CuCN catalyzed one pot synthesis of γ-keto diesters: Domino double Michael addition followed by Nef reaction

Article abstract of DOI:10.1016/j.tetlet.2012.04.071

An efficient one pot synthesis of γ-keto diesters through double Michael addition coupled with Nef reaction in the presence of CuCN catalyst and Cs₂CO₃ base is described. The reaction proceeds rapidly in DCM to give the products in good yields. A plausible mechanism is proposed.

Full text of DOI:10.1016/j.tetlet.2012.04.071

Tetrahedron Letters 53 (2012) 3305–3309
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Tetrahedron Letters
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CuCN catalyzed one pot synthesis of
c
-keto diesters: domino double
Michael addition followed by Nef reaction
Saleem Farooq a, Payare L. Sangwan a, , Rajeshwar R. Aleti a, Praveen K. Chinthakindi a,
⇑
Mushtaq A. Qurishi b, Surrinder Koul a,
⇑
a Bio-organic Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India
b Department of Chemistry, University of Kashmir, HazratBal, Srinagar 190 006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one pot synthesis of c-keto diesters through double Michael addition coupled with Nef reac-
Received 16 January 2012
Revised 17 April 2012
Accepted 17 April 2012
Available online 25 April 2012
tion in the presence of CuCN catalyst and Cs2CO3 base is described. The reaction proceeds rapidly in DCM
to give the products in good yields. A plausible mechanism is proposed.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Michael reaction
Copper cyanide
Nef reaction
c
-Keto diesters
While in contemporary organic synthesis, catalysis by nonhaz-
and carbon monoxide, carbonylative dimerization of siloxycyclo-
propane, carbonylative arylation of siloxycyclopropane, conjugate
addition of nitroalkanes to enones followed by reduction of nitro
group to carbonyl group.8 Most of the previously reported methods
suffer from drawbacks such as requirement of a stoichiometric
amount of the Lewis acid, elongated reaction time, hazardous car-
bon monoxide as source for carbonyl group, and above all expen-
sive and highly toxic catalysts.3 Surprisingly, apart from these
ardous and environmentally benign organic molecules is a major
breakthrough, rapid construction of structurally complex and func-
tionally dense molecules from simple and readily available precur-
sors in one operation, referred as a domino reaction, is an exciting
prospect.1 An important strategy in the area of synthetic organic
chemistry is the post replacement of activity groups (that promote
the C–C bond formation) by other functional entities once their
assistance in the targeted synthetic strategy is accomplished.2 In
this respect, nitroalkanes symbolize themselves as viable starting
materials due to their easy conversion into corresponding nucleo-
philic nitronate anions. The latter act as suitable Michael donors in
the C–C bond formation.3,4 Further, Nef reaction of the resulting
C–N bond and its conversion into carbonyl group results in the
generation of required electrophilic function to result in the forma-
tion of spiroketal framework.5
valuable strategies for the generation of c-keto diesters, there ex-
ists no general one pot method available for the synthesis of the
said class. Hence, more efficient and practical alternative methods
using inexpensive and easily available reagents are warranted.
Herein, we unveil one pot synthesis of c-keto diesters in the pres-
ence of Cs2CO3 through CuCN catalyzed domino double Michael
reaction followed by Nef reaction to afford the target products,
achieved in few minutes, with moderate to good yields.
The spiroketal moiety is a key motif in the plethora of natural
compounds present in plants, fungi, insect secretions, shellfish tox-
in, and other living organisms with promising biological activities
like antibiotics.6 Synthesis of such biologically significant cyclic
compounds rely on the elaboration of polycarbonyl compounds,
During our initial studies, the reaction of ethyl acrylate 1
(1 equiv) and nitro methane 2 (1 equiv) in DMSO in the presence
of K2CO3 (1.1 equiv) as a base and CuCN as the catalyst at 20–25 °C
afforded two products (3a and 3b) (Scheme 1) in disproportionate
ratio9 (Table 1), which were isolated in good yields and the products
identified by spectral analysis (1H NMR, 13C NMR, IR, and MS)10 and
derivatization (reduction of 3a to amino ester and of 3b to hydroxy
ester). Prolonged reaction time though known to influence the ratio
of the products3,11 did not result in any incremental increase of 3b
content even after extending the reaction up to 8 days.
among which 1,4-dicarbonyls have proven particularly useful.7
A
few approaches toward the synthesis of such functional arrange-
ments involve multicomponent coupling of siloxycyclopropane
⇑
Corresponding authors. Tel.: +91 191 2569021; fax: +91 191 25693333 (S.K.).
E-mail addresses: plsangwan@iiim.ac.in (P.L. Sangwan), skoul@iiim.ac.in, skoul@
In the absence of CuCN, only Michael reaction product 3a was
obtained. Further, the reaction when carried out on the nitro
iiim.res.in (S. Koul).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.071

