Isocyanide-based four-component synthesis of benzo[ a ]pyrano[2,3- c ]phena-zines

Article abstract of DOI:10.1055/s-0031-1289968

An efficient and simple method for the synthesis of biologically interesting benzo[a]pyrano[2,3-c]phenazines by a four-component reaction of o-phenylenediamines, 2-hydroxynaphthalene-1,4-dione, isocyanides, and dialkyl acetylenedicarboxylates in N,N-dimethylformamide at 100 C is reported. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289968

PAPER
235
Isocyanide-Based Four-Component Synthesis of Benzo[a]pyrano[2,3-c]phena-
zines
F
our-Componen
a
t
Synthesi
y
s
of
B
enzo[
a
e
]pyrano[2,3
b
-
c
]phenazine
e
s
h Amanpour, Peiman Mirzaei, Ayoob Bazgir*
Department of Chemistry, Shahid Beheshti University, General Campus, Tehran 1983963113, Iran
Fax +98(22)431663; E-mail: a_bazgir@sbu.ac.ir
Received 4 October 2011; revised 16 November 2011
cidal,13 and antiplatelet14 effects, and are either isolated
Abstract: An efficient and simple method for the synthesis of bio-
logically interesting benzo[a]pyrano[2,3-c]phenazines by a four-
component reaction of o-phenylenediamines, 2-hydroxynaphtha-
lene-1,4-dione, isocyanides, and dialkyl acetylenedicarboxylates in
N,N-dimethylformamide at 100 °C is reported.
from natural sources or synthetically constructed. Some
benzophenazines are dual inhibitors of topoisomerase I
and II, two key enzymes that affect the topology of DNA
at different points in the cell cycle.15–18 Also, the antitu-
mor activity of pyridophenazinediones and pyridazi-
nophenazinedione derivatives was reported.19,20 Due to
the wide range biological activity of phenazines, research
in this area continues to thrive and mostly is directed to-
ward the synthesis of compounds with enhanced biologi-
cal activity.9,21–27 A literature survey reveals that a limited
number of synthetic routes for the preparation of benzopy-
ranophenazines have been reported. Recently, the two-
step synthesis of benzopyranophenazines under harsh
conditions and with long reaction time was described by
Perez-Sacau and co-workers.28 To the best of our knowl-
edge, there is only one report of the synthesis of benzopy-
ranophenazines via a multicomponent reaction.29
Key words: isocyanide, benzo[a]pyrano[2,3-c]phenazine, dialkyl
acetylenedicarboxylates, phenazine, phenylenediamines
Within the past decade, the resurgence of interest in mul-
ticomponent reactions (MCRs) has been driven, not only
due to their convergent nature, superior atom economy,
and straightforward experimental procedures, but also be-
cause of their value in pharmaceutical industry for the
construction of low-molecular-weight compound libraries
through combinatorial strategies and parallel synthesis.1,2
Isocyanide-based multicomponent reactions are particu-
larly interesting as they are more versatile and diverse
than other MCRs.3 The great potential of isocyanides for
the development of multicomponent reactions lies in the
diversity of the available bond-forming processes, func-
tional group tolerance, and the high levels of chemo-,
regio-, and stereoselectivity often observed. MCRs in-
volving isocyanides have emerged as valuable tools for
the preparation of structurally diverse chemical libraries
of drug-like heterocyclic compounds.4–8 In this context,
phenazine derivatives show interesting features that make
them attractive for use in isocyanide-based multicompo-
nent reactions.
Although isocyanide-based multicomponent reactions
have been applied for the synthesis of various heterocy-
cles,30 to date, the synthesis of benzo[a]pyrano[2,3-
c]phenazines has not been reported by this route.
As part of our current studies on the development of mul-
ticomponent reactions,31–35 in this paper, we report an ef-
ficient method for the preparation of benzo[a]pyrano[2,3-
c]phenazines, which proceeds via the formation of five
new bonds, [2 N–C + 2 C–C + C–O] by a isocyanide-
based four-component strategy.
