Dimethyl Sulfoxide Involved One-Pot Synthesis of Quinoxaline Derivatives

Article abstract of DOI:10.1021/acs.joc.6b02977

An efficient, green, and novel method for the synthesis of N-heterocycle-fused quinoxalines is reported herein. Dimethyl sulfoxide was used as both a reactant and a solvent in this reaction. A wide range of products in moderate to excellent yields were obtained, including pyrrolo[1,2-a]quinoxalines, indolo[1,2-a]quinoxalines, 1H-pyrrolo[3,2-c]quinolines, and benzo[4,5]imidazo[1,2-c]quinazolines.

Full text of DOI:10.1021/acs.joc.6b02977

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Article
Dimethyl Sulfoxide Participated One-pot Synthesis of Quinoxaline Derivatives
Caixia Xie, Zeyuan Zhang, Danyang Li, Jian Gong, Xushuang Han, Xuan Liu, and Chen Ma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02977 • Publication Date (Web): 03 Mar 2017
Downloaded from http://pubs.acs.org on March 3, 2017
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Dimethyl Sulfoxide Participated Oneꢀpot
Synthesis of Quinoxaline Derivatives
Caixia Xie,a Zeyuan Zhang,a Danyang Li,a Jian Gong,a Xushuang Han,a Xuan Liu,a
and Chen Ma a,b
*
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a Key Laboratory of Special Functional Aggregated Materials, Ministry of Education,
School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100,
P. R. China. School of Chemistry and Chemical Engineering, Shandong University,
Jinan, 250100, P. R. China.
bState Key Laboratory of Bioactive Substance and Function of Natural Medicines,
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union
Medical College, Beijing, 100050, P. R. China.
Email: chenma@sdu.edu.cn
An efficient, green and novel method for the synthesis of Nꢀheterocycle fused
quinoxalines is reported herein. Dimethyl sulfoxide was used as both a reactant and a
solvent in this reaction. A wide range of products in moderate to excellent yields was
obtained
including,
pyrrolo[1,2ꢀa]quinoxalines,
indolo[1,2ꢀa]quinoxalines,
1Hꢀpyrrolo[3,2ꢀc]quinolines and benzo[4,5]imidazo[1,2ꢀc]quinazolines.
INTRODUCTION
Dimethyl sulfoxide is an important polar solvent and mild oxidant that is routinely
used in the synthesis of organic compounds and pharmaceuticals1 due to its low
toxicity and ready availability. In addition, it has been used as reactant in organic
synthesis in recent years as well, especially in the transformation of DMSO into –
SMe,2 ꢀCHO,3 ꢀCN4 and ꢀSO2Me5 for the synthesis of more complex organic
compounds, which are the key to production of medicinal and natural products
(Scheme 1). Although DMSO has been used in syntheses to introduce functional
groups, to the best of our knowledge, only a few6 researchers have used DMSO to
synthesize heterocyclic compounds such as Zhang`s work6a published in 2013 using
Cu(OTf)2 as catalyst (Scheme 2).
Pyrrolo[1,2ꢀa]quinoxaline derivatives are indispensable in heterocyclic organic
chemistry and have enjoyed extensive application in organic functional materials,
pharmaceuticals and biological studies. Many unique and excellent properties in a
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number of products have been revealed, such as the Dꢀloop activity of RAD51
inhibitors,7 5ꢀHTR affinities,8 the human protein kinase CK2 inhibitors,9 glucagon
receptor antagonists,10 antimalarial activities11 and others.12 For this reason, numerous
methods have been reported to construct this structural skeleton.13 However, many
inevitable drawbacks have been encountered, such as the use of expensive and toxic
reactants,14 transitionꢀmetal catalysts15 and harsh conditions of microwave
irradiation16 and amberlite.17 Our group has devoted continuously to explore the
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Scheme 1 Reactions employing DMSO as a reactant
Scheme 2 Synthesis of heterocyclic compounds employing DMSO
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efficient and simple methods to resolve these challenges.18 Based on our previous
work19 on heterocyclic synthesis and the referenced literature reports, we herein
describe a simple, metalꢀ free and environmentalꢀfriendly method to obtain this class
of compounds using 2ꢀ(1Hꢀpyrrolꢀ1ꢀyl)anilines and DMSO as reactants.
8
RESULTS AND DISCUSSION
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Our initial experiment began with the observation that 2ꢀ(1Hꢀpyrrolꢀ1ꢀyl)aniline could
react with DMSO at 130 ºC in the presence of TsOH·H2O. And the desired product
was obtained in a 41% yield (Table 1, entry 1). Hence, several Bronsted acids were
examined for use in this reaction strategy. It was found that AcOH was the most
effective Bronsted acid with a yield of 87% (Table 1, entries 2ꢀ9). The next step
entailed optimizing the concentration of AcOH in the reaction, but no improvement in
product yield occurred (Table 1, entries 1 and 10ꢀ11). Besides, the reaction
temperature had an obvious influence (Table 1, entries 12ꢀ13). A long reaction time
was required to yield the desired product when the reaction temperature was less than
130 oC. At 140 oC the quantity of byꢀproducts was high resulting in a low yield of the
desired product. Interestingly, the reaction occurred without the presence of an acid
Table 1 Optimization of the reaction conditionsa
Entry Acid
Equiv
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO/H2O
DMSO
DMSO
T / oC
130
130
130
130
130
130
130
130
130
130
130
120
140
130
130
130
130
Yield / %b
41
63
87
22
58
66
50
41
1
TsOH·H2O
1
2
MsOH
1
3
4
5
CH3COOH
CF3COOH
Ph2PO2H
1
1
1
6
7
8
9
10
11
12
13
14
15
16
17
HOCH2COOH
NCCH2COOH
ClCH2COOH
C(CH3)3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
None
1
1
1
1
0.5
2
1
1
ꢀꢀꢀꢀ
1
50
73
77
41
65
42
CH3COOH
CH3COOH
CH3COOH
21c
54d
N.R.e
1
1
a1a (0.5 mmol, 0.079 g), DMSO (2 mL), acid (0.5 mmol), in a sealed tube, 130 oC
(TLC monitored); bIsolated yields; cDMSO / H2O = 1:1; dunder oxygen atmosphere;
eunder nitrogen atmosphere.
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and a yield of 42% was obtained after three days of reaction at 130 °C (Table 1, entry
14). No product was detected when the reaction was performed under nitrogen
atmosphere (Table 1, entry 17). This result indicated that oxygen played an essential
role in this reaction. However, the reaction proceeded well under O2 atmosphere with
a lower yield, possibly because of the side reactions (Table 1, entry 16). It was worth
noting that the reaction was hindered when water was present in the reaction system
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Scheme 3 Substrate scope of 2ꢀ(1Hꢀpyrrolꢀ1ꢀyl)aniline 1a,b
N
N
N
N
N
N
O
2c (70%)
2a (87%)
2b (59%)
N
N
N
N
F
N
Cl
N
2f (57%)
2d (93%)
2e (94%)
Cl
N
N
O
N
N
N
N
2i (81%)
2g (0%)
2h (44%)
F
N
Cl
Cl
N
N
N
N
N
2l (71%)
2j (61%)
2k (57%)
N
N
N
N
F
F
N
N
N
N
2m (58%)
2n (18%)
2o (78%)
N
N
N
N
N
N
N
N
N
2r
2p
2q
(58%)
(82%)
(79%)
a1 (0.5 mmol), DMSO (2 mL), CH3COOH (0.5 mmol), 130 C in a sealed tube for
o
about 20 h, (TLC monitored); bIsolated yields.
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(Table 1, entry 15). Under the optimized reaction conditions (Table 1, entry 3), the
desired product 3a was isolated in a yield of 87%.
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With these established reaction conditions ， the scope of the
2ꢀ(1Hꢀpyrrolꢀ1ꢀyl)aniline reaction was evaluated. It was found that compounds 1
bearing electronꢀwithdrawing groups gave better yields than those bearing
electronꢀdonating groups (Scheme 3, 2bꢀ2e). Among the compounds with
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Scheme 4 Substrate scope of 2ꢀ(1Hꢀindolꢀ1ꢀyl)anilinea,b
a3 (0.5 mmol), DMSO (2 mL), CH3COOH (0.5 mmol), 130 C in a sealed tube for
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about 20 h, (TLC monitored); bIsolated yields.
