Synthesis of pyrrolo[1,2-a]quinoxalines via gold(I)-mediated cascade reactions

Article abstract of DOI:10.1021/co1000844

In this study, we developed an efficient tandem process of hydroamination and hydroarylation using a gold catalyst to enable and study the reactions between pyrrole-substituted anilines and alkynes. The gold(I)-catalyzed reactions were achieved in toluene

Full text of DOI:10.1021/co1000844

LETTER
pubs.acs.org/acscombsci
Synthesis of Pyrrolo[1,2-a]quinoxalines via Gold(I)-Mediated
Cascade Reactions
Guannan Liu,†,‡ Yu Zhou,† Daizong Lin,† Jinfang Wang,† Lei Zhang,† Hualiang Jiang,† and Hong Liu†,*
†The Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China
‡Department of Pharmacy, College of Life Sciences, China Jiliang University, Hangzhou 310018, P. R. China.
S Supporting Information
b
ABSTRACT: In this study, we developed an efficient tandem process
of hydroamination and hydroarylation using a gold catalyst to enable
and study the reactions between pyrrole-substituted anilines and
alkynes. The gold(I)-catalyzed reactions were achieved in toluene at
80 °C over a reaction time of 1ꢀ6 h. These reactions are applicable to a
variety of aromatic amino compounds and both the terminal and
internal alkynes. Substituted pyrrolo[1,2-a]quinoxalines were obtained
in moderate to excellent yields. A presumed mechanism involving
intermolecular CꢀN bond formation and intramolecular nucleophilic
reaction via a cationic gold complex has been proposed on the basis of
the deuterium labeling studies.
KEYWORDS: gold-catalyst, cascade reaction, hydroamination, hydroarylation
fficiency is an important characteristic for the design and
increasing the range of structural diversity accessible in the
products. Furthermore, only a small quantity of gold catalyst
(1 mol %) is needed, without other additives, and short reaction
times (1ꢀ6 h) are required.
E
development of innovative strategies in chemical synthesis.
One of the most effective methods of achieving synthetic
efficiency is to implement a cascade reaction to enable multiple
bond-forming and bond-cleaving events to occur in a single
synthetic operation.1 Among these are transition metal-catalyzed
domino reactions for the synthesis of various fused polycyclic
heterocyclic compounds.2 Gold-catalyzed reaction cascades have
attracted much interest as a result of the ability of gold ions to
activate alkyne, alkene, and allene functionality under mild
conditions and at low catalyst loadings.3
Preliminary experiments directed toward optimizing the reac-
tion conditions of the transformation were carried out using
commercially available 2-(1H-pyrrol-1-yl)aniline (1A) and phe-
nylacetylene (2a) in the presence of gold catalysts in toluene.
The results are shown in Table 1.
No reaction occurred in the absence of catalysts (Table 1,
entry 1), and AuCl3 provided the target product in only 25% yield
(Table 1, entry 2). However, certain cationic gold(I) complexes
were found to be exhibit significantly better activity in this
reaction (Table 1, entries 3 to 7). Among these species, catalyst
4 ([Au{P(t-Bu)2(o-biphenyl)}{CH3CN}]SbF6) was found to
be superior, with the target product being obtained in 95% yield
(Table 1, entry 7). Doubling the amount of Au catalyst (to 2 mol
%) provided no faster or higher yielding reaction (Table 1, entry
8), and Ag(I) salts were found to be ineffective as cocatalysts
(Table 1, entries 9 and 10).
The nature of the solvent plays an important role in this
transformation. Toluene, acetonitrile, and ethanol provided
significantly better yields than dichloromethane, THF, acetone,
N,N-dimethylformamide, and water (Table 1, entries 7, 11ꢀ17).
Changing the reaction temperature to 25 °C, 60 °C, or 100 °C
adjusted the reaction times as one would expect but did not
improve yields (Table 1, entries 18ꢀ20). Thus, optimal results
Although pyrrolo[1,2-a]quinoxalines and their 4,5-dihydro
derivatives play important roles in drug discovery as biologi-
cally active compounds and valuable synthetic intermediates,4
the available strategies for the synthesis of these compounds
are limited. So far, only a few methods have been described for
the assembly of 4,5-dihydropyrrolo[1,2-a]quinoxalines, which
normally require additional additives, long reaction times,
limited reaction tolerance, and low reaction selectivity.5
Recently, Patil et al developed the PtBr2- and Au(I)-catalyzed
hydroamination-hydroarylation cascade reactions of 2-(1H-
pyrrol-1-yl)anilines with alkynes to form 4,5-dihydropyrrolo-
[1,2-a]quinoxalines.6 Although these transformations are en-
couraging, they are limited to the terminal alkynes and require
long reaction times.
