CuSO4-catalyzed diazo decomposition in water: a practical synthesis of β-keto esters

Article abstract of DOI:10.1016/j.tetlet.2006.10.059

CuSO₄ was found to be an efficient catalyst for the diazo decomposition of β-hydroxy α-diazoesters in water. 1,2-H shift occurred efficiently to give β-keto esters in high yields. No O-H bond insertion products were identified.

Full text of DOI:10.1016/j.tetlet.2006.10.059

Tetrahedron Letters 47 (2006) 8859–8861
CuSO4-catalyzed diazo decomposition in water: a
practical synthesis of b-keto esters
Mingyi Liao and Jianbo Wang*
Beijing National Laboratory of Molecular Sciences (BNLMS), Green Chemistry Center (GCC)
and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking University, Beijing 100871, China
Received 28 June 2006; revised 11 October 2006; accepted 12 October 2006
Available online 31 October 2006
Abstract—CuSO4 was found to be an efficient catalyst for the diazo decomposition of b-hydroxy a-diazoesters in water. 1,2-H shift
occurred efficiently to give b-keto esters in high yields. No O–H bond insertion products were identified.
Ó 2006 Elsevier Ltd. All rights reserved.
b-Keto esters are multicoupling reagents having both
electrophilic carbonyl and nucleophilic carbon, which
make them valuable intermediates for the synthesis of
complex molecules. This type of compound is one of
the basic building blocks in total synthesis.1 Therefore,
many methods have been developed to synthesize b-keto
esters. Among these methods, the condensation of ethyl
diazoacetate (EDA) with aldehydes catalyzed by acids is
a facile and efficient way.2,3 This reaction has been
catalyzed by a variety of Lewis acids and Brønsted acids
such as BF3, ZnCl2, ZnBr2, AlCl3, SnCl2, GeCl2, SnCl4,
NbCl5, HBF4, zeolite and montmorillonite.3 Another
approach to prepare the b-keto esters from aldehydes
and EDA involved a two-step procedure.4 First, the
aldol-type condensation of aldehydes and EDA formed
a-diazo-b-hydroxyesters. Then, metal-catalyzed decom-
position of a-diazo-b-hydroxyesters afforded b-keto
esters. However, these reactions were all performed in
organic solvent under an anhydrous condition. Re-
cently, Nishida and co-workers have reported the
PTC-promoted one-pot synthesis of a-diazo-b-hydroxy-
esters from NaN3 under aqueous basic conditions.5
vent has been widely used for organic reactions over
the past decade.6 Recently, several groups have been
exploring the transition metal-catalyzed reaction of a-
diazocarbonyl compounds in water. Charette and Wurz
demonstrated that cyclopropanation reactions involving
ethyl diazoacetate and olefins proceeded with a high effi-
ciency in water using Rh(II) carboxylates.7 Later Afonso
and co-workers reported that Rh2(OAc)4-catalyzed
intramolecular C–H insertion of diazo substrates could
be efficiently performed in water.8 More recently Francis
and Antos found that metallocarbenoids derived from
stabilized vinyl diazo compounds can react with 3-
methylindole in a highly efficient manner in an aqueous
solution. This reaction has been used to modify trypto-
phan residues on protein substrates.9 However, to the
best of our knowledge, metal-catalyzed decomposition
of the a-diazo-b-hydroxyesters in water has not been re-
ported. Encouraged by these results and as a continua-
tion of our research interest in 1,2-migration of metal
carbene,10 we report here the CuSO4-catalyzed reaction
of a-diazo-b-hydroxyesters in water.
Cyclopropanation
(ref. 7)
Metal-catalyzed diazo decomposition is usually per-
formed in dry organic solvent due to the high reactivity
of the metal carbene intermediate, which could react
with water to give O–H insertion product. Water as
the most inexpensive and environmentally benign sol-
N2
MLn
MLn
H2O
C-H insertion
(ref. 8)
O
O
1,2-H Shift
(This work)
Initially, we chose ethyl 2-diazo-3-hydroxy-3-phenyl-
propanoate 1a as the substrate to investigate the reac-
tion in water (Table 1). The decomposition of 1a could
Keywords: Diazo compounds; Carbenoids; 1,2-H shift; b-Keto esters;
Water as solvent.
*
Corresponding author. E-mail: wangjb@pku.edu.cn
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.059

