Cobalt-Catalyzed α-Arylation of Substituted α-Halogeno β-Lactams

Article abstract of DOI:10.1021/acs.orglett.9b02122

The treatment of 3-bromo β-lactams by an aryl Grignard, in the presence of CoCl₂ (2 mol %) and TMEDA (2 mol %) in THF, produces 3-aryl β-lactams in good yields and excellent diastereoselectivity.

Full text of DOI:10.1021/acs.orglett.9b02122

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cobalt-Catalyzed α‑Arylation of Substituted α‑Halogeno β‑Lactams
†,∥
†
‡,§
Vanessa Koch,‡,†,∥ Melanie M. Lorion,
Etienne Barde, Stefan Brase, and Janine Cossy*,†
́
̈
†Molecular, Macromolecular Chemistry and Materials (C3M), ESPCI Paris, CNRS, PSL University, 10 rue Vauquelin, 75231 Paris
Cedex 05, France
‡Institute for Organic Chemistry (IOC), Karlsruhe Institute for Technology (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
§Institute for Toxicology and Genetics (ITG), Hermann-von-Helmholtz Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
S
* Supporting Information
ABSTRACT: The treatment of 3-bromo β-lactams by an aryl Grignard, in
the presence of CoCl2 (2 mol %) and TMEDA (2 mol %) in THF,
produces 3-aryl β-lactams in good yields and excellent diastereoselectivity.
ore than 90 years after Fleming’s discovery of the
antibiotic effects of the fungal metabolite penicillin,1
dehalogenation or β-elimination than palladium catalysts,
allowing the functionalization of alkyl halides.
M
β‑lactam antibiotics are still one of the most powerful medicines
to treat infections. However, the first synthesis of a β‑lactam was
reported in 1907 by Staudinger,2 and several years of intense
research were required to determine the structure of penicillin3
and to connect the core structure with a Staudinger β-lactam
(Figure 1). Since then, β-lactams and azetidin-2-ones have been
intensively studied, their relevance as antibiotics increased, and
other β-lactam antibiotics such as cephalosporins, carbapenems,
and monobactams appeared on the market.4,5 In addition,
β‑lactams are considered interesting building blocks6 for the
synthesis of nitrogen-containing compounds of biological
relevance which resulted in Ojima’s introduction of the so-
called “β-lactam synthon method” strategy.7 Because of the ring
strain, β-lactams can be easily opened by nucleophiles and are
therefore well-known precursors of β‑amino alcohols and
β‑amino acids. In addition, their rearrangements can lead to
N‑containing heterocyclic compounds of medicinal interest
such as pyrrolidines, pyridones, and oxazinones.6,8
Following up on our previous work on cobalt-catalyzed cross-
couplings between α-bromo amides and Grignard reagents,10b,14
we would like to report herein a cobalt-catalyzed α-arylation of
3-halogeno β-lactams by utilizing inexpensive and commercially
available or easily accessible Grignard reagents to access
potential pharmaceutically interesting 3‑aryl azetidin-2-ones
(Scheme 1).
Scheme 1. Co-Catalyzed α-Arylation of Amides and Lactams
by Grignard Reagents
A Staudinger [2+2]-cycloaddition of aryl imines with α-halo
acetyl halides under basic conditions was selected for the
synthesis of the trans-3-halo 4-aryl-β-lactams 1.15 Based on our
previous results on the Co-catalyzed cross-coupling of α‑bromo
amides, we started our investigations on the trans-3-bromo
4‑aryl-β-lactam 1a, using an equimolar mixture of CoCl2 (10
mol %) and XantPhos (10 mol %) as the catalytic system. The
Grignard reagent, the p-tolylmagnesium bromide (p-TolMgBr)
(1.50 equiv) in THF (c = 0.76 M) was added dropwise to the
reaction mixture at 0 °C. After 3 h, the desired trans‑3‑aryl
Figure 1. β-Lactam antibiotics.
