One-pot synthesis of heterocyclic β-chlorovinyl aldehydes using vilsmeier reagent

Article abstract of DOI:10.1021/jo9608432

3-Chloro-1H-indole-2-carboxaldehydes are obtained in moderate yields by the one-pot reaction of various substituted 2-[(carboxymethyl)amino]benzoic acids (1a-d) using Vilsmeier reagent (DMF/ POCl₃). The benzfused acyclic diacide analogous to 1a in which nitrogen was replaced by oxygen and sulfur also underwent the reaction smoothly. 3-Chloro-1H-pyrrole-2,4-dicarboxaldehyde was obtained as the only product by the reaction of N-carboxymethyl β-alanine.

Full text of DOI:10.1021/jo9608432

J . Org. Chem. 1996, 61, 6523-6525
6523
On e-P ot Syn th esis of Heter ocyclic â-Ch lor ovin yl Ald eh yd es Usin g
Vilsm eier Rea gen t
Vattoly J . Majo and Paramasivan T. Perumal*
Organic Chemistry Division, Central Leather Research Institute, Adyar, Madras-600 020, India
Received May 7, 1996X
3
-Chloro-1H-indole-2-carboxaldehydes are obtained in moderate yields by the one-pot reaction of
various substituted 2-[(carboxymethyl)amino]benzoic acids (1a -d ) using Vilsmeier reagent (DMF/
POCl ). The benzfused acyclic diacids analogous to 1a in which nitrogen was replaced by oxygen
3
and sulfur also underwent the reaction smoothly. 3-Chloro-1H-pyrrole-2,4-dicarboxaldehyde was
obtained as the only product by the reaction of N-carboxymethyl â-alanine.
1
â-Chlorovinyl aldehydes are versatile intermediates
in organic synthesis. There is a wealth of patent litera-
ture on the use of the 2-carboxaldehydes of five-
membered benzfused heterocycles in the preparation of
Sch em e 1
2
a
2b
lipoxygenase inhibitors, antitumor agents, psycho-
tropics,2 organoleptic agents, serotoninergic antagonist
pyrimidoindolone derivatives, and fungicides among
other drug classes.
c
2d
2
e
2f
Recently, we have been attempting to exploit the
cyclization potential of halomethyleniminium salts for
developing new strategies toward the synthesis of hetero-
entry
1, 2
X
R
1
2
3
4
5
6
a
b
c
d
e
f
NH
NH
NH
NH
O
H
CH3
Cl
Br
H
3
cyclic compounds. The halomethyleniminium salts which
are the intermediates involved in the Vilsmeier-Haack-
4
Arnold reaction are extensively used for formylation of
S
H
activated aromatic compounds and carbonyl compounds.
The Vilsmeier reagent also finds application in the
synthesis of large number of heterocyclic compounds.5
Herein, we wish to report a facile route for the one-pot
conversion of acyclic diacids to heterocyclic â-chlorovinyl
aldehydes, under Vilsmeier conditions.
A DMF solution of 2-[(carboxymethyl)amino]benzoic
acid (1a ) (5 mmol) was added dropwise with stirring at
0 °C to excess Vilsmeier reagent (6 equiv) previously
X
Abstract published in Advance ACS Abstracts, August 15, 1996.
(1) (a) Pulst, M.; Weissenfels, M. Z. Chem. 1976, 16, 337. (b) Barton,
prepared from DMF and POCl
3
.
The mixture was
D. H. R.; Dressaire, G.; Willis, B. J .; Barret, A. G. M.; Pfoffer, M. J .
Chem. Soc., Perkin Trans. 1 1982, 665. (c) Frejd, T.; Karlsson, J . O.;
Gronowitz, S. J . Org. Chem. 1981, 46, 3132. (d) Katritzky, A. R.;
Marson, C. M. J . Am. Chem. Soc. 1983, 105, 3279. (e) Aubert, T.;
Farnier, M.; Meunier, I.; Guilard, P. J . Chem. Soc., Perkin Trans. 1
gradually allowed to attain rt and refluxed for further 6
h at 90 °C on a water bath and cooled and neutralized
with crushed ice. The crude product was filtered and
chromatographed (petroleum ether:ethyl acetate 80:20)
to give 3-chloro-1H-indole-2-carboxaldehyde (2a ) in 75%
yield. The substituted 2-[(carboxymethyl)amino]benzoic
acids 1b-d also underwent the reaction smoothly (Scheme
1
(
5
989, 2095. (f) Guzman, A.; Romero, M. J . Org. Chem. 1990, 55, 5793.
g) Al-awar, R. S.; J oseph, S. P.; Comins, D. L. J . Org. Chem. 1993,
8, 7732.
