Highly efficient microwave assisted α-trichlorination reaction of α-methylated nitrogen containing heterocycles

Article abstract of DOI:10.1016/j.tet.2006.05.081

A new methodology permitting the chlorination of different α-methylated nitrogen containing heterocycles into N-α-trichloromethylated derivatives is described here. The combination of microwave technology with a PCl₅/POCl₃ protocol has allowed to reach trichloromethyl derivatives with high yields in a few minutes.

Full text of DOI:10.1016/j.tet.2006.05.081

Tetrahedron 62 (2006) 8173–8176
Highly efficient microwave assisted a-trichlorination reaction
of a-methylated nitrogen containing heterocycles
a
Pierre Verhaeghe, Pascal Rathelot, Armand Gellis, Sylvain Rault and Patrice Vanelle
a
a
b
a,*
a
Laboratoire de Chimie Organique Pharmaceutique (LCOP), UMR CNRS 6517, Universite´ de la Me´diterrane´e,
Faculte´ de Pharmacie, 27 Boulevard Jean Moulin, 13385 Marseille cedex 05, France
Centre d’Etudes et de Recherche sur le Me´dicament de Normandie (CERMN), UPRES EA 3915, Faculte´ des Sciences
b
Pharmaceutiques, Universite´ de Caen, 5 rue Vaube´nard, 14032 Caen cedex, France
Received 7 March 2006; revised 30 May 2006; accepted 30 May 2006
Available online 22 June 2006
Abstract—A new methodology permitting the chlorination of different a-methylated nitrogen containing heterocycles into N-a-trichloro-
methylated derivatives is described here. The combination of microwave technology with a PCl /POCl protocol has allowed to reach
5
3
trichloromethyl derivatives with high yields in a few minutes.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
ERC1 reactions with nitroalkane salts, leading to original
vinyl chloride products.
4
Trichloromethyl compounds are well-known precursors in the
one-step synthesis of the corresponding trifluoromethyl struc-
tures, using fluorinating agents like SbF or SbF . Among
trifluorinated structures, mefloquine can be mentioned as a
major molecule of pharmaceutical interest (Scheme 1).
H C
CH3
NO2
CH3
N
3
N
TBAOH
1
,2
H
CH3
5
3
O N
2
CCl3
SRN1 + ERC
1
O N
2
N
CH3
N
CH3
Cl
Scheme 2.
HN
HO
The methyl group trichlorination can be performed through
radical mechanisms using N-chlorosuccinimide or chlo-
5
6
rine with, respectively, purification and technical complica-
tions. Chupp’s method is also an original possibility for
7
N
CF3
realizing this reaction in the case of methyl groups with
acid protons, but has a more complicated protocol. More-
over, it presents real high yields when chloromethyl groups
are transformed into trichloromethyl ones.
CF3
Scheme 1.
In order to optimize the global production of trifluoromethyl
drug analogs, the efficient synthesis of the corresponding
trichloromethyl substrates remains a preoccupation.
8
–10
Kato
described another method concerning the specific
trichlorination of a few a-methylated nitrogen containing
heterocycles, using both phosphorus pentachloride and
phosphorus oxychloride, providing medium yields, and
requiring long reaction times.
Aromatic a-trichloromethylated nitrogen containing hetero-
cycles present another synthetic interest in the field of radi-
3
cal reactions, which are developed in our research team. As
shown in Scheme 2, trichloromethyl compounds, after being
nitrated, are excellent substrates for consecutive SRN1 and
Our laboratory being involved in the study of the microwave
irradiation influence in organic chemistry,
3
,11
we investi-
gated the possibility of realizing such chlorination reactions
through a microwave synthesis in order to optimize them and
obtain the trichloromethyl derivatives in higher yields and
much shorter reaction times. Applying this simple method,
we studied the synthesis of various trichloromethyl com-
pounds in quinoline, quinoxaline, quinazoline, benzoxazole,
benzothiazole, and imidazo[2,1-b]thiazole series.
Keywords: Ionic polychlorination; Microwave assisted reactions; Nitrogen
containing heterocycles.
