Methods for the Synthesis of Substituted Azetines

Article abstract of DOI:10.1021/acs.orglett.7b02847

Spurred on by the recent emerging interest from the chemical community for unsaturated four-membered heterocycles, an unprecedented approach to nitrogen-containing four-membered rings has been designed. 3,4-Disubstituted 2-azetines were synthesized from c

Full text of DOI:10.1021/acs.orglett.7b02847

Letter
pubs.acs.org/OrgLett
Methods for the Synthesis of Substituted Azetines
Andreas N. Baumann,†,∥ Michael Eisold,†,∥ Arif Music,† Geoffrey Haas,‡ Yu Min Kiw,§
and Dorian Didier*,†
†Department of Chemistry and Pharmacy, Ludwig-Maximilians-University, Butenandtstraße 5-13, 81377 Munich, Germany
‡Pierre and Marie Curie University, 4 place Jussieu, Paris 75252 Cedex 05, France
§Ecole Nationale Super
́
́
ieure de Chimie de Rennes, 11 allee de Beaulieu, Rennes 35708 Cedex 7, France
S
* Supporting Information
ABSTRACT: Spurred on by the recent emerging interest from
the chemical community for unsaturated four-membered hetero-
cycles, an unprecedented approach to nitrogen-containing four-
membered rings has been designed. 3,4-Disubstituted 2-azetines
were synthesized from commercially available substrates, allowing
for a straightforward access to a new library of chiral
functionalized azetidines and amino alcohols. This original
approach was applied to efficiently prepare functionalized
azobenzenes, an emerging class of molecules with a large potential in photopharmacology.
Recently, the group of Baran et al. developed a new route for
mall, strained ring systems have recently received increased
Sattention due to their large applicability in drug discovery
and development. However, generating these systems is often
limited by the availability of efficient and straightforward
methods. Among them, azetidines and their unsaturated
analogues 2-azetines1−4 are particularly interesting as they
represent a promising pattern for further pharmacological
studies.
Apart from the well-known β-lactams penicillin and
cephalosporin derivatives, several fused azetidine-containing
substances have shown interesting antitumor activities5 and
antinociceptive effects6 (Figure 1).
introducing 3-substituted azetidines by using the ring strain of
azabicyclo[1.1.0]butane to efficiently modify lead compounds of
pharmacological interests.9 Concurrently, Carreira demonstra-
ted the propensity of spiro-azetidines to modulate biological
properties of different targets in drug discovery.10 While smaller
and larger N-containing heterocycles have been extensively
studied,1 only a few reports relate the general formation of
azetines.2,11
With the ambitious objective of generalizing access to
polysubstituted azetine architecturesthat represent versatile
building blocks en route to sophisticated azetidineswe first
took on the challenge of identifying a sequence allowing for the
regioselective introduction of diverse substituents at positions 3
and 4 (Scheme 1), involving a lithiated species as the key
intermediate. While direct functionalization of 4-azetinyllithium
could be easily performed in the presence of alkyl, silyl or
carbonyl derivatives (conditions A), a more challenging arylation
was designed through cross-coupling of the corresponding
organoboronate derivatives, obtained through a simple trans-
metalation. As a matter of fact, transmetalation with ZnCl2 only
furnished the cross-coupled compound in low yield (27%,
Hodgson et al.). Alternatively, a boron-relayed catalyst-free
arylation of azetinyllithium was developed.
Fused β-lactams have also proven to be adequate precursors of
azabicyclo[3.2.1]octanes.7 In the polyoxin family, antibiotic
properties were observed on 3-alkylideneazetidine-modified
structures.8
Starting from commercial sources of N-Boc-3-azetidinone 1,12
the introduction of the substituent at position 3 (R1) was simply
performed by employing an adequate organometallic reagent,
such as organolithium, organomagnesium, or PhMe2SiLi.
Methylation of the resulting crude tertiary alcohol afforded
2a−f in good to excellent yields over two steps (up to 98%,
Scheme 2).13 α-Lithiation of 2 assisted by coordination of the
Figure 1. Examples of biologically active azetidine-containing structures
or precursors.
