A practical and efficient vilsmeier synthesis of 3-chloroindole-2- carboxaldehydes

Full text of DOI:10.1080/00304948.2010.514793

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A Practical and Efficient Vilsmeier
Synthesis of 3-Chloroindole-2-
carboxaldehydes
Z. H. Li a , Z. R. Hu a , R. E. Chen a & W. K. Su a
a Key Laboratory of Pharmaceutical Engineering of Ministry of
Education, College of Pharmaceutical Sciences, Zhejiang University
of Technology, Hangzhou, P. R. China
Version of record first published: 01 Oct 2010.
To cite this article: Z. H. Li , Z. R. Hu , R. E. Chen & W. K. Su (2010): A Practical and Efficient
Vilsmeier Synthesis of 3-Chloroindole-2-carboxaldehydes, Organic Preparations and Procedures
International: The New Journal for Organic Synthesis, 42:5, 479-484
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Organic Preparations and Procedures International, 42:479–484, 2010
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304948.2010.514793
OPPI BRIEFS
A Practical and Efficient Vilsmeier Synthesis
of 3-Chloroindole-2-carboxaldehydes
Z. H. Li, Z. R. Hu, R. E. Chen, and W. K. Su
Key Laboratory of Pharmaceutical Engineering of Ministry of Education,
College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou, P. R. China
The indole ring is regarded as a priviledged structural moiety in many naturally oc-
curring alkaloids1 or synthetic drugs.2 In particular, 3-chloroindole-2-carboxaldehyde
derivatives display important pharmacological properties such as anti-HIV3, antitumor4
and anticancer activities.5 Recently, some important papers have been published on the
synthesis and functionalization of indoles.6–8 Although the Vilsmeier cyclization of 2-
[(carboxymethyl)amino]benzoic acids 1 has provided an effective and more convenient
approach for the construction of indole derivatives without any metal catalysts, it suffers
the disadvantages of low efficiency with some substrates and unsatisfactory yields.9 Herein,
we disclose an efficient and practical process for the improved synthesis of 3-chloroindole-
2-carboxaldehydes 2 from readily accessible 2-[(carboxymethyl)amino]benzoic acids 1
(Scheme 1).
Initially, 2-[(carboxymethyl)amino]benzoic acid (1a) was used as a representative
substrate to examine the best reaction conditions. Treatment of 1a with the Vilsmeier
reagent (6.0 equiv.) prepared from DMF and bis-(trichloromethyl) carbonate (BTC) at
75◦C proceeded smoothly in 1,2-dichloroethane as indicated by TLC and furnished only
one product after work-up and purification by column chromatography. The product was
1
characterized as 3-chloroindole-2-carboxaldehyde (2a, Scheme 1) by its H NMR, 13C
NMR and MS data. Based on our previous studies10 and encouraged by these results, the
reaction conditions including solvent, temperature and the ratio of 1a to DMF/BTC were
investigated. In order to avoid the use of 1,2-dichloroethane, much effort was made to select
a suitable solvent. To our delight, it was found that 2-methyltetrahydrofuran (2-MeTHF)
was the better choice than 1,2-dichloroethane, toluene, CH3CN and THF. As an eco-friendly
Submitted December 4, 2009.
Address correspondence to W. K. Su, Key Laboratory of Pharmaceutical Engineering of
Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou 310014, P. R. China. E-mail: pharmlab@zjut.edu.cn
479

