Synthesis of unsymmetrical 2,20-Biindolyl derivatives by a Cu-Catalyzed N-Arylation/ Pd-catalyzed direct arylation sequential process

Article abstract of DOI:10.1021/jo101899a

A one-pot synthesis of unsymmetrical 2,20-biindolyl derivatives through a Cu-catalyzed N-arylation/Pd-catalyzed direct arylation sequence was described. The reaction involved easily prepared o-gem-dibromovinyl substrates, and the desired biindolyls were obtained in moderate to good yields.

Full text of DOI:10.1021/jo101899a

pubs.acs.org/joc
biosynthesis of eumelanine;4 IV are macrocyclic Ni(II) com-
Synthesis of Unsymmetrical 2,20-Biindolyl
Derivatives by a Cu-Catalyzed N-Arylation/
Pd-Catalyzed Direct Arylation Sequential Process
plexes containing the 2,20-biindolyl moiety;5 and V is claimed
to be a colorimetric anion receptor6 (Figure 1, I-V).
Zhi-Jing Wang,† Fan Yang,† Xin Lv,‡ and Weiliang Bao*,†
†Department of Chemistry, Zhejiang University, Hangzhou
310028, P. R. China, and ‡Zhejiang Key Laboratory for
Reactive Chemistry on Solid Surfaces, College of Chemistry
and Life Sciences, Zhejiang Normal University, Jinhua,
Zhejiang, 321004, P. R. China
wlbao@css.zju.edu.cn
Received September 26, 2010
FIGURE 1. Several 2,20-biindolyl derivatives reported as biologi-
cally active compounds and pharmaceutical products.
In this regard, the synthesis of 2,20-biindolyls is one of the
most extensive areas of research, and a number of approaches
to prepare these compounds have been developed.7 Among
them, the protocol from 1,10-carbonyldiindole was more
convenient and milder.7b The method involved an initial step
to form 1,10-carbonyl-2,20-biindolyl, which could easily un-
dergo a hydrolysis to obtain 2,20-biindolyl.7c But the neces-
sity of equimolar quantity of Pd(OAc)2 made large-scale
synthesis by this procedure less amenable. Besides, most
strategies could only synthesize symmetrical 2,20-biindolyls,
while the preparations of unsymmetrical ones were not well
documented.7c,g,h Therefore, more efficient and economical
routes to synthesize unsymmetrical 2,20-biindolyls under
mild conditions are needed.
A one-pot synthesis of unsymmetrical 2,20-biindolyl deriv-
atives through a Cu-catalyzed N-arylation/Pd-catalyzed
direct arylation sequence was described. The reaction
involved easily prepared o-gem-dibromovinyl substrates,
and the desired biindolyls were obtained in moderate to
good yields.
In recent years, Cu-catalyzed reactions have been success-
fully applied to assemble various heterocyclic compounds
via one-pot strategies, due to their efficiency and low cost.8
The direct arylation approach has received substantial attention
The indole framework represents a privileged structural
motif of established value in biologically active natural products
and pharmaceutical compounds.1 The indole-incorporated
2,20-biindolyls have drawn much attention because of their
structural features and potential therapeutic applications.
For example, 2,20-biindolyls-derived indolocarbazole alka-
loid rebeccamycin (I) is an inhibitor of DNA topoisomerase
I,2 while staurosporine (II) targets protein kinase C,3 both of
which display antitumor activity; III could be used for the
(6) Lee, G. W.; Kim, N.-K.; Jeong, K.-S. Org. Lett. 2010, 12, 2634.
(7) For selected examples of synthesis of 2,20-biindolyls, see:
(a) Madelung, W. Ber. 1912, 45, 1128. (b) Bergman, J.; Eklund, N. Tetra-
hedron 1980, 36, 1439. (c) Palmisano, G.; Santagostini, M. Helv. Chim. Acta
1993, 76, 2356. (d) Hudkins, R. L.; Diebold, J. L.; Marsh, F. D. J. Org. Chem.