*
Corresponding author. Tel.: +33 4 91 83 55 80; fax: +33 4 91 79 46 77;
e-mail: patrice.vanelle@pharmacie.univ-mrs.fr
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.081

8174
P. Verhaeghe et al. / Tetrahedron 62 (2006) 8173–8176
2
. Results and discussion
Table 1. Optimal synthetic conditions and corresponding yields of monotri-
chlorination reactions
From 1967 to 1981, Kato presented, in several publica-
tions,
‘
atom in pyridine and quinoline series. This method uses
phosphorus pentachloride as a powerful ionic chlorinating
agent, and phosphorus oxychloride as a solvent, the reaction
mixture being heated to reflux for a long time (from 12 to
Compound
number
Product
n equiv Classical
MW
conditions
8
–10
a
b
a protocol permitting the trichlorination of the
activated’ methyl group in a-position of the sp nitrogen
of PCl
5
conditions
2
Time Yield Time Yield
(h)
(%) (min) (%)
1
2
4
5
12
89
61
5
98
83
N
CCl3
6
0 h). The limitation of such a procedure rapidly appears
because of the small or medium yields obtained (from 4 to
1%), depending on the substrate, considering the impor-
NO2
O N
2
6
24
20
tance of reaction time needed.
N
CCl3
In continuation of our studies exploring the chemical reactiv-
ity of a-trichloromethylated nitrogen containing hetero-
cycles in electron transfer reactions, we tried to improve
this chlorination synthesis procedure as far as obtaining the
optimal procedure. We first started toworkon the progression
of this methodology in classical operating conditions, acting
on two main parameters: reaction time and quantity of chlo-
rinating agent used. For each substrate, repeating Kato’s pro-
tocol, several times of reaction were investigated, and so was
N
3
4
CCl3
4
4
12
12
74
81
20
30
75
86
O
N
S
CCl3
N
CCl3
5
4
5
12
84
10
15
89
84
S
O N
2
done for various quantities of PCl . The minimal required
5
N
N
time for the reaction to proceed in a quantitative way is
more often situated between 12 and 24 h. With longer times,
the yield of the reaction decreases because of the highly reac-
tive nature of the refluxed reaction mixture that damages the
6
1.5 75
CCl3
a
3
Reaction mixture heated to reflux of POCl .
Reaction mixture heated to reflux of POCl
irradiation.
b
3
under 800 W microwave
product previously formed. Optimal PCl amount has then
5
been determined. It always has to be superior to the number
of hydrogen atoms that have to be substituted by chlorine
ones, knowing that each PCl molecule is able to liberate
optimization work on both classical and microwave assisted
conditions. We synthesized the expected product 2,3-bis(tri-
chloromethyl)quinoxaline 7, but with lower yields compared
to the products obtained with monomethylated substrates.
Steric hindrance most probably explains this result, espe-
cially when we consider that the main product is 2-dichloro-
methyl-3-trichloromethylquinoxaline 8. Here, the PCl5
equivalent number has to be quite elevated so as to compete
with steric limitations. Our optimal results are presented in
Table 2.
5
9
a single chlorine atom for the chlorination reaction.
Consequently, in order to trichlorinate our substrates, the use
of 4 equiv of PCl usually provides the best yields, whereas
5
some substrates require one more for being maximally trans-
formed. Then, we decided to realize the same synthesis with
a microwave assisted protocol using a microwave power of
8
00 W and studying the two same operating parameters.
The global comparison between classical and microwave
assisted conditions was then done, permitting to demonstrate
the consequent contribution of the microwave technology
in this synthetic approach (Scheme 3). Table 1 summarizes
our optimal results in both conditions. It appears that in
the microwave assisted reactions, times were massively re-
duced, and that the reaction yields were slightly increased
or have, at least, remained constant.
N
CH3
N
CCl3
N
CHCl2
n eq. PCl5
+
POCl3, ∆
N
CH3
N
7
CCl3
N
CCl3
8
Scheme 4.
