Facile synthesis of 6-trichloromethylpterin and 2-chloro-3- trichloromethylquinoxaline along with a library of trichloromethyl heterocycles using N-chlorosuccinimide and triphenyl phosphine

Article abstract of DOI:10.1246/cl.2007.552

A general synthesis of 6-trichloromethylpterin, 2-chloro-3- trichloromethylquinoxaline and 2-amino-7-trichloromethyl-1,8-naphthyridine along with a series of trichloromethyl heterocycles (1-11) has been reported in one-pot mild neutral condition in good yield. This method is compared with the usual method using phosphorus pentachloride in phosphorus oxychloride. Copyright

Full text of DOI:10.1246/cl.2007.552

5
52
Chemistry Letters Vol.36, No.4 (2007)
Facile Synthesis of 6-Trichloromethylpterin and 2-Chloro-3-trichloromethylquinoxaline
along with a Library of Trichloromethyl Heterocycles Using N-Chlorosuccinimide
and Triphenyl Phosphine
ꢀ
1
1
2
Shyamaprosad Goswami, Annada C. Maity, and Hoong-Kun Fun
Department of Chemistry, Bengal Engineering and Science University, Shibpur, Howrah-711 103, India
X-ray Crystallography Unit, School of Physics, University Sains Malaysia, 11800 USM, Penang, Malaysia
1
2
(Received January 30, 2007; CL-070116)
A general synthesis of 6-trichloromethylpterin, 2-chloro-3-
were made by reported procedures.9,10 Lactam group in the
pyrimidine ring of methylpterin 1 (Entry 1) was not converted
to the chloro derivative and only the methyl group was trans-
formed into trichloromethyl group. But the methylquinoxaline
lactam 4 (Entry 4) and 5 (Entry 5) gave 2a and 5a where both
the trimethyl and the lactam moiety were smoothly converted
to the chlorinated product. A plausible mechanism is also sug-
trichloromethylquinoxaline and 2-amino-7-trichloromethyl-1,8-
naphthyridine along with a series of trichloromethyl heterocy-
cles (1–11) has been reported in one-pot mild neutral condition
in good yield. This method is compared with the usual method
using phosphorus pentachloride in phosphorus oxychloride.
1
2
gested for the formation of 3a and given in the Supporting In-
1
4
The halogen-substituted ꢀ-depletion heteroaromatic nuclei
e.g. pterin, quinoxaline, naphthyridine, or pyridine derivatives)
formation. All the compounds made here are well character-
1
13
(
ized by spectroscopic studies ( H NMR, C NMR, and MS) as
well as by comparison of melting points with authentic samples.
The reaction conditions and yields are summarized in Table 1.
The experimental procedure is as follows: In a round-
bottomed flask, 10 equiv. of N-chlorosuccinimide was added
to a solution of 2 equiv. of triphenylphosphine in carbon tetra-
1
are important intermediates in modern organic chemistry.
These are versatile key compounds in manifold synthesis of ar-
2
tificial receptors for molecular recognition. These intermediates
react with different nucleophiles such as amines to give the
corresponding substituted products. 2-Amino-6-bromomethyl-
4(3H)-pteridinone and 6-bromomethyl-2,4-pteridinediamine
are the key intermediates for the synthesis of nutrient cofactor
folic acid and anticancer drug methotrexate. Pharmacophore
based synthesis of 3-chloroquinoxaline-2-carboxamide as se-
Table 1. Synthesis of the series of ꢁ-trichloromethyl-substitut-
ed heterocyclic compounds (1–11)
3
Reaction conditiona,c Yield
NCS and PPh3 in CCl4 /%
b
Entry
Starting material
O
Product
Reference
rotonin3 (5-HT3) receptor antagonist was designed and prepared
4
O
N
CH
3
N
CCl3
1
t
O
HN
O
HN
from 3-chloro-2-quinoxalinylchloride.
7
h
76
84
90
11
t
Bu
N
N
N
N
Bu
N
H
N
N
N
It is well known that ꢁ-methylheterocyclic compounds are
chlorinated to give ꢁ-trichloromethylheterocyclic compounds
using phosphorus pentachloride in phosphorus oxychloride.5
These reagents are, however, very moisture-sensitive and also
isolation of the products from phosphorus oxychloride is diffi-
cult. Thus, the development of new modes of ꢁ-methyl halogen-
ation without using a halogenating reagent such as phosphorus
oxychloride would be advantageous for many chemists. Recent-
ly, a facile halogenation of some hydroxyheterocycles using
H
1
2
3
1a
2a
3a
CH
3
CCl
Cl
3
2
6 h
11
5b
N
N
Cl
CH
N
N
CCl
3
3
5
7
h
h
3
4
N
N
N
N
CH
O
3
CCl
Cl
3
85
75
90
11
11
1d
N
H
N
4
2a
Br
N
CH3
O
Br
N
N
CCl3
Cl
6
7
h
h
5
N
N
N
6
5 H
5
a
triphenylphosphine and N-halosuccinimide was reported. We
have previously reported side chain bromination in the presence
or absence of water and without radical initiator under micro-
wave.7
We report here a useful, straightforward, economic and
efficient method for the synthesis of 6-trichloromethylpterin,
6
7
H
3
C
N
N
N
CH
3
Cl
3
C
N
N
CCl
3
6a
7a
6
6 h
92
95
11
1c
11
H
2
N
N
CH
3
H
2
N
N
N
CCl
3
7
7
7
h
h
8
9
2-chloro-3-trichloromethylquinoxaline and a series of methyltri-
N
N
N
N
8a
8
Cl
3
C
CCl
3
H
3
C
CH
3
chloro-substituted heterocyclic compounds in good yield using
N-chlorosuccinimide and triphenylphosphine in carbon tetra-
chloride by one-step reaction under mild and neutral conditions.
