Diastereoselective synthesis of functionalized tetrahydrocarbazoles via a domino-ring opening-cyclization of donor-acceptor cyclopropanes with substituted 2-vinylindoles

Article abstract of DOI:10.1021/ol501763n

A new domino synthetic approach for the synthesis of highly functionalized tetrahydrocarbazoles via DROC of various functionalized DA-cyclopropanes with 2-indolylnitroethylene and indole-substituted alkylidene malonate is described. The tetrahydrocarbazol

Full text of DOI:10.1021/ol501763n

Letter
pubs.acs.org/OrgLett
Diastereoselective Synthesis of Functionalized Tetrahydrocarbazoles
via a Domino-Ring Opening−Cyclization of Donor−Acceptor
Cyclopropanes with Substituted 2‑Vinylindoles
Ranadeep Talukdar, Deo Prakash Tiwari, Amrita Saha, and Manas K. Ghorai*
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
S
* Supporting Information
ABSTRACT: A new domino synthetic approach for the
synthesis of highly functionalized tetrahydrocarbazoles via
DROC of various functionalized DA-cyclopropanes with 2-
indolylnitroethylene and indole-substituted alkylidene malo-
nate is described. The tetrahydrocarbazoles were obtained with
excellent diastereoselectivity having cis alignment of the 1,4-
appendages across the six-membered carbocyclic ring.
etrahydrocarbazole1 is one of the most important classes of
Scheme 1. Synthesis of Tetrahydrocarbazoles via DROC of 2-
Activated Olefin-Tethered Indoles with DA-cyclopropanes
Tindole-based molecular frameworks. These heterocycles
contain a saturated six-membered carbacycle fused to indole at
the C-2 and C-3 positions. They are integral parts of several
biologically active natural products2 and other pharmaceutically
relevant synthetic compounds.3
Over the years, several interesting synthetic routes have been
devised for the synthesis of substituted tetrahydrocarbazoles and
their analogues.4,5 Some of the most important strategies include
For this purpose, we have prepared indole substrates with
intramolecular allylic arylation,4a,b Friedel−Crafts-type cycliza-
activated olefinic moieties, 2a and 2b, following literature
reports.10 At the outset of our study, we performed the reaction
of DA-cyclopropane 1a with 2-indolylnitroethylene (2a) in the
presence of a catalytic amount of Yb(OTf)3 (20 mol %) as the
Lewis acid (LA) catalyst in THF, and the product tetrahy-
drocarbazole 3a was obtained in only 14% yield (Table 1, entry
1). In order to optimize the reaction conditions, we screened
different solvents and Lewis catalysts. The optimal result came
with 1.0 equiv of 1a and 2a in 1,2-dichloroethane in the presence
of 20% LA, which afforded the tetrahydrocarbazole 3a in high
yield (69%) as a single diastereomer (Table 1, entry 2).
The structure of 3a was determined by spectroscopic
techniques and the relative stereochemistry was confirmed by
X-ray crystallographic analysis where aryl and nitro methyl
groups were found to possess cis appendages (Figure 1).
To generalize this approach, a number of DA-cyclopropanes
with a variety of aryl substituents were studied for the DROC
with 2-indolylnitroethylene 2a, and the results are shown in
Table 2. In the case of the reaction of 2a with 2-phenyl-
cyclopropanedicarboxylate 1b, the corresponding tetrahydro-
carbazole 3b was obtained as a single diastereomer in comparable
yield. 4-Methylphenylcyclopropanedicarboxylate 1c behaved
similar to 2a and generated tetrahydrocarbazole 3c. Fluorinated
tetrahydrocarbazole 3d was also synthesized in high yield when
1d was reacted with 2a (Table 2, entry 4).
tion reactions,4c,d and [4 + 2] cycloaddition of indole derivative
bearing an unsaturated functionality at the C-2 or C-3 position
with various kinds of dienophiles.5 Kerr and co-workers reported
an elegant [3 + 3] annulative strategy based upon the reaction of
donor−acceptor (DA)-cyclopropanes with 2-alkynylindoles for
the synthesis of substituted tetrahydrocarbazoles.6 Development
of a highly stereoselective route to substituted tetrahydrocarba-
zoles is still a challenging job and certainly would add value to the
overall efforts toward tetrahydrocarbazole synthesis.
