Efficient synthesis of γ-keto esters from enamines and EDA

Article abstract of DOI:10.1081/SCC-200050387

The reaction of enamines with ethyl diazoacetate (EDA) catalyzed by dirhodium and copper complexes provided γ-keto esters in good yields. The influences of catalyst, reaction solvent, temperature, and structure of enamines on this transformation were inve

Full text of DOI:10.1081/SCC-200050387

Synthetic Communicationsw, 35: 745–750, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200050387
Efficient Synthesis of g-Keto Esters from
Enamines and EDA
Dan Huang
Department of Chemistry and Chemical Engineering, Suzhou University,
Suzhou, Jiangsu, China and Department of Chemistry, Nantong Teachers
College, Jiangsu, China
Ming Yan, Wei-Jie Zhao, and Qi Shen
Department of Chemistry and Chemical Engineering, Suzhou University,
Suzhou, Jiangsu, China
Abstract: The reaction of enamines with ethyl diazoacetate (EDA) catalyzed by
dirhodium and copper complexes provided g-keto esters in good yields. The influences
of catalyst, reaction solvent, temperature, and structure of enamines on this transform-
ation were investigated.
Keywords: Enamines, ethyl diazoacetate (EDA), catalysis, g-keto esters
g-Keto esters are important intermediates for preparation of a large number of
heterocyclic compounds such as pyrroles, furans, lactones, b-lactam anti-
biotics, isoquinolines, lactonic sex pheromones, and alkoxythiophenes.[1]
The efficient synthesis of g-keto esters has been the goal of numerous research
efforts. Zercher et al. developed a zinc-mediated chain extension reaction to
prepare g-keto esters from b-keto esters.[2] Ballini et al. reported one-pot
synthesis of g-keto esters from nitroalkanes and a,b-unsaturated ketones or
esters.[3] Nakamura et al. developed a palladium-catalyzed acylation of
Received in Japan 15 October 2004
Address correspondence to Ming Yan, Department of Chemistry and Chemical
Engineering, Suzhou University, Suzhou, Jiangsu 215006, China. Fax: þ86 (512)
65224783; E-mail: yanm@suda.edu.cn

746
D. Huang et al.
siloxycyclopropanes to prepare g-keto esters in good yield.[4] Parker et al.
reported a conjugate aroylation reaction of a,b-unsaturated ester gave
g-keto esters.[5] Reissig et al. studied the addition of methyl diazoacetate to
enol silyl ethers and obtained the siloxycyclopropanecarboxylate, which
underwent a fluoride-catalyzed rearrangement to give g-keto esters in a
moderate to good yield.[6] Although these methods were successfully used
to prepare a lot of g-keto esters with diversified structures, many of them
suffered from drawbacks such as the requirement of harsh conditions, employ-
ment of expensive chemicals, tedious procedure, and low yields.
Recently we found an unusual, highly effective synthesis of 2-aryl-g-keto
esters from aryldiazoacetates and enamines.[7] This new discovery suggested a
new, general synthetic route to g-keto esters via the catalyzed reaction of the
enamines with diazo carbonyl compounds. In this paper we report the reaction
of ethyl diazoacetate (EDA) with a variety of enamines leading to g-keto
esters in good yields.
The reaction of N-(1-styryl)morpholine (1a) with ethyl diazoacetate
(EDA) catalyzed by Rh2(OAc)4 provided ethyl 4-oxo-4-phenylbutanoate
(2a) in 47% yield. Furthermore a variety of copper complexes were tested
as catalysts and the results were summarized in Table 1. The property of
the copper complex showed profound effect on the yield. The Cu(hfacac)2
was found to be the best catalyst concerning the yield and catalytic activity.
Table 1. Catalytic reaction of EDA with N-(styryl)morpholine (1a)a
Entry
Catalyst
None
Mol (%)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
0
1
3
3
3
3
3
24
2
0
47
10
52
69
72
29
Rh2(OAc)4
CuI
1
c
Cu(OTf )2
2
Cu(acac)2
Cu(hfacac)2
CuPF6
1
d
0.5
1.5
aThe reactions were carried out with 1 mmol EDA and 1.5 mmol enamine in
refluxing fluorobenzene.
bIsolated yields after column chromatography.
cCu(OTf )2 ¼ copper (II) bis(trifluoromethanesulfonate).
dCu(hfacac)2 ¼ bis(hexafluoroacetylacetonate) copper (II).

Synthesis of g-Keto Esters
747
Table 2. Reaction of EDA with N-(styryl)morpholine (1a) at different temperaturea
Entry
T (8C)
Time (h)
Yield (%)b
1
2
3
4
0
25
40
80
2
64
65
71
72
1
0.5
0.5
aThe reactions were carried out with 1 mmol EDA, 1.5 mmol enamine and
0.03 mmol Cu(hfacac)2 in fluorobenzene.
bIsolated yield after column chromatography.
The screen of several frequently used solvents for diazo decomposition
revealed that fluorobenzene and dichloroethane afforded higher chemical
yield than did other solvents such as benzene, toluene, and dichloromethane.1
The influence of temperature on the yield was also investigated and the results
were summarized in Table 2. The reaction occurred even in zero degrees to
provide 2a in 64% yield and higher chemical yield could be achieved in
refluxing fluorobenzene.
After careful examination of the effects of other reaction factors, the
optimum reaction conditions for this transformation were identified as
following: slow addition of EDA (1.0 equiv.) to a stirred refluxing fluoroben-
zene solution of enamine (1.5 equiv) and Cu(hfacac)2 (3 mol%) under an
argon atmosphere. The scope of the reaction was explored with a variety of
enamines and the results were summarized in Table 3. In most cases g-keto
esters were obtained in good yields. The substituents on the 4-position of
the phenyl ring showed neglectable effects on this reaction (Table 3, entries
1–5). 2-Substituted enamines (1f and 1g) were able to react with EDA,
providing corresponding g-keto esters in moderate yields. The enamine 1h
derived from b-naphthyl methyl ketone gave lower yield of product, presum-
ably due to its intense steric hindrance. The enamine 1i prepared from dialkyl
ketone also afforded low yield of product and a reasonable explanation of the
result could not be achieved at the present time.
In the reaction of enamines with aryldiazoacetate, we found that the
reaction proceeded via a 1,2-proton transfer step to form substituted
enamines as transient intermediates, which were hydrolyzed over silica gel
1The yields of 2a obtained in different solvents: ClCH2CH2Cl, 70%; CH2Cl2, 52%;
benzene, 62%; PhF, 72%; toluene, 38%.

