Large-scale solvent-free chlorination of hydroxy-pyrimidines,-pyridines,- pyrazines and-amides using equimolar POCl3

Article abstract of DOI:10.3390/molecules17044533

Chlorination with equimolar POCl₃ can be efficiently achieved not only for hydroxypyrimidines, but also for many other substrates such as 2-hydroxy-pyridines,-quinoxalines, or even-amides. The procedure is solvent-free and involves heating in a sealed reactor at high temperatures using one equivalent of pyridine as base. It is suitable for large scale (multigram) batch preparations.

Full text of DOI:10.3390/molecules17044533

Molecules 2012, 17, 4533-4544; doi:10.3390/molecules17044533
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Large-Scale Solvent-Free Chlorination of Hydroxy-Pyrimidines,
-Pyridines, -Pyrazines and -Amides Using Equimolar POCl3
Han Wang 1,2, Kun Wen 2, Le Wang 2, Ye Xiang 2, Xiaocheng Xu 2, Yongjia Shen 1,* and
Zhihua Sun 2,*
1
School of Chemistry and Molecular Engineering, East China University of Science and Technology,
Shanghai, 200237, China
2
College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science,
Shanghai, 201620, China
* Authors to whom correspondence should be addressed; E-Mails: yjshen@ecust.edu.cn (Y.S.);
zhihuasun@sues.edu.cn (Z.S.); Tel./Fax: +86-21-6779-1432 (Z.S.).
Received: 7 March 2012; in revised form: 31 March 2012 / Accepted: 6 April 2012 /
Published: 16 April 2012
Abstract: Chlorination with equimolar POCl3 can be efficiently achieved not only for
hydroxypyrimidines, but also for many other substrates such as 2-hydroxy-pyridines,
-quinoxalines, or even -amides. The procedure is solvent-free and involves heating in a
sealed reactor at high temperatures using one equivalent of pyridine as base. It is suitable
for large scale (multigram) batch preparations.
Keywords: solvent-free; chlorination; phosphorous oxychloride (POCl3)
1. Introduction
The reaction of hydroxypyrimidines with phosphorous oxychloride (POCl3) is a simple procedure
known for over 100 years and used widely in preparing chlorinated pyrimidine final products or
intermediates for further transformations [1–3]. Over the years, the experimental conditions used for
such chlorination reactions have changed little, and generally involve heating a hydroxy-containing
substrate in excess POCl3 to reflux in the presence of an organic base. While such a protocol may be
adequate for small scale synthesis in a research laboratory, it becomes an environmental burden to deal
with the excess POCl3 in large scale preparations. Furthermore, even the process of quenching excess
POCl3 in large scale needs safety attention due to the potential for latent exothermic events [4].

Molecules 2012, 17
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Therefore, improvements in reducing the amount of POCl3 used in large scale chlorination procedures
would be welcomed for economic, environmental, and safety considerations [5,6].
We recently reported a protocol for large scale (milligram to kilogram batches) chlorination of
hydroxypyrimidines using equimolar or less POCl3 with heating in a sealed reactor under solvent-free
or low solvent conditions [7]. Our procedure has simple work up steps involving filtration or
distillation, and generally gives high yields and purity of final products. Except one, the examples used
in our original report are essentially all pyrimidine derivatives (single or fused ring systems). In this
report, we sought to expand the scope of our original study by applying our procedure to a wider range
of starting materials to probe the potential for generalization of this solvent-free protocol.
2. Results and Discussion
Because our previous report only covered four examples of single-ring hydroxypyrimidines, we
tested six more pyrimidines here with mono-chloro, bromo, methyl, or amino substitution at various
positions. All the reactions were carried out at a scale of 0.3 moles (~30–60 g of pyrimidine starting
materials) with equimolar POCl3 per OH group and one equivalent of pyridine as base. The reactions
were performed in sealed reactors for 2 hours as before, but at 160 °C instead of the 180 °C used in our
original procedure. Despite the slightly lower reaction temperature, all trials gave satisfactory results
(>80% isolated yields), as summarized in Table 1.
Table 1. Chlorination of hydroxypyrimidines at 0.3 mole scale.
X
1:1 POCl3 per OH
Y
1 eq pyridine
N
N
R
R
160 °C, 2 h
N
OH
N
Cl
X = H or OH
Y = H or Cl
Entry Starting Material
Scale
Product
Yield
Lit. Yield (Scale, Time)
Cl
OH
Br
Br
N
N
1
57 g
38 g
91%
88%
89%
88% (10 g, 1.7 hours) [8]
N
OH
N
Cl
Cl
1a
1b
OH
N
N
2
3
4
92% (252 g, 20 hours) [9]
69% (25 g, 3 hours) [10]
27% (10 g, 10 hours) [11]
70% (10 g, 3 hours) [12]
N
Cl
N
OH
2b
2a
OH
Cl
Cl
Cl
N
N
44 g
38 g
N
OH
OH
N
Cl
Cl
Cl
3a
4a
3b
4b
OH
N
N
85%
95%
H2N
N
H2N
N
Cl
OH
N
N
5
6
38 g
33 g
N
OH
5a
N
N
Cl
Cl
5b
6b
N
N
83% 59% (alternative reaction) [13]
H2N
OH
H2N
N
6a

