RuHCl(CO)(PPh3)3-catalyzed reductive dimerization of α,β-unsaturated aldehydes leading to α-hydroxymethyl ketones

Article abstract of DOI:10.1055/s-2006-951518

The reductive dimerization α,β-unsaturated aldehydes to give saturated ketones was achieved using RuHCl(CO)(PPh₃)₃ as a catalyst in the presence of secondary alcohols as hydrogen source. The reaction is likely to proceed via the hydroruthenation of α,β-unsaturated aldehydes followed by aldol reaction of the resultant ruthenium enolates with α,β-unsaturated aldehydes to give unsaturated α-hydroxymethyl ketones, which undergo transfer hydrogenation to give α-hydroxymethyl ketones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951518

LETTER
3013
RuHCl(CO)(PPh3)3-Catalyzed Reductive Dimerization of a,b-Unsaturated
Aldehydes Leading to a-Hydroxymethyl Ketones
R
eductive Dime
a
r
ization of
k
a
,
b
-Unsatur
a
ated
A
ldehy
s
des hi Doi, Takahide Fukuyama, Satoshi Minamino, Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
Fax +81(72)2549695; E-mail: ryu@c.s.osakafu-u.ac.jp
Received 26 April 2006
(10 mol%) at reflux for 10 hours, 2-hydroxymethyl-5-
dodecanone (2a) was formed in 59% yield (Scheme 2). A
small amount of 1-hexanol was formed as a by-product.
The use of some other ruthenium complexes, such as Ru-
Abstract: The reductive dimerization a,b-unsaturated aldehydes to
give saturated ketones was achieved using RuHCl(CO)(PPh3)3 as a
catalyst in the presence of secondary alcohols as hydrogen source.
The reaction is likely to proceed via the hydroruthenation of a,b-un-
saturated aldehydes followed by aldol reaction of the resultant ru- HCl(PPh3)3 and RuH2(PPh)4, under similar conditions
thenium enolates with a,b-unsaturated aldehydes to give
unsaturated a-hydroxymethyl ketones, which undergo transfer hy-
drogenation to give a-hydroxymethyl ketones.
was unsuccessful, and resulted in the recovery of 1a in
92% and 83% yields, respectively.
Key words: ruthenium enolates, aldol reaction, a-hydroxymethyl
ketones, a,b-unsaturated aldehydes, transfer hydrogenation
O
10 mol% RuHCl(CO)(PPh3)3
2-PrOH (1.0 equiv)
C6H6, reflux, 10 h
H
1a
O
Metal-catalyzed coupling reactions have found a tremen-
dous number of applications in organic synthesis.1 We re-
cently reported unusual dimerization of unsaturated
primary alcohols to give a-hydroxymethyl ketones, which
was catalyzed by RuHCl(CO)(PPh3)3 (first equation of
Scheme 1).2 We also found that transfer hydrogenation of
unsaturated ketones leading to saturated ketones took
place using the same Ru-catalyst and secondary alcohols,
such as 2-propanol, as hydrogen source.3 We became in-
terested in whether the reductive dimerization reaction of
a,b-unsaturated aldehydes under the transfer hydrogena-
tion conditions would occur to give the dimerization prod-
ucts or not (second equation of Scheme 1). Herein we
report that RuHCl(CO)(PPh3)3 indeed catalyzes reductive
dimerization of a,b-unsaturated aldehydes 1 leading to
good to modest yields of a-hydroxymethyl ketones 2.
+
OH
OH
2a
59%
3%
Scheme 2
The results of the reductive dimerization of a series of a,b-
unsaturated aldehydes 1 are summarized in Table 1. Some
other secondary alcohols, such as cyclohexanol and 2-oc-
tanol, could be employed as a hydrogen source (entries 1
and 2). Crotyl aldehyde (1b) underwent dimerization re-
action, leading to the hydroxymethyl ketone 2b in 56%
isolated yield (entry 3). Whereas the reaction of cinnam-
aldehyde (1c) in the presence of 1.2 equivalents of 2-pro-
panol gave the corresponding a-hydroxymethyl ketone
2c, along with small amount of unsaturated hydroxymeth-
yl ketone 3c (entry 4), the formation of 3c was suppressed
by using a larger amount of 2-propanol (entry 5). No
dimerization product was obtained in the reaction of 2-
methyl-2-pentanal, (entry 7). The reaction of 2-decenal
(1i), having a long alkyl chain, gave 2i in 47% together
with 6% yield of unsaturated dimer 3i (entry 11).
When a benzene solution of 2-hexenal (1a, 0.16 M) and 2-
propanol (1.0 equiv) was treated with RuHCl(CO)(PPh3)3
previous work, see ref. 2
O
OH
RuHCl(CO)(PPh3)3
OH
We carried out time-course experiment of the reaction us-
ing 1a as a model substrate, whose results are summarized
in Scheme 3. Thus, it was found that 1a was consumed
within 15 minutes, and unsaturated dimer 3a4 was formed
as a primary product. Then 3a was converted into saturat-
ed dimer 2a by transfer hydrogenation.3 After 10 hours,
conversion of 3a to 2a was complete.
this work
O
O
RuHCl(CO)(PPh3)3
[H2]
+
OH
H
(from secondary alcohols)
Scheme 1 Two types of dimerization reactions leading to a-hydro-
xymethyl ketones
Taking the results into consideration, a possible mecha-
nism for the present reductive dimerization is outlined in
Scheme 4. Hydroruthenation of 1a would give ruthenium
enolate A,5 which then undergoes aldol reaction with
1a.6,7 b-Elimination from the resulting aldol adduct B, fol-
lowed by transfer hydrogenation of an aldehyde moiety
SYNLETT 2006, No. 18, pp 3013–3016
0
3
.1
1
.2
0
0
6
Advanced online publication: 25.10.2006
DOI: 10.1055/s-2006-951518; Art ID: S09806ST
© Georg Thieme Verlag Stuttgart · New York

