Quinoxalino[2,3- c ]cinnolines and their 5- N -oxide: Alkoxylation of methyl-substituted quinoxalino[2,3- c ]cinnolines to acetals and orthoesters

Article abstract of DOI:10.1021/jo201687x

We report the alkoxylation of methyl-substituted quinoxalino[2,3-c] cinnolines to give acetals and orthoesters in high yields. Routes to the precursors of this alkoxylation reaction as well as other quinoxalino[2,3-c] cinnoline and their 5-oxide derivativ

Full text of DOI:10.1021/jo201687x

ARTICLE
pubs.acs.org/joc
Quinoxalino[2,3-c]cinnolines and Their 5-N-Oxide: Alkoxylation of
Methyl-Substituted Quinoxalino[2,3-c]cinnolines to Acetals and
Orthoesters
Makhluf J. Haddadin,*,† Mirna El-Khatib,† Tharallah A. Shoker,† Christine M. Beavers,‡
Marilyn M. Olmstead,‡ James C. Fettinger,‡ Kelli M. Farber,‡ and Mark J. Kurth*,‡
†Department of Chemistry, American University of Beirut, Beirut, Lebanon
‡Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, United States
S Supporting Information
b
ABSTRACT: We report the alkoxylation of methyl-substituted
quinoxalino[2,3-c]cinnolines to give acetals and orthoesters in
high yields. Routes to the precursors of this alkoxylation
reaction as well as other quinoxalino[2,3-c]cinnoline and their
5-oxide derivatives are reported. Most of these quinoxalino[2,3-c]
cinnolines were prepared by cyclization of the corresponding
2-amino-3-(2-nitrophenyl)quinoxaline, which, in turn, result
from an unusual Beirut reaction from benzofurazan oxides
plus 2-nitrobenzylcyanides. Mechanistic explanations for these
intriguing reactions are presented.
’ INTRODUCTION
Current interest in the chemistry of heterocyclic di-N-oxides
stems from their biological activities as they are known to be
effective growth-promoting additives in animal feed as exemplified
by quinoxaline 1,4-dioxides 1.1 Some of these compounds are
reported to have antimalarial, anti-Chagas disease, and anticancer
properties.2À7 We have established the anticancer activity of 1b.8
Tirapazamine (2; SR 4223) is currently in stage 3 clinical trials
(Figure 1).9 It is believed that the anticancer activities of both 1b
and 2 are initiatedbybioreductive processingof thenitronemoiety
in these compounds. Therefore, we envisaged that synthetic access
to additional N-oxides might broaden and enhance the activity
profile of such heterocycles.10
As a continuation of our efforts in this field, we predicted that
quinoxaline 1,4-dioxides with an amino group at position 2 would
bear a resemblance to tirapazamine (2). Furthermore, the synthesis
of 2-amino-3-(2-nitrophenyl)quinoxaline 1,4-dioxides such as 5a and
subsequent cyclization to quinoxalino[2,3-c]cinnoline 5,7,12-tri-N-
oxide (7a) would result in an unknown and potentially more active
tri-N-oxide. However, as reported here, this objective (5a f 7a;
Scheme 1) was not realized experimentally, even in refluxing 10%
KOH in MeOH for 3 h, presumably because of the poor nucleo-
philicity of the 2-amino group in 5a. The failure of this transformation
(5a f 7a) caused us to focus our attention on the second
unexpected product (6aÀi) of the Beirut reaction as detailed below.
Figure 1. Bioactive heterocyclic di-N-oxides.
a catalyst, at room temperature, gave the corresponding 2-amino-
3-(2-nitrophenyl)quinoxaline 1,4-dioxide (5a). It was surprising
to find that the second product of this reaction, formed in almost
equivalent amount, was the deoxygenated 2-amino-3-(2-nitro-
phenyl)quinoxaline (6a; Scheme 1).
Because the Beirut reaction of 3 + 4 has taken an unusual
course, namely, the formation of 2-aminoquinoxaline derivatives
6aÀi in addition to the 2-aminoquioxaline 1,4-dioxide derivative
5a, this paper focuses on the chemistry of these 2-amino-3-(2-
phenyl)quinoxaline products 6aÀi. The possibility that the
unusual quinoxaline 6a could have arisen from deoxygenation
of the quionxaline 1,4-dioxide 5a was dismissed when it was
found that 5a, when subjected to these reaction conditions, was
unchanged even after one week. Mechanistic considerations led
us to speculate that formation of quinoxaline 6a was caused
by the generation of 2-nitrosoaniline (8) which, in turn, reacted
with 2-nitrobenzylcyanide (4) to give 2-amino-3-(2-nitrophe-
nyl)quinoxalines (Scheme 2).
’ RESULTS AND DISCUSSION
The Beirut reaction of a number of benzofurazan oxides (3)
with 2-nitrobenzylcyznides (4) in acetonitrile with pyrrolidine as
Received: August 14, 2011
Published: September 09, 2011
r
2011 American Chemical Society
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Scheme 1. Beirut Reaction to Quinoxaline Derivatives
Scheme 3. Independent Route to Quinoxaline 6a
derivatives, which did not include the parent ring system. They
stated that these quinoxalinocinnoline 5-N-oxides were impure
and obtained in small quantities which “precluded further work on
these compounds”.13,14 As outlined in Scheme 4, we report the
preparation of the parent system (10a) and a number of deriva-
tives via a new, simple, and efficient sythetic route. Structures for
quinoxalino[2,3-c]cinnoline 5-N-oxides 10aÀc,g were corrobo-
rated by full spectral data (IR/1H NMR/13C NMR/HRMS), and
the structure of 10a was confirmed by X-ray crystallography (see
the Supporting Information, Figure 2SI).
