Palladium-catalyzed amination with benzophenone imine as a new, safe and practical alternative to nitration for the synthesis of 7-amino-2,1,3-benzothiadiazoles

Article abstract of DOI:10.1002/jhet.5570400425

Palladium-catalyzed amination of 7-bromo-4 -methyl-2,1,3-benzothiadiazole (7) with benzophenone imine as an ammonia equivalent is described as a new, safe and practical alternative to nitration for the synthesis of 7-amino-4-methyl-2,1,3-benzothiadiazole

Full text of DOI:10.1002/jhet.5570400425

Jul-Aug 2003
Palladium-Catalyzed Amination with Benzophenone Imine as a New,
Safe and Practical Alternative to Nitration for the Synthesis of
7-Amino-2,1,3-benzothiadiazoles
713
Yugang Liu,* Mahavir Prashad,* Oljan Repicˇ and Thomas J. Blacklock
Process R & D, Chemical & Analytical Development
Novartis Pharmaceuticals Corporation
One Health Plaza, East Hanover, New Jersey 07936, U.S.A.
Received April 11, 2003
Palladium-catalyzed amination of 7-bromo-4-methyl-2,1,3-benzothiadiazole (7) with benzophenone imine
as an ammonia equivalent is described as a new, safe and practical alternative to nitration for the synthesis of
7-amino-4-methyl-2,1,3-benzothiadiazole (1) in high yield. This methodology was successfully scaled-up in
the pilot plant on 14.0-kg scale of 7 and was also utilized for the synthesis of 7-amino-4,6-dimethyl-2,1,3-ben-
zothiadiazole (12) by the amination of 7-bromo-4,6-dimethyl-2,1,3-benzothiadiazole (10).
J. Heterocyclic Chem., 40, 713(2003).
7-Amino-2,1,3-benzothiadiazoles, such as 7-amino-4-
diazole (4) made the nitration route for the synthesis of
7-amino-4-methyl-2,1,3-benzothiadiazole (1) impractical
for large scale. Another limitation of this route was the
safety concerns associated with the nitration reaction on a
large scale. This led us to develop an alternative to nitra-
tion for the synthesis of 7-amino-4-methyl-2,1,3-benzo-
thiadiazole (1) that is safe and amenable for the pilot plant.
We have previously reported [5-6] the synthesis of anilines
via a palladium-catalyzed amination [7] of aromatic
halides with benzophenone imine as an ammonia equiva-
lent originally reported by Buchwald [8]. Herein, we
report a safer and efficient synthesis of 7-amino-4-methyl-
2,1,3-benzothiadiazole (1) via the palladium-catalyzed
amination of 7-bromo-4-methyl-2,1,3-benzothiadiazole
(7) with benzophenone imine as an alternative to nitration
methyl-2,1,3-benzothiadiazole (1) and 7-amino-4,6-
dimethyl-2,1,3-benzothiadiazole (12), are interesting
intermediates in the synthesis of biologically important
molecules [1]. Regioselective nitration of 4-methyl-2,1,3-
benzothiadiazole (2) at the 7-position to give 7-nitro-4-
methyl-2,1,3-benzothiadiazole (4), followed by the reduc-
tion, would afford the synthesis of 7-amino-4-methyl-
2,1,3-benzothiadiazole (1). Whereas the nitration of
4-ethyl-2,1,3-benzothiadiazole (3) was reported to be com-
pletely regioselective to afford the 7-nitro regioisomer (6)
exclusively in 83% yield, surprisingly, the nitration of
4-methyl-2,1,3-benzothiadiazole (2) yielded a mixture of
7-nitro (4) and 5-nitro (5) regioisomers in 53% and 12%
yields respectively (Scheme 1) [2-3]. Nitration of
4-chloromethyl-2,1,3-benzothiadiazole was also known to
be completely regioselective to afford exclusively 7-nitro-
4-chloromethyl-2,1,3-benzothiadiazole in 81% yield [4].
