A direct synthesis of 2-arylpropenoic acid esters having nitro groups in the aromatic ring: A short synthesis of (±)-coerulescine and (±)-horsfiline

Article abstract of DOI:10.1016/S0040-4039(02)02267-0

A short synthesis of 2-arylpropenoic acid esters that possess nitro groups in their phenyl ring using common and less expensive reagents is described. The usefulness of this methodology is substantiated by the efficient total syntheses of (±)-coerulescine and (±)-horsfiline from the 2-arylpropenoic acid esters obtained.

Full text of DOI:10.1016/S0040-4039(02)02267-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9175–9178
A direct synthesis of 2-arylpropenoic acid esters having nitro
groups in the aromatic ring: a short synthesis of ( )-coerulescine
and ( )-horsfiline†
N. Selvakumar,* A. Malar Azhagan, D. Srinivas and G. Gopi Krishna
Department of Discovery Chemistry, Discovery Research, Dr. Reddy’s Laboratories Ltd., Miyapur, Hyderabad 500 050, India
Received 14 August 2002; revised 23 September 2002; accepted 4 October 2002
Abstract—A short synthesis of 2-arylpropenoic acid esters that possess nitro groups in their phenyl ring using common and less
expensive reagents is described. The usefulness of this methodology is substantiated by the efficient total syntheses of
( )-coerulescine and ( )-horsfiline from the 2-arylpropenoic acid esters obtained. © 2002 Elsevier Science Ltd. All rights reserved.
2-Arylpropenoic acids signify a medicinally important
class of non-steroidal anti-inflammatory agents.1 2-
Arylpropenoic acids possessing nitro groups in their
aromatic rings such as 2 are potential starting materials
for the preparation of several analgesic and anti-inflam-
matory 2-(4-aminophenyl)propionic acid derivatives of
type 1 (Fig. 1).2 In addition, these compounds have
served as potential intermediates in certain natural
product syntheses3,4 and other purposes.5 There have
been a few reports concerning the syntheses of this class
of compounds. While the procedure of Cho et al.
started with p-nitroacetophenone,6 the other two proce-
dures warranted p-nitrophenylacetic acids as starting
materials.7,8 Furthermore, the first procedure involves
reaction of dichlorocarbene in a two-phase system
using a phase-transfer catalyst and is not commonly
followed in the literature. The classical procedure that
is frequently used in the preparation of these com-
pounds involves reacting the appropriate phenylacetic
acid ester with ethyl oxalate under basic conditions
followed by treating the resultant oxalo-ester with aq.
formaldehyde in the presence of K2CO3.7 The third
procedure involved a Mannich reaction in converting
p-nitrophenylacetic acid to the target compound.8 Very
recently, a palladium-catalyzed coupling of an a-stan-
nyl acrylate to a nitro-aryl iodide has been disclosed as
a method of preparing these compounds.9 Herein, we
report a direct and straightforward synthesis of the title
compounds from readily available starting materials in
two steps employing less expensive reagents.
Our synthesis started from commercially available aro-
matic nitro compounds having leaving groups in either
the ortho or para position with respect to the nitro
group. The aromatic nucleophilic substitution of
dimethyl malonate onto 2-fluoronitrobenzene
3
afforded the nitro-malonate 4 as reported earlier from
this laboratory (Scheme 1).10 The treatment of nitro-
malonate 4 with aq. formaldehyde in the presence of
K2CO3 cleanly afforded the nitro-aryl propenoate 5.
This conversion was expected to occur with initial
decarboxylation followed by the aldol condensation of
the resultant aryl acetic acid derivative with formalde-
hyde in one-pot and this was eventually confirmed by
carrying out the conversion in a stepwise manner. Thus,
treatment of nitro-malonate 4 with aq. K2CO3 resulted
in decarboxylation giving the nitro-phenyl acetate 6,
which underwent aldol condensation with formalde-
hyde leading to the nitro-aryl propenoate 5.11 This
preparation of compound 5 from commercially avail-
able 2-fluoronitrobenzene in two steps constitutes a
short synthesis of a 2-arylpropenoic acid ester possess-
ing a nitro group in the aromatic ring.
Keywords: 2-arylpropenoic acid; anti-inflammatory agents; aromatic
nucleophilic substitution; aldol condensation; oxindole alkaloids; 1,3-
dipolar cycloaddition.
* Corresponding author. Tel.: 91-40-3045439; fax: 91-40-3045438;
e-mail: selvakumarn@drreddys.com
† DRL Publication No. 234.
Figure 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02267-0

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N. Sel6akumar et al. / Tetrahedron Letters 43 (2002) 9175–9178
the systems, the second step had varied yields from
moderate to very good. The diversity with which the
2-arylpropenoic acid esters could be prepared as shown
in Table 1 reveals the potential of this method in the
synthesis of this type of compound.
