Tributyltin hydride in NMP-promoted reduction of acid chlorides to aldehydes under transition-metal-free conditions

Article abstract of DOI:10.1055/s-0029-1219796

Tributyltin hydride in N-methyl-2-pyrrolidinone (NMP) was used for the partial reduction of various functionalized acid chlorides at room temperature. This transition-metal-free procedure allows the synthesis of a range of (hetero)aromatic- and aliphatic aldehydes in good to excellent yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219796

LETTER
1101
Tributyltin Hydride in NMP-Promoted Reduction of Acid Chlorides to
Aldehydes under Transition-Metal-Free Conditions
N
MP-Promote
a
d
R
eductio
t
n of
A
c
r
id
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hlor
i
ides to
c
Aldehydesk Le Ménez, Abdallah Hamze,* Olivier Provot, Jean-Daniel Brion, Mouâd Alami*
Univ Paris-Sud, CNRS, BioCIS UMR 8076, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie,
5 Rue J.-B. Clément, Châtenay-Malabry 92296, France
Fax +33(1)46835828; E-mail: mouad.alami@u-psud.fr; E-mail: abdallah.hamze@u-psud.fr
Received 17 December 2009
Table 1, showed that treatment of 1a with Bu3SnH (1.1
equiv) in tetrahydrofuran (THF) was ineffective, and only
trace amounts of over-reduced 3a was detected (entry 1).
For comparison, with addition of tetrakis(triphenylphos-
phine)palladium(0) (5 mol%), Bu3SnH in THF was found
to affect the reduction of 1a, furnishing 4-methoxybenzal-
dehyde (2a) in 72% yield along with a small amount of
benzyl alcohol (3a; <5%, data not shown). When the reac-
tion was carried out without transition-metal catalyst in
N,N-dimethylacetamide (DMA) or N,N¢-dimethyl propy-
leneurea (DMPU) as solvents, the conversion rose to
~50%, but a noticeable amount of over-reduced 3a was
detected in the crude reaction mixture (entries 2 and 3).
Finally, when the reaction was performed in NMP as sol-
vent, we were pleased to observe that the reduction of 1a
with Bu3SnH (1.05 equiv) at room temperature for one
hour successfully furnished the desired 4-methoxybenzal-
dehyde (2a) in 81% yield (entry 5). Only a trace of over-
reduced by-product 3a was detected.
Abstract: Tributyltin hydride in N-methyl-2-pyrrolidinone (NMP)
was used for the partial reduction of various functionalized acid
chlorides at room temperature. This transition-metal-free procedure
allows the synthesis of a range of (hetero)aromatic- and aliphatic al-
dehydes in good to excellent yields.
Key words: acid chlorides, aldehydes, reduction, tributyltin hy-
dride, N-methyl-2-pyrrolidinone, free-metal conditions
The partial reduction of acid chlorides to aldehydes seems
to be a simple reaction, yet this type of transformation re-
mains a desirable tool. Over the past decades, a variety of
methods have been developed. Besides the traditional hy-
drogenolysis with Pd/BaSO4 (Rosenmund reduction),1
many metallic hydrides have been extensively used for
such transformations, including, lithium or sodium tri-t-
butoxyaluminium hydride,2 sodium borohydride,3 hyper-
valent silicon hydrides,4 transition-metal borohydrides,5
anionic transition-metal reductants,6 and others.7 Howev-
er, such methods have limitations, which include over-
reduction, lack of generality, low yield and functional
group incompatibility. Alternative methods involve the
use of organosilicon8 or tributyltin hydrides9 in the pres-
ence of a transition-metal catalyst. Since the pioneering
work of Guibé, tributyltin hydride9a,10 mediated reduction
of acid chlorides to aldehydes in the presence of palladi-
um catalyst appears to be superior and this procedure has
been successfully applied to the synthesis of complex
molecules.11
Table 1 Effect of Solvents on the Reduction of 4-Methoxybenzoyl
Chloride (1a) to Aldehyde 2a with Bu3SnH under Metal-Free Condi-
tions
O
O
Bu3SnH
solvent, r.t
Cl
H
OH
+
MeO
MeO
MeO
1a
2a
3a
Entry Solvent
Time
(h)
Temp
Bu3SnH
(equiv)
Ratio (%)a
1a/2a/3a
(°C)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
50
As part of our research program on the hydrostannation of
arylalkynes12 and enynes,13 we have noticed the crucial in-
fluence of the solvent, particularly with N-methyl-2-pyr-
rolidinone (NMP), where a partial addition of tributyltin
hydride across the carbon–carbon triple bond occurred in
the absence of palladium catalyst. These findings have
prompted us to investigate the particular reactivity of the
Bu3SnH/NMP system toward other functionalities, such
as the partial reduction of acid chlorides under metal-free
conditions. Herein, we wish to report on our successful
results.
1
2
3
4
5
6
7
8
THF
1
1.1
96:0:4
DMA
DMPU
DMF
NMP
NMP
NMP
NMP
1
1.05
1.05
1.05
1.05
1.05
1.05
1.5
46:44:10
43:50:7
90:10:0
10:85b:5
15:47:38
12:70:18
22:48:30
1.5
2
1
8
1
First, we studied the reduction of 4-methoxybenzoyl chlo-
ride (1a) as a model substrate. The results, summarized in
1
r.t.
a Determined by the 1H NMR ratio of the crude product.
b Compound 2a was isolated in a 81% yield after column chromatog-
raphy.
SYNLETT 2010, No. 7, pp 1101–1103
Advanced online publication: 23.03.2010
DOI: 10.1055/s-0029-1219796; Art ID: D36709ST
x
x.
x
x.
2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

