[Cp*IrCl2]2 catalyzed formation of 2,2′-biindoles from 2-ethynylanilines

Article abstract of DOI:10.1021/ol5000692

[Cp*IrCl₂]₂ catalyzes the cyclization of 2-ethynylanilines to 2,2′-biindoles via intramolecular hydroamination. A reaction pathway has been proposed on the basis of deuterium labeling experiments and computational studies.

Full text of DOI:10.1021/ol5000692

Letter
pubs.acs.org/OrgLett
[Cp*IrCl2]2 Catalyzed Formation of 2,2′-Biindoles from
2‑Ethynylanilines
Elumalai Kumaran,† Wai Yip Fan,‡ and Weng Kee Leong*,†
†Division of Chemistry and Biological Chemistry, Nanyang Technological University, 21 Nanyang Link, Singapore 637371
‡Department of Chemistry, National University of Singapore, Science Drive 3, Singapore 117543
S
* Supporting Information
ABSTRACT: [Cp*IrCl2]2 catalyzes the cyclization of 2-ethynylanilines to 2,2′-
biindoles via intramolecular hydroamination. A reaction pathway has been
proposed on the basis of deuterium labeling experiments and computational
studies.
itrogen heterocyclic compounds occupy a very important
Nrole in synthetic organic chemistry because of the useful
properties of many members of this class of compounds.1 Over
50 naturally occurring alkaloids containing the 2,2′-biindole
subunit have been isolated and characterized.2 This subunit is
stable and can be found in a vast number of biologically active
natural products such as the tjipanazoles, staurosporine, ent-
staurosporine, holyrine, arcyriaflavin, rebeccamycin, and stauro-
sporinone3 and has also been utilized in synthetic biologically
active molecules such as (−)-K252a4 and in anion sensor
organic materials.5 The 2,2′-biindole structure can be prepared
by the condensation of N-aryl oxamide derivatives (Madelung
cyclization),3a,6 intramolecular cyclization of the corresponding
1,3-diynes,7 or coupling of the corresponding indole deriva-
tives.8 In most cases, however, low-yield multistep syntheses8 or
harsh reaction conditions are required,3a,6 although a two-step
conversion of 2-ethynylanilines to 2,2′-biindoles can proceed in
very good overall yields.7 The development of an efficient new
synthetic route to 2,2′-biindole derivatives would therefore be
of interest to synthetic organic chemists.
We have recently reported that the reaction of [Cp*IrCl2]2,
1, with an aniline and a terminal alkyne led to the formation of
an orthometalated iridium amino-carbene.9 The proposed
reaction pathway involved the formation of a vinylidene
intermediate, followed by nucleophilic attack of aniline at the
α-carbon and a proton transfer to an aminocarbene, and
orthometalation (Scheme 1).9
It occurred to us that an intramolecular hydroamination
using a 2-ethynylaniline, 2a, would lead to an iridium amino-
carbene which cannot undergo orthometalation due to ring
strain. This amino-carbene may instead undergo dimerization
and isomerization to afford 2-indolylindoline. What we have
found, however, was that the reaction proceeded cleanly to
afford fluorescent 2,2′-biindole, 3a (Scheme 2).
Scheme 2. Reaction of 1 and 2a; Proposed Formation of 2-
Indolylindoline and the Observed Formation of 2,2′-
Biindole
The biindole has been completely characterized, including by
a single-crystal X-ray structural analysis. Cyclization of an
alkynylaniline such as 2a to an indole is known to be catalyzed
by a number of transition metal complexes, including those of
rhodium,10 ruthenium,11 gold,7d and molybdenum,12 and
several iridium complexes have also been reported to catalyze
the cyclization of internal 2-alkynylanilines to the correspond-
ing indole derivatives.13 There is also a recent report on a one-
pot, two-step synthesis of 3,3′-biindoles through the cyclization
of internal alkynylanilines using a gold catalyst.14 Besides a long
reaction time and high temperature (4 d and 70 °C), this
reaction also tended to yield a mixture of the indole and the
3,3′-biindole which was substrate-dependent.
To the best of our knowledge, there has been no report on a
single-step synthesis of 2,2′-biindoles from simple and readily
available alkynylanilines.
An optimization study showed that a good yield could be
obtained at elevated temperature (Table 1, entries 1, 3, and 4)
or at ambient temperature albeit with a longer reaction time
Scheme 1. Formation of Iridium Amino-carbenes
Received: January 8, 2014
Published: February 17, 2014
© 2014 American Chemical Society
1342
dx.doi.org/10.1021/ol5000692 | Org. Lett. 2014, 16, 1342−1345