480
Su et al.
R1
R1
Cl
R2
R3
R2
R3
CO2H
BTC/DMF
2-MeTHF
CHO
N
N
H
CO2H
H
R4
R4
2a-l
1a-l
a) R1 = R2 = R3 = R4 = H; b) R1 = R3 = R4 = H, R2 = Cl; c) R1 = R3 = R4 = H,
R2 = Br; d) R1 = R3 = R4 = H, R2 = CH3; e) R1 = R2 = R3 = H, R4 = Cl; f)
R1 = R3 = R4 = H, R2 = NO2; g) R1 = R3 = H, R2 = R4 = Br; h) R1 = R3 = H,
R2 = R4 = CH3; i) R1 = R3 = H, R2 = CH3, R4 = Br; j) R1 = R2 = R4 = H, R3 =
F; k) R1 = R4 = H, R2 = R3 = Cl; l) R1 = R2 = Cl, R3 = R4 = H
Scheme 1
solvent, 2-MeTHF derived from renewable sources can be efficiently recovered according
to a known procedure11 and the reaction afforded in high yields. A series of experiments
revealed that the optimal results were obtained when the reaction of 1a was performed with
5.0 equiv. of BTC/DMF in 2-MeTHF at 80◦C for 4 h, whereby the reaction afforded 2a
exclusively in 84% yield (Table 1).
To explore the effect of the substituents on the phenyl ring in the reaction of
2-[(carboxymethyl)amino]benzoic acids 1 with BTC/DMF, a series of substrates with
diverse electronic properties were then investigated. As illustrated in Table 1, var-
ious 3-chloroindole-2-carboxaldehydes 2 were obtained from the corresponding 2-
[(carboxymethyl)amino]benzoic acids 1. Generally, the results demonstrated that the reac-
tivity of substrates with an electron-withdrawing group (especially at the 5,7-position) is
much higher than those with an electron-donating substituent. The structures of the known
compounds were confirmed by comparison of their mps. with literature mps. and spec-
tral data (IR, 1H-NMR). The new products were fully characterized by IR, mass spectra,
1H-NMR, 13C NMR (Table 2) and elemental analysis (Table 3).
Based on these results and a previous report,9 a plausible mechanism can be proposed
(Scheme 2). First, the cyclization of the dicarboxylic acid 1a promoted by one equiv. of
halomethyleniminium salt gave intermediate B. This is followed by the formylation of B
to provide adduct C, which then undergoes intramolecular attack along with elimination
of carbon dioxide to afford intermediate E. F was then readily formed by chlorination
of E.
In summary, a highly efficient and practical method for the synthesis of the substituted
3-chloroindole-2-carboxaldehydes in an eco-friendly solvent has been developed. Studies
on the extension of this protocol are currently on-going in our laboratories.
Experimental Section
2-[(Carboxymethyl)amino]benzoic acid (1a) was prepared using the literature procedure.12
The substituted 2-[(carboxymethyl)amino]benzoic acids (except 1f) were prepared by
the treatment of corresponding substituted anthranilic acids with chloroacetic acid
in alkaline medium.13 Substituted anthranilic acids were prepared from substituted

Synthesis of 3-Chloroindole-2-carboxaldehydes
481
Table 1
Synthesis of Indoles 2a–l using BTC /DMF
Producta Yield Time mp (◦C)
IR
1H NMR (δ)
(%)
(h)
(lit. mp) (cm−1
)
2a
84
4
171–172 1653 1H NMR (CDCl3) δ: 10.06 (s, 1 H, CHO),
(1729)
3290
3443
9.05 (br s, 1 H, NH), 7.75–7.77 (m, 1 H,
PhH), 7.41–7.47 (m, 2 H, PhH),
7.23–7.27 (m, 1 H, PhH)
2bb
88
86
82
3
3
4
192–193 1654 1H NMR (DMSO–d6) δ: 12.49 (br s, 1 H,
(1939)
3280
3415
NH), 10.01 (s, 1 H, CHO), 7.74 (s, 1 H,
PhH), 7.51 (d, 1 H, J = 8.8 Hz, PhH),
7.43 (dd, 1 H, J1 = 2.0 Hz, J2 = 8.8 Hz,
PhH)
2c
208–209 1653 1H NMR (DMSO-d6) δ: 12.51 (br s, 1 H,
(2109)
3265
3452
NH), 10.01 (s, 1 H, CHO), 7.88 (d, 1 H,
J = 1.6 Hz, PhH), 7.56 (dd, 1 H, J1 =
2.0 Hz, J2 = 8.8 Hz, PhH), 7.45 (d, 1 H,
J = 8.8 Hz, PhH)
2d
175–176 1646 1H NMR (CDCl3) δ: 10.03 (s, 1 H, CHO),
(1759)
3287
3454
8.98 (br s, 1 H, NH), 7.52 (s, 1 H, PhH),
7.31 (d, 1 H, J = 8.4 Hz, PhH), 7.27
(d, 1 H, J = 7.2 Hz, PhH), 2.47 (s, 3 H,
CH3)
2eb
2f
87
92
3
3
168–169 1676 1H NMR (CDCl3) δ: 10.08 (s, 1 H, CHO),
3299
3448
9.04 (br s, 1 H, NH), 7.66–7.69 (m, 1 H,
PhH), 7.45 (dd, 1 H, J1 = 0.8 Hz, J2 =
7.6 Hz, PhH), 7.17–7.25 (m, 1 H, PhH)
242–245 1654 1H NMR (DMSO-d6) δ: 12.96 (br s, 1 H,
3263
3448
NH), 10.07 (s, 1 H, CHO), 8.59 (s, 1 H,
PhH), 8.24 (d, 1 H, J = 9.2 Hz, PhH),
7.65 (d, 1 H, J = 9.2 Hz, PhH)
2gb
2h
2ib
2j
90
80
85
88
3
5
4
3
232–234 1636 1H NMR (400 MHz, DMSO-d6) δ: 12.81
3453
(br s, 1 H, NH), 10.06 (s, 1 H, CHO),
7.90 (s, 1 H, PhH), 7.86 (s, 1 H, PhH)
202–203 1667 1H NMR (CDCl3) δ: 10.02 (s, 1 H, CHO),
3319
3451
8.87 (br s, 1 H, NH), 7.36 (s, 1 H, PhH),
7.07 (s, 1 H, PhH), 2.46 (t, 6 H, 2 CH3)
216–217 1657 1H NMR (CDCl3) δ: 10.05 (s, 1 H, CHO),
3302
3455
8.88 (br s, 1 H, NH), 7.47 (s, 1 H, PhH),
7.45 (s, 1 H, PhH), 2.46 (s, 3 H, CH3)
196–198 1656 1H NMR (CDCl3) δ: 10.00 (s, 1 H, CHO),
3280
3442
9.37 (br s, 1 H, NH), 7.71 (dd, 1 H, J1 =
5.2 Hz, J2 = 8.8 Hz, PhH), 7.00–7.14
(m, 2 H, PhH)
(Continued on next page)

