Ag(I)-Catalyzed Domino Cyclization-Addition Sequence with Simultaneous Carbonyl and Alkyne Activation as a Route to 2,2′-Disubstituted Bisindolylarylmethanes

Article abstract of DOI:10.1021/acs.orglett.6b02321

An efficient synthesis of symmetrical 3, 3′-bisindolylarylmethanes with various substituents on the indole moiety has been developed by Ag(I)-catalyzed cycloisomerization and an deoxygenative addition sequence on o-alkynylanilines and aryl aldehydes. Ag(I) is proposed to activate alkyne unit and carbonyl moiety simultaneously leading to a domino first 5-endo-dig indole annulation, addition to C=O, second indole annulation, and its dehydroxylative addition.

Full text of DOI:10.1021/acs.orglett.6b02321

Letter
pubs.acs.org/OrgLett
Ag(I)-Catalyzed Domino Cyclization−Addition Sequence with
Simultaneous Carbonyl and Alkyne Activation as a Route to 2,2′-
Disubstituted Bisindolylarylmethanes
Swastik Karmakar,*,† Prasanta Das,† Debjyoti Ray,† Subhankar Ghosh,‡ and Shital K. Chattopadhyay*,‡
†Department of Chemistry, Basirhat College, Basirhat 743412, West Bengal India
‡Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal India
S
* Supporting Information
ABSTRACT: An efficient synthesis of symmetrical 3, 3′-bisindolylarylmethanes with various substituents on the indole moiety
has been developed by Ag(I)-catalyzed cycloisomerization and an deoxygenative addition sequence on o-alkynylanilines and aryl
aldehydes. Ag(I) is proposed to activate alkyne unit and carbonyl moiety simultaneously leading to a domino first 5-endo-dig
indole annulation, addition to CO, second indole annulation, and its dehydroxylative addition.
ndoles are probably one of the most ubiquitous structures
Iamong heterocyclic compounds due to their presence in
various natural products, pharmaceuticals, and agrochemicals1
of proven biological record.1,2 Novel 3,3′-bisindolylmethane
alkaloids (BIMs), e.g., 1−5 (Figure 1), have been isolated from
various terrestrial and marine natural sources,1n,3 many of
which display remarkable biological activities.4 This, in turn, has
encouraged the design and synthesis of analogues of these
natural products.3c,5
A majority of synthetic methods reported involve con-
densation of indoles with carbonyl compounds (or their
synthetic equivalents) in the presence of acid or base to obtain
BIMs with different structural features.3c,5 Some metal-
catalyzed processes have been developed employing similar
resources,6 such as the Re-catalyzed addition,6d the Pt-catalyzed
bis-indolylation,6f and gold-catalyzed transformation,6c among
others. Transition-metal-catalyzed cycloisomerization of o-
alkynylanilines has become an important tool for the
construction of indoles during the past two decades.7 Recently,
Campagne et al. reported the synthesis of BIMs via one-pot
annulation/Friedel−Crafts alkylation employing dual catalysis
of Fe(III)−Pd(II) on o-alkynylanilines in moderate yield.8
However, a one-pot domino methodology for BIM formation
using dual activation of o-alkynylanilines and aldehydes under
suitable metal catalysis may offer distinct advantages. Moreover,
BIMs with additional substitution in the pyrrole nucleus have
been little explored to the best of our knowledge. In this paper,
we report a one-pot domino process that allows quick
generation of 2,2′-disubstituted 3,3′-bisindolylarylmethanes
(BIAMs) from easily available starting materials using silver
catalysis.
Received: August 4, 2016
Figure 1. Privileged structures of 3,3′-bisindolylmethanealka-loids.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02321
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The economic attractiveness and milder nature of silver-
based catalysts have made their use significant in large-scale
catalytic reactions. This led us to exploration of a silver-
catalyzed process for the synthesis of substituted BIAMs in view
of previous success on silver-catalyzed indole formation.9,10 We
wondered whether Ag(I) might be able to make aldehydes
susceptible to nucleophilic addition with simultaneous cyclo-
isomerization of appropriately substituted alkynylanilines,
which could possibly lead to BIAM derivative 3 (Figure 1).
