CAN-catalyzed syntheses of 3,4-dihydroquinoxalin-2-amine derivatives based on isocyanides

Article abstract of DOI:10.1016/j.tetlet.2009.09.022

Starting from readily available o-phenylenediamines 1, ketones 2 and isocyanides 3, a variety of highly substituted 3,4-dihydroquinoxalin-2-amine derivatives 4 were efficiently synthesized in the presence of catalytic amount of cerium(IV) ammonium nitrate

Full text of DOI:10.1016/j.tetlet.2009.09.022

Tetrahedron Letters 50 (2009) 6502–6505
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
CAN-catalyzed syntheses of 3,4-dihydroquinoxalin-2-amine derivatives
based on isocyanides
*
*
Jian Li , Yuejin Liu, Chunju Li, Xueshun Jia
Department of Chemistry, Shanghai University, 99 Shangda Road, Shanghai 200444, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 July 2009
Revised 1 September 2009
Accepted 3 September 2009
Available online 12 September 2009
Starting from readily available o-phenylenediamines 1, ketones 2 and isocyanides 3, a variety of highly
substituted 3,4-dihydroquinoxalin-2-amine derivatives 4 were efficiently synthesized in the presence
of catalytic amount of cerium(IV) ammonium nitrate at room temperature. The flexibility of this protocol
also opens a new route to the structurally unique spirocyclic analogs when cyclic ketones are employed.
Ó 2009 Elsevier Ltd. All rights reserved.
In the past decades, multicomponent reactions (MCRs) have
drawn considerable interests owing to its exceptional synthetic
efficiency.1 Compared with conventional methods, multicompo-
nent process exhibits high levels of efficiency and diversity, as it al-
lows more than two simple and flexible building blocks to be
combined in practical, time-saving one-pot operations. Among
the known multicomponent reactions, isocyanide based MCRs
(IMCRs) are particularly valuable.2 In addition to the added diver-
sity of bond formation and functional group tolerance, the out-
standing position of IMCRs can also be traced back to the
exceptional reactivity of isocyanide. As we know, no other func-
tional group reacts with nucleophiles and electrophiles at the same
atom.3 Consequently, MCRs involving isocyanides have been
widely applied to organic synthesis, especially in drug discovery.4
Quinoxaline derivatives are a common occurrence in many
pharmacological active substances of natural or synthetic origin.5
Many known antibiotics including echinomycin, actinomycin,
and leromycin possess the basic skeleton.6 Moreover, quinoxaline
analogs also serve as dyes, organic semiconductors as well as other
useful materials,7–10 which build up the attractiveness for their
syntheses. On the other hand, as the most notable one electron oxi-
dant, cerium(IV) ammonium nitrate (CAN) has been utilized exten-
sively for oxidative transformations. Additionally, advantages such
as excellent solubility in water, inexpensiveness, ecofriendly nat-
ure, simple handling and high reactivity make CAN a powerful cat-
alyst in organic syntheses.11 As a continuation of our interest in
lanthanide reagents and the search for potential drug structures,12
herein we wish to report an efficient synthesis of 3,4-dihydroqui-
noxaline-2-amine derivative 4 catalyzed by CAN.
screened and cerium(IV) ammonium nitrate (CAN) seemed to be
best choice. In the presence of catalytic amount of CAN, 3,4-dihy-
droquinoxaline-2-amine 4a was afforded in 92% yield at room
temperature (Table 1, entry 1).13 A variety of substituted o-pheny-
lenediamines 1, ketones 2 and isocyanides 3 were carried out to
establish the scope and the generality of the present transforma-
tion (Scheme 1) and the results were summarized in Table 2. Sev-
eral structurally diversed isocyanides
3 including tert-butyl,
cyclohexyl, benzyl and 2,6-dimethylphenyl substituted ones were
firstly used and the expected products 4 were isolated in good to
excellent yields (Table 2, entry 1–4). These results indicate that
the excellent reactivity of isocyanide component 3 must play an
important role in the whole process as the condensation of o-
phenylenediamines 1 with 2 equiv carbonyl compounds 2 is very
easy to take place.14 In our runs, however, the reactions are quite
clean and no other side reactions are observed. Various diamines
1 and ketones 2 gave satisfactory results (Table 2, entry 5–9). It
was important to note that the present reaction was quite
Table 1
Optimization of reaction conditionsa
Entry
Catalyst
Time (h)
Yieldb (%)
1
2
3
4
5c
6
7
8
9
FeCl3
InCl3
Ce (NH4)2(NO3)6
ZnCl2
8
8
3
24
3
8
24
24
24
65
80
92
No reaction
79
85
BF3ÁEt2O
BiCl3
CuBr2
Zn(OAc)2
Cu(OAc)2
15
In our initial experiments, 4-nitro-1,2-phenylenediamine, ace-
tone and tert-butyl isocyanide were employed to optimize the
reaction conditions. As shown in Table 1, a series of catalysts were
No reaction
No reaction
a
Until otherwise noted, all reactions were carried out with 5 mol % catalyst in
5 mL ethanol at room temperature.
b
Yields of product 4 after silica gel chromatography.
In such case, 1 equiv BF3ÁEt2O was used.
* Corresponding author. Tel./fax: +86 21 66132408.
E-mail addresses: lijian@shu.edu.cn (J. Li), xsjia@mail.shu.edu.cn (X. Jia).
c
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.022

