Gold-catalyzed annulations of 1-(2,3-butadienyl)-1H-indole derivatives

Article abstract of DOI:10.1002/chem.201001754

Gold-ringing! Modification of the substitution at C2 drives an entirely different cyclization of N-tethered allenylindoles. An efficient cycloisomerization takes place for the case of R being hydrogen, that is, compatible with additional functional groups. A methyl at C2 precludes this possibility and launches a stepwise process that can be tuned to yield macrocyclic trimers.

Full text of DOI:10.1002/chem.201001754

COMMUNICATION
DOI: 10.1002/chem.201001754
Gold-Catalyzed Annulations of 1-(2,3-Butadienyl)-1H-Indole Derivatives
Josꢀ Barluenga,* Marꢁa Piedrafita, Alfredo Ballesteros, ꢂngel L. Suꢃrez-Sobrino, and
Josꢀ M. Gonzꢃlez[a]
The discovery of catalytic functionalization reactions of
privileged heterocyclic scaffolds holds major interest. The
vast prevalence and biological significance associated with
the indole ring has led to its definition as “The Lord of
Rings” at the time of reviewing advances towards its catalyt-
ic functionalization,[1] Indole is also a key compound for the
study of new arylation strategies,[2] and the search for transi-
tion metal-catalyzed preparations and modifications of this
heterocyclic core remains an active research area.[3,4] Gold-
catalyzed organic reactions are subject of major attention,[5]
Scheme 1. Gold(I)-catalyzed annulations of allenylindoles 1.
and powerful modifications of indole based on gold catalysis
have been disclosed.[6] Widenhoefer and his group reported
advances in the activation of indole towards allene in hydro-
arylation reactions, and proved useful catalysts to accom-
plish this goal.[7] Thus, cyclization of 2-allenyl derivatives of
N-methyl indole following 6- and 7-exo-cyclization modes
and yielding C3 functionalized annulated compounds are
now well documented. Herein, recent findings on gold(I)-
catalyzed cyclization reactions of 1-(2,3-butadienyl)-1H-
indole derivatives are reported, as graphically outlined in
Scheme 1.
This study originates from our interest in both indole
chemistry[8] and electrophilic arylation of allenes.[9] In addi-
tion, the catalytic 6-endo allene hydroarylation reaction has
been introduced[10–12] and is considerably less studied than
the related 6-exo cyclization.[13] On this basis, we picked the
N-tethered 2,3-butadienyl 1H-idole 1a as a model to explore
the catalytic 6-endo cycloisomerization process.[14] Gratify-
ingly, exposure of 1a to gold(I) catalysis resulted in its clean
Scheme 2. Cycloisomerization via 6-endo allene hydroarylation giving
isolable pyrido[1,2-a]-1H-indole derivatives.
AHCTUNGTRENNUNG
The ancillary ligand was selected considering precedents
for catalytic allene hydroarylation reactions. Triphenylphos-
phine[13d] and di-tert-butyl(ortho-biphenyl)phosphine, [P-
AHCTUNGTRENNUNG
(tBu)2(o-biphenyl), JOHNPHOS][7,10a] were chosen. As the
counteranion for gold(I), bis(trifluoromethanesulfonyl)imi-
date (NTf2) appeared to be an interesting choice. As early
pointed out by Gagosz, it behaves similar to other weakly
coordinating anions and avoids addition of a silver(I) salt to
render a more electrophilic gold center, a process typically
associated with alternative chloride precatalyst.[15]
conversion to 6,9-dihydro-pyrido
(Scheme 2).