1995, 60, 6218. (e) Shin, K.; Ogasawara, K. Synlett 1995, 859. (f) Koza, D. J.;
Euler, W. B. Heterocycl. Commun. 1999, 5, 399. (g) Merlic, C. A.; You, Y.;
Mclnnes, D. M.; Zechman, A. L.; Miller, M. M.; Deng, Q. L. Tetrahedron
2001, 57, 5199. (h) Koradin, C.; Dohle, W. A.; Rodriguez, L.; Schmid, B.;
Knochel, P. Tetrahedron 2003, 59, 1571.
(8) For selected examples of synthesis of heterocycles via Cu-catalyzed one-
pot processes: (a) Joyce, L. L.; Evindar, G.; Batey, R. A. Chem. Commun. 2004,
446. (b) Martin, R.; Rivero, M. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006,
45, 7079. (c) Zou, B.; Yuan, Q.; Ma, D. Org. Lett. 2007, 9, 4291. (d) Zheng, N.;
Buchwald, S. L. Org. Lett. 2007, 9, 4749. (e) Viirre, R. D.; Evindar, G.; Batey,
R. A. J. Org. Chem. 2008, 73, 3452. (f) Yang, D.; Fu, H.; Hu, L.; Jiang, Y.; Zhao,
Y. J. Org. Chem. 2008, 73, 7841. (g) Wang, B.; Lu, B.; Jiang, Y.; Zhang, Y.; Ma,
D. Org. Lett. 2008, 10, 2761. (h) Yao, P.-Y.; Zhang, Y.; Hsung, R. P.; Zhao, K.
Org. Lett. 2008, 10, 4275. (i) Kim, J.; Lee, S. Y.; Lee, J.; Do, Y.; Chang, S. J. Org.
Chem. 2008, 73, 9454. (j) Verma, A. K.; Kesharwani, T.; Singh, J.; Tandon, V.;
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Zhang, X.; Jiang, Y.; Ma, D. Org. Lett. 2009, 11, 1309. (l) Zhu, J.; Xie, H.; Chen,
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Clardy, J. Tetrahedron Lett. 1985, 26, 4011. (b) Pereira, E. R.; Belin, L.;
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DOI: 10.1021/jo101899a
r
Published on Web 01/12/2011
J. Org. Chem. 2011, 76, 967–970 967
2011 American Chemical Society

Wang et al.
JOCNote
SCHEME 1. Synthesis of o-gem-Dibromovinyl Substrates
TABLE 1. Optimization of the C-N Bond Formation Reaction
Conditionsa
for its sustainable and environmentally benign features.9
However, there were only limited examples of reactions in
which direct arylations were coupled with another process.10
Therefore, the combination of Cu-catalyzed coupling reactions
with direct arylation to obtain structurally complex hetero-
cyclic compounds is of significance.
o-gem-Dihalovinylanilines11 have been recently developed
for the synthesis of various 2-substituted indole derivatives
via domino processes.12-14 Our group has also reported a
one-pot method to synthesize pyrimido[1,6-a]indol-1(2H)-
one derivatives through a nucleophilic addition/Cu-catalyzed
N-arylation/Pd-catalyzed C-H activation sequential pro-
cess, in which the reactive ortho position of anilines under-
went direct arylations.15
The C-2 position of indoles is also of high reactivity, on
which direct arylations may easily be conducted.16 Thus, we
envisaged that indoles could also be applicable under our
catalytic system.
aUnless otherwise noted, the reactions were carried out using 1a (0.5
mmol), Cu source (0.05 mmol), ligand (0.1 mmol), and base (1.0 mmol)
in solvent (4.0 mL) under N2, for 12 h. b1,10-Phen = 1,10-phenanthro-
line. cDMEDA = N,N0-dimethylethylenediamine. dn.r. = no reaction.
(9) For recent reviews on direct arylation, see: (a) Dyker, G., Ed.
Handbook of C-H Transformations; Wiley-VCH: Weinheim, 2005; Vols. 1
and 2. (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
(c) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (d) Campos,
K. R. Chem. Soc. Rev. 2007, 36, 1069. (e) Li, C.-J. Acc. Chem. Res. 2009, 42,
335. (f) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38, 2447.
