Gold(I)-catalyzed tandem reactions initiated by 1,2-indole migrations

Article abstract of DOI:10.1002/anie.200802660

(Chemical Equation Presented) Take your pick! Indene-containing indole scaffolds have been catalytically prepared from C3-propargylated indoles by tandem reactions involving an initial 1,2-indole migration. This unprecedented process generates a gold carbene complex and proceeds through either a formal C-H insertion or a Nazarov cyclization (see scheme).

Full text of DOI:10.1002/anie.200802660

Communications
DOI: 10.1002/anie.200802660
Gold Catalysis
Gold(I)-Catalyzed Tandem Reactions Initiated by 1,2-Indole
Migrations**
Roberto Sanz,* Delia Miguel, and FØlix Rodríguez
Dedicated to Professor Rafael Pedrosa on the occasion of his 60th birthday
Recent years have witnessed tremendous growth in the
number of gold-catalyzed transformations.[1] Most of these
new processes are based on the ability of gold complexes to
activate alkynes. Particularly interesting is the chemistry of
propargylic esters because of their propensity to undergo 1,2-
and 1,3-acyl migration reactions.[2] Notably, the 1,2-acyl
migration reaction leads to the formation of a Au–carbene
complex, which can be poised for subsequent reactions to
ultimately afford a range of diverse products (Scheme 1).[3]
catalyzed tandem reactions of propargylic indoles which are
initiated by an unprecedented 1,2-indole migration.
Our research group has been involved in the development
of new catalytic methods for the direct substitution of the
hydroxy group in alcohols by nucleophiles.[6] In this context,
we have reported the C3-selective propargylation of indoles
with alcohols catalyzed by Brønsted acids.[7] Mindful of the
importance of indoles in organic and medicinal chemistry,[8]
we thought that these C3-propargylated indoles could be
interesting precursors for elaborated indole derivatives, and
which could be obtained through gold-catalyzed processes.[9]
Initially, we used indole 1a as a model substrate (Table 1).
Thus, 1a was treated with a catalytic amount of several gold
and platinum complexes in dichloromethane at room temper-
ature. No reaction was observed with [AuCl(Ph3P)], AuCl3,
Scheme 1. Gold-promoted 1,2-migration reactions.
Table 1: Effect of the catalyst on the reactivity of 1a.
Very recently, propargylic sulfides have been shown to
participated in related 1,2-sulfur migration reactions
(Scheme 1).[4] In this context, highly interesting processes
would be the 1,2-migration of propargylic alkyl or aryl groups,
as they would imply the rupture and formation of carbon–
carbon bonds (Scheme 1).[5] However, as far as we know,
these reactions have not been reported and herein we present
the first examples. In particular, we describe new gold-
EntrysCtataly
t [h]
2a/3a[a]
Yield [%][b]
1
2
3
4
5
6
7
8
[AuCl(Ph3P)]
AuCl3
[PtCl2(cod)]
[PtCl2(cod)]/AgSbF6
[AuCl(Ph3P)]/AgSbF6
[AuNTf2(Ph3P)]
[AuNTf2(SPhos)]
[AuCl(IMe)]/AgSbF6
24
24
24
24
2
1
2
2
–
–
–
–
12:1
12:1
10:1
3:1
0[c]
0[c]
0[c]
0[c]
74
[*] Dr. R. Sanz, D. Miguel
rea de Química Orgµnica, Departamento de Química
Facultad de Ciencias, Universidad de Burgos
Pza. Misael Baæuelos, s/n, 09001 Burgos (Spain)
Fax: (+34)94-725-8831
E-mail: rsd@ubu.es
Homepage: http://web.ubu.es/investig/grupos/cien_biotec/qo-3/
index_eng.html
79
76
55[d]
[a] Determined by 1H NMR analysis of the crude reaction mixture.
[b] Yield of isolated 2a based on indole 1a. [c] Indole 1a was recovered.
