Palladium-catalyzed domino double n-arylations (inter- and intramolecular) of 1,2-diamino(hetero)arenes with o,o-dihalo(hetero)arenes for the synthesis of phenazines and pyridoquinoxalines

Article abstract of DOI:10.1002/ejoc.201301091

Domino reactions for the synthesis of phenazines have been developed that start from 1,2-diaminoarenes and 1,2-dihaloarenes and proceed through palladium-catalyzed double N-arylations (inter- and intramolecular) followed by an in situ oxidation. A variety of functional groups, which include base-sensitive groups, were well tolerated under the optimized reaction conditions to afford phenazines in good to excellent yields. The protocol was extended to the synthesis of pyridoquinoxalines by employing either o-phenylenediamines and 2,3-dihalopyridines or 1,2-diaminopyridines and 1,2-dihaloarenes. Domino reactions for the synthesis of phenazines have been developed that start from 1,2-diaminoarenes and 1,2-dihaloarenes and proceed through palladium-catalyzed double N-arylations (inter- and intramolecular) followed by an in situ oxidation. The protocol was extended to the synthesis of pyridoquinoxalines. Copyright

Full text of DOI:10.1002/ejoc.201301091

FULL PAPER
DOI: 10.1002/ejoc.201301091
Palladium-Catalyzed Domino Double N-Arylations (Inter- and Intramolecular)
of 1,2-Diamino(hetero)arenes with o,oЈ-Dihalo(hetero)arenes for the Synthesis
of Phenazines and Pyridoquinoxalines
Joydev K. Laha,*[a] K. S. Satyanarayana Tummalapalli,[a] and Ankur Gupta[a]
Keywords: Medicinal chemistry / Nitrogen heterocycles / Domino reactions / Palladium / Arenes / Oxidation
Domino reactions for the synthesis of phenazines have been
developed that start from 1,2-diaminoarenes and 1,2-di-
haloarenes and proceed through palladium-catalyzed double
N-arylations (inter- and intramolecular) followed by an in situ
oxidation. A variety of functional groups, which include
base-sensitive groups, were well tolerated under the opti-
mized reaction conditions to afford phenazines in good to ex-
cellent yields. The protocol was extended to the synthesis of
pyridoquinoxalines by employing either o-phenylenedi-
amines and 2,3-dihalopyridines or 1,2-diaminopyridines and
1,2-dihaloarenes.
propriate ortho-substituted diphenylamines in the presence
or absence of a metal catalyst. Although reductive cycliza-
tions of o-nitro-,[7] o,oЈ-dinitro-,[8] and o-nitro-oЈ-fluorodi-
arylamines[9] have been reported to obtain phenazines with
limited substitution patterns, an oxidative cyclization was
effected on o,oЈ-diaminodiarylamines[10] under harsh condi-
tion to yield phenazines. The palladium-catalyzed intramo-
lecular N-arylation of o-amino-oЈ-bromodiarylamines, per-
formed in multiple steps, has also been realized.[11] Recently,
phenazines were prepared in good yields under acidic or
basic conditions from o-nitrosodiphenylamine.[12] Very re-
cently, the palladium[13] or copper-catalyzed[14] homocou-
pling of 2-halogenoanilines was reported to yield symmetri-
cally substituted phenazines. A general structure–activity
relationship analysis is difficult to derive from the literature,
as a large number of diverse targets have been used to eval-
uate biological activity. This is likely because there is not
an adequate, concise, general approach to synthesize phen-
azines.[1]
The palladium-catalyzed C–N bond forming reaction be-
tween (hetero)arylamines and (hetero)aryl halides has
found wide applications in the synthesis of pharmaceutical
drugs, natural products, and compounds that are useful for
materials science.[15] However, reports describing tandem
C–N bond formation through a reaction between 1,2-di-
amino(hetero)arenes and 1,2-dihalo(hetero)arenes are
scarce.[16] Since the early 1900s, Hinsberg’s reaction with
1,2-diaminoarenes and activated 1,2-dihaloheteroarenes
(1,2-dichloroquinoxaline or 1,2-dichloropyrazine) at or
above 150 °C has been used to prepare dihydrodiazacenes
in good yields.[17] Recently, it has been demonstrated that
tandem N,NЈ-arylations of 1,4-disubstituted 2,3-diamino-
naphthalene with activated 1,2-dichloroquinoxaline are not
successful under Hinsberg’s conditions. Subsequently, Bunz
Introduction
Natural and synthetic phenazines display a wide spec-
trum of biological properties that include antibacterial,
antitricholonal, antimalerial, and antitumor activities.[1]
The mode of action for phenazines is proposed to involve
the intercalation into duplex DNA or the generation of
toxic anionic radicals that are involved in redox cycling.