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electronꢀwithdrawing groups, substituents at various positions on the benzene ring
produced obvious differences and substituents at the 5ꢀposition on the ring were found
to have a better effect on the reaction than groups located at the 4ꢀposition (Scheme 3,
2dꢀ2j). However, none of the desired product was obtained when
3ꢀmethylꢀ2ꢀ(1Hꢀpyrrolꢀ1ꢀyl)aniline was used in this reaction, which might be the
result of steric effects (Scheme 3, 2g). In addition, when imidazolyl was used in place
of pyrrolyl, low yields of the desired product resulted. A great improvement in the
yield resulted when there was a methyl group in imidazole ring (Scheme 3, entries
2nꢀ2p).20 2ꢀ(1Hꢀpyrrolꢀ1ꢀyl)pyridinꢀ3ꢀamine could also react with DMSO and
provided the desired product in moderate yields (Scheme 3, entries 2q, 2r).
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Encouraged by these results, 2ꢀ(1Hꢀindolꢀ1ꢀyl)aniline was used as the reactant and
a 12% yield of the desired product was obtained (Scheme 4, 4a). To our delight, the
yield was significantly improved when 2ꢀ(3ꢀmethylꢀ1Hꢀindolꢀ1ꢀyl)aniline was used as
a substrate (Scheme 4, 4b). This was probably due to the competitive reaction
N
O
S
N
N
AcOH, TEMPO
130 oC
(a)
Me
Me
Me
Me
NH2
42%
29%
N
O
S
N
N
AcOH, BHT
130 oC
(b)
(c)
NH2
N
O
S
N
N
AcOH
130 oC
D
D
NH2
D
D
D/H
D
D
2s / 2a = 13.3 : 1
86%
N
N
(d)
(e)
dioxane
O
AcOH, 130 oC
n
NH2
N
48%
N
dioxane
AcOH, 130 oC
N. R.
NH2
N
N
O
S
N
S S
AcOH
130 o
N
C
NH2
N
(f)
53% 4p
Scheme 5 Control experiments
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between the 2ꢀposition and 3ꢀposition of indolyl and the electronꢀdonating effect of
alkyl group.20 A wide range of 2ꢀ(3ꢀmethylꢀ1Hꢀindolꢀ1ꢀyl)anilines with different
substituents were tolerated in our protocol (Scheme 4, 4cꢀ4k). Interestingly, the
desired product was also obtained when 2ꢀ(1Hꢀindolꢀ2ꢀyl)aniline was selected as
substrate (Scheme 4, 4l). And substituted 2ꢀ(1Hꢀbenzo[d]imidazolꢀ2ꢀyl)anilines also
proceeded well in this reaction (Scheme 4, 4mꢀ4o), which greatly extended the scope
of this synthesis strategy.
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To obtain further insight into the reaction mechanism, several control experiments
were conducted (Scheme 5). Initially, radical inhibitors (TEMPO and BHT) were
added to the reaction and the yields were found to be reduced to 42% and 29% (Eq a,
Eq b). Thus, it appeared that a radical process cannot be excluded in this reaction.
Then to determine the source of the carbon, an isotope experiment was performed and
1
the product 2s was obtained with the radio of 2s:2a = 13.3: 1 (Eq c, H NMR of 2s
see supporting information). This result suggested that the CꢀH bond cleavage of
DMSO had occurred and the carbon atom in the desired product was obtained from
DMSO. Next, paraformaldehyde was reacted with 2ꢀ(1Hꢀpyrrolꢀ1ꢀyl)aniline in
dioxane and the desired product was obtained, but in the absence of paraformaldehyde,
no desired product resulted(Eq d, Eq e). To further explore this mechanism,
tetrahydrothiophene 1ꢀoxide was used as a solvent and the desired product
3ꢀ(pyrrolo[1,2ꢀa]quinoxalinꢀ4ꢀyl)propaneꢀ1ꢀthiol was not obtained, but a coupling
product of SꢀS bond was detected in a yield of 53% (Eq f).
Based on the control experiments and the previous literature, we suspect that two
mechanistic pathways may be possible in this reaction. The first one may be a radical
process, 21, 3b, d, f, e where ·CH3 may be produced by DMSO participated by O2 at high
temperature and then, CH2O was produced through a process that ·CH3 was trapped
by oxygen to give peroxy radical. Then the imine formation and electrophilic
aromatic substitutions occur to produce the desired products.22 In addition, according
to the previous literature, 23, 5b DMSO could decompose and produce CH2O directly at
high temperature, which may form a second reaction pathway to the desired product.
CONCLUSION
In conclusion,
a
simple, green and efficient way to construct
pyrrolo[1,2ꢀa]quinoxalines was developed as well as other Nꢀheterocycle fused
quinoxalines under mild conditions. In particular, it was found that oxygen could be
used as a cheap oxidant and no metal catalysts were needed. This new reaction
strategy can provide access to a wide range of processes in organic and medicinal
chemistry synthesis.
EXPERIMENTAL SECTION
1H and 13C NMR spectra of the products were recorded using a 300 MHz or a 400
MHz MNR instrument in CDCl3 or DMSOꢀd6, and tetramethylsilane (TMS) as the
internal standard. HRMS spectra were determined using a QꢀTOF spectrograph.
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Compounds 1a-1r and 3a-3o were prepared according to the literature. Other reagents
were commercially available and were used without further purification. All reactions
were monitored using thinꢀlayer chromatography (TLC).
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General experimental procedures for the synthesis of pyrrolo [1,2-a]quinoxalines
9
A mixture of 2ꢀ(1Hꢀpyrrolꢀ1ꢀyl)aniline (0.5 mmol) and DMSO (2mL) with AcOH
(0.5 mmol) were stirred at 130 oC for 20ꢀ25 h (TLC monitored). Then the mixture was
extracted with ethyl acetate three times (3×30 mL). The combined organic layers were
dried with MgSO4 and the solvent was removed in vacuo to produce a residue. The
residue was purified by column chromatography on silica gel using petroleum ether /
ethyl acetate to provide the desired product.
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Pyrrolo[1,2-a]quinoxalines (2a)13b
Light yellow solid. 73 mg (87% yield). Mp: 137ꢀ139 oC. 1H NMR (300 MHz, CDCl3):
δ = 8.78 (s, 1H), 7.95 (dd, J = 7.8 Hz, 1.5 Hz, 1H), 7.87 (d, J = 1.2 Hz, 1H), 7.81 ( d,
J = 6.3 Hz, 1H), 7.50ꢀ7.38 (m. 2H), 6.87ꢀ6.83 (m, 2H); 13C NMR (75 MHz, CDCl3):
δ = 145.7, 135.8, 130.1, 128.0, 127.7, 126.4, 125.1, 114.1, 113.7, 113.7, 107.2; HRMS
(ESI) calcd for C11H8N2 [(M+H)+]:169.0760; found, 169.0761.
7-Methylpyrrolo[1,2-a]quinoxaline (2b)24
Light yellow solid. 54 mg (59% yield). Mp: 112ꢀ113 oC. 1H NMR (400 MHz, CDCl3):
δ = 8.78 (s, 1H), 7.87 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.33 (dd, J = 8.3 Hz, 1.2 Hz,
1H), 6.87ꢀ6.94 (m, 2H), 2.94 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 145.7, 135.7,
13, 128. 9, 128.9, 126.4, 125.9, 114.0, 113.7, 113.5, 107.0; HRMS (ESI) calcd for
C12H10N2 [(M+H)+]: 183.0917; found,183.0913.
7-Methoxypyrrolo[1,2-a]quinoxaline (2c)13c
o
Yellow solid. 69 mg (70% yield). Mp: 99ꢀ101 C. 1H NMR (300 MHz, CDCl3): δ =
8.79 (s, 1H), 7.86 (t, J = 1.4 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 9.0 Hz,
1H), 7.15 (dd, J = 9.0 Hz, 3.0 Hz, 1H), 6.89ꢀ6.84 (m, 2H), 3.92 (s, 3H); 13C NMR (75
MHz, CDCl3): δ = 157.1, 146. 0, 136.9, 126.2, 122.3, 116.8, 114.7, 113.9, 113.7,
111.4, 107.1, 55.7; HRMS (ESI) calcd for C12H10N2O [(M+H)+]: 199.0866; found,
199.0869.
7-Chloropyrrolo[1,2-a]quinoxaline (2d)18a
o
Yellow solid. 94 mg (93% yield). Mp: 135ꢀ137 C.1H NMR (300 MHz, CDCl3): δ =
7.92 (d, J = 2.4 Hz, 1H), 7.88 (t, J = 1.2 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.47 (dd,
8.7 Hz, 2.4 Hz, 1H), 6.92ꢀ6.87 (m, 2H); 13C NMR (75 MHz, CDCl3): δ = 146.7, 136.7,
130.3, 129.5, 127. 8, 126.6, 126.3, 114.9, 114.5, 114.4, 108.0; HRMS (ESI) calcd for
C11H7N2Cl [(M+H)+]: 203.0371; found, 203.0372.
