A new approach to the preparation of 1,3,4-triarylpyrroles

Article abstract of DOI:10.1055/s-2006-932452

A class of 1,3,4-triaryl-2,5-dihydropyrroles were synthesized using the McMurry coupling reaction as the key step. The non-catalytic photoconversion of 1,3,4-triaryl-2,5-dihydropyrroles furnished 1,3,4-triarylpyrroles in good yields (63-89%). It was found

Full text of DOI:10.1055/s-2006-932452

LETTER
490
A New Approach to the Preparation of 1,3,4-Triarylpyrroles
P
reparation of 1,3,
e4-TriarylpyrrolesXing Zeng, Yi Chen*
Technical Institute of Physics and Chemistry, The Chinese Academy of Sciences, Beijing 100101, P. R. of China
Fax +86(10)64879375; E-mail: yichen@mail.ipc.ac.cn
Received 16 November 2005
1,3,4-Triaryl-2,5-dihydropyrroles 1a–f13 were prepared
according to the synthetic route shown in Scheme 2 by
employing the McMurry coupling reaction as the key
step.
Abstract: A class of 1,3,4-triaryl-2,5-dihydropyrroles were synthe-
sized using the McMurry coupling reaction as the key step. The
non-catalytic photoconversion of 1,3,4-triaryl-2,5-dihydropyrroles
furnished 1,3,4-triarylpyrroles in good yields (63–89%). It was
found that the photoconversion was facile and very reliable; the
solvent was found to play an important role.
R1
R1
O
Key words: 1,3,4-triaryl-2,5-dihydropyrrole, 1,3,4-triarylpyrrole,
photoconversion, McMurry reaction
O
R1
R1
Br
O
Br
O
R2
R3
TiCl4, Zn
THF
N
O
NH2
Synthesis of 1,3,4-trisubstituted pyrroles is an attractive
area in heterocyclic chemistry due to the fact that many
pyrroles are subunits of natural products,1 pharmaceutical
drugs,2 and agrochemicals.3 In particular, 3,4-disubstitut-
ed pyrroles have generated considerable interest owing to
their remarkable diversity of biological activity.4 A num-
ber of these compounds have been shown to possess
antidiabetic, fungicidal, herbicidal, or antibacterial prop-
erties. However, it is also noteworthy that the 3,4-disub-
stituted pyrrole system is probably the most difficult to
obtain: selective substitutions at one or more of the b-po-
sitions are a challenge because of the tendency of this pyr-
role system to undergo aromatic substitution reactions at
the more electronically favorable a-position of the hetero-
cyclic ring. There are many methodologies for the prepa-
ration of 3,4-disubstituted pyrroles: 1) coupling of imines
and nitroalkanes;5 2) Friedel–Crafts acylation with an
electron-withdrawing group on the pyrrole nitrogen;6 3)
from 3,4-silylated precursors;7 4) from Michael acceptors
with tosylmethyl isocyanide (TOSMIC);8 5) by palladi-
um-catalyzed cyclization of amino allenes;9 6) by reduc-
tion of 3-and 4-pyrrolin-2-ones with 9-BBN;10 7) by
multicomponent coupling reactions;11 and 8) many other
methods.12 In this communication, we present a new
approach to the preparation of 1,3,4-triarylpyrroles by
simple non-catalytic photoconversion of 1,3,4-triaryl-2,5-
dihydropyrroles (Scheme 1). It was found that the photo-
conversion was facile and very reliable.
NH
N
R2
R2
R3
R2
1a–1f
R3
Scheme 2
When both substituents R2 and R3 were same, the first two
steps could be combined in one reaction just by changing
the ratio of 2-bromoacetophenone or other 2-bromoace-
tone derivatives and aniline derivatives from 1:1 to 2:1.
The last coupling reaction offered excellent yield whether
the substituents were the same or not (Table 1).
Table 1 1,3,4-Triaryl-2,5-dihydropyrroles 1a–f
Compd R1
R2
R3
Yield (%)
74
1a
1b
1c
1d
H
H
H
H
H
H
H
OMe
Cl
85
66
80
OMe
Me
Me
Me
O
Me
Me
O
1e
1f
OMe
OMe
78
61
N
N
O
Me
O
Me
Me
Me
H
Me
S
R1
N
R1
N
1,3,4-Triarylpyrroles 2a–f14 were produced by simple
non-catalytic photoconversion of 1,3,4-triaryl-2,5-dihy-
dropyrroles 1a–f in solution. Irradiating a solution of 1a in
acetonitrile with UV light (high-pressure Hg lamp, 500
W) produced 2a in an excellent yield of 84%. The chemi-
cal structure of 2a was identified by 1H NMR spectrosco-
py and MS analysis. It was found that the typical signal at
4.57 ppm arising from the 2,5-dihydropyrrole bridging
unit of 1a disappeared and a new signal at low field
hν
R2
R3
R2
R3
2
1
Scheme 1
SYNLETT 2006, No. 3, pp 0490–0492
Advanced online publication: 06.02.2006
DOI: 10.1055/s-2006-932452; Art ID: W09005ST
© Georg Thieme Verlag Stuttgart · New York
1
5.