Organic Letters
Letter
functional group tolerance was excellent, and a wide range of
functional groups (alkyls, halides, CN, NO2, and esters) was
tolerated, although the reaction failed with secondary alkynyl-
anilines (N-methyl and N-benzyl-2-ethynylanilines). Substitu-
tion at the 5- instead of the 4-position was also tolerated (entry
10), and a reaction with a larger scale of 2b (250 mg) gave a
78% yield, demonstrating that the reaction was amenable to
scaling-up.
A number of possible reaction pathways to 3 were
considered. Pathways involving the intermediate formation of
2-indolylindoline (Scheme 2), followed by 1-catalyzed
dehydrogenation of the indoline moiety, could be ruled out,
as 1 failed to react with indoline to afford indole under similar
conditions (Scheme 3 top); the computed ΔG° for the carbene
Table 1. Optimization Study for 1-Catalyzed Cyclization of
2a to 3a
a
c
entry
catalyst (mol %)
solvent
T (°C)
yield (%)
1
2
3
4
5
1 (5)
DCE
40
50
80
80
80
40
80
80
80
60
60
80
40
80
80
58
68
82
81
71
78
−
1 (5)
DCE
1 (5)
DCE
1 (2.5)
DCE
1 (1)
DCE
b
6
1 (2.5)
DCE
7
[Cp*RhCl2]2 (2.5)
[Ir(cod)Cl]2 (2.5)
1 (2.5)
DCE
8
DCE
−
Scheme 3. Attempted Reactions of 1 with Indoline and
Indole
9
toluene
THF
75
77
−
87
89
60
70
10
11
12
1 (2.5)
1 (2.5)
MeOH
ACN
ACN
DMF
CH2Br2
1 (2.5)
b
13
1 (2.5)
14
15
1 (2.5)
1 (2.5)
a
The cyclization of 2a (0.05 mmol) was carried out in the presence of
b
1 in a solvent (3 mL) at various temperatures for 12 h. Reaction was
carried out for 24 h. Isolated yields.
c
dimerization needed was also high (+64 kJ mol−1). Pathways
involving the intermediate formation of indole, via intra-
molecular cyclization, presumably followed by oxidative
coupling catalyzed by 1, were also ruled out, as the reaction
of 1 with indole did not give 3a (Scheme 3 bottom).
Isotopic labeling experiments employing 2-ethynylaniline and
D2O afforded deuteration of the 3 and 3′ positions in 3a; with
d3-ethynylaniline alone, deuteration at these positions was not
observed (Scheme 4). These results clearly pointed to water as
(Table 1, entries 6 and 13). A lower catalyst loading could be
tolerated somewhat (Table 1, entries 3−5), as well as a range of
solvents, from toluene to acetonitrile (Table 1, entries 9−15);
the last is optimal, but the use of methanol afforded the
hydration product, 2-aminoacetophenone. Two other catalytic
systems, viz., [Cp*RhCl2]2 and [Ir(cod)Cl]2, were also tested,
but they failed to furnish 3a under similar conditions (entries 7
and 8).
This reaction represents a very attractive route to biindoles,
as straightforward synthetic routes to 2-ethynylanilines are
available.10a For example, Sonogashira cross-coupling of 2-iodo-
4-methylaniline with trimethylsilylacetylene followed by proto-
desilylation provided the desired substrate 2b in an overall yield
of 81%. The substrate scope study (Table 2) showed that
Scheme 4. Isotope Labelling Studies
a
Table 2. Cyclization of 2 to 3 Catalyzed by 1
b
entry
R
yield (%)
1
2
3
4
5
6
7
8
9
H
3a, 89
3b, 81
3c, 79
3d, 86
3e, 84
3f, 89
3g, 73
3h, 79
3i, 87
3j, 78
CH3
tBu
the source for the 3 and 3′ protons in 3a and are consistent
with the formation of a vinylidene intermediate via an
intermolecular 1,2-H shift in the reaction pathway.9,14
Our proposed reaction pathway is given in Figure 1; the
energetics for the various steps (for 2-ethynylaniline) have also
been computed with density functional theory, and the
computed free energies (ΔG°, in kJ mol−1) are also shown.
The reaction free energies indicate that the proposed steps are
not unreasonable.
Br
Cl
NO2
CN
CO2CH3
CO2C2H5
CH3
c
10
a
As has been proposed earlier, cleavage of dimeric 1 is most
probably through coordination of the amine group of the
aminoalkyne but this is probably in equilibrium with
The cyclization of 2a (0.05 mmol) was carried out in the presence of
b
1 (0.0125 mmol) in acetonitrile (3 mL) at 40 °C for 24 h. Isolated
yields. R = 5-CH3.
c
1343
dx.doi.org/10.1021/ol5000692 | Org. Lett. 2014, 16, 1342−1345