7-Fluoropyrrolo[1,2-a]quinoxaline (2e)13b
o
1
Light yellow solid. 87 mg (94% yield). Mp: 166ꢀ168 C. H NMR (400 MHz,
CDCl3): δ = 7.90 (t, J = 1.2 Hz, 1H),7.84 (dd, J = 9.0 Hz, 5.0 Hz, 1H), 7.65 (dd, J =
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9.4 Hz, 2.8 Hz, 1H), 7.29ꢀ7.24 (m, 1H), 6.93 (dd, J = 4.0 Hz, 1.1 Hz, 1H), 6.89ꢀ6.88
(m, 1H); 13C NMR (100 MHz, CDCl3): δ = 161.0 (d, 1JC, F = 242 Hz), 146. 8, 137.1 (d,
2
2
3JC, F = 11 Hz), 126.27, 124.68, 115.7 (d, JC, F = 22 Hz), 115.5 (d, JC, F = 22 Hz),
3
115.0 (d, JC, F = 9 Hz), 114.5, 114.2, 107.8; HRMS (ESI) calcd for C11H7N2F
[(M+H)+]: 187.0666; found, 187.0660.
8-Methylpyrrolo[1,2-a]quinoxaline (2f)24
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Light yellow solid. 52 mg (57% yield). Mp: 127ꢀ129 oC. 1H NMR (400 MHz, CDCl3):
δ = 8.79 (s, 1H), 7.91 (s, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.68 (s, 1H), 7.29 ꢀ 7.27 (m,
1H), 6.90 (d, J = 1.8 Hz, 2H), 2.58 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 144.9,
138.3, 133.8, 129.8, 127.8, 126.6, 126.4, 113.9, 113.8, 106.9, 21.8; HRMS (ESI) calcd
for C12H10N2 [(M+H)+]: 183.0917; found, 183.0917.
8-Methoxypyrrolo[1,2-a]quinoxaline (2h)15b
Light yellow solid. 44 mg (44% yield). Mp: 110ꢀ112 oC. 1H NMR (400 MHz, CDCl3):
δ = 8.71 (s, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.82 (s, 1H), 7.26 (d, J = 2.7 Hz, 1H), 7.05
(dd, J = 8.9 Hz, 2.6 Hz, 1H), 6.89ꢀ6.86 (m, 1H), 3.96 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 159.3, 143.3, 131.3, 130.2, 128.8, 126.4, 114.1, 113.7, 112.7, 106.7, 97.6,
55.8; HRMS (ESI) calcd for C12H10N2O [(M+H)+]: 199.0866; found, 199.0862.
8-Chloropyrrolo[1,2-a]quinoxaline (2i)24
Light yellow solid. 82 mg (81% yield). Mp: 224ꢀ226 oC. 1H NMR (300 MHz, CDCl3):
δ = 8.78 (s, 1H), 7.89 (d, J = 9.3 Hz, 3H), 7.41 (d, J = 7.2 Hz, 1H), 6.91 (s, 2H); 13C
NMR (75 MHz, CDCl3): δ = 145.8, 134.4, 133.2, 131.3, 128.6, 126.3, 125.6, 114.6,
114.4, 113.9, 107.8; HRMS (ESI) calcd for C11H7N2Cl [(M+H)+]: 203.0371; found,
203.0374.
8-Fluoropyrrolo[1,2-a]quinoxaline (2j)24
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White solid. Mp: 57 mg (61% yield). 174ꢀ175 C. H NMR (400 MHz, CDCl3): δ =
8.77 (s, 1H), 7.96ꢀ7.92 (m, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.54 (dd, J = 9.2 Hz, 2.7 Hz,
1H), 7.19 (td, J = 8.5 Hz, 2.7 Hz, 1H), 6.91 (d, J = 1.9 Hz, 2H); 13C NMR (100 MHz,
CDCl3): δ = 162.8 (d, 1JC, F = 247 Hz), 144.9 (d, 4JC, F = 2 Hz), 132.4, 132.0 (d, 3JC, F
=
2
9 Hz),128.8, 126.1, 114.5, 114.4, 113.2 (d, JC, F = 23 Hz), 107.6, 100.8 (d, 2JC, F = 26
Hz); HRMS (ESI) calcd for C11H7N2F [(M+H)+]: 187.0666; found, 187.0669.
7,8-Dimethylpyrrolo[1,2-a]quinoxaline (2k)
Light yellow solid. 56 mg (57% yield). Mp: 127ꢀ129 oC. 1H NMR (400 MHz, CDCl3):
δ = 8.73 (s, 1H), 7.83 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 6.84 (dd, J = 6.0 Hz, 3.6 Hz,
2H), 2.43 (s, 3H), 2.38 (s, 3H); 1C NMR (100 MHz, CDCl3): δ = 144.8, 137.3, 134.0,
134.0, 130.2, 126.5, 125.9, 114,2, 113.6, 106.7, 20.3, 19.6; HRMS (ESI) calcd for
C13H12N2 [(M+H)+]: 197.1073; found, 197.1071
7,8-Dichloropyrrolo[1,2-a]quinoxaline (2l)
Light yellow solid. 84 mg (71% yield). Mp: 235ꢀ236 oC. 1H NMR (400 MHz, CDCl3):
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δ = 8.78 (s, 1H), 8.04 (s,1H), 7.95 (s,1H), 7.85 (s, 1H), 6.96ꢀ6.91 (m, 2H); C NMR
(100 MHz, CDCl3): δ =146.74, 135.2, 131.5, 131.0, 128.9, 127.1, 126.2, 115.5, 115.0,
108.7; HRMS (ESI) calcd for C11H6Cl2N2 [(M+H)+]: 236.9981; found,236.9980.
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7,8-Difluoropyrrolo[1,2-a]quinoxaline (2m)
Light yellow solid. 59 mg (58% yield). Mp: 190ꢀ192 oC. 1H NMR (400 MHz, CDCl3):
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δ = 8.77 (s, 1H), 7.77 (dd, J = 10.4 Hz, 8 Hz, 2H), 7.65 (dd, J = 10.4 Hz, 5.4 Hz, 1H),
6.93ꢀ6.90 (m, 2H); 1C NMR (100 MHz, CDCl3): δ = 151.0 (dd, 1JC,F = 250 Hz, 2JC,F
=
15 Hz), 149.2 (dd, 1JC,F = 246 Hz, 2JC,F = 13 Hz), 146.0 (dd, 3JC,F = 12 Hz),132.6 (dd,
3JC,F =9 Hz, 4JC,F = 3 Hz), 126.0, 124.5 (d, JC,F =9 Hz), 117.7, 114.7, 114.5, 108.0,
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102.5 (d, 2JC,F =22 Hz); HRMS (ESI) calcd for C11H6N2F2 [(M+H)+]: 205.0572; found,
205.0573.
Imidazo[1,5-a]quinoxaline (2n)25
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Light yellow solid. 15 mg (18% yield). Mp: 175ꢀ177 C. H NMR (400 MHz,
DMSOꢀd6): δ = 9.28 (s, 1H), 9.06 (s, 1H), 8.41 (dd, J = 6Hz, 0.9 Hz, 1H), 7.95ꢀ7.92
(m, 2H), 7.70 (td, J = 6.0 Hz, 0.9 Hz, 1H), 7.61ꢀ7.57 (m, 1H); 13C NMR (100 MHz,
DMSOꢀd6): δ = 146.0, 135.8, 131.3, 130.0, 129.3, 127.6, 127.4, 125.5, 124.4, 116.1;
HRMS (ESI) calcd for C10H7N3 [(M+H)+]: 170.0713 ; found, 170.0714.
3-Methylimidazo[1,5-a]quinoxaline (2o)
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Light yellow solid. 71 mg (78% yield). Mp: 147ꢀ149 C. H NMR (300 MHz,
DMSOꢀd6): δ = 9.15 (s, 1H), 9.03 (s, 1H), 8.33 (dd, J = 8.1 Hz, 1.2 Hz, 1H), 7.90 (dd,
J = 7.8 Hz, 1.2 Hz, 1H), 7.65 (td, J = 7.5 Hz, 1.5 Hz, 1H), 7.57 (td, J = 7.5 Hz, 1.2
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Hz, 1H), 2.57 (s, 3H)； C NMR (75 MHz, DMSOꢀd6): δ = 145.3, 136.2, 135.4, 129.4,
129.3, 128.4, 126.7, 125.1, 120.5, 115.3, 12.5; HRMS (ESI) calcd for C11H9N3
[(M+H)+]: 184.0869; found, 184.0873.
