Base-determinant chemodivergent transformations of chiral 2,3-dibromopropanamide derivative

Article abstract of DOI:10.1016/j.mencom.2020.05.017

Depending on the base used, reactions of 2,3-dibromo-2-methyl-N-[(1R)-1-phenylethyl]propanamide with DBU, Bu^tOK and NaH in THF lead to β-bromomethacryloylamides, α-methylidene-β-lactam and azetidin-2-ones, respectively.

Full text of DOI:10.1016/j.mencom.2020.05.017

Mendeleev
Communications
Mendeleev Commun., 2020, 30, 313–314
Base-determinant chemodivergent transformations
of chiral 2,3-dibromopropanamide derivative
Natalya K. Selezneva,a Adeliya M. Galeeva,a Leonard M. Khalilov,b
Zuleykha R. Valiullinaa and Mansur S. Miftakhov*a
a Ufa Institute of Chemistry, Ufa Federal Research Centre of the Russian Academy of Sciences, 450054 Ufa,
Russian Federation. E-mail: bioreg@anrb.ru
b Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 450071 Ufa, Russian Federation
DOI: 10.1016/j.mencom.2020.05.017
Br
Br
Br
Depending on the base used, reactions of 2,3-dibromo-2-
methyl-N-[(1R)-1-phenylethyl]propanamide with DBU,
ButOKandNaHinTHFleadto b-bromomethacryloylamides,
a-methylidene-b-lactam and azetidin-2-ones, respectively.
Br
Me
H
bases
N
Ph
O
or
or
Me
NH
Me
N
Ph
N
Ph
O
O
O
Me
Me
Me
Me
Ph
Keywords: chemodivergent synthesis, b-lactams, azetidin-2-ones, a-methylidene-b-lactams, b-bromomethacryloylamides, dehydro-
bromination, diastereomers.
H
Monocyclic b-lactams represent the ring part of antibacterial
H2N
Ph
Cl
N
Ph
i
monobactam and sulbactam,1 an Ezetimibe cholesterol absorption
inhibitor,2 azetidinones for carbapenems,3,4 b-lactam synthons for
incorporation of Taxol b-amino ester fragment into the aglycone
structure,5,6 serve as potential models in the study of drug
resistance of b-lactams.7 a-Methylidene-b-lactams (aMbLs) can
undergo the Michael reactions, electrophilic addition and lactam
ring opening. A number of methods for synthesizing aMbLs have
been published, including a synthesis of those containing CF3 at
C3 by methylenation of the corresponding 3-oxo derivatives,8 a
synthesis employing Pd-catalyzed oxidative carbonylation of
N-allylamines,9 approaches to densely functionalized aMbLs
from nitrodiene structures,10 asymmetric allylic amination of
Baylis–Hillman adducts with amines followed by cyclization,11
PPh3-catalyzed Umpolung cyclization of propylamides.12
In the present study, we attempted to construct methylidene-b-
lactam moiety by dehydrobrominative cyclization of 2,3-dibromo-
2-methylpropanamide derivatives which, in turn, can be prepared
by bromination of methacrylamides. Dehydrobromination of
2,3-dibromo-2-methylpropanamides can also afford bromoalkene-
type products which were used in the Heck cross-coupling,13 the
Nozaki–Hiyama–Kishi aldol condensation,14 and for generation
of vinyl radicals. We supposed that the choice of proper base and
reactionconditionswoulddrivethereactiontowardsthecyclization
route involving amide nitrogen atom.
+
Me
Me
Me
O
O
Me
1
Br
Br
Br
Br
H
N
H
ii, iii
Ph
N
Ph
+
Me
Me
O
Me
O
Me
2b (less polar)
2a (more polar)
Scheme 1 Reagents and conditions: i, Et3N, CH2Cl2, 0 ® 20 ºC, 4 h,
83%; ii, Br2, CH2Cl2, room temperature, 1 h, 73%; iii, SiO2, column
chromatography.
Compounds 2a,b are of interest primarily for possible
base-promoted intramolecular cyclization reactions. Reaction
of dibromide 2 with DBU gives a mixture of dehydro-
bromination products 3a and 3b in a 2 : 1 ratio (Scheme 2).
The vinyl proton signal is characteristic in the assignment of
isomeric vinyl bromides 3a and 3b. For isomer 3a, it is shifted
μ(MoKa) = 5.784 mm–1, dcalc = 1.660 g cm–3, F(000) = 1376.0, S = 0.842.
Refinement was converged with R1 = 0.0542, wR2 = 0.0681 [9526
reflections with I > 2s(I)] and R1 = 0.1819, wR2 = 0.1055 for all data
(13857 reflections). The X-ray diffraction measurements were performed
on an Agilent XCalibur (Eos, Gemini) automated four-circle diffracto-
meter (graphite monochromator, MoKa radiation, l = 0.71073 Å, ω-scan
mode, 2qmax = 62°) at ambient temperature (293–298 K). The collected
data were processed using the CrysAlisPro program.15 The structures were
solved by direct methods and refined by the full-matrix least-squares method
in the anisotropic approximation for non-hydrogen atoms. All hydrogen
atoms were generated using the proper HFIX command and refined
isotropically using the riding model. The structure was solved with the
ShelXT16 structure solution program using Intrinsic Phasing and refined with
the ShelXL17 refinement package using Least Squares minimisation.
CCDC 1972715 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.
In our experiments, amide 1 obtained from commercially
available methacryloyl chloride and (R)-(+)-a-methylbenzyl-
amine was brominated to give a diastereomeric mixture of
dibromo derivatives 2 (Scheme 1). Though analytical samples of
diastereomers 2a,b were isolated by column chromatography on
SiO2 and the structure of (S,R)-2b was confirmed by XRD
(Figure 1),† a more accessible diastereomeric mixture of 2a,b
was used in the subsequent reactions.
†
Crystal data for 2b. C12H15Br2NO (M = 349.05), monoclinic,
space group P21,
a
=
9.9212(5),
b
=
16.9866(10) and
c = 16.8457(10) Å, b = 100.250(5)º, V = 2793.7(3) Å3, Z = 8, T = 293(2) K,
© 2020 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 313 –

Italian Oral Surgery, 30 (2020) 313-314. doi:10.1016/j.mencom.2020.05.017