Cobalt-Catalyzed α-Arylation of Substituted α-Bromo α-Fluoro β-Lactams with Diaryl Zinc Reagents: Generalization to Functionalized Bromo Derivatives

Article abstract of DOI:10.1002/chem.202001721

A cobalt-catalyzed cross-coupling of α-bromo α-fluoro β-lactams with diarylzinc or diallylzinc reagents is herein disclosed. The protocol proved to be general, chemoselective and operationally simple allowing the C4 functionalization of β-lactams. The substrate scope was expanded to α-bromo lactams and amides, α-bromo lactones and esters as well as N- and O-containing heterocycles.

Full text of DOI:10.1002/chem.202001721

Accepted Article
Accepted Article
Title: Cobalt-Catalyzed α-Arylation of Substituted α-Bromo α-
Fluoro β-Lactams with Diaryl Zinc Reagents. Generalization to
Functionalized Bromo Derivatives.
Authors: Melanie Marie Lorion, Vanessa KOCH, Martin Nieger, yi-hung
chen, Aiwen Lei, Stefan Braese, and Janine Cossy
This manuscript has been accepted after peer review and appears as an
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202001721
Link to VoR: https://doi.org/10.1002/chem.202001721
01/2020

10.1002/chem.202001721
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Cobalt-Catalyzed α-Arylation of Substituted α-Bromo α-Fluoro
β-Lactams with Diaryl Zinc Reagents. Generalization to
Functionalized Bromo Derivatives.
Mélanie M. Lorion,[a]ϯ Vanessa Koch,[a],[b]ϯ Martin Nieger,[c] Hi Yung Chen,[d] Aiwen Lei,[d] Stefan Bräse,[b]
and Janine Cossy*[a]
[a]
Prof. Dr. Janine Cossy
Molecular, Macromolecular Chemistry and Materials (C3M), ESPCI Paris, CNRS, PSL University, 10 rue Vauquelin, 75231 Paris Cedex 05, France
E-mail: janine.cossy@espci.fr
[b]
Prof. Dr. Stefan Bräse
Institute of Organic Chemistry (IOC), Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany //
Institute for Biological and Chemical Systems (IBCS-FMS), Hermann-von-Helmholtz Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Dr. Martin Nieger, Department of Chemistry, University of Helsinki, P.O. Box 55, 00014 University of Helsinki, Finland
Prof. Dr Aiwen Lei, and Dr Yi-Hung Chen,The Institute for Advanced Studies, Wuhan University, Wuhan, China, 430072
[c]
[d]
Supporting information for this article is given via a link at the end of the document.
Abstract:
A Cobalt-catalyzed cross-coupling of α-bromo α-fluoro β-lactams
with diarylzinc or diallylzinc reagents is herein disclosed. The
protocol proved to be general, chemoselective and operationally
simple allowing the C4 functionalization of β-lactams. The substrate
scope was expanded to α-bromo lactams and amides, α-bromo
lactones and esters as well as N- and O-containing heterocycles.
Figure 1. Medicinally important bioactive β-lactams (1–3).
Introduction
The incorporation of fluorine into bioactive compounds to
improve their pharmacological properties has been well-
established in the drug research resulting in more than 100
fluorine-containing compounds being approved by the FDA
(Food and Drug Administration) in the US. Notably, the vast
majority of the top-selling drugs worldwide include at least one
fluorine atom.[1] The remarkable changes in biological and
pharmacological properties induced by the replacement of a
hydrogen atom by a fluorine atom can be explained by its unique
properties such as its lipophilicity, high electronegativity and
oxidation potential (–3.06 V), the high C–F bond strength and
the capacity of a fluorine atom to be involved in polar
interactions and hydrogen bonding while maintaining the size of
the molecule (the radius of a fluorine is only 12.5% larger than
that of hydrogen).[2] These properties are influencing important
β-Lactams are a class of bioactive compounds with antibacterial
properties[4] (Figure 1) as well as useful chiral building blocks in
organic synthesis as they can be transformed to β-amino acids
by ring-opening.[5] Besides to β-lactams with antibacterial activity
such as penicillin (e.g. amoxicillin 1) and cephalosporin (e.g.
