Synthesis of 3-acyl-2-arylindole via palladium-catalyzed isocyanide insertion and oxypalladation of alkyne

Article abstract of DOI:10.1021/ol4016699

The synthesis of 3-acyl-2-arylindole derivatives was performed through palladium-catalyzed isocyanide insertion and oxypalladation of an alkyne. As a result of the introduction of internal nucleophiles, domino cyclization was also achieved for the synthes

Full text of DOI:10.1021/ol4016699

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of 3‑Acyl-2-arylindole via
Palladium-catalyzed Isocyanide Insertion
and Oxypalladation of Alkyne
Takeshi Nanjo, Sho Yamamoto, Chihiro Tsukano, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan
takemoto@pharm.kyoto-u.ac.jp
Received June 13, 2013
ABSTRACT
The synthesis of 3-acyl-2-arylindole derivatives was performed through palladium-catalyzed isocyanide insertion and oxypalladation of an alkyne.
As a result of the introduction of internal nucleophiles, domino cyclization was also achieved for the synthesis of several tetracyclic indole
derivatives. Imidoylpalladium generated by isocyanide insertion is a key intermediate in these reactions.
Isocyanides are valuable building blocks in the synthesis
of nitrogen-containing compounds and are mainly used
for multicomponent reactions such as the Passerini and
Ugi reactions.1 It is known that isocyanides coordinate to
transition-metal centers, and the insertion reaction pro-
ceeds similarly to that of carbon monoxide.2,3 However,
palladium-catalyzed isocyanide insertion is still a develop-
ing area, in contrast to the well-developed chemistry of
carbon monoxide, probably because of the difficulty of
controlling the isocyanide reactivity.1a,b In recent years,
there has been a focus on palladium-catalyzed coupling
reactions to form CÀN and CÀO bonds via isocyanide
insertion.4 However, the formation of two CÀC bonds via
isocyanide insertion has rarely been reported.5 Further-
more, in most of the previously reported studies, isocya-
nides were simply used instead of carbon monoxide as a C1
unit. Webelieve thatmulti CÀC bondformation reactions,
in which the C and N atoms of the isocyanide are both
(4) For recent examples of CÀN and CÀO bond formation via
isocyanide insertion, see: (a) Geden, J. V.; Pancholi, A. K.; Shipman,
M. J. Org. Chem. 2013, 78, 4158. (b) Liu, B.; Yin, M.; Wu, W.; Jiang, H.
J. Org. Chem. 2013, 78, 3009. (c) Bochatay, V. N.; Boissarie, P. J.;
Murphy, J. A.; Suckling, C. J.; Lang, S. J. Org. Chem. 2013, 78, 1471. (d)
Fei, X.-D.; Ge, Z.-Y.; Tang, T.; Zhu, Y.-M.; Ji, S.-J. J. Org. Chem. 2012,
77, 10321. (e) Qiu, G.; Liu, G.; Pu, S.; Wu, J. Chem. Commun. 2012, 48,
2903. (f) Liu, B.; Li, Y.; Jiang, H.; Yin, M.; Huang, H. Adv. Synth. Catal.
2012, 354, 2288. (g) Wang, Y.; Zhu, Q. Adv. Synth. Catal. 2012, 354,
1902. (h) Vlaar, T.; Ruijter, E.; Znabet, A.; Janssen, E.; de Kanter,
F. J. J.; Maes, B. U. W.; Orru, R. V. A. Org. Lett. 2011, 13, 6496. (i)
Wang, Y.; Wang, H.; Peng, J.; Zhu, Q. Org. Lett. 2011, 13, 4604. (j)
Miura, T.; Nishida, Y.; Morimoto, M.; Yamauchi, M.; Murakami, M.
