Dimethyl malonate as a one-carbon source: A novel method of introducing carbon substituents onto aromatic nitro compounds

Article abstract of DOI:10.1016/S0040-4039(01)01809-3

A number of carbon substituents possessing various functional groups could be introduced onto aromatic nitro compounds using dimethyl malonate as a one-carbon source and linker. Decarboxylation of both the ester groups originating from dimethyl malonate in this methodology is particularly significant.

Full text of DOI:10.1016/S0040-4039(01)01809-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8395–8398
Dimethyl malonate as a one-carbon source: a novel method of
introducing carbon substituents onto aromatic nitro compounds†
N. Selvakumar,* B. Yadi Reddy, G. Sunil Kumar and Javed Iqbal
Discovery Chemistry (Synthesis), Dr. Reddy’s Research Foundation, Bollaram Road, Miyapur, Hyderabad 500 050, India
Received 20 July 2001; accepted 21 September 2001
Abstract—A number of carbon substituents possessing various functional groups could be introduced onto aromatic nitro
compounds using dimethyl malonate as a one-carbon source and linker. Decarboxylation of both the ester groups originating
from dimethyl malonate in this methodology is particularly significant. © 2001 Elsevier Science Ltd. All rights reserved.
Alkylation of aromatic rings is one of the important
transformations in organic synthesis. While the Friedel–
Crafts alkylation procedure continues to occupy center
stage for the alkylation of numerous aromatic rings, it
does not proceed successfully with aromatic substrates
having electron withdrawing groups.1 In addition, the
Friedel–Crafts method has the disadvantage of rear-
rangement of the alkyl group being used and it often
leads to alkylation at more than one site.2 The other
possibility for the alkylation of electron deficient aro-
matics is to introduce carbon nucleophiles onto such
aromatics possessing leaving groups such as halides.
Even though introducing ‘N’ and ‘O’ nucleophiles to
such aromatics is a standard aromatic nucleophilic
substitution reaction in organic synthesis, there are not
many successful examples of arylation of carbanions by
nucleophilic aromatic substitution. The major limita-
tion for this addition–elimination process is that the
nitro aromatics often react with carbanions by electron-
transfer processes.3
reactive functional groups such as esters, nitriles,
olefins, ketones, etc. to aromatic nitro compounds.
Thus, the reaction of dimethyl malonate 2 with an
aromatic compound 3 under basic conditions, followed
by alkylation with an alkyl halide 1, produces a product
4 (Scheme 1). After introducing the carbon substituents
onto the aromatic nitro compound using dimethyl mal-
onate, both the ester functionalities can be removed
under suitable conditions leading to the alkylated com-
pound 5. The overall protocol of preparing compound
5 from a nitro compound 3 constitutes an indirect
method of alkylating the aromatic nitro compounds.
For example, the treatment of dimethyl malonate 2
with 3,4-dichloronitrobenzene 6 under basic conditions
afforded the nitro-diester 7 in good yield (Scheme 2).4,7
The stabilized anion obtained by the treatment of the
resultant diester 7 with NaH underwent alkylation with
benzyl bromide to give the alkylated compound 8 in
72% yield.7 Having introduced two fragments onto
dimethyl malonate, both the ester functionalities were
removed under Kraphcho’s decarboxylation conditions
leading to the nitro compound 10 in high yield.5,7 The
overall transformation of 3,4-dichloronitrobenzene 6
In this communication, we present the use of dimethyl
malonate as a one-carbon source and linking agent for
attaching a variety of carbon substituents possessing
E
E
Base
+
R X
MeO2C
CO2Me
+
X
NO2
NO2
NO2
R
R
1
2
3
4
5
E = CO2Me
Scheme 1.
Keywords: decarboxylation; alkylation; Friedel–Crafts reaction; rearrangement; Michael addition.