Organic Letters
Letter
Scheme 6. Formation of Side Product 4
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental and computational details. This material is
available free of charge via the Internet at http://pubs.acs.org
Figure 1. Proposed catalytic cycle for the formation of 3. Numbers in
red are the computed free energies in kJ mol−1.
AUTHOR INFORMATION
Corresponding Author
■
intermediate A, in which the CC bond is coordinated.9,15
A
rapid rearrangement to the vinylidene B follows,9 and
nucleophilic attack of the amine group at the α-carbon,
followed by HCl elimination as the ammonium salt and
coordination of another molecule of aminoalkyne, gives
intermediate C. Up to this point, the pathway is similar to
that which we have proposed earlier for the rhodium
metallacyclic complexes.15 From C, a second vinylidene
rearrangement to D, followed by a 1,2-migratory insertion of
the indolyl unit into the vinylidene, affords intermediate E. A
Meisenheimer-type rearrangement (Scheme 5) of this affords
the biindole and the hydride species F. In the final step,
protonolysis of F (presumably by the ammonium salt)
regenerates A.16
*E-mail: chmlwk@ntu.edu.sg.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Nanyang Technological University
and the Ministry of Education (Research Grant No.
M4011017). Assistance on the crystallographic studies by Dr.
Rakesh Ganguly is acknowledged, and one of us (E.K.) thanks
the university for a Research Scholarship.
REFERENCES
■
(1) (a) Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic Chemistry;
Stanley Thornes: Cheltenham, 1998. (b) Li, J. J.; Gribble, G. W.
Palladium in Heterocyclic Chemistry; Elsevier Science; Oxford, 2000.
(2) (a) Bergman, J. Stud. Nat. Prod. Chem., Part A 1988, 1, 3.
(b) Gribble, G. W.; Berthel, S. J. Stud. Nat. Prod. Chem. 1993, 12, 365.
(c) Steglich, W. Fortschr. Chem. Org. Naturst. 1987, 51, 216.
(d) Omura, S.; Sasaki, Y.; Iwai, Y.; Takeshima, H. J. Antibiot. 1995,
48, 535.
Scheme 5. Meisenheimer-Type Rearrangement for the
Formation of 3
(3) (a) Wood, J. L.; Stoltz, B. M.; Dietrich, H. J.; Pflum, D. A.;
Petsch, D. T. J. Am. Chem. Soc. 1997, 119, 9641. (b) Link, J. T.;
Raghavan, S.; Danishefsky, S. J. Am. Chem. Soc. 1995, 117, 552.
(c) Somei, M.; Kodama, A. Heterocycles 1992, 34, 1285. (d) Somei, M.;
Hayashi, H.; Ohmoto, S. Heterocycles 1997, 44, 169. (e) Hayashi, H.;
Ohmoto, S.; Somei, M. Heterocycles 1997, 45, 1647. (f) Joyce, R. P.;
Gainor, J. A.; Weinreb, S. M. J. Org. Chem. 1987, 52, 1177. (g) Wada,
Y.; Nagasaki, H.; Tokuda, M.; Orito, K. J. Org. Chem. 2007, 72, 2008.
(h) Shintani, A.; Toume, K.; Rifai, Y.; Arai, M. A.; Ishibashi, M. J. Nat.
Prod. 2010, 73, 1711.
Attempts to detect the elimination of H2 (by mass spectral
analysis of the headspace, including analysis for the presence of
HD or D2 from a reaction in the presence of D2O) failed. The
presence of styrene, a possible byproduct if there is H transfer
to an alkyne, was also not detected.
Nevertheless, support for this pathway is the observation of a
side product 4 (3% yield) from the reaction. This side product
could have been formed via a 1,2-alkyne insertion in C to form
the intermediate E′, with subsequent protonolysis, hydro-
genation, and rearrangement (Scheme 6). Although the precise
pathway to 4 is unclear, its formation suggests that the
proposed intermediate E is reasonable.
In conclusion, we have described a novel, clean, and efficient
iridium-catalyzed process for the synthesis of 2,2′-biindole from
2-ethynylanilines. A reaction pathway has been proposed, on
the basis of experimental and computational studies, which
involves the formation of a vinylidene intermediate, intra-
molecular hydroamination, and a subsequent insertion reaction.
(4) Wood, J. L.; Stoltz, B. M.; Dietrich, H. J. J. Am. Chem. Soc. 1995,
117, 10413.
(5) (a) Lin, C. I.; Selvi, S.; Fang, J. M.; Chou, P. T.; Lai, C. H.;
Cheng, Y. M. J. Org. Chem. 2007, 72, 3537. (b) Curiel, D.; Cowley, A.;
Beer, P. D. Chem. Commun. 2005, 236. (c) Kim, N. K.; Chang, K. J.;
Moon, D.; Lah, M. S.; Jeong, K. S. Chem. Commun. 2007, 3401.
(6) (a) Pelly, S. C.; Parkinson, C. J.; Van Otterlo, W. A. L.; Koning,
C. B. J. Org. Chem. 2005, 70, 10474.
(7) (a) Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schimid, B.;
Knochel, P. Tetrahedron 2003, 59, 1571. (b) Abbiati, G.; Arcadi, A.;
Beccalli, E.; Bianchi, G.; Marinelli, F.; Rossi, E. Tetrahedron 2006, 62,
3033. (c) Saulnier, M. G.; Frennesson, D. B.; Deshpande, M. S.; Vyas,
D. M. Tetrahedron Lett. 1995, 36, 7841. (d) Arcadi, A.; Bianchi, G.;
Marinelli, F. Synthesis 2004, 610. (e) Lee, J. Y.; Lee, M. H.; Jeong, K. S.
1344
dx.doi.org/10.1021/ol5000692 | Org. Lett. 2014, 16, 1342−1345

