Synthesis of Highly Substituted Azepanones from 2 H-Azirines by a Stepwise Annulation/Ring-Opening Sequence

Article abstract of DOI:10.1021/acs.orglett.9b00999

Bicyclic aziridines possessing a 1-azabicyclo[4.1.0]heptan-2-one core were prepared from 2H-azirines by a stepwise annulation sequence involving a diastereoselective allylindanation, an N-acylation, and a ring-closing metathesis to construct the six-membe

Full text of DOI:10.1021/acs.orglett.9b00999

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Highly Substituted Azepanones from 2H‑Azirines by a
Stepwise Annulation/Ring-Opening Sequence
†
†
‡
,†
́
Alexandre Dupas, Pierre-Alexandre Lhotellier, Gerard Guillamot, Christophe Meyer,*
and Janine Cossy*,†
†Molecular, Macromolecular Chemistry, and Materials, ESPCI Paris, CNRS (UMR7167), PSL University, 10 rue Vauquelin, 75231
Paris Cedex 05, France
‡PCAS Porcheville, ZI de Limay, 2-8 rue de Rouen, 78440 Porcheville, France
S
* Supporting Information
ABSTRACT: Bicyclic aziridines possessing a 1-azabicyclo[4.1.0]heptan-2-
one core were prepared from 2H-azirines by a stepwise annulation sequence
involving a diastereoselective allylindanation, an N-acylation, and a ring-
closing metathesis to construct the six-membered ring. After hydrogenation
or functionalization of the olefin, regioselective ring opening of the resulting
azabicyclic compounds with carboxylic acids (or sulfur nucleophiles)
afforded highly substituted azepanones possessing an ester moiety or a
trifluoromethyl group and a tetrasubstituted carbon at the α and β positions of the nitrogen atom, respectively.
ubstituted nitrogen heterocycles belong to the group of the
(Scheme 1, eq 1).8,9 By contrast, the ring opening of bicyclic
1
Smost important scaffolds in medicinal chemistry. Whereas aziridines D has been considerably less investigated to access
piperidines and pyrrolidines lie in the top ten of the most
frequently encountered heterocycles in marketed drugs,2
Scheme 1. Ring Opening of Bicyclic Aziridiniums and
azepanes and their derivatives are also attracting an increasing
interest in new lead compound discovery.3 The fungal
metabolite protein kinase inhibitor balanol is undoubtedly
the most cited example of a natural product incorporating an
azepane ring.4 Additional examples of bioactive synthetic
azepane derivatives include the opioid analgesic meptazinol,5
the 11β-hydroxy-steroid type 1 dehydrogenase inhibitor 1,6
and azepanone 2,7 which is a neurokinin-1 receptor antagonist
(Figure 1).
Aziridines toward Azepanes
azepanes E, besides examples dealing with substrates in which
the shared C−N bond lies at the benzylic position of an
electron-rich (fused) aromatic group (Scheme 1, eq 2).10,11
Herein, we report our studies of the ring opening of azabicyclic
compounds G incorporating an N-acyl aziridine, readily
assembled from 2H-azirines F by a stepwise annulation
sequence featuring a ring-closing metathesis to construct the
fused six-membered ring, as a route to azepane derivatives H
(Scheme 1, eq 3).
Figure 1. Bioactive azepanes and azepanones.
In this context, the development of synthetic strategies for
azepane derivatives with unique substitution patterns is of
prime interest. Among the different routes toward these seven-
membered heterocycles, the nucleophilic ring opening of 1-
azoniabicyclo[4.1.0]heptanes A (usually generated by intra-
molecular nucleophilic substitution) offers an interesting entry
to azepanes B substituted at the β position of the nitrogen
atom.8,9 The regioselectivity of the ring opening, which can
concurrently lead to piperidines C, depends on the
substituents, the nucleophiles, and the reaction conditions
Although the nucleophilic ring opening of bicyclic
sulfonamides, sulfamates, or oxazolidinones incorporating an
Received: March 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00999
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
aziridine has been well investigated,12 the synthesis and
reactivity of azabicyclic compounds G, substituted at both
C1 and C2, have not been explored.13 From these latter
substrates, formation of the desired azepanones H requires that
the nucleophilic attack occur at the most substituted carbon
atom (C2) so the choice of the substituents (R1 and R2)
appears to be crucial for controlling the regioselectivity.