[d] 3a was isolated in 18% yield.
Dr. F. Rodríguez
Instituto Universitario de Química Organometµlica “Enrique
Moles”, Universidad de Oviedo
C/Juliµn Clavería, 8, 33006 Oviedo (Spain)
[PtCl2(cod)], or the cationic platinum complex which was
generated in situ by mixing [PtCl2(cod)] and AgSbF6 (Table 1,
entries 1–4; cod = cycloocta-l,5-diene). Gratifyingly, com-
plete conversion of 1a into the 2-indenylindole derivative
2a was observed by using (as catalysts) the cationic gold(I)
complex which was generated in situ from [AuCl(Ph3P)] and
AgSbF6, or the bis(trifluoromethanesulfonyl)imidate deriva-
tives [AuNTf2(Ph3P)] and [AuNTf2(SPhos)] (Table 1,
entries 5–7; SPhos = 2-dicyclohexylphosphino-2’,6’-dimeth-
[**] We gratefullythank Ministerio de Educación yCiencia (MEC) and
FEDER (CTQ2007-61436/BQU), and Junta de Castilla yLeón
(BU012A06) for financial support. D.M. thanks MEC for a
predoctoral FPU fellowship. F.R. is grateful to MEC and Fondo
Social Europeo for a Ramón yCajal contract. We also thank Dr.
Jacinto Delgado (SCAI-Universidad de Burgos) for help with the X-
raystructure determination.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802660.
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oxybiphenyl).[10] In these reactions we also observed the
formation of trace quantities of isomeric 1-indenylindole
derivative 3a. The amount of 3a generated increased by using
the cationic gold(I) complex derived from [AuCl(IMe)] with
an N-heterocyclic carbene ligand (Table 1, entry 8; IMe =
1,3,4,5-tetramethylimidazol-2-ylidene).[11]
atives 1 as starting materials (Table 2). The results shown in
Table 2 correspond, in general, to reactions performed with
[AuNTf2(Ph3P)] as the catalyst. This catalyst was chosen for
its availability and for ease of handling. However, similar
Table 2: Preparation of 3-(1H-inden-2-yl)-1H-indoles 2 bytandem 1,2-
Taking into consideration investigations by Nolan and co-
workers on the reactivity of propargylic esters,[12] the for-
mation of the minor indene derivative 3a might be expected.
This compound is generated by a simple intramolecular
hydroarylation of the triple bond, which is favored by an
initial coordination of the gold complex to the alkyne.
However, the reaction leading to the 2-indenylindole deriv-
ative 2a is much more interesting. The structure of this
compound indicates that a 1,2-indole migration has occurred
at some point in the catalytic process. A tentative mechanism
for the formation of 2a is proposed in Scheme 2. Thus, an
initial coordination of the gold complex to the triple bond of
1a generates the intermediate 5. Intramolecular attack of the
À
indole migration/C H insertion reactions of C3-propargylated indole
derivatives 1.[a]
Entry
1
R1
R2
R3
R4
Et
R5
R6
2
Yield [%][b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
Ph
H
H
H
H
2a
2b
2c
2d
79
75
76
73
79[c]
50
60
nPr Ph
iPr Ph
iPr nBu
Me nBu Cl 2e
Me Ph
nPr Ph
Me nBu
H
H
H
H
H
H
H
H
2 f
2g
2h 66
2i
2j
2k
2l
9
CO2Me Et
nBu
70
10
11
12
13
1j
1k
1l
H
H
Br
H
H
H
Me nBu
Me Ph
Me Ph
Me Ph
69
68
Me Me
1m Me Ph
68[c]
2m 73
[a] Reaction mixtures stirred at room temperature until the starting
material was consumed (as evident byGC-MS analsyis; 0.5–7 h).