1-Methylimidazo[1,5-a]quinoxaline (2p)
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Light yellow solid. 75 mg (82% yield). Mp: 111ꢀ113 C. H NMR (400 MHz,
DMSOꢀd6): δ = 8.93 (s, 1H), 8.29 (dd, J = 8.2 Hz, 1.1 Hz, 1H), 7.91 (dd, J = 7.8 Hz,
1.6 Hz, 1H), 7.77 (s, 1 H), 7.64ꢀ7.54 (m, 2 H), 3.03 (s, 3H); 13C NMR (100 MHz,
DMSOꢀd6): δ = 146.2, 142.3, 137.0, 129.9, 128.6, 127.4, 126.8, 126.1, 126.0, 116.9,
18.5; HRMS (ESI) calcd for C11H9N3 [(M+H)+]: 184.0869 ; found, 184.0870.
Pyrido[3,2-e]pyrrolo[1,2-a]pyrazine (2q)13c
Light yellow solid. 67 mg (79% yield). Mp: 94ꢀ95 oC. 1H NMR (300 MHz, CDCl3): δ
= 8.80 (s, 1H), 8.56 (dd, J = 4.5 Hz, 1.5 Hz, 1H), 8.39 (t, J = 0.9 Hz, 1H), 8.26 (dd, J
= 7.8 Hz, 1.5 Hz, 1H), 7.46 (dd, J = 8.1 Hz, 4.5 Hz, 1H), 7.00ꢀ6.91 (m, 2H); 13C
NMR (75 MHz, CDCl3): δ = 147.0, 146.5, 137.4, 130.7, 127.9, 121.5, 115.6, 114.6,
108.9; HRMS (ESI) calcd for C10H7N3 [(M+H)+]:170.0713; found, 170.0732.
2-Methylpyrido[3,2-e]pyrrolo[1,2-a]pyrazine (2r)26
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Light yellow solid. 53 mg (58% yield). Mp: 108ꢀ110 C. H NMR (400 MHz,
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CDCl3): δ = 8.75 (s, 1H), 8.39 (s, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.29ꢀ7.26 (m, 1H),
6.96 (dd, J = 3.9 Hz, 1.0 Hz, 1H), 6.91ꢀ6.89 (m, 1H), 2.71 (s, 3H); 13C NMR (100
MHz, CDCl3): δ = 157.1, 145.4, 139.1, 137.4, 128.3, 128.0, 121.5, 115.3, 114.3, 108.4,
24.6; HRMS (ESI) calcd for C11H9N3 [(M+H)+]: 184.0869; found, 184.0864.
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4-D-pyrrolo[1,2-a]quinoxaline (2s)
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Light yellow solid. H NMR (400 MHz, CDCl3): δ = 8.82 (s, 0.07H), 7.98ꢀ7.94 (m,
2H), 7.89 (d, J = 8.0 Hz, 1H), 7.55ꢀ7.51 (m, 1H), 7.48ꢀ7.43 (m, 1H), 6.92ꢀ6.88 (m,
2H).
Indolo[1,2-a]quinoxaline (4a)13b
Yellow solid. 13 mg (12% yield). Mp: 104ꢀ106 C. 1H NMR (300 MHz, CDCl3): δ =
o
8.95 (s, 1H), 8.48ꢀ8.42 (m, 2H), 8.02ꢀ7.96 (m, 2H), 7.65ꢀ7.54 (m, 2H), 7.48ꢀ7.41 (m,
2H), 7.16 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 147.9, 135.8, 132.7, 131.0, 130.4,
129.8, 129.2, 128.8, 124.5, 124.2, 122.9, 122.7, 114. 9, 114.6, 101.0; HRMS (ESI)
calcd for C15H10N2 [(M+H)+]: 219.0917; found, 219.0919.
7-Methylindolo[1,2-a]quinoxaline (4b)
o
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Yellow solid. 95 mg (82% yield).Mp: 149ꢀ150 C. H NMR (300 MHz, CDCl3): δ =
8.33ꢀ8.30 (m, 2H), 7.94 (dd, J = 8.1 Hz, 1.8 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H),
7.56ꢀ7.49 (m, 2H), 7.45ꢀ7.40 (m, 1H), 7.39ꢀ7.33 (m, 1H), 2.62 (s, 3H); C NMR (75
MHz, CDCl3): δ = 146.5, 135.9, 131.9, 131.1, 130.2, 129.3, 128.5, 126.6, 124.50,
123.7, 122.0, 120.7, 114.5, 114.3, 109.6, 8.0; HRMS (ESI) calcd for C16H12N2
[(M+H)+]: 233.1073; found,233.1073.
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o
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Yellow solid. 90 mg (73% yield).Mp: 179ꢀ181 C. H NMR (300 MHz, CDCl3): δ =
8.88 (s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.84 (d,
J = 8.1 Hz, 1H), 7.57ꢀ7.52(m, 1H), 7.47ꢀ7.42 (m, 1H), 7.20 (dd, J = 8.1 Hz, 0.9 Hz,
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1H), 2.65 (s, 3H), 2.59 (s, 3H); C NMR (75 MHz, CDCl3): δ = 145.5, 139.0, 133.8,
131.9, 131.0, 129.9, 129.5, 126.7, 124.8, 124.3, 122.0, 120.7, 114.9, 114.5, 109.3,
22.2, 8.0; HRMS (ESI) calcd for C17H14N2 [(M+H)+]: 247.1230 ; found,247.1237.
2-Methoxy-7-methylindolo[1,2-a]quinoxaline (4d)
Yellow solid. 97 mg (74% yield). Mp: 126ꢀ128 oC. 1H NMR (300 MHz, CD2Cl2): δ =
8.77 (s, 1H), 8.29 (m, 1H), 7.92ꢀ7.88 (m, 1H), 7.84 (d, J = 9.0Hz, 7.78 (d, J = 2.7 Hz,
1H), 7.56ꢀ7.43 (m, 2 H), 6.96 (dd, J = 8.7 Hz, 2.7 Hz, 1H), 4.00 ( s, 3H), 2.62 (S, 3H);
1C NMR (75 MHz, CD2Cl2): δ = 159.8, 143.6, 131.8, 131.6, 131.0, 130.4, 129.6,
126.6, 123.9, 121.9, 120.4, 114.1, 109.4, 108.7, 100.0, 55.70, 7.6; HRMS (ESI) calcd
for C17H14N2O [(M+H)+]: 263.1179; found, 263.1194.
2-Chloro-7-methylindolo[1,2-a]quinoxaline (4e)
Yellow solid. 104 mg (78% yield). Mp: 179ꢀ181 oC. H NMR (300 MHz, CD2Cl2): δ
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= 8.60 (d, J = 4.5 Hz, 1H), 8.23ꢀ8.18 (m, 2H), 7.89ꢀ7.79 (m, 2H), 7.57ꢀ7.52 (m, 1H),
7.47ꢀ7.42 (m, 1H), 7.31 (d, J = 8.1 Hz, 1H), 2.61 (s, 3H); 1C NMR (75 MHz, CD2Cl2):
δ = 146.5, 134.5, 133.8, 131.8, 131.6, 131.0, 129.5, 126.3, 125.0, 123.8, 122.4, 120.8,
114.6, 114.1, 110.4, 8.0; HRMS (ESI) calcd for C16H11N2Cl [(M+H)+]: 267.0684;
found, 267.0686.
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2-Fluoro-7-methylindolo[1,2-a]quinoxaline (4f)
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Yellow solid. 99 mg (79% yield). Mp: 192ꢀ194 C. 1H NMR (400 MHz, CDCl3): δ =
8.86 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.00 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.91 (t, J =
7.8 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.09 (td, J = 8.4 Hz,
2.0Hz, 1H), 2.63 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 163.3 (d, 1JC,F = 247 Hz),
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145.6 (d, JC,F = 2 Hz), 132.4, 131.8, 131.6 (d, JC,F = 10 Hz), 129.6 , 126.1, 124.8,
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122.4, 120.81, 114.0, 111.0 (d, JC,F = 22 Hz), 110.0, 102.0 (d, JC,F = 28 Hz), 8.0;
HRMS (ESI) calcd for C16H11FN2 [(M+H)+]: 251.0979; found, 251.0976.
3,7-Dimethylindolo[1,2-a]quinoxaline (4g)
Yellow solid. 114 mg (93% yield). Mp: 131ꢀ132 oC. 1H NMR (400 MHz, CDCl3): δ =
8.87 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.0 Hz,
1H),7.70 (d, J = 1.2 Hz, 1H), 7.52ꢀ7.47 (m, 1H), 7.42 (t, J = 7.4 Hz, 1H), 7.32 (dd, J
= 8.4 Hz, 1.2 Hz, 1H), 2.61 (s, 3H), 2,46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ =
146.4, 135.8, 133.4, 131.8, 130.3, 129.3, 129.2, 128.8, 126.6, 124.3, 121.8, 120.6,
114.3, 114.2, 109.2, 20.8, 8.0; HRMS (ESI) calcd for C17H14N2 [(M+H)+]: 247.1230 ;
found,247.1235.
