Synthesis of 3-acylindoles by visible-light induced intramolecular oxidative cyclization of o -alkynylated N,N -dialkylamines

Article abstract of DOI:10.1021/ol501276j

A visible-light photoredox synthesis of 3-acylindoles through intramolecular oxidative cyclization of o-alkynylated N,N-dialkylamines is developed. The reaction proceeds effectively under mild reaction conditions using air as the oxidant, and only water is generated as a side product. A plausible mechanism involving the addition of α-amino alkyl radicals to alkynes, followed by C-O bond formation, is proposed.

Full text of DOI:10.1021/ol501276j

Letter
pubs.acs.org/OrgLett
Synthesis of 3‑Acylindoles by Visible-Light Induced Intramolecular
Oxidative Cyclization of o‑Alkynylated N,N-Dialkylamines
Ping Zhang, Tiebo Xiao, Shengwei Xiong, Xichang Dong, and Lei Zhou*
School of Chemistry and Chemical Engineering, Sun Yat-Sen University, 135 Xingang West Road, Guangzhou 510275, China
S
* Supporting Information
ABSTRACT: A visible-light photoredox synthesis of 3-
acylindoles through intramolecular oxidative cyclization of o-
alkynylated N,N-dialkylamines is developed. The reaction
proceeds effectively under mild reaction conditions using air as
the oxidant, and only water is generated as a side product. A
plausible mechanism involving the addition of α-amino alkyl
radicals to alkynes, followed by C−O bond formation, is proposed.
3-Acylindoles represent an important class of biologically active
heterocyclic compounds which have been widely employed as
core structures for developing pharmaceutically important
molecules.1 For example, pravadoline (Figure 1, I) is a
pling of o-alkynylated N,N-dialkylamines.13a A similar protocol
was also realized by Patel using a catalytic amount of CuI
without the requirement of palladium as the cocatalyst.13b Both
reactions were proposed to proceed via an iminium
intermediate with excess amounts of TBHP as oxidants at
high temperatures.
On the other hand, α-amino alkyl radicals have also been
proven as reactive intermediates in various transformations.14
The photoinduced one-electron oxidation of a tertiary amine
followed by deprotonation under UV light irradiation is a well-
established method for the generation of α-amino radicals.15
Compared to high energy UV light, visible light is infinitely
available, environmentally benign, and easy to handle. Its green
chemistry features make visible-light promoted chemical
reactions receive considerable attention in recent years.16
With tris(bipyridine) ruthenium or iridium complexes as the
photoredox catalysts, visible-light induced in suit generation of
α-amino alkyl radicals and their addition to electron-deficient
alkenes,17 isocyanates,18 and azodicarboxylate esters19 have
been described by several groups. In the presence of oxygen,
Yu20a and Rueping20b demonstrated the radical addition/
cyclization reactions between tertiary anilines with electron-
deficient alkenes. Moreover, Rueping also reported the
photoredox catalyzed synthesis of indole-3-carbaldehydes
through a sequential C−C bond formation/aromatization/
carbon−carbon bond cleavage process involving α-amino alkyl
radicals (Scheme 1a).20b However, to our knowledge, visible-
light promoted radical addition to alkynes followed by C−O
bond formation was rarely reported to date.16 We hypothesized
that α-amino alkyl radicals A generated from tertiary amines 1
could undergo intramolecular radical addition to C−C triple
bonds to produce vinyl radicals B. Subsequently, intermediate
B could be captured by molecular oxygen or superoxide anion
Figure 1. Examples of bioactive 3-acylindoles.
