculture, studentships to G.B., S.D., and
ꢀ
F.L.), Actions de Recherches Concertees (ARC 08/13-
012), and the Universite catholique de Louvain is grate-
ꢀ
In summary, the reduction of ketones and methyl esters
in the presence of aldehydes was achieved with high yields
and excellent chemoselectivity. The method is efficient for
both aliphatic and aromatic substrates and tolerates
fully acknowledged.
Supporting Information Available. Full experimental
and characterization details for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Since the resulting hydroxy aldehydes were in equilibrium with
their hemiacetal forms, they were acetylated in order to obtain unam-
biguous characterization data.
(16) Diethylaluminum benzenethiolate is easily prepared in situ from
triethylaluminum and thiophenol.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
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