2) (a) Brooks, D. W.; Horrom, B. W.; Rodriques, K. E.; Mazdiyasni
(
Eur. Pat. EP 436,199, 1991; Chem. Abstr. 1991, 115, 279483w. (b)
Nagai, T.; Myokan, I.; Keishi, F.; Ohta, K.; Taya, N.; Miyabara, S.;
Shibata, M.; Mikami, H.; Hori, T. Ger. Offen. DE 4,034,687, 1991;
Chem. Abstr. 1991, 115, 27992m. (c) Debaret, M.; Berthelot, P.;
Vaccher, C. Eur. Pat. EP 463,969, 1992; Chem. Abstr. 1992, 116,
1
).
As vinyl chloride has been identified to be the inter-
mediate leading to the formation of â-chlorovinyl alde-
1
94138h. (d) Winter, M.; Gautschi, F.; Flament, I.; Stoll, M.; Goldman,
6,1g
hyde in a few cases,
we pursued reaction conditions
I. M. US Pat. 3,989,713, 1976; Chem. Abstr. 1977, 86, 43556d. (e) Kato,
M.; Nishino, S.; Ito, K.; Takasugi, H. Eur. Pat. EP 420,086, 1991; Chem.
Abstr. 1991, 115, 71637s. (f) Bhandari, K.; Murti, V. A.; J ain, P. C.;
Anand, N. Indian J . Chem. Sect. B. 1979, 17B, 246.
that would likely favor the formation of vinyl chloride
group but prevent its subsequent formylation. But not
even traces of vinyl chloride were isolated under mild
conditions. Also when a methyl group was introduced
on the carbon adjacent to the heteroatom of 2a , 2b, and
(3) (a) Balasundaram, B.; Venugopal, M.; Perumal, P. T. Tetrahedron
Lett. 1993, 34, 4249. (b) Venugopal, M.; Perumal, P. T. Synth.
Commun. 1991, 21, 515. (c) Venugopal, M.; Umarani, R.; Perumal, P.
T.; Rajadurai, S. Tetrahedron Lett. 1991, 32, 3235.
2
c, the cyclization reaction was completely prevented.
(
4) (a) For a recent review see Marson, C. M. Tetrahedron 1992,
8, 3659-3726. (b) J utz, C. In Advances in Organic Chemistry; Taylor,
E. C., Ed.; J ohn Wiley & Sons: New York, 1976; Vol. 9, pp 225-342.
4
Neither the formation of vinyl chloride nor that of
â-chlorovinyl aldehyde could be detected by GC-MS
analysis of the reaction mixture. When the reaction was
performed on 1a at rt using excess Vilsmeier reagent for
(
c) Seshadri, S. J . Sci. Ind. Res. 1973, 32, 128-149. (d) Burn, D. Chem.
Ind. (London) 1973, 870. (e) Church, R.; Trust, R.; Albright, J . D.;
Powell, D. W. J . Org. Chem. 1995, 60, 3750.
(5) (a) Meth-Cohn, O.; Tarnowski, B. Adv. Heterocycl. Chem. 1982,
3
1, 207-236. (b) Meth-Cohn, O. Heterocycles 1993, 35, 539. (c) Meth-
Cohn, O.; Taylor, D. L. Tetrahedron Lett. 1993, 34, 3629. (d) J ackson,
A.; Meth-Cohn, O. J . Chem. Soc., Chem. Commun. 1995, 1319. (e)
Meth-Cohn, O.; Taylor, D. L. J . Chem. Soc., Chem. Commun. 1995,
(6) (a) Brown, P. E.; Marcus, W. Y.; Anastasis, P. J . Chem. Soc.,
Perkin Trans. 1 1985, 1127. (b) Vinyl chlorides were obtained as the
only products under mild conditions in some cases. See Mewshaw, R.