The starting material 2-amino-6-methyl-3H-pteridin-4-one
60
62
H
3
C
N
9
CH
3
3
Cl
3
C
N
9a
CCl
3
6 h
6 h
5
1
a
2
10
N
CH
N
CCl3
8
was made by following our microwave procedure and its 2-piv-
aloyl derivative 1 was prepared owing to extremely poor solubil-
1
0
10a
N
N
1
1
54
ity of pterin in both organic and aqueous media. Thus, the
1
N
CH
3
N
CCl3
1
1
11a
H NMR spectroscopic studies of the chloro-substituted pterins
were performed with the 2-pivaloyl derivative. Similarly starting
compounds 3-methyl-2(1H)-quinoxalinone (4) and 2-amino-7-
methyl-1,8-naphthyridine (7) respectively for Entries 4 and 7
a
b
Reactions were monitored by TLC analysis. Yields refer to the
isolated pure products after column chromatography. Reaction
was carried out at 80–85 C.
c
ꢁ
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.4 (2007)
553
Newkome, G. E. Kiefer, W. E. Puckett, T. Vreeland, J. Org.
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5, 2838. e) S. P. Goswami, R. Mukherjee, Tetrahedron Lett.
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Figure 1. X-ray structure of the compound 2a: ORTEP diagram
of the compound with atom numbering scheme and supramolec-
ular architecture within non-hydrogen inter-molecular contacts
(view along a axis). X-ray structure of the compound 2: (a)
ORTEP diagram of the compound with atom numbering scheme.
2
3
4
(
b) Packing of molecules 2 in the crystal lattice. (c) ClꢄꢄꢄCl inter-
action of chloro and trichloromethyl groups giving helix-like
conformation along b axis. (d) Supramolecular architecture
within non-hydrogen inter-molecular contacts (view along a
axis).
2
7, 1403.
5
a) T. Kato, N. Katagiri, A. Wagai, Tetrahedron 1978, 34, 3445.
b) D. Cartwright, J. R. Ferguson, T. Giannopoulos, G. V.
Varvounis, B. J. Wakefield, J. Chem. Soc., Perkin Trans. 1
1
995, 2595. c) T. Kato, N. Katagiri, T. Takahashi, Y. Katagiri,
chloride (60 mL), and stirred at room temperature for 25 min. A
solution of 3-methyl-2(1H)-quinoxalinone (4) (1 g, 5.25 mmol)
was added to the suspension and the reaction mixture was stirred
and heated under reflux for 7 h. The solution was cooled and fil-
tered. The evaporated filtrate was washed with saturated aqueous
NaHCO3 and extracted with CHCl3. After drying over anhy-
drous Na2SO4, the solvent was removed under reduced pressure.
The crude product was purified with column chromatography
using silica gel and elution with 1% ethyl acetate in pet ether
afforded 2-chloro-3-trichloromethylquinoxaline (2a) (1.47 g,
J. Heterocycl. Chem. 1979, 16, 1575. d) F. Korodi, J. Hetero-
cycl. Chem. 1991, 28, 1549.
O. Sugimoto, M. Mori, K. Tanji, Tetrahedron Lett. 1999, 40,
6
7
7
477.
a) S. P. Goswami, S. Dey, S. Jana, A. K. Adak, Chem. Lett.
2004, 33, 916. b) S. P. Goswami, K. Gosh, R. Mukherjee,
A. K. Adak, A. K. Mahapatra, J. Heterocycl. Chem. 2001,
3
8, 173.
S. P. Goswami, A. K. Adak, Tetrahedron Lett. 2002, 43,
371.
8
9
8
a) O. Hinsberg, Liebigs Ann. Chem. 1896, 292, 245. b) C. L.
Leese, H. N. Rydon, J. Chem. Soc. 1955, 303. c) D. C. Morrison,
J. Am. Chem. Soc. 1954, 76, 4483.
0 S. P. Goswami, R. Mukherjee, S. Jana, A. C. Maity, A. K. Adak,
Molecules 2005, 10, 929.
84%) as a white crystalline solid.
