An improved method for chlorination of nitrogen-containing π-deficient heteroaromatics using triphenylphosphine and trichloroisocyanuric acid

Article abstract of DOI:10.3987/COM-04-10245

Phosphorus compound prepared by reaction of triphenylphosphine with trichloroisocyanuric acid was found to be applied to chlorination of nitrogen-containing π-deficient heteroaromatics. As self-decomposition of the chlorinating reagent hardly proceeds, the reagent is more useful than phosphorus compound prepared by triphenylphosphine and N-chlorosuccinimide.

Full text of DOI:10.3987/COM-04-10245

HETEROCYCLES, Vol. 65, No. 1, 2005
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HETEROCYCLES, Vol. 65, No. 1, 2005, pp. 181 - 185
Received, 8th October, 2004, Accepted, 17th November, 2004, Published online, 19th November, 2004
AN
IMPROVED
METHOD
FOR
CHLORINATION
OF
NITROGEN-CONTAINING
π-DEFICIENT
HETEROAROMATICS
USING TRIPHENYLPHOSPHINE AND TRICHLOROISOCYANURIC
ACID
Osamu Sugimoto* and Ken-ichi Tanji*
Laboratory of Organic Chemistry, School of Food and Nutritional Sciences,
University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan
osamu@smail.u-shizuoka-ken.ac.jp; tanji@smail.u-shizuoka-ken.ac.jp
Abstract – Phosphorus compound prepared by reaction of triphenylphosphine
with trichloroisocyanuric acid was found to be applied to chlorination of
nitrogen-containing π-deficient heteroaromatics. As self-decomposition of the
chlorinating reagent hardly proceeds, the reagent is more useful than phosphorus
compound prepared by triphenylphosphine and N-chlorosuccinimide.
Since many nitrogen-containing π-deficient heteroaromatics (abbreviated as heteroaromatics) have
biological activities, derivatives of these compounds have been prepared in order to find more available
lead-compounds. Chloroheteroaromatics are a versatile synthetic precursor to synthesize derivatives of
2
the heteroaromatics: Chloroheteroaromatics react with nucleophiles such as carbanions,1 amines,
alkoxides,3 or thiols4 to introduce nucleophilic substituents into the heteroaromatic moiety. Metalation of
chloroheteroaromatics via tellurium-lithium exchange5-8 or oxidative addition of magnesium9,10 provides
electrophilic substituents into the heteroaromatic moiety.
Chloroheteroaromatics are synthesized by the reaction of hydroxyheteroaromatics with phosphoryl
chloride,11 phosphorus pentachloride, 12 or N-chlorosuccinimide / triphenylphosphine (1).13,14 Although
phosphoryl chloride or phosphorus pentachloride has been used for the chlorination of
hydroxyheteroaromatics for more than 100 years, addition of water to the reaction mixture at the work-up
process results in evolution of hydrochloric acid and heat from the exothermic reaction. The use of 1 as a
chlorinating reagent is of greater advantage than the use of phosphoryl chloride or phosphorus
pentachloride from the reaction due to its inertness to water. However, the black byproduct derived from