In addition to the anticipated use of these compounds
in preparing analogues of anti-inflammatory com-
pounds, we have also used them as starting materials
for the synthesis of oxindole alkaloids in a bid to
substantiate the potential of these compounds in
organic synthesis. (−)-Horsfiline 15 was the first alka-
loid isolated in 1991, among other known alkaloids,
from a Malaysian medicinal tree Horsfieldia superba
Warb. belonging to the Horsfieldia genus by Bodo and
co-workers.13 Recently, Colegate and co-workers iso-
lated a related oxindole alkaloid (−)-coerulescine 8 from
Phalaris coerulescens.14 Horsfiline had attracted wide
attention from synthetic chemists and many method-
ologies were applied to its synthesis.15 We report the
syntheses of both the natural alkaloids in their racemic
form from the 2-arylpropenoic acid esters obtained
using the above methodology.
Scheme 1. Reagents and conditions: (a) NaH, dimethyl mal-
onate, THF, rt, 83%; (b) K2CO3, formalin, 60°C, 75%; (c)
K2CO3, H2O, 60°C, 70%; (d) K2CO3, formalin, 60°C, 62%.
Having obtained a 2-arylpropenoic acid ester possess-
ing a nitro group in the aromatic ring in two steps from
commercial materials, we turned our attention to gener-
alize the protocol and the results are summarized in
Table 1. A wide variety of aromatic nitro compounds
possessing functional groups ranging from halogens
such as chlorine (entries 2 and 3) and fluorine (entries 5
and 6) to methyl (entry 7) and trifluoromethyl groups
(entry 8) were chosen as starting materials for the
study. While the first step of aromatic nucleophilic
substitution occurred in excellent yields in almost all
The 2-arylpropenoic acid ester 5 obtained in two steps
from 2-fluoronitrobenzene was converted to ( )-
coerulescine 8 in two further steps using the route
reported byPalmisano and co-workers.15a Thus, the 1,3-
dipolar cycloaddition of the nitro-ester 5 to a N-methyl-
azomethine ylide, generated from N-methylglycine and
paraformaldehyde, afforded smoothly the pyrrolidine
nitro-ester 7 in very good yield (Scheme 2). Subsequent
hydrogenation of the compound resulted in clean
cyclization leading to ( )-coerulescine 8 in only two
steps from the nitro-ester 5 obtained using our method.
Thus, the synthesis of ( )-coerulescine was achieved in
four steps from commercial material with an overall
yield of 45%.
Table 1. Examples of the preparation of 2-arylpropenoic
acid esters
Entry
Starting material
Yield of
compound
analogous to
4 (%)
5 (%)
Analogously, the synthesis of ( )-horsfiline 15 war-
ranted the synthesis of nitro-ester 13 possessing a
methoxy group in the aromatic ring starting the synthe-
sis from 2,4-difluoronitrobenzene (Scheme 3). Our ini-
tial plan was to introduce a methoxy group to the
fourth position of 2,4-difluoronitrobenzene by a selec-
tive aromatic nucleophilic substitution but this proce-
dure failed as the reaction occurred at both fluorine
atoms resulting in 2,4-dimethoxynitrobenzene. Thus, we
changed our strategy to introduce initially dimethyl
malonate, though we expected both regioisomers, and
1
2
3
4
5
6
7
8
1-Chloro-2,4-dinitrobenzene
3,4-Dichloronitrobenzene
1,2,3-Trichloro-5-nitrobenzene
1-Fluoro-4-nitrobenzene
3,4-Difluoronitrobenzene
3,4,5-Trifluoronitrobenzene
3-Fluoro-4-nitrotoluene
89
85a
80
88a
89
83
62
86
59
70
48
33b
32b
24b
52
2-Chloro-3,5-dinitrobenzotrifluoride
41
a Reported from this laboratory before.10
b The poor yield is due to the formation of a Michael addition
product (ca. 25%).12
,
Scheme 2. Synthesis of ( )-coerulescine. Reagents and conditions: (a) Sarcosine, (CH2O)n, 3 A molecular sieves, toluene, reflux
86%; (b) H2, 10% Pd/C, MeOH, 84%.

N. Sel6akumar et al. / Tetrahedron Letters 43 (2002) 9175–9178
9177
Scheme 3. Synthesis of ( )-horsfiline. Reagents and conditions: (a) NaH, dimethyl malonate, THF, rt, 73%; (b) H2, 10% Pd/C,
MeOH, 62%; (c) NaH, MeOH, rt then 60°C, 51%; (d) K2CO3, formalin, 60°C, 80%; (e) NaH, MeOH, rt, 76%; (f) Sarcosine,
,
(CH2O)n, 3 A molecular sieves, toluene, reflux 66%; (g) H2, 10% Pd/C, MeOH, 83%.
subsequently introduce the methoxy group to the para
position of the 2-isomer. To this end, the treatment of
dimethyl malonate with 2,4-difluoronitrobenzene and
NaH was carried out and we obtained predominantly
one isomer in good yield (the other isomer formed in
less than 5%). We identified the major isomer as the
required ortho-addition product 9 based on the similar-
ity of its aromatic splitting pattern in the 1H NMR
spectrum with that of commercially available 2-nitro-4-
fluorotoluene. The structure of 9 was unambiguously
confirmed by hydrogenating to the oxindole compound
10, which exists as the aromatic indole compound.