Fluorescent phenazine derivatives that demonstrate photo-
sensitizing activity in photodynamic therapy (PDT)[2] and
bis(triazolyl) phenazine derivatives that exhibit metal-ion
sensor properties in aqueous solution[3] have also been syn-
thesized. A majority of the methods to synthesize phen-
azines involve generating the fused tricyclic skeleton
through the construction of the central heterocyclic ring.
An early approach, which employs a Wohl–Aue procedure,
involves heating aniline and nitrobenzene above 200 °C to
yield phenazines in moderate yields along with the forma-
tion of a significant amount of byproduct.[4] Methods to
prepare phenazine-N-oxide and phenazine-N,NЈ-dioxide are
also known, and upon deoxygenation these compounds af-
ford phenazines in moderate yields.[5] The condensation of
o-phenylenediamines with ortho-benzoquinones, generated
in situ from the corresponding catechols, has been an im-
portant route that directly leads to phenazines.[6] A widely
used approach based on this preparation is followed by an
intramolecular reductive or oxidative cyclization of the ap-
[a] Department of Pharmaceutical Technology (Process
Chemistry), National Institute of Pharmaceutical Education
and Research,
S. A. S. Nagar, Punjab 160062, India
E-mail: jlaha@niper.ac.in
http://www.niper.nic.in/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301091.
8330
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8330–8335

Synthesis of Phenazines and Pyridoquinoxalines
et al. demonstrated that successful coupling could be formation of the N-monoarylated product in varying yields
achieved by a tandem intra- or intermolecular N-arylation (see Table 1, Entries 18 and 19). The reduced yield of the
that employs Pd-ligand catalysts.[18]
phenazine as a result of the lower catalyst loadings may be
Earlier, we demonstrated that a one-pot palladium-cata- explained by the oxidation of dihydrophenazine into phen-
lyzed N-arylation of 1,2-dihalopyridines followed by an in- azine, which could lead to the reductive poisoning of some
tramolecular C–H arylation gave various substituted of the palladium catalyst.[18]
carbolines.[19] Herein, we report a one-pot synthesis of
Table 1. Optimization study for the synthesis of phenazine (1).[a]
phenazines that employs readily available 1,2-diamino-
arenes and unactivated 1,2-dihaloarenes and proceeds
through palladium-catalyzed domino inter- and intramo-
lecular N-arylations followed by an oxidation. Further-
more, an extension of this protocol is also described to syn-
thesize pyridoquinoxalines by utilizing either o-phenylene-
Entry
Metal
source
Ligand
Base
Solvent
%
Yield
diamines and 2,3-dihalopyridines or 1,2-diaminopyridines
and 1,2-dihaloarenes.
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
PdCl2
PPh3
PPh3
PCy3
NaOtBu
Cs2CO3
Cs2CO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
o-Xyl[b]
DMA[b]
toluene
toluene
trace
trace
30
trace
20
0
89
88
85
51
63
30
65
0
60
58
40
35
45
DPEPhos[b] Cs2CO3
Results and Discussion
Xantphos[b] Cs2CO3
DPPF
Cs2CO3
Cs2CO3
Cs2CO3
NaOtBu
NaOtBu
K3PO4
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Initially, a one-pot domino approach was investigated
that involved o-phenylenediamine and 1,2-dibromobenzene
as the two coupling partners to prepare phenazine. Heating
o-phenylenediamine and 1,2-dibromobenzene in the pres-
ence of 10 mol-% Pd(OAc)2, 20 mol-% PPh3, and 2.2 equiv.
of the strong base NaOtBu or 3.3 equiv. of the weak base
Cs2CO3 at 110 °C in toluene produced phenazine in only a
detectable amount (see Table 1, Entries 1 and 2). Changing
the ligand from PPh3 to PCy3 (Cy = cyclohexyl) resulted in
a significant conversion to afford phenazine (1)[7a] in 30%
yield (see Table 1, Entry 3). Next, we investigated the effects
of a few other ligands commonly used in the N-arylation
reactions of arylamines (typically 10 mol-% of the ligand
was used; see Table 1, Entries 4–8). Among them, 2-dicyclo-
hexylphosphino-2Ј,6Ј-dimethoxybiphenyl (S-Phos) and
2,2Ј-bis(diphenylphospino)-1,1Ј-binapthyl (BINAP) had
comparable effects in the presence of 3.3 equiv. of Cs2CO3
to enable the formation of 1 in 89 and 88% yields, respec-
tively. Evidently, when the reaction presented in Entry 8 was
carried out for only 4 h, phenazine (1) and the N-monoaryl-
S-Phos
BINAP
S-Phos
BINAP
S-Phos
S-Phos
S-Phos
S-Phos
S-Phos
S-Phos
S-Phos
S-Phos
BINAP
9
10
11
12
13[c]
14
15
16
17
18[d]
19[e]
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[a] Diamine (0.50 mmol), dibromobenzene (0.50 mmol), Pd(OAc)2
(0.05 mmol), ligand (0.05 mmol), base (1.10 or 1.65 mmol), solvent
(250 mm), 110 °C, 16 h. [b] DPEPhos = (oxydi-2,1-phenylene)-
bis(diphenylphosphine), Xantphos = 4,5-bis(diphenylphosphino)-
9,9-dimethylxanthene, o-Xyl = o-xylene, DMA = N,N-dimethyl-
acetamide. [c] Employed 5 mol-% Pd2(dba)3. [d] Employed 5 mol-
% Pd(OAc)2 and 5 mol-% S-Phos. [e] Used 5 mol-% Pd(OAc)2 and
5 mol-% BINAP.