Org. Lett. 2011, 13, 1429. (k) Jiang, H.; Liu, B.; Li, Y.; Wang, A.;
Huawen, H. Org. Lett. 2011, 13, 4604. (l) Baelen, G. V.; Kuijer, S.;
(1) For recent reviews, see: (a) Lang, S. Chem. Soc. Rev. 2013, 42,
4867. (b) Qiu, G.; Ding, Q.; Wu, J. Chem. Soc. Rev. 2013, 42, 5257.
(c) Tobisu, M.; Chatani, N. Chem. Lett. 2011, 40, 330. (d) Sadjadi, S.;
Heravi, M. M. Tetrahedron 2011, 67, 2707. (e) Lygin, A. V.; de Meijere,
€
A. Angew. Chem., Int. Ed. 2010, 49, 9094. (f) Domling, A. Chem. Rev.
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Rycek, L.; Sergeyev, S.; Janssen, E.; de Kanter, F. J. J.; Maes, B. U. W.;
2006, 106, 17.
Ruijter, E.; Orru, R. V. A. Chem.;Eur. J. 2011, 17, 15039. (m) Saluste,
C. G.; Whitby, R. J.; Furber, M. Angew. Chem., Int. Ed. 2000, 39, 4156.
(5) (a) Tang, T.; Fei, X.-D.; Ge, Z.-Y.; Chen, Z.; Zhu, Y.-M.; Ji, S.-J.
J. Org. Chem. 2013, 78, 3170. (b) Tobisu, M.; Imoto, S.; Ito, S.; Chatani,
N. J. Org. Chem. 2010, 75, 4835. (c) Curran, D. P.; Du, W. Org. Lett.
2002, 4, 3215. (d) Onitsuka, K.; Suzuki, S.; Takahashi, S. Tetrahedron
Lett. 2002, 43, 6197. (e) Ishiyama, T.; Oh-e, T.; Miyaura, N.; Suzuki, A.
Tetrahedron Lett. 1992, 33, 4465.
(2) (a) Organotransition Metal Chemistry; from Bonding to Catalysis;
Hartwig, J. F., Ed; University Science Books: Sausalito, 2010. (b) Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed;
Wiley-VCH: Weinheim, 2002.
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(3) (a) Chicote, M.-T.; Vicente-Harnandez, I.; Jones, P. G.; Jicente, J.
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Organometallics 2012, 31, 6252. (b) Vincente, J.; Abad, J.-A.; Fortsch,
W. Organometallics 2001, 20, 2704 and references therein.
r
10.1021/ol4016699
XXXX American Chemical Society

incorporated as ring components, would be atom-economical
for the synthesis of heterocycles. However, to the best of
our knowledge, there are only two reports on this type of
palladium-catalyzed reaction: the synthesis of tetracyclic
quinazolines by Curran5c and of indoles by Takahashi.5d
derivatives,10 and direct construction of the 3-acylindole
skeleton from acyclic precursors has received less atten-
tion.11 We envisioned that the reaction shown in eq 2
could be a new approach for the direct construction of
3-acyl-2-arylindoles, using both the C and N atoms of the
isocyanide. In this letter, we describe the synthesis of 3-acyl-
2-arylindoles using palladium-catalyzed isocyanide inser-
tion and oxypalladation of an alkyne.
Scheme 1. Synthesis of 3-Acyl-2-arylindole via Palladium-
catalyzed Isocyanide Insertion and Oxypalladation of Alkyne
Our initial efforts focused on optimization of the reac-
tion conditions, using 2a and 3a (Table 1). Treatment
of 2a and 3a with 10 mol % Pd(OAc)2, 20 mol %
di(1-adamantyl)-n-butylphosphine (Ad2PnBu) and 3 equiv
of Cs2CO3 in toluene at 100 °C gave the indole 1a in 43%
yield (entry 1). The addition of 10 equiv of H2O accelerated
the reaction and increased the yield of 1a to 61% (entry 2).
