Lewis Acid Catalyzed Diastereoselective Cycloaddition Reactions of Donor-Acceptor Cyclopropanes and Vinyl Azides: Synthesis of Functionalized Azidocyclopentane and Tetrahydropyridine Derivatives

Article abstract of DOI:10.1021/acs.orglett.6b03276

Lewis acid catalyzed [3 + 2]-cycloaddition reaction of donor-acceptor cyclopropanes with vinyl azides has been developed to obtain diastereomerically enriched azidocyclopentane derivatives. In addition, thermal chemoselective ring expansion of azidocyclopentanes to tetrahydropyridine derivatives and further diastereospecific reduction to a substituted piperidine derivative, with an excellent yield, was also achieved.

Full text of DOI:10.1021/acs.orglett.6b03276

Letter
pubs.acs.org/OrgLett
Lewis Acid Catalyzed Diastereoselective Cycloaddition Reactions of
Donor−Acceptor Cyclopropanes and Vinyl Azides: Synthesis of
Functionalized Azidocyclopentane and Tetrahydropyridine
Derivatives
Raghunath Dey and Prabal Banerjee*
Department of Chemistry, Indian Institute of Technology Ropar, Nangal Road, Rupnagar, Punjab 140001, India
S
* Supporting Information
ABSTRACT: Lewis acid catalyzed [3 + 2]-cycloaddition reaction of donor−acceptor cyclopropanes with vinyl azides has been
developed to obtain diastereomerically enriched azidocyclopentane derivatives. In addition, thermal chemoselective ring
expansion of azidocyclopentanes to tetrahydropyridine derivatives and further diastereospecific reduction to a substituted
piperidine derivative, with an excellent yield, was also achieved.
itrogen-containing heterocycles and carbocycles are
distinctive structural frameworks present in a wide
partners5,6 have been reported. Our group has also explored
varieties of annulation and cycloaddition reactions of DACs
with oxaziridines, aziridines, nitrosocarbonyls, and epoxides for
the synthesis of various heterocyclic and carbocyclic com-
pounds relevant to pharmaceutical applications.7
We recently reported a [3 + 2]-cycloaddition reaction of
DAC with enamines to synthesize N-functionalized cyclo-
pentanes in an enantioselective manner (Scheme 1A).8
Following the success of this work, we became interested in
assessing the reactivity of DACs with vinyl azides (VAs) as they
can also act as an enamine.10 During the preparation of this
manuscript, Kerr’s group reported an interesting annulation
reaction of DACs with VAs for the formation of azabicycles,9
where they utilized VA as the generator of vinyl nitrene at
elevated temperature.
N
range of bioactive compounds.1,2 Among them, N-function-
alized cyclopentanes and tetrahydropyridines are of particular
importance, as these scaffolds constitute the cyclic core
structures of varieties of bioactive heterocycles. Pyrazole
acids, acting as agonists of G-protein-coupled receptor
GPR109a,3 are representative examples of drugs, containing
N-functionalized cyclopentane rings (Figure 1). The distinctive
We started the present investigation with the assumption of
Lewis acid catalyzed ring opening of DACs resulting from an
enamine type nucleophilic attack by VAs, followed by
cyclization of the ring opened intermediate. Azidocyclo-
pentanes (3) were formed as the sole product in all cases.
The structure and geometry of the cycloadduct (3aa) were
determined by routine spectroscopic techniques and X-ray
analysis (Figure 2).11 The salient feature of these azidocyclo-
pentanes is the attachment of azide functionality to a
quaternary carbon atom.12 This drew our attraction toward
investigating the ring expansion through elimination of nitrogen
to form tetrahydropyridine derivatives (4), as there is no report
Figure 1. Tetrahydropyridine and N-functionalized carbocycles
present in natural product.
examples of alkaloids having tetrahydropyridine as a core
structural motif are Solacongestidine and 6-heptadecyl-2,3,4,5-
tetrahydropyridine, which exhibit antifungal activities.4 There-
fore, the development of efficient protocols for stereoselective
construction of these molecular architectures from readily
available starting material is of great interest.
In that perspective, due to ease of preparation and
foreseeable reactivity, donor−acceptor cyclopropanes (DACs)
have frequently been used as building blocks in organic
synthesis.5 In the past few decades, a large number of [3 + n]-
cycloaddition reactions of DACs with numerous reactive
Received: November 1, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03276
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Organic Letters
Letter
Scheme 1. Reactivity of DACs with Enamines and Vinyl
Azides
Table 1. Lewis Acid Catalyzed [3 + 2]-Cycloadditions of VA
and DAC: Optimization of Reaction Conditions
a
LA
(mol %)
yield
b
time
(h)
e
entry Lewis acid
solvent
(%)
dr
c
1
−
MgI2
−
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
xylene
DCM
DCM
n.r.