cefuroxim 2), they can also inhibit different types of enzymes.[6]
For example, ezetimibe 3 is used to treat high blood cholesterol
by inhibiting the cholesterol transporter NPC1L,[7] showing that
modifications at the C3 and C4 positions of the β-lactam ring has
an impact on the biological activity of β-lactams. Thus, it is
important to develop efficient methods allowing the introduction
of different substituents and/or fluorine atoms at the C4 position
of a β-lactam to modify and/or increase the bioactivity of these
lactams. The incorporation of fluorine atoms onto a β-lactam ring
has been mainly pioneered by Tarui et al. who explored the
synthesis of several racemic and optically active fluorinated
β-lactams.[8] In addition, a diversity of substituted β-lactams
were synthesized either by Ni-catalyzed cross-coupling
(Scheme 1),[9] or by direct alkylation or aldolization.[10]
parameters of
a
drug such as its solubility, stability,
bioavailability and its binding to proteins which can therefore
lead to significant effects on its absorption, distribution and
clearance.[1-2, 3]
Herein, we report the α-arylation of α-bromo α-fluoro β-lactams
which could not be conducted using Grignard reagents under
cobalt-catalyzed cross-coupling, using the conditions developed
in one of our group,[11a] but could be achieved by using diarylzinc
1
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and diallylzinc reagents (Scheme 1). The reaction is general and
can be applied to a range of α-bromo carbonyl derivatives such
as α-bromo β-lactams and amides as well as α-bromo lactones
and esters.
Scheme 2. Synthesis of α-bromo-β-lactam 1 and α-bromo α-fluoro-β-lactams,
1a–1j.
Based on our previous results on cobalt-catalyzed cross-
coupling of α-bromo β-lactams with aryl Grignard reagents, we
started our investigations on the trans-3-bromo 3-fluoro 4-aryl
β-lactam 1a using CoCl2 (10 mol %), tetramethylethylene
diamine (TMEDA, 1.9 equiv) and the Grignard reagent
p-TolMgBr 2a (1.5 equiv), in THF at 0 °C. Under these
conditions, only traces of the desired product 3aa were observed
(less than 15%).[11b] Due to this failure, organo-zinc reagents,
which show a greater functional group tolerance and are
therefore widely utilized in cross-couplings,[13] were envisaged.
While the use of the heteroleptic arylzinc reagent, p-TolZnCl,
was not effective, the use of freshly prepared bis(p-tolyl)zinc
(Tol2Zn) led to the formation of the desired cross-coupling
product 3aa. The relative configurations of the cross-coupled
product were determined by measurement of the 1H NMR
coupling constant between the fluorine atom at C3 and the
proton at C4 (3J ~ 3.5 Hz) which corresponds to the coupling
constant reported for α-fluoro β-lactams with
a
trans
configuration (related to the position of F/H).[8b, The cross-
coupling was performed by adding a solution of p-Tol2Zn in THF
(2.0 equiv, c was determined each time by titration) over 15 min
using a syringe pump, to a solution of 1a (0.25 mmol) containing
CoCl2 (10 mol %) and TMEDA (1.9 equiv) at 0 °C. After stirring
for 3 h at 0 °C and after raising up the temperature to rt, the
desired 3-fluoro 3-p-tolyl β-lactam 3aa was formed in 75% yield
which was calculated by 1H NMR analysis (Table 1, entry 1).
While lowering the amount of Tol2Zn to 1.5 equiv did not impact
the outcome of the reaction, the use of only 0.6 equiv did not
result in full conversion of the starting material 1a and, as
consequence, a modest yield of 55% in 3aa was obtained
(evaluated by 1H NMR) (Table 1, entries 2–3). To our delight, the
reaction could be run at rt without any remarkable influence on
the reaction outcome (Table 1, entry 4) and, in addition, the
reaction time could be reduced to 2 h affording 3aa in 79%
isolated yield (Table 1, entry 5). The influence of TMEDA was
also studied revealing that a catalytic amount of TMEDA
(20 mol %) was not sufficient as the yield in 3aa dropped to 50%
(Table 1, entry 7). It is worth mentioning, that an enhancement
of the yield of the products resulting of the cross-coupling
between α-bromo α-fluoro compounds and arylzinc reagents
was already observed by Araki et al. when an arylzinc-TMEDA
complex was utilized.[14] These results suggest that TMEDA can
act both as a ligand and an additive. Nevertheless, the amount
of TMEDA could be successfully reduced to 1.1 equiv (Table 1,
entry 6). Noteworthy, the amount of CoCl2 could also be reduced
9]
Scheme 1. α-Arylation and α-alkylation of lactams and lactones.
Results and Discussion
Different methods have been developed to access β-lactams
including the cyclization of β-amino-acids or Staudinger
reactions
and
transition-metal
catalyzed
reactions,
photocatalysis or C–H activation/amidation.[12] Among these
methods, we chose the Staudinger (2+2)-cycloaddition between
α-bromo acetyl halide (A) and the aryl imines B which allow the
access to α-bromo β-lactams 1 (Scheme 2). A Reformatsky-type
8c]
reaction,[8b,
involving ethyl dibromofluoroacetate (A’) and
imines B, in the presence of an excess of Et2Zn was utilized to
synthesize α-bromo α-fluoro β-lactams (1a–1j). The relative
configuration was reported to be cis (related to the position of
F/H) with a coupling constant of 3J ~ 10.3 Hz between the
fluorine atom at C3 and the proton of C4[8b, 9] and the structure of
1h was confirmed by X-ray diffraction of 1h (see SI).
2
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to 2.0 mol % without any decrease of the yield in 3aa (Table 1,
entry 8). Control experiments showed the importance of the
cobalt catalyst and of the ligand as, without them, the formation
of the desired product was not observed (Table 1, entries 9 and
10).
representative of heterocycles, was not detrimental to the
coupling reaction as 3ka was isolated in 77% yield.
Table 1. Optimization of the cross-coupling conditionsa.
Entry
CoCl2
(x mol %)
TMEDA
(y equiv)
Tol2Zn
(z equiv)
T [°C]
t
Yield [%]
(h)
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
10
2
1.9
1.9
1.9
1.9
1.9
1.1
0.2
1.1
1.1
-
2.0
0
16
16
16
16
2
75
1.5
0
71
0.6
0
55
1.5
25
25
25
25
25
25
25
79
1.5
79
1.5
16
16
2
80 [72]
1.5
50 [51]
Scheme 3. Cobalt-catalyzed cross-coupling of C4-substituted α-bromo α-
fluoro β-lactams (1b–1j) with bis(p-tolyl)zinc 2a. * 3da product was isolated as
a mixture with the dehalogenated cross-coupled product (12%).
1.05
1.05
1.05
78 [75]
-
2
-
-
-
2
In order to introduce a diversity of substituents at C3 on the
α-fluoro β-lactam ring, different diarylzinc reagents were
synthesized and involved in the cross-coupling. The expected
cross-coupling products 3aa–3al were isolated with overall good
yields, ranging from 59% to 80% (Scheme 4). Both electron-rich
as well as electron-poor diarylzinc reagents were successfully
coupled to the α-bromo α-fluoro β-lactam 1a regardless of the
electronic nature of the aryl group of the diarylzinc reagent. We
were also able to show that several functional groups can be
tolerated on the aryl group of the diarylzinc reagents such as a
OBoc (2d), a SMe (2e), and an amino substituent (2f), as well as
a carbazole (2g). The corresponding coupling products 3ad–3ag
were isolated in good yields (59–80%). While the meta-
functionalization did not cause any problems as shown with the
presence of a m-methoxy group on the diarylzinc reagent (3ah:
67%), a significant drop in yield was observed when an ortho
substituent is present on the aryl group as the use of the
bis(o-methoxyphenyl)zinc reagent led to 3ai in only 27% yield.[15]
In order to improve the yield of 3ai, 10 mol % CoCl2 were used
and, under these conditions, 3ai was isolated in 67% yield.
