Synthesis of new riminophenazines with pyrimidine and pyrazine substitution at the 2-N position

Article abstract of DOI:10.3390/molecules16086985

New riminophenazines with pyrimidine and pyrazine substituents at the 2-position were successfully synthesized. The key step is the 2-N-arylation of riminophenazines with pyrimidine and pyrazine. The optimized reaction conditions involve the use of a Pd

Full text of DOI:10.3390/molecules16086985

Molecules 2011, 16, 6985-6991; doi:10.3390/molecules16086985
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of New Riminophenazines with Pyrimidine and
Pyrazine Substitution at the 2-N Position
Gang Zhang, Hao Zhang, Xiaojian Wang, Chun Li, Haihong Huang and Dali Yin *
Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substance Discovery and
Drugability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese
Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China
* Author to whom correspondence should be addressed; E-Mail: yindali@imm.ac.cn;
Tel.: +86-10-63037952; Fax: +86-10-63037952.
Received: 11 July 2011; in revised form: 6 August 2011 / Accepted: 9 August 2011 /
Published: 16 August 2011
Abstract: New riminophenazines with pyrimidine and pyrazine substituents at the
2-position were successfully synthesized. The key step is the 2-N-arylation of
riminophenazines with pyrimidine and pyrazine. The optimized reaction conditions involve
the use of a Pd2(dba)3/DPPF/Cs2CO3/toluene combination.
Keywords: riminophenazine; N-arylation; palladium catalyst
1. Introduction
Riminophenazines such as clofazimine (Figure 1) are of great interest to many medicinal chemists
due to their various biological activities in the anti-mycobacterial [1,2], anti-tumor [3] and
anti-inflammatory areas [4-6], especially for multidrug resistant tuberculosis (MDR-TB) [7]. In our
ongoing search for novel antituberculotic riminophenazines, a series of new compounds were
designed, including riminophenazines with heteroaromatic substituents at the 2-N position.
There are generally two methods for the preparation of riminophenazines. Condensation of two
molecules of N-chlorophenyl-1,2-diaminobenzene by oxidation with FeCl3 to form the tricyclic core of a
riminophenazine gives the same substituents on the 2-N-phenyl and 5-phenyl rings [8]. For the compounds
with different substituents in the 2-N and 5 positions, a method developed by Andre Girard [9] allows
step by step introduction of different substituted anilines into the molecules. The synthesis of

Molecules 2011, 16
6986
riminophenazine with peripheral heteroaromatic substituents in the molecule has not been reported.
Herein we report the synthesis of new riminophenazines with pyrimidine and pyrazine substitutions at
the 2-N position.
Figure 1. Chemical structures of clofazimine and known riminophenazine derivatives.
2. Results and Discussion
An initial investigation of the synthesis of target compounds followed known procedures [9]
(Scheme 1). Unfortunately, the key intermediate 1 could not be converted into the desired
iminophenazine 2. Only a black tar was obtained, possibly due to instability of the intermediates with
pyrimidine substituents.
Scheme 1. Cyclization of riminophenazine core with pyrimidine substituent.
Cl
Cl
NH
NO2
N
N
NH
1)H2, Pd/C
2)Air, rt.
N
N
H
NO2
N
N
N
H
HN
N
1
2
To overcome the difficulties in the key cyclization step of the synthesis, the synthetic procedures
were modified and the attachment of heteroaromatic substituents was moved to the last step of the
synthesis to avoid decomposition of the intermediates (Scheme 2). Thus, the synthesis was started
from 1,5-difluoro-2,4-dinitrobenzene (4), which is more reactive towards amine substitution. The two
fluoro groups of compound 4 was subsequently replaced by N-(4-chlorophenyl)benzenediamine (3)
and ammonia to give the key intermediate 6. The dinitro groups of 6 were reduced either by catalytic
hydrogenation over Pd-C or by zinc powder reduction and the intermediate 7, without isolation, was
exposed to air and cyclized to form the desired riminophenazin core 8 with an amino group pending in
the 2-position. Compound 9 was obtained by displacement of the imino moiety with isopropylamine in
a sealed bomb. When the palladium catalyzed N-arylation, better known as the Buchwald-Hartwig