During the course of this work, a serendipitous reaction was
found to occur with some methyl-substituted 2-aminoquinox-
alines (6dÀf,h,i). These analogues underwent cyclization and
alkoxylation at the benzylic carbon with subsequent deoxygena-
tion of the anticipated 5-N-oxide to yield an acetal, an orthoester
(using methanol/10% KOH), or a 1,3-dioxolane (using ethylene
glycol/10% KOH) (11À16; Scheme 5). The structure of
diacetal 11 was established by X-ray crystallography (see the
Supporting Information, Figure 2SI), and a postulated mechan-
ism for its formation is presented in Scheme 6. In contrast, when
6i was heated with ethylene glycol, under the same reaction
conditions but for 10 min, alkoxylation occurred at the methyl
carbon of the 2-nitrophenyl group to give 17, whereas when the
reaction was extended to 30 min, a di- and tri-1,3-dioxolane-
containing mixture was obtained (18).
Scheme 2. Formation of 6a: Mechanistic Considerationsa
a Formation of 8 from 3 and 4 is detailed in the Supporting Information
(Scheme 2SI).
Indeed, the mother liquor from 3 + 4 showed the presence of
trace amounts of 2-nitrosoaniline (8), the identity of which was
confirmed by comparison with an authentic sample. Further-
more, reaction of independently prepared 2-nitrosoaniline (8)11
with 2-nitrobenzyl cyanide, under the same reaction conditions
(Scheme 3), yielded quinoxaline 6a in high yield. The postulated
mechanism is supported by the fact that the reaction of 2-ni-
trosoaniline with cyanide 4 gave intermediate 9 as a deep red
solid. Upon heating in 10% methanolic KOH, 9 gave quinoxaline
6a. The structures of quinoxaline 1,4-dioxide 5a and quinoxalines
6aÀi are supported by full spectral data (IR, 1H NMR, 13C NMR,
and HRMS).
It is intriguing to speculate whether the 5-N-oxide function-
ality is lost during or after the alkoxylation reaction (Scheme 5).
Although we have no solid evidence to indicate at which step
deoxygenation takes place, it is believed that this deoxygenation
occurs during the alkoxylation reaction because the formation of
quinoxalino[2,3-c]cinnoline 10a and its further heating under
cyclization conditions (10% KOH/MeOH) did not result in
deoxygenation. This postulate is supported by the fact that the
5-N-oxide bond length in 10a is quite short (Supporting
Information, Figure 2SI) and there is a similar shortness in
the 5NÀ6N bond indicating substantial conjugation with the
5-N-oxide.
This easy formation of a series of 2-amino-3-(2-nitrophe-
nyl)quinoxalines (6aÀc,g) prompted us to investigate their
cyclization to the novel corresponding quioxalino[2,3-c]cinnoline
5-oxides (10aÀd,h). Indeed, this type of cyclization to form
cinnoline N-oxides is well-known.12 Heating methanolic KOH
solutions of quinoxalines 6aÀc,g gave novel quioxalino[2,3-
c]cinnoline 5-oxides 10aÀc,g in high yields (80À90%). Smith
and co-workers have published elegant work on the preparation
and reactions of quinoxalino[2,3-c]cinnolines using a different
method that proceeded in relatively lowyields. Theyalso reported
the preparation of three quioxalino[2,3-c]cinnoline 5-N-oxide
Another aspect of this alkoxylation reaction requires com-
ment: namely, the absence of monoalkoxylated products. It
seems that introduction of the first alkoxy group (methoxy) at
the benzylic carbon enhances the acidity of the remaining
benzylic hydrogens and renders the next alkoxylation faster than
the first. However, where two adjacent methyl groups are found
(i.e., 6e and 6i), steric hindrance limits alkoxylation to two
methoxylations at each of the two benzylic carbons (i.e., acetal
formation: positions 9 and 10) compared to three methoxyla-
tions (i.e., ortho ester formation) at the benzylic carbon at
position 2 in quinoxalino[2,3-c]cinnoline (6i f 17).
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Scheme 4. Synthesis of Quinoxalino[2,3-c]cinnoline 5-N-Oxides
Scheme 5. Benzylic Alkoxylation of Methyl-Substituted 2-Aminoquioxalines
It is intriguing that the 5-N-oxide functionality does not appear to
be essential for benzylic methoxylation. As outlined in Scheme 7, this
assumption is supported by the fact that 9,10-dimethylquinoxalino-
[2,3-c]cinnoline (20), which was prepared by reduction (H2/Pd) of
2-amino-3-(2-nitrophenyl)-4,5-dimethylquinoxaline (6e) followed
by subsequent ring cyclization of 19 with Clorox, underwent alko-
xylation under the same conditions to give diacetal 16 in a high yield.
It is interesting to note that the alkoxylation reaction proceeds
well with primary alcohols, such as methanol, ethanol, or ethylene
glycol in 10% KOH, but fails with isopropyl or tert-butyl alcohols
presumably because of decreased nuceophlicity.
in addition to their expected 1,4-dioxides, can be easily prepared
and converted to novel quinoxalino[2,3-c]cinnoline 5-N-oxide
which are rare in the literature. The highlight of this report is
the fortuitous finding that the methyl substituents of some of
quinoxalino[2,3-c]cinnolines, or their presumed 5-N-oxides inter-
mediates, can be easily converted to acetals or orthoesters which
we believe to be unprecedented.
’ EXPERIMENTAL SECTION
All chemicals and solvents were purchased from commercial suppli-
1
ers. The H NMR and 13C NMR spectra were recorded in solution of
In conclusion, a new route for the Beirut reaction is revealed in
which a number of novel 2-amino-3-(2-nitrophenyl)quinoxalines,
CDCl3 or DMSO-d6 with tetramethylsilane (TMS) as the internal standard.
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Scheme 6. Postulated Mechanism for the Formation of 11
(m, b), 668.0 (w), 533.2 (w, b) cmÀ1; HRMS (ESI) calcd for C14H11N4O4
[M + 1] m/z 299.07775, found 299.0775.
