Synthesis of polysubstituted pyrroles via [3 + 2]-annulation of aziridines and -nitroalkenes under aerobic conditions

Article abstract of DOI:10.1039/c3ob42324g

Polysubstituted pyrroles were regioselectively synthesized in moderate to good yields via the copper acetate-catalyzed [3 + 2] annulation reaction of readily accessible aziridines and nitroalkenes. This reaction was proposed to proceed through a key azomethine ylide intermediate generated by selective C-C bond cleavage of the aziridine followed by annulation with nitroalkenes under aerobic conditions.

Full text of DOI:10.1039/c3ob42324g

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. Wang, Z.
Xiancui, Z. Chai and S. Wang, Org. Biomol. Chem., 2013, DOI: 10.1039/C3OB42324G.
This is an Accepted Manuscript, which has been through the RSC Publishing peer
Organic &
review process and has been accepted for publication.
Biomolecular
Accepted Manuscripts are published online shortly after acceptance, which is prior
to technical editing, formatting and proof reading. This free service from RSC
Publishing allows authors to make their results available to the community, in
citable form, before publication of the edited article. This Accepted Manuscript will
be replaced by the edited and formatted Advance Article as soon as this is available.
Chemistry
www.rsc.org/obc
Volume 8 | Number 3 | 7 February 2010 | Pages 481–716
To cite this manuscript please use its permanent Digital Object Identifier (DOI®),
which is identical for all formats of publication.
More information about Accepted Manuscripts can be found in the
Information for Authors.
Please note that technical editing may introduce minor changes to the text and/or
graphics contained in the manuscript submitted by the author(s) which may alter
content, and that the standard Terms & Conditions and the ethical guidelines
that apply to the journal are still applicable. In no event shall the RSC be held
responsible for any errors or omissions in these Accepted Manuscript manuscripts or
any consequences arising from the use of any information contained in them.
ISSN 1477-0520
PERSPECTIVE
FULL PAPER
Laurel K. Mydock and
AlexeiV. Demchenko
Shuji Ikeda et al.
Hybridization-sensitive fluorescent
DNA probe with self-avoidance ability
Mechanism of chemical O-glycosylation:
from early studies to recent discoveries
1477-0520(2010)8:3;1-H
www.rsc.org/obc
Registered Charity Number 207890

View Article Online
DOI: 10.1039/C3OB42324G
Organic & Biomolecular Chemistry
Page 1 ofO6 rganic &
Biomolecular
Chemistry
Dynamic Article Links ►
Cite this: DOI: 10.1039/c0xx00000x
PAPER
www.rsc.org/xxxxxx
Synthesis of Polysubstituted Pyrroles via [3 + 2]-Annulation of
Aziridines and β-Nitroalkenes Under Aerobic Conditions
Shaoyin Wang,†,‡ Xiancui Zhu,‡ Zhuo Chai,*, ‡ Shaowu Wang*,‡,§
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Polysubstituted pyrroles were regioselectively synthesized in moderate to good yields via the copper
acetate-catalyzed [3 + 2] annulation reaction of readily accessible aziridines and nitroalkenes. This
reaction was proposed to proceed through a key azomethine ylide intermediate generated by selective C-
C bond cleavage of the aziridine followed by annulation with nitroalkenes under aerobic conditions.
polysubstituted pyrroles from α-diazoketones, nitroalkenes, and
45 amines.12a Our group have been interested in the utilization of
aziridines as three-atom building-blocks in annulation reactions
for the syntheses of useful nitrogen-containing heterocyclic
compounds.12b Inspired by the researches described above, we
report herein an efficient cascade reaction of aziridines with β-
50 nitroalkenes13 through selective C-C cleavage of aziridines
catalyzed by Cu(OAc)2·H2O, enabling facile access to 2,3,5-
trisubstituted and 2,3,4,5-tetrasubstituted pyrroles.
10 Introduction
Pyrroles and their derivatives are an important family of
heterocyclic compounds with various applications in organic
synthesis, functional materials and pharmaceuticals.1-2 The
development of efficient synthetic approaches to pyyroles has
15 attracted long-standing interests among organic chemists. Besides
classic methods like the Hantzsch reaction,3 and the Paal-Knorr
synthesis,4 various cycloaddition methods5 and metal-catalyzed
approaches6 have also been developed. Despite these advances,
the development of efficient methods for the synthesis of pyrroles
20 from simple and readily available starting materials, especially
Results and discussion
Initial optimization of the reaction conditions were done with the
those with rich substitution types, is still of a great importance 55 model reaction between aziridine 1a and β-nitrostyrene 2a in
given their broad utilities in diverse fields.
dimethyl sulphoxide (DMSO) under air (Table 1). In the absence
of a catalyst, the desired product 3a was obtained in only 20%
yield (entry 1). The addition of the catalyst Cu(OAc)2·H2O
greatly improved the yield, and a screen of catalyst loading
Owing to the electronegativity of the nitrogen atom and the
ring strain of the three-membered ring, aziridines exhibited
25 intriguing and diverse reactivity, and thus have become unique
and versatile synthons in organic synthesis.7 The ring of aziridine 60 amount revealed that 5 mol % was best for the reaction (entry 3).
