Rhodium(iii)-catalyzed C2-selective carbenoid functionalization and subsequent C7-alkenylation of indoles

Article abstract of DOI:10.1039/c4cc01593b

Here a new, mild and versatile method for efficient synthesis of a diverse range of 2-acetate substituted indoles via Rh(iii)-catalyzed and alcohol-mediated C2-selective carbenoid insertion functionalization of indoles by α-diazotized Meldrum's acid has been developed. Furthermore, for the first time, a Rh(iii)/Cu(ii)-catalyzed direct C7-alkenylation of such functionalized products has also been demonstrated. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01593b

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Rhodium(III)-catalyzed C2-selective carbenoid
functionalization and subsequent C7-alkenylation
of indoles†
Cite this: Chem. Commun., 2014,
50, 6483
Received 3rd March 2014,
Accepted 30th March 2014
Jingjing Shi,a Yunnan Yan,ab Qiu Li,a H. Eric Xu*ac and Wei Yi*a
DOI: 10.1039/c4cc01593b
www.rsc.org/chemcomm
Here a new, mild and versatile method for efficient synthesis of a diverse these approaches require pre-functionalized acetates as substrates,
range of 2-acetate substituted indoles via Rh(III)-catalyzed and alcohol- which result in formation of stoichiometric amounts of salt waste as
mediated C2-selective carbenoid insertion functionalization of indoles byproducts. Moreover, the lower yield and/or poor regioselectivity were
by a-diazotized Meldrum’s acid has been developed. Furthermore, for also found in their catalysis. In 2010, Kerr and co-workers also
the first time, a Rh(III)/Cu(II)-catalyzed direct C7-alkenylation of such developed the Cu(II)-catalyzed direct C2-functionalization of indoles
functionalized products has also been demonstrated.
for synthesizing this type of molecule. However, this catalysis needed
an additional substituent at the C3-position of indoles for blocking
Indoles are commonly occurring structural motifs found in numerous this position.7d Therefore, the development of new strategies for
natural products, pharmaceuticals, and biologically active com- efficient construction of valuable 2-acetate substituted indoles is still
pounds, which are very attractive synthetic targets for synthetic highly desirable.
medicinal chemists.1 Driven by their potential biological application,
In recent years, the acceptor–acceptor substituted diazo com-
developing mild and highly efficient methods for the synthesis of pounds, in particular those derived from malonates or b-ketoesters,
functionalized indoles has attracted considerable attention in modern have been widely used as powerful cross-coupling partners for direct
organic chemistry.2 Among these, transition-metal-catalyzed C–H C–H functionalization in transition-metal-catalyzed reactions,8 of
functionalization has in recent years emerged as one of the most which Rh complexes have occupied a prevalent position. However,
powerful tools for preparing organic building blocks in a step- and the Rh(III)-catalyzed insertion of carbenoids into C(sp2)–H bonds of
atom-economical fashion.3 Since the pioneering work by the research heterocycles, especially for the C2–H bonds of indole cores, is still
groups of Lewis,4a Murai4b and Fujiwara,4c significant progress has underexplored, and thus, such a useful coupling is worth further
been made in this hot area of research. Nevertheless, compared with development.
C3–H functionalization,5 the methods that allow for C2–H functiona-
Motivated by this and our continuing interest in developing
lization of indole are still limited due to the weak reactivity of the C–H Rh(III)-catalyzed C–H bond functionalizations,6e,g,9 in this com-
bond at the C-2 position of indole.6 A particular challenge is the direct munication, we report for the first time a Rh(III)-catalyzed and
regioselective C2-alkylation for the synthesis of 2-acetate substituted alcohol-mediated C2-selective carbenoid insertion functionalization
indoles despite the potential utility of such products, for which very of indoles by a-diazotized Meldrum’s acid and subsequent
few metal-catalyzed protocols have been reported.7 For example, decarboxylation to give access to 2-acetate substituted indoles
Baciocchi,7a Ricciardi7b and Heaney7c have independently reported (eqn (1)). Additionally, we also demonstrated the first example of
the C2-alkylation for building 2-acetate substituted indoles. However, direct C7-alkenylation of such functionalized indole products in
this classical Rh(III)/Cu(II) catalysis.6g,9
a 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, P.R. China.
