The synthesis of polysubstituted pyrroles via the coupling of phenyliodonium ylides and enamine esters

Article abstract of DOI:10.1002/adsc.200900379

The boron trifluoride etherate (BF_--Et₂O)-catalyzed reactions between phenyliodonium ylides and enamine esters provide an efficient method for the synthesis of polysubstituted pyrroles.

Full text of DOI:10.1002/adsc.200900379

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DOI: 10.1002/adsc.200900379
The Synthesis of Polysubstituted Pyrroles via the Coupling of
Phenyliodonium Ylides and Enamine Esters
Jun-Yan Wang,a Xian-Pei Wang,a Zheng-Sen Yu,a and Wei Yua,*
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, Peopleꢀs Republic of China
Fax : (+86)-931-891-2582; e-mail: yuwei@lzu.edu.cn
Received: May 31, 2009; Published online: September 10, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900379.
Abstract:
The
boron
trifluoride
etherate
catalyst, electron-rich olefins such as enamine esters
might also react with iodonium ylides, giving rise to
coupling product A, which could undergo further re-
actions to form pyrroles (Scheme 1). As both enamine
esters and phenyliodonium ylides can be easily ac-
cessed from simple starting materials, it was expected
that this strategy, if successful, would constitute a con-
venient approach for the synthesis of polysubstituted
pyrroles.
ACHTUNGTRENNUNG(BF3·Et2O)-catalyzed reactions between phenylio-
donium ylides and enamine esters provide an effi-
cient method for the synthesis of polysubstituted
pyrroles.
Keywords: coupling reactions; enamine esters; phe-
nyliodonium ylides; pyrroles
Pyrroles constitute an important category of heterocy-
clic ring systems which exist in many naturally occur-
ring products.[1] Many pyrrole-containing compounds
exhibit important biological and pharmaceutical activ-
ities,[2] and are found to be of great utility in materials
sciences.[3] Consequently, great efforts have been
made to find efficient synthetic methodologies to gain
access to pyrroles.[4] While many new synthetic ap-
ACHTUNGTRENNUNGproches toward the pyrrole skeleton have been estab-
lished in recent years,[5] it is still highly desirable to
develop simple, convenient methods for the synthesis
of polysubstituted pyrroles. Herein we wish to report
a new protocol for the synthesis of polysubstituted
pyrroles which employs the coupling reactions be-
tween phenyliodonium ylides and enamine esters.
Phenyliodonium ylides derived from 1,3-dicarbonyl
compounds are useful synthetic imtermediates which
have aroused much attention during the last decade.[6]
Phenyliodonium ylides can be transformed to carbe-
Scheme 1.
To achieve this goal, firstly the reaction conditions
noids by the catalysis of transitional metals such as were explored using iodonium ylide 1a and enamine
À
copper(I) and Rh(II), and subsequently undergo C H ester 2a as the substrates, and the reaction was per-
insertion or addition to alkenes.[7] On the other hand, formed in CH2Cl2. To our delight, we found that, with
the reactions of phenyliodonium ylides under metal- several commonly used acids as the catalysts, the pyr-
free conditions are far less explored. It was reported role product 3aa was formed just as expected
recently that phenyliodonium ylides could be coupled (Table 1). The best result was obtained when
with electron-rich arenes in the presence of Lewis BF3·Et2O was used (Table 1, entry 2). The reaction
acids.[8] Considering the electrophilic character of io- was complete in just 10 min, and the yield of 3aa
donium ylides, we envisioned that by using acids as reached 96%. By comparison, the reaction did not
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Jun-Yan Wang et al.
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Table 1. The reactions between 1a and 2a under various con-
labile chloromethyl group, pyrrole products were ob-
tained as the mixture of 2-chloromethyl-substituted
pyrroles (3fh-1 and 3fm-1) and their 2-hydroxymeth-
yl-substituted counterparts (3fh-2 and 3fm-2)
(Table 3, entries 19 and 20). Products 3fh-2 and 3fm-2
were probably generated as the result of in situ substi-
tution of the chlorine atom by a hydroxy group after
the pyrroles had formed, as 1f was found to be stable
to water. Although the substitution of the chlorine
atom by a hydroxy group could not be avoided under
the reaction conditions, the combined yields of the
pyrrole products were quite high, demonstrating the
mildness of the reaction conditions and the potential
usefulness of the method for the synthesis of complex
pyrrole structures.
In conclusion, a new method employing the cou-
pling reactions of phenyliodonium ylides with enam-
ine esters has been developed for the synthesis of
polysubstituted pyrroles. This method is advantageous
in terms of simplicity and mildness, and hopefully
could find wide application in the synthesis of com-
plex pyrrole-containing compounds.
ditions.[a]
Entry Catalyst
(equiv.)
Reaction Conversion Yield [%][b]
G
time
[%]
of 3aa
1
2
3
4
5
6
7
8
none
2 days
10 min
1 day
10 min
10 min
trace
100
75
100
90
100
84
80
trace
96
60
22
79
71
80
73
BF3·Et2O (0.2)
CSA (0.2)
TfOH (0.2)
Tf2O (0.2)
CF3COOH (0.2) 1 hour
CuCl (0.2)
CuI (0.2)
1 day
1 day
[a]
The reactions were carried out in CH2Cl2 at room tem-
perature.
Isolated yield.
[b]
take place in the absence of catalyst (Table 1, Experimental Section
entry 1). Further experiments showed that the reac-
Phenyliodonium ylides (1)[9] and enamine esters (2)[10] were
prepared according to the reported procedures.
tion proceeded well in several solvents, among which
CH2Cl2 and acetonitrile led to the best results
(Table 2). It is interesting to see that copper(I) salts
could also catalyze the reaction, but the conversion
was not complete even after one day (Table 1, en-
tries 7 and 8).
General Procedure for the Reactions
To a mixture of enamine esters (2) (0.2 mmol) and iodonium
ylides (1) (0.2 mmol) in CH2Cl2, (0.5 mL) was added
BF3·Et2O (0.04 mmol), and the mixture was stirred at the
room temperature under an argon atmosphere. After the re-
action was finished as indicated by TLC, the mixture was
concentrated under reduced pressure, and the residue was
worked-up by flash column chromatography to give product
3.
Table 2. Solvent effects on the reaction between 1a and 2a.[a]
Entry Solvent
Reaction
time
Conversion Yield
[%]
[%][b]
In a typical experiment, to a solution of 41 mg of 2a
(0.2 mmol) in CH2Cl2 (0.5 mL) were added 64 mg of 1a
(0.2 mmol). The suspension was stirred at room temperature
under an argon atmosphere. Then 0.005 mL of BF3·Et2O
(0.04 mmol) were added to the mixture. The reaction was
finished in 10 min. The mixture was concentrated under re-
duced pressure, and the residue was worked-up with flash
column chromatography (petroleum ether/EtOAc: 7/1) to
give 3aa; yield: 58 mg (96%).
[min]
of 3aa
1
2
3
4
5
6
7
CH2Cl2
CHCl3
CH3CN
10
10
10
100
100
100
82
80
100
71
96
92
96
73
68
90
51
CF3CH2OH 240
CH3OH
THF
DMF
240
60
240
[a]
[b]
The reactions were carried out at room temperature.
Isolated yield.
Acknowledgements
The authors thank the National Natural Science Foundation
of China (No. 20772053) for financial support.
This protocol could be used to synthesize a variety
of differently substituted pyrroles, and the yields were
generally high (Table 3). It is noteworthy that when
iodonium ylide 1e was used, pyrroles 3 was obtained
as the single regioisomer (Table 3, entries 15–18). In
the case of iodonium ylide 1f which contains the
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The Synthesis of Polysubstituted Pyrroles via the Coupling of Phenyliodonium Ylides
Table 3. Synthesis of pyrroles from phenyliodonium ylides (1) and enamine esters (2).[a]
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Entry
Iodonium ylides
Enamine ester
Reaction time [min]
Product/Yield [%][c}
1
R1
R2
2
R3
R4
R5
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
1e
1e
1e
1e
1f
1f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
OMe
OMe
OMe
OMe
OEt
OEt
OEt
Me
Me
Me
Me
OEt
OEt
OEt
Ph
Ph
Ph
2a
2b
2c
2d
2e
2f
2g
2b
2g
2h
2i
2h
2j
2l
2d
2h
2j
2l
2h
2m
Me
Me
Me
n-Pr
Ph
Bn
Me
Et
Et
10
10
15
10
240
240
20
30
30
45
20
20
20
30
30
30
35
30
10
10
3aa/96
3ab/95
3ac/96
3ad/96
3be/70
3bf/74
3bg/96
3cb/94
3cg/91
3ch/93
3ci/91
3dh/84
3dj/85
3dl/92
3ed/91
3eh/93
n-Bu
allyl
n-Bu
H
H
Bn
n-Bu
Bn
allyl
Bn
allyl
n-Bu
allyl
n-Bu
allyl
n-Bu
allyl
allyl
Ph
Et
Me
Me
Et
Et
Et
Me
Et
Me
Me
Et
Me
Me
Me
Me
Me
n-Pr
Me
Me
n-Pr
n-Pr
Me
Me
n-Pr
Me
Me
9
10
11
12
13
14
15
16
17
18
19[b]
20[b]
Ph
Ph
Me
Me
Me
Me
ClCH2
ClCH2
Et
Me
Me
Et
Me
Me
3ej/97
3el/89
3fh-1/36; 3fh-2/57
3fm-1/52; 3fm-2/44
Ph
OEt
OEt
[a]
The reactions were carried out at room temperature.
The reactions were carried out at 08C.
Isolated yields.
[b]
[c]
References
trate, F. Gagosz, Org. Lett. 2007, 9, 3181; f) S. Chiba,
Y.-F. Wang, ; G. Lapointe, K. Narasaka, Org. Lett.
2008, 10, 313; g) O. A. Attanasi, G. Favi, P. Filippone,
G. Giorgi, F. Mantellini, G. Moscatelli, D. Spinelli, Org.
Lett. 2008, 10, 1983; h) S. Cacchi, G. Fabrizi, E. Filisti,
Org. Lett. 2008, 10, 2629; i) Y.-F. Wang, Toh, K. K. S.
Chiba, K. Narasaka, Org. Lett. 2008, 10, 5019; j) X.
Liu, L. Huang, F. Zheng, Z. Zhan, Adv. Synth. Catal.
2008, 350, 2778; k) F. A. Davis, V. A. Bowen, H. Xu, V.
Velvadapu, Tetrahedron 2008, 64, 4174; l) M. J. R. P.
Queiroz, A. Begouin, G. Pereira, P. M. T. Ferreira, Tet-
rahedron 2008, 64, 10714; m) B. Alcaide, P. Almendros,
R. Carrascosa, M. C. Redondo, Chem. Eur. J. 2008, 14,
637; n) B. Tan, Z. Shi, P. J. Chua, Y. Li, G. Zhong,
Angew. Chem. Int. Ed. 2009, 48, 758; o) A. V. Lygin,
O. V. Larionov, V. S. Korotkov, A. de Meijere, Chem.
Eur. J. 2009, 15, 227; p) D. Tejedor, S. Lo¯pez-Tosco, J.
[1] A. Fꢂrstner, Angew. Chem. 2003, 115, 3706; Angew.
Chem. Int. Ed. 2003, 42, 3582.
[2] a) J. W. Huffman, Curr. Med. Chem. 1999, 6, 705; b) S.
Agarwal, S. Cꢃmmerer, S. Filali, W. Frçhner, J. Knçll,
M. P. Krahl, K. R. Reddy, H. J. Knçlker, Curr. Org.
Chem. 2005, 9, 1601.
[3] V. M. Domingo, C. Aleman, E. Brillas, L. Julia, J. Org.
Chem. 2001, 66, 4058.
[4] a) T. L. Gilchrist, J. Chem. Soc. Perkin Trans. 1 2001,
2491; b) G. Balme, Angew. Chem. 2004, 116, 6396;
Angew. Chem. Int. Ed. 2004, 43, 6238.
[5] For some recent examples of pyrrole synthesis, see:
a) S. Su, J. A. Porco Jr, J. Am. Chem. Soc. 2007, 129,
7744; b) D. J. St. Cyr, N. Martin, B. A. Arndtsen, Org.
Lett. 2007, 9, 449; c) M. R. Rivero, S. L. Buchwald,
Org. Lett. 2007, 9, 973; d) L. Peng, X. Zhang, J. Ma, Z.
Zhong, J. Wang, Org. Lett. 2007, 9, 1445; e) F. M. Is-
˘
Gozꢄlez-Platas, F. Garcia-Tellado, Chem. Eur. J. 2009,
15, 838; q) Y. Kim, J. Kim, S. B. Park, Org. Lett. 2009,
Adv. Synth. Catal. 2009, 351, 2063 – 2066
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2065

