Palladium-catalyzed reduction of acid chlorides to aldehydes with hydrosilanes

Article abstract of DOI:10.1055/s-0032-1317155

An efficient synthesis of aldehydes from acid chlorides with hydrosilanes as a reducing agent in the presence of a palladium catalyst has been achieved. A simple mixture of commercially available Pd(dba)₂ and Mes ₃P as a catalyst realized the reduction of various acid chlorides including aliphatic acid chlorides and a, P-unsaturated acid chlorides to the corresponding aldehydes in good to high yields under mild reaction conditions. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0032-1317155

LETTER
▌2389
letter
Palladium-Catalyzed Reduction of Acid Chlorides to Aldehydes with Hydro-
silanes
Reduction of Acid Chlorides to Aldehydes
Tetsuaki Fujihara, Cong Cong, Tomohiro Iwai, Jun Terao, Yasushi Tsuji*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan
Fax +81(75)3832514; E-mail: ytsuji@scl.kyoto-u.ac.jp
Received: 06.07.2012; Accepted after revision: 31.07.2012
of decarbonylation and β-hydrogen elimination which
Abstract: An efficient synthesis of aldehydes from acid chlorides
have been two major intrinsic problems in transition-
with hydrosilanes as a reducing agent in the presence of a palladium
metal-catalyzed reactions.11 During the course of these
studies, we found that a palladium complex successfully
catalyst has been achieved. A simple mixture of commercially
available Pd(dba)2 and Mes3P as a catalyst realized the reduction of
various acid chlorides including aliphatic acid chlorides and α,β- catalyzes the reduction of acid chlorides with hydrosi-
unsaturated acid chlorides to the corresponding aldehydes in good
to high yields under mild reaction conditions.
lanes to the corresponding aldehydes in good to high
yields. In the reaction, a simple mixture of commercially
13
available12 Pd(dba)2 and Mes3P13 shows high catalytic
Key words: acid chloride, aldehyde, hydrosilane, palladium, phos-
phine
activity, and various acid chlorides including aliphatic
acid chlorides and aroyl chlorides can be used as sub-
The transformation of carboxylic acid derivatives to alde-
Table 1 Effect of Ligands and Hydrosilanes on the Palladium-Cata-
hydes is one of the most classical and essential reactions
in organic synthesis.1 Among them, conversion of acid
chlorides into the corresponding aldehydes has been in-
tensively investigated. The reduction of acid chlorides
with molecular hydrogen over supported palladium cata-
lysts (Pd–BaSO4) is well-known as the Rosenmund reduc-
tion.2 However, during the reaction the uptake of
hydrogen must be monitored to avoid over-reduction. Fur-
thermore, various reducing agents such as aluminum hy-
drides,3 sodium hydrides,4 and tin hydrides5 were also
employed in the reduction of acid chlorides to aldehydes.
lyzed Reduction of 3-Phenylpropionyl Chloride (1a)a
O
O
Pd(dba)2 (2.5 mol%)
ligand (5.0 mol%)
H
Cl
hydrosilane (1.1 equiv)
PhMe, 40 °C, 1.5 h
2a
1a
Entry
Ligand
Hydrosilane
Yield (%)b
1
2
none
HSiEt3
0
Ph3P
HSiEt3
trace
trace
99 (77)c
12
On the other hand, hydrosilanes, which are stable, easy-
to-handle, and efficient reducing reagents,6 were also
known as possible reducing agents for the conversion of
acid chlorides into aldehydes.7 Recently, aroyl chlorides
were effectively converted into the corresponding alde-
hydes employing polymethylhydrosiloxane (PMHS) in
the presence of palladium catalysts.8 However, in the re-
action, aliphatic acid chlorides could not be used as sub-
strates.8 Very recently, the reduction of aliphatic acid
chlorides and aroyl chlorides with HSiMe2Ph has been re-
ported in the presence of {Cp[(i-Pr)3P]Ru(NCMe)2}[PF6]
as catalyst.9 However, in this Ru-catalyzed reaction, α,β-
unsaturated acid chlorides could not be employed as sub-
strates. Therefore, it is highly desirable to develop a sim-
ple and effective catalyst system to cover a wide variety
of substrates.