A mixture of phenylenediamines 1, 2-hydroxynaphtha-
lene-1,4-dione (2), isocyanides 3, and dialkyl acetylenedi-
carboxylates 4 in the absence of any catalyst in N,N-
dimethylformamide under thermal and one-pot conditions
More than 6000 phenazine-containing compounds have
been identified and reported during the past century.9 Sev-
eral hundreds of the known phenazines possess biological
activity, including antimalarial,10,11 trypanocidal,12 fungi-
R2O
O
H
R2OOC
N
R1
O
COOR2
OH
NH2
NH2
N
N
O
DMF
+ R1NC +
+
100 °C
COOR2
O
1a–d
2
3a–c
4a, b
5a–n
Scheme 1 The synthesis of benzo[a]pyrano[2,3-c]phenazines 5
SYNTHESIS 2012, 44, 235–240
x
x
.x
x
.2
0
1
1
Advanced online publication: 15.12.2011
DOI: 10.1055/s-0031-1289968; Art ID: N94411SS
© Georg Thieme Verlag Stuttgart · New York

236
T. Amanpour et al.
PAPER
Table 1 The Synthesis of Benzopyranophenazines 5 (continued)
leads to the formation of benzo[a]pyrano[2,3-c]phenazine
derivatives 5a–k after 20 hours in good yields
(Scheme 1). When the 2,3-diaminomaleonitrile 1d was
used, the desired 5H-benzo[h]pyrano[3,2-f]quinoxaline-
5,6-dicarboxylates 5l–n were obtained in good yields.
Product 5
Yield (%)
80
5e
COOMe
MeOOC
N
H
N
To explore the scope and limitations of the reaction and
obtain various substituted benzo[a]pyrano[2,3-c]phena-
zines, we extended the procedure to four diamines 1a–d,
three isocyanides 3a–c, and two acetylenic esters 4a,b
(Scheme 1). In this method, fourteen new compounds 5
were selectively synthesized by the one-pot, four-compo-
nent condensation reaction in good yields. The results are
O
N
5f
92
85
COOEt
EtOOC
N
H
N
1
summarized in Table 1. H NMR spectra of the crude
O
products clearly indicated the formation of benzo[a]pyra-
no[2,3-c]phenazine 5. As anticipated from our original re-
sults, these reactions proceeded very cleanly under mild
conditions, and no undesirable side reactions were ob-
served. In addition, as the starting materials are ready ac-
cessible, a modular approach to the synthesis of
benzopyranophenazine is possible. The workup of these
very clean reactions involves only filtration and simple
washing with diethyl ether.
N
5g
COOEt
EtOOC
H
N
N
O
N
Table 1 The Synthesis of Benzopyranophenazines 5
5h
81
90
80
COOMe
MeOOC
N
H
N
Product 5
Yield (%)
84
5a
O
COOMe
MeOOC
N
N
H
N
O
N
5i
COOMe
MeOOC
N
Cl
Cl
Cl
H
N
Cl
Cl
Cl
O
5b
5c
5d
86
85
86
COOEt
EtOOC
N
N
H
N
O
N
5j
COOMe
MeOOC
N
H
N
O
COOMe
MeOOC
N
N
H
N
O
N
5k
95
83
COOEt
EtOOC
N
H
N
O
COOEt
EtOOC
N
N
H
N
O
N
5l
COOMe
MeOOC
H
NC
N
N
O
NC
N
Synthesis 2012, 44, 235–240
© Thieme Stuttgart · New York

PAPER
Four-Component Synthesis of Benzo[a]pyrano[2,3-c]phenazines
237
Table 1 The Synthesis of Benzopyranophenazines 5 (continued)
We have not established a detailed mechanism for the for-
mation of benzopyranophenazine 5, however, a reason-
able possibility is shown in Scheme 2. The formation of 5
is expected to proceed via initial condensation of 1 and 2
to afford benzo[a]phenazin-5-ol 6. Then, the 1:1 zwitter-
ionic ionic intermediate 7, formed from the isocyanide
and the acetylenic ester, is protonated by 6 to furnish in-
termediate 8, which is attacked by the anion of the CH-
acidic 9 in a Michael fashion to produce ketenimine 10.
The latter then can undergo cyclization under the reaction
conditions to afford the benzopyranophenazine 5. Indeed,
we demonstrated that this process can be conducted step-
wise by condensing 1a with 2 and isolating ben-
zo[a]phenazin-5-ol 6a in a quantitative yield. Compound
6a was further reacted with cyclohexyl isocyanide (3a)
and dimethyl acetylenedicarboxylate (4a) under the same
reaction conditions and gave a comparable yield of 5a
(Scheme 3).
Product 5
Yield (%)
94
5m
COOMe
MeOOC
N
H
N
NC
O
NC
N
5n
95
COOEt
EtOOC
N
H
N
NC
O
NC
N
All compounds described in the paper were synthesized
for the first time and the products were characterized by
IR, mass spectroscopy, NMR, and elemental analysis.
In conclusion, we have described an efficient and one-pot
synthesis of benzo[a]pyrano[2,3-c]phenazines starting
from simple and readily available precursors under neu-
tral conditions without activation or modifications. The
CO2R2
C
1 + 2
N
3 + 4
R2O2C
HC
C
8
OH
R1
R1-N C C C CO2R2
N
N
9
O
CO2R2
N
7
6
R2O2C
R2O2C
C
NR1
N
N
OH
5
10
Scheme 2 Proposed mechanism of the reaction
O
NH2
+
OH
N
OH
DMF
100 °C
NH2
N
1a
O
2
6a
MeO
O
O
H
N
NC
MeOOC
N
COOMe
N
N
OH
DMF
100 °C
+
+
COOMe
N
6a
3a
4a
5a
82%
Scheme 3 Benzo[a]phenazin-5-ol 6 as intermediate in the reaction
© Thieme Stuttgart · New York
Synthesis 2012, 44, 235–240

238
T. Amanpour et al.
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Dimethyl 3-(tert-Butylamino)-1H-benzo[a]pyrano[2,3-c]phena-
zine-1,2-dicarboxylate (5c)
Yellow powder; yield: 401 mg (85%); mp 237–239 °C.
IR (KBr): 3200, 1737, 1671 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.60 (s, 9 H, CH3), 3.49 (s, 3
H, OCH3), 3.77 (s, 3 H, OCH3), 5.64 (s, 1 H, CH), 7.97–8.37 (m, 7
H, HAr), 9.09 (s, 1 H, NH), 9.28–9.31 (m, 1 H, HAr).
13C NMR (75 MHz, CDCl3): d = 30.6, 36.4, 51.2, 51.3, 52.3, 52.5,
72.9, 112.7, 122.0, 125.7, 126.2, 128.4, 128.5, 129.2, 129.5, 129.6,
130.0, 131.1, 140.4, 141.1, 141.6, 142.6, 142.7, 147.7, 161.4, 170.3,
174.0.
products are of potential synthetic and pharmacological
interest. The simplicity of the presented procedure makes
it an interesting alternative to the complex multistep ap-
proaches for the synthesis of phenazine derivatives. More-
over, it is worth noting that in total two C–C, two N–C,
and one C–O bonds were formed with concomitant cre-
ation of a fused phenazine ring in this one-pot, four-com-
ponent process.
The chemical used in this work were obtained from Fluka and
Merck and were used without purification. Melting points were
measured on an Electrothermal 9100 apparatus and are uncorrected.
Mass spectra were recorded on a Finnigan-MAT 8430 mass spec-
trometer operating at an ionization potential of 70 eV. 1H and 13C
NMR spectra were recorded on a Bruker DRX-300 Avance spec-
trometer at 300.13 and 75.47 MHz. 1H and 13C NMR spectra were
obtained in solns in DMSO-d6 and CDCl3 using TMS as internal
standard. IR spectra were recorded using an FTIR apparatus,
Bomem MB-series. Elemental analyses were performed using a
Heracus CHN-O-Rapid analyzer.
MS (EI, 70eV): m/z = 471 (M+).
Anal. Calcd for C27H25N3O5: C, 68.78; H, 5.34; N, 8.91. Found: C,
68.85; H, 5.41; N, 8.84.
Diethyl 3-(tert-Butylamino)-1H-benzo[a]pyrano[2,3-c]phena-
zine-1,2-dicarboxylate (5d)
Yellow powder; yield: 430 mg (86%); mp 239–241 °C.
IR (KBr): 3200, 1721, 1669 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.08 (t, J = 6.9 Hz, 3 H, CH3),
1.31 (t, J = 6.4 Hz, 3 H, CH3), 1.60 (s, 9 H, CH3), 3.97 (m, 2 H,
OCH2), 4.25 (ABq, J = 6.4 Hz, 2 H, OCH2), 5.60 (s, 1 H, CH), 8.00–
8.38 (m, 7 H, HAr), 9.14 (s, 1 H, NH), 9.34–9.37 (m, 1 H, HAr).
13C NMR: due to very low solubility 5d, the 13C NMR data could
not be recorded.
Benzopyranophenazines 5; General Procedure
To a magnetically stirred soln of diamine 1 (1 mmol) and 2-hydroxy-
naphthalene-1,4-dione (2, 1 mmol) in DMF (3 mL) at 100 °C were
added, after 2 h, isocyanide 3 (1 mmol) and dialkyl acetylenedicar-
boxylate 4 (1 mmol). The mixture was finally stirred for 20 h at 100
°C. After completion of the reaction, the mixture was cooled to r.t.
The solvent was evaporated and the residue was washed with Et2O
(10 mL) to afford the pure product 5.
MS (EI, 70eV): m/z = 499 (M+).
Anal. Calcd for C29H29N3O5: C, 69.72; H, 5.85; N, 8.41. Found: C,
69.63; H, 5.92; N, 8.50.
Dimethyl 3-(Cyclohexylamino)-1H-benzo[a]pyrano[2,3-
c]phenazine-1,2-dicarboxylate (5a)
Yellow powder; yield: 418 mg (84%); mp 225–227 °C.
IR (KBr): 3267, 1742, 1677 cm–1.
Dimethyl 3-(2,4,4-Trimethylpentan-2-ylamino)-1H-ben-
zo[a]pyrano[2,3-c]phenazine-1,2-dicarboxylate (5e)
Yellow powder; yield: 423 mg (80%); mp 197–199 °C.
IR (KBr): 3300, 1744, 1674 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 0.96 (s, 9 H, CH3), 1.62 (s, 3
H, CH3), 1.65 (s, 3 H, CH3), 2.02 (s, 2 H, CH2), 3.47 (s, 3 H, OCH3),
3.77 (s, 3 H, OCH3), 5.65 (br s, 1 H, CH), 7.98–8.38 (m, 7 H, HAr),
9.20 (s, 1 H, NH), 9.27–9.30 (m, 1 H, HAr).
13C NMR (75 MHz, CDCl3): d = 31.1, 31.4, 31.6, 31.8, 36.4, 51.2,
52.2, 53.1, 56.1, 72.6, 113.0, 122.1, 125.8, 126.2, 128.6, 129.5,
129.5, 129.6, 130.0, 131.2, 140.4, 141.2, 141.6, 141.7, 147.8, 161.1,
161.4, 170.3, 173.9.
1H NMR (300 MHz, CDCl3): d = 1.38–2.23 (m, 10 H, 5 Cy-CH2),
3.63 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 4.10 (br s, 1 H, CHN),
5.78 (s, 1 H, CH), 7.84–8.36 (m, 7 H, HAr), 8.85 (d, J = 7.4 Hz, 1 H,
NH), 9.38–9.41 (m, 1 H, HAr).
13C NMR (75 MHz, CDCl3): d = 24.6, 24.7, 25.6, 33.6, 33.9, 36.7,
50.6, 51.2, 52.3, 72.2, 112.7, 121.5, 125.6, 126.3, 128.6, 129.5,
129.6, 130.0, 130.1, 131.1, 141.1, 141.7, 142.6, 147.4, 160.1, 170.1,
174.1.
MS (EI, 70eV): m/z = 497 (M+).
Anal. Calcd for C29H27N3O5: C, 70.01; H, 5.47; N, 8.45. Found: C,
69.90; H, 5.41; N, 8.36.
MS (EI, 70eV): m/z = 527 (M+).
Anal. Calcd for C31H33N3O5: C, 70.57; H, 6.30; N, 7.96. Found: C,
70.50; H, 6.36; N, 7.88.
Diethyl 3-(Cyclohexylamino)-1H-benzo[a]pyrano[2,3-c]phena-
zine-1,2-dicarboxylate (5b)
Yellow powder; yield: 452 mg (86%); mp 184–186 °C.
IR (KBr): 3240, 1720, 1669 cm–1.
Diethyl 3-(2,4,4-Trimethylpentan-2-ylamino)-1H-benzo[a]pyr-
ano[2,3-c]phenazine-1,2-dicarboxylate (5f)
Yellow powder; yield: 512 mg (92%); mp 176–178 °C.