(10) For selected examples, see: (a) Cuny, G.; Bois-Choussy, M.; Zhu, J.
Angew. Chem., Int. Ed. 2003, 42, 4774. (b) Cuny, G.; Bois-Choussy, M.; Zhu,
J. J. Am. Chem. Soc. 2004, 126, 14475. (c) Bedford, R. B.; Betham, M. J. Org.
Chem. 2006, 71, 9403. (d) Thansandote, P.; Raemy, M.; Rudolph, A.;
Lautens, M. Org. Lett. 2007, 9, 5255. (e) Ackermann, L.; Althammer, A.
Angew. Chem., Int. Ed. 2007, 46, 1627. (f) Watanabe, T.; Ueda, S.; Inuki, S.;
Oishi, S.; Fujii, N.; Ohno, H. Chem. Commun. 2007, 4516. (g) Jensen, T.;
Pedersen, H.; Bang-Andersen, B.; Madsen, R.; Jørgensen, M. Angew. Chem.,
TABLE 2. Optimization of the Second Cyclization: Intramolecular
Direct Arylation Conditionsa
ꢀ
Int. Ed. 2008, 47, 888. (h) Hostyn, S.; Van Baelen, G.; Lemiere, G. L. F.;
Maesa, B. U. W. Adv. Synth. Catal. 2008, 350, 2653. (i) Buden, M. E.;
Vaillard, V. A.; Martin, S. E.; Rossi, R. A. J. Org. Chem. 2009, 74, 4490.
(j) Zhu, B.; Wang, G.-W. Org. Lett. 2009, 11, 4334. (k) Pinto, A.; Neuville, L.;
Zhu, J. Tetrahedron Lett. 2009, 50, 3602.
entry
Pd catalyst
base
yield (%)
ꢁ
1
2
3
4
5
6
7
PdCl2
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
KOAc
55
75
45
trace
60
62
b
Pd(dppf)Cl2
Pd(OAc)2
Pd(dba)2
c
(11) Thiegles, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett.
2004, 45, 907.
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
(12) (a) Fang, Y.-Q.; Lautens, M. Org. Lett. 2005, 7, 3549. (b) Yuen, J.;
Fang, Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 653. (c) Fayol, A.; Fang, Y.-Q.;
Lautens, M. Org. Lett. 2006, 8, 4203. (d) Fang, Y.-Q.; Karisch, R.; Lautens,
M. J. Org. Chem. 2007, 72, 1341. (e) Fang, Y.-Q.; Yuen, Y.; Lautens, M.
J. Org. Chem. 2007, 72, 5152. (f) Nagamochi, M.; Fang, Y.- Q.; Lautens, M.
Org. Lett. 2007, 9, 2955. (g) Fang, Y.-Q.; Lautens, M. J. Org. Chem. 2008, 73,
538. (h) Bryan, C. S.; Lautens, M. Org. Lett. 2008, 10, 4633. (i) Chai, D. I.;
Lautens, M. J. Org. Chem. 2009, 74, 3054. (j) Newman, S. G.; Lautens, M.
J. Am. Chem. Soc. 2010, 132, 11416.
87
aUnless otherwise noted, the reactions were carried out using 2a (0.5
mmol), Pd source (0.05 mmol), and base (1.5 mmol) in solvent (4.0 mL)
b
under N2, at 120 °C for 24 h. dppf = 1,10-bis(diphenyphosphino)-
ferrocene. cdba=1,5-diphenylpenta-1,4-dien-3-one.
(13) Viera, T. O.; Meaney, L. A.; Shi, Y.-L.; Alper, H. Org. Lett. 2008, 10,
4899.
(14) Arthuis, M.; Pontikis, R.; Florent, J.-C. Org. Lett. 2009, 11, 4608.
(15) Wang, Z.-J.; Yang, J.-G.; Yang., F.; Bao, W. Org. Lett. 2010, 12,
3034.