Having obtained the required isomer 9, we next turned
our attention to introduce the methoxy group to the
para position. Thus, treatment of nitro-diester 9 with
NaOMe in methanol at rt resulted only in recovery of
starting material. However, at 60°C substitution of the
methoxy group to the fourth position occurred with
concurrent decarboxylation yielding the unwanted
nitro-ester 11. Consequently, we planned to introduce
the methoxy group after forming the 2-arylpropenoic
acid ester moiety, which was accomplished under the
usual conditions giving the nitro-acrylate 12. Treatment
of 12 with NaOMe in methanol cleanly gave the desired
methoxy nitro-acrylate 13 in 76% yield.15a,16 The further
steps to complete the synthesis of ( )-horsfiline 15 were
performed as usual. Thus, the synthesis of ( )-horsfiline
was achieved in five steps from a commercially avail-
able substance with an overall yield of 24%. The spec-
rials and less expensive reagents than those previously
reported. We believe that the methodology, which led
to the accessibility of a wide range of nitro-acrylates,
would be useful in the preparation of analogues of
anti-inflammatory drugs. The potential of this method
was substantiated by the short syntheses of the oxindole
alkaloids ( )-coerulescine 8 and ( )-horsfiline 15 in
excellent overall yields from commercially available
starting materials and the syntheses should be amenable
for the preparation of the natural products in large
scale for biological evaluation.
Acknowledgements
We thank Dr. K. Anji Reddy for his continued encour-
agement in this work. The help extended by Dr. R.
Rajagopalan and Dr. Sanjay Trehan is greatly acknowl-
edged. We appreciate the services rendered by the Ana-
lytical Research Department of Discovery Research,
Dr. Reddy’s Laboratories for this communication.
References
1. Rieu, J.-P.; Boucherle, A.; Cousse, H.; Mouzin, G. Tetra-
hedron 1985, 41, 4095.
tral data of synthetic ( )-coerulescine
8
and
2. Dumaitre, B.; Fouquet, A.; Perrin, C.; Cornu, P. J.;
Boucherle, A.; Plotka, C.; Domage, G.; Streichenverger,
G. Eur. J. Med. Chem.-Chim. Ther. 1979, 14, 207 (CA:
1979, 91, 157398n).
( )-horsfiline 15 were comparable in all respects with
those of literature values.17
In conclusion, we have developed a short and direct
method for the preparation of 2-arylpropenoic acid
esters possessing nitro groups in their phenyl rings. The
synthesis involves commercially available starting mate-
3. Jefford, C. W.; Zaslona, A. Tetrahedron Lett. 1985, 26,
6035.
4. Jefford, C. W.; Kubota, T.; Zaslona, A. Helv. Chim. Acta
1986, 69, 2048.

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N. Sel6akumar et al. / Tetrahedron Letters 43 (2002) 9175–9178
5. Schauble, J. H.; Freed, E. H.; Swerdloff, M. D. J. Org.
Chem. 1971, 36, 1302.
6. Cho, Y. S.; Yeo, J. H. Soul Taehakkyo Yakhak Nonmun-
chemistry 1998, 48, 437; (b) Somei, M.; Noguchi, K.;
Yamagami, R.; Kawada, Y.; Yamada, K.; Yamada, F.
Heterocycles 2000, 53, 7; (c) Kuehne, M. E.; Roland, D.
M.; Hafter, R. J. Org. Chem. 1978, 43, 3705.
jip 1984, 9, 37 (CA: 1986, 104, 186092a).
7. (a) Ksander, G. M.; McMurry, J. E.; Johnson, M. J. Org.
Chem. 1977, 42, 1180; (b) Schinz, H.; Hinder, M. Helv.
Chim. Acta 1947, 30, 1349; (c) Ames, G. R.; Davey, W. J.
Chem. Soc. 1958, 1794.
8. Schauble, J. H.; Hertz, E. J. Org. Chem. 1970, 35, 2529.
9. Levin, J. I. Tetrahedron Lett. 1993, 34, 6211.
10. Selvakumar, N.; Reddy, B. Y.; Kumar, G. S.; Iqbal, J.
Tetrahedron Lett. 2001, 42, 8395.