Received: September 12, 2017
© XXXX American Chemical Society
A
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Letter
second α-metalation of the C(sp2) can take place to obtain the
key 4-azetinyllithium intermediate C. Addition of H2O, D2O,
MeI, or TMSCl allowed the formation of 3-substituted azetines
3a−g in up to 97% yield (Scheme 2). Aromatic and
heteroaromatic aldehydes were also engaged as electrophiles in
the reaction, furnishing azetinecarbinols 3h−p with up to 97%
yield.
Scheme 1. Our Contribution to the Efficient Synthesis of
Disubstituted Azetines
Second, a similar sequence was designed to in situ generate a
boronate derivative D (Scheme 3) by trapping the corresponding
4-azetinyllithium C with boron isopropoxide. Being a stable
species at room temperature, this organoboronate is an excellent
candidate to subsequently undergo a Suzuki cross-coupling in a
one-pot process. Thus, following the double-lithiation/boryla-
tion sequence, a range of aromatic halides were engaged in the
Scheme 3. In Situ Generated 4-Azetinylboronates for Direct
Suzuki Coupling
Scheme 2. Our Contribution to the Efficient Synthesis of
Disubstituted Azetines
directing group (Boc) on the amine using s-BuLi in the presence
of TMEDA triggers a β-elimination (A, Scheme 2) and
intermediary forms a 2-azetine (B). With an excess of s-BuLi, a
B
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presence of Pd(dppf)Cl2·CH2Cl2 (4 mol %) in THF, and
products 4−8 were isolated after 48 h at room temperature. Aryl
iodides reacted usually faster than the corresponding bromides,
leading to the expected compounds in better yields. A wide range
of aromatic halides were introduced in this strategy, using 3-
arylated (4a−o and 5a−c), 3-alkynyl (6a−f), and 3-alkyl
substrates (7a−f and 8a,b), resulting in 4-arylated structures in
good to excellent yields (up to 96%). Additionally, the great
functional group tolerance of organoboronates allowed us to
introduce aromatic aldehydes 4i and 7d as well as heteroaromatic
moieties (4m−o, 5c, 6e,f, and 7f) in good yields up to 92%,
independently from the nature of the substituent at position 3.
Structures of these unsaturated N-heterocycles were supported
by X-ray analysis (6d and 8a).14 Although full conversion was
monitored for the formation of 4k bearing a free amine,
decomposition of the product on silica was noticed and the final
azetine could only be isolated in 33% yield. In a more general
manner, electron-enriched aromatics led to moderate yields due
to fast decomposition (mainly ring opening products) in slightly
acidic conditions during purification.
A one-pot sequence terminated by a palladium-catalyzed
Suzuki coupling with 4-bromodiazobenzenes led to conjugated
systems 10a−c in good yields (Scheme 5). In the dark, 10a−c are
Scheme 5. Application to the Synthesis of 4-
Azetinylazobenzenes
We then pushed the methodology further by developing an
unprecedented catalyst-free cross-coupling of the 4-azetinyl-
lithium species, successfully adapting the Zweifel-type olefination
strategy. Boronic ester was then added to the in situ generated
intermediate C (Scheme 4), giving the bis-organoboronate E.
present in their thermally stable trans-configuration. Irradiation
with UV light (λ = 305−365 nm) triggers isomerization to the cis-
configuration, while irradiation at 385−435 nm allows instant
switching to the trans-configuration. Performing iteratively on
and off photoswitching on these azetinyl-derived azobenzenes
did not show any fatigue of the four-membered ring over time,
proving the structural stability of the system. Finally, we showed
the applicability of 3,4-substituted azetines to the formation of
syn-2,3-disubstituted azetidines through simple hydrogenation
(Scheme 6). Compounds 3e, 3c, and 4n were engaged in the
Scheme 4. Catalyst-Free Zweifel Arylation of 4-
Azetinyllithium Species
Scheme 6. Straightforward Access to Stereodefined Azetidines
Subsequent addition of iodine furnishes an iodonium F that
undergoes 1,2-metalate rearrangement, giving the α,β-iodobor-
onic ester G. The addition of a base finally triggers a cis-
elimination, resulting in 3,4-disubstituted azetines 4−9. 3-Alkyl-,
alkynyl-, and arylazetinyllithium were used with aromatic boronic
esters and compounds 4a,b, 6a−c, and 7a, were obtained with
reasonable yields (up to 72%), given the absence of a palladium
catalyst. Interestingly, heteroaromatic substrates led to similar
results and 9b was isolated in 38% yield.