Jun-Yan Wang et al.
COMMUNICATIONS
11, 17; r) Y. Lu, X. Fu, H. Chen, X. Du, X. Jia, Y. Liu,
Adv. Synth. Catal. 2009, 351, 129.
779; d) B. Moreau, A. B. Charette, J. Am. Chem. Soc.
2005, 127, 18014.
[6] a) V. V. Zhdankin, P. J. Stang, Chem. Rev. 2002, 102,
2523; b) V. V. Zhdankin, P. J. Stang, Chem. Rev. 2008,
108, 5299; c) X.-C. Huang, Y.-L. Liu, Y. Liang, S.-F. Pi,
F. Wang, J.-H. Li, Org. Lett. 2008, 10, 1525.
[7] For reviews, see: a) P. Mꢂller, Acc. Chem. Res. 2004,
37, 243; b) R. M. Moriarty, J. Org. Chem. 2005, 70,
2853; for several recent examples: c) P. Mꢂller, Y. Al-
lenbach, E. Robert, Tetrahedron: Asymmetry 2003, 14,
[8] S. Telu, S. Durmus, G. F. Koser, Tetrahedron Lett. 2007,
48, 1863.
[9] K. Schank, C. Lick, Synthesis 1983, 392.
[10] a) Z.-H. Zhang, L. Yin, Y.-M. Wang, Adv. Synth. Catal.
2006, 348, 184; b) W. Tang, W. Wang, Y. Chi, X. Zhang,
Angew. Chem. 2003, 115, 3633; Angew. Chem. Int. Ed.
2003, 42, 3509.
2066
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2063 – 2066