Mn(III)-catalyzed synthesis of pyrroles from vinyl azides and 1,3-dicarbonyl compounds

Article abstract of DOI:10.1021/ol802120u

(Chemical Equation Presented) Polysubstituted N-H pyrroles with a wide variety of substituents were prepared from vinyl azides and 1,3-dicarbonyl compounds by using Mn(III) complexes as catalysts.

Full text of DOI:10.1021/ol802120u

ORGANIC
LETTERS
2008
Vol. 10, No. 21
5019-5022
Mn(III)-Catalyzed Synthesis of Pyrroles
from Vinyl Azides and 1,3-Dicarbonyl
Compounds
Yi-Feng Wang, Kah Kah Toh, Shunsuke Chiba,* 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 September 10, 2008
ABSTRACT
Polysubstituted N-H pyrroles with a wide variety of substituents were prepared from vinyl azides and 1,3-dicarbonyl compounds by using
Mn(III) complexes as catalysts.
Pyrroles are one of the most prevalent heterocyclic com-
pounds, being present as the basic cores in many natural
products,1 potent pharmaceutical compounds,2 and various
kinds of functional materials.3 Despite numerous diverse
approaches toward the synthesis of pyrroles developed so
far,4 it is still challenging to prepare polysubstituted pyrroles
with various substituents from readily available building
blocks. Recently, we have reported a synthetic method to
prepare pyrroles by Cu(II)-catalyzed reactions of vinyl azides
and ethyl acetoacetate.5 In this reaction, however, introduc-
tion of an alkoxycarbonyl group at the R-position of vinyl
azides is indispensable to realize high yield. It is probably
because this transformation proceeds by 1,4-anionic addition
of ethyl acetoacetate to vinyl azides.6 Furthermore, 1,3-
diketones such as acetylacetone could not be utilized for this
Cu(II)-catalyzed method. Based on these backgrounds, we
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Chem. Soc. 2004, 126, 13898. (o) Dhawan, R.; Arndtsen, B. A. J. Am.
Chem. Soc. 2004, 126, 468. (p) Kel’in, A. V.; Sromek, A. W.; Gevorgyan,
V. J. Am. Chem. Soc. 2001, 123, 2074. (q) Boger, D. L.; Boyce, C. W.;
Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54.
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Farmaco 2004, 59, 175. (d) Huffman, J. W. Curr. Med. Chem. 1999, 6,
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10.1021/ol802120u CCC: $40.75
Published on Web 10/09/2008
2008 American Chemical Society

have strived to develop a more general method for pyrrole
synthesis by applying a radical mechanism. Herein, we report
Mn(III)-catalyzed pyrrole formation from vinyl azides with
a variety of substituents and various 1,3-dicarbonyl com-
pounds such as ꢀ-keto esters and 1,3-diketones.
To achieve pyrrole formation from a wide range of vinyl
azides, we turned our attention to a radical pathway in which
R-carbonyl radicals generated from 1,3-dicarbonyl com-
pounds add to vinyl azides to afford iminyl radicals.7 The
resulting iminyl radicals would cyclize with an intramoelcular
carbonyl moiety to give pyrroles.8
giving iminyl radical II with release of Mn(II) species and
dinitrogen (Scheme 1). The resulting iminyl radical II
Scheme 1. Proposed Mechanisms
At first, a stoichiometric amount (1.5 equiv) of Mn(III)
acetate, which has been widely used for oxidative radical
formations from carbonyl compounds,9,10 was employed for
the reaction of R-azidostyrene (1a) and ethyl acetoacetate
(2a) in some solvents under N2 atmosphere. It was found
that the reaction proceeds smoothly in MeOH11 at 40 °C to
give pyrrole 3aa in 84% yield (Table 1, entry 1). Interest-
Table 1. Reaction of Vinyl Azide 1a with Ethyl Acetoacetate
2a by the Use of Mn(OAc)3·2H2Oa
undergoes intramolecular additon to a carbonyl group to give
alkoxyl radical III. Reduction of this alkoxyl radical III by
Mn(II) species gives Mn(III) alkoxide IV (path a). Alterna-
tively, reaction of iminyl radical II with Mn(II) species
affords alkylideneaminomanganese(III) V, nucleophilic attack
of which to a carbonyl group yields addition intermediate
IV (path b).12 Finally, protonation of IV with acetic acid
followed by dehydration yields pyrrole 3aa along with
regeneration of Mn(III). Most of the reported radical reactions
of 1,3-dicarbonyl compounds with alkenes using Mn(III)
acetate are performed in a stoichiometric manner, although
there are a few reports on catalytic usage of Mn(III) acetate
in the presence of reoxidants.13-16 Thus, this catalytic pyrrole
formation prompted us to investigate the further potential
for a synthetic method.
entry Mn(OAc)3 2H2O (equiv) additive time/h yieldb/%
1
2
3
1.5
0.2
0.1
2
8
2
84
90
AcOH
94 (90)c
a Reactions were performed under N2 atomsphere using 0.3 mmol of
1a. b Isolated yield. c Isolated yield using 1.0 mmol of 1a.
ingly, even with the use of a catalytic amount (20 mol %)
of Mn(III) acetate, pyrrole 3aa was obtained in 90% yield
(entry 2). Addition of acetic acid (2 equiv) accelerated the
reaction and reduced the catalyst loading to 10 mol % (entry
3).
This catalytic reaction may be initiated by addition of
Mn(III) enolate I to vinyl azide 1a via a radical pathway,
Using Mn(III) acetate as a catalyst, we next examined the
scope of this pyrrole formation. First, the reactions of various
vinyl azides 1 with ethyl acetoacetate (2a) were examined
as shown in Table 2. R-Aryl vinyl azides reacted smoothly
to afford pyrroles 3aa-ia in good yield (entries 1-9).
(6) For an example, the reaction of R-azidostyrene (1a) with ethyl
acetoacetate (2a) gave the corresponding pyrrole 3aa in only 9% yield;
see ref 5.
(7) 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.
(12) For an example of addition of aminyl radicals to carbonyl groups,
see: Kim, S.; Joe, G. H.; Do, J. Y. J. Am. Chem. Soc. 1993, 115, 3328.
(13) For the catalytic radical reactions using the Mn(II)/Co(II)/O2 redox
system, see: (a) Kagayama, T.; Fuke, T.; Sakaguchi, S.; Ishii, Y. Bull. Chem.
Soc. Jpn. 2005, 78, 1673. (b) Hirase, K.; Iwahama, T.; Sakaguchi, S.; Ishii,
Y. J. Org. Chem. 2002, 67, 970. (c) Iwahama, T.; Sakaguchi, S.; Ishii, Y.
(8) For reviews of the synthesis of aza-heterocycles using iminyl radicals,
see: (a) Stella, L. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, p 407. (b) Mikami, T.,
Narasaka, K. In AdVances in Free Radical Chemistry; Zard, S. Z., Ed.;
JAI: Stamford, 1999; Vol. 2, p 45. (c) Fallis, A. G.; Brinza, I. M.
Tetrahedron 1997, 53, 17543. (d) Zard, S. Z. Synlett 1996, n/a, 1148.
(9) For reviews, see: (a) Melikyan, G. G. Org. React. 1997, 49, 427.
Chem. Commun. 2000, n/a, 2317
.
(14) For peroxidation of alkenes with Mn(III) acetate under oxygen
(b) Snider, B. B. Chem. ReV. 1996, 96, 339
.
atomsphere, see: (a) Asahi, K.; Nishino, H. Tetrahedron 2005, 61, 11107.
(10) The structure of Mn(III) acetate is actually an oxo-centered triangle
of Mn(III) bridged by acetoxy ions. For the report on the crystal structure
of anhydrous Mn(III) acetate, see: Hessel, L. W.; Romers, C. Recl. TraV.
(b) Rahman, M. T.; Nishino, H. Tetrahedron 2003, 59, 8383.
(15) For the use of electrooxidation, see: (a) Shundo, R.; Nishiguchi,
I.; Matsubara, Y.; Hirashima, T. Tetrahedron 1991, 47, 831. (b) Coleman,
J. P.; Hallcher, R. C.; McMackins, D. E.; Rogers, T. E.; Wagenknecht,
J. H. Tetrahedron 1991, 47, 809. (c) Ne´de´lec, J. Y.; Nohair, K. Synlett
Chim. Pays-Bas 1969, 88, 545
.
(11) Other solvents such as DMF, CH3CN, and EtOH were not so
effective for this reaction.
1991, 659
.
5020
Org. Lett., Vol. 10, No. 21, 2008

Table 2. Mn(OAc)3·2H2O-Catalyzed Synthesis of Pyrroles 3 from Vinyl Azides 1 and Ethyl Acetoacetate (2a)a
a Reactions were performed in MeOH at 40 °C with 1.5 equiv of ethyl acetoacetate (2a) under N2 atomsphere. b Isolated yield. c Vinyl azide 1j was
recovered in 25% yield. d Vinyl azide 1p was recovered in 10% yield. e Vinyl azide 1s was recovered in 15% yield.
Relatively longer reaction time or higher catalyst loading
was necessary in the cases of vinyl azides bearing electron-
rich aryl groups (entries 6-8). Trisubstituted vinyl azide
ꢀ-methyl-R-azidostyrene (1i) also reacted with ethyl ac-
etoacetate to give tetrasubstituted pyrrole 3ia in good yield
(entry 9). The reaction of R-pyrrolyl vinyl azide 1j proceeded
to give the corresponding dipyrrole 3ja in 68% yield in spite
of the slower reaction rate (24 h) (entry 10). 1,4-Dipyrroyl-
benzene 3ka could be obtained in 48% yield17 by treatment
of bis(R-azidovinyl)benzene 1k with 40 mol % of Mn(III)
acetate (entry 11). The reaction of R-alkyl vinyl azides with
some functional groups also gave the corresponding pyrroles
3la-qa in good yield (entries 12-17). From 1-azidocy-
clooctene (1p), bicyclic pyrrole 3pa was obtained in 60%
yield (entry 16). Vinyl azide 1q with a chiral polyol function
prepared from D-glucal derivatives18 could be transformed
to pyrrole 3qa in 74% yield without cleavage of silyloxy
moieties by employing 40 mol % of Mn(III) acetate (entry
17). Vinyl azides having an ethoxycarbonyl group at the
R-position could also be employed in this pyrrole synthesis
(entries 18 and 19). In the case of the reaction of ethyl
2-azidoacrylate (1r), the use of only 5 mol % of Mn(III)
acetate was sufficient to complete the reaction within 2 h,
affording pyrrole 3ra almost quantitatively (entry 18).
Although tetrasubstituted pyrrole 3sa were obtained in good
yield, the reaction of ꢀ-aryl vinyl azides 1s required a longer
reaction time (24 h) even by the use of 20 mol % of Mn(III)
acetate, probably due to steric hindrance (entry 19).
Next, the generality of 1,3-dicarbonyl compounds was
examined using R-azidostyrene (1a) and ethyl 2-azidoacrylate
(1r) as shown in Table 3. By employing ꢀ-keto esters 2b-d,
phenyl, ethoxymethyl, and cyclopropyl groups were suc-
cessfully installed at the C2-position of pyrroles 3 (entries
1-6). A slow reaction rate was observed when acetylacetone
(2e) was employed (entry 7), and the yield of the obtained
pyrrole 3ae was low (21%) along with recovery of 1a (63%)
even after 24 h. The formation of pyrrole 3ae, however,
encouraged us to improve the product yield by modification
of Mn(III) complexes because the previous Cu(II)-catalyzed
(16) For the use of sonochemical conditions, see: (a) Bosman, C.;
D’Annibale, A.; Resta, S.; Trogolo, C. Tetrahedron 1994, 50, 13847. (b)
Allegretti, M.; D’Annibale, A.; Trogolo, C. Tetrahedron 1993, 49, 10705.
(17) The low yield of pyrrole 3ka is probably due to instability of 3ka
in the present reaction conditions.
(18) Alonso-Cruz, C. R.; Kennedy, A. R.; Rodríguez, M. S.; Sua´rez, E.
Org. Lett. 2003, 5, 3729.
Org. Lett., Vol. 10, No. 21, 2008
5021

Table 3. Mn(OAc)3·2H2O-Catalyzed Synthesis of Pyrroles 3
from Vinyl Azides 1 and 1,3-Dicarbonyl Compounds 2a
Table 4. Mn(pic)3-Catalyzed Pyrrole Formation from Vinyl
Azides 1 and 1,3-Diketones 2a
a Reactions were performed in MeOH at 40 °C using 20 mol % of
Mn(pic)3 with 1.5 equiv of 1,3-diketones under N2 atomsphere. b Isolated
yield. c Vinyl azide 1i was recovered in 21% yield. d Vinyl azide 1a was
recovered in 17% yield.
azides 1e, 1f, 1i, and 1n with acetylacetone (2e) under the
same reaction conditions led to the formation of pyrroles 3
in good to moderate yield (entries 2-5). The reaction of
unsymmetrical 1,3-diketone benzoylacetone (2f) with vinyl
azide 1a proceeded to afford pyrrole 3af in 61% yield as a
sole product via C-N bond formation with a less hindered
acetyl group (entry 6).
a Reactions were performed in MeOH at 40 °C with 1.5 equiv of 1,3-
dicarbonyl compounds under N2 atomsphere. b Isolated yield. c Vinyl azide
1a was recovered in 63% yield.
In summary, a Mn(III)-catalyzed method has been devel-
oped for synthesis of tri- and tetrasubstituted N-H pyrroles
from readily available vinyl azides and 1,3-dicarbonyl
compounds. Further studies on the scope, mechanism, and
synthetic applications of this reaction are in progress.
reaction5 with any 1,3-diketone did not give the correspond-
ing pyrrole at all.
Interestingly, when the reaction of acetylacetone (2e) with
1a was tried using 20 mol % of Mn(III) tris(2-pyridinecar-
boxylate) [Mn(pic)3],19,20 pyrrole 3ae was afforded in 76%
yield after 20 h (Table 4, entry 1).21 Treatment of some vinyl
Acknowledgment. This work was supported by funding
from Nanyang Technological University, Singapore Ministry
of Education, and Science & Engineering Research Council
(A*STAR Grant No. 082 101 0019).
(19) Mn(III) tris(2-pyridinecarboxylate) has a monomeric octahedral
structure; see: Figgis, B. N.; Raston, C. L.; Sharma, R. P.; White, A. H.
Aust. J. Chem. 1978, 31, 2545
.
(20) For the oxidative radical reaction by using Mn(III) tris(2-pyridin-
ecarboxylate) as an oxidant, see: (a) Iwasawa, N.; Funahashi, M.; Hayakawa,
S.; Ikeno, T.; Narasaka, K. Bull. Chem. Soc. Jpn. 1999, 72, 85. (b) Narasaka,
K. Pure Appl. Chem. 1997, 69, 601. (c) Vo, N. H.; Snider, B. B. J. Org.
Chem. 1994, 59, 5419. (d) Snider, B. B.; McCarthy, B. A. J. Org. Chem.
Supporting Information Available: Experimental pro-
cedures and characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1993, 58, 6217, and references therein
.
(21) The reaction of vinyl azide 1a with ethyl acetoacetate (2a) using
10 mol % of Mn(III) tris(2-pyridinecarboxylate) proceeded at 40 °C more
slowly than using Mn(III) acetate, giving 28% yield of pyrrole 3aa along
with recovery of 1a (55%) after 22 h.
OL802120U
5022
Org. Lett., Vol. 10, No. 21, 2008