Gold-catalyzed synthesis of tetrahydrocarbazole derivatives through an intermolecular cycloaddition of vinyl indoles and N-allenamides

Article abstract of DOI:10.1039/c3cc41514g

A gold-catalyzed formal [4+2] cycloaddition of vinyl indoles and N-allenamides leading to tetrahydrocarbazoles is described. Moreover, new multicomponent reactions of vinyl indoles with two allene molecules are reported.

Full text of DOI:10.1039/c3cc41514g

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Gold-catalyzed synthesis of tetrahydrocarbazole
derivatives through an intermolecular cycloaddition
of vinyl indoles and N-allenamides†
Cite this: Chem. Commun., 2013,
49, 3594
Received 27th February 2013,
Accepted 12th March 2013
b
b
a
Valentina Pirovano,ab Laura Decataldo, Elisabetta Rossi* and Ruben Vicente*
´
DOI: 10.1039/c3cc41514g
www.rsc.org/chemcomm
A gold-catalyzed formal [4+2] cycloaddition of vinyl indoles and and N-allenamides, as well as, gold-catalyzed multicomponent
N-allenamides leading to tetrahydrocarbazoles is described. More- reactions, leading to densely functionalized tetrahydrocarbazoles.
over, new multicomponent reactions of vinyl indoles with two
allene molecules are reported.
At the outset, we evaluated the reaction of vinyl indoles with
representative allenes. Among various allenes probed,12 we found
that the use of vinyl indoles 1a-b with allenamide 2a gave rise to
Recent developments in homogeneous gold catalysis have hydroarylation products 3a-b in moderate yields when using the
impacted on organic chemistry, becoming nowadays a common cationic gold catalyst [Au(PPh3)(NTf2)].13 Assuming that the reac-
and valuable synthetic tool.1 Intramolecular gold-catalyzed cycli- tion took place via intermediate I, enhancement of the electro-
zations have been broadly studied offering a forthright access philicity of the b-carbon on the vinyl moiety might likely facilitate
to a plethora of relevant scaffolds. Among unsaturated sub- the ring closure. Indeed, when we employed vinyl indole 1c,
strates involved in these transformations, allenes offered an bearing a carbamate at N-1, under the previous reaction condi-
incomparable versatility since they participate in [2+2], [4+2] or tions, the desired tetrahydrocarbazole 4a was obtained, along with
[4+3] cyclizations.2 In contrast, intermolecular gold-catalyzed the unexpected compound 5a (81% combined yield) (Scheme 1).
cycloadditions with allenes have been less studied.3 In this The formation of 5a is remarkable since it resulted from a three-
sense, significant gold-catalyzed intermolecular [2+2]4 and component reaction involving two allene molecules. To our
[4+2]5 cycloadditions have been recently reported,6 including knowledge, there are no reports on this transformation in gold
examples of enantioselective versions.7,8
Besides, tetrahydrocarbazole derivatives are important conditions and evaluated the scope of these transformations.
catalysis with allenes. Therefore, we searched for selective reaction
structures which are key motifs in natural alkaloids and bio-
An extensive screening led us to find reaction conditions which
logically active compounds.9 Thus, the development of syn- enabled a selective access to the desired products (Scheme 2a).14
thetic approaches to this class of compounds constitutes a
relevant field of research. Due to our interest in the preparation
of functionalized carbazole derivatives10 and based on the
5b
˜
recent work of Mascarenas et al., we decided to study the
viability of gold-catalyzed intermolecular cycloadditions of allenes
and vinyl indoles,11 which might offer a simple and selective
access to these relevant structures. Herein, we report our
findings on selective formal [4+2]-cycloadditions of vinyl indoles
a
´
´
Instituto Universitario de Quımica Organometalica ‘‘Enrique Moles’’ and
´
´
´
Departamento de Quımica Organica e Inorganica, Universidad de Oviedo,
´
´
c/Julian Claverıa 8, 33007 Oviedo, Spain. E-mail: vicenteruben@uniovi.es;
Tel: +34 985103075
b Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Generale e Organica
`
‘‘A. Marchesini’’, Universita degli Studi di Milano, Via Venezian 21,
20133 Milano, Italy. E-mail: elisabetta.rossi@unimi.it; Fax: +39 0250314476
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data and NMR spectra of new compounds. CCDC
923923 (4a), 923924 (4a0) and 924119 (5a). For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c3cc41514g
Scheme 1 Gold-catalyzed reactions of vinyl indoles 1a–1c with allene 2a: initial
findings (isolated yields with respect to 1).