Molecules 2012, 17
4535
In these trials, liquid final products were isolated by distillation after extraction (entries 1–3,5) and
solid products (entries 4 and 6) were isolated by filtration after quenching the reaction with cold water.
For comparison with literature reported results, we sought to compare our results with those with
similar reaction scales and using POCl3 as reagent. As shown in Table 1, our protocol produced
comparable results to others (entries 1 and 2) and sometimes better yields than reported cases.
Given the safety concerns of quenching large scale POCl3 as studied in a recent report [4], we also
investigated the event of quenching in our protocol. After the completion of reaction, due to the
efficiency of our protocol and the fact that no excess of POCl3 was used, we expect that quenching of
the reaction mixture will not involve hydrolysis of significant amount of POCl3 itself. Therefore, no
significant exotherm was of concern upon initial quenching of the reaction. Instead, we believe that
quenching of species such as phosphorodichloridic acid as a possible end product was the major event [4].
This was supported by the low and delayed heat release during the first hour of quenching of a large
scale reaction with cold water (see Figure 1), by which time the desired product was already separated
from the quenching solution. In the particular example shown in Figure 1, 1.4 mole of POCl3 was used
in the reaction and the final reaction mixture was quenched with 500 mL of cold water. This quenching
ratio was smaller than the quenching process detailed in a report by Amgen scientists [4], yet the
temperature raise was also lower in our case. Therefore, any delayed heat release due to the hydrolysis
of phosphorodichloridic acid and alike could be safely handled aside without significantly affecting the
isolation of the desired products.
Figure 1. Temperature change after quenching a 100-gram scale reaction.
Product
isolation
at 30 min
Next, our attention was turned to chlorination of pyridine derivatives. We used seven
2-hydroxypyridines and one quinolone. It was interesting to discover that the reactions could be
efficiently carried out at an even lower temperature of 140 °C. Furthermore, no additional pyridine was
needed for reactions involving 2-hydroxypyridines, as all the pyridine starting materials can effectively
act as base. For the reaction with quinolone, 0.6 equivalents of pyridine were added. The reaction
scales and yields were summarized in Table 2.