DA-cyclopropanes are versatile intermediates in synthetic
organic chemistry7,8 and have been utilized for the synthesis of a
number of organic compounds including several bioactive
natural products and drugs. Our recent ongoing research activity
and success on DROC of DA-cyclopropanes for the construction
of substituted carbocyclic rings9 prompted us to investigate the
synthesis of diastereomerically pure substituted tetrahydrocarba-
zoles.
We anticipated that the ring-opening of DA-cyclopropanes
with indoles bearing an activated olefin would generate the
corresponding substituted malonate anion which would further
react with the tethered olefinic moiety via an intramolecular
Michael reaction in a domino fashion leading to the
diastereoselective formation of tetrahydrocarbazole scaffolds
(Scheme 1). Herein, we report a new protocol for the synthesis of
highly substituted tetrahydrocarbazoles via DROC of DA
cyclopropanes with substituted 2-vinylindoles.
Received: June 18, 2014
© XXXX American Chemical Society
A
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Letter
Table 1. Optimization Study
Table 2. Reaction of DA-cyclopropanes with 2-
a,b
Indolylnitroethylene 2a
a
b
entry
conditions
time
12 h
yield (%)
1
Yb(OTf)3 (20 mol %), THF, rt to 60 °C
Yb(OTf)3 (20 mol %), DCE, rt to 65 °C
Yb(OTf)3 (1.0 equiv), DCE, rt to 65 °C
Yb(OTf)3 (20 mol %), DCE, rt
14
69
69
67
58
62
55
10
25
30
2
30 min
20 min
2 days
1 day
3
4
5
Yb(OTf)3 (20 mol %), DCM, rt
6
Sc(OTf)3 (20 mol %), DCE, rt to 65 °C
Zn(OTf)2 (20 mol %), DCE, rt to 65 °C
Cu(OTf)2 (20 mol %), DCE, rt to 65 °C
AlCl3 (20 mol %), DCE, rt to 65 °C
FeCl3 (20 mol %), DCE, rt to 65 °C
Yb(OTf)3 (20 mol %), toluene, rt to 65 °C
45 min
4 h
7
8
5 min
20 min
3 h
9
10
11
50 min
44
a
b
In all cases, 1.0 equiv of 1a was reacted with 1.0 equiv of 2a. The
product was obtained as a single diastereomer.
a
b
Yields of isolated products. The compounds were obtained as single
diastereomers.
The relative stereochemistry of 3p was also found to be cis as
determined by single-crystal X-ray diffraction data (Figure 2).
The scope of our strategy was further extended employing
styrylcyclopropanedicarboxylate 1m as the DA-cyclopropane.
When 1m was reacted with 2a and 2b, the corresponding
tetrahydrocarbazoles 3q and 3r, respectively, were obtained in
high yields (Scheme 2, eqs 1 and 2). Although the carbazole 3q
was obtained as a single diastereomer, 3r was produced as a
mixture of diastereomers (dr 4:1).
In the case of the reaction of 1m with 2a, a trace amount of the
uncyclized product 4 was also isolated. This clearly indicated that
the two steps, ring opening and intramolecular Michael addition,
take place sequentially in a domino fashion.
Figure 1. X-ray crystal structure of 3a with 50% thermal ellipsoids.
Similarly, naphthyl and thiophene-yl tetrahydrocarbazoles (3e
and 3f, respectively) were generated in high yields via DROC of
the corresponding DA-cyclopropanes 1e and 1f, respectively,
with 2a (Table 2, entries 5 and 6, respectively).
Next, to extend the scope of our methodology, reactions of
several functionalized DA-cyclopropanes 1a−c,f−l were carried
out with indole substituted alkylidene malonate 2b under the
same optimized reaction conditions, and the results are
summarized in Table 3.