The low yield (53%) of 7-nitro-4-methyl-2,1,3-benzothia-
Scheme
2
Scheme
1

714
Y. Liu, M. Prashad, O. Repicˇ and T. J. Blacklock
Vol. 40
Table 2
(Scheme 2). Palladium-catalyzed amination of hetero-
cyclic halides is a topic of current interest [9].
Comparison of Two Routes to 7-Amino-4-methyl-
2,1,3-benzothiadiazole (1)
Our new approach for the synthesis of 1 relied on the
regioselective bromination of 4-methyl-2,1,3-benzothiadia-
zole (2) at the 7-position to give 7-bromo-4-methyl-2,1,3-
benzothiadiazole (7). Contrary to nitration, the bromination
of 4-methyl-2,1,3-benzothiadiazole (2) [4] was reported to
be completely regioselective affording 7-bromo-4-methyl-
2,1,3-benzothiadiazole (7) exclusively and in excellent
yield [10-11]. Thus, the bromination of 2 with bromine in
aqueous acetic acid at 55-60 °C afforded 7 regioselectively
in 81.4% yield with >99% purity (Scheme 2). The product
7 crystallized from the reaction mixture during the bromine
addition and was isolated by a simple filtration. This
process scaled-up well in the pilot plant on a 13.0-kg scale
of 2 to afford 7 in 86% yield. Palladium-catalyzed amina-
tion of 7 with benzophenone imine (1.05 equiv) in the pres-
ence of sodium methoxide (1.4 equiv), [5] tris(dibenzylide-
neacetone)-dipalladium(0) (0.25 mol%), and (±)-2,2'-
bis(diphenylphosphino)-1,1'-binaphthyl (0.75 mol%) in
toluene at 85 °C for 24 h afforded a crude solution of imine
intermediate 8 after an aqueous work-up and phase separa-
tion. Hydrolysis of 8 in toluene with aqueous HCl at 70 °C
afforded the crystalline HCl salt of 1 that crystallized during
hydrolysis and was isolated by filtration. Neutralization of
this salt with 5 N sodium hydroxide afforded 7-amino-4-
methyl-2,1,3-benzothiadiazole (1) in 90.7% yield with
>99% purity. This procedure scaled-up successfully in the
pilot plant on a 14.0-kg scale of 7 to afford 1 in 86% yield
(Table 1). The palladium content of 1 was 40 ppm but was
reduced to <2 ppm in subsequent steps. A closed system
was necessary for the amination reaction to avoid the escape
of an unknown basic gas that was produced during the reac-
tion. Use of sodium t-butoxide as the base also afforded 1 in
90% yield.
Nitration Route
Pd-Catalyzed
Amination Route
Overall Yield (%) of 1
Advantages
Disadvantages
40
73.8
Safe route
Costly catalyst
and ligand
Cheap raw materials
Safety concerns
imine (1.2 equiv) in the presence of sodium t-butoxide (1.4
equiv), Pd (dba) (0.24 mol%), and BINAP (0.75 mol%) in
2
3
toluene at 110 °C for 4 hours afforded 7-amino-4,6-
dimethyl-2,1,3-benzothiadiazole (12) in 88% yield after the
hydrolysis of the resulting imine (11) with aqueous HCl and
neutralization with 5 N sodium hydroxide. Use of sodium
methoxide [5] as the base also afforded 12 in 85% yield.
In summary, palladium-catalyzed amination of
7-bromo-4-methyl-2,1,3-benzothiadiazole (7) with benzo-
phenone imine as an ammonia equivalent provided a new,
safe and practical alternative to nitration for the synthesis
of 7-amino-4-methyl-2,1,3-benzothiadiazole (1) in high
yield. This methodology was successfully scaled-up in the
pilot plant on 14.0-kg scale of 7 and was also utilized for
the synthesis of 7-amino-4,6-dimethyl-2,1,3-benzothiadi-
azole (12) by the amination of 7-bromo-4,6-dimethyl-
2,1,3-benzothiadiazole (10).
EXPERIMENTAL
7-Bromo-4-methyl-2,1,3-benzothiadiazole (7).