Table 2. Optimal synthetic conditions and corresponding yields of double
trichlorination reaction
X
N
n eq. PCl5
X
N
Compound
number
Product
n equiv Classical
of PCl5 conditions
MW
conditions
R
R
R
R
a
b
POCl , ∆
3
CH3
CH3
CCl3
CCl3
Time Yield Time Yield
(%)
n eq. PCl5
(h)
(min) (%)
Z
Z
POCl , ∆
3
N
N
CCl3
N
N
7
15
15
24
35
30
30
30
60
R = H or NO2 X = C or N Z = O or S
CCl3
Scheme 3.
N
N
CHCl2
8
24
50
CCl3
This single trichlorination reaction studied, we evaluated
the possibility of performing a double trichlorination reac-
tion in similar conditions, using 2,3-dimethylquinoxaline
as a substrate (Scheme 4). Once more, we realized a parallel
a
3
Reaction mixture heated to reflux of POCl .
Reaction mixture heated to reflux of POCl
irradiation.
b
3
under 800 W microwave

P. Verhaeghe et al. / Tetrahedron 62 (2006) 8173–8176
8175
1
2
13
Dehoff and Smith showed that the chlorination of
-methylquinazolin-4-one with PCl5 and PCl3 logically
Table 4. Optimal operating conditions and corresponding yields for the for-
mation of (10)
2
affects the carbonyl group of the lactam ring, forming the
aromatic tetrachlorinated product 4-chloro-2-trichloro-
methylquinazoline 9 with a maximum yield of 53%. We
realized Kato’s reaction on this substrate (Scheme 5), and
optimized it. Table 3 presents the optimal results that we
obtained in both operating conditions. Even without the use
of microwaves, the yield of the reaction has been increased.
Compound
number
Product
Method n equiv Classical
MW
conditions
a
b
of PCl
5
conditions
Time Yield Time Yield
(h)
(%) (min) (%)
Cl
CCl3
A
B
5
5
24
24
86
89
10
10
85
88
1
0
N
S
N
O
N
Cl
a
3
Reaction mixture heated to reflux of POCl .
Reaction mixture heated to reflux of POCl3 under 800 W microwave
irradiation.
H
b
n eq. PCl5
N
N
POCl , ∆
3
CH3
N
CCl3
9
3. Conclusion
Scheme 5.
The application of microwave assisted reaction to the chlo-
rination protocol described by Kato proved to be a very
efficient methodology in order to synthesize a-trichloro-
methylated nitrogen containing heterocycles. This very sim-
ple procedure provides high yields in a minimal time of
reaction. Then, different types of chemical reactivity for
the trichloromethyl group offer synthetic possibilities such
as nucleophilic and polynucleophilic substitutions, vinyl
chloride access and present a real pharmaceutical interest
as the main synthetic pathway to trifluoromethyl com-
pounds, very numerous among the therapeutic arsenal.
Table 3. Optimal synthetic conditions and corresponding yields for the
synthesis of (9)
Compound
number
Product
n equiv
of PCl
Classicala
conditions
MW
conditions
b
5
Time Yield Time Yield
(
h)
(%)
(min) (%)
Cl
N
9
6
24
76
15
75
N
CCl3
a
3
Reaction mixture heated to reflux of POCl .
Reaction mixture heated to reflux of POCl
irradiation.
b
4. Experimental
3
under 800 W microwave
4.1. General
Finally, we developed this chlorination reaction on the
imidazo[2,1-b]thiazole nucleus. As described in Scheme 6,
Microwave assisted reactions were done in a multimode
microwave oven ETHOS Synth Lab Station (Ethos start,
Milestone Inc.). Melting points were determined with a
6
-methylimidazothiazole (case A) and 6-methyl-5-nitroimi-
dazothiazole (case B) were used as substrates for optimizing
the trichlorination reaction in both classical and microwave
operating conditions. Starting with two distinct substrates,
the reaction product is the same compound: 5-chloro-6-tri-
chloromethylimidazo[2,1-b]thiazole 10.