3-Chloro-7-methylindolo[1,2-a]quinoxaline (4h)
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Yellow solid. 90 mg (68% yield). Mp: 208ꢀ210 C. H NMR (400 MHz, CDCl3): δ =
8.81 (s, 1H), 8.24 (dd, J = 15.2 Hz, 8.8 Hz, 2H), 7.91ꢀ7.88 (m, 2H), 7.57ꢀ7.43 (m,
3H), 2.63 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 147.5, 136.8, 131.9, 129.7, 129.6,
129.4, 128.6, 128.2, 126.4, 125.0, 122.3, 121.0, 115.4, 114.1, 110.6, 8.0; HRMS (ESI)
calcd for C16H11ClN2 [(M+H)+]: 267.0684 ; found, 267.0688.
3-Fluoro-7-methylindolo[1,2-a]quinoxaline (4i)
Yellow solid. 101 mg (81% yield). Mp: 127ꢀ129 oC. 1H NMR (300 MHz, CDCl3): δ =
8.91 (s, 1H), 8.28ꢀ8.23 (m, 2H), 7.92 (d, J = 7.8 Hz, 1H), 7.64 (dd, J = 9.1 Hz, 3.0 Hz,
1H), 7.57ꢀ7.52 (m, 1H), 7.29ꢀ7.22 (m, 1H), 2.64 (s, 3H); 13C NMR (75 MHz, CDCl3):
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δ = 160.2 (d, JC, F = 242 Hz), 147.5, 137.2 (d, JC, F = 11 Hz), 131.8, 129.2, 127.7,
126.4, 125.0, 122.1, 121.0, 116.1 (d, 2JC, F = 22 Hz), 115.5 (d, 2JC, F = 22 Hz), 115.4 (d,
3JC, F = 9 Hz), 113.9, 110.2, 8.0; HRMS (ESI) calcd for C16H11N2F [(M+H)+]:
251.0979; found, 251.0990.
3-Bromo-7-methylindolo[1,2-a]quinoxaline (4j)
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Yellow solid. 85 mg (55% yield).Mp: 215ꢀ217 C. H NMR (400 MHz, CDCl3): δ =
8.88 (s, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 2.4 Hz,
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1H), 7.92 (d, J = 8.4 Hz, 1H), 7.61ꢀ7.53 (m, 2H), 7.48ꢀ 7.44 (m, 1H), 2.63 (s, 3H)； C
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NMR (100 MHz, CDCl3): δ = 147.5，137.2, 132.6, 131.9，131.0, 130.1, 129.4, 126.4,
125.0, 122.3, 121.0, 115.9, 115.7, 114.2, 110.6, 8.0; HRMS (ESI) calcd for
C16H11BrN2 [(M+H)+]: 311.0170; found, 311.0170.
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2,3-Dichloro-7-methylindolo[1,2-a]quinoxaline (4k)
Yellow solid. 102 mg (68% yield).Mp: 219ꢀ220 oC. 1H NMR (300 MHz, CD2Cl2): δ =
8.92 (s, 1H), 8.38 (s, 1H), 8.25 (d, J = 8.7 Hz, 1H), 7.98 (s, 1H), 7,96 (d, J = 8.4 Hz,
1H), 7.64ꢀ7.58 (m, 1H), 7.52 (t, J = 7.2 Hz, 1H), 2,66 (s, 3H); 13C NMR (75 MHz,
CD2Cl2): δ = 147.4, 135.1, 132.1, 131.7, 130.4, 130.2, 129.6, 126.8, 126.1, 125.6,
122.7, 121.2, 116.0, 113.9, 7.8; HRMS (ESI) calcd for C16H10N2Cl2 [(M+H)+]:
301.0294; found, 301.0297.
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11H-indolo[3,2-c]quinoline (4l)27
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White solid. 75 mg (69% yield). Mp: >300 C. H NMR (300 MHz, DMSOꢀd6): δ =
9.62 (s, 1H), 8.56 (d, J = 7.5 Hz, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 7.8 Hz,
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1H), 7.78ꢀ7.68 (m, 3H), 7.54 (t, J = 7.5 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H); C NMR
(75 MHz, DMSOꢀd6): δ = 145.4, 144.8, 139.7, 138.7, 129.5, 127.9, 125.6, 125.5,
122.0, 121.8, 120.5, 120.0, 117.0, 114.2, 111.8; HRMS (ESI) calcd for C15H10N2
[(M+H)+]: 219.0919; found, 219.0914.
Benzo[4,5]imidazo[1,2-c]quinazoline (4m)28
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White solid. 74 mg (68% yield). Mp: 229ꢀ231 C. H NMR (300 MHz, CDCl3): δ =
9.14 (s, 1H), 8.71 (dd, J = 7.8 Hz, 1.2 Hz, 1H), 8.04ꢀ7.96 (m, 3H), 7.83 (td, J = 7.5
Hz, 1.6 Hz, 1H), 7.73 (td, J = 7.5 Hz, 1.2 Hz, 1H), 7.61 (td, J = 7.5 Hz, 1.2 Hz, 1H),
7.53 (td, J = 8.1 Hz, 0.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ = 146.3, 143.9,
142.6, 136.1, 131.8, 128.7, 128.5, 128.1, 126.2, 124.3, 123.3, 120.3, 119.3, 110.1;
HRMS (ESI) calcd for C14H9N3 [(M+H)+]: 220.0869; found, 220.0863.
9,10-Dimethylbenzo[4,5]imidazo[1,2-c]quinazoline (4n)29
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White solid. 77 mg (62% yield).Mp: 229ꢀ231 C. H NMR (400 MHz, DMSOꢀd6): δ
= 9.58 (s, 1H), 8.51 (d, J = 7.0 Hz, 1H), 8.11 (s, 1H), 7.94 (dd, J = 7.5 Hz, 1H), 7.83
(t, J = 6.8 Hz, 1H), 7.73ꢀ7.67 (m, 2H), 2.42 (d, J =6.2 Hz, 6H); 13C NMR (100 MHz,
DMSOꢀd6): δ = 142.5, 138.9, 135.1, 132.4, 131.9, 128.7, 128.6, 127.3, 124.0, 119.8,
119.4, 112.3, 20.7; HRMS (ESI) calcd for C16H13N3 [(M+H)+]: 248.1182; found,
248.1183.
9,10-Difluorobenzo[4,5]imidazo[1,2-c]quinazoline (4o)
o
1
White solid. 43 mg (34% yield).Mp: 185ꢀ187 C. H NMR (400 MHz, DMSOꢀd6): δ
= 9.41 (s, 1H), 8.34 (t, J = 9.0 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.76 (m, 2H), 7.69
( t, J = 7.2 Hz, 1H), 7.57 (t, J = 7.0 Hz, 1H); 13C NMR (100 MHz, DMSOꢀd6): δ
1
=150.5 (dd, JC, F = 241 Hz, 2JC, F = 15 Hz), 148.5 (dd, 1JC, F = 240 Hz, 2JC, F = 15 Hz),
147.5, 142.2, 139.7, 138.6, 132.5, 129.0, 128.6, 124.4 (d, 3JC, F = 11 Hz), 124.0, 118.8,
2
2
107.4 (d, JC, F = 20 Hz), 101.5 (d, JC, F = 24 Hz); HRMS (ESI) calcd for
C14H7N3F2[(M+H)+]: 256.0681; found, 256.0687.
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1,2-bis(3-(pyrrolo[1,2-a]quinoxalin-4-yl)propyl)disulfane (4p)
o
1
White solid. 64 mg (53% yield).Mp: 185ꢀ187 C. H NMR (400 MHz, CDCl3): δ =
7.87ꢀ7.86 (m, 4H), 7.79ꢀ7.77 (m, 2H), 7.46ꢀ7.37 (m, 4H), 6.91 (dd, J = 4.0 Hz, 1.1 Hz,
2H), 6.82 (dd, J = 3.8 Hz, 2.8 Hz, 2H), 3.13 (t, J = 7.3 Hz, 4H), 2.87 (t, J = 7.0 Hz,
4H), 2.35ꢀ2.28 (m, 4H); 13C NMR (100 MHz, CDCl3): δ = 156.2, 135.9, 129.5, 127.2,
127.0, 125.9, 125.1, 114.3, 113.6, 113.6, 106.3, 38.5, 34.0, 27.4. HRMS (ESI) calcd
for C28H26N4 S2[(M+H)+]: 483.1672; found, 483.1672.