With the optimized conditions [Pd(OAc)2 (10 mol-%), S-
ated product N1-(2-bromophenyl)benzene-1,2-diamine Phos (10 mol-%), Cs2CO3 (3.3 equiv.), toluene (250 mm),
[1(i)],[20] (see Supporting Information) were isolated in 30 110 °C, 16 h] in hand, we next examined the scope of sub-
and 45% yield, respectively. Remarkably, the formation of strates that were commercially available. 4-Methoxy-o-
N-monoarylated product 1(i) suggests that the reaction fol- phenylenediamine was treated with 1,2-dibromobenzene
lows a domino reaction pathway. Employing the S-Phos li- under the optimized conditions to yield phenazine 2[11b] in
gand produced similar result in the presence of NaOtBu to 78% yield (see Table 2, Entry 1).
give 1 in 85% yield, whereas BINAP produced inferior re-
It is noteworthy that Beifuss et al. published a report
sults and furnished 1 in 51% yield (see Table 1, Entries 9 based on the synthesis of compound 2 through various
and 10). Furthermore, the yield of 1 was lower when S- methods, wherein compound 2 was best obtained in three
Phos was used in the presence of K3PO4 or K2CO3 (see steps with an overall 44% yield.[11b] Also, methyl 3,4-diami-
Table 1, Entries 11 and 12). Although replacing Pd(OAc)2 nobenzoate afforded phenazine 3[21] in 85% yield, which
with Pd2(dba)3 (dba = dibenzylideneacetone) was detrimen- indicated that the ester group tolerated the mild reaction
tal (see Table 1, Entry 13), the formation of 1 was not ob- conditions (see Table 2, Entry 2). However, an electron-de-
served when PdCl2 was employed in the reaction (see ficient o-phenylenediamine such as 4-trifluoromethyl-o-
Table 1, Entry 14). A solvent other than toluene had a sig- phenylenediamine underwent a less effective reaction with
nificant impact on the outcome of the reaction as reflected 1,2-dibromobenzene to afford phenazine 4 in 45% yield (see
in Entries 15–17.
A lower catalyst loading [5 mol-% Table 2, Entry 3). Similarly, o-phenylenediamine derivatives
Pd(OAc)2 and 5 mol-% of either S-Phos or BINAP] resulted were treated with 1,2-dibromo-4,5-(methylenedioxy)benz-
in significantly lower yields of phenazine (1) along with the ene under the optimized conditions to obtain phenazines
Eur. J. Org. Chem. 2013, 8330–8335
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8331

J. K. Laha, K. S. Satyanarayana Tummalapalli., A. Gupta
FULL PAPER
Table 2. Synthesis of various substituted phenazines.[a]
[a] Diamine (0.50 mmol), dibromobenzene (0.50 mmol), Pd(OAc)2 (0.05 mmol), S-Phos (0.05 mmol), Cs2CO3 (1.65 mmol), solvent
(250 mm), 110 °C, 16 h.
8332
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8330–8335

Synthesis of Phenazines and Pyridoquinoxalines
5–7 in good to excellent yields (see Table 2, Entries 4–6). Table 3. Synthesis of pyridoquinoxalines.[a]
Gratifyingly, the o-phenylenediamines that were treated
with 1,2-dichlorobenzene under the optimized conditions
also furnished phenazines 1–4 in 24–52% yields (see
Table 2, Entries 7–10). A similar trend was observed, but
with reduced reactivity between the o-phenylenediamines
and 1,2-dichlorobenzene. Furthermore, o-phenylenediam-
ine underwent a reaction with 3,4-dichlorobenzonitrile un-
der the one-pot domino reaction conditions to afford phen-
azine 8[22] in 62% yield (see Table 2, Entry 11). Similarly, 4-
methoxy-o-phenylenediamine gave a separable 3:2 mixture
of regioisomeric phenazines 9 and 10 with a combined 75%
yield (see Table 2, Entry 12). The reaction of methyl 3,4-
diaminobenzoate and 3,4-dichlorobenzonitrile gave a crude
product, which upon isolation provided phenazine 11[22] in
54% yield (see Table 2, Entry 13).