General Procedure B. o-Nitrosoaniline (8; 2 g, 16.4 mmol) and
2-nitrobenzylcyanide (4; 2.65 g, 16.4 mmol) were dissolved in acetoni-
trile (25À30 mL) at room temperature. Pyrrolidine (3 mL) was added
dropwise, resulting in a solution color change from light to deep black.
Water (10 mL) was added. The reaction mixture was allowed to stand at
room temperature for 12 h. The basic solution was quenched with either
acetic acid or dilute hydrochloric acid. The yellow solid was filtered to
afford the desired product.
3-(2-Nitrophenyl)quinoxalin-2-amine (6a). This product was
synthesized as a yellow solid according to general procedure A (20%
yield) or B (93% yield): mp 260 °C (lit. mp 260À261 °C); 1H NMR
(DMSO-d6) δ 6.66 (s, 2H, s), 7.45 (m,1H), 7.66 (d, J = 3.6 Hz, 2H), 7.77
(m, 2H), 7.87 (m, 1H), 8.02 (m, 1H), 8.34 (d, J = 8.1 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6) δ 123.9, 125.0, 125.1, 128.3, 129.8, 130.5, 131.6,
132.1, 134.7, 136.0, 141.6, 144.8, 147.7, 151.5; FTIR (KBr) 3458.5 (s),
3304.5 (w), 3104.6 (m, b), 1647.4 (m), 1522.1 (s), 1437.2 (m), 1433.1
(m). 1344.1 (s), 756.7 (m) cmÀ1; HRMS (ESI) calcd for C14H11N4O2
[M + 1] m/z 267.0877, found 267.0878.
6-Chloro-3-(2-nitrophenyl)quinoxalin-2-amine (6b). This
product was synthesized according to general procedure A as a yellow
solid in 12% yield: mp 270 °C; 1H NMR (DMSO-d6) δ 6.72 (2H, s),
7.65 (m, 3H), 7.82 (m, 2H), 7.93 (t, J = 7.2 Hz, 1H), 8.29 (d, J = 8.2 Hz,
1H); 13C NMR (DMSO-d6) δ 125.1, 126.9, 126.9, 127.6, 130.2, 130.8,
131.5, 131.6, 134.9, 136.2, 140.3, 146.1, 147.5, 151.7; FTIR (KBr)
3466.4 (s), 3299.8 (w,b), 3140.2 (m, b), 1642.7 (s), 1613.3 (w), 1572.0
(w), 1561.6 (w), 1529.6 (s), 1489.3 (w), 1453.8 (m), 1427.7 (w), 1342.2
(s), 1301.8 (w), 1012.1 (m), 871.6 (w), 830.3 (m), 789.2 (m), 754.0
(w), 721.4 (w), 696.9 (w) cmÀ1; HRMS (ESI) calcd for C14H10N4O2Cl
[M + 1] m/z 301.0487, found 301.0494.
Scheme 7. Evidence that the 5-N-Oxide Moiety Is Not Es-
sential for Benzylic Alkoxylation
6-Methoxy-3-(2-nitrophenyl)quinoxalin-2-amine (6c).
This product was synthesized according to general procedure A as a
1
yellow solid in 26% yield: mp 214 °C; H NMR (DMSO-d6) δ 3.83
(s, 3H), 6.31 (bs, 2H), 7.21(s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.54 (d, J =
9.3 Hz, 1H), 7.69 (d, J= 6.6 Hz, 1H), 7.79 (m, 1H), 7.92(m, 1H), 8.26 (d, J=
8.4 Hz, 1H); 13C NMR (DMSO-d6) δ 48.6, 107.6, 121.4, 125.0, 126.2,
130.4, 131.6, 132.3, 134.5, 136.7, 136.8, 144.3, 147.8, 150.4, 156.0; FTIR
(KBr) 3450.1 (s), 2924.0 (w, b), 1643.0 (w), 1522.7 (w), 1499.2 (w),
1457.4 (w), 1449.7 (m), 1437.6 (m), 1430.9 (m), 1380.2 (w), 1358.2
(w), 1032.3 (m), 468.1 (w) cmÀ1; HRMS (ESI) calcd for C15H13N4O3
[M + 1] m/z 297.0982, found 297.0983.
6-Methyl-3-(2-nitrophenyl)quinoxalin-2-amine (6d). This
product was synthesized according to general procedure A as a yellow
solid in 17% yield or procedure B in 84% yield: mp 235 °C; 1H NMR
(CDCl3) δ 4.69 (bs, 2H), 7.49 (dd, J = 1.2, 8.4 Hz, 1H), 7.69 (m, 4H),
7.83 (td, J = 1.2, 7.5 hz, 1H), 8.25 (d, J = 1.2, 7.5 Hz, 1H), 8.25 (d, J = 8.3
Hz, 1H); 13C NMR (CDCl3) δ 20.7, 124.9, 125.0, 127.4, 130.5, 131.6,
131.7, 132.2, 133.3, 134.6, 136.0, 139.7, 144.4, 147.8, 151.1; FTIR (KBr)
3466.0 (s, b), 2923.2 (m), 2852.5 (w), 1653.6 (w), 1458.3 (m), 1450.2
(m), 1448.4 (m), 1437.1 (m), 1419.8 (m), 1345.0 (w), 1032.8 (m, b),
465.8 (w) cmÀ1; HRMS (ESI) calcd for C15H13N4O2 [M + 1] m/z
281.1039, found 281.1033.
1H NMR spectra often include a water peak. Mass spectra were measured
using high-resolution MS. Benzofurazan oxide (3) and its derivatives were
synthesized according to a modified literature procedure.
General Procedure A. Derivatives of benzofurazan oxide (15
mmol) were dissolved in acetonitrile. A solution of 2-nitrobenzylcyanide
(1 equiv) dissolved in acetonitrile was added. Dropwise addition of
pyrrolidine (5 mL) resulted in a solution color change from yellow to dark
blue-black. Water (10 mL) was added, and the reaction was left at room
temperature for 12 h. The base was quenched with acetic acid. The resulting
yellow solid was filtered to afford products 6aÀi. Product 5a remained in
solution, and its purification required column chromatography.
