Gold-catalyzed tandem reaction of 2-alkynylanilines followed by 1,6-conjugate addition to: P -quinone methides: Efficient access to unsymmetrical diarylindolylmethanes

Article abstract of DOI:10.1039/c8nj03955k

A simple, mild, efficient and chemoselective catalytic method for the straightforward synthesis of an interesting class of 2-aryl/alkyl-substituted-3-diaryl indolyl methanes in high yield is reported. This atom-efficient method proceeds via a gold-catalyzed one-pot sequential intramolecular hydroamination (C-N bond formation) of 2-alkynylanilines followed by a 1,6-conjugate addition to p-quinonemethides. The p-quinonemethides, which contain aldehyde functional groups, preferentially participate in 1,6-conjugate addition, while the aldehyde functional group remains unreactive.

Full text of DOI:10.1039/c8nj03955k

NJC
View Article Online
View Journal
PAPER
Gold-catalyzed tandem reaction of
2-alkynylanilines followed by 1,6-conjugate
addition to p-quinone methides: efficient
access to unsymmetrical diarylindolylmethanes†
Cite this:DOI: 10.1039/c8nj03955k
Raveendra Jillella,
Dong hwan Oh and Chang Ho Oh
*
A simple, mild, efficient and chemoselective catalytic method for the straightforward synthesis of an
interesting class of 2-aryl/alkyl-substituted-3-diaryl indolyl methanes in high yield is reported. This
atom-efficient method proceeds via a gold-catalyzed one-pot sequential intramolecular hydroamination
(C–N bond formation) of 2-alkynylanilines followed by a 1,6-conjugate addition to p-quinonemethides. The
p-quinonemethides, which contain aldehyde functional groups, preferentially participate in 1,6-conjugate
addition, while the aldehyde functional group remains unreactive.
Received 6th August 2018,
Accepted 12th September 2018
DOI: 10.1039/c8nj03955k
rsc.li/njc
Introduction
Triarylmethane scaffolds represent one of the privileged structural
motifs in organic synthesis due to their significant contributions
in several areas including as leuco dye precursors,1 photochromic
agents,2 substrates for theoretical3 and biological studies4 and
suitable building blocks for generating dendrimers.5 They are
also important in medicinal chemistry as anti-tubercular,6 anti-
Fig. 1 Unsymmetrical triarylmethane-based drugs.
proliferative,7 and anti-cancer agents.8 Several methods have triarylmethanes19b through a Pd-catalyzed sequential arylation
been reported for the synthesis of symmetrical triarylmethanes approach. Lately, the Zhang20 group developed a phosphine
via the Friedel–Crafts reaction of electron-rich heteroarenes with catalysed synthesis of triarylmethanes using the Friedel–Crafts
aromatic aldehydes, using Brønsted9 or Lewis acid10 catalysts. reaction of naphthols with para-quinone methides and asym-
However, the synthesis of unsymmetrical triarylmethane deriv- metric diarylmethanes using the reaction of alkyl vinyl ketones
atives exhibiting various biological properties (Fig. 1) is much with para-quinone methides.
less developed.