1
B-540 B €u chi melting point apparatus. H NMR (200 MHz)
1
3
and C NMR (50 MHz) spectra were recorded on a Br €u ker
ARX 200 spectrometer in CDCl solution at the Facult ꢀe de
3
1
13
Pharmacie de Marseille. H and C NMR chemical shifts
(
d) are reported in parts per million with respect to CDCl
3
1
13
7
.26 ppm ( H) and 77.16 ppm ( C). Elemental analyses
CH3
were carried out at the Centre de Microanalyses de la Facultꢀe
A
N
des Sciences et Techniques de Saint-Jerome. The following
adsorbent was used for flash column chromatography: silica
gel 60 (Merck, particle size 0.063–0.200 mm, 70–230 mesh
ASTM). TLC were performed on 5 cmꢀ10 cm aluminum
plates coated with silica gel 60F-254 (Merck) in appropriate
solvent.
ꢀ ˆ
N
Cl
S
CCl3
n eq. PCl5
N
N
S
POCl , ∆
O N
3
2
CH3
N
S
10
N
B
4.2. Experimental procedure
Scheme 6.
1
4
2-Trichloromethylquinoxaline(6) was described previously.
In case A, the chlorination of the methyl group is associated
to the chlorination of the 5-position. In case B, the same
methyl trichlorination is accompanied with the substitution
of the nitro group by a chlorine atom. Such behavior for a
nitro group was already noted by Kato who performed
the same substitution on 2-methyl-3-nitroquinoline deriva-
tives. Table 4 presents our optimal results for the two distinct
synthesis access to 10 with both traditional and microwave
assisted methodologies.
4.2.1. General trichlorination procedure in classical
operating conditions. The required equivalent number of
phosphorus pentachloride and twice as much equivalents of
1
0
ꢁ
phosphorus oxychloride were added to the substrate at 0 C.
The mixture was then heated to reflux and stirred for the
adapted time, depending on the substrate. After cooling, the
mixture was alkalinized with a saturated sodium carbonate
solution and extracted with chloroform. Purification was

8176
P. Verhaeghe et al. / Tetrahedron 62 (2006) 8173–8176
conducted by flash chromatography on a silica gel column
eluting with dichloromethane–petroleum ether (1:1).
4.2.9. 2-Dichloromethyl-3-trichloromethylquinoxaline
ꢁ
1
(8). Colorless crystals, mp 160 C. H NMR (200 MHz;
CDCl ): d 7.81 (1H, s, CHCl ), 7.93 (2H, m, H , H ), 8.21
3
2
6
7
1
3
4.2.2. General microwave assisted trichlorination reac-
tion. The required equivalent number of phosphorus penta-
(1H, m, H ), 8.30 (1H, m, H ). C NMR (50 MHz;
8 5
CDCl ): d 67.1 (CH), 95.7 (C), 129.0 (CH), 129.8 (CH),
3
chloride and twice as much equivalents of phosphorus
ꢁ
132.6 (CH), 132.7 (CH), 138.8 (C), 142.4 (C), 145.6 (C),
149.2 (C). Anal. Calcd for C H Cl N (330.5): C, 36.35;
H, 1.53; N, 8.48. Found C, 36.23; H, 1.49; N, 8.47.
oxychloride were added to the substrate at 0 C. The mixture
1
0
5
5 2
was placed in the microwave oven irradiating with 800 W,
heating to reflux for the adapted time, depending on the
substrate. After cooling, the mixture was alkalinized with
a saturated sodium carbonate solution and extracted with
chloroform. Purification was conducted by flash chromato-
graphy on a silica gel column eluting with dichloro-
methane–petroleum ether (1:1). Recrystallization wasn’t
necessary for compounds 1, 2, 7–10, which were pure
enough for elementary analysis.
4.2.10. 4-Chloro-2-trichloromethylquinazoline (9). White
ꢁ
12,13
1
powder, mp 127 C (lit.