2-Amino-3-(2-nitrophenyl)quinoxaline 1,4-Dioxide (5a).
This product was synthesized according to general procedure A as a
yellow solid in 20% yield: hygroscopic; 1H NMR (CDCl3) δ 7.37 (2H,
s), 7.65(t, J = 1.2 Hz, 1H), 7.81 (d, J = 7.65 Hz, 1H), 7.89 (q, J = 12.7 Hz,
2H), 8.00 (t, J = 7.6 Hz, 1H), 8.31 (t, J = 8.4 Hz, 1H), 8.38 (m, 3H); 13C
NMR (75 MHz, DMSO-d6) δ 117.5, 123.1, 124.9, 131.8, 132.2, 135.2,
148.2, 170.3, 174.6; FTIR (KBr) 3426.0 (s, b), 1652.8 (w), 1635.3
6,7-Dimethyl-3-(2-nitrophenyl)quinoxalin-2-amine (6e).
This product was synthesized according to general procedure A as a
yellow solid in 21% yield: mp >300 °C; 1H NMR (DMSO-d6) δ 2.34
(s, 3H), 2.38 (s, 3H), 6.39 (s, 2H), 7.39 (s, 1H), 7.50 (m, 1H), 7.80
(m, 1H), 7.90 (m, 1H), 8.24 (d, J = 8.1 Hz, 1H); 13C NMR (DMSO-d6)
δ 19.2, 19.9, 124.7, 124.9, 127.6, 130.3, 131.6, 132.3, 133.2, 134.4, 134.9,
139.5, 140.1, 143.2, 147.9, 151.1; FTIR (KBr) 3448.1 (s), 1643.1 (w),
1521.2 (m), 1433.0 (m), 1352.4 (w), 1031.0 (w), 874.9 (w) cmÀ1
;
HRMS (ESI) calcd for C16H15N4O2 [M + 1] m/z 295.1190, found
295.1190.
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3-(5-Methyl-2-nitrophenyl)quinoxalin-2-amine (6f). This
product was synthesized according to general procedure A as a yellow
solid in 23% yield or procedure B in 87% yield: mp 245 °C; 1H NMR
(CDCl3) δ 8.17À8.20 (1H, d, J = 8.4 Hz), 7.88À7.91 (1H, dd, J = 7.8,
0.9 Hz), 7.71À7.74 (1H, dd, J = 8.1, 1.2 Hz), 7.61À7.67 (1H, td, J = 6.9,
1.5 Hz), 7.42À7.50 (3H, m), 4.81 (2H, s, b), 2.53 (3H, s); 13C NMR
(CDCl3) δ 150.19, 146.26, 145.63, 144.14, 141.36, 137.46, 132.05,
132.02, 131.16, 130.38, 128.86, 126.01, 125.58, 125.44, 21.56; FTIR
(KBr) 3457.69 (m), 3308.37 (w, b), 3135.92 (m, s), 1586.93 (m), 1650
(w), 1516.38 (m), 1470.75 (w), 1441.44 (m), 1338.99 (w), 1253.51 (s),
1187.06 (s), 1143.47 (s), 1093.30 (s), 1037.68 (s), 954.15 (s), 916.49
(s), 839.58 (m), 755.52 (m), 698.75 (s), 614.24 (s) cmÀ1; HRMS (EI)
calcd for C15H12N4O2 m/z 280.0960, found 280.0957.
J1 = 7.8 Hz, J2 = 1.5 Hz), 7.84À7.87 (1H, dd, J1 = 7.8 Hz, J2 = 0.9 Hz),
7.73À7.78 (1H, dt, J1 = 7.5 Hz, J2 = 1.2 Hz), 7.64À7.70 (1H, dt, J1 = 7.8
Hz, J2 = 1.5 Hz), 7.58À7.61 (1H, dd, J1 = 4.2 Hz, J2 = 1.2 Hz), 7.18À7.28
(1H, dt, J1 = 8.4 Hz, J2 = 1.2 Hz), 6.74À6.81 (2H, m), 4.26 (2H, s, b);
13C NMR (CDCl3) δ 148.30, 144.42, 132.57, 132.10, 132.05, 131.74,
130.90, 129.98, 129.11, 124.51, 118.95, 117.88, 116.18, 111.90; FTIR
(KBr) 3493.50 (m), 3452.21 (s), 3386.91 (s), 3356.80 (s), 3032.24 (w),
2209.89 (m), 1617.46 (s), 1550 (m), 1479.74 (m) cmÀ1; HRMS (ESI)
calcd for C14H10N4O2 [M + 1] m/z 267.0882, found 267.0877.
GeneralProcedure D. Theappropriate2-amino-3-(2-nitrophenyl)
quinoxaline 6 (2.60 mmol) was dissolved in 10% methanolic base (KOH,
30 mL). The yellow solution was heated at 60 °C for 2 h, and then the
reaction mixture was cooled to room temperature affording a yellow-
orange solid. In cases where no solid precipitated, the solvent was
removed at reduced pressure and the residue was extracted with
dichloromethane (50 mL Â 4). The organic extracts were combined,
dried over MgSO4, and purified by silica gel column chromatography.
Quinoxalino[2,3-c]cinnoline 5-Oxide (10a). This product was
synthesized according to general procedure D as a yellow solid in 92%
3-(4-Methyl-2-nitrophenyl)quinoxalin-2-amine (6g). This
product was synthesized according to general procedure A as a yellow
1
solid in 20% yield: mp 279 °C; H NMR (CDCl3) δ 8.07 (1H, s),
7.87À7.90 (1H, dd, J = 8.4, 1.2 Hz), 7.72À7.75 (1H, dd, J = 8.4 Hz, 1.2
Hz), 7.61À7.67 (2H, dt, J = 6.9, 1.5 Hz), 7.46À7.53 (2H, m), 4.72 (2H,
s, b), 2.56 (3H, s); 13C NMR (CDCl3) δ 150.2, 148.0, 143.8, 141.6,
141.4, 137.6, 135.0, 131.3, 130.4, 129.2, 128.9, 126.0, 125.6, 125.6, 21.3;
FTIR (KBr) 3453.81 (s), 3106.04 (w, b), 1646.46 (s), 1568.10 (m),
1530 (s), 1495.23 (s), 1430 (s), 1361.11 (s), 1146.64 (m), 1011.77 (m),
838.32 (m), 799.91 (m), 760.01 (s) cmÀ1; HRMS (ESI) calcd for
C15H13N4O2 [M + 1] m/z 281.1033, found 281.1031.
1
yield: mp 246 °C; H NMR (CDCl3) δ 9.20À9.23 (1H, dd, J = 7.8,
1 Hz), 8.78À8.81 (1H, d, J = 8.4 Hz), 8.31À8.38 (2H, m), 8.04À8.14
(1H, td, J = 8.1, 1.2 Hz), 7.92À8.03 (3H, m); 13C NMR (75 MHz,
DMSO-d6) δ 121.7, 124.1, 128.1, 129.0, 129.4, 131.9, 132.1, 133.0,
133.2, 134.0, 140.3, 141.6, 143.3, 146.6; FTIR (KBr) 3447.2 (m, b),
1469.4 (m), 1409.5 (w), 1344.2 (m), 1016.9 (s), 771.2 (m), 656.4 (s),
6-Methyl-3-(5-methyl-2-nitrophenyl)quinoxalin-2-amine
(6h). This product was synthesized according to general procedure A as
a yellow solid in 18% yield: mp 264 °C; 1H NMR (CDCl3) δ 8.16À8.19
(1H, d, J = 8.4 Hz), 7.68 (1H, s), 7.62À7.65 (1H, d, J = 8.4 Hz),
7.46À7.50 (2H, m), 7.42 (1H, s), 4.66 (2H, s, b), 2.53 (3H, s), 2.51 (3H,
s); 13C NMR (CDCl3) δ 149.7, 146.1, 145.7, 143.9, 139.5, 137.5, 135.7,
132.5, 132.2, 132.0, 131.0, 128.0, 125.6, 125.4, 21.6, 21.4; FTIR (KBr)
3457.38 (m), 3123.15 (m, b), 1649.31 (m), 1587.29 (w), 1584.71 (w),
1517.96 (s), 1420 (m), 1357.91 (s), 1227.29 (w), 1039.95 (m), 819.47
(s) cmÀ1; HRMS (ESI) calcd for C16H15N4O2 [M + 1] m/z 295.1190,
found 294.1190.
596.2 (s), 524.9 (s) cmÀ1; UV (methanol) λmax (nm) (εmax
M
À1 cmÀ1
 103) 287 (113), 401 (78.49); HRMS (ESI) calcd for C14H9N4O
[M + 1] m/z 249.0776, found 249.0768. The structure of 10a was
confirmed by X-ray crystallography as indicated in the Supporting
Information.
10-Chloroquinoxalino[2,3-c]cinnoline 5-Oxide (10b). This
product was synthesized according to general procedure D as a yellow
solid in 74% yield: mp 260 °C dec; 1H NMR (DMSO-d6) δ 7.71 (m,
2H), 8.18 (m, 1H), 8.68 (d, J = 8.4 Hz, 1H), 9.08 (d, J = 7.2 Hz, 1H); 13C
NMR (DMSO-d6) δ 105.7, 121.7, 124.0, 126.5, 128.1, 130.6, 132.9,
133.8, 140.1, 143.6, 145.1, 161.8; FTIR (KBr) 3447.6 (m, b), 1623.9
(w), 1481.7 (m), 1402.0 (s), 1208.6 (w), 1199.5 (w), 1128.5 (w), 1016.0
(w) cmÀ1; HRMS (ESI) calcd for C14H8N4OCl [M + 1] m/z 283.0387,
found 283.0377.
10-Methoxyquinoxalino[2,3-c]cinnoline 5-Oxide (10c).
This product was synthesized according to general procedure D as a
yellow solid in 98% yield: mp 274 °C; 1H NMR (300 MHz, DMSO-d6)
δ 4.10 (3H, s), 7.70 (1H, m), 7.74 (1H, d, J = 3 Hz), 8.13 (1H, t,
J = 1.5 Hz), 8.23 (2H, m), 8.68 (1H, d, J = 8.55 Hz), 9.08 (1H, d, J =
7.35 Hz); 13C NMR (75 MHz, DMSO-d6) δ56.34, 105.73, 121.64,
123.98, 126.45, 128.08, 130.61, 132.89, 133.79, 140.10, 143.62,
161.84; FTIR (KBr) 3447.5 (m, b), 1623.6 (m), 1480.9 (s), 1401.6
(s), 1208.4 (m), 1198.8 (m), 1127.7 (w), 1014.3 (w), 834.9 (w), 541.3
(w), 527.4 (w) cmÀ1; HRMS (ESI) calcd for C15H11N4O2 [M + 1]
m/z 279.0882, found 279.0876.
6,7-Dimethyl-3-(5-methyl-2-nitrophenyl)quinoxalin-2-
amine (6i). This product was synthesized according to general
1
procedure A as a yellow solid in 22% yield: mp >264 °C; H NMR
(CDCl3) δ 8.15À8.18 (1H, d, J = 8.4 Hz), 7.65 (1H, s), 7.50 (1H, s),
7.45À7.48 (1H, dd, J = 9.6, 1.2 Hz), 7.41À7.42 (1H, d, J = 1.2 Hz), 4.60
(2H, s, b), 2.52 (3H, s), 2.45 (3H, s), 2.41 (3H, s); 13C NMR (CDCl3) δ
149.8, 146.0, 145.8, 142.8, 140.7, 134.0, 136.4, 135.5, 132.3, 132.1, 130.9,
128.2, 125.6, 125.4, 21.6, 20.5, 19.9; FTIR (KBr) 3453.24 (m), 3307.81
(w), 3131.63 (m, b), 1620 (m), 1609.00 (w), 1588.16 (w), 1562.41 (w),
1516.47 (s), 1440.53 (m), 1354.07 (s), 1308.40 (w), 1236.69 (w),
1177.88 (w), 1040.00 (w), 1002.91 (w), 872.28 (m), 826.71 (m), 758.58
(w), 701.52 (w), 453.83 (w) cmÀ1; HRMS (ESI) calcd for C17H17N4O2
[M + 1] m/z 309.1352, found 309.1349.