3014
T. Doi et al.
LETTER
a
Table 1 Reductive Dimerization of a,b-Unsaturated Aldehydes 1 to 2-Hydroxymethyl Ketones 2 Catalyzed by RuHCl(CO)(PPh3)3
Entry
Substrate
Alcohol (equiv)
Product
Yield (%)b
O
O
O
1
2
Cyclohexanol (1.4)
2-Octanol (1.2)
64
62
OH
H
H
1a
2a
O
OH
3
4
2-PrOH (1.2)
2-PrOH (1.2)
56
1b
2b
O
O
O
Ph
OH
Ph
OH
Ph
H
Ph
3c
1c
Ph
2c
49
65
5
5
6
1c
2-PrOH (2.0)
2-PrOH (2.0)
<1
O
O
Ar
OH
Ar
H
53
1d
Ar
Ar = p-MePh
2d
O
H
7
8
2-PrOH (1.3)
2-PrOH (2.0)
Not formedc
1e
O
O
OH
57
55
55
H
1f
2f
O
O
OH
9
10
11
2-PrOH (2.0)
2-PrOH (2.0)
2-PrOH (1.4)
H
O
1g
1h
1i
2g
2h
2i
O
OH
H
O
O
OH
47
6
H
O
n
OH
m
(m + n = 6)
3i
a General conditions: substrate (1 mmol), alcohol (1.2–2.0 mmol), RuHCl(CO)(PPh3)3 (10 mol%), C6H6 (6 mL), reflux, 10 h.
b Isolated yields. In all cases, sat. alcohols were formed as by-product. For examples, entry 3: 5%, entry 5: 11%, entry 9: 6%.
c Unreacted 1e, 2-methylpentanal, and 2-methyl-1-pentanol were obtained as a mixture.
Synlett 2006, No. 18, 3013–3016 © Thieme Stuttgart · New York