The functionalization of heterocycles by cross-coupling has
proved to be powerful tools to access a library of compounds
from a lead in order to find a molecule with better biological
activity than the lead itself. While tremendous advances have
been achieved through the use of the well-established palladium-
catalyzed cross-couplings9 in the past 50 years, focus has been
shifted toward the use of earth-abundant and inexpensive 3d-
metal catalysts.10−13 Besides the low costs of the catalytic
system, these metal catalysts are less prone to induce
Received: June 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02122
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
β‑lactam 2a was isolated in 34% yield (Table 1, entry 1). While
the use of both mono- and bidentate phosphine ligands such as
PPh3, dppf, or dppe did not lead to any improvement in the yield
of 2a (see Table S1, Supporting Information (SI)), nitrogen-
based ligands such as tetramethyl ethylenediamine (TMEDA)
and trans-tetramethyl cyclohexan-1,2-diamine (TMCD) proved
to be determining for the yield in the cross-coupling product, as
2a was isolated in 68% when TMEDA was used and in 66% yield
when TMCD was utilized (Table 1, entries 2−3).
3‑bromo β-lactam 1a was involved in the coupling, the desired
3‑aryl β‑lactam 2a was isolated with a lower yield of 52%,
nevertheless still satisfactory (Table 1, entry 16).
With the optimized conditions in hand, the substrate scope
was explored, starting with a range of 3-bromo β-lactams 1a−q,
substituted at C4 by different aryl groups (Scheme 2).
Scheme 2. Variation of the α-Bromo β-Lactams 1
To our delight, the inexpensive CoCl2 proved to be superior
to other cobalt sources such as CoF2, CoBr2, CoI2, Co(acac)2,
and Co(OAc)2 (Table 1, entries 5−9). The importance of the
cobalt catalyst and ligand was demonstrated by control
experiments, as without the catalyst or ligand, no conversion
or poor conversion of 1a was obtained (Table 1, entries 4 and
11). It is worth mentioning that if a turbo Grignard reagent
(Mg/LiCl then addition of Dibal-H followed by the addition of
p-TolBr) was used instead of the commercially available
Grignard reagent, only 32% of 2a was isolated (versus 68%)
which goes along with the poor yield obtained when LiCl was
introduced in the reaction media as an additive (see SI). When
the reaction was conducted at −20 °C instead of 0 °C, the yield
of 2a was increased to 67% (Table 1, entry 10). Further
improvements were achieved by adding the Grignard reagent
with a syringe pump (2.4 mL/h for 1.5 mL of p-TolMgBr
solution in THF, c = 0.76 M) resulting in a 76% yield of 2a on a
0.75 mmol scale (Table 1, entry 12). Noteworthy, the amount of
CoCl2 and TMEDA could be lowered to 2 mol % without any
decrease of the yield in 2a (Table 1, entries 13−14). Moreover,
the reaction could be performed on a 2.0 mmol scale without
affecting the yield of the coupling product (Table 1, entry 15). It
worth mentioning that when 3-chloro β‑lactam 1a′ instead of
a
a
Table 1. Optimization of the Cross-Coupling Conditions
Obtained as a mixture of 2g, double-coupling product and
dehalogenated product in a ratio of 1:0.16:0.06 according to
b
1H NMR spectra analysis (see SI). Using 3,4-cis-1j.
Regardless of the electronic character of the substituent at the
para-position of the aryl group present at C4, e.g. an electron-
donating or an electron-withdrawing substituent, the corre-
sponding cross-coupling products were obtained with good
yields ranging from 64% to 79%. Even the presence of a
p‑bromo- (1g) or a p-chloro- (1h) substituent on the aromatic
was well-tolerated allowing further derivatization. In the case of a
p‑bromo substituent (1g), the coupling product 2g was isolated
along with a small amount of the double coupled product and
the debrominated product (see SI), showing that the cross-
coupling of the p-TolMgBr with the halide on the β-lactam ring
was strongly favored over the coupling with the aryl halide.