General Procedure C. o-Nitrosoaniline (8; 2 g, 16.4 mmol) and
2-nitrobenzylcyanide (4; 2.65 g, 16.4 mmol) were dissolved in acetoni-
trile (25À30 mL) at room temperature. Pyrrolidine (3 mL) was added
dropwise resulting in a solution color change from light to deep black.
Water (10 mL) was added, and the reaction mixture was allowed to stand
at room temperature for 30 min. The basic solution was quenched with
either acetic acid or dilute hydrochloric acid, and the resulting deep red
solid was collected by filtration, washed with cold methanol, dried, and
identified as N-(2-aminophenyl)-2-nitrobenzimidoylcyanide (9). This
deep red solid can be converted to the corresponding quinoxaline by
dissolving it in 10% MeOH/KOH and heating for 2 min; the resulting
yellow solid was collected by filtration, washed with cold methanol,
dried, and identified as 2-amino-3-(2-nitrophenyl)quinoxaline (6a).
N-(2-Aminophenyl)-2-nitrobenzimidoyl Cyanide (9). This
product was synthesized according to general procedure C as a deep red
solid in 86% yield: mp 96 °C; 1H NMR (CDCl3) δ 7.95À7.98 (1H, dd,
3-Methylquinoxalino[2,3-c]cinnoline 5-Oxide (10g). This
product was synthesized according to general procedure D as a yellow
solid in 88% yield: mp 279 °C; 1H NMR (CDCl3) δ 9.07À9.09 (1H, d,
J = 8.1 Hz), 8.59 (1H, s), 8.24À8.35 (2H, m), 7.88À7.94 (3H, m), 2.70
(3H, s); 13C NMR (CDCl3) δ 145.4, 143.1, 141.7, 139.6, 134.1, 131.8,
130.6, 130.5, 129.2, 128.2, 125.0, 123.4, 120.9, 21.2; FTIR (KBr)
3082.20 (w), 2921.93 (w, b), 1520.82 (m), 1483.70 (m), 1473.04
(m), 1411.44 (m), 1394.74 (s), 1335.85 (w), 1295.89 (m), 1216.88
(m), 1141.28 (m), 1036.19 (s), 820 (s), 781.08 (w), 768.77 (s), 595.05
(m), 548.74 (m), 529.05 (m) cmÀ1; HRMS (ESI) calcd for C15H11N4O
[M + 1] m/z 263.0933, found 263.0925; UV (methanol) λmax (nm)
(εmax
M
10-(Dimethoxymethyl)quinoxalino[2,3-c]cinnoline (11).
À1 cmÀ1 Â 103) 289 (53.99), 405 (29.34), 427 (24.19).
This product was synthesized according to general procedure D as a
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yellow solid in 93% yield: mp 190 °C; 1H NMR (CDCl3) δ 9.29À9.32
(1H, dd, J = 5.7, 2.4 Hz), 8.94À8.97 (1H, dd, J = 5.7, 2.1 Hz), 8.55À8.59
(2H, m), 8.11À8.19 (3H, m), 5.74 (1H, s), 3.49 (6H, s); 13C NMR
(CDCl3) δ 53.1, 102.1, 121.3, 123.1, 127.3, 130.8, 131.0, 131.6, 132.0,
133.1, 133.4, 143.7, 143.9, 145.5, 145.6, 146.7; FTIR (KBr) 3438.7 (w,
yellow solid in 65% yield: mp 198 °C; 1H NMR (CDCl3) δ 9.12À9.15
(1H, dd, J = 7.8, 1.2 Hz), 8.70À8.73 (1H, dd, J = 8.4, 0.9 Hz), 8.36
(2H, d, J = 1.8 Hz), 8.28À8.32 (2H, d, J = 9.0 Hz), 7.91À8.09 (4H,
m), 6.06 (1H, s), 4.10À4.18 (5H, m); 13C NMR (CDCl3) δ 146.9,
144.6, 144.2, 142.9, 142.3, 142.1, 141.8, 140.7, 133.7, 132.9, 132.7,
130.5, 130.1, 129.8, 129.7, 128.3, 128.1, 127.1, 124.7, 124.7, 122.4,
102.9, 65.7; FTIR (KBr) 2890.19 (w, b), 1466.16 (m), 1405 (s),
1349.36 (w), 1177.96 (m), 1080.59 (m), 1017.11 (w), 896.52 (w),
776.26 (w) cmÀ1; HRMS (ESI) calcd for C17H13N4O2 [M + 1] m/z
305.1039, found 305.1036.
b), 2934.8 (s, b), 1438.0 (m), 1095.2 (m), 1075.6 (w), 1005.1 (s) cmÀ1
;
HRMS (ESI) calcd for C17H15N4O2 [M + 1] m/z 307.1195, found
307.1191; UV (methanol) λmax (nm) (εmax MÀ1 cmÀ1 Â 103) 282
(309), 382 (87.86). The structure of 11 was confirmed by X-ray
crystallography as indicated in the Supporting Information.
10-(Trimethoxymethyl)quinoxalino[2,3-c]cinnoline (12).
