Rhenium-catalyzed regiodivergent addition of indoles to terminal alkynes

Article abstract of DOI:10.1021/ol203199m

An efficient rhenium-catalyzed site-switchable addition of indoles to terminal alkynes is described. A variety of bisindolylalkane derivatives are expeditiously synthesized in high yields with excellent regioselectivity. Preliminary mechanistic study shed

Full text of DOI:10.1021/ol203199m

ORGANIC
LETTERS
2012
Vol. 14, No. 2
588–591
Rhenium-Catalyzed Regiodivergent
Addition of Indoles to Terminal Alkynes
Dexin Xia,† Yin Wang,‡ Zhenting Du,‡ Qi-Yu Zheng,† and Congyang Wang*,†
Beijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China, and College of Science, Northwest A&F University, Yangling,
Shaanxi 712100, China
wangcy@iccas.ac.cn
Received December 1, 2011
ABSTRACT
An efficient rhenium-catalyzed site-switchable addition of indoles to terminal alkynes is described. A variety of bisindolylalkane derivatives are
expeditiously synthesized in high yields with excellent regioselectivity. Preliminary mechanistic study sheds light on the observed regiodivergent
addition.
Indoles are prevalent motifs in a wide range of biologi-
cally active molecules, pharmaceuticals, and natural oc-
curring compounds.1 As a consequence, the synthesis of
indole derivatives has attracted comprehensive and con-
tinuous interest from chemical communities. Among a
myriad of methods to approach functionalized indoles,
the direct hydroindolation of alkynes represents one of the
most straightforward, highly efficient, and atom-economic
strategies to access a variety of indole derivatives.1,2
Althoughgreat successhasbeen achieved in such processes,
the control of regioselectivity in the addition of indoles to
terminal alkynes is still an important challenge.3
To address this issue, activated alkynes containing
electron-withdrawing groups such as ester, amide, and
sulfone are frequently employed as substrates.4 Thus,
the addition of indoles occurs preferentially in an anti-
Markovnikov manner due to the biased CÀC triple bonds.
For the widely occurring unactivated terminal alkynes,
however, the Markovnikov addition of indoles has been
predominantly developed via a variety of transition metal
catalysts (Scheme 1, a).5,6b The electronic unbalance of the
triple bonds in key transition-metal-alkyne complexes is
ascribed to govern the regiospecific attack of indoles to the
internal C-atom of terminal alkynes, thus resulting in the
formation of Markovnikov adducts. In sharp contrast,
the anti-Markovnikov regioselective addition of indoles to
† Institute of Chemistry, Chinese Academy of Sciences.
‡ Northwest A&F University.
(1) For excellent reviews, see: (a) Sundberg, R. J. Indoles; Academic
Press: London, U.K., 1996. (b) Humphrey, G. R.; Kuethe, J. T. Chem. Rev.
2006, 106, 2875. (c) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed.
2009, 48, 9608. (d) Kochanowska-Karamyan, A. J.; Hamann, M. T.
Chem. Rev. 2010, 110, 4489. (e) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011,
111, PR215.
(2) For related reviews on hydroindolations, see: (a) Nevado, C.;
Echavarren, A. M. Synthesis 2005, 167. (b) Kirsch, S. F. Synthesis 2008,
3183. (c) Kitamura, T. Eur. J. Org. Chem. 2009, 1111.
(3) For an excellent review, see: Beller, M.; Seayad, J.; Tillack, A.;
Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368.
(4) For selected examples, see: (a) Lu, W.; Jia, C.; Kitamura, T.;
Fujiwara, Y. Org. Lett. 2000, 2, 2927. (b) Li, Z.; Shi, Z.; He, C. J.
Organomet. Chem. 2005, 690, 5049. (c) Donets, P. A.; Van Der Eycken,
E. V.; Hecke, K. V.; Meervelt, L. V. Org. Lett. 2009, 11, 3618. (d) Li, X.;
Wang, J.-Y.; Yu, W.; Wu, L.-M. Tetrahedron 2009, 65, 1140. (e)
Buscemi, G.; Biffis, A.; Tubaro, C.; Basato, M.; Graiff, C.; Tiripicchio,
A. Appl. Organomet. Chem. 2010, 24, 285. (f) Xie, M.-H.; Xie, F.-D.; Lin,
G.-F.; Zhang, J.-H. Tetrahedron Lett. 2010, 51, 1213.