3306
S. Farooq et al. / Tetrahedron Letters 53 (2012) 3305–3309
O
O
O
O
O
O
K2CO3, CuCN
+
CH3NO2
O2N
O
+
O
DMSO, rt,
O
1
2
O
O
3a
3b
Scheme 1. Reaction of ethyl acrylate and nitro methane.
Table 1
Reaction of ethyl acrylate and nitro methane with CuCN as the catalyst at different temperatures in presence of different bases in DMSO and DCM solvents
aRatio of products calculated based on isolated yields.
Table 2
Reaction of ethyl acrylate and nitro methane in different solvents with Cs2CO3 as the base, and CuCN as catalyst
S. No.
Solvent
Temp (°C)
Time (h)
Ratioa of 3a:3b
Isolated yieldsb (%)
1
2
3
4
5
6
7
8
DMSO
DCM
DMF
CH3CN
THF
CH3OH
H2O
30–32
30–32
30–32
30–32
30–32
30–32
30–32
30–32
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
22:78
16:84
34:66
35:65
88
90
86
86
85
—
39:61
No reaction
No reaction
No reaction
—
—
Ethylene glycol
a
Ratio of products calculated based on isolated yields.
Combined yield of pure isolated products.
b
intermediate in the absence of the catalyst, no keto product was
formed. However, the same reaction in the presence of CuCN affor-
ded the desired keto product 3b. In a bid to switch over the reac-
tion more predominantly toward the production of 3b due to its
biological and synthetic importance as described earlier, the reac-
tion conditions were optimized in terms of solvent, base, and
temperature. The results of these experiments are summarized in
Table 1.
Best results were obtained at 30–32 °C with Cs2CO3/K2CO3 as
base and DCM as solvent of choice in high yields (85–90%). With
organic bases, 3a was obtained as the sole product. Reaction at
elevated temperature (>40 °C) failed to furnish 3b. Since the reac-
tion at higher temperature failed to afford 3b, microwave and
sonication methods were tried. Microwave assisted reaction of
methyl acrylate and nitro methane adsorbed on silica gel (mesh
60–120) at 55 °C for 2 min with Cs2CO3 as base and CuCN as cata-
lyst failed to furnish product 3b. However, under ultrasonication at
30 °C with reaction time of 30 min, 3b was isolated as the major
product (ratio of 3a:3b/1:3.5, combined isolated yields 90%). From
the above results, it may be concluded that the temperature affects
not only the ratio of the products, their yields, but also the reaction
time. With protic solvents like H2O, and CH3OH, the reaction did
not take place while in aprotic solvents such as DMSO, ACN,
DMF, THF, and DCM, best results were obtained in DCM (reaction
temp 30–32 °C) to achieve a ratio of >5:1 for 3b:3a (Table 2).
Further optimization study was carried out using different cop-
per salts and the best results were obtained with CuCN catalyst
(Table 3).