48
36
36
24
25
22
4
−
2
05
10
20
20
20
20
20
20
20
20
20
40
20
20
20
20
38
63
58
47
91:09
91:09
91:09
70:30
70:30
−
71:29
78:22
75:25
74:26
67:33
67:33
67:33
78:22
65:35
3
MgI2
4
MgI2
5
MgBr2
Mg(OTf)2
BF3.OEt2
TiCl4
6
d
7
c.m.
8
48
78
80
83
95
95
75
85
89
5
9
Cu(OTf)2
Sc(OTf)3
Sn(OTf)2
InCl3
34
3
10
11
12
13
14
15
16
2
0.6
0.6
3
InCl3
InCl3
InI3
1.5
1
In(OTf)3
a
Reactions were carried out with 1 equiv of 1b and 1 equiv of 2a in the
b
c
presence of molecular sieves (4 Å). Isolated yields. n.r. = no reaction.
d
e
c.m. = complex mixture. DCM = dichloromethane. dr =
diastereomeric ratio was determined by 1H NMR analysis of the
reaction mixture.
Figure 2. X-ray structure of 3aa and 4bb (Hydrogen atoms are
omitted for the sake of clarity).
Scheme 2. [3 + 2]-Cycloaddition Reaction between VA and
DAC: Substrate Scope
a
about the cyclopropanes based preparation of tetrahydro-
pyridine. After attempting various conditions, we obtained the
expected result in xylene under reflux condition in a facile
manner; the transformation did not require any reagent or
catalyst and also did not produce any byproduct.
At the beginning of our studies, dimethoxy-substituted
phenyl ring containing DAC 1b and VA 2a were chosen as
model substrates to optimize the conditions for [3 + 2]-
cycloaddition reactions. An extensive screening of Lewis acids
revealed following two reaction conditions: (1) using MgI2 (20
mol %) in DCM (condition A) reaction proceeds with excellent
diastereoselectivity, but it required a longer time and gave a
moderate yield (Table 1, entry 4); (2) with InCl3 (20 mol %)
in DCM (condition B) reaction proceeds with low diaster-
eoselectivity within a very short time and gave an excellent yield
(Table 1, entry 12).
Under both optimized reaction conditions, the scope and
limitations of the reaction were explored with various DACs
and VAs, and the results are depicted in Scheme 2. More
activated DACs bearing electron-donating functionalities in the
vicinal phenyl ring took part in the reaction more effectively.
Employing condition B, DAC bearing a mono-, di-, and
trimethoxy-substituted phenyl ring (1a, 1b, and 1c, respec-
tively) gave an excellent yield in a short reaction time although
the diastereoselectivity observed was very poor. Whereas, under
condition A, these DACs gave a moderate yield with excellent
diastereoselectivity. A DAC incorporating heterocycle (1h) was
also tested in both reaction conditions, and the same result was
reflected as in the cases of DACs bearing electron-donating
groups. Less activated DACs such as p-tolyl, a phenyl ring
containing DACs (1i, 1j), did not take part in the reaction
under condition A; however, they gave the desired cycloadduct
a
Unless otherwise specified, all reactions were carried out in DCM at
rt with 1 equiv of 1 and 1 equiv of 2 in the presence of a Lewis acid
(20 mol %) and 4 Å molecular sieves (200 wt %). Isolated yields,
reaction time, and diastereomeric ratios with MgI2. Isolated yield,
reaction time, and diastereomeric ratios with InCl3 (for details see the
Supporting Information).
b
c
B
DOI: 10.1021/acs.orglett.6b03276
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Organic Letters
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under condition B, with low diastereoselectivity. A DAC
bearing ortho-substituted phenyl ring, such as o-tolyl (1k), did
not take part in the reaction under both conditions. This may
be due to the steric repulsion of substituents. Varieties of other
DACs containing different ester groups (1d, 1f, 1g) were tested
to check the effect of the size of ester group in the
transformation, but no such profound effect was noticed.
Subsequently, the substrate scope with respect to VA was
evaluated. Both VAs containing a p-methyl (2b) and p-tert-
butyl (2c) substituted phenyl ring gave almost the same result
as VA (2a) bearing a simple phenyl ring. A VA containing an
ortho-substituted phenyl ring (2d) did not give the desired
product in both conditions. A VA containing a p-methoxy-
substituted phenyl ring (2e) also failed to give the desired
product.