IR (KBr): 3400, 1731, 1666 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 0.96 (s, 9 H, CH3), 1.05 (t,
J = 7 Hz, 3 H, CH3), 1.30 (t, J = 7.1 Hz, 3 H, CH3), 1.61 (s, 3 H,
CH3), 1.64 (s, 3 H, CH3), 2.03 (s, 2 H, CH2), 3.95 (m, 2 H, OCH2),
4.24 (ABq, J = 7 Hz, 2 H, OCH2), 5.62 (s, 1 H, CH), 7.99–8.39 (m,
7 H, HAr), 9.25 (s, 1 H, NH), 9.34–9.36 (m, 1 H, HAr).
1H NMR (300 MHz, CDCl3): d = 1.21 (t, J = 5.6 Hz, 3 H, CH3),
1.42–2.22 (m, 13 H, 5 Cy-CH2, CH3), 4.09 (br s, 3 H, CHN, OCH2),
4.35 (ABq, J = 5.6 Hz, 2 H, OCH2), 5.74 (s, 1 H, CH), 7.85–8.33
(m, 7 H, HAr), 8.87 (br s, 1 H, NH), 9.40 (br s, 1 H, HAr).
13C NMR (75 MHz, CDCl3): d = 14.3, 14.8, 24.7, 25.6, 33.6, 33.9,
37.0, 50.5, 59.6, 60.8, 72.3, 112.7, 121.6, 125.5, 126.4, 128.6,
129.4, 129.5, 129.9, 130.1, 131.1, 140.5, 141.0, 141.9, 142.6, 147.4,
159.9, 169.8, 174.2.
13C NMR: due to very low solubility 5f, the 13C NMR data could not
be recorded.
MS (EI, 70eV): m/z = 525 (M+).
MS (EI, 70eV): m/z = 555 (M+).
Anal. Calcd for C31H31N3O5: C, 70.84; H, 5.94; N, 7.99. Found: C,
70.72; H, 5.99; N, 7.93.
Anal. Calcd for C33H37N3O5: C, 71.33; H, 6.71; N, 7.56. Found: C,
71.44; H, 6.76; N, 7.49.
Synthesis 2012, 44, 235–240
© Thieme Stuttgart · New York

PAPER
Four-Component Synthesis of Benzo[a]pyrano[2,3-c]phenazines
239
Diethyl 3-(Cyclohexylamino)-11,12-dimethyl-1H-benzo[a]pyr-
ano[2,3-c]phenazine-1,2-dicarboxylate (5g)
Yellow powder; yield: 471 mg (85%); mp 200–205 °C.
Diethyl 11,12-Dichloro-3-(2,4,4-trimethylpentan-2-ylamino)-
1H-benzo[a]pyrano[2,3-c]phenazine-1,2-dicarboxylate (5k)
Yellow powder; yield: 594 mg (95%); mp 195–205 °C.
IR (KBr): 3400, 1721, 1671 cm–1.
IR (KBr): 3300, 1723, 1669 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.20 (t, J = 6.9 Hz, 3 H, CH3),
1.42–2.23 (m, 19 H, 5 Cy-CH2, 3 CH3), 4.09 (br s, 3 H, CHN,
OCH2), 4.39 (ABq, J = 6.9 Hz, 2 H, OCH2), 5.75 (s, 1 H, CH), 7.84–
8.21 (m, 5 H, HAr), 8.87 (d, J = 7.2 Hz, 1 H, NH), 9.38 (br s, 1 H,
HAr).
13C NMR (75 MHz, CDCl3): d = 14.3, 14.8, 20.6, 24.7, 25.6, 33.6,
33.9, 37.0, 50.5, 59.5, 60.7, 72.4, 112.8, 121.4, 125.3, 126.2, 128.1,
128.2, 128.3, 128.4, 129.6, 131.3, 139.8, 140.2, 140.4, 141.0, 141.1,
141.8, 146.8, 160.0, 169.8, 174.1.
1H NMR (300 MHz, CDCl3): d = 1.03 (s, 9 H, CH3), 1.18 (s, 3 H,
CH3), 1.43 (s, 3 H, CH3), 1.66 (s, 3 H, CH3), 1.71 (s, 3 H, CH3), 2.06
(s, 2 H, CH2), 4.06 (br s, 2 H, OCH2), 4.27–4.39 (m, 2 H, OCH2),
5.73 (s, 1 H, CH), 7.89–9.33 (m, 7 H, HAr, NH).