Molecules 2012, 17
4536
Table 2. Chlorination of 2-hydroxypydridines at 0.5 mole scale.
1:1 POCl3 per OH
R
R
140 °C, 2 h
N
OH
N
Cl
Entry Starting Material Scale
Product
Yield
Lit. Yield (Scale, Time)
Br
Br
Br
1
2
3
87 g
127 g
70 g
95%
92%
93%
49–83% * [14,15]
66% * [16]
N
N
Cl
Br
7b
8b
9b
N
N
OH
Br
7a
8a
9a
Br
Cl
OH
OH
O2N
O2N
66%, 89% (12 g, 3 hours)
[17,18]
N
N
Cl
Br
N
Br
N
4
87 g
91%
52% * [19]
Cl
Br
10b
11b
OH
Br
10a
5
6
7
8
87 g
94 g
90%
91%
93%
88%
65% * [20]
N
Cl
N
OH
11a
Br
Br
48–50% * [21,22]
N
Cl
N
OH
12b
12a
13a
Br
NO2
Br
NO2
109 g
81 g
65% (3.1 g, overnight) [23]
94% (2 g, 24 hours) [24]
N
Cl
13b
14b
N
OH
Cl
N
OH
N
Cl
OH
14a
*: alternative reactions.
All reactions for pyridines were performed at 0.5 moles scale, with 70–126 g of hydroxyl pyridine
or quinoline starting materials. All trials for the pyridine substrates gave 90% or more isolated yields.
Except for entry 4 in Table 2 where the product was isolated by distillation after extraction with ethyl
acetate, all other products were solids and were isolated using filtration after quenching the reaction
with cold water and adjusting pH to 8–9. For pyridine analogous, few reported examples used POCl3
for chlorination. For those that did, our method is comparable or better (entries 3 and 7, Table 2).
Compared to reported synthesis using alternative protocols, our method is generally better in terms of
isolated yields. Entry 8 of Table 2 also showed an interesting case of good atom economy. There were
two OH groups in the quinolone, and only 0.5 equivalent of POCl3 per OH was used. Yet, the isolated
yield was very good at 88% for the dichloro product, indicating that each POCl3 provided more than
one chlorine atom to form the final product. This result is consistent with findings in our original
report that in some cases even substoichiometric amount of POCl3 was sufficient to produce
respectable results using our solvent-free protocol [7].
The third class of starting materials we used were benzopyrazines (quinoxalines) or pyridopyrazine.
Four different starting materials with either one or two hydroxyl groups were tested using our protocol
at 0.3 moles scale. In those cases, high yield conversion required conditions similar to that of the

Molecules 2012, 17
4537
pyrimidine cases, with one equivalent POCl3 per OH group, one equivalent of pyridine, and heating
at 160 °C for 2 hours. The results were summarized in Table 3. All final products were isolated by
filtration after quenching the reactions.
Table 3. Chlorination of hydroxyl benzopyrazions and pyridopyrazine (0.3 mole scale).
1:1 POCl3 per OH
N
X
N
Y
1 eq pyridine
R
R
160 °C, 2 h
A
N
OH
A
N
Cl
X = H or OH
A = C or N
Y = H or Cl
A = C or N
Entry Starting Material Scale
Product
Yield Lit. Yield (Scale, Time)
N
N
56% (60 g, 2 hours) [25]
94%
1
2
3
4
44 g
49 g
54 g
73 g
88% (15 g, 0.7 hour) [26]
N
N
OH
OH
15a
16a
Cl 15b
N
N
Cl
96% 93% (64 g, 4 hours) [27]
86% 40% (164 g, 0.5 hour) [28]
94% 5% (6 g, 1.5 hours) [29]
N
OH
N
Cl 16b
Cl
N
Cl
N
N
N
N
OH
Cl
17a
18a
17b
Br
N
Cl
Br
OH
N
N
Cl
18b
N
N
OH
Given the excellent results of chlorination for the above three classes of aromatic starting materials,
we thought about the possibility of using the same procedure of chlorination to convert a normal amide
to an imidoylchloride, but imidoylchlorides are generally not stable enough for aqueous workup and
purification. Therefore, we choose to test three examples where the imidoylchloride is either stable or
can be further transformed during the reaction to another stable compound (Scheme 1). The first
example was the conversion of N-trifluoroacetylaniline to the corresponding imidoylchloride, which
can be isolated. The conversion achieved 83% isolated yield after 4 hours of reaction. However, unlike
previous cases of product isolation through either distillation of filtration, the imidoylchloride needs to
be purified by silica gel chromatography. In literature reporting synthesis of the same compound, an
alternative method was used and a 66% yield was achieved [30]. Similarly, two 2,5-piperazinediones
(dimeric condensation product from α-amino acids) were treated using the same protocol for 2 hours
and were converted to the corresponding pyrazines instead of imidoylchlorides in 72–76% yields after
purification by silica gel chromatography. Again, these results compare favourably with literature
reported results of 25% and 41% for the two dichloropyrazines [31,32].

