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An efficient synthetic route to carbocyclic
Cite this: Chem. Commun., 2013,
enaminonitriles via Lewis acid catalysed domino-ring-
49, 8205
opening-cyclisation (DROC) of donor–acceptor
Received 17th June 2013,
Accepted 17th July 2013 cyclopropanes with malononitrile†
DOI: 10.1039/c3cc44533j
Manas K. Ghorai,* Ranadeep Talukdar and Deo Prakash Tiwari
www.rsc.org/chemcomm
A highly efficient strategy for the synthesis of functionalised
carbocyclic enaminonitriles in excellent yields has been described.
The reaction utilises Yb(OTf)3 catalysed C–C bond cleavage and two
simultaneous C–C bond formations of donor–acceptor (DA)-cyclopro-
panes with malononitrile anions in a domino fashion.
Enaminonitriles have been extensively utilised as versatile building
blocks for the synthesis of a large variety of heterocyclic compounds
e.g. dihydropyridines, tetrahydropyridines, aminopyrazoles and
pyrimidine derivatives, etc.1 Enaminonitriles have also been utilised
for the synthesis of various natural products2 and pharmaceutical
agents.3 Enaminonitriles are generally synthesised4,5 via Thorpe
reaction4a–d involving a base catalysed dimerisation of nitriles or
intramolecular cyclisation of the corresponding dinitriles (Thorpe–
Ziegler cyclisation).4e–h Gewald reaction5 is another prominent
reaction in this respect where an a-methylene carbonyl compound,
an a-cyanoester/malononitrile and sulphur react under muti-
component reaction conditions. However, these protocols could
provide only a limited variety of enaminonitriles. To address this
problem, further development of new and alternative synthetic
strategies is highly desirable.
Considering their inherent high ring strain, thereby, special
reactivity patterns of donor–acceptor (DA) cyclopropanes, they
have been utilised for the synthesis of various acyclic, hetero- and
carbocyclic compounds6–8 of contemporary interest. In recent
years, DA-cyclopropane chemistry has become very important as
these cyclopropanes could serve as suitable building blocks
towards various synthetic targets. Newer synthetic methodologies
could be developed based on their structural motifs,8 e.g. several
domino strategies have been evolved utilising DA-cyclopropanes.9
Application of domino synthetic protocols are well known in
the literature.10
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India.
E-mail: mkghorai@iitk.ac.in; Fax: +91-512-2597436; Tel: +91-512-2597518
† Electronic supplementary information (ESI) available: Experimental proce-
dures, X-ray crystallographic analysis of 3a, 3e and 3k, spectral data, NMR spectra
and crystal structure of 3a, 3e, and 3k. CCDC 939509 (3a), 939510 (3e), 939511
(3k). For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3cc44533j
This journal is c The Royal Society of Chemistry 2013
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Inspired by our success in exploiting domino-ring-opening-
cyclisation (DROC) of aziridines and azetidines11 for the synthesis
of various aza-heterocyclic compounds, we intended to explore
it further utilising DA-cyclopropanes as the substrates. Based on
our recent achievement for the synthesis of 4,5-dihydropyrroles
containing enaminonitrile functionality1a via DROC of N-sulfonyl
aziridines with malononitrile, we envisioned that carbocyclic
enaminonitriles 3 could easily be synthesised via a similar Lewis
acid catalysed reaction of DA-cyclopropanes with malononitrile
anions (Scheme 1). We have successfully developed a new and
unprecedented methodology for this purpose and, herein, report
our preliminary results as a communication.
Our study began with the reaction of cyclopropane 1a12 with
malononitrile 2 using NaH as base in the presence of stoichio-
metric amounts of Sc(OTf)3 as a Lewis acid (LA) in THF at 60 1C.
To our pleasure, carbocyclic enaminonitrile 3a was produced in
46% yield in 30 min (Table 1, entry 1). With a view to optimising the
reaction conditions for maximum yield and the lesser reaction time,
we screened several LA catalysts like Ti(OiPr)4, Zn(OTf)2, Cu(OTf)2,
BF3
OEt2 and Yb(OTf)3 (entry 2–6). To our great pleasure, Yb(OTf)3
catalysed reaction using THF as the solvent afforded the product 3a
in excellent yield (87%) in 10 min (entry 6). We also observed that
20 mol% of the Yb(OTf)3 was sufficient to catalyse the reaction
without affecting the yield and the reaction time (entry 8). Further
reduction in the amount of LA catalyst resulted in lower yield of the
product, though the reaction time was found to be comparable
(entry 9). When the reaction was performed at room temperature it
took 9 h for completion (entry 10). When t-BuOK was used as the
base instead of NaH, 3a was produced in lower yield (entry 11). The
reaction did not proceed at all without using any LA catalyst.
Under the optimised reaction conditions, we employed our
protocol for the synthesis of a large variety of highly functionalised
Scheme 1 Proposed DROC of DA-cyclopropanes with malononitrile.
Chem. Commun., 2013, 49, 8205--8207 8205
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Table 1 Optimisation study

Scheme 2 Synthesis of styryl substituted carbocyclic enaminonitrile.