LETTER
Reductive Dimerization of a,b-Unsaturated Aldehydes
3015
Acknowledgment
I.R. acknowledges a Grant-in-Aid for Scientific Research on Priori-
ty Areas ‘Advanced Molecular Transformations of Carbon Re-
sources’ from MEXT Japan. T.F. acknowledges a Grant-in-Aid for
Young Scientists (B) from MEXT Japan for financial support.
References and Notes
(1) (a) Transition Metals for Organic Synthesis, Vols. 1 and 2;
Beller, M.; Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998.
(b) Applied Homogeneous Catalysis with Organometallic
Compounds, Vols. 1 and 2; Cornils, B.; Herrmann, W. A.,
Eds.; VCH: Weinheim, 1996.
(2) Doi, T.; Fukuyama, T.; Minamino, S.; Husson, G.; Ryu, I.
Chem. Commun. 2006, 1875.
(3) Doi, T.; Fukuyama, T.; Horiguchi, J.; Okamura, T.; Ryu, I.
Synlett 2006, 721.
(4) After 15 min, 3a contained ca. 17% of double-bond isomers.
(5) For studies on ruthenium enolate complexes, see:
(a) Hartwig, J. F.; Bergman, R. G.; Andersen, R. A.
Organometallics 1991, 10, 3326. (b) Tasley, B. T.; Rapta,
M.; Kulawiec, R. J. Organometallics 1996, 15, 2852.
(6) For Ru-catalyzed aldol-type reactions, see: (a) Matsuda, I.;
Shibata, M.; Sato, S. J. Organomet. Chem. 1988, 340, C5.
(b) Sato, S.; Matsuda, I.; Shibata, M. J. Organomet. Chem.
1989, 377, 347. (c) Naota, T.; Taki, T.; Mizuno, M.;
Murahashi, S.-I. J. Am. Chem. Soc. 1989, 111, 5954.
(d) Mizuho, Y.; Kasuga, N.; Komiya, S. Chem. Lett. 1991,
2127. (e) Murahashi, S.-I.; Naota, T.; Taki, H.; Mizuno, M.;
Takaya, H.; Komiya, S.; Mizuho, Y.; Oyasato, N.; Hiraoka,
M.; Hirano, M.; Fukuoka, A. J. Am. Chem. Soc. 1995, 117,
12436. (f) Uma, R.; Davies, M.; Crévisy, C.; Grée, R.
Tetrahedron Lett. 2001, 42, 3069. (g) Wang, M.; Yang, X.-
F.; Li, C.-J. Eur. J. Org. Chem. 2003, 998. (h) Yang, X.-F.;
Wang, M.; Varma, R. S.; Li, C.-J. Org. Lett. 2003, 5, 657.
(i) Yang, X.-F.; Wang, M.; Varma, R. S.; Li, C.-J. J. Mol.
Catal. A: Chem. 2004, 214, 147. (j) Martín-Matute, B.;
Bogár, K.; Edin, M.; Kaynak, F. B.; Bäckvall, J.-E. Chem.
Eur. J. 2005, 11, 5832.
Scheme 3 Time course of the reaction of 1a
gives unsaturated dimer 3a. The second transfer hydroge-
nation of 3a then takes place to give a-hydroxymethyl ke-
tone 2a.
In conclusion, the reductive dimerization of a,b-unsatur-
ated aldehydes 1 to a-hydroxymethyl ketones 2 is cata-
lyzed effectively by RuHCl(CO)(PPh3)3 in the presence of
secondary alcohols as hydrogen source.8 The reaction pro-
ceeds via aldol reaction of ruthenium enolates with a,b-
unsaturated aldehydes, followed by transfer hydrogena-
tion to give unsaturated dimer 3 as a primary product. Se-
lective transfer hydrogenation of the C=C bond gave
saturated dimer 2 as the final product. Extension of the
present work to cross-coupling reactions is now being
pursued in our laboratory and will be reported in due
course.
[Ru]
O
O
[Ru]
O
[Ru]-H
O
1a
H
aldol reaction
H
A
1a
B
– [Ru]-H
O
O
O
[Ru]-H
OH
H
OH
O
OH
O
C
3a
[Ru]-H
O
OH
2a
Scheme 4 Possible mechanism of reductive dimerization
Synlett 2006, No. 18, 3013–3016 © Thieme Stuttgart · New York

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T. Doi et al.
LETTER
(8) General Procedure for the RuHCl(CO)(PPh3)3-
(7) For reviews on catalytic reductive aldol coupling, see:
(a) Motherwell, W. B. Pure Appl. Chem. 2002, 74, 135.
(b) Huddleston, R. R.; Krische, M. J. Synlett 2003, 12.
(c) Jang, H.-Y.; Krische, M. J. Eur. J. Org. Chem. 2004,
3953. (d) Jang, H.-Y.; Krische, M. J. Acc. Chem. Res. 2004,
37, 653. (e) Chiu, P. Synthesis 2004, 2210.
Catalyzed Reductive Dimerization of a,b-Unsaturated
Aldehyde.
A mixture of 1a (103 mg, 1.03 mmol), 2-PrOH (63 mg, 1.05
mmol), and RuHCl(CO)(PPh3)3 (96.0 mg, 0.1 mmol) in
benzene (6 mL) was stirred at reflux for 10 h under an
atmosphere of N2. Purification by silica gel column
chromatography and preparative HPLC equipped with GCP
column gave a-hydroxymethyl ketone 2a (59.0 mg, 59%).
Synlett 2006, No. 18, 3013–3016 © Thieme Stuttgart · New York