Thus, our trial commenced with unprotected o-alkynylanilines
and aldehydes as the starting materials using Ag(I) as a catalyst
as a possible domino process. Initially, the reaction was allowed
to run with several silver catalysts (AgNO3, Ag2CO3, AgOAc)
that are soluble in polar protic solvents. However, none of these
catalyzed the reaction even at elevated temperature (70−80
°C) in different reaction media (entries 1−4, Table 1), and a
silver mirror was observed at the bottom of the flask, perhaps as
a result of oxidation of the aldehyde with Ag(I) in such types of
solvents and reaction conditions.
we found that better result could be obtained using CF3CO2Ag
as catalyst in toluene at 80 °C (entry 8). We then decided to
examine the catalytic activity of AgOTf in toluene at 80 °C for
this domino process. Pleasingly, 2,2′-diaryl-3,3′-bisindolylaryl-
methane 8a was produced in very good yield (88%) within 2.5
h (entry 9). Comparatively lower yield (75%) was obtained
when NaHCO3 was added as an additive in the above reaction
(entries 10a and 10b). However, Brønsted acids (TfOH) and
dehydrative conditions could not furnish BIAMs under these
reaction conditions (entries 11 and 12). Consequently, AgOTf
proved to be the catalyst of choice for this transformation
(entry 9).
Moreover, a controlled experiment was conducted in order
to investigate if 2-substituted indole could be condensed with
aldehydes under the same reaction conditions (Scheme 1).
BIAMs 8 were obtained in poor yield when the 2-substituted
indoles 9a−c were generated prior to the addition of aldehyde
into the reaction mixture.
Scheme 1. Controlled Experimentation with 2-Substituted
Indoles and Aldehydes
a
Table 1. Optimization of the Reaction Conditions
b,c
yield
(%)
catalyst
(5 mol %)
temp time
entry
solvent
(°C)
(h)
8a
9a
1
2
AgNO3
AgNO3
AcOH + EtOH (1:1)
70
80
16
16
0
0
0
0
To rationalize this domino process, we could propose a
plausible mechanism where Ag(I) would be supposed to initiate
the coordination with alkyne unit11 and carbonyl moiety
simultaneously (pathway a, I, Scheme 2). This mode of
activation could induce sequential 5-endo-dig indole annulation
followed by addition of the C3 of the first indole moiety to the
carbonyl carbon of aryl aldehyde to furnish an Ag(I) alkoxide
intermediate II. Ag(I) of this intermediate may then activate
the alkyne unit of the second molecule of o-alkynylaniline
leading ultimately to second indole annulation. Addition of the
C-3 of second indole moiety to the benzylic carbon of bis-aryl
methoxide within II would proceed with the substitution of
Ag(I)-bound oxygen. This tandem bond-breaking−bond-
forming cascade would produce our desired products 2,2′-
disubstituted 3,3′-bisindolylarylmethanes (BIAMs) and water
and regenerate the catalyst AgOTf as shown in Scheme 2.
An alternate possibility is the consequential domino process
shown in pathway b (Scheme 2). First, the indolyl silver
intermediate IV is formed, which next condenses with the
aldehyde to form the alkoxysilver intermediate V. Finally,
condensation between V and VI gives the desired product with
simultaneous regeneration of silver triflate.12
To demonstrate generality, the scope of the synthesis of
BIAMs was examined for this domino process using various
unprotected o-alkynylanilines 6 and aldehydes 7 as the starting
materials (Table 2). We observed that substituents on the
aromatic aldehyde have an impact on the product yield. A
better yield could be achieved when electron-withdrawing
substituents were present in the aromatic aldehyde (entries 1, 5,
9, and 13). Moreover, ortho-substituted aryl aldehyde, e.g., 2-
chlorobenzaldehyde, also underwent smooth transformation
toluene + EtOH +
H2O
3
4
Ag2CO3
AgOAc
toluene + EtOH +
H2O
80
80
16
16
0
0
0
0
toluene + EtOH +
H2O
5
6
7
8
9
AgOTf
DMSO
DMF
80
80
60
80
80
80
16
16
16
16
2.5
2.5
0
0
25
20
25
10
0
AgOTf
AgOTf
THF
30
40
88
75
CF3CO2Ag
AgOTf
toluene
toluene
toluene
10a AgOTf +
NaHCO3
0
10b AgOTf +
NaHCO3
toluene
80
16
75
0
11
12
TfOH
toluene
80
80
16
16
0
0
0
0
toluene + n-decane +
MgSO4 + molecular
sieves (4 Å)
a
Reaction conditions: 6a (0.2 mmol), 7a (0.1 mmol), catalyst (0.005
mmol), solvent (1 mL). Isolated yield. Under argon.