Entry Conditions Time (min) Yield (%)
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1 NaH, Sc(OTf)3 (1 equiv.), THF, RT-60 1C 30 min 46

2 NaH, Ti(OiPr)4 (1 equiv.), THF, RT-60 1C 10 min 21
3 NaH, Zn(OTf)2 (1 equiv.), THF, RT-60 1C 1h 70
4 NaH, Cu(OTf)2 (1 equiv.), THF, RT-60 1C 30 min 5
5 NaH, BF3
OEt2 (1 equiv.), THF, RT-60 1C 5 min 11
6 NaH, Yb(OTf)3 (1 equiv.), THF, RT-60 1C 10 min 87
7 NaH, Yb(OTf)3 (1 equiv.), toluene, RT-60 1C 45 min 39
8 NaH, Yb(OTf)3 (20 mol%), THF, RT-60 8C 15 min 88
9 NaH, Yb(OTf)3 (10 mol%), THF, RT-60 1C 20 min 70
10 NaH, Yb(OTf)3 (20 mol%), THF, RT 9h 86
t
11 BuOK, Yb(OTf)3 (20 mol%), THF, RT-60 1C 15 min 80 Scheme 3 Synthesis of heteroaryl substituted carbocyclic enaminonitriles.

Table 2 Scope of the reaction

Scheme 4 Proposed mechanism.

respectively, with malononitrile 2. To our delight, the corre-

carbocyclic enaminonitriles (Table 2). Cyclopropanes 1c and 1d with
electron donating groups on the phenyl ring produced the corre-
sponding products 3c and 3d, respectively, in excellent yields. Halo
substituted analogues 3e–i were obtained in excellent yields from the
corresponding cyclopropanes 1e–i. Naphthyl substituted carbocyclic
enaminonitriles 3j–k were also generated when corresponding DA
cyclopropanes (1j–k) were reacted with malononitrile.
Interestingly, cyclopropane 1o with a styryl substituent provided
the corresponding product 3o in excellent yield (Scheme 2). 3o could
easily be converted into a large variety of useful compounds upon
further synthetic manipulations like aziridination, epoxidation and
dihydroxylation of the styryl double bond, etc.
To extend the scope of our strategy for the synthesis of heteroaryl
substituted carbocyclic enaminonitriles, we performed reactions
of the furyl and thiophenyl substituted cyclopropanes 1m and 1n,
sponding products 3m and 3n were obtained in excellent yields
(Scheme 3).
The mechanism of the reaction is depicted in Scheme 4. The
Lewis acid activated complex of the substrate (A) undergoes SN2
attack7a of the malononitrile anion at the benzylic position
providing complex B which undergoes cyclisation via attack of
the generated enolate on one of the nitrile moieties to produce
C. Upon quenching followed by tautomerisation, C provides
carbocyclic enaminonitrile 3 (Scheme 4).
In summary, we have developed a simple and efficient protocol
for synthesis of carbocyclic enaminonitriles via reaction of substi-
tuted DA-cyclopropanes with malononitrile in a domino fashion.
The reaction is also useful for the synthesis of heteroaryl and styryl
substituted carbocyclic enaminonitriles, which could be attractive
substrates for synthesis of valuable scaffolds.
A general procedure for the ring opening cyclisation of
dialkyl-2-arylcyclopropane-1,1-dicarboxylates 1 to dialkyl-2-amino-
3-cyano-4-arylcyclopent-2-ene-1,1-dicarboxylates 3: to a suspension

8206 Chem. Commun., 2013, 49, 8205--8207 This journal is c The Royal Society of Chemistry 2013

ChemComm
of NaH (1.275 mmol) in THF (1.0 mL), malononitrile 2
(1.275 mmol) was added at room temperature under a nitrogen
atmosphere and the reaction mixture was stirred until evolu-
tion of H2 ceased. Cyclopropane 1 (0.425 mmol) dissolved in
THF (1.0 mL) and Yb(OTf)3 (0.085 mmol) dissolved in THF
(1.0 mL) were added sequentially to the reaction mixture and it
was stirred at 60 1C for an appropriate time. After usual workup
Published on 18 July 2013. Downloaded by Indian Institute of Technology Kanpur on 2/15/2024 2:47:36 PM.
and column chromatographic purification13 the pure products
were obtained as white crystalline solids.
MKG is thankful to IIT Kanpur and DST, India. RT thanks
CSIR and DPT thanks UGC and IIT Kanpur, India, for financial
support.
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13 See ESI† for details.
Chem. Commun., 2013, 49, 8205--8207 8207