E-mail: yiwei.simm@simm.ac.cn, eric.xu@simm.ac.cn;
Fax: +86-21-20231000-1715; Tel: +86-21-20231000-1715
b College of Pharmaceutical Sciences, Gannan Medical University, Ganzhou,
(1)
Jiangxi 341000, P.R. China
c Laboratory of Structural Sciences, Program on Structural Biology and Drug
At the outset, we examined this Rh(III)-catalyzed carbenoid
Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
insertion reaction in EtOH at 80 1C for 15 h employing [Cp*Rh-
(MeCN)3](SbF6)2 as the catalyst and using indole 1a bearing a
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc01593b
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Table 1 Selected optimization of reaction conditionsa
Entry
R
Catalyst system (mol%)
T (1C) Yieldb (%)
1
2
3
2-Pyrimidyl [Cp*Rh(MeCN)3](SbF6)2 (5)
(CH3)2NCO [Cp*Rh(MeCN)3](SbF6)2 (5)
80
80
80
89
0
0
H
[Cp*Rh(MeCN)3](SbF6)2 (5)
4
5
2-Pyrimidyl [Cp*RhCl2]2 (5) + AgSbF6 (40) 80
52
0
2-Pyrimidyl
—
80
6
2-Pyrimidyl [Cp*Rh(MeCN)3](SbF6)2 (5)
2-Pyrimidyl [Cp*Rh(MeCN)3](SbF6)2 (2)
2-Pyrimidyl [Cp*Rh(MeCN)3](SbF6)2 (5)
2-Pyrimidyl [Cp*Rh(MeCN)3](SbF6)2 (5)
R.T.
80
80
0
7
56
87
85
8c
9d
80
a
Reaction conditions: 1 (0.12 mmol, 1.2 eq.), 2 (0.1 mmol, 1.0 eq.), Rh
b
catalyst (X mol%), EtOH (0.5 mL), 15 h, under air. Isolated yields.
c
d
H2O (0.2 mmol, 2.0 eq.) was added. Performed on a 5.0 mmol scale.
Scheme 1 Scope of indoles. a The reaction was carried out using 1a–o
(0.12 mmol), 2 (0.10 mmol), Rh(III) catalyst (5.0 mol%), and EtOH (0.5 mL)
under air at 80 1C for 15 h. Isolated yields. b Performed on a 1.0 mmol scale.
readily removable N-2-pyrimidyl group as the model substrate, which
had been a success story in our recent studies.6e,g To our delight, the
anticipated product 3a was cleanly obtained as the sole coupling
product in 89% isolated yield with excellent regioselectivity (Table 1,
entry 1). The brief directing group (DG) screening showed that the
N-2-pyrimidyl moiety is an ideal metal-directing group (Table 1,
entries 1–3), which is in good agreement with the previous investi-
gations.2c,6d,10 Changing the catalyst [Cp*Rh(MeCN)3](SbF6)2 to
another well known catalyst [Cp*RhCl2]2 obviously inhibited the
process (Table 1, entry 4). No desired product was formed in the
absence of catalyst (Table 1, entry 5) or at room temperature (Table 1,
entry 6). It is notable that the amount of the catalyst was critical to
the catalytic activity, as the reduction of the amount of catalyst led to
a significant decrease in the product yield (Table 1, entry 7). In
summary, the optimal conditions in EtOH were [Cp*Rh(MeCN)3]-
(SbF6)2 (5.0 mol%) at 80 1C for 15 h under air. Finally, we were
pleased to find that the reaction was compatible with water (Table 1,
entry 8) and could also be performed on a 5.0 mmol scale under the
optimized conditions without significant decrease in the product
yield (Table 1, entry 9).
With this efficient catalytic system in hand, we sought to
study the scope of indoles and generality of this reaction
(Scheme 1). As shown in Scheme 1, substrate 2 efficiently
coupled with a variety of substituted indoles in EtOH to give
the corresponding C2-ethyl acetate substituted indoles in good
to excellent yields (62–92%) with exclusive region and site
selectivities. Substitutions at the C3- (3b), C4- (3c–d), C5- (3e–l),
C6- (3m–n), or C7- (3o) positions were all well tolerated. More
importantly, the reaction showed good compatibility with many
valuable functional groups such as methoxy (3c and 3h), cyano
(3d and 3j), fluoro (3e and 3m), chloro (3f and 3n), nitro (3i),
and ester (3k) substituents. Tolerance to the fluoro, chloro,
cyano, and ester functional groups is especially noteworthy
since they are useful intermediates for further transformation
through standard cross-coupling reactions. Furthermore, we
were pleased to find that indole 1l, bearing a bulkier BnNHCO-
substituent (a very important functional group found in many
PPARg modulators11), also smoothly reacted with 2 on 1.0 mmol
scale to deliver the desired product 3l in 83% yield, which could
provide an attractive strategy for rapidly building new
potential PPARg modulators for the treatment of diabetes
mellitus (DM).