b
c
We then decided to carry out this process in polar aprotic
solvents (DMSO, DMF). Considering the solubility in the
reaction medium, AgOTf was employed as catalyst. Unfortu-
nately, the only fruitful result of the reaction was the formation
of the indole 9a in low yield (entries 5 and 6). However,
indicatively, AgOTf showed moderate catalytic activity in dry
THF at 60 °C. BIAM 8a indeed formed under the stated
conditions (entry 7), but the yield was too low to be
synthetically useful (30%). In this reaction, indole 9a was
formed as a side product (25%). After some experimentation,
B
DOI: 10.1021/acs.orglett.6b02321
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Plausible Mechanism for Formation of BIAMs
Table 2. Scope of 2,2′-Disubstituted 3,3′-
a
Bisindolylarylmethanes 8
into the desired BIAMs (entries 17−19). Pleasingly, heteroaryl
aldehydes like 2-thiophene-yl and 2-furanyl aldehydes re-
sponded to this domino process rapidly with similar efficiency
(entries 22−25). 2-Alkynylaniline having a further substitution
on the aromatic ring (entries 20 and 21) followed the course of
the process in a similar fashion.
Interestingly, substituents on the alkyne unit also influenced
the efficiency of this domino reaction. Substrates having a butyl
or ethyl ester group on their alkyne unit responded well in this
transformation. The yield of BIAMs became relatively high
(entries 5, 6, 13, 14, etc.) compared to that from the substrates
with a phenyl substituent. Substrates bearing an aliphatic
hydroxyl group on the alkyne unit did not respond well toward
this catalytic reaction. BIAM was obtained in only 55% yield
when 6c and vanillin were allowed to undergo a domino indole
annulation and deoxygenative addition sequence even in the
presence of 10 mol % of AgOTf at 80 °C for 6 h (entry 12).
Longer reaction time and higher catalyst loading were required
to obtain a moderate yield (55−70%; entries 9−13) for this
type of substrates.
a
Reaction conditions: 6 (0.2 mmol), 7 (0.1 mmol), catalyst (0.01
mmol otherwise mentioned; 5 mol % with respect to alkyne), solvent
(0.5 mL). Isolated yield. Under argon.
b
c
Although the gross structure of each of the products was
secured from spectral analysis, a crystallographic confirmation
was obtained on compound 8a (ORTEP, Figure 2).
In conclusion, we have developed a facile domino process for
the construction of symmetrical BIAMs having various
substitutions at the 2,2′-positions of the indole from
unprotected o-alkynylaniline and aldehyde employing Ag(I)
as a metal catalyst, which involves simultaneous activation of
the alkyne unit and carbonyl moiety. As BIMs are important
biologically relevant scaffolds, this moiety with further
substitutions at the indole ring13 could find use in medicinal
chemistry. The methodology developed is atom- as well as pot-
economic and involves the use of catalytic amounts of more
Figure 2. ORTEP diagram of 8a.
accessible silver salts, which may render it adaptable for large-
scale synthesis.
C
DOI: 10.1021/acs.orglett.6b02321
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
X.; Wang, X.; Chang, W.; Wu, M. Adv. Synth. Catal. 2013, 355, 1911.