). H NMR (200 MHz; CDCl ):
3
d 7.86 (1H, m, H ), 8.08 (1H, m, H ), 8.22 (1H, dd, J¼8.5
6
7
1
3
and 0.5 Hz, H ), 8.36 (1H, dd, J¼8.4 and 0.6 Hz, H ). C
NMR (50 MHz; CDCl ): d 95.9 (C), 122.9 (C), 126.0
5
8
3
(CH), 129.7 (CH), 130.6 (CH), 135.9 (CH), 150.2 (C),
159.9 (C), 164.0 (C).
4
crystals, mp 127 C. H NMR (200 MHz; CDCl ): d 7.71
.2.3. 8-Nitro-2-trichloromethylquinoline (1). Pale yellow
ꢁ
4.2.11. 5-Chloro-6-trichloromethylimidazo[2,1-b]thia-
ꢁ
1
1
zole (10). Colorless crystals, mp 84 C. H NMR
(200 MHz; CDCl ): d 7.02 (1H, d, J¼4.5 Hz, H ), 7.40
3
(
1H, dd, J¼8.0 and 7.8 Hz, H ), 8.10 (2H, m, H , H ),
6
5
7
3
2
1
3
8
.18 (1H, d, J¼8.8 Hz, H ), 8.43 (1H, d, J¼8.8 Hz, H ).
(1H, d, J¼4.5 Hz, H ). C NMR (50 MHz; CDCl ):
4
3
3
3
1
3
C NMR (50 MHz; CDCl ): d 97.1 (C), 119.4 (CH),
3
d 90.2 (C), 107.7 (C), 115.6 (CH), 116.6 (CH), 142.1 (C),
145.5 (C). Anal. Calcd for C H Cl SN (276.0): C, 26.11;
H, 0.73; N, 10.15. Found: C, 26.28; H, 0.72; N, 9.84.
1
1
24.8 (CH), 127.2 (CH), 128.4 (C), 131.4 (CH), 136.7 (C),
38.3 (CH), 148.2 (C), 159.0 (C). Anal. Calcd for
6
2
4
2
C H Cl N O (291.5): C, 41.20; H, 1.73; N, 9.61. Found:
1
0
5
3 2 2
C, 41.55; H, 1.67; N, 9.99.
Acknowledgements
4
crystals, mp 152 C. H NMR (200 MHz; CDCl ): d 8.24
.2.4. 6-Nitro-2-trichloromethylquinoline (2). Pale yellow
ꢁ
1
This work was supported by the CNRS and the University of
Aix-Marseille II. P.V. thanks the Assistance Publique—
H oˆ pitaux de Marseille for hospital appointment. The authors
thank C. Castera Ducros and T. Terme for their cooperation,
M. Noailly and V. R ꢀe musat for the H and C NMR spectra
recording and are thankful to G. Lanzada and F. Sifredi for
their technical support.
3
(
(
1H, d, J¼8.9 Hz, H ), 8.35 (1H, d, J¼9.3 Hz, H ), 8.53
4
8
1H, d, J¼8.9 Hz, H ), 8.58 (1H, dd, J¼9.3 and 2.5 Hz,
3
1
3
H ), 8.85 (1H, d, J¼2.5 Hz, H ). C NMR (50 MHz;
7
5
1
13
CDCl ): d 97.2 (C), 119.5 (CH), 123.8 (CH), 123.9 (CH),
3
1
1
4
26.8 (C), 132.1 (CH), 139.9 (CH), 146.8 (C), 147.9 (C),
60.5 (C). Anal. Calcd for C H Cl N O (291.5): C,
1.20; H, 1.73; N, 9.61. Found: C, 41.70; H, 1.71; N, 9.84.
1
0
5
3 2 2
References and notes
4.2.5. 2-Trichloromethylbenzoxazole (3). Colorless crystals,
mp 61 C (lit. : 60 C). H NMR (200 MHz; CDCl ): d 7.47
ꢁ
2H, m, H , H ), 7.62 (1H, m, H ), 7.86 (1H, m, H ). C NMR
15
ꢁ
1
1. Singh, B.; Lesher, G. J. Heterocycl. Chem. 1983, 20, 491.
2. Beer, R. H.; Jimenez, J.; Drago, R. S. J. Org. Chem. 1993, 58,
1746.