J. Li et al. / Tetrahedron Letters 50 (2009) 6502–6505
6503
H
N
R2
R3
NH2
NH2
O
CAN (5 mol%)
R1
+
R4
N C
+
R1
R2
R3
EtOH, r. t.
N
N
H
R4
Scheme 1. Syntheses of 3,4-dihydroquinoxalin-2-amine derivatives.
Table 2
Efficient syntheses of 3,4-dihydroquinoxalin-2-amine derivatives 4a
Entry
Amine 1
Ketone 2
Isocyanide 3
tert-Butyl
Product 4
Yieldb,c (%)
H
N
O2N
1
4-Nitro-1,2-phenylenediamine
Acetone
90
92
N
N
H
4a
H
N
O2N
O2N
2
3
4
5
6
4-Nitro-1,2-phenylenediamine
4-Nitro-1,2-phenylenediamine
4-Nitro-1,2-phenylenediamine
o-Phenylenediamine
Acetone
Acetone
Acetone
Acetone
Acetone
Cyclohexyl
N
N
H
4b
H
N
2,6-Dimethylphenyl
80
87
75
96
N
N
H
4c
H
N
O2N
Benzyl
N
N
H
Ph
4d
H
N
2,6-Dimethylphenyl
1,1,3,3-Tetramethylbutyl
N
N
H
4e
H
N
o-Phenylenediamine
N
N
H
4f
O
H
N
Ph
7
8
3,4-Diaminobenzophenone
3,4-Diaminotoluene
Acetone
Acetone
Cyclohexyl
Cyclohexyl
88
95
N
N
H
4g
4h
H
N
H3C
N
N
H
O
H
N
Ph
Ph
9
3,4-Diaminobenzophenone
3,4-Diaminobenzophenone
2-Butanone
1,1,3,3-Tetramethylbutyl
93
86
N
N
H
4i
O
H
N
10
Cyclopentanone
tert-Butyl
N
N
H
4j
(continued on next page)