c
3594 Chem. Commun., 2013, 49, 3594--3596
This journal is The Royal Society of Chemistry 2013

View Article Online
Communication
ChemComm
Scheme 3 Gold-catalyzed selective [4+2]-cycloadditions leading to tetrahydro-
carbazoles 4/40 (isolated yields in parentheses).
with lower yields. Modifications of the allenamide were probed as
well using allenes derived from 2-pyrrolidone (2b) and tosylamides
(2c-d). In this manner, the corresponding derivatives 4h–4j were
selectively obtained in good yields. Besides, using reaction conditions
B, representative examples of isomeric tetrahydrocarbazoles 40 were
prepared, generally in good yields and with complete selectivity
(Scheme 3). Other substitution patterns of the vinyl moiety notice-
ably affected the reaction outcome. Thus, the use of an a-phenyl
substituted 2-vinyl indole gave rise to 4k sluggishly under conditions
A, however, under conditions B, compound 4k0 was obtained almost
quantitatively. Moreover, the use of a b,b-disubstituted 2-vinyl indole
afforded the hydroarylation product (see ESI† for details).
Scheme 2 Gold-catalyzed selective cycloadditions of 1c with 2a: (a) optimized
reaction conditions; (b) mechanistic probes.
Thus, tetrahydrocarbazole 4a was obtained in 83% yield as the
only reaction product using AuCl3 at ꢀ50 1C in CH2Cl2 (0.1 M)
with a dropwise addition of a solution of the allene (0.9 equiv.,
conditions A). Interestingly,
a change of the catalyst to
[Au(JohnPhos)(NTf2)], under similar reaction conditions, gave rise
solely to isomeric tetrahydrocarbazole 4a0 in 80% yield as a single
diastereoisomer (conditions B). As expected, the formation of multi-
component cycloadduct 5a was favoured using an excess of the
allene (2.5 equiv.). For this transformation, [Au(JohnPhos)(NTf2)]
provided 5a with complete selectivity in almost quantitative yield
(95%, conditions C). It should be noted that PtCl2 did not promote
any reaction, while PtBr2(cod) afforded the hydroarylation product
6a (conditions D). The structure of compounds 4–5a was established
using NMR studies and confirmed using X-Ray analysis.† Moreover,
various experiments showed that both 4a and 5a arise from
compound 4a0 (Scheme 2b). Thus, treatment of 4a0 with AuCl3 or
[Au(PPh3)(NTf2)] led to the aromatized product 4a (>95%). In
contrast, the use of [Au(JohnPhos)(NTf2)] as catalyst in the presence
of 2a (1.5 equiv.) gave rise to 5a (90%) likely through a hydroaryl-
ation process.15,16 Interestingly, compound 6a could not be con-
verted into 4–5a under optimized reaction conditions, pointing out
that the cyclization occurred through the proposed intermediate I.16
With optimized reaction conditions in hand, we next evaluated
the scope of these cycloadditions. First, we focused on isomeric
tetrahydrocarbazoles 4/40 (Scheme 3). Under reaction conditions A
using allenamide 2a, we tested various vinyl indoles bearing arenes
with different electronic properties at the b-position. In this manner,
compounds 4a–4e were obtained in good yields as single Z-stereo-
isomers. Similarly, b-alkyl substituted vinyl indoles (R1 = Pr, Bn)
Next, we focused our studies on the preparation of the multi-
component-derived tetrahydrocarbazoles 5 (Scheme 4). As before,
various vinyl indoles were evaluated using allenamide 2a. Under
the optimized conditions C, highly substituted tetrahydrocarbazole
Scheme 4 Gold-catalyzed multicomponent synthesis of tetrahydrocarbazoles 5
were also converted into the desired tetrahydrocarbazoles 4f-g, albeit (isolated yields in parentheses).
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 3594--3596 3595

View Article Online
ChemComm
Communication
and M. Sabater, Chem. Rev., 2011, 111, 1657; (e) Modern Gold
Catalyzed Synthesis, ed. A. S. K. Hashmi and F. D. Toste,
Wiley-VCH, Weinheim, 2012.
´
2 For representative examples, see: (a) P. Mauleon, R. M. Zeldin,
´
A. Z. Gonzalez and F. D. Toste, J. Am. Chem. Soc., 2009, 131, 6348;
´
´
(b) B. Trillo, F. Lopez, S. Montserrat, G. Ujaque, L. Castedo, A. Lledos
˜
and J. L. Mascarenas, Chem.–Eur. J., 2009, 15, 3336; (c) B. Trillo,
´
´
˜
F. Lopez, M. Gulıas, L. Castedo and J. L. Mascarenas, Angew. Chem.,
Int. Ed., 2008, 47, 951; (d) H. Teller, S. Flu¨gge, R. Goddard and
A. Fu¨rstner, Angew. Chem., Int. Ed., 2010, 49, 1949; (e) I. Alonso,
´
´
B. Trillo, F. Lopez, S. Montserrat, G. Ujaque, L. Castedo, A. Lledos
˜
and J. L. Mascarenas, J. Am. Chem. Soc., 2009, 131, 13020.