Gratifyingly, the reaction was not sensitive to steric hindrance, as
the 3-bromo β-lactams, substituted at C4 by a p-, o-, or
m‑methoxy-phenyl group, were efficiently coupled with
p‑TolMgBr, delivering the expected β-lactams 2c, 2j, and 2l
with very good yields (around 80%). Interestingly, when the 3,4-
cis-1j and 3,4-trans-1j were separately subjected to the cross-
coupling conditions, both compounds exclusively led to the 3,4-
trans β‑lactam 2j (see SI). The assignment of the relative
configuration of the substituents was achieved by measurements
of the 1H NMR coupling constants between the protons at C3
and C4 of the obtained products (3J ∼ 2.2 Hz) which correspond
to those reported for trans-β-lactams.16 Moreover, polysub-
stituted aromatics can be present at the C4 position of the
entry
[Co] (x mol %)
ligand (y mol %)
T (°C)
yield
1
2
3
4
5
6
7
8
9
CoCl2 (10)
CoCl2 (10)
CoCl2 (10)
−
XantPhos (10)
TMEDA (10)
TMCD (10)
TMEDA (10)
TMEDA (10)
TMEDA (10)
TMEDA (10)
TMEDA (10)
TMEDA (10)
TMEDA (10)
−
TMEDA (10)
TMEDA (5)
TMEDA (2)
TMEDA (2)
TMEDA (2)
0
0
0
0
0
0
0
0
0
−20
0
0
0
0
34%
68%
66%
0%
CoF2 (10)
CoBr2 (10)
CoI2 (10)
Co(acac)2 (10)
Co(OAc)2 (10)
CoCl2 (10)
CoCl2 (10)
CoCl2 (10)
CoCl2 (5)
CoCl2 (2)
CoCl2 (2)
CoCl2 (2)
0%
47%
45%
41%
31%
67%
20%
76%
82%
79%
73%
52%
b
10
11
12
13
14
15
16
c
c
c
d
0
0
ce
,
a
Reaction conditions: 1a (0.225 mmol), p-TolMgBr (2.00 equiv),
3 h; yields of isolated products. At 25 °C, the yield is similar (69%)
but leads to a tedious purification due to the presence of
dehalogenated byproducts. 1a (0.750 mmol), p-TolMgBr (1.50
equiv). 1a (2.00 mmol), p-TolMgBr (1.50 equiv). Using 3,4-trans-
3-chloro 1-isopropyl-4-phenylazetidin-2-one 1a′.
b
c
d
e
B
DOI: 10.1021/acs.orglett.9b02122
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
β‑lactam without any decrease of the yield as 2m was isolated in
68% yield when a 3,4,5-trimethoxy substituted aryl group is
present. When the β-lactam is substituted by a 1-naphthyl
substituent (1n), the coupling product 3n was successfully
formed in 75% yield. Heterocycles are also well-tolerated as
shown for β‑lactams substituted at C4 by a 3-pyridyl, 3-furyl, and
2‑thiophenyl, as 3‑aryl β-lactams 2o, 2p, and 2q were isolated in
48%, 70%, and 65% yields, respectively.
Moreover, the nitrogen protecting group of the β-lactam has
no impact on the yield of the cobalt-catalyzed cross-coupling
between 3-bromo β-lactams and aryl Grignard reagents
(Scheme 4). Thus, when the N-isopropyl group was replaced
by removable protecting groups such as an N-allyl- or an
N‑p‑methoxybenzyl- (PMB) group, and by using p-tolylmagne-
sium bromide as the Grignard reagent, the cross-coupling
products 8 and 9 were obtained in good yields (76%−78%).
Furthermore, when a trifluoromethyl group is present at C3 on
the β-lactam instead of an aryl group, the outcome of the cross-
coupling was not influenced. In this case, the thermodynamically
favored cross-coupling product was the trans-3-tolyl 4‑trifluoro-
methyl-β-lactam 10 which was exclusively formed from the
corresponding cis-3-bromo 4-trifluoromethyl-β-lactam.
To diversify the β-lactam substituents at C3, various aryl
Grignard reagents were involved in the cross-coupling with
3‑bromo 4-phenyl β-lactam 1a (Scheme 3). Both electron-rich
p‑methoxyphenylmagnesium bromide and electron-poor
p‑fluorophenylmagnesium bromide were efficiently coupled to
the 3-bromo β-lactam 1a, delivering the corresponding coupling
products 4a and 4b in good yields (= 70%). When the 3-chloro
β-lactam 1a′ was used, the cross-coupling was less efficient than
with the 3-bromo β-lactam 1a, resulting in the formation of 4a
and 4b in lower yields of 49% and 39%, respectively, along with
nonidentified side products. We could also demonstrate that
several functional groups such as a N,N‑dimethyl-amino-,
trimethylsilyl-, and trifluoromethoxy group on the aryl Grignard
reagents 3 were tolerated, as the coupling products 4c−4e were
isolated in satisfying yields (41−64%). The aromatic system of
the aryl Grignard can also be successfully extended to biphenyl-
4-yl (1f) and 2-naphthyl (1i) systems. While ortho-functional-
ization of the aryl Grignard reagents did not lead to full
conversion of 1a, a meta-substitution was well-tolerated and gave
the corresponding products in good yields as shown when
m‑methoxyphenyl-magnesium bromide (4g: 63%), 3,5-dime-
thoxyphenyl-magnesium bromide (4j: 63%), and m-(trifluoro-
methyl)phenylmagnesium bromide were used. To our delight,
also a benzo[1,3]dioxole moiety could be introduced with 65%
yield (4k). Although with a lower yield, a pyridyl substituent can
be introduced at the C3 position of the β-lactam (4l).