1102
P. Le Ménez et al.
LETTER
Table 2 Reduction of Acid Chlorides with the HSnBu3/NMP Sys-
tem at Room Temperature
Increasing the reaction time, the temperature, or the
amount of Bu3SnH led to a decline in yield of aldehyde 2a
with increased formation of the over-reduced by-product
3a (entries 6–8). In our system, it appeared that the use of
NMP heightened the reactivity of the tributyltin hydride to
the point that acid chloride 1a could be converted into the
aldehyde 2a without the need for a palladium catalyst.
With optimized conditions in hand,14 our investigation
shifted to an exploration of the reaction scope, and a series
of commercially available acid chlorides was reacted with
the Bu3SnH/NMP system at room temperature, as shown
in Table 2.
O
O
HSnBu3 (1.05 equiv)
NMP, r.t.
R
Cl
R
H
2
1
Entry Acide chloride 1
Aldehyde 2
Yield
(%)a
CHO
CHO
COCl
1
2
81
60
MeO
2a
MeO
1a
MeO
COCl
MeO
The partial reduction of acid chlorides 1a–o with Bu3SnH
in NMP led to aldehydes 2a–o, respectively, in good
yields, without exception, demonstrating a broad reaction
scope and tolerance of a range of functional groups. Aro-
matic acid chlorides 1a–f, bearing an electron-donating
group, were successfully transformed into their corre-
sponding aldehyde derivatives 2a–f in good to excellent
yields (entries 1–6). It should be noted that the position of
the substituent on the aromatic ring had no influence on
either the yield or selectivity. An important aspect of this
transition-metal-free procedure is the survival of an O-
allyl protecting group during the Bu3SnH partial reduction
(entry 6). It should be noted that such a transformation
could not be selectively realized under the Guibé protocol
[Bu3SnH/Pd(PPh3)4/THF] as these conditions are well
known to result in cleavage of an O-allyl ether function.15
As shown in entries 8–10, the presence of an electron-
withdrawing group on the aryl ring also did not affect the
yield of the reduction, and the reaction provided alde-
hydes 2h–j in good yields. It is particularly notable that a
potentially reducible NO2 substituent was tolerated under
the reaction conditions (74%, entry 9). The reduction of
other aromatic and heteroaromatic systems, such as 1-
naphthoyl acid chloride (1k) or 2-thienoyl acid chloride
(1l) by Bu3SnH in NMP worked equally well, to give 2k
and 2l in 90% and 93% yield, respectively (entries 11 and
12). a,b-Unsaturated acid chloride 1m (entry 13) reacted
well with 1.05 equivalents of tributyltin hydride in NMP
to give the a,b-unsaturated aldehyde 2m in a good 85%
yield with no trace of the saturated aldehyde. Because few
methods could achieve complete efficiency with both ar-
omatic and aliphatic acid chlorides, it was important to
test the partial reduction of aliphatic substrates. Thus, as
shown in entry 14, the Bu3SnH/NMP protocol was found
to be optimal for the conversion of aliphatic acid chloride
1n into aldehyde 2n, demonstrating the generality of the
method. Finally, the reduction of citronelloyl chloride
(1o; entry 15), gave only citronellal (2o), which is in con-
trast to the reduction of 1o in the presence of azobis(isobu-
tyronitrile) (AIBN), which has been reported to give the
cyclic compound menthone.16 This observation led us to
exclude a radical mechanism for the Bu3SnH/NMP-medi-
ated reduction of acid chlorides.
OMe
OMe
1b
2b
COCl
COCl
3
4
5
80
87
63
Me
Me
1c
2c
COCl
Me
CHO
Me
1d
2d
COCl
CHO
CHO
BnO
BnO
2e
1e
COCl
6
7
8
70
87
90
AllylO
AllylO
1f
2f
COCl
CHO
2g
1g
COCl
CHO
CHO
Br
Br
1h
2h
COCl
9
74
O2N
O2N
1i
2i
COCl
CHO
10
86b
ClOC
OHC
1j
2j
COCl
COCl
CHO
CHO
11
12
90
93
2k
1k
S
S
1l
2l
Synlett 2010, No. 7, 1101–1103 © Thieme Stuttgart · New York

