Stereospecific syntheses of enaminonitriles and β-Enaminoesters via Domino Ring-Opening Cyclization (DROC) of Activated Cyclopropanes with Pronucleophilic Malononitriles

Article abstract of DOI:10.1021/acs.joc.7b03033

Two novel synthetic protocols for the syntheses of highly functionalized five-membered carbocyclic enaminonitriles and β-enaminoesters have been developed via domino ring-opening cyclization (DROC) and DROC/decarboxylative tautomerization of activated cyc

Full text of DOI:10.1021/acs.joc.7b03033

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Article
Stereospecific Syntheses of Enaminonitriles and #-
Enaminoesters via Domino Ring-Opening Cyclization (DROC)
of Activated Cyclopropanes with Pronucleophilic Malononitriles
Amrita Saha, Aditya Bhattacharyya, Ranadeep Talukdar, and Manas K. Ghorai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03033 • Publication Date (Web): 17 Jan 2018
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Stereospecific Syntheses of Enaminonitriles and βꢀ
Enaminoesters via Domino RingꢀOpening Cyclization (DROC)
of Activated Cyclopropanes with Pronucleophilic Malononitriles
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Amrita Saha, Aditya Bhattacharyya, Ranadeep Talukdar and Manas K. Ghorai*
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
Fax: (+91)ꢀ512ꢀ2597436; Phone: (+91)ꢀ512ꢀ2597518; email: mkghorai@iitk.ac.in
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
Two novel synthetic protocols for the syntheses of highly functionalized fiveꢀmembered
carbocyclic enaminonitriles and βꢀenaminoesters have been developed via domino ringꢀopening
cyclization (DROC) and DROC/decarboxylative tautomerization of activated cyclopropanes with
malononitrile pronucleophiles, respectively. Both of the efficient strategies (yield up to 93%)
have been generalized with various donorꢀacceptor and acceptor cyclopropanes as well as with
malononitrile derivatives. The stereospecific variants of the two SN2ꢀtype DROC strategies have
also been developed by employing enantiopure donorꢀacceptor (DA) cyclopropanes to synthesize
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the corresponding nonracemic products with excellent stereoselectivities (dr up to >99:1, ee up to
>99%).
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Introduction
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Fiveꢀmembered carbocyclic enaminonitriles and βꢀenaminoesters, as shown in Figure 1, are
ubiquitous structural motifs in natural products and other synthetic compounds with a wide
spectrum of biological activities. I having a fiveꢀmembered enaminonitrile framework exhibits
antiviral activity against HSVꢀ1 and HIVꢀ11 and II, also possessing the same structural core,
exhibits a limited antimicrobial activity.2 On the other hand, fiveꢀmembered βꢀenaminoester
motifꢀbearing compounds III and IV exhibit lifespanꢀaltering properties in eukaryotic
organisms.3
Figure 1. Biologically Active FiveꢀMembered Carbocyclic Enaminonitriles and βꢀ
Enaminoesters
Owing to the presence of the aforementioned enaminonitrile scaffold in beneficial bioactive
compounds, a number of reports exists in the literature for the synthesis of fiveꢀmembered
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carbocyclic enaminonitriles.4 A few strategies engage cyclopropanes as the substrates for this
purpose such as radical cyclization of dicyanocyclopropanes,5 Feꢀcatalyzed allylic substitution of
vinyl cyclopropane with malononitrile,6 and the ringꢀexpansion reaction of
cyclopropanedicarboximides with malononitrile.7 There are also a few reports available for the
synthesis of fiveꢀmembered carbocyclic βꢀenaminoesters that describe trapping of Blaise reaction
intermediates with alkynes,8 amination of cyclic βꢀketoesters,9 superacidꢀcatalyzed
intramolecular cyclization reactions of arylcyanopropionates,10 cyclization of cyanoꢀsubstituted
unsaturated esters11 etc. Ren and coꢀworkers have also observed the formation of the carbocyclic
βꢀenaminoesters from the reaction of cyclopropanedicarboximides with ethyl cyanoacetate.7
However, the existing reports could only provide a few varieties of enaminonitriles and
enaminoesters. As the highly functionalizable appendages (nitrile, amino or ester groups) confer
biological activities to these classes of fiveꢀmembered carbocyclic compounds,4 it is challenging
and highly desirable to develop new protocols for the construction of these frameworks with the
required architectural and stereogenic complexity.
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In recent years, donorꢀacceptor (DA) cyclopropanes have become one of the important classes of
building blocks and the related chemistry has made significant contributions to organic
synthesis.12 Synthetic exploration of DA cyclopropanes by utilizing their inherent proclivity to
undergo a wide range of ringꢀopening transformations with functionalized nucleophiles has led
to the development of interesting routes to various carboꢀ13 and heterocyclic14 compounds. For
over a decade and a half we have been exploring and utilizing a wide variety of SN2ꢀtype ringꢀ
opening transformations of activated small ring azaꢀheteroꢀ and carbacycles15 to conveniently
access a number of heterocyclic16 and carbocyclic compounds,4e,17 respectively, of contemporary
interest. We are keenly interested in designing convenient and economical synthetic plans for
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various carbocyclic frameworks via stateꢀofꢀtheꢀart domino ringꢀopening cyclization (DROC)
strategies employing a wide range of donorꢀacceptor (DA) cyclopropanes and functionalized
amphiphilic species bearing both nucleophilic and electrophilic termini.4e,15b,17 We earlier
communicated the preparative procedures for carbocyclic enaminonitriles4e and βꢀ
enaminoesters17c via SN2ꢀtype DROC and DROC/decarboxylative tautomerization of DA
cyclopropanes with malononitrile and substituted malononitrile pronucleophiles, respectively.
Owing to the sustained and everꢀincreasing pharmaceutical significance and synthetic potentials
of the aforementioned product classes, we have explored further for generalization and enhanced
flexibility of the two protocols in terms of reactivity and functionalizability of the cyclopropane
and malononitrile substrates. We have also aimed to develop a highly desirable extension to their
enantiospecific variants. Herein, we wish to record the comprehensive results of our endeavours
as an article.
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Results And Discussion
Based on our report for the synthesis of 4,5ꢀdihydropyrroles containing enaminonitrile moiety
via DROC of Nꢀsulfonylaziridines with malononitrile,18 we envisaged that carbocyclic
enaminonitriles could easily be synthesized via DROC of DA cyclopropanes with malononitrile
nucleophile under appropriate reaction conditions. To realize our idea, we studied the reaction of
dimethyl 2ꢀphenylcyclopropaneꢀ1,1ꢀdicarboxylate (1a) with malononitrile (2a) in THF at rt–60
°C. Stoichiometric amount of Sc(OTf)3 was used as the Lewis acid (LA) to further activate 1a
and 3.0 equiv of NaH was used as the base to generate the active nucleophile from 2a. To our
pleasure, the reaction completed in 30 min and the desired carbocyclic enaminonitrile derivative
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3a was produced in 46% yield (Scheme 1). The compound 3a was characterized by spectral data
and its structure was unambiguously confirmed by single crystal Xꢀray analysis.4e
Scheme 1. Synthesis of Carbocyclic Enaminonitrile 3a via Lewis Acid Mediated DROC of
DA Cyclopropane 1a and Malononitrile (2a)
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To optimize the reaction condition for obtaining enhanced yield of the product 3a, we screened
several Lewis acids such as Ti(iPrO)4, Zn(OTf)2, Cu(OTf)2, BF3—OEt2, and Yb(OTf)3. Yb(OTf)3
was found to be the most effective LA and 3a was produced in 87% yield within 10 min (entry 6,
Table 1). Altering the solvent from THF to toluene drastically reduced the yield of 3a (39%,
entry 7, Table 1). The use of catalytic amount of Yb(OTf)3 (20 mol %) in THF at rt–60 °C was
found to be the best condition (88% yield, entry 8, Table 1). Further reduction in the catalyst
t
loading (entry 9), or dropping the temperature (entry 10), or using BuOK instead of NaH (entry
11) were found to have adverse effect on the efficiency of the transformation. Notably, the
reaction did not proceed at all in the absence of any Lewis acid (entry 12). All the results are
summarized in Table 1.
Table 1. Optimization Studies for the Synthesis of Carbocyclic Enaminonitrile 3a via Lewis
Acid Catalyzed DROC of DA Cyclopropane 1a and Malononitrile (2a)
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entry Lewis acid (mol %)
basea
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
tBuOK
NaH
solvent
THF
THF
THF
THF
THF
THF
toluene
THF
THF
THF
THF
THF
temp (°C)
rt–60
rt–60
rt–60
rt–60
rt–60
rt–60
rt–60
rt–60
rt–60
Rt
time
30 min
10 min
1 h
yield (%)
1
2
Sc(OTf)3 (100)
Ti(OiPr)4 (100)
Zn(OTf)2 (100)
Cu(OTf)2 (100)
BF3—OEt2 (100)
Yb(OTf)3 (100)
Yb(OTf)3 (100)
Yb(OTf)3 (20)
Yb(OTf)3 (10)
Yb(OTf)3 (20)
Yb(OTf)3 (20)
ꢀ
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70
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30 min
5 min
10 min
45 min
15 min
20 min
9 h
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70
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ꢀ
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rt–60
rt–60
15 min
12 h
a3.0 equiv of base was used in all of the reactions.
Under the optimized reaction conditions, we next generalized our approach employing a wide
range of DA cyclopropanes possessing different substituents of varying electronic and steric
properties with malononitrile and the results are described in Table 2. The reaction proceeded
well with diethyl 2ꢀphenylcyclopropaneꢀ1,1ꢀdicarboxylate (1b) giving rise to the corresponding
product 3b in 83% yield (entry 2). With electronꢀdonating groups such as 4ꢀMe, 4ꢀOMe, and 2,3ꢀ
(OMe)2 on the 2ꢀaryl groups of the DA cyclopropanes (1c–e), the corresponding products 3c–e
were obtained in high yields (up to 90%, entries 3–5). The reactions of halogenꢀsubstituted DA
cyclopropanes (1f–j) with malononitrile were successful and the corresponding carbocyclic
enaminonitriles 3f–j were obtained in excellent yields (up to 92%, entries 6–10). Naphthylꢀ
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substituted carbocyclic enaminonitriles 3k–l were also obtained in high yields (up to 82%) when
the corresponding DA cyclopropanes 1k–l were reacted with malononitrile under the optimized
conditions (entries 11–12). The lower yield and longer reaction time required for the formation
of 3k was presumably due to the steric crowding exerted by the 1ꢀnaphthyl group, rendering the
corresponding DA cyclopropane 1k less reactive towards nucleophilic attack. To extend the
scope of our strategy for the synthesis of heteroarylꢀsubstituted carbocyclic enaminonitriles, we
performed reactions of the 2ꢀfuryl and 2ꢀthienylꢀsubstituted cyclopropanes 1m and 1n,
respectively, with 2a. To our delight, the corresponding products 3m and 3n were obtained in
excellent yields (91% and 93%, entries 13 and 14). The DA cyclopropane with a styryl
substituent at its 2ꢀposition (1o) provided the corresponding product 3o in excellent yield (93%,
entry 15). It is pertinent here to note that the presence of highly functionalizable synthetic units
in the 2ꢀaryl groups of the cyclopropanes such as halogens in 1f–j and olefin in 1o could allow
further structural elaboration, thereby adding further values to the protocol.
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Table 2. Generalization and Substrate Scope for the Synthesis of Carbocyclic
Enaminonitriles via Lewis Acid Catalyzed DROC of DA Cyclopropanes with Malononitrile
time
entry
DA cyclopropane (1)
βꢀenaminonitrile (3)
yield (%)
(min)
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Inspired by these results, we extended the scope of the strategy for the synthesis of
enantioenriched carbocyclic enaminonitrile derivatives employing optically pure dimethyl (S)ꢀ2ꢀ
phenylcyclopropaneꢀ1,1ꢀdicarboxylate (S)ꢀ1a as the substrate.19 When (S)ꢀ1a (>99% ee) was
treated with 3.0 equiv of malononitrile (2a) in the presence of 20 mol % Yb(OTf)3 and 3.0 equiv
of sodium hydride in anhydrous tetrahydrofuran at rt–60 °C,4e to our delight, the desired
nonracemic carbocyclic enaminonitrile derivative (R)ꢀ3a was obtained within 15 min in 88%
yield with excellent enantiopurity (>99% ee, Scheme 2).
Scheme 2. Synthesis of Enantioenriched Carbocyclic Enaminonitrile (R)ꢀ3a via Domino
RingꢀOpening Cyclization of DA Cyclopropane (S)ꢀ1a with Malononitrile (2a)
To accommodate additional functionalities in the products as well as to generalize the
methodology with comparatively less reactive DA cyclopropanes, we employed dimethyl 2ꢀ
vinylcyclopropaneꢀ1,1ꢀdicarboxylate (1p)12l as the substrate that could easily be functionalized
but was expected to be less reactive due to weaker πꢀelectronꢀdonating ability of the vinyl group
compared to its aryl analogues. When 1p along with malononitrile (2a, 3.0 equiv) were exposed
to the optimized DROC conditions in the presence of 20 mol % Yb(OTf)3 and 3.0 equiv of NaH
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in THF, the corresponding carbocyclic enaminonitrile derivative 3p was obtained within 40 min
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in high yield (78%, Scheme 3).
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Scheme 3. Synthesis of Highly Functionalizable Carbocyclic Enaminonitrile 3p via DROC
of 2ꢀVinyl Substituted DA Cyclopropane 1p with Malononitrile (2a)
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We generalized our methodology further by employing even less reactive DA cyclopropanes
possessing weaker donor groups such as alkyl groups at the 2ꢀposition that could stabilize the
incipient electrophilic center probably through hyperconjugation. To achieve this, dimethyl 2ꢀ
methylcyclopropaneꢀ1,1ꢀdicarboxylate (1q)20 was reacted with malononitrile (2a, 3.0 equiv) in
the presence of 50 mol % Yb(OTf)3 and 3.0 equiv of NaH in THF at rt–60 °C. Although the
conversion was found to be sluggish, the expected carbocyclic enaminonitrile derivative 3q was
obtained in considerably good yield after 3 d (72%, Scheme 4). It is worth noting that the
relatively low propensity of the 2ꢀmethyl DA cyclopropane to undergo nucleophilic ringꢀopening
transformations compared to their 2ꢀaryl or 2ꢀvinyl analogues necessitated the use of the
additional amount (50 mol %) of Lewis acid.
Scheme 4. Synthesis of Methyl Substituted Carbocyclic Enaminonitrile via DROC of 2ꢀ
Methyl Substituted DA Cyclopropane 1q with Malononitrile (2a)
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Our success in generalizing the methodology incited us to evaluate the effectiveness of the
cyclopropanes bearing no electronꢀdonating groups at the vicinal position of the two electronꢀ
accepting ester groups for the syntheses of carbocyclic enaminonitriles. Therefore, diethyl
cyclopropaneꢀ1,1ꢀdicarboxylate (1r), synthesized following a literature report,20 was subjected to
the DROC protocol with malononitrile (2a) in the presence of 50 mol % Yb(OTf)3 and 3.0 equiv
of NaH in THF at rt–60 °C. In this case also the reaction was found to be sluggish and the
corresponding carbocyclic enaminonitrile derivative 3r was obtained in good yield after 3 days
(68%, Scheme 5).
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Scheme 5. Synthesis of Carbocyclic Enaminonitrile via DROC of Acceptor Cyclopropane
with Malononitrile
After successfully generalizing the methodology for the synthesis of a wide range of substituted
and functionalized carbocyclic enaminonitriles in their racemic and nonracemic forms via DROC
of the corresponding activated cyclopropanes with malononitrile, we intended to further explore
the scope of the aboveꢀdescribed DROC transformation of activated cyclopropanes with 2ꢀ
substituted malononitriles. We expected the reaction to give rise to a new class of ketonic
compound VI as shown in Scheme 6. For this purpose, as a preliminary experiment, when 1a
was reacted with 2ꢀbenzylmalononitrile (2b) in the presence of 20 mol % Yb(OTf)3 as the Lewis
acid and 3.0 equiv of NaH as the base to generate the active nucleophile in THF at rt–60 °C, to
our great surprise the carbocyclic
β
ꢀenaminoester derivative 4a bearing an allꢀcarbon quaternary
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stereocenter was obtained as a single diastereomer presumably via a sequence of oneꢀpot DROC
followed by an in situ decarboxylation and tautomerization in very high yield (81%, Scheme 6).
The formation of the ketonic compound VI was not observed at all. The structure of 4a was
unambiguously determined by spectroscopic analysis.21
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Scheme 6. Diastereoselective Synthesis of Carbocyclic βꢀEnaminoester 4a via
DROC/Decarboxylative Tautomerization of 1a with 2ꢀBenzylmalononitrile (2b)
NH
O
NaH (3.0 equiv)
Yb(OTf)3 (20 mol %)
Bn
NC
Bn
NC
CO2Me
CO2Me
CO2Me
CO2Me
THF, rt-60 C
V
VI
Ph
Ph
NC
CN
Bn
CO2Me
CO2Me
+
Ph
1a
2b
NH2
NaH (3.0 equiv)
Yb(OTf)3 (20 mol %)
Bn
NC
CO2Me
THF, rt-60 C, 40 min
4a, 81%
>99:1 dr
Ph
In order to optimize the reaction conditions, several other Lewis acids such as Cu(OTf)2,
Zn(OTf)2, and Sc(OTf)3 were screened. However, the best result was obtained with 20 mol %
Yb(OTf)3 and 3.0 equiv of NaH in THF at rt–60 °C. Reduced loading of Yb(OTf)3 resulted in
incompletion of the reaction. When the reaction was performed at room temperature, 1a
remained unreacted and 2b was found to be converted into a polymeric material in the reaction
mixture. Hence, elevated temperature was required for successful completion of the reaction.
Cognizant of the biological relevance of the substituted carbocyclic βꢀenaminoesters, subsequent
studies were focused towards the generalization of the developed methodology by employing a
wide range of 2ꢀaryl, 2ꢀheteroaryl and 2ꢀstyrylꢀsubstituted DA cyclopropanes of different
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stereoelectronic nature with various 2ꢀalkyl, 2ꢀallyl, and 2ꢀcycloalkylꢀsubstituted malononitriles.
All the results are summarized in Table 3. When an electronꢀrich substrate, dimethyl 2ꢀ(4ꢀ
methoxyphenyl)cyclopropaneꢀ1,1ꢀdicarboxylate (1d) was reacted with 2ꢀbenzylmalononitrile
(2b) under the optimized reaction conditions, the reaction completed in 30 min and the
corresponding carbocyclic βꢀenaminoester derivative 4b was obtained in 85% yield as a single
diastereomer (entry 2, Table 3). Subsequently, 2b was employed as the pronucleophile for
relatively electronꢀdeficient 4ꢀfluorophenylꢀsubstituted DA cyclopropane 1f and 2ꢀstyrylꢀ
substituted DA cyclopropane 1o and in both of the cases, we gratifyingly observed the
formations of the corresponding products 4c and 4d, respectively, in very high yields (85%,
entry 3 and 87%, entry 4, Table 3). Interestingly, it was discovered that malononitriles with
benzyl or heteroaryl groups attached to their 2ꢀposition could impart excellent diastereocontrol to
the transformation. Accordingly, when 2ꢀ(4ꢀmethylbenzyl)malononitrile (2c) and 2ꢀ(furanꢀ2ꢀ
ylmethyl)malononitrile (2d) were employed as the pronucleophiles in the
DROC/decarboxylative tautomerization protocol with DAꢀcyclopropane 1a under the optimized
reaction conditions, the corresponding carbocyclic βꢀenaminoesters 4e and 4f, respectively,
formed in excellent yields (up to 84%) as single diastereomers (dr >99:1, entries 5 and 6, Table
3). Interestingly, when 1a and 1f were reacted with 2ꢀmethylmalononitrile (2e), the
diastereoselectivity of the reaction was notably reduced and the corresponding carbocyclic βꢀ
enaminoesters 4g and 4i were obtained in very high yields as a mixture of separable
diastereomers (entries 7 and 9, Table 3). However, electronꢀrich 1d upon reacting with 2e
afforded the desired product 4h in 80% yield as a single diastereomer (entry 8, Table 3). When
relatively more sterically encumbered malononitrile derivative 2f with a 3ꢀpentyl group at its 2ꢀ
position was used as the pronucleophile, the corresponding carbocyclic βꢀenaminoester 4j was
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obtained in excellent yield (81%, entry 10, Table 3) as a single diastereomer. When DA
cyclopropane 1a reacted with 2ꢀallylmalononitrile (2g) under the optimized
DROC/decarboxylative tautomerization conditions, the corresponding βꢀenaminoesters 4k and
4k′ were obtained in excellent yields as a mixture of separable diastereomers with moderate
diastereoselectivity (dr 1.32:1, entry 11, Table 3). The relative stereochemistry of the major and
the minor diastereomers were determined to be syn and anti, respectively, by single crystal Xꢀray
analysis.21 When highly electronꢀrich DA cyclopropanes such as 1d and 1e and relatively
electronꢀdeficient DA cyclopropanes such as 1g and 1h were reacted with 2ꢀallylmalononitrile
(2g) under the identical conditions, the corresponding fiveꢀmembered carbocyclic βꢀ
enaminoesters 4l–o formed in excellent yields as single diastereomers (dr >99:1, up to 86%
yield, entries 12–15, Table 3). Similar observations were recorded when 1ꢀnaphthyl substituted
DA cyclopropane 1k and 2ꢀthienyl substituted DA cyclopropane 1n were reacted with 2g under
the optimized reaction conditions, the desired products 4p and 4q were obtained in excellent
yields as single diastereomers (entries 16 and 17, Table 3). However, when 2ꢀstyryl substituted
DA cyclopropane 1o was reacted with 2g, the corresponding carbocyclic βꢀenaminoesters 4r and
4r′ were obtained with 7:1 diastereomeric ratio (entry 18, Table 3). When cyclopentylꢀ
substituted malononitrile derivative 2h along with 1a was exposed to the optimized conditions,
the corresponding carbocyclic βꢀenaminoesters 4s and 4s′ were obtained in good yields with
moderate diastereoselectivity (dr 1:0.43, entry 19, Table 3). Notable enhancement in the
diastereoselectivity was observed (dr 9:1) when cyclohexylꢀsubstituted malononitrile 2i was
employed and the major diastereomer of the corresponding product 4t was isolated (76%, entry
20, Table 3). Lastly, 1a was reacted with 2ꢀphenylmalononitrile (2j) under the optimized reaction
conditions. However, no advancement of the reaction was observed (entry 21, Table 3)
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18
19
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21
22
23
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25
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29
30
31
32
33
34
35
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37
38
39
40
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50
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presumably due to the increased steric hindrance and high degree of stabilization of the incipient
carbanion generated in situ by the phenyl group rendering it less nucleophilic towards the
cyclopropane.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Synthesis of Densely Substituted Carbocyclic βꢀEnaminoesters via Domino Ringꢀ
Opening Cyclization/Decarboxylative Tautomerization of DA Cyclopropanes with 2ꢀ
Substituted Malononitriles
time yld
dra
entry
1
major (4)
minor (4′)
1
2
(min) (%)
ꢀ
40
30
81
85
>99:1
>99:1
1a
2
ꢀ
1d
3
4
ꢀ
ꢀ
35
15
85
87
>99:1
>99:1
1f
1o
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Ph
CO2Me
NH2
NC
4e
ꢀ
ꢀ
40
35
82
>99:1
1a
1a
7
8
9
5
6
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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29
30
31
32
33
34
35
36
37
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39
40
41
42
43
44
45
46
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48
49
50
51
52
53
54
55
56
57
58
59
60
84 >99:1
7
8
35
30
85
80
1:0.86
>99:1
1a
1d
ꢀ
9
45
75
3:1
1f
10
11
45
40
81
86
>99:1
1.32:1
1a
1a
ꢀ
NC
2g
CN
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NC
2g
CN
CN
12
13
ꢀ
ꢀ
30
25
86
86
>99:1
>99:1
1d
1e
10
11
12
13
14
15
16
17
18
19
20
21
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49
50
51
52
53
54
55
56
57
58
59
60
NC
2g
NC
2g
CN
CN
14
15
ꢀ
ꢀ
40
40
80
82
>99:1
>99:1
1g
1h
NC
2g
NC
2g
CN
16
ꢀ
ꢀ
60
80
>99:1
1k
NC
2g
CN
17
18
15
15
82
87
>99:1
7:1
1n
1o
NC
2g
CN
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NC
CN
CN
2h
19
60
74
1:0.43
1a
NC
10
11
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18
19
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2i
20b
21
60
76
ꢀ
9:1
ꢀ
1a
1a
NC
NC
Ph
2j
NR
NR
120
aThe diastereomeric ratio have been determined by H NMR analysis of the crude reaction
1
mixture. bOnly the major diastereomer could be isolated.
In order to obtain highly functionalizable carbocyclic βꢀenaminoesters utilizing our strategy,
reactions of 2ꢀvinyl substituted DA cyclopropane with substituted malononitriles were explored.
A wide range of 2ꢀsubstituted malononitriles containing various alkyl, cycloalkyl, aryl, and
heteroaryl groups were deployed for this purpose and the results are detailed in Table 4. When
1p was reacted with 2ꢀmethylmalononitrile (2e, 3.0 equiv) in the presence of 20 mol % Yb(OTf)3
and 3.0 equiv of NaH in THF, the corresponding vinylꢀsubstituted carbocyclic βꢀenaminoesters
4u and 4u′ were obtained in good yields with good diastereoselectivity (dr 3.41:1, entry 1, Table
4). The relative stereochemistry at the 3 and 4ꢀpositions of the products were confirmed by single
crystal Xꢀray analysis of both of these diastereomers.21 Next, when cyclohexylꢀsubstituted
malononitrile derivative 2i was reacted with 1p under the optimized reaction conditions, the
corresponding carbocyclic βꢀenaminoesters 4v and 4v′ formed in good yields with moderate
diastereomeric ratio (1.83:1, entry 2, Table 4). Based on our previous studies (Table 3) we
attempted to improve the diastereoselectivity of the products by introducing a benzylꢀsubstituted
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malononitrile derivative as the pronucleophile. When 2b together with 1p were exposed to the
optimized reaction conditions, the corresponding products 4w and 4w′ were obtained in good
yields with significantly increased diastereomeric ratio (6.18:1, entry 3, Table 4). Finally,
excellent diastereoselectivity was observed when 2ꢀfurylꢀsubstituted malononitrile derivative
(2d) was reacted with 1p and the corresponding carbocyclic βꢀenaminoester 4x was obtained
exclusively in good yield (dr >99:1, entry 4, Table 4).
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
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35
36
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Synthesis of Highly Functionalizable Carbocyclic βꢀEnaminoesters via
DROC/Decarboxylative Tautomerization of 2ꢀVinyl Substituted DA Cyclopropanes with
Substituted Malononitriles
time yield
entry
1
malononitrile (2)
βꢀenaminoester (4) βꢀenaminoester (4′)
dra
(min) (%)
50
75
75
72
3.41:1
1.83:1
NC
CN
2i
2b
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3b
60
55
73
70
6.18:1
>99:1
9
10
11
12
13
14
15
16
17
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21
22
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59
60
CO2Me
NC
4
ꢀ
4x
NH2
O
aThe diastereomeric ratio have been determined by analyzing the H NMR spectra of the crude
1
reaction mixture. bOnly the major diastereomer could be isolated.
Next, we endeavored to synthesize highly substituted carbocyclic βꢀenaminoester via
DROC/decarboxylative tautomerization of 2ꢀmethyl substituted DA cyclopropane 1q with 2ꢀ
benzyl malononitrile (2b, 3.0 equiv) in the presence of 50 mol % Yb(OTf)3 and 3.0 equiv of NaH
in THF at 60 °C. The reaction completed in 3 d and the corresponding products 4y and 4y′
formed as a mixture of diastereomers in good combined yields (71%) with moderate
diastereoselectivity (dr 1:0.68, Scheme 7).
Scheme 7. Synthesis of Highly Substituted Carbocyclic βꢀEnaminoesters via
DROC/Decarboxylative Tautomerization of 2ꢀMethyl Substituted DA Cyclopropane with
Substituted Malononitrile
Inspired by our result for the synthesis of enaminonitriles from acceptor cyclopropane, we
subsequently studied the reaction of acceptor cyclopropane with 2ꢀsubstituted malononitrile to
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synthesize substituted carbocyclic βꢀenaminoester. When 1r was reacted with 2ꢀ(pentanꢀ3ꢀ
yl)malononitrile (2f, 3.0 equiv) in the presence of 50 mol % Yb(OTf)3 and 3.0 equiv of NaH in
THF at 60 °C, the corresponding carbocyclic βꢀenaminoester 4z was obtained after 3 d in
relatively reduced yield (65%, Scheme 8).
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11
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13
14
15
16
17
18
19
20
21
22
23
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34
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 8. Synthesis of Carbocyclic βꢀEnaminoester via DROC/Decarboxylative
Tautomerization of Acceptor Cyclopropane with Substituted Malononitrile
Finally, the synthetic significance of our strategy was demonstrated by developing the
enantiospecific variant of the DROC/decarboxylative tautomerization protocol to obtain the
carbocyclic βꢀenaminoesters in enantioenriched forms. When the enantiopure 2ꢀphenyl DAꢀ
cyclopropane (S)ꢀ1a (>99% ee) was reacted with substituted malononitriles (2) under the
optimized reaction conditions, the corresponding highly substituted carbocyclic βꢀenaminoesters
4 and 4′ were obtained with excellent ee. The results are summarized in Table 5 (cf. Table 3).
When (S)ꢀ1a was reacted with 2ꢀmethylmalononitrile (2e, 3.0 equiv) in the presence of 20 mol %
Yb(OTf)3 and 3.0 equiv of NaH in THF at 60 °C, the corresponding products were obtained as a
mixture of separable diastereomers (dr 1:0.86, see entry 1, Table 3). Both of the diastereomers,
(3S,4R)ꢀ4g and (3R,4R)ꢀ4g′, were found to possess excellent enantiomeric excess (98% and
>99% ee, respectively, entry 1, Table 5).21 A marginal decrease in enantiopurity was observed in
case of 2ꢀallylmalononitrile (2g) wherein both of the diastereomers of the corresponding
carbocyclic βꢀenaminoesters, (3S,4R)ꢀ4k and (3R,4R)ꢀ4k′, formed with 92% enantiomeric excess
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(enantiospecificity 97%, entry 2, Table 5). When cyclopentylꢀsubstituted malononitrile
derivative 2h was employed as the pronucleophile with (S)ꢀ1a, the corresponding products
(1S,5R)ꢀ4s and (1R,5R)ꢀ4s′ formed with 95% and 94% ee, respectively (enantiospecificities
>99% and 99%, entry 3, Table 5). When (S)ꢀ1a was exposed to the optimized
DROC/decarboxylative tautomerization conditions with 2ꢀcyclohexylmalononitrile (2i), the
corresponding major diastereomer of the carbocyclic βꢀenaminoester (3S,4R)ꢀ4t was obtained
with 96% ee (enantiospecificity 98%, entry 4, Table 5). DROC/decarboxylative tautomerization
of (S)ꢀ1a could be accomplished with malononitriles bearing either a 2ꢀfuryl group (2d) or a
benzyl group (2b) at their 2ꢀpositions and the corresponding products (3S,4R)ꢀ4f and (3S,4R)ꢀ4a,
respectively, formed as single diastereomers with >99% ee (entries 5 and 6, Table 5).
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11
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Stereospecific Synthesis of Enantioenriched βꢀEnaminoesters via
DROC/Decarboxylative Tautomerization of Enantiopure DA Cyclopropane with
Substituted Malononitriles
malononitrile
ee
βꢀenaminoester
(4′)
es
ee
es
drc
entry
βꢀenaminoester (4)
(%)b
(%)a (%)b
(2)
(%)a
1
98
>99 1:0.86
98
>99
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NC
2g
CN
2d
3d
4e
97
92
97 1.32:1
92
94
ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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29
30
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49
50
51
52
53
54
55
56
57
58
59
60
NC
CN
CN
2h
>99
95
99 1:0.43
NC
2i
98
96
ꢀ
ꢀ
9:1
5
6
>99
>99
ꢀ
ꢀ
ꢀ
ꢀ
>99:1
>99:1
>99
>99
ꢀ
ꢀ
aEnantiomeric excesses have been determined by chiral HPLC analysis. Enantiospecificity (es) =
b
c
[ee of product / ee of starting material] × 100%. The diastereomeric ratio have been determined by
1H NMR analysis of the crude reaction mixture. The enantiomeric excess of the starting material
d
was 95%. eThe enantiomeric excess of the starting material was 98%.
Mechanism
Based on our experimental observations and previous reports,4e,17c we have proposed two
mechanistic pathways for the formation of the nonracemic carbocyclic enaminonitriles and βꢀ
enaminoesters. Scheme 9 depicts the mechanism of the enantiospecific formation of the
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carbocyclic enaminonitriles from enantiopure DA cyclopropanes. At first, (S)ꢀ1a gets activated
by the chelation of the Lewis acid, Yb(OTf)3, with the two carbonyl oxygen atoms of the two
ester (acceptor) groups (B). NaH abstracts a proton from the malononitrile to generate the naked
anionic nucleophile A which subsequently attacks the benzylic position of the DA cyclopropane
in an SN2 fashion to generate the ringꢀopening intermediate C. Concomitant intramolecular
cyclization and ringꢀclosure in a 5ꢀexoꢀdig fashion in intermediate C generates another cyclic
intermediate D which upon protonation and tautomerization furnishes the carbocyclic
enaminonitrile (R)ꢀ3a as the final product in good yield.
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11
12
13
14
15
16
17
18
19
20
21
22
23
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34
35
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 9. Mechanistic Pathway for the Formation of Enantioenriched Carbocyclic
Enaminonitrile via SN2ꢀType DROC of Enantiopure DA Cyclopropane with Malononitrile
MeO
-
O
+
LA
Ph
O
SN2
NaH
MeO B
NC
CN
NC
Na
2
CN
A
CO2Me
CO2Me
Ph
(S)-1a
LA
LA = Yb(OTf)3
LA
O
O
MeO
OMe
NNa
Ph
NC
C
Ph
Ph
Ph
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
aq. NH4Cl
NC
D
NC
(R)-3a
NC
E
N Na
NH2
NH
tautomerization
On the other hand, the formation of enantioenriched carbocyclic βꢀenaminoesters from
enantiopure DA cyclopropanes follows a different and comparatively complex mechanistic
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pathway as shown in Scheme 10.17c It is worth noting that a Lewis acidꢀcatalyzed
decarboxylation process takes place from the complex H which forms after the initial SN2ꢀtype
ring opening of the activated cyclopropane species (B) with the substituted malononitrile
nucleophile (F) and concomitant ringꢀclosure in a 5ꢀexoꢀdig fashion. Subsequently, the final
product, fiveꢀmembered carbocyclic βꢀenaminoester (3S,4R)ꢀ4 is generated following a sequence
of decarboxylation, protonation, and tautomerization of the corresponding synthetic
intermediates.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
28
29
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 10. Mechanistic Pathway for the Formation of Enantioenriched Carbocyclic βꢀ
Enaminoesters via DROC/Decarboxylative Tautomerization of Enantiopure DA
Cyclopropane with Substituted Malononitriles
OMe
O
O
OMe
O
O
Me
Ph
Ph
Me
O
LA
NC
O
NC
LA
O
O
MeO
N
N
R
R
LA
OMe
H
I
Ph
Na
O
OMe
N
Ph
NC
MeO
O
Ph
N
LA
Na
R
NC
Na
(S)-1a
B
R
J
G
O
OMe
OMe
Na
MeO
Ph
NC
-
O
O
+
LA
O
Ph
N
R
K
SN2
MeO
R
Na
B
H2O
NC
LA, NaH
tautomerization
F
CN
NaH (3.0 equiv)
Yb(OTf)3 (20 mol %)
Ph
NC
CO2Me
NC
CN
CO2Me
CO2Me
+
2
Ph
R
(S)-1a
NH2
(3S,4R)-4
major diastereomer
R
THF, rt-60 C
LA = Yb(OTf)3
R = Me, allyl, cyclopentyl,
Cy, 2-furyl, Bn
Conclusion
We have developed simple synthetic strategies for the syntheses of carbocyclic enaminonitriles
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and βꢀenaminoesters via domino ringꢀopening cyclization and domino ringꢀopening
cyclization/decarboxylative tautomerization of donorꢀacceptor cyclopropanes, respectively, with
malononitrile(s). We have generalized our approach employing a number of donorꢀacceptor
cyclopropanes with different electronꢀdonating groups or without any donor groups at the 2ꢀ
position of DA cyclopropanes. We have successfully developed the enantiospecific variants of
the aforementioned protocols to furnish the enaminonitriles and βꢀenaminoesters with excellent
ee from enantiopure DAꢀcyclopropanes. We strongly believe that the synthetic strategies will
find wide applications in synthetic organic and medicinal chemistry for accessing such valuable
and functionalizable carbocyclic frameworks.
