A convenient method for the synthesis of 3,5,6-trisubstituted-2- chloropyridines with bis-(trichloromethyl) carbonate

Full text of DOI:10.1080/00304940903324531

Organic Preparations and Procedures International, 41:533–538, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940903324531
OPPI BRIEFS
A Convenient Method for the Synthesis
of 3,5,6-Trisubstituted-2-chloropyridines
with bis-(Trichloromethyl) Carbonate
Z. H. Li, B. Hong, 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 pyridine ring system is found in a large number of naturally occurring alkaloids
and synthetic products of biological interest.1–4 Therefore, continuing studies forward the
synthesis of pyridines are important in the field of drug design. As shown in Figure 1 , 3,5,6-
trisubstituted-2-chloropyridines have been extensively used as versatile building blocks for
the synthesis of many heterocyclic systems with potential biological activity.5,6
The Vilsmeier-Haack reaction has evolved into a powerful synthetic tool for the
construction of many important heterocyclic compounds such as quinolines,7 indoles,8
quinazolines,9 pyridines,10 etc. Typically the reactions of active methylene compounds
with Vilsmeier type reagents afford β-chloromethyleneiminium salts or β-chlorovinyl
aldehydes,11 which have been recognized as useful intermediates in heterocyclic syn-
thesis. Recently, Asokan and co-workers have reported a method for preparation of 2-
chloronicotinonitriles in three-component reactions under Vilsmeier conditions.12 However,
this approach still has room for improvement because of the use of phosphorus trichloride,
the long reaction time, and the unsatisfactory yields.
As a white stable solid, bis-(trichloromethyl) carbonate (BTC) has emerged as a ver-
satile readily handled and safer alternative for the synthesis of some important organic
compounds.13 In light of our recent success using this reagent,14–22 herein, we provide an
improved method for the preparation of 3,5,6-trisubstituted-2-chloropyridines from simple
enolizable ketones and aliphatic nitriles using BTC and DMF for the generation of the
Vilsmeier reagent (Scheme 1).
Exploratory experiments determined that the best ratio of acetophenone (1a) to
BTC/DMF in 1,2-dichloroethane should be 1:1:3. In comparison with the reported methods
Submitted February 2, 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: suweike@zjut.edu.cn
533

534
Li, Hong, and Su
Figure 1
Various applications of 3,5,6-Trisubstituted-2-chloropyridines
Scheme 1
using phosphorus oxychloride,12 our procedure has some advantages such as higher yields
and more environmentally friendly. A variety of 3,5,6-trisubstituted-2-chloropyridines
were obtained in relatively good yields (Table 1). Enolizable ketones bearing electron-
withdrawing groups (e. g. p-NO2C6H4) or electron-donating groups (e. g. p-CH3OC6H4)
proceeded in relatively lower yields. While enolizable ketones with neutral substituent
groups (e. g. p-CH3C6H4, p-ClC6H4) proceeded in good to excellent yields. The structures
were confirmed by 1H-NMR, IR, MS and elemental analysis23 and those of compounds 2m
and 2n were further confirmed by 13C NMR and MS (Table 2).
In summary, an improved method for preparation of 3,5,6-trisubstituted-2-
chloropyridines using BTC and DMF as Vilsmeier reagent has been developed.
Experimental Section
Melting points were obtained on a capillary melting point apparatus and are uncorrected.
1
Infrared spectra were recorded on a Thermo Nicolet Avatar 370 spectrophotometer. H