0
2.
2
0
0
6

LETTER
Preparation of 1,3,4-Triarylpyrroles
491
1
appeared in the H NMR spectrum of 2a, which corre-
sponded to protons on the pyrrole ring. Furthermore, the
mass spectra of 1a and 2a showed the relative abundance
of both molecular ion peaks (1a m/z = 297, 2a m/z = 295)
was 100%. In addition to the above evidence, the absorp-
tion maximum band of 2a (lmax = 270 nm, MeCN) was
red shifted by as much as 28 nm compared to that of 1a
(lmax = 242nm, MeCN). Similar results were obtained
when other compounds 1b–f were irradiated with UV
light in acetonitrile, and 1,3,4-triarylpyrroles 2b–f were
obtained in good yields (Tables 2, 63ndash;89%), indicat-
ing that the photoconversion was facile and very reliable.
Acknowledgment
This work was supported by the National Science Foundation of
China (NO 60337020 and NO 60277001).
References and Notes
(1) Amima, R.; Evan, T.; Aknin, N.; Kashman, Y. J. Nat. Prod.
2000, 63, 832.
(2) (a) Unverferth, K.; Engel, J.; Hofgen, N.; Rostock, A.;
Gunther, R.; Lankau, H. J.; Menzer, M.; Rolfs, A.;
Liebscher, L.; Muller, B. J. Med. Chem. 1998, 41, 63.
(b) Dannhardt, G.; Kiefer, W.; Kramer, G.; Maehrlein, S.;
Nowe, U.; Fiebich, B. Eur. J. Med. Chem. 2000, 35, 499.
(3) (a) Jacobi, P. A.; Coults, L. D.; Guo, J. S.; Leung, S. L. J.
Org. Chem. 2000, 65, 205. (b) Boger, D. L.; Boyce, C. W.;
Labrili, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc. 1999,
121, 54.
(4) (a) Holland, G. F. U. Patent 4,282,242, 1981; Chem. Abstr.
1981, 95, 187068e. (b) Koho, K. T. (Nippon Soda Co., Ltd.)
JP 81 79,672, 1981; Chem. Abstr. 1981, 95, 187069f.
(c) Bettarini, F.; Meazza, G.; Castoro, P.; Portoso, D. Patent
PCT Int. Appl. WO 02 70476, 2002; Chem. Abstr. 2002,
137, 232545. (d) Umio, S.; Kariyone, K. JP 68 14,699, 1968;
Chem. Abstr. 1969, 70, 87560z.
(5) Shiraishi, H.; Nishitani, T.; Nishihara, T.; Sakaguchi, S.;
Ishii, Y. Tetrahedron 1999, 55, 13957.
(6) Zelikin, A.; Shastri, V. R.; Langer, R. J. Org. Chem. 1999,
64, 3379.
(7) Liu, J.-H.; Chan, H.-W.; Wong, H. N. J. Org. Chem. 2000,
65, 3274.
(8) (a) Airaksinen, A. J.; Ahlgren, M.; Vepsalainen, J. J. Org.
Chem. 2002, 67, 5019. (b) Smith, N. D.; Huang, D.;
Cosford, N. D. P. Org. Lett. 2002, 4, 3537.
Table 2 1,3,4-Triarylpyrroles 2a–f
Compd R1
R2
R3
Yield (%)
84
2a
2b
2c
2d
H
H
H
H
H
H
H
OMe
Cl
89
63
76
OMe
Me
Me
Me
O
Me
Me
O
2e
2f
OMe
OMe
73
70
N
N
O
Me
O
Me
Me
Me
H
Me
S
(9) Dieter, R. K.; Yu, H. Org. Lett. 2001, 3, 3855.
(10) Verniest, G.; De Kimpe, N. Synlett 2003, 2013.
(11) (a) Balme, G. Angew. Chem. Int. Ed. 2004, 43, 6238.
(b) Dhawan, R.; Arndtsen, B. A. J. Am. Chem. Soc. 2004,
126, 468.