Because the nucleophilic ring opening of aziridines in the
presence of a Lewis or a Brønsted acid promoter is known to
be disfavored at the adjacent position of an ester and a
trifluoromethyl group,14 those two latter substituents were
selected at C1 in compounds G. The requisite substrates were
prepared from 2H-azirines 3a−3k,15,16 which were first
involved in a diastereoselective allylation (with allylindium
sesquibromide, THF, rt) leading to aziridines 4a−4k,
respectively (>95:5 dr).17 Acylation of the nitrogen atom
with acryloyl chloride and subsequent ring-closing metathesis
of dienes 5a−5k in the presence of Grubbs second-generation
catalyst (CH2Cl2, reflux) enabled the construction of the six-
membered ring and afforded azabicyclic compounds 6a−6k,
respectively.18 Our investigations of the ring opening of the
three-membered ring were first carried out on bicyclic
aziridines 7a−7k obtained by hydrogenation of unsaturated
compounds 6a−6k, respectively, catalyzed by PtO2 (EtOAc,
rt). Diversely substituted 1-azabicyclo[4.1.0]heptan-2-ones
armed with a tert-butyl ester at C1 and possessing either an
aryl (7a−7e) or an alkyl substituent (7j−7k) at C2 or with a
trifluoromethyl substituent at C1 and an aryl substituent at C2
(7f−7h) were thus obtained in moderate to good overall yields
(16−69%, four steps from the corresponding azirines 3a−3k)
as single diastereomers (>95:5 dr) (Scheme 2).
atom in 85% yield. The relative configuration of the major
diastereomer 8a, which was unambiguously established by X-
ray diffraction analysis,19 showed that this latter compound
arises from ring opening of 7a by AcOH with inversion of
configuration at C2. The phenyl group at C2 that is able to
stabilize an adjacent carbocation may explain the formation of
the minor epimer of 8a at C2.20 The ring opening is very
sensitive to steric hindrance, and azepanone 8b could not be
obtained from 7b possessing an o-bromophenyl group at C2.
No reaction occurred at rt, and substrate 7b underwent
decomposition under harsher conditions. Substitution of the
aryl group at the meta or para position was tolerated as
illustrated with the isolation of azepanones 8c−8e (53−68%).
Substrates 7f−7h also reacted well and delivered trifluoro-
methylated azepanones 8f (85%), 8g (66%), and 8h (70%),
respectively.21 It is worth noting that less diastereocontrol
(85:15 dr) was observed in the case of 8g possessing a p-
methoxyphenyl group, which is best able to stabilize a
carbocation at C2, compared to the other products 8c−8h.
Although substrate 7i possessing a methyl group at C2
smoothly reacted under these conditions, the expected
azepanone 8i was isolated in modest yield (60%) because
the tertiary alkyl fluoride 9i (31%) was formed as a byproduct.
Ring opening of activated aziridines or epoxides by fluoride has
already been reported in the presence of BF3·OEt2.22 This side
reaction may become competitive in the case of 7i, which
presumably reacts with AcOH at a rate slower than that of the
analogous aziridine 7a possessing a phenyl group, which can
stabilize a positive charge at C2 in the transition state.23 The
relative configuration of 8c−8i was assigned by analogy with
azepanone 8a (ring opening proceeding with inversion of
configuration at C2) (Scheme 3).
The ring opening of azabicyclic compounds 7a−7i was first
attempted with acetic acid as the nucleophile in the presence of
BF3·OEt2 as a Lewis acid promoter (CH2Cl2, 0 °C).14g Under
these mild conditions, the ring opening of 7a proceeded
regioselectively and led to a 90:10 diastereomeric mixture of
azepanone 8a and its epimer at the tetrasubstituted carbon
Solvolysis in acetic acid (65 °C, 2 h) was then investigated as
an alternative method.14d Under these conditions, substrate 7a
led to a 70:30 mixture of azepanone 8a and unsaturated lactam
10, arising from the ring opening of the aziridine by an
elimination reaction, which could not be separated by flash
chromatography.24 By contrast, solvolytic conditions turned
a
Scheme 2. Preparation of Azabicyclic Compounds 7a−7k
Scheme 3. Ring Opening of Azabicyclic Compounds 7a−7i
with AcOH Promoted by BF3·OEt2
a
Overall yields from the corresponding azirines (four steps).
B
DOI: 10.1021/acs.orglett.9b00999
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out to be appropriate for achieving the ring opening of
aziridines 7i−7k possessing an alkyl group at C2, which
afforded azepanones 8i (99%) (2.7 mmol scale), 8j (83%), and
8k (87%), respectively, in high yields and as single
diastereomers (Scheme 4).
aromatic acids (Table 1, entries 11−13), and α,β-unsaturated
carboxylic acids (Table 1, entries 14 and 15) were involved as
nucleophiles in the ring opening of 7i to produce the
corresponding azepanones 15−24 (38−85%) (Table 1).25
The reactivity of bicyclic aziridines 7a and 7i was also
investigated in the presence of sulfur nucleophiles. Ring
opening of 7a with benzyl mercaptan in the presence of BF3·
OEt2 proceeded regioselectively and produced thioether 25 in
high yield (85%) as a single diastereomer. On the other hand,
solvolysis of 7i in thioacetic acid led to azepanone 26 (71%,
>95:5 dr) (Scheme 5).