Molecules 2012, 17
4538
Scheme 1. Chlorination of amides at 0.3 mole scale.
3. Experimental
3.1. General
All reactions were carried out in Teflon-lined stainless steel reactors. Analytical HPLC-MS (6130
Single Quandrupole LC/MS system, Aglilent, Santa Clara, CA, USA) was performed using a C18
reverse phase column (5 μm, 4.6 × 250 mm) with aqueous TFA and CH3CN gradients monitored at
230 nm for purity and detected with electrospray ionization (ESI) single quadruple mass spectrometer
(6130 Single Quandrupole LC/MS system, Aglilent, Santa Clara, CA, USA) for MS. NMR was
1
13
recorded at 400 MHz for H and 100 MHz for C. All known compounds were positively identified
with MS and satisfactory changes in 1H or 13C-NMR (ARX400, Bruker, Fällanden, Switzerland) from
starting materials. Melting points (mp) were determined with a WRS-1B digital melting-point
apparatus (Shanghai, China).
3.2. Procedures for Chlorination of Pyrimidines, Benzo- and Pyrido-pyrazines, and Amides
To a 150 mL Teflon-lined stainless steel reactor was added the hydroxyl-containing substrate
(0.3 moles), POCl3 (0.3 or 0.6 moles, 1 equivalent POCl3 per reactive OH or amide group), and
pyridine (0.3 moles). After closing the reactor, the reaction mixture was heated to 160 °C for 2 hours
(4 hours for trifluoroacetylaniline). After cooling, the reactor was carefully opened, and the contents
were quenched with cold water (~0 °C, 100 mL), and the solution’s pH was adjusted to 8–9 with
saturated Na2CO3 solution. For liquid sample, it was extracted with ethyl acetate, dried, removed
solvent, and then distilled. Solid products were collected after filtration, and washing with a small
amount of methyl t-butyl ether, and dried. Amide substrates that gave either imidoylchloride or
pyrazine were extracted with 100 mL ethyl acetate, dried, and purified on a silica gel column after
solvent removal.
3.3. Pyrimidine Products
2,4-Dichloro-5-bromopyrimidine (1b). Obtained from 2,4-dihydroxy-5-bromopyrimidine (57.3 g),
POCl3 (54 mL), and pyridine (24.3 mL) after distillation (110–112 °C/760 mm Hg). Yield: 61.9 g,
1
90.5%; Purity: 98%; H-NMR (CDCl3, δ, ppm): 8.69 (s, 1H). 13C-NMR (CDCl3, δ, ppm): 161.6;
161.4; 158.9; 118.8. MS (ESI, m/z): 226.9.