can easily undergo C–N/C-C bond cleavage to serve as useful
three-atom synthons with extensive applications in organic
synthesis.7-9 Many efforts have been devoted to the selective ring
30 opening of the aziridine ring for specific purpose. Particularly,
Varying the reaction temperature (entries 5-6), using other cupric
salt catalysts such as Cu(NO3)2, nano CuO, Cu(OTf)2, CuCl2 or
cuprous salt catalysts such as CuCl, CuBr (entries 7-12) all failed
to improve the results significantly. Notably, the reaction
aziridines are known to react by thermal or photochemical ring- 65 proceeded smoothly under darkness (entry 17), which was not in
opening via C–C bond cleavage to give azomethine ylides as
useful reactive species for a wide range of synthetic applications.9
For example, Schirmeister9f has confirmed the intermediacy of
35 the azomethine ylide species in the reactions of aziridine-2,2-
support of photochemical ring-opening of the aziridine ring for
this reaction and thus a thermal process might be considered.9
Moreover, some other solvents such as DMF, 1,4-dioxane, THF
and toluene were also examined to give inferior results (entries
dicarboxylates with dipolarophiles (alkenes or aldehydes) under 70 14-17), and the yield dropped sharply when the reaction was run
thermal conditions. Some Lewis acids catalyzed C–C bond
heterolysis of aziridines under mild conditions to form
corresponding azomethine ylides have also been reported.10
40 Engels also investigated the breakages of the C–N vs. C–C bonds
under argon atmosphere (entry 18). Generally, unreacted β-
nitrostyrene 2a and some unidenfiable mixture (probably due to
the decomposition of aziridine 1a) accounted for the mass
balance where the yields were modest or poor. Thus, the reaction
of aziridines through computation methods.11 On the other hand, 75 was best performed in DMSO at 110 oC for 18 h under air in the
a similar azomethine ylide have been proposed as the key
intermediate in the Cu(I)-catalyzed three-component synthesis of
presence of 5 mol % of Cu(OAc)2·H2O (entry 3).
Next, the scope of the reaction was investigated under the
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

View Article Online
Organic & Biomolecular Chemistry
DOI: 10.1039/C3OB42P32a4gGe 2 of 6
optimized reaction conditions, and the results were presented in
should hold great promise for application and further useful
Table 2. With regard to the tolerance of β-nitroalkenes, different
substituted β-nitroalkenes 2a–2n were studied with aziridine 1a.
conversion of these products in organic synthesis and related
fields. Also notable is the excellent regioselectivity observed in
For β-nitroalkenes derived from substituted benzaldehydes, 30 all these examples examined, which allows for facile access to
5
substrates with electron-donating substituents on the benzene ring
generally gave better yields than those with electron-withdrawing
ones (entries 2-8), while the influence of the position of the
substitutent seemed negligible. The heterocyclic substrate with a
furan ring was also tolerated in the reaction (entry 9). Moreover,
these polysubstituted pyrroles.
Table 2 Scope study with different nitroalkenes 2a
R2
R1
H
N
Cu(OAc)2 .H2O
(5 mol%)
NO2
R1
O
Ph
+
Ph
Ph
N
H
3
R2
DMSO
10 nitroalkenes derived from aliphatic aldehydes (entries 10-11), and
disubstituted nitroalkenes (gave tetrasubstituted pyrrole products)
also participated in the reaction, albeit with somewhat decreased
yields (entries 12-14).
O
110 oC, 18 h
Ph
1a
2
Entry
R1/ R2
Ph/H (2a)
Yield (%)b
72
3
1
3a
Table 1 Screen of reaction conditionsa
2
82
78
74
73
71
68
70
66
47
51
41
45
52
3b
3c
3d
3e
3f
2-MeOC6H4/H (2b)
4-MeOC6H4/H (2c)
2-NO2C6H4/H (2d)
2-ClC6H4/H (2e)
3-ClC6H4/H (2f)
3,4-Cl2C6H3/H (2g)
2-BrC6H4/H (2h)
2-Furyl/H (2i)
Ph
H
N
3
catalyst
solvent
NO2
O
Ph
+
Ph
Ph
Ph
4
temperature
N
H
O
Ph
1a
2a
3a
5
15
6
Catalyst
(mol %)
Temp
(oC)
Time
(h)
Yield
(%)b
Entry
Solvent
7
3g
3h
3i
1
2
3
4
No catalyst
110
110
110
18
18
18
DMSO
DMSO
DMSO
20
52
72
8
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (5)
9
10
11
12
13
14
3j
n-Pr/H (2j)
Cu(OAc)2·H2O
(10)
110
18
DMSO
70
3k
3l
i-Pr/H (2k)
5
Cu(OAc)2·H2O (5)
Cu(OAc)2·H2O (5)
Cu(NO3)2·H2O (5)
40 nm CuO (5)
Cu(OTf)2 (5)
100
120
110
110
110
110
110
110
110
110
24
18
18
18
18
18
18
18
18
18
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
68
72
70
71
68
65
60
56
70c
10
C6H5/Me (2l)
6
3m
3n
4-MeOC6H4/Me (2m)
4-ClC6H4/Me (2n)
7
8
aReaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), Cu(OAc)2·H2O
9
35 (0.025 mmol), DMSO (2 mL), under air. bYield of the isolated product.
10
11
12
13
14
15
Table 3 Scope study with different aziridines 1a
CuCl2·2H2O (5)
CuCl(5)
Ph
H
N
Cu(OAc)2 .H2O
(5 mol%)
NO2
R4
CuBr (5)
O
+
Ph
R3
R3
N
H
3
DMSO
R4
Cu(OAc)2·H2O (5)
Cu(OAc)2·H2O (5)
O
110 oC, 18 h
1
2a
Entry
R3/R4
Yield(%)b
74
3
1,4-
dioxane
Cu(OAc)2·H2O (5)
reflux
18
60
1
2
3
4
5
6
7
8
9
3o
4-MeOC6H4/Ph (1b)
4-ClC6H4/Ph (1c)
2,4-Cl2C6H3/Ph (1d)
1-naphthyl/Ph (1e)
Ph/4-MeOC6H4 (1f)
Ph /4-PhC6H4 (1g)
Ph /4-FC6H4 (1h)
Ph /4-BrC6H4 (1i)
Ph /2-furyl (1j)
16
17
18
Cu(OAc)2·H2O (5)
Cu(OAc)2·H2O (5)
Cu(OAc)2·H2O (5)
reflux
110
36
22
22
THF
46
63c
13d
81
83
80
73
80
62
56
70
3p
3q
3r
3s
Toluene
Toluene
110
aReaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), solvent (2 mL), the
reaction was monitored by TLC. bYield of the isolated product. cUnder
darkness. dUnder argon atmosphere.