A mixture of 87.0 g (0.58 mol) of 4-methyl-2,1,3-benzothiadi-
azole (2) [4], 400 mL of acetic acid, and 100 mL of water was
heated to an internal temperature of 55-57 °C and 139.0 g (0.87
mol) of bromine was added over a period of 1.5 hours while
maintaining the internal temperature at 55-60 °C. A solid crys-
tallized during the bromine addition. The mixture was heated for
an additional 1.5 hours at 55-60 °C. Water (400 mL) was added
in 20 minutes at 45-55 °C, and the mixture was stirred for an
additional 1 hour. The reaction mixture was cooled to an internal
temperature of 20-25 °C over a period of 3 hours and the solid
was collected by filtration. The solid was washed sequentially
with 200 mL of 10% sodium thiosulfate, 600 mL of water, and
300 mL of cold (0-5 °C) ethanol, and dried to afford 7-bromo-4-
methyl-2,1,3-benzothiadiazole (7), 108.0 g (81.4%), m.p. 133-
135 °C, lit. (11) m.p. 136-138 °C; 1H NMR (CDCl3): d 2.68 (s,
3H), 7.22 (d, 1H, J=8.93 Hz), 7.73 (d, 1H, J=8.93 Hz).
Table 1
Scale-up of Bromination and Amination Steps
Lab Scale (% Yield) Pilot Plant
Scale (% Yield)
Bromination of 2
Pd-Catalyzed Amination of 7 0.107 kg (90.7%)
0.087 kg (81.4%)
13.0 kg (86.0%)
14.0 kg (86.0%)
Thus, a new, safe and practical alternative to the nitra-
tion for the synthesis of 7-amino-4-methyl-2,1,3-benzo-
thiadiazole (1) in high yield was developed (Table 2).
This new route was also used to synthesize 7-amino-4,6-
dimethyl-2,1,3-benzothiadiazole (12), which was originally
prepared using the nitration route [1]. Thus, regioselective
bromination of 4,6-dimethyl-2,1,3-benzothiadiazole (9)
[12] with bromine in 48% HBr at 65-70 °C afforded 7-
bromo-4,6-dimethyl-2,1,3-benzothiadiazole (10) in 90%
yield after a recrystallization from acetonitrile and water.
Palladium-catalyzed amination of 10 with benzophenone
Anal. Calcd. for C7H5BrN2S: C, 36.70; H, 2.20; N, 12.23; S,
14.00. Found: C, 36.62; H, 2.10; N, 12.29; S, 13.97.
7-Bromo-4,6-dimethyl-2,1,3-benzothiadiazole (10).
A mixture of 130.0 g (0.79 mol) of 4,6-dimethyl-2,1,3-ben-
zothiadiazole (9) [12] and 700 mL of 48% HBr was heated to an
internal temperature of 65 °C and 202.9 g (1.268 mol) of bromine
was added over a period of 45 minutes while maintaining the

Jul-Aug 2003
Palladium-Catalyzed Amination with Benzophenone Imine
715
internal temperature at 65-80 °C. A solid crystallized during
the bromine addition. The mixture was heated for an additional
30 minutes at 65-70 °C. The reaction mixture was cooled to an
internal temperature of 20-25 °C over a period of 2 hours and
the solid was collected by filtration. The solid was washed
twice with 200 mL each of water and dried to afford 190.5 g of
crude product. This crude product was suspended in 1.0 L of
acetonitrile and heated to reflux. Water (80 mL) was added at
78-80 °C to obtain a clear solution. The solution was cooled to
25 °C over a period of 2.5 hours and then to 0 °C over 30 min-
utes. The suspension was stirred at 0-5 °C for an additional 2
hours. The solid was collected by filtration, washed twice with
200 mL each of 50% acetonitrile-water mixture, and dried to
afford 7-bromo-4,6-dimethyl-2,1,3-benzothiadiazole (10),
mmol) of (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
(BINAP), 66.5 g (692.0 mmol) of sodium t-butoxide, 1.13 g (1.2
mmol) of tris(dibenzylideneacetone)-dipalladium(0) (Pd2(dba)3),
and 107.3 g (593.0 mmol) of benzophenone imine and dry and
deairated toluene (1.2 L). The mixture was stirred, evacuated and
flushed with nitrogen twice. The mixture was heated to an inter-
nal temperature at 110 °C in 15 minutes and stirred at this tem-
perature for an additional 4 hours. The reaction mixture was con-
centrated under reduced pressure to collect 950 mL of toluene.
To the resulting residue was added isopropyl acetate (1.0 L) and
water (400 mL), and the mixture was heated to an internal tem-
perature of 70 °C in 15 minutes. After stirring for 30 minutes at
this temperature, the bottom aqueous layer was discarded and to
the top organic layer was added concentrated HCl (95.0 mL) dur-
ing 10 minutes while maintaining the internal temperature at 70
°C. The mixture was cooled to an internal temperature of 20-25
°C over a period of 2 hours. The resulting solid was collected by
filtration and washed with isopropyl acetate (400 mL) to afford
the hydrochloride salt of 7-amino-4,6-dimethyl-2,1,3-benzothia-
diazole (12). This solid was dissolved in water (1.0 L) by heating
the suspension to an internal temperature at 50 °C. A 5 N sodium
hydroxide solution (200.0 mL) was added over 10 minutes while
maintaining the internal temperature at 50-60 °C. After stirring
for 1 hour at 50 °C, the suspension was cooled to 22-25 °C over a
period of 1 hour, and the resulting red solid was collected by fil-
tration. After washing the solid with water (400 mL), it was dried
to afford 86.0 g of crude 7-amino-4,6-dimethyl-2,1,3-benzothia-
diazole (12). This crude product was suspended in methanol (1.0
L) and refluxed to obtain a clear solution. To this clear solution
was added water (200 mL) over a period of 30 minutes while
maintaining the internal temperature at 65 °C. The solution was
cooled to an internal temperature at 20-25 °C over 3 hours and
then to 0 °C in 30 minutes. After stirring at this temperature for
an additional 2 hours, the solid was collected by filtration and
washed with a 50% mixture of methanol and water (400 mL).
The solid was dried to afford 7-amino-4,6-dimethyl-2,1,3-ben-
zothiadiazole (12), 78.0 g (88%), m.p.116-118 °C, contained 80
1
173.5 g (90%), m.p.109-110 °C; H NMR (CDCl3): d 2.48 (s,
3H), 2.60 (s, 3H), 7.28 (s, 1H).
Anal. Calcd. for C8H7BrN2S: C, 39.52; H, 2.90; N, 11.52; S,
13.19. Found: C, 39.30; H, 2.75; N, 11.39; S, 13.07.
7-Amino-4-methyl-2,1,3-benzothiadiazole (1).
A 2-L flask was charged sequentially with 107.0 g (467.0
mmol) of 7-bromo-4-methyl-2,1,3-benzothiadiazole (7), 2.18 g
(3.5 mmol) of (±)-2,2'-bis(diphenyl-phosphino)-1,1'-binaphthyl
(BINAP), 35.3 g (653.8 mmol) of sodium methoxide, 1.07 g
(1.17 mmol) of tris(dibenzylideneacetone)-dipalladium(0)
(Pd2(dba)3), and 88.9 g (490.4 mmol) of benzophenone imine
and was evacuated and flushed with nitrogen twice. Dry and
deairated toluene (700 mL) was added. The mixture was stirred,
evacuated and flushed with nitrogen twice. The mixture was
heated to an internal temperature of 83-87 °C in 30 minutes with
the nitrogen outlet valve open. The nitrogen outlet valve was
closed when the internal temperature reached 83-87 °C, and the
mixture was stirred at this temperature for an additional 24 hours
under a positive pressure of nitrogen. The reaction mixture was
cooled to an internal temperature of 23-27 °C, and toluene (400
mL) and water (300 mL) were added. After stirring for 10 min-
utes, the organic layer was separated and heated to an internal
temperature at 68-72 °C. Concentrated HCl (53.5 mL) was
added during 30 minutes while maintaining an internal tempera-
ture at 70-80 °C. The mixture was stirred at this temperature for
an additional 30 minutes and cooled to 23-27 °C over a period of
2 hours. The resulting solid was collected by filtration, washed
with isopropyl acetate (200 mL) and dried to afford 107.0 g of the
hydrochloride salt of 7-amino-4-methyl-2,1,3-benzothiadiazole
(1). This solid was dissolved in water (500 mL) by heating the
suspension to an internal temperature at 55-65 °C. A 5 N sodium
hydroxide solution (80.0 mL) was added over a period of 20 min-
utes while maintaining the internal temperature at 55-70 °C to
adjust the pH to 7-9. The suspension was cooled to 22-25 °C
over 2 hours, and the resulting red solid was collected by filtra-
tion. After washing the solid with water (300 mL), it was dried to
afford 7-amino-4-methyl-2,1,3-benzothiadiazole (1), 70.0 g
1
ppm palladium; H NMR (CDCl3): d 2.26 (s, 3H), 2.57 (s, 3H),
4.35 (bs, 2H), 7.08 (s, 1H).