S. Farooq et al. / Tetrahedron Letters 53 (2012) 3305–3309
3307
Table 3
Study of different Cu-salts on time, space, and yield of the reaction products of ethyl acrylate and nitro methane
S. No
Catalyst
Ratio of 3a:3b in DCM, with base
Ratio of 3a:3b in DMSO, with base
K2CO3
Cs2CO3
K2CO3
Cs2CO3
1
2
3
4
5
6
CuCN
CuCl
CuI
Cu(CN)2
CuCl2
CuI2
25:75
31:69
28:72
16:84
26:74
24:76
27:73
36:64
30:70
22:78
30:70
27:73
Exclusive product 3a obtained
Exclusive product 3a obtained
Exclusive product 3a obtained
Reaction time: 0.5 h, temp: 30–32 °C.
R1 NO2
R1
R
O
Cs2CO3,
CuCN
O
O
O
R
R
+
R
CH3NO2
+
O
O
O
O
O
R1
DCM,
R1
3b
R1
rt, 0.5 h
O
R
O
1
2
3a
1 =H, R =C2H5
3a-I R1 =H, R =CH3
3a-II R1 =H, R =n-C4H9
3b R1 =H, R =C2H5
3b-I R1 =H, R =CH3
3b-II R1 =H, R =n-C4H9
1
R1 =H, R =C2H5
3a
R
1a R1=H, R =CH3
1b R1 =H, R =n-C4H9
1c R1 =CH3, R =C2H5
3a-III R1 =CH3, R =C2H5
3b-III R1 =CH3, R =C2H5
1d R1 =CH3, R =Me
3a-IV R1 =CH3, R =Me
3b-IV R1 =CH3, R =Me
1e R1 =CH3, R =n-C4H9
3a-V R1 =CH3, R =n-C4H9 3b-V R1 =CH3, R =n-C4H9
Scheme 2. Reaction of different alkyl acrylates with CH3NO2.
Cs2CO3,
O
O
O
CuCN
+
R
CH3CH2NO2
O2N
R
+
H3C
R
O
O
O
DCM,
R1
CH3 R1
O
5b
R1
rt, 0.5 h
1
4
5a
5a R1 =H, R =C2H5
5a-I R1 =H, R =CH3
5a-II R1 =H, R =n-C4H9
5b R1 =H, R =C2H5
5b-I R1 =H, R =CH3
5b-II R1 =H, R =n-C4H9
1
R1 =H, R =C2H5
1a R1 =H, R =CH3
1b R1 =H, R =n-C4H9
5a-III R1 =CH3, R =C2H5
5b-III R1 =CH3, R =C2H5
1c R1 =CH3, R =C2H5
5a-IV R1 =CH3, R =Me
5b-IV R1 =CH3, R =Me
1d R1 =CH3, R =Me
5a-V R1 =CH3, R =n-C4H9
5b-V R1 =CH3, R =n-C4H9
1e R1 =CH3, R =n-C4H9
Scheme 3. Reaction of different alkyl acrylates with CH3CH2NO2.
Table 4
Reaction of different alkyl acrylates with CH3NO2 and C2H5NO2 in presence of CuCN catalyst, Cs2CO3 base in DCM
S. No.
Substrate
Reaction with CH3NO2
Yield (%) combined
Reaction with C2H5NO2
Yield (%) combined
3a:3b Ratio
5a:5b Ratio
1
2
3
4
5
6
Ethyl acrylate
Methyl acrylate
Butyl acrylate
Methyl methacrylate
Ethyl methacrylate
Butyl methacrylate
16:84
19:79
28:72
27:73
29:71
30:70
83–90
80–85
70–72
69–70
65–70
66–70
22:78
26:74
30:70
25:75
22:68
32:68
85–88
80–83
67–70
67–73
65–68
66–68
Reaction time: 0.5 h, temp: 30–32 °C.
Furtherreactionswere carriedout tovalidate thefeasibilityof the
methodology using six different acrylates and subjecting them to re-
act with nitro methane (Scheme 2) and nitro ethane (Scheme 3) un-
der the optimized reaction conditions of temperature (30–32 °C),
base (Cs2CO3), solvent (DCM) using CuCN as the catalyst.
The reactions proceeded smoothly with good to excellent over-
all yields and with substituted acrylates (Table 4), the desired
product was obtained as single entity (diastereoisomeric ratio:
>99%, confirmed by spectral analysis, entries 3b-III–V and 5a-III–
V). The proton spectrum of compound 3b-IV on the addition of
CSA [S(+)-1-(9-anthryl)-2,2,2-triflouro-ethanol] showed fine split-
ting of methyl and methine proton signals (Fig. 1) leading thereby
to conclude that the diastereoisomer is apparently a racemic mix-
ture rather than a meso compound. The splitting pattern of proton
signals was also observed for 5a-IV (spectra are provided in
Supplementary data).

3308
S. Farooq et al. / Tetrahedron Letters 53 (2012) 3305–3309
Figure 1. 1H NMR spectra of 3b-IV in the absence and presence of CSA. 1a: Spectra in absence of CSA and 1c and 1e its expanded spectra. 1b: Spectra in presence of CSA and
1d and 1f its expanded spectra.
O
O
O
CH2NO2
O2N
+
O2N
O2N
O
O
O
H+
x
1
Cs2CO3
O
O
CuCN
O
O
O
O
O
O
O
+
CuCN
O
N
O
O2N
H
O
O
O
y
3a
O
O
O
CuCN
O
O
O
H
O
O
HO
N
O
H2O
O
O
H
H
OH
N
N
O
O
HO
H
O
HO
H
O
-H2O
O
O
z
O
O
O
O
O
O
O
N
O H
O
+
HNO
O
3b
O
Scheme 4. Proposed mechanism.
Next, we tried to expand the scope of the reaction on other
a
,b-
From mechanistic point of view, account for the formation of
the keto diester, a plausible mechanism has been proposed as
shown in Scheme 4. The mechanism involves the attack of the
carbanion (:CH2NO2) on the ethyl acrylate under basic conditions
to give Michael product ‘x’ (a carbanion) which attacks the second
unsaturated systems such as citral, acrolein, carvone, and cinnamal-
dehyde. However, all these substrates failed to furnish the desired
products. These results lead to imply that the ester group of the
acrylates apparently seems to contribute for the reaction to click.