3. Electron Transfer Reactions in Organic Synthesis; Vanelle, P.,
Ed.; Research Signpost: Trivandrum, 2002.
4. Vanelle, P.; Benakli, K.; Giraud, L.; Crozet, M. P. Synlett 1999,
801.
3
1
3
(
(
(
5 6 4 7
50 MHz; CDCl ): d 86.0 (C), 111.4 (CH), 121.7 (CH), 125.7
3
CH), 127.5 (CH), 139.9 (C), 151.5 (C), 160.0 (C).
4
tals, mp 38 C (lit. : 37 C). H NMR (200 MHz; CDCl ):
.2.6. 2-Trichloromethylbenzothiazole (4). Yellow crys-
ꢁ
15
ꢁ
1
3
d 7.54 (2H, m, H , H ), 7.91 (1H, m, H ), 8.15 (1H, m,
5
H7). C NMR (50 MHz; CDCl ): d 91.3 (C), 121.7 (CH),
3
5. Newkome, G. R.; Kiefer, G. E.; Xia, Y. J.; Gupta, V. K.
Synthesis 1984, 676.
6
4
1
3
1
1
24.8 (CH), 127.1 (CH), 127.2 (CH), 136.5 (C), 157.1 (C),
69.5 (C).
6. Mizuno, Y.; Adachi, K.; Kanda, S. J. Pharm. Soc. Japan 1952,
72, 1263.
7
. Chupp, J. P.; Grabiak, R. C.; Leschinsky, K. L.; Neumann, T. L.
Synthesis 1986, 224.
4
crystals, mp 110 C (lit. : 113 C). H NMR (200 MHz;
.2.7. 6-Nitro-2-trichloromethylbenzothiazole (5). Yellow
ꢁ
6
ꢁ
1
8. Kato, T.; Hayashi, H.; Anzai, T. Yakugaku Zasshi 1967, 87, 387.
9. Kato, T.; Katagiri, N.; Wagai, A. Tetrahedron 1978, 34, 3445.
10. Kato, T.; Katagiri, N.; Wagai, A. Chem. Pharm. Bull. 1981, 29,
1069.
CDCl ): d 8.26 (1H, d, J¼9.1 Hz, H ), 8.45 (1H, dd, J¼9.1
3
4
1
3
and 2.3 Hz, H ), 8.88 (1H, d, J¼2.3 Hz, H ). C NMR
5
7
(
50 MHz; CDCl ): d 90.3 (C), 118.5 (CH), 122.5 (CH),
3
1
25.4 (CH), 136.7 (C), 146.1 (C), 155.6 (C), 174.8 (C).
11. Boufatah, N.; Gellis, A.; Maldonado, J.; Vanelle, P.
Tetrahedron 2004, 60, 9131.
4
crystals, mp 176 C. H NMR (200 MHz; CDCl ): d 7.95
.2.8. 2,3-Bis(trichloromethyl)quinoxaline (7). Colorless
ꢁ
12. Dehoff, L. H. J. Prakt. Chem. 1890, 42, 352.
13. Smith, R. F.; Kent, R. A. J. Org. Chem. 1964, 30, 1312.
14. Cartwright, D.; Ferguson, J. R.; Giannopoulos, T.; Varvounis,
G.; Wakefield, B. J. J. Chem. Soc., Perkin Trans. 1 1995, 2595.
15. Holan, G.; Samuel, E. L.; Ennis, B. C.; Hinde, R. W. J. Chem.
Soc. C 1967, 20.
1
3
1
3
(
CDCl ): d 96.8 (2C), 128.9 (2CH), 133.1 (2CH), 138.8
2H, m, H , H ), 8.22 (2H, m, H , H ). C NMR (50 MHz;
6 7 5 8
3
(
2C), 146.6 (2C). Anal. Calcd for C H Cl N (364.9): C,
10 4 6 2
3
2.92; H, 1.10; N, 7.68. Found C, 32.99; H, 1.08; N, 7.68.