Similar results were obtained when using the bis(o-tolyl)zinc 2j
reagent giving the corresponding product 2aj in 68% yield.
Moreover, double functionalized diarylzinc reagents were
efficiently cross-coupled with 1a delivering 3ak and 3al in 68%
and 66%, respectively.
[a] Reaction conditions: 1a (0.25 mmol); yields are based on 1H NMR analysis
of the crude reaction using 1,3,5-trimethoxybenzene as internal standard;
yields for the isolated products 2a are given in brackets.
With the optimized conditions in hand, the substrate scope was
explored, starting with a range of different C4-substituted
α-bromo α-fluoro β-lactams (1b–1j) (Scheme 3). No dependency
on the electronic character of the substituent at the para-position
of the aryl group present at C4 was observed as the
corresponding cross-coupling products (3ba–3fa) were obtained
with yields ranging from 56% to 80%. A p-chloro- (3ca, 74%)
and p-bromo (3da, 58%) as well as the p-TMS-ethynyl (3ea,
56%) substituents were well-tolerated and could further be
involved in cross-couplings. In the case of a p-bromophenyl
substituent, the coupling product (3da) was isolated along with
the debrominated cross-coupled product (12%) (see SI). Due to
the higher functional group tolerance of the (p-Tol)2Zn reagent
compared to the (p-Tol)MgBr, an ester group remained
untouched, giving the cross-coupled product 3fa in good yield
(80%). A 2-naphthyl substituent or a strong electron-withdrawing
3,4,5-trifluorophenyl substituent
at C4 delivered the
corresponding products in 3ga in 56% and 3ha in 85% yield,
respectively. Furthermore, the reaction is not sensitive to steric
hindrance, since both an o-methoxy and a m-trifluoromethyloxy
substituent did not influence the reaction outcome as the
coupling products were isolated in 64% (3ia) and 67% yield (3ja).
The presence of a 2-thiophenyl moiety at C4 as a prominent
3
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Scheme 5. Cobalt-catalyzed cross-couplings of α-fluoro α-bromo β-lactams
and α-bromo β-lactams (top) or 7a (bottom) with diallylzinc (4).
Following up with previous reports on cobalt-catalyzed α-
arylation of α-bromo amides with Grignard reagents,[15a, 17] we
were keen to discover whether the conditions for the cobalt-
catalyzed cross-coupling with diarylzinc reagents can be applied
to α-bromo carbonyl compounds other than α-bromo β-lactams
e.g. lactams and lactones, α-bromo amides and α-bromo esters
(Scheme 6). To our delight, the procedure that we have tuned
up is broadly applicable to the envisioned substrates affording
the cross-coupled products in yields ranging from 53% to 99%.
α-Bromo lactams 7a and 7b with different ring sizes, α-bromo
amides (primary bromides 7c–7e, secondary bromides: 7f–7g
and tertiary bromides 7h) as well as nitrogen-containing
heterocycles were included in our investigations. Pleasingly, the
α-arylation of 5- and 6-membered lactams worked as well as for
β-lactams delivering the products 9aa and 9ba in 85% and 77%
yield, respectively. Comparable results were obtained for
primary and secondary α-bromo amides showing the robustness
and the excellent applicability of the coupling (9ca–9ga). Even a
α-bromo, α,α-difluoroamide proved to be a suitable substrate as
9ha was isolated in 81% yield. Motivated by the robustness of
the cross-coupling conditions, α-bromo lactones (8a and 8b)
were subjected to the developed cross-coupling conditions, and
10aa13i and 10ab were obtained in 74% and 85% yield,
respectively. Also, α-bromo esters including an α-bromo α-fluoro
and an α-bromo α,α-difluoro ester were suitable substrates (8c–
8e) furnishing the cross-coupled products 10ca, 10da and 10ea
in satisfying yields ranging from 53% to 61%. It is worth
mentioning that α-bromo lactams 7a was transformed to 9a
using diallylzinc (4) (62%) (Scheme 5).