Considering the remarkably broad substrate scope displayed
by the Rh(III) catalyst in ethanol, we performed mechanistic studies
to delineate its mode of action. To this end, a competition experi-
ment between differently substituted indoles was carried out. As
shown in Scheme 2, the result indicated that electron-rich indoles
were preferentially converted, suggesting that they were better
substrates than electron-deficient indoles.
Since ethanol was employed not only as the solvent but
also as the reagent in the above C–H activation reaction,
subsequently, several alkyl alcohols were tested in the current
catalyst system. As illustrated in Scheme 3, the reaction in all
the selected alcohols proceeded successfully to afford the
desired products 3p–t in synthetically useful yields (63–86%).
Notably, the reaction also worked well in CD3OD to afford
the methyl-deuterated product 3u in good yield, along with
additional deuterium incorporation at the C2-a-, C3- and
C7-positions of the indole (for detail, see ESI†). This result implied
that these synthesized C2-alkylated indole products can serve as
useful platforms for further synthetic manipulations.
Indeed, it is well known that the a-position in esters and the
C3-position of indole cores are the inherently reactive sites for
Claisen-type condensation12 and Friedel–Crafts-type chemistry,5
Scheme 2 Intermolecular competition experiment.
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be involved in the formation step of 3v, even though such a
pathway has been deduced in a recent work.8g
(2)
Based on these observations and literature precedents, we
proposed a possible mechanism as illustrated in Scheme 5.
First, the coordination of substrate 1 to a [Cp*Rh(III)] species is
the key step for the regioselective C2–H bond cleavage to form a
five-membered rhodacyclic intermediate A. Subsequently, the
region-selective transfer of alcohol-mediated carbenoid insertion
forms six-membered rhodacycle intermediate B with the emission
of N2 and acetone. Finally, protonolysis and decarboxylation of B
generate the desired C2-functionalized product 3 and the active Rh
catalyst.
Scheme 3 Scope of alcohols. The reaction was carried out using 1a or 1i
(0.12 mmol), 2 (0.10 mmol), Rh(III) catalyst (5.0 mol%), and the corre-
sponding alcohol (0.5 mL) under air at 80 1C for 15 h. Isolated yields.
Due to the importance of free-NH indoles for further synthetic
transformations, we finally attempted to deprotect the pyrimidyl
group of the indoles. As shown in Scheme 6, the deprotection of the
pyrimidyl group of product 3l was conveniently achieved by treat-
ment with EtONa in dry DMSO at 80 1C to provide free-NH indole
derivative 7 as the final product in good yield,13 in which the
C5-amido moiety of the indole was untouched. This could provide
an efficient and versatile route for the synthesis of new potential
PPARg modulators for antidiabetic drug discovery.
In conclusion, we have developed the first example of a
Rh(III)-catalyzed and alcohol-mediated direct carbenoid inser-
tion C2-alkylation of indoles by using the pyrimidyl group as a
readily installable and removable directing group. The remark-
able features of this reaction include mild reaction conditions,
high product yields, broad functional group tolerance, and
exclusive region and site selectivities, thus rendering it a highly
versatile alternative to the existing methods for synthesizing
the important 2-acetate substituted indole unit. Moreover, we
respectively. However, so far the transformation for direct
functionalization of the C7-position is still unexplored in the
literature. Inspired by this, we have been interested to probe the
C7–H functionalization of 2-acetate substituted indoles with
methyl acrylate by employing the recently popular transition-
metal-catalyzed C–H activation strategy. Therefore, the reactions
of 3g, 3h and 3p, respectively, with methyl acrylate were examined
in the most representative and classical Rh(III)/Cu(II) catalysis
(Scheme 4). As expected, these couplings occurred at 80 1C
in DMF within 6 h to give the corresponding C7-alkenylated
products in good isolated yields (68–78%). To the best of our
knowledge, this is the first report of Rh(III)-catalyzed direct C7–H
functionalization of indoles.
To further probe the role of alcohols in this coupling
process, an experiment using either DCE, toluene or THF to
replace alcohol was performed under otherwise identical con-
ditions. Notably, the reaction of 1a and 2 did not proceed at all
(eqn (2)). The result showed that the introduction of alcohols
was crucial for starting this reaction, and suggested that the
Rh(III)-catalyzed carbene insertion coupling process might not
Scheme 5 Proposed mechanism.
Scheme 4 C7–H functionalization of 2-acetate substituted indoles.
Scheme 6 Deprotection of the pyrimidyl group.
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6486 | Chem. Commun., 2014, 50, 6483--6486
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