3
(2-Tol)3P
Mes3P
Cy3P
HSiEt3
4
HSiEt3
5
HSiEt3
6
dpped
HSiEt3
0
7
dppfd
HSiEt3
0
8
rac-BINAPd
Mes3P
Mes3P
Mes3P
Mes3P
Mes3P
Mes3P
HSiEt3
trace
97
9
HSiMe2Ph
HSiMePh2
HSi(i-Pr)3
HSi(OEt)3
H2SiPh2
H3SiPh
10
11
12
13
14
94
65
7
57
Recently, we have reported an iridium-catalyzed addition
reaction of acid chlorides to terminal alkynes.10 Impor-
tantly, aliphatic acid chlorides as well as aroyl chlorides
could be used in the addition reaction10a with suppression
trace
a Reaction conditions: 3-phenylpropionyl chloride (1a, 0.50 mmol),
hydrosilane (0.55 mmol), Pd(dba)2 (0.0125 mmol, 2.5 mol%), ligand
(0.025 mmol, 5.0 mol%, P/Pd = 2) in toluene (1.0 mL) at 40 °C for
1.5 h.
b Yield based on the GC internal standard technique.
c Isolated yield employing HSiMePh2 as a hydrosilane.
d A mixture of Pd(dba)2 (0.0125 mmol) and bidentate phosphine
(0.0125 mmol) was used.
SYNLETT 2012, 23, 2389–2392
Advanced online publication: 11.09.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317155; Art ID: ST-2012-U0571-L
© Georg Thieme Verlag Stuttgart · New York

2390
T. Fujihara et al.
LETTER
Table 2 The Palladium-Catalyzed Reduction of Acid Chlorides to
strates with suppression of decarbonylation and β-hydro-
gen elimination. Noteworthy is that α,β-unsaturated acid
chlorides successfully afford the corresponding aldehydes
in high yields.
the Corresponding Aldehydesa (continued)
Pd(dba)2 (2.5 mol%)
O
O
Mes3P (5.0 mol%)
HSiEt3 (1.1 equiv)
PhMe, 40 °C, 1.5 h
R
H
R
Cl
First, the reaction of 3-phenylpropionyl chloride (1a) with
HSiEt3 was carried out in the presence of a catalytic
amount of Pd(dba)2 with a ligand in toluene at 40 °C (Ta-
ble 1).14 Without a ligand, 1a did not convert at all (Table
1, entry 1). With an addition of a monodentate phosphine
ligand such as Ph3P and (2-Tol)3P,13 only a trace amount
of 3-phenylpropanal (2a) was afforded with low conver-
sion of 1a (Table 1, entries 2 and 3). In contrast, the use of
Mes3P as a ligand dramatically improved the catalytic ac-
tivity, giving 2a quantitatively (Table 1, entry 4). A bulky
and basic phosphine, Cy3P,13 was not so efficient (Table
1, entry 5). Bidentate phosphines such as dppe,13 dppf,13
and rac-BINAP13 were not effective at all (Table 1, entries
6–8). As for hydrosilanes, HSiMe2Ph and HSiMePh2 were
effective (Table 1, entries 9 and 10), while HSi(i-Pr)3,
HSi(OEt)3, H2SiPh2, and H3SiPh were less efficient (Ta-
ble 1, entries 11–14). As a solvent, the reaction in CH2Cl2
provided 2a in 97% yield, but in THF the yield of 2a de-
creased considerably to 62%.14 PdCl2(PhCN)2 can be used
as a palladium precursor giving 2a in 97% yield, while
Pd(OAc)2 decreased the yield of 2a to 24%.14
2
1
Entry Acid chloride
Aldehyde
Yield
(%)b
O
O
C7H15
2d
3c
(91)d
74
C7H15
Cl
H
1d
O
O
4e
Cl
H
1e
1f
2e
O
O
Cl
H
5e
(88)d
(85)d
72
2f
O
O
Cl
H
6
7
Efficacy of the present catalyst system was confirmed em-
ploying various acid chlorides (Tables 2 and 3). Acid
chlorides 1b–p listed in Table 2 were smoothly converted
into the corresponding aldehydes 2b–p in good to high
yields (Table 2, entries 1–15). Among them, sterically
more congested substrates 1f and 1g gave the products
smoothly (Table 2, entries 5 and 6). 3-Arylpropionyl chlo-
rides 1h–l would afford thermodynamically stable conju-
gated alkenes after decarbonylation followed by β-
hydrogen elimination (Table 2, entries 7–11). However, in
these cases, the desired aldehydes 2h–l were obtained in
good yield. Furthermore, ester (1m) and ketone (1n) func-
tionalities were tolerated in the reaction (Table 2, entries
12 and 13).