Considering the versatility of both arylation sequences and the
recent interest brought by the community on diazobenzenes as
promising photoswitchable systems for pharmacologic applica-
tions,15 functionalization of azetines at position 4 was explored as
a proof of concept.
presence of palladium and hydrogen to give 11a−c under
smooth conditions in good yields and with an excellent
diastereoisomeric ratio (dr >99:1).12 Subsequent amine
deprotection ultimately led to free azetidines 12a,b in
quantitative yields. It is worth noting that this represents a
powerful approach to syn-azetidines, as most reports relate the
formation of anti-azetidines.16
β-Amino alcohols are important functionalities in organic
chemistry as they can serve as ligands in catalysis and are present
in a large number of natural and bioactive substances.17 In an
attempt to synthesize stereodefined β-amino alcohols embedded
in an azetidine core, we representatively demonstrated (Scheme
C
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Vaquero, J. J., Barluenga, J., Eds.; Wiley-VCH Verlag, 2011; pp 163−
268.
(2) For recent examples of azetine synthesis, see: (a) Barluenga, J.;
6) that the reduction of chiral 4-azetinylcarbinol rac-3i could take
place with high diastereoselectivities, furnishing rac-13 as a single
isomer (dr >99:1:0:0, the relative configuration was determined
by X-ray crystallography).14 The high degree of stereoselectivity
observed in this reaction can be attributed to the coordination of
the hydroxyl moiety to the palladium in the reduction process.
For steric reasons, the aromatic group on the carbinol prefers to
be oriented out of the plane, avoiding unfavorable interactions
with the large Boc protecting group (H) (Scheme 6). This
procedure certainly paves the way to new subclasses of chiral
strained β-aminoalcohols.
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efficient synthetic approach to novel 3,4-disubstituted azetine
architectures, paving a new way toward stereodefined 2,3-
azetidines. Two parallel approaches have been developed for the
facile introduction of aryl and heteroaryl substituents at the
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photoswitchable molecules, demonstrating their long-term
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ASSOCIATED CONTENT
* Supporting Information
■
S
CThe Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02847.
(10) (a) Burkhard, J. A.; Carreira, E. M. Org. Lett. 2008, 10, 3525.
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HRMS, and 1H and 13C NMR data) for all new
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dorian.didier@cup.uni-muenchen.de.
ORCID
Michael Eisold: 0000-0002-2314-3990
Dorian Didier: 0000-0002-6358-1485
Author Contributions
∥These A.N.B. and M.E. contributed equally.
(12) Dejaegher, Y.; Kuz’menok, N. M.; Zvonok, A. M.; De Kimpe, N.
Chem. Rev. 2002, 102, 29.
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(14) CCDC 1568210 (6d), CCDC 1568208 (8a), and CCDC
1568209 (13) contain the supplementary crystallographic data for this
manuscript.
(15) For a general review on photoswitchable systems and their
applications in pharmacology, see: Broichhagen, J.; Frank, J. A.; Trauner,
D. Acc. Chem. Res. 2015, 48, 1947.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(16) (a) Kurteva, V. B.; Lyapova, M. J. ARKIVOC 2005, xiii, 8. (b) Kiss,
D.D., M.E., and A.N.B. are grateful to the Fonds der Chemischen
Industrie, the Deutsche Forschungsgemeinschaft (DFG Grant
No. DI 2227/2-1), and the SFB749 for Ph.D. funding and
financial support. G.H. and Y.M.K. thank the Erasmus program.
Dr. Peter Mayer (LMU, Munich) is kindly acknowledged for X-
ray measurements.
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DOI: 10.1021/acs.orglett.7b02847
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