[1,2-a]-1H-indole (2a)
For 1a, higher yield of 2a and shorter reaction times were
noticed in the gold-catalyzed reaction with the Buchwald-
type biaryl ligand than with related triphenylphosphine.[16]
At room temperature, the cyclization also took place, but
required longer reaction time to get a similar yield. This effi-
cient cyclization led to a clean isolation of the assembled
[a] Prof. Dr. J. Barluenga, M. Piedrafita, Dr. A. Ballesteros,
Dr. ꢀ. L. Suꢁrez-Sobrino, Prof. J. M. Gonzꢁlez
Department of Organic and Inorganic Chemistry and
Instituto Universitario de Quꢂmica Organometꢁlica “Enrique Moles”
Universidad de Oviedo, Juliꢁn Claverꢂa 8, 33006 Oviedo (Spain)
Fax : (+34)98510-3450
pyridoACTHUNRTGNEUNG[1,2-a]-1H-indole scaffold, adding preparative interest
to the process. Moreover, the obtained pyridoindole is a sig-
nificant heterocyclic scaffold.[17] The scope of the process
concerning the indole substitution was investigated in this
preliminary study and is outlined in Table 1. Interestingly,
E-mail: barluenga@uniovi.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001754.
Chem. Eur. J. 2010, 16, 11827 – 11831
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11827

Table 1. Gold-catalyzed 6-endo cyclosiomerization of allenylindoles.
Allenylindole 1
T [8C] t [h] Product 2
Yield [%][a]
1b: R=OMe
1c: R=Br
80
80
1
1.5
2b: R=OMe
2c: R=Br
89
79
Scheme 3. Cyclotrimerization of 2-substituted N- allenylindoles.
1d
80
80
3
2d
86
87
the early noticed clean cycloisomerization process. The al-
ternative formation of these macrocyles can be rationalized
assuming initial allene activation by the carbophilic catalyst,
followed by trapping of the resulting cationic species by
indole, involving now the usual nucleophilic C3 position.
This process keeps evolving to give a macrocycle.[18] Allyl-
homologated indolo-cyclotriveratrylene analogs with a dis-
tinctive 1,3’-linkage were accessed.[19] The proposed stepwise
nature for this trimerization is consistent with the isolation
of the dimer 4j (14%) from the crude mixture leading to 3j.
Also, tiny amounts of an open-chain trimer 5j were isolated
from the same reaction crude, and further provided support
to this hypothesis.[20] Furthermore, 4k was synthesized in
25% yield using alternative experimental conditions to
those used in the preparation of 3k.[21]
1e: R=Br
1 f: R=4-MeO-C6H4 80
1.5
16
2e: R=Br
2 f: R=4-MeO-C6H4 60
1g: R=Me
1h: R=CHO
20
120
1
8
2g: R=Me
2h: R=CHO
93[b]
78[c]
1i
65
16
2i
71
[a] Isolated yield upon chromatographic purification. [b] Reaction using
[Ph3PAuNTf2]. [c] Reaction at 808C for 15 h resulted in the formation of
2h in comparable yield.
Upon confirming the key role of the substitution pattern
at the indole C2 position, additional experiments were con-
ducted to gain mechanistic insight into the formation of het-
erocycles 2. As depicted in Scheme 4, 2-deutero derivatives
of 1a and 1g were prepared and subjected to the cycloiso-
merization conditions, and gave deuterated 2a and 2g, re-
spectively. These products show the deuterium label mostly
attached at a different ring position. Thus, while for 2a deu-
terium was incorporated at two different positions (C10 and
C8),[22,23] only one deuterated cyclization product was no-
ticed for 2g. A direct sequence based on electrophilic cycli-
this cyclization shows broad functional group tolerance.
Thus, contrary to the scope found in the precedents, this cyc-
lization is not restricted to the case of strong electron-donor
substituents. Thus, far from activating groups (strong OMe
or weak Me, aryl), this catalytic reaction is nicely compati-
ble with weak (Br) or even more strong (CHO) deactiva-
tors. These substituents were tested at different positions in
indole, with satisfactory results in all cases. The cyclization
was also efficient for an internal allene (1i), suggesting inter-
esting opportunities for subsequent developments in this
context.