1g
2g
O
O
Cl
H
Me
Me
1h
2h
O
O
Cl
H
8
70
76
79
MeO
MeO
1i
2i
O
O
Cl
H
Table 2 The Palladium-Catalyzed Reduction of Acid Chlorides to
9e,f
the Corresponding Aldehydesa
Cl
Cl
Pd(dba)2 (2.5 mol%)
O
1j
2j
O
Mes3P (5.0 mol%)
O
O
HSiEt3 (1.1 equiv)
PhMe, 40 °C, 1.5 h
R
H
R
Cl
2
Cl
H
1
10e
F3C
F3C
Entry Acid chloride
Aldehyde
Yield
(%)b
1k
2k
O
O
O
O
Cl
H
1
2
90
68
C21H43
Cl
Cl
C21H43
H
11e
77
1b
2b
F
F
O
O
1l
2l
C13H27
C13H27
H
1c
2c
Synlett 2012, 23, 2389–2392
© Georg Thieme Verlag Stuttgart · New York

LETTER
Reduction of Acid Chlorides to Aldehydes
2391
Table 2 The Palladium-Catalyzed Reduction of Acid Chlorides to
Table 3 The Palladium-Catalyzed Reduction of Aroyl Chlorides and
α,β-Unsaturated Acid Chloridesa
the Corresponding Aldehydesa (continued)
Pd(dba)2 (2.5 mol%)
O
Pd(dba)2 (2.5 mol%)
Mes3P (5.0 mol%)
O
O
O
Mes3P (5.0 mol%)
HSiEt3 (1.1 equiv)
PhMe, 40 °C, 1.5 h
R
H
HSiEt3 (1.1 equiv)
PhMe, 40 °C, 1.5 h
R
Cl
R
Cl
R
H
2
1
1
2
Entry Acid chloride
Aldehyde
Yield
(%)b
Entry Acid chloride
Aldehyde
Yield
(%)b
O
O
O
O
O
O
12g
73
Cl
H
Cl
H
MeO
MeO
1
84
6
6
1m
2m
1q
2q
O
O
O
O
O
O
Cl
H
13e
65
Ph
Ph
2
2
Cl
H
2c
(79)d
1n
2n
1r
2r
O
O
O
O
14g,h
(99)d
Cl
O
H
Cl
H
1o
2o
3c
73
MeO
MeO
O
1s
2s
Cl
H
15e
83
O
O
Cl
H
1p
2p
4c,e
73
86
a Reaction conditions: acid chloride (1, 0.50 mmol), HSiEt3
Cl
Cl
(0.55 mmol), Pd(dba)2 (0.0125 mmol, 2.5 mol%), Mes3P (0.025 mmol,
5.0 mol%) in toluene (1.0 mL) at 40 °C for 1.5 h.
b Isolated yield.
1t
2t
O
O
c For 3 h.
Cl
H
d Yield based on the GC internal standard technique.
e HSiMePh2 was used in place of HSiEt3.
f At 60 °C.
5f
1u
2u
g HSiMe2Ph was used in place of HSiEt3.
h For 5 h.