Molecules 2011, 16
6987
reaction [10], was applied to the 2-N arylation of 9 with 2-bromopyrimidine under the usual reaction
conditions, none of the desired product was formed. After screening of condition variables, such as
Pd catalyst, ligand, base, and solvent, a combination suitable for the N-arylation of 9 with
2-bromo-pyrimidine was found (Entry 7). The target compound 11a was thus obtained in 95.8% yield.
Scheme 2. New synthetic route for riminophenazines with heteroaromatic substituents.
Cl
H
N
O2N
F
NO2
F
NH
NO2
ammonia,THF
70 , 98%
MeOH, rt
+
Et3N, 85%
℃
NH2
Cl
N
H
NO2
F
5
4
3
Cl
Cl
Cl
N
NH
NO2
NH
NH2
Air, rt
81%
H2, Pd/C
NH
NH2
N
H
NO2
NH2
N
H
NH2
NH2
N
8
6
7
Cl
N
Cl
N
11a R3 =
R3-X (10)
Pd2(dba)3
N
isopropylamine
N
N
N
N
N
1,4-dioxane, 100
82%
℃
DPPF, Cs2CO3
Toluene
NH2
11b
R3 =
R3
N
N
N
H
9
11
When the optimized combination was used for the coupling of 9 with 2-bromopyrazine, the desired
product 11b was also obtained in 95.2% yield.
Table 1. Optimization of N-arylation of riminophenazines a,b.

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Table 1. Cont.
Entry
Catalyst
Ligand
IPr·HCl d
P(o-tolyl)3
DPPF
Base
Solvent
1,4-dioxane
xylene
T(°C)/Time(h)
100/24
110/24
110/8
Yield(%) c
1 [11]
Pd2(dba)3
PdCl2
t-BuOK
t-BuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
0
2 [12]
0
3
PdCl2
toluene
THF
57.6
0
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
DPPF
68/8
5
DPPF
toluene
toluene
toluene
toluene
70/24
25.1
31.3
95.8
88.9
6
7
DPPF
110/8
DPPF
110/2
8 [13]
rac-BINAP
110/12
a
Reaction conditions: 9 (1.0 equiv, 0.20mmol), 2-bromopyrimidine (1.5 equiv), catalyst
b
(2 mol %), ligand (8 mol %), base (1.5 equiv); The product were purified by flash
c
silica gel chromatography; All yields are reported for isolated and purified products;
d IPr·HCl = 1,3-bis(2,6-diisopropylphenyl)-imidazolium chloride.
3. Experimental
3.1. General
All chemicals and reagents were purchased from commercial sources and used without further
purification. All reactions were monitored by TLC. Chromatography refers to open column
chromatography (CC) on silica gel (SiO2; 160–200 mesh). Melting points were determined on a
Yanaco micrometer and are uncorrected. 1H- and 13C-NMR spectra were recorded on Varian Mercury
300 MHz and 400 MHz spectrometers; chemical shifts δ in ppm rel. to TMS or DMSO-d6 as internal
standards. High resolution mass spectra were recorded on an Agilent LC/MSD TOF spectrometer.
N-(4-Chlorophenyl)-N’-(5-fluoro-2,4-dinitrophenyl)benzene-1,2-diamine (5): 2-(4-Chloroanilino)-aniline
(20 mmol) and triethylamine (3 mL) were added to a solution of 1,5-difluoro-2,4-dinitrobenzene
(20 mmol) in methanol (100 mL). The reaction mixture was stirred at rt for 4 h, then filtered, and the
cake was washed with methanol and dried to give compound 5 in 85% yield. mp: 209–211 °C,
1H-NMR (300 MHz, DMSO-d6): δ 9.97 (s, 1H), 8.88 (d, J = 8.1 Hz, 1H), 7.89 (s, 1H), 7.31 (m, 3H),
7.22 (d, J = 8.1 Hz, 2H), 7.06 (m, 1H), 6.97 (d, J = 8.1 Hz, 2H), 6.47 (d, J = 14.1 Hz, 1H); 13C-NMR
(100 MHz, DMSO-d6) δ: 158.6 (d, J = 249.9 Hz), 148.2, 148.1, 141.7, 139.1, 128.8, 128.2, 126.8,
126.4, 125.8, 125.7, 123.9, 121.6, 119.5, 118.8, 103.1 (d, J = 27.4 Hz); HRMS (ESI-TOF+): m/z
[M+H]+ calcd. for C18H13ClFN4O4: 403.0604; found: 403.0608.
N-(5-Amino-2,4-dinitrophenyl)-N’-(4-chlorophenyl)benzene-1,2-diamine (6): A mixture of compound
5 (15 mmol), 25% ammonia (10 mL) and THF (20 mL) was heated to 70 °C for 12 h in a sealed bomb,
then about 20 mL of THF was removed under reduced pressure. After being cooled to rt. the
suspension was filtered, and the cake was washed with CH2Cl2 to give compound 6 in 98% yield. mp:
1
248–249 °C, H-NMR (300 MHz, DMSO-d6): δ 8.92 (s, 1H), 7.77 (m, 3H), 7.28 (m, 5H), 7.06 (m,
1H), 7.00 (m, 2H), 6.15 (s, 1H), 5.76 (s, 1H); 13C-NMR (100 MHz, DMSO-d6) δ: 149.6, 146.3, 144.3,
142.4, 138.9, 128.7, 127.9, 127.8, 127.6, 125.0, 123.9, 123.6, 121.7, 119.3, 118.9, 96.8; HRMS
(ESI-TOF+): m/z [M+H]+ calcd. for C18H15ClN5O4: 400.0807; found: 400.0806.