Recently, the transition metal-catalyzed tandem cyclization
Recently, various research groups have reported a cross-coupling- of 2-alkynylanilines followed by C3-functionalization, particu-
based approach for the synthesis of triarylmethane derivatives. larly for 2,3-difunctionalized indoles,21 has been developed
For instance, Molander et al.11 and Kuwano12 independently with extraordinary improvements in terms of productivity and
described the synthesis of unsymmetrical triarylmethanes scope of application. In our on-going efforts with tandem
through the Pd-catalyzed Suzuki–Miyura coupling of diarylmethyl cyclization reactions, the development of 3-substituted indoles
carbonates with boronic acids. Later on, Walsh,13 Oshima,14 stimulated by metal or Au is of growing interest. Previously, we
Zhang,15 and Crudden16 independently developed the Pd-catalyzed reported an efficient Ag-catalyzed domino process for the synthesis
direct arylation of benzylic derivatives to access triarylmethanes. of 2,3-disubstituted indoles from alkyne imino ethers.22 Further-
Jarvo17 and Watson18 demonstrated enantioenriched triaryl- more, the Cu-catalyzed one pot synthesis of 2-[(2-alkyl-1H-indol-3-yl)
methanes through the Ni-catalyzed coupling of diarylmethanol methylene]malonates from 2-alkynylanilines, triethyl orthoformate
derivatives with arylboronic acids and boronic esters, respec- and diethyl malonate, followed by a Sc-catalyzed intramole-
tively. Subsequently, Nambo and Crudden reported a protocol cular Friedel–Crafts reaction to form the resultant heterocyclic
for the synthesis of asymmetrical triarylacetonitriles19a and compounds, was reported.23 Very recently, we developed a
Cu-catalyzed tandem reaction of 2-alkynylanilines with benzo-
quinones to access 3-indolylquinones (eqn (2), Scheme 1).24
Department of Chemistry and Research Institute of Natural Science,
Similarly, a Pd-catalyzed domino process to access unsymme-
Hanyang University, Seoul 04763, South Korea. E-mail: changho@hanyang.ac.kr
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8nj03955k trical diarylindolylmethanes (eqn (1), Scheme 1) was reported
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018
New J. Chem.

View Article Online
Paper
NJC
Table 1 Optimization of the reaction conditionsa
Yieldb (%)
3aa
4aa
S. no. Catalyst
Solvent Temp (1C) Time (h)
1
2
3
4
5
6
7
8
CuCN
Cu(OAc)2
CuI
DMF
DMF
DMF
DMF
100
100
100
100
r.t.
r.t.
r.t.
100
100
50
100
50
50
50
50
24
24
24
24
24
24
24
24
24
24
24
24
24
24
6
90
72
80
85
20
60
65
68
82
73
69
60
55
30
ND
ND
5
ND
65c
25c
20c
ND
ND
10
CuCl
NaAuCl4Á3H2O DCM
AuBr3
Au(I)Cl
I2
DCM
DCM
DCE
DMF
DCM
DCE
DCM
DCM
DCM
Scheme 1 Methods of synthesis of diarylindolylmethanes.
9
AgCl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Pd(OAc)2
InCl3
BiCl3
FeCl3
PTSA
ND
ND
ND
ND
by Anand et al.25 However, this reaction needs high catalyst
loading and inert reaction conditions, which make it expensive.
We herein describe an effective and air stable Au-catalysed tandem
cyclization of 2-alkynylanilines, followed by 1,6-conjugate addition
to p-quinone methides, as an efficient access to unsymmetrical
diarylindolylmethanes.
NaAuCl4Á3H2O DCM
Trace 90c
AuBr3
AuCl
DCM
DCM
50
50
50
50
6
6
20
15
10
60c
52c
20
NaAuCl4Á3H2O DMF
24
24
24
24
24
24
NaAuCl4Á3H2O DMSO
Trace 30
10
o5
ND
ND
NaAuCl4Á3H2O Toluene 50
75
85
68
ND
The cyclization of 2-alkynylanilines followed by functionalization
at the C3-position of free (N–H) indoles is a highly complex step as it
often suffers from selective addition towards bis-electrophilic centres
in the coupling partner, such as p-quinone methides and
aldehydes,26 under gold catalysis. Nevertheless, the present
study also exploits the highly chemoselective 1,6-conjugative
addition towards p-quinone methides in which the aldehyde
group remains unreactive. This concept is reported here for the
first time in the presence of two electrophilic centres.
NaAuCl4Á3H2O EtOH
NaAuCl4Á3H2O ACN
NaAuCl4Á3H2O THF
50
50
50
a
All the reactions were performed with 1a (0.2 mmol) and 2a (0.24 mmol)
b
c
in air with 20 mol% catalyst. All the yields are isolated yields. Reaction
with 2 mol% gold catalysts. ND denotes not determined.
90%, 60% and 52%, respectively (entries 15–17, Table 1). The
obtained results from screening reactions of 2-alkynylaniline
(1a) and p-quinone methide (2a) with common organic solvents
in the presence of 2 mol% NaAuCl4Á2H2O revealed that all
the solvents (except THF) promoted the tandem process in
Results and discussion
We commenced optimization studies using readily available moderate to good yields (entries 18–23, Table 1). Eventually, a
2-alkynylaniline 1a and p-quinone methide (2a, 1.2 eq.) as gold catalyst (2 mol%) was identified to be the optimal combi-
coupling partners. Although our initial attempts with copper nation, resulting in 90% yield at 50 1C and a short reaction time
catalysts such as CuCN, Cu(OAc)2, CuI and CuCl led to only the in DCM solvent (Table 1, entry 15).
indole product, p-quinone methide (2a) remains unreacted
With the optimized reaction conditions, we then explored
(entries 1–4, Table 1). Extensive optimization experiments the efficiency and generality of this tandem heterocyclization
revealed that only gold catalysts such as NaAuCl4Á2H2O, AuBr3 process using the reaction of 2-alkynylaniline (1a) with various
and AuCl (2 mol%) at room temperature afford the desired p-quinone methides prepared from various substituted (–OMe,
product of diarylindolylmethane with 65%, 25% and 20% –Me, –F, –Br) aromatic aldehydes (2a–f) using NaAuCl4Á2H2O
yields, respectively (entries 5–7, Table 1). These results (2 mol%) as an efficient catalyst (Table 2). In all cases,
prompted us to examine various Lewis-acid catalysed tandem the expected diarylindolylmethanes were obtained in good to
heterocyclization reactions in detail. In this context, a variety of excellent yields (4aa–4af). In the case of p-quinone methide derived
catalysts such as I2, BiCl3, InCl3, AgCl, Pd(OAc)2 and p-TSA as well from p-conjugated aromatic aldehydes such as naphthalene,
known alkyne bond activators were examined for this tandem pyrene and phenanthrene aldehydes, these underwent smooth
cyclization process, as shown in Table 1 (entries 8–14, Table 1), conversion to their corresponding diarylindolylmethane deriv-
using dichloromethane (DCM) as solvent. However, all the catalysts atives, 4ag, 4ah and 4ai, in 88%, 85% and 89% yields, respectively.
afford the tandem cyclization product of 2-alkynylaniline without Surprisingly, a highly chemoselective reaction was observed
further conjugative addition to p-quinone methide. Further with p-quinone methide bearing an aldehyde functional group,
extensive studies of gold catalysts such as NaAuCl4Á2H2O, AuBr3 where nucleophilic 1,6-conjugate addition occurs only on the
and AuCl at 50 1C predominantly result in quantitative yields of quinone motif without influencing the aldehyde functional
New J. Chem.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018

View Article Online
NJC
Paper
Table 2 Tandem cyclization of 2-alkynylanilines with p-quinone methides
Scheme 2 Application of product 4aa.
Scheme 3 Control experiments.
The reaction was carried out with 1 (0.2 mmol), 2 (0.24 mmol) and
NaAuCl4Á2H2O (2 mol%) in DCM (2 mL) at 50 1C for 6 h
group, demonstrating the excellent chemoselectivity (entries
4aj & 4ak, 95% & 96%) with superb yields.
To further investigate the substrate scope, we examined
various 2-alkynylanilines (1a–j) with 2a under the optimized
conditions, and the results are summarized in Table 2.
2-Substituted ethynylanilines (R1 = phenyl, ethyl benzene,
biphenyl, 1-methyl napthyl) (1b–f) were reacted efficiently
with p-quinone methide (2a), leading to the desired products
Scheme 4 Proposed mechanism.
