Regio- and stereoselective direct N-alkenylation of indoles via Pd-catalyzed aerobic oxidation

Article abstract of DOI:10.1021/ol402503z

With two different sets of Pd catalyst systems in hand, indoles, whether bearing a C3-substituent or not, can be directly alkenylated on their nitrogen atoms using a sterically and electronically diverse array of alkenes, in which the high regio- and stereoselectivity are dependent on the nature of the alkenes used. This process proceeds in generally good yields and is compatible with a broad range of functional groups.

Full text of DOI:10.1021/ol402503z

ORGANIC
LETTERS
2013
Vol. 15, No. 20
5278–5281
Regio- and Stereoselective Direct
N‑Alkenylation of Indoles via
Pd-Catalyzed Aerobic Oxidation
Ge Wu and Weiping Su*
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the
Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350002, China
wpsu@fjirsm.ac.cn
Received August 31, 2013
ABSTRACT
With two different sets of Pd catalyst systems in hand, indoles, whether bearing a C3-substituent or not, can be directly alkenylated on their
nitrogen atoms using a sterically and electronically diverse array of alkenes, in which the high regio- and stereoselectivity are dependent on the
nature of the alkenes used. This process proceeds in generally good yields and is compatible with a broad range of functional groups.
The rapid progress in the metal-catalyzed oxidative
cross-coupling (e.g., CÀH functionalization) has allowed
chemists to consider straightforward constructions of
CÀC and CÀX (X = heteroatoms) bonds from inexpen-
siveand readily available substrates, opening a newdoor to
the ideal chemical synthesis.1 When the substrates have
more than one possible reaction site, however, control of
the selectivity in these transformations remains the impor-
tant but challenging issue. Thus, an effective strategy to
address the selective issue in the metal-catalyzed oxidative
cross-coupling is a highly attractive goal for the advance-
ment of chemical synthesis.
of useful methods have been developed for the selective
CÀH functionalization of indoles, such as CÀH arylation,3
alkenylation,4 cyanation,5 amination,6 trifluoromethylation,7
carbonylation,8 and alkylation.9 Although most of these
reported methods employed N-substituted indoles as starting
materials to achieve the direct functionalization of CÀH
bonds on either the C-2 or C-3 position of indoles, a few of
these methods enabled free NÀH indoles to undergo selective
(3) For arylation of indole using Pd(II) catalysis: (a) Stuart, D. R.;
Fagnou, K. Science 2007, 316, 1172. (b) Yang, S.-D.; Sun, C.-L.; Fang,
Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1473.
€
(c) Kirchberg, S.; Frohlich, R.; Studer, A. Angew. Chem., Int. Ed. 2009,
48, 4235. (d) Potavathri, S.; Pereira, K. C.; Gorelsky, S. I.; Pike, A.;
LeBris, A. P.; DeBoef, B. J. Am. Chem. Soc. 2010, 132, 14676.
(4) For olefination of indole using Pd(II) catalysis: (a) Jia, C.; Lu, W.;
Kitamura, T.; Fujiwara, Y. Org. Lett. 1999, 1, 2097. (b) Abbiati, G.;
Beccalli, E. M.; Broggini, G.; Zoni, C. J. Org. Chem. 2003, 68, 7625. (c)
Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew.
Chem., Int. Ed. 2005, 44, 3125. (d) Chen, W.-L.; Gao, Y.-R.; Mao, S.;
Zhang, Y.-L.; Wang, Y.-F.; Wang, Y.-Q. Org. Lett. 2012, 14, 5920.
(5) For cyanation of indole using Pd(II) catalysis: (a) Yan, G.;
Kuang, C.; Zhang, Y.; Wang, J. Org. Lett. 2010, 12, 1052. (b) Ding,
S.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374. (c) Ren, X.; Chen, J.;
Chen, F.; Cheng, J. Chem. Commun. 2011, 47, 6725. (d) Reddy, B. V. S.;
Begum, Z.; Reddy, Y. J.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 3334.
