Angewandte
Communications
Chemie
Fused-Ring Systems
Cobalt(II) Porphyrin-Catalyzed Intramolecular Cyclopropanation of
N-Alkyl Indoles/Pyrroles with Alkylcarbene: Efficient Synthesis of
Polycyclic N-Heterocycles
Annapureddy Rajasekar Reddy, Fei Hao, Kai Wu, Cong-Ying Zhou,* and Chi-Ming Che*
Abstract: A protocol on chemoselective cobalt(II) porphyrin-
catalyzed intramolecular cyclopropanation of N-alkyl indoles/
pyrroles with alkylcarbenes has been developed. The reaction
enables the rapid construction of a range of nitrogen-contain-
ing polycyclic compounds in moderate to high yields from
readily accessible materials. These N-containing polycyclic
compounds can be converted into a variety of N-heterocycles
with potential synthetic and biological interest. Compared to
their N-tosylhydrazone counterparts, the use of bulky N-2,4,6-
triisopropylbenzenesulfonyl hydrazones as carbene precursors
allows cyclopropanation to occur under milder reaction
conditions.
to polycyclic N-heterocycles often requires a lengthy
sequence of reactions. Thus, there has been considerable
interest in the design of new and efficient methods for rapid
construction of N-atom-containing polycyclic compounds
from readily available starting materials. In this regard,
transition metal catalyzed reaction of heteroaromatics with
diazo compounds is an appealing strategy for the synthesis of
[1]
complex N-heterocyclic compounds, as numerous hetero-
aromatics are commercially available. Dirhodium carboxy-
lates and copper complexes are well-known to be effective in
catalyzing the reactions of indoles/pyrroles with a-diazocar-
bonyl compounds to give cyclopropanation products or CÀH
[1b,d,7]
functionalization products.
The chemoselectivity of this
T
ransition metal catalyzed reactions of heteroaromatics with
a-diazocarbonyl compounds are powerful methods which can
chemistry has been found to be dependent on N substitution
of indoles/pyrroles. When the N substituent is an electron-
withdrawing group, indoles/pyrroles preferentially undergo
cyclopropanation, whereas N-alkyl-substituted indoles/pyr-
be used both to construct diverse heterocycles and in natural
[
1]
product synthesis. However, the reactions involving alkyl-
diazomethanes are underexplored. In general, the low
stability and inaccessibility of the alkyldiazomethanes,
which are used to generate alkylcarbenes, presents a hurdle
for development in this area. Recently, relatively stable N-
tosylhydrazones have been used as precursors for in situ
generation of nonstabilized diazo compounds in transition
[1b,d,7]
roles often result in CÀH insertion products.
The
preferential CÀH insertion for N-alkyl indoles/pyrroles is
attributed to an electronically favorable zwitterionic inter-
mediate wherein the positive charge is stabilized by the lone
pair of electrons on the N atom of the indole/pyrrole, and the
negative charge is stabilized by the acceptor group of the
[
2,3]
[1b,d]
metal catalyzed or metal-free cross coupling reactions.
We
carbenoid component.
The zwitterionic intermediate
have also reported that alkyldiazomethanes, generated in situ
from N-tosylhydrazones, underwent ruthenium porphyrin
catalyzed intramolecular carbene CÀH insertion to give
usually undergoes a rapid proton transfer to give CÀH
insertion products. As alkylcarbene does not have an acceptor
group for stabilizing the zwitterionic intermediate, it is likely
to undergo cyclopropanation with N-alkyl indoles/pyrroles.
Described herein are the findings on cobalt(II) porphyrin-
catalyzed intramolecular cyclopropanation of N-alkyl
indoles/pyrroles with alkyldiazomethanes, generated in situ
substituted tetrahydrofurans and pyrrolidines in high yields
[4]
with excellent diastereoselectivity. This in situ protocol,
based on ruthenium porphyrin catalysts, circumvents the
problem encountered in the isolation of labile nonstabilized
diazo compounds (especially for alkyldiazomethanes),
thereby expanding the scope of substrates for carbene-
transfer reactions.
[
8,9]
from hydrazones.
The reaction enables rapid construction
of a range of nitrogen-containing polycycles in good yields
from readily accessible materials (Scheme 1). These poly-
cycles can be readily converted into a variety of N hetero-
cycles having potential biological interest.
Nitrogen-containing polycyclic compounds are widely
[
5]
found in natural alkaloids and bioactive molecules. The
rigid structure of polycyclic compounds confers significant
Cyclopropane-fused indolines are structural motifs in
many natural products and bioactive molecules, and serve as
[
6]
impact on their biological activities. The synthetic approach
[10]
useful building blocks in organic synthesis. At the outset of
our investigation, we examined cyclopropanation of the
indolyl N-tosylhydrazone 1a for the synthesis of the cyclo-
propane-fused indoline 2a by using [Ru(TTP)(CO)]
[
*] A. R. Reddy, F. Hao, K. Wu, C.-Y. Zhou, Prof. Dr. C.-M. Che
HKU Shenzhen Institute of Research & Innovation
Shenzhen (China)
and
[
(
H TPP = meso-tetrakis(4-tolyl)porphyrin] as the catalyst
Scheme 2). The N-tosylhydrazone 1a and its derivatives
2
State Key Laboratory of Synthetic Chemistry and Department of
Chemistry, The University of Hong Kong, Pokfulam Road
Hong Kong (China)
[4]
can be readily synthesized from commercially available
[11]
indoles as shown in the literature. Treatment of 1a with
E-mail: cyzhou@hku.hk
K CO3 (3 equiv) and [Ru(TTP)(CO)] (2 mol%) in 1,4-
2
dioxane at 1058C for 10 hours led to the cyclopropane 2a in
20% yield. The structure of 2a was inferred by the X-ray
1
810
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1810 –1815