8860
M. Liao, J. Wang / Tetrahedron Letters 47 (2006) 8859–8861
afford two products: 1,2-hydrogen migration to give
b-keto ester 2a, and 1,2-phenyl migration to afford 3a.
In most cases 1,2-hydrogen migration was predomi-
nant.4 When we treated 1a in 5 mL water in the presence
of Rh2(OAc)4, the reaction finished within 20 min. As
expected, 2a was isolated in a 91% yield (Table 1, entry
1). No water insertion product was obtained. However,
it should be noted that rhodium(II) catalyst is a very
expensive catalyst. Consequently, we next aim to find
a cheaper and more easily available catalyst.
For comparison, the decomposition of 1a catalyzed by
CuSO4 in CH2Cl2 was also tested. The reaction pro-
ceeded much slower than in water (Table 1, entry 11).
Subsequently, with 1 or 5 mol % CuSO4 as the catalyst,
various a-diazo-b-hydroxyesters were decomposed in
water to afford b-keto esters in good to excellent yields
(Table 2).12 A range of b-aryl substituted substrates
were suitable for this reaction, regardless of the position
and electronic property of the substituent in the phenyl
ring (Table 2, entries 1–9). b-Aliphatic substituted sub-
strates also reacted smoothly to generate b-keto esters
in high yields (Table 2, entries 11–14). This method even
worked with b-2-furanyl, alkenyl and alkynyl substi-
tuted substrates though the yields were moderate (Table
2, entries 10, 15 and 16). The reaction time ranged from
30 min to 39 h, which were also affected to some extent
by the situation of stirring, as well as the solubility of the
substrate in water. For example, 1k can totally dissolve
in water, and the reaction was completed in 1 h. For
diazo compounds 1d–f and 1n, 5 mol % CuSO4 was used
instead because the reaction was too slow when carried
out with 1 mol % catalyst loading.
We were delighted to find that the decomposition of 1a
catalyzed by 10 mol % CuSO4 gave 2a in a 79% yield in
16 h (Table 1, entry 2). The catalyst loading could be
reduced to 1 mol % (entries 3 and 4). Other catalysts
were also examined. Using 10 mol % MgSO4 or ZnCl2
led to very low conversions of the starting materials even
after 24 h (entries 5 and 6). Surprisingly, when catalyzed
by 5 mol % FeCl3Æ6H2O, 1,2-phenyl migration product
3a was obtained as a major product. Considering the
easy hydrolysis of FeCl3 to generate HCl in water, we
speculated that protonic acid might be the real catalyst
in this case. As expected, when 15 mol % HCl was used
as a catalyst similar result was observed (Table 1, entries
7 and 8). More recently, Fructos and co-workers
described the first example of a gold-based catalyst for
the decomposition of ethyl diazoacetate.11 Hence, gold
catalysts were also explored in our system. The reaction
was completed within 20 min when 2 mol % AuCl was
used, whereas longer reaction times (20 h) were required
when AuCl3 was involved. In both cases 2a was sepa-
rated as the major product (Table 1, entries 9 and 10).
It should be noted that the above reaction conditions
did not work well for the solid substrates such as b-(4-
methoxyphenyl), b-(2,4-dichlorophenyl) and b-(2,6-
dichlorophenyl) substituted a-diazo-b-hydroxyesters.
Moreover, this approach was not suitable for b,b-disub-
stituted a-diazo-b-hydroxyesters.
In summary, we have demonstrated that the decomposi-
tion of a-diazo-b-hydroxyesters catalyzed by CuSO4 can
be efficiently performed in water to afford b-keto esters
in high yields. This method has the following advanta-
Table 1. Diazo decomposition in water
O
O
O
Table 2. CuSO4-catalyzed diazo decomposition in water12
Ph
H
OEt
OH
O
2a
+
catalyst
H2O, r.t.
OH
O
O
O
Ph
OEt
CuSO4
OH
N2
1a
R
OEt
R
OEt
H2O, r.t.
OEt
N2
1a-p
Entry Diazo compounds (R =) Reaction time Yielda (%)
Ph
3a
2a-p
Entry
Catalyst (mol %)
Reaction timea
Yieldb (%)
1
2
3
4b
5b
6b
7
8
9
10
11
12
13
14b
15
16
1a, C6H5
24 h
39 h
39 h
4 h
36 h
4 h
30 min
21 h
1 h
14 h
1 h
5 h
24 h
3 h
5 h
20 h
91
88
90
84
81
84
92
86
89
41
72
92
90
91
69
53
2a
3a
1b, o-CH3C6H4
1c, m-BrC6H4
1d, m-CNC6H4
1e, m-CF3C6H4
1f, p-CH3C6H4
1g, p-FC6H4
1h, p-ClC6H4
1i, 3,5-(MeO)2C6H3
1j, 2-Furanyl
c
1
2
3
4
5
6
7
8
9
Rh2(OAc)4 (0.5)
CuSO4Æ5H2O (10)
CuSO4Æ5H2O (5)
CuSO4Æ5H2O (1)
MgSO4
ZnCl2
FeCl3Æ6H2O (5)
HCl (15)
20 min
16 h
16 h
24 h
24 h
24 h
16 h
3 h
91
79
96
—
—
—
—
—
—
58
56
91
<10d
<10d
29
28
79
69
78
1k, CH3CH2
AuCl (2)
AuCl3 (2)
CuSO4 (10)
20 min
20 h
72 h
Trace
Trace
—
1l, CH3(CH2)5
1m, (CH3)2CHCH2
1n, cyclopentyl
1o, trans-C6H5CH@CH
1p, C6H5C„C
10
11e
a Reaction conditions: Diazo substrate 1a (0.3 mmol) was stirred with
catalyst in 5 mL water.
b Isolated yields after column chromatography.
c Not observed in TLC.
a Isolated yields after column chromatography.
b 5 mol % CuSO4Æ5H2O was used in these cases. For other substrates,
1 mol % CuSO4Æ5H2O was applied.
d Estimated by TLC.
e The reaction performed in CH2Cl2 at room temperature.

M. Liao, J. Wang / Tetrahedron Letters 47 (2006) 8859–8861
8861
5. Arai, S.; Hasegawa, K.; Nishida, A. Tetrahedron Lett.
2004, 45, 1023–1026.
ges: (1) water (the most ‘green’ solvent) as solvent; (2) an
inexpensive and easily available catalyst; (3) low catalyst
loading; (4) the only byproduct is nitrogen. These
advantages should enable this reaction to become a use-
ful preparative method of b-keto esters. Other metallo-
carbenoid reactions in water are under investigation in
our group.
6. For recent reviews, see: (a) Lindstrom, U. M. Chem. Rev.
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Acknowledgements
The project is generously supported by the Natural
Science Foundation of China (Grant Nos. 20572002,
20521202, 20225205, 20390050) and the Ministry of
Education of China (Cheung Kong Scholars Program).
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