[b] Yield of isolated product based on indole 1. [c] Reaction performed
with [AuCl(Ph3P)]/AgSbF6 as the catalyst.
results were obtained by using the more sophisticated
[AuNTf2(SPhos)] catalyst or the cationic complex which was
generated in situ from [AuCl(Ph3P)] and AgSbF6. Table 2
outlines the allowed substituents of alkyne 1 at both the
propargylic position (R4) and at the terminal position (R5).
Regarding the indole moiety, not only N-methylindole
derivatives but also N-unsubstituted indole derivatives
(including those with electron-withdrawing substituents) as
well as 2-methylindole derivatives were appropriate sub-
strates for this reaction (Table 2, entries 1–13). In general,
high yields of the corresponding 2-indenylindole derivative 2
were obtained, and only trace amounts of the corresponding
isomeric derivatives analogous to 3a were detected in the
crude samples for some of the reactions. Structural assign-
ments of all new compounds were based on a series of NMR
studies. Additionally, the structures of 2c and 2e were
confirmed by single-crystal X-ray diffraction analysis.[14]
Mindful that the starting indole-containing alkyne deriv-
atives 1 were synthesized from the corresponding propargylic
alcohols by our reported Brønsted acid catalyzed procedure,[7]
we wondered if access to indene derivatives 2 from readily
available propargylic alcohols, by using a concurrent tandem
catalysis protocol, was possible.[15]
Scheme 2. Proposed mechanism for the formation of 2a from 1a.
À
Tandem 1,2-indole migration/C H insertion reactions. L=ligand.
indole on the activated alkyne gives the vinyl–gold complex 6,
which becomes the gold carbene complex 7 through a 1,2-
migration of the indole. Carbene complex 7 can also be
represented as the resonance form 7’. Further intramolecular
nucleophilic attack of the phenyl group on the carbene carbon
center leads to the formation of intermediate 8. Finally, a
rearomatization step and subsequent protodemetalation
affords the final product 2a and regenerates the catalytic
gold species. Formation of 2a from carbene intermediate 7
À
can also be explained through a simple C H insertion
reaction.[13] Alternatively, the intramolecular nucleophilic
attack of the phenyl group on the vinyl–gold intermediate 6
to give 8 could also be considered.[3b]
Whichever mechanism is invoked, this new reaction may
be considered a tandem sequence involving a 1,2-indole
À
migration followed by a formal intramolecular C H insertion
reaction. To evaluate the scope of the process we performed a
set of experiments using the C3-propargylated indole deriv-
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Thus, as shown in Scheme 3, the consecutive reaction of
contrast, as shown in Scheme 2, the formation of 2-indenyl-
indole derivatives 2 supposes the reaction of the aryl group at
the propargylic position. Structural assignments of the new
compounds 12 were based on a series of NMR studies.
Additionally, the structures of 12a and 12b were confirmed
by single-crystal X-ray diffraction analysis.[14]
propargylic alcohol 9 and N-methylindole (10) with PTSA
(5 mol%) and [AuNTf2(Ph3P)] (5 mol%) led to the forma-
tion of 1-methyl-3-(3-isopropyl-1-phenyl-1H-inden-2-yl)-1H-
Shown in Scheme 4 is a tentative mechanism for the
formation of 2-indenylindole derivatives 12. The initial steps
Scheme 3. One-pot synthesis of 2c from propargylic alcohol 9 and N-
methylindole (10).
indole (2c) in 70% yield. Notably, this one-pot process does
not require any solvent change or removal of PTSA prior to
the addition of the gold catalyst. By following this strategy the
isolation of the indole-containing alkynes 1 is avoided, and
the reaction can be performed from readily available
propargylic alcohols and indoles in a straightforward syn-
thetic protocol.
To further study the new 1,2-indole migration reaction,
and in particular the reactivity of gold carbene intermediates
analogous to 7 (Scheme 2), we performed a set of experiments
with indole-containing alkynes 11 (Table 3). These starting
Scheme 4. Proposed mechanism for the formation of 12 from 11.