* Corresponding author. Tel.: 91-40-3045439; fax: 91-40-3045438; e-mail: nselva123@rediffmail.com
† DRF Publication No. 164.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01809-3

8396
N. Sel6akumar et al. / Tetrahedron Letters 42 (2001) 8395–8398
d
Cl
Cl
E
Cl
E
E
NO2
d
NO2
NO2
c
10
9
8
Cl
Cl
b
e
MeO2C
MeO2C
a
NO2
+
Cl
NO2
MeO2C
MeO2C
7
2
6
Cl
Cl
Cl
E
E
E
NO2
NO2
NO2
f
g
13
12
11
O
O
O
g
E=CO2Me
Scheme 2. (a) NaH, THF, 0“60°C, 75%; (b) NaH, DMF, BnBr, rt, 72%; (c) NaCl, DMSO, 110°C, 73%; (d) NaCl, DMSO,
155°C, 85%; (e) NaOMe, methyl vinyl ketone, MeOH, rt, 100%; (f) NaCl, DMSO, 110°C, 70%; (g) NaCl, DMSO, 155°C, 56%.
into the ester 10 constitutes a novel method of alkyla-
tion of aromatic nitro compounds. Even though the
monodecarboxylation of malonates to esters is a con-
ventional transformation, the decarboxylation of the
second ester group is interesting and is realized probably
because it is situated on a benzylic carbon of an electron
deficient aromatic ring. The experiment could also be
performed under controlled conditions so as to stop the
reaction at monodecarboxylation product 9 at will. This
option offers an opportunity to have an access for
further functionalization whenever necessary.
aromatic nitro compounds, we further pursued the
generality of the method. A summary of several nitro-
diesters, obtained by treatment of a number of alkyl
halides and Michael acceptors with compound 7, and
the corresponding decarboxylation products, is given in
Table 1. This method is flexible for the alkylation of
diester 7 with allyl halides, benzyl halides and halides
having a a-carbonyl functionality (entries 1 to 4, Table
1). However, the alkylated compound 22 obtained from
an unsubstituted alkyl halide did not undergo the decar-
boxylation as expected (entry 5, Table 1).
In addition, the nitro-diester 7 also underwent a
Michael addition with methyl vinyl ketone leading to
the keto-diester 11 in quantitative yield (Scheme 2).6,7
As expected, the decarboxylation of the compound 11
resulted in the nitro compound 13 in 56% yield. The
monodecarboxylated product 12 could also be obtained
from the nitro-diester 11 at a slightly lower temperature.
In a similar fashion, methyl acrylate and acrylonitrile
gave alkylated compounds 24 and 26, respectively
(entries 6 and 7, Table 1).
In order to establish the generality of this approach with
other aromatic rings, the nitro-diester 28 which was
prepared from 4-fluoronitrobenzene 27 and dimethyl
malonate, was found to undergo alkylation with allyl
bromide to give the compound 29 (Scheme 3). The
nitro-diester 29 was in turn decarboxylated, giving the
alkylated nitro compound 30 in 61% yield.
The alkylated compounds prepared in this communica-
tion have potential as intermediates or starting materials
in organic chemistry. For instance, the nitro-diester 32
obtained by the reaction of 2-fluoronitrobenzene 31
Having established a protocol for the alkylation of
MeO2C
MeO2C
MeO2C
a
+
NO2
F
NO2
MeO2C
b
28
27
2
E
c
E
NO2
NO2
E=CO2Me
30
29
Scheme 3. (a) NaH, THF, 60°C, 65%; (b) NaH, allyl bromide, rt, 55%; (c) NaCl, DMSO, 155°C, 61%.

N. Sel6akumar et al. / Tetrahedron Letters 42 (2001) 8395–8398
Table 1. Examples of the preparation of various alkylated nitrobenzenesa
8397
a E represents CO2Me.
b Only starting material was recovered.
c Yields based on recovered starting materials which ranges between 10 and 15%.
d The corresponding monodecarboxylated product of ca. 10% was also isolated.
with dimethyl malonate underwent alkylation with ethyl
bromoacetate to afford the nitro-triester 33 in 58%
yield over the two steps (Scheme 4). The hydrogenation
of nitro-diester 34, obtained by the controlled decar-
boxylation of compound 33, resulted in the bicyclic lac-
tams 35 and 36 in the ratio of 4:1 in four steps
and in good yields. This would constitute a short
synthesis of substituted 3,4-dihydro-2(1H)quinolinones
of type 35.
