Synthesis of tetrahydroindolones and tetrahydrocarbazolones via palladium catalyzed C–H activation

Article abstract of DOI:10.1016/j.tetlet.2018.11.029

The treatment of bromo homoallyl pyrrolyl/indolyl ketone derivatives with Pd(OAc)₂ in the presence of PPh₃ and Cs₂CO₃ in DMF resulted in the formation of tetrahydroindolones and tetrahydrocarbazolones in moderate to good isolated yields.

Full text of DOI:10.1016/j.tetlet.2018.11.029

Accepted Manuscript
Synthesis of tetrahydroindolones and tetrahydrocarbazolones via palladium cat-
alyzed C-H activation
Tiantian Zhang, Hongjin Xu, Chuanjun Song, Junbiao Chang
PII:
S0040-4039(18)31357-1
https://doi.org/10.1016/j.tetlet.2018.11.029
TETL 50414
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 October 2018
3 November 2018
9 November 2018
Please cite this article as: Zhang, T., Xu, H., Song, C., Chang, J., Synthesis of tetrahydroindolones and
tetrahydrocarbazolones via palladium catalyzed C-H activation, Tetrahedron Letters (2018), doi: https://doi.org/
10.1016/j.tetlet.2018.11.029
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Synthesis of tetrahydroindolones and tetrahydrocarbazolones via palladium catalyzed C‒H
activation
Tiantian Zhang,a Hongjin Xu,a Chuanjun Song,*a and Junbiao Chang*a,b
a College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China
b
Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province,
Zhengzhou 450001, China
chjsong@zzu.edu.cn; changjunbiao@zzu.edu.cn
Abstract: The treatment of bromo homoallyl pyrrolyl/indolyl ketone derivatives with Pd(OAc)2 in the
presence of PPh3 and Cs2CO3 in DMF resulted in the formation of tetrahydroindolones and
tetrahydrocarbazolones in moderate to good isolated yields.
Keywords: palladium; C‒H alkenylation; tetrahydroindolone; tetrahydrocarbazolone
Introduction
The indole and carbazole moieties are important structural motifs found in many natural
products and bioactive molecules.1 Therefore, the development of efficient strategies toward these
molecules has become a central theme in organic synthesis.1d,e,2 Among them, the transition metal-
catalyzed intramolecular C‒H activation of indoles has emerged as an attractive method to access the
scaffolds of carbazoles and analogues.3-5 However, literature reports concerning the intramolecular
C‒H functionalization of pyrroles for the assembly of indoles and related analogues are rare.3g,5a,c,6 As
part of our continued interest in transition metal catalyzed C‒H activation7,8 and application in natural
product synthesis,9 we have developed valuable approaches toward indeno[2,1-b]pyrrol-8-ones via the
palladium catalyzed intramolecular C‒H arylation of pyrroles.8 Herein, we report our recent findings
for the synthesis of tetrahydroindolones and tetrahydrocarbazolones via palladium catalyzed C‒H
alkenylation.
Results and Discussion
Our investigation started with compound 1a. The desired tetrahydroindolone 2a was obtained
in 41% isolated yield after exposing 1a to Pd(OAc)2 and K2CO3 in DMF7c at 100 oC for 15 h (Table 1,
entry 1). Further palladium catalyst screening indicated that Pd(OAc)2 was the best choice (Entries 2–
8). Next, different bases were explored. No reaction occurred in the presence of the organic base
t
DIPEA (Entry 9) or the strong inorganic base BuOK (Entry 12). While K3PO4 gave less satisfactory
results (Entry 11), Cs2CO3 led to the formation of 2a in much higher yield than K2CO3 (Entry 10 vs 1).
With Pd(OAc)2 as catalyst and Cs2CO3 as base, other solvents (NMP, DMSO, 1,4-dioxane) were
explored. However, none of these provided better yields than DMF (Entries 13‒15 vs 10). The reaction
could not be driven to completion when the catalyst loading was reduced to 5 mol% (Entry 17 vs 10),
while other side reactions began to take place in the presence of 20 mol% catalyst loading (Entry 16 vs
10). Reduced yields were obtained in both cases. Further study indicated that the yield could be
1