Scheme 4. Solvolysis of 7a and 7i−7k in AcOH
Scheme 5. Ring Opening of 7a and 7i with Sulfur
Nucleophiles
Solvolysis of aziridine 7i was then achieved by heating in
propionic acid, 4-pentenoic acid, and methoxyacetic acid
(conditions A, Table 1, entries 1−3) to afford azepanones 11
With the goal of accessing azepanones possessing additional
stereocenters, the functionalization of the α,β-unsaturated N-
acyl-aziridine 6i, the precursor of aziridine 7i, was investigated.
Thus, 1,4-addition of a magnesium phenylcuprate (generated
from PhMgCl and CuI) to 6i afforded a diastereomeric
mixture of azabicyclic compounds 27 and 27′ in an 85:15 ratio.
The relative configuration of the major diastereomer 26
indicated that the addition of the organocuprate preferentially
occurred on the convex face of azabicyclic compound 6i.26
Solvolysis of the 27/27′ mixture in AcOH afforded a
diastereomeric mixture of ring-opened products 28 and 28′
from which the major diastereomer 28 was isolated in 62%
yield. Substrate 6i was also engaged in a 1,3-dipolar
cycloaddition with the azomethine ylide generated in situ
from reagent 29 (cat. TFA, toluene, 60 °C), and the crude
cycloadduct 30 was directly solvolyzed in AcOH to afford
bicyclic azepanone 31 (73%, two steps from 6i) (Scheme 6).26
Table 1. Ring Opening of Aziridine 7i with Carboxylic Acids
Scheme 6. Functionalization of 6i and Subsequent Ring
Opening with AcOH
(68%), 12 (71%), and 13 (81%), respectively. With the more
acidic bromoacetic acid, significant decomposition of 7i was
observed and the ring-opening product 14 was isolated in low
yield (26%) (Table 1, entry 4). An improvement was observed
upon using an excess of bromoacetic acid (7 equiv), although
heating in chloroform (100 °C, 24 h) was now required to
trigger the ring opening of 7i (conditions B). With this
alternative procedure, azepanone 14 was isolated in 49% yield
(Table 1, entry 5) and the scope was then extended to a variety
of carboxylic acids that could not be used as a solvent.
Substituted benzoic acids (Table 1, entries 6−10), hetero-
Azepanones can serve as precursors of substituted azepanes.
Thus, reduction of azepanone 8i with LiAlH4 delivered
azepane 32 (70%) containing a primary alcohol and a tertiary
alcohol. Chemoselective reduction of the amide in 8i could be
carried out using BH3·THF to afford azepane 33 in 61% yield,
albeit with some epimerization (90:10 dr) (Scheme 7).
In conclusion, we have reported the synthesis of new
scaffolds possessing a 1-azabicyclo[4.1.0]heptan-2-one core
C
DOI: 10.1021/acs.orglett.9b00999
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Scheme 7. Access to Azepanes 32 and 33
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00999.
■
S
Experimental procedures, characterization data, and
spectra for all new compounds (PDF)
Accession Codes
CCDC 1900066 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
́
Angew. Chem., Int. Ed. 2009, 48, 3802−3805. (g) Malik, G.; Esteoule,
A.; Retailleau, P.; Dauban, P. J. Org. Chem. 2011, 76, 7438−7448.
(h) Rigoli, J. W.; Boralsky, L. A.; Hershberger, J. C.; Marston, D.;
Meis, A. R.; Guzei, I. A.; Schomaker, J. M. J. Org. Chem. 2012, 77,
2446−2455. (i) Goto, A.; Yoshimura, S.; Nakao, Y.; Inai, M.;
Asakawa, T.; Egi, M.; Hamashima, Y.; Kondo, M.; Kan, T. Org. Lett.
2017, 19, 3358−3361.
(13) One previous example of a substrate of type G, unsubstituted at
C1, has been reported. Subsequent nucleophilic additions occur either
at C1 or on the carbonyl group: Wu, X.; Toppet, S.; Compernolle, F.;
Hoornaert, G. J. Tetrahedron 2003, 59, 1483−1491.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: christophe.meyer@espci.fr.
*E-mail: janine.cossy@espci.fr.
ORCID
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Christophe Meyer: 0000-0003-3420-5584
Janine Cossy: 0000-0001-8746-9239
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
A.D. thanks PCAS for a CIFRE grant.
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NMR (NOESY). See the Supporting Information.
E
DOI: 10.1021/acs.orglett.9b00999
Org. Lett. XXXX, XXX, XXX−XXX