This product was synthesized according to general procedure D as a
yellow solid in 37% yield, but the reflux was continued for 24 h: mp
162 °C; 1H NMR (CDCl3) δ 9.2À9.21 (1H, m), 8.84À8.87 (1H, m),
8.72 (1H, s), 8.34À8.48 (1H, d, J = 8.7 Hz), 8.05À8.11(3H, m), 3.20
(9H, s); 13C NMR (CDCl3) δ 145.6, 144.5, 144.2, 142.8, 141.5, 132.4,
132.2, 131.1, 130.6, 130.1, 129.9, 127.9, 122.0, 120.2, 113.2, 49.1; FTIR
(KBr) 2956.9 (w, b), 2838.6 (w), 1726.9 (s), 1474.8 (w), 1379.8 (w),
1342.4 (m), 1306.1 (m), 1249.8 (s), 1223.2 (w), 1185.4 (m), 1092.9
(m), 1059.7 (s), 1004.2 (w), 978.0 (w), 925.1 (m), 894.1 (w), 817.5
(m), 773.7 (s), 604.2 (m), 528.9 (m) cmÀ1; HRMS (EI) calcd for
C18H16N4O3 m/z 336.1222, found 336.1224; UV (methanol) λmax
2-(1,3-Dioxolan-2-yl)quinoxalino[2,3-c]cinnoline (15). This
product was synthesized according to general procedure E as a yellow
solid in 60% yield: 1H NMR (CDCl3) δ 9.40À9.41 (1H, d, J = 1.8 Hz),
8.95(1H, d, J = 8.1Hz), 8.56À8.59 (1H, dd, J = 8.1, 1.8Hz),8.45(1H, dd,
J = 7.8, 1.5 Hz), 8.24 (1H, dd, J = 8.4, 1.5 Hz), 8.02À8.13 (2H, m), 6.22
(1H, s), 4.25À4.28 (4H, m), 4.20À4.23 (4H, m); 13C NMR (CDCl3) δ
146.6, 146.0, 142.8, 142.3, 132.5, 130.9, 130.8, 130.0, 129.0, 128.4, 123.4,
123.0, 120.2, 118.1, 101.9, 64.7; FTIR (KBr) 3453.2 (w, b), 2889.8
(w, b), 1585.8 (m), 1485.9 (w), 1464.3 (m), 1405.6 (s), 1348.8 (m), 1292.7
(w), 1177.7 (m), 1075.5 (s), 1016.7 (m), 941.0 (w), 895.8 (w), 803.4
(w), 777.1 (m), 745.1 (w), 726.7 (w), 672.5 (w), 658.3 (m), 606.4 (w),
531.9 (m) cmÀ1; HRMS (ESI) calcd for C17H13N4O2 [M + 1] m/z
305.1039, found 305.1035.
(nm) (εmax
M
À1 cmÀ1 Â 103) 282 (118.6), 381(33.27).
2-(Trimethoxymethyl)quinoxalino[2,3-c]cinnoline (14).
This product was synthesizedaccording to general procedure D as a yellow
solid. The reaction mixture was extracted with dichloromethane/water and
purified through a short column of silica gel using hexane/ethyl acetate (1:1
ratio) as eluent (76% yield): mp 215 °C; 1H NMR (CDCl3) δ 9.53À9.54
(1H, d, J = 1.5 Hz), 8.95À8.98 (1H, d, J = 8.4 Hz), 8.57À8.60 (1H, dt, J =
8.1, 0.9 Hz), 8.47À8.50 (1H, dt, J = 8.1 Hz, 0.6 Hz), 8.33 (1H, dd, J 8.4 Hz,
1.8 Hz), 8.05À8.14 (2H, m), 3.27 (9H, s); 13C NMR (CDCl3) δ 146.5,
145.9, 145.6, 143.8, 142.2, 133.6, 133.2, 132.0, 131.7, 131.1, 131.0, 129.4,
122.7, 121.0, 114.4, 50.1; FTIR (KBr) 3079.5 (w, b), 2948.1 (w, b), 1725.8
(s), 1594.0 (w), 1531.1 (w), 1489.8 (w), 1462.4 (w), 1433.5 (w), 1395.1
(w), 1370.4 (w), 1334.4 (w), 1272.0 (m), 1207.1 (m), 1165.5 (m), 1117.8
(m), 1086.5 (w), 1023.4 (w), 982.8 (w), 921.9 (w), 898.6 (w), 869.0 (w),
799.1 (w), 762.3 (s), 655.7 (m), 605.4 (m), 561.1 (w) cmÀ1; HRMS (EI)
calcd for C18H16N4O3 m/z 336.1222, found 336.1218; UV (methanol)
2-(1,3-Dioxolan-2-yl)-9,10-dimethylquinoxalino[2,3-c]-
cinnoline (17). This product was synthesized according to general
procedure E (reflux was done only for 10 min) as a yellow solid in 32%
yield: mp 207 °C; 1H NMR (300 MHz, CDCl3) δ 8.97 (1H, s),
8.71À8.73 (1H, d, J = 8.4 Hz), 8.51 (1H, s), 8.24 (1H, s), 7.83À7.87
(1H, dd, J1 = 8.4 Hz, J2 = 1.8 Hz), 6.19 (1H, s), 4.11À4.21 (4H, m), 2.72
(3H, s), 2.71 (3H, s); 13C NMR (75 MHz, CDCl3) δ 145.87, 145.55,
144.42, 143.83, 143.62, 142.99, 141.72, 133.31, 132.84, 131.35, 130.65,
125.99, 122.24, 121.44, 101.50, 65.51, 22.68, 22.43; FTIR (KBr) 2910
(m), 2853.30 (w), 1466.06 (w), 1383.76 (w), 1345.16 (m),1260 (m),
1177.08 (w), 1146.93 (m), 1067.33 (m), 971.09 (w), 940.99 (w), 872.94
(w), 814.97 (w) cmÀ1; UV (methanol) λmax (nm) (εmax
M
À1 cmÀ1
Â
103) 287 (22.69), 390 (6.82); MS (ESI) calcd forC19H17N4O2 [M + 1]
m/z 333.4, found 333.1
3-(2-Aminophenyl)-6,7-dimethylquinoxalin-2-amine (19).