On the basis of our previous experience with gold catalysts in
the preparation of heterocycles,7 we describe here the scope and
mechanism of an improved version of the gold-catalyzed inter-
molecular C—N bond formation and intramolecular nucleophi-
lic reaction. Both terminal and internal alkynes can be used,
Received: December 6, 2010
Revised:
February 22, 2011
Published: April 13, 2011
r
2011 American Chemical Society
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|

ACS Combinatorial Science
LETTER
Table 1. Optimization of the Reaction Conditionsa
Table 2. Gold(I)-Catalyzed Reaction of 2-(1H-pyrrol-1-
yl)aniline 1A and Alkynes 2a
entry
catalystb
solvent
temp (°C)
time (h)
yield (%)c
1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH3CN
CH2Cl2
EtOH
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
r.t.
60
100
1
1
0
25
2
AuCl3
3
Au(PPh3)Cl
catalyst 1
catalyst 2
catalyst 3
catalyst 4
catalyst 4
catalyst 4
catalyst 4
catalyst 4
catalyst 4
catalyst 4
catalyst 4
catalyst 4
catalyst 4
catalyst 4
catalyst 4
catalyst 4
catalyst 4
1
42
4
1
85
5
1
82
6
1
76
7
1
95
8 d
9 e
10 f
11
12
13
14
15
16
17
18
19
20
1
93
1
88
1
86
1
84
1
63
1
90
H2O
1
trace
trace
0
THF
1
DMF
1
acetone
toluene
toluene
toluene
1
trace
91
36
3
89
1
92
a 1A (0.40 mmol), 2a (0.44 mmol), catalyst (1 mol %), Ar protection.
b Catalyst 1 = [Au{P(t-Bu)2(o-biphenyl)}]Cl; catalyst 2 = [Au{1,3-
bis(2,6-di-iso-propylphenyl)imidazol-2-yli-dene}]Cl; catalyst 3 = [Au{P-
(2,4-di-tert-butylphenoxy)3}]Cl; catalyst 4 = [Au{P(t-Bu)2(o-biphenyl)}-
{CH3CN}]SbF6. c Isolated yields based on 1A. d 2 mol % catalyst 4 used.
f
e AgSbF6 (5 mol %) used as cocatalyst. AgOTf (5 mol %) used as
cocatalyst.
were obtained when 2-(1H-pyrrol-1-yl)aniline (0.40 mmol, 1A)
and phenylacetylene (0.44 mmol, 2a) in toluene were treated
with 1 mol % of catalyst 4 in a sealed tube under Ar at 80 °C for 1 h.
To evaluate the scope of the catalytic method, we investigated
the reaction of 2-(1H-pyrrol-1-yl)aniline (1A) and a variety of
alkynes (2) under the above optimized conditions. As shown in
Table 2, a series of aromatic and aliphatic terminal alkynes gave
the desired products 3Aaꢀ3Ak in moderate to good yields
(53ꢀ98%) (Table 2, entries 1ꢀ11). Yields with ortho-substi-
tuted phenylacetylene derivatives were significantly lower than
for substrates with meta- and para-substituents (2bꢀ2d), pre-
sumably because of steric effects (Table 2, entries 2ꢀ4). Sub-
strate 2e, which possesses a 4-tert-butylphenyl group, was
incorporated with no difficulty (Table 2, entry 5). Electronic
effects were also indicated by the slight reduction in yield of
substrate 2f having an electron-donating p-methoxyphenyl group
(Table 2, entry 6). Excellent yields were obtained irrespective of
the presence of electron-withdrawing or halide groups at the R1
position (Table 2, entries 7ꢀ9). However, the 2-pyridyl group of
2-ethynylpyridine (2l) was not tolerated; the desired product 3Al
was not formed and the starting materials were completely
recovered (Table 2, entry 12).
a Reaction conditions: 1A (0.40 mmol), 2 (0.44 mmol), catalyst 4 (1 mol
%), Ar protection. b Isolated yield based on 1A. c The reaction was
carried out for 2 h. d The reaction was carried out for 6 h.
We were also pleased to find that the reaction was not limited
to substrates with aryl groups at the R1 position. Compounds
possessing alkyl groups were transformed smoothly into the
products 3Aj and 3Ak in good yield (Table 2, entries 10 and 11).
