One-pot gold-catalyzed synthesis of azepino[1,2-a]indoles

Article abstract of DOI:10.1002/anie.201205463

Indoles from scratch: A gold(I)/N-heterocyclic carbene complex (IPr=1,3-di(isopropylphenyl)imidazol-2-ylidene) was found to be particularly effective as a catalyst, enabling the one-pot synthesis of tricyclic azepinoindoles by an unprecedented cascade reaction. Readily available substrates, high chemoselectivity, good yields, and water as the only stoichiometric by-product are some of the main advantages of this method. Copyright

Full text of DOI:10.1002/anie.201205463

Angewandte
Chemie
DOI: 10.1002/anie.201205463
Gold Catalysis
One-Pot Gold-Catalyzed Synthesis of Azepino[1,2-a]indoles**
Gianpiero Cera, Stefano Piscitelli, Michel Chiarucci, Giancarlo Fabrizi, Antonella Goggiamani,
Rubꢀn S. Ramꢁn, Steven P. Nolan, and Marco Bandini*
Indoles are one of the most abundant heteroaromatic
compounds found in nature, and is ranked third (after
benzene and pyridine) amongst the most prevalent architec-
tures found in bioactive molecules.[1] In this context, it is not
surprising to note a beehive of activity in the development of
Figure 1. Examples of pharmacologically active azepino[1,2-a]indoles.
cHex=cyclohexyl.
sustainable methods for the synthesis[2] and functionaliza-
tion[3] of the indolyl core. Over the past ten years, advances in
catalysis have revolutionized the field by bringing unexpected
levels of efficiency, selectivity, and sustainability into practice.
However, catalytic methods that simultaneously address
synthesis and derivatization of indoles are still far from
common.[4] Some leading metal-assisted examples deal prin-
cipally with the construction of the pyrrolyl ring with a final
C3-functionalization through alkylations[5] or cross-coupling
reactions.[2d,6] Among them, gold(I)/(III) catalysis has played
a major role[7] in generating chemical diversity/complexity
under mild and selective conditions.
tives has recently been documented,[11] stepwise synthetic
sequences starting from a preformed indolyl nucleus are
generally necessary to build up the fused polycyclic system.[12]
With the existing laborious and multistep approaches in
mind, we herein describe an unprecedented gold-assisted
cascade reaction for the synthesis of azepino[1,2-a]indoles
starting from readily available 2-alkynylanilines. Our working
hypothesis was hinged on the suitability of 2-(propargylic
alcohol)-anilines (1) in providing nucleophilic 2-vinylindole
intermediates (C) through a gold-triggered 5-endo-dig hydro-
amination/dehydration sequence.[13] At this stage, the pre-
installation of a complementary (electrophilic) group (such as
carbonyl) tethered to the aniline nitrogen atom was thought
to allow the second cyclization reaction to take place,
providing a N1–C2 fusion to produce the indole core
(Scheme 1).
As a part of our ongoing interest in organo-[8a] and metal-
catalyzed synthesis of the indole/indoline polycyclic architec-
tures,[8b–f] we turned our attention to the azepinoindole
scaffold, which is commonly encountered in biologically
active compounds.[9]
More specifically, azepino[1,2-a]indoles, which feature
a fused seven-membered ring through the N1–C2 connection,
have displayed fascinating pharmacological activities, such as
acting in the inhibition of HCV NS5B polymerase (A;
Figure 1)[10a,b] and as modulators for CNS neurotransmitter
receptors (B).[10c,d] In the case of this species, although the
metal-catalyzed synthesis of 6H-azepino[1,2-a]indole deriva-
A survey of reaction conditions was carried out to identify
the optimal catalytic system, with aniline 1a as the model
substrate (Table 1). Among the metal species utilized
[*] G. Cera, S. Piscitelli, Dr. M. Chiarucci, Prof. M. Bandini
Dipartimento di Chimica “G. Ciamician”
Alma Mater Studiorum—Universitꢀ di Bologna
via Selmi 2, 40126 Bologna (Italy)
Scheme 1. Proposed reaction sequence.