(e) Hikawa, H.; Yokoyama, Y. RSC Adv. 2013, 3, 1061. (f) Lucarini, S.;
Mari, M.; Piersanti, G.; Spadoni, G. RSC Adv. 2013, 3, 19135.
(g) Brahmachari, G.; Banerjee, B. ACS Sustainable Chem. Eng. 2014, 2,
2802. (h) Zhuo, M. H.; Jiang, Y. J.; Fan, Y. S.; Gao, Y.; Liu, S.; Zhang,
S. Org. Lett. 2014, 16, 1096. (i) Qi, S.; Liu, C. Y.; Ding, J. Y.; Han, F. S.
Chem. Commun. 2014, 50, 8605. (j) Ishikura, M.; Abe, T.; Ikeda, T.;
Itoh, T.; Hatae, N.; Toyota, E. Heterocycles 2014, 88, 187. (k) Lin, L.
P.; Yuan, P.; Jiang, N.; Mei, Y. N.; Zhang, W. J.; Wu, H. M.; Zhang, A.
H.; Cao, J. M.; Xiong, Z. X.; Lu, Y.; Tan, R. X. Org. Lett. 2015, 17,
2610. (l) Mendes, S. R.; Thurow, S.; Penteado, F.; da Silva, M. S.;
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02321.
■
S
General procedures, 1H and 13C NMR spectra of
compounds 8a−y, and X-ray structure of 8a (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Gariani, R. A.; Perin, G.; Lenardao, E. J. Green Chem. 2015, 17, 4334.
̃
(m) Halimehjani, A. Z.; Hooshmand, S. E.; Shamiri, E. V. RSC Adv.
2015, 5, 21772.
*E-mail: swastik.karmakar@gmail.com.
*E-mail: skchatto@yahoo.com.
Notes
(6) (a) de La Herran, G.; Segura, A.; Csaky, A. G. Org. Lett. 2007, 9,
́
́
̈
961. (b) Guo, X.; Pan, S.; Liu, J.; Li, Z. J. Org. Chem. 2009, 74, 8848.
(c) Praveen, C.; Wilson Sagayaraj, Y.; Perumal, P. T. Tetrahedron Lett.
2009, 50, 644. (d) Xia, D.; Wang, Y.; Du, Z.; Zheng, Q.; Wang, C. Org.
Lett. 2012, 14, 588. (e) Zhang, L.; Peng, C.; Zhao, D.; Wang, Y.; Fu,
The authors declare no competing financial interest.
H. J.; Shen, Q.; Li, J. X. Chem. Commun. 2012, 48, 5928. (f) Munoz,
M. P.; de La Torre, M. C.; Sierra, M. A. Chem. - Eur. J. 2012, 18, 4499.
(g) Beltra, J.; Gimeno, M. C.; Herrera, R. P. Beilstein J. Org. Chem.
́
2014, 10, 2206.
̃
ACKNOWLEDGMENTS
■
Financial support from the Department of Science and
Technology (DST), Government of India (Grant No. SERB/
F/4912/2013-14), and University of Kalyani is gratefully
acknowledged. We sincerely thank Professor Gautam Brahma-
chari of Visva-Bharati for X-ray crystallographic data of 8a.
(7) (a) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Org. Lett.
2006, 8, 2803. (b) Lu, B. Z.; Zhao, W.; Wei, H. X.; Dufour, M.; Farina,
V.; Senanayake, C. H. Org. Lett. 2006, 8, 3271. (c) Isono, N.; Lautens,
M. Org. Lett. 2009, 11, 1329. (d) Ohta, Y.; Oishi, S.; Fujii, N.; Ohno,
H. Org. Lett. 2009, 11, 1979. (e) Cacchi, S.; Fabrizi, G.; Goggiamani,
A.; Perboni, A.; Sferrazza, A.; Stabile, P. Org. Lett. 2010, 12, 3279.
(f) Han, X.; Lu, X. Org. Lett. 2010, 12, 3336. (g) Chen, Z.; Zheng, D.;
Wu, J. Org. Lett. 2011, 13, 848. (h) Shu, D.; Winston-McPherson, G.