Molecules 2012, 17
4539
2,4-Dichloro-5-methylpyrimidine (2b). Obtained from 2,4-dihydroxy-5-methylpyrimidine (37.8 g),
POCl3 (54 mL), and pyridine (24.3 mL) after distillation (114–116 °C/1 mm Hg). Yield: 43.0 g, 88%;
1
13
Purity: 98%; H-NMR (CDCl3, δ, ppm):8.36 (s, 1H), 2.30(d, J = 0.4 Hz, 3H); C-NMR (CDCl3, δ,
ppm):162.3, 160.0, 157.9, 129.0, 15.7; MS (ESI, m/z): 163.1.
2,4,5-Trichloropyrimidine (3b). Obtained from 2,4-dihydroxy-5-chloropyrimidine (44.1 g), POCl3 (54 mL)
and pyridine (24.3 mL) after distillation (94–96 °C/12 mm Hg). Yield: 48.9 g, 89%; Purity: 96%;
13
1H-NMR (CDCl3, δ, ppm):8.59 (s, 1H); C-NMR (CDCl3, δ, ppm): 159.9, 158.7, 157.9, 129.2; MS
(ESI, m/z): 183.0.
2,4-Dichloro-6-aminopyrimidine (4b). Obtained from 6-amino-2,4-dihydroxypyrimidine (38 g), POCl3
(54 mL) and pyridine (24.3 mL) after filtration. Yield: 41.8 g, 85%; Purity: 97%; m.p.: 253–254 °C;
1H-NMR (DMSO, δ, ppm): 7.75 (d, br, J = 32 Hz, 2H), 6.45(s, 1H); 13C-NMR (DMSO, δ, ppm):
166.4, 159.4, 158.4, 102.2; MS (ESI, m/z): 164.1.
2,4-Dichloro-6-methylpyrimidine (5b). Obtained from 2,4-dihydroxy-6-methylpyrimidine (37.8 g),
POCl3 (54 mL) and pyridine (24.3 mL) after distillation (98–100 °C/1 mm Hg). Yield: 41.8 g, 85%;
Purity: 98%; m.p.: 46–47 °C; 1H-NMR (CDCl3, δ, ppm): 7.19 (d, J = 2.8 Hz, 1H), 2.54(d, J = 4.4 Hz,
3H); 13C-NMR (CDCl3, δ, ppm): 171.8, 162.3, 160.4, 119.4, 23.8; MS (ESI, m/z): 163.1.
2-Chloro-6-aminopyrimidine (6b). Obtained from 6-amino-2-hydroxypyrimidine (33 g), POCl3 (27 mL)
and pyridine (24.3 mL) after filtration. Yield: 31.0 g, 83%; Purity: 97%; m.p.: 205–207 °C;
1H-NMR (CDCl3, δ, ppm): 7.94 (d, J = 6 Hz, 1H), 7.39 (s, br, 2H), 6.39 (d, J = 5.6 Hz, 1H); 13C-NMR
(CDCl3, δ, ppm): 165.7, 160.3, 157.2, 104.5; MS (ESI, m/z): 130.1.
3.4. Quinoxaline and Pyridopyrazine Products
2-Chloroquinoxaline (15b). Obtained from 2-hydroxyquinoxaline (43.8 g), POCl3 (27 mL) and
pyridine (24.3 mL) after filtration. Yield: 48.5 g, 94%; Purity: 98%; m.p.: 48–50 °C; 1H-NMR (CDCl3,
13
δ, ppm): 8.78 (s, 1H), 8.07 (m, 1H), 7.97 (m, 1H), 7.75 (m, 2H); C-NMR (CDCl3, δ, ppm): 147.3,
144.9, 141.9, 140.9, 131.1, 130.1, 129.3, 128.5; MS (ESI, m/z): 165.1.
2,3-Chloroquinoxaline (16b). Obtained from 2,3-dihydroxyquinoxaline (48.6 g), POCl3 (54 mL) and
1
pyridine (24.3 mL) after filtration. Yield: 57.3 g, 96%; Purity: 97%; m.p.: 148–150 °C; H-NMR
(CDCl3, δ, ppm): 8.04 (m, 2H), 7.82 (m, 2H); 13C-NMR (CDCl3, δ, ppm): 145.4, 140.6, 131.2, 128.2;
MS (ESI, m/z): 200.1.
2,6-Chloroquinoxaline (17b). Obtained from 2-hydroxy-6-chloroquinoxaline (54.2 g), POCl3 (27 mL)
1
and pyridine (24.3 mL) after filtration. Yield: 51.4 g, 86%; Purity: 98%; m.p.: 156–158 °C; H-NMR
(CDCl3, δ, ppm): 8.04 (m, 2H), 7.82 (m, 2H); 13C-NMR (CDCl3, δ, ppm): 145.4, 140.6, 131.2, 128.2;
MS (ESI, m/z): 199.0.
7-Bromo-2,3-dichloropyrido[2,3-b]pyrazine (18b). Obtained from 2,3-dihydroxy-7-bromo pyrido[2,3-
b]pyrazine (73.0 g), POCl3 (54 mL) and pyridine (24.3 mL) after filtration. Yield: 79.0 g, 94%; Purity:

Molecules 2012, 17
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98%; m.p.: 138–140 °C; 1H-NMR (CDCl3, δ, ppm): 9.17 (d, J = 2.4 Hz, 1H), 8.57 (d, J = 2.4 Hz, 1H);
13C-NMR (CDCl3, δ, ppm): 156.1, 149.0, 147.8, 147.2, 138.6, 136.2, 122.4; MS (ESI, m/z): 277.9.
3.5. Imidoylchloride and Pyrazine Products
N-Phenyltrifluoroacetimidoyl chloride. Obtained as an oil from trifluoroacetyl aniline (56.7 g), POCl3
(27 mL) and mL pyridine (24.3) after silica gel chromatography (eluent: petroleum ether/ethyl acetate
1
20:1). Yield: 51.7 g, 83%; Purity: 98%; H-NMR (CDCl3, δ, ppm): 7.48 (m, 2H), 7.34 (m, 1H), 7.13
13
(d, J = 8 Hz, 2H); C-NMR (CDCl3, δ, ppm): 143.5, 131.9, 129.1 (2C), 127.4, 120.7 (2C), 117.5;
19F-NMR (CDCl3, δ, ppm): −71.6; MS (ESI, m/z): 208.1.
2,5-Dichloro-3,6-dimethylpyrazine. Obtained as a white solid from 3,6-dimethylpiperazine-2,5-dione
(42.6 g), POCl3 (54 mL) and pyridine (24.3 mL) after silica gel chromatography (eluent: petroleum
ether/ethyl acetate 10:1). Yield: 38.2 g, 72%; Purity: 98%; m.p.: 63–65 °C; 1H-NMR (CDCl3, δ, ppm):
2.60 (s, 6H); 13C-NMR (CDCl3, δ, ppm): 149.8 (2C), 145.6 (2C), 29.7, 21.3; MS (ESI, m/z): 177.1.
2,5-Dichloro-3,6-dibenzylpyrazine. Obtained as a white solid from 3,6-dibenzylpiperazine-2,5-dione
(88.2 g), POCl3 (54 mL) and pyridine (24.3 mL) after silica gel chromatography (eluent: petroleum
1
ether/ethyl acetate 15:1). Yield: 74.0 g, 76%; Purity: 98%; m.p.: 109–111 °C; H-NMR (CDCl3, δ,
ppm): 7.29 (m, 10H), 4.27 (s, 4H); 13C-NMR (CDCl3, δ, ppm): 152.1, 145.8, 136.4, 129.1, 128.6,
127.0, 40.4; MS (ESI, m/z): 330.1.
3.6. Procedures for Chlorination of 2-Hydroxypyridines and 2,4-Dihydroxyquinoline
To a 150 mL Teflon-lined stainless steel reactor was added the hydroxy-containing substrate
(0.5 moles) and POCl3 (0.5 moles; for quinoline starting material, 0.3 mole of pyridine was also used).
After closing the reactor, the reaction mixture was heated to 140 °C for 2 hours. After cooling, the
reactor was carefully opened, and the content was quenched with 100 mL cold water (~0 °C), and the
solution’s pH was adjusted to 8–9 with saturated Na2CO3 solution. The solid product was precipitated
out and collected after filtration, washed with a small amount of methyl t-butyl ether, and dried. For
liquid sample, it was extracted with ethyl acetate, dried, removed solvent, and then distilled.
2-Chloro-5-bromopyridine (7b). Obtained from 2-hydroxy-5-bromopyridine (87.0 g) and POCl3
1
(45 mL) after filtration. Yield: 91.0 g, 95%; Purity: 97%; m.p.: 69–71 °C; H-NMR (CDCl3, δ, ppm):
13
8.48 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 2.4 Hz, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H); C-NMR
(CDCl3, δ, ppm): 150.7, 150.1, 141.2, 125.6, 119.1; MS (ESI, m/z): 192.0.
2-Chloro-3,5-dibromopyridine (8b). Obtained from 2-hydroxy-3,5-dibromopyridine (126.5 g) and
POCl3 (45 mL) after filtration. Yield: 124.7 g, 92%; Purity: 97%; m.p.: 41–43 °C; 1H-NMR (CDCl3, δ,
ppm): 8.38 (d, J = 2.4 Hz, 1H), 8.06 (t, J = 2 Hz, 1H); 13C-NMR (CDCl3, δ, ppm): 149.6, 148.8, 144.0,
120.8, 118.7; MS (ESI, m/z): 269.9.
2-Chloro-5-nitropyridine (9b). Obtained from 2-hydroxy-5-nitropyridine (70.0 g) and POCl3 (45 mL)
after filtration. Yield: 73.5 g, 93%; Purity: 98%; m.p.: 109–111 °C; 1H-NMR (CDCl3, δ, ppm): 9.25 (d,