E-mail: marco.bandini@unibo.it
Homepage: http://www.mbandini-group.com
Prof. G. Fabrizi, Dr. A. Goggiamani
Dip. di Chimica e Tecnologia del Farmaco Sapienza
Universitꢀ di Roma (Italy)
(entries 1–3,5) gold(I) showed the highest catalytic activity.
However, indolyl-alcohol 2a and 2-vinyl-indole 3a were
obtained exclusively in the presence of phosphine-based
gold(I) complexes (entries 5–7). The use of an N-heterocyclic
R. S. Ramꢁn, Prof. Dr. S. P. Nolan
EaStCHEM School of Chemistry, University of St Andrews (UK)
[**] Acknowledgements are made to the Progetto FIRB “Futuro in
Ricerca” Innovative sustainable synthetic methodologies for C-H
activation processes, (MIUR, Rome) and the Universitꢀ di Bologna.
For support of the work in St. Andrews, the ERC (Advanced
Researcher Award FUNCAT to S.P.N.) and the EPSRC are gratefully
acknowledged. We also thank Prof. M. Monari for the X-ray analysis
of 4a. S.P.N. is a Royal Society Wolfson Research Merit Award
holder.
carbene
(NHC)-bearing
system,
[Au(IPr)Cl]/AgBF4
(5 mol%; IPr= 1,3-di(isopropylphenyl)imidazol-2-ylidene),
in refluxing toluene for 4 h, provided the desired 8-methyl-
10-phenyl-6H-azepino[1,2-a]indole (4a) in 34% yield
(Table 1, entry 11). As the use of [Au(NHC)] systems is
becoming more widespread in organic synthesis,[14] and as the
synthetic routes to a series of congeners have been reported,
we envisioned the possibility of increasing the chemical yield
of the reaction sequence by examining the role of the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205463.
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Table 1: Optimization of the catalytic system.[a]
To unequivocally establish the atom connectivity present
in 4a, its structure was determined by single-crystal X-ray
analysis (Table 1, scheme inset).[16]
After optimizing the reaction conditions, the generality of
the method was next explored by subjecting a series of alkynyl
anilines 1b–p to the cascade ring-closing procedure. The
results are summarized in Table 2. Structural modifications
Table 2: Scope of the reaction.[a]
Entry Cat.
Yield of
Yield of
Yield of
2a [%][b]
3a [%][b]
4a [%][b]
1[c]
2[c]
3
In(OTf)3
FeCl3
AgOTf
TfOH
[Au(PPh3)NTf2]
[(AuNTf2)2dppf]
[(AuPPh3)3O]BF4
AuCl3
6
7
–
–
–
–
64
15
35
–
–
–
–
–
–
–
–
–
–
–
23
–
36
–
–
–
–
–
–
–
–
–
Entry
R/R1/R2
Ar(R3)/X
4
Yield [%][b]
4[c]
5
1
2
3
4
H/Me/Me
H/Me/Me
H/Me/Me
H/Me/Me
H/Me/Me
H/Me/Me
H/Ph/Me
p-FC6H4/H
p-BrC6H4/H
p-MeC6H4/H
Ph/p-F
p-FC6H4/p-F
p-NO2C6H4/H
Ph/H
Ph/H
Ph/H
m-MeC6H4/H
Ph/H
Ph/p-Me
Ph/H
4b
4c
4d
4e
4 f
4g
4h
4j
4k
4i
94
88
64
93
59
92
75
65
48[d]
78
59
70
82
70
55[g]
50
6[d]
7[d]
8[c]
9
10
11
12
13
14
–
–
5
98
90
35
76
–
–
35
–
–
–
6[c]
7
[Au(IPr)Cl]/AgBF4
[Au(IPr)Cl]/AgOTs
[Au(IPr)Cl]/AgSbF6
[Au(IPr)Cl]/AgOTf
34
23
89
96
53
68
8
9
Me/Me/Me
H/Et/Me
10
11
12
13[e]
14
15[f]
16[f]
H/Me/Me
H/p-ClC6H4/Me
H/Me/Me
H/Me/CD3
H/Me/Me
H/Me/Me
H/Me/Me
4l
15[e] [Au(IPr)Cl]/AgOTf
16
4m
[H]-4a
4n
4o
4p
[Au(IPr)(OH)]/
TfOH
[Au(IAd)Cl]/AgOTf
[Au(ItBu)Cl]/
AgOTf
Me/H
Et/H
iPr/H
17
18
–
–
61
57
traces
traces
19[f] [Au(IPr)Cl]/AgOTf
–
–
75
[a] All reactions were carried out under a nitrogen atmosphere. [b] Yield
of isolated product after flash chromatography. [c] Reaction time of 1 h.
