Synthesis of polysubstituted N-H pyrroles from vinyl azides and 1,3-dicarbonyl compounds

Article abstract of DOI:10.1021/ol702727j

(Chemical Equation Presented) Two synthetic methods for tetra- and trisubstituted N-H pyrroles are presented: (i) the thermal pyrrole formation by the reaction of vinyl azides with 1,3-dicarbonyl compounds via the 1,2-addition of 1,3-dicarbonyl compounds to 2H-azirine intermediates generated in situ from vinyl azides; (ii) the Cu(II)-catalyzed synthesis of pyrroles from α-ethoxycarbonyl vinyl azides and ethyl acetoacetate through the 1,4-addition reaction of the acetoacetate to the vinyl azides. By applying these two methods, regioisomeric pyrroles can be prepared selectively starting from the same vinyl azides.

Full text of DOI:10.1021/ol702727j

ORGANIC
LETTERS
2008
Vol. 10, No. 2
313-316
Synthesis of Polysubstituted N-H
Pyrroles from Vinyl Azides and
1,3-Dicarbonyl Compounds
Shunsuke Chiba,* Yi-Feng Wang, Guillaume Lapointe,† and Koichi Narasaka*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 637371, Singapore
shunsuke@ntu.edu.sg; narasaka@ntu.edu.sg
Received November 10, 2007
ABSTRACT
Two synthetic methods for tetra- and trisubstituted N-H pyrroles are presented: (i) the thermal pyrrole formation by the reaction of vinyl
azides with 1,3-dicarbonyl compounds via the 1,2-addition of 1,3-dicarbonyl compounds to 2H-azirine intermediates generated in situ from
vinyl azides; (ii) the Cu(II)-catalyzed synthesis of pyrroles from
r-ethoxycarbonyl vinyl azides and ethyl acetoacetate through the 1,4-addition
reaction of the acetoacetate to the vinyl azides. By applying these two methods, regioisomeric pyrroles can be prepared selectively starting
from the same vinyl azides.
Pyrroles are an important class of compounds in the
pharmaceutical1 and material sciences.2 Although there have
been reported many methods for the synthesis pyrroles,3 it
is still challenging to prepare polysubstituted pyrroles with
various substituents directly from readily available building
blocks. In this communication, we present two synthetic
methods for tetra- and trisubstituted N-H pyrroles from vinyl
azides and 1,3-dicarbonyl compounds, which give regioiso-
meric pyrroles selectively.
During the course of our study on the reactions of 2H-
azirine derivatives with various transition metals,4 we found
that the reaction of 2H-azirine 1a with Cu(acac)2 in 1,2-
dichloroethane gave tetrasubstituted pyrrole 2a in 94% yield.
The reaction with acetylacetone instead of Cu(acac)2 also
provided pyrrole 2a in quantitative yield (Scheme 1).
(3) For recent reports on the synthesis of polysubstituted pyrroles, see:
(a) Su, S.; Porco, J. A., Jr. J. Am. Chem. Soc. 2007, 129, 7744. (b) Shindo,
M.; Yoshimura, Y.; Hayashi, M.; Soejima, H.; Yoshikawa, T.;
Matsumoto, K.; Shishido, K. Org. Lett. 2007, 9, 1963. (c) Rodr´ıguez
Rivero, M.; Buchwald, S. L. Org. Lett. 2007, 9, 973. (d) Cyr, D. J. S.;
Martin, N.; Arndtsen, B. A. Org. Lett. 2007, 9, 449. (e) Binder, J. T.;
Kirsch, S. F. Org. Lett. 2006, 8, 2151. (f) Gorin, D. J.; Davis, N. R.; Toste,
F. D. J. Am. Chem. Soc. 2005, 127, 11260. (g) Bharadwaj, A. R.;
Scheidt, K. A. Org. Lett. 2004, 6, 2465. (h) Dhawan, R.; Arndtsen, B. A.
J. Am. Chem. Soc. 2004, 126, 468. (i) Kel’in, A. V.; Sromek, A. W.;
Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074. (j) Boger, D. L.; Boyce,
C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121,
54.
† Current address: Department fur Chemie und Biochemie, Universitat
Bern, Freiestrasse 3, CH-3012, Switzerland.
(1) (a) Gribble, G. W. In ComprehensiVe Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: Oxford,
UK, 1996; Vol. 2, p 207. (b) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-
Jones, A. Nat. Prod. Rep. 2006, 23, 517. (c) Huffman, J. W. Curr. Med.
Chem. 1999, 6, 705.
(2) (a) Lee, C. F.; Yang, L. M.; Hwu, T. Y.; Feng, A. S.; Tseng, J. C.;
Luh, T. Y. J. Am. Chem. Soc. 2000, 122, 4992. (b) Novak, P.; Mu¨ller, K.;
Santhanam, K. S. V.; Haas, O. Chem. ReV. 1997, 97, 207.
(4) Chiba, S.; Hattori, G.; Narasaka, K. Chem. Lett. 2007, 36, 52.
10.1021/ol702727j CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/23/2007

Table 1. Reaction of Vinyl Azides 3 with Acetylacetonea
Scheme 1. Pyrrole Formation from 2H-Azirine 1a
vinyl
entry azide 3
pyrrole
2
R1
R2
yield/%b
1
2
3a
3b
3c
3d
3e
3f
2,6-CL2-C6H3 CO2Et
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
86
93
90
89
96
90
87
81
94
74
quant
75
82
96
77
85
Ph
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Although the reaction of 2H-azirine 1a with acetylacetone
in THF has been reported, the yield of pyrrole 2a was low.5
The high yield of 2a in the above reaction prompted us to
study the pyrrole formation in detail. The reaction may
proceed through the addition of acetylacetone to the imino
carbon of 1a,6 followed by the intramolecular nucleophilic
attack of the nitrogen of the resulting aziridine to a carbonyl
group with the ring opening of the strained three-membered
ring as reported in the reactions with ketone enolates or
enamines.7 Although this reaction seemed to be useful to
synthesize pyrroles, most 2H-azirines were found to be
difficult to prepare and to handle due to their instability.8
Accordingly, we planned to use vinyl azides as precursors
of 2H-azirines, which can be easily synthesized8,9 and are
known to be transformed to the corresponding 2H-azirines
in situ by thermal elimination of dinitrogen (Scheme 2).8
3
4-Me-C6H4
2-Me-C6H4
3-NO2-C6H4
4-Br-C6H4
4-NC-C6H4
4
5
6
7
3g
3h
3i
8c
9
4-MeO-C6H4 CO2Et
3-pyridyl
Ph
CO2Et
COMe
CONMe2
H
10d
11
12
13
14g
15
16h
3j
3k
3le
3mf
3n
3o
3p
Ph
Ph
EtO2C
PhCH2
H
CO2Et
CO2Et
CO2CH2Ph
Ph
H
a 1.2 equiv of acetylacetone was used. b Isolated yield. c The reaction
was performed at 85 °C for 16 h. d The reaction was pefromed at 85 °C for
20 h in the presence of 2 equiv of acetyl acetone. e E:Z ) 1:1. f Z-isomer.
g The reaction was performed at reflux for 5 h. h The reaction was perormed
at 100 °C for 24 h.
drawing groups (entries 2-8) but also with a pyridyl moiety
(entry 9). Instead of R-ethoxycarbonyl vinyl azides, R-acetyl
(entry 10) and N,N-dimethylaminocarbonyl (entry 11) vinyl
azides 3j and 3k could be employed to give the correspond-
ing pyrroles (R2 ) COCH3 or CONMe2). The reaction of
â-azidostyrene (3l) gave trisubstituted pyrrole 2l in good
yield (entry 12). It is known that the pyrrolysis of â-aryl
vinyl azides results in the formation of indoles via intramo-
lecular C-H amination,10,11 while the reaction with acety-
lacetone gave pyrroles selectively without any indole for-
mation (entries 2-12). For the â-substituents of vinyl azides
(R1), ethoxycarbonyl (3m), alkyl (3n), and hydrogen (3o,
3p) could be introduced, giving the corresponding pyrroles
in good yield (entries 13-16).
Scheme 2. Synthesis of Pyrroles from Vinyl Azides and
1,3-Dicarbonyl Compounds
As expected, when a mixture of vinyl azide 3a and
acetylacetone was heated in toluene at 100 °C, pyrrole 2a
was obtained in 86% yield (Table 1, entry 1). Various R-aryl
pyrroles (R1 ) aryl) were prepared not only with phenyl
substituents possessing both electron-donating and -with-
Treatment of vinyl azides 3b, 3c, and 3l with a â-keto
ester, ethyl acetoacetate, also gave pyrroles 2q, 2r, and 2s
in 30, 30, and 58% yield, respectively (Table 2, entries 1-3).
A â-oxo aldehyde reacted smoothly with vinyl azides (entries
4 and 5), whereas tri- and tetrasubstituted pyrroles were
obtained in almost 1:1 ratio via the nucleophilic attack of
the nitrogen atom to both carbonyl groups (Scheme 2, AfB).
(5) Alves, M. J.; Gilchrist, T. L.; Sousa, J. H. J. Chem. Soc., Perkin
Trans. 1 1999, 1305.
(6) (a) Alves, M. J.; Ferreira, P. M. T.; Maia, H. L. S.; Monteiro, L. S.;
Gilchrist, T. L. Tetrahedron Lett. 2000, 41, 4991. (b) Carlson, R. M.; Lee,
S. Y. Tetrahedron Lett. 1969, 10, 4001. (c) Leonard, N. J.; Zwanenburg,
B. J. Am. Chem. Soc. 1967, 89, 4456.
(7) (a) Law, K. W.; Lai, T. F.; Sammes, M. P.; Katritzky, A. R.; Mak,
T. C. W. J. Chem. Soc., Perkin Trans. 1 1984, 111. (b) Laurent, A.; Mison,
P.; Nafti, A.; Pellissier, N. Tetrahedron 1979, 35, 2285. (c) Padwa, A.;
Kulkarni, Y. Tetrahedron Lett. 1979, 20, 107. (d) Faria dos Santos Filho,
P.; Schuchardt, U. Angew. Chem., Int. Ed. Engl. 1977, 16, 647.
(8) (a) Time´n, Å. S.; Risberg, E.; Somfai, P. Tetrahedron Lett. 2003,
44, 5339. (b) So¨derberg, B. C. G. Curr. Org. Chem. 2000, 4, 727. (c) Knittel,
D. Synthesis 1985, 186.
(9) (a) Nair, V.; George, T. G. Tetrahedron Lett. 2000, 41, 3199. (b)
Gilchrist, T. L.; Mendonc¸a, R. Synlett 2000, 1843. (c) Palacios, F.; Aparicio,
D.; de los Santos, J. M.; Perez de Heredia, I.; Rubiales, G. Org. Prep.
Proced. Int. 1995, 27, 171.
(10) (a) Moody, C. J. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Ley, S., Eds.; Pergamon: Oxford, 1991; Vol. 7, p 21. (b)
Smolinsky, G.; Pryde, C. A. J. Org. Chem. 1968, 33, 2411. (c) L’abbe´, G.
Angew. Chem., Int. Ed. Engl. 1975, 14, 775. (d) Hemetsberger, H.; Knittle,
D.; Weidmann, H. Monatsh. Chem. 1970, 101, 161. (e) MacKenzie, A. R.;
Moody, C. J.; Rees, C. W. J. Chem. Soc., Chem. Commun. 1983, 1372. (f)
Bolton, R. E.; Moody, C. J.; Pass, M.; Rees, C. W.; Tojo, G. J. Chem.
Soc., Perkin Trans. 1 1988, 2491.
(11) Recently, Rh(II)-catalyzed indole formation from azidocinnamates
was reported, see: Stokes, B. J.; Dong, H.; Lesile, B. E.; Pumphrey, A. L.;
Driver, T. G. J. Am. Chem. Soc. 2007, 129, 7500.
314
Org. Lett., Vol. 10, No. 2, 2008

Table 2. Reaction of Vinyl Azides with â-keto Ester and
Table 3. Optimization of Reaction Conditions
Aldehydea
â-keto ester
(equiv)
yield/
a
entry
Cu cat.
additive conditions
%
1
2
3
4
5
1.2
1.2
3.0
3.0
3.0
Cu(OTf)2
s
60 °C, 16 h 34
Cu(OTf)2
H2O 60 °C, 18 h 55
H2O 40 °C, 30 h 78
H2O 40 °C, 24 h 80
H2O 40 °C, 24 h 44 (46)
Cu(OTf)2
Cu(NTf2)2
Cu(PF6)(CH3CN)4
a Isolated yield. b Recovery of vinyl azide 3b.
Vinyl azides 3c,e-h,n,o having an ethoxycarbonyl group
at the R-position were transformed to pyrroles 4 in good to
moderate yield (Table 4, entries 1-7). The reaction of vinyl
a 1.2 equiv of 1,3-dicarbonyls, toluene, 100 °C, 2 - 4 h. b Isolated yield.
Table 4. Cu(II)-Catalyzed Pyrrole Formation
The use of any additives such as acids, bases, etc.12 could
not improve the yield of the reaction of azide 3c with ethyl
acetoacetate, whereas the reaction in the presence of a
stoichiometric amount of Cu(OTf)2 gave an unexpected
pyrrole 4a,13 which has a reverse substitution pattern (R-
ethoxycarbonyl, â-p-tolyl) compared with that of the ex-
pected 2r (R-p-tolyl, â-ethoxycarbonyl) (Scheme 3).
Scheme 3. Unexpected Pyrrole Formation
Even by the catalytic use (5 mol %) of Cu(OTf)2, the
reaction of azide 3b with ethyl acetoacetate proceeded
smoothly in CH3CN at 60 °C, giving pyrrole 4b in 34% yield
(Table 3, entry 1). The addition of 5 equiv of water and the
use of 3 equiv of ethyl acetoacetate increased the yield of
a Isolated yield. b The reaction was performed by the use of 5 mol % of
Cu(OTf)2. c Vinyl azide 3p was recovered in 43% yield.
azide 3p with an R-phenyl group, however, gave the
corresponding pyrrole 2s in only 9% yield (entry 8).
Since the Cu-catalytic reaction was performed at 40-
60 °C, a 2H-azirine intermediate is unlikely to be on the
reaction course.15 The reaction may be initiated by the 1,4-
addition of copper enolate I to vinyl azide 3, the internal
nitrogen of which coordinates to copper (Scheme 4).16
14
4b to 78% (entry 3). Cu(NTf2)2 exhibited the catalytic
activity for this pyrrole formation as well as Cu(OTf)2 (entry
4), whereas Cu(PF6)(MeCN)4 afforded 4b in moderate yield
(entry 5).
(12) We examined the following additives; AcOH, PPTS, TfOH, MgBr2,
Mg(OTf)2, K2CO3, CuCO3, DABCO, H2O, and MS 4Å.
(13) The structure of 4a was secured by X-ray crystallographic analysis.
CCDC-295066 contains the supplementary crystallographic data for com-
pound 4a. These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data
Center, 12 Union Road, Cambridge, CB21 EZ, UK; fax: (+44)1223-336-
033; or e-mail deposit@cdc.cam.ac.uk). See Supporting Information.
(14) Earle, M. J.; Hakala, U.; McAuley, B. J.; Nieuwenhuyzen, M.;
Ramani, A.; Seddon, K. R. Chem. Commun. 2004, 1368.
(15) No reaction was observed by the treatment of vinyl azide 3b with
a stoichometric amount of Cu(OTf)2 and Cu(NTf2)2 in CH3CN at 40-
60 °C.
Org. Lett., Vol. 10, No. 2, 2008
315