Scheme 4. Cobalt-catalyzed cross-coupling of α-bromo α-fluoro β-lactam 1a
with diarylzinc reagents 2a–2m.[a] 10 mol % of CoCl2 was used.
In contrast to the cobalt-catalyzed cross-coupling with Grignard
reagents, we were able to efficiently introduce an allyl group at
the C3 position of β-lactams as the use of diallylzinc (4)
delivered the corresponding cross-coupled products 5a–5f and
6a–6c in yields ranging from 48% to 65% yield (Scheme 5).[16]
Regardless of the amount of CoCl2 (2 or 10 mol %), the cross-
coupled α-fluoro β-lactam 5a was obtained in comparable yields
of 55% and 59%. For comparison, when the non-fluorinated
β-lactam was treated with diallylzinc under the same conditions,
the cross-coupled product 6a was isolated in a comparable yield
of 61%. Interestingly, neither the electronic character of the
functional group present on the aryl at C4 nor the steric
hindrance, showed an effect on the cross-coupling as shown for
the β-lactams 5b and 5e respectively substituted at C4 by
p-bromophenyl (5b: 54%), or o-methoxyphenyl (5e: 56%). We
have to mention that when a p-bromophenyl substituent is
present at C4, the cross-coupled product 5b was obtained along
with 17% of debrominated product, but a second cross-coupling
did not take place on the aryl group, showing the highly
chemoselectivity of the cross-coupling (see SI). Again, the high
functional group compatibility was showcased for a p-methyl
ester substituent, present at C4, affording the corresponding
cross-coupled product 5f and 6b in 57% yield. As shown for a
3-furyl and a 2-thiophenyl substituent at C4 position of the -
lactam, heterocycles are also tolerated (6c: 52% and 6d: 54%).
It is worth mentioning that a similar result was obtained for the
cross-coupling of α-bromo γ-butyrolactam 7a with diallylzinc (4)
as the corresponding product 7a4 was isolated in 52% yield.
4
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cleaved under oxidative conditions (CAN, MeCN/H2O), and 15
was isolated in 62% yield (Scheme 8).
Scheme 8. Deprotection of the cross-coupled α-fluoro β-lactam 3aa.
Conclusion
In summary, a convenient, highly efficient and inexpensive
cobalt-catalyzed cross-coupling of α-bromo, α-fluoro β-lactams
with diarylzinc and diallylzinc reagents was developed by
utilizing only 2 mol % of CoCl2. By using these zinc reagents as
cross-coupling partners, a wide array of functional groups,
including ester groups, were well-tolerated. As different
diarylzinc reagents can be prepared easily, a diversity of
substituents at the C3 position of β-lactams could be introduced
allowing a fast construction of a β-lactam library. To our delight,
the developed protocol showed a great versatility as the reaction
conditions could be directly applied to several other carbonyl
compounds including α-bromo lactams and lactones, α-bromo
amides and esters as well as N-Boc 4-halogeno piperidines, N-
Boc 3-iodo azetidines, 4-bromo tetrahydropyran and 3-bromo
oxetanes.
Scheme 6. Cobalt-catalyzed cross-coupling of α-bromo lactams (7a–7b),
amides (7c–7h), α-bromo lactones (8a–8b) and esters (8c–7e) with diarylzinc
reagents 2a and 2d.
Pleasingly, halogeno-substituted nitrogen- and oxygen-
containing heterocycles were also suitable substrates (Scheme
7).