(5) For selected examples, see: (a) Yadav, J. S.; Reddy, B. V. S.;
Padmavani, B.; Gupta, M. K. Tetrahedron Lett. 2004, 45, 7577. (b)
Bhuvaneswari, S.; Jeganmohan, M.; Cheng, C.-H. Chem.;Eur. J. 2007,
13, 8285. (c) Tsuchimoto, T.; Nagase, Y.; Miyamura, T.; Matsubayashi,
H.; Kaneko, M.; Shirakawa, E. J. Am. Chem. Soc. 2008, 130, 15823. (d)
ꢀ ~ ꢀ
Barluenga, J.; Fernandez, A.; Rodrıguez, F.; Fananas, F. J. Chem.;
´
Eur. J. 2009, 15, 8121. (e) Cadierno, V.; Francos, J.; Gimeno, J. Chem.
Commun. 2010, 46, 4175. (f) Bhaskar, G.; Saikumar, C.; Perumal, P. T.
Tetrahedron Lett. 2010, 51, 3141. (g) Gao, R.; Yi, C. S. J. Org. Chem.
2010, 75, 3144. (h) Zhang, Y.-Q.; Zhu, D.-Y.; Jiao, Z.-W.; Li, B.-S.;
Zhang, F.-M.; Tu, Y.-Q.; Bi, Z. Org. Lett. 2011, 13, 3458. (i)
Tsuchimoto, T.; Kanbara, M. Org. Lett. 2011, 13, 912. (j) Wang,
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r
10.1021/ol203199m
Published on Web 12/29/2011
2011 American Chemical Society

unactivated terminal alkynes is rarely reported.6 Echavarren
et al. elegantly described a Au-catalyzed intramolecular anti-
Markovnikov hydroindolation of terminal alkynes lead-
ing to the formation of six- to eight-membered rings.6aÀc
Barluenga et al. demonstrated that the intermolecular addi-
tion of indoles to terminal alkynes bearing a properly posi-
tioned hydroxyl “directing group” proceeded in a highly
selective anti-Markovnikov pattern via Au catalysis.6d To
the best of our knowledge, intermolecular anti-Markovnikov
hydroindolation of simple unactivated terminal alkynes
without any “directing groups” is still an unmet challenge.
Herein, we disclose the first general solution to this chal-
lenge by resorting to Re catalysis (Scheme 1b). Also, the
regioselectivity can be readily reversed to the Markovnikov
pattern while using the same catalyst, which highlights the
unique features of Re catalysis.7,8
used as catalysts (entries 4,5). Toluene was the superior
solvent (entries 6À10). A higher temperature is detrimental
to the reaction presumably due to the decomposition of 3a
(entries 11,12).9 The increased amount of 2a and reaction
concentration gave the highest conversion of 1a (entries
13À15). The catalyst loading can be further reduced to
5 mol % while maintaining the same conversion, and 3a
was isolated as a pure product in 89% yield (entry 16).
Other variations gave no better results (entries 17À19).
Importantly, no Markovnikov adduct 4a was detected
during the screening of reaction conditions. To the best of
our knowledge, this represents the first successful example
of intermolecular anti-Markovnikov addition of indoles
to unactivated terminal alkynes without directing groups.
Table 1. Optimization of Reaction Parametersa
Scheme 1. Intermolecular Hydroindolation of Unactivated
Terminal Alkynes
catalyst
(mol %)
2a
t
convn
(%)b
entry
(equiv)
solvent
(°C)
c
1
Mn(CO)5Br (10)
Mn2(CO)10 (10)
Re2(CO)10 (10)
Re(CO)5Cl (10)
Re(CO)5Br (10)
Re(CO)5Br (10)
Re(CO)5Br (10)
Re(CO)5Br (10)
Re(CO)5Br (10)
Re(CO)5Br (10)
Re(CO)5Br (10)
Re(CO)5Br (10)
Re(CO)5Br (10)
Re(CO)5Br (10)
Re(CO)5Br (10)
Re(CO)5Br (5)
Re(CO)5Br (5)
Re(CO)5Br (5)
Re(CO)5Br (2)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
2.0
1.5
1.5
1.5
1.5
1.5
toluene
toluene
toluene
toluene
toluene
xylene
THF
100
100
100
100
100
100
100
100
100
100
120
90
À
c
c
2
À
À
3
4
33
55
46
5
6
First, the reaction of N-methylindole 1a and 1-hexyne 2a
was examined with a wide range of parameters (Table 1).
No conversion was observed withcatalysts of Mn(CO)5Br,
Mn2(CO)10, or Re2(CO)10 (entry 1À3). To our delight, the
anti-Markovnikov adduct, bisindolylalkane 3a, was form-
ed as a single product when Re(CO)5X (X = Cl, Br) were
c
7
À
8
dioxane
DMF
20
c
9
À
10
11
12
13
14
15d
16d
17d,f
18d
19d
DCE
30
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
30
60
90
76
(6) For intramolecular examples, see: (a) Ferrer, C.; Echavarren,
A. M. Angew. Chem., Int. Ed. 2006, 45, 1105. (b) Ferrer, C.; Amijs,
C. H. M.; Echavarren, A. M. Chem.;Eur. J. 2007, 13, 1358. (c) Ferrer,
C.; Escribano-Cuesta, A.; Echavarren, A. M. Tetrahedron 2009,
65, 9015. For an intermolecular hydroxyl-directed example, see:(d)
90
73
90
92
90
92 (89)e
68
90
80
66
ꢀ
~ ꢀ
Barluenga, J.; Fernandez, A.; Rodrıguez, F.; Fananas, F. J. J. Organo-
´
met. Chem. 2009, 694, 546.
(7) For an excellent review, see: Kuninobu, Y.; Takai, K. Chem. Rev.
2011, 111, 1938.
90
71
a All reactions were carried out on 0.1 mmol scale in 1 mL of solvent
for 24 h unless otherwise noted. b The conversion of 1a was determined
by 1H NMR of the reaction mixtures. c No conversion was detected.
d 0.5 mL of toluene. e Isolated yield of pure product 3a on 0.5 mmol scale.
f Reaction time: 18 h.
(8) For selected examples, see: (a) Kennedy-Smith, J. J.; Staben, S. T.;
Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526. (b) Hua, R.; Tian, X. J.
Org. Chem. 2004, 69, 5782. (c) Kuninobu, Y.; Kawata, A.; Takai, K.
Org. Lett. 2005, 7, 4823. (d) Kusama, H.; Yamabe, H.; Onizawa, Y.;
Hoshino, T.; Iwasawa, N. Angew. Chem., Int. Ed. 2005, 44, 468. (e)
Chung, L. W.; Lee, H. G.; Lin, Z.; Wu, Y.-D. J. Org. Chem. 2006, 71,
6000. (f) Yudha, S. S.; Kuninobu, Y.; Takai, K. Org. Lett. 2007, 9, 5609.
(g) Takaya, H.; Ito, M.; Murahashi, S.-I. J. Am. Chem. Soc. 2009, 131,
10824. (h) Saito, K.; Onizawa, Y.; Kusama, H.; Iwasawa, N. Chem.;
Eur. J. 2010, 16, 4716. (i) Kuninobu, Y.; Matsuzaki, H.; Nishi, M.;
With the optimized conditions in hand, the scope of the
reaction was investigated with a variety of indoles and
alkynes(Table 2). While N-Hand -acyl indoles affordedno
products, N-alkyl or -benzyl indoles proved to be suitable
substrates for this reaction (entries 1À2). Both electron-
donating and -withdrawing substituents on the indole core
are well tolerated in this protocol (entries 3À7). It is of note
that halogen groups remain intact after the reaction, which
leaves easy handles for further synthetic elaborations
(entries 5À7). It was observedthat many alkyl alkynes with
Takai, K. Org. Lett. 2011, 13, 2959. (j) Dudle, B.; Rajesh, K.; Blacque,
ꢀ
a-Alvarez, J.;
O.; Berke, H. J. Am. Chem. Soc. 2011, 133, 8168. (k) Garcı
´
Dı
´
ez, J.; Gimeno, J.; Seifried, C. M. Chem. Commun. 2011, 47, 6470. (l)
Liu, Q.; Li, Y.-N.; Zhang, H.-H.; Chen, B.; Tung, C.-H.; Wu, L.-Z. J.
Org. Chem. 2011, 76, 1444. (m) Ettedgui, J.; Diskin-Posner, Y.; Weiner,
L.; Neumann, R. J. Am. Chem. Soc. 2011, 133, 188.
(9) For more details, see Supporting Information (SI).