[d] A mixture of compounds derived from the final endo and exo
dehydration event was obtained (see the Supporting Information).
[e] [H]-4a/[D]-4a >25:1 by NMR spectroscopy. [f] With 10 mol% of
catalyst. [g] A 6:1 mixture of isomers was obtained (see the Supporting
Information).
[a] All reactions were carried out under a nitrogen atmosphere. [b] Yield
of isolated product after flash chromatography. [c] Decomposition of 1a
occurred. [d] Large amounts of unreacted 1a were recovered from the
reaction crude. [e] With reagent-grade toluene and under air. [f] In the
presence of 2.5 mol% of catalyst. dppf=1,1’-bis(diphenylphosphino)-
ferrocene, IAd=1,3-di(adamantyl)imidazol-2-ylidene, IPr=1,3-di(iso-
propylphenyl)imidazol-2-ylidene, ItBu=1,3-di(tert-butyl)imidazol-2-yli-
dene Tf=trifluoromethanesulfonyl, Ts=p-toluenesulfonyl.
were performed at several positions on the molecule: 1) on
the aniline ring, 2) on the ketone chain, and 3) on the
propargylic alcohol substituents. As long as aryl tertiary
alcohols were involved, the process proved to be highly
selective towards substituents on the aromatic framework.[17]
Electron-withdrawing substituents on the aryl groups were
well tolerated and lead to the corresponding azepinoindoles
4b,c,f,g in good yields (59–94%; Table 2, entries 1,2,5,6).
Analogously, p-tolyl and m-tolyl derivatives 1d and 1i
smoothly underwent the double ring-closing process (64–
78% yield, entries 3 and 10). With regards to the aniline
chain, the introduction of a methyl unit at the b-position of
the ketone group did not significantly affect the reaction (4j,
65%, entry 8).
Analogously, substrates 1h and 1l, which bear an aromatic
substituent on the carbonyl group (R1 = Ph, p-ClC6H4),
performed well under the optimized conditions, leading to
4h and 4l in 75% and 59%, respectively (entries 7 and 11).
When R1 = Et (1k) was employed in the reaction sequence,
an inseparable mixture of azepinoindole isomers (see the
Supporting Information for details) was obtained in 48%
counterion (entries 12–14). Among these, AgOTf (Tf = tri-
fluoromethanesulfonyl) provided 4a in nearly quantitative
yield (96%, entry 14). Gold catalysis proved essential in this
transformation, as the decomposition of 1a, along with the
modest formation of 3a, was observed to occur to a varying
degree when the reaction was conducted using AgOTf or
TfOH (5 mol%) in the absence of gold. The silver-free
[Au(IPr)(OH)]/TfOH system (5 mol%)[15] promoted the
gold-catalyzed cascade sequence in 68% yield, whereas
attempts to carry out the reaction at lower temperatures or
catalyst loadings led to a significant erosion in the yield of the
desired product. Different N-heterocyclic carbene/gold com-
plexes, such as [Au(IAd)Cl] (IAd = 1,3-di(adamantyl)imida-
zol-2-ylidene and [Au(ItBu)Cl)] (ItBu = 1,3-di(tert-butyl)imi-
dazol-2-ylidene), were also tested, but modest results were
obtained compared to those obtained with the [Au(IPr)Cl]
congener (entries 17–18).