One important note that 2-chloro-3-dichloromethylpyrazine
was prepared by chlorination of 2-chloro-3-methylpyrazine in
1
ꢁ
acetic acid at 100 C where no 2-chloro-3-trichloromethylpyra-
zine was formed is indicative of the steric crowding about the di-
11 6-Trichloromethyl-2-pivaloylaminopteridin-4(3H)-one
ꢁ
(1a):
Yellow crystals; mp 187–189 C. FT-IR (Kari): 3420, 1698,
chloromethyl group.1 But in case of quinoxalines for Entries 2,
3
ꢂ1
1
1
(
410, 1262, 782 cm . H NMR (CDCl3, 300 MHz): ꢂ 12.49
br s, 1H, NH), 9.32 (s, 1H, C7–H), 8.67 (br s, 1H, NH), 1.35
4
(
, and 5, they formed 2-chloro-3-trichloromethylquinoxaline
2a) and 7-bromo-3-chloro-2-trichloromethylpyrido[2,3-b]pyra-
zine (5a). The structure of the compound 2a obtained was
þ
(s, 9H). MS (FAB): m=z (%): 364 (M , 45%). 2-Chloro-3-
trichloromethylquinoxaline (2a): White crystals; mp 152–
1
13
confirmed by spectroscopic methods (IR, H NMR, C NMR,
and MS). Final confirmation of 2a was obtained by an X-ray
crystallographic investigation (Figure 1). The molecule is
relatively planar. This planar arrangement leads to a compact
packing structure in parallel layers. The four molecules are
present in the unit cell.
ꢁ
ꢂ1
1
53 C. FT-IR (KBr): 1536, 1478, 1335, 1277, 774 cm .
1
H NMR (CDCl3, 500 MHz): ꢂ 8.21 (d, 1H, J ¼ 7:5 Hz), 8.11
(d, 1H, J ¼ 10 Hz), 7.91 (m, 2H). MS (FAB): m=z (%): 282
þ
(M , 50%). X-ray data for 2a: C9H4Cl4N2: Mr ¼ 281:94,
orthorhombic, Pnma (No. 62), a ¼ 14:4605ð2Þ, b ¼ 6:7113ð1Þ,
˚
˚ 3
c ¼ 10:8469ð2Þ A, V ¼ 1052:68ð3Þ A , Z ¼ 4, Dcalcd ¼ 1:779
3
g/cm . A total of 2482 unique reflections were measured at
In summary, the simple and clean reaction procedure
and also the work-up, use of low volumes of solvent, fast
reaction rates, mild and neutral reaction conditions, good yields
with no tar formation make this method for the synthesis of
trichloromethyl heterocycles an attractive and useful addition
to the current methodologies.
3
room temperature from a 0:25 ꢃ 0:28 ꢃ 0:36 mm colorless
crystal. Atomic coordinates, bond lengths, bond angles, and
thermal parameters have been deposited with the Cambridge
Crystallographic Data Center (CCDC No. 295218). 2-Amino-
7-trichloromethyl-1,8-naphthyridine (7a): White crystals; mp
ꢁ
202–203 C. FT-IR (KBr): 3478, 2360, 1626, 1482, 1418,
ꢂ1
1
1
270, 764 cm . H NMR (CDCl3, 300 MHz): ꢂ 8.47 (d, 1H,
J ¼ 8:66 Hz), 8.07 (d, 1H, J ¼ 8:43 Hz), 8.01 (d, 1H, J ¼
We thank DST [SR/S1/OC-13/2005], Govt. of India for
financial support. ACM thanks UGC, Govt. of India for research
fellowship. HKF would like to thank the Malaysian Government
and University Saints Malaysia for the Scientific Advancement
Grant Allocation (SAGA) grant No. 304/PFIZIK/653003/
A118.
5
:61 Hz), 7.72 (d, 1H, J ¼ 8:41 Hz), 5.75 (br s, 2H, NH2).
2
1
,6-Bis(trichloromethyl)pyridine (9a): White crystals; mp
15–117 C. FT-IR (KBr): 1542, 1480, 1275, 770 cm
ꢁ
ꢂ1
.
1
H NMR (CDCl3, 200 MHz): ꢂ 8.06 (m, 3H).
1
2 a) T. Mukaiyama, T. Obata, O. Mitsunobu, Bull. Chem. Soc.
Jpn. 1965, 38, 1088. b) S. Trippett, J. Chem. Soc. 1962, 2337.
3 E. J. J. Grabowski, E. W. Tristram, R. Tull, P. I. Pollak, Tetra-
hedron Lett. 1968, 9, 5931.
14 Supporting Information is available electronically on the CSJ
Journal Web Site; http://www.csj.jp/journals/chem-lett/.
1
References and Notes
1
a) E. C. Taylor, P. S. Ray, I. S. Darwish, J. L. Johnson, K. V.
Rajagopalan, J. Am. Chem. Soc. 1989, 111, 7664. b) G. R.
Published on the web (Advance View) March 21, 2007; doi:10.1246/cl.2007.552