Furthermore, certain internal alkynes were also found to be
compatible (Table 2, entries 13ꢀ18). The methoxycarbonyl
substituents of compounds 2mꢀ2o facilitated efficient transfor-
mation, and the desired products were obtained in excellent
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ACS Combinatorial Science
LETTER
Scheme 1. Gold(I)-Catalyzed Reaction of 2-(1H-pyrrol-1-
yl)aniline 1A and Ethyl Propiolate 2s
Table 3. Gold(I)-Catalyzed Reaction of Pyrrole- and Indole-
Substituted Anilines 1 and Phenylacetylene 2aa
yields, up to 98% (Table 2, entries 13ꢀ15). In contrast, internal
alkyne substrates bearing more electron-rich (or noncoordinating)
R2 groups, such as ethyl and phenyl, reacted more slowly. For
example, 3Ap was obtained in 63% yield after 6 h (Table 2, entry
16), and phenyl-containing alkynes gave lower yields of the desired
products 3Aq and 3Ar (26% and 20% yield, respectively; Table 2,
entries 17 and 18). Unexpectedly, the 7-member ring-closure
product ethyl 6,7-dihydro-5H-benzo[b]pyrrolo[1,2-d][1,4]diazepine-
6-carboxylate (3As) was formed in excellent yield from the reaction of
the starting material (1A) with ethyl propiolate (2s).8
To further expand the scope of this transformation, gold-
catalyzed cyclizations of phenylacetylene 2a with various pyrrole-
and indole-substituted anilines 1 were investigated (Table 3).
These results demonstrated that the proposed reaction could be
extended to generate substituted-4-methyl-4-phenyl-4,5-dihydro-
pyrrolo[1,2-a]quinoxalines (3Baꢀ3Fa). However, the reaction
was significantly effected by the nature of the R3 substituent on
the aniline ring. Thus, while 3-, 4-, and 5-methyl-substituted
substrates gave similar results (Table 3, entries 1ꢀ3), a much
lower yield was obtained for the electron-rich 4-methoxy analogue
(Table 3, entry 4). In contrast, the electron-withdrawing 4-cyano
group led to smooth conversion to the desired product (Table 3,
entry 5). Good yields were also obtained for a pyrrole-substituted
heterocyclic amine (Table 3, entry 6) and for the N-methylated
aniline 1H (Table 3, entry 7). Use of a benzylic amine (1I) insteadof
aniline did not give the desired product (Table 3, entry 8).
Substitution on the pyrrole ring of 2-(substituted-1H-pyrrol-
1-yl)anilines was also found to be important. Ethyl and methyl
groups provided good yields (Table 3, entries 9, 10), but a
2-cyano-pyrrol-1-yl group and a 1H-pyrazol-1-yl group each gave
no conversion (Table 3, entries 11, 12). The latter result presu-
mably derives from the significantly decreased nucleophilicity of
the C5 atoms of the 2-cyanopyrrole and pyrazole, respectively.
Gratifyingly, indole-substituted aniline bearing a variety of
substituents gave cyclized products 3Naꢀ3Qa in good to
excellent yields (71ꢀ92%, Table 3, entries 13ꢀ16).
a Reaction conditions: 1 (0.40 mmol), 2a (0.44 mmol), catalyst 4 (1 mol
%), Ar protection. b Isolated yield based on 1. c The reaction was carried
out for 3 h. d The reaction was carried out for 6 h.
All the pyrrolo[1,2-a]quinoxalines synthesized were charac-
terized by spectral and analytical data. As shown in Figure 1, the
absolute configuration of the product was determined by X-ray
analysis of 3Ai.9
the R-position of the carbonyl group (44%) without significant
exchange to other positions (Scheme 2, eq 3). In addition, a
deuterium-incorporation pattern was also observed for the reac-
tion of N-deuterated 2-(1H-pyrrol-1-yl)aniline d-1A with methyl
propiolate 2s (Scheme 2, eq 4); in this case, the deuterium was
selectively incorporated into the methylene group (42%) of d-3As.
