Cu-catalyzed synthesis of tryptanthrin derivatives from substituted indoles

Article abstract of DOI:10.1021/ol401144m

A concise method for the preparation of tryptanthrins from indoles via the copper-catalyzed aerobic oxidation is described. The reactions can be carried out under mild reaction conditions with varying functional group tolerance.

Full text of DOI:10.1021/ol401144m

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Cu-Catalyzed Synthesis of Tryptanthrin
Derivatives from Substituted Indoles
Chen Wang, Lianpeng Zhang, Anni Ren, Ping Lu,* and Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
pinglu@zju.edu.cn; orgwyg@zju.edu.cn
Received April 24, 2013
ABSTRACT
A concise method for the preparation of tryptanthrins from indoles via the copper-catalyzed aerobic oxidation is described. The reactions can be
carried out under mild reaction conditions with varying functional group tolerance.
Tryptanthrin can be formed by Candida lipolytica in the
presence of tryptophan.1 Its structure is slightly twisted
with aromatic character according to its single crystal
analysis.2 IUPAC numbering of the tryptanthrin ring is
shown in Figure 1. Tryptanthrin and its derivatives are indolo-
quinazoline alkaloids found in many kinds of plants.3 There
are eight indoloquinazolines in the methanol extraction of
Phaius mishmensis. They are tryptanthrin and its analogues
phaitanthrins AÀE, methylisatoid, and candidine. Among
these compounds, tryptanthrin was documented with excel-
Figure 1. Structures of tryptanthrin and its IUPAC numbering.
lent cytotoxicity against human breast carcinoma (MCF-7),
lung carcinoma (NCI-H460), and central nervous system
carcinoma (SF-268) cell lines.4 Several tryptanthrin deriva-
Due to the scarcity of the natural existence of tryptan-
thrins as well as their unique bioactivities, the synthesis of
this important class of heterocycles has attracted extensive
attention (Scheme 1). Classically, tryptanthrin can be con-
structed from isatin. For example, cathodic reduction of
isatin afforded tryptanthrin in moderate yield.1b Treat-
ment of isatin with POCl34,7 or KMnO48 could also lead to
the formation of tryptanthrin. However, the structural
diversity of tryptanthrins is much confined by these meth-
ods due to the single starting material. The diversity could
be achieved by the condensation between isatins and
isatoic anhydrides in the presence of triehtylamine9 or in
aqueous β-cyclodextrin solution.10 An alternative condensa-
tion is the one between isatin and ortho-aminobenzoic acid in
tives were found to exhibit remarkable antileishmanial activ-
ity and are potential succedaneums of sodium stibogluconate
(Pentostam) and meglumine antimonate (Glucantime),
which are the current treatments for leishmaniases yet show-
ing hazardous side effects and even alarming cardiotoxicity.5
More recently, it was also discovered that tryptanthrins are
potential antitubercular agents.6
(1) (a) Lee, E. S.; Park, J. G.; Jahng, Y. Tetrahedron Lett. 2003, 44,
1883–1886. (b) Batanero, B.; Barba, F. Tetrahedron Lett. 2006, 47, 8201–
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r
10.1021/ol401144m
XXXX American Chemical Society