À
zation, proton elimination and protonolysis of the C Au
À
Interestingly, this cycloisomerization entails a catalytic C
bond by the generated acid, though in agreement with cycli-
H functionalization of indole that takes place overriding a
strong competitive intermolecular activation of the more nu-
cleophilic indole C3 position towards an electrophilic activa-
tion. To validate this assumption we explored related sys-
tems bearing an alkyl substituent at indole ring C2 position.
Thus, reactions of methyl indole derivatives 1j and 1k were
investigated (Scheme 3).
Under the initial conditions used substantial polymeri-
zation occurred. However, a careful control of the experi-
mental protocol, specifically the reaction time and the con-
centration, enabled the isolation of well-defined adducts, al-
though in modest yield. Thus, 1j (R=H, reaction for 9 h, 3ꢄ
10À2 m) and 1k (R=Br, 16 h, 2ꢄ10À2 m) gave 3j and 3k, re-
spectively. This type of cyclization is clearly different from
Scheme 4. Cycloisomerization of deuterated 1a and 1g: differential label-
ling, as revealed by NMR monitoring of the reaction.
11828
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Chem. Eur. J. 2010, 16, 11827 – 11831

Gold-Catalyzed Annulations
COMMUNICATION
zation of deuterated 1g, is not consistent with the observed
deuterium distribution in the reaction of 1a. Furthermore, a
control experiment conducted exposing either 1a or 1g to
the gold catalyst in [D8]toluene, at 808C, afforded 2a and
2g, respectively, without deuterium incorporation. More-
over, 2-deutero-1-methyl-1H-indole was treated with the
gold catalyst and the process monitored NMR. No evidence
for scrambling of deuterium between C2 and C3 was gath-
ered.[24] In another NMR experiment, 1a (0.04m in
[D8]toluene) remained unaltered after treatment for 12 h, at
room temperature, with triflimide (HNTf2, 20 mol%). Also,
lack of cyclization was noticed after a related reaction for
8 h at 808C though, in this case, partial decomposition
began to be observable. On this experimental basis, a tenta-
tive mechanistic description is outlined in Scheme 5.
to this alternative mechanistic picture.[29] Finally, product
formation based on the direct electrophilic auration of the
reactive indole C3 position, competitively with the assumed
key allene p-activation, can not be safely ruled out at pres-
ent.[30]
In summary, well-defined examples of a catalytic allene
hydroarylation following the 6-endo cyclization mode are
presented. The methodology is applied in a straight synthe-
sis of the relevant 6,9-dihydro-pyridoACTHNUTRGNE[NUG 1,2-a]-1H-indole core.
Substitution at C2 in the indole moiety precludes the cycloi-
somerization to occur and rather, a careful control over the
reaction conditions drives an interesting cyclotrimerization
reaction furnishing macrocyclic compounds. Moreover, ex-
perimental work done to scrutinize this new transformation
revealed valuable information that add further and distinc-
tive features to this catalytic chemistry and prompt further
efforts to uncover mechanistic aspects.
Experimental Section
Typical procedure for the gold-catalyzed 6-endo allene hydroarylation ex-
emplified for 2a: To a solution of 1-(buta-2,3-dienyl)-1H-indole (1a;
0.2 mmol, 34 mg) in toluene (5 mL, 0.04m), JOHNPHOSAuNTf2
(5 mmol%, 8 mg) was added under argon atmosphere, at 808C. The mix-
ture was stirred for further 50 min at this temperature. Then, the volume
of the solution was reduced to ca. 1 mL, by partial removal of solvent
under high vacuum. The resulting concentrated solution was charged into
Scheme 5. Isomerization of 1 to 2: working mechanistic hypothesis.
a chromatographic column to isolate 6,9-dihydro-pyridoACTHNUTRGNEU[GN 1,2-a]indole (2a)
[silica gel; hexane/AcOEt/40:1 (Rf =0.3) as the eluent] as a white solid
(27 mg, 80%; m.p. 136.1–138.38C).
This proposal assumes an initial interaction of cationic
gold(I) with the allene to give a p-complex. A subsequent
slippage of gold through the unsaturation would afford a
cationic intermediate, with gold attached to the central
carbon of the former allene, that is a suitable species to
attack the indole ring.[25] The topology of the substrate
would override the incorporation of this electrophile at the
indole C3 position, otherwise a usual process, because of the
high strain associated with this cyclization. This allows an al-
ternative pyrrole-like reactivity to be observed and, as a
consequence, cyclization at the indole C2 position occurs.
Next, the cyclization would yield intermediate A, that devel-
oped a positive charge at C3 as result of the electrophilic
ring-closure.[26] It might evolve to enjoy stabilization by the
lone pair of electrons residing at nitrogen without disrupting
the aromaticity of the benzene moiety to afford a cationic
species B that,[27] ultimately, would aromatize and furnish
cyclization product 2, showing the observed deuterium dis-
tribution.
Although alternative proposals could be discussed they
seem less likely on the basis of the data available. In this
regard, driven by initial coordination of gold to the allene,[28]
a selective electrophilic auration at C2 could be invoked
and different ways for its conversion to 2 envisaged. Howev-
er, the product distribution observed for the reaction of deu-
terated 1a, and the experimentally determined value for the
primary kinetic isotopic effect [PKIE, kH/kD (1a, 258C)=
1.10, and kH/kD (1g, 258C)=1.04] are difficult to harmonize
Acknowledgements
We are grateful to the Ministerio de Educaciꢅn of Spain (Grant CTQ-
2007-61048) and the Principado de Asturias (Grant IB 08-088). M.P.
thanks the Ministerio de Educaciꢅn and the European Union (Fondo
Social Europeo) for a predoctoral fellowship. We are also grateful to our
colleague Dr. E. Rubio and to Dr. I. Merino (Servicios Cientꢂfico Tꢆcni-
cos, Universidad de Oviedo) for her assistance in the collection of the 2D
NMR data.
À
Keywords: allenes · C H functionalization · cyclization ·
gold · indoles
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carry out the hydroarylation of ethyl 2-benzyl-2,3-alkadienoates.
[11] For selected 6-endo carbocyclizations of allenes with other types of
unsaturated motifs: a) T. Miura, K. Kiyota, H. Kusama, K. Lee, H.
[20] Compound 5j was isolated in 5% yield, see the Supporting Informa-
tion.
[21] For the synthesis of 4k, reaction temperature was 808C, the concen-
tration of 1k was 3ꢄ10À2 m; 10 mol% of the catalyst was added and
the reactions time was extended up to 16 h.
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Chem. Eur. J. 2010, 16, 11827 – 11831

Gold-Catalyzed Annulations
COMMUNICATION
[22] For the NMR experiment, the deuterium retention in 2a was estab-
lished considering the excess of the integral for H7 with respect to
the corresponding signal for H8 and the information supply by the
integral for H10 (for a copy of the spectrum and further details, see
the Supporting Information). Control experiments proved that 10-
[29] For aromatic electrophilic substitution reactions, the measured KIE
take their value on a wide range. As a result, for some representa-
À
tive reactions, as the case of aromatic nitration, C H cleavage is not
involved in the rate-determining step. However, in a closer process
to auration, as it is the case of electrophilic mercuration, a large
value consistent with proton-loss occurring at the rate determining
step has been recorded: a) A. J. Kresge, J. F. Brennan, J. Org. Chem.
1967, 32, 752–755; b) C. W. Fung, M. Khorramdel-Vahed, R. C.
Ranson, R. M. G. Roberts, J. Chem. Soc. Perkin Trans. 2 1980, 267–
272.
[D]-6,9-dihydro-pyridoACHTNUTRGNE[NUG 1,2-a]-1H-indole (2a) undergoes D/H ex-
change in both, deuterated chloroform and toluene solutions of
standard grade, as a function of the time. So the integral for H10
may experience appreciable deviations on standing 10-[D]-2a in the
solvent. Also, attempts to isolate deuterated products 2a upon rou-
tine column chromatography resulted in complete lost of deuterium,
though confirm a proper mass balance for the cyclization.