marketed anti-inflammatory and analgesic drug.2 Ramosetron
(Figure 1, II) has been used as a serotonin 5-HT3 receptor
antagonist for the treatment of nausea and vomiting.3 3-
Aroylindole compound III (BPR0L075, Figure 1) exhibits
potent in vitro activity against a variety of human tumor cell
lines.4 As a consequence, the development of an efficient
method for the synthesis of 3-acylindoles has become a subject
of great interest.5−12 The classical methods to synthesize 3-
acylindoles are Friedel−Crafts reaction,5 Vilsmeier−Haack
reaction,6 and indole Grignard reaction.7 The other significant
approaches include transition-metal-catalyzed C3−H activation
of indoles by using α-oxocarboxylic acids,8 anilines,9 nitriles,10
and electron-rich olefins11 as the acyl sources. Although
excellent preparative methods for the synthesis of 3-acylindoles
using preformed indoles have been developed, the assembly of
3-acylindoles from readily available nonindole core starting
materials using a simple and expedient procedure still remain
scarce.12,13 In this context, Liang and co-workers reported an
elegant method for the synthesis of 3-acylindoles via
palladium−copper-cocatalyzed intramolecular oxidative cou-
•−
radical O2 to provide vinyl peroxides C, whereby intra-
molecular abstraction of the hydrogen atom occurs to form 3-
Received: May 5, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol501276j | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Visible-Light Photoredox Synthesis of 3-
Acylindoles
Table 1. Optimization of Reaction Conditions
b
entry
photocatalyst (mol %)
base (equiv)
yield (%)
1
Ru(bpy)2Cl2·6H2O (5)
Ir(ppy)2(dtbbpy)PF6 (5)
Ru(phen)3Cl2 (5)
none
40
60
45
43
46
50
28
75
65
60
65
21
80
2
none
3
none
4
Ru(bpz)3Cl2 (5)
none
5
fac-Ir(ppy)3 (5)
none
6
Eosin Y (10)
none
7
Rose Bengal (10)
none
8
Ir(ppy)2(dtbbpy)PF6 (5)
Ir(ppy)2(dtbbpy)PF6 (5)
Ir(ppy)2(dtbbpy)PF6 (5)
Ir(ppy)2(dtbbpy)PF6 (5)
Ir(ppy)2(dtbbpy)PF6 (5)
Ir(ppy)2(dtbbpy)PF6 (1.5)
K2CO3 (3)
KH2PO4 (3)
K3PO4 (3)
NaOAc (3)
K2CO3(3)
K2CO3 (3)
9
10
11
c
12
d
13
a
A solution of 1a (0.2 mmol) and photocatalyst in DMSO (4 mL) was
b
irradiated by 5 W blue LED under air at rt for 36 h. Yields were
measured by H NMR with mesitylene as the internal standard. The
reaction was carried out in 2 mL of MeCN. A mixture of DMSO (2
c
1
acylindoles (Scheme 1b). As a continuation of our interest in
visible-light photoredox radical chemistry,21 we now report a
visible-light induced intramolecular oxidative cyclization for the
synthesis of 3-acylindoles, in which air was used as the oxidant
with water as the only side product.
d
mL) and MeCN (2 mL) was used as the solvent; reaction time 16 h.
donating groups such as p-Me, m-Me, p-tBu, p-OMe and
electron-withdrawing groups such as p-F, p-Cl, p-CF3 on the
phenyl ring of the benzyl moiety could be well-tolerated. In
another case, 2-(2-naphthyl)-3-acylindole 2i was successfully
assembled from 1i in a yield of 62% under the irradiation of
blue LED. One of the important attributes of this approach is
its possibility to introduce various substituted aryl groups onto
the 2-position of indoles under mild conditions. In addition, we
were delighted to find that o-alkynylated N,N-dimethylamines
1j was also suitable for the reaction. Notably, the substrates
with a five-membered ring (1k) and a six-membered ring (1l)
underwent intramolecular cyclization smoothly, affording the
corresponding 3-aroylindoles 2k and 2l in yields of 61% and
52% respectively. Next, the present protocol was extended to
the substrates with other triple-linked aromatics (1m−q) and a
heteroaromatic ring (1r), and they all worked efficiently and
gave good yields of the desired products. It is worth mentioning
that ortho-alkylacetylenic substituted N,N-dibenzylamine 1s also
worked well to give the indole product 2s in moderate yield.