the presence of SOCl2.11 The lithiation of ortho-bromophenyl
isocuanide, followed by the addition of electrophilic methyl
2-isocyanatobenzoate, is an unusal method.12
Scheme 2. Oxidative Self-Condensation of Indoles
Scheme 1. Literature Methods Leading to Tryptanthrins
Under the optimized reaction conditions, we tested
various indoles (Scheme 2). Indoles 1bÀ1f, with either an
electron-donating (CH3, CH3O) or electron-withdrawing
(F, Cl, Br) group on its 5-position, worked for this reaction
and provided correspondingtryptanthrin derivatives inthe
yields ranging from 51% to 71%. 4- and 7-Methyl indoles
furnished 2h and 2i in 68% and 59% yields, respectively.
When methyl 1H-indole-6-carboxylate (1j) was used, 2j
was obtained with a much lower yield (32%) along with
3-iodoindole as the byproduct (43% yield). With a strong
electron-withdrawing group attached toindole, 5-cyanoin-
dole and 5-nitroindole afforded 3-iodo-5-cyanoindole
(58% yield) and 3-iodo-5-nitroindole (40% yields), respec-
tively, without the desired tryptanthrin.
Since isatins (indoline-2,3-diones) were speculated to be
the key intermediate for the formation of tryptanthrins,
we then turned our attention to the two-component conden-
sation between indoles and isatins in order to afford tryptan-
thrins with a broad diversity. In the primary examination, it
was exciting to find that the reaction of 1a with 5-methyl-
indoline-2,3-dione (3b) in DMSO in the presence of CuI and
oxygen yielded tryptanthrin 4a (Scheme 3). The structure of
4a was unambiguously determined by single crystal analysis
(Figure 2). After the reaction conditions were screened for the
best formation of 4a, NMP was found to be the optimal
solvent (Table S2).
In our previous research, indole (1a) was dimerized to
tryptanthrin (2a) in 46% yield in DMF under air at 100 °C
for 34 h, accompanied by 3-formylindole in 16% yield.13
Based on this result and motivated by the significance of
tryptanthrin and its derivatives, we optimized reaction
conditions in order to achieve the highly selective forma-
tion of 2a (see Table S1). Initially, an oxygen atmosphere
was foundtobenecessary(Table S1, entries 1À3). Withthe
oxygen balloon, tryptanthrin was isolated in 52% yield
while it could not be detected when the reaction was
conducted under nitrogen. However, other oxidants, such
as t-BuOOH, DDQ, BPO, DTBP, and mCPBA, did not
produce satisfactory yields (Table S1, entries 4À8). Cu-
prous iodide was found to be the best catalyst when
compared to other cuprous salts, such as CuBr, CuCl,
and Cu2O (Table S1, entries 9À11). It is worth mentioning
that cupric salts, such as CuBr2, CuCl2, and Cu(OAc)2,
work for the reaction, but with lower yields (Table S1,
entries 12À14). The suitable amount of CuI was deter-
mined to be 1.2 equiv by gradually varying the ratio of CuI
to indole (Table S1, entries 15À18). A breathtaking yield
was obtained when DMSO was used (Table S1, entries
19À22). In this case, formylation on the 3-position of
indole was efficiently inhibited. Finally, the reaction tem-
perature and time were optimized to be 80 °C and 24 h,
respectively (Table S1, entries 23À26). Thus, the optimal
reaction conditions were established (Table S1, entry 19).
(8) Honda, G.; Tabata, M. Planta Med. 1979, 36, 85–86.
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Chen, Y. H. Acta Pharmacol. Sin. 2010, 31, 259–264.
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51–54.
(11) (a) Jahng, K. C.; Kim, S. I.; Kim, D. H.; Seo, C. S.; Son, J. K.;
Lee, S. H.; Lee, E. S.; Jahng, Y. D. Chem. Pharm. Bull. 2008, 56, 607–
609. (b) Liang, J. L.; Park, S. E.; Kwon, Y. J.; Jahng, Y. D. Bioorg. Med.
Chem. 2012, 20, 4962–4967.
(12) Lygin, A. V.; de Meijere, A. Org. Lett. 2009, 11, 389–392.
(13) Zhang, L. P.; Wen, Q. D.; Jin, J. S.; Wang, C.; Lu, P.; Wang,
Y. G. Tetrahedron 2013, 69, 4236–4240.
Figure 2. X-ray crystal structure of compound 4a.
Org. Lett., Vol. XX, No. XX, XXXX
B