3t
Then different aziridines 1a–1j were studied in the reaction
3u
3v
3w
20 with trans-nitrostyrene 2a (Table 3). Aziridines bearing electron-
withdrawing substituents on the benzene ring of R3 seemed to be
favored over those with electron-donating groups (entries 1-3),
while a reversed electronic effect was observed in the case of R4
(entries 5-8). Notably, when R4 was 2-furyl, the reaction still
25 proceeded uneventfully to give the desired product in good yield
(entry 9). The tolerance of heterocyclic structures like furans
aReaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), Cu(OAc)2·H2O
(0.025 mmol), DMSO (2 mL), under air. bYield of the isolated product.
40
A probable mechanism for the present cascade reaction was
shown in Scheme 1. Under the thermal conditions,9f
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

View Article Online
DOI: 10.1039/C3OB42324G
Page 3 of 6
Organic & Biomolecular Chemistry
regioselective C-C bond cleavage of aziridine 1a would form a
key azomethine ylide A (this process might be facilitated by the
reference methods.15
General procedure for the preparation of pyrrole derivatives
3a−w
presence of Cu(II) salts), which has previously been presumed to
be generated from α-diazoketones and benzylamine under Cu(I)
catalysis.12a A would then regioselectively react with trans-
nitrostyrene 2a to produce the pyrrolidine B via a copper-
catalyzed [3 + 2] annulation process.14 After elimination of HNO2
and a dehydrogenative aromatization process, the polysubstituted
pyrrole 3a was obtained. The significantly lower yield obtained
10 when the reaction was performed under argon atmosphere (Table
1, entry 15) suggests that the oxygen in air should be crucial for
the dehydrogenative aromatization process.
50 A solution of aziridine 1 (0.5 mmol), β-nitroalkenes 2 (0.5 mmol)
5
and Cu(OAc)2·H2O (0.025 mmol) in DMSO (5 mL) was stirred
o
under air at 110 C for 18 h. After being cooled down to room
temperature, the mixture was diluted with ethyl acetate (20 mL),
washed with saturated NaCl solution (10 mL) and dried over
55 anhydrous Na2SO4. The solvent was rotaevaporated and the crude
product was purified by silica gel column chromatography with
hexane-EtOAc (10:1, v/v).
(3,5-Diphenyl-1H-pyrrol-2-yl)(phenyl)methanone(3a).12a
o
1
Cu(II)
O
Cu(II)
O
NO2
H
N
Yellow solid (116.4 mg, 72%); M.p. 162-163 C; H NMR (300
60 MHz, CDCl3) δ 10.09 (s, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.50 –
7.35 (m, 5H), 7.28 – 7.21 (m, 1H), 7.05 – 6.95 (s, 7H), 6.70 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 187.0, 138.0, 137.5, 135.4,
131.2, 130.8, 129.7, 129.4, 129.0, 128.3, 128.0, 127.7, 127.5,
126.6, 125.2, 110.4; IR (KBr) 3292, 3066, 1601, 1568, 1452,
65 1290 cm-1; HRMS: m/z calcd for ([C23H17NO + H]+): 324.1383;
found: 324.1383.
O
Ph
Cu(II)
-H+
2a
H
H
N
N
Ph
Ph
[3+2]-annulation
+H+
Ph
Ph
1a
Ph
Ph
A
A'
H2O
O
H
O
H
O
H
N
N
O2
N
Ph
O2N
Ph
Ph
-HNO2
Ph
Ph
Ph
Ph
Ph
Ph
C
B
3a
Scheme 1 Possible mechanism for the [3+2] annulation.
(3-(2-Methoxyphenyl)-5-phenyl-1H-pyrrol-2-yl)(phenyl)
methanone (3b). Yellow solid (144.9 mg, 82%); M.p. 171 – 172
15 Conclusions
1
oC; H NMR (300 MHz, CDCl3) δ 10.09 (s, 1H), 7.70 (d, J = 7.1
In summary, we have developed an efficient approach to
polysubstituted pyrroles via copper acetate-catalyzed cascade
reactions of aziridines wtih β-nitroalkenes under aerobic
conditions. The cascade process was proposed to involve a
20 regioselective C-C bond cleavage of aziridines to give an
azomethine ylide, which would undergo [3+2] cycloaddition
with β-nitroalkenes. The easy availability of the starting materials,
simple operation and broad substrate scope may make this
method practically useful for the synthesis of pyrroles for
25 applications to organic synthesis and related fields.
70 Hz, 2H), 7.58 – 7.14 (m, 7H), 7.13 – 6.95 (m, 3H), 6.92 – 6.75 (m,
1H), 6.65 (s, 1H), 6.41 (d, J = 8.0 Hz, 1H), 3.36 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ 187.2, 155.8, 138.1, 137.5, 131.0,
130.9, 130.8, 129.8, 128.8, 128.7, 128.6, 127.8, 126.9, 125.2,
125.0, 120.2, 110.8, 109.7, 54.6; IR (KBr) 3288, 1609, 1427,
75 1275, 1248, 907, 750, 733 cm-1; HRMS: m/z calcd for
([C24H19NO2 + H]+): 354.1489; found: 354.1486.
(3-(4-Methoxyphenyl)-5-phenyl-1H-pyrrol-2-yl)(phenyl)
methanone (3c).12a Yellow solid (137.8 mg, 78%); M.p. 208 –
209 oC; 1H NMR (300 MHz, CDCl3) δ 10.12 (s, 1H), 7.71 (d, J =
80 7.1 Hz, 2H), 7.57 – 7.20 (m, 6H), 7.18 – 6.94 (m, 4H), 6.75 –
6.47 (m, 3H), 3.72 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 186.9,
158.5, 138.1, 137.4, 135.2, 131.1, 130.8, 130.7, 129.3, 129.0,
128.2, 127.8, 127.5, 125.1, 113.2, 110.2, 55.2; IR (KBr) 3311,
1597, 1523, 1427, 1275, 908, 737 cm-1; HRMS: m/z calcd for
85 ([C24H19NO2 + H]+): 354.1489; found: 354.1489.