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General experimental procedures for the starting materials.
A
mixture
of
substituted
2ꢀnitroaniline
(20
mmol)
and
2,
5ꢀdimethoxytetrahydrofuran(20 mmol) in acetic acid (100 mL) was refluxed for 2 h
with vigorous stirring. After cooling, the reaction mixtures were poured into water
(300 mL) and extracted with EtOAc three times (3×50 mL). The organic layers were
dried with MgSO4 and the solvent was removed in vacuo to afford a residue. The
residue was added to iron powder (80 mmol) and NH4Cl (20 mmol) in water (50 mL)
and reflux for 4 h. After cooling, the reaction mixtures were poured into water (300
mL) and extracted with ethyl acetate three times (3×50 mL). The combined organic
layers were dried with MgSO4 and the solvent was removed in vacuo to afford a
residue. The residue was purified by column chromatography on silica gel using
petroleum ether / EtOAc = 100: 1 as eluent to provide the desired product(1a-1m, 1q
and 1r)18b
.
2-(1H-pyrrol-1-yl)aniline (1a)18c
1H NMR (400 MHz, CDCl3): δ = 7.16ꢀ7.12 (m, 2H), 6.82 (t, J = 2.1 Hz, 2H),
6.79ꢀ6.75 (m, 2H), 6.33 (t, J = 2.0, 2H), 3.68 (s, 2H); 13C NMR (100 MHz, CDCl3): δ
= 142.1, 128.6, 127.5, 127.2, 121.7, 118.4, 116.1, 109.4.
General experimental procedures for the synthesis of starting materials
5-Methyl-2-(1H-pyrrol-1-yl)aniline (1b)18c
1H NMR (400 MHz, CDCl3): δ = 7.03 (d, J = 7.7 Hz, 1H), 6.80 (t, J = 2.1 Hz, 2H),
6.60 ( d, J = 9.2 Hz, 2H ), 6.32 (t, J = 2.0Hz, 2H), 3.61 (s, 2H)，2.29 (s. 2H); 13C
NMR (100 MHz, CDCl3): δ =141.9, 138.6, 127.0, 125.3, 121.9, 119.2, 116.6, 109.3,
21.2.
5-Methoxy-2-(1H-pyrrol-1-yl)aniline (1c) 18c
1H NMR (400 MHz, CDCl3): δ = 7.07 (dd, J = 8.8 Hz, 3.6 Hz, 1H), 6.77 (t, J = 2.8Hz,
2H ), 6.35ꢀ6.31 (m, 4H), 3.78 (s, 3H ), 3.67 (s, 2H); 13C NMR (100 MHz, CDCl3): δ =
159.9, 143.4, 128.2, 122.1, 121.2, 109.2, 103.7, 102.1, 55.4.
5-Chloro-2-(1H-pyrrol-1-yl)aniline (1d) 18c
1H NMR (400 MHz, CDCl3): δ = 7.05 (d, J = 8.3 Hz, 1H), 6.78ꢀ6.76 (m, 3H), 6.74
(dd, J = 8.3 Hz, 2.2 Hz, 1H), 6.34 (t, J = 2.06 Hz, 2H), 3.76 (s, 2H); 13C NMR (100
MHz, CDCl3): δ = 143.152, 134.0, 128.2, 126.0, 121.7, 118.2, 115.6, 109.8.
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5-Fluoro-2-(1H-pyrrol-1-yl)aniline (1e) 18c
1H NMR (400 MHz, CDCl3): δ =7.08ꢀ7.04 (m, 1H), 6.76 (t, J=2.0 Hz, 2H), 6.47ꢀ6.42
(m, 2H), 6.33 (t, J = 2.0 Hz, 2H), 3.78 (s, 2H); 13C NMR (100 MHz, CDCl3): δ =
1
3
3
164.0 (d, JC, F = 243 Hz), 143.9 (d, JC, F = 12 Hz), 128.6 (d, JC, F = 11 Hz), 123.6,
121.9, 109.6, 104.9 (d, 2JC, F = 23 Hz), 102.6 (d, 2JC, F = 26 Hz).
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4-Methyl-2-(1H-pyrrol-1-yl)aniline (1f)30
1H NMR (300 MHz, CDCl3): δ = 6.97 (d, J = 5.4 Hz, 2H), 6.82 (d, J = 1.8 Hz, 2H),
6.71 (dd, J = 5.7 Hz, 3.0 Hz, 1H), 6.33 (d, J = 1.8 Hz, 2H), 3.55 (s, 2H), 2.26 (s, 3H);
13C NMR (75 MHz, CDCl3): δ = 139.4, 129.1, 128.0, 127.6, 127.5, 121.7, 116.3,
109.3, 20.3.
3-Methyl-2-(1H-pyrrol-1-yl)aniline (1g)30
1H NMR (400 MHz, CDCl3): δ = 7.66 (dd, J = 8.0Hz, 0.6 Hz, 1H), 7.53 (d, J = 7.5
Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 6.66 (t, J = 2.1 Hz, 2H), 6.35 (t, J = 2.1 Hz, 2H),
2.15 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 148.3, 139.3, 134.4, 133.1, 128.5,
11.2, 121.7, 110.0, 17.2.
4-Methoxy-2-(1H-pyrrol-1-yl)aniline (1h)30
1H NMR (300 MHz, CDCl3): δ = 6.85 (t, J = 2.1Hz, 2H), 6.80ꢀ6.72 (m, 3H), 6.34 (t,
2.1Hz, 2H), 3.74 (s, 3H), 3.42 (s, 2H); 13C NMR (75 MHz, CDCl3): δ = 152.5, 135.4,
128.1, 121.6, 117.3, 114.8, 112.5, 109.5, 55.9.
4-Chloro-2-(1H-pyrrol-1-yl)aniline (1i)18c
1H NMR (300 MHz, CDCl3): δ = 7.13ꢀ7.09 (m, 2H), 6.80 (m, J = 1.8 Hz, 2H), 6.71 (d,
J = 8.4 Hz, 1H), 6.33 (d, J = 2.1 Hz, 2H), 3.70 (s, 2H); 13C NMR (75 MHz, CDCl3):
δ = 140.7, 128.4, 128.1, 127.0, 122.6, 121.5, 116.9, 109.9.
4-Fluoro-2-(1H-pyrrol-1-yl)aniline (1j)18c
1H NMR (300 MHz, CDCl3): δ = 6.93ꢀ6.86 (m, 2H), 6.83 (t, J = 2.1 Hz, 2H), 6.75 (dd,
J = 9.6 Hz, 5.1 Hz, 1H), 6.34ꢀ6.31 (m, 2H), 3.65 (s,2H); 13C NMR (75 MHz, CDCl3):
δ = 157.1 (d, 1JC, F = 236 Hz), 137.9, 127.9 (d, 3JC, F = 9 Hz), 121.5, 116.9 (d, 3JC, F
8 Hz), 115.3 (d, 2JC, F = 23 Hz), 114.1 (d, 2JC, F = 23 Hz), 109.9.
=
4,5-Dimethyl-2-(1H-pyrrol-1-yl)aniline (1k)31
1H NMR (400 MHz, CDCl3): δ =6.91 (s, 1H), 6.80 (t, J = 2.1Hz, 2H), 6.61 (s, 1H),
6.31 (t, J = 2.1Hz, 2H), 3.49 (s, 3H), 2.16 (s, 3H); 13CNMR (100 MHz, CDCl3): δ =
139.5, 137.0, 128.0, 126.6, 125.4, 121.9, 117.6, 109.1, 19.5, 18.6.
4,5-Dichloro-2-(1H-pyrrol-1-yl)aniline (1l)32
1H NMR (400 MHz, CDCl3): δ = 7.26 (d, J = 12.0 Hz, 1H), 6.88 (S,1H), 6.79 (t, J =
2.2 Hz, 2H), 6.35 (t, J = 2.0 Hz, 2H), 3.79 (s, 2H); 13C NMR (100 MHz, CDCl3): δ =
7.3, 7.2, 6.9, 6.8, 6.8, 6.8, 6.4, 6.3, 6.3.
