Ruthenium-Catalyzed [3 + 2] Cycloaddition of 2H-Azirines with Alkynes: Access to Polysubstituted Pyrroles

Article abstract of DOI:10.1021/acs.joc.6b02322

A ruthenium-catalyzed intermolecular [3 + 2] cycloaddition of 2H-azirines and activated alkynes is reported, which provides polysubstituted pyrroles in moderate to good yields. This approach features a C-N bond cleavage of 2H-azirines by a ruthenium catal

Full text of DOI:10.1021/acs.joc.6b02322

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Note
Ruthenium-Catalyzed [3+2] Cycloaddition of 2H-
azirines with alkynes: Access to Polysubstituted Pyrroles
Tengfei Li, Hao Yan, Xincheng Li, Chunxiang Wang, and Boshun Wan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02322 • Publication Date (Web): 04 Nov 2016
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Ruthenium-Catalyzed [3+2] Cycloaddition of 2H-azirines with
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alkynes: Access to Polysubstituted Pyrroles
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Tengfei Li,1,2† Hao Yan,1,2† Xincheng Li,1 Chunxiang Wang*1 and Boshun Wan*1
1Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan
Road, Dalian 116023, China
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2University of Chinese Academy of Sciences, Beijing 100049, China
† These authors contribute equally to this work.
ABSTRACT
A rutheniumꢀcatalyzed intermolecular [3+2] cycloaddition of 2Hꢀazirines and
activated alkynes is reported, which provides polysubstituted pyrroles in moderate to
good yields. This approach features a C–N bond cleavage of 2Hꢀazirines by a
ruthenium catalyst. The results of this study would provide a complementary method
to synthesize polysubstituted pyrroles from the known 2Hꢀazirine approaches and
advance the 2Hꢀazirines chemistry.
Polysubstituted pyrrole derivatives are important skeletal units that are widely
distributed in numerous natural products, pharmaceuticals and material science
(Figure 1).1 Owing to the significant bioactive and therapeutic properties of the
pyrrole moiety, many efforts have been devoted to the preparation of
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pyrroleꢀcontaining heterocycles in recent decades.2 Generally, the construction of the
pyrrole ring involves a multistep process from preformed intermediates, such as the
classical Hantzsch and Paal−Knorr reactions.3 Recently, some more efficient
approaches, including using new building blocks4 as well as oxidative cyclization of
allylimines or enamides5 and multicomponent reactions,2b,6 have been developed to
access functionalized pyrroles. Although much progress have been made in the
synthesis of pyrrole derivatives, direct access to polysubstituted pyrroles in an atomꢀ
and stepꢀeconomic manner still remains challenging and highly desirable.
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Figure 1. Examples of biologically and therapeutically active molecules
containing pyrrole scaffold.
Recently, cycloadditions or cyclizations of strained rings have been recognized as
one of the most powerful strategies for constructing carbocycles and heterocycles.7
2Hꢀazirines are highly strained threeꢀmembered heterocyclic compounds and have
been exploited as valuable threeꢀatom building units such as vinyl nitrenes and nitrile
ylides.8 Therefore, 2Hꢀazirines have been employed in the synthesis of various
nitrogen containing heterocycles, such as pyrroles,9 indoles,10 pyridines,11 oxazoles,12
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pyrazines13 and others14. Among these transformations, [3+2] cycloaddition of
2Hꢀazirines with alkynes has proven to be a direct and powerful strategy to produce
pyrroles with high atom efficiency. Xiao and Lu developed a practical pyrrole
synthesis by means of a visibleꢀlightꢀinduced photocatalytic formal [3+2] reaction of
2Hꢀazirines with electronꢀdeficient alkynes (Scheme 1a).9c This reaction is initiated
by singleꢀelectron oxidation of the 2Hꢀazirines in the presence of an excited
photocatalyst, followed by homolytic cleavage of the C−C bond. Subsequently, an
effective goldꢀcatalyzed intermolecular nitrene transfer by the reaction of 2Hꢀazirines
and ynamides has been achieved by Huang9d and Liu9e respectively, which provides
highly substituted pyrroles in good to excellent yields (Scheme 1b). It is noteworthy
that the bond cleavage mode of 2Hꢀazirine is quite crucial in determining the position
of introduced substituents in the pyrrole ring. For example, electronꢀwithdrawing
(EWG) groups were introduced into 3ꢀ and 4ꢀpositions of pyrrole ring in Xiao and
Lu’s work by C−C bond cleavage of 2Hꢀazirine,9c while amino groups were
incorporated at 2ꢀposition by C–N or C=N bond cleavage.9d,9e In this regard, precise
introduction of substituents into a certain position of the pyrrole ring by controlling
the bond cleavage mode of 2Hꢀazirine is of great interest and importance.
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Scheme 1. Pyrroles Synthesis via Cycloaddition of 2H-azirines with Alkynes.
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Recently, we are interested in the metalꢀcatalyzed cycloaddition reactions.15 As
a part of our work, we have developed the Cuꢀcatalyzed ring opening reaction of
2Hꢀazirines with terminal alkynes to access 3ꢀalkynylated pyrroles, in which the
alkyne moiety was incorporated as a substituent (Scheme 1c).15f The in situ generated
copper acetylide is proved to initialize the reaction, and thus internal alkynes failed to
provide the desired products. Very recently, we also reported a rutheniumꢀcatalyzed
cycloaddition of 2Hꢀazirines with diynes for constructing azepine architectures
(Scheme 1d).15h [3+2+2] rather than [3+2] cycloadducts were preferentially generated
in this reaction. As our continue interest in the 2Hꢀazirine chemistry, we envisioned
that 2Hꢀazirines could be converted to pyrroles by [3+2] cycloaddition with internal
alkynes (Scheme 1e). Unlike our previous work,15h however, C–N bond cleavage of
2Hꢀazirine was observed in the presence of ruthenium catalyst. Consequently,
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electronꢀwithdrawing groups were introduced at 3ꢀposition of the resulting pyrrole
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products, which would provide
a
complementary method to synthesize
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polysubstituted pyrroles from the known 2Hꢀazirine approaches (Scheme 1e vs
Scheme 1a,b).9cꢀ9e Herein, we report our results.
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Table 1. Optimization of the reaction conditions.a
Entry
1d
2
Solvent
DCE
Tempb
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
25 °C
50 °C
100°C
80 °C
80 °C
80 °C
1a : 2a
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1:3
Yieldc
29
35
11
16
35
25
%
%
%
%
%
%
DCE
3
DMF
toluene
DCM
THF
4
5
6
7
MeOH
DCE
0
8
9%
9
DCE
22%
10
11
12
13e
DCE
34
%
%
DCE
38
DCE
1:5
55%
DCE
1:5
45%
aReaction conditions: 2Hꢀazirine 1a (0.20 mmol), alkyne 2a,
[Cp*RuCl2]2 (5 mol%) in solvent (2 mL) for 12 h unless otherwise
c
stated. bThe temperature of oil bath. Determined by HPLC using
naphthalene as an internal standard. dCp*Ru(COD)Cl (10 mol%).
e2.5 mol% of [Cp*RuCl2]2 was used as catalyst.
At the outset, 2,3ꢀdiphenylꢀ2Hꢀazirine 1a and methyl 3ꢀphenylpropiolate 2a were
chosen as model substrates for the optimization of the reaction conditions. The results
are summarized in Table 1. In agreement with our previous observations in the
[3+2+2] cycloaddition,15h most ruthenium(II) catalysts such as [Cp*RuCl]4,
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Cp*Ru(CH3CN)PF6, [Ru(COD)Cl2]n and [Ru(pꢀcymene)Cl2]2 failed to provide any
desired product. Pleasingly, by employing Cp*Ru(COD)Cl as catalyst which has
shown the best performance in our previous study,15h the reaction of 2Hꢀazirine 1a
and alkyne 2a proceeded under relatively mild conditions (80 °C, in DCE), affording
the desired product pyrrole 3a in 29% yield (Table 1, entry 1). Replacing the
ruthenium(II) catalyst by a ruthenium(III) catalyst [Cp*RuCl2]2, led to a slightly
higher yield (35%, entry 2). Subsequently, examination of different solvents revealed
that DCE or DCM showed the best performance (entries 3–7). Furthermore, a simple
inspection on the reaction temperatures indicated that lowering or raising the
temperature did not improve the yields (entries 8–10). A higher product yield can be
achieved by increasing the ratio of 2a to 1a (55%, entry 12). However, attempts to
lower the catalyst loading to 2.5 mol% resulted in a decreased yield (45%, entry 13).
It is noteworthy that dimerization of 2Hꢀazirine was commonly detected under
ruthenium catalyst, which slightly lowered the yield of 3a. Unfortunately, the reaction
with slow addition of 2Hꢀazirine 1a into the mixture of catalyst and alkyne 2a in 3
hours via syringe pump did not afford any desired product. Similar result was also
observed when a mixture of 1a and 2a was slowly added into the catalyst solution.
Importantly, the structure of 3a was unambiguously confirmed by Xꢀray crystal
diffraction of its analogous 3h and 3w,16 revealing that the C–N bond of 2Hꢀazirine
was cleaved in the reaction. It is interesting that the alkyne carbons are incorporated
into the 2ꢀ and 3ꢀpositions of the pyrrole product, rather than the 3ꢀ and 4ꢀpositions
observed in the lightꢀinduced versions of this formal cycloaddition.17
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Scheme 2. Substrate scope.
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R2
R1
EWG
R3
N
[Cp*RuCl2
]
2
R3
EWG
+
R1
R2
DCE, 80
C
N
H
3
1
2
Ph
CO2Me
Ph
CO2Me
Ph
Ph
CO2Me
Ph
9
Ph
Ph
CO2Me
Ph
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Ph
N
H
N
H
N
N
H
Me
MeO
Cl
H
3a
, 52%
3b, 54%
3c, 55%
3d, 54%
Ph CO2Me
Ph
Ph
CO2Me
Ph
Ph
CO2Me
Ph
Ph
CO2Me
Ph
N
N
N
H
N
H
H
H
F
Me
Me
3g, 42%
3e
, 52%
3f
, 59%
3h
, 58%
O2N
Ph
nBu
CO2Me
Ph
Ph
CO2Me
Ph
CO2Me
CO2Me
Ph
Ph
Ph
N
H
N
N
H
Ph
N
H
S
H
3i, 81%
3j, 50%
3k, 54%
3l, 56%
O
Ph
CO2tBu
Ph
Ph
CO2Et
Ph
CO2Me
Ph
Ph
MeO
Ph
Ph
N
N
N
N
H
H
H
H
S
S
S
3o
, 35%
3m, 53%
3n, 74%
3p
, 65%
O
Ph
Ph
Ph
Ph
EWG
Ph
Ph
CO2Et
Ph
CO2Et
N
H
N
N
H
N
H
S
H
S
S
S
3q, 16%
3v
, 71%
3r, EWG = COOH, NR
, EWG = CN, NR
3t, EWG = CONMe2, NR
3u, 50%
3s
Ph
CO2Et
Ph
CO2Et
Ph
CO2Et
N
H
N
N
S
H
OMe
H
S
X
S
R
3z, R = Me, trace
3z'
3w, 71%
3x
, X = F, 79%
3y, X = Br, 79%
, R = Br, trace
aReaction conditions: 2H-azirine 1 (0.2 mmol) and alkynes 2 (1.0 mmol) with [Cp*RuCl2
]2 (5 mol %)
in DCE (2 mL) at 80 °C for 12 h. Isolated yields are given. NR = No reaction.
With the optimized reaction conditions in hand, we set out to screen the scope of
both 2Hꢀazirines and alkynes for this [3+2] cycloaddition. Variations of R1 group on
the C=N double bond moiety of 2Hꢀazirines were first examined. As highlighted in
Scheme 2, both electronꢀdonating and electronꢀwithdrawing groups on the phenyl ring
could be successfully introduced, thus providing the corresponding polysubstituted
pyrroles (3b–3g) in moderate yields. A 2Hꢀazirine with an orthoꢀmethyl group on the
phenyl ring afforded product 3g in 42% yield due to the steric effect, while 2Hꢀazirine
bearing a sterically demanding naphthyl group gave pyrrole 3h in 58% yield. The
electronic effect may be the dominant reason for the moderate yield of 3h. Moreover,
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2ꢀthienyl group was compatible to provide the desired product 3i with good yield.
Replacement of the aryl group with an alkyl substituent also led to the effective
formation of the corresponding pyrrole in moderate yield (3j). Notably, the electronic
and steric nature of the R2 substituent had no great effect on this reaction. Different
groups at para or ortho position of the phenyl ring were tolerated as well (3k–3m).
Subsequently, we turned our attention to investigate various alkynes with thienyl
2Hꢀazirine 1i. Both esterꢀ (2a, 2n, 2o) and ketoneꢀderived alkynes (2p, 2q) reacted
well with 1i to afford the corresponding tetrasubstituted pyrroles. However, it seems
that the reactivity is quite sensitive to the steric effect of the carbonyl substituents, as
sterically demanding alkynes 2o and 2q provided the desired product with much
lower yields (35% and 16%). Moreover, other electronꢀwithdrawing groups such as
carboxylic acid (COOH), nitrile (CN) and amide (CONMe2) failed to provide any
products (3r–3t). The variations of R3 group on the alkynes were further evaluated. It
was found that ethyl butꢀ2ꢀynoate was suitable substrate, thus providing the desired
product 3u in moderate yield. When R3 was a phenyl group, this reaction was
sensitive to steric effect of the R3 substituent on alkynes. Alkynes having
electronꢀdeficient groups on the para position of the phenyl ring showed similar
reactivity as the ones bearing electronꢀrich groups (3v–3y). However, alkynes bearing
an orthoꢀsubstituted phenyl ring (2z, 2z’) were hardly reactive, even at higher
temperature.
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To account for the results of the present catalytic reaction, we propose the
mechanism shown in Scheme 3. The catalytic cycle starts with the oxidative addition
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of 2Hꢀazirine 1 on the ruthenium center to form the azaruthenacyclobutene
intermediate A.8a,18 Subsequently, coordination of the activated alkyne 2 converts the
ruthenacyclobutene A into the complex B, which readily undergoes the alkyne
insertion into Ru–C single bond to deliver the sixꢀmembered ruthenacycle
intermediate C. The site of alkyne insertion switches depends on the nature of alkynes,
as Cheng et al.19 explained for their Nꢀcyclization reaction. Then, the reductive
elimination of the intermediate C provides the intermediate D and regenerates the
catalyst for the next catalytic cycle. Finally, isomerization of the intermediate D
provides the thermodynamically stable product pyrrole 3. However, the possibility
that the imine double bond in intermediate C isomerizes to the enamine E before the
reductive elimination cannot be completely excluded at present time. In the case of
the alkynes 2z and 2z’, the steric repulsion between ortho groups and ligand on Ru
catalyst may cause the diminished yields in products. It is noteworthy that our
hypothesis is mechanistically similar to the previously reported procedures for
2,3ꢀdihydropyrroles synthesis from aziridines and alkynes.20
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Scheme 3. Plausible Catalytic Cycles for the Pyrrole Synthesis.
■ CONCLUSION
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In summary, we have reported a rutheniumꢀcatalyzed formal [3+2] cycloaddition
of 2Hꢀazirines with the activated alkynes, which provides a straightforward approach
to fully substituted pyrroles in moderate to good yields. A possible mechanism
involving the azaruthenacyclobutene intermediate is proposed for the generation of
desired products and specific selectivity of pyrroles. The results of this study would
provide a complementary method to synthesize polysubstituted pyrroles from the
known 2Hꢀazirine approaches and advance the 2Hꢀazirines chemistry.
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■ EXPERIMENTAL SECTION
General Information. Unless otherwise stated, all manipulations and reactions
were performed under inert atmosphere using standard Schlenk techniques or in an
argonꢀfilled gloveꢀbox. All chemicals were purchased from commercial sources and
were used without further purification. Solvents were treated prior to use according to
the standard methods. Column chromatography was carried out on silica gel (200–300
mesh) using a forced flow of eluent at 0.3–0.5 bar pressure. NMR Spectra were
recorded at room temperature in CDCl3 on 400 MHz spectrometers. The chemical
1
shifts for H NMR were recorded in ppm downfield from tetramethylsilane (TMS)
with CDCl3 (7.26 ppm) as the internal standard. The chemical shifts for 13C NMR
were recorded in ppm downfield using the central peak of CDCl3 (77.16 ppm) as the
internal standard. Coupling constants (J) are reported in hertz and refer to apparent
peak multiplications. The abbreviations s, d, t, q and m stand for singlet, doublet,
triplet, quartet and multiplet in that order. HRMS data were obtained with
HPLCꢀQꢀTOF mass spectrometer (ESI).
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General procedure for the preparation of 2H-azirines:
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The 2Hꢀazirines are prepared by the following procedure according to literature
report.9d Reaction scheme is shown in the supporting information.
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A mixture of ketone 4 (1 equiv), NH2OH·HCl (1.5 equiv) and sodium acetate
(1.5 equiv) was added to a mixture solvent of MeOH/H2O (10:1) in a round bottom
flask. The resulting solution was stirred at room temperature and monitored by TLC.
After reaction completed, the solvent was removed in vacuo and DCM was added.
Then, the mixture was sequentially washed with sat. aq. NaHCO3 and brine. The
organic layer was dried over Na2SO4. Concentration led to the oxime 5, which was
used directly for the next step.
To a solution of the crude oxime (1 equiv) in dry THF was added triethylamine
(1.5 equiv) and methanesulfonyl chloride (1.5 equiv) sequentially at room temperature.
The solution got cloudy after the addition of methanesulfonyl chloride. The resulting
mixture was stirring for 30 min, and DBU (1.5 equiv) was then added over 1 min.
After stirred for additional 30 min, the reaction mixture was passed through a pad of
silica gel, and washed with EtOAc. The mixture was concentrated in vacuo and
purified by silica gel column chromatography to give the 2Hꢀazirine 1.
Representative procedure for the synthesis of pyrrole
Catalyst [Cp*RuCl2]2 (6.1 mg, 0.01 mmol, 5 mol%) was weighed in the glove
box and placed in a dried Schlenk tube. Subsequently, 2 mL of solvent (DCE) was
added. The resulting mixture was stirred at room temperature. After 5 min, 2Hꢀazirine
1a (0.2 mmol, 1 equiv) was added followed by alkyne 2a (1.0 mmol, 5.0 equiv). The
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reaction mixture was stirred at 80 °C (oil bath) for 12 h. The solvent was evaporated
and the crude product was directly purified by silica gel column chromatography to
give the desired product (eluent: petroleum ether/ethyl acetate = 10:1~8:1).
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Methyl 2,4,5-triphenyl-1H-pyrrole-3-carboxylate (3a). White solid; 36.7 mg (52%
1
yield), m.p. 156–158 °C; H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.59–7.52 (m,
2H), 7.38 (m, 3H), 7.29 (d, J = 4.4 Hz, 5H), 7.23–7.12 (m, 5H), 3.46 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 166.0, 136.4, 135.4, 132.3, 131.9, 130.7, 129.5, 128.7,
128.6, 128.4, 128.3, 127.9, 127.2, 127.1, 126.7, 124.2, 113.3, 51.0; HRMS Calcd for
C24H20NO2 [M+H]+ 354.1489, found 354.1488.
Methyl 2,4-diphenyl-5-(p-tolyl)-1H-pyrrole-3-carboxylate (3b). White solid; 39.4
1
mg (54% yield), m.p. 158–159 °C; H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.49
(d, J = 7.1 Hz, 2H), 7.31 (dt, J = 15.1, 7.0 Hz, 3H), 7.26–7.15 (m, 5H), 6.95 (q, J =
13
8.1 Hz, 4H), 3.40 (s, 3H), 2.20 (s, 3H); C NMR (100 MHz, CDCl3) δ 166.1, 136.9,
136.1, 135.5, 132.4, 130.7, 129.7, 129.4, 129.1, 128.7, 128.4, 128.3, 127.9, 127.1,
126.6, 123.8, 113.2, 51.0, 21.3; HRMS Calcd for C25H22NO2 [M+H]+ 368.1645,
found 368.1658.
Methyl 5-(4-methoxyphenyl)-2,4-diphenyl-1H-pyrrole-3-carboxylate (3c). White
solid; 41.8 mg (55% yield), m.p. 173–174 °C; 1H NMR (400 MHz, CDCl3) δ 8.50 (s,
1H), 7.57 (dd, J = 8.0, 1.5 Hz, 2H), 7.44–7.34 (m, 3H), 7.32–7.22 (m, 5H), 7.11–7.04
(m, 2H), 6.79–6.69 (m, 2H), 3.73 (s, 3H), 3.48 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 166.1, 158.8, 135.9, 135.5, 132.4, 130.7, 129.6, 128.7, 128.6, 128.5, 128.2, 127.9,
126.6, 124.6, 123.4, 114.1, 113.1, 55.3, 50.9; HRMS Calcd for C25H22NO3 [M+H]+
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384.1594, found 384.1602.
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Methyl 5-(4-chlorophenyl)-2,4-diphenyl-1H-pyrrole-3-carboxylate (3d). White
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solid; 41.8 mg (54% yield), m.p. 93–94 °C; H NMR (400 MHz, CDCl3) δ 8.65 (s,
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1H), 7.49–7.44 (m, 2H), 7.34–7.26 (m, 3H), 7.22–7.15 (m, 5H), 7.09–7.05 (m, 2H),
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7.00–6.95 (m, 2H), 3.38 (s, 3H); C NMR (100 MHz, CDCl3) δ 166.0, 136.8, 135.1,
132.8, 132.1, 130.6, 130.4, 128.80, 128.79, 128.5, 128.43, 128.41, 128.38, 128.0,
126.9, 124.7, 113.3, 51.0; HRMS Calcd for C24H19ClNO2 [M+H]+ 388.1099, found
388.1105.
Methyl 5-(4-fluorophenyl)-2,4-diphenyl-1H-pyrrole-3-carboxylate (3e). White
solid; 38.7 mg (52% yield), m.p. 167–169 °C; 1H NMR (400 MHz, CDCl3) δ 8.57 (s,
1H), 7.60–7.54 (m, 2H), 7.44–7.36 (m, 3H), 7.32–7.25 (m, 5H), 7.15–7.10 (m, 2H),
6.94–6.88 (m, 2H), 3.49 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.0, 161.9 (d, J =
247.4 Hz), 136.4, 135.2, 132.2, 130.7, 129.1 (d, J = 7.9 Hz), 128.8, 128.7, 128.44,
128.41, 128.1 (d, J = 3.4 Hz), 128.0, 126.8, 124.2, 115.7 (d, J = 21.7 Hz), 113.2, 51.0;
19F NMR (377 MHz, CDCl3) δ ꢀ114.5; HRMS Calcd for C24H19FNO2 [M+H]+
372.1394, found 372.1392.
Methyl 2,4-diphenyl-5-(m-tolyl)-1H-pyrrole-3-carboxylate (3f). Yellow oil; 43.5
mg (59% yield); 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.61–7.56 (m, 2H), 7.43
(dd, J = 8.3, 6.6 Hz, 2H), 7.40–7.36 (m, 1H), 7.27–7.10 (m, 9H), 3.58 (s, 3H), 1.99 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 166.5, 137.7, 135.7, 135.2, 132.3, 131.8, 131.1,
130.5, 130.0, 129.7, 128.54, 128.47, 128.3, 127.7, 126.3, 125.9, 125.0, 112.0, 51.1,
20.2; HRMS Calcd for C25H22NO2 [M+H]+ 368.1645, found 368.1656.
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Methyl 2,4-diphenyl-5-(o-tolyl)-1H-pyrrole-3-carboxylate (3g). White solid; 30.7
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mg (42% yield), m.p. 139–140 °C; H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H),
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7.54–7.47 (m, 2H), 7.39–7.28 (m, 3H), 7.26–7.14 (m, 5H), 7.00 (t, J = 7.6 Hz, 1H),
6.91 (d, J = 8.9 Hz, 2H), 6.84 (d, J = 7.7 Hz, 1H), 3.42 (s, 3H), 2.15 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 166.0, 138.3, 136.2, 135.5, 132.4, 131.9, 130.7, 129.7, 128.8,
128.5, 128.4, 128.3, 127.90, 127.87, 127.7, 126.7, 124.5, 124.2, 113.3, 51.0, 21.5;
HRMS Calcd for C25H22NO2 [M+H]+ 368.1645, found 368.1660.
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Methyl 5-(naphthalen-1-yl)-2,4-diphenyl-1H-pyrrole-3-carboxylate (3h). White
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solid; 46.9 mg (58% yield), m.p. 60–62 °C; H NMR (400 MHz, CDCl3) δ 8.46 (s,
1H), 7.91–7.72 (m, 3H), 7.60–7.51 (m, 2H), 7.47–7.25 (m, 7H), 7.20–7.12 (m, 2H),
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7.13–6.98 (m, 3H), 3.54 (s, 3H); C NMR (100 MHz, CDCl3) δ 166.4, 136.0, 134.9,
133.7, 132.5, 132.1, 130.1, 129.7, 129.4, 128.7, 128.55, 128.54, 128.45, 128.4, 128.2,
127.5, 126.6, 126.2, 126.1, 125.8, 125.7, 125.4, 112.3, 51.1; HRMS Calcd for
C28H22NO2 [M+H]+ 404.1645, found 404.1658.
Methyl 2,4-diphenyl-5-(thiophen-2-yl)-1H-pyrrole-3-carboxylate (3i). White solid ;
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58.1 mg (81% yield), m.p. 149–151 °C; H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H),
7.62–7.55 (m, 2H), 7.48–7.31 (m, 8H), 7.09 (d, J = 5.1 Hz, 1H), 6.89 (dd, J = 5.1, 3.7
Hz, 1H), 6.82 (d, J = 3.6 Hz, 1H), 3.48 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.6,
136.5, 135.1, 133.9, 132.1, 130.8, 128.9, 128.54, 128.45, 128.0, 127.2, 124.7, 124.6,
124.4, 123.9, 113.4, 51.0; HRMS Calcd for C22H18NO2S [M+H]+ 360.1053, found
360.1057.
Methyl 5-butyl-2,4-diphenyl-1H-pyrrole-3-carboxylate (3j). White oil; 33.4 mg
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(50% yield); H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.57–7.52 (m, 2H),
7.44–7.34 (m, 5H), 7.32–7.24 (m, 3H), 3.50 (s, 3H), 2.59–2.50 (m, 2H), 1.53 (t, J =
7.7 Hz, 2H), 1.29 (q, J = 7.4 Hz, 2H), 0.85 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.2, 135.8, 135.0, 132.7, 130.8, 130.3, 128.7, 128.3, 128.0, 127.7, 126.3,
123.7, 111.5, 50.8, 32.2, 25.4, 22.5, 13.9; HRMS Calcd for C22H24NO2 [M+H]+
334.1802, found 334.1811.
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Methyl 2,5-diphenyl-4-(p-tolyl)-1H-pyrrole-3-carboxylate (3k). White solid; 39.8
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mg (54% yield), m.p. 135–137 °C; H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H),
7.60–7.54 (m, 2H), 7.45–7.35 (m, 3H), 7.27–7.15 (m, 7H), 7.11 (d, J = 7.8 Hz, 2H),
3.51 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.1, 136.21, 136.19,
132.4, 132.2, 132.1, 130.5, 129.5, 128.73, 128.66, 128.4, 128.3, 127.2, 127.1, 124.3,
113.4, 51.0, 21.4; HRMS Calcd for C25H22NO2 [M+H]+ 368.1645, found 368.1670.
Methyl 4-(4-nitrophenyl)-2,5-diphenyl-1H-pyrrole-3-carboxylate (3l). Yellow
solid ; 44.5 mg (56% yield), m.p. 198–199 °C; 1H NMR (400 MHz, CDCl3) δ 8.71 (s,
1H), 8.18–8.10 (m, 2H), 7.62–7.55 (m, 2H), 7.44 (dtd, J = 12.5, 6.8, 5.8, 3.6 Hz, 5H),
7.26 (dd, J = 5.3, 1.9 Hz, 3H), 7.14 (dt, J = 6.9, 2.4 Hz, 2H), 3.52 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 165.5, 146.6, 143.0, 137.5, 131.9, 131.6, 131.1, 130.6, 128.99,
128.96, 128.8, 128.5, 127.9, 127.6, 123.2, 122.0, 112.7, 51.1; HRMS Calcd for
C2 H19N2O4 [M+H]+ 399.1339, found 399.1342.