Finally, the reaction was found to be not significantly affected
by the methyl group para to the nitrogen atom, in which the
desired indole 2t was isolated in 68% yield.
When N-benzyl-N-methyl-2-(phenylethynyl) aniline 1u was
employed as the substrate, the reaction gave a mixture of 3-
benzoylindole 2u and 2u′ in isolated yields of 40% and 22%
respectively. This result indicates that the benzyl group more
easily undergoes the single-electron oxidation than the methyl
group under the present reaction conditions (Scheme 3).
In principle, all the reactions were carried out under
anhydrous conditions. In the presence of H2O18 (5 equiv),
the photoredox reaction of 1a gave 3-acylindole 2a with a
diminished yield (52%) without any 18O enriched at its
carbonyl group. This result indicates that oxygen atom in the
ketone did not originate from the water. Therefore, a tentative
mechanism for this reaction is proposed in Scheme 4.22
We initially prepared N,N-dibenzyl-2-(phenylethynyl) aniline
1a through the Sonogashira coupling of phenylacetylene with 2-
iodoaniline followed by benzylation of the resulted o-
alkynylated amine under basic conditions. Irradiation substrate
1a with 5 W blue LED in the presence of Ru(bpy)3Cl2·6H2O in
DMSO for 36 h gave the desired 3-benzoylindole 2a in 40%
yield (Table 1, entry 1). The yield was significantly improved
when 5 mol % of Ir(ppy)2(dtbbpy)PF6 was used as the
photocatalyst (Table 1, entry 2). Other Ru or Ir complexes
such as Ru(phen)3Cl2, Ru(bpz)3Cl2, fac-Ir(ppy)3 were also
examined, but they were not better than Ir(ppy)2(dtbbpy)PF6
(Table 1, entries 3−5). Notably, organic dyes eosin Y and Rose
Bengal were also effective catalysts for the reaction, albeit
affording the products with diminished yields (Table 1, entries
6 and 7). Further optimization on the reaction conditions
revealed the addition of bases could effectively increase the
yields of 2a, and the use of K2CO3 gave the best results (Table
1, entries 8−11). A survey of solvents demonstrated that
DMSO is the best choice (see Table S1 in Supporting
Information (SI)). However, when MeCN was used as the
solvent, o-alkynylated amine 1a was completely consumed in 10
h, giving a mixture of 2a and several unidentified byproducts
(Table 1, entry 12). This observation promoted us to examine
the use of the mixture of MeCN and DMSO as the solvents, in
which the reaction might be accomplished in a shorter time.
Finally, the reaction was found to give a neat conversion to 2a
in the 1:1 mixture of MeCN and DMSO in 16 h, and the
catalyst loading could be further reduced to 1.5 mol % (Table 1,
entry 13).
To demonstrate the generality of this new reaction, different
dibenzyl substituted substrates 1b−i were examined under the
optimized reaction conditions. As shown in Scheme 2, the
transformation proceeded quite smoothly and afforded the
desired 3-aroylindoles 2b−i in good yields. Both electron-
B
dx.doi.org/10.1021/ol501276j | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
,b
Scheme 2. Synthesis of 3-Acylindoles 2 from Amines 1
Scheme 4. A Plausible Mechanism
In summary, we have developed a simple and efficient
method for the synthesis of 3-acylindoles by means of visible-
light irradiation of o-alkynylated N,N-dialkylamines. Various 2-
aryl-3-acylindoles were assembled in good yields under mild
conditions using air as the oxidant and carbonyl sources. This
protocol allows the formation of C−C and C−O bonds
simultaneously through an intramolecular oxidative path
involving the α-amino alkyl radical.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, characterization data, NMR spectra of all
new products. This material is available free of charge via the
Internet at http://pubs.acs.org.
a
Reaction conditions: amine 1 (0.2 mmol), Ir(ppy)2(dtbbpy)PF6 (1.5
mol %), K2CO3 (0.6 mmol), DMSO/MeCN (1:1, 4 mL), 5 W blue
LED, rt, air balloon, 16 h. Isolated yield. The reaction was carried
out on 13.4 mmol scale.