Table 1. Oxidative Condensation between Indols and Isatinsa
entry
1 (R1)
1a (H)
3 (R2)
2 (yield, %)b
4 (R1, R2) (yield, %)b
1
3b (5-CH3)
À
4a (H, 2-CH3) (60)
4b (8-CH3, H) (68)
4c (8-OCH3, H) (53)
4d (8-Cl, H) (47)
4e (8-Br, H) (42)
4f (7-Cl, H) (49)
2
1b (5-CH3)
1c (5-OCH3)
1d (5-Cl)
1e (5-Br)
1g (4-Cl)
1h (4-CH3)
1i (7-CH3)
1j (6-CO2CH3)
1c
3a (H)
À
3
3a
À
4
3a
2d (11)
2e (13)
2g (12)
À
5
3a
6
3a
7
3a
4g (7-CH3, H) (67)
4h (10-CH3, H) (41)
4i (9-COOCH3, H) (47)
4j (8-OCH3, 2-CH3) (53)
4k (8-Cl, 2-CH3) (30)
4l (8-Br, 2-CH3) (35)
4m (7-CH3, 2-CH3) (59)
4n (10-CH3, 2-CH3) (52)
4o (8-CH3, 2-OCH3) (38)
4p (8-CH3, 2-Cl) (31)
4q (8-CH3, 2-Br) (30)
À
8
3a
2i (15)
2j (9)
À
9
3a
10
11
12
13
14
15
16
17
18
19
20
3b
1d
3b
2d (25)
2e (11)
2h (<5)
2i (<5)
2b (12)
2b (29)
2b (15)
2a (39)
ND
1e
3b
1h
3b
1i
3b
1b
3c (5-OCH3)
3d (5-Cl)
3e (5-Br)
3f (5-NO2)
3a
1b
1b
1a
1k (5-CN)
1l (5-NO2)
ND
NRc
3a
NRc
a Reaction conditions: 1 (0.25 mmol), 3 (0.25 mmol), CuI (0.3 mmol), NMP (2 mL), O2, 80 °C, 16 h. b Isolated yields refer to 1. c NR = no reaction.
Scheme 3. Formation of Compound 4a
Scheme 4. Controlled Experiments with 1a, 3a, and 5
Subsequently, we investigated the substrate diversity for
the oxidative condensation between indoles 1aÀ1l and
isatins 3aÀ3f, and the results are listed in Table 1. When
isatin 3a was used, indoles (1bÀ1j) worked for the reaction
and afforded corresponding 4bÀ4i in yields from 41% to
68%. An electron-donating group on the 5-position of
indole (1b, 1c) fostered the reaction giving higher yields
(Table 1, entries 1À4). A methyl group on the 7-position of
indole (Table 1, entry 7) afforded 4h in 41% yield. Less
reactive indoles (1d, 1e, 1g, 1i, and 1j), affected by either
electron-withdrawing or steric hindrance, produced the
self-condensation products along with the desired prod-
ucts (Table 1, entries 4À6, 8, and 9). Similar phenomena
were observed from these indoles with 5-methyl isatin (3b)
(Table 1, entries 11À14). It was noticeable that relatively
lower yields were obtained in cases of isatins with either a
strong electron-donating or -withdrawing group on its
5-position (Table 1, entries 15À17). Reaction of indole
(1a) with 5-nitroisatin (3f) only yielded the self-condensa-
tion product 2a (Table 1, entry 18), while reactions of isatin
(3a) and 5-nitroindole (1k) or 5-cyanoindole (1l) did not
afford any expected alkaloids with the recovery of starting
materials (Table 1, entries 19 and 20).
Controlled experiments were carried out in NMP. In
the solvent of NMP, both the formylation of indole in
DMF and possible oxidation by DMSO could be avoided.
Using an equivalent molar ratio of indole (1a) and isatin
(3a), a better yield (63%) of 2a could be obtained than the
Org. Lett., Vol. XX, No. XX, XXXX
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Scheme 5. Controlled Experiments with 6, 7, and 8
Scheme 6. Proposed Mechanism
yield (46%) obtained from self-condensation of indole
(Scheme 4). However, the reaction did not occur when the
substrate was only the isatin (3a). By using indolin-2-one (5)
instead of indole, no desired condensation product was
detected, only the recovery of isatin.
With shifting of the methyl group on the indole ring
from the 1- to 2- and finally to the 3-position, tryptanthrin
was only isolated in 18% yield in the case where 2-methy-
lindole (7) was used(Scheme 5). Neither 1-methylindole (6)
nor 3-methylindole (8) afforded tryptanthrin, which indi-
cated that the necessity of both NÀH and C(3)ÀH of
indole in the reaction.
Based on these results, we postulated a possible mechan-
ism for this transformation as shown in Scheme 6. Initially,
1a was aerobically oxidized to indolin-3-one (A), which
could further oxidize to isatin (3a).14 Then, 3a underwent
hydrolysis to form R-oxoacetic acid B. Copper-catalyzed
decarboxylative coupling between A and B furnished C.15
C was sequentially oxidized to imminium D via copper-
catalyzed oxidation. Then, intramolecularly nucleophilic
addition of amino to imminium formed the fused ring
intermediate E. Finally, 2a was obtained after dehydro-
genative aromatization of E. In the whole process, C(3)ÀH
of indole is necessary for the oxidation of indole, while
NÀH of indole is required for the copper-catalyzed dec-
arboxylative coupling. For the reaction of 2-methylindole
(7) with 3a to give 2a in 18% yield (Scheme 5), the
aromatization could occur by elimination of methane.16
In conclusion, we developed a concise method for the
preparation of tryptanthrins from indoles. The cascade pro-
cess is believed to involve copper-catalyzed aerobic oxidation
of indole, hydrolysis of amide, the copper-catalyzed decar-
boxylative coupling, intramolecularly nucleophilic addition,
and oxidative aromatization. The reactions could be carried
out under mild reaction conditions with varying functional
group tolerance. Moreover, the substituent diversity could be
quickly expanded by the condensation between the substi-
tuted indoles and the substituted isatins via this strategy.
Acknowledgment. We thank the financial support from
the National Natural Science Foundation of China (Nos.
21272203, 21032005, and J1210042).
(14) For examples for oxidation of indole to indolin-3-one and isatin,
see: (a) Tatsugi, J.; Tong, Z.; Izawa, Y. ARKIVOC 2001, No. i, 67–73. (b)
Burd, V. N.; Bantleon, R.; van Pee, K. H. Appl. Biochem. Microbiol.
2001, 37, 248–250.
(15) For examples for decarboxylative coupling, see: (a) Goossen,
L. J.; Rudolphi, F.; Oppel, C.; Rodriguez, N. Angew. Chem., Int. Ed.
2008, 47, 3043–3045. (b) Yu, L.; Li, P. H.; Wang, L. Chem. Commun.
2013, 49, 2368–2370.
Supporting Information Available. Experimental pro-
cedures, characterization data as well as 1H and 13C NMR
spectra for all products, and crystallographic information
file (CIF) for compound 4a. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) For an example for elimination of methane, see: Schmittel, M.;
ꢀ
Steffen, J. P.; Angel, M. W.; Engels, B.; Lennartz, C.; Hanrath, M.
Angew. Chem., Int. Ed. 1998, 37, 1562–1564.
The authors declare no competing financial interest.
D
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