N.; Song, W.; Tang, W. Org. Lett. 2013, 15, 4162. (i) Xia, G.; Han, X.;
Lu, X. Org. Lett. 2014, 16, 2058. (j) Ha, T. M.; Yao, B.; Wang, Q.; Zhu,
J. Org. Lett. 2015, 17, 1750. (k) Reddy, V.; Anand, R. V. Org. Lett.
2015, 17, 3390.
REFERENCES
■
(1) (a) Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2000,
122, 5662. (b) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2001, 66,
412. (c) Lerchner, A.; Carreira, E. M. J. Am. Chem. Soc. 2002, 124,
14826. (d) Kusama, H.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc.
2002, 124, 11592. (e) Ackermann, L. Org. Lett. 2005, 7, 439.
(f) Segraves, N. L.; Crews, P. J. Nat. Prod. 2005, 68, 1484. (g) Cacchi,
S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (h) Smith, A. B., III; Kurti,
̈
(8) Terrasson, V.; Michaux, J.; Gaucher, A.; Wehbe, J.; Marque, S.;
Prim, D.; Campagne, J.-M. Eur. J. Org. Chem. 2007, 2007, 5332.
(9) For some reports on silver-mediated synthesis of indole
derivatives, see: (a) Hua, H.-L.; Zhang, B.-S.; He, Y.-T.; Qiu, Y.-F.;
Wu, X.-X.; Xu, P.-F.; Liang, Y.-M. Org. Lett. 2016, 18, 216. (b) James,
M. J.; Clubley, R. E.; Palate, K. Y.; Procter, T. J.; Wyton, A. C.;
O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P. Org. Lett. 2015, 17, 4372.
(c) Mothe, S. R.; Novianti, M. L.; Ayers, B. J.; Chan, P. W. H. Org.
Lett. 2014, 16, 4110. (d) Feng, X.; Wang, H.; Yang, B.; Fan, R. Org.
Lett. 2014, 16, 3600. (e) McNulty, J.; Keskar, K. Eur. J. Org. Chem.
2014, 2014, 1622. (f) Yang, L.; Ma, Y.; Song, F.; You, J. Chem.
Commun. 2014, 50, 3024. (g) Liu, J.; Xie, X.; Liu, Y. Chem. Commun.
2013, 49, 11794. (h) Pirovano, V.; Facoetti, D.; Dell’Acqua, M.; Della
Fontana, E.; Abbiati, G.; Rossi, E. Org. Lett. 2013, 15, 3812. (i) Wang,
H.-L.; Li, Z.; Wang, G.-W.; Yang, S.-D. Chem. Commun. 2011, 47,
11336.
L.; Davulcu, A. H. Org. Lett. 2006, 8, 2167. (i) Burton, R. R.; Tam, W.
Org. Lett. 2007, 9, 3287. (j) Stokes, B. J.; Dong, H.; Leslie, B. E.;
Pumphrey, A. L.; Driver, T. G. J. Am. Chem. Soc. 2007, 129, 7500.
(k) Bell, M. G.; Gernert, D. L.; Grese, T. A.; Belvo, M. D.; Borromeo,
P. S.; Kelley, S. A.; Kennedy, J. H.; Kolis, S. P.; Lander, P. A.; Richey,
R.; Sharp, V. S.; Stephenson, G. A.; Williams, J. D.; Yu, H.;
Zimmerman, K. M.; Steinberg, M. I.; Jadhav, P. K. J. Med. Chem. 2007,
50, 6443. (l) Peifer, C.; Selig, R.; Kinkel, K.; Ott, D.; Totzke, F.;
Schachtele, C.; Heidenreich, R.; Rocken, M.; Schollmeyer, D.; Laufer,
S. J. Med. Chem. 2008, 51, 3814. (m) Kerber, V. A.; Passos, C. S.; Verli,
H.; Fett-Neto, A. G.; Quirion, J. P.; Henriques, A. T. J. Nat. Prod.
