Aldol reaction via in situ olefin migration in water

Article abstract of DOI:10.1016/S0040-4039(02)00562-2

In the presence of a catalytic amount of RuCl₂(PPh₃)₃, aldehydes reacted with allyl alcohols to give aldol-type products in water and under an atmosphere of air.

Full text of DOI:10.1016/S0040-4039(02)00562-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3589–3591
Aldol reaction via in situ olefin migration in water
Mingwen Wang and Chao-Jun Li*
Department of Chemistry, Tulane University, New Orleans, LA 70118, USA
Received 4 March 2002; accepted 18 March 2002
Abstract—In the presence of a catalytic amount of RuCl2(PPh3)3, aldehydes reacted with allyl alcohols to give aldol-type products
in water and under an atmosphere of air. © 2002 Elsevier Science Ltd. All rights reserved.
The aldol reaction is one of the most important reac-
tions for forming carbonꢀcarbon bonds. However,
under the classical aldol reaction conditions,1 dimeriza-
tion, polymerization, and self-condensation also occur.
To alleviate such competing processes, an important
modification of the classical aldol reaction has been
developed by reacting the enol silyl ether with carbonyl
compounds in the presence of Lewis acids (the
Mukaiyama aldol reaction).2 Recently, attention has
been focused on developing cross-aldol reactions by
alternative approaches. Toward this, Trost reported a
highly efficient formation of aldol-type products via
vanadium-catalyzed coupling of propargyl alcohols
with aldehyde.3 Recent developments also include
hydrometalation-aldol4 and a-C–H activation-aldol
reactions of carbonyl compounds.5 Motherwell devel-
oped the Rh- and Ni-catalyzed isomerization of allylic
lithium alkoxide to lithium enolate that undergoes fur-
ther aldol reaction.6 Gre´e7 recently reported the isomer-
ization of allyl alcohol to enol catalyzed by Fe(CO)5
under photolytic conditions, which then reacted with
aldehydes to give aldol products (together with other
by-products).
ketone (Fig. 1, route b). The formation of this product
was rationalized by the competing process involving the
break of the allylic CꢀH bond (instead of the CꢀO
bond) to form a ruthenium–enol complex,15 which was
then hydrolyzed to give the ketone. We postulated that
in the presence of an aldehyde, such a ruthenium–enol
complex may be captured.16 Herein we wish to report
the formation of aldol products via a RuCl2(PPh3)3-cat-
alyzed cross coupling of allyl alcohols and aldehydes
(Scheme 1).
To begin our study, 3-buten-2-ol was stirred with benz-
aldehyde and a catalytic amount of RuCl2(PPh3)3 (3
mol%) in water for 5 h at 110°C (oil bath), no desired
product was obtained. The benzaldehyde was found to
have been partially oxidized into benzoic acid. No
reaction was observed when the solvent was switched to
toluene. When the reaction was performed in a 1:4
(volume) mixture of water and toluene, a smooth reac-
OH
OH
R
R
OH
[Ru]
OH
H2O
Recently, interest has been growing to develop organic
reactions in aqueous media.8 For aqueous aldol-type
condensations, Chan developed the tin and zinc-medi-
ated cross-couplings of halo-ketones with aldehydes.9
Lubineau,10 Kobayashi,11 Loh,12 and others13 devel-
oped the aqueous Mukaiyama-type reactions.
R
O
[Ru]
R
R
[Ru]
Figure 1.
Previously, we reported that in the presence of a cata-
lytic amount of RuCl2(PPh3)3 functional groups of
homoallyl alcohols and allyl alcohols underwent
reshuffling in air and water (Fig. 1, route a).14 A side
product of the isomerization is the formation of a
OH
O
O
OH
cat. RuCl2(PPh3)3
H2O
+
Ar
Me
Ar
H
Me
Me
* Corresponding author.
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00562-2