Scheme 4. Variation of the N-Protecting Groups and C4
Substituents
To show the synthetic utility of the prepared α-aryl β‑lactams,
synthetic transformations of these latter were realized (Scheme
5). For example, treatment of 2a with AlH3 provided azitidine 11
in 80% yield showing that the carbonyl group of the azetidin-3-
one can be easily removed. We also demonstrated that the N-
PMB group can be cleaved to afford the free β-lactams 12 and
13. Furthermore, the α-aryl β-lactam 1a was reductively opened
with LiAlH4 to give access to the corresponding γ-amino alcohol
14 and the acidic methanolysis of the α-aryl β-lactam delivered
the N-protected β-amino ester 15 in good yield (67%).
Scheme 3. Variation of the Grignard Reagents 3
In summary, a highly efficient and inexpensive cobalt-
catalyzed α-arylation of pharmaceutically and biologically
relevant β-lactams was developed with only 2 mol % of CoCl2
and TMEDA. An array of functional groups is tolerated by the
herein reported reaction conditions, and different Grignard
reagents can be involved in the cross-coupling providing a
diversity of α-aryl β-lactams in good yields.
Scheme 5. Diversification of the α-Arylated β-Lactams
a
The Grignard reagent was prepared using Mg turnings in THF.
b
Using 3,4-trans-3-chloro 1-isopropyl-4-phenylazetidin-2-one 1a′.
C
DOI: 10.1021/acs.orglett.9b02122
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Markiewicz, J. T.; Knochel, P. Chem. - Eur. J. 2015, 21, 8242−8249.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02122.
■
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(e) Gonnard, L.; Guerinot, A.; Cossy, J. Chem. - Eur. J. 2015, 21,
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1
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13C, and 19F NMR spectra for all compounds (PDF)
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Stansfield, I.; Meerpoel, L.; Reymond, S.; Cossy, J. J. Org. Chem. 2013,
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: janine.cossy@espci.fr.
ORCID
́
Melanie M. Lorion: 0000-0002-5816-9103
Janine Cossy: 0000-0001-8746-9239
́
Org. Lett. 2009, 11, 277−280. (o) Gosmini, C.; Begouin, J.-M.;
Moncomble, A. Chem. Commun. 2008, 3221−3233. (p) Cahiez, G.;
Chaboche, C.; Duplais, C.; Giulliani, A.; Moyeux, A. Adv. Synth. Catal.
2008, 350, 1484−1488. (q) Ohmiya, H.; Tsuji, T.; Yorimitsu, H.;
Oshima, K. Chem. - Eur. J. 2004, 10, 5640−5648. (r) Tsuji, T.;
Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2002, 41, 4137−4139.
(11) For a review on iron-catalyzed cross-couplings, see: Kuzmina, O.
M.; Steib, A. K.; Moyeux, A.; Cahiez, G.; Knochel, P. Synthesis 2015, 47,
1696−1705.
Author Contributions
∥V.K. and M.M.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
V.K. thanks SFB/TR88 3MET for a grant, and E.B. thanks the
■
(12) For a review on copper-catalyzed cross-couplings, see: Thapa, S.;
Shrestha, B.; Gurung, S. K.; Giri, R. Org. Biomol. Chem. 2015, 13, 4816−
4827.
̀
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French Ministere de l’Enseignement Superieur et de la
Recherche for a grant.
(13) For nickel-catalyzed cross-couplings of 3-bromo azetidin-2-ones,
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