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4,5-Difluoro-2-(1H-pyrrol-1-yl)aniline (1m)33
1H NMR (400 MHz, CDCl3): δ =7.01 (dd, J = 10.2 Hz, 8.2 Hz, 1H), 6.77 (t, J = 2.0
Hz, 2H), 6.59(dd, J = 11.6 Hz, 7.6 Hz, 1H), 6.34 (t, J = 2.1 Hz, 2H), 3.63 (s, 3H);
13C NMR (100 MHz, CDCl3): δ = 151.4 (dd, 1J C,F = 237 Hz, J C,F = 13 Hz), 143.8
2
(dd, 1J C,F = 240 Hz, 2JC ,F = 14 Hz), 139.1 (d, 3J C,F = 7 Hz), 122.5 (d, 3J C,F = 5 Hz),
121.7, 116.1, 115.9 (d, 4J C,F = 2 Hz), 110.0, 104.2 (d, 2J C,F = 21 Hz).
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2-(1H-imidazol-1-yl)aniline (1n)18c
1H NMR (300 MHz, DMSOꢀd6): δ =7.75 (s, 1H), 7.30 (s, 1H), 7.17ꢀ7.11 (m, 1H),
7.11 (s, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 8.1 Hz, 1H), 6.67 (t, J = 7.5 Hz,
1H), 4.94 (s, 2H); 13C NMR (75 MHz, DMSOꢀd6): δ =143.2, 137.4, 129.0, 128.9,
126.7, 122.4, 120.3, 116.3, 116.1.
2-(4-Methyl-1H-imidazol-1-yl)aniline (1o)18c
1H NMR (300 MHz, DMSOꢀd6): δ = 7.59 (s, 1H), 7.14ꢀ7.09 (m, 1H), 7.02ꢀ6.99 (m,
2H), 6.86 (d, J = 7.8 Hz, 1H), 6.65 (m, 1H), 4.93 (s, 2H), 2.17 (s, 3H); 13C NMR (75
MHz, DMSOꢀd6): δ = 143.2, 137.2, 136.6, 128.8, 126.6, 122.6, 116.5, 116.3, 116.0,
13.6.
2-(2-Methyl-1H-imidazol-1-yl)aniline (1p)18b
1H NMR (300 MHz, DMSOꢀd6): δ = 7.18ꢀ7.12 (m, 1H), 7.04 (d, J = 1.2 Hz, 1H),
6.99 (dd, J = 7.8 Hz, 1.2 Hz, 1H), 6.93 (d, J = 1.2 Hz, 1H), 6.87 (dd, J = 8.1 Hz, 1.2
Hz, 1H), 6.66 (td, J = 7.5 Hz, 1.2 Hz, 1H), 4,85 (s, 2H), 2.09 (s, 3H); 13C NMR (75
MHz, DMSOꢀd6): δ = 144.4, 144.2, 129.4, 127.8, 127.4, 122.2, 120.6, 116.1, 115.7,
12.7.
2-(1H-pyrrol-1-yl)pyridin-3-amine (1q)26
1H NMR (400 MHz, CDCl3): δ = 7.91 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 7.14ꢀ7.13 (m,
2H), 7.09ꢀ7.03 (m, 2H), 6.35 (t, J = 2.0 Hz, 2H), 3.86 (s, 2H); 13C NMR (100 MHz,
CDCl3): δ = 139.7, 138.4, 136.0, 124.2, 123.0, 120.2, 109.9.
2-(1H-indol-1-yl)aniline (3a)18c
A mixture of 2ꢀnitroaniline (2 mmol), Nꢀheterocycle (2 mmol) and NaOH (2 mmol) in
DMSO (4 mL) was stirred vigorously for 2h at room temperature. After cooling, the
reaction mixture was poured into water (30 mL) and extracted with ethyl acetate three
times (3×30 mL). The combined organic layers were dried with MgSO4 and the
solvent was removed in vacuo to afford a residue. The residue was added to iron
powder (16 mmol) and NH4Cl (1 mmol) in water (30 mL) and refluxed for 4 h. After
cooling, the reaction mixture was poured into water (100 mL) and extracted with ethyl
acetate three times (3×30 mL). The combined organic layers were dried with MgSO4
and the solvent was removed in vacuo to afford a residue. The residue was purified by
column chromatography on silica gel using petroleum ether / ethyl acetate as eluent to
provide the desired product (3a-3k, 1n-1p).18c 1H NMR (400 MHz, CDCl3): δ =
7.69ꢀ7.67 (m, 1H), 7.23ꢀ7.14 (m, 6H), 6.83ꢀ6.80 (m, 2H), 6.67 (d, J = 3.16 Hz, 1H),
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3.49 (s, 2H); 13C NMR (100 MHz, CDCl3): δ = 143.2, 136.4, 129.2, 128.7, 128.6,
124.9, 122.3, 121.0, 120.2, 118.6, 116.3, 110.8, 103.3.
2-(3-Methyl-1H-indol-1-yl)aniline (3b)18c
1H NMR (400 MHz, CDCl3): δ = 7.80ꢀ7.77 (m, 1H), 7.35ꢀ7.24 (m, 5H), 7.09 (s, 1H),
6.96ꢀ6.89 (m, 2H), 3.48 (s, 2H), 2.54 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 143.3,
136.9, 129.1, 129.0, 128.7, 126.3, 125.2, 122.4, 119.7, 119.2, 118.6, 116.4, 112.5,
110.8, 9.8.
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4-Methyl-2-(3-methyl-1H-indol-1-yl)aniline (3c)34
1H NMR (400 MHz, CDCl3): δ = 7.63ꢀ7.60(m, 1H), 7.19ꢀ7.09 (m, 3H),7.03ꢀ7.00 (m,
1H), 6.95 (d, J = 4.2Hz, 2H), 6.75 (d, J = 8.1Hz, 1H), 3.41 ( s, 2H), 2.37 (s, 3H), 2,
26 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 140.5, 136.7, 129.5, 129.0, 128.9, 128.1,
126.2, 125.2, 122.2, 119.5, 119.1, 116.4, 112.3, 110.7, 20.4, 9.7.
4-Methoxy-2-(3-methyl-1H-indol-1-yl)aniline (3d)
Light yellow liquid. 1H NMR (300 MHz, CDCl3): δ = 7.69ꢀ7.66 (m, 1H), 7.26ꢀ7.14
(m, 3H), 7.07 (d, J = 1.2 Hz, 1H), 6.92ꢀ 6.85 (m, 2H), 6.82 (d, J = 2.4 Hz, 1H), 3.78
(s, 3H), 3.38 (s, 2H), 2.45 (d, J = 1.2 Hz, 3H); 1C NMR (74 MHz, CDCl3): δ = 152.5,
136.8, 136.6, 129.0, 126.0, 125.7, 122.1, 119.4, 118.9, 117.3, 115.2, 113.4, 112.4,
110.5, 55.7, 9.3. HRMS (ESI) calcd for C16H16N2 O [(M+H)+]: 253.1335; found,
253.1337.
4-Chloro-2-(3-methyl-1H-indol-1-yl)aniline (3e)
Light yellow liquid. 1H NMR (400 MHz, CDCl3): δ = 7.68ꢀ7.65 (m, 1H), 7.24ꢀ7.19
(m, 4H), 7.14ꢀ7.12 (m, 1H), 6.97 (d, J = 0.9 Hz, 1H), 6.78ꢀ6.75 (m, 1H), 3.60 (s, 2H),
2.42 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 141.8, 136.5, 129.2, 128.8, 128.4,
125.8, 125.8, 122.5, 119.9, 119.3, 117.1, 113.1, 110.6, 9.7. HRMS (ESI) calcd for
C15H13N2 Cl [(M+H)+]: 257.0840; found, 257.0846.
4-Fluoro-2-(3-methyl-1H-indol-1-yl)aniline (3f)20
1H NMR (400 MHz, CDCl3): δ = 7.61 (dd, J = 6.4 Hz, 2.0 Hz, 1H), 7.18ꢀ7.12 (m,
1H), 7.09ꢀ7.07 (m, 1H), 6.94ꢀ6.88 (m, 3H), 6.73 (dd, J = 8.8 Hz, 5,2 Hz, 1H), 3.38
1
(s,1H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 156.7 (d, JC, F = 237 Hz),
4
3
139.4 (d, JC, F = 3Hz), 136.6, 129.2, 125.8, 125.6 (d, JC, F =10 Hz), 122.5, 119.9,
119.2, 116.9 (d, 3JC, F =7Hz),115.7 (d, 2JC, F = 22 Hz), 115.3 (d, 2JC, F = 23 Hz), 113.1,
110.6, 9.6.