Next, we turned our attention to the development of
metal-catalyzed domino reactions that employ either o-
phenylenediamines and 2,3-dihalopyridines or 1,2-diamino-
pyridines and 1,2-dihaloarenes for the synthesis of pyrido-
quinoxalines (see Table 3).[23] Disappointingly, we observed
that the treatment of o-phenylenediamine with 2,3-dibro-
mopyridine under the optimized conditions afforded pyr-
ido[2,3-b]quinoxaline 12[24] in Ͻ10% yield. Previously,
we[19] and others[25] realized that palladium-catalyzed N-
arylation reactions between anilines and 1,2-dihalopyrid-
ines could be best effected in the presence of a strong base
(NaOtBu). To our delight, o-phenylenediamine underwent
a reaction with either 2,3-dibromopyridine or 2,3-dichloro-
5-trifluoromethylpyridine under modified conditions
[a] Pd(OAc)2 (10 mol-%), S-Phos (10 mol-%), NaOtBu (3.5 equiv.),
[Pd(OAc)2 (10 mol-%), S-Phos (10 mol-%), NaOtBu
(3.5 equiv.), toluene/dioxane (3:1, 250 mm), 110 °C, 16 h] to
afford pyrido[2,3-b]quinoxalines 12[24] and 13 in 86 and
30% yields, respectively (see Table 3, Entries 1 and 2). Sub-
sequently, the reaction between 2,3- or 3,4-diaminopyridine
and 1,2-dibromobenzene under the modified conditions
gave 12 and pyrido[3,4-b]quinoxaline 14 in 52 and 88%
yields, respectively (see Table 3, Entries 3 and 4). Pleasingly,
when 3,4-diaminopyridine was treated with 1,2-dichloro-
benzene, 14 was isolated in 70% yield (see Table 3, Entry 5).
The reaction between 3,4-diaminopyridine and 1,2-di-
bromo-4,5-(methylenedioxy)benzene gave pyrido[3,4-b]-
quinoxaline 15, albeit in the low yield of 31% (see Table 3,
Entry 6).
toluene/dioxane (3:1, 250 mm), 110 °C, 16 h.
ines in good to excellent yields. In so doing, we developed
general metal-catalyzed domino inter- and intramolecular
N-arylations of 1,2-diamino(hetero)arenes with 1,2-di-
halo(hetero)arenes, which were largely unexplored pre-
viously. The present method may allow easy access to vari-
ous substituted phenazines and pyridoquinoxalines for a ge-
neral structure–activity relationship study.
Experimental Section
General Methods: All reagents and solvents were purchased from
commercial sources and used as received. All of the 1,2-diami-
no(hetero)arenes and 1,2-dihalo(hetero)arenes were purchased
from commercial vendors. All palladium-catalyzed domino reac-
tions were degassed and performed in screw-capped vials under
argon. The 1H and 13C NMR spectroscopic data were recorded
with a 400 MHz spectrometer and are reported in δ units. The sam-
ples were dissolved in CDCl3, and the coupling constants (J values)
are reported in Hz. Column chromatography was performed on
silica gel (100–200 or 230–400 mesh). High resolution mass spectra
(HRMS) were obtained with a Bruker-Maxis. All melting points
were recorded with a melting point apparatus that was equipped
with a calibrated thermometer. All new compounds were charac-
Conclusions
In summary, we have developed domino reactions for
synthesis for phenazines by employing palladium-catalyzed
double N-arylation reactions (inter- and intramolecular)
and starting from readily available 1,2-diaminoarenes and
1,2-dihaloarenes. The protocol was extended to the synthe-
sis of pyridoquinoxalines by utilizing o-phenylenediamines
and 2,3-dihalopyridines or 1,2-diaminopyridines and 1,2-
dihaloarenes. A variety of functional groups, which in-
cluded base-sensitive groups, were tolerated under the opti-
1
terized by using melting point (for solids), H and 13C NMR, IR,
mized conditions to afford phenazines or pyridoqunioxal- and HRMS data.
Eur. J. Org. Chem. 2013, 8330–8335
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8333

J. K. Laha, K. S. Satyanarayana Tummalapalli., A. Gupta
FULL PAPER
General Procedure for the Synthesis of Phenazines: In a screw-
capped vial that was equipped with a rubber septum, a mixture of
the o-phenylenediamine (0.5 mmol), the 1,2-dibromobenzene
(0.5 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), S-Phos (20.5 mg,
0.05 mmol), and Cs2CO3 (537 mg, 1.65 mmol) in toluene (2 mL)
was purged with argon for approximately 10 min and then heated
at 110 °C for 16 h under argon. The reaction mixture was cooled
to room temperature and then diluted with an excess amount of
ethyl acetate. The obtained suspension was filtered through a Celite
bed, and the filtrate was concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel (pe-
troleum ether/ethyl acetate, 4:1 to 3:2) to give the phenazine.
