Rhodium(iii)-catalyzed intramolecular amidoarylation and hydroarylation of alkyne via C-H activation: Switchable synthesis of 3,4-fused tricyclic indoles and chromans

Article abstract of DOI:10.1039/c4cc02398f

The controllable intramolecular amidoarylation and hydroarylation of alkynes has been achieved via rhodium(iii)-catalyzed C-H activation. The merger of two distinct reaction pathways allows for the development of atom- and step-economic protocols for the

Full text of DOI:10.1039/c4cc02398f

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Rhodium(III)-catalyzed intramolecular amidoarylation
and hydroarylation of alkyne via C–H activation:
switchable synthesis of 3,4-fused tricyclic indoles
and chromans†
Cite this: Chem. Commun., 2014,
50, 7306
Received 1st April 2014,
Accepted 20th May 2014
Xue Zhang,‡ Yifei Li,‡ Hui Shi, Lunan Zhang, Shanshan Zhang, Xianxiu Xu* and
DOI: 10.1039/c4cc02398f
Qun Liu*
www.rsc.org/chemcomm
The controllable intramolecular amidoarylation and hydroarylation development of Rh(III)-catalyzed C–H activation,24 herein, we pre-
of alkynes has been achieved via rhodium(III)-catalyzed C–H activa- sent the Rh(III)-catalyzed intramolecular amidoarylation and hydro-
tion. The merger of two distinct reaction pathways allows for the arylation for the switchable synthesis of 3,4-fused tricyclic indoles
development of atom- and step-economic protocols for the switch- (pathway a) and chromans (pathway b) from alkyne tethered
able synthesis of 3,4-fused indoles and chromans, respectively.
acetanilides via C–H activation (eqn (2)). It is worth mentioning
that the construction of two distinct types of complex molecules
The 3,4-fused tricyclic indole structural motif forms the core of from the identical starting materials is achieved simply by a slight
many natural products with pharmacological relevance, such as change in reaction conditions.
fargesine,1 dehydrobufotenine,2 welwistatin,3 lysergic acid,4 drag-
macidin E,5 decursivine,6 communesin F,7 and indolactam V.8 The
formation of the 3,4-fused indole framework generally involves
building the third ring onto a preformed indole moiety.2–15 Very
recently, Boger16 and Jia17 independently reported a palladium-
catalyzed intramolecular Larock indole process for the preparation
of such polycyclic indoles from 2-bromo- or 2-iodoanilines with an
alkyne tethered at the 3-position (eqn (1)).
Due to its high atom- and step-economy, the rhodium(III)-
catalyzed C–H activation has gained significant interest in recent
years.18 In 2008, Fagnou and co-workers reported a novel strategy
for indole synthesis via a Rh-catalyzed intermolecular amidoaryla-
tion of internal alkynes with acetanilides.19 Other directing strate-
gies for the divergent synthesis of N–H and N-alkyl indoles were
Initially, N-(3-((4-(4-methoxyphenyl)but-3-yn-1-yl)oxy)phenyl)-
later developed.20 On the other hand, (Cp*RhCl2)2 has emerged as acetamide 1a was subjected to Fagnou’s intermolecular reaction
an efficient catalyst for alkyne hydroarylation with the aryl C–H conditions19a (Table 1, entry 1). We found that treatment of 1a
bond via a novel concerted deprotonation–metalation pathway.21 with (Cp*RhCl2)2 (1 mol%), AgSbF6 (4 mol%) and Cu(OAc)2ÁH2O
Several examples of intermolecular hydroarylation of alkynes have (210 mol%) in t-AmOH at 120 1C gave the desired 3,4-fused
recently been reported.21,22 Although the Rh(III)-catalyzed intra- tricyclic indole 2a in 87% yield (Table 1, entry 1, condition A).
molecular amidoarylation and hydroarylation of alkenes were However, under the identical conditions the substrate N-(3-((4-
documented last year,23 to our knowledge, the controllable intra- (4-chlorophenyl)but-3-yn-1-yl)oxy)phenyl)acetamide 1d gave the
molecular version of the above two pathways of alkyne has amidoarylation product 2d only in 26% yield along with the
remained unexplored. As part of our continuing interest in the hydroarylation product 3d in 51% yield (Table 1, entry 2). These
results indicated that the electronic effect of the aryl groups
Department of Chemistry, Northeast Normal University, Changchun 130024, China.
E-mail: xuxx677@nenu.edu.cn, liuqun@nenu.edu.cn; Fax: +86 431 85099759;
Tel: +86 431 85099759
attached to the triple bond has a strong effect on the pathways of
amidoarylation and hydroarylation. Then, the reaction condi-
tions of both the amidoarylation product 2d and the hydroaryla-
tion product 3d were further optimized. The aprotic solvent
acetonitrile increased the yield of tricyclic indole 2d to 85%
(Table 1, entry 3, condition B), and replacement of Cu(OAc)2 with
† Electronic supplementary information (ESI) available: Experimental details and
spectral data for 3. CCDC 993319. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4cc02398f
‡ Both authors contributed equally to this work.
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Table 1 Optimization of reaction conditionsa
Table 2 Synthesis of tricyclic indoles 2a
Yieldb (%)
Entry
Substrates
Conditions
Time (h)
2
3
1
2
3
4
1a
1d
1d
1d
A
A
B
C
0.3
0.3
3.0
0.3
2a (87)
2d (26)
2d (85)
—
—
3d (51)
—
3d (98)
a
Reactions conducted on a 0.2 mmol scale. Condition A: (Cp*RhCl2)2
(1 mol%), AgSbF6 (4 mol%), Cu(OAc)2ÁH2O (2.1 equiv.), t-AmOH (0.1 M),
120 1C; condition B: (Cp*RhCl2)2 (5 mol%), AgSbF6 (20 mol%), Cu(OAc)2ÁH2O