13C NMR (75 MHz, CDCl3): d = 14.2, 14.8, 31.2, 31.6, 31.8, 36.5,
53.1, 56.1, 56.2, 59.7, 60.8, 72.6, 96.1, 122.3, 125.9, 128.9, 129.8,
130.6, 130.7, 134.0, 141.1, 169.7, 169.8, 173.6.
MS (EI, 70eV): m/z = 624 (M+).
Anal. Calcd for C33H35Cl2N3O5: C, 63.46; H, 5.65; N, 6.73. Found:
C, 63.55; H, 5.71; N, 6.68.
MS (EI, 70eV): m/z = 553 (M+).
Anal. Calcd for C33H35N3O5: C, 71.59; H, 6.37; N, 7.59. Found: C,
71.51; H, 6.30; N, 7.53.
Dimethyl 2,3-Dicyano-7-(cyclohexylamino)-5H-benzo[h]pyra-
no[3,2-f]quinoxaline-5,6-dicarboxylate (5l)
Dimethyl 3-(tert-Butylamino)-11,12-dimethyl-1H-benzo[a]pyr-
ano[2,3-c]phenazine-1,2-dicarboxylate (5h)
Yellow powder; yield: 405 mg (81%); mp 223–227 °C.
IR (KBr): 3350, 1729, 1667 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.68 (s, 9 H, CH3), 2.57 (s, 6
H, CH3), 3.61 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 5.84 (s, 1 H,
CH), 7.28–8.42 (m, 5 H, HAr), 9.20 (s, 1 H, NH), 9.40 (br s, 1 H,
HAr).
13C NMR (75 MHz, CDCl3): d = 20.5, 20.6, 30.6, 36.5, 51.2, 52.2,
52.5, 73.0, 112.9, 121.9, 125.4, 126.0, 128.1, 128.2, 128.3, 129.6,
131.3, 140.4, 140.6, 140.9, 141.0, 141.9, 147.1, 161.6, 170.3, 174.0.
Yellow powder; yield: 414 mg (83%); mp 198–202 °C (dec).
IR (KBr): 3200, 2150, 1741, 1677 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.26–2.20 (m, 10 H, 5 Cy-CH2),
3.64 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 4.06 (br s, 1 H, CHN),
5.63 (s, 1 H, CH), 7.97–8.33 (m, 3 H, HAr), 8.77 (d, J = 7.3 Hz, 1 H,
NH), 9.25 (d, J = 7.9 Hz, 1 H, HAr).
13C NMR (75 MHz, CDCl3): d = 24.5, 25.4, 31.4, 33.5, 33.8, 35.9,
36.5, 50.8, 51.3, 52.6, 71.9, 112.6, 113.6, 113.8, 122.0, 126.4,
127.1, 129.0, 130.3, 132.6, 140.0, 141.7, 151.1, 159.4, 162.5, 169.4,
173.0.
MS (EI, 70eV): m/z = 497 (M+).
MS (EI, 70eV): m/z = 499 (M+).
Anal. Calcd for C27H23N5O5: C, 65.18; H, 4.66; N, 14.08. Found: C,
65.11; H, 4.61; N, 13.99.
Anal. Calcd for C29H29N3O5: C, 69.72; H, 5.85; N, 8.41. Found: C,
69.61; H, 5.92; N, 8.32.
Dimethyl 7-(tert-Butylamino)-2,3-dicyano-5H-benzo[h]pyra-
no[3,2-f]quinoxaline-5,6-dicarboxylate (5m)
Yellow powder; yield: 444 mg (94%); mp 210–211 °C (dec).
IR (KBr): 3200, 2231, 1739, 1668 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.65 (s, 9 H, CH3), 3.64 (s, 3 H,
OCH3), 3.87 (br s, 3 H, OCH3), 5.65 (s, 1 H, CH), 8.00–8.53 (m, 3
H, HAr), 9.12 (s, 1 H, NH), 9.25 (d, J = 7.4 Hz, 1 H, HAr).
13C NMR (75 MHz, CDCl3): d = 30.6, 35.6, 51.4, 52.6, 52.8, 72.7,
112.6, 113.6, 113.8, 122.5, 126.5, 126.9, 128.2, 129.1, 130.2, 130.6,
132.6, 140.0, 141.6, 151.3, 160.6, 169.7, 172.9.
Dimethyl 11,12-Dichloro-3-(cyclohexylamino)-1H-ben-
zo[a]pyrano[2,3-c]phenazine-1,2-dicarboxylate (5i)
Yellow powder; yield: 510 mg (90%); mp 253–255 °C (dec).