(12) (a) De Kimpe, N.; Tehrani, K. A.; Stevens, C.; De Cooman,
P. Tetrahedron 1997, 53, 3693. (b) Tehuani, K. A.;
Borremans, D.; De Kimpe, N. Tetrahedron 1999, 55, 4133.
(c) Verniest, G.; Claessens, S.; De Kimpe, N. Tetrahedron
2005, 61, 4631. (d) Verniest, G.; Claessens, S.; Bombeke,
F.; Van Thienen, T.; De Kimpe, N. Tetrahedron 2005, 61,
2879. (e) Keppens, M.; De Kimpe, N.; Fonck, G. Synth.
Commun. 1996, 26, 3097.
(13) 1a–f; General Procedure 2-Bromoacetophenone or 2-
bromoacetone derivative (20 mmol), Na2CO3 (20 mmol),
and p-anisidine (10 mmol) or aniline derivatives (10 mmol)
were dissolved in EtOH (95 %; 20 mL). The mixture was
stirred for 0.5 h at ambient temperature followed by heating
to reflux for 4 h. The reaction mixture was cooled and
diluted with H2O. The solid was obtained and purified by
recrystallization from EtOH. To a suspension of Zn powder
(0.3 mol) in THF (350 mL) under nitrogen flux was added
TiCl4 (10 mL) at 0 °C by syringe. The mixture was then
refluxed for 1 h. To the mixture was added the solid (15
mmol) obtained above in THF (250 mL) very slowly at
ambient temperature. The reaction mixture was stirred for
another 24 h in darkness then quenched with K2CO3 (40%;
80 mL). The solid was filtered and washed with Et2O (50
mL). The combined organic phases were concentrated to 50
mL under reduced pressure. H2O (50 mL) was then added to
the residue. The product was extracted with Et2O (50 mL)
and dried over MgSO4. After evaporation of the solvent, the
crude product was purified by flash column
The solvent was found to play an important role in the
photoconversion although the mechanism is not clear.
Solvents such as CHCl3, CH2Cl2, and CH3CN were excel-
lent for the photoconversion. While the photoconversion
could also be accomplished in THF and toluene, longer
irradiation times were required. When hexane or cyclo-
hexane was employed as solvent, the photoconversion
was unsuccessful.
Oxygen also played a role in the photoconversion of
1,3,4-triaryl-2,5-dihydropyrroles to 1,3,4-triarylpyrroles
in solution. It was found that oxygen increased, on the one
hand, the velocity of the photoconversion, resulting in a
shorter reaction time, but on the other hand the yield de-
creased. Take for example 2c, in acetonitrile (1 × 10–4 M)
the reaction took five minutes in the presence of oxygen,
eight minutes in the presence of air, and 12 minutes in the
presence of nitrogen with yields of 51%, 63%, and 70%,
respectively. Other compounds showed similar results.
This suggests that the yield from the photoconversion
could be increased by irradiating in an atmosphere of
nitrogen gas.
In conclusion, a facile and reliable synthetic approach to
the preparation of 1,3,4-triarylpyrroles from 1,3,4-triaryl-
2,5-dihydropyrroles has been developed. The simple pro-
cedure, good yield, and absence of catalyst are advantages
of this reaction.
Synlett 2006, No. 3, 490–492 © Thieme Stuttgart · New York

492
D. X. Zeng, Y. Chen
LETTER
chromatography. For 1f 2-bromoacetonephenone was
treated with p-anisidine first, followed by reaction with 3-
(2,5-dimethyl)-1¢-bromoacetylthiophene. 1a: 1H NMR: d =
7.30–7.19 (m, 12 H), 6.66 (d, 3 H, J = 7.6 Hz), 4.57 (s, 4 H).
MS (EI): m/z = 297 (M+, 100). HRMS: m/z calcd for C22H19N
[M+]: 297.3991; found: 297.4056. 1b: 1H NMR: d = 7.30–
7.27 (m, 10 H), 6.88 (d, 2 H, J = 8.8 Hz), 6.63–6.60 (d, 2 H,
J = 8.9 Hz), 4.54 (s, 4 H), 3.69 (s, 3 H). MS (EI): m/z = 327
(M+, 100). HRMS: m/z calcd for C23H21NO [M+]: 327.4259;
found: 327.6128. 1c: 1H NMR: d = 7.30–7.27 (m, 10 H), 7.22
(d, 2 H, J = 8.2 Hz), 6.67 (d, 2 H, J = 8.8 Hz), 4.57 (s, 4 H).