Interestingly, when 4-methoxystyrylcyclopropanedicarboxy-
late 1m was reacted with 2b, cyclopentene dicarboxylate 5 was
obtained in 90% yield as the sole product; this was generated via
intramolecular rearrangement of 1m upon interaction with the
LA catalyst (Scheme 3). It is worth mentioning that construction
of substituted cyclopentenes has always been an important goal
in organic synthesis.11
The mechanism of the reaction is depicted in Scheme 4. The
Lewis acid activates the cyclopropane ring generating a complex
D, which upon attack of the indole nucleophile generates
intermediate E. The ring-opened intermediate E undergoes
attack of its malonate anion moiety to the tethered activated
olefin in Michael fashion to produce the tetrahydrocarbazoles.
The intermediate E can adopt two different cyclohexene like half-
chair conformations F and G. In the conformer F, the Michael
acceptor adopts a pseudoaxial position and faces a gauche
interaction with one of the ester moieties, whereas the Michael
acceptor adopts a pseudoequatorial position in the conformer G
and suffers from a severe gauche interaction with both the ester
groups. The more stable conformer F is preferred over G
When the reaction of 1a was performed with 2b, the product
tetrahydrocarbazole tetraester 3g was obtained in excellent yield
as a single diastereomer (Table 3, entry 1). Similarly, DA-
cyclopropanes 1b and 1c reacted with 2b to provide the
corresponding products 3h and 3i, respectively. Heteroaryl
tetrahydrocarbazole tetraesters 3j and 3k could also be generated
when thiophene-2-yl and 2-furyl cyclopropane dicarboxylates 1f
and 1g were reacted with 2b. DA-cyclopropanes having electron-
donating substituents on the aromatic rings also afforded the
corresponding tetrahydrocarbazoles (3l,m) in excellent yields
(Table 3, entries 6 and 7, respectively). Halo-substituted DA-
cyclopropanes 1j,k served as excellent substrates for this reaction
and produced the corresponding products 3n,o in good yields.
The Michael acceptor 2b gave the corresponding tetraester
products 3g−p in excellent yields.
B
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Organic Letters
Letter
Table 3. Reaction of DA-cyclopropanes with Indole-
a,b
Substituted Alkylidene Malonate 2b
Figure 2. X-ray crystal structure of 3p with 50% thermal ellipsoids.
Scheme 2. Synthesis of Styryl-Substituted
Tetrahydrocarbazoles 3q and 3r
Scheme 3. Synthesis of Cyclopentene Dicarboxylate via
Intramolecular Rearrangement of 4-
Methoxystyrylcyclopropanedicarboxylate
Scheme 4. Mechanism of the Reaction and Origin of
Diastereoselectivity
a
b
Yields of isolated products. Unless otherwise noted, all the
c
compounds were obtained as single diastereomers. Obtained as a
7:2 diastereomeric mixture.
excellent diastereoselectivity (de up to 99%) via domino ring-
opening cyclization (DROC) of DA-cyclopropanes with 2-
indolylnitroethylene 2a and indole-substituted alkylidene
malonate 2b. The reaction proceeds via a half chairlike transition
state where the activated olefin adopts a more stable pseudoaxial
providing tetrahydrocarbazoles with a cis orientation of the 1,4-
substituents on the cyclohexyl ring.
In conclusion, we have developed an efficient protocol for the
synthesis of highly functionalized tetrahydrocarbazoles with
C
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Letter
W.-J. Tetrahedron 2011, 67, 446. (e) Gioia, C.; Bernardi, L.; Ricci, A.
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ASSOCIATED CONTENT
* Supporting Information
■
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Detailed experimental procedures, characterization data and X-
ray crystallographic analysis of 3a and 3p. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mkghorai@iitk.ac.in. Fax: (+91)-512-2597436. Tel:
(+91)-512-2597518.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
M.K.G. is thankful to IIT Kanpur and DST, India. R.T. thanks
CSIR, D.P.T. thanks UGC and IIT Kanpur, and A.S. thanks IIT
Kanpur, India, for financial support.
DEDICATION
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Int. Ed. 2011, 50, 6167. (h) Rivero, A. R.; Fernandez, I.; Sierra, M. A. Org.
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