3 For selected examples on intermolecular cycloadditions with gold,
´
excluding allenes, see: (a) V. Lopez-Carrillo and A. M. Echavarren,
Scheme 5 Gold-catalyzed intermolecular cycloadditions: with (a) 3-vinyl indole
7; (b) and benzofuran 10 (isolated yields in parentheses).
´
J. Am. Chem. Soc., 2010, 132, 9292; (b) J. Barluenga, M. A. Fernandez-
´
´
´
Rodrıguez, P. Garcıa-Garcıa and E. Aguilar, J. Am. Chem. Soc., 2008,
130, 2764; (c) A. D. Melhado, M. Luparia and F. D. Toste, J. Am.
Chem. Soc., 2007, 129, 12638; (d) B. W. Gung, L. N. Bailey and
J. Wonser, Tetrahedron Lett., 2010, 51, 2251; (e) N. D. Shapiro and
F. D. Toste, J. Am. Chem. Soc., 2008, 130, 9244; ( f ) N. Asao,
K. Takahashi, S. Lee, T. Kasahara and Y. Yamamoto, J. Am. Chem.
Soc., 2002, 124, 12650. For a review on [4+2]-cycloadditions using
o-alkynylbenzaldehyde derivatives, see: (g) N. Asao, Synlett, 2006,
1645. For recent reviews on gold-catalyzed cycloadditions, see:
(h) F. Lopez and J. L. Mascarenas, Beilstein J. Org. Chem., 2011,
7, 1075; (i) D. Garayalde and C. Nevado, ACS Catal., 2012, 2, 1462.
4 (a) X.-X. Li, L.-L. Zhu, W. Zhou and Z. Chen, Org. Lett., 2012, 14, 436;
(b) S. Suarez-Pantiga, C. Hernandez-Dıaz, M. Piedrafita, E. Rubio and
J. M. Gonzalez, Adv. Synth. Catal., 2012, 354, 1651; (c) H. Faustino,
derivatives 5a–5e bearing aryl substituents (R1) were obtained
in good yields. Similarly, vinyl indoles with alkyl groups gave
rise to compounds 5f-g efficiently. Further modifications of the
allene proved difficult, since complex mixtures of isomers
arising from the multicomponent process were detected.17
However, in a preliminary experiment accomplished by means
of a sequential addition of the allenes (2b and 2a), tetrahydro-
carbazole 5h was prepared in good yield.
´
˜
´
´
´
´
´
˜
P. Bernal, L. Castedo, F. Lopez and J. L. Mascarenas, Adv. Synth. Catal.,
2011, 354, 1658.
Finally, we extended our study to related substrates (Scheme 5).
Thus, the reaction of 3-vinyl indole 7 with allenamide 2a using the
optimized reaction conditions led to tetrahydrocarbazole deriva-
tives 8 and 9. Importantly, compounds 8 and 9 display a com-
plementary substitution pattern to those obtained previously,
which could be relevant for a rational synthetic design for these
relevant scaffolds. Moreover, we applied this methodology to the
corresponding vinyl benzofuran 10, which could be converted into
the tricycle 11 in moderate yield.
5 (a) G. Wang, Y. Zou, Z. Li, Q. Wang and A. Goeke, Adv. Synth. Catal.,
2011, 353, 550; (b) H. Faustino, F. Lopez, L. Castedo and
J. L. Mascarenas, Chem. Sci., 2011, 2, 633.
6 For a platinum-catalyzed [3+2] cycloaddition with allenes as C3
synthons, see: H. Kusama, M. Ebisawa, H. Funami and N. Iwasawa,
J. Am. Chem. Soc., 2009, 131, 16352.
´
˜
´
´
´
7 Asymmetric [2+2]: S. Suarez-Pantiga, C. Hernandez-Dıaz, E. Rubio
´
and J. M. Gonzalez, Angew. Chem., Int. Ed., 2012, 51, 11552.