Synthesis of 3,5,6-Trisubstituted-2-chloropyridines
535
Table 1
Synthesis of 3,5,6-Trisubstituted-2-chloropyridines using BTC and DMF
Yield
Producta (%)
mp (◦C)
(lit. m.p.)
IR
(cm−1
1H NMR
)
(δ)
2a
72
110–112
(112–11412)
3040
2220
1580
7.31 (d, 1 H, J = 11.2 Hz,
PyH), 7.47–7.55 (m, 3 H,
ArH), 7.80 (d, 2 H, J = 8.4
Hz, ArH), 8.08 (d, 1 H, J =
11.6 Hz, PyH)
2b
2c
79
56
122–124
140–142
3113
2222
1617
2.44 (s, 3 H, CH3), 7.27–7.31
(m, 3 H, PyH, ArH), 7.70 (d,
2 H, J = 8.0 Hz, ArH), 8.07
(d, 1 H, J = 11.2 Hz, PyH)
3.90 (s, 3 H, OCH3), 6.98–7.01
(m, 2 H, ArH), 7.40 (d, 1 H,
J = 8.8 Hz, PyH), 7.47 (d, 1
H, J = 12.4 Hz, ArH), 7.79
(d, 1 H, J = 8.8 Hz, ArH),
8.06 (d, 1 H, J = 11.6 Hz,
PyH)
3129
2210
1642
2d
2e
68
62
140–141
132–134
3122
2228
1620
7.30 (s, 1 H, PyH), 7.43 (t, 1 H,
J = 8.0 Hz, ArH), 7.51 (d, 1
H, J = 8.4 Hz, ArH), 7.67 (d,
1 H, J = 8.0 Hz, ArH), 7.77
(m, 1 H, ArH), 8.05 (d, 1 H,
J = 11.2 Hz, PyH)
3126
2231
1617
7.30 (s, 1 H, PyH), 7.43 (t, 1 H,
J = 8.0 Hz, ArH), 7.52 (d, 1
H, J = 8.4 Hz, ArH), 7.67 (d,
1 H, J = 8.0 Hz, ArH), 7.77
(s, 1 H, ArH), 8.05 (d, 1 H,
J = 11.2 Hz, PyH)
2f
71
56
95–97
3127
2230
1574
7.18 (t, 1 H, J = 8.8 Hz, PyH),
7.24 (d, 2H, J = 12.4 Hz,
ArH), 7.80–7.84 (m, 2 H,
ArH), 8.05 (d, 1 H, J = 11.6
Hz, PyH)
7.23 (d, 1 H, J = 12.0 Hz,
PyH), 7.32 (d, 1 H, J = 12.0
Hz, ArH), 7.63 (d, 2 H, J =
8.8 Hz, ArH), 8.33 (s, 1 H,
PyH), 8.38 (d, 1 H, J = 9.2
Hz, ArH)
2g
122–124
3118
2224
1610
(Continued on next page)

536
Li, Hong, and Su
Table 1
Synthesis of 3,5,6-Trisubstituted-2-chloropyridines using BTC and DMF (Continued)
Yield
Producta (%)
mp (◦C)
(lit. m.p.)
IR
(cm−1
1H NMR
)
(δ)
2h
50
125–127
3121
2222
1613
7.36 (d, 1 H, J = 11.2 Hz,
PyH), 7.72 (d, 1 H, J = 7.6
Hz, ArH), 8.06–8.11 (m, 2 H,
ArH), 8.41 (d, 1 H, J = 8.4
Hz, PyH), 8.64 (s, 1 H, ArH)
2.52 (s, 3 H, CH3), 7.31–7.36
(m, 3 H, ArH), 7.38–7.52 (m,
3 H, PyH, ArH)
6.93 (d, 1 H, J = 11.6 Hz, CH
= CH), 7.00 (d, 1 H, J = 15.2
Hz, CH = CH), 7.40 (m, 3 H,
PyH, ArH), 7.47–7.52 (m, 3
H, ArH), 8.01 (d, 1
2ib
2j
58
60
100–102
244–246
3131
2224
1617
3133
2226
1617
H, J = 11.6 Hz, PyH)
2k
2l
63
73
240–242
124–126
3132
2230
1616
6.93 (d, 1 H, J = 11.6 Hz, CH
= CH), 7.00 (d, 1 H, J = 15.2
Hz, CH = CH), 7.40 (m, 3 H,
PyH, ArH), 7.47–7.52 (m, 2
H, ArH), 8.01
(d, 1 H, J = 11.6 Hz, PyH)
1.39 (t, 3 H, J = 6.8 Hz, CH3),
4.34–4.40 (m, 2 H, CH2),
7.32 (d, 1 H, J = 12.0 Hz,
PyH), 7.46–7.50 (m, 3 H,
ArH), 7.78–7.81 (m, 2 H,
ArH), 8.44 (d, 1 H, J = 11.6
Hz, PyH)
3129
1715
1598
2mb
2n
65
80
110–112
142–144
3128
2231
1618
2.52 (s, 3 H, CH3), 7.16 (d, 1 H,
J = 7.6 Hz, ArH), 7.30–7.43
(m, 3 H, ArH), 7.49 (d, 1 H, J
= 8.0 Hz, PyH)
3131
1724
1617
1.38 (t, 3 H, J = 7.2 Hz, CH3),
2.42 (s, 3 H, CH3), 4.34–4.39
(m, 2 H, CH2), 7.25–7.31 (m,
4 H, PyH, ArH), 7.70 (d, 1 H,
J = 8.4 Hz, ArH), 8.44
(d, 1 H, J = 11.6 Hz, PyH)
a) Yellow solids unless otherwise stated. b) White solid.

