Unusual reaction of aryldiazoacetates with enamines: Highly effective synthesis of γ-ketoesters

Article abstract of DOI:10.1016/j.tetlet.2004.06.086

The reaction of aryldiazoacetates with enamines catalyzed by copper and dirhodium complexes provides exclusively γ-ketoesters in high yields. The reaction of aryldiazoacetates with enamines catalyzed by copper and rhodium complexes provided γ-ketoesters in good yields. Careful analysis of the crude reaction mixture revealed a substituted enamine as the primary product, which was hydrolyzed over silica gel to give a γ-ketoester as the final product. A reaction mechanism involving nucleophilic addition of an enamine to a metal carbene and subsequent hydrogen transfer was proposed.

Full text of DOI:10.1016/j.tetlet.2004.06.086

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6365–6367
Unusual reaction of aryldiazoacetates with enamines:
highly effective synthesis of c-ketoesters
Ming Yan,* Wei-Jie Zhao, Dan Huang and Shun-Jun Ji
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou University,
1 Shizi St. Suzhou 215006, Jiangsu, China
Received 5 April 2004; revised 4 June 2004; accepted 7 June 2004
Abstract—The reaction of aryldiazoacetates with enamines catalyzed by copper and rhodium complexes provided c-ketoesters in
good yields. Careful analysis of the crude reaction mixture revealed a substituted enamine as the primary product, which was hydro-
lyzed over silica gel to give a c-ketoester as the final product. A reaction mechanism involving nucleophilic addition of an enamine to
a metal carbene and subsequent hydrogen transfer was proposed.
Ó 2004 Elsevier Ltd. All rights reserved.
Transition metal catalyzed decomposition of diazo com-
pounds and consequent transformations have consti-
tuted various synthetic useful reactions in the past
decades.1 Cyclopropanation of olefins with diazo com-
pounds have been extensively studied. Wenkert reported
the cyclopropanation of enol ether with diazo com-
pounds catalyzed by copper salts provided oxycyclopro-
panes.2 However the reaction of enamines with ethyl
diazoacetae (EDA) in the presence of cuprous chloride
or silver oxide unexpectedly gave a-diazo-b-aminoester
in good yield.3 The reaction was probably proceeded
via a nucleophilic addition of EDA to iminium cation
formed by isomerization of enamine under the reaction
conditions. On the other hand Wang et al. studied the
addition of EDA to enamine catalyzed by N-a-(4-chlo-
rophenyl)isobutyl-(salicylaldimino)copper complex and
obtained the aminocyclopropane product in 12% yield.4
Muck and Wilson reported the addition of diazometh-
ane to enamine catalyzed by cuprous chloride gave ami-
nocyclopropane derivatives in good yields.5 In the
absence of transition metal catalysts, the addition of
EDA to enamines could provide either dihydro pyraz-
oles or azo coupling products depending on the struc-
ture of the enamine.6 In this paper we report an
unusual reaction of aryldiazoacetates with enamines cat-
alyzed by copper and dirhodium complexes leading to c-
ketoesters in good yields.
Reaction of methyl phenyldiazoacetate (1) with N-(1-
styryl)morpholine (2) in the presence of 1mol%
Rh2(OAc)4 afforded a white solid after flash chromato-
graphy over silica gel (Scheme 1). This product was
unambiguously confirmed as methyl 4-oxo-2,4-diphe-
nylbutanoate (3) by combination of 1H NMR, 13C
NMR and mass spectral analyses.7 None of the expected
aminocyclopropane product was found after careful
examination of the reaction mixture. It is known
that aminocyclopropane is stable even under acidic
O
N2
O
COOMe
Ph
Rh2(OAc)4
CH2Cl2
N
+
Ph
COOMe
Ph
Ph
1
3
2
Scheme 1.
Keywords: Enamine; Diazo compound; Catalysis; c-Ketoesters; Dirhodium tetraacetate; Copper salt.
*
Corresponding author. Tel.: +86-512-67189862; fax: +86-512-65224783; e-mail: yanm@suda.edu.cn
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.086