6504
J. Li et al. / Tetrahedron Letters 50 (2009) 6502–6505
Table 2 (continued)
Entry
11
Amine 1
Ketone 2
Isocyanide 3
Product 4
Yieldb,c (%)
H
N
2-Nitro-1,2-phenylenediamine
Cyclopentanone
Cyclopentanone
Cyclohexanone
Cyclohexanone
tert-Butyl
tert-Butyl
tert-Butyl
Cyclohexyl
70
N
N
H
NO2
4k
H
N
12
13
14
3,4-Diaminotoluene
62
91
83
H3C
N
N
H
4l
H
N
O2N
4-Nitro-1,2-phenylenediamine
4-Nitro-1,2-phenylenediamine
N
N
H
4m
H
N
O2N
N
N
H
4n
CH3
O
H
N
71d
Ph
15
3,4-Diaminobenzophenone
4-Methylacetophenone
tert-Butyl
N
N
H
4o
a
b
c
Until otherwise noted, all reactions finished within 3 h in 5 mL EtOH at room temperature.
All new compounds were characterized by 1H NMR, 13C NMR, EA, MS and IR spectroscopy.
Isolated yields.
d
In such case, only 80% conversion was observed in 20 h.
regioselective. The 1H NMR and 13C NMR spectroscopy of com-
pound 4 showed that only one isomer was produced.15 This can
be explained by the presence of electron-withdrawing nitro or
benzoyl group, which controls the selectivity by deactivating the
para-amino group. Thus the formation of iminium ion intermediate
had to be initiated from the meta-amino group. And this rule works
well for all the diamines substituted by electron-withdrawing
groups. In contrast, the regioselectivity essentially turned when
3,4-aminotoluene was used. In such cases, the reactivity of para-
amino group was enhanced by the electron-donating methyl group
(Table 2, entry 8). Furthermore, cyclic ketones were then intro-
duced to prepare structurally interesting spirocyclic compounds
(Table 2, entry 10–14). Characterized by the quaternary carboncen-
ter and two fused rings, to our knowledge, these compounds are
usually found as subunits in natural compounds.16,17 As shown in
Table 1, the desired spirocyclic analogs 4j–n were all efficiently
afforded. Notably, somewhat lower yield (70%) and long reaction
time (20 h) were observed when 2-nitro-1,2-phenylenediamine
was used, which might contribute to its steric hindrance (Table
2, entry 11). In addition, aromatic ketone also underwent smooth
conversion to the corresponding product 4o with acceptable result
(Table 2, entry 15). Since compound 4o was yellow, it made detec-
tion and isolation easier.
R2
R3
H
N
CAN
1
2
R1
+
C
N
R4
NH2
3
A
R2
R2
H
N
H
R3
N
R3
N
-H
4
R1
R1
NH2
N
H
C
R4
N
R4
B
Scheme 2. Proposed mechanism for the synthesis of 4.
gen atom with CAN, thus could facilitate the formation of iminium
cation A.14 The nucleophilic addition of isocyanide 32a followed by
an intramolecular cyclization of B essentially could result in the
generation of C, which then should be isomerized to final product
4. Although Ce(IV) derivatives are generally employed as single
electron transfer (SET) oxidants, we believe CAN serves as lewis
acid in the above process same as in other carbon–carbon and car-
bon–heteroatom bond forming reactions.18
The mechanism of the present reaction has not been unequivo-
cally established, but a possible one is outlined in Scheme 2. Firstly,
the carbonyl group could be activated by the coordination of oxy-
In conclusion, we have disclosed an efficient strategy to synthe-
size highly substituted 3,4-dihydroquinoxalin-2-amine deriva-
tives.19 This method also allows to prepare a class of structurally

