Access to novel functionalized trifluoromethyl β-lactams by ring expansion of aziridines

Article abstract of DOI:10.1039/c4ob01262c

From carboxylic acid trifluoromethyl aziridines, halogeno β-lactams were obtained stereoselectively by ring expansion. Different conditions such as radical, organometallic reactions allowed easy and selective access to CF ₃-β-lactams substitute

Full text of DOI:10.1039/c4ob01262c

Organic &
Biomolecular Chemistry
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Access to novel functionalized trifluoromethyl
β-lactams by ring expansion of aziridines†
Cite this: Org. Biomol. Chem., 2014,
12, 6345
S. Decamps, L. Sevaille, S. Ongeri and B. Crousse*
Received 17th June 2014,
Accepted 8th July 2014
DOI: 10.1039/c4ob01262c
www.rsc.org/obc
From carboxylic acid trifluoromethyl aziridines, halogeno at the C-4 position and their functionalization at the C-3 posi-
β-lactams were obtained stereoselectively by ring expansion. tion (Scheme 1). From fluorinated imine derivatives14 and
Different conditions such as radical, organometallic reactions α-chloroamine
(N-tosyl-1-chloro-2,2,2-trifluoroethylamine),15
14b
allowed easy and selective access to CF3-β-lactams substituted at β-lactams were obtained with OBn,14a NBn2
or alkyl groups
the C-3 position.
at the C-3 position.14c Finally, another group used the nucleo-
philic ring opening of aziridines followed by Grignard-
mediated intramolecular cyclisation to obtain the 3-chloro-
and 3-(tertbutyltrimethylsilyloxy)-4-trifluoromethyl-β-lactams.16
However, these approaches did not allow access to a wide
range of 4-CF3 β-lactams functionalized at the C-3 position.
Herein, we disclose the synthesis and the functionalization of
halogenated CF3 β-lactams available in one step by ring expan-
sion of aziridines.
Most of the published syntheses using aziridines to
produce β-lactams involved ring-opening and closure in two
steps16 and carbonylated reactions.17 However, a straight-
forward approach to chloro-β-lactams which has been very less
studied is the ring expansion of carboxylic aziridines. Both
Clough18 and Sharma19 showed the elegant use of non-fluori-
nated sodium carboxylate aziridine in a one-step rearrange-
ment with thionyl chloride or oxalyl chloride to form 3-chloro-
2-azetidinones in moderate yields (Scheme 2).
Introduction
More than 80 years after Fleming’s discovery,1 β-lactams con-
tinue to be of major interest not only for their biological pro-
perties but also for their usefulness as intermediates in
organic synthesis. They represent a major structural part of
antibiotic families such as penicillins, cephalosporins, carba-
penem and monobactams.2 Besides their fundamental role in
the fight against pathogenic bacteria, β-lactams, and more pre-
cisely monobactams, have recently exhibited interesting inhibi-
tory activities on proteases like thrombin,3 human
cytomegalovirus protease,4 tryptase,5 human leukocyte elas-
tases6 and chimases.7 After the first synthesis of lactams by
Staudinger in 1907,8 many synthetic methods of β-lactams
were then developed including rearrangement of heterocyclic
compounds, cyclization reactions and carbene insertion reac-
tions.9 The introduction of the “β-lactam synthon” method by
Ojima nearly 20 years ago10 led to great interest in azetidin-
2-one as building blocks and valuable intermediates to access
a variety of high-added value products such as peptidomi-
metics and nitrogen heterocycles.
Introduction of fluorine into a biologically active molecule
usually increases its pharmacological properties.11,12 Although
fluorine-containing compounds have been widely used in the
field of medicinal chemistry,13 it is safe to say that 4-CF3
monobactams diversely functionalized at C-3 are rather rare
and scarcely explored. To the best of our knowledge, only few
examples described the synthesis of trifluoromethylated rings
Scheme 1 Access to trifluoromethylated β-lactams.
Laboratoire BioCIS-CNRS, Faculté de Pharmacie, LabEx LERMIT, Univ. Paris-Sud,
rue J. B. Clément, F-92296 Châtenay-Malabry, France. E-mail: benoit.crousse@u-psud.fr
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ob01262c
Scheme 2 Ring expansion of aziridines.
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Table 1 Ring expansion of aziridines with various halogenating
reagents
Results and discussion
Firstly, both previous conditions were attempted for the ring
expansion of the cis-CF3-aziridine carboxylic acid (cis-1a).20
After saponification of the corresponding ester, the sodium
salt of cis-1a reacted in the presence of the oxalyl chloride and
after 24 h in refluxing toluene, led to the β-lactam 2a in 50%
yield as a mixture of diastereomers (cis/trans: 85/15). Perform-
ing the reaction with thionyl chloride and a catalytic amount
of NaH (10%) in THF at room temperature for 48 h lowered
the yield (40%) and the diastereoselectivity (cis/trans: 40/60) of
the reaction (Scheme 3).
However, after optimization of the reaction conditions, the
yields and diastereoselectivities were improved by carrying out
the reaction of the carboxylic acid CF3-aziridines with NaH
(1.2 eq.) and thionyl chloride in toluene at 70 °C (Scheme 4).
Aziridines cis-1a and trans-1a16 afforded the corresponding
cis β-lactam cis-2a and trans β-lactam trans-2a in 58% and 55%
yields respectively. Moreover, the stereoselectivities were excel-