b
c
AUTHOR INFORMATION
Corresponding Author
■
Scheme 3. Reaction of N-Benzyl-N-methyl-2-
(phenylethynyl) Aniline 1u
*E-mail: zhoul39@mail.sysu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Grant Nos. 21202207 and J1103305), the Research Fund for
Guangzhou Peal River New Star of Science and Technology
(Grant No. 2013J2200017), the Fundamental Research Funds
for the Central Universities, and the Program for Changjiang
Scholars and Innovative Research Team in University of China
(Grant No. IRT1298) for the financial support.
Initially, photoexcitation of Ir(III) by visible-light generates
excited Ir(III)*. Single-electron transfer (SET) from substrate 1
to Ir(III)* generates Ir(II) and radical cation A, which
undergoes facile deprotonation to give α-amino alkyl radical
B.20 Intramolecular radical addition to C−C triple bonds occurs
to produce vinyl radicals C.23 Intermediate C is captured by
oxygen, leading to the formation of superoxide radical D.24
Single-electron reduction of D by Ir(II) regenerates the Ir(III)
catalyst with concomitant formation of intermediate E. Another
possible route to get access to E is the regeneration of Ir(III)
via aerobic oxidation, followed by addition of superoxide radical
REFERENCES
■
(1) (a) Nicolaou, I.; Demopoulos, V. J. J. Med. Chem. 2003, 46, 417.
(b) Barreca, M. L.; Ferro, S.; Rao, A.; De Luca, L.; Zappala, M.;
Monforte, A. M.; Debyser, Z.; Witvrouw, M.; Chimirri, A. J. Med.
Chem. 2005, 48, 7084. (c) 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. J. Med. Chem. 2009, 52, 4941. (d) La Regina, G.; Sarkar, T.;
Bai, R.; Edler, M. C.; Saletti, R.; Coluccia, A.; Piscitelli, F.; Minelli, L.;
Gatti, V.; Mazzoccoli, C. J. Med. Chem. 2009, 52, 7512.
•−
anion O2 to vinyl radicals C. Finally, the protonation of E
(2) Haubrich, D. R.; Ward, S. J.; Baizman, E.; Bell, M. R.; Bradford, J.;
Ferrari, R.; Miller, M.; Perrone, M.; Pierson, A. K.; Saelens, J. K.;
Luttinger, D. J. Pharmacol. Exp. Ther. 1990, 255, 511.
gives vinyl hydrogen peroxide F, whereby intramolecular
abstraction of the hydrogen atom affords the 3-acylindoles 2.25
C
dx.doi.org/10.1021/ol501276j | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3) Fujii, Y.; Saitoh, Y.; Tanaka, H.; Toyooka, H. Anesth. Analg. 2000,
90, 72.
(4) Kuo, C. C.; Hsieh, H. P.; Pan, W. Y.; Chen, C. P.; Liou, J. P.; Lee,
S. J.; Chang, Y. L.; Chen, L. T.; Chen, C. T.; Chang, J. Y. Cancer Res.
2004, 64, 4621.
(20) (a) Ju, X.; Li, D.; Li, W.; Yu, W.; Bian, F. Adv. Synth. Catal.
2012, 354, 3561. (b) Zhu, S.; Das, A.; Bui, L.; Zhou, H.; Curran, D. P.;
Rueping, M. J. Am. Chem. Soc. 2013, 135, 1823.
(21) (a) Xiao, T.; Dong, X.; Tang, Y.; Zhou, L. Adv. Synth. Catal.
2012, 354, 3195. (b) Dong, X.; Xu, Y.; Liu, J.; Hu, Y.; Xiao, T.; Zhou,
L. Chem.Eur. J. 2013, 19, 16928. (c) Xiao, T.; Li, L.; Lin, G.; Wang,
Q.; Zhang, P.; Mao, Z.-W.; Zhou, L. Green. Chem. 2014, 16, 2418.