S. Farooq et al. / Tetrahedron Letters 53 (2012) 3305–3309
3309
3. (a) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017–1047; (b) Ballini, R.;
Fiorini, D.; Palmieri, A. Tetrahedron Lett. 2004, 45, 7027–7029; (c) Ballini, R.;
Barboni, L.; Giarlo, G. J. Org. Chem. 2003, 68, 9173–9176.
4. (a) Luzzio, F. A. Tetrahedron 2001, 57, 915–945; (b) Perlmutter, P. Conjugate
Addition Reactions in Organic Synthesis; Pergamon Press: Oxford, 1992.
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M. A.; Fares, A. F. Tetrahedron 1999, 55, 7661–7706; (c) Rodriguez, S.; Wipf, P.
Synthesis 2004, 2767–2783; (d) Mead, K. T.; Brewer, B. N. Curr. Org. Chem. 2003,
7, 227–256.
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Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105, 4406–4440.
7. (a) Rodriguez, S.; Wipf, P. Synthesis 2004, 2767–2783; (b) Mead, K. T.; Brewer,
B. N. Curr. Org. Chem. 2003, 7, 227–256.
ethyl acrylate molecule to give 4-nitro diester (3a). The nitro group
of the latter forms a complex with CuCN which undergoes depro-
tonation of C-4 to form ‘y’, followed by attack of water molecule
to form intermediate ‘z’ and subsequent expulsion of HNO group
to result in the formation of keto diester 3b.
In conclusion, we have developed a copper catalyzed one pot
synthesis of
c-keto diesters using simple available substrates in
desirable yields. The procedure described is simple and involves
relatively mild reaction conditions.
8. (a) Aoki, S.; Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1988, 29, 1541–1542;
(b) Aoki, S.; Nakamura, E. Tetrahedron 1991, 47, 3935–3946; (c) Stang, P. J.;
Hanack, M.; Subramanian, R. Synthesis 1982, 2, 85–126.
Acknowledgments
The authors (S.F., R.R.A., and P.K.C.) are grateful to the CSIR–UGC
for providing research fellowship. Thanks are also due to Dr. Ram
Vishwakarma, Director IIIM, Jammu for the support of the research
work.
9. General Procedure: To DMSO or DCM solution (10 mL) of nitro methane
(1 equiv) was added K2CO3/ or Cs2CO3 (1 equiv) and the contents stirred for
5 min, followed by the addition of ethyl acrylate solution (1 equiv, in 3 mL
DMSO) and catalytic amount of CuCN (pinch) and the reaction mixture stirred
at 20–25 °C. On completion of the reaction, the contents were diluted with
water, the organic layer separated and the aqueous portion extracted with
DCM (3 Â 50 mL). The combined organic layer was washed with water
(2 Â 10 mL), dried over anhydrous sodium sulfate, and concentrated under
reduced pressure at <40 °C. The crude reaction product was purified by column
chromatography over silica gel (mesh 60–120) using hexane and ethyl acetate
(19:1) as eluent to obtain products 3a and 3b.
Supplementary data
Supplementary data associated with this article can be found, in
theonline version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.071.
10. Diethyl 4-nitroheptanedioate (3a): Viscous liquid (157 mg); 1H NMR (200 MHz,
CDCl3): d 4.61–4.70 (m, 1H), 4.15 (q, J = 7.15 Hz, 4H), 2.10–2.42 (m; 8H), 1.26 (t,
J = 7.15 Hz, 6H); 13C NMR (50 MHz, CDCl3): d 171.7, 86.6, 60.9, 30.1, 28.6, 14.1;
IR (neat) mmax 1773, 1660, 1554, 1444, 1376 cmÀ1; MS at m/z 284 (M++Na).
Diethyl 4-oxoheptanedioate (3b): Viscous liquid (915 mg); 1H NMR (200 MHz,
CDCl3): d 4.12 (q, J = 7.1 Hz, 4H), 2.78 (t, J = 6.5 Hz, 4H), 2.60 (t, J = 6.5 Hz, 4H),
1.25 (t, J = 7.1 Hz, 6H); 13C NMR (50 MHz, CDCl3): d 207.0, 172.7, 60.6, 37.1,
References and notes
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28.0, 14.1; IR (neat)
m ;
max 2983, 1735, 1660, 1554, 1444, 1376, 1183, 1030 cmÀ1
MS at m/z 253 (M++Na).
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5235.