E. Tetrahedron Lett. 1989, 30, 3753.
1
463. (f) Megati, S.; Rao, K. G. S. Tetrahedron Lett. 1995, 36, 5819.
S0022-3263(96)00843-2 CCC: $12.00 © 1996 American Chemical Society

6
524 J . Org. Chem., Vol. 61, No. 19, 1996
Majo and Perumal
Ta ble 1. Syn th esis of â-Ch lor ovin yl Ald eh yd es fr om Dia cid s Usin g Vilsm eier Rea gen t
entry
product
method
mp, °C (lit.)
yield (%)
1
2
3
4
5
6
7
8
3-chloro-1H-indole-2-carboxaldehyde (2a )
3-chloro-5-methyl-1H-indole-2-carboxaldehyde (2b)
3,5-dichloro-1H-indole-2-carboxaldehyde (2c)
5-bromo-3-chloro-1H-indole-2-carboxaldehyde (2d )
3-chlorobenzofuran-2-carboxaldehyde (2e)
3-chlorobenzo[b]thiophene-2-carboxaldehyde (2f)
3-chloroindole-1,2-dicarboxaldehyde (3)
A
B
A
B
A
A
172 (172-3)11
175
192
75
45
70
61
21
51
53
30
210
73 (75)9a
103 (110)9b
123
a
A
b
3-chloro-1H-pyrrole-2,4-dicarboxaldehyde (8)
B
150
a
Stirred for 1 h at rt and neutralized. b Crude product was extracted with CHCl3 (3 × 50 mL).
Sch em e 2
chlorovinyl aldehydes make use of the corresponding
heterocyclic precursors as the starting material. But
8
indoxyls which are unsubstituted at nitrogen are un-
stable and rapidly undergo aerobic oxidative dimerization
to indigo.9 Therefore 3-chloro-1H-indole-2-carboxalde-
1
0
hydes were previously prepared by the reaction of
N-protected indoxyls followed by the removal of protect-
ing group from the product. Since indoxyls are generated
in situ in our reaction and are rapidly converted to the
products, the need for handling unstable indoxyls is
avoided.
In analogy to the synthesis of indole series, the reaction
was successfully extended for the synthesis of other
benzfused heterocycles such as 3-chlorobenzofuran-2-
carboxaldehyde (2e) and 3-chlorobenzo[b]thiophene-2-
carboxaldehyde (2f) (Scheme 1). When Vilsmeier-Haack
reaction was performed on N-carboxymethyl â-alanine
7
, the only product that could be isolated was 3-chloro-
1
H-pyrrole-2,4-dicarboxaldehyde (8) in 30% yield. This
implies that benzfusion is not an essential factor for the
cyclization of diacids. The results are summarized in
Table 1.
2
h, 3-chloroindole-1,2-dicarboxaldehyde (3) was obtained
as the major product in 53% yield along with traces of
a . This indicates that 3 is a likely intermediate involved
2
in the formation of 2a .
Exp er im en ta l Section
Melting points were measured in capillary tubes and are
uncorrected. Analytical thin layer chromatography was per-
formed on precoated sheets of silica gel with 0.25 mm thickness
containing PF 254 indicator (Merck, Darmstadt). Column
chromatography was performed with silica gel (60-120 mesh;
SD fine, Boisar).
N-Carboxymethyl â-alanine11 was prepared following the
literature procedure. 2-(Carboxymethoxy)benzoic acid and
Although it is premature to propose a detailed mech-
anism at this stage, based on the above results a
plausible mechanism can be proposed (Scheme 2).7 The
formylation and decarboxylation of the dicarboxylic acid
2
-[(carboxymethyl)thio]benzoic acid were prepared from sali-
cylic acid and thiosalicylic acid, respectively, on treatment with
an alkaline solution of chloroacetic acid. The substituted
2
-[(carboxymethyl)amino]benzoic acids were prepared by the
1
a along with subsequent intramolecular cyclization
1
2
treatment of corresponding substituted anthranilic acids with
chloroacetic acid in alkaline medium.
gives the intermediate 4 which is then readily converted
to the chloro derivative 5. The hydrolysis of 5 yields the
diformylated product 3. However, under vigorous reac-
tion conditions 5 is deformylated to 6 which on hydrolysis
yields 2a . The present study is the first of its kind where
a carbonyl group is generated in situ under Vilsmeier
conditions by the ortho-interactions of two COOH groups.
