A practical and highly chemoselective hydrogenation of aldehydes with a copper catalyst

Article abstract of DOI:10.1055/s-0028-1216726

A practical hydrogenation of aldehydes mediated by an inexpensive and easily available base metal, copper, is reported. A copper complex associated with 1,4-bis(diphenylphosphino)butane (DPPB) hydrogenates α,β- unsaturated aldehydes in a highly chemoselective fashion to give allylic alcohols with improved catalytic productivities. The reaction system was also effective for the conversion of simple aldehydes to the corresponding alcohols. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1216726

LETTER
1295
A Practical and Highly Chemoselective Hydrogenation of Aldehydes with a
Copper Catalyst
Chemoselective
H
i
ydroge
d
A
ld
e
ehydes
w
it
o
h
a
C
opper Catalys
S
t
himizu,* Noboru Sayo, Takao Saito
Research & Development Division, Takasago International Corporation, 1-4-11, Nishi-yawata, Hiratsuka City, Kanagawa 254-0073, Japan
Fax +81(463)252093; E-mail: hideo_shimizu@takasago.com
Received 27 January 2009
plex.6 They demonstrated that [CuH(PPh3)]6, together
Abstract: A practical hydrogenation of aldehydes mediated by an
with PhPMe2 and an excess amount of t-BuOH, catalyzed
hydrogenation with excellent 1,2-selectivity to give 1. Al-
though the use of an inexpensive base metal was very at-
inexpensive and easily available base metal, copper, is reported. A
copper complex associated with 1,4-bis(diphenylphosphino)butane
(DPPB) hydrogenates a,b-unsaturated aldehydes in a highly
chemoselective fashion to give allylic alcohols with improved cata- tractive, the downside was a somewhat low turnover
number.7 Obviously, higher catalytic productivity was
lytic productivities. The reaction system was also effective for the
conversion of simple aldehydes to the corresponding alcohols.
needed for Cu catalysis to be more practical.
Key words: hydrogenation, aldehydes, copper, homogeneous ca-
Recently, we reported an asymmetric hydrogenation of ar-
talysis, chemoselectivity
omatic ketones mediated by a copper catalyst.8 In that
study, we found that the catalytic productivity greatly de-
pended on the ligand used. Specifically, bisphosphine
The reduction of aldehydes is a fundamental method for
ligands with C3–C4 alkylene linkers tend to give higher
preparing primary alcohols. Among the many methods
turnover numbers (up to 3000). Thus, we envisioned that,
that are available for reduction, hydrogenation is desir-
for aldehydes, a similar system with a proper choice of
able, especially for reactions beyond a laboratory scale,
bisphosphine ligand could drastically improve the catalyt-
because of good atom economy, low waste, and ease of
ic productivity to a practical level.
workup.
We started our study by screening bisphosphine ligands
with alkyl linkers of various lengths, with
In the hydrogenation of a,b-unsaturated aldehydes,
chemoselectivity is crucial. In many cases, only allylic al-
cohol 1 is desired among three potential products (1, sat-
H2 (5.0 MPa)
[Cu(NO3)(PPh3)2] (S/C = 1000)
Ph2P(CH2)nPPh2 (1 equiv to Cu)
NaOH (10 equiv to Cu)
urated alcohol 2, and saturated aldehyde 3; Scheme 1).1
CHO
Thus, high chemoselectivity in favor of the carbonyl
OH
group is indispensable.
EtOH, 50 °C, 16 h
Various heterogeneous2 and homogeneous3 hydrogena-
tion systems have been investigated for this purpose, and
in most cases platinum group metals (such as Ir and Ru)
have been used as a catalyst. However, with a few excep-
tions,4 this subject remains challenging, since many of the
reported examples suffer from overreduction and/or limit-
ed substrate scope. The most successful results were ob-
tained with a homogeneous diamine-modified Ru catalyst
developed by Noyori and co-workers.5 The use of
RuCl2(PPh3)3 in the presence of NH2(CH2)2NH2 and KOH
gave rise to highly carbonyl-selective hydrogenation to
give 1 virtually without any generation of 2 or 3.
E/Z = 99:1
96% (n = 4)
E/Z = 99:1
100
80
60
40
20
0
n =
2
3
4
5
6
On the other hand, Stryker and co-workers pioneered a
base-metal-catalyzed hydrogenation using a Cu com-
Scheme 2 Hydrogenation of (E)-2-methyl-3-phenylprop-2-enal
R2
H2
catalyst
R2
R2
R2
CHO
CHO
+
+
R1
R1
OH
R1
OH
R1
R3
R3
R3
R3
1
2
3
Scheme 1 Hydrogenation of a,b-unsaturated aldehydes
SYNLETT 2009, No. 8, pp 1295–1298
x
x.
x
x.
2
0
0
9
Advanced online publication: 17.04.2009
DOI: 10.1055/s-0028-1216726; Art ID: U00709ST
© Georg Thieme Verlag Stuttgart · New York