Tandem 1,2-indole migration/Nazarov cyclization reactions.
Table 3: Preparation of 3-(2-indenyl)indoles 12 bygold-catazlyed
reactions of propargylated indole derivatives 11.[a]
are analogous to those previously proposed in Scheme 2. Thus
we suppose the formation of the gold carbene complex 15 by a
gold-mediated 1,2-indole migration and through intermedi-
ates 13 and 14. The cationic pentadienyl resonance form 15’
contributes to the gold carbene complex 15. This intermediate
may evolve through a Nazarov-type cyclization to give 16 and,
ultimately, after a rearomatization and protodemetalation,
the isolated product 12. To the best of our knowledge, tandem
sequences involving 1,2-migration reactions followed by
Nazarov-type cyclizations have not been described previ-
ously. [16]
In summary, we have discovered that C3-propargylated
indoles react under gold-catalyzed conditions through unpre-
cedented 1,2-indole migrations. These are the first examples
where the migrating group at the propargylic position is not
an heteroatom-centered moiety, and so these are the first
examples where the 1,2-migration reaction supposes the
rupture and formation of carbon–carbon bonds. Thus, new
Entry
11
R1
R2
R3
R4
12
Yield [%][b]
1
2
3
4
5
6
11a
11b
11c
11d
11e
11 f
Me
Me
Me
Me
H
H
H
H
Me
H
Me
Et
Me
Me
Me
Me
Me
Et
c-C3H5
Me
c-C3H5
c-C3H5
12a
12b
12c
12d
12e
12 f
82
55
87
72
75
80
H
Me
[a] Reaction mixtures stirred at reflux until the starting material was
consumed (as evident byGC-MS analysis; 1–24 h). [b] Yield of isolated
product was based on indole 11.
À
tandem processes involving 1,2-indole migration/C H inser-
tion reactions and 1,2-indole migration/Nazarov cyclization
reactions have been described. Different indene-containing
indole scaffolds have been easily prepared by these protocols.
These new compounds contain two medicinally relevant
substructures, the indole unit and the indene unit,[8,17] there-
fore the strategy described here could be applied to the
synthesis of compounds that could be potentially bioactive.
The possibility of performing the reactions following a
concurrent tandem catalysis protocol starting from readily
available propargylic alcohols and indoles should also be
noted. Further studies to extend the scope of the 1,2-indole
materials differ from alkynes 1 in that they do not bear an
aryl substituent at the propargylic position, and so the
À
subsequent formal C H insertion reaction is not possible.
When alkynes 11 were treated with 5 mol% of [AuNTf2-
(Ph3P)] in methylene chloride at reflux, the new 2-indenyl-
indole derivatives 12 were obtained exclusively in high yields
(Table 3, entries 1–6). Surprisingly, in these reactions the
phenyl group that participates in the formation of the indene
skeleton is that at the terminal position of the triple bond. In
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rez, F. Rodríguez, Org. Lett. 2007, 9, 2027 – 2030; e) R. Sanz, A.
migration reaction and the development of other indole
migration processes are in progress.
Martínez, V. Guilarte, J. M. lvarez-GutiØrrez, F. Rodríguez,
Eur. J. Org. Chem. 2007, 4642 – 4645; f) R. Sanz, A. Martínez, D.
Miguel, J. M. lvarez-GutiØrrez, F. Rodríguez, Synthesis 2007,
3252 – 3256.
Received: June 5, 2008
Published online: August 8, 2008
[7] R. Sanz, D. Miguel, J. M. lvarez-GutiØrrez, F. Rodríguez,
Synlett 2008, 975 – 978.
[8] R. J. Sundberg, The Chemistry of Indoles, Academic Press, New
York, 1996.
À
Keywords: C C coupling · cyclization · gold ·
homogeneous catalysis · indoles
.