The in situ generation of carbonyl group has an ad-
ditional advantage in the synthesis of indole-2-carbox-
aldehydes. The previous syntheses of heterocyclic â-
Syn t h esis of Het er ocyclic â-Ch lor ovin yl Ald eh yd es.
Gen er a l P r oced u r e A. The Vilsmeier reagent was prepared
(8) (a) Anmo, Y.; Tsuruta, Y.; Ito, S.; Noda, K. Yakugaku. Zasshi.
1963, 83, 807; Chem. Abstr. 1963, 59, 15239b. (b) Ricci, A.; Balucani,
D.; Buu-Hoi, N. P. J . Chem. Soc. (C) 1967, 779. (c) Ghaisas, V. V.;
Kane, B. J .; Nord, F. F. J . Org. Chem. 1958, 23, 560.
(
9) (a) J ulian, P. L.; Meyer, E. W.; Printy, H. C. In Heterocyclic
Compounds; Elderfield, R. C., Ed.; J ohn Wiley & Sons: New York,
952; Vol. 3, p 195. (b) Sundberg, R. J . The Chemistry of Indoles;
Academic Press: New York, 1970; p 365.
10) Velezheva, V. S.; Smushkevich, V. Yu.; Romanova, O. B.;
1
(
(
7) Aldoketene is proposed to be the intermediate involved in the
Kurkovskaya, L. N.; Suvorov, N. N. Zh. Org. Khim. 1986, 22, 2434.
(11) McKinney, L. L.; Setzkorn, E. A.; Uhing, E. H. J . Am. Chem.
Soc. 1952, 74, 1942.
formation of vinamidinium salts from the Vilsmeier reaction of RCH
COOH. For the mechanism see Reichardt, C.; Hallbritter, K. Leibigs.
Ann. Chem. 1970, 737, 99.
2
-
(12) Dunn, G. E.; Prysiazniuk, R. Can. J . Chem. 1961, 39, 285.

Synthesis of Heterocyclic â-chlorovinyl Aldehydes
J . Org. Chem., Vol. 61, No. 19, 1996 6525
+
by the dropwise addition of POCl
DMF (5 mL) under constant stirring. The dicarboxylic acid
5 mmol) was dissolved in 5 mL of DMF and added dropwise
to the Vilsmeier reagent. The reaction mixture was gradually
allowed to attain rt, stirred for further 30 min, refluxed on a
water bath maintained at 60-80 °C for 4-6 h. After the
completion of the reaction, the reaction mixture was cooled
and neutralized with crushed ice. The filtration and column
chromatography of the crude product afforded the cyclized
products in given yields.
3
(2.8 mL, 30 mmol) to cooled
Hz); MS m/e (rel intensity) 259 (M , 100), 230 (12), 203 (12),
150 (19), 123 (13), 114 (13), 87 (11), 44 (63); IR (KBr) 3269,
-
1
(
1657 cm . Anal. Calcd for C
N, 5.42. Found: C, 42.06; H, 2.06; N, 5.83.
-Ch lor ob en zofu r a n -2-ca r b oxa ld eh yd e (2e). General
procedure A was applied to 2-(carboxymethoxy)benzoic acid
9 5
H BrClNO: C, 41.81; H, 1.95;
3
1
(
1e) (5 mmol, 0.91 g) to afford 2e in 21% yield: mp 73 °C; H
NMR (300 MHz, CDCl ) δ 10.04 (s, 1H), 6.93-6.80 (m, 4H);
MS m/e (rel intensity) 180 (M , 100), 152 (15), 123 (37), 89
71), 63 (23), 39 (11); IR (KBr) 1680 cm . Anal. Calcd for
ClO : C, 59.85; H, 2.80. Found: C, 60.03; H, 2.91.