Acknowledgements
This work was supported by the Natural Science Foundation of
Anhui Province (1308085QB25), the Research Fund for the
Doctoral Program of Wannan Medical College, the Science
30 Foundation for Post-doctoral Scientists of Anhui Province, and
the National Natural Science Foundation of China (21372010,
21072004, 21202001).
(3-(2-Nitrophenyl)-5-phenyl-1H-pyrrol-2-yl)(phenyl)
methanone (3d). Yellow solid (136.3 mg, 74%); M.p. 223 – 224
1
oC; H NMR (300 MHz, CDCl3) δ 10.18 (s, 1H), 7.80 – 7.62 (m,
3H), 7.55 (d, J = 7.2 Hz, 2H), 7.48 – 7.31 (m, 3H), 7.30 – 7.13 (m,
90 6H), 7.13 – 6.94 (m, 3H), 6.56 (s, 1H). 13C NMR (75 MHz,
CDCl3) δ 186.2, 149.0, 138.0, 137.7, 133.5, 131.5, 131.2, 130.4,
130.3, 129.6, 129.1, 128.7, 128.7, 128.5, 127.9, 127.6, 125.2,
123.7, 109.9; IR (KBr) 3302, 1593, 1435, 1300, 1238, 824, 694
cm-1; HRMS: m/z calcd for ([C23H16N2O3 + H]+): 369.1234;
95 found: 369.1233.
Experimental
General methods
35 Flash column chromatography was performed using silica gel
(200–400 mesh). For thin-layer chromatography (TLC), silica gel
plates (HSGF 254) were used and compounds were visualized by
irradiation with UV light. H NMR (300 MHz) and 13C NMR (75
1
(3-(2-Chlorophenyl)-5-phenyl-1H-pyrrol-2-yl)(phenyl)
methanone (3e).12a Yellow solid (130.6 mg, 73%); M.p. 235 –
236 oC; 1H NMR (300 MHz, CDCl3) δ 10.24 (s, 1H), 7.72 (d, J =
7.1 Hz, 2H), 7.57 – 7.30 (m, 5H), 7.29 – 7.13 (m, 2H), 7.12 - 6.86
100 (m, 5H), 6.70 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 186.8, 138.0,
137.2, 134.7, 133.4, 132.5, 131.4, 131.1, 130.7, 129.1, 129.0,
129.0, 128.9, 128.3, 128.3, 127.2, 126.0, 125.2, 111.2; IR (KBr)
3277, 1585, 1465, 1431, 1298, 766 cm-1; HRMS: m/z calcd for
([C23H16ClNO + H]+): 358.0993; found: 358.0991.
MHz) spectra were recorded at 300 MHz NMR spectrometer in
40 CDCl3. All chemical shifts (δ) are given in ppm relative to TMS
(δ = 0 ppm) as internal standard. Data are reported as follows:
chemical shift, multiplicity, coupling constants and integration.
Melting points were uncorrected. IR spectra were reported in
frequency of absorption (cm-1). High resolution mass spectral
45 (HRMS) data were obtained with an ionization mode of ESI and
a TOF analyzer. The aziridines 1 were synthesized according to
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

View Article Online
Organic & Biomolecular Chemistry
DOI: 10.1039/C3OB42P32a4gGe 4 of 6
(3-(4-Chlorophenyl)-5-phenyl-1H-pyrrol-2-yl)(phenyl)
(t, J = 7.4 Hz, 2H), 7.44 – 7.32 (m, 3H), 7.18 (t, J = 6.9 Hz, 1H),
methanone (3f). White solid (127.0 mg, 71%); M.p. 178 – 179 60 7.12 – 6.94 (m, 7H), 2.17 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
1
oC; H NMR (300 MHz, CDCl3) δ 10.24 (s, 1H), 7.72 (d, J = 7.1
Hz, 2H), 7.57 – 7.30 (m, 5H), 7.29 – 7.13 (m, 2H), 7.12 – 6.86 (m,
5H), 6.70 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 187.0, 138.0,
137.9, 137.2, 133.9, 133.5, 131.5, 130.6, 129.6, 129.2, 129.0,
186.8, 138.1, 135.2, 134.7, 134.4, 131.9, 130.8, 130.7, 128.94,
128.9, 128.0, 127.8, 127.5, 127.2, 126.4, 118.2, 11.1. IR (KBr)
3289, 2962, 1595, 1572, 1450, 1418, 1296, 1230, 736, 694 cm-1;
HRMS: m/z calcd for ([C24H19NO + H]+): 338.1539; found:
5
128.8, 128.4, 128.2, 127.8, 127.6, 126.6, 125.3, 110.2. IR (KBr) 65 338.1539.
3275, 1589, 1571, 1464, 1429, 1273, 762 cm-1; HRMS: m/z calcd
for ([C23H16ClNO + H]+): 358.0993; found: 358.0991.
(3-(4-Methoxyphenyl)-4-methyl-5-phenyl-1H-pyrrol-2-yl)
(phenyl)methanone (3m). Yellow solid (82.7 mg, 45%); M.p.
220 – 221 oC; 1H NMR (300 MHz, CDCl3) δ 9.60 (s, 1H), 7.71 –
7.57 (m, 2H), 7.55 – 7.43 (m, 2H), 7.44 – 7.33 (m, 3H), 7.20 (t, J
10
(3-(3,4-Dichlorophenyl)-5-phenyl-1H-pyrrol-2-yl)(phenyl)
methanone (3g). White solid (133.4 mg, 68%); M.p. 207 – 208
1
oC; H NMR (300 MHz, CDCl3) δ 10.25 (s, 1H), 7.71 (d, J = 7.1 70 = 7.4 Hz, 1H), 7.12 – 6.99 (m, 2H), 6.99 – 6.88 (m, 2H), 6.70 –
Hz, 2H), 7.61 – 7.29 (m, 6H), 7.23 – 7.03 (m, 4H), 6.90 (d, J =
6.56 (m, 2H), 3.72 (s, 3H), 2.17 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 186.8, 158.2, 138.2, 135.4, 134.2, 131.9, 131.8, 130.6,
129, 128.8, 127.9, 127.5, 127.2, 127.0, 118.1, 113.0, 55.2, 11.2.