2
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overall yield. Finally, the introduction of electron-donating
and electron-withdrawing substituents onto the aniline ring
was tolerated (59-93% yield; 4e–f,m) and bis(alkyl)-substi-
tuted tertiary propargylic alcohols (1n–p) also proved to be
competent precursors, providing the corresponding tricyclic
compounds 4n–p in good yields (entries 14–16).
The present cascade sequence leads to several mechanistic
questions. For example, gold(I) species could exert both p and
s acidity at different point during the reaction. Moreover, the
potential for co-catalysis by the Brønsted acids formed in situ
(such as TfOH when AgOTf is used) cannot be ruled out.
Interestingly, the identification of compounds 2 and 3 as
reaction intermediates facilitated the mechanistic investiga-
tion and allowed for the monitoring of individual reaction
steps.
First, the hydroamination of the triple bond was found to
proceed by gold catalysis (Scheme 2, step 1). This is supported
by the unsatisfactory chemical outcomes when the reaction
Scheme 3. a) Step 3 of the [Au]-catalyzed cyclization cascade. b) Con-
trol experiments carried out with [D3]-1a. Cat.=[Au(IPr)Cl]/AgOTf
(5 mol%).
found that [Au(IPr)(OTf)] catalyzed the selective cyclizations
of [D3]-1a![D3]-2a and [D3]-2a![D2]-3a when the reac-
tions were conducted at 708C and 908C, respectively.
Surprisingly, when deuterated 2-vinylindole [D2]-3a was
refluxed in toluene in the presence of [Au(IPr)(OTf)],
[H]-4a was exclusively isolated in 82% yield and with
complete proton/deuterium exchange.[20] This finding clearly
suggests that a cationic AuI/NHC species might insert into the
Scheme 2. Steps 1 and 2 of the [Au]-catalyzed cyclization cascade.
IPr=1,3-di(isopropylphenyl)imidazol-2-ylidene.
[14a,21,22]
=
electron-rich C C,
leading to the nucleophilic vinyl–
gold species E (Scheme 4).[23] This would strongly suggest that
the intramolecular condensation of E with the ketone
group[24] would produce 4a upon dehydration and 1,3-
proton-transfer/protodeauration.[25]
was carried out in the presence of AgOTf or TfOH,
(entries 3–4, Table 1). At this stage, the reaction sequence
could proceed through a protodeauration of the 3-[Au]-
indolyl species D and subsequent dehydration (Scheme 2,
step 2).[18,19]
This mechanistic rationalization was further supported by
a D/H exchange observed in the control experiment carried
Next, the condensation of 2-vinyl indole 3a on the
carbonyl unit takes place, resulting in an annulated inter-
mediate with the formation of a seven-membered ring. A
ring-closing process promoted by a Lewis acid (LA) or
a Brønsted acid (Prins-type condensation) does not ade-
quately account for the observed reactivity, as 1) treating 3a
with a catalytic amount of TfOH (5 mol% in refluxing
toluene, or 15 mol% at RT) produced 4a in only trace
amounts up to 25% yield, and 2) a [AuI]/LA-type assisted
mechanism does not properly explain the unique reactivity
observed with Au-NHC species when compared to more
electrophilic phosphine-based gold complexes. Furthermore,
the quantitative proton/deuterium exchange observed with
the deuterated alcohol [D3]-1a (Table 2, entry 13) suggested
possible interactions of the vinylindole intermediate with the
Au-NHC catalyst.
To shed light on the final reaction step of the sequence,
a control experiment in the presence of [D3]-1a was
performed (Scheme 3) and the effect of varying the reaction
temperature was examined for each step of the process. It was
+
=
Scheme 4. Hypothetical C C/[Au] insertion leading to the formation
of vinyl-gold(I) intermediate E.
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In summary, an unprecedented gold-catalyzed cascade
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The reaction sequence features generally high yields with
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Received: July 11, 2012
Published online: && &&, &&&&
Keywords: cascade reactions · gold · homogeneous catalysis ·
.
indoles · synthetic methods
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4
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Chemie
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[17] Ene-yne compound 1a’ was considered as a possible synthetic
alternative to alcohol 1a. However, 1a’ led to extensive
decomposition when subjected to the optimized reaction con-
ditions (4a, 15%).