-Ch lor ob en zo[b]t h iop h en e-2-ca r b oxa ld eh yd e (2f).
3
+
-1
(
Gen er a l P r oced u r e B. The dicarboxylic acid (5 mmol) was
dissolved in 10 mL of DMF, and the solution was cooled to 0
C
9
H
5
2
3
°C. POCl
3
(2.8 mL, 30 mmol) was added dropwise with stirring
General procedure A was applied to 2-[(carboxymethyl)thio]-
benzoic acid (1f) (5 mmol, 1.06 g). The crude product was
over a period of 10 min. The reaction mixture was allowed to
attain rt and refluxed for further 4-6 h at 80-90 °C. After
the completion of the reaction, the reaction mixture was cooled
and neutralized with saturated aq NaOAc solution. The crude
product was filtered and chromatographed to afford the
products in requisite yields.
chromatographed (60:40 petroleum ether:ethyl acetate) to
1
afford 2f in 51% yield: mp 103 °C; H NMR (300 MHz, CDCl
3
+
DMSO) δ 10.35 (s, 1H), 8.04-7.51 (m, 1H), 7.89-7.87 (m,
+
1
1
1
2
H), 7.62-7.51 (m, 2H); MS m/e (rel intensity) 196 (M , 100),
68 (24), 132 (16), 123 (14), 89 (22), 69 (8), 44 (19); IR (KBr)
3
-Ch lor o-1H-in dole-2-car boxaldeh yde (2a). General pro-
cedure A was applied to 2-[(carboxymethyl)amino]benzoic acid
a (5 mmol, 0.975 g). The crude product was chromatographed
80:20 petroleum ether:ethyl acetate) to afford pale yellow
-1
216, 1664 cm . Anal. Calcd for C
.57. Found: C, 55.32; H, 2.78.
-Ch lor oin d ole-1,2-d ica r boxa ld eh yd e (3). 2-[(Carboxy-
methyl)amino]benzoic acid (1a ) (5 mmol, 0.975 g) dissolved in
.5 mL of DMF was added dropwise to the cooled solution of
previously prepared Vilsmeier reagent as in procedure A. The
solution was gradually allowed to attain rt and stirred for
further 1 h. The reaction mixture was neutralized by the
addition of crushed ice. The crude product was chromato-
graphed (80:20 petroleum ether:ethyl acetate) to afford yellow
9 5
H ClOS: C, 54.97; H,
1
3
(
1
needles of 2a in 75% yield: mp 172 °C; H NMR (300 MHz,
CDCl ) δ 11.83 (br s, 1H), 10.05 (s, 1H), 7.68 (t, 1H, J ) 4.1
Hz), 7.49 (d, 1H, J ) 8.4 Hz), 7.37 (t, 1H, J ) 7.7 Hz), 7.18 (t,
6
3
+
1
H, J ) 7.5 Hz); MS m/e (rel intensity) 179 (M , 100), 150
(23), 129 (29), 89 (25), 63 (12), 39 (5); IR (KBr) 1654, 2849,
-
1
3
291 cm . Anal. Calcd for C
.80. Found: C, 60.54; H, 3.48; N, 8.06.
-Ch lor o-5-m eth yl-1H-in d ole-2-ca r boxa ld eh yd e (2b).
General procedure B was applied to 2-[(carboxymethyl)amino]-
-methylbenzoic acid (1b) (5 mmol, 1.045 g). The crude
9 6
H ClNO: C, 60.18; H, 3.37; N,
7
1
needles of 3 in 53% yield: mp 123 °C; H NMR (300 MHz,
3
CDCl
3
) δ 10.21 (s, 1H), 10.20 (s, 1H), 8.54 (d, 1H, J ) 8.5 Hz),
.78 (d, 1H, J ) 8.0 Hz), 7.67-7.62 (m, 1H), 7.49-7.44 (m,
H); 13C NMR (75 MHz, CDCl
) δ 180.25, 160.62, 136.12,
31.75, 130.34, 129.28, 126.24, 125.74, 120.64, 117.55; MS m/e
7
1
1
5
3
product was chromatographed (40:60 petroleum ether:ethyl
acetate) to afford red crystals of 2b in 45% yield: mp 175 °C;
+
(
rel intensity) 207 (M , 9), 179 (100), 150 (18), 123 (28), 89
1
H NMR (300 MHz, CDCl
3
) δ 10.02 (s, 1H), 9.19 (br s, 1H),
); MS m/e (rel
intensity) 193 (M , 100), 164 (32), 158 (22), 137 (11), 128 (12),
02 (20), 77 (17), 51 (15), 39 (5); IR (KBr) 1661, 3281 cm-1
Anal. Calcd for C10 ClNO: C, 62.02; H, 4.17; N, 7.24.