To a 100 mL round-bottom flask containing 6,7-dimethyl-2-amino-3-(2-
nitrophenyl)quinoxaline (6e; 0.5 g, 1.9 mmol) were added methanol
(50 mL) and 5% pd/carbon (0.1 g). The mixture was placed in the
hydrogenator (3À4 bar) for 8 h. The mixture was subjected to suction
filtration through Celite, and the filtrate (10 mL) was diluted with water
(20 mL), whereby a green-yellow solid was formed. The latter was
collected by suction filtration, washed with cold ethanol, dried under
vacuum, and identified as 3-(2-aminophenyl)-6,7-dimethylquinoxalin-2-
amine (19) (90% yield): 1H NMR (CDCl3) δ 7.66 (1H, s), 7.44À7.46
(2H, m), 7.22À7.28 (1H, m), 6.84À6.89 (2H, m), 5.05 (2H, s, b), 4.38
(2H, s,b), 2.44 (3H, s), 2.41 (3H, s); 13C NMR (CDCl3) δ 150.66,
145.38, 143.50, 140.33, 139.65, 136.38, 135.02, 130.54, 129.26, 127.93,
125.21, 121.02, 118.63, 117.31, 20.42, 19.90; HRMS (ESI) calcd for
C16H17N4 [M + 1] m/z 265.1453, found 265.1447.
9,10-Dimethylquinoxalino[2,3-c]cinnoline (20). To a 100 mL
round-bottom flask containing 3-(2-aminophenyl)-6,7-dimethylquinoxa-
lin-2-amine(19; 0.2 g, 0.76 mmol) was added methanol(30mL) followed
by Clorox (10 mL). The dark red solution was allowed to stand at room
temperature for 5 min. The reaction was quenched by addition of water
and extracted with dichloromethane. The organic layer was dried and
evaporated, and the crude product was purified by chromatography over a
short column of silica. The obtained yellow product was identified as 9,10-
dimethylquinoxalino[2,3-c]cinnoline (20) (88% yield): mp 190 °C; 1H
NMR (CDCl3) δ 9.25À9.26 (1H, m), 8.89À8.92 (1H, m), 8.28 (1H, s),
8.17 (1H, s), 8.08À8.11 (2H, m), 2.66 (7H, s); 13C NMR (CDCl3) δ
146.61, 145.82, 145.56, 145.12, 143.58, 143.13, 132.75, 132.40, 131.47,
λmax (nm) (εmax
M
À1 cmÀ1 Â 103) 286 (74.13), 384 (31.87).
9,10-Bis(dimethoxymethyl)quinoxalino[2,3-c]cinnoline (16).
This product was synthesized according to general procedure D as a yellow
solid. The reaction mixture was extracted with dichloromethane/water and
purified through a short column of silica gel using hexane/ethyl acetate (1:1
ratio) as eluent (60% yield): mp 168 °C; 1H NMR (CDCl3) δ 9.27À9.30
(1H, dd, J = 6 Hz, 2.1 Hz), 8.91À8.94 (1H, dd, J = 6.6,2.4 Hz), 8.80 (1H, s),
8.70 (1H, s), 8.06À8.16 (2H, m), 6.02 (1H, s), 5.97 (1H, s), 3.47 (12H, s);
13C NMR (CDCl3) δ 146.7, 145.8, 145.3, 143.3, 141.9, 140.1, 133.7, 133.0,
131.9, 131.6, 129.5, 127.9, 123.1, 121.4, 100.3, 100.1, 53.4, 53.4; FTIR (KBr)
3447.5 (m, b), 2961.6 (w, b), 2923.7 (w, b), 2850.1 (w, b), 1437.6 (w),
1261.3 (m), 1087.1 (w), 1049.2 (w), 1030.6 (w), 801.8 (w, b) cmÀ1; UV
(methanol) λmax (nm) (εmax
HRMS (ESI) calcd for C20H21N4O4 [M + 1] m/z 381.1563, found
381.1539.
M
À1 cmÀ1 Â 103): 284 (146), 384 (38.29);
General Procedure E. The appropriate 2-amino-3-(2-nitrophe-
nyl)quinoxaline 6 (2.60 mmol) was dissolved in 10% tert-butyl alcohol/
KOH (30 mL). Ethylene glycol (10 mL) was added, and the blackish
solution was heated at 80 °C for 30 min. After cooling, the solvent was
removed at reduced pressure, and the brown residue was extracted with
dichloromethane (50 mL Â 4). The organic extracts were combined,
dried over MgSO4, and purified by silica gel column chromatography
(1:1 ethyl acetate/hexane) to obtain the corresponding quinoxalino[2,3-c]
cinnoline as a yellow-orange solid.
10-(1,3-Dioxolan-2-yl)quinoxalino[2,3-c]cinnoline (13).
This product was synthesized according to general procedure E as a
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ARTICLE
131.39, 129.20, 127.79, 122.92, 121.75, 21.08, 20.83; FTIR (KBr) 2923.46
(w, b), 1477.78 (m), 1462.63 (m), 1375.65 (s), 1341.83 (s), 1166.86 (w),
1025.54 (w), 1001.40 (m), 865.12 (m), 782.06 (m), 720.87 (w), 594.83
(w), 530.54 (m) cmÀ1; UV (methanol) λmax (nm) (εmax
M
À1 cmÀ1
Â
103) 287 (81.62), 392 (25.28); HRMS (ESI) calcd for C16H13N4 [M + 1]
m/z 261.1140, found 261.1134.
’ ASSOCIATED CONTENT
Supporting Information. 1H NMR and 13C NMR spec-
S
b
tra as well as crystallographic data for 10a and 11, including CIF
files. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: haddadin@aub.edu.lb; mjkurth@ucdavis.edu.
’ ACKNOWLEDGMENT
We thank Professor Samir Zard of Polytechnique, France, and
Professor Musa Z. Nazer of the University of Jordan for high-
resolution mass spectral data.
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