(2.1 equiv.), CH3CN (0.1 M), 120 1C; condition C:(Cp*RhCl2)2 (2.5 mol%),
AgSbF6 (10 mol%), PivOH (5.0 equiv.), t-AmOH (0.1 M), 120 1C. b Yields of
isolated products.
pivalic acid (5.0 equiv.)21 resulted in the hydroarylation product
3d exclusively (Table 1, entry 4, condition C).
With the optimal conditions in hand, we surveyed various
substrates to determine the scope of the amidoarylation reaction.
Under the reaction conditions A or B, the reactions proceeded
smoothly to afford tricyclic indoles 2 in good to excellent yields
(Table 2). The substituents on the alkyne (R1 group) were well
tolerated with electron-rich and electron-deficient aryl, phenyl,
alkyl and trimethylsilyl groups and gave the tricyclic indoles in
good to high yield (2a–f) along with the hydroarylation by-
products in the cases of 2b, 2c and 2e. These results reveal that
the amidoarylation pathway is quite sensitive to the electronic
effect of the substituents on the alkyne. In comparison, sub-
strates with both electron-rich and electron-deficient R2 groups
resulted in the amidoarylation products exclusively in excellent
yields under condition A, no matter which substituents were
attached to the alkyne group (2j–q). It is most likely that the steric
a
Reactions conducted on a 0.2 mmol scale. Condition A: (Cp*RhCl2)2
(1 mol%), AgSbF6 (4 mol%), Cu(OAc)2ÁH2O (2.1 equiv.), t-AmOH (0.1 M),
120 1C; condition B: (Cp*RhCl2)2 (5 mol%), AgSbF6 (20 mol%), Cu(OAc)2Á
b
H2O (2.1 equiv.), CH3CN (0.1 M), 120 1C. Yields of the corresponding
hydroarylation products 3 are in parentheses. Condition A: (Cp*RhCl2)2
(10 mol%), 0.01 M. Yields of products 2a and 2d are in parentheses
(from the dechlorination of 2p and 2q respectively).
c
d
effect of the R2 groups facilitates this amidoarylation process. Substrates with different substituents on the alkyne (R1), such as
Compared with the palladium-catalyzed 3,4-fused tricyclic indole electron-rich and -deficient aryl, phenyl and alkyl groups, were
synthesis,17 the rhodium(III)-catalyzed protocol is more practical well tolerated (3a–f). Substrates with both electron-donating
due to its low catalyst loading (1mol% in most cases vs. 20 mol%) and electron-withdrawing R2 groups participated in this reaction
without high dilution (0.1 M vs. 0.01 M). In addition, the (3g–i).Unlike the amidoarylation, the hydroarylation pathway
intramolecular reaction could be extended to generate 3,4- has a slight effect on the electronic and steric effect of the R1
medium-ring fused indoles (2g–i), which are especially difficult and R2 substituents. Furthermore, these reactions gave the
to prepare.25
alkene products with E selectivity, and the results are consistent
The intramolecular amidoarylation process mentioned above with those obtained from the intermolecular version of the
represents a very simple and efficient methodology for the hydroarylation reaction.21 The configuration of 3f was estab-
construction of 3,4-fused tricyclic indoles which is highly atom- lished by the X-ray single crystal analysis,27 and others were
and step-economic. Since the construction of distinct types of determined by analogy with their NMR spectra.
complex molecules from identical starting materials is an attrac-
On the basis of the above results (Tables 1–3) and the related
tive and challenging task in organic synthesis,26 the preparation work,19,21,23 a mechanistic pathway is proposed (Scheme 1). First,
of chromans 3 from the hydroarylation reactions of N-(3-((but-3- C–H bond cleavage of 1 occurs to produce a six-membered
yn-1-yl)oxy)phenyl)acetamides 1 was also investigated. In the rhodacycle intermediate A. Next, alkyne coordination to rhodium
presence of (Cp*RhCl2)2 (2.5 mol%), AgSbF6 (10 mol%) and and migratory insertion of alkyne into the rhodium–carbon bond
pivalic acid (5.0 equiv.), the reactions proceeded smoothly at results in the formation of intermediate B. Then two pathways
120 1C to afford chromans in good to excellent yields (Table 3). may exist, in pathway a, the carbon–nitrogen bond is formed to
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Table 3 Synthesis of chromans 3a
intermediate in the formation of tricyclic indole product 2 from
the amidoarylation of 1 under these conditions.
In summary, we have developed a Rh(III)-catalyzed intra-
molecular amidoarylation and hydroarylation for the switch-
able syntheses of 3,4-fused tricyclic indoles and chromans from
alkyne tethered acetanilides via aryl C–H bond activation. In
this process, two distinct types of complex molecules from the
identical starting materials are achieved simply by a slight
change of reaction conditions. The reaction features atom-
and step-economy, high product yields and a practical proce-
dure. Studies on the synthetic applications of this protocol are
being carried out in our laboratory.
Financial support for this research provided by the NNSFC
(21172030 and 21272034), the Young Scientific Research Foun-
dation of Jilin Province (20140520083JH) and the Fundamental
Research Funds for the Central Universities (12QNJJ010) is
greatly acknowledged.
Notes and references
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a
Reactions conducted on a 0.2 mmol scale. Condition C: (Cp*RhCl2)2
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