IR (KBr): 3200, 1730, 1668 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.39–2.22 (m, 10 H, 5 Cy-CH2),
3.62 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 4.09 (br s, 1 H, CHN),
5.67 (s, 1 H, CH), 7.82–8.43 (m, 5 H, HAr), 8.83 (d, J = 7.5 Hz, 1 H,
NH), 9.27 (d, J = 7.3 Hz, 1 H, HAr).
13C NMR (75 MHz, CDCl3): d = 24.6, 25.5, 33.6, 33.8, 36.5, 50.6,
51.2, 52.4, 72.1, 121.6, 125.7, 126.5, 128.9, 129.7, 130.6, 134.0,
134.7, 139.5, 141.0, 141.1, 142.3, 148.2, 159.9, 169.9, 173.8.
MS (EI, 70eV): m/z = 471 (M+).
Anal. Calcd for C25H21N5O5: C, 63.69; H, 4.49; N, 14.85. Found: C,
63.75; H, 4.45; N, 14.93.
MS (EI, 70eV): m/z = 566 (M+).
Anal. Calcd for C29H25Cl2N3O5: C, 61.49; H, 4.45; N, 7.42. Found:
C, 61.55; H, 4.31; N, 7.48.
Diethyl 2,3-Dicyano-7-(2,4,4-trimethylpentan-2-ylamino)-5H-
benzo[h]pyrano[3,2-f]quinoxaline-5,6-dicarboxylate (5n)
Yellow powder; yield: 528 mg (95%); mp 221–223 °C.
IR (KBr): 3400, 2200, 1743, 1670 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.02 (s, 9 H, CH3), 1.24 (t, J = 6.5
Hz, 3 H, CH3), 1.42 (t, J = 6.5 Hz, 3 H, CH3), 1.66 (s, 3 H, CH3),
1.71 (s, 3 H, CH3), 2.03 (br s, 2 H, CH2), 4.08 (m, 2 H, OCH2), 4.33
(ABq, J = 6.5 Hz, 2 H, OCH2), 5.62 (s, 1 H, CH), 8.00–8.55 (m, 3
H, HAr), 9.24–9.28 (m, 2 H, NH, HAr).
Dimethyl 3-(tert-Butylamino)-11,12-dichloro-1H-benzo[a]pyra-
no[2,3-c]phenazine-1,2-dicarboxylate (5j)
Yellow powder; yield: 433 mg (80%); mp 237–239 °C.
IR (KBr): 3200, 1737, 1671 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.59 (s, 9 H, CH3), 3.50 (s,
3 H, OCH3), 3.76 (s, 3 H, OCH3), 5.54 (s, 1 H, CH), 7.95–8.52 (m,
5 H, HAr), 9.06 (s, 1 H, NH), 9.15 (d, J = 7.2 Hz, 1 H, HAr).
13C NMR: due to very low solubility 5j, the 13C NMR data could not
be recorded.
MS (EI, 70eV): m/z = 540 (M+).
13C NMR (75 MHz, CDCl3): d = 14.1, 14.7, 31.1, 31.4, 31.7, 31.8,
36.0, 53.4, 56.4, 60.0, 61.3, 72.4, 112.8, 113.7, 113.9, 122.5, 126.5,
127.0, 128.2, 129.1, 130.2, 130.6, 132.5, 140.0, 141.8, 151.4, 160.4,
169.4, 172.9.
Anal. Calcd for C27H23Cl2N3O5: C, 60.01; H, 4.29; N, 7.78. Found:
C, 60.11; H, 4.21; N, 7.86.
MS (EI, 70eV): m/z = 555 (M+).
© Thieme Stuttgart · New York
Synthesis 2012, 44, 235–240

240
T. Amanpour et al.
PAPER
(17) Wang, S.; Miller, W.; Milton, J.; Vicker, N.; Stewart, A.;
Anal. Calcd for C31H33N5O5: C, 67.01; H, 5.99; N, 12.60. Found: C,
67.09; H, 6.06; N, 12.66.
Charlton, P.; Mistry, P.; Hardick, D.; Denny, W. Bioorg.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
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Suh, M.-E.; Lee, H. J.; Ryu, C.-K.; Park Choo, H. Y. Bioorg.
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Acknowledgement
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
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Synthesis 2012, 44, 235–240
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