(10) For cyclopropyl alkyne as a radical clock, see: (a) Back, T. G.;
Muralidharan, K. R. J. Org. Chem. 1989, 54, 121. (b) Gottschling, S. E.;
Grant, T. N.; Milnes, K. K.; Jennings, M. C.; Baines, K. M. J. Org.
Chem. 2005, 70, 2686 and references therein.
Org. Lett., Vol. 14, No. 2, 2012
589

of the addition may not be possible (entry 11).10 Remark-
ably, all the reactions of alkylacetylenes with indoles pro-
ceed in a sole anti-Markovnikov fashion. Phenylacetylene
derivatives proved to be more challenging substrates; how-
ever, good to perfect levels of regiocontrol can be obtained
by subtle tuning of the reaction conditions and/or with the
presence of a di-tert-butyl peroxide additive, which pre-
sumablyprovidesweak coordination to the Re centerof the
active catalyst (entries 13À18).9
Table 2. Re-Catalyzed Anti-Markovnikov Addition of Indoles
to Unactivated Terminal Alkynesa
During the survey of reaction parameters for aromatic
alkynes, it occurred to us that the reaction concentration is
very crucial for the site selectivity of the addition.9 Surpris-
ingly, the regioselectivity of the reaction can be greatly
reoriented to the Markovnikov pattern favoring the for-
mation of bisindolylalkane 4 when the reaction was under-
taken simply under neat conditions (Scheme 2). Spe-
cifically, indole 1a reacted with phenylacetylene in the
absence of toluene affording Markovnikov adduct 4m in ex-
cellent yield while no formation of anti-Markovnikov pro-
duct 3m was observed. An array of alkynes bearing electron-
varied and synthetically useful groups, such as methyl,
methoxyl, halo, and ester, is well tolerated under the reaction
conditions (4nÀu). 3-Thienylacetylene, as an example of
heteroaromatic alkyne, is also amenable to this protocol
(4v). Also, indoles containing electron-withdrawing or
-donating substituents also work giving rise to the corre-
sponding Markovnikov adducts (4wÀx). Notably, both the
Markovnikov and anti-Markovnikov additions are pro-
moted by the same Re catalyst, [Re(CO)5Br], which features
a superb regiodiverse selectivity under the slightly different
reaction conditions (e.g., Table 2, 3q vs Scheme 2, 4q).
Scheme 2. Re-Catalyzed Markovnikov Addition of Indoles to
Unactivated Terminal AlkynesaÀc
a Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), Re(CO)5Br
(0.05 mmol), toluene (2.5 mL), 90 °C, 24 h unless otherwise noted.
b Isolated yield of pure products 3. c Determined by 1H NMR of the re-
action mixtures. d No ratio was shown in cases of 3 as the only regioi-
somers observed. e Re(CO)5Br (0.025 mmol). f Reaction on 0.2 mmol
scale. g 2m (2.5 mmol), (t-BuO)2 (0.5 mmol), toluene (7.5 mL). h 2n
(2 mmol), (t-BuO)2 (0.8 mmol), toluene (3.5 mL). i 2o (2 mmol),
(t-BuO)2 (0.5 mmol), toluene (5 mL). j 2p (2 mmol), (t-BuO)2 (1.0 mmol),
toluene (5 mL). k (t-BuO)2 (0.5 mmol), toluene (5 mL). l Toluene (1.5 mL).
a Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), Re(CO)5Br (0.025
mmol), neat, 90 °C, 24 h. bIsolated yield of pure products 4. cOnly
products 4 were observed unless otherwise noted. dToluene (0.1 mL) was
added. eThe ratio of 4w/3w was listed in brackets and determined by 1H
NMR of the reaction mixtures.
linear or cyclic functional groups are amenable to this pro-
tocol leading to 3 in good to excellent yields (entries 8À12).
It is worth pointing out that no ring-opened product was
found when a radical clock type substrate, cyclopropylace-
tylene 2k, was employed, which implies a radical pathway
To probe the reaction mechanism, several insightful
experiments were undertaken. First, 3-styrylindole 5 was
synthesized via Wittig olefinnation and then treated with
590
Org. Lett., Vol. 14, No. 2, 2012

indole 1a under aforementioned conditions (Scheme 3, eq 1).