(6) For amination of indole using Pd(II) catalysis: Liu, X.-Y.; Gao,
P.; Shen, Y.-W.; Liang, Y.-M. Org. Lett. 2011, 13, 4196.
The prevalence of indoles in natural products and
bioactive compounds has prompted the development of
indole chemistry.2 Recently, by using Pd catalysts, a number
(1) For selective reviews: (a) Kakiuchi, F.; Chatani, N. Adv. Synth.
Catal. 2003, 345, 1077. (b) Sigman, M. S.; Schultz, M. J. Org. Biomol.
Chem. 2004, 2, 2551. (c) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43,
3400. (d) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200. (e) Li, B.-J.;
Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949. (f) Chen, X.; Engle, K. M.;
Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (g) Lyons,
T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (h) Liu, C.; Zhang, H.;
Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780. (i) Cho, S. H.; Kim, J. Y.;
Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (k) Yeung, C. S.;
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Chen, S.; Zhen, X.; Liu, G. Chem.;Eur. J. 2011, 17, 6039.
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Chem., Int. Ed. 2009, 48, 9608. (b) Cacchi, S.; Fabrizi, G. Chem. Rev.
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Liu, D.; Chen, C.; Liu, C.; Lei, A. Chem.;Eur. J. 2011, 17, 9581. (b)
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r
10.1021/ol402503z
Published on Web 10/10/2013
2013 American Chemical Society

CÀH functionalization.4,8,9 In contrast to the significant
advance in the CÀH functionalization of indoles, only one
example of the metal-catalyzed oxidative cross-coupling
for the N-functionalization of indoles has been reported to
date (Scheme 1a).10 Recently, in the mechanistic studies on
the norbornene-mediated 2-alkylation of free NÀH indoles,
the reaction of stoichiometric Pd(OAc)2 with free NÀH
indole and norbornene was observed to proceed via amino-
palladation of norbornene to form a palladacycle complex.9b
Herein, we report that the N-alkenylation of free NÀH
indoles can be achieved by Pd-catalyzed oxidative cross-
coupling between indoles and alkenes using readily available
dioxygen as an oxidant (Scheme 1b).11 The N-alkenylated
indoles are ubiquitous structural motifs in numerous natural
products and small molecule pharmaceuticals,12 and versatile
synthetic intermediates.13 In fact, the conventional methods
for the syntheses of N-alkenylated indoles, such as the
addition to alkynes14 and the cross-coupling between indoles
and vinyl(pseudo)halides,15 usually require prefunctionalized
starting materials, strong bases, and inconvenient separation
of a mixture of E and Z isomers, thereby adding to the cost
and reducing the scope of substrates.
Scheme 1. Pd-Catalyzed Oxidative Cross-Coupling Reactions
of Indoles with Alkenes
Nevertheless, our target reaction is quite different from the
oxidative coupling of alkenes with amides, in which free
NÀH indoles have several accessible reaction positions. To
obtain a high level of regioselectivity, the catalyst system
for the direct N-alkenylation of indoles must suppress the
indole CÀH alkenylation. In the Pd-catalyzed CÀH ake-
nylation reactions of free NÀH indoles, carboxylic acids are
essential for a high level of efficiency for the following
reasons: (1) carboxylic acids are helpful for generating more
electrophilic Pd species by facilitating dissociation of an
anionic ligand from a Pd precatalyst;17 (2) carboxylic acids
can retard the activation of NÀH via formation of a
hydrogen bond between the NÀH moiety and carboxylic
acid. Therefore, we reasoned that the direct N-alkenylation
of indoles would take place in the absence of Brønsted acids.
Guidedby theabovehypothesis, wescreeneda variety of
reaction parameters to optimize reaction conditions using
the reaction of methyl indole-3-carboxylate (1a) with
styrene (2a) as a model system (Table 1). 1a was chosen
as a representative substrate in the model reaction to
preclude the complication arising from the reaction on
the C3 position of indole. Three critical reaction param-
eters have a remarkable effect on the reaction outcomes.
First, a weak base was necessary for the model reaction to
occur probably because bases were required to abstract
the proton from indole NÀH and therefore trigger the
reaction.18 The effect of bases on the reaction was also
observed to depend on the amounts of bases and their
counter cations (entries 7, 8). The best result was obtained
when 10 mol % LiOAc was used (entry 3). Second, when
the reaction was carried out in polar solvents such as
DMF, DMSO, the starting material was not completely
converted; this may be due to their strong coordination to
prevent palladium from interacting with indole and styr-
ene. Although apolar toluene resulted in partial decomposi-
tion to generate a partial unidentifiable product, we were
pleased to find that using weak coordinating DME as the
solvent gave a satisfactory 82% yield. Finally, a catalytic
amount of CuCl2 (5 mol %) as a cocatalyst significantly
improve the yield of the cross-coupling reaction of 1a with
A series of elegant studies on the oxidative coupling of
alkenes with amides16 provided useful starting points for
our investigation of the direct N-alkenylation of indoles.
(9) For alkylation of indole using Pd(II) catalysis: (a) Jiao, L.; Bach,
T. J. Am. Chem. Soc. 2011, 133, 12990. (b) Jiao, L.; Herdtweck, E.; Bach,
T. J. Am. Chem. Soc. 2011, 134, 14563. (c) Broggini, G.; Barbera, V.;
Beccalli, E. M.; Borsini, E.; Galli, S.; Lanza, G.; Zecchi, G. Adv. Synth.
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C. A.; Baran, P. S. Angew. Chem., Int. Ed. 2009, 48, 7025.
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Pd reviews: Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012,
41, 3381. (b) Wu, W.; Jiang, H. Acc. Chem. Res. 2012, 45, 1736. Select
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Soc. 2003, 125, 9578. (d) Mei, T.-S.; Werner, E. W.; Burckle, A. J.;
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(b) Verma, A. K.; Kesharwani, T.; Singh, J.; Tandon, V.; Larock, R. C.
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Chem.;Eur. J. 2012, 18, 5180.
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Org. Lett., Vol. 15, No. 20, 2013
5279

Table 1. Reaction Optimizationa
Scheme 2. Scope of Alkenes in the Direct N-Alkenylation of
Indolea
entry
solvent
base
yield (%)b
1
DMF
LiOAc
LiOAc
LiOAc
none
30
0
2
DMSO
DME
DME
dioxane
toluene
DME
DME
DME
DME
DME
DME
3
89(82)c
0
4
5
LiOAc
LiOAc
NaOAc
KOAc
LiOAc
LiOAc
LiOAc
LiOAc
43
40
23
4
6
7
8
9d
10e
11f
12g
12
9
77
13
a Reaction conditions: a mixture of methyl indole-3-carboxylate
(0.4 mmol), styrene (3 equiv), Pd(CH3CN)2Cl2 (5 mol %), CuCl2
(5 mol %), and base (10 mol %) in solvent (2 mL) at 70 °C for 7 h under
1 atm of O2. b Yield determined with GC by using dodecane as an
internal standard. c Yield of isolated product. d In the absence of CuCl2.
e Benzoquinone (1.0 equiv) was used instead of CuCl2. f Cu(OAc)2
(5 mol %) was used instead of CuCl2. g Under N2.
a Reaction conditions: a mixture of methyl indole-3-carboxylate (0.4
mmol), alkenes (3 equiv), Pd(CH3CN)2Cl2 (5 mol %), CuCl2 (5 mol %),
and LiOAc (10 mol %) in DME (2 mL) at 70 °C for 7 h under 1 atm of O2;
isolated yields. b The ratio of isomers was determined by 1H NMR spectros-
copy; ratio in parentheses is isomer shown/all other observed isomers.
c Reaction conditions: a mixture of methyl indole-3-carboxylate (0.4 mmol),
methyl acrylate (3 equiv), Pd(TFA)2 (5 mol %), Cu(OAc)2 (5 mol %), in
toluene (2 mL) at 100 °C for 24 h under 1 atm of O2; isolated yields.
2a (entry 3 vs 9). A control experiment showed that the
cross-coupling failed completely when the reaction was
carried out in the absence of a Pd catalyst.
Under the optimized reaction conditions, a sterically and
electronically diverse array of alkenes (Scheme 2) could be
used for the direct N-alkenylation of indoles. Styrenes bearing
a variety of substituents, as well as 2-vinylnaphthalene, were
observed to afford exclusively 1,1-disubstituted products
(Markovnikov-type adducts) in good-to-excellent yields
(3aÀ3i). The regioselectivity was also observed in the reaction
of indole with unactivated vinyl cyclohexane (3j). We rea-
soned that the regioselectivity for Markovnikov-type adducts
could result from the stability of the partial positive charge on
the benzylic carbon that was produced in the aminopallada-
tion of the double bond. Cyclic alkenes were suitable sub-
strates in this reaction to afford the regular product as well as
olefin isomerizations (3k and 3l). Interestingly, allylic ethers
afforded Z-configuration products (anti-Markovnikov-type
adducts) with exclusive selectivity (3oÀ3t). However, when
moving oxo-functionality away from the allylic position in
ethers, the selectivity for Z-configuration products decreased
rapidly (3u). A proposal was made to rationalize the high
selectivity in the reactions of allylic ethers (Scheme 3). The
oxygen atom of the allylic ether coordinates to Pd center and
undergoes cis-aminopalladation19 to form the CÀN bond
on the terminal position of the alkene and then β-H
Scheme 3. Possible Reaction Pathway for the N-Alkenylation of
Indole with Allylic Ether
elimination to generate the stereoselective Z-configuration
product. In the case of electron-deficient methyl acrylate, the
standard conditions did not work well. However, by using
Pd(TFA)2 (5 mol %)/Cu(OAc)2 (5 mol %) as a combina-
tion catalyst and toluene as the solvent, the reaction of
electron-deficient acylates occurred in the absence of base
to form E-configuration products (3m and 3n), presumably
because alkenes are able to bind to the Pd center for
activation under the modified reaction conditions.
The substituent effects of 3-substitued indoles on the
reaction were also examined using 4-methylstyrene as a
coupling partner (Scheme 4). Similar to the methyl carbox-
ylate group, a variety of electron-withdrawing substituents
on the 3-position of indoles, such as formyl (4eÀ4j), acyl
(4a, 4b), and cyano (4c) groups, provided good yields. An
array of substituents on the benzene ring of indoles, such as
(19) (a) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328. (b)
Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179. (c) Ney, J. E.;
Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 8644. (d) Nakhla, J. S.; Kampf,
J. W.; Wolfe, J. P. J. Am. Chem. Soc. 2006, 128, 2893. (e) Ye, X.; Liu, G.;
Popp, B. V.; Stahl, S. S. J. Org. Chem. 2011, 1031.
5280
Org. Lett., Vol. 15, No. 20, 2013

Scheme 4. Scope of 3-Substituted Indoles in the Direct
N-Alkenylation of Indolea
Scheme 5. Scope of Simple Indolesa
a Reaction conditions: a mixture of indole (0.4 mmol), styrene
(5 equiv), Pd(TFA)2 (5 mol %), 3-nitropyridine (10 mol %), BQ
(20 mol %), and MgCO3 (4.0 equiv) in toluene (2 mL) was stirred under
1 atm of O2 at 100 °C for 24 h; isolated yields.
Gratifyingly, the N-alkenylation of unsubstituted free NÀH
indole could be achieved in 52% yield (Scheme 5, 5a) along
with oxidative decomposition of some of the product,20
when the reaction of indole with 5 equiv of 4-methylstyrene
was conducted in toluene (2 mL) at 100 °Cunder1atmofO2
using Pd(TFA)2 (5 mol %)/3-nitropyridine (10 mol %)3a/
1,4-benzoquinone (20 mol %)21 as a catalyst system and
insoluble MgCO3 as a base. As shown in Scheme 5, a variety
of indoles lacking the 3-substituent could undergo the N-al-
kenylation with good selectivity in reasonable yields. Some
functional substituents such as F, Cl, CHO, NO2, and
CO2Me were compatible under current conditions. Unfortu-
nately, the presence of the electron-donating 5-OMe group
reduced the yield (<20%), suggesting that the 5-OMe group
made the parental pyrrole moiety more nucleophilic and
therefore impeded the interaction of palladium with styrene.
It is noteworthy that the alkenylation occurred exclusively at
the N-position of the indoles without any side product from
C2, or C3-alkenylation of indole.
In conclusion, two different sets of protocols have been
developed for the direct N-alkenylations of indoles bearing
or lacking 3-substituents with alkenes. These two protocols
complement each other to cover a broad range of substrate
scope for both of the coupling partners, and allow this aerobic
oxidative cross-coupling to proceed with excellent selectivity
in generally good yields. The ongoing work is to investigate
the origins of regioselectivity of indoles and alkene-dependent
stereoselectivity in this oxidative cross-coupling reaction.
a Reaction conditions: indole (0.4 mmol), styrene (3 equiv), Pd-
(CH3CN)2Cl2 (5 mol %), CuCl2 (5 mol %), and LiOAc (10 mol %) in
DME (2 mL) at 70 °C for 7 h under O2; isolated yields.
methyl (4e), fluoride (4f), chloride (4g), bromide (4h), and
methoxyl (4i, 4j), were observed to have little influence on the
reactivity and selectivity of the N-alkenylation. Carbazoles,
which could undergo Pd-catalyzed oxidative cross-coupling
with alkenes in the presence of a Ag salt as an oxidant,16l
proved to be suitable substrates under our standard condi-
tions (4k). When the introduction of a methyl group occupied
the C-2 position, no expected product was detected (4m).
However, when deuterium was put into the C-2 position,
ssswe obtained the deuterium fully incorporated product
(4n). To investigate whether N-alkenylation of functionalized
pyrroles could occur, pyrrole-2-carboxaldehyde, pyrrole-2-
trifluoroacetyl, methyl pyrrole-2-carboxylate, and pyrrole-2-
carbontrile were subjected to the optimized reaction condi-
tions, but this results in only slight decomposition of the
starting material without the desired products.
When expanding the substrate scope to indoles lacking a
3-substituent, we found that the standard reaction condi-
tions did not afford the desired N-alkenylation products,
instead leading to decomposition of these indoles. Con-
sidering that the reaction conditions established above for
electron-deficient methyl acrylate avoided competition for
binding to the Pd center between methyl acrylate and other
components by using noncoordinating toluene and remov-
ing the base from the reaction system, we reasoned that
these indoles had a stronger ability to coordinate to Pd
than the indole bearing electron-withdrawing groups on
C3, impeding coordination of alkenes to the Pd center.
Acknowledgment. Financial support from the 973 Pro-
gram (2011CB932404, 2001CBA00501), NSFC (20925102,
21202164), and National Key Technology R & D Program
(2012 BAE 06B08) is greatly appreciated.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) When the 5a product under the standard conditions was stirred
for 24 h at 100 °C, the product decomposition was 32%.
(21) BQ is a well-known oxidant and electron carrier in the Pd-
catalyzed oxidation reactions; for selective examples: (a) Piera, J.;
€
Backvall, J.-E. Angew. Chem., Int. Ed. 2008, 47, 3506. (b) Fraunhoffer,
K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129, 7274.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 20, 2013
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