Rhodium-catalyzed intramolecular annulation via C-H activation leading to fused tricyclic indole scaffolds

Article abstract of DOI:10.1039/c4cc02947j

The rhodium(iii)-catalyzed intramolecular annulation of alkyne-tethered acetanilides for the synthesis of fused tricyclic indole scaffolds via C-H activation has been developed, which has the potential for the synthesis of many indole alkaloids. This reaction proceeds under mild reaction conditions and with tolerance to a variety of functional groups.

Full text of DOI:10.1039/c4cc02947j

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Rhodium-catalyzed intramolecular annulation via
C–H activation leading to fused tricyclic indole
scaffolds†
Cite this: Chem. Commun., 2014,
50, 7367
Received 21st April 2014,
Accepted 20th May 2014
Pengyu Taoa and Yanxing Jia*ab
DOI: 10.1039/c4cc02947j
www.rsc.org/chemcomm
The rhodium(III)-catalyzed intramolecular annulation of alkyne- now available.7 However, the development of conceptually
tethered acetanilides for the synthesis of fused tricyclic indole different synthetic approaches is still of great interest.8
scaffolds via C–H activation has been developed, which has the
In connection with some of our studies on the total synthesis
potential for the synthesis of many indole alkaloids. This reaction of 3,4-fused indole alkaloids,1a,b,2a,4b,c,5b–d,6a we have recently
proceeds under mild reaction conditions and with tolerance to a developed a new strategy for the construction of such skeletons
variety of functional groups.
via intramolecular Larock indolization,9 and achieved the total
synthesis of fargesine by using this methodology (Scheme 1,
The 3,4-fused tricyclic indole nucleus is found in a number eqn (1)).10 Meanwhile, Boger independently reported a similar
of biologically active natural products and pharmaceuticals, methodology (Scheme 1, eqn (2)).11 However, these methods
such as lysergic acid,1 rugulovasine A,2 dehydrobufotenine,3 require ortho-halogenated anilines as starting materials thus
clavicipitic acid,4 decursivine,5 and indolactam V (Fig. 1).6
Accordingly, the syntheses of these natural products have been
the subject of intensive research, and a number of strategies are
Fig. 1 Selected examples of 3,4-fused indole alkaloids.
a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China.
E-mail: yxjia@bjmu.edu.cn; Fax: +86-10-82805166; Tel: +86-10-82805166
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, China
Scheme 1 Intramolecular annulation strategies for the synthesis of fused
† Electronic supplementary information (ESI) available: Experimental details and
tricyclic indoles.
spectroscopic characterization. See DOI: 10.1039/c4cc02947j
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adding cost12 and limiting its further application. Recently, the was used, the yield of 2a remained the same (Table 1, entry 5);
rhodium-catalyzed C–H activation reaction has received signifi- when the amount of [Rh] catalyst was decreased to 2.5 mol%,
cant interest because of its high atom-economy, selectivity, and a slight decrease of the yield was observed (Table 1, entry 6). The
functional-group tolerance.13 In 2008, Fagnou and co-workers solvent was further screened, replacement of acetone with DCE led
reported an elegant method for the synthesis of indoles via to a 30% yield (Table 1, entry 7). When cyclohexanone was used as
rhodium-catalyzed oxidative annulation of acetanilides with internal the solvent, the reaction did not work at all (Table 1, entry 8). It is
alkynes. (Scheme 1, eqn (3)).14 A major advantage of this method is worth mentioning that treatment of 1a under the first-generation
that it employs more readily available N-acetyl anilines as starting Fagnou’s intermolecular reaction conditions by simply changing
materials thus minimizing the substrate preactivation. Based the solvent to acetone at room temperature provided the desired
on these observations, we became interested in the rhodium- indole 2a in 62% yield. Considering the use of molecular oxygen
catalyzed intramolecular reaction of alkyne-tethered acetanilides more green and economical than the use of stoichiometric
(Scheme 1, eqn (4)). Although the rhodium-catalyzed intramolecular amounts of a metal oxidant (2.1 equiv. of Cu(OAc)2), the reaction
C–H activation reactions have been very recently reported, to the best conditions were optimized to be [Cp*Rh(MeCN)3][SbF6]2 (5 mol%),
of our knowledge, the intramolecular reaction of alkyne-tethered Cu(OAc)2ÁH2O (20 mol%) under O2 in acetone (0.01 M) at room
acetanilides has never been reported.15 The successful development temperature (Table 1, entry 5).
of this reaction would lead to a more efficient and economical
synthesis of 3,4- and 3,5-fused tricyclic indoles. Herein, we wish to examined the substrate scope of the reaction. Under our optimized
report these results. reaction conditions, the reaction proceeded smoothly to give a
With the optimized reaction conditions in hand, we next
To test our hypothesis, compound 1a was employed as a series of 3,4-fused tricyclic indoles in moderate to excellent
model substrate and subjected to the first-generation Fagnou’s yields (Table 2). Firstly, the electronic effects of aryl groups attached