[30] Actually, low temperature NMR monitoring for the reaction of 1a
with the gold complex gave preliminary evidence for partial incor-
poration of the phosphine–gold fragment into C3, yielding the aurat-
ed intermediate indoleninium cation, en route to obtain the product
of electrophilic aromatic substitution by gold at that position (see
the Supporting Information). Then, further allene activation by the
generated proton followed by cyclization should render intermediate
A’, where the carbocation would benefit from stabilization by the at-
tached gold at C3. Subsequent evolution by favorable 1,2-migration
of deuterium would account well for the noticed product distribu-
tion for 1a, though it will require a different mechanism operating
for 1g. However, no evidence for a clean and full conversion to C3-
[23] For a related rapid 1,2-shift, involving high deuterium retention yet
incomplete, see for instance: A. Fꢇrstner, F. Stelzer, H. Szillat, J.
Am. Chem. Soc. 2001, 123, 11863–11869.
À
[24] For relevant synthetic studies on C3 C2 metal migration on indole
scaffolds, see for instance: a) palladium(II), N. P. Grimster, C. Gaun-
tlett, C. R. A. Godfrey, M. J. Gaunt, Angew. Chem. 2005, 117, 3185–
3189; Angew. Chem. Int. Ed. 2005, 44, 3125–3129; b) copperACHTUNTRGNEUNG(III):
R. J. Phipps, N. P. Grimster, M. J. Gaunt, J. Am. Chem. Soc. 2008,
130, 8172–8174; c) for a detailed mechanistic study on the regiose-
lectivity of indole arylation reactions and the role of electrophilic
palladation involving palladium-containing indoleninium cations:
B. S. Lane, M. A. Brown, D. Sames, J. Am. Chem. Soc. 2005, 127,
8050–8057.
[25] For cationic gold activation of an allene giving rise to an isolable al-
kenyl–gold intermediate: a) L.-P. Liu, B. Xu, M. S. Mashuta, G. B.
Hammond, J. Am. Chem. Soc. 2008, 130, 17642–17643. For a recent
study on isolable vinylgold complexes derived from alkynes:
b) A. S. K. Hashmi, A. M. Schuster, F. Rominger, Angew. Chem.
2009, 121, 8396–8398; Angew. Chem. Int. Ed. 2009, 48, 8247–8249.
[26] For an authoritative review on electrophilic addition and cyclization
reactions of allene, see: S. Ma, Acc. Chem. Res. 2009, 42, 1679–
1688.
[27] Whether this is a true 1,2-deuterium shift or a stepwise process that
entails elimination and subsequent competitive neutralization by
aurated compounds, even in the presence of bases or using a model
compounds lacking the allene moiety, as N-methylindole, were ob-
tained to provide support to this alternative hypothesis (see also
ref. [6i]). For important work on a clean conversion of indole into a
C3 aurated indolenium cation and for an efficient synthesis of C3
aurated indoles, see above reference [6h].
À
either the basic C3 indole position or, alternatively, by the carbon
gold bond, is not unequivocally established.
[28] For recent studies on processes involving regioselective directed pal-
ladation of indoles at C2 position: a) A. Garcꢂa-Rubia, R. Gꢅmez
Arrayꢁs, J. C. Carretero, Angew. Chem. 2009, 121, 6633–6637;
Angew. Chem. Int. Ed. 2009, 48, 6511–6515; b) E. Capito, J. M.
Brown, A. Ricci, Chem. Commun. 2005, 1854–1856; c) for a review
on metal complexes involving indole rings: Y. Shimazaki, T. Yajima,
M. Takani, O. Yamauchi, Coord. Chem. Rev. 2009, 253, 479–492.
Received: June 21, 2010
Published online: September 8, 2010
Chem. Eur. J. 2010, 16, 11827 – 11831
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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