[9] For interesting examples of gold-catalyzed reactions involving
indoles, see: a) L. Zhang, J. Am. Chem. Soc. 2005, 127, 16804 –
16805; b) C. Ferrer, A. M. Echavarren, Angew. Chem. 2006, 118,
1123 – 1127; Angew. Chem. Int. Ed. 2006, 45, 1105 – 1109; c) C.
Ferrer, C. H. M. Amijs, A. M. Echavarren, Chem. Eur. J. 2007,
13, 1358 – 1373; d) S. Bhuvaneswari, M. Jeganmohan, C.-H.
Cheng, Chem. Eur. J. 2007, 13, 8285 – 8293; e) G. Zhang, X.
Huang, G. Li, L. Zhang, J. Am. Chem. Soc. 2008, 130, 1814 –
1815.
[10] For bis(trifluoromethanesulfonyl)imidate-based gold catalysts,
see: N. MØzailles, L. Ricard, F. Gagosz, Org. Lett. 2005, 7, 4133 –
4136; for biphenylphosphine-based gold catalysts, see: C. Nieto-
Oberhuber, S. López, A. M. Echavarren, J. Am. Chem. Soc.
2005, 127, 6178 – 6179.
[11] P. de FrØmont, N. M. Scott, E. D. Stevens, S. P. Nolan,Organo-
metallics 2005, 24, 2411 – 2418.
[12] N. Marion, S. Díez-Gonzµlez, P. de FrØmont, A. R. Noble, S. P.
Nolan, Angew. Chem. 2006, 118, 3729 – 3732; Angew. Chem. Int.
Ed. 2006, 45, 3647 – 3650.
[13] a) K. Miki, K. Ohe, S. Uemura, J. Org. Chem. 2003, 68, 8505 –
8513; b) B. A. Bhanu Prasad, F. K. Yoshimoto, R. Sarpong, J.
Am. Chem. Soc. 2005, 127, 12468 – 12469.
[14] CCDC 689754 (2c), 689755 (2e), 689756 (12a), and 689757
(12b) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
[15] For excellent accounts on concurrent tandem catalysis, see: a) J.-
C. Wasilke, S. J. Obrey, R. T. Baker, G. C. Bazan, Chem. Rev.
2005, 105, 1001 – 1020; b) A. M. Walji, D. W. C. MacMillan,
Synlett 2007, 1477 – 1489.
[16] For gold-catalyzed tandem reactions involving an initial
[3,3] rearrangement followed by a Nazarov-type cyclization,
see: a) L. Zhang, S. Wang, J. Am. Chem. Soc. 2006, 128, 1442 –
1443; b) G. Lemi›re, V. Gandon, K. Cariou, T. Fukuyama, A.-L.
Dhimane, L. Fensterbank, M. Malacria, Org. Lett. 2007, 9, 2207 –
2209; c) F.-Q. Shi, X. Li, Y. Xia, L. Zhang, Z.-X. Yu, J. Am.
Chem. Soc. 2007, 129, 15503 – 15512; for a platinum-catalyzed
tandem reaction involving an initial 6-exo-dig cyclization
[1] For recent reviews on gold catalysis, see: a) N. Bongers, N.
Krause, Angew. Chem. 2008, 120, 2208 – 2211; Angew. Chem. Int.
Ed. 2008, 47, 2178 – 2181; b) J. Muzart, Tetrahedron 2008, 64,
5815 – 5849; c) H. C. Shen, Tetrahedron 2008, 64, 3885 – 3903;
d) D. J. Gorin, D. Toste, Nature 2007, 446, 395 – 403; e) A.
Fürstner, P. W. Davies, Angew. Chem. 2007, 119, 3478 – 3519;
Angew. Chem. Int. Ed. 2007, 46, 3410 – 3449; f) E. JimØnez-
Nfflæez, A. M. Echavarren, Chem. Commun. 2007, 333 – 346;
g) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180 – 3211; h) L.