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HETEROCYCLES, Vol. 65, No. 1, 2005
decomposition of 1 interferes with the purification of chloroheteroaromatics. In this paper we wish to
report an improved chlorination of hydroxyheteroaromatics.
It is reported that chlorinating reagent (2), prepared by the reaction of triphenylphosphine with
trichloroisocyanuric acid (Scheme 1), reacts with alcohol to afford alkyl chloride.15
Scheme 1 Chlorinating reagent (2) generated from triphenylphosphine and trichloroisocyanuric acid
O-
O
OPPh3Cl
N
Cl
Cl
O
solvent
rt
N
N
N
N
N
3 PPh3
+
-O
3
N
O-
+PPh3Cl
O
N
ClPh3PO
N
OPPh3Cl
Cl
2
So we applied 2 to the chlorination of 2(1H)-quinolinone as shown in Table 1. When an equimolecular
amount of 2 was used and heated to reflux in toluene for 2 h, 2-chloroquinoline was obtained in 50%
yield (entry 1). Elongation of the reaction time gave an analogous result (entry 2), and xylene (bp 137-140
°C) was used as a solvent instead of toluene (bp 109 °C). However, the yield of 2-chloroquinoline was
slightly lowered (entry 3). On the other hand, when two equivalents of 2 was used, the yield of
2-chloroquinoline was improved (entry 4).
Table 1 Optimization for chlorination of 2(1H)-quinolinone using 2
2, solvent, reflux
N
O
N
Cl
H
entry
amount of 2 (eq.)
solvent
toluene
toluene
xylene
condition
reflux, 2 h
reflux, 8 h
reflux, 8 h
reflux, 4 h
yield (%)
1
2
3
4
1
1
1
2
50
53
38
73
toluene
Next, chlorination of fused
diazinones
(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one,
2(1H)-quinoxalinone, 4(3H)-quinazolinone) and fused diazinedione (2,4(1H,3H)-quinazolinedione) using
two equivalents of 2 was carried out (Table 2).
A mixture of 1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 2 in toluene was heated to reflux for
4 h and 8 h, and 4-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine was obtained in 61% and 65% yields,

HETEROCYCLES, Vol. 65, No. 1, 2005
183
respectively (entries 1,2). Differences in the yield of 4-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine
were not observed between the reaction times, 4 h and 8 h.
Both 2(1H)-quinoxalinone and 4(3H)-quinazolinone were chlorinated using two equivalents of 2 to afford
2-chloroquinoxaline and 4-chloroquinazoline in good yields (entries 3,4). However, chlorination of
2,4(1H,3H)-quinazolinedione gave 2,4-dichloroquinazoline only in 11% yield (entry 5). From these
results, it was clarified that chlorination of azinones or diazinones proceeded smoothly than dichlorination
of diazinediones.
Table 2 Chlorination of fused diazinones or fused diazinedione using 2
2 (2 eq.), solvent, reflux
substrate
substrate
O
product
product
Cl
entry
1
solvent
toluene
condition
reflux, 4 h
yield (%)
61
NH
N
N
N
N
N
2
3
toluene
toluene
reflux, 8 h
reflux, 4 h
65
77
Ph
Ph
N
N
N
N
O
Cl
H
O
Cl
NH
N
4
5
toluene
xylene
reflux, 3.5 h
reflux, 3 h
89
11
N
N
O
Cl
N
NH
N
N
O
Cl
H
Chlorination of azinone using two equivalents of 2 proceeded smoothly to give a chloro compound,
whereas chlorination using 1 required up to five equivalents of 1 and the resulting mixture turned black
resulting from a side reaction of 1.
In summary, chlorination of nitrogen-containing π-deficient heteroaromatics was accomplished by the
reaction of the corresponding hydroxyheteroaromatics with 2. Compared with the usual chlorinating
reagents such as phosphoryl chloride, phosphorus pentachloride, or 1, 2 provided more facile
chlorination.