Synthesis of 3,5,6-Trisubstituted-2-chloropyridines
537
Table 2
Elemental Analysis for Compounds 2b–2n23
Elemental Analysis Calcd (Found)
Compound 2
C
H
N
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2ma
2nb
68.28(68.36)
63.81(63.94)
57.86(57.97)
57.86(57.95)
61.95(62.08)
55.51(55.40)
55.51(55.39)
68.28(68.11)
69.86(70.05)
61.12(61.25)
64.25(64.39)
59.34(59.18)
65.44(65.28)
3.97(3.92)
3.71(3.68)
2.43(2.41)
2.43(2.42)
2.60(2.58)
2.33(2.34)
2.33(2.30)
3.97(3.98)
3.77(3.74)
2.93(2.94)
4.62(4.62)
3.06(3.05)
5.12(5.11)
12.25(12.22)
11.45(11.42)
11.25(11.23)
11.25(11.26)
12.04(12.01)
16.18(16.20)
16.18(16.16)
12.25(12.21)
11.64(11.62)
10.18(10.16)
5.35(5.34)
10.65 (10.67)
5.08 (5.09)
a) MS(EI): m/z(%) 262 (M+, 15), 264 ([M + 2]+, 6), 266 ([M + 4]+, 2),192 (100);
13C NMR(CDCl3): δ 17.3, 112.4, 114.1, 128.2, 129.0, 129.7, 130.4, 130.7, 131.3, 135.3, 138.1,
149.6, 156.6. b) MS(EI): m/z(%) 275 (M+, 6), 277 ([M + 2]+, 2), 212 (100); 13C NMR(CDCl3): δ
14.1, 21.3, 61.5, 113.1, 119.3, 123.9, 127.4, 129.0, 129.7, 135.7, 139.7, 150.2, 155.2, 160.0, 162.0.
NMR spectra were measured on a Varian Mercur plus-400 spectrometer (400 MHz) in
CDCl3 using TMS as internal standard. 13C NMR spectra were determined in CDCl3 on
Varian Mercur plus-100 spectrometer (100 MHz) with TMS as internal standard. Mass
spectra were obtained on a Trace DSQ mass spectrometer (Table 1). Elemental analysis
was performed on a VarioEL-3 instrument. All chemicals were obtained from commercial
sources (Table 2).
General Procedure for the Preparation of 3,5,6-Trisubstituted-2-chloropyridines
The Vilsmeier type reagent was prepared by the slow addition of a solution of BTC (0.3 g,
1 mmol) in ClCH2CH2Cl (4 mL) to DMF (0.3 mL, 3 mmol) in ClCH2CH2Cl (4 mL) at 0◦C
followed by stirring at room temperature for 20 min. Then appropriate enolizable ketone
1 (1 mmol) was added. The resulting mixture was heated to 60◦C and maintained at that
temperature for 6 h, followed by addition of the nitrile (2 mmol) and heating reflux for 2 h.
After completion of the reaction, the mixture was poured into saturated NaHCO3 (50 mL),
and extracted with ethyl acetate (30 mL × 3). After evaporation of the organic solvent, the
residue was subjected to column chromatography on silica gel. Elutions with petroleum
ether/ethyl acetate = 20:1 afforded the pure products.
Acknowledgement
We are grateful to National Natural Science Foundation of China (No. 20876147) and
National Key Technology R&D Program 2007BAI34B02 for financial support.

538
Li, Hong, and Su
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