Molecules 2011, 16
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5-(4-Chlorophenyl)-3-imino-3,5-dihydrophenazin-2-amine (8): Compound 6 (10 mmol) was
suspended in anhydrous methanol (100 mL). The mixture was hydrogenated at 40 psi over 10% Pd-C
(0.4 g). Then the Pd-C was removed by filtration. The filtrate containing compound 7 was stirred at rt
in contact with air overnight. The solid formed was filtered, washed with methanol, and dried to give
1
compound 8 in 81% yield. mp: 238–240 °C, H-NMR (300 MHz, DMSO-d6): δ 7.86 (d, J = 8.7 Hz,
2H), 7.76 (m, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.31 (m, 2H), 6.78 (brs, 2H), 6.57 (m, 1H), 6.49 (s, 1H),
5.45 (s, 1H); 13C-NMR (100 MHz, DMSO-d6) δ: 149.8, 149.3, 148.1, 136.0, 135.6, 134.5, 133.2, 131.4,
130.8, 130.5, 128.2, 127.7, 123.2, 114.3, 99.8, 96.0; HRMS (ESI-TOF+): m/z [M+H]+ calcd. for
C18H14ClN4: 321.0902; found: 321.0894.
5-(4-Chlorophenyl)-3-(isopropylimino)-3,5-dihydrophenazin-2-aminee (9): Compound 8 (5 mmol),
isopropylamine (25 mmol) and dioxane (100 mL) were mixed in a sealed bomb and stirred at 110 °C
for 24 h. After being cooled to rt, water was added, and the mixture was suction filtered, washed with
water and dried to give a dark solid. The solid was purified by flash column chromatography
(EtOAc/hexane 1:2) to give compound 9 in 82% yield. mp: 234–235 °C, 1H-NMR (300 MHz, DMSO-d6):
δ 7.84 (d, J = 8.4 Hz, 2H), 7.59 (m, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.14 (m, 2H), 6.39 (m, 3H), 6.27 (s,
13
1H), 5.11 (s, 1H), 3.29 (m, 1H), 0.98 (d, J = 6.3 Hz, 6H); C-NMR (100 MHz, DMSO-d6) δ: 150.7,
150.3, 149.5, 136.2, 135.3, 134.2, 133.9, 131.5, 131.0, 130.7, 127.2, 126.6, 122.4, 113.8, 97.9, 88.2,
48.8, 23.4; HRMS (ESI-TOF+): m/z [M+H]+ calcd. for C21H20ClN4: 363.1371; found: 363.1367.
5-(4-Chlorophenyl)-3-(isopropylimino)-N-pyrimidin-2-yl-3,5-dihydrophenazin-2-amine (11a): Under
an atmosphere of N2, toluene (50 mL), 2-bromopyrimidine (3 mmol), compound 9 (2 mmol), Pd2(dba)3
(0.1 mmol), DPPF (0.4 mmol) and Cs2CO3 (3 mmol) were subsequently added to a two-necked
round-bottomed flask with a reflux condenser. The mixture was refluxed for 2 h, allowed to cool to rt,
and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash
silica gel chromatography (EtOAc/hexane 1:2) to give compound 11a in 95.8% yield. mp: 232–235 °C,