Found: C, 62.47; H, 4.24; N, 7.08.
,5-Dich lor o-1H-in d ole-2-ca r boxa ld eh yd e (2c). General
-
1
(
48), 63 (22), 39 (17); IR (KBr) 1675, 1723 cm . Anal. Calcd
ClNO : C, 57.88; H, 2.92; N, 6.75. Found: C, 58.13;
H, 3.06; N, 6.46.
-Ch lor o-1H-p yr r ole-2,4-d ica r boxa ld eh yd e (8). Gen-
eral procedure B was applied to N-(carboxymethyl) â-alanine
7) (5 mmol, 0.735 g). The crude product was extracted with
CHCl
(3 × 50 mL), organic layer was washed with brine and
dried over Na SO , and solvent was evaporated and column
chromatographed (20:80 petroleum ether:ethyl acetate) to
7
.50 (s, 1H), 7.32-7.23 (m, 2H), 2.46 (s, 3H, CH
3
for C10
H
6
2
+
1
.
3
H
8
(
3
3
procedure A was applied to 5-chloro-2-[(carboxymethyl)amino]-
benzoic acid (1c) (5 mmol, 1.145 g). The crude product was
chromatographed (40:60 petroleum ether:ethyl acetate) to
2
4
1
1
afford 8 in 30% yield: mp 150 °C; H NMR (300 MHz, CDCl
3
afford 2c in 70% yield: mp 192 °C; H NMR (300 MHz, DMSO)
+
DMSO) δ 12.45 (br s, 1H), 9.31 (s, 1H), 9.18 (s, 1H), 7.10 (s,
δ 12.34 (br s, 1H), 10.00 (s, 1H), 7.71 (s, 1H), 7.50-7.35 (m,
13
+
1H); C NMR (75 MHz, CDCl
3
+ DMSO) δ 183.48, 177.45,
2
1
1
2
H), MS m/e (rel intensity) 213 (M , 100), 184 (16), 157 (24),
+
1
30.31, 128.82, 122.40; MS m/e (rel intensity) 156 (M , 100),
50 (22), 123 (33), 114 (13), 87 (17), 73 (11), 40 (13); IR (KBr)
-
1
-
1
128 (20), 100 (62), 73 (60), 37 (51); IR (KBr) 3248, 1663 cm .
662, 3281 cm . Anal. Calcd for C
.36; N, 6.55. Found: C, 50.82; H, 2.40; N, 6.43.
-Br om o-3-ch lor o-1H -in d ole-2-ca r b oxa ld eh yd e (2d ).
General procedure B was applied to 5-bromo-3-chloro-2-
(carboxymethyl)amino]benzoic acid (1d ) (5 mmol, 1.345 g).
9 5 2
H Cl NO: C, 50.50; H,
Anal. Calcd for C
Found: C, 46.07; H, 2.87; N, 8.63.
6 4 2
H ClNO : C, 45.73; H, 2.56; N, 8.89.
5
[
Ack n ow led gm en t. V.J .M. is grateful to CSIR, New
Delhi, for a fellowship. We are grateful to R. Radhakrish-
nan for recording mass spectra.
The crude product was chromatographed (20:80 petroleum
1
ether:ethyl acetate) to afford 2d in 61% yield: mp 210 °C; H
NMR (300 MHz, DMSO) δ 12.20 (br s, 1H), 9.99 (s, 1H), 7.68
(d, 1H, J ) 8.2 Hz), 7.48-7.42 (m, 1H), 7.23 (d, 1H, J ) 7.2
J O9608432