O
O
Cl
H
6f
76
71
In addition, aroyl chlorides 1q–t also afforded the corre-
sponding aldehydes in good yields (Table 3, entries 1–4).
It is noteworthy that the reactions of α,β-unsaturated acid
chloride 1u–w were selectively converted into the corre-
sponding aldehyde 2u–w in good to high yield (Table 3,
entries 5–7). In the recent ruthenium-catalyzed reaction,9
2u was obtained in low yield (18%) due to considerable
1,4-hydrosilylation of 2u in 82% yield.
Cl
Cl
1v
2v
O
O
7f
C10H21
Cl
C10H21
H
1w
2w
a Reaction conditions: acid chloride (1, 0.50 mmol), HSiEt3 (0.55
mmol), Pd(dba)2 (0.0125 mmol, 2.5 mol%), Mes3P (0.025 mmol,
5.0 mol%) in toluene (1.0 mL) at 40 °C for 1.5 h.
b Isolated yield.
Next, the present method was applied to synthesize alde-
hyde-d1. Compared to former procedures,15 our method is
efficient to provide the aldehydes-d1. In Scheme 1, ali-
phatic, aromatic, and α,β-unsaturated aldehydes-d1 3b,q,u
were easily synthesized employing the corresponding
c A mixture of Pd(dba)2 (0.025 mmol), Mes3P (0.050 mmol), and
HSiEt3 (1.1 mmol) in toluene (2.0 mL) was used.
d Yield based on the GC internal standard technique.
e For 3 h.
16a
acid chlorides 1b,q,u with DSiEt3 (for 1b and 1q) or
f HSiMePh2 was used in place of HSiEt3.
16b
DSiMePh2 (for 1u) under the standard reaction condi-
tions.14,17
shows high catalytic activity. Noteworthy is that a wide
variety of acid chlorides including aliphatic acid chlo-
rides, aroyl chlorides, and α,β-unsaturated acid chlorides
can be employed in the reaction.
In conclusion, we have developed the palladium-cata-
lyzed reduction of acid chlorides with hydrosilanes to the
corresponding aldehydes. A mixture of a commercially
available palladium precursor and a phosphine ligand
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2389–2392

2392
T. Fujihara et al.
LETTER
1979, 35, 567. (c) Cha, J. S.; Brown, H. C. J. Org. Chem.
1993, 58, 4732.
Pd(dba)2 (2.5 mol%)
Mes3P (5.0 mol%)
O
O
(4) (a) Babler, J. H.; Invergo, B. J. Tetrahedron Lett. 1981, 22,
11. (b) Babler, J. H. Synth. Commun. 1982, 12, 839.
(5) (a) Four, P.; Guibe, F. J. Org. Chem. 1981, 46, 4439.
(b) Inoue, K.; Yasuda, M.; Shibata, I.; Baba, A. Tetrahedron
Lett. 2000, 41, 113. (c) Malanga, C.; Mannucci, S.; Lardicci,
L. Tetrahedron Lett. 1997, 38, 8093.
R
D
R
Cl
DSiR'3 (1.1 equiv)
PhMe, 40 °C, 1.5 h
1
3
1b R = C21H43 with DSiEt3
3b 92% yield (99% D)
3q 74% yield (98% D)
3u 80% yield (97% D)
1q R = Naph with DSiEt3
1u R = (E)-CH=CHPh with DSiMePh2
(6) (a) Ojima, I. In The Chemistry of Organic Silicon
Compounds; Patai, S.; Rapport, Z., Eds.; Wiley: Chichester,
1989, 1479–1526. (b) Modern Reduction Methods;
Andersson, P. G.; Munslow, I. J., Eds.; Wiley-VCH:
Weinheim, 2008.
(7) (a) Citron, J. D. J. Org. Chem. 1969, 34, 1977. (b) Dent, S.
P.; Eaborn, C.; Pidcock, A. J. Chem. Soc., Chem. Commun.
1970, 1703. (c) Courtis, B.; Dent, S. P.; Eaborn, C.; Pidcock,
A. J. Chem. Soc., Dalton Trans. 1975, 2460. (d) Dent, S. P.;
Eaborn, C.; Pidcock, A. J. Chem. Soc., Dalton Trans. 1975,
2646.