The reaction mechanism shown in Figure 2 is proposed to
account for these observations, consistent with previous investi-
gations of gold-catalyzed reactions.3,11 First, the carbonꢀcarbon
triple bond of 2 is activated by coordination with the gold catalyst
to form the gold-alkyne π-complex I. Intermolecular hydroamination
of 2-(1H-pyrrol-1-yl)aniline 1A gives the enamine intermediate
II, which is followed by proton transfer to produce the cationic
To gain insights into the mechanism of the reaction, we
performed labeling studies with deuterated starting materials.10
The reaction of 2-(1H-pyrrol-1-yl)aniline 1A with DCtCPh
d-2a under our gold catalysis conditions yielded the product
d-3Aa-1, with deuterium incorporation on the 4-methyl group
(26%) as confirmed by 1H NMR (Scheme 2, eq 1). Conversely,
28% of the 4-methyl hydrogen of d-3Aa-2 was found to contain
deuterium when N-deuterated 2-(1H-pyrrol-1-yl)aniline d-1A was
reacted with HCtCPh 2a (Scheme 2, eq 2). A similar result was
obtained when the internal alkyne was used in the reaction. The
treatment of d-1A with methyl 3-phenylpropiolate 2n resulted in
synthesis of the product d-3An, with deuterium incorporation at
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ACS Combinatorial Science
LETTER
Figure 1. X-ray Crystal Structure of 3Ai.9
Scheme 2. Deuterium-Labeling Study
Figure 2. Possible mechanism for Au(I)-catalyzed reaction.
tion flask containing toluene (5 mL) under argon was added
2-(1H-pyrrol-1-yl)aniline (63.2 mg, 0.40 mmol), phenylacetylene
(48 μL, 0.44 mmol), and [Au{P(t-Bu)2(o-biphenyl)}{CH3CN}]S-
bF6 (3 mg, 1 mol %). The resulting mixture was heated at 80 °C
for 1 h, and then diluted with 20 mL of EtOAc, washed with water
and brine, and dried by anhydrous Na2SO4. The solvent was
evaporated under reduced pressure, and the product was isolated
by column chromatography with Petro Ether (PE)/EtOAc (25/
1, v/v) as eluent to yield the desired product: (78 mg, 95%) as
intermediate III. The intramolecular nucleophilic reaction can then
proceed via either path 1 or path 2 to form the imine intermediates IV
and IV0, respectively. Most of the reactions proceed though path 1 to
give the 6-membered intermediate IV. However, presumably owing to
the electron-withdrawing nature of the carbonyl group, the use of ethyl
propiolate 3s as a starting material affords the 7-member ring-closure
intermediate IV0 via path 2. Finally, protonation of the resulting
organogold complexes IV and IV0 provides the final products 3 and
3As, respectively, with regeneration of the gold catalyst.
In summary, we have described a versatile and efficient synthetic
method in which a gold catalyst is used under mild reaction
conditions to produce a broad range of functionalized 4,5-dihydro-
pyrrolo[1,2-a]quinoxalines and 5,6-dihydroindolo[1,2-a]quinox-
alines, which are useful as versatile synthetic intermediates and
potentially as biologically active compounds. Deuterium labeling
studies support a mechanism featuring a sequence of intermolecular
hydroamination and nucleophilic pyrrole cyclization steps. We
expect that the resulting biologically intriguing structures will have
broad applications in our related medicinal chemistry program.
1
white solid; H NMR (300 MHz, CDCl3) δ = 7.32ꢀ7.22 (m,
5H), 7.19ꢀ7.16 (m, 2H), 6.97ꢀ6.91 (m, 1H), 6.81ꢀ6.76 (m,
2H), 6.36ꢀ6.34 (t, J = 3.3 Hz, 1H), 6.07ꢀ6.06 (m, 1H), 1.90
ppm (s, 3H); 13C NMR (75 MHz, CDCl3) δ = 146.3, 135.1,
132.9, 128.2, 126.9, 125.7, 124.7, 119.3, 115.8, 114.6, 114.3,
109.9, 104.5, 56.9, 29.3 ppm; MS (ESI, 70 eV) m/z (%) 261
(100) [M þ H]þ; HRMS (ESI) calcd for C18H17N2 [M þ H]þ
261.1392, found 261.1407.
’ ASSOCIATED CONTENT
S
Supporting Information. Additional experimental de-
b
tails, general information, and 1H and 13C NMR spectra for all
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
’ AUTHOR INFORMATION
’ EXPERIMENTAL PROCEDURES
Corresponding Author
*Phone: þ86-21-50807042. Fax: þ86-21-50807042. E-mail:
General Procedure for the Preparation of 4-Methyl-4-phenyl-
4,5-dihydropyrrolo[1,2-a]quinoxaline 3Aa. To a 10 mL reac-
hliu@mail.shcnc.ac.cn.
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ACS Combinatorial Science
LETTER
Funding Sources
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product ethyl 5H-benzo[b]pyrrolo[1,2-d][1,4]diazepine-6-carboxylate.
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We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Grants 20872153,
21021063 and 81025017).
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