In conclusion, we have developed a methodology to
introduce alkyl substituents possessing various functional
groups onto aromatic nitro compounds. In addition,
compounds 17 and 10 could be potential intermediates
in the preparation of chalcones and stilbenes, respectively,
with one of the aromatic rings containing a nitro group.
The preparation of chalcones, stilbenes and further work
to utilize the compounds prepared above in organic
chemistry is currently underway in our laboratory.

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N. Sel6akumar et al. / Tetrahedron Letters 42 (2001) 8395–8398
NO2
CO2Me
NO2
NO2
MeO2C
MeO2C
2
a
b
+
CO2Et
F
MeO2C CO2Me
CO2Me
32
31
33
c
H
N
H
N
O
NO2
d
O
+
CO2Et
CO2Me
34
CO2Et
CO2Me
35
36
Scheme 4. (a) NaH, THF, rt, 80%; (b) NaH, DMF, ethyl bromoacetate, rt, 72%; (c) NaCl, DMSO, 110°C, 58%; (d) H2, Pd on
C, THF, 73% (4:1 ratio of 35 to 36).
Acknowledgements
an Ar atmosphere followed by benzyl bromide (1.76 g, 10.4
mmol). After stirring the resultant mixture at rt overnight,
it was quenched with saturated NH4Cl and extracted with
ethyl acetate (4×60 mL). The combined organic extracts
were washed with water, brine and dried. The residue
obtained upon evaporation of the solvents was purified on
a column of silica gel to afford compound 8 as a colorless
oil (1.89 g, 72%). IR (neat, w cm−1): 1744, 1527, 1352, 1211,
767; lH (200 MHz, CDCl3): 3.82 (s, 8H), 6.85–7.31 (m,
6H), 7.88 (dd, J=2.4 and 8.8 Hz, 1H), 8.26 (d, J=2.4 Hz,
1H); lC (50 MHz, CDCl3): 39.47, 53.42 (2C), 64.77, 120.70,
125.45, 127.00, 127.81 (2C), 130.23 (2C), 132.14, 134.44,
135.13, 142.23, 146.91, 168.68 (2C); Mass (CI method): 378
(M+H)+, 348, 288, 91.
We thank Dr. A. Venkateswarlu and Dr. R. Rajago-
palan for their continued encouragement in this work.
We also thank D. Srinivas, A. Malar Azhagan and M.
Sudhakar Rao for their assistance in this project.
References
1. Friedel–Crafts and Related Reactions, Vols. I–IV; Olah, G.
A., Ed.; Wiley-Interscience: New York, 1962–1964.
2. Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry,
Part B; Plenum Press: New York, 1991.
Preparation of compound 10: A solution of compound 8
(500 mg, 1.32 mmol), NaCl (232 mg, 3.97 mmol) and H2O
(0.3 mL) in distilled DMSO (8 mL) was heated to 155°C
overnight. The reaction mixture was allowed to cool to rt
and then worked up by adding water and extracting with
ethyl acetate (4×60 mL). The combined organic extracts
were washed with water, brine and dried. The residue
obtained upon evaporation of the solvents was purified on
a column of silica gel to afford compound 10 as an orange
colored solid (294 mg, 85%). Mp 60°C; IR (neat, w cm−1):
1521, 1350, 909, 734; lH (200 MHz, CDCl3): 2.95–3.20 (m,
4H), 7.18–7.46 (m, 6H), 8.04 (dd, J=2.4 and 8.3 Hz, 1H),
8.29 (d, J=2.4 Hz, 1H); lC (50 MHz, CDCl3): 35.19, 35.70,
121.53, 124.51, 126.30, 128.31 (2C), 128.42 (2C), 130.88,
134.64, 140.17 (2C), 146.67; Mass (CI method): 262 (M+
H)+, 91. Anal. calcd for C14H12ClNO2: C, 64.26; H, 4.62;
N, 13.55. Found: C, 64.06; H, 4.68; N, 13.38.