It was found that 3m was obtained in 74% conversion
implying 3-styrylindole 5 might be the possible reaction
intermediate. Furthermore, no conversion was observed in
the absence of a Re catalyst demonstrating its essential role
in this hydroindolation step. Second, deuterium-labeled
p-chlorophenylacetylene D-2 was employed to react with
1a in order to investigate the possible pathways underlying
the distinct regioselectivity (eq 2). It was shown that
D-atom remains intact in the Markovnikov adduct D-4
(eq 2, right). Incontrast, the incorporation of40% D-atom
on the benzylic carbon of adduct D-3 was found indicating
alternative pathways might operate in the anti-Markovnikov
addition reactions (eq 2, left).9
Scheme 4. A Plausible Mechanism Diagram
obtained through the second Re-catalyzed hydroindolation
process.9
Scheme 3. Investigations on the Reaction Mechanism
In summary, the first general procedure for the intermo-
lecular anti-Markovnikov addition of indoles to unacti-
vated terminal alkynes was successfully developed via Re
catalysis. Furthermore, the site selectivity of the addition
can be readily reversed to the Markovnikov pattern by
subtle tuningof the reaction conditions. Thus, a wide spec-
trum of regioisomeric bisindolylalkanes are expeditiously
synthesized in high yield with excellent selectivity.12 Pre-
liminary mechanistic study showedthat the involvement of
key Re-alkyne complexes or Re-vinylidene intermediates
might account for the observed regiodiverse selectivity.
Further studies on the reaction mechanism and related Re-
catalyzed transformations are underwayin our laboratory.
On the basis of these results, plausible mechanisms are
proposed though the detailed reaction pathways are still
unclear at this stage (Scheme 4). Coordination of Re with
alkyne D-2 affords intermediate I (path a). Under the neat
reaction conditions, direct nucleophilic attack of 1a on the
internal carbon of the CÀC triple bond leads to the
formation of 3-alkenylindole D-5a. Note that the regios-
electivity in this step is frequently observed in other
transition-metal catalyzed hydroindolations of alkynes.5
Subsequently, the second hydroindolation of D-5a pro-
moted by a Re catalyst gives the final Markovnikov pro-
duct D-4. Yet, the 1,2- or 1,3-shift of the D-atom in inter-
mediate I or II respectively might take place preferentially
leading to Re-vinylidene III when the reaction was conducted
under the dilute solution of toluene (path b).11 The nucleo-
philic attack of indole 1a on the carbon R to the Re center of
III followed by protonolysis affords 3-alkenylindole D-5b.
Similarly, the anti-Markovnikov adduct D-3 was eventually
Acknowledgment. Generous financial support from the
National Science Foundation of China (21002103) and
Institute of Chemistry, CAS is gratefully acknowledged.
We also thank Prof. Zhenfeng Xi (Peking University) for
sustained support.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) For selected examples of bisindolylalkanes in natural occurring
compounds and of biological and pharmacological importance, see: (a)
Garbe, T. R.; Kobayashi, M.; Shimizu, N.; Takesue, N.; Ozawa, M.;
Yukawa, H. J. Nat. Prod. 2000, 63, 596. (b) Veluri, R.; Oka, I.; Wagner-
Dobler, I.; Laatsch, H. J. Nat. Prod. 2003, 66, 1520. (c) Bowman, A. L.;
Nikolovska-Coleska, Z.; Zhong, H.; Wang, S.; Carlson, H. A. J. Am.
Chem. Soc. 2007, 129, 12809. (d) Noguchi-Yachide, T.; Tetsuhashi, M.;
Aoyama, H.; Hashimoto, Y. Chem. Pharm. Bull. 2009, 57, 536. (e)
Giannini, G.; Marzi, M.; Marzo, M. D.; Battistuzzi, G.; Pezzi, R.;
Brunetti, T.; Cabri, W.; Vesci, L.; Pisano, C. Bioorg. Med. Chem. Lett.
2009, 19, 2840. (f) Cai, S.-X.; Li, D.-H.; Zhu, T.-J.; Gu, Q.-Q.; Wang,
F.-P.; Xiao, X. Helv. Chim. Acta 2010, 93, 791.
(11) For leading reviews on the catalysis involving metal-vinylidenes,
see: (a) Bruneau, C.; Dixneuf, P. Metal Vinylidenes and Allenylidenes in
Catalysis; Wiley-VCH: Weinheim, Germany, 2008. (b) Trost, B. M.;
McClory, A. Chem.;Asian J. 2008, 3, 164.
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