5-Methyl-2-(3-methyl-1H-indol-1-yl)aniline (3g)
1
Light yellow liquid. H NMR (400 MHz, CDCl3): δ = 7.62 (dd, J = 6.4 Hz, 2.4 Hz,
1H), 7.20ꢀ7.08 (m, 3H), 7.04 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 0.8 Hz, 1H), 6.64 (d,
J= 10.0 Hz, 2H), 3.46 (s, 2H), 2.37 (s, 3H), 2.33 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ =142.8, 139.0, 136.9, 129.0, 128.4, 126.3, 122.8, 122.1, 119.5, 119.4,
119.0, 116.8, 112.2, 110.6, 21.3, 9.7. HRMS (ESI) calcd for C16H16N2 Cl [(M+H)+]:
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1
Light yellow liquid. H NMR (400 MHz, CDCl3): δ = 7.63 (dd, J = 6.2 Hz, 2.2 Hz,
1H), 7.22ꢀ7.15 (m, 2H), 7.08ꢀ7.05 (m, 2H), 6.91 (s, 1H), 6.81 (d, J = 2.2 Hz, 1H),
6.78 (dd, J = 8.3 Hz, 2.2 Hz, 1H), 3.59 (s, 2H), 2.37 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 144.2, 136.6, 134.3, 129.6, 129.1, 125.9, 123.6, 122.4, 119.8, 119.2,
118.4, 115.8, 112.9, 110.5, 9.7. HRMS (ESI) calcd for C15H13N2 Cl [(M+H)+]:
257.0840; found, 257.0842.
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1
Light yellow liquid. H NMR (300 MHz, CDCl3): δ = 7.63ꢀ7.60 (m, 1H), 7.18ꢀ7.14
(m, 2H), 7.09ꢀ7.03 (m, 2H), 6.89 (d, J = 1.2 Hz, 1H)，6.50ꢀ6.45 (m, 2H), 3.56 (s, 2H),
2.36 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 164.6 (d, 1JC, F = 243 Hz), 145.0 (d, 3JC,
3
4
= 11 Hz), 136.9, 130.1 (d, JC, F = 11 Hz), 129.0, 126.2, 122.4, 121.1 (d, JC, F = 2
F
2
2
Hz), 119.7, 119.2, 112.6, 110.5, 105.2 (d, JC, F = 23 Hz), 102.7 (d, JC, F = 26 Hz).
HRMS (ESI) calcd for C15H13N2F [(M+H)+]: 241.1136; found, 241.1134.
5-Bromo-2-(3-methyl-1H-indol-1-yl)aniline (3j)
1
Light yellow liquid. H NMR (400 MHz, CDCl3): δ =7.62 (dd, J = 5.8 Hz, 2.6 Hz,
1H), 7.19ꢀ7.13 (m, 2H), 7.06 (dd, J = 5.8 Hz, 2.6 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H),
6.93 (d, J = 2.4 Hz, 1H), 6.91ꢀ6.88 (m, 2H), 3.54 (s,2H), 2.36 (s. 3H); 13C NMR (100
MHz, CDCl3): δ = 144.4, 136.6, 129.9, 129.1, 125.8, 124.1, 122.5, 122.3, 121.4, 119.8,
119.2, 118.7, 113.0, 110.5, 9.7. HRMS (ESI) calcd for C15H13N2Br [(M+H)+]:
301.0334; found, 301.0330.
4,5-Dichloro-2-(3-methyl-1H-indol-1-yl)aniline (3k)
1
Light yellow liquid. H NMR (400 MHz, CDCl3): δ = 7.62 (dd, J = 6.4 Hz, 2,4 Hz,
1H), 7.23 (s, 1H), 7.19ꢀ7.16 (m, 2H), 7.07 (dd, J = 6.0 Hz, 2,0 Hz, 1H), 6.88 (s, 2H),
3.62 (s, 2H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 142.7, 136.5, 132.4,
129.8, 129.2, 125.6, 124.5, 122.7, 120.6, 120.1, 119.3, 117.0, 113.5, 110.4, 9.7.
HRMS (ESI) calcd for C15H12N2Cl2 [(M+H)+]: 291.0540; found, 291.0448.
2-(1H-indol-2-yl)aniline (3l)
A mixture of phenylhydrazine (10 mmol) and 1ꢀ(2ꢀaminophenyl)ethanone (10mmol)
in 20mL EtOH with AcOH (5 mmol%) were stirred at room temperature for 6 hours,
and then 20 mL PPA was added and the temperature rised to 100 oC for 2h. Next, the
reaction mixture was poured into water (100 mL), and Na2CO3 was added slowly until
the PH =7. And the mixture was extracted with ethyl acetate three times (3×30 mL).
The combined organic layers were dried with MgSO4 and the solvent was removed in
vacuo to afford a residue. The residue was purified by column chromatography on
silica gel using petroleum ether / ethyl acetate as eluent = 1:2 to provide the desired
product.35 1H NMR (300 MHz, CDCl3): δ = 7.64 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 7.8
Hz, 1H), 7.22ꢀ7.10 (m, 3H), 6.93ꢀ6.84 (m, 2H), 6.72 (t, J = 0.9 Hz, 1H), 4.40 (s, 2H);
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13C NMR (75 MHz, CDCl3): δ = 143.9, 136.2, 135.9, 129.3, 129.1, 128.9, 122.2,
120.4, 120.2, 119.2, 118.9, 116.6, 110.8, 101.6.
2-(1H-benzo[d]imidazol-2-yl)aniline (3m)36
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9
A
mixture
of
benzeneꢀ1,2ꢀdiamine
(10
mmol)
and
c
1Hꢀbenzo[d][1,3]oxazineꢀ2,4ꢀdione (10 mmol) were refluxed in AcOH in 100oC for
2h. Then the mixture was extracted with ethyl acetate three times (3×30 mL). The
combined organic layers were dried with MgSO4 and the solvent was removed in
vacuo to afford a residue. The residue was purified by column chromatography on
silica gel using petroleum ether / ethyl acetate as eluent = 1:2 to provide the desired
product (3m-3o). 1H NMR (400 MHz, DMSOꢀd6): δ = 12.65 (s, 1H), 7.85 (dd, J = 8.0
Hz, 1.2 Hz, 1H), 7.58 (s, 2H), 7.20 (m, 5H), 6.85 (dd, J = 8.0Hz, 0.8 Hz, 1H), 6.68 (m,
1H); 13C NMR (400 MHz, DMSOꢀd6): δ = 163.0, 148.7, 130.9, 127.7, 122.2, 116.6,
115.4, 110.6.
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2-(5,6-Dimethyl-1H-benzo[d]imidazol-2-yl)aniline (3n)36
1H NMR (400 MHz, DMSOꢀd6): δ = 12.38 (s, 1H), 7.81 (dd, J = 7.8 Hz, 1.0Hz, 1H),
7.41 (s, 1H)， 7.26ꢀ7.21 (m, 3H), 7.14ꢀ7.10 (m, 1 H), 6.82 (d, J = 7.6 Hz, 1H),
6.65ꢀ6.61 (m, 1H), 2.32 (s, 6H); 13C NMR (100 MHz, DMSOꢀd6): δ = 152.2, 148.5,
142.1, 132.5, 131.3, 130.5, 130.0, 127.5, 118.8, 116.5, 115.4, 111.3, 111.0, 20.5.
2-(5,6-Difluoro-1H-benzo[d]imidazol-2-yl)aniline (3o)
1
Light yellow solid. H NMR (400 MHz, DMSOꢀd6): δ = 12.90 (s, 1H), 7.83 (dd, J =
8.0 Hz, 1.2 Hz, 1H), 7.70 (s, 1H), 7.53 (s, 1H), 7.20 (td, J = 7.6 Hz, 1.2 Hz, 3H), 6.87
(dd, J = 8.0 Hz, 0.8 Hz, 1H), 6.67 (m, 1H); 13C NMR (100 MHz, DMSOꢀd6): δ
=155.0, 148.6, 148.6 (dd, JC, F = 239 Hz, 2JC, F = 15 Hz), 148.1 (dd, JC, F = 235 Hz,
2JC, F = 15 Hz), 138.9 (d, 3JC, F =9 Hz), 131.2, 129.6 (d, 3JC, F = 12 Hz), 127.7, 116.9,
115.5, 110.1, 106.1 (d, 2JC, F = 20 Hz), 99.4 (d, 2JC, F = 21 Hz). HRMS (ESI) calcd for
C13H11N3F2 [(M+H)+]:248.0993; found, 248.0990.
1
1
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: chenma@sdu.edu.cn
ACKNOWLEDGMENT
We are grateful to the National Science Foundation of China (No. 21572117) and
State Key Laboratory of Bioactive Substance and Function of Natural Medicines,
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union
Medical College (No. GTZK201405) for financial support of this research.
ASSOCIATED CONTENT
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Supporting Information Available: The detailed experimental procedure and
copies of 1H NMR and 13C NMR spectra of all compounds is available free of charge
via the Internet:// pubs. acs. org.
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