Stereoselective synthesis and applications of nitrogen substituted donor-acceptor cyclopropanes (N-DACs) in the divergent synthesis of azacycles

Article abstract of DOI:10.1039/c2ob06591f

A new, highly stereoselective intramolecular cyclopropanation of vinylogous carbamates with carbenes in the presence of Cu(acac)₂ as the catalyst has been developed for the construction of cyclopropapyrrolidinones. The 'syn' isomer of N-DAC can be converted to the 'anti' isomer by simple silica gel treatment. Regioselective cleavage of each of the cyclopropane bonds of these two acceptor substituted N-DACs led to a diverse array of azacycles.

Full text of DOI:10.1039/c2ob06591f

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COMMUNICATION
Stereoselective synthesis and applications of nitrogen substituted donor–
acceptor cyclopropanes (N-DACs) in the divergent synthesis of azacycles†
Santosh J. Gharpure,* U. Vijayasree and S. Raja Bhushan Reddy
Received 19th September 2011, Accepted 7th December 2011
DOI: 10.1039/c2ob06591f
complete regiocontrol is conspicuous by its absence. Herein, we
describe a highly regio- and stereoselective synthesis of N-DACs
employing intramolecular cyclopropanation of vinylogous carba-
mates. Further, we demonstrate that each of the cyclopropane
bonds of these N-DACs can be cleaved with complete regiocon-
trol, generating a diverse array of azacycles.
A new, highly stereoselective intramolecular cyclopropana-
tion of vinylogous carbamates with carbenes in the presence
of Cu(acac)2 as the catalyst has been developed for the con-
struction of cyclopropapyrrolidinones. The ‘syn’ isomer of
N-DAC can be converted to the ‘anti’ isomer by simple silica
gel treatment. Regioselective cleavage of each of the cyclopro-
pane bonds of these two acceptor substituted N-DACs led to
a diverse array of azacycles.
Recently, we developed a new method for stereoselective syn-
thesis of the oxygen substituted DACs employing intramolecular
cyclopropanation of vinylogous carbonates.9 These DACs were
used in the divergent synthesis of THF, THP and lactone deriva-
tives. In continuation of our interest in using vinylogous func-
tional groups in the synthesis of heterocycles,10 we envisioned
that the N-DAC 1 could be readily assembled by copper(I) cata-
lysed intramolecular cyclopropanation11 of the vinylogous carba-
mate moiety in the diazoketone 2 (Scheme 1). The diazoketone
2 could in turn be readily prepared from the acid 3, which itself
is obtained from readily available enantiomerically enriched
α-amino acids. The choice of the nitrogen protecting group was
previously noted as very important since β-ACCs or N-DACs
without an electron withdrawing substituent on nitrogen are
extremely susceptible to ring opening reactions.1 Protecting
groups such as tosyl and carbamates were thus chosen for this
study.
The diazoketones 2 required for the study were readily pre-
pared from the acids 3. Reaction of the acid 3a with oxalyl chlor-
ide followed by treatment of the acid chloride with ethereal
diazomethane generated the diazoketone 2a. Decomposition of
the diazoketone 2a in refluxing CH2Cl2 using Cu(acac)2 as the
catalyst furnished the N-DAC 1a in very good yield with excel-
lent diastereoselectivity (Table 1, entry 1). Delighted by success
of this reaction, the scope of this intramolecular cyclopropana-
tion of vinylogous carbamate with carbene was studied with
various N-carbamate and N-tosyl protected diazoketones 2. The
reaction was found to work efficiently with the N-carbamate pro-
tected diazoketone derivatives 2b–d as well, which gave rise to
Recent years have seen the emergence of donor–acceptor substi-
tuted cyclopropanes (DACs) as valuable synthons in organic
synthesis.1 Vicinally substituted DACs where an oxygen is the
donor substituent have been extensively studied for their reactiv-
ity with electrophiles and nucleophiles.2 These DACs have been
used in the synthesis of a variety of natural3 and un-natural4 pro-
ducts bearing ether and lactone moieties. In contrast, the
majority of the efforts on the synthesis and utility of the corre-
sponding nitrogen substituted DACs (N-DACs) have focused on
using them as conformationally restricted β-alanine analogues,
namely, β-aminocyclopropanecarboxylic acids (β-ACCs).5 Sur-
prisingly, the “push–pull” effect present in N-DACs has not been
exploited to a significant extent from a synthetic point of view.