lent. The relative conformations of the products were deter-
mined by 1H-NMR according to the coupling constant of cis
(6 Hz) and trans (3 Hz). The mechanism leading to this stereo-
specificity has been reported to involve a bicyclic ammonium
intermediate.18,19 Given these very encouraging results, we
were interested in the use of other halogenated reagents to
prepare other halogenated β-lactams (Table 1).
Time
(h)
T
Yield
(%)
Entry Reagent
Base Solvent
(°C) dr
1
2
3
4
5
6
7
PCl5
NaH Toluene
NaH Toluene
NaH Toluene
2
1.5
1
80
80
80
0
0
rt
100/0 60
100/0 76
90/10 40
Traces
Traces
100/0 70
100/0 85
POCl3
SOBr2
BBr3
PBr3
PPh3/NBS
PPh3Br2
—
—
—
—
DCM
DCM
DCM
DCM
1
—
—
24
0.5
0.5
rt
Table 2 Formation of 3-bromo 4-CF3 β-lactams
Entry
R
cis/trans
Product
Yielda (%)
Both phosphorus pentachloride and phosphoryl chloride
allowed improving the yield and the diastereoselectivity in the
formation of 3-chloro-4-CF3-β-lactam cis-2a (entries 1 and 2).
The new cis-3-bromo-4-CF3-β-lactam cis-3a was formed when
1
2
3
4
Bn cis-1a
100/0
100/0
100/0
100/0
cis-3a
cis-3b
cis-3c
cis-3d
85
81
81b
38
PMB cis-1b
PMP cis-1c
Ph2CH cis-1d
a Isolated yield. b Ph3P/NBS was used instead of Ph3PBr2.
the reaction was performed with thionyl bromine despite a low
yield and a good diastereoselectivity (entry 3). From other bro-
minating agents such as BBr3 and PBr3, only traces of the com-
pound were observed. Finally, the expected product cis-3a was
satisfactorily obtained with triphenylphosphine/NBS (entry 6,
70%) and triphenylphosphine dibromide (entry 7, 85%) in
excellent yield and diastereoselectivity in less than 30 minutes.
Our efforts to introduce the iodine with Ph3PI2 or Ph3P/NIS
failed and afforded a mixture of compounds. These optimized
conditions were applied to other aziridines having different
protective groups (Table 2). The formation of the corres-
ponding bromo-β-lactams cis-3b and cis-3c was not disturbed
with the p-methoxy benzyl and p-methoxy phenyl (entries
2 and 3). In contrast, with the diphenyl group, only 38% of
3-bromo-β-lactam cis-3d was obtained (entry 4). This low yield
could be explained by the bromination between the two
phenyl rings of the biphenyl which led to the decomposition
of the product. Whatever be the protective group, the
diastereoselectivity was excellent.
Scheme 3 Classical reactions.
The ring expansion conditions were also effective on the
trans aziridine trans-1a to afford stereospecifically the corres-
ponding trans 4-Br-3-CF3 β-lactam trans-3a in 50% yield
(Scheme 5).
Scheme 4 Ring expansion of CF3-aziridines.
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Condensation with aldehydes provided the corresponding
alcohols 5c and 7–11 in moderate to good yields.22 Unfortu-
nately, from enolizable substrates, only compound 6 was
obtained. However, carbon dioxide and methyl iodide reacted
with the enolate intermediate to lead to the β-lactams 12 and
13 in 50% and 66% yields respectively. Nitrogen incorporation
could be achieved from the ditertbutyl azodicarboxylate, gen-
erating the corresponding hydrazine 14. The reaction was
stereoselective, and addition occurred exclusively from the
opposite side of the bulky trifluoromethyl substituent.
Scheme 5 Ring expansion of the trans-CF3-aziridine 1a.
With different brominated lactams in hand, we investigated
their reactivity under different conditions in order to provide
functionalized CF3 β-lactams. First the substitution of chloride
and bromide cis and trans lactams with a nucleophile such as
sodium azide, amines and alcoholates failed totally, and start-
ing materials were recovered unchanged. Fortunately, radical
reaction was effective and diastereoselective with allyltin and
AIBN21 to lead exclusively to trans 4-allyl-3-CF3 β-lactams 4a–c.
The radical addition occurred at the opposite side of the CF3
group (Scheme 6).
We also studied the reactivity of these 3-bromo-β-lactams
with various organometallic reagents. We attempted the Refor-
matsky reaction in the presence of activated zinc and benz-
aldehyde (Table 3).
Under these conditions, benzaldehyde was trapped by the
organozinc reagents to afford the corresponding 3-functiona-
lized β-lactams 5a–c as a mixture of diastereomers.22 However,
for each reaction, the side product 6 was always observed in
around 20–30% yields.
Scheme 7 The halogen-metal exchanges.
Scheme 6 Radical reaction.
Table 3 Reformatsky reaction
Conclusions
In conclusion, we achieved a convenient highly diastereoselec-
tive one-pot synthesis of 3-halogenated-4-trifluoromethyl cis and
trans-β-lactams by ring expansion of aziridines. We showed that
3-bromo-4-CF3 β-lactams reacted under various reaction con-
ditions such as radical and nucleophilic reactions. Such novel
structures are now available to be exploited for medicinal purposes.
Entry
R
de 5
Yields 5a/6b (%)
1
2
3
Bn, 5a
PMB, 5b
PMP, 5c
1 : 1.7
1 : 1.7
1 : 2.0
70/30
40/20
60/27
Acknowledgements
S.D. thanks the LabEx LERMIT (ANR-10-LABX-0033-LERMIT)
for a PhD fellowship.
a Isolated yield. b Determined by 19F NMR.
Notes and references
In order to avoid the formation of the reduced product 6,
we undertook the halogen–metal exchange. After several con-
ditions were studied, here we report the best one: nBuLi at
−100 °C in THF (Scheme 7).
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2 The organic Chemistry of β-lactams, ed. G. I. Georg, VCH,
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