4ba–4fa in good to excellent yields (76–91%). Halogen substi- 2-phenylindole (1 equiv.) was treated with p-quinone methide
tuted alkynyl anilines also produce moderate to good yields. (1.2 equiv.) in the presence or absence of the Au-catalyst at
Electron-rich substituted alkynyl anilines, with substituents 50 1C in DCM. The product 4aa was obtained in 95% yield in 3 h
such as methoxy groups, lead to 4ga and 4ha in 90% and in the presence of the Au-catalyst, whereas no such product
85% yields, respectively. Conversely, TMS substituted 2-alkynyl was observed even after 24 h in the absence of the Au-catalyst.
aniline (2j) does not undergo domino cyclization due to the low Based on these observations, a plausible mechanism for the
electrophilicity of the p-activated TMS alkyne (1j). However, it formation of diarylindolylmethane was proposed, as shown in
leads to the 1,6-conjugate addition product of amine to p-quinone Scheme 4. This transformation pathway is initiated by the
methide (2a) in a quantitative yield (4ja, 95%). In addition, the formation of the adduct between Au(III) and 2-alkynyl aniline,
diaryl indolylmethane (4aa) studied under Pd catalysis furnished which undergoes further cyclization to form intermediate A.
the oxidation product of 4aa, p-quinone indolyl methide 5a, with The intermediate A undergoes protonolysis in the presence of
85% yield as shown in Scheme 2.
strong hydrochloric acid, which was generated during the
Finally, several control experiments have been performed aminoauration to afford the 2-substituted indole derivative (B).
to understand the reaction mechanism (Scheme 3). First, Finally, the formed 2-substituted indole reacted with p-quinone
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018
New J. Chem.

View Article Online
Paper
NJC
7 R. A. Al-Qawasmeh, Y. Lee, M. Y. Cao, X. P. Gu, A. assilakos,
J. A. Wright and A. Young, Bioorg. Med. Chem. Lett., 2004,
14, 347.
methide in the presence of NaAuCl3Á2H2O to give the resultant
final product 4aa.
8 (a) A. K. Srivastava, R. Sharma, R. Mishra, A. K. Balapure,
P. S. R. Murthy and G. Panda, Bioorg. Med. Chem., 2006,
14, 1497; (b) R. Palchaudhuri and P. J. Hergenrother, Bioorg.
Med. Chem. Lett., 2008, 18, 5888; (c) R. Palchaudhuri,
V. Nesterenko and P. J. Hergenrother, J. Am. Chem. Soc., 2008,
130, 10274; (d) K. Risberg, I. J. Guldvik, R. Palchaudhuri, Y. G.
Xi, J. F. Ju, O. Fodstad, P. J. Hergenrother and Y. J. Andersson,
Immunotherapy, 2011, 34, 438.
9 (a) S. Shirakawa and S. Kobayashi, Org. Lett., 2006, 8, 4939;
(b) S. Kumar, V. Malik, N. Kaur and K. Kaur, Tetrahedron
Lett., 2006, 47, 8483; (c) Q. L. He, F. L. Sun, X. J. Zheng and
S. L. You, Synlett, 2009, 1111; (d) M. Wilsdorf, D. Leichnitz
and H. U. Reissig, Org. Lett., 2013, 15, 2494.
Conclusions
In summary, we developed a novel Au-catalysed synthesis of
diarylindolylmethane from 2-ethynylanilines and p-quinone
methides via a tandem-type cyclization followed by 1,6-conjugative
addition. Subsequently, chemoselective conjugative addition to
C–C bond formation with p-quinone methide, in which the
aldehyde groups in 4aj and 4ak remain unreactive, leads to
excellent yields. We are extending this protocol to the construc-
tion of other poly aromatic compounds, the details of which
will be reported in due course.
10 (a) L. Yu, D. Chen, J. Li and P. G. Wang, J. Org. Chem., 1997,
62, 3575; (b) J. S. Yadav, B. V. S. Reddy, C. V. S. R. Murthy,
G. M. Kumar and C. Madan, Synthesis, 2001, 783;
(c) R. Nagarajan and P. T. Perumal, Tetrahedron, 2002,
58, 1229; (d) S. J. Ji, M. F. Zhou, D. G. Gu, Z. Q. Jiang and
T. P. Loh, Eur. J. Org. Chem., 2004, 1584; (e) V. Nair,
K. G. Abhilash and N. Vidya, Org. Lett., 2005, 7, 5857;
( f ) S. Podder, J. Choudhury, U. K. Roy and S. Roy, J. Org.