Next, several bases were screened; it was found that car-
bonates were effective, and Cs2CO3 gave the best results in
thisreaction(entries 2À7). WhenN,N-dimethylformamide
(DMF) was used insteadoftoluene, the reactionproceeded
effectively and the product 1a was obtained in 80% yield
(entry 8). Lowering the amount of the catalyst did not
significantly influence the yields, using DMF as a solvent
without H2O (entry 9). Finally, screening of various ligands
revealed that Ad2PnBu was the best ligand (entries 10À13).
The conditions used in entry 9 were therefore the best for
this reaction.
Weinvestigatedthesubstratescope of the reaction under
the optimal conditions (Scheme 2). Initially, various aryl
iodides were used as the coupling partner. The reactions of
aryl iodides bearing electron-donating groups and chlorine
at the para position gave the desired products 1bÀ1d in
good yields. Strong electron-withdrawing groups such as
ester, nitrile, and trifluoromethyl groups decreased the
yields of products 1eÀ1g. Introducing a methyl group
at the meta and ortho positions maintained high yields
(1h and 1i). Next, the reaction was performed using several
o-alkynylphenyl isocyanides. The reactions of substrates
bearing chloro and methoxy groups at the para position
of the isocyanide gave the corresponding products 1j and
1k in 41 and 69% yields, respectively. The electronic state
of the alkyne did not significantly influence the reaction
(1l and 1m).
Recently, we reported a palladium-catalyzed cascade
process consisting of sequential insertions of an isocyanide
and analkyne, and C(sp3)ÀH activation toformpolycyclic
carbazoles.6 During this reaction, we obtained 3-acyl-2-
arylindole 1 as a byproduct (Scheme 1, eq 1). We supposed
that addition of the oxygen nucleophile to the alkyne,7,8
activated by internal imidoylpalladium, followed by CÀC
reductive elimination, gave 3-acyl-2-arylindole 1 (Scheme 1,
eq 2). The indole moiety is present in a wide range of
natural products and pharmaceuticals, and 3-acylindoles
are particularly useful intermediates for the preparation
of important therapeutic agents.9 Various methods have
therefore been used for their preparation. The majority
of these methods involve acylation of preformed indole
(6) Nanjo, T.; Tsukano, C.; Takemoto, Y. Org. Lett. 2012, 14, 4270.
(7) For examples of oxypalladation with external nucleophiles, see:
(a) Zhou, P.; Jiang, H.; Huang, L.; Li, X. Chem. Commun. 2011, 47, 1003.
(b) Zhao, L.; Lu, X.; Xu, W. J. Org. Chem. 2005, 70, 4059. (c) Okumoto,
H.; Nishihara, S.; Nakagawa, H.; Suzuki, A. Synlett 2000, 217.
(d) Kataoka, Y.; Matsumoto, O.; Ohashi, M.; Yamagata, T.; Tani, K.
Chem. Lett. 1994, 1283. (e) Utimoto, K. Pure Appl. Chem. 1983, 55, 1845.
(8) For selected examples of nucleophilic addition to alkyne activated
by acyl or aryl Pd(II) species, see: (a) Lu, Z.; Cui, W.; Xia, S.; Bai, Y.;
Luo, F.; Zhu, G. J. Org. Chem. 2012, 77, 9871. (b) Arcadi, A.; Cacchi, S.;
Fabrizi, G.; Marinelli, F.; Parisi, L. M. Tetrahedron 2003, 59, 4661.
(c) Hu, Y.; Zhang, Y.; Yang, Z.; Fathi, R. J. Org. Chem. 2002, 67, 2365.
(d) Dai, G.; Larock, R. C. Org. Lett. 2002, 4, 193. (e) Dai, G.; Larock,
R. C. Org. Lett. 2001, 3, 4035. (f) Arcadi, A.; Cacchi, S.; Carnicelli, V.;
Marinelli, F. Tetrahedron 1994, 50, 437. (g) Arcadi, A.; Cacchi, S.;
Marinelli, F. Tetrahedron Lett. 1992, 33, 3915.