(22) A possible pathway involving an iminium intermediate cannot
be excluded completely at this stage, but it is less likely in this reaction.
See the SI.
(23) For reviews on radical addition to alkynes, see: (a) Wille, U.
Chem. Rev. 2013, 113, 813. (b) Gilmore, K.; Alabugin, I. V. Chem. Rev.
2011, 111, 6513.
(24) (a) Eskola, A. J.; Timonen, R. S. Phys. Chem. Chem. Phys. 2003,
5, 2557. (b) Mebel, A. M.; Diau, E. W. G.; Lin, M. C.; Morokuma, K. J.
Am. Chem. Soc. 1996, 118, 9759. (c) Knyazev, V. D.; Slagle, I. R. J.
Phys. Chem. 1995, 99, 2247. (d) Fahr, A.; Laufer, A. H. J. Phys. Chem.
1988, 92, 1229.
(5) (a) Bergman, J.; Backvall, J. E.; Lindstron, J. O. Tetrahedron 1973,
29, 971. (b) Watanabe, T.; Kobayashi, A.; Nishiura, M.; Takahashi, H.;
Usui, T.; Kamiyama, I.; Mochizuki, N.; Noritake, K.; Yokoyama, Y.;
Murakami, Y. Chem. Pharm. Bull. 1991, 39, 1152. (c) Ketcha, D. M.;
Gribble, G. W. J. Org. Chem. 1985, 50, 5451. (d) Okauchi, T.; Itonaga,
M.; Minami, T.; Owa, T.; Kitoh, K.; Yoshino, H. Org. Lett. 2000, 2,
1485. (e) Ottoni, O.; Neder, A. D. F.; Dias, A. K. B.; Cruz, R. P. A.;
Aquino, L. B. Org. Lett. 2001, 3, 1005. (f) Wynne, J. H.; Lloyd, C. T.;
Jensen, S. D.; Boson, S.; Stalick, W. M. Synthesis 2004, 2277.
(g) Yeung, K.-S.; Qiu, Z.; Farkas, M. E.; Xue, Q.; Regueiro-Ren, A.;
Yang, Z.; Bender, J. A.; Good, A. C.; Kadow, J. F. Tetrahedron Lett.
2008, 49, 6250. (h) Guchhait, S. K.; Kashyap, M.; Kamble, H. J. Org.
Chem. 2011, 76, 4753.
(25) Wong, Y.-C.; Hsieh, M.-T.; Amancha, P. K.; Chin, C.-L.; Liao,
C.-F.; Kuo, C.-W.; Shia, K.-S. Org. Lett. 2011, 13, 896.
(6) (a) Anthony, W. J. Org. Chem. 1960, 25, 2049. (b) Powers, J. C. J.
Org. Chem. 1965, 30, 2534.
(7) Bergman, J.; Venemalm, L. Tetrahedron Lett. 1987, 28, 3741.
(8) (a) Yu, L.; Lia, P.; Wang, L. Chem. Commun. 2013, 49, 2368.
(b) Gu, L.-J.; Liu, J.-Y.; Zhang, L.-Z.; Xiong, Y.; Wang, R. Chin. Chem.
Lett. 2014, 25, 90. (c) Wang, C.; Wang, S.; Li, H.; Yan, J.; Chi, H.;
Chen, X.; Zhang, Z. Org. Biomol. Chem. 2014, 12, 1721.
(9) Wu, W.; Su, W. J. Am. Chem. Soc. 2011, 133, 11924.
(10) (a) Jiang, T.; Wang, G. Org. Lett. 2013, 15, 788. (b) Ma, Y.; You,
J.; Song, F. Chem.Eur. J. 2013, 19, 1189.
(11) Li, Y.; Xue, D.; Lu, W.; Fan, X.; Wang, C.; Xiao, J. RSC Adv.
2013, 3, 11463.
(12) For selected recent examples, see: (a) Nanjo, T.; Yamamoto, S.;
Tsukano, C.; Takemoto, Y. Org. Lett. 2013, 15, 3754. (b) Coffman, K.
