An efficient synthesis of substituted pyrroles with the aid of a low-valent titanium reagent

Article abstract of DOI:10.1055/s-2004-831295

A short and efficient synthesis of substituted pyrroles was accomplished in good yields via the novel coupling cyclization reaction of 1,3-diketones with imines or oximes promoted by TiCl₄/ Zn system.

Full text of DOI:10.1055/s-2004-831295

LETTER
2239
An Efficient Synthesis of Substituted Pyrroles with the Aid of a Low-Valent
Titanium Reagent
Efficient
S
ynthesis
a
of Substitu
q
ted Pyrrolesing Shi,*a–c Chuling Shi,a Xiangshan Wang,a,b Qiya Zhuang,a,b Shujiang Tu,a,b Hongwen Huc
a
b
c
Department of Chemistry, Xuzhou Normal University, Xuzhou 221116, P. R. China
The Key Laboratory of Biotechnology for Medical Plants of Jiangsu Province, Xuzhu 221116, P. R. China
Department of Chemistry, Nanjing University, Nanjing 210093, P. R. China
Fax +86(516)3403164; E-mail: dqshi@263.net
Received 7 June 2004
pounds and are attracting increasing interest in organic
synthesis.12 Many other functional groups can be react-
ed.13 Recently, we have reported the low-valent titanium-
induced intermolecular reductive coupling reaction of
carboxylic derivatives with aromatic ketones,14 the in-
tramolecular reductive coupling reaction of 4,4-dicyano-
1,3-diaryl-1-butanone15 and the cyclodimerization of a,b-
unsaturated ketones.16 In the course of our work on the ap-
plication of low-valent titanium reagents in the prepara-
tion of bioactive heterocyclic compounds, we have
reported the synthesis of quinazolin-4(3H)-ones, quinazo-
lines and imidazo[1,2-c]quinazolines with the aid of low-
valent titanium reagent.17 Here we wish to describe a
method induced by the TiCl4/Zn system for the prepara-
tion of pyrroles using 1,3-diketones, imines and oximes as
the starting materials.
Abstract: A short and efficient synthesis of substituted pyrroles
was accomplished in good yields via the novel coupling cyclization
reaction of 1,3-diketones with imines or oximes promoted by TiCl4/
Zn system.
Key words: pyrrole, low-valent titanium reagent, synthesis
The pyrrole ring constitutes a basic heteroaromatic struc-
ture. It is a vital building block for the construction of por-
phyrins and alkaloids.1 Several substituted pyrroles have
potential as fungicids and bactericides and as active com-
ponents of nonsteroidal anti-inflammatory drugs inhibit-
ing human cyclooxygenase.2 Although there are a number
of potentially useful methods for the synthesis of pyr-
roles,3 the Knorr4 method is a classical method. Recently,
several methods have been developed for the synthesis of
this heterocyclic system, e.g. Ishii et al. have reported the
synthesis of pyrroles via samarium-catalyzed three-com-
ponent coupling reaction of aldehydes, amines and ni-
troalkanes,5 and one-pot synthesis of pyrroles via three-
component condensation of a carbonyl compound, an
amine and a nitroalkene in a molten ammonium salt.6
Ranu et al.7 have also reported the synthesis of pyrroles on
the surface of silica gel and alumina under microwave ir-
radiation. Some one-pot pyrroles synthesis starting from
imines have been reported recently, e.g. Gao et al. have re-
ported the synthesis of substituted pyrroles from alkynes,
imines, carbon monoxide via an organotitanium
intermediate8 or from alkynes, nitriles, imines and titani-
um-imine complexes.9 Lee et al. have reported a one-pot
synthesis of substituted pyrroles from propargylic dithio-
acetals,10 and Katritzky et al. have also reported the
synthesis of 1,2,3-triarylpyrroles from 1-benzylbenzotri-
azoles via [1+2+2] annulation.11 However, these are not
always satisfactory with respect to ease of operation, yield
and general applicability. Therefore, the development of
novel and convenient synthetic methods for the prepara-
tion of pyrrole derivatives still remains as active research
area.
When 1,3-diketone 1 and imine 2 were treated with low-
valent titanium prepared from titanium tetrachloride and
zinc powder in anhydrous THF, the coupling cyclization
products 1,2,3,5-tetrasubstituted pyrroles 318 were ob-
tained in good yields (Scheme 1). The results are summa-
rized in Table 1.
R2
O
O
TiCl4–Zn
THF
R4 N C R3
H
R1
R3
+
R1
R2
N
R4
3
1
2
Scheme 1
From Table 1, it was found that the TiCl4/Zn system could
efficiently promote the reductive cyclization of 1,3-dike-
tone and imine to give pyrroles with different substitution
patterns. In particular, the substituents at N and C-2 on the
newly formed heteroatomic ring can be easily varied by
condensation of aromatic aldehydes with different aro-
matic amines. Unfortunately, when 2,4-pentanedione (3k)
or ethyl acetoacetate (3l) and 2a was treated with TiCl4/Zn
system under the same reaction conditions they failed to
give the desired pyrrole products and only the self-cou-
pling product of imine was obtained. It seems that both, R1
and R2, should be aryl groups; otherwise, the reductive
cross-coupling process could not take place. The inertness
of these two substrates toward TiCl4/Zn system may be
Low-valent titanium reagents have an exceeding high
ability to promote reductive coupling of carbonyl com-
SYNLETT 2004, No. 12, pp 2239–2241
0
1
.1
0
.2
0
0
4
Advanced online publication: 06.08.2004
DOI: 10.1055/s-2004-831295; Art ID: U16104ST
© Georg Thieme Verlag Stuttgart · New York