3-Acyl-2-arylindole is a useful intermediate for the
construction of polycyclic indole derivatives such as car-
bolines and carbazoles.12 We therefore used this reaction
(10) (a) Wu, C.-Y.; Hu, M.; Liu, Y.; Song, R.-J.; Lei, Y.; Tang, B.-X.;
Li, R.-J.; Li, J.-H. Chem. Commun. 2012, 48, 3197. (b) Ali, M. A.;
Punniyamurthy, T. Synlett 2011, 623. (c) Bernini, R.; Fabrizi, G.;
Sferrazza, A.; Cacchi, S. Angew. Chem., Int. Ed. 2009, 48, 8078.
(d) Yu, W.; Du, Y.; Zhao, K. Org. Lett. 2009, 11, 2417. (e) Yin, Y.;
Ma, W.; Chai, Z.; Zhao, G. J. Org. Chem. 2007, 72, 5731. (f) Shimada,
T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 10546.
(g) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Synthesis 2004, 1889.
(11) (a) Qiu, G.; Chen, C.; Yao, L.; Wu, J. Adv. Synth. Catal. 2013,
355, 1579. (b) Hu, Z.; Liang, D.; Zhao, J.; Huang, J.; Zhu, Q. Chem.
Commun. 2012, 48, 7371. (c) Kamijo, S.; Yamamoto, Y. J. Am. Chem.
Soc. 2002, 124, 11940. (d) Ottoni, O.; Neder, A. de V. F.; Dias, A. K. B.;
Cruz, R. P. A.; Aquino, L. B. Org. Lett. 2001, 3, 1005. (e) Faul, M. M.;
Winneroski, L. L. Tetrahedron Lett. 1997, 38, 4749. (f) Bergman, J.;
Venemalm, L. Tetrahedron 1990, 46, 6061. (g) Ketcha, D. M.; Gribble,
G. W. J. Org. Chem. 1985, 50, 5451. (h) Eyley, S. C.; Giles, R. G.;
Heaney, H. Tetrahedron Lett. 1985, 26, 4649.
(9) (a) Wu, Y.-S.; Coumar, M. S.; Chang, J.-Y.; Sun, H.-Y.; Kuo,
F.-M.; Kuo, C.-C.; Chen, Y.-J.; Chang, C.-Y.; Hsiao, C.-L.; Liou, J.-P.;
Chen, C.-P.; Yao, H.-T.; Chiang, Y.-K.; Tan, U.-K.; Chen, C.-T.; Chu,
C.-Y.; Wu, S.-Y.; Yeh, T.-K.; Lin, C.-Y.; Hsieh, H.-P. J. Med. Chem.
2009, 52, 4941. (b) Barreca, M. L.; Ferro, S.; Rao, A.; De Luca, L.;
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Zappala, M.; Monforte, A.-M.; Debyser, Z.; Witvrouw, M.; Chimirri,
A. J. Med. Chem. 2005, 48, 7084. (c) Pais, G. C. G.; Zhang, X.;
Marchand, C.; Neamati, N.; Cowansage, K.; Svarovskaia, E. S.; Pathak,
V. K.; Tang, Y.; Nicklaus, M.; Pommier, Y.; Burke, T. R. J. Med. Chem.
2002, 45, 3184.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Investigation of Reaction Conditionsa
Scheme 2. Substrate Scopea,b
entry
x
ligand
base
additive solvent yieldb (%)
1
10 Ad2PnBu Cs2CO3
10 Ad2PnBu Cs2CO3
10 Ad2PnBu K2CO3
10 Ad2PnBu CsF
none
H2O
H2O
H2O
H2O
H2O
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
43
61
30
7
2
3
4
5
10 Ad2PnBu Et3N
10 Ad2PnBu CsOAc
8
6
24
45
80
78
69
39
24
29
7
10 Ad2PnBu CsOH•H2O H2O
8
10 Ad2PnBu Cs2CO3
H2O
9
5
5
5
5
5
Ad2PnBu Cs2CO3
none DMF
a Isocyanides were added dropwise to the solution of ArI, Pd(OAc)2,
Ad2PnBu and Cs2CO3 for 3 h by using syringe pump. b Isolated yield.
c Ten mol % of Pd(OAc)2 and 20 mol % of Ad2PnBu were used.