8 Asymmetric [4+2]: J. Francos, F. Grande-Carmona, H. Faustino,
´
´
J. Iglesias-Sigu¨enza, E. Dıez, I. Alonso, R. Fernandez, J. M. Lassaletta,
´
˜
F. Lopez and J. L. Mascarenas, J. Am. Chem. Soc., 2012, 134, 14322.
In summary, we have reported a modular approach to synthesis
of a relevant class of compounds like tetrahydrocarbazoles through a
gold-catalyzed intermolecular [4+2]-cycloaddition of readily available
2-vinyl indoles and N-allenamides. An appropriate selection of the
substituent at N-1 on the indole and the reaction conditions enabled
the selective preparation of isomeric tetrahydrocarbazoles 4 and 40.
Interestingly, we also found conditions which led to carbazole
derivatives 5 arising from unusual gold-catalyzed multicomponent
cycloaddition cascade sequences with participation of two allene
molecules.18 An extension of this methodology to 3-vinyl indoles
enables the preparation of complementarily substituted carbazoles 8
and 9. Further studies concerning the asymmetric version of these
reactions and the scope extension for multicomponent gold-
catalyzed reactions are currently ongoing in our laboratories.
We thank the MINECO-Spain (Grant CTQ2012-20517-C02-01
¨
9 For reviews, see: (a) H.-J. Knolker and K. R. Reddy, Chem. Rev., 2002,
102, 4303; (b) J. Roy, A. K. Jana and D. Mal, Tetrahedron, 2012,
68, 6099. Selected examples of intramolecular gold-catalyzed trans-
formation for the preparation of (tetrahydro)carbazole derivatives:
(c) L. Wang, G. Li and Y. Liu, Org. Lett., 2011, 13, 3786; (d) Y. Qiu,
W. Kong, C. Fu and S. Ma, Org. Lett., 2012, 14, 6198; M. Bandini,
A. Bottoni, M. Chiarucci, G. Cera and G.-P. Miscione, J. Am. Chem.
Soc., 2012, 134, 20690.
10 (a) G. Abbiati, V. Canevari, D. Facoetti and E. Rossi, Eur. J. Org.
Chem., 2007, 517; (b) V. Pirovano, G. Abbiati, M. Dell’Acqua,
D. Facoetti, M. Giordano and E. Rossi, Synlett, 2012, 2910.
11 For
a review on [4+2]-cycloadditions with vinyl indoles, see:
(a) R. F. Kester, S. J. Berthel and F. Firooznia, Top. Heterocycl. Chem.,
2010, 26, 327. For selected examples, see: (b) C. Gioia, A. Hauville,
L. Bernardi, F. Fini and A. Ricci, Angew. Chem., Int. Ed., 2008,
´
47, 9236; (c) B. Tan, G. Hernandez-Torres and C. F. Barbas III,
J. Am. Chem. Soc., 2011, 133, 12354; (d) S. B. Jones, B. Simmons and
D. W. C. MacMillan, J. Am. Chem. Soc., 2009, 131, 13606.
12 Under various reaction conditions, we tested 1,1-dimethylallene,
phenylallene and ethyl 2,3-butadienoate.
13 For previous reports on N-allenamide hydroarylations, see: (a) M. C.
Kimber, Org. Lett., 2010, 12, 1128; (b) S. Singh, M. R. J. Elsegook and
M. C. Kimber, Synlett, 2012, 565.
´
and Ramon
y Cajal fellowship to R.V.) and MIUR-Italy
(PhD fellowship to V. P.) for financial support. Dr J. Borge and
´
A. L. Suarez-Sobrino are acknowledged for the X-ray analysis. We
14 See ESI† for a detailed screening.
´
thank Prof. Dr J. M. Gonzalez for helpful discussions.
15 See ref. 4c for gold-catalyzed [2+2]-cycloadditions with enamides.
16 For a mechanistic proposal on these transformations, see ESI†.
17 When using allenes 2c and 2d an unseparable mixture of isomers arising
from multicomponent reactions was observed by GC-MS analysis. All
attempts to purification/characterization of the mixtures failed.
Notes and references
1 For the pioneering work on homogeneous gold catalysis, see:
(a) A. S. K. Hashmi, L. Schwarz, J.-H. Choi and T. M. Frost, Angew. 18 A reaction involving the addition of two enol ethers to o-alkynyl-
Chem., Int. Ed., 2000, 39, 2285. Selected reviews: (b) A. S. K. Hashmi
and M. Bu¨hrle, Aldrichimica Acta, 2010, 43, 27; (c) N. Krause and
benzaldehydes has been very recently reported, see: D. Malhotra,
L.-P. Liu, M. S. Mashuta and G. B. Hammond, Chem.–Eur. J., 2013,
19, 4043.
´
C. Winter, Chem. Rev., 2011, 111, 1994; (d) A. Corma, A. Perez-Leyva
c
3596 Chem. Commun., 2013, 49, 3594--3596
This journal is The Royal Society of Chemistry 2013