3590
M. Wang, C.-J. Li / Tetrahedron Letters 43 (2002) 3589–3591
was used, the use of water alone as the solvent provided
OH
O
OH
the desired product in 76% isolated yield. The use of
aliphatic aldehydes provided a complicated mixture and
efforts are currently underway to improve the reactions
with such aldehydes.
Ar
Me
Me
Me
[Ru]
O
A tentative mechanism for the product formation is
depicted in Scheme 2. The ruthenium complex isomer-
izes the allyl alcohol to an enol that is coordinated with
the ruthenium catalyst; an in situ reaction between the
enol–ruthenium complex with the aldehyde generates
the aldol product. The formation of primarily syn iso-
mer (Tables 1 and 2) is consistent with previous studies
on Mukaiyama aldol reactions in aqueous media.
Ar
H
OH
OH
Me
Me
Me
H
[Ru]
[Ru]
OH
In conclusion, we have developed an aldol-type reac-
tion via the cross-coupling of aldehyde and allyl alco-
hols catalyzed by RuCl2(PPh3)3 in water. The scope,
mechanism, and synthetic applications of the reaction
are under investigation. A typical experimental proce-
dure is as follows.
Me
H
[Ru]
Scheme 2. Tentative mechanism for the ruthenium-catalyzed
aldol reaction via olefin migration.
A mixture of aldehyde (1 mmol), 3-buten-2-ol (2.5
mmol) and RuCl2(PPh3)3 (0.03 mmol) in water (10 ml)
and under an atmosphere of air was stirred at 110°C.
After 5 h, the reaction mixture was cooled to room
temperature, extracted with ethyl ether, washed with
brine and dried over anhydrous Na2SO4. The mixture
was then concentrated under reduced pressure. The
residue was purified by flash chromatography on silica
gel (eluent: hexane/EtOAc) to afford the desired aldol
product.
tion occurred to give the desired aldol product (with a
syn:anti ratio of 70:30) in 50% isolated yield. Changing
the solvent to 4:1 (water–toluene) further increased the
yield (76%) and the syn:anti ratio (73:27) of the aldol
product. The use of water–ethanol (4:1) mixture
decreased both the yield (40%) and the diastereoselec-
tivity (syn:anti=60:40). Subsequently, a variety of aro-
matic aldehydes were examined under the same reaction
conditions. In most cases, the desired aldol product was
obtained in good yield. When 3-fluorobenzaldehyde
Table 1. Optimization of conditions for aldol reactions between allyl alcohols and aldehydes
Entry
Substrate (R)
Catalyst (3 mol%)
Solvent
Temp. (°C)
Time (h)
Yield (%)a
syn:antib
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Ph
RuCl2(PPh3)3
RuCl2(PPh3)3
RuCl2(PPh3)3
RuCl2(PPh3)3
RuCl2(PPh3)3
RuCl2(PPh3)3+3%
NaHCO3
H2O
Toluene
H2O–Toluene (1:4)
H2O–Toluene (1:4)
H2O–Toluene (4:1)
H2O–Toluene (4:1)
110
Reflux
70
110
110
110
5
5
5
5
5
5
0
0
Trace
50
76
70/30
73/27
Trace
7
Ph
RuCl2(PPh3)3
H2O–EtOH (4:1)
110
5
40
60/40
a Isolated yields were referred.
b syn:anti were determined by the 1H NMR of the product mixture.
Table 2. Aldol-type reaction between allyl alcohols and aldehydes in water
Entry
Substrate (R)
Solvent
Time (h)
Yield (%)a
syn:antib
1
2
3
4
5
6
7
m-F–Ph
p-Cl–Ph
p-Cl–Ph
p-MeO–Ph
p-Br–Ph
p-Ph–Ph
2-Naphthyl
H2O
H2O
5.5
5.5
5
5
5
72
35
70
68
73
27
44
66/34
60/40
74/26
51/49
79/21
67/33
63/37
H2O–Toluene (4:1)
H2O–Toluene (4:1)
H2O–Toluene (4:1)
H2O–Toluene (4:1)
H2O–Toluene (4:1)
5
5
Reaction conditions: 3% mol RuCl2(PPh3)3 at 110°C (oil bath temperature).
a Isolated yields were referred.
b syn:anti were determined by the 1H NMR of the product mixture.

M. Wang, C.-J. Li / Tetrahedron Letters 43 (2002) 3589–3591
3591
Acknowledgements
observed without the lithium co-reagent. See: Uma, R.;
Davis, M.; Cre´visy, C.; Gre´e, R. Tetrahedron Lett. 2001,
42, 3069.
We are grateful to NSF (CAREER Award), the NSF-
EPA joint program for a sustainable environment for
partial support of our research.
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