Experimental Section
4-Bromo- and 4-iodopiperidine (11a and 11a’), as well as
3-iodo-azetidine (11b) were successfully cross-coupled forming
13aa and 13ba in high yields. Interestingly, no differences
between the 4-bromo- and 4-iodopiperidine were noticed in term
of reactivity contrary to the use of Grignard reagents[15a]. The
same reaction conditions could be also applied to 4-bromo
General procedure for the cobalt-catalyzed cross-coupling
In a 25 mL round bottom flask, α-bromo α-fluoro β-lactam 1 (0.25 mmol,
1.00 equiv) was dissolved in dry THF (at the end, the concentration of
1 is 0.05 M) under an argon atmosphere at rt. CoCl2 (0.005 mmol, 0.10
mL of 0.05 M solution in THF, 2.0 mol %) and TMEDA (0.275 mmol, 0.40
mL of 0.69 M solution in THF, 1.10 equiv) were added. The zinc reagent
2 or 4 in THF (0.275 mmol, 1.10 equiv) was added over 15 min with a
syringe pump. After stirring for 2 h at rt, the reaction was quenched with a
saturated aqueous solution of NH4Cl (0.30 mL) and extracted with
CH2Cl2 (1×30 mL) and then with EtOAc (2×20 mL). The combined
organic phases were washed with brine (20 mL) and dried over Na2SO4.
After filtration, the solvent was removed in vacuo and the crude product
was purified by flash column chromatography on silica gel
(n-pentane/EtOAc).
tetrahydropyran
and
3-bromo
oxetane
whereby
the
corresponding cross-coupled compounds were obtained in 51%
and 53% yield, respectively.
Acknowledgements
V.K. thanks SFB/TR88 3MET for a grant.
Scheme 7. Cobalt-catalyzed cross-coupling of bromo N-containing and O-
containing heterocycles with bis(p-tolyl)zinc 2a. a) alkyliodide was used.
Authors Contributions
ϯ M.M.L. and V.K. contributed equally.
In order to demonstrate that the cross-coupled products 3 can
be transformed to a variety of N-substituted -lactams, and in
order to have a proof of concept, the N-PMB group of 3aa was
Keywords: cross-coupling • β-lactam • cobalt • bis(organo)zinc
reagents • catalysis
5
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2019, 11, 5188-5197; (h) C. Dorval, E. Dubois, Y. Bourne-
Branchu, C. Gosmini, G. Danoun, Adv. Synth. Catal. 2019,
361, 1777-1780; (i) M. S. Hofmayer, A. Sunagatullina, D.
Brösamlen, P. Mauker, P. Knochel, Org. Lett. 2020, 22,
1286-1289; For 5-membered ring aryl lactones, in our
conditions and in Knochel et al. conditions, a similar yield
was obtained, such as for 10aa. (j) F. H. Lutter, L.
Grokenberger, P. Spieß, J. M. Hammann, K. Karaghiosoff,
P. Knochel, Angew. Chem. Int. Ed. 2020, 59, 5546-5550.
K. Araki, M. Inoue, Tetrahedron 2013, 69, 3913-3918.
(a) L. Gonnard, A. Guérinot, J. Cossy, Chem. Eur. J. 2015,
21, 12797-12803; (b) In contrast to α-fluoro β-lactam 1a,
the cross-coupling is working for non-fluoro β-lactam 1
[14]
[15]
when treated with
2 mol % CoCl2 and the bis(o-
methoxyphenyl)zinc reagent 2i as the cross-coupled
product 3i was isolated in 76% yield.
[16]
The allylation of the α-fluoro β-lactam 1a” under basic
conditions (LDA, -78 °C, followed by the addition of allyl
bromide) led to the corresponding product 6a in 59% (see
SI). Due to the chemoselectivity of the cross-coupling, this
6
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10.1002/chem.202001721
Chemistry - A European Journal
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A cobalt-catalyzed cross-coupling of -bromo carbonyl derivatives and bromo heterocycles with diarylzinc and diarylzinc reagents
has revealed to be very chemoselective and general producing the cross-coupled products in good yields
7
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