13C NMR (100 MHz, CDCl3): δ = 166.5, 153.3, 152.7, 144.1,143.7,
143.2, 140.6, 132.0, 130.4, 129.1, 128.3, 103.3, 103.1, 102.9,
52.6 ppm. HRMS: calcd. for C15H11N2O4 [M + H]+ 283.0719;
found 283.0710. IR (KBr): ν = 2318, 1725, 1635, 1446, 1275, 1260,
˜
1082, 764, 749 cm–1.
Phenazine-2-carbonitrile (8):[22] Yellow solid; m.p. 212–214 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.67 (d, J = 1.3 Hz, 1 H), 8.34 (d,
J = 8.9 Hz, 1 H), 8.25–8.29 (m, 2 H); 7.90–7.97 (m, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 144.6, 144.4, 143.8, 141.8, 136.6,
132.4, 131.8, 131.5, 130.0, 129.8, 129.6, 118.0, 113.8 ppm. HRMS:
calcd. for C13H8N3 [M + H]+ 206.0718; found 206.0709. IR (KBr):
ν = 1635, 1446, 1275, 1260, 1083, 1020, 764, 750 cm–1.
˜
N1-(2-Bromophenyl)benzene-1,2-diamine [1(i)]:[20] Pale yellow li-
7-Methoxyphenazine-2-carbonitrile (9): Yellow solid; m.p. 190–
194 °C. 1H NMR (400 MHz, CDCl3): δ = 8.58 (d, J = 1.2 Hz, 1
H), 8.31 (d, J = 8.8 Hz, 1 H), 8.12 (d, J = 9.5 Hz, 1 H), 7.86 (dd,
J = 8.8, 1.6 Hz, 1 H), 7.61 (dd, J = 9.5, 2.7 Hz, 1 H), 7.41 (d, J =
2.6 Hz, 1 H), 4.07 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 162.3, 146.2, 142.3, 142.2, 141.8, 135.6, 131.4, 130.8, 128.7, 128.4,
118.2, 113.6, 104.4, 56.1 ppm. HRMS: calcd. for C14H10N3O [M +
H]+ 236.0824; found 236.0818.
1
quid. H NMR (400 MHz, CDCl3): δ = 7.50 (dd, J = 7.9, 1.3 Hz,
1 H), 7.10 (m, 3 H), 6.84 (dd, J = 7.8, 1.2 Hz, 1 H), 6.79 (dt, J =
7.5, 1.3 Hz, 1 H), 6.67 (dt, J = 7.8, 1.4 Hz, 1 H), 6.58 (dd, J = 8.1,
1.4 Hz, 1 H), 5.73 (s, 1 H), 3.83 (s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 143.1, 143.0, 132.5, 128.3, 127.1, 127.0, 126.6, 119.5,
119.0, 116.0, 114.2, 110.2 ppm. HRMS: calcd. for C12H12BrN2 [M
+ H]+ 263.0184; found 263.0180. IR (Nujol): ν = 3456, 3375, 1275,
˜
1260, 764, 749 cm–1.
8-Methoxyphenazine-2-carbonitrile (10): Yellow solid; m.p. 251–
253 °C. 1H NMR (400 MHz, CDCl3): δ = 8.64 (d, J = 1.2 Hz, 1
H), 8.26 (d, J = 8.9 Hz, 1 H), 8.13 (d, J = 9.5 Hz, 1 H), 7.91 (dd,
J = 8.9, 1.76 Hz, 1 H), 7.60 (dd, J = 9.5, 2.7 Hz, 1 H), 7.42 (d, J
= 2.6 Hz, 1 H), 4.07 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 162.8, 146.5, 143.9, 142.0, 140.3, 136.5, 131.1, 130.6, 129.9,
128.1, 118.3, 112.1, 104.3, 56.1 ppm. HRMS: calcd. for C14H10N3O
[M + H]+ 236.0824; found 236.0812.
2-Methoxyphenazine (2):[11b] Yellow solid; m.p. 123–125 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 8.4 Hz, 1 H), 8.17 (d,
J = 9.5 Hz, 1 H), 8.10 (d, J = 9.5 Hz, 1 H), 7.74–7.84 (m, 2 H),
7.51 (dd, J = 9.5, 2.7 Hz, 1 H), 7.41 (d, J = 2.7 Hz, 1 H), 4.02 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.3, 145.0, 143.3,
141.9, 140.7, 130.6, 130.4, 129.6, 129.0, 128.8, 126.4, 104.4,
55.9 ppm. HRMS: calcd. for C13H11N2O [M + H]+ 211.0871;
found 211.0871.