(16) For selected examples of direct arylation on the C-2 position of
indoles, see: (a) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005,
127, 4996. (b) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005,
127, 8050. (c) Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005,
127, 13148. (d) Bremner, J. B.; Sengpracha, W. Tetrahedron 2005, 61, 5489.
(e) Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72, 1476.
(f) Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926. (g) Zhao, J.;
Zhang, Y.; Cheng, K. J. Org. Chem. 2008, 73, 7428. (h) Joucla, L.;
Djakovitch, L. Adv. Synth. Catal. 2009, 351, 673.
Herein, as a part of our continuing effort, we report a
novel and efficient protocol to the synthesis of unsymmet-
rical 1,10-carbonyl-2,20-biindolyls through a Cu-catalyzed
N-arylation/Pd-catalyzed direct arylation sequential process.
Initially, o-gem-dibromovinylphenyl isocyanate and in-
dole were employed as the model substrates. However, the
nucleophilic addition was unsuccessful. So we decided to
change the synthetic route, and o-gem-dibromovinylaniline
and indole-1-carboxylic acid were selected as the starting
materials. Indole-1-carboxylic acid was treated with oxalyl
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Wang et al.
JOCNote
TABLE 3. Cu-Catalyzed N-Arylation/Pd-Catalyzed Direct Arylation Sequential Reaction of Substituted o-gem-Dibromovinyl Substratesa,b
aUnless otherwise noted, the reactions were carried out using o-gem-dibromovinyl substrates 1 (0.5 mmol), CuI (0.05 mmol), DMEDA (0.1 mmol),
and K2CO3 (1.0 mmol) in toluene (4.0 mL), under N2 at 120 °C, then Pd(dppf)Cl2 (0.05 mmol) and KOAc(1.5 mmol), in toluene (4.0 mL), under N2 at 120
°C. bFor times for Cu-Catalyzed N-arylation and time for Pd-catalyzed direct arylation, see the Supporting Information.
chloride to form corresponding acid chloride, which reacted
with o-gem-dibromovinylaniline to afford the desired acylation
product (1a) successfully (Scheme 1).17 Then we screened the
reaction conditions of C-N bond formation using 1a, and
the results are shown in Table 1.
Preliminary investigation found that ligand has a signifi-
cant influence on this reaction. After a range of common
ligands were tested, DMEDA was selected as the optimal
(Table 1, entry 4). Various bases and solvents were then
screened, and K2CO3 and toluene proved to be the most
efficient. The research also found that the yield decreased
while reducing the temperature (entries 9-10). When the Cu
source was switched to CuBr or Cu2O, the result deteriorated
(entries 14 and 15). Therefore, the reaction conditions de-
scribed in entry 4 were the optimal.
To achieve the “one-pot” process, toluene was utilized as
the solvent for the direct arylation of 2a. Several different Pd
sources were examined, and the result was remarkably
improved when Pd(dppf)Cl2 was employed for the second
cyclization to produce 1,10-carbonyl-2,20-biindolyl (3a) (Table 2,
entry 2). After several bases were screened, KOAc turned out
to be the best base to promote the intramolecular direct
arylation (entry 7).
The one-pot protocol was then examined. When the
formation of 2a completed, Pd(dppf)Cl2 and KOAc were
directly added to the reaction mixture without further puri-
fication, and 3a were obtained successfully in good yield.
Since the two steps of reactions required different metal
catalysts and bases, we also attempted to use only one metal
(17) (a) Boger, D. L.; Pate1, M. J. Org. Chem. 1987, 52, 2319. (b) Boger,
D. L.; Pate1, M. J. Org. Chem. 1987, 52, 3934.
J. Org. Chem. Vol. 76, No. 3, 2011 969

Wang et al.
JOCNote
catalyst such as Pd(dppf)Cl2 and one of the two bases K2CO3
and KOAc to promote the two steps of arylations, but failed.
Under the above optimized reaction conditions, the gen-
erality of the reaction was investigated, and the results are
summarized in Table 3.
direct arylation sequential process. A variety of o-gem-
dibromovinyl substrates were applicable for this process,
and moderate to good yields are obtained. The products are
potentially useful for their biological and pharmacological
activities. Studies are ongoing in our laboratory to discover
the synthetic applications.
All the substituted N-(2-(2,2-dibromovinyl)phenyl)-1H-
indole-1-carboxamides reacted smoothly and afforded the
desired products 3a-m. The protocol proved to be a general
and efficient method for the preparation of 2,20-biindolyl
derivatives. When the substituents on the phenyl ring were
different from the ones on the indole ring, unsymmetrical
1,10-carbonyl-2,20-biindolyls were attained. o-gem-Dibro-
movinyl substrates with both electron-donating substituents
(4,5-diMeO) (entry 2) and electron-withdrawing ones (4-Cl,
4-Br, 5-Br) (entries 3-5) on the phenyl ring could afford the
corresponding products 3b-e. It was noteworthy that this reac-
tion seemed not sensitive to steric hindrance. 3-Substituted
indoles 3f,g could be provided from the corresponding
substrates in good yields (entries 6 and 7). The reactions of
substrates from electron-rich indoles(30-Me, 40-Me, 50-Me,
60-Me, 50-MeO) afforded the corresponding products 3g-k
with good results (entries 7-11). Unsymmetrical 1,10-carbonyl-
2,20-biindolyls with electron-donating substituents on both
indole rings, or the ones bearing electron-rich substituents
on one indole ring, while electron-deficient groups on the
other indole ring, were obtained easily (entries 12 and 13).
However, the access to unsymmetrical products bearing
electron-deficient groups on the both indole rings was un-
successful, for the indole-1-carboxylic acids with an electron-
withdrawing group, such as 5-NO2, 5-Br and 5-CN, seemed
unstable, and could not be obtained. When we replaced
indole with pyrrole, the reactions could also undergo smoothly
to attain the products in moderate yields (entries 14-16).
In summary, we have developed a one-pot strategy for the
assembly of unsymmetrical 1,10-carbonyl-2,20-biindolyl de-
rivatives through a Cu-catalyzed N-arylation/Pd-catalyzed
Experimental Section
Typical Procedure for the Synthesis of 1,10-Carbonyl-2,20-
biindolyls. To a solution of N-(2-(2,2-dibromovinyl)phenyl)-
1H-indole-1-carboxamide 1a (210 mg, 0.50 mmol) in toluene
(4 mL) at rt under N2 atmosphere were added CuI (10 mg,
0.05 mmol, 10 mol %), DMEDA (9 mg, 0.10 mmol, 20 mol %),
and K2CO3 (138 mg, 1.0 mmol) and the mixture heated with
stirring at 120 °C for 12 h. Then to the reaction mixture were
added Pd(dppf)Cl2 (37 mg, 0.05 mmol, 10 mol %) and KOAc
(147 mg, 1.5 mmol), and the resulting mixture was stirred at
120 °C for another 24 h. After that, the reaction mixture was
filtered through Celite and washed with CH2Cl2 (10 mL ꢀ 3),
and the filtrate was evaporated under reduced pressure. The
residue was purified by a quick flash chromatography on silica
gel using petroleum ether/EtOAc (20:1) as eluent to afford 1,10-
carbonyl-2,20-biindolyl 3a as a pale yellowish-green solid (96 mg,
74%): mp 290-292 °C (lit.7b mp 293-294 °C); not well soluble
in CDCl3 or DMSO-d6; 1H NMR (400 MHz, CDCl3) δ 7.88 (d,
J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.33 (t, J=7.6 Hz, 2H),
7.21 (t, J = 7.8 Hz, 2H), 6.70 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 102.5, 112.7, 122.5, 123.9, 126.0, 130.4, 133.2, 134.0,
144.4; EI-MS 258; IR (neat) 3052, 2904, 1756, 1607, 1475, 1303,
1009, 929, 824, 743 cm-1
.
Acknowledgment. This work was financially supported by
the Natural Science Foundation of China (No. 21072168).
Supporting Information Available: Experimental proce-
dure, characterization data, and copies of 1HNMR and
13CNMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
970 J. Org. Chem. Vol. 76, No. 3, 2011