J. Li et al. / Tetrahedron Letters 50 (2009) 6502–6505
6505
12. (a) Li, J.; Li, S. Y.; Jia, X. S. Synlett 2008, 1529; (b) Li, J.; Xu, H.; Zhang, Y. M.
Tetrahedron Lett. 2005, 46, 1931; (c) Li, J.; Qian, W. X.; Zhang, Y. M. Tetrahedron
2004, 60, 5793.
13. The significance of the CAN was also verified by the blank experiments. In the
absence of CAN, no reaction took place at all.
unique spirocyclic compounds. Considering the advantages such as
readily available starting materials, simple operations as well as
the high yields, our method will potentially find its application in
organic synthesis or even in pharmaceutical industry.
14. Ceric ammonium nitrate can act as efficient catalyst for the preparation of 1,5-
benzodiazepine derivatives with substituted o-phenyleneamines and ketones:
Varala, R.; Enugala, R.; Nuvula, S.; Adapa, S. R. Synlett 2006, 1009.
Acknowledgments
15. All new compounds have been characterized by 1H NMR, 13C NMR, EA, MS and
IR spectroscopy.
We thank the National Natural Science Foundation of China
(No. 20872087) and Innovation Fund of Shanghai University for
financial support.
16. Cui, C. B.; Kakeya, H.; Osada, H. Tetrahedron 1997, 53, 59.
17. Sannigrahi, M. Tetrahedron 1999, 55, 9007.
18. Nair, V.; Balagopal, L.; Rajan, R.; Mathew, J. Acc. Chem. Res. 2004, 37, 21.
19. Typical procedure for the synthesis of substituted 3,4-dihydroquinoxalin-2-amine
4: To a solution of 1 mmol o-phenylenediamine 1, 1 mmol ketone 2, 1 mmol
isocyanide 3 in 5 mL ethanol, 5 mol % CAN was added quickly. The above
reaction mixture was stirred at room temperature until the completion (by
TLC). After usual workup, the crude product was purified by silica gel column
chromatography using EtOAc–PE (1:3) as eluent to afford the pure product 4.
Selected data: Compound 4f: yellow solid, mp: 59–61 °C. IR (KBr/cmÀ1): 3459,
3360, 2951, 1615, 1513, 1226, 741. 1H NMR (500 MHz, CDCl3): d (ppm) = 7.04–
7.03 (m, 1H), 6.80–6.73 (m, 2H), 6.53–6.52 (m, 1H), 4.25 (br s, 1H, NH), 3.43 (br
s, 1H, NH), 1.89 (s, 2H), 1.53 (s, 6H), 1.24 (s, 6H), 1.03 (s, 9H). 13C NMR
(125 MHz, CDCl3): d (ppm) = 157.2, 135.0, 124.1, 122.7, 119.7, 113.8, 56.0, 52.4,
50.8, 32.1, 32.0, 29.4, 26.4. MS: m/z (%) = 287 (M+, 27), 272 (11), 175 (32), 160
(100). Anal. Calcd for C18H29N3: C, 75.21; H, 10.17; N, 14.62. Found: C, 75.36; H,
10.20; N, 14.79. Compound 4h: yellow solid, mp: 153–155 °C. IR (KBr/cmÀ1):
3446, 3353, 2960, 1636, 1562, 1480. 1H NMR (500 MHz, CDCl3): d (ppm) = 7.76
(d, 2H, J = 7.0 Hz),7.53 (t, 1H, J = 7.0 Hz), 7.44 (t, 2H, J = 7.5 Hz), 7.18 (dd, 1H,
J = 8.0 Hz), 7.14 (s, 1H), 7.02 (d, 1H, J = 8.0 Hz), 4.53 (br s, 1H, NH), 3.76 (br s, 1H,
NH), 2.06 (d, 1H, J = 15.0 Hz), 1.72 (d, 1H, J = 15.0 Hz), 1.61–1.46 (m, 2H), 1.59
(s, 3H), 1.54 (s, 3H), 1.31 (s, 3H), 1.04 (s, 9H), 0.91 (t, 3H, J = 7.5 Hz). 13C NMR
(125 MHz, CDCl3): d (ppm) = 196.4, 158.6, 140.3, 139.2, 134.7, 131.5, 129.9,
128.1, 123.7, 122.8, 114.6, 56.4, 53.7, 52.7, 31.9, 31.8, 31.4, 29.2, 29.0, 24.2, 8.0.
MS: m/z (%) = 405 (M+, 27), 376 (61), 264 (100), 105 (22). Anal. Calcd for
C26H35N3O: C, 77.00; H, 8.70; N, 10.36. Found: C, 77.24; H, 8.76; N, 10.56.
Compound 4j: yellow solid, mp: 203–205 °C. IR (KBr/cmÀ1): 3431, 3337, 2958,
1634, 1561, 1466, 725. 1H NMR (500 MHz, CDCl3): d (ppm) = 7.76–7.43 (m,
5H), 7.23–7.17 (m, 1H), 7.17 (s, 1H), 7.05 (d, 1H, J = 8.0 Hz), 4.49 (br s, 1H, NH),
3.88 (br s, 1H, NH), 1.83–1.70 (m, 8H), 1.50 (s, 9H). 13C NMR (125 MHz, CDCl3):
d (ppm) = 196.4, 159.3, 141.1, 139.1, 135.1, 131.5, 131.2, 129.8, 128.0, 124.1,
122.9, 115.2, 61.7, 52.2, 37.1, 29.0, 24.0. MS: m/z (%) = 361 (M+, 100), 305 (62),
276 (54), 105 (35). Anal. Calcd for C23H27N3O: C, 76.42; H, 7.53; N, 11.62.
Found: C, 76.17; H, 7.56; N, 11.73. Compound 4m: red solid, mp: 174–175 °C. IR
(KBr/cmÀ1): 3413, 2923, 1615, 1525, 1310. 1H NMR (500 MHz, DMSO-d6): d
(ppm) = 7.77 (d, 1H, J = 3.0 Hz), 7.46 (m, 1H), 6.83 (d, 1H, J = 8.5 Hz), 6.39 (s, 1H,
NH), 6.05 (s, 1H, NH), 1.70–1.16 (m, 10H), 1.42 (s, 9H). 13C NMR (125 MHz,
DMSO-d6): d (ppm) = 161.3, 141.9, 141.3, 135.2, 121.6, 114.2, 107.8, 51.9, 51.5,
31.2, 28.5, 24.5, 19.7. MS: m/z (%) = 316 (M+, 100), 260 (75), 217 (77). Anal.
Calcd for C17H24N4O2: C, 64.53; H, 7.65; N, 17.71. Found: C, 64.40; H, 7.80; N,
17.53.
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