15. (a) Cravotto, G.; Giovenzana, G. B.; Pilati, T.; Sisti, M.;
Palmisano, G. J. Org. Chem. 2001, 66, 8447; (b) Lizos,
D.; Tripoli, R.; Murphy, J. A. Chem. Commun. 2001, 1,
2732; (c) Kumar, U. K. S.; Ila, H.; Junjappa, H. Org.
Lett. 2001, 3, 4193; (d) Bascop, S.-I.; Sapi, J.; Laronze,
J.-Y.; Levy, J. Heterocycles 1994, 38, 725; (e) Pellegrini,
C.; Strassler, C.; Weber, M.; Borschberg, H.-J. Tetra-
hedron: Asymmetry 1994, 5, 1979.
11. Procedure for the preparation of compound 5 from nitro-
diester 4: To a mixture of nitro-diester 4 (2 g, 7.9 mmol)
in formalin (37–41%, 15 mL) was added a solution of
K2CO3 (1.63 g, 11.85 mmol) in water (5 mL). The
resultant mixture was heated to 60°C for 2 h and then
cooled to rt. The reaction mixture was added to water
and extracted with ether (4×50 mL). The combined
organic extracts were washed with brine and dried. The
residue obtained upon evaporation of the volatiles was
purified on a column of silica gel to afford the nitro-acry-
late 5 as a colorless oil (1.2 g, 75%). IR (neat, w cm−1):
1728, 1528, 1351, 1210; lH (200 MHz, CDCl3): 8.15 (d,
J=8.3 Hz, 1H), 7.68–7.52 (m, 2H), 7.42 (d, J=7.3 Hz,
1H), 6.57 (s, 1H), 5.91 (s, 1H), 3.75 (s, 3H); mass (CI
method): 208 (M++1), 176.
16. The methoxy-acrylate 13 was used by Palmisano et al. as
an intermediate in the synthesis of (−)-horsfiline. How-
ever, their 13C NMR had an extra peak at l 114.0. Thus,
we completed the synthesis of ( )-horsfiline 15 along the
lines reported by them to confirm our structure 13. Data
of compound 13: mp 109°C; IR (KBr, w cm−1): 1710,
1512, 1322, 1254; lH (200 MHz, CDCl3): 8.19 (d, J=9.1
Hz, 1H), 6.96 (dd, J=9.1, 2.7 Hz, 1H), 6.83 (d, J=2.7
Hz, 1H), 6.51 (s, 1H), 5.83 (s, 1H), 3.92 (s, 3H), 3.74 (s,
3H); lC (50 MHz, CDCl3): 165.12, 163.38, 140.42, 140.17,
133.45, 127.0, 126.57, 117.25, 113.40, 55.83, 52.00; mass
(CI method): 238 (M++1), 206.
17. Spectral data of synthetic ( )-coerulescine 8 (lit.14a): mp
110°C; IR (neat, w cm−1): 3210, 1710, 1619, 1471; lH (200
MHz, CDCl3): 8.57 (br s, 1H), 7.40 (d, J=7.3 Hz, 1H),
7.20 (t, J=7.5 Hz, 1H), 7.04 (t, J=7.3 Hz, 1H), 6.90 (d,
J=7.8 Hz, 1H), 2.89 (s, 2H), 3.10–2.70 (m, 2H), 2.47 (s,
3H), 2.50–2.00 (m, 2H); lC (50 MHz, CDCl3): 183.30,
140.48, 135.73, 127.47, 122.79, 122.35, 109.60, 65.77,
56.40, 53.50, 41.51, 37.59; mass (CI method): 203 (M++1).
Spectral data of synthetic ( )-horsfiline 15 (lit.13): mp
153°C; IR (neat, w cm−1): 1707, 1488, 1206, 1032; lH (400
MHz, CDCl3): 8.35 (br s, 1H), 7.07 (d, J=2.4 Hz, 1H),
6.80 (d, J=8.6 Hz, 1H), 6.73 (dd, J=8.6, 2.4 Hz, 1H),
3.81 (s, 3H), 3.11–3.06 (m, 1H), 2.96–2.79 (m, 3H), 2.51
(s, 3H), 2.46–2.09 (m, 2H); lC (50 MHz, CDCl3): 183.14,
156.00, 135.03, 133.76, 112.48, 110.06 (2C), 65.77, 56.51,
55.70, 54.08, 41.58, 37.85; mass (CI method): 233 (M++1).
12. We have observed some quantities of adducts in these
cases corresponding to the following structure, which are
formed by the Michael addition of compounds analogous
to 4 onto the 2-arylpropenoic acid esters 5.
13. Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.; Bodo,
B. J. Org. Chem. 1991, 56, 6527.
14. (a) Anderton, N.; Cockrum, A. P.; Colegate, S. M.;
Edgar, J. A.; Flower, K.; Vit, I.; Willing, R. I. Phyto-