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HETEROCYCLES, Vol. 65, No. 1, 2005
EXPERIMENTAL
Melting points were not corrected. 1H-NMR spectra were measured with HITACHI R-90H spectrometer
using TMS as an internal standard.
Preparation of 2-chloroquinoline: Trichloroisocyanuric acid (1549 mg, 6.66 mmol) was added to a
solution of triphenylphosphine (5246 mg, 20.0 mmol) in toluene (250 mL) and the reaction mixture was
stirred at rt for 23 h. To the reaction mixture, 2(1H)-quinolinone (1452 mg, 10.0 mmol) was added and
the mixture was heated to reflux for 4 h. After toluene was removed from the resulting mixture under
reduced pressure, the residue was treated with silica gel column chromatography (eluted with
hexane-ethyl acetate (6:1)) to afford 2-chloroquinoline (1197 mg, 73%). White solids. mp 31-32 °C (lit.,16
37-38 °C). 1H-NMR (CDCl3) ppm: 7.37 (1H, d, J=8.6 Hz, C3-H), 7.47-7.66 (1H, m, C6-H), 7.66-7.87 (2H,
m, C5 and C7-H), 8.03 (1H, d, J=8.6 Hz, C8-H), 8.09 (1H, d, J=8.6 Hz, C4-H).
Preparation of 4-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine: Trichloroisocyanuric acid (232 mg, 1.00
mmol) was added to a solution of triphenylphosphine (787 mg, 3.00 mmol) in toluene (25 mL) and the
reaction
mixture
was
stirred
at
rt
for
17
h.
To
the
reaction
mixture,
1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (318 mg, 1.50 mmol) was added and the mixture was
heated to reflux for 8 h. After toluene was removed from the resulting mixture under reduced pressure,
the residue was treated with silica gel column chromatography (eluted with hexane-ethyl acetate (9:1)) to
afford 4-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (226 mg, 65%). White solids. mp 131-132 °C
1
(lit.,17 126-127 °C). H-NMR (CDCl3) ppm: 7.32-7.70 (3H, m, phenyl-H), 8.07-8.29 (2H, m, phenyl-H),
8.34 (1H, s, C3-H), 8.87 (1H, s, C6-H).
Preparation of 2-chloroquinoxaline: Trichloroisocyanuric acid (2324 mg, 10.0 mmol) was added to a
solution of triphenylphosphine (7869 mg, 30.0 mmol) in toluene (300 mL) and the reaction mixture was
stirred at rt for 23.5 h. To the reaction mixture, 2(1H)-quinoxalinone (2192 mg, 15.0 mmol) was added
and the mixture was heated to reflux for 4 h. After toluene was removed from the resulting mixture under
reduced pressure, the residue was treated with silica gel column chromatography (eluted with
hexane-ethyl acetate (10:1)) to afford 2-chloroquinoxaline (1890 mg, 77%). Pale yellow solids. mp
47-47.5 °C (lit.,18 46-47 °C). 1H-NMR (CDCl3) ppm: 7.67-7.93 (2H, m, C5 and C8-H), 7.93-8.23 (2H, m,
C6 and C7-H), 8.78 (1H, s, C3-H).
Preparation of 4-chloroquinazoline: Trichloroisocyanuric acid (1549 mg, 6.66 mmol) was added to a
solution of triphenylphosphine (5246 mg, 20.0 mmol) in toluene (300 mL) and the reaction mixture was
stirred at rt for 19 h. To the reaction mixture, 4(3H)-quinazolinone (1462 mg, 10.0 mmol) was added and
the mixture was heated to reflux for 3.5 h. After toluene was removed from the resulting mixture under

HETEROCYCLES, Vol. 65, No. 1, 2005
185
reduced pressure, the residue was treated with silica gel column chromatography (eluted with
hexane-ethyl acetate (4:1)) to afford 4-chloroquinazoline (1473 mg, 89%). White solids. mp 97-98 °C
1
(lit.,12 96.5-97.5 °C). H-NMR (CDCl3) ppm: 7.73 (1H, ddd, J=8.1, 6.4, 1.7Hz, C6-H), 7.91-8.17 (2H, m,
C7 and C8-H), 8.28 (1H, dd, J=8.1, 0.8 Hz, C5-H), 9.05 (1H, s, C2-H).
Preparation of 2,4-dichloroquinazoline: Trichloroisocyanuric acid (620 mg, 2.67 mmol) was added to a
solution of triphenylphosphine (2098 mg, 8.00 mmol) in xylene (120 mL) and the reaction mixture was
stirred at rt for 46 h. To the reaction mixture, 2,4(1H,3H)-quinazolinedione (324 mg, 2.00 mmol) was
added and the mixture was heated to reflux for 3 h. After xylene was removed from the resulting mixture
under reduced pressure, the residue was treated with silica gel column chromatography (eluted with
hexane-ethyl acetate (5:1)) to afford 2,4-dichloroquinazoline (42 mg, 11%). White solids. mp 121 °C
(lit.,19 120 °C). 1H-NMR (CDCl3) ppm: 7.57-7.90 (1H, m, C6-H), 7.90-8.09 (2H, m, C7 and C8-H), 8.25
(1H, dd, J=8.1, 0.9 Hz, C5-H).
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