Methyl 7-Cyanophenazine-2-carboxylate (11):[22] Yellow solid; m.p.
Methyl Phenazine-2-carboxylate (3):[21] Dark brown solid; m.p.
152–154 °C. 1H NMR (400 MHz, CDCl3): δ = 9.03 (d, J = 1.6 Hz,
1 H), 8.42 (dd, J = 9.0, 1.6 Hz, 1 H), 8.27–8.32 (m, 3 H), 7.88–7.94
(m, 2 H), 4.07 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
166.2, 144.7, 144.3, 144.1, 142.5, 133.0, 131.7, 131.6, 131.0, 130.0,
129.9, 129.7, 129.3, 52.7 ppm. HRMS: calcd. for C14H11N2O2 [M
1
242–245 °C. H NMR (400 MHz, CDCl3): δ = 9.03 (s, 1 H), 8.72
(d, J = 9.1 Hz, 1 H), 8.48 (d, J = 8.8 Hz, 1 H), 8.35–8.42 (m, 2 H),
7.98 (d, J = 8.8 Hz, 1 H), 4.08 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 145.5, 143.8, 142.7, 136.7, 133.3, 133.1, 132.9, 131.8,
131.6, 131.1, 130.7, 130.6, 130.3, 130.1, 52.9 ppm. HRMS: calcd.
for C15H10N3O2 [M + H]+ 264.0773; found 264.0763. IR (KBr): ν
˜
+ H]+ 239.0821; found 239.0815. IR (KBr): ν = 1725, 1617, 1275,
˜
= 1725, 1621, 1446, 1275, 1260, 1083, 1020, 764, 750 cm–1.
1260, 764, 749 cm–1.
Pyrido[2,3-b]quinoxaline (12):[24] Dark brown solid; m.p. 145–
147 °C. 1H NMR (400 MHz, CDCl3): δ = 9.37 (dd, J = 3.8, 1.9 Hz,
1 H), 8.62 (dd, J = 8.6, 1.9 Hz, 1 H), 8.39 (dd, J = 6.6, 3.4 Hz, 1
H), 8.29 (dd, J = 6.6, 3.4 Hz, 1 H), 7.91–7.95 (m, 2 H), 7.79 (dd,
J = 8.6, 3.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
156.5, 149.5, 145.0, 144.2, 139.1, 138.5, 131.6, 131.4, 130.3, 129.4,
125.5 ppm. HRMS: calcd. for C11H8N3 [M + H]+ 182.0718; found
182.0718.
2-(Trifluoromethyl)phenazine (4): Pale yellow solid; m.p. 170–
172 °C. H NMR (400 MHz, CDCl3): δ = 8.61 (s, 1 H), 8.39 (d, J
1
= 9.1 Hz, 1 H), 8.27–8.30 (m, 2 H), 7.98 (dd, J = 9.1, 1.9 Hz, 1 H),
7.90–7.96 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.5,
144.2, 143.7, 142.0, 132, 131.7, 131.6, 131.3, 131.2, 129.9, 129.8,
128.1, 128.0, 125.5, 124.9 (q, J = 275 Hz) ppm. HRMS: calcd. for
C13H8F3N2 [M + H]+ 249.0640; found 249.0631.
[1,3]Dioxolo[4,5-b]phenazine (5): Pale brown solid; m.p. 170–171 °C.
1H NMR (400 MHz, CDCl3): δ = 8.13 (dd, J = 10, 2.6 Hz, 2 H),
7.75 (dd, J = 9.32, 2.6 Hz, 2 H), 7.39 (s, 2 H), 6.22 (s, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 152.2, 142.8, 141.6, 129.2, 128.8,
103.2, 102.6 ppm. HRMS: calcd. for C13H9N2O2 [M + H]+
225.0664; found 225.0662.
3-(Trifluoromethyl)pyrido[2,3-b]quinoxaline (13): Yellow solid; m.p.
115–117 °C. 1H NMR (400 MHz, CDCl3): δ = 9.52 (d, J = 2.4 Hz,
1 H), 8.93 (d, J = 1.2 Hz, 1 H), 8.31–8.44 (m, 2 H), 7.99–8.04 (m,
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.5, 150.0, 146.0,
145.0, 137.0, 136.9, 136.8, 133.0, 132.4, 130.4, 129.7, 128.9, 127.6,
127.5, 127.3, 126.3, 124.1 (q, J = 275 Hz), 121.4, 119.5, 117.4 ppm.
HRMS: calcd. for C12H7F3N3 [M + H]+ 250.0592; found 250.0589.
7-Methoxy-[1,3]dioxolo[4,5-b]phenazine (6): Pale yellow solid; m.p.