improved to 76% in the presence of added PPh3 (Entry 18 vs 10). However, no reaction occurred
o
without the base (Entry 21). Finally, the reaction temperatures were briefly screened, and 100 C gave
the highest yield (Entries 19, 20 vs 18).
Table 1. Reaction conditions optimization for the synthesis of tetrahydroindolone 2a.
Entry
1
Catalyst
Ligand a
Base b
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DIPEA
Cs2CO3
K3PO4
tBuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
-
Solvent
DMF
Temp (oC)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
90
Yield (%) c
d
Pd(OAc)2
-
41
18
13
24
0
d
2
PdCl2
-
DMF
d
3
PdCl2(PPh3)2
-
DMF
d
4
PdCl2(CH3CN)2
PdCl2(dppf)d
Pd/C d
-
DMF
5
-
DMF
6
-
DMF
0
d
7
Pd(dba)3
-
DMF
16
30
0
d
8
Pd(PPh3)4
-
DMF
d
9
Pd(OAc)2
-
DMF
d
10
11
12
13
14
15
16
17
18
19
20
21
Pd(OAc)2
-
DMF
70
24
0
d
Pd(OAc)2
-
DMF
d
Pd(OAc)2
-
DMF
d
Pd(OAc)2
-
NMP
40
24
56
49
64
76
71
65
0
d
Pd(OAc)2
-
-
DMSO
1,4-dioxane
DMF
d
Pd(OAc)2
e
Pd(OAc)2
-
f
Pd(OAc)2
-
DMF
d
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
DMF
DMF
d
Pd(OAc)2
d
Pd(OAc)2
DMF
110
100
d
Pd(OAc)2
DMF
a 10 mol%; b 2 equiv.; c Isolated yield; d 10 mol%; e 20 mol%; f 5 mol%.
With the optimal conditions in hand, the substrate scope was explored (Table 2). A variety of
2-(2-bromoallyl)-3-(N-methylpyrrolyl)-3-oxo-1-carboxylates 1a‒f could be effectively converted into
the corresponding tetrahydroindolones 2a‒f in good isolated yields. Under the reaction conditions, the
N-methylindolyl derivatives 1g,h could also be successfully converted into tetrahydrocarbazolones
2g,h, although slightly higher reaction temperatures were required to drive the reaction to completion.
2

Next, the palladium catalyzed intramolecular C‒H alkenylation of the benzyl group protected
substrates 1i,j was investigated, which provided tetrahydrocarbazolones 2i,j in moderate isolated yields.
Similarly, the reaction of N-butenylindole derivative 1k proceeded to give tetrahydrocarbazolone 2k in
51% isolated yield, ring-closing metathesis of which provided tetrahydropyrido[3,2,1-jk]carbazolone 3
in an unoptimized 67% isolated yield (Scheme 1). Finally, we explored the palladium catalyzed C‒H
alkenylation reaction of 1l. Without an extra 2-substituent, this type of 2-(2-bromoallyl)-1,3-dicarbonyl
compound can easily give rise to the formation of furans.7a,10 Gratifyingly, under our reaction
conditions, indole-5-carboxylate 4 could be isolated in 35% yield (Scheme 2). We believe that
compound 4 was formed through the desired palladium catalyzed pyrrolyl C‒H alkenylation and
subsequent double-bond isomerization.
Table 2. Substrate scope for the synthesis of tetrahydroindolones and tetrahydrocarbazolones via
palladium catalyzed C‒H alkenylation.
a 100 oC; b 110 oC; c 21 h; d 24 h.
3

Scheme 1. Synthesis of tetrahydropyrido[3,2,1-jk]carbazolone 3 via ring-closing metathesis of 2k.
Scheme 2. Synthesis of indole-5-carboxylate 4 via palladium catalyzed C‒H alkenylation of 1l.
Conclusion
In summary, we have developed an efficient strategy toward the synthesis of
tetrahydroindolones and tetrahydrocarbazolones via palladium catalyzed intramolecular C‒H
alkenylation of the corresponding pyrrolyl and indolyl derivatives. This strategy is well adapted to the
synthesis of indole and carbazole natural products, which is currently underway in our laboratory.
Acknowledgment
We are grateful to the NSFC (#81330075) for financial support.
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


Palladium catalyzed synthesis of tetrahydroindolones has been developed;
Palladium catalyzed synthesis of tetrahydrocarbazolones has been developed;
Tetrahydropyrido[3,2,1-jk]carbazolone has been synthesized.
7