Cinellu in Modern Gold Catalyzed Synthesis (Eds.: A. S. K.
Hashmi, F. D. Toste), Wiley-VCH, Weinheim, 2012, chap. 7,
p. 175, and references therein.
[22] For representative examples of the gold(I)-catalyzed isomer-
=
ization of C C and corresponding H/D exchange, see: a) C.-G.
Yang, C. He, J. Am. Chem. Soc. 2005, 127, 6966; b) A. R. Jagdale,
J. H. Park, S. W. Youn, J. Org. Chem. 2011, 76, 7204.
[23] For general reviews and reports on the isolation of organogold
intermediates, see: a) A. S. K. Hashmi, A. M. Schuster, F.
Rominger, Angew. Chem. 2009, 121, 8396; Angew. Chem. Int.
Ed. 2009, 48, 8247; b) L.-P. Liu, G. B. Hammond, Chem. Soc.
Rev. 2012, 41, 3129; c) D. Weber, M. A. Tarselli, M. R. Gagnꢃ,
Angew. Chem. 2009, 121, 5843; Angew. Chem. Int. Ed. 2009, 48,
5733.
[18] A. S. K. Hashmi, T. D. Ramamurthi, F. Rominger, Adv. Synth.
Catal. 2010, 352, 971.
[24] a) M. Zhang, Y. Wang, Y. Yang, X. Hu, Adv. Synth. Catal. 2012,
354, 981.
[25] The in situ formation of a nucleophilic 3-gold-indolyl derivative
[19] Refluxing 2a in toluene for a few hours in the absence of acid
sources led to the quantitative recovery of unreacted alcohol.
[20] When [D2]-3a was reacted in the presence of TfOH (5 mol%) at
RT, [D]-4a was isolated in 25%, whereas refluxing conditions
led to decomposition of the starting material.
[21] a) T. J. Brown, M. G. Dickens, R. A. Widenhoefer, J. Am. Chem.
Soc. 2009, 131, 6350; b) T. J. Brown, M. G. Dickens, R. A.
Widenhoefer, Chem. Commun. 2009, 6451; c) D. Zuccaccia, L.
Belpassi, F. Tarantelli, A. Macchioni, J. Am. Chem. Soc. 2009,
131, 3170; d) N. Salvi, L. Belpassi, D. Zuccaccia, F. Tarantelli, A.
Macchioni, J. Organomet. Chem. 2010, 695, 2679. See also: M. A.
ꢀ
seems unlikely, as [Au(IPr)Cl]-assisted aromatic C H activation
was observed only for electron-deficient arenes (pKa ꢁ 31) and
in the presence of Ag2O; see: P. Lu, T. C. Boorman, A. M. Z.
Slawin, I. Larrosa, J. Am. Chem. Soc. 2010, 132, 5580, and
ref. [14d] for discussion. Moreover, when H2-5 was treated with
ꢀ
[Au(IPr)(OTf)] ([D8]-toluene, reflux) activation of the C3 H
position of the indole core was not observed by NMR
spectroscopy.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Gold Catalysis
G. Cera, S. Piscitelli, M. Chiarucci,
G. Fabrizi, A. Goggiamani, R. S. Ramꢁn,
S. P. Nolan, M. Bandini*
&&&& — &&&&
One-Pot Gold-Catalyzed Synthesis of
Azepino[1,2-a]indoles
Indoles from scratch: A gold(I)/N-heter-
ocyclic carbene complex (IPr=1,3-di-
(isopropylphenyl)imidazol-2-ylidene) was
found to be particularly effective as
a catalyst, enabling the one-pot synthesis
of tricyclic azepinoindoles by an unpre-
cedented cascade reaction. Readily avail-
able substrates, high chemoselectivity,
good yields, and water as the only
stoichiometric by-product are some of the
main advantages of this method.
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!