Manganese(III)-catalyzed formal [3+2] annulation of vinyl azides and ?-keto acids for synthesis of pyrroles

Article abstract of DOI:10.1055/s-0030-1259920

Manganese(III)-catalyzed formal [3+2] annnulation of vinyl azides and -keto acids has been developed for the synthesis of substituted NH pyrroles with a wide range of substituents. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259920

LETTER
783
Manganese(III)-Catalyzed Formal [3+2] Annulation of Vinyl Azides and
b-Keto Acids for Synthesis of Pyrroles
Formal [3+2]
A
i
nnulati
l
on of
V
e
inyl
A
zide
e
s
and
b
-Ke
t
n
oAcids Pei Jian Ng, Yi-Feng Wang, Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, 637371 Singapore
Fax +6567911961; E-mail: shunsuke@ntu.edu.sg
Received 2 December 2010
cursor/equivalent of a-carbonyl radicals and on the inves-
tigation of their addition reactions toward vinyl azides.
We recently succeeded in the manganese(III)-catalyzed
formal [3+2] annulation by the combined use of vinyl
azides and 1,3-dicarbonyl compounds such as b-keto es-
ters and 1,3-diketones, where manganese(III) acetate
[Mn(OAc)3·2H2O] and manganese(III) tris(2-pyridinecar-
boxylate) [Mn(pic)3] were respectively utilized to prepare
densely functionalized pyrroles.8b
Abstract: Manganese(III)-catalyzed formal [3+2] annnulation of
vinyl azides and b-keto acids has been developed for the synthesis
of substituted NH pyrroles with a wide range of substituents.
Key words: manganese(III) catalysts, radical reactions, vinyl
azides, b-keto acids, pyrroles
Pyrroles are one of the most prevalent heterocyclic com-
pounds, being present as the basic cores in a lot of natural
products,1 potent pharmaceutical compounds,2 and vari-
ous kinds of functional materials.3 Although diverse ap-
proaches toward the synthesis of pyrroles have been
developed,4,5 versatile and flexible methodologies to con-
struct pyrroles with selective control of substitution pat-
terns using readily accessible building blocks are still
needed.
b-Keto acids have been utilized as an equivalent of either
a-carbonyl anions9 or radicals10 with elimination of car-
bon dioxide. As it was found that vinyl azides exhibited
good reactivity toward the a-carbonyl radicals derived
from b-keto esters and 1,3-diketones with manganese(III)
catalysts, we intended to study the reaction of vinyl azides
and b-keto acids. In this communication, we report a reac-
tion of vinyl azides and b-keto acids for the synthesis of
substituted pyrroles catalyzed by manganese(III) acetyl-
acetonate [Mn(acac)3].
We have recently been interested in the application of vi-
nyl azides as a three-atom unit including one nitrogen to
synthesize azaheterocycles. One of our reaction designs
involves the addition of a carbon radical to the C=C bond
of a vinyl azide to provide a new C–C bond with genera-
tion of an iminyl radical.6 The iminyl radical then in-
tramolecularly forms a C–N bond by the cyclization with
an unsaturated bond (Scheme 1).7,8 Our current study has
focused on the use of 1,3-dicarbonyl compounds as a pre-
Firstly, a suitable catalytic system was explored using a-
azidostyrene (1a) and b-keto acid 2a with manganese(III)
complexes (Table 1). The reaction with 10 mol% of
Mn(OAc)3·2H2O required long reaction time (30 h) to
consume vinyl azide 1a, affording the desired bicyclic
pyrrole (4,5,6,7-tetrahydro-1H-indole) 3aa in 51% yield
(Table 1, entry 1). Although utilization of Mn(pic)3 accel-
concept:
formation of iminyl radicals by addition of C radicals to vinyl azides
– successive C–N bond formation
Table 1 Reactions of Vinyl Azide 1a with b-Keto Acid 2a Using
Manganese(III) Complexesa
a newly formed C–C bond
R
O
O
•
R
C
R
cat. Mn(III)
–N
+N
N
HO
C
C
C
+
N
H
solvent, r.t.
conditions
N
C
N
– N2
•
N3
1a
C
X
•
2a
(3.0 equiv)
3aa
X
X
iminyl radical
a newly formed C–N bond
Entry Mn(III) (equiv)
Solvent
DMF
Time (h) Yield (%)b
this work: Mn(III)-catalyzed reactions of vinyl azides and β-keto acids
1
2
3
4
5
Mn(OAc)3⋅2H2O (0.1)
30
1
51
59
83
0
R2
R1
R4
R3
O
O
R1
N3
cat. Mn(acac)3
+
Mn(pic)3 (0.2)
Mn(acac)3 (0.1)
Mn(acac)3 (0.1)
Mn(acac)3 (0.1)
DMF
R3
OH
R2
– N2, – CO2, – H2O
R4
N
H
DMF
5
Scheme 1 A concept for the synthesis of azaheterocycles from vinyl
azides
MeOH
MeCN
17
36
76
SYNLETT 2011, No. 6, pp 0783–0786
Advanced online publication: 16.03.2011
DOI: 10.1055/s-0030-1259920; Art ID: D31310ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1
a Reactions were performed under N2 atmosphere using 0.3 mmol of
1a.
b Isolated yield.

784
E. P. J. Ng et al.
LETTER
erated the reaction (entry 2), the yield of 3aa was compa- pyrroles in good yields (entries 1–5). Notably, the reaction
rable with that obtained with Mn(OAc)3·2H2O (entry 1). of vinyl azide 1f possessing an a-indole substituent led to
The yield of pyrrole 3aa was further improved to 83% by the formation of an interesting 2,2¢-bisindole derivative
employing Mn(acac)3 (entry 3).11 It was noted that the 3fa (entry 6). Moreover, a-ethoxycarbonyl vinyl azides 1g
choice of solvent was crucial to this reaction. No reaction and 1h also could be applied to this reaction, giving the
was observed in methanol, which gave the best results in corresponding bicyclic pyrroles 3ga and 3ha in good
the Mn(OAc)3·2H2O- and Mn(pic)3-catalyzed pyrrole for- yields (entries 7 and 8). In the case of vinyl azide 1h, the
mation with b-keto esters and 1,3-diketones, respectively presence of ethoxycarbonyl at the b-position did not re-
(entry 4).8b The reaction in acetonitrile needed longer re- tard the reaction, providing tetrasubstituted pyrrole 3ha in
action time, while providing the desired pyrrole 3aa in 74% yield (entry 8).
good yield (entry 5).
With the optimized reaction conditions in hand, the gen-
erality of this reaction was investigated by employing a
Table 3 Substrate Scope on b-Keto Acidsa,b
R4
range of vinyl azides 1 and b-keto acids 2 with Mn(acac)3
O
O
cat. Mn(acac)3
DMF, r.t.
as a catalyst. The reactions of various vinyl azides 1 with
b-keto acid 2a are summarized in Table 2. The reaction of
a-aryl vinyl azides with 2a provided the desired bicyclic
+
R3
OH
R3
N
H
R4
N3
1a
2
3
Table 2 Substrate Scope on Vinyl Azidesa,b
(1.5–3 equiv)
O
O
Entry
b-Keto acid 2
Pyrrole 3/yield (%)
R2
R1
N3
R2
cat. Mn(acac)3
DMF, r.t.
OH
O
O
+
O
R1
N
H
3
OH
1
2
N
H
1
2a
(1.5–3 equiv)
O
2b
2c
3ab (70)c
3ac (65)d
Entry
Vinyl azide 1
Pyrrole 3/yield (%)
O
O
OH
R
N
H
R
N
H
N3
1a (R = H)
O
3aa (83)c
3ba (92)d
3ca (68)d
3da (91)d
3ea (87)d
O
1
2
3
4
5
OH
n
1b (R = 4-Br)
1c (R = 4-CO2Me)
1d (R = 2-MeO)
1e (R = 4-MeO)
N
H
n
3
4
2d (n = 1)
2e (n = 2)
3ad (81)e
3ae (82)e
Me
O
O
OH
R
Et
N
H
6
Me
N
N
N
Ts
Ts
H
5
6
2f (R = Et)
2g (R = Ph)
3af (84)e
3ag (82)e
N3
3fa (76)c
1f
EtO2C
7
8
EtO2C
O
O
N3
N
H
7
1g
N
H
3ga (68)c
EtO2C
OH
2h
EtO2C
CO2Et
3ah (23)f
a Reactions were performed in DMF at r.t. with 1.5–3.0 equiv of
b-keto acid 2 under N2.
EtO2C
N3
N
H
1h
b Isolated yields were noted above.
c Mn(acac)3 used: 30 mol%.
3ha (74)c
a Reactions were performed in DMF at r.t. with 1.5–3.0 equiv of
b-keto acids 2 under N2 atmosphere.
b Isolated yields were noted above.
c Mn(acac)3 used: 10 mol%.
d Mn(acac)3 used: 40 mol%; b-keto acid 2c was added through a
syringe pump over 1 h.
e Mn(acac)3 used: 20 mol%.
f Mn(pic)3 used: 1 equiv. Utilization of Mn(acac)3 (1 equiv) afforded
d Mn(acac)3 used: 20 mol%.
pyrrole 3ah in only 10% yield.
Synlett 2011, No. 6, 783–786 © Thieme Stuttgart · New York

LETTER
Formal [3+2] Annulation of Vinyl Azides and b-Keto Acids
785
O
O
R4
[MnIII]
Ph
–N
[MnII]
N2, CO2
O
R3
2
+N
I
H+
N
1a
R4
R4
[MnII]
path b
O
MnIII(acac)3
Ph
Ph
O
R3
[MnIII]
N
N
R3
II
•
V
H+
R4
R3
R4
R3
path a
[MnII]
R4
R3
Ph
Ph
N
N
O
O
[MnIII]
•
III
Ph
N
OH
IV
VI
3
H2O
Scheme 2 A proposed catalytic cycle.
Next, the scope of b-keto acids 2 was investigated with vi- In summary, Mn(acac)3-catalyzed formal [3+2] annula-
nyl azide 1a (Table 3). Tetrahydropyrano[4,3-b]pyrrole tion of vinyl azides and b-keto acids was successfully de-
3ab and 4,5-dihydro-1H-benzo[g]indole 3ac were assem- veloped for the synthesis of N–H pyrroles with a variety
bled in good yields by employing b-keto acids 2b and 2c, of substituents.14 Further investigation to explore other
respectively (entries 1 and 2). As the b-keto acid 2c was modes of annulation reactions of vinyl azides to prepare
labile in such oxidative conditions, the slow addition of 2c azaheterocycles is in progress.
through a syringe pump was required (entry 2). Bicyclic
pyrroles bearing larger carbocycles 3ad and 3ae could be
Acknowledgment
obtained by treatment with b-keto acids 2d and 2e (entries
This work was supported by funding from the Nanyang Technolo-
gical University, the Singapore Ministry of Education, and the Sci-
ence & Engineering Research Council (A*STAR grant No. 082 101
0019).
3 and 4). In addition, the reactions of linear b-keto acids
2f and 2g proceeded, affording the trisubstituted pyrroles
3af and 3ag, respectively, in good yields, (entries 5 and 6).
However, b-keto acid 2h, which could generate a primary
a-carbonyl radical, was not viable for the reaction, deliv-
ering only 23% yield of the desired pyrrole 3ah even by References and Notes
using a stoichiometric amount of the manganese(III) com-
plexes (entry 7).
(1) For recent reviews, see: (a) Walsh, C. T.; Garneau-
Tsodikova, S.; Howard-Jones, A. R. Nat. Prod. Rep. 2006,
23, 517. (b) Fürstner, A. Angew. Chem. Int. Ed. 2003, 42,
3582. (c) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753.
(2) (a) Hall, A.; Atkinson, S.; Brown, S. H.; Chessell, I. P.;
This catalytic reaction may be initiated by addition of
manganese(III) carboxylate I to vinyl azide 1a via a radi-
cal pathway,12 giving iminyl radical II with release of
Chowdhury, A.; Giblin, G. M. P.; Goldsmith, P.; Healy,
M. P.; Jandu, K. S.; Johnson, M. R.; Michel, A. D.; Naylor,
manganese(II) species, N2, and CO2 (Scheme 2). The re-
sulting iminyl radical II undergoes intramolecular addi-
tion to a carbonyl group to give alkoxy radical III.
Reduction of this alkoxy radical III by manganese(II) spe-
cies gives manganese(III) alkoxide IV (path a). Alterna-
tively, the reaction of iminyl radical II with
manganese(II) species affords iminylmanganese(III) V,
which attacks a carbonyl group to yield the addition inter-
mediate IV (path b).13 Finally, protonation of IV followed
by dehydration produces pyrrole 3 along with regenera-
tion of manganese(III).
A.; Sweeting, J. A. Bioorg. Med. Chem. Lett. 2007, 17,
1200. (b) Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213.
(c) Micheli, F.; Di Fabio, R.; Benedetti, R.; Capelli, A. M.;
Cavallini, P.; Cavanni, P.; Davalli, S.; Donati, D.; Feriani,
A.; Gehanne, S.; Hamdan, M.; Maffeis, M.; Sabbatini, F. M.;
Tranquillini, M. E.; Viziano, M. V. A. Farmaco 2004, 59,
175. (d) Huffman, J. W. Curr. Med. Chem. 1999, 6, 705.
(e) Roth, B. D.; Blankley, C. J.; Chucholowski, A. W.;
Ferguson, E.; Hoefle, M. L.; Ortwine, D. F.; Newton, R. S.;
Sekerke, C. S.; Sliskovic, D. R.; Stratton, C. D.; Wilson,
M. W. J. Med. Chem. 1991, 34, 357.
(3) (a) Plitt, P.; Gross, D. E.; Lynch, V. M.; Sessler, J. L. Chem.
Eur. J. 2007, 13, 1374. (b) Zhao, W.; Carreira, E. M. Chem.
Synlett 2011, No. 6, 783–786 © Thieme Stuttgart · New York

786
E. P. J. Ng et al.
LETTER
Eur. J. 2006, 12, 7254. (c) Gale, P. A. Acc. Chem. Res.
2006, 39, 465. (d) Nadeau, J. M.; Swager, T. M.
Tetrahedron 2004, 60, 7141. (e) Sessler, J. L.; Camiolo, S.;
Gale, P. A. Coord. Chem. Rev. 2003, 240, 17. (f) Yoon, D.
W.; Hwang, H.; Lee, C. H. Angew. Chem. Int. Ed. 2002, 41,
1757. (g) Seidel, D.; Lynch, V.; Sessler, J. L. Angew. Chem.
Int. Ed. 2002, 41, 1422. (h) Miyaji, H.; Sato, W.; Sessler, J.
L. Angew. Chem. Int. Ed. 2000, 39, 1777. (i)Depraetere, S.;
Smet, M.; Dehaen, W. Angew. Chem. Int. Ed. 1999, 38,
3359.
M. L.; Goljer, I.; Jenkins, D. J.; Mehlmann, J. F.; Nogle, L.;
Dooley, R.; Mahaney, P. E. Org. Lett. 2006, 8, 5837.
(x) Hiroya, K.; Matsumoto, S.; Ashikawa, M.; Ogiwara, K.;
Sakamoto, T. Org. Lett. 2006, 8, 5349. (y) Binder, J. T.;
Kirsch, S. F. Org. Lett. 2006, 8, 2151. (z) Gorin, D. J.;
Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,
11260.
(6) For prior studies on iminyl radical formation from vinyl
azides, see: (a) Montevecchi, P. C.; Navacchia, M. L.;
Spagnolo, P. J. Org. Chem. 1997, 62, 5846. (b) Bamford,
A. F.; Cook, M. D.; Roberts, B. P. Tetrahedron Lett. 1983,
24, 3779.
(7) For reviews of synthesis of azaheterocycles using iminyl
radicals, see: (a) Stella, L. In Radicals in Organic Synthesis,
Vol. 2; Renaud, P.; Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, 2001, 407–426. (b) Mikami, T.; Narasaka, K.
In Advances in Free Radical Chemistry, Vol. 2; Zard, S. Z.,
Ed.; JAI: Greenwich, 1999, 45–88. (c) Fallis, A. G.; Brinza,
I. M. Tetrahedron 1997, 53, 17543. (d) Zard, S. Z. Synlett
1996, 1148.
(4) For recent reviews on the synthesis of pyrroles, see:
(a) Estévez, V.; Villacampa, M.; Menéndez, J. C. Chem. Soc.
Rev. 2010, 39, 4402. (b) Ferreira, V. F.; de Souza, M.;
Cunha, A. C.; Pereira, L. O. R.; Ferreira, M. L. G. Org. Prep.
Proced. Int. 2001, 33, 411. (c) Balme, G. Angew. Chem. Int.
Ed. 2004, 43, 6238. (d) Joshi, U.; Pipelier, M.; Naud, S.;
Dubreuil, D. Curr. Org. Chem. 2005, 9, 261. (e) Patil, N.
T.; Yamamoto, Y. ARKIVOC 2007, (x), 121. (f) Schmuck,
C.; Rupprecht, D. Synthesis 2007, 3095.
(5) For recent selected reports on the synthesis of
polysubstituted pyrroles, see: (a) Rakshit, S.; Patureau,
F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9585.
(b) Morin, M. A. T.; St-Cyr, D. J.; Arndtsen, B. A. Org. Lett.
2010, 12, 4916. (c) Wang, H.-Y.; Mueller, D. S.; Sachwani,
R. M.; Londino, H. N.; Anderson, L. L. Org. Lett. 2010, 12,
2290. (d) Saito, A.; Konishi, T.; Hanzawa, Y. Org. Lett.
2010, 12, 372. (e) Zhao, X.; Zhang, E.; Tu, Y.-Q.; Zhang,
Y.-Q.; Yuan, D.-Y.; Cao, K.; Fan, C.-A.; Zhang, F.-M. Org.
Lett. 2009, 11, 4002. (f) Fu, X.; Chen, J.; Li, G.; Liu, Y.
Angew. Chem. Int. Ed. 2009, 48, 5500. (g) Saito, A.;
Konishi, T.; Hanzawa, Y. Org. Lett. 2009, 12, 372. (h) Lu,
Y.; Arndtsen, B. A. Org. Lett. 2009, 11, 1369. (i) Liu, W.;
Jiang, H.; Huang, L. Org. Lett. 2009, 12, 312. (j) Kiren, S.;
Hong, X.; Leverett, C. A.; Padwa, A. Org. Lett. 2009, 11,
1233. (k) Fontaine, P.; Masson, G.; Zhu, J. Org. Lett. 2009,
11, 1555. (l) Davies, P. W.; Martin, N. Org. Lett. 2009, 11,
2293. (m) Aponick, A.; Li, C.-Y.; Malinge, J.; Marques, E.
F. Org. Lett. 2009, 11, 4624. (n) Mizuno, A.; Kusama, H.;
Iwasawa, N. Angew. Chem. Int. Ed. 2009, 48, 8318.
(o) Ackermann, L.; Sandmann, R.; Kaspar, L. T. Org. Lett.
2009, 11, 2031. (p) Lu, Y.; Arndtsen, B. A. Angew. Chem.
Int. Ed. 2008, 47, 5430. (q) Cacchi, S.; Fabrizi, G.; Filisti, E.
Org. Lett. 2008, 10, 2629. (r) Attanasi, O. A.; Favi, G.;
Filippone, P.; Giorgi, G.; Mantellini, F.; Moscatelli, G.;
Spinelli, D. Org. Lett. 2008, 10, 1983. (s) St. Cyr, D. J.;
Arndtsen, B. A. J. Am. Chem. Soc. 2007, 129, 12366.
(t) Cadierno, V.; Gimeno, J.; Nebra, N. Chem. Eur. J. 2007,
13, 9973. (u) Su, S.; Porco, J. A. Jr. J. Am. Chem. Soc. 2007,
129, 7744. (v) Martín, R.; Rodríguez Rivero, M.; Buchwald,
S. L. Angew. Chem. Int. Ed. 2006, 45, 7079. (w) Crawley,
(8) For our previous communications based on this concept for
the synthesis of azaheterocycles, see: (a) Wang, Y.-F.;
Chiba, S. J. Am. Chem. Soc. 2009, 131, 12570. (b) Wang,
Y.-F.; Toh, K. K.; Chiba, S.; Narasaka, K. Org. Lett. 2008,
10, 5019.
(9) Fortner, K. C.; Shair, M. D. J. Am. Chem. Soc. 2007, 129,
1032.
(10) Narasaka, K.; Miyoshi, N.; Iwakura, K.; Okauchi, T. Chem.
Lett. 1989, 18, 2169.
(11) Mn(OAc)3, Mn(pic)3, and Mn(acac)3 possess different redox
potentials, see: Richert, S. A.; Tsang, P. K. S.; Sawyer, D. T.
Inorg. Chem. 1988, 27, 1814.
(12) For the addition of manganese(III) enolate to alkenes to give
alkyl radicals, see: Snider, B. B.; Patricia, J. J.; Kates, S. A.
J. Org. Chem. 1988, 53, 2137.
(13) 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.
(14) General Procedure for Mn(acac)3-Catalyzed Pyrrole
Formation from Vinyl Azides and b-Keto Acids: To a
solution of a-azido styrene (1a; 52.8 mg, 0.364 mmol) and
2-oxocyclohexanecarboxylic acid (2a; 155.2 mg, 1.09
mmol) in DMF (3.6 mL) was added Mn(acac)3 (12.8 mg,
0.0364 mmol) and the mixture was stirred for 5 h. The
reaction mixture was quenched with a pH 9 ammonium
buffer, and then extracted with Et2O (2 ×). The combined
organic extracts were washed with brine, dried over MgSO4
and concentrated. Purification of the crude product by flash
column chromatography (florisil; hexane–EtOAc = 97:3)
afforded 3aa (59.5 mg, 0.302 mmol) in 83% yield.
Synlett 2011, No. 6, 783–786 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.