(8) Lee, K.; Maleczka, R. E. Jr. Org. Lett. 2006, 8, 1887.
(9) Gutsulyak, D. V.; Niknov, G. I. Adv. Synth. Catal. 2012,
354, 607.
(10) (a) Iwai, T.; Fujihara, T.; Terao, J.; Tsuji, Y. J. Am. Chem.
Soc. 2012, 134, 1268. (b) Iwai, T.; Fujihara, T.; Terao, J.;
Tsuji, Y. J. Am. Chem. Soc. 2009, 131, 6668.
Scheme 1 Synthesis of aldehydes-d1 from acid chlorides and DSiEt3
Typical Procedure for the Palladium-Catalyzed Reduction of 3-
Phenylpropionyl Chloride (1a) with HSiEt3 (Table 1, Entry 4)
Pd(dba)2 (7.2 mg, 0.0125 mmol) and Mes3P (9.7 mg, 0.025 mmol)
were added to a 10 mL Schlenk flask with a magnetic stir bar. The
flask was evacuated and backfilled with argon three times. Then,
toluene (1.0 mL) was added to the flask, and the resultant solution
was stirred at r.t. for 10 min. HSiEt3 (88 μL, 0.55 mmol) and 1a (74
μmL, 0.50 mmol) were added to the flask in this order, and the re-
action mixture was stirred at 40 °C for 1.5 h under an argon atmo-
sphere. After cooling to r.t., the reaction mixture was diluted with
diethyl ether (5.0 mL), and tetradecane (50 μL, 0.19 mmol) as an in-
ternal standard was added. The yield of 3-phenylpropanal (2a; 99%)
was analyzed by GC. When 2a was isolated, HSiMePh2 (110 μL,
0.55 mmol) was employed as the hydrosilane. After the reaction
mixture was cooled to r.t., 2a was isolated by silica gel column
chromatography (hexane–EtOAc = 13: 1). A colorless oil (52 mg)
was obtained in 77% yield.
(11) Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke, R. G.
Principles and Applications of Organotransition Metal
Chemistry; University Science Books: Mill Valley / CA,
1987, Chap. 5.
(12) Pd(dba)2 and Mes3P are commercially available from TCI
and Aldrich.
Acknowledgment
(13) Abbreviations: dba: dibenzylideneacetone, Mes3P:
tris(2,4,6-trimethylphenyl)phosphine, (2-Tol)3P: tri-ortho-
tolylphosphine, Cy3P: tricyclohexylphosphine, dppe: 1,3-
bis(diphenylphosphino)ethane, dppf: 1,1′-
This work was supported by Grant-in-Aid for Scientific Research
on Innovative Areas (‘molecular activation directed toward
straightforward synthesis’ and ‘organic synthesis based on reaction
integration’) from MEXT, Japan. T. F. is acknowledged to The
Sumitomo Foundation for financial support.
bis(diphenylphosphino)ferrocene, rac-BINAP: 2,2′-
bis(diphenylphosphino)-1,1′-binaphthyl.
(14) See Supporting Information for detail.
Supporting Information for this article is available online at
(15) (a) Franzen, V. V. Justus Liebigs Ann. Chem. 1956, 600,
109. (b) Burgstahler, A. W.; Walker, D. E. Jr.; Kuebrich,
J. P.; Schowen, R. L. J. Org. Chem. 1972, 37, 1272.
(c) Seebach, D.; Erickson, B. W.; Singh, G. J. Org. Chem.
1966, 31, 4303. (d) Yamashita, M.; Miyoshi, K.; Nakazono,
Y.; Suemitsu, R. Bull. Chem. Soc. Jpn. 1982, 55, 1663.
(e) Spletstoser, J. T.; White, J. M.; Georg, G. I. Tetrahedron
Lett. 2004, 45, 2787.
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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Synlett 2012, 23, 2389–2392
© Georg Thieme Verlag Stuttgart · New York