2008, 71, 697. (n) Kochanowska-Karamyan, A. J.; Hamann, M. T.
Chem. Rev. 2010, 110, 4489. (o) Trost, B. M.; Xie, J.; Sieber, J. D. J.
Am. Chem. Soc. 2011, 133, 20611. (p) Platon, M.; Amardeil, R.;
Djakovitch, L.; Hierso, J.-C. Chem. Soc. Rev. 2012, 41, 3929.
(q) Inman, M.; Moody, C. J. Chem. Sci. 2013, 4, 29.
(10) For some reviews on silver-mediated synthesis of heterocycles,
(2) (a) Patil, S. A.; Patil, R.; Miller, D. D. Future Med. Chem. 2012, 4,
2085. (b) Biersack, B.; Schobert, R. Curr. Drug Targets 2012, 13, 1705.
(c) Ahmad, A.; Biersack, B.; Li, Y.; Kong, D.; Bao, B.; Schobert, R.;
Padhye, S. B.; Sarkar, F. H. Anti-Cancer Agents Med. Chem. 2013, 13,
see: (a) Weibel, J.-M.; Blanc, A.; Pale, P. Chem. Rev. 2008, 108, 3149.
́
(b) Alvarez-Corral, M.; Munoz-Dorado, M.; Rodríguez-García, I.
̃
Chem. Rev. 2008, 108, 3174. (c) Patil, N. T.; Yamamoto, Y. Chem. Rev.
2008, 108, 3395.
̈
1002. (d) Olgen, S. Mini-Rev. Med. Chem. 2013, 13, 1700.
(11) (a) Oh, C. H.; Karmakar, S.; Park, H. S.; Ahn, Y. C.; Kim, J. W.
J. Am. Chem. Soc. 2010, 132, 1792. (b) Klausmeyer, K. K.; Feazell, R.
P.; Reibenspies, J. H. Inorg. Chem. 2004, 43, 1130. (c) Zhao, J.;
Hughes, C. O.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 7436.
(d) Bera, M.; Roy, S. J. Org. Chem. 2009, 74, 8814. (e) Binder, J. T.;
Kirsch, S. F. Org. Lett. 2006, 8, 2151.
(12) We thank one of the reviewers for suggesting this alternative
possibility.
(13) Hassam, M.; Basson, A. E.; Liotta, D. C.; Morris, L.; van Otterlo,
(3) (a) Bifulco, G.; Bruno, I.; Minale, L.; Riccio, R.; Calignano, A.;
Debitus, C. J. Nat. Prod. 1994, 57, 1294. (b) Bell, R.; Carmeli, S.; Sar,
N. J. Nat. Prod. 1994, 57, 1587. (c) Shiri, M.; Zolfigol, M. A.; Kruger,
H. G.; Tanbakouchian, Z. Chem. Rev. 2010, 110, 2250.
(4) (a) Bonnesen, C.; Eggleston, I. M.; Hayes, J. D. Cancer Res. 2001,
61, 6120. (b) Hong, C.; Firestone, G. L.; Bjeldanes, L. F. Biochem.
Pharmacol. 2002, 63, 1085. (c) Safe, S.; Papineni, S.; Chintharlapalli, S.
Cancer Lett. 2008, 269, 326. (d) Rahimi, M.; Huang, K. L.; Tang, C. K.
Cancer Lett. 2010, 295, 59.
(5) (a) Thirupathi, P.; Soo Kim, S. J. Org. Chem. 2010, 75, 5240.
(b) Abe, T.; Nakamura, S.; Yanada, R.; Choshi, T.; Hibino, S.;
Ishikura, M. Org. Lett. 2013, 15, 3622. (c) Sun, C.; Zou, X.; Li, F.
Chem. - Eur. J. 2013, 19, 14030. (d) Huo, C.; Wang, C.; Sun, C.; Jia,
W. A. L.; Pelly, S. C. ACS Med. Chem. Lett. 2012, 3, 470.
D
DOI: 10.1021/acs.orglett.6b02321
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