In this context, some notable examples include deployment of
N-DACs as 1,3-dipoles in dipolar cycloaddition reactions,
homo-Nazarov cyclization and in ring-opening reactions with
various electrophiles and nucleophiles.6 This interesting reactiv-
ity of the N-DACs has also been exploited in the synthesis of
natural products.7 In spite of these developments in this area,
some challenges still remain. In many cases, methods developed
for the synthesis of N-DACs suffer from limitations such as low
yields and/or poor stereoselectivities.8 Moreover, the N-DACs
bearing 1,2-donor–acceptor or 1,1-bisacceptor substituents allow
for cleavage of only one of the cyclopropane bonds with very
high regioselectivity. A systematic study demonstrating that each
of the cyclopropane bonds of N-DACs can be cleaved with
Department of Chemistry, Indian Institute of Technology Madras,
Chennai, 600036 Tamil Nadu, India. E-mail: sjgharpure@iitm.ac.in;
Fax: +91-44-2257 4202; Tel: +91-44-2257 4228
†Electronic supplementary information (ESI) available: Synthetic pro-
cedures and characterization data for all the new compounds. CCDC
reference numbers 826028–826029. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2ob06591f
Scheme 1 Intramolecular cyclopropanation of vinylogous carbamate
for the synthesis of N-DACs.
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Table 1 Scope of the intramolecular cyclopropanation of vinylogous
carbamates
diastereoselectivity (Table 1, entry 5). However, the stereo-
chemistry obtained was ‘syn’ rather than ‘anti’ as was observed
for the N-DACs 1c–d. This trend in stereochemical reversal was
observed for all other diazoketones 2f–j bearing N-tosyl protec-
tion where the corresponding N-DACs 1f–j were formed in good
yields and diastereoselectivities (Table 1, entries 6–10).
Yielda
Entry Acid 3
Step 1 Step 2 Product(s) 1b
1
71
50
63
69
78
71
Interestingly, when these N-DACs 1e–g were purified by
gravity column using silica gel, the centre α to ketone was found
to undergo isomerisation (Table 1, entries 5–8). As a representa-
2
3
1
tive example, the H NMR spectra of the cyclopropapyrrolidi-
none 1e recorded under various conditions is depicted in Fig. 2.
It could be noted that the 1H NMR spectrum of the crude sample
suggested the presence of a single diastereomer which was
similar to that obtained by flash column. Purification of the
sample by gravity column on the other hand showed the pres-
ence of a mixture of diastereomers as against the single dias-
tereomer of the crude sample. One set of signals clearly
corresponded to the cyclopropapyrrolidinone 1e obtained from
flash column whereas the other set matched with N-DAC 1e′
(vide infra). Moreover, the ratio of the diastereomers 1e and 1e′
varied depending on the amount of the silica gel used and the
contact time of the compound with the silica gel. Further, com-
plete isomerisation of the N-DAC 1e to 1e′ could be effected by
its prolonged exposure (∼15 days) to the silica gel (Scheme 2).
Interestingly, this isomerisation could also be carried out very
efficiently within ca. 10 min. by treating N-DAC 1e with a base
like DBU in benzene. This feature is particularly attractive as it
gives ready access to both the stereoisomers of N-DACs.
4
76
60
5
6
7
70
70
52
75
69
57
8
47
53
48
75c
58
9
63d
The stereochemistry of these isomerised N-DACs 1e′–g′ was
confirmed by NOE experiments. Further unambiguous confir-
mation was obtained by subjecting the N-DAC 1g′ to single
crystal X-ray diffraction† studies (Fig. 1).12 Based on the crystal
structure of the N-DACs obtained upon isomerisation, it is clear
10
a Isolated yield. b In all the cases, dr was determined on the crude
1
reaction mixtures by H NMR and was found to be ≥19:1. c Combined
yield of the ketones 1h and 4 (1h : 4 = 2 : 1). d Reaction was performed
at room temperature.
the corresponding cyclopropapyrrolidinone derivatives 1b–d,
respectively, in good yield and excellent ‘anti’ diastereoselectivity
for 1c–d (Table 1, entries 2–4). The stereochemistry of these pro-
ducts was assigned on the basis of NOE experiments. This was
further confirmed by single crystal X-ray diffraction studies† on
the ketone 1c (Fig. 1).12 This stereochemical outcome for the
formation of N-DAC 1c–d is consistent with our earlier obser-
vations in the case of vinylogous carbonates.9 Cyclopropanation
reactions of the N-tosyl protected diazoketones 2e–j bearing
alkyl substitution were particularly interesting. The reaction of
the diazoketone 2e with Cu(acac)2 under optimized conditions
followed by purification by flash chromatography on silica
gel furnished the N-DAC 1e in good yield with excellent
Fig. 2 1H NMR spectra of the ketones 1e and 1e′.
Fig. 1 ORTEP diagrams for the N-DAC 1c and 1g′.
1736 | Org. Biomol. Chem., 2012, 10, 1735–1738
Scheme 2 Isomerisation studies on the N-DAC 1e.
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that the ‘anti’ isomer will be thermodynamically more stable
compared to the ‘syn’ isomer. This is due to the steric interaction
between the alkyl substituent and the cyclopropane proton α to
the ester in the ‘syn’ isomer, which will be absent in the ‘anti’
isomer. Formation of the less stable ‘syn’ isomer in the case of
N-DACs bearing tosyl protection is clearly an outcome of
kinetic control, though its origin is not completely understood at
this juncture. It was also interesting to note that this isomerisa-
tion on silica gel was neither observed for the N-DACs 1i–j nor
for the N-DACs 1c–d, perhaps due to the branching on the alkyl
group in the former case and the relatively lower acidity of the
proton α to the carbonyl group in the latter case.
It is pertinent to mention here that in the case of the diazoke-
tone 2h, along with the N-DAC 1h, ketone 4 was formed as a
by-product via C–H insertion of carbene into the methine of the
isobutyl group (Table 1, entry 8). Again, this was contrary to our
observation in the case of intramolecular cyclopropanation of
vinylogous carbonates where analogous substrate did not give
any of the C–H insertion product while using copper salts as the
catalyst.9
Scheme 4 Tandem regioselective ring opening–lactonization of
N-DACs. Reagents and conditions: (a) LAH, THF, −78 °C, 75%;
(b) H2SO4, MeOH, 0 °C–rt, 64%; (c) TMSOTf, Et3SiH, CH2Cl2,
−10 °C–rt, 92%; (d) TMSOTf, m-CPBA, CH2Cl2, −10 °C–rt, 74%;
(e) TMSOTf, 1,3,5-(MeO)3C6H3 (11), CH2Cl2, −10 °C–rt, 91%;
(f) TMSOTf, PhSH (13), CH2Cl2, −10 °C–rt, 91%; (g) TMSOTf,
HS(CH2)2SH (15), CH2Cl2, −10 °C–rt, 70%; (h) nBu3SnAllyl,
TMSOTf, CH2Cl2, −10 °C, then Et3SiH, 67%.
After the successful stereoselective synthesis, attention was
turned towards studying the reactivity of the synthesised
N-DACs. The reactivity of these N-DACs paralleled that
observed for oxygen substituted DACs in our earlier studies.
Thus, treatment of cyclopropapyrrolidinones 1a, 1c and 1e with
tributyltinhydride and AIBN in refluxing benzene furnished the
corresponding pyrrolidinone derivatives 5a, 5c and 5e, respect-
ively, in excellent yield (Scheme 3).13 On the other hand, their
reaction with TMSOTf furnished the corresponding piperidinone
derivatives 6 via preferentially coordinating with the ketone
rather than the ester leading to the formation of iminium ion fol-
lowed by elimination of β-proton. The piperidinone derivatives 6
are complementary to those described by Georg et al. recently
using trapping of ketene with vinylogous carbamates.14
Regioselective cleavage of the third cyclopropane bond of
N-DAC required activation of the carbonyl of the ester moiety
with Lewis or Brønsted acid. Towards this end, the ketone 1a
was chemo- and stereoselectively reduced using lithium alu-
minium hydride to furnish the alcohol 7 (Scheme 4). The cyclo-
propane bond of the alcohol 7 could be cleaved under a variety
of conditions leading to a diverse array of heterocyclic skeletons.
Thus, reaction of the alcohol 7 in methanol in the presence of a
catalytic amount of sulfuric acid furnished the pyrrole derivative
8. The iminium ion intermediate generated by reaction of the
alcohol 7 with TMSOTf could be reduced with Et3SiH or oxi-
dised with m-CPBA along with concomitant lactonization to
give lactone 9 and furopyrrolodione 10, respectively. The inter-
mediate iminium ion could be trapped even with a carbon
nucleophile like 1,3,5-trimethoxybenzene (11) leading to the
arylated furopyrrolone 12 in very good yield with excellent dia-
stereoselectivity. The iminium ion intermediate trapping with
sulfur nucleophiles was found to be particularly interesting.
Thiophenol (13), when used as nucleophile, led to the formation
of the lactone 14. On the other hand using ethanedithiol (15) as
the nucleophile furnished the γ-butyrolactone derivative 16 by
tandem ring opening–iminium ion trapping with ethanedithiol,
thioacetalization and subsequent lactonization. Finally, the ter-
tiary alcohol intermediate generated by allylation of the ketone
1a using TMSOTf and allyltributyltin could be further reacted
with triethylsilane in situ to furnish the substituted lactone
derivative 17. This study thus unambiguously demonstrated that
the N-DACs can give rise to a diverse array of azacycles.
Conclusions
We have developed a highly stereoselective synthesis of
N-DACs employing intramolecular cyclopropanation of vinylo-
gous carbamates with carbenes in the presence of Cu(acac)2 as
the catalyst. Stereochemical assignment of these cyclopropapyr-
rolidinones 1 was done with the help of NOE and X-ray diffrac-
tion studies. The reactivity of two acceptor substituted N-DACs
allowed for the regioselective cleavage of each of the cyclopro-
pane bonds by an appropriate choice of reagents, leading to the
divergent synthesis of azacycles.
Acknowledgements
We thank DST and CSIR, New Delhi for financial support. We
thank Mr Ramkumar of X-ray facility of the Department of
Chemistry, IIT Madras for collecting the crystallographic data
and SAIF, IIT Madras for NMR data. We thank Prof. Indrapal
Singh Aidhen for helpful discussions. We are grateful to CSIR,
New Delhi for the award of research fellowship to SRBR.
Scheme 3 Ring opening of N-DAC 1 for the synthesis of pyrrolidin-3-
ones and piperidin-3-one.
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