2240
D. Shi et al.
LETTER
Table 1 The Synthesis of 1,2,3,5-Tetrasubstituted Pyrroles Promot- genation to form radical E. The radical E loses two hydro-
ed by Low-Valent Titanium
gen atoms to form the pyrrole 3.
Product R1
R2
R3
R4
Isolated
yield (%)
Moreover, treatment of dibenzoylmethane 1 and oximes 4
with TiCl4/Zn system in anhydrous THF under the same
reaction conditions, the cross-coupling products 2,3,5-
trisubstituted pyrroles 5 were obtained in moderated
yields (Scheme 3). The results are summarized in Table 2.
3a
3b
3c
3d
3e
3f
C6H5 C6H5
C6H5 C6H5
C6H5 C6H5
C6H5 C6H5
C6H5 C6H5
C6H5 C6H5
C6H5 C6H5
C6H5 C6H5
C6H5 C6H5
C6H5 C6H5
C6H5
C6H5
75
4-CH3C6H4
4-ClC6H4
4-CH3C6H4 70
C6H5
71
80
Ph
O
O
4-CH3OC6H4 C6H5
4-ClC6H4
4-CH3OC6H4 4-CH3C6H4 81
TiCl4–Zn
THF
Ph
Ar
Ar C N OH
H
+
N
Ph
Ph
4-CH3C6H4 79
H
5
1
4
Scheme 3
3g
3h
3i
4-ClC6H4
4-ClC6H4
C6H5
77
75
68
69
0
4-CH3C6H4
4-CH3C6H4
Table 2 The Synthesis of 2,3,5-Trisubstituted Pyrroles Promoted
by Low-Valent Titanium
4-ClC6H4
Product
5a
Ar
Isolated yield (%)
3j
4-CH3OC6H4 4-ClC6H4
3,4-(CH3O)2C6H3
3,4-OCH2OC6H3
2,4-Cl2C6H3
4-BrC6H4
72
69
65
62
3k
3l
CH3
CH3
CH3
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
5b
OC2H5 4-CH3C6H4
0
5c
due to the instability of the possibly formed ketyl interme-
diate resulting from an acetyl.
5d
A plausible mechanistic pathway to pyrrole is illustrated
in Scheme 2, though the details are unclear as yet.
1
The structures 3 and 5 were identified by IR, H NMR,
MS and elemental analysis.19 The structure of 3g was fur-
ther confirmed by X-ray analysis (Figure 1).20
O
O
O
O
Ti(0)
Ph
Ph
Ph
Ph
Coupling
1
A
Ti(0)
Ar2 N CH Ar1
Ar2
N
CH Ar1
2
B
Ti(I)
O
O
O
N
OTi(I)
Ph
Ar2
Ph
CH Ar1
Deoxygenation
Ph
Ph
Ar1
N
Ar2
C
D
Ph
Ph
Ph
Ph
2H
N
N
Ar2
Ar1
Ar2
Ar1
E
3
Scheme 2
Figure 1 ORTEP diagram of 3g
TiCl4 is reduced by Zn dust to give low-valent titanium. In
the initial steps, and electron is transferred from low-va-
lent titanium to 1,3-diketone 1 or imine 2 to give radical
anion A and B, respectively, the two radical anions then
couple to form the carbon-carbon bond and generates in-
termediate C. The latter then takes place by nucleophilic
addition to give the intermediate D, which occurs deoxy-
In summary, a series of 1,2,3,5-tetrasubstituted pyrroles
and 2,3,5-trisubstituted pyrroles were synthesized via
coupling cyclization of 1,3-diketones with imines or
oximes induced by the TiCl4/Zn system. The advantages
of our method are the easily accessible starting materials,
convenient manipulation and moderate to high yields.
Synlett 2004, No. 12, 2239–2241 © Thieme Stuttgart · New York

LETTER
Efficient Synthesis of Substituted Pyrroles
2241
(14) Shi, D. Q.; Chen, J. X.; Chai, W. Y.; Chen, W. X.; Kao, T.
Y. Tetrahedron Lett. 1993, 34, 2963.
(15) Shi, D. Q.; Mu, L. L.; Lu, Z. S.; Dai, G. Y. Synth. Commun.
1997, 27, 4121.
(16) Zhou, L. H.; Shi, D. Q.; Dai, G. Y.; Chen, W. X.
Tetrahedron Lett. 1997, 38, 2729.
Acknowledgment
We are grateful to the Natural Science Foundation of Jiangsu Edu-
cation Department (No. 03KJB150136) and Foundation of the Key
Laboratory of Biotechnology for Medical Plants of Jiangsu Pro-
vince (No. 02AXL13) for financial support.
(17) (a) Shi, D. Q.; Rong, L. C.; Wang, J. X.; Zhuang, Q. Y.;
Wang, X. S.; Hu, H. W. Tetrahedron Lett. 2003, 44, 3199.
(b) Shi, D. Q.; Wang, J. X.; Shi, C. L.; Rong, L. C.; Zhuang,
Q. Y.; Hu, H. W. Synlett 2004, 1098.
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(18) The general procedure is represented as follows: TiCl4 (1.65
mL, 15 mmol) was added dropwise using a syringe to a
stirred suspension of Zn powder (1.95 g, 30 mmol) in freshly
distilled dry THF (20 mL) at r.t. under a N2 atmosphere. The
mixture was refluxed for 2 h. The suspension of low-valent
titanium reagent formed was cooled to r.t. and a solution of
1,3-diketone(1) (5 mmol) and imine 2 (5 mmol) in THF (5
mL) was added carefully. The reaction mixture was stirred
for 4 h at r.t. On completion of the reaction most of the
solvent was removed in vacuo. The residue was poured into
5% HCl (100 mL) and extracted with CHCl3 (4 × 30mL).
The combined organic layer was washed with H2O (4 × 30
mL), dried (Na2SO4), and the solvent was removed to give
the crude product, which was purified by column
chromatography [silica gel, acetone–petroleum ether (bp
60–90ºC), 1:6] to give pure 3.
(19) Typical data for representative compounds: Compound 3a,
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1600, 1495, 1450, 1370, 1075, 1030, 915, 760, 695 cm–1. 1H
NMR (400 MHz, CDCl3): = 6.71 (1 H, s, C4-H), 6.98–6.99
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C, 90.53; H, 5.70; N, 3.77%. Found: C, 90.56; H, 5.59; N,
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760, 695 cm–1. 1H NMR (400 MHz, CDCl3): d = 3.66 (6 H,
s, 2 × CH3O), 6.47 (1 H, s,C4-H), 6.87–7.40 (13 H, m, ArH),
8.43 (1 H, s, NH). MS: m/z (%) = 355 (100), 340 (22). Anal.
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C, 81.28; H, 5.82; N, 3.85%.
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crystals, 0.54 × 0.50 × 0.50 mm, monoclinic, space group
P21/c, a = 9.952 (2), b = 9.863 (2), c = 23.460 (6) Å,
b = 99.62 (2)°, V = 2270.4 (9) Å3, Z = 4, Dc = 1.288 gcm–3.
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were measured and 2267 reflections with I>2s(I) were used
in the refinement. The structure was solved by direct
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refinement was converged to R = 0.0387 and wR = 0.0793.
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Synlett 2004, No. 12, 2239–2241 © Thieme Stuttgart · New York