MS (EI): m/z = 330 (M+ – 1, 99), 138 (100). HRMS: m/z
calcd for C22H18ClN [M+]: 331.8542; found: 332.0014. 1d:
1H NMR: d = 6.92 (d, 2 H, J = 9.0 Hz), 6.57 (d, 2 H, J = 6.0
Hz), 5.87 (s, 2 H), 4.35 (s, 4 H), 3.79 (s, 3 H), 2.24 (s, 6 H),
2.06 (s, 6 H). MS (EI): m/z = 363 (M+, 100). HRMS: m/z
calcd for C23H25NO3 [M+]: 363.5225; found: 363.5249. 1e:
1H NMR: d = 7.93 (d, 4 H, J = 9.0 Hz), 7.28 (d, 4 H, J = 9.0
Hz), 6.93 (d, 2 H, J = 9.0 Hz), 6.68 (d, 2 H, J = 9.0 Hz), 4.64
(s, 4 H), 3.79 (s, 3 H), 2.41 (s, 6 H), 2.06 (s, 6 H). MS (EI):
m/z = 517 (M+, 52), 119 (100). HRMS: m/z calcd for
C33H31N3O3 [M+]: 517.6259; found: 517.6164. 1f: 1H NMR:
d = 7.30–7.25 (m, 5 H), 6.88 (d, 2 H, J = 9.0 Hz), 6.68 (s, 1
H), 6.62 (d, 2 H, J = 9.0 Hz), 4.59 (t, 2 H, J = 4.5 Hz), 4.36
(t, 2 H, J = 4.5 Hz), 3.71 (s, 3 H), 2.41 (s, 3 H), 1.95 (s, 3 H).
MS (EI): m/z = 361 (M+, 100). HRMS: m/z calcd for
(14) 2a–f; General Procedure A solution of 1,3,4-trisubstituted
2,5-dihydropyrroles (0.5 mmol) in CH2Cl2 (100 mL) was
irradiated with UV light (high-pressure Hg lamp, 500 W)
until the starting material was no longer detected by TLC.
After the solvent was evaporated the crude product were
purified by column chromatography (EtOAc–PE). 2a: 1H
NMR: d = 7.71 (d, 2 H, J = 7.7 Hz), 7.53 (d, 2 H, J = 7.4 Hz),
7.48 (s, 2 H), 7.34–7.21 (m, 11 H). MS (EI): m/z = 295 (M+,
100). HRMS: m/z calcd for C22H17N [M+]: 295.3833; found:
295.4122. 2b: 1H NMR: d = 7.57 (d, 2 H, J = 9.0 Hz), 7.32–
7.17 (m, 12 H), 7.05 (d, 2 H, J = 8.8 Hz), 3.81 (s, 3 H). MS
(EI): m/z = 325 (M+, 100). HRMS: m/z calcd for C23H19NO
[M+]: 325.4101; found: 325.4708. 2c: 1H NMR: d = 7.72 (d,
2 H, J = 8.8 Hz), 7.52 (d, 2 H, J = 8.7 Hz), 7.46 (s, 2 H),
7.31–7.20 (m, 8 H). MS (EI): m/z = 329 (M+, 100). HRMS:
m/z calcd for C22H16ClN [M+]: 329.8384; found: 329.9123.
2d: 1H NMR: d = 7.36 (d, 2 H, J = 8.8 Hz), 6.98 (d, 2 H,
J = 9.0 Hz), 6.94 (s, 2 H), 5.86 (s, 2 H), 3.85 (s, 3 H), 2.25 (s,
6 H), 2.18 (s, 3 H). MS (EI): m/z = 361 (M+, 100). HRMS:
m/z calcd for C23H23NO3 [M+]: 361.4387; found: 361.4401.
2e: 1H NMR: d = 7.96 (d, 4 H, J = 9.0 Hz), 7.45 (d, 2 H,
J = 9.0 Hz), 7.32 (s, 2 H), 7.27 (d, 4 H, J = 8.9 Hz), 7.00 (d,
2 H, J = 8.9 Hz), 3.85 (s, 3 H), 2.41 (s, 6 H), 2.12 (s, 6 H).
MS (EI): m/z = 515 (M+, 65), 119 (100). HRMS m/z calcd for
C33H29N3O3 [M+]: 515.6106; found: 515.6164. 2f: 1H NMR:
d = 7.43–7.30 (m, 6 H), 7.25–7.23 (m, 2 H), 7.02–7.00 (m, 3
H), 6.57 (s, 1 H), 3.87 (s, 3 H), 2.45 (s, 3 H), 2.22 (s, 3 H).
MS (EI): m/z = 359 (M+, 100). HRMS: m/z calcd for
C23H23NOS [M+]: 361.5067; found: 361.5095.
C23H21NOS [M+]: 359.4909; found: 359.4972.
Synlett 2006, No. 3, 490–492 © Thieme Stuttgart · New York