Preparation of compound 11: To a solution of the nitro-
diester 7 (1.0 g, 3.5 mmol) and methyl vinyl ketone (0.714
g, 10.2 mmol) in absolute MeOH (10 mL) was added a
catalytic amount of sodium methoxide at rt under Ar. The
reaction mixture was stirred for 40 h at the same tempera-
ture and then diluted with CH2Cl2 (200 mL). The resultant
mixture was washed with water, brine and dried. The
residue obtained upon evaporation of the solvents was
purified on a column of silica gel to give compound 11 as
a colorless oil (1.18 g, 95%). IR (neat, w cm−1): 1737 (br),
1628, 1352, 1257, 893; lH (200 MHz, CDCl3): 2.10 (s, 3H),
2.47–2.76 (2t, 4H), 3.78 (s, 6H), 7.51 (d, J=8.8 Hz, 1H),
8.12 (dd, J=2.4 and 8.8 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H);
lC (50 MHz, CDCl3): 27.93, 29.77, 39.13, 53.24 (2C), 61.85,
121.56, 125.88, 129.99, 135.11, 142.54, 147.31, 169.00 (2C),
206.43; Mass (CI method): 358 (M+H)+, 326, 111.
3. Comprehensive Carbanion Chemistry, Part A; Durst, T.,
Ed.; Elsevier: Amsterdam, 1980; Chapter 5.
4. Snyder, H. R.; Merica, E. P.; Force, C. G.; White, E. G.
J. Am. Chem. Soc. 1958, 80, 4622.
5. Kraphcho, A. P.; Lovey, A. J. Tetrahedron Lett. 1973, 14,
957.
6. Kaiser, E. W.; Mao, C. L.; Hauser, C. F.; Hauser, C. R. J.
Org. Chem. 1970, 35, 410.
7. Selected experimental procedures:
Preparation of compound 7: To a suspension of NaH (60%,
5.49 g, 137.5 mmol) in dry DMF (80 mL) under ice cooling
was added dimethyl malonate (16.5 g, 125 mmol) dropwise
over a period of 10 min followed by a solution of 3,4-
dichloronitrobenzene (12.0 g, 62.5 mmol) in dry DMF (15
mL) under an Ar atmosphere. The resultant mixture was
stirred at 70°C overnight and then allowed to cool to rt.
The reaction mixture was quenched with saturated NH4Cl
and extracted with ethyl acetate (4×200 mL). The com-
bined organic extracts were washed with water, brine and
dried (Na2SO4). The residue obtained upon evaporation of
the solvents was purified on a column of silica gel to afford
the nitro-diester 7 as a light yellow solid (13.5 g, 75%). Mp
109°C; IR (neat, w cm−1): 1748 (br), 1523, 1349, 1230, 1155,
738; lH (200 MHz, CDCl3): 3.81 (s, 6H), 5.32 (s, 1H), 7.74
(d, J=8.3 Hz, 1H), 8.17 (dd, J=2.4 and 8.3 Hz, 1H), 8.31
(d, J=2.4 Hz, 1H); Mass (CI method): 288 (M+H)+; Anal.
calcd for C11H10ClNO6: C, 45.94; H, 3.50; N, 4.87. Found:
C, 46.12; H, 3.44; N, 4.80.
Preparation of compound 8: To a suspension of NaH (60%,
390 mg, 9.75 mmol) in dry DMF (15 mL) under ice cooling
was added a solution of the compound 7 (2 g, 6.96 mmol)
in dry DMF (5 mL) dropwise over a period of 5 min under