Anal. Calcd. for C8H9N3S: C, 53.60; H, 5.06; N, 23.44; S,
17.89. Found: C, 53.79; H, 4.94; N, 23.36; S, 17.16.
Acknowledgments.
We thank Judy Wong for the scale-up of bromination and ami-
nation reactions in the pilot plant.
REFERENCES AND NOTES
[1] B. P. Neumann, World Patent WO 99/40089, August 12,
(1999); Chem. Abstr., 131, 144607 (1999).
[2] K. Pilgram, J. Heterocyclic Chem., 11, 835 (1974).
[3] D. D. M. Casoni, E. Sandri, C. Brizzi,Ann. Chim. (Rome), 54,
462 (1964).
1
(90.7%), m.p. 80-82 °C, contained 40 ppm palladium; H NMR
(CDCl3): d 2.58 (s, 3H), 4.50 (bs, 2H), 6.55 (d, 1H, J=8.82 Hz),
7.13 (d, 1H, J=8.82 Hz).
[4] P. Vanelle, C. T. Liegeois, J. Meuche, J. Maldonado and
M.P.Crozer, Heterocycles, 45, 955 (1997).
Anal. Calcd. for C7H7N3S: C, 50.89; H, 4.27; N, 25.43; S,
19.41. Found: C, 50.79; H, 4.04; N, 25.26; S, 19.26.
[5] M. Prashad, B. Hu, Y. Lu, R. Draper, D. Har, O. Repicˇ and T.
J. Blacklock, J. Org. Chem., 65, 2612 (2000).
[6] M. Prashad, B. Hu, D. Har, O. Repicˇ and T. J. Blacklock, M.
Acemoglu, Adv. Synth. Catal., 343, 461 (2001).
[7] A. R. Muci and S. L. Buchwald, Top. Curr. Chem., 219, 131
(2002).
7-Amino-4,6-dimethyl-2,1,3-benzothiadiazole (12).
A 3-L flask was charged with 120.0 g (494.0 mmol) of
7-bromo-4,6-dimethyl-2,1,3-benzothiadiazole (10), 2.46 g (3.7

716
Y. Liu, M. Prashad, O. Repicˇ and T. J. Blacklock
Vol. 40
[8] J. P. Wolfe, J. Ahman, J. P. Sadighi, R. A. Singer and S. L.
Buchwald, Tetrahedron Lett., 38, 6367 (1997).
[9] M. W. Hooper, M. Utsunomiya and J. F. Hartwig, J. Org.
Chem., 68, 2861 (2003).
36050 (1971).
[11] K. Pilgram, M. Zupan and R. Skiles, J. Heterocyclic Chem., 7,
629 (1970).
[12] S. Mataka, K. Takahashi, S. Shiwaku and M. Tashiro,
[10] K. H. Pilgram, US 3577427, May 4, (1971); Chem. Abstr., 75.
J.Chem. Soc., Chem. Commun., 1136 (1983).