A general strategy for the synthesis of α-trifluoromethyl- And α-perfluoroalkyl-β-lactamsviapalladium-catalyzed carbonylation

Article abstract of DOI:10.1039/d1sc02212a

β-Lactam compounds play a key role in medicinal chemistry, specifically as the most important class of antibiotics. Here, we report a novel one-step approach for the synthesis of α-(trifluoromethyl)-β-lactams and related products from fluorinated olefins, anilines and CO. Utilization of an advanced palladium catalyst system with the Ruphos ligand allows for selective cycloaminocarbonylations to give diverse fluorinated β-lactams in high yields.

Full text of DOI:10.1039/d1sc02212a

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A general strategy for the synthesis of a-
trifluoromethyl- and a-perfluoroalkyl-b-lactams
via palladium-catalyzed carbonylation†
Cite this: Chem. Sci., 2021, 12, 10467
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Yang Li, *ab Cai-Lin Zhang,
a
b
a
a
Wei-Heng Huang, Ning Sun, Meng Hao,
b
b
Helfried Neumann
and Matthias Beller
*
b-Lactam compounds play a key role in medicinal chemistry, specifically as the most important class of
antibiotics. Here, we report a novel one-step approach for the synthesis of a-(trifluoromethyl)-b-lactams
and related products from fluorinated olefins, anilines and CO. Utilization of an advanced palladium
catalyst system with the Ruphos ligand allows for selective cycloaminocarbonylations to give diverse
fluorinated b-lactams in high yields.
Received 21st April 2021
Accepted 30th June 2021
DOI: 10.1039/d1sc02212a
rsc.li/chemical-science
immunomodulatory capabilities as well as interesting material
Introduction
13–15
properties.
Despite the synthesis of many structural vari-
The synthesis of uorinated organic molecules has become one ants, relatively few examples of a-uoroalkyl-substituted deriv-
1,2
of the most active and dynamic areas in chemistry. In fact, the atives are known. So far, such products and especially a-
launch of modern pharmaceuticals and plant protection agents (triuoromethyl)-b-lactams are based on multistep
or special methods such as hydrogenolysis of
21,22
as well as precise materials, e.g. for energy technologies syntheses,
batteries, etc.), would be impossible without appropriate N–O bonds, 1,3-dipolar cycloadditions of nitrones to uo-
1
6
(
17
organouorine compounds. In this respect, the development of roalkenes, and metal-catalyzed intramolecular C–H amida-
18–20
new synthetic methodologies for the preparation of such tions (Scheme 1).
molecules is crucial, too. Although in the past decades, many
elegant protocols to directly introduce uorine atoms or uo-
roalkyl groups into a given organic substrate have been dis-
Unfortunately, all these methods have
3
–6
closed, there is a continuing interest in complementary and
improved procedures, specically the development of new
methods potentially applicable on a practical scale.
Among the established synthetic toolbox for incorporation of

uorine-containing units, in particular processes for intro-
ducing CF -groups are important. Notable examples include
triuoromethylated arenes, olens,
3
7
8,9
10
ethers, and allylic
1
1
compounds.
heterocycles
In addition, especially triuoromethylated
are emerging as promising building blocks for
11,12
many life science and material applications.
b-Lactam molecules (azetidin-2-ones) belong to a family of
heterocycles, which are most known for their antibiotic prop-
erties (Scheme 1); however, it has been shown that several
members of this group present many other pharmaceutical
effects, e.g. neuroprotective, antioxidant, analgesic or
a
Xi'an Key Laboratory of Textile Chemical Engineering Auxiliaries, School of
Environmental and Chemical Engineering, Xi'an Polytechnic University, No. 19
Jinhua South Road, 710048, Xi'an, China. E-mail: liyang@xpu.edu.cn
b
Leibniz-Institut f u¨ r Katalyse e.V., RostockAlbert-Einstein-Straße 29a, 18059, Rostock,
Germany. E-mail: Matthias.Beller@catalysis.de
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/d1sc02212a
Scheme 1 Selected examples of bio-relevant b-lactams and known
synthesis routes for a-(trifluoromethyl)-b-lactams.
1
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certain shortcomings, which limit their applications to small Table 1 Palladium-catalyzed carbonylation of 4-methoxyaniline with
2
1
2-bromo-3,3,3-trifluoro-1-propene: screening of the reaction
conditions
scale.
Based on our long-standing interest in carbonylation reac-
a
22
tions and inspired by palladium-catalyzed three component
23
coupling reactions, we got the idea to build up the central 4-
membered ring of a-uoroalkyl-b-lactams by a novel palladium-
catalyzed aminocarbonylation of a-halo-a-uoroalkylolens,
anilines and CO (Scheme 1). At this point, it is worthwhile
mentioning that transition metal-catalyzed carbonylation reac-
tions are not only of value for a variety of organic syntheses, but
can be easily upscaled as shown by the industrial production of
b
Entry Catalyst
Ligand
Base
Solvent
Yield (%)
24
many ne and even bulk chemicals. Following our concept,
apart from the inexpensive and readily available C1 source and
ubiquitous anilines, also selected a-halo-uoroalkenes are
commercially available and are used to prepare various uori-
nated products at present.
Herein, we report useful methodology for a direct synthesis
of a-(triuoromethyl)-b-lactams and related uoroalkyl deriva-
tives by selective three component carbonylation reaction in the
presence of a specic palladium catalyst.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
PdCl
Pd(OAc)
Pd(MeCN)
2
PCy
PCy
PCy
PCy
PCy
PCy
DPPP
X-Phos
JohnPhos
3
3
3
3
3
3
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
3
3
3
3
3
3
3
3
3
3
3
3
Dioxane
6
2
Dioxane 45
Dioxane 19
Dioxane 36
Dioxane 31
Dioxane 26
Dioxane 19
Dioxane 38
Dioxane 41
Dioxane 51
Dioxane 58
Dioxane 72
Dioxane 16
Dioxane 78
Dioxane 49
2
Cl
2
Pd(PPh
Pd(PPh
3
)
)
2
Cl
2
3
4
Pd(TFA)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0
1
2
3
4
5
6
7
8
Dave-Phos NaHCO
S-Phos
NaHCO
NaHCO
Ru-Phos
Ru-Phos
Ru-Phos
Ru-Phos
Ru-Phos
Ru-Phos
Ru-Phos
Ru-Phos
Ru-Phos
Results and discussion
Na
2
HPO
4
NEt
3
Initially, the carbonylation of 4-methoxyaniline (1a) with
commercially available 2-bromo-3,3,3-triuoro-1-propene (2) as
the triuoromethylation reagent was used as the model system
to study the general reaction sequence and optimize the
2 3
K CO
NEt
NEt
NEt
NEt
NEt
3
3
3
3
3
MeCN
THF
DMF
MePh
MePh
23
35
14
89, 83
c
conditions (Table 1). In rst experiments various palladium 19
d
c
2
0
Pd–Ru-Phos
72
precursors (2 mol%) were tested in the presence of PCy
3
ꢀ
Structure of ligands
(5 mol%) as the ligand in 1.4-dioxane at 100 C and comparably
low CO pressure (8 bar). To our delight, the desired product 3a
was afforded in up to 45% yield demonstrating the feasibility of
our approach (Table 1, entries 1–6). Next, several phosphine
ligands including monodentate and bidentate ones were tested.
Amongst these, the sterically hindered Ru-Phos, introduced by
Buchwald and co-workers for Negishi cross-coupling reac-
tions, showed the best result, and the reaction yield of 3a
increased to 72% (Table 1, entries 7–12). In general, the
improved catalytic activity of Ruphos compared to other ligands
25
a
Reaction conditions: 1a (1.0 mmol), 2 (2.0 mmol), catalyst (5 mol%),
ꢀ
base (2.0 mmol), solvent (2.0 mL), CO (8 atm), 100 C, 12 h.
b
19
Determined by F NMR analysis using (triuoromethoxy)benzene as
internal standard. Isolated yield. A commercially available 3rd
c
d
in this palladium-catalyzed coupling process is attributed to its generation Buchwald palladacycle (CAS: 1445085-77-7) was used.
electron-richness and steric bulk. The specic structural
features stabilize highly reactive LPd(0) intermediates during
the catalytic cycle and allow for the most efficient activation of 2-
We assume that this reaction proceeds via the following
bromo-3,3,3-triuoro-1-propene 2. Changing the base from steps: rst, the active Pd(0) catalyst is generated from the more
sodium bicarbonate to triethylamine, the yield of the target stable Pd(II) precursor by reduction with phosphine, base or CO.
compound slightly increased to 78% (Table 1, entries 13–15). Then, oxidative addition of Pd(0) into 2-bromo-3,3,3-triuoro-1-
Finally, the effect of solvents on this aminocarbonylation propene forms intermediate A. Subsequent CO coordination
process was investigated. Here, dipolar aprotic solvents gave (intermediate B) and carbonyl insertion through ligand migra-
much worse results than non-polar ones indicating that the tion forms acyl palladium compound C. Nucleophilic attack of
solvent also plays an important role in the selectivity (Table 1, the amine occurs to provide amide D, which nally undergoes
entries 16–20). With toluene as the optimal solvent, 3a was an intramolecular Michael addition to obtain b-lactam E.
detected in 89% yield and isolated aer separation in 83%.
To explore the mechanism of this novel carbonylation reac-
Further to the envisioned cycloaminocarbonylation process, tion, several control experiments were performed (Scheme 3).
several unwanted side-reactions may take place here (Scheme 2, First, we synthesized amide 4 by reaction of 2-bromo-1,1,1-
below). Nevertheless, the combination of Pd(OAc) /Ru-Phos triuoro-1-propene and phenyl isocyanate under microwave
2
under the optimized conditions gave excellent selectivity for conditions. Indeed, 4 easily convert by an intramolecular
3a and no amines or b-amino-acrylates were observed.
Michael addition to product 3a in the presence or absence of the
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that uoroalkyl groups play a pivotal role in this overall
transformation.
Aer having optimal reaction conditions in hand, the
selective cyclocarbonylation of several anilines was investigated
(Table 2). Aer completion, the reaction mixtures were puried
by column chromatography, and isolated product yields were
determined. The results show that the electronic property of
Table 2 Palladium-catalyzed synthesis of a-trifluoromethyl-b-lac-
a
tams: variation of anilines
Scheme 2 Proposed mechanism and potential side reactions.
Scheme 3 Control experiments.
palladium catalyst with excellent yield. Next, the potential
intermediate 5 was prepared by addition of 4-methoxy-1-
iodobenzene to 2-bromo-1,1,1-triuoropropylamine and
subsequently reacted with carbon monoxide in the presence of
the palladium catalyst under standard conditions. However, in
this case, we did not observe target compound 3a. To investigate
the importance of the triuoromethyl group for this trans-
formation, 2-bromopropene 6 was applied as reagent under
standard reaction conditions. Notably, the related b-lactam 7
a
Reaction conditions: aniline (1.0 mmol), 2 (2.0 mmol), Pd(OAc)
(2.0 eq.) and MePh (2.0 mL), CO (8
2
(2 mol%), Ru-Phos (5 mol%), NEt
3
ꢀ
b
was not obtained, but instead amide 8 was formed, which shows atm), 100 C, 12 h. Isolated yield.
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substituents on the aniline have no pronounced effect on the
Aer studying the reactions of 2-bromo-3,3,3-triuoro-1-
conversion and selectivity. In general, anilines with electron- propene as available uorinated building block, we investi-
rich substituents in ortho-, para- or meta-position such as gated reactions of the related 2-bromo-3,3,4,4,4-pentauoro-1-
alkoxy, alkyl, and amino provided the corresponding lactam butene 9 with various aromatic amines. Except for 4-thio-
products in high yield.
methylaniline 1b, all anilines delivered the corresponding
Interestingly, more demanding methylthio, hydroxyl, and products 10 in good yield (Table 3). Interestingly, in case of 1b
amino groups as well as heterocycles (indole, triazole) are well partial dehydrouorination reaction occurred to give the a,b-
tolerated, too (Table 2, entries 3a–3i, 3q, 3v–3w). Similarly, unsaturated amide 11 as a cis/trans mixture (4 : 1). Furthermore,
anilines with electron-decient substituents in meta- and para- the domino aminocarbonylation sequence was tested with
position, e.g. uorine, chlorine, nitrile, and ester groups, led to methyl 2-chloro-acrylate as another olen. However, no desired
the corresponding triuoromethylated lactams in 63–88% yield product was observed, probably due to polymerization of the
(
Table 2, entries 3j–3l). Further investigations utilizing di- and highly reactive olen.
tri-substituted anilines proceeded well, too (Table 2, entries 3r– Apart from the preparation of novel uorinated b-lactam
t). Finally, we investigated the cyclocarbonylations of p-phe- building blocks, we envisioned that this methodology would be
3
nylenediamine and m-phenylenediamine. Here, depending on amenable to more biologically relevant substrates. To demon-
the substitution pattern, selectively mono- or double-b-lactam strate this potential, two case studies were performed: imatinib
formation can be observed using an excess amount (4 equiv.) of mesylate, a synthetic tyrosine kinase inhibitor widely used in the
2
6,27
triuoromethyl reagent (Table 2, entries 3x, 3y). We explain this clinical treatment of chronic myeloid leukemia
and prostatic
28
behaviour by the decreased nucleophilicity of the second amino hyperplasia, was subjected to the cycloaminocarbonylation
group aer the rst aminocarbonylation reaction in case of 1,4- reaction with 2 to give the target compound 13 in 78% isolated
phenylenediamine.
yield (Scheme 4). In addition, 3-aminoestrone 14, a versatile
In addition, we explored the reactivity of alkyl amines, precursor of various biologically active compounds to treat
29
including linear and branched ones as well as N-heterocycles. hormone-sensitive diseases such as prostate and breast cancers,
Unfortunately, none of these amines furnished the desired led to b-lactam 15 in high isolated yield (84%). Notably, in both
products. Apparently, the increased nucleophilicity/basicity of cases no further optimization of the reaction conditions was
these substrates signicantly decrease the activity of the catalyst necessary showing the robustness of the procedure.
by blocking coordination sides.
Having a general protocol vide supra for the functionaliza-
tion of aromatic amines to the corresponding a-
Table 3 Palladium-catalyzed cycloaminoarbonylation of 2-bromo-
a
3
,3,4,4,4-pentafluoro-1-butene
a
Reaction conditions: aniline (1.0 mmol), 9 (2.0 mmol), Pd(OAc)
2
(
2 mol%), Ru-Phos (5 mol%), NEt
3
(2.0 eq.) and MePh (4.0 mL), CO (8 Scheme 4 Synthesis of biologically relevant a-trifluoromethyl-b-
ꢀ
b
atm), 100 C, 12 h. Isolated yield.
lactams and derivatizations.
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triuoromethylated b-lactams and related compounds in hand,
this straightforward and practical methodology offers also
access to a variety of other interesting uoroalkyl building
blocks following standard procedures. For example, a-tri-
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
uoromethyl-b-arylamino acid derivatives should be easily
available by classic amide hydrolysis, while (catalytic) reduc-
tions offer an entr ´e e to 2-triuoromethyl-3-aminopropanols
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hydrogen chloride methanol solution gave 16. Furthermore,
using 3b the respective amino alcohol 17 is obtained by
reduction with NaBH or LiAlH . Alternatively, 17 can be formed
4
4
by Ru-catalyzed hydrogenation (for details see ESI†).
Conclusion
In summary, we developed a general and convenient palladium-
catalyzed cycloaminocarbonylation of 2-uoroalkyl-2-halo-
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olens. Through this novel reaction, a-CF
3
– and related

uoroalklyl-substituted lactams can be synthesized in one step
from commercially available 3 and anilines. The palladium
catