Gold(I)-catalyzed cyclization of β-allenylhydrazones: An efficient synthesis of multisubstituted N-aminopyrroles

Article abstract of DOI:10.1021/ol101889h

Figure Presented. The gold(I)-catalyzed cycloisomerization of β-allenylhydrazones provides an efficient access to multisubstituted N-aminopyrroles, which are obtained in good to excellent yields. This new intramolecular cyclization method can be applied either to alkyl- or aryl-substituted allenes. The reaction proceeds under mild conditions with short reaction times through a selective intramolecular 1,2-alkyl or -aryl migration extending the general scope of the reaction.

Full text of DOI:10.1021/ol101889h

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4396-4399
Gold(I)-Catalyzed Cyclization of
ꢀ-Allenylhydrazones: An Efficient
Synthesis of Multisubstituted
N-Aminopyrroles
Erica Benedetti,†,‡ Gilles Lemie`re,† Laure-Lise Chapellet,† Andrea Penoni,‡
Giovanni Palmisano,‡ Max Malacria,*,† Jean-Philippe Goddard,*,† and
Louis Fensterbank*,†
Institut Parisien de Chimie Mole´culaire (UMR CNRS 7201), FR 2769 UPMC-Paris 06,
C. 229, 4 Place Jussieu, 75005, Paris, France, and Dipartimento di Scienze Chimiche e
Ambientali, UniVersita` degli Studi dell’Insubria, 11 Via Valleggio, 22100, Como, Italy
louis.fensterbank@upmc.fr; jean-philippe.goddard@upmc.fr; max.malacria@upmc.fr
Received August 11, 2010
ABSTRACT
The gold(I)-catalyzed cycloisomerization of ꢀ-allenylhydrazones provides an efficient access to multisubstituted N-aminopyrroles, which are
obtained in good to excellent yields. This new intramolecular cyclization method can be applied either to alkyl- or aryl-substituted allenes. The
reaction proceeds under mild conditions with short reaction times through a selective intramolecular 1,2-alkyl or -aryl migration extending the
general scope of the reaction.
Platinum- and gold-catalyzed cycloisomerization of poly-
unsaturated compounds has attracted considerable attention
due to the significant increase in molecular complexity
achieved in a single synthetic step.1 In the past few years,
our group and others have reported several examples of
enyne and allenyne cycloisomerizations to form (poly)cyclic
compounds.
Recently, we envisaged developing straightforward pro-
cedures employing functionalized allenes for the synthesis
of heterocyclic compounds.2 In particular, we focused our
attention on highly substituted pyrroles.
† Institut Parisien de Chimie Mole´culaire.
‡ Universita` degli Studi dell’Insubria.
(1) For selected reviews, see: (a) Hashmi, A. S. K. Chem. ReV. 2007,
107, 3181. (b) Jime´nez-Nu´n˜ez, E.; Echavarren, A. M. Chem. ReV. 2008,
108, 3326. (c) Fu¨rstner, A. Chem. Soc. ReV. 2009, 38, 3208. (d) Michelet,
V.; Toullec, P. Y.; Genet, J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268. For
recent contributions of our group, see: (e) Moreau, X.; et al. AdV. Synth.
Catal. 2008, 350, 43. (f) Moreau, X.; Hours, A.; Fensterbank, L.; Goddard,
J. P.; Malacria, M.; Thorimbert, S. J. Organomet. Chem. 2009, 694, 561.
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Dhimane, A. L.; Fensterbank, L.; Malacria, M. J. Am. Chem. Soc. 2009,
131, 29930. (h) Marion, N.; et al. Chem.sEur. J. 2009, 15, 3243. (i) Harrak,
Y.; Simonneau, A.; Malacria, M.; Gandon, V.; Fensterbank, L. Chem.
Commun 2010, 46, 865. For recent contributions of other groups, see: (j)
Molawi, K.; Delpont, N.; Echavarren, A. M. Angew. Chem., Int. Ed. 2010,
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Org. Lett. 2009, 11, 2888.
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M.; Apuzzo, G.; Simonetti, H. G.; Strippoli, V. J. Med. Chem. 1995, 38,
4223. (b) Carson, J. R.; Carmosin, R. J.; Pitis, P. M.; Vaught, J. L.; Almond,
H. R.; Stables, J. P.; Wolf, H. H.; Swinyard, E. A.; White, H. S. J. Med.
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10.1021/ol101889h  2010 American Chemical Society
Published on Web 09/08/2010

These compounds are ubiquitous constituents in pharma-
ceuticals3 or natural products4 and are also frequently used
as subunits in material sciences.5 Several groups are currently
investigating transition-metal-catalyzed synthesis of these
heteroaromatic compounds.6 However, many procedures still
present limitations in terms of substituents, which in turn
narrow the substrate scope. Thus, the development of
versatile methods for the direct access to functionalized
pyrroles is highly desirable.
Herein, we report a new gold(I)-catalyzed cycloisomer-
ization of ꢀ-allenylimines and ꢀ-allenylhydrazones, which
allows the formation of 2,3,5-substituted pyrroles through a
selective intramolecular [1,2] alkyl or aryl shift extending
the scope of the reaction.
screened, and catalyst I was found to promote the desired
cycloisomerization in THF, at 100 °C, under microwave
irradiation (30 W) for 20 min. Under these conditions, pyrrole
3 could be isolated as the only product, albeit in a low but
encouraging 15% yield.
The anticipated reduced nucleophilicity and stability of
ꢀ-allenylimines prompted us to examine the gold(I)-catalyzed
cycloisomerization of ꢀ-allenylhydrazones, readily available
from the corresponding ꢀ-allenylaldehydes and easily purified
by silica gel chromatography.8
The proposed cycloisomerization was first investigated
using ꢀ-allenylhydrazone 4a under microwave conditions in
dichloroethane (DCE) at 100 °C for 20 min with 5 mol %
of Echavarren’s catalyst (I). Gratifyingly, the expected
cycloisomerization/1,2-alkyl migration proceeded smoothly
to give the corresponding pyrrole 5a in 57% yield (Table 1,
To probe the viability of this cycloisomerization process,
we first investigated the reactivity of ꢀ-allenylimine7 2 as
model. Treatment of this compound with 5 mol % of AuCl,
AuCl3, and catalysts I or II, respectively (Scheme 1), in
Table 1. Catalysts Screening for Pyrrole Synthesisa
Scheme 1. Cycloisomerization Reactions of ꢀ-Allenylimines
entry
catalyst
solvent
product (%)
1
2
3
4
5
6
7
8
I
I
THF
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
51
57
SM
SM
55
SM
traces
SM
SM
SM
SM
SM
SM
AuCl3
AuCl
II
AgNO3
AgSbF6
AgOTf
CuI
Cu(OTf)2
FeCl3
TfOH
HN(OTf)2
CH2Cl2 at room temperature resulted in the recovery of the
starting material. A set of different reaction conditions were
9
10
11
12
13
(4) See, for example: (a) Fu¨rstner, A.; Grabowski, E. J. ChemBioChem
2001, 2, 706. (b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582. (c)
Fu¨rstner, A.; Reinecke, K.; Prinz, H.; Waldmann, H. ChemBioChem 2004,
5, 1575. (d) Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213. (e) McArthur,
K. A.; Mitchell, S. S.; Tsueng, G.; Rheingold, A.; White, D. J.; Grodberg,
J.; Lam, K. S.; Potts, B. C. M. J. Nat. Prod. 2008, 71, 1732. (f) Mao, S. C.;
Liu, Y.; Morgan, J. B.; Jekabson, M. B.; Zhou, Y. D.; Nagle, D. G. J. Nat.
Prod. 2009, 72, 1927.
a Conditions: 0.2 mmol of 4a (c ) 57 mM), 5 mol % of catalyst, µW,
100 °C, 20 min.
(5) (a) Curran, D.; Grimshaw, J.; Perera, S. D. Chem. Soc. ReV. 1991,
20, 391. (b) Facchetti, A.; Abbotto, A.; Beverina, L.; Van der Boom, M. E.;
Dutta, P.; Evmenenko, G.; Pagani, G. A.; Marks, T. J. Chem. Mater. 2003,
15, 1064. (c) Is, O. D.; Koyuncu, F. B.; Koyuncu, S.; Ozdemir, E. Polymer
2010, 51, 1663.
entry 2). Other catalysts known to induce isomerization
processes (Au(I), Au(III) Ag(I),9 Cu(I),10 Cu(II), and
Fe(III)11) were screened, but catalysts I and II turned out to
be the most effective (Table 1, entries 2 and 5).
(6) (a) Dieter, R. K.; Yu, H. Org. Lett. 2001, 3, 3855. (b) Kim, J. T.;
Kel’in, A.; Gevorgyan, V. Angew. Chem., Int. Ed. 2003, 42, 98. (c) Gorin,
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Binder, J. T.; Kirsch, S. F. Org. Lett. 2006, 8, 3855. (f) Zhang, Z.; Liu, C.;
Kinder, R. E.; Han, X.; Quian, H.; Widenhoefer, R. A. J. Am. Chem. Soc.
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P. Chem. Commun. 2010, 5157.
(8) For the synthesis of ꢀ-allenylhydrazones, see the Supporting
Information. For radical cyclizations of ꢀ-allenylhydrazones, see: (a) Marco-
Contelles, J.; Blame, G.; Bouyssi, D.; Destabel, C.; Henriet-Bernard, C. D.;
Grimaldi, J.; Hatem, J. M. J. Org. Chem. 1997, 62, 1202. (b) Departure,
M.; Grimaldi, J.; Hatem, J. M. Eur. J. Org. Chem. 2001, 941.
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8755. (b) Cordier, P.; Aubert, C.; Malacria, M.; Lacoˆte, E.; Gandon, V.
Angew. Chem., Int. Ed. 2009, 48, 8757. (c) Belmont, P.; Parker, E. Eur. J.
Org. Chem. 2009, 6075.
(10) Cu-catalyzed cyclization of iminoallenes to pyrroles has been
reported; see: (a) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am.
Chem. Soc. 2001, 123, 2074. (b) Nedolya, N. A.; Brandsma, L.; Tplmachev,
S. V. Chem. Heterocycl. Compd. 2002, 38, 745. (c) Brandsma, L.; Nedolya,
N. A.; Tplmachev, S. V. Chem. Heterocycl. Compd. 2002, 38, 54. (d)
Tsuhako, A.; Oikawa, D.; Sakai, K.; Okamoto, S. Tetrahedron Lett. 2008,
49, 6529.
(7) For the synthesis of ꢀ-allenylaldehydes and ꢀ-allenylimines, see the
Supporting Information. In our hands, ꢀ-allenylaldehydes have not been
reactive under gold catalysis.
Org. Lett., Vol. 12, No. 19, 2010
4397

These promising results incited us to explore the scope of
the reaction using various ꢀ-allenylhydrazones (Table 2).
Table 3. Cycloisomerization Reactions of
2,4-Dinitrophenylhydrazones and Carboxymethyl Hydrazones
Table 2. Cycloisomerization Reactions of Tosylhydrazones
a Conditions: 0.2 mmol of SM (c ) 57 mM), 5 mol % of catalyst I,
µW, DCE, 100 °C, 20 min. b Conditions: 0.2 mmol of SM (c ) 57 mM),
5 mol % of catalyst II, µW, DCE, 100 °C, 20 min.
Under the optimized conditions, isomerization of ꢀ-allenyl-
hydrazones 4a-h afforded the desired pyrroles 5a-h in good
to excellent yields. A variety of aryl and alkyl groups were
tolerated at the allenyl terminus position. Interestingly,
selective 1,2 migration of ethyl group over the methyl group
occurred both in ꢀ-allenylhydrazones 4f and 4g to give
products 5f and 5g in 94% and 71% yields, respectively
(Table 2, entries 6 and 7). An analogous selective 1,2
migration of the phenyl group over the methyl group was
also observed in the cyclization of ꢀ-allenylhydrazone 4h,
which is in accordance with the results of Gevorgyan (Table
2, entry 8).12
Substitution influence at the nitrogen atom was then
examined with ꢀ-allenyl-2,4-dinitrophenylhydrazones 6a-j
as shown in Table 3.
a Conditions: 0.2 mmol of SM (c ) 57 mM), 5 mol % of catalyst I,
µW, DCE, 100 °C, 20 min. b Conditions: 0.2 mmol of SM (c ) 57 mM),
5 mol % of catalyst II, µW, DCE, 100 °C, 20 min.
(11) For selected reviews, see: (a) Bolm, C.; Legros, J.; Le Paih, J.;
Zani, L. Chem. ReV. 2004, 104, 6217. (b) Correa, A.; Garcia Mancheño,
O.; Bolm, C. Chem. Soc. ReV. 2008, 37, 1108. (c) Nieto-Oberhuber, C.;
Muñoz, M. P.; López, S.; Jiménez-Núñez, E.; Nevado, C.; Herrero-Gómez,
E.; Raducan, M.; Echavarren, A. M. Chem.-Eur. J. 2006, 12, 1677.
(12) (a) Dudnik, A. S.; Sromek, A. W.; Rubina, M; Kim, J. T.; Kel’in,
A. V.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 1440. (b) Dudnik,
A. S.; Xia, Y.; Li, Y.; Gevorgyan, V. J. Am. Chem. Soc. 2010, 132, 7645.
In this case, the cyclization took place to produce 7a-j
in excellent yields. Once again, selective 1,2-migration of
the ethyl and phenyl groups over the methyl group yielded
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Org. Lett., Vol. 12, No. 19, 2010