1296
H. Shimizu et al.
LETTER
[Cu(NO3)(PPh3)2]9 and NaOH as components of a catalyst chemoselectivity and virtually only (E)-2-methyl-3-phe-
precursor and EtOH as a solvent. As expected, conversion nylprop-2-en-1-ol was generated (Scheme 2). Herein, the
was greatly influenced by the linkers, and in the case of use of PhPMe2 (2 equiv to Cu) as ligand resulted in 13%
(E)-2-methyl-3-phenylprop-2-enal as a substrate, a C4 en- conversion.
tity, 1,4-bis(diphenylphosphino)butane (DPPB), was the
We then investigated the substrate generality and some
ligand of choice, and the reaction was complete at a rea-
reaction conditions using the Cu–DPPB system at S/C = 500
sonable catalyst loading [molar ratio of substrate to cata-
(Table 1).10 We found that the protocol can be applied to
lyst (S/C) = 1000]. The reaction proceeded with excellent
other a,b-unsaturated aldehydes with excellent conver-
Table 1 Hydrogenation of a,b-Unsaturated Aldehydesa
Entry
Substrate (E/Z)b
Conversion (%)b
Yield of 1 + 2 (%)c
1/2b
E/Z of 1b
CHO
1
>99
>99
>99
99
95
91
>99:1
>99:1
>99:1
99:1
99:1
98:2
2d
3e
(99:1)
CHO
4
5
>99
>99
98
68
>99:1
>99:1
95:5
(95:5)
CHO
>99:1
(>99:1)
6
98
96
>99:1
n.a.
CHO
CHO
7f
>99
>99
92
96
>99:1
>99:1
>99:1
>99:1
8f,g
O
(>99:1)
CHO
9
>99
98
72
87
32:1
96:4
91:9
(99:1)
(94:6)
CHO
10
16:1h
CHO
11
98
94
35:1
92:8
(93:7)
CHO
12
13
98
92
–
51:1
–
n.a.
–
>99i
CHO
a Unless otherwise noted, reactions were carried out at 50 °C for 16 h in EtOH (1.1–1.5 M) in the presence of [Cu(NO3)(PPh3)2] (S/C = 500),
DPPB (1 equiv to Cu) and NaOH (10 equiv to Cu). The initial hydrogen pressure was 5.0 MPa.
b Determined by GC analysis using a BC-WAX column or HP-1 column.
c Isolated yield.
d Hydrogen pressure of 1.0 MPa was adopted.
e Cu(NO3)2·3H2O was used in place of [Cu(NO3)(PPh3)2].
f S/C = 566.
g [CuH(PPh3)]6 (S/C = 500 based on Cu metal) and Ph3P (3 equiv to Cu) were used in place of [Cu(NO3)(PPh3)2] and NaOH.
h Substrate contained ca. 3% of 2-ethylhexan-1-ol.
i A complex mixture.
Synlett 2009, No. 8, 1295–1298 © Thieme Stuttgart · New York