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Experimental Section
General Procedures. Analytical thin layer chromatography (TLC) was carried out using silica
gel 60 F254 precoated plates. Visualization was accomplished with UV lamp or I2 strain. Silica
gel 230ꢀ400 mesh size was used for flash chromatography using the combination of ethyl acetate
and petroleum ether as eluent. Unless noted otherwise, all of the reactions were carried out in
ovenꢀdried glassware under an atmosphere of nitrogen/argon using anhydrous solvents. Where
appropriate, all of the reagents were purified prior to use following the guidelines of Armarego
and
phenylcyclopropaneꢀ1,1ꢀdicarboxylate,19 dimethyl 2ꢀvinylcyclopropaneꢀ1,1ꢀdicarboxylate,14a
2ꢀmethylcyclopropaneꢀ1,1ꢀdicarboxylate20
Chai.22
Dimethyl
2ꢀphenylcyclopropaneꢀ1,1ꢀdicarboxylate,23
dimethyl
(S)ꢀ2ꢀ
dimethyl
and
diethyl
cyclopropaneꢀ1,1ꢀ
dicarboxylate20 were prepared using literature procedure. 2ꢀSubstituted malononitriles were
synthesized using literature method.17c,24 All of the other commercial reagents were used as
received. Proton nuclear magnetic resonance (1H NMR) spectra were recorded at 400 or 500
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MHz. The chemical shifts were recorded in parts per million (ppm, δ) relative to tetramethyl
5
6
1
silane (δ 0.00). H NMR splitting patterns are designated as singlet (s), broad singlet (br s),
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doublet (d), doublet of doublets (dd), doublet of doublet of doublets (ddd), triplet (t), AB quartet
(ABq), multiplet (m). Protonꢀdecoupled carbon nuclear magnetic resonance (13C{1H} NMR)
were recorded at 100 or 125 MHz. High resolution mass spectra (HRMS) were obtained using an
ESI mass spectrometers (TOF). KBr plates were used for IR spectra of solid compounds,
whereas liquid compounds were recorded neat. The melting point measurements were made
using a hotꢀstage apparatus and are reported as uncorrected. The enantiomeric excess (ee) was
determined by chiral HPLC using a Chiralcel ODꢀH or celluloseꢀ2 column (detection at 254 nm).
Optical rotations were measured using a 6.0 mL cell with 1.0 dm path length and are reported as
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[α]25 (c in g per 100 mL of solvent) at 25 °C. Diastereomeric ratio (dr) were determined by
D
analysis of 1H NMR spectra of the crude reaction mixtures.
General Experimental Procedure for the DROC and DROC/Decarboxylative
Tautomerization of DA Cyclopropanes with Malononitrile and Substituted Malononitriles.
Method A.4e,17c To a suspension of NaH (25.6 mg, 0.640 mmol, 3.0 equiv) in 0.5 mL THF, a THF
solution (0.5 mL) of malononitrile derivative (for Scheme 2, 36 ꢁL, 0.640 mmol, 3.0 equiv) was
added and the reaction mixture was stirred at room temperature under argon atmosphere until the
evolution of H2 gas ceased. Then, appropriate racemic or enantiopure dimethyl 2ꢀ
phenylcyclopropaneꢀ1,1ꢀdicarboxylate (for (S)ꢀ1a, Scheme 2, 50.0 mg, 0.213 mmol, 1.0 equiv)
or dimethyl 2ꢀvinylcyclopropaneꢀ1,1ꢀdicarboxylate (1.0 equiv) and Yb(OTf)3 (26.5 mg, 0.043
mmol, 0.2 equiv) dissolved in THF (0.5 mL) were added sequentially to the reaction mixture at
the same temperature and it was stirred at 60 °C until the reaction was complete. After complete
consumption of the starting material (monitored by TLC) the reaction mixture was quenched by
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saturated aqueous NH4Cl solution. The organic phase was separated and the aqueous phase was
extracted with ethyl acetate (3 × 5.0 mL). The combined organic extract was washed with brine
solution and dried over anhydrous sodium sulphate. After removal of the organic solvent under
reduced pressure, the crude reaction mixture was purified by flash column chromatography on
silica gel (230–400 mesh) using 10–20% ethyl acetate in petroleum ether as the eluent to give the
diastereomers in pure form.
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Method B. To a suspension of NaH (34.8 mg, 0.871 mmol, 3.0 equiv) in 0.5 mL THF, a THF
solution (0.5 mL) of malononitrile derivative (for Scheme 4, 48 ꢁL, 0.871 mmol, 3.0 equiv) was
added and the reaction mixture was stirred at room temperature under argon atmosphere until the
evolution of H2 gas ceased. Then, dimethyl 2ꢀmethylcyclopropaneꢀ1,1ꢀdicarboxylate (for
Scheme 4, 50.0 mg, 0.290 mmol, 1.0 equiv) or diethyl cyclopropaneꢀ1,1ꢀdicarboxylate (1.0
equiv) and Yb(OTf)3 (36.0 mg, 0.058 mmol, 0.5 equiv) dissolved in THF (0.5 mL) were added
sequentially to the reaction mixture at the same temperature and it was stirred at 60 °C until the
reaction was complete. After complete consumption of the starting material (monitored by TLC)
the reaction mixture was quenched by saturated aqueous NH4Cl solution. The organic phase was
separated and the aqueous phase was extracted with ethyl acetate (3 × 5.0 mL). The combined
organic extract was washed with brine solution and dried over anhydrous sodium sulphate. After
removal of the organic solvent under reduced pressure, the crude reaction mixture was purified
by flash column chromatography on silica gel (230–400 mesh) using 10–20% ethyl acetate in
petroleum ether as the eluent to give the diastereomers in pure forms, wherever applicable.
The general method A described above was followed to prepare the enaminonitrile derivatives
3b–3o and their data were provided in our previous report.4e The general method A described
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