pyrroles 7f, 7g, and 7h in very high yields from the
corresponding ꢀ-allenylhydrazones 6f, 6g, and 6h (Table 3,
entries 6-8). Clear NOE correlations between the proton of
the pyrrole ring and the methyl group confirmed the
regiochemistry of compounds 7f and 7h.13
Scheme 2. Proposed Mechanism
To our delight, cyclization and subsequent ring expansion
of cyclopentylallenyl hydrazone 6i provided fused pyrrole
7i in quantitative yield (Table 3, entry 9). Cyclohexylallenyl
hydrazone 6j was also employed affording the desired fused
bicyclic product 7j in 83% yield (Table 3, entry 10).
We then demonstrated the feasibility of this cycloisomer-
ization process using ꢀ-allenylmethylhydrazone carboxylates
8a-c, which would constitute an interesting atom-economi-
cal approach to this convenient pyrrole synthesis. Under the
optimized conditions, isomerization proceeded smoothly to
yield pyrroles 9a-c with good reaction efficiency (Table 3,
entries 11-13). Moreover, this type of compounds could
possess valuable antitubercular activity.14
through a [1,2] alkyl or aryl shift.16 Final rearomatization
of intermediate B provides the desired pyrrole C.
In conclusion, we developed an original and easy to handle
gold(I)-catalyzed cycloisomerization of ꢀ-allenylhydrazones
for the synthesis of functionalized pyrroles. Selective in-
tramolecular 1,2-alkyl or -aryl migrations were observed,
extending the general scope of this reaction. This protocol
was effective for a broad range of N-substituted precursors
and tolerated both alkyl and aryl groups at the terminal
allenyl atom.
Finally, structure of pyrrole 7d was confirmed by X-ray
crystallographic analysis, clarifying the general scope of the
reaction (Figure 1).15
Development of a convenient one-pot reaction for the rapid
conversion of readily available ꢀ-allenylaldehydes into
multisubstituted pyrroles is currently under investigation in
our laboratory.
Acknowledgment. This work was supported by MRES,
CNRS, IUF, and the ANR Blan 0302 “Alle`nes”. Special
thanks to G. Gontard (UPMC) for the X-ray structure
determination of 7d and to M. Amatore (UPMC) for her
careful reading of the manuscript.
Figure 1. X-ray structure of compound 7d.
A possible mechanism for these cyloisomerizations is
outlined in Scheme 2. An initial π-complexation of the allene
moiety to the Au(I) entity triggers the nitrogen nucleophilic
attack at the central atom of the allene. This leads to the
reactive zwitterion A, which evolves to the formation of B
Supporting Information Available: Experimental pro-
cedures and spectral data for all new products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL101889H
(13) The regiochemistry of 5f, 5g, 5h, and 7g has been assigned by
analogy with compounds 7f and 7h.
(14) Hearn, M. J.; Chen, M. F.; Terrot, M. S.; Webster, E. R.; Cynamon,
M. H. J. Heterocycl. Chem. 2010, 47, 707.
(16) For a review, see: (a) Corne, B.; Kirsch, S. F. Chem.sEur. J. 2008,
14, 3514. For tutorial discussion about migratory aptitudes, see: Smith,
M. B.; March, J. AdVanced Organic Chemistry: Reactions, Mechanisms,
and Structure, 4th ed.; Wiley & Sons: New York, 1992; Chapter 18, p
1051.
(15) CCDC 784441 contains the supplementary crystallographic data
for 7d that can be obtained, free of charge, from the Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/conts/retrieving.html.
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