LETTER
NMP-Promoted Reduction of Acid Chlorides to Aldehydes
1103
Table 2 Reduction of Acid Chlorides with the HSnBu3/NMP Sys-
tem at Room Temperature (continued)
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O
O
HSnBu3 (1.05 equiv)
NMP, r.t.
R
Cl
R
H
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2
1
Entry Acide chloride 1
Aldehyde 2
Yield
(%)a
COCl
CHO
13
85
1m
1n
2m
2n
COCl
COCl
CHO
CHO
14
15
96
65
(8) (a) Citron, J. D. J. Org. Chem. 1969, 34, 1977. (b) Courtis,
B.; Dent, S. P.; Eaborn, C.; Pidcock, A. J. Chem. Soc.,
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Jr. Org. Lett. 2006, 8, 1887.
1o
2o
a Isolated pure product after column chromatography.
b Bu3SnH (2.1 equiv) was used.
(9) (a) Guibé, F.; Four, P.; Rivière, H. J. Chem. Soc., Chem.
Commun. 1980, 432. (b) Four, P.; Guibé, F. J. Org. Chem.
1981, 46, 4439. (c) Malanga, C.; Mannucci, S.; Lardicci, L.
Tetrahedron Lett. 1997, 38, 8093. (d) Inoue, K.; Yasuda,
M.; Shibata, I.; Baba, A. Tetrahedron Lett. 2000, 41, 113.
(10) For reviews, see: (a) Neumann, W. P. Synthesis 1987, 665.
(b) Mitchell, T. N. J. Organomet. Chem. 1986, 304, 1.
(11) (a) Stern, E.; Muccioli, G. G.; Bosier, B.; Hamtiaux, L.;
Millet, R.; Poupaert, J. H.; Henichart, J. P.; Depreux, P.;
Goossens, J. F.; Lambert, D. M. J. Med. Chem. 2007, 50,
5471. (b) Chelliah, M. V.; Chackalamannil, S.; Xia, Y.;
Eagen, K.; Clasby, M. C.; Gao, X. B.; Greenlee, W.; Ahn,
H. S.; Agans-Fantuzzi, J.; Boykow, G.; Hsieh, Y. S.; Bryant,
M.; Palamanda, J.; Chan, T. M.; Hesk, D.; Chintala, M.
J. Med. Chem. 2007, 50, 5147. (c) Gracia, J.; Thomas, E. J.
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(12) (a) Liron, F.; Le Garrec, P.; Alami, M. Synlett 1999, 246.
(b) Alami, M.; Liron, F.; Gervais, M.; Peyrat, J.-F.; Brion,
J.-D. Angew. Chem. Int. Ed. 2002, 41, 1578. (c) Liron, F.;
Gervais, M.; Peyrat, J.-F.; Alami, M.; Brion, J.-D.
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72, 3868. (e) Hamze, A.; Veau, D.; Provot, O.; Brion, J.-D.;
Alami, M. J. Org. Chem. 2009, 74, 1337.
In summary, we have developed a simple, efficient and
general process for the partial reduction of acid chlorides
using tributyltin hydride in NMP at room temperature.
This mild and transition-metal-free procedure works well
with (hetero)aromatic as well as aliphatic acid chlorides
and allows the efficient preparation of a variety of func-
tionalized aldehydes in good to excellent yields. In the
present method, the survival of an O-allyl ether function,
which is commonly used as an alcohol-protecting group,
must be highlighted as it constitutes a real advantage
when compared with palladium-catalyzed procedures.
Due to its simplicity and versatility, we believe that this
methodology should find broad applications in synthetic
organic chemistry.
Acknowledgment
The CNRS is gratefully thanked for support of this research.
References and Notes
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E.; Mozingo, R. Org. React. 1948, 4, 362. (b)Larsen, R. D.;
King, A. O. In Handbook of Organopalladium Chemistry for
Organic Synthesis, Vol. 2; Negishi, E., Ed.; John Wiley and
Sons: New York, 2002, Chap. VI. 2.4, 2473.
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(3) Babler, J. H.; Invergo, B. J. Tetrahedron Lett. 1981, 22, 11.
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Lett. 1988, 29, 1271.
(5) (a) Sorrell, T. N.; Spillane, R. J. Tetrahedron Lett. 1978, 19,
2473. (b) Fleet, G. W. J.; Fuller, C. J.; Harding, P. J. C.
Tetrahedron Lett. 1978, 19, 1437. (c) Fleet, G. W. J.;
(14) Typical procedure: Acid chloride 1 (1 mmol) was dissolved
in NMP (1 mL) under an argon atmosphere. Bu3SnH (1.05
mmol) was added dropwise and the resulting mixture was
stirred at r.t. for 1 h. Then, H2O (2 mL) was added and the
mixture was extracted with EtOAc (3 × 5 mL). The
combined organic phases were washed with an aq sat.
NH4Cl (3 × 5 mL), dried over MgSO4 and concentrated. The
crude mixture was purified by column chromatography on
silica gel to give the desired aldehyde 2
(15) (a) Guibe, F.; Dangles, O.; Balavoine, G. Tetrahedron Lett.
1986, 27, 2365. (b) L’Hermite, N.; Peyrat, J.-F.; Hildgen, P.;
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(16) Cekovic, Z. Tetrahedron Lett. 1972, 13, 749.
Synlett 2010, No. 7, 1101–1103 © Thieme Stuttgart · New York