Chem., 2007, 72, 3100.
11 G. A. Molander and M. D. Elia, J. Org. Chem., 2006, 71, 9198.
12 J. Y. Yu and R. Kuwano, Org. Lett., 2008, 10, 973.
13 (a) G. I. McGrew, J. Temaismithi, P. J. Carroll and P. J. Walsh,
Angew. Chem., Int. Ed., 2010, 49, 5541; (b) J. Zhang, A. Bellomo,
A. D. Creamer, S. D. Dreher and P. J. Walsh, J. Am. Chem. Soc.,
2012, 134, 13765; (c) A. Bellomo, J. Zhang, N. Trongsiriwat and
P. Walsh, Chem. Sci., 2013, 4, 849; (d) J. Zhang, A. Bellomo,
N. Trongsiriwat, T. Jia, P. J. Carroll, S. D. Dreher, M. T. Tudge,
H. Yin, J. R. Robinson, E. J. Schelter and P. J. Walsh, J. Am.
Chem. Soc., 2014, 136, 6276.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by a grant from the National Research
Foundation of Korea (NRF), funded by the Korean Government,
through the Center for New Directions in Organic Synthesis
(NRF-2014R1A5A1011165).
Notes and references
1 (a) P. Ryss and H. Zollinger, Fundamentals of the Chemistry
and Application of Dyes, Wiley-Interscience, New York, 1972;
(b) A. R. Katritzky, V. Gupta, C. Garot, C. V. Stevens and
M. F. Gordeev, Heterocycles, 1994, 38, 345; (c) R. Muthyala,
A. R. Katritzky and X. F. Lan, Dyes Pigm., 1994, 25, 303.
2 (a) R. Aldag, Molecules and Systems, ed. H. Du¨rr and
H. Bouas-Laurent, Elsevier, London, 1990; (b) M. Irie,
J. Am. Chem. Soc., 1983, 105, 2078.
14 T. Niwa, H. Yorimitsu and K. Oshima, Org. Lett., 2007,
9, 2373.
15 Y. Xia, F. Hu, Z. Liu, P. Qu, R. Ge, C. Ma, Y. Zhang and
J. Wang, Org. Lett., 2013, 15, 1784.
16 M. Nambo and C. M. Crudden, Angew. Chem., Int. Ed., 2014,
53, 742.
3 (a) M. S. Baptista and G. L. Indig, J. Phys. Chem., 1998,
102, 4678; (b) M. Terrier, T. Boubaker, L. Xiao and
P. G. Farrell, J. Org. Chem., 1992, 57, 3924.
17 B. L. H. Taylor, M. R. Harris and E. R. Jarvo, Angew. Chem.,
Int. Ed., 2012, 51, 7790.
18 Q. Zhou, H. D. Srinivas, S. Dasgupta and M. P. Watson,
J. Am. Chem. Soc., 2013, 135, 3307.
19 (a) M. Nambo, M. Yar, J. D. Smith and C. M. Crudden, Org.
Lett., 2015, 17, 50; (b) M. Nambo and C. M. Crudden, Angew.
Chem., Int. Ed., 2014, 53, 742.
20 (a) T. Zhou, S. Li, B. Huang, C. Li, Y. Zhao, J. Chen, A. Chen,
Y. Xiao, L. Liu and J. Zhang, Org. Biomol. Chem., 2017,
15, 4941; (b) S. Li, Y. Liu, B. Huang, T. Zhou, H. Tao,
Y. Xiao, L. Liu and J. Zhang, ACS Catal., 2017, 7, 2805.
21 (a) K. Hiroya, S. Itoh and T. Sakamoto, J. Org. Chem., 2004,
69, 1126; (b) Y. Chen, C. H. Cho and R. O. Larock, Org. Lett.,
2009, 11, 173; (c) I. Ambrogio, A. Arcadi, S. Cacchi, G. Fabrizi
and F. Marinelli, Synlett, 2007, 1775; (d) M. Alfonsi,
4 For the use of photosensitizers in photodynamic therapy against
cancer, see: (a) M. R. Detty, S. L. Gibson and S. J. Wagner, J. Med.
Chem., 2004, 47, 3897; (b) M. Wainwright, D. A. Phoenix,
S. M. Burrow and J. Waring, J. Chemother., 1999, 11, 61;
(c) R. A. Al-Qawasmeh, Y. Lee, M.-Y. Cao, X. Gu, A. Vassilakos,
J. A. Wright and A. Young, Bioorg. Med. Chem. Lett., 2004, 14, 347.
5 L. A. Baker, L. Sun and R. M. Crooks, Bull. Korean Chem.
Soc., 2002, 23, 647.
6 (a) S. K. Das, G. Panda, V. Chaturvedi, Y. S. Manju,
A. Galkwad and S. Sinha, Bioorg. Med. Chem. Lett., 2007,
17, 5586; (b) G. Panda, J. K. Mishra, V. Chaturvedi, A. K.
Srivastava, R. Srivastava and B. S. Srivastava, Bioorg. Med.
Chem., 2004, 12, 5269; (c) M. K. Parai, G. Panda,
V. Chaturvedi, Y. K. Manju and S. Sinha, Bioorg. Med. Chem.
Lett., 2008, 18, 289.
New J. Chem.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018

View Article Online
NJC
Paper
A. Arcadi, M. Aschi, G. Bianchi and F. Marinelli, J. Org.
Chem., 2005, 70, 2265; (e) Y. J. Guo, R. Y. Tang, J. H. Li,
V. Kavala, C. W. Kuo, T. S. Kuo, C. H. He and C. F. Yao,
Tetrahedron, 2013, 69, 3323.
P. Zhong and X. G. Zhang, Adv. Synth. Catal., 2009, 22 C. H. Oh, S. Karmakar, H. Park, Y. Ahn and J. W. Kim, J. Am.
351, 2615; ( f ) N. K. Swamy, A. Yazici and S. G. Pyne, Chem. Soc., 2010, 132, 1792.
J. Org. Chem., 2010, 75, 3412; (g) J. P. Brand, C. Chevalley 23 C. H. Oh, H. S. Park, N. Park, S. Y. Kim and L. Piao, Synlett,
and J. B. Waser, J. Org. Chem., 2011, 7, 565; (h) C. Xu, 2014, 0579.
V. K. Murugan and S. A. Pullarkat, Org. Biomol. Chem., 2012, 24 J. Raveendra and C. H. Oh, RSC Adv., 2018, 8, 22122.
10, 3875; (i) B. Gabriele, L. Veltri, R. Mancuso, G. Salerno 25 V. Reddy and R. V. Anand, Org. Lett., 2015, 17, 3390.
and M. Costa, Eur. J. Org. Chem., 2012, 2549; ( j) Q. Wang, 26 (a) C. Praveen, K. Karthikeyan and P. T. Perumal, Tetrahedron,
L. Huang, X. Wu and H. Jiang, Org. Lett., 2013, 15, 5940;
(k) A. Arcadi, E. Pietropaolo, A. Alvino and V. Michelet,
Org. Lett., 2013, 15, 2766; (l) Z. Hu, S. Luo and Q. Zhu,
Adv. Synth. Catal., 2015, 357, 1060; (m) D. Janreddy,
2009, 65, 9244; (b) C. Praveen, Y. Wilson Sagayaraj and
P. T. Perumal, Tetrahedron Lett., 2009, 50, 644; (c) G. Abbiati,
A. Arcadi, M. Chiarini, F. Marinelli, E. Pietropaolob and
E. Rossi, Org. Biomol. Chem., 2012, 10, 7801.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018
New J. Chem.