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4-(2-methoxyphenyl)-2,5-diphenyl-1H-pyrrole-3-carboxylate
(3m).
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Yellow oil; 40.8 mg (53% yield); H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H),
7.57–7.50 (m, 2H), 7.37–7.25 (m, 3H), 7.23–7.08 (m, 6H), 7.04 (dd, J = 7.5, 1.7 Hz,
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1H), 6.87–6.76 (m, 2H), 3.61 (s, 3H), 3.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
166.0, 157.7, 136.2, 132.5, 132.3, 132.0, 129.7, 128.9, 128.6, 128.4, 128.3, 128.2,
127.0, 126.9, 124.6, 120.5, 120.0, 113.9, 110.7, 55.5, 50.8; HRMS Calcd for
C25H22NO3 [M+H]+ 384.1594, found 384.1600.
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Ethyl 2,4-diphenyl-5-(thiophen-2-yl)-1H-pyrrole-3-carboxylate (3n). Yellow oil ;
54.9 mg (74% yield); 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.62–7.54 (m, 2H),
7.46–7.27 (m, 8H), 7.07 (dd, J = 5.1, 1.2 Hz, 1H), 6.87 (dd, J = 5.1, 3.6 Hz, 1H), 6.82
(dd, J = 3.6, 1.2 Hz, 1H), 3.94 (q, J = 7.1 Hz, 2H), 0.85 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 164.2, 135.5, 134.3, 133.0, 131.0, 129.9, 128.0, 127.5, 127.3,
127.0, 126.2, 126.1, 123.8, 123.4, 123.2, 122.7, 112.8, 58.8, 12.7; HRMS Calcd for
C23H20NO2S [M+H]+ 374.1209, found 374.1222.
tert-Butyl 2,4-diphenyl-5-(thiophen-2-yl)-1H-pyrrole-3-carboxylate (3o). Yellow
solid, yield: 28.1 mg (35%), m.p. 180–182 °C; 1H NMR (400 MHz, CDCl3) δ 8.45 (s,
1H), 7.61 (d, J = 7.1 Hz, 2H), 7.43 (t, J = 7.3 Hz, 2H), 7.37 (m, 5H), 7.09 (d, J = 5.1
Hz, 1H), 6.89 (dd, J = 5.0, 3.7 Hz, 1H), 6.82 (dd, J = 3.6, 0.9 Hz, 1H), 1.17 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 164.5, 135.8, 135.7, 134.1, 132.1, 130.9, 128.8, 128.5,
128.4, 128.0, 127.2, 127.1, 124.6, 124.3, 123.9, 123.6, 115.6, 80.1, 27.9; HRMS
Calcd for C25H24NO2S [M+H]+ 402.1522, found 402.1520.
1-(2,4-Diphenyl-5-(thiophen-2-yl)-1H-pyrrol-3-yl)ethanone (3p). White solid; 44.9
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mg (65% yield), m.p. 190–191 °C; H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H),
7.60–7.53 (m, 2H), 7.39 (m, 8H), 7.09 (d, J = 5.0 Hz, 1H), 6.89 (dd, J = 5.0, 3.7 Hz,
1H), 6.83 (d, J = 3.6 Hz, 1H), 1.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.3,
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135.4, 135.3, 133.8, 132.2, 131.0, 129.1, 128.69, 128.66, 128.5, 127.7, 127.2, 124.5,
124.2, 124.0, 123.84, 123.81, 31.4; HRMS Calcd for C22H18NOS [M+H]+ 344.1104,
found 344.1113.
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(2,4-Diphenyl-5-(thiophen-2-yl)-1H-pyrrol-3-yl)(phenyl)methanone (3q). Yellow
solid, yield: 13.0 mg (16%), m.p. 191–194 °C; 1H NMR (400 MHz, CDCl3) δ 8.57 (s,
1H), 7.63 (d, 2H), 7.31 (d, 2H), 7.21–7.15 (m, 5H), 7.13–7.04 (m, 7H), 6.88–6.84 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 194.3, 138.7, 134.2, 134.1, 133.9, 132.4, 131.4,
130.8, 130.0, 128.7, 128.1, 128.0, 127.9, 127.8, 127.4, 127.0, 125.0, 124.7, 124.5,
124.0, 122.5; HRMS Calcd for C27H20NOS [M+H]+ 406.1260, found 406.1263.
Ethyl
2-methyl-4-phenyl-5-(thiophen-2-yl)-1H-pyrrole-3-carboxylate
(3u).
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Yellow oil; 31.2 mg (50% yield); H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H),
7.37–7.25 (m, 5H), 7.03 (d, J = 5.1 Hz, 1H), 6.89–6.80 (m, 1H), 6.75 (d, J = 3.7 Hz,
1H), 4.04 (d, J = 7.1 Hz, 2H), 2.58 (s, 3H), 0.99 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 165.6, 135.9, 135.7, 134.4, 130.9, 127.8, 127.1, 126.9, 123.9, 123.8,
123.0, 122.3, 112.8, 59.4, 14.0, 13.9; HRMS Calcd for C18H18NO2S [M+H]+
312.1053, found 312.1064.
Ethyl 4-phenyl-5-(thiophen-2-yl)-2-(p-tolyl)-1H-pyrrole-3-carboxylate (3v). White
solid; 55.2 mg (71% yield), m.p. 114–115 °C; 1H NMR (400 MHz, CDCl3) δ 8.51 (s,
1H), 7.49 (d, J = 7.9 Hz, 2H), 7.40–7.29 (m, 5H), 7.24–7.17 (m, 2H), 7.07 (dd, J = 5.1,
1.1 Hz, 1H), 6.87 (dd, J = 5.1, 3.7 Hz, 1H), 6.81 (dd, J = 3.7, 1.1 Hz, 1H), 3.95 (q, J =
7.1 Hz, 2H), 2.38 (s, 3H), 0.86 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
165.2, 138.4, 136.7, 135.5, 134.0, 130.9, 129.1, 128.9, 127.9, 127.2, 127.1, 124.7,
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124.3, 124.0, 123.6, 113.5, 59.7, 21.5, 13.7; HRMS Calcd for C24H22NO2S [M+H]+
388.1366, found 388.1375.
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(3w). Yellow solid; 57.2 mg (71% yield), m.p. 142–143 °C; H NMR (400 MHz,
CDCl3) δ 8.51 (s, 1H), 7.51–7.40 (m, 2H), 7.26 (d, J = 3.3 Hz, 5H), 6.97 (dd, J = 5.1,
1.2 Hz, 1H), 6.88 – 6.81 (m, 2H), 6.78 (dd, J = 5.0, 3.7 Hz, 1H), 6.74 (dd, J = 3.7, 1.2
Hz, 1H), 3.85 (q, J = 7.1 Hz, 2H), 3.73 (s, 3H), 0.77 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 165.3, 159.8, 136.7, 135.6, 134.1, 130.9, 130.4, 127.9, 127.1,
127.0, 124.7, 124.4, 124.2, 123.8, 123.5, 113.7, 113.2, 59.7, 55.4, 13.7; HRMS Calcd
for C24H22NO3S [M+H]+ 404.1315, found 404.1321.
Ethyl
2-(4-fluorophenyl)-4-phenyl-5-(thiophen-2-yl)-1H-pyrrole-3-carboxylate
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(3x). Yellow oil; 62.0 mg (79% yield); H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H),
7.54–7.39 (m, 2H), 7.25 (d, J = 2.7 Hz, 5H), 6.96 (t, J = 7.8 Hz, 3H), 6.76 (dd, J = 8.7,
3.6 Hz, 2H), 3.82 (qd, J = 7.1, 2.2 Hz, 2H), 0.75 (t, J = 6.5 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 164.2, 161.8 (JC-F = 248.4 Hz), 134.7, 134.3, 132.8, 130.0 (JC-F = 8.1
Hz), 129.9, 127.0 (JC-F = 3.5 Hz), 126.9, 126.14, 126.05, 123.7, 123.5, 123.3, 122.8,
114.2 (JC-F = 21.7 Hz), 112.5, 58.8, 12.6; 19F NMR (377 MHz, CDCl3) δ ꢀ112.8;
HRMS Calcd for C23H19FNO2S [M+H]+ 392.1115, found 392.1125.
Ethyl 2-(4-bromophenyl)-4-phenyl-5-(thiophen-2-yl)-1H-pyrrole-3-carboxylate
(3y). Yellow solid; 70.9 mg (79% yield), m.p. 72–74 °C; 1H NMR (400 MHz, CDCl3)
δ 8.64 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.26 (s, 5H), 6.99 (d,
J = 5.0 Hz, 1H), 6.78 (t, J = 4.3 Hz, 1H), 6.75 (d, J = 3.6 Hz, 1H), 3.84 (q, J = 7.1 Hz,
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2H), 0.77 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.2, 135.20, 135.17,
133.7, 131.4, 130.9, 130.8, 130.6, 128.0, 127.2, 127.1, 124.9, 124.7, 124.6, 123.9,
122.6, 113.9, 59.9, 13.7; HRMS Calcd for C23H19BrNO2S [M+H]+ 452.0314, found
452.0322.
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■ ASSOCIATED CONTENT
Supporting information
The Supporting Information is available free of charge on the ACS Publications
1
website. Crystallographic data (CIF), Xꢀray structure of products, and copies of H
and 13C NMR spectra data for all products (PDF).
■ AUTHOR INFORMATION
Corresponding authors
*Eꢀmail: cxwang@dicp.ac.cn
*Eꢀmail: bswan@dicp.ac.cn
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China (21372219) for
financial support.
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