LETTER
Chemoselective Hydrogenation of Aldehydes with a Copper Catalyst
1297
Table 2 Hydrogenation of Aldehydesa
sion and with high chemoselectivities for 1,2-reduction.
Specifically, with cinnamic aldehyde type substrates, vir-
tually only allylic alcohols 1 were obtained without any
disorder in geometry (entries 1–8). On the other hand, in
the case of substrates with only alkyl substituents, saturat-
ed alcohol 2 was obtained in a yield of several percent, al-
though the chemoselectivity to give 1 remained high
(entries 9–12). In the latter case, a small drop in the E/Z
ratio was observed. In every case, little (<1%) or no satu-
rated aldehyde 3 was observed. With a few substrates, the
reaction was accompanied by the generation of unidenti-
fied byproducts, presumably oligomeric compounds,
which led to a decrease in isolated yields (entries 5 and 9).
On the other hand, the reaction with a simply substituted
substrate, (E)-undec-2-enal, gave a complex mixture and
only trace amount of the allylic alcohol was detected (en-
try 13).
Entry Substrate
Conversion Yield
(%)b
(%)c
CHO
1
>99
91
98
CHO
O
2
>99
>99
O
CHO
3
87
O
CHO
4
>99
>99
96
85
S
CHO
5
While the reactions were routinely conducted at an initial
hydrogen pressure of 5.0 MPa, comparable results were
obtained when this level was lowered to 1.0 MPa (entry
2). With regard to the catalyst precursor, Cu(NO3)2⋅3H2O
could be used in place of [Cu(NO3)(PPh3)2] (entry 3).
[CuH(PPh3)]6 with additional Ph3P also worked equally
well even in the absence of NaOH (entry 8).
N
CHO
6
>99
97
90
76
7
CHO
The protocol was also effective with other aldehydes such
as aryl, heteroaryl, and alkyl compounds (Table 2). In
most cases, hydrogenation proceeded smoothly to give the
corresponding alcohols in high yield (entries 1–7). How-
ever, the protocol had some limitations with aldehydes
without a substituent at the a-position; the reactions of 3-
CHO
8
88
97
10
9
9
CHO
phenylpropanal and undecanal resulted in low yields (en- a Reactions were carried out at 50 °C for 16 h in EtOH (1.3–1.5 M) in
the presence of [Cu(NO3)(PPh3)2] (S/C = 500), DPPB (1 equiv to Cu)
try 8 and 9) due to the generation of respective byproducts
4 and 5 derived from aldol-type reactions (Figure 1). With
2-pyridinecarboaldehyde as substrate, the reaction result-
ed in incomplete conversion, giving a mixture of several
products. With 1H-pyrrole-2-carbaldehyde, no reaction
was observed (Figure 1).
and NaOH (10 equiv to Cu). The initial hydrogen pressure was 5.0
MPa.
b Determined by GC using a BC-WAX column.
c Isolated yield.
of Cu metal, which need to be solved for industrial appli-
cation. The influence of linkers of phosphine ligand on
catalytic productivity, as well as the cause of small drop
in E/Z ratio in some cases, will require further investiga-
tion. A mechanistic study is currently under way. Also,
extension of this protocol to a,b-unsaturated ketones is in
progress and will be reported in due course.
OH
OH
5
CHO
CHO
NH
no reaction
N
4
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
conv. 56%
mixture of several products
Figure 1
References and Notes
(1) (a) Chapuis, C.; Jacoby, D. Appl. Catal., A 2001, 221, 93.
(b) Common Fragrance and Flavor Materials; Surburg, H.;
Panten, J., Eds.; Wiley-VCH: Weinheim, 2006. (c) Saudan,
L. A. Acc. Chem. Res. 2007, 40, 1309.
(2) Gallezot, P.; Richard, D. Catal. Rev. 1998, 40, 81.
(3) Recent review: Clarke, M. L.; Roff, G. J. Handbook of
Homogeneous Hydrogenation, Vol. 1; de Vries, J. G.;
Elsevier, C. J., Eds.; Wiley-VCH: Weinheim, 2007, Chap.
15, 413–454.
In summary, we have developed a method for hydrogenat-
ing aldehydes using an inexpensive and easily available
Cu catalyst with a practical level of catalytic productivity.
The protocol generally gives the corresponding alcohols
in high yield, although it has some limitations with a few
substrate types. In the case of a,b-unsaturated aldehydes,
the reaction led to the exclusive formation of allylic alco-
hols. The reaction infrequently produced a small amount
Synlett 2009, No. 8, 1295–1298 © Thieme Stuttgart · New York

1298
H. Shimizu et al.
LETTER
(9) [Cu(NO3)(PPh3)2] can be prepared from Cu(NO3)2·3H2O
(4) (a) Grosselin, J. M.; Mercier, C.; Allmang, G.; Glass, F.
Organometallics 1991, 10, 2126; and references cited
therein. (b) Milone, C.; Tropeano, M. L.; Gulino, G.; Neri,
G.; Ingoglia, N. R.; Galvagno, S. Chem. Commun. 2002,
868.
(5) (a) Ohkuma, T.; Ooka, H.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 10417. (b) Noyori, R.; Ohkuma, T.
Angew. Chem Int. Ed. 2001, 40, 40.
(6) (a) Chen, J.-X.; Daeuble, J. F.; Brestensky, D. M.; Stryker,
J. M. Tetrahedron 2000, 56, 2153. (b)Chen, J.-X.;Daeuble,
J. F.; Stryker, J. M. Tetrahedron 2000, 56, 2789.
(7) Our attempt to hydrogenate (–)-4-(prop-1-en-2-yl)cyclo-
hexen-1-carbaldehyde [(–)-perilaldehyde] at S/C = 500
with the condition described in ref. 6b, resulted in trace
conversion. The reaction reportedly completed at S/C = 20,
which was reproduced by us.
and Ph3P. See: Gysling, H. J. Inorg. Chem. 1979, 19, 92.
(10) Representative Procedure (Table 1, Entry 1)
To a 100 mL stainless steel autoclave equipped with a glass
inner lining and a Teflon-coated stirring bar were added
[Cu(NO3)(PPh3)2] (11.7 mg, 0.018 mmol) and DPPB (7.7
mg, 0.018 mmol). The atmosphere was replaced with N2,
and an EtOH solution (0.03 M) of NaOH (6.0 mL, 0.18
mmol) and (E)-2-methyl-3-phenylprop-2-enal (E/Z = 99:1;
1.26 mL, 9.0 mmol) were then added. Hydrogen gas was
initially introduced into the autoclave at a pressure of 1.0
MPa before being reduced to 0.1 MPa by carefully releasing
the stop valve. After this procedure was repeated three times,
H2 was introduced at 5.0 MPa and the solution was stirred at
50 °C for 16 h. Silica gel chromatography (Et2O–hexane =
1:1) after removal of the solvent gave (E)-2-methyl-3-phenyl-
prop-2-en-1-ol (1.32 g, 99%, E/Z = 99:1).
(8) Shimizu, H.; Igarashi, D.; Kuriyama, W.; Yusa, Y.; Sayo,
N.; Saito, T. Org. Lett. 2007, 9, 1655.
Synlett 2009, No. 8, 1295–1298 © Thieme Stuttgart · New York

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