Molecules 2012, 17
4541
J = 2.8 Hz, 1H), 8.47 (dd, J = 2.8 Hz, J = 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H); 13C-NMR (CDCl3, δ,
ppm): 157.1, 145.4, 143.4, 133.6, 124.8; MS (ESI, m/z): 159.1.
2-Chloro-4-bromopyridine (10b). Obtained from 2-hydroxy-4-bromopyridine (87.0 g) and POCl3 (45
mL) after distillation (108–110 °C/0.5 mm Hg). Yield: 87.0 g, 91%; Purity: 98%; 1H-NMR (CDCl3, δ,
ppm): 8.21 (d, J = 5.6 Hz, 1H), 7.51 (d, J = 5.6 Hz, 1H), 7.38 (dd, J = 1.6 Hz, J = 5.2 Hz, 1H);
13C-NMR (CDCl3, δ, ppm): 147.4, 145.3, 129.4, 122.6, 121.1; MS (ESI, m/z): 192.0.
2-Chloro-3-bromopyridine (11b). Obtained from 2-hydroxy-3-bromopyridine (87.0 g) and POCl3
1
(45 mL) after filtration. Yield: 86.0 g, 90%; Purity: 96%; m.p.: 54–56 °C; H-NMR (CDCl3, δ, ppm):
8.35 (td, J = 1.2 Hz, J = 8 Hz, 1H), 7.95 (dd, J = 1.2 Hz, J = 8 Hz, 1H), 7.14 (dd, J = 8 Hz, J = 4.4 Hz,
1H); 13C-NMR (CDCl3, δ, ppm): 150.9, 147.9, 142.2, 123.3, 120.4; MS (ESI, m/z): 192.0.
2-Chloro-4-methyl-5-bromopyridine (12b). Obtained from 2-hydroxy-4-methyl-5-bromopyridine (94.0 g)
1
and POCl3 (45 mL) after filtration. Yield: 94.0 g, 91%; Purity: 97%; m.p.: 115–117 °C; H-NMR
(CDCl3, δ, ppm): 8.43 (dd, J = 14 Hz, J = 7.2 Hz, 1H), 7.23 (td, J = 6.4 Hz, 1H), 2.39 (dd,
J = 6.4 Hz, J = 12 Hz, 3H); 13C-NMR (CDCl3, δ, ppm): 150.8, 150.8, 150.2, 149.9, 126.0, 122.0; MS
(ESI, m/z): 206.0.
2-Chloro-3-nitro-5-bromopyridine (13b). Obtained from 2-hydroxy-3-nitro-5-bromopyridine (109.0 g)
1
and POCl3 (45 mL) after filtration. Yield: 110.0 g, 93%; Purity: 97.5%; m.p.: 67–68 °C; H-NMR
13
(CDCl3, δ, ppm): 8.71 (d, J = 2 Hz, J = 7.2 Hz, 1H), 8.38 (d, J = 2 Hz, 1H); C-NMR (CDCl3, δ,
ppm): 153.4, 144.6, 142.1, 136.5, 118.8; MS (ESI, m/z): 239.1.
2,4-Dichloroquinoline (14b). Obtained from 2,4-dihydroxyquinoline (81.0 g), POCl3 (45 mL) and
1
pyridine (24.3 mL) after filtration. Yield: 79.0 g, 88%; Purity: 97%; m.p.: 188–190 °C; H-NMR
(CDCl3, δ, ppm): 8.15 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.78 (td, J = 7.2 Hz, J = 1.2 Hz,
1H), 7.63 (td, J = 7.2 Hz, J = 1.2 Hz, 1H), 7.47 (d, J = 2 Hz, 1H); 13C-NMR (CDCl3, δ, ppm): 149.8,
148.1, 144.3, 131.5, 129.0, 127.8, 125.1, 124.1, 121.9; MS (ESI, m/z): 198.1.
4. Conclusions
A variety of hydroxylated nitrogen-containing heterocycles as well as amides can be efficiently
chlorinated using equimolar POCl3 in a sealed reactor for just 2 hours at 140–160 °C using pyridine as
a base. It seems that the protocol is broadly applicable to many substrates and works equally well
or better in terms of yield, less reagent, and shorter reaction time than conventional protocols that
involve heating to reflux in POCl3. It is quite suitable for large scale preparation of the relevant
chlorinated products.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/17/4/4533/s1.

Molecules 2012, 17
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Acknowledgments
Financial support of this work was provided by Shanghai Saijia Chemicals Ltd., funding of
Shanghai University of Engineering Science (2011XZ02,2011Q11), and the Special Scientific
Foundation for Outstanding Young Teachers in Shanghai Higher Education Institutions (shgcjs023),
Shanghai, China.
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Sample Availability: Electronic Supplementary Information (ESI) available: NMR spectra (1H, 13C,
and 19F when applicable) of all compounds are available from the authors.
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