6366
M. Yan et al. / Tetrahedron Letters 45 (2004) 6365–6367
O
O
O
COOMe
Ph
TiCl4
N
COOMe
Ph
+
Hexane
Ph
N
H
Ph
3
4
Scheme 2.
conditions.8 Accordingly, the product 3 could not be
formed via the decomposition of an aminocyclopropane
intermediate.
a competitive hydrogen transfer step was proposed.1
Davies et al. also suggested the involvement of zwitteri-
onic intermediates in rhodium-catalyzed reaction of
vinyldiazoacetates with electron-rich dienes.10 Based
on these suggestions and our present experiment results,
a possible mechanism for the reaction of enamine with
phenyldiazoacetate was proposed (Scheme 3). Nucleo-
philic addition of enamine to highly electron-deficient
metal carbene (I) produced a zwitterionic intermediate
(II). The developed positive charge at the carbon could
be stabilized efficiently by nitrogen atom through reso-
nance structure (III). The hydrogen transfer occurred
with complete preference over the competitive cyclo-
propanation process and provided enamine 4, which
was hydrolyzed over silica gel to give c-ketoester 3 as
the final product.
1
Analysis of the crude reaction mixture with H NMR
revealed only very weak signals assigned for 3. Instead,
another compound was found to be the major compo-
nent in the reaction mixture, which provided the follow-
1
ing H NMR spectrum: 7.36–7.19 (m, 10H), 5.08 (d,
J=10.4Hz, 1H), 4.18 (d, J=10.4Hz, 1H), 3.87–3.78
(m, 2H), 3.71–3.65 (m, 2H), 3.63 (s, 3H), 3.10–2.96 (m,
2H), 2.83–2.74 (m, 2H). Its IR spectrum revealed two
strong absorption bands at 1731.38 and 1615cmÀ1, indi-
cating existence of a carbonyl group and a double bond.
According to these data this compound was assigned as
an enamine (4). Further attempt to purify and character-
ize 4 was unsuccessful due to its unstable property. Thus
a control test was carried out to verify the structure of 4.
Treatment of 3 with morpholine in the presence of TiCl4
gave a crude product, which provided identical 1H
NMR and IR spectra with 4 obtained above (Scheme 2).
Several copper complexes were also tested as the catalyst
in the reaction of 1 with 2 and the results were summa-
rized in Table 1. The reaction did not occur in the ab-
sence of a catalyst (entry 1). In addition to Rh2(OAc)4,
the copper (II) salts are also highly effective catalysts
for this transformation. Even cuprous iodide, a catalyst
with low catalytic activity for decomposition of diazo
compounds, could afford 3 in the moderate yield (entry
7). It was noticeable that copper catalysts were found to
be less effective than Rh2(OAc)4 for the reaction involv-
Alonso and Fernandez reported apparent vinyl C–H
insertion in the reaction of vinyl ether with diazomalo-
nates and suggested an addition–elimination mechanism
through highly polarized zwitterionic intermediates.9
Doyle et al. suggested a similar explanation, in which
O
N
N2
MLn
COOMe
MLn
- N2
Ph
Ph
COOMe
Ph
I
1
O
O
O
N
N
N
COOMe
Ph
COOMe
Ph
COOMe
Ph
- MLn
Ph
Ph
Ph
MLn
H
MLn
H
H
H
H
IV
H
II
III
O
N
H
1,2-H
transfer
H+/H2O
O
COOMe
Ph
COOMe
Ph
Ph
Ph
H
4
3
Scheme 3.

