Rhodium (III)-catalyzed regioselective direct C-2 alkenylation of indoles assisted by the removable N-(2-pyrimidyl) group

Article abstract of DOI:10.1002/adsc.201300700

The C-2-alkenylindole unit is a key component of numerous natural products and pharmacophores. However, the intermolecular direct construction of the core structural motif remains challenging in organic synthesis. Here we report a new, efficient, and versatile methodology for the synthesis of C-2-alkenylindoles through rhodium (III)-catalyzed direct C-H functionalization of indoles with acrylates under air by employing a metal-directing group strategy. This strategy gives a rare selectivity for the alkenylation N-(2-pyrimidyl)indoles at the C-2 position and provides the functionalized C-2- alkenylindoles under mild conditions with broad substrate tolerance. An expansion of the methodology has also been demonstrated to, for example, the direct alkenylation of pyrrole and facile deprotection of the pyrimidyl group. All the results suggest that this methodology could be served as a highly attractive alternative for the direct construction of biologically important C-2-alkenylindoles.

Full text of DOI:10.1002/adsc.201300700

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DOI: 10.1002/adsc.201300700
Rhodium(III)-Catalyzed Regioselective Direct C-2 Alkenylation
U
of Indoles Assisted by the Removable N-(2-Pyrimidyl) Group
Binwei Gong,+a,b Jingjing Shi,+b Xiaowei Wang,a,b Yunnan Yan,b,d Qiu Li,b,c
Yanqiu Meng,a H. Eric Xu,b,e,* and Wei Yib,*
a
College of Pharmaceutical and Biological Engineering, Shenyang University of Chemical Technology, Shenyang 110142,
Peopleꢀs Republic of China
b
VARI/SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research,
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, Peopleꢀs Republic of China
Fax : (+86)-21-2023-1000-1715; e-mail: eric.xu@vai.org or yiwei.simm@simm.ac.cn
Nano Science and Technology Institute, University of Science and Technology of China, Suzhou, Jiangsu 215123, Peopleꢀs
c
Republic of China
d
College of Pharmaceutical Sciences, Gannan Medical University, Ganzhou, Jiangxi 341000, Peopleꢀs Republic of China
Laboratory of Structural Sciences, Program on Structural Biology and Drug Discovery, Van Andel Research Institute,
e
Grand Rapids, Michigan 49503, USA
+
B. G. and J. S. contributed equally to this work.
Received: August 3, 2013; Revised: November 14, 2013; Published online: January 13, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300700.
Abstract: The C-2-alkenylindole unit is a key com-
ponent of numerous natural products and pharma-
cophores. However, the intermolecular direct con-
struction of the core structural motif remains chal-
lenging in organic synthesis. Here we report a new,
efficient, and versatile methodology for the synthe-
building the indole motif has attracted considerable
attention in organic synthesis.[2] As a result, direct ap-
proaches toward their construction have become com-
petitive with more traditional protocols based on sub-
strate preactivation. Indeed, methods involving transi-
tion metal-catalyzed direct functionalization of the
indole nucleus are emerging as attractive alternatives
because they allow for the atom-economical synthesis
sis of C-2-alkenylindoles through rhodium
(III)-cata-
À
lyzed direct C H functionalization of indoles with
acrylates under air by employing a metal-directing
group strategy. This strategy gives a rare selectivity
for the alkenylation N-(2-pyrimidyl)indoles at the
C-2 position and provides the functionalized C-2-
alkenylindoles under mild conditions with broad
substrate tolerance. An expansion of the methodol-
ogy has also been demonstrated to, for example,
the direct alkenylation of pyrrole and facile depro-
tection of the pyrimidyl group. All the results sug-
gest that this methodology could be served as
a highly attractive alternative for the direct con-
struction of biologically important C-2-alkenylin-
doles.
À
of biologically important indoles via C H activation/
cleavage.[3] However, compared with the much more
[4,5]
À
developed C H arylations of indoles,
catalysts that
À
allow the direct C H alkenylation are still limited de-
spite the potential utility of such products.[6,7] A par-
ticularly challenging transformation is the intermolec-
ular direct C-2 alkenylation of indole with acrylates
due to the electrophilic nature of the C-2 position, for
which very few metal-catalyzed protocols that only
used Pd(II) or Ru(II) as the catalyst have been re-
ported (Scheme 1).[8]
Despite these important advances, there is room for
innovation, both in increasing the efficiency of the re-
action and in improving the current limited scope of
the substrates. For example, Gaunt and co-workers re-
ported Pd(II)-catalyzed and solvent-controlled C-3 or
C-2 alkenylation of free NH indoles. However, de-
creased yields were found in the C-2 alkenylation.[8a]
Ricci and co-workers described an efficient Pd(II)-
catalyzed C-2 alkenylation of indoles. However,
Keywords: acrylates; C-2 alkenylation; indoles; N-
(2-pyrimidyl) group; rhodiumACTHNUTRGNE(NUG III) catalysts
Since indole structures are widely found in numerous a non-removable N-(2-pyridylmethyl) group was used
natural products, pharmacophores, and synthetic as the directing group in their catalysis.[8b] Recently
building blocks,[1] the development of methods for Miura and co-workers disclosed a versatile Pd(II)-cat-
Adv. Synth. Catal. 2014, 356, 137 – 143
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
137

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Binwei Gong et al.
[7c,12]
À
À
(CH3)2 NCO
groups for C H bond activation
have attracted particular attention, of which some ver-
satile protocols have stand out. For example, Yoshikai
and co-workers developed cobalt-catalyzed C H
À
functionalization of indoles by using the N-(2-pyri-
midyl) as an easily removable directing group.[5a,7a,11a,b]
Very recently, Kim and co-workers described an effi-
À
cient RhACTHNUTRGNEUG(N III)-catalyzed C H bond activation of in-
doles with allylic acetates to afford C-2-allylated in-
À
À
doles, where the N
the directing group.[12c] Given these successful exam-
ples, we hypothesized that Rh(III) catalysis could be
ACHTUGNTRENUN(GN CH3)2 NCO was employed as
AHCTUNGTRENNUNG
directed toward regioselective C-2 alkenylation of in-
doles with acrylates using such a directing group strat-
egy.
To test this hypothesis, we first selected well known
[Cp*RhCl2]2 as the catalyst, used CuACTHNURTGNE(UNG OAc)2·H2O as
an oxidant, and employed n-butyl acrylate and N-
functionalized indoles bearing various easily attacha-
À
À
À
À
À
À
ble groups [N H, N Me, N Boc, N Ac, N
NCO, N phenylsulfonyl, and N-(2-pyrimidyl)] as the
substrates for reaction development, with the aim to
(CH3)2
À
find a suitable directing group in the RhACTHNUTRGENU(GN III) system.
As shown in Table 1, the reactions of indoles 1a–g
with 2a were examined under [Cp*RhCl2]2 catalysis
(5.0 mol%) with CuACHTNUTRGNE(UGN OAc)2·H2O (1 equiv.) as an oxi-
dant under air. To our delight, when the N-(2-pyri-
midyl) group was employed as the directing group,
the reaction occurred at 808C in DCE and for 5 h to
afford the desired product 3ga in 69% yield (Table 1,
entry 7). Changing DCE to other selected solvents in-
hibited the process (Table 1, entries 8–12). Among
a variety of temperatures, the reaction at 608C was
found to allow the most efficient catalysis with an im-
proved yield of 85% (Table 1, entries 13–15). No
product was obtained in the absence of [Cp*RhCl2]2
or Cu
ACHTUNGTRENNUNG
ing the oxidant from CuAHCTUNTGRENNUNG
AgOAc gave lower conversion (Table 1, entries 18
and 19). In summary, the optimal conditions in DCE
À
Scheme 1. The direct C-2 alkenylation of indoles via C H
functionalization.
comprise [Cp*RhCl2]2 (5.0 mol%) and Cu
(1 equiv.) at 608C for 5 h under air. It is furthermore
alyzed site-selective C-2 alkenylation of indoles. How- noteworthy that the inherently reactive C-3 position
ever, this catalysis needed an additional carboxy of indole was untouched in the Rh(III) catalysis.
With the optimized catalytic system in hand, we
ACHTUNGTERN(NUNG OAc)2·H2O
AHCTUNGTRENNUNG
group at the C-3 position of indoles for blocking this
position.[8c] Therefore it is of utmost importance to subsequently explored its scope in the C-2 alkenyla-
develop a new methodology as an alternative to the tion of diverse N-(2-pyrimidyl)indoles (Table 2). In
existing methods for the efficient construction of bio- general, the reaction proceeded smoothly to give the
logically important C-2-alkenylindoles in synthetic or- desired products in good to excellent yields [48–93%,
ganic chemistry.
except 3ha (25%), the reason for the low yield might
On the other hand, so far transition metal-catalyzed be due to the steric effect] and the electronic nature
À
C H functionalization reactions of various aromatic of the substituents on the indole ring did not play
substrates have been successfully developed by em- a key role. Both electron-rich and electron-poor in-
À
ploying a directing group-assisted C H activation doles were good substrates. Substitutions at the C-3
strategy.[3,10–12] Among various aromatic substrates and (Table 2, entry 2), C-4 (Table 2, entries 3–5), C-5
directing groups, indole units bearing the readily in- (Table 2, entries 6–11), both C-3 and C-5 (Table 2, en-
stallable and removable N-(2-pyrimidyl)[5a,7a,11] or N
tries 12 and 13), and C-6 (Table 2, entries 14-17) posi-
À
138
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RhodiumACHTUNTRGNEU(GN III)-Catalyzed Regioselective Direct C-2 Alkenylation
Table 1. Selected optimization of reaction conditions.[a]
Entry
R
Indole
Temperature [oC]
Solvent
Product
Yield[b]
1
2
3
4
5
6
7
8
H
1a
1b
1c
1d
1e
1f
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
80
80
80
80
80
80
80
80
80
80
80
80
100
60
40
60
60
60
60
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
dioxane
ethanol
DMF
CH3CN
DCE
DCE
DCE
DCE
DCE
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ga
3ga
3ga
3ga
3ga
3ga
3ga
3ga
3ga
3ga
3ga
3ga
0
0
0
0
Me
Boc
Ac
A
0
phenylsulfonyl
2-pyrimidyl
2-pyrimidyl
2-pyrimidyl
2-pyrimidyl
2-pyrimidyl
2-pyrimidyl
2-pyrimidyl
2-pyrimidyl
2-pyrimidyl
2-pyrimidyl
2-pyrimidyl
2-pyrimidyl
2-pyrimidyl
15%
69%
50%
43%
37%
57%
45%
48%
85%
52%
0
9
10
11
12
13
14
15
16[c]
17[d]
18[e]
19[f]
0
DCE
DCE
8%
39%
[a]
Reaction conditions: 1a–g (0.25 mmol), 2a (0.30 mmol), [Cp*RhCl2]2 (5.0 mol%), and Cu
vent (1.0 mL) under air for 5 h.
Isolated yields.
ACHTUGNRTEN(NUGN OAc)2·H2O (0.25 mmol), in sol-
[b]
[c]
[d]
[e]
[f]
The reaction was carried out in the absence of [Cp*RhCl2]2.
The reaction was carried out in the absence of Cu
Using Ag2CO3 as the oxidant.
ACHTUNGTERN(NUNG OAc)2·H2O.
Using AgOAc as the oxidant.
tions were all well tolerated. Furthermore, the reac- ly. This result further illustrates the remarkable ro-
tion showed good compatibility with many valuable bustness of our Rh(III) system.
functional groups such as methoxy, fluoro, chloro, Encouraged by the above results, we were interest-
AHCTUNGTRENNUNG
bromo, iodo, ester, cyano, and nitro substituents (3ia– ed in expanding the versatility of the N-(2-pyrimidyl)
ta and 3va–wa). Tolerance to the fluoro (3ma and group in the alkenylation of other nitrogen heterocy-
3va), chloro (3ka, 3na and 3wa), bromo (3ra), iodo cles such as pyrroles, which rival indoles in biological
(3sa), and ester (3qa–sa) functional groups is especial- significance and as valuable synthons.[13] Thus, the re-
ly noteworthy since they are useful for subsequent action was investigated using N-(2-pyrimidyl)pyrrole
cross-coupling reactions.
1y and n-butyl acrylate 2a as the model substrates
We also tested several alkyl acrylates with 1g as with different times at varied temperatures (Table 3).
a model substrate. As shown in Scheme 2, methyl ac- Very interestingly, the reaction for 1 h in the devel-
rylate (2b) coupled efficiently with 1g to give the cor- oped RhACTHNUGRTENUNG(III) catalysis occurred to give the C-2 mono-
responding C-2 alkenylation product 3gb with excel- alkenylation product 3ya-a and the C-2,C-5 dialkeny-
lent regioselectivity and in synthetically useful yield lation product 3ya-b in 21% and 16% yields, respec-
(89%). Interestingly, very recently Lanke and Prabhu tively (Table 3, entry 1). Notably, prolonging the reac-
reported that N-benzoylindoles reacted with tert-butyl tion time resulted in an enhancement of the yield of
acrylate (2c) in their Ru(II) catalysis to furnish the 3ya-b from 16% to 39% accompanied by a decrease
tert-butyl-deprotected C-2-acrylic acid indole products in the yield of 3ya-a from 21% to traces (Table 3, en-
in moderate yields (52%–62%).[8f] However, in the tries 1 vs. 2 vs. 3). Inspired by the results, we decided
developed RhACHTUNGTRENNUNG(III) catalysis, the reaction of 1g with 2c to increase the stoichiometry of n-butyl acrylate to
offered the desired product 3gc in a good yield 3.0 equivalents in the reaction. As expected, the reac-
(76%), where the tert-butyl part was retained perfect- tion resulted in the regioselective formation of C-2,C-
5 dialkenylated 3ya-b as the sole product in a syntheti-
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Binwei Gong et al.
Table 2. Scope of of the reaction of functionalized indoles with 2a.[a]
Entry
Indole
R1 (C-3)
R2 (C-4)
R3 (C-5)
R4 (C-6)
Yield[b]
1
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
1t
1u
1v
1w
H
CH3
H
H
H
H
H
H
H
H
H
Br
I
H
H
OCH3
CN
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
F
Cl
CN
NO2
COOMe
COOMe
H
H
H
H
H
H
H
H
H
H
H
H
85%
25%
79%
72%
51%
65%
81%
67%
62%
79%
93%
58%
60%
78%
48%
75%
63%
2[c]
3
4
5
6
7
8
9
10
11
12[d]
13[d]
14
15
16
17
COOMe
H
H
H
H
H
H
H
H
H
OCH3
CH3
F
Cl
[a]
The reaction was carried out using 1g–w (0.25 mmol), 2 (0.30 mmol), [Cp*RhCl2]2 (5.0 mol%), and CuACHTUNGTRENNUNG
(0.25 mmol) under air at 608C for 5 h.
Isolated yields.
The reaction time was 12 h.
The reaction time was 72 h.
[b]
[c]
[d]
cally useful yield of 75% (Table 3, entry 4). No reac-
tion was observed at room temperature under other-
wise identical conditions (Table 3, entry 5).
Considering the remarkably broad substrate scope
displayed by the RhACTHUNGTRENNG(U III) catalysis, we performed
mechanistic studies to delineate its mode of action
(Scheme 3). To this end, the competition experiments
between differently substituted indoles indicated that
electron-rich indoles were preferentially converted,
suggesting they were better substrates than electron-
poor indoles.
Due to its importance for further functionalization
of the indole moiety, we attempted to deprotect the
pyrimidyl group. As illustrated in Scheme 4, the de-
protection was easily achieved by heating 3ga with
EtONa in DMSO for 2 h to provide free-NH indole
derivative 4 as the final product in good yield
(86%).[14] The obtained product is a very useful syn-
thon, which can be transformed into a variety of natu-
ral products and pharmacophores such as Trp-P-2[15]
and potent anti-inflammatory drug MK-7246,[16] re-
spectively. Furthermore, C-2 alkenylation and then
deprotection reactions could be performed on a 5.0-
Scheme 2. Scope of the reaction between indole 1g and
acrylic esters 2a–c.[a]
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RhodiumACHTUNTRGNEU(GN III)-Catalyzed Regioselective Direct C-2 Alkenylation
À
Table 3. C H Alkenylation of N-(2-pyrimidyl)pyrrole.
Entry
Temperature [oC]
Time [h]
Yield of 3ya-a[b]
Yield of 3ya-b[b]
1
2
60
60
60
60
r.t.
1
2
5
5
5
21%
11%
trace
0
16%
29%
39%
75%
0
3
4[c]
5
0
[a]
Reaction conditions: 1y (0.25 mmol), 2a (0.30 mmol), [Cp*RhCl2]2 (5.0 mol%), and CuACHTNUTRGNE(NUG OAc)2·H2O (0.25 mmol), in DCE
(1.0 mL) under air.
Isolated yields.
3.0 equiv. of 2a (0.75 mmol) were used in the reaction.
[b]
[c]
Scheme 3. Competition experiment.
mmol scale without any significant decrease in the
corresponding product yield.[17]
Scheme 4. Deprotection and hydrolysis.
In conclusion, a mild, versatile, and highly efficient
Rh
ACHTUNGTRENNUNG(III)-catalyzed C-2 alkenylation strategy for in-
doles has been demonstrated. This protocol strongly
relies on the use of the easily attachable pyrimidyl logically important C-2-alkenylindole unit. Further-
group as the metal-directing group. To the best of our more, the deprotection of the metal-directing pyri-
knowledge, this is the first report of such an Rh
catalyzed direct C-2 alkenylation of N-(2-pyrimidyl)- results in the C-2 acrylic acid-substituted free-NH
indoles with alkyl acrylates. The remarkable features indole, a valuable synthon for many important natural
of this methodology including good product yields, products and pharmacophore syntheses. The method
wide tolerance of various functional groups, and ex- reported here deepens the understanding of Rh(III)-
ACHTUNGTREN(NUNG III)- midyl group is very simple and straightforward, which
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
cellent regio-/site-specificities, thus render this meth- mediated catalytic behavior and will promote future
odology as a highly versatile and atom-economical al- applications in the synthesis of more biologically im-
ternative to the existing methods for building the bio- portant indole derivatives.
Adv. Synth. Catal. 2014, 356, 137 – 143
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Binwei Gong et al.
Chem. Eur. J. 2011, 17, 12706; c) D. Nandi, Y. M. Jhou,
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Experimental Section
À
General Procedure for C H Activation Reaction
The mixture of [Cp*RhCl2]2 (7.8 mg, 0.0125 mmol,
0.05 equiv.), CuACHTUNGTRENNUNG(OAc)2·H2O (50 mg, 0.25 mmol, 1.0 equiv.),
substrate A (0.25 mmol, 1.0 equiv.), substrate B (0.30 mmol,
1.2 equiv.) and DCE (1 mL) was stirred at 608C for 5 h
under air. The resulting mixture was cooled to room temper-
ature and subjected to silica gel column chromatography di-
rectly to give the desired product.
[6] For selected examples on the C-3 alkenylation of in-
doles, see: a) T. Itara, K. Kawasaki, F. Ouseto, Synthe-
sis 1984, 236; b) Y. Yokoyama, T. Matsumoto, Y. Mura-
kami, J. Org. Chem. 1995, 60, 1486; c) Y. Nakao, K. S.
Kanyiva, S. Oda, T. Hiyama, J. Am. Chem. Soc. 2006,
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[7] For selected examples on the C-2 alkenylation of in-
doles with alkynes, see: a) Z. Ding, N. Yoshikai,
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Acknowledgements
The authors thank the Jay and Betty Van Andel Foundation,
Amway (China) and the Chinese Postdoctoral Science Foun-
dation (2012MM511158 and 2013T60477) for financial sup-
port of this study.
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[12] For selected examples on metal-catalyzed C H func-
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