IR (KBr) 3311, 2961, 1597, 1523, 1427, 1275, 908, 737, 694 cm-1;
8.1 Hz, 1H), 6.67 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 186.6,
15 137.9, 137.7, 135.4, 132.5, 131.6, 131.3, 130.7, 130.4, 129.5,
129.2, 129.1, 128.8, 128.6, 128.1, 127.8, 125.2, 110.1. IR (KBr)
3302, 1589, 1574, 1462, 1427, 1273, 812, 762 cm-1; HRMS: m/z 75 HRMS: m/z calcd for ([C25H21NO2 + H]+): 368.1645; found:
calcd for ([C23H15Cl2NO + H]+): 392.0603; found: 392.0603.
(3-(2-Bromophenyl)-5-phenyl-1H-pyrrol-2-yl)(phenyl)
20 methanone (3h). Yellow solid (140.8 mg, 70%); M.p. 234 – 235
368.1644.
(3-(4-Chlorophenyl)-4-methyl-5-phenyl-1H-pyrrol-2-yl)
(phenyl)methanone (3n). White solid (96.7 mg, 52%); M.p. 248
– 249 oC; 1H NMR (300 MHz, CDCl3) δ 9.61 (s, 1H), 7.67 – 7.56
1
oC; H NMR (300 MHz, CDCl3) δ 9.61 (s, 1H), 7.67 – 7.56 (m,
2H), 7.56 – 7.46 (m, 2H), 7.45 – 7.33 (m, 3H), 7.31 – 7.21 (m, 80 (m, 2H), 7.56 – 7.46 (m, 2H), 7.45 – 7.33 (m, 3H), 7.31 – 7.21 (m,
1H), 7.12 – 7.00 (m, 4H), 6.99 – 6.91 (m, 2H), 2.15 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ 186.8, 138.0, 137.1, 136.6, 133.2,
25 132.6, 132.4, 131.1, 130.7, 129.1, 129.0, 128.5, 128.3, 127.2,
126.6, 125.2, 124.0, 111.3. IR (KBr) 3310, 1601, 1571, 1464,
1H), 7.12 – 7.00 (m, 4H), 6.99 – 6.91 (m, 2H), 2.15 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ 186.6, 138.0, 135.4, 133.2, 133.0,
132.5, 131.9, 131.7, 130.9, 128.9, 128.1, 127.8, 127.7, 127.5,
127.4, 118.1, 11.1. IR (KBr) 3307, 2962, 1591, 1571, 1470, 1435,
1427, 1277, 760 cm-1; HRMS: m/z calcd for ([C23H16BrNO + 85 1294, 1277, 762 cm-1; HRMS: m/z calcd for ([C24H18ClNO +
H]+): 402.0488; found: 402.0487.
H]+): 372.1150; found: 372.1149.
(3-(Furan-2-yl)-5-phenyl-1H-pyrrol-2-yl)(phenyl)
30 methanone (3i).12a Yellow solid (103.4 mg, 66%); M.p. 175 –
176 C; H NMR (300 MHz, CDCl3) δ 9.87 (s, 1H), 7.82 – 7.56
(5-(4-Methoxyphenyl)-3-phenyl-1H-pyrrol-2-yl)(phenyl)
methanone (3o). Yellow solid (130.8 mg, 74%); M.p. 96 – 97 oC;
1H NMR (300 MHz, CDCl3) δ 10.71 (s, 1H), 7.75 (d, J = 6.9 Hz,
o
1
(m, 4H), 7.54 – 7.28 (m, 6H), 7.13 (s, 1H), 6.86 (s, 1H), 6.23 (s, 90 1H), 7.51 (d, J = 6.8 Hz, 2H), 7.40 - 7.20(m, 2H), 7.19 – 6.97 (m,
2H). 13C NMR (75 MHz, CDCl3) δ 186.5, 148.6, 141.6, 138.8,
137.6, 131.5, 130.6, 129.0, 128.8, 128.3, 128.1, 127.3, 125.2,
35 123.9, 111.2, 109.1, 108.6. IR (KBr) 3290, 1593, 1570, 1452,
1423, 1288, 813, 735, 696 cm-1; HRMS: m/z calcd for
([C21H15NO2 + H]+): 314.1176; found: 314.1175.
8H), 6.77 (s, 1H), 4.04 (s, 3H). 13C NMR (75 MHz, CD2Cl2) δ
186.3, 156.0, 138.4, 135.5, 134.9, 134.1, 131.0, 129.6, 129.2,
129.1, 127.7, 127.6, 127.5, 126.9, 126.5, 121.4, 118.8, 111.7,
110.6, 55.8. IR (KBr) 3290, 1605, 1576, 1550, 1460, 1431, 1294,
95 1274, 750, 694 cm-1. ; HRMS: m/z calcd for ([C24H19NO2 + H]+):
354.1489; found: 354.1489.
(5-(4-Chlorophenyl)-3-phenyl-1H-pyrrol-2-yl)(phenyl)
methanone (3p).12a White solid (144.9 mg, 81%); M.p. 237 –
238 oC; 1H NMR (300 MHz, CDCl3) δ 10.29 (s, 1H), 7.78 – 7.57
Phenyl(5-phenyl-3-propyl-1H-pyrrol-2-yl)methanone (3j).
1
Yellow solid (68.0 mg, 47%); M.p. 134 – 135 oC; H NMR (300
40 MHz, CDCl3) δ 9.60 (s, 1H), 7.83 – 7.19 (m, 10H), 6.51 (s, 1H),
2.35 (t, J = 7.3 Hz, 2H), 1.62 – 1.36 (m, 2H), 0.77 (t, J = 6.9 Hz,
3H). 13C NMR (75 MHz, CDCl3) δ 186.6, 140.1, 137.5, 136.2, 100 (m, 2H), 7.56 – 7.31 (m, 3H), 7.31 – 7.18 (m, 1H), 7.17 – 6.92 (m,
131.1, 130.9, 129.0, 128.8, 128.3, 128.1, 128.1, 125.0, 110.0,
29.5, 24.1, 13.9. IR (KBr) 3302, 2953, 1589, 1468, 1435, 1298,
45 1277, 762 cm-1; HRMS: m/z calcd for ([C23H17NO + H]+):
324.1383; found: 324.1383.