1H-NMR (300 MHz, CDCl3) δ: 9.76 (1H, br s), 8.56 (2H, d, J = 4.5 Hz), 8.49 (s, 1H), 7.77 (1H, d,
J = 6.9 Hz), 7.71 (2H, m), 7.32 (2H, m), 7.17 (2H, m), 6.83 (1H, m), 6.44 (1H, d, J = 6.9 Hz), 5.28
13
(1H, s), 3.47 (1H, m), 1.10 (6H, d, J = 6.0 Hz); C-NMR (100 MHz, CDCl3) δ: 159.3, 157.9, 151.8,
150.1, 140.2, 136.0, 135.7, 135.0, 132.0, 131.7, 130.5, 128.8, 128.3, 122.8, 113.7, 113.5, 108.4, 89.0,
49.4, 23.6; HRMS (ESI-TOF+): m/z [M+H]+ calcd. for C25H22ClN6: 441.1589; found: 441.1585.
5-(4-Chlorophenyl)-3-(isopropylimino)-N-pyrazin-2-yl-3,5-dihydrophenazin-2-amine (11b): Under an
atmosphere of N2, toluene (50 mL), 2-bromopyrazine (3 mmol), compound 9 (2 mmol), Pd2(dba)3
(0.1 mmol), DPPF (0.4 mmol) and Cs2CO3 (3 mmol) were added in turn to a two-necked
round-bottomed flask with a reflux condenser. The mixture was refluxed for 2 h, allowed to cool, and
filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash
silica gel chromatography (EtOAc/hexane 1:2) to give compound 11b in 95.2% yield. mp: 228–230 °C,
1H-NMR (300 MHz, CDCl3) δ: 8.43 (1H, s), 8.29 (2H, m), 8.05 (1H, d, J = 2.4 Hz), 7.77 (1H, d,
J = 6.9 Hz), 7.71 (2H, d, J = 8.1 Hz), 7.31 (2H, d, J = 8.1 Hz), 7.17 (2H, m), 6.45 (1H, d,
13
J = 7.8 Hz), 5.28 (1H, s), 3.47 (1H, m), 1.11 (6H, d, J = 6.3 Hz); C-NMR (100 MHz, CDCl3) δ:
151.4, 151.0, 150.4, 141.6, 140.0, 136.4, 135.9, 135.8, 135.5, 135.1, 131.7, 130.4, 128.9, 128.4, 123.0,

Molecules 2011, 16
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113.8, 107.5, 88.9, 49.3, 23.6; HRMS (ESI-TOF+): m/z [M+H]+ calcd. for C25H22ClN6: 441.1589;
found: 441.1581.
4. Conclusions
In summary, we have successfully synthesized riminophenazines with a pyrimidine or pyrazine
substituent on the molecule. To our knowledge, this is the first synthesis of heteroaromatic-substituted
riminophenazine derivatives and it should prove valuable for the study of the chemistry and biological
activity of this class of compounds.
Acknowledgments
The authors thank Global Alliance for TB Drug Development and National Science and
Technology Project of China (No. 2009ZX09102-054) for financial support on this project.
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Sample Availability: Samples of the compounds 5-9, 11a and 11b are available from the authors.
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