intermolecular reaction conditions. We found that treatment of to the terminal alkyne were first examined (Table 2, 2a–e).
1a with [Cp*Rh(MeCN)3][SbF6]2 (10 mol%) and Cu(OAc)2ÁH2O
(210 mol%) in t-AmOH at 80 1C under an Ar atmosphere
afforded the desired 3,4-fused tricyclic indole 2a in 31% yield
(Table 1, entry 1). Increasing the reaction temperature to 100 1C
gave almost the same result (Table 1, entry 2). When compound 1a
was treated with the second-generation Fagnou’s intermolecular
reaction conditions by using molecular oxygen as the terminal
oxidant in conjunction with a catalytic amount of Cu(OAc)2ÁH2O
at 60 1C, the yield of indole 2a was slightly increased to 37%
(Table 1, entry 3). To our delight, when acetone was used as the
solvent at room temperature, the desired indole 2a could be
obtained in 61% yield (Table 1, entry 4). Further optimization
of the amount of the catalyst showed that: when 5 mol% [Rh]
Table 2 Substrate scope for the formation of 3,4-fused indolesa
Table 1 Optimization of reaction conditionsa
Equiv.
of [Rh]
Equiv.
of [Cu]
Temp.
(1C)
Yield
(%)
Entry
Solvent
1b
2b
3
4
5
0.10
0.10
0.10
0.10
0.05
0.025
0.05
0.05
0.05
2.10
2.10
0.50
0.50
0.20
0.20
0.20
0.20
2.10
t-AmOH
t-AmOH
t-AmOH
Acetone
Acetone
Acetone
DCE
80
100
60
RT
RT
RT
RT
RT
RT
31
33
37
61
63
53
30
0
6
7
8
Cyclohexanone
Acetone
9b
62
a
Reaction conditions: 1a (0.1 mmol), [Cp*Rh(MeCN)3][SbF6]2 (5 mol%),
a
Reaction conditions: 1a (0.1 mmol), [Cp*Rh(MeCN)3][SbF6]2, Cu(OAc)2ÁH2O, Cu(OAc)2ÁH2O (20 mol%), under O2, acetone (10 mL), room tempera-
b
under O2, acetone (10 mL), room temperature. Isolated products are ture. Isolated products are given. Yield based on recovered starting
given. Reaction performed under an Ar atmosphere.
b
material in parentheses.
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Compounds 1a and 1b with electron-donating groups gave the good to excellent yields (Table 2, 2i–p), although the yield of
desired products 2a and 2b in 63% and 60% yield, respectively. the substrate leading to an 8-membered ring 2n was relatively
Compound 1c with an electron-neutral group provided the low. As mentioned above, substrates with electron-rich R1 groups
corresponding product 2c in 55% yield. Compound 1d with gave the desired 3,4-fused tricyclic indoles in a better yield
an electron-withdrawing group provided the corresponding (Table 2, 2k, 2l, 2o and 2p).
product 2d in 48% yield. These results indicated that electronic
Encouraged by the results for the 3,4-fused tricyclic indoles,
factors of the phenyl moiety indeed affected the reactivity of this without individual optimization, the scope of the intramolecular
transformation. The triethylsilyl-group substrate also tolerated reaction was examined for the preparation of 3,5-fused tricyclic
the reaction conditions and produced the desired indole in 55% indoles from the corresponding acetanilides (Table 3). The reaction
yield (Table 2, 2e).
was found to be very general and compatible with a variety of ring
The electronic effects of acetanilides were next examined sizes. Although the 10-membered tricyclic product 4a was formed
(Table 2, 2f–h). Surprisingly, substrates 1f and 1g with electron- in moderate yield, the 3,5-macrocycle (Z12-membered ring) indole
rich R1 groups gave the desired products in excellent yields products 4b–f could be obtained in good to excellent yields.
under the optimized reaction conditions (Table 2, 2f and 2g).
In summary, we have developed the first rhodium-catalyzed
However, the substrate with an electron-deficient R1 group intramolecular annulation of alkyne-tethered acetanilides for
resulted in only moderate yield (Table 2, 2h). These results the synthesis of fused tricyclic indoles via C–H bond activation.
imply that the acetanilide metalation step was extremely sensi- This reaction proceeds under mild reaction conditions (room
tive to electronic effects. Most likely, the electron-withdrawing temperature) and with tolerance to a variety of functional
effect of the R1 group had a strong influence on the C–H groups, and employs molecular oxygen as the stoichiometric
activation process. The reaction was then extended to prepare terminal oxidant. We expect that this intramolecular protocol
3,4-medium ring (7- and 8-membered rings). We were pleased will find widespread use in chemical synthesis.
to find that the desired indole products were still obtained in
We gratefully acknowledge the financial support of the National
Natural Science Foundation of China (No. 21372017 and 21290183),
the National Basic Research Program of China (973 Program,
NO. 2010CB833200), and the PhD Programs Foundation of
Ministry of Education of China (No. 20120001110100).
Table 3 Substrate scope for the formation of 3,5-fused indolesa
Notes and references
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a
Reaction conditions: 1sa (0.1 mmol), [Cp*Rh(MeCN)3][SbF6]2 (5 mol%),
Cu(OAc)2ÁH2O (20 mol%), under O2, acetone (10 mL), room temperature.
b
Isolated products are given. Yield based on recovered starting material
in parentheses.
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