C.; Palazzo, T. A.; Hartley, T. P.; Fettinger, J. C.; Tantillo, D. J.; Kurth,
M. J. Org. Lett. 2013, 15, 2062. (c) Gao, D.; Back, T. G. Chem.Eur. J.
2012, 18, 14828. (d) Fukamachi, S.; Konishi, H.; Kobayashi, K.
Synthesis 2009, 11, 1786. (e) Bernini, R.; Fabrizi, G.; Sferrazza, A.;
Cacchi, S. Angew. Chem., Int. Ed. 2009, 48, 8078.
(13) (a) Xia, X.-F.; Zhang, L.-L.; Song, X.-R.; Niu, Y.-N.; Liu, X.-Y.;
Liang, Y.-M. Chem. Commun. 2013, 49, 1410. (b) Gogoi, A.; Guin, S.;
Rout, S. K.; Patel, B. K. Org. Lett. 2013, 15, 1802.
(14) For reviews, see: (a) Robertson, J.; Pillai, J.; Lush, R. K. Chem.
Soc. Rev. 2001, 30, 94. (b) Renaud, P.; Giraud, L. Synthesis 1996, 913.
(15) (a) Hoffmann, N. J. Photochem. Photobiol. C 2008, 9, 43.
(b) Hoffmann, N. Chem. Rev. 2008, 108, 1052. (c) Hoffmann, N. Pure
Appl. Chem. 2007, 79, 1949. (d) Hoffmann, N.; Bertrand, S.;
Marinkovic, S.; Pesch. J. Pure Appl. Chem. 2006, 78, 2227.
(16) For reviews on visible-light photoredox catalysis, see: (a) Schultz,
D. M.; Yoon, T. P. Science 2014, 343, 985. (b) Xie, J.; Jin, H.; Xu, P.;
Zhu, C. Tetrahedron Lett. 2014, 55, 36. (c) Reckenthalera, M.;
̈
Griesbeck, A. G. Adv. Synth. Catal. 2013, 355, 2727. (d) Xuan, J.; Lu,
L.-Q.; Chen, J.-R.; Xiao, W.-J. Eur. J. Org. Chem. 2013, 6755. (e) Zou,
Y.-Q.; Chen, J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2013, 52, 11701.
(f) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013,
113, 5322. (g) Xi, Y.; Yi, H.; Lei, A. Org. Biomol. Chem. 2013, 11, 2387.
(h) Hari, D. P.; Konig, B. Angew. Chem., Int. Ed. 2013, 52, 4734.
̈
(i) Shi, L.; Xia, W. J. Chem. Soc. Rev. 2012, 41, 7687. (j) Xuan, J.; Xiao,
W. J. Angew. Chem., Int. Ed. 2012, 51, 6828. (k) Narayanam, J. M. R.;
Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102. (l) Yoon, T. P.;
Ischay, M. A.; Du, J. N. Nat. Chem. 2010, 2, 527. (m) Zeitler, K.
Angew. Chem., Int. Ed. 2009, 48, 9785.
(17) (a) Kohls, P.; Jadhav, D. D.; Pandey, G.; Reiser, O. Org. Lett.
2012, 14, 672. (b) Miyake, Y.; Nakajima, K.; Nishibayashi, Y. J. Am.
Chem. Soc. 2012, 134, 3338. (c) Miyake, Y.; Ashida, Y.; Nakajima, K.;
Nishibayashi, Y. Chem. Commun. 2012, 48, 6966. (d) Espelt, L. R.;
Wiensch, E. M.; Yoon, T. P. J. Org. Chem. 2013, 78, 4107.
(18) Zhou, H.; Lu, P.; Gu, X.; Li, P. Org. Lett. 2013, 15, 5646.
(19) Miyake, Y.; Nakajima, K.; Nishibayashi, Y. Chem.Eur. J. 2012,
18, 16473.
D
dx.doi.org/10.1021/ol501276j | Org. Lett. XXXX, XXX, XXX−XXX