Reductive aldol-type reaction of α,β-unsaturated esters with aldehydes or ketones in the presence of Rh catalyst and Et2Zn

Article abstract of DOI:10.1016/j.tetlet.2013.08.109

The reaction of RhCl(PPh₃)₃ with Et₂Zn easily generated a rhodium-hydride complex (Rh-H) that added to α,β-unsaturated esters to form rhodium enolate complexes by formal 1,4-reduction. These rhodium enolates gave the corre

Full text of DOI:10.1016/j.tetlet.2013.08.109

Tetrahedron Letters 54 (2013) 5913–5915
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Reductive aldol-type reaction of a,b-unsaturated esters
with aldehydes or ketones in the presence of Rh catalyst and Et2Zn
Kazuyuki Sato, Motoyuki Isoda, Yoriko Tokura, Keiko Omura, Atsushi Tarui, Masaaki Omote,
⇑
Itsumaro Kumadaki, Akira Ando
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of RhCl(PPh3)3 with Et2Zn easily generated a rhodium–hydride complex (RhÀH) that added
Received 17 July 2013
Revised 20 August 2013
Accepted 26 August 2013
Available online 3 September 2013
to
a,b-unsaturated esters to form rhodium enolate complexes by formal 1,4-reduction. These rhodium
enolates gave the corresponding Reformatsky-type reagents through transmetalation, and they reacted
with various aldehydes and ketones to give reductive aldol-type products in good to excellent yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Reductive aldol reaction
Reformatsky–Honda reaction
RhCl(PPh3)3
Diethyl zinc
Rh–H complex
Various intermolecular reductive aldol-type reactions with
aldehydes using metals such as copper,1 cobalt,2 and rhodium cat-
alysts3 have been reported, and synthetic versatility was shown
with high stereoselectivity in many cases. However reductive al-
dol-type reaction with ketones has still been rare owing to the poor
nucleophilicity, and this might be the reason why hydrosilanes
(R3Si–H) or hydrogen was used as the reductant in most of the
reports.4 Recently we reported the reductive Reformatsky–Honda
reaction with various electrophiles to give the corresponding prod-
ucts in good to excellent yields, even if ketones were used as the
electrophile.5 In the current study we examine the reductive al-
OH O
R3
R4
O
O
Et2Zn
OR1
+
R1O
R2 R3 R4
RhCl(PPh3)3
R2
1
2
3
Scheme 1. Reductive aldol-type reaction under Reformatsky–Honda reaction
condition.
Next, we investigated various other substrates and the results
are summarized in Table 2.7 Both of electron withdrawing and
electron donating groups on benzaldehyde did not affect the yields
and the reaction gave the desired products (3a–f) in excellent
yields. Naphthyl aldehydes and aliphatic aldehydes also reacted
smoothly and they gave the products (3g–j) in good yields, respec-
tively. It is interesting that benzophenone and cyclohexanone gave
the products (3k and 3l) in good yields, since there are only a few
examples of the intermolecular reductive aldol reaction with
ketones.4 However all products did not give the satisfiable diaste-
reoselectivity. So we then changed the alkyl part of ester from
methyl to tert-butyl or phenyl. These gave the corresponding prod-
uct (3m and 3n) in excellent yields but the selectivity was not
much improved. Furthermore methyl crotonate and 2(5H)-fura-
none gave the corresponding products (3o and 3p) in moderate
to good yields, but methyl cinnamate only gave a complex mixture.
RhÀH complex must have played an important role on the basis
of previous result,8 since the reaction did not give the desired
dol-type reaction of a,b-unsaturated esters with various aldehydes
and ketones under the Reformatsky–Honda reaction condition (the
combination of RhCl(PPh3)3 and Et2Zn),6 with a focus on the scope
and limitations of this reaction (Scheme 1).
Firstly, the best reaction condition was sought by using methyl
acrylate (1a) and benzaldehyde (2a) as shown in Table 1. Under the
previous condition,5b the desired product (3a) was obtained in an
excellent yield (entries 1 and 2). On the other hand, the product
was not 3a but methyl 2-(1-hydroxy-1-phenylmethyl)pentanoate
(4a) in the absence of Rh catalyst as shown in entry 3. This shows
the importance of Rh catalyst. Most of the solvents gave 3a in good
to excellent yields, although insolubility of the Rh catalyst in hex-
ane or Et2O led to the low yield (entries 8–13). Among various
examinations, entry 14 was the best condition.
⇑
Corresponding author.
E-mail address: aando@pharm.setsunan.ac.jp (A. Ando).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.109

5914
K. Sato et al. / Tetrahedron Letters 54 (2013) 5913–5915
Table 1
Optimization of the reaction condition
OH O
OH O
O
O
Et2Zn
Ph
OMe
+
Ph
OMe
3a
RhCl(PPh3)3
H
OMe
Ph
1a
2a
4a
Entry
2a (equiv)
Solv.
RhCl(PPh3)3
Et2Zn (equiv)
Temp (°C)
Time (h)
Yielda (%)
(anti:syn)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2
1
1
1
1
1
1
1
1
1
1
1
1
1
THF
THF
THF
THF
THF
THF
THF
THF
Hexane
Et2O
DME
CH3CN
CH2Cl2
THF
2 mol %
2 mol %
None
1.5
1.5
1.5
1.5
0.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
0
0
0
0
3
1
3
3
95
95
0c
64
48
0
93
94
34
48
93
92
94
95
(53:47)
(49:51)
1 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
(50:50)
(50:50)
0
3
À78
À45
rt
rt
rt
rt
rt
rt
rt
24
10
0.5
1
5
1
0.5
0.5
0.5
(51:49)
(51:49)
(50:50)
(50:50)
(54:46)
(47:53)
(52:48)
(52:48)
a
b
c
Isolated yield.
Diastereomeric ratio after purification.
Compound 4a was obtained in 99%.
product (3a) but 4a in the absence of Rh catalyst. Furthermore,
methyl vinyl ketone (5) did not give the corresponding reductive
aldol product (6) in the reaction with benzaldehyde, but methyl
acrylate (1a) gave the product (3a) in an excellent yield (Scheme 2).
These results suggest that a Reformatsky-type reagent could gen-
erate from 1 with Et2Zn because of the formation of 4a. The stron-
ger nucleophilicity of
a metal enolate delivered from a,b-
unsaturated ester (1) would be concerned in the reaction.
Table 2
Scope and limitation of the reaction with various aldehydes and ketones
OH O
R3
O
O
Et2Zn
OR1
R4
+
R1O
R2 R3 R4
RhCl(PPh3)3
R2
1
2
3
Entry
3
Time (h)
Yielda (%)
dr
1
2
3
4
5
6
Y@H
CF3
Cl
COOMe
Me
3a
3b
3c
3d
3e
3f
0.5
0.5
0.5
2
3
2
95
96
94
95
93
95
(52:48)b
(48:52)b
OH O
OMe
(50:50)b
(43:57)b
(49:51)b
(48:52)b
OMe
Y
Y
OMe
7
8
9
Y=1-naphthyl
2-naphthyl
Ph–C2H4-
3g
3h
3i
3j
3
9
5
1
82
70
76
81
(53:47)b
OH O
(41:59)b
(45:55)c
(42:58)d
10
cyclohexyl
OH O
11
3k
7
77
OMe
OH O
12
3l
5
5
75
91
OMe
OH O
13e
3m
(40:60)d
(63:37)d
OtBu
OH O
14e
3n
3
90
O

K. Sato et al. / Tetrahedron Letters 54 (2013) 5913–5915
5915
Table 2 (continued)
Entry
3
Time (h)
Yielda (%)
56
dr
OH O
15
16
3o
3p
24
1
(52:48)b
(61:39)b
OMe
OH
O
80
O
a
Isolated yield.
b
Diastereomeric ratio (syn:anti) after purification.
Diastereomeric ratio (syn:anti) by GLC.
Diastereomeric ratio (syn:anti) by 1H NMR.
The reaction was carried out at 0 °C.
c
d
e
In conclusion, we synthesized various b-hydroxyesters from the
,b-unsaturated esters with aldehydes and ketones in good to
excellent yields. It is especially interesting to note that this reduc-
tive aldol reaction gave the product from ketones in good yields. In
future research we will investigate the enantioselective reductive
aldol reaction.
O
OH
a
O
O
Et2Zn
+
Ph
Et
OH O
OMe
4a
H
H
H
Ph
Ph
Ph
MeO
O
0°C, THF
2a
1a
(3h, 99%)
O
Et2Zn
RhCl(PPh3)3
0°C, THF
+
Ph
References and notes
2a
5
6 (24h, n.d.)
O
OH
1. For Cu-catalyzed reductive aldol reactions: (a) Ooi, T.; Doda, K.; Sakai, D.;
Maruoka, K. Tetrahedron Lett. 1999, 40, 2133–2136; (b) Lam, H. W.; Joensuu, P.
M. A. Org. Lett. 2005, 7, 4225–4228; (c) Welle, A.; Díez-González, S.; Tinant, B.;
Nolan, S. P.; Riant, O. Org. Lett. 2006, 8, 6059–6062.
2. For Co-catalyzed reductive aldol reactions: (a) Isayama, S.; Mukaiyama, T. Chem.
Lett. 1989, 2005–2008; (b) Baik, T. G.; Luis, A. L.; Wang, L. C.; Krische, M. J. J. Am.
Chem. Soc. 2001, 123, 5112–5113; (c) Wang, L. C.; Jang, H.-Y.; Roh, Y.; Lynch, V.;
Schultz, A. J.; Wang, X.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 9448–9453; (d)
Lam, H. W.; Joensuu, P. M.; Murray, G. J.; Fordyce, E. A. F.; Prieto, O.; Luebbers, T.
Org. Lett. 2006, 8, 3729–3732; (e) Lumby, R. J. R.; Joensuu, P. M.; Lam, H. W. Org.
Lett. 2007, 9, 4367–4370.
3. For Rh-catalyzed reductive aldol reactions: (a) Revis, A.; Hilty, T. K. Tetrahedron
Lett. 1987, 28, 4809–4812; (b) Nishiyama, H.; Shiomi, T.; Tsuchiya, Y.; Matsuda,
I. J. Am. Chem. Soc. 2005, 127, 6972–6973; (c) Willis, M. C.; Woodward, R. L. J. Am.
Chem. Soc. 2005, 127, 18012–18013; (d) Bee, C.; Han, S. B.; Hassan, A.; Iida, H.;
Krische, M. J. J. Am. Chem. Soc. 2008, 130, 2746–2747; (e) Hashimoto, T.; Ito, J.;
Nishiyama, H. Tetrahedron 2008, 64, 9408–9412; (f) Shiomi, T.; Adachi, T.; Ito, J.;
Nishiyama, H. Org. Lett. 2009, 11, 1011–1014.
4. For intermolecular reductive aldol reactions with ketones: (a) Zhao, D.; Oisaki,
K.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2006, 47, 1403–1407; (b)
Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew. Chem., Int. Ed.
2006, 45, 1292–1297; (c) Shiomi, T.; Nishiyama, H. Org. Lett. 2007, 9, 1651–
1654; (d) Lumby, R. J. R.; Joensuu, P. M.; Lam, H. W. Tetrahedron 2008, 64, 7729–
7740; (e) Kato, M.; Oki, H.; Ogata, K.; Fukuzawa, S. Synlett 2009, 1299–1302.
5. (a) Sato, K.; Yamazoe, S.; Yamamoto, R.; Ohata, S.; Traui, A.; Omote, M.; Ando, A.;
Kumadaki, I. Org. Lett. 2008, 10, 2405–2408; (b) Sato, K.; Isoda, M.; Ohata, S.;
Morita, S.; Tarui, A.; Omote, M.; Kumadaki, I.; Ando, A. Adv. Synth. Catal. 2012,
354, 510–514.
O
O
Et2Zn
RhCl(PPh3)3
0°C, THF
+
Ph
OMe
MeO
2a
1a
3a (3h, 95%)
Scheme 2. Mechanistic studies on Rh-catalyzed reductive aldol reaction.
EtZnO
R1O
H
Rh X
Et2Zn
R2
Int A
O
Rh(I)
XZn Et
R1O
Rh Et
8
7
R2
H
10
O
Rh H
9
ethylene
R1O
R2
1
Figure 1. Proposed reaction mechanism of the reductive aldol-type reaction by
6. (a) Kanai, K.; Wakabayashi, H.; Honda, T. Org. Lett. 2000, 2, 2549–2551; (b)
Kanai, K.; Wakabayashi, H.; Honda, T. Heterocycles 2002, 58, 47–51; (c) Honda,
T.; Wakabayashi, H.; Kanai, K. Chem. Pharm. Bull. 2002, 50, 307–308.
using Reformatsky–Honda reaction condition.
7. General procedure for the reductive aldol-type reaction of
follows: ,b-unsaturated ester (1; 1 mmol) and aldehyde (2; 1 mmol) were
added to solution of RhCl(PPh3)3 (2 mol %) in THF (2.5 mL) at ambient
a,b-unsaturated ester is as
a
Thus we proposed the following mechanism (Fig. 1).
RhCl(PPh3)3 reacted with Et2Zn to give the rhodium hydride com-
plex (9) through ethyl rhodium complex (7) along with the elimi-
a
temperature. Then, 1.0 M Et2Zn in hexane (1.2 mmol) was gradually added to
the mixture, and the mixture was stirred at same temperature. After the time in
Table 2, the mixture was quenched with 10% HCl and extracted with AcOEt. The
AcOEt layer was washed with satd NaCl and dried over MgSO4. The solvent was
removed in vacuo, and the residue was purified by column chromatography
(AcOEt:hexane = 1:4) to give each diastereomer of b-hydroxyester (3) as a sole
compound.
nation of ethylene. The 1,4-reduction of a,b-unsaturated ester by 9
to form rhodium enolate (10) is followed by transmetalation by a
zinc species to give Reformatsky-type reagent (Int A). The higher
nucleophile of Reformatsky-type reagent promptly reacted with
electrophiles to give the corresponding b-hydroxyesters (3) even
if ketones were used as the electrophile.
8. Sato, K.; Ishida, Y.; Murata, E.; Oida, Y.; Mori, Y.; Okawa, M.; Iwase, K.; Tarui, A.;
Omote, M.; Kumadaki, I.; Ando, A. Tetrahedron 2007, 63, 12735–12739.