252–254 °C. 1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 9.3 Hz,
1 H), 7.41 (dd, J = 9.3, 2.7 Hz, 1 H), 7.33–7.36 (m, 3 H), 6.19 (s,
2 H), 3.99 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.4,
152.1, 151.0, 143.1, 142.6, 140.8, 138.5, 129.8, 124.2, 104.6, 103.4,
102.9, 102.4, 55.7 ppm. HRMS: calcd. for C14H11N2O3 [M + H]+
255.0770; found 255.0760.
Pyrido[3,4-b]quinoxaline (14): Yellow solid; m.p. 171–173 °C. 1H
NMR (400 MHz, CDCl3): δ = 9.81 (s, 1 H), 8.85 (d, J = 6.1 Hz, 1
H), 8.35 (d, J = 8.5 Hz, 1 H), 8.29 (d, J = 8.0 Hz, 1 H), 8.08 (d, J
= 6.1 Hz, 1 H), 7.92–8.01 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 156.7, 146.2, 145.6, 144.5, 144.3, 138.1, 132.9, 131.4,
130.5, 129.7, 121.1 ppm. HRMS: calcd. for C11H8N3 [M + H]+
182.0718; found 182.0707.
Methyl [1,3]Dioxolo[4,5-b]phenazine-7-carboxylate (7): Brown solid;
m.p. 239–241 °C. 1H NMR (400 MHz, CDCl3): δ = 8.88 (d, J =
1.5 Hz, 1 H), 8.31 (dd, J = 8.9, 1.7 Hz, 1 H), 8.16 (d, J = 4.7 Hz,
1 H), 7.41 (s, 1 H), 7.40 (s, 1 H), 6.26 (s, 2 H), 4.03 (s, 3 H) ppm.
[1,3]Dioxolo[4,5-g]pyrido[3,4-b]quinoxaline (15): Tan solid; m.p.
1
287–290 °C. H NMR (400 MHz, CDCl3): δ = 9.63 (s, 1 H), 8.76
8334
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8330–8335

Synthesis of Phenazines and Pyridoquinoxalines
[13]
[14]
[15]
J. D. Winkler, B. M. Twenter, T. Gendrineau, Heterocycles
2012, 84, 1345–1353.
L. Yu, X. Zhou, D. Wu, H. Xiang, J. Organomet. Chem. 2012,
705, 75–78.
(d, J = 6.0 Hz, 1 H), 7.94 (d, J = 6.0 Hz, 1 H), 7.45 (s, 1 H), 7.41
(s, 1 H), 6.29 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
155.2, 145.2, 136.6, 120.6, 103.6, 103.1, 103.0 ppm. HRMS: calcd.
for C12H8N3O2 [M + H]+ 226.0617; found 226.0608.
a) L. Janga, S. L. Buchwald, in: Metal-Catalyzed Cross-Cou-
pling Reactions (Eds.: A. de Meijere, F. Diederich), Wiley-VCH,
2008, p. 699–760; b) J. F. Hartwig, Acc. Chem. Res. 2008, 41,
1534–1544; c) D. S. Surry, S. L. Buchwald, Angew. Chem. 2008,
120, 6438; Angew. Chem. Int. Ed. 2008, 47, 6338–6361.
For related palladium-catalyzed reactions of aliphatic 1,2-di-
amines with 1,2-dihalobenzenes reported by Beletskaya et al.,
see: a) I. P. Beletskaya, A. G. Bessmertnykh, R. Guilard, Syn-
lett 1999, 9, 1459–1461; b) I. P. Beletskaya, A. G. Bessmert-
nykh, A. D. Averin, F. Denath, R. Guilard, Eur. J. Org. Chem.
2005, 261–280; c) I. P. Beletskaya, A. D. Averin, A. A. Bori-
senko, F. Denat, R. Guilard, Tetrahedron Lett. 2003, 44, 1433–
1435; d) E. Ranyuk, A. Uglov, M. Meyer, A. B. Lemeune, F.
Denat, A. Averin, I. Beletskaya, R. Guilard, Dalton Trans.
2011, 40, 10491–10502.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra for all new com-
pounds are provided.
[16]
Acknowledgments
The authors greatly appreciate the financial support from the
NIPER S.A.S. Nagar and the Council of Scientific and Industrial
Research (CSIR), New Delhi. K. S. S. T. and A. G. thank the
CSIR, New Delhi for the award of the Junior Research Fellowship
and Research Associateship, respectively.
[1] a) J. B. Laursen, J. Nielsen, Chem. Rev. 2004, 104, 1663–1685;
b) A. Cimmino, A. Evidente, V. Mathieu, A. Andolfi, F. Lefr-
anc, A. Kornienko, R. Kiss, Nat. Prod. Rep. 2012, 29, 487–501.
[2] B. B. Fischer, A. Krieger-Liszkay, R. I. L. Eggen, Environ. Sci.