748
D. Huang et al.
Table 3. Synthesis of g-keto esters from enamines and EDA.a
Entry
1
Enamines
g-Keto Estersb
Yield (%)c
72
2
76
3
4
72
71
5
71
6
7
65
56
8
9
45
45
aThe reactions were carried out with 1 mmol EDA, 1.5 mmol enamine and
0.03 mmol Cu(hfacac)2 in refluxing fluorobenzene.
bAll products were fully characterized by 1H NMR, 13C NMR, HRMS, and
elemental analysis.
cIsolated yields after column chromatography.

Synthesis of g-Keto Esters
749
Scheme 1. The proposed reaction pathways.
to give g-keto esters as final products.[7] In the reaction of enamine 1a
1
with EDA, analysis of the crude reaction mixture with H NMR and IR
spectra allowed us to identify undoubtedly an enamine intermediate 3
(Scheme 1).2 The results implied the generality of 1,2-proton transfer
mechanism in the transition metal catalyzed reactions of enamines with
diazo compounds.
In conclusion, we have developed a facile and efficient synthetic route to
g-keto esters via the catalyzed reaction of enamines with EDA. The distinct
advantages of this methodology are the ease of preparation of enamines, the
simple reaction procedure, and the good yields. Further efforts are under
way to expand the scope of enamines and diazo compounds as well as to
explore the synthetic utilities of this reaction.
Typical Experimental Procedure
To a round-bottomed flask equipped with a stirrer and an additional funnel
under argon atmosphere, was charged N-(styryl)morpholine (1a) (0.284 g,
1.5 mmol), Cu(hfacac)2 (14.3 mg, 0.03 mmol), and fluorobenzene (3 mL).
The reaction solution was heated in an oil bath and kept refluxing. The
addition funnel was charged with a solution of EDA (0.114 g, 1 mmol) in
fluorobenzene (4 mL), which was added dropwise to the reaction solution
over 20 minutes. The reaction mixture was refluxed for an additional 30
minutes. After the solvent was evaporated under vacuum, the crude product
was purified by flash column chromatography (petroleum ether: ethyl
acetate ¼ 10:1) over silica gel to give ethyl 4-oxo-4-phenylbutanoate (2a)
1
as a light yellow oil (0.149 g, 72% yield). IR (KBr): 1732, 1687 cm21; H
NMR (CDCl3, 400 MHz): d 7.99 (d, J ¼ 6.8 Hz, 2 H), 7.57 (t, J1 ¼ 8.0 Hz,
J2 ¼ 9.6 Hz, 1 H), 7.46 (t, J1 ¼ 7.6 Hz, J2 ¼ 8.0 Hz, 2 H), 4.16
(q, J ¼ 7.6 Hz, 2 H), 3.31 (t, J1 ¼ 7.6 Hz, J2 ¼ 5.2 Hz, 2 H), 2.75
1
2Characteristic spectral peaks of enamine 3: H NMR (400 MHz, CDCl3) d 7.32
(d, J ¼ 5.6 Hz, 2 H), 7.11 (t, J ¼ 7.2 Hz, 1 H), 7.06 (t, J1 ¼ 14.4 Hz, J2 ¼ 8.8 Hz,
2 H), 4.75 (t, J ¼ 7.2 Hz, 1H, –C55CH), 4.16 (q, J ¼ 7.2 Hz, 2 H), 3.75 (m, 4 H),
2.95 (d, J ¼ 7.2 Hz, 2H, –CH2–COOEt), 2.76 (m, 4 H), 1.26 (t, J ¼ 7.2 Hz, 3 H); IR
(film): 1733 cm21 (s, –CO–OEt), 1595 cm21 (s, –C55C–).

750
D. Huang et al.
(t, J1 ¼ 7.6 Hz, J2 ¼ 5.2 Hz, 2 H), 1.26 (t, J ¼ 7.6 Hz, 3 H); 13C NMR (CDCl3,
100 MHz): d 198.4, 173.2, 136.8, 133.5, 128.9, 128.3, 0.96, 33.7, 28.6,
14.5 ppm. HRMS (EIþ) calcd. for C12H1403: 206.0944; found 206.0943.
Anal. calcd. for C12H1403: C, 69.88; H, 6.84. Found: C, 70.68; H, 7.05.
ACKNOWLEDGMENTS
Financial supports from the National Natural Science Foundation of China
(Project number 20472061) and Suzhou University (Project number
Q4109308) are gratefully acknowledged.
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