482
Su et al.
Table 1
Synthesis of Indoles 2a–l using BTC/DMF (Continued)
Producta Yield Time mp (◦C)
IR
(lit. mp) (cm−1
)
1H NMR (δ)
(%)
(h)
2k
2l
91
3
252–253 1654 1H NMR (DMSO-d6) δ: 12.59 (br s, 1 H,
3290
3445
NH), 10.01 (s, 1 H, CHO), 7.98 (s, 1 H,
PhH), 7.69 (s, 1 H, PhH)
89
3
248–249 1654 1H NMR (400 MHz, DMSO-d6) δ: 12.81
3290
3445
(br s, 1 H, NH), 10.03 (s, 1 H, CHO),
7.56 (d, 1H, J = 8.8 Hz, PhH), 7.46
(d, 1 H, J = 8.8 Hz, PhH)
a) Yellow solids unless otherwise stated. b) Red solid.
anilines.14–16 2-(Carboxymethylamino)-5-nitrobenzoic acid (1f) was prepared from
2-chloro-4-nitrobenzoic acid.17 1H NMR and 13C NMR spectra were recorded on a Var-
ian 400 MHz instrument in CDCl3 or DMSO-d6 as the solvent, and chemical shifts are
expressed in δ using TMS as internal standard. Mass spectra were measured on a Trace
Finnigan DSQ. Elemental analyses were performed on a VarioEL-3 instrument. Infrared
spectra were determined on a Thermo Nicolet Avatar 370 spectrophotometer. Melting points
were obtained on a capillary melting point apparatus and are uncorrected.
O
O
NH
-H+
H
O
Me2N=CHCl
NMe2
OH
O
O
OH
-HCONMe2
O
N
H
O
N
H
O
O
1a
A
B
O
O
O
O
O
O
-CO2
NMe2
Me2N=CHCl
O
NMe2
N
N
N
NMe2
Me2N CH
NMe2
Me2N
CH
HC
C
D
E
Cl
Cl
Me2N=CHCl
H2O
CH=NMe2
NMe2
CHO
N
3-4 h, 75-80 o
C
N
H
HC
F
2a
Scheme 2

Synthesis of 3-Chloroindole-2-carboxaldehydes
483
Table 2
13C NMR and Mass Spectra for Compounds 2e-l
Product
13C NMR
MS (EI)
2e
13C NMR (CDCl3): 179.9, 133.5, 130.7, m/z (%) = 213 (100), 184 (18), 157
127.3, 126.7, 122.4, 119.2, 118.1,
117.8
(12), 123 (11), 114 (14), 87 (6)
2f
13C NMR (DMSO-d6): 180.9, 142.2,
138.8, 133.3, 123.7, 121.9, 117.0,
116.0, 114.6
m/z (%) = 224 (100), 194 (13), 178
(30), 168 (4), 123 (21), 114 (22),
87 (8)
2g
2h
2i
13C NMR (DMSO-d6): 181.1, 133.8,
132.1, 131.8, 127.0, 121.2, 113.6,
112.6, 107.2
m/z (%) = 337 (100), 308 (81), 281
(6), 230 (5)
13C NMR (CDCl3): 180.0, 134.7, 131.7, m/z (%) = 207 (100), 192 (34), 178
130.9, 130.1, 125.4, 121.7, 117.1, 21.4, (18), 115 (10)
16.2
13C NMR (CDCl3): 179.7, 133.4, 132.9, m/z (%) = 273 (100), 244 (5), 192
132.3, 130.7, 126.5, 119.0, 117.2,
105.5, 21.2
(38), 164 (11), 128 (12)
2j
13C NMR (CDCl3): 179.6, 164.6, 162.2, m/z (%) = 197 (100), 168 (24), 141
122.3, 122.2, 112.1, 111.8, 98.7, 98.5
13C NMR (DMSO-d6): 180.6, 134.9,
132.1, 129.9, 124.5, 124.1, 120.8,
114.9, 113.2
(15), 132 (11), 84 (15)
2k
m/z (%) = 247 (100), 218 (13), 184
(22), 157 (17), 148 (9), 121 (6)
2l
13C NMR (DMSO-d6): 181.0, 136.0,
132.3, 128.5, 125.0, 123.5, 121.3,
114.1, 113.0
m/z (%) = 247 (100), 220 (18), 184
(20), 157 (15), 148 (12), 121 (4)
Table 3
Elemental Analysis for Compounds 2e-l
Elemental Analysis Found (Calcd)
Cmpd 2
C
H
N
2e
2f
2g
2h
2i
2j
2k
2l
50.42 (50.50)
48.06 (48.13)
32.11 (32.04)
63.58 (63.62)
44.03 (44.07)
54.66 (54.71)
43.56 (43.50)
43.52 (43.50)
2.39 (2.35)
2.28 (2.24)
1.14 (1.19)
4.91 (4.85)
2.55 (2.59)
2.50 (2.55)
1.69 (1.62)
1.67 (1.62)
6.49 (6.54)
12.44 (12.47)
4.09 (4.15)
6.69 (6.75)
5.18 (5.14)
7.14 (7.09)
5.58 (5.64)
5.59 (5.64)

484
Su et al.
Typical Procedure for the Preparation of 3-Chloroindole-2-carboxaldehydes
The Vilsmeier reagent was prepared by adding a solution of BTC (2.97 g, 10 mmol) in
2-MeTHF (10 mL) to a solution of DMF (3 mL, 30 mmol) in 2-MeTHF (25 mL) immersed
in an ice-water bath under constant stirring, then the ice-water bath was removed. The
temperature was raised to 25◦C and was stirred for an additional 20 min, followed by the
addition of 2-[(carboxymethyl)amino]benzoic acid (1a, 6 mmol) to the Vilsmeier reagent.
The reaction mixture was maintained at 25◦C and stirred for further 20 min, then heated to
reflux for 4 h at 80◦C. After completion of the reaction, the reaction mixture was cooled and
poured into ice-water and was extracted by 2-MeTHF (3 × 30 mL). The combined organic
phase was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered
and the solvent was recovered under reduced pressure. The crude product was purified by
flash silica gel chromatography (petroleum ether/ethyl acetate 4:1 v/v) to give pure 2a as a
yellow solid.
Acknowledgement
We are grateful to National Key Technology R&D Program 2007BAI34B00 and the Natural
Science Foundation of Zhejiang province (No. 202095) and the Natural Science Foundation
of China (No. 20876147) and the Opening Foundation of Zhejing Provincial Top Key
Pharmaceutical Discipline for financial help.
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