Technol. 2004, 38, 6307–6313.
[3] J. J. Bryant, Y. Zhang, B. D. Linder, E. A. Davey, A. L. Apple-
ton, X. Qian, U. H. F. Bunz, J. Org. Chem. 2012, 77, 7479–
7486.
[17]
[18]
O. Hinsberg, Justus Liebigs Ann. Chem. 1901, 319, 257–286.
O. Tverskoy, F. Rominger, A. Peters, H. J. Himmel, U. H. F.
Bunz, Angew. Chem. 2011, 123, 3619; Angew. Chem. Int. Ed.
2011, 50, 3557–3560.
a) J. K. Laha, P. Petrou, G. D. Cuny, J. Org. Chem. 2009; 74,
3152–3155; b) J. K. Laha, S. M. Barolo, R. A. Rossi, G. D.
Cuny, J. Org. Chem. 2011, 76, 6421–6425.
[19]
[4] A. Wohl, W. Aue, Ber. Dtsch. Chem. Ges. 1901, 34, 2442–2450.
[20] E. Merisor, U. Beifuss, Tetrahedron Lett. 2007, 48, 8383–8387.
[5] a) E. Bamberger, W. Ham, Justus Liebigs Ann. Chem. 1911, [21] P. Silvio, M. Silvio, R. Angelamaria, Ann. Chim. 1953, 43, 227–
82, 382–385; b) M. J. Haddadin, C. H. Issidorides, Tetrahedron
Lett. 1965, 6, 3253–3256.
[6] a) A. R. Surrey, Org. Synth. 1955, 3, 753; b) J. M. Khurana, A.
Chaudhary, A. Lumb, B. Nand, Green Chem. 2012, 14, 2321–
2327.
231.
[22] D. L. Vivian, J. L. Hartwell, H. C. Henry, J. Org. Chem. 1955,
20, 797–802.
[23] For recent syntheses of quinoxalines, see: a) P. Ghosh, A. Man-
dal, Tetrahedron Lett. 2012, 53, 6483–6488; b) J. Song, X. Li,
Y. Chen, M. Zhao, Y. Dou, B. Chen, Synlett 2012, 23, 2416–
2420; c) P. Ghosh, A. Mandal, Green Chem. Lett. Rev. 2013, 6,
45–54; d) M. Lian, Q. Li, Y. Zhu, G. Yin, A. Wu, Tetrahedron
2012, 68, 9598–9605; e) V. O. Iaroshenko, M. Zahid, S.
Mkrtchyan, A. Gevorgyan, K. Altenburger, I. Knepper, A. Vil-
linger, V. Y. Sosnovskikh, P. Langer, Tetrahedron 2013, 69,
2309–2318.
[7] a) D. L. Vivian, J. Org. Chem. 1956, 21, 565–566; b) M. E.
Flood, R. B. Herbert, F. G. Holliman, J. Chem. Soc. Perkin
Trans. 1 1972, 622–626.
[8] B. Cross, P. J. Williams, R. E. Woodall, J. Chem. Soc. C 1971,
2085–2090.
[9] G. W. Rewcastle, W. A. Denny, Synth. Commun. 1987, 17,
1171–1179.
[10] a) M. L. Tomlinson, J. Chem. Soc. 1939, 158–163; b) R. C. El-
derfield, W. J. Gensler, O. Birstein, J. Org. Chem. 1946, 11, 812–
822; c) G. Gaertner, A. Gray, F. G. Holliman, Tetrahedron
1962, 18, 1105–1114.
[11] a) T. Emoto, N. Kubosaki, Y. Yamagiwa, T. Kamikawa, Tetra-
hedron Lett. 2000, 41, 355–358; b) M. Tietze, A. Iglesias, E.
Merisor, J. Conrad, I. Klaiber, U. Beifuss, Org. Lett. 2005, 7,
1549–1552.
[24] R. G. R. Bacon, S. D. Hamilton, J. Chem. Soc. Perkin Trans. 1
1974, 1965–1969.
[25] For selected references, see: a) T. H. M. Jonckers, B. U. W.
Maes, G. L. F. Lemiere, R. Dommisse, Tetrahedron 2001, 57,
7027–7034; b) S. Hostyn, G. Van Baelen, G. L. F. Lemiere,
B. U. W. Maes, Adv. Synth. Catal. 2008, 350, 2653–2660; c) M.
Koley, L. Wimmer, M. Schnuerch, M. D. Mihovilovic, Eur. J.
Org. Chem. 2011, 1971–1979.
[12] A. Kwast, K. Stachowska, A. Trawczyski, Z. Wróbel, Tetrahe-
dron Lett. 2011, 52, 6484–6488.
Received: July 23, 2013
Published Online: November 14, 2013
Eur. J. Org. Chem. 2013, 8330–8335
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8335