6H), 6.68 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 186.9, 158.5,
138.1, 137.4, 135.2, 131.1, 130.8, 130.7, 129.3, 129.0, 128.2,
127.8, 127.5, 125.1, 113.2, 110.2, 55.2. IR (KBr) 3279, 1591,
1466, 1416, 1296, 1275, 933, 764, 739 cm-1; HRMS: m/z calcd
105 for ([C23H16ClNO + H]+): 358.0993; found: 358.0993.
(3-Isopropyl-5-phenyl-1H-pyrrol-2-yl)(phenyl)methanone
o
1
(3k). White solid (73.8 mg, 51%); M.p. 180 – 181 C; H NMR
(300 MHz, CDCl3) δ 9.44 (s, 1H), 7.71 (d, J = 7.0 Hz, 2H), 7.66 –
50 7.19 (m, 8H), 6.58 (s, 1H), 3.07 – 2.74 (m, 1H), 1.14 (d, J = 6.5
Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 186.5, 143.2, 140.2, 137.5,
(5-(2,4-Dichlorophenyl)-3-phenyl-1H-pyrrol-2-yl)(phenyl)
methanone (3q). White solid (162.8 mg, 83%); M.p. 229 – 230
1
oC; H NMR (300 MHz, CDCl3) δ 10.15 (s, 1H), 7.61 (d, J = 8.3
Hz, 1H), 7.56 – 7.42 (m, 2H), 7.39 – 7.19 (m, 2H), 7.18 – 6.95 (m,
131.2, 130.9, 129.0, 128.3, 128.1, 128.1, 127.7, 125.0, 107.0, 110 6H), 6.76 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 186.9, 137.6,
25.6, 24.2. IR (KBr) 3307, 2963, 1591, 1571, 1470, 1454, 1435,
1294, 1277, 762 cm-1; HRMS: m/z calcd for ([C20H19NO + H]+):
55 290.1539; found: 290.1538.
135.0, 134.4, 133.9, 133.0, 131.8, 131.5, 130.8, 130.6, 129.7,
129.3, 128.1, 128.0, 127.8, 127.6, 126.8, 113.7. IR (KBr) 3301,
1589, 1575, 1462, 1427, 1275, 812, 762 cm-1; HRMS: m/z calcd
for ([C23H15Cl2NO + H]+): 392.0603; found: 392.0602.
(4-Methyl-3,5-diphenyl-1H-pyrrol-2-yl)(phenyl)methanone
(3l).12a White solid (69.2 mg, 41%); M.p. 176 – 177 oC; 1H NMR 115 (5-(Naphthalen-1-yl)-3-phenyl-1H-pyrrol-2-yl)(phenyl)
(300 MHz, CDCl3) δ 9.67 (s, 1H), 7.62 (d, J = 7.7 Hz, 2H), 7.49
methanone (3r). Yellow solid (149.4 mg, 80%); M.p. 181 – 182
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

View Article Online
DOI: 10.1039/C3OB42324G
Page 5 of 6
Organic & Biomolecular Chemistry
1
oC; H NMR (300 MHz, CDCl3) δ 9.84 (s, 1H), 8.37 (d, J = 4.6
Hz, 1H), 8.04 – 7.82 (m, 2H), 7.78 – 7.64 (m, 1H), 7.63 – 7.42 (m,
5H), 7.26 (s, 1H), 7.20 – 6.94 (m, 7H), 6.71 (s, 1H). 13C NMR
(75 MHz, CDCl3) δ 186.9, 137.9, 136.5, 135.4, 134.6, 133.9,
131.2, 131.1, 129.8, 129.5, 129.4, 129.0, 128.5, 127.8, 127.7,
127.4, 127.0, 126.8, 126.6, 126.2, 125.4, 113.9. IR (KBr) 3306,
1591, 1572, 1429, 1277, 908, 760 cm-1; HRMS: m/z calcd for
([C27H19NO + H]+): 374.1539; found: 374.1538.
Notes and references
†Department of Chemistry, Wannan Medical College, Wuhu, Anhui
60 241002, P. R. China. ‡ Key Laboratory of Functional Molecular Solids,
Ministry of Education, Anhui Laboratory of Molecule-Based Materials,
Institute of Organic Chemistry, School of Chemistry and Materials
Science, Anhui Normal University, Wuhu, Anhui 241000, P. R. China.
§State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
65 Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P.
R. China E-mail: swwang@mail.ahnu.edu.cn;
5
(3,5-Diphenyl-1H-pyrrol-2-yl)(4-methoxyphenyl)
chaizhuo@mail.ahnu.edu.cn
10 methanone (3s).12a Yellow solid (129.0 mg, 73%); M.p. 189 –
190 oC; 1H NMR (300 MHz, CDCl3) δ 10.09 (s, 1H), 7.70 (d, J =
7.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.44 (t, J = 7.0 Hz, 2H),
7.38 – 7.30 (m, 1H), 7.22 – 7.01 (m, 5H), 6.71 (s, 1H), 6.56 (d, J
= 8.0 Hz, 2H), 3.73 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 185.9,
15 162.2, 137.0, 135.6, 134.5, 131.8, 130.9, 130.4, 129.6, 129.0,
128.1, 127.8, 126.5, 125.1, 112.8, 110.1, 55.3. IR (KBr) 3217,
1604, 1582, 1566, 1429, 1254, 910, 764 cm-1; HRMS: m/z calcd
for ([C24H19NO2 + H]+): 354.1489; found: 354.1489.
†Electronic Supplementary Information (ESI) available: Detailed
experimental procedures, characterization data, copies of 1H and 13C
70 NMR spectra for 3a–3w. See DOI: 10.1039/b000000x/
1
Recent reviews: (a) B. B. Lohray and V. Lohray, Pure Appl. Chem.,
2005, 77, 179-184; (b) J. Huffman, Cannabimimetic Indoles,
Pyrroles, and Indenes: Structure–Activity Relationships and Receptor
Interactions. In The Cannabinoid Receptors, P. Reggio, Ed. Humana
Press: 2009, 49-94; (c) M. Fujita, Y. Nakao, S. Matsunaga, M. Seiki,
Y. Itoh, J. Yamashita, R. W. M. van Soest and Fusetani, N. J. Am.
Chem. Soc., 2003, 125, 15700-15701; (d) A. Grube and M. Köck,
Org. Lett., 2006, 8, 4675-4678; (e) H. Fan, J. Peng, M. T. Hamann
and J.-F. Hu, Chem. Rev., 2008, 108, 264-287; (f) P. Novák, K.
Müller, K. S. V. Santhanam and O. Haas, Chem. Rev., 1997, 97, 207-
282; (g) S. Gabriel, M. Cécius, K. Fleury-Frenette, D. Cossement, M.
Hecq, N. Ruth, R. Jérôme and C. Jérôme, Chem. Mater., 2007, 19,
2364-2371.
75
80
Biphenyl-4-yl(3,5-diphenyl-1H-pyrrol-2-yl)methanone (3t).
20 Yellow solid (159.8 mg, 80%); M.p. 205 – 206 oC; 1H NMR (300
MHz, CDCl3) δ 10.05 (s, 1H), 7.72 (d, J = 7.2 Hz, 2H), 7.54 (d, J
= 7.8 Hz, 2H), 7.51 – 7.32 (m, 8H), 7.31 – 7.21 (m, 2H), 7.20 –
6.97 (m, 5H), 6.72 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 186.6,
143.8, 140.4, 137.8, 136.8, 135.5, 130.8, 130.0, 129.7, 129.0,
25 128.7, 128.3, 128.2, 127.7, 127.7, 127.1, 126.5, 126.1, 125.3,
110.3. IR (KBr) 3292, 1600, 1569, 1452, 1290, 910, 731 cm-1;
HRMS: m/z calcd for ([C29H21NO + H]+): 400.1696; found:
400.1696.
(3,5-Diphenyl-1H-pyrrol-2-yl)(4-fluorophenyl)methanone
30 (3u). White solid (105.8 mg, 62%); M.p. 181 – 182 oC; 1H NMR
(300 MHz, CDCl3) δ 10.29 (s, 1H), 7.72 (d, J = 6.9 Hz, 2H), 7.63
– 7.30 (m, 5H), 7.22 – 7.00 (m, 5H), 6.88 – 6.63 (m, 3H). 13C
NMR (75 MHz, CDCl3) δ 185.5, 164.5 (d, JC-F = 250.5 Hz),
137.9, 135.5, 135.3, 134.2, 131.9 (JC-F = 9.0 Hz) 130.7, 129.7,
35 129.0, 128.3, 127.9, 127.8, 126.8, 125.3, 114.5 (d, JCF = 21.7 Hz),
110.4. IR (KBr) 3273, 1599, 1582, 1462, 1433, 1294, 1273, 1225,
910, 761 cm-1; HRMS: m/z calcd for ([C23H16FNO + H]+):
342.1289; found: 342.1288.
2
R. B. Thompson, The FASEB Journal, 2001, 15, 1671-1676.
85 3 A. Hantzsch, Ber., 1890, 23, 1474-1476.
4
(a) L. Knorr, Ber., 1884, 17, 1635-1642; (b) C. Paal, Ber., 1885, 18,
367-371; (c) B. M. Trost and G. A. Doherty, J. Am. Chem. Soc., 2000,
122, 3801-3810.
5
(a) D. J. St. Cyr and B. A. Arndtsen, J. Am. Chem. Soc., 2007, 129,
12366-12367; (b) Y.-L. Zhao, C.-H. Di, S.-D. Liu, J. Meng and Q.
Liu, Adv. Synth. Catal., 2012, 354, 3545-3550; (c) C.-Q. Ren, C.-H.
Di, Y.-L. Zhao and J.-P. Zhang, Tetrahedron Lett., 2013, 54, 1478-
1481.
90
95
6
(a) A. V. Gulevich, A. S. Dudnik, N. Chernyak and V. Gevorgyan,
Chem. Rev., 2013, 113, 3084-3213; (b) T. Miura, K. Hiraga, T.
Biyajima, T. Nakamuro and M. Murakami, Org. Lett., 2013, 15,
3298-3301; (c) D. R. Magar, Y.-J. Ke and K. Chen, Asian J. Org.
Chem., 2013, 2, 330-335; (d) K. Iida, T. Miura, J. Ando, S. Saito,
Org. Lett., 2013, 15, 1436-1439; (e) R. J. Billedeau, K. R. Klein, D.
Kaplan and Y. Lou, Org. Lett., 2013, 15, 1421-1423.
100
105
110
115
120
125
7
8
(a) H. M. I. Osborn and J. Sweeney, Tetrahedron: Asymmetry, 1997,
8, 1693-1715; (b) X. E. Hu, Tetrahedron, 2004, 60, 2701-2743; (c) J.
B. Sweeney, Chem. Soc. Rev., 2002, 31, 247-258; (d) S. Stankovic,
M. D'Hooghe, S. Catak, H. Eum, M. Waroquier, V. Van Speybroeck,
N. De Kimpe and H.-J. Ha, Chem. Soc. Rev., 2012, 41, 643-665.
(a) I. D. G. Watson, L. Yu and A. K.Yudin, Acc. Chem. Res., 2006,
39, 194-206; (b) J.-O. Baeg, C. Bensimon and H. Alper, J. Am. Chem.
Soc., 1995, 117, 4700-4701; (c) I. Ungureanu, P. Klotz and A. Mann,
Angew. Chem. Int. Ed., 2000, 39, 4615-4617; (d) T. Munegumi, I.
Azumaya, T. Kato, H. Masu and S. Saito, Org. Lett., 2006, 8, 379-
382; (e) P. A. Wender and D. Strand, J. Am. Chem. Soc., 2009, 131,
7528-7529.
(4-Bromophenyl)(3,5-diphenyl-1H-pyrrol-2-yl)methanone
40 (3v).12a Yellow solid (112.6 mg, 56%); M.p. 220 – 221 C; H
NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 7.73 (d, J = 6.8 Hz,
2H), 7.53 – 7.28 (m, 5H), 7.24 – 6.99 (m, 7H), 6.70 (s, 1H). 13C
NMR (75 MHz, CDCl3) δ 185.6, 138.0, 136.8, 135.7, 135.1,
130.0, 130.6, 129.6, 129.1, 128.4, 127.8, 126.9, 125.9, 125.2,
45 110.5. IR (KBr) 3277, 1585, 1464, 1431, 1292, 1273, 908, 760
cm-1; HRMS: m/z calcd for ([C23H16BrNO + H]+): 402.0488;
found: 402.0487.
o
1
9
(a) H. W. Heine and R. Peavy, Tetrahedron Lett., 1965, 6, 3123-3126;
(b) A. Padwa and L. Hamilton, Tetrahedron Lett., 1965, 6, 4363-
4367; (c) R. Huisgen, W. Scheer, G. Szeimies and H. Huber,
Tetrahedron Lett., 1966, 7, 397-404; (d) R. Huisgen, W. Scheer and
H. Huber, J. Am. Chem. Soc., 1967, 89, 1753-1755; (e) F. Texier, R.
Carrie and J. Jaz, J. Chem. Soc., Chem. Comm., 1972, 199-200; (f) T.
Schirmeister, Liebigs Ann. / Recueil, 1997, 1895-1899; (g) O. A.
Attanasi, P. Davoli, G. Favi, P. Filippone, A. Forni, G. Moscatelli
and F. Prati, Org. Lett., 2007, 9, 3461-3464; (h) A. S. Pankova, V. V.
Voronin and M. A. Kuznetsov, Tetrahedron Lett., 2009, 50, 5990-
5993.
(3,5-Diphenyl-1H-pyrrol-2-yl)(furan-2-yl)methanone (3w).
Yellow solid (109.7 mg, 70%); M.p. 176 – 177 oC; 1H NMR (300
50 MHz, CDCl3) δ 10.03 (s, 1H), 7.79 – 7.59 (m, 2H), 7.57 – 7.17
(m, 9H), 6.85 (s, 1H), 6.71 (s, 1H), 6.32 (s, 1H). 13C NMR (75
MHz, CDCl3) δ 172.1, 152.1, 145.3, 137.2, 136.0, 135.1, 130.8,
129.2, 129.1, 128.2, 128.0, 127.2, 126.9, 125.1, 118.6, 111.9,
110.6. IR (KBr) 3306, 1603, 1572, 1452, 1427, 1275, 907, 760
55 cm-1; HRMS: m/z calcd for ([C21H15NO2 + H]+): 314.1176; found:
314.1176.
10 (a) M. Vaultier and R. Carrié, Tetrahedron Lett., 1978, 19, 1195-
1198; (b) P. D. Pohlhaus, R. K. Bowman and J. S. Johnson, J. Am.
Chem. Soc., 2004, 126, 2294-2295; (c) X. Wu, L. Li and J. Zhang,
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

View Article Online
Organic & Biomolecular Chemistry
DOI: 10.1039/C3OB42P32a4gGe 6 of 6
Chem. Commun., 2011, 47, 7824-7826; (d) S. Wang, Y. Zhu, Y.
Wang and P. Lu, Org. Lett., 2009, 11, 2615-2618.
11 A. Paasche, M. Arnone, R. F. Fink, T. Schirmeister and B. Engels, J.
Org. Chem., 2009, 74, 5244-5249.
5 12 (a) D. Hong, Y. Zhu, Y. Li, X. Lin, P. Lu and Y. Wang, Org. Lett.,
2011, 13, 4668-4671. (b) S. Wang, Z. Chai, S. Zhou, X. Zhu and Y.
Wei, Org. Lett., 2013, 15, 2628-2631.
13 For selected examples using nitroalkenes for the synthesis of pyrroles:
(a) D. H. R. Barton, S. Z. Zard, J. Chem. Soc., Chem. Comm., 1985,
10
1098-1100; (b) A. W. Trautwein and G. Jung, Tetrahedron Lett.,
1998, 39, 8263-8266; (c) N. Ono and K. Maruyama, Bull. Chem. Soc.
Jpn., 1988, 61, 4470-4472.
14 As suggested by previous studies, under the catalysis of a metal salt,
this [3+2]-annulation is probably a stepwise process initiating with
the Michael addition of azomethine ylide A to nitroalkene followed
by an intramolecular nitro-Mannich-type addition (unfortunately, we
failed to isolate the Michael addition intermediate in our system): (a)
X.-X, Yan, Q. Peng, Y. Zhang, K. Zhang, W. Hong, X.-L. Hou and
Y.-D. Wu, Angew. Chem. Int. Ed., 2006, 45, 1979-1983. (b) S.
Vivanco, B. Lecea, A. Arrieta, P. Prieto, I. Morao, A. Linden and F.
P. Cossío, J. Am. Chem. Soc., 2000, 122, 6078-6092. (c) M. Ayerbe,
A. Arrieta and F. P. Cossío, J. Org. Chem., 1998, 63, 1795-1805. The
presence of electron-withdawing substituents on the R3 group of
aziridines 1 was favored (Table 3, entries 1-3) probably due to that it
might weaken the C-C bond of the aziridine ring and thus would
facilitate the formation of the key azomethine ylide A. Elucidation of
the detailed mechanism of the present reaction still requires further
studies.
15
20
25
30
15 A. Armstrong, C. A. Baxter, S. G. Lamont, A. R. Pape, R. Wincewicz,
Org. Lett. 2007, 9, 351-353.
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]