M. Yan et al. / Tetrahedron Letters 45 (2004) 6365–6367
6367
Table 1. Reaction of 1 with 2 catalyzed by copper and dirhodium
complexesa
Table 2. The catalytic addition of aryldiazoacetates to enaminesa
Entry
Ar1
Ar2
Yield (%)b
Entry
MLn
Mol (%)
Time (h)
Yield (%)b
1
2
3
4
5
6
4-Br–C6H4
1-Naphthyl
2-Naphthyl
2-Thiophenyl
Ph
Ph
Ph
85
77
83
56
80
33
1
2
3
4
5
6
7
None
NAc
24
0.5
0.5
0.5
0.5
1
0
63
59
64
75e
60
50
Rh2(OAc)4
Cu(hfacac)2
Cu(hfacac)2
Cu(hfacac)2
1
1
3
3
3
3
Ph
Ph
d
4-MeO–C6H4
2-MeO–C6H4
Ph
f
Cu(OTf)2
CuI
a The reactions were carried out with 1mmol aryldiazoacetate,
1.5mmol enamine and 0.03mmol Cu(hfacac)2 in refluxing dichloro-
methane.
10
a The reactions were carried out with 1mmol 1 and 1mmol 2 in
refluxing dichloromethane.
b Isolated yield after column chromatography.
c Not applicable.
b Isolated yield after column chromatography.
d Cu(hfacac)2 =bis-hexafluoroacetoacetonato copper (II).
e 1.5mmol enamine was used in this case.
f Cu(OTf)2 =copper (II) bis-trifluoromethanesulfonate.
Acknowledgements
We thank Suzhou University (Project number
Q4109308) and Key Laboratory of Organic Synthesis
of Jiangsu Province (Project number: JSK004) for finan-
cial support of this study.
ing phenyldiazoacetate.11 The ratio of enamine to diazo
compound also played an important role for the yield of
the final product. Increasing the amount of enamine
from 1 to 1.5equiv could improve the chemical yield
from 64% to 75% (entries 4 and 5), probably due to
the decomposition of a small amount of enamine 2 un-
der the reaction conditions.
References and notes
1. Reviews: (a) Doyle, M. P.; Mckervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Com-
pounds; John Wiley and Sons: New York, 1998; (b) Davies,
H. M. L.; Antoulinakis, E. J. Org. React. 2001, 57, 1.
2. Wenkert, E. Acc. Chem. Res. 1980, 13, 27–31.
3. (a) Wenkert, E.; Cpherson, C. A. J. Am. Chem. Soc. 1972,
94, 8084–8090; (b) Wenkert, E.; Alonso, M. E.; Gottlieb,
H. E.; Sanchez, E. L. J. Org. Chem. 1977, 42, 3945–3949.
4. Wang, M.; Wang, M. A.; Hu, B. F. Chin. Chem. Lett.
1995, 6, 557–558.
Though many efficient methods have been developed to
prepare a- and b-ketoesters, the available synthetic
routes leading to c-ketoesters are deficient. The c-keto-
ester 3 had been prepared by conjugate addition of
cyanide to chalcone or by 1,3-dipolar addition of a-
diazoketone to olefins followed by a consequent acid
catalyzed hydrolysis.12 The present method via direct
addition of aryldiazoacetates to enamines is more con-
venient and efficient for the preparation of 3 as well as
other c-ketoesters. The lower price of Cu(hfacac)2 than
Rh2(OAc)4 makes it the preferred catalyst for this reac-
tion. Several aryldiazoacetates were examined in the
reaction with enamines (Scheme 4) and the results were
summarized in Table 2.
5. Muck, D. L.; Wilson, E. R. J. Org. Chem. 1968, 33,
419–422.
6. (a) Huisgen, R.; Reissig, H. U. Angew. Chem., Int. Ed.
Engl. 1979, 18, 330–331; (b) Huisgen, R.; Bihlmaier, W.;
Reissig, H. U. Angew. Chem., Int. Ed. Engl. 1979, 18,
331–332.
7. The 1H NMR spectrum is identical with the reported data
of 4-oxo-2,4-diphenylbutanoate, see: Hussain, S. A. M. T.;
Ollis, W. D.; Smith, C.; Stoddart, J. F. J. Chem. Soc.,
Perkin Trans. 1 1975, 1480–1492.
Moderate to excellent yields were obtained for the most
of tested aryldiazoacetates and enamines. However N-1-
(2-methoxystyryl)morpholine gave low yield of the
product, presumably due to its intensed steric hindrance.
8. Wenkert, E.; Mueller, R. A.; Reardon, E. J.; Sathe, S. S.;
Scharf, D. J.; Tosi, G. J. Am. Chem. Soc. 1970, 92,
7428–7436.
9. Alonso, M. E.; Fernandez, R. Tetrahedron 1989, 45,
3313–3320.
10. Davies, H. M. L.; Clark, T. J.; Kimmer, G. F. J. Org.
Chem. 1991, 56, 6440–6447.
11. (a) Davies, H. M. L.; Panaro, S. A. Tetrahedron 2000, 56,
4871–4880; (b) Doyle, M. P.; Yan, M. Tetrahedron Lett.
2002, 43, 5929–5931, and unpublished experiment results.
12. (a) Davey, W.; Tivey, D. J. J. J. Chem. Soc. 1958,
1230–1235; (b) Graziano, M. L.; Iesce, M. R.; Scarpati, R.
J. Heterocycl. Chem. 1986, 23, 553–556.
In conclusion we have discovered an unusual reaction of
aryldiazoacetates with enamines leading to c-ketoesters
in good yields. A reaction mechanism involving nucleo-
philic addition of an enamine to a metal carbene and
subsequent hydrogen transfer was proposed. Further
studies are under the way to elucidate the scope and lim-
itation of this reaction and to develop a catalytic asym-
metric synthesis of c-ketoesters.
O
3 mol%
Cu(hfacac)2
CH2Cl2
O
COOMe
Ar1
N2
N
+
Ar2
Ar1
COOMe
Ar2
Scheme 4.