Scheme 4. Formal [3 + 3]-Cycloaddition Reactions of DAC
and VA
Scheme 5. Chemical Transformations of 3ba and 4ba
Having prepared a series of [3 + 2]-cycloadducts, the
feasibility of the rearrangement reaction was examined (Scheme
3). The first aryl (Ar) ring has a minor effect on this
Scheme 3. Ring Expansion of Azidocyclopentanes (3) to
Tetrahydropyridines (4)
transformation, a new stereogenic center was generated. The
geometry of 6ba was determined using NOE studies.
a
On the basis of previous reports and our observations, a
plausible mechanism for both, cycloaddition and ring expansion
reactions, is given in Scheme 6. Initially, the Lewis acid activates
Scheme 6. Plausible Mechanism
a
Unless otherwise specified, all reactions were carried out in xylene
under reflux conditions.
rearrangement, as in all the cases (4aa, 4ba, 4ha, 4ia, and 4ja)
the yields and reaction times are almost the same. In this
context, the variation of the ester functionality played a
significant role in both the reaction rate and yield. A gradual
increase in the size of the ester functionality from methyl ester
to tert-butyl ester (4fa−4ga) led to a lower yield and longer
reaction time. This might be due to the steric hindrance on the
reaction center. The substituent on the second aryl ring (Ar′)
(4bb, 4bc) also altered the reaction time and yield of the
reaction.
To achieve the formal [3 + 3]-cycloaddition, we led the
transformation in one pot by starting the reaction of 1b and 2a
using InCl3 as the catalyst in xylene (Scheme 4). We could
gratifyingly attain the desired product (4ba), although the yield
(35%) was not impressive.
Furthermore, to show the potential of the developed
methodology, the azidocyclopentane 3ba was subjected to an
azide−alkyne click reaction13 to obtain triazole derivative 5ba
(Scheme 5), which is the structural scaffold for bioactive
compounds.14 A diastereospecific reduction of tetrahydro-
pyridine derivative 4ba was also performed, using NaBH4,15
to synthesize piperidine 6ba, as a single diastereomer. In this
the DAC to form intermediate A. Upon an enamine type
nucleophilic attack of VA on intermediate A, an open chain
intermediate B is formed (Scheme 6A). The nucleophilic attack
happened in an almost SN2 fashion which was experimentally
proven by carrying the cycloaddition reaction with enantio-
mercally pure DAC, which in turn gave an enantioenriched
cycloadduct (for details see the Supporting Information).
Intermediate B undergoes a cyclization reaction through either
re-face or si-face attack. In the re-face attack, reaction proceeds
through TS-C, whereas, in the si-face attack, reaction proceeds
through TS-D. TS-C contains two bulky substituents (Aryl
ring) on different sides, whereas TS-D contains two bulky
substituents on the same side. Therefore, TS-C becomes the
C
DOI: 10.1021/acs.orglett.6b03276
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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(a) Pandey, A. K.; Ghosh, A.; Banerjee, P. Isr. J. Chem. 2016, 56, 512.
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favored TS and TS-D the disfavored one. Subsequently,
cyclization through the TS-C led to the formation of anti
isomer 3 as a major diastereomer while cyclization through TS-
D led to syn isomer 3 as a minor diastereomer.
On heating, azidocyclopentane 3 undergoes ring expansion
in a chemoselective manner, through elimination of nitrogen, to
give tetrahydropyridine 4 (Scheme 6B).
In conclusion, [3 + 2]-cycloaddition reactions between
donor−acceptor cyclopropanes and vinyl azides, using various
Lewis acid catalysts, have been explored to obtain diaster-
eomerically enriched azide functionalized cyclopentane deriv-
atives. Using the ring expansion of azidocyclopentanes, we
report the first DAC-based preparation of tetrahydropyridines.
Additionally, we also demonstrate the concise chemical
conversion of azidocyclopentane and tetrahydropyridine to a
triazole and piperidine derivative, respectively. Further
application of this protocol toward natural product synthesis
and development of a catalytic enantioselective version of the
present transformation are in progress in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03276.
(10) Zhang, F.-L.; Wang, Y.-F.; Lonca, G. H.; Zhu, X.; Chiba, S.
Angew. Chem., Int. Ed. 2014, 53, 4390.
Copies of 1H, 13C NMR, and IR spectra, mass data of all
new compounds, single-crystal X-ray data (PDF)
Crystallographic data (CIF, CIF)
(11) (a) CCDC 1508151 contains supplementary crystallographic
data for the compound 3aa. (b) CCDC 1510563 contains
supplementary crystallographic data for the compound 4bb.
(12) Alberici, G. F.; Andrieux, J.; Adam, G.; Plat, M. M. Tetrahedron
Lett. 1983, 24, 1937.
(13) Zhang, X.; Yang, X.; Zhang, S. Synth. Commun. 2009, 39, 830.
(14) Asif, M. IJARCS. 2014, 1, 22.
(15) Blackburn, L.; Taylor, R. J. K. Org. Lett. 2001, 3, 1637.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: prabal@iitrpr.ac.in.
ORCID
Prabal Banerjee: 0000-0002-3569-7624
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors wish to acknowledge financial assistance from the
Department of Science and Technology, New Delhi (Project
No. EMR/2015/002332). R.D. thanks IIT Ropar for his
research fellowship. The authors also acknowledge Dr. C. M.
Nagaraja, Department of Chemistry, IIT Ropar, for solving the
single-crystal structures presented in this work.
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DOI: 10.1021/acs.orglett.6b03276
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