10
11
12
13
PPh3
Cs2CO3
Cs2CO3
Cs2CO3
none
none
none
none
DMF
DMF
DMF
DMF
DPPEc
BINAPc
biphPCy2 Cs2CO3
a Isocyanide 2a was added dropwise to the solution of PhI,
Pd(OAc)2, ligand, base and additive for 3 h by using a syringe pump.
b Isolated yield. c 5 mol % of ligand was used. Ad = 1-adamantyl,
biph = 2-biphenyl.
Scheme 3. Synthesis of Tetracyclic Indole Derivatives by
Domino Cyclization of Internal Nucleophiles
to achieve domino cyclization using internal nucleophiles
(Scheme 3). o-Iodoaniline (4) and isocyanide 3a coupled in
the presence of a palladium catalyst to give the tetracyclic
γ-carboline 5 in 56% yield. This strategy was applied to the
reaction of o-iodophenol (6), and the corresponding pro-
duct 7 was obtained in 73% yield. This is the first example
of the construction of a chromeno[4,3-b]indole skeleton
bearing a characteristic conjugated system. The reaction of
o-iodobenzyl cyanide (8) also gave the desired tetracyclic
carbazole 9 in 68% yield.13 Interestingly, when DMF,
which is an effective solvent for the formation of 1a, was
used instead of toluene, the reactions using o-iodoaniline
(4) and o-iodophenol (6) did not give 5 and 7, respectively.
The reaction of o-iodobenzyl cyanide with toluene did not
give product 9, similar to the synthesis of 1a.
In order to gain insight into the reaction, the following
experiments were performed (Scheme 4). When bromo-
benzene was used as the substrate instead of iodobenzene,
the yield was low (Scheme 4, eq 1). Also, the addition of a
silver salt significantly inhibited the reactions of both iodo-
and bromo-benzene (not shown). These results suggest
that halides play an important role in the reaction. Based
on this hypothesis, we examined the addition of some
iodide sources, and found that tetrabutylammonium
iodide (TBAI, 1 equiv) increased the yield of 1a to 41%.
We also performed labeling experiments to identify the
oxygen source in product 1a (Scheme 4, eq 2). The 18O-
incorporated product 1a-18O was formed in the presence
of H218O as the additive, and the ratio of 1a-18O:1a was
69:31.14 These results and examination of the reaction condi-
tions (Table 1) suggested that H2O is one of the oxygen
sources, and other species such as acetate and carbonate can
also supply an oxygen atom.
A plausible mechanism is shown in Figure 1. First,
oxidative addition of Pd(0) to aryl iodide, followed by
isocyanide insertion, generates imidoylpalladium A.15 Imi-
doylpalladium effectively activates the internal alkyne, and
oxypalladation6,16 with acetate, carbonate, or hydroxide
(14) The treatment of 1a with H218O, Pd(OAc)2, Ad2PnBu, Cs2CO3 in
DMF at 100 °C did not give 1a-18O. This result denies the possiblity of
the exchange of the oxygen atom of 1a.
€
€
(12) (a) Wahlstrom, N.; Slatt, J.; Stensland, B.; Ertan, A.; Bergman,
J.; Janosik, T. J. Org. Chem. 2007, 72, 5886. (b) Pathak, R.; Nhlapo,
J. M.; Govender, S.; Michael, J. P.; van Otterlo, W. A. L.; de Koning,
C. B. Tetrahedron 2006, 62, 2820. (c) de Koning, C. B.; Michael, J. P.;
Nhlapo, J. M.; Pathak, R.; van Otterlo, W. A. L. Synlett 2003, 705.