Organic Letters
Letter
Supramol. Chem. 2007, 19, 257. (f) Kim, U.; Suk, J. M.; Naidu, V. R.;
Jeong, K. S. Chem.Eur. J. 2008, 14, 11406.
̀
(8) (a) Rubia, A. G.; Urones, B.; Arrayas, R. G.; Carretero, J. C.
Chem.Eur. J. 2010, 16, 9676. (b) Bergman, J.; Eklund, N.
Tetrahedron 1980, 36, 1439. (c) Merlic, C. A.; You, Y.; McInnes, D.
M.; Zechman, A. L.; Miller, M. M.; Deng, Q. Tetrahedron 2001, 57,
5199. (d) Hudkins, R. L.; Diebold, J. L.; Marsh, F. D. J. Org. Chem.
1995, 60, 6218.
(9) Kumaran, E.; Sridevi, V. S.; Leong, W. K. Organometallics 2010,
29, 6417.
(10) (a) Trost, B. M.; McClory, A. Angew. Chem. Int. ed. 2007, 46,
2074. (b) Burling, S.; Field, L. D.; Messerle, B. A. Organometallics
2000, 19, 87.
́ ́
(11) (a) Fernandez, A. V.; Varela, J. A.; Saa, C. Adv. Synth. Catal.
2011, 353, 1933. (b) Kondo, T.; Okada, T.; Suzuki, T.; Mitsudo, T. J.
Organomet. Chem. 2001, 622, 149. (c) Nair, R. N.; Lee, P. J.;
Rheingold, A. R.; Grotjahn, D. B. Chem.Eur. J. 2010, 16, 7992.
(12) McDonald, F. E.; Chatterjee, A. K. Tetrahedron. Lett. 1997, 38,
7687.
(13) (a) Kennedy, D. F.; Messerle, B. A.; Rumble, S. L. New J. Chem.
2009, 33, 818. (b) Li, X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H.
Org. Lett. 2005, 7, 5437. (c) Lai, R. Y.; Surekha, K.; Hayashi, A.;
Ozawa, F.; Liu, Y. H.; Peng, S. M.; Liu, S. T. Organometallics 2007, 26,
1062.
(14) Perea-Buceta, J. E.; Wirtanen, T.; Laukkanen, O. V.; Makela, M.
̈
̈
K.; Nieger, M.; Melchionna, M.; Huittinen, N.; Lopez-Sanchez, J. A.;
Helaja, J. Angew. Chem., Int. Ed. 2013, 52, 11835.
(15) Sridevi, V. S.; Fan, W. Y.; Leong, W. K. Organometallics 2007,
26, 1173−1177.
(16) O’Connor, J. M.; Pu, L.; Rheingold, A. L. J. Am. Chem. Soc.
1990, 112, 6232−6247.
1345
dx.doi.org/10.1021/ol5000692 | Org. Lett. 2014, 16, 1342−1345