2s from R-azido styrene (3p) in spite of the quite low yield
(entry 8). Further studies on the scope, mechanism, and
synthetic applications of this reaction are in progress.
Scheme 4. Proposd Reaction Mechanism
Acknowledgment. This paper is dedicated to the late
Professor Yoshihiko Ito for his outstanding contribution
to synthetic organic chemistry. We acknowledge the
Nanyang Technological University for funding of this
research. We thank Dr. Junji Kobayashi (Department of
Chemistry, Graduate School of Science, The University
of Tokyo) for assistance with the X-ray crystallographic
analysis.
Supporting Information Available: Experimental pro-
cedures, characterization of new compounds, and CIF files
giving crystallographic data for 4a (CCDC-656009). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Simultaneus elimination of dinitrogen affords alkylidene-
aminocopper II, which undergoes intramolecular nucleophilic
attack to the carbonyl group, affording pyrrole with the
elimination of water.
The radical pathway via the generation of iminyl radical17
is not completely excluded due to the formation of pyrrole
OL702727J
(16) (a) For a report on the coordination of the internal nitrogen of an
organic azide with a Cu(II) complex, see: Barz, M.; Herdweck, E.; Thiel,
W. R. Angew. Chem., Int. Ed. 1998, 37, 2262. (b) For a review on the
coordination of organic azides with transition metals: Cenini, S.; Gallo,
E.; Caselli, A.; Ragaini, F.; Fantauzzi, S.; Piangiolino, C. Coord. Chem.
ReV. 2006, 250, 1234.
(17) For prior studies on the iminyl radical formation from vinyl azides,
see: (a) Montevecchi, P. C.; Navacchia, M. L.; Spagnolo, P. J. Org. Chem.
1997, 62, 5864. (b) Bamford, A. F.; Cook, M. D.; Roberts, B. P. Tetrahedron
Lett. 1983, 24, 3779.
316
Org. Lett., Vol. 10, No. 2, 2008