Zhang, J. Sun, S. A. Kozmin, Adv. Synth. Catal. 2006, 348, 2271 –
2296; i) A. S. K. Hashmi, G. J. Hutchings, Angew. Chem. 2006,
118, 8064 – 8105; Angew. Chem. Int. Ed. 2006, 45, 7896 – 7936;
j) R. A. Widenhoefer, X. Han, Eur. J. Org. Chem. 2006, 4555 –
4563; k) A. Hoffmann-Röder, N. Krause, Org. Biomol. Chem.
2005, 3, 387 – 391; l) A. S. K. Hashmi, Gold Bull. 2004, 37, 51 –
65.
[2] For excellent accounts see the following and references therein:
a) A. Correa, N. Marion, L. Fensterbank, M. Malacria, S. P.
Nolan, L. Cavallo, Angew. Chem. 2008, 120, 730 – 733; Angew.
Chem. Int. Ed. 2008, 47, 718 – 721; b) N. Marion, S. P. Nolan,
Angew. Chem. 2007, 119, 2806 – 2809; Angew. Chem. Int. Ed.
2007, 46, 2750 – 2752; c) J. Marco-Contelles, E. Soriano, Chem.
Eur. J. 2007, 13, 1350 – 1357.
[3] For some leading works involving 1,2-acyl migrations promoted
by gold complexes, see: a) V. Mamane, T. Gress, H. Krause, A.
Fürstner, J. Am. Chem. Soc. 2004, 126, 8654 – 8655; b) X. Shi,
D. J. Gorin, F. D. Toste, J. Am. Chem. Soc. 2005, 127, 5802 – 5803;
c) M. J. Johansson, D. J. Gorin, S. T. Staben, F. D. Toste, J. Am.
Chem. Soc. 2005, 127, 18002 – 18003; d) C. H. M. Amijs, V.
López-Carrillo, A. M. Echavarren, Org. Lett. 2007, 9, 4021 –
4024; e) D. J. Gorin, I. D. G. Watson, F. D. Toste, J. Am. Chem.
Soc. 2008, 130, 3736 – 3737; f) G. Li, G. Zhang, L. Zhang, J. Am.
Chem. Soc. 2008, 130, 3740 – 3741.
[4] L. Peng, X. Zhang, S. Zhang, J. Wang, J. Org. Chem. 2007, 72,
1192 – 1197.
[5] For a gold-catalyzed 1,2-alkyl and -aryl migration in allenyl
ketones, see: A. S. Dudnik, V. Gevorgyan, Angew. Chem. 2007,
119, 5287 – 5289; Angew. Chem. Int. Ed. 2007, 46, 5195 – 5197.
[6] a) R. Sanz, A. Martínez, J. M. lvarez-GutiØrrez, F. Rodríguez,
Eur. J. Org. Chem. 2006, 1383 – 1386; b) R. Sanz, A. Martínez, D.
Miguel, J. M. lvarez-GutiØrrez, F. Rodríguez, Adv. Synth.
Catal. 2006, 348, 1841 – 1845; c) R. Sanz, D. Miguel, A. Martínez,
J. M. lvarez-GutiØrrez, F. Rodríguez, Org. Lett. 2007, 9, 727 –
730; d) R. Sanz, D. Miguel, A. Martínez, J. M. lvarez-GutiØr-
reaction followed by
a
Nazarov-type cyclization, see:
d) S. M. A. Sohel, S.-H. Lin, R.-S. Liu, Synlett 2008, 745 – 750.
[17] a) I.-M. Karaguni, K.-H. Glüsenkamp, A. Langerak, C. Geisen,
V. Ullrich, G. Winde, T. Möröy, O. Müller, Bioorg. Med. Chem.
Lett. 2002, 12, 709 – 713; b) A. Kort, J. Legros, C. Bolm, Synlett
2004, 2397 – 2399.
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