(d) Cacchi, S.; Fabrizi, G.; Pace, P.; Marinelli, F. Synlett 1999, 620.
(13) The structure of 9 was determined by X-ray crystallography. See
Supporting Information.
(15) For selected examples of isocyanide insertion into the PdÀC
bond, see: (a) Yamamoto, Y.; Yamazaki, H. Inorg. Chim. Acta 1980, 41,
229. (b) Albert, J.; D’Andrea, L.; Granell, J.; Zafrilla, J.; Font-Bradia,
M.; Solans, X. J. Organomet. Chem. 2007, 692, 4895. (c) Vincent, J.;
ꢀ
Saura-Llamas, I.; Garcı
´
a-Lopez, J.-A.; Bautista, D. Organometallics
2009, 28, 448.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Mechanistic Studies
proceeds, to give the six-membered palladacycle B. CÀC
reductive elimination regenerates the Pd(0) species, and
subsequent hydrolysis or isomerization of C produces the
desired product D. In the oxypalladation step, the halide
leaves the palladium center, along with PdÀC bond for-
mation, so the higher leaving ability of IÀ probably gives a
better result than BrÀ.17 Tetracyclic indole derivatives E
could be generated by cyclization of internal nucleophiles
of D. However, when iodoaniline (4) or iodophenol (6) was
used, the domino cyclization in DMF did not give good
results,18 in contrast to the synthesis of 3-acylindole 1. We
therefore suggest that these reactions in toluene proceeded
via another pathway involving carbopalladation of A and
intramolecular CÀX reductive elimination of vinylpalla-
dium intermediate F. The related complex of intermediate
F was isolated by Takahashi and co-workers,19 and a
similar reaction pathway was proposed for the synthesis
of heterocycles.20 However, the best reaction solvent for
Figure 1. Plausible mechanism.
iodobenzyl cyanide (8) is the same as that for the synthesis
of 3-acylindole 1, so carbazole 9 was probably formed via
3-acylindole D.
In summary, we have developed palladium-catalyzed
isocyanide insertion and alkyne functionalization for the
synthesis of 2-arylindole derivatives, including tetracyclic
carbazoles. In this process, the formation of two CÀC
bonds via isocyanide insertion was achieved, and isocya-
nide was effectively used by incorporating both the C and
N atoms as components of the indole skeleton. We are
currently extending this strategy to convergent synthesis
of nitrogen-containing polycycles and examining further
details of the reaction mechanisms.
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research on the Innovation
Area “Molecular Activation Directed toward Straightfor-
ward Synthesis” from The Ministry of Education, Culture,
Sports, Science, and Technology, Japan (C.T.), and a JSPS
Research Fellowships for Young Scientists (T.N.)
(16) We also tried the introduction of other nulceophiles such as
amine or alcohols, but the reaction did not give the corresponding
products. The reason would be that o-alkynylphenylisocyanide 3a
reacted with nucleophiles to give an undesired product without involve-
ment of palladium catalystunder these conditions. Please see: Suginome,
M.; Fukuda, T.; Ito, Y. Org. Lett. 1999, 1, 1977.
(17) Gabriele, B.; Salerno, G.; Lauria, E. J. Org. Chem. 1999, 64,
7687.
(18) Because isocyanide 3a would react with phenol and aniline in
DMF under these conditions.
(19) Onitsuka, K.; Segawa, M.; Takahashi, S. Organometallics 1998,
17, 4335.
(20) (a) Larock, R. C.; Yum, E.-K.; Refvik, M. D. J. Org. Chem.
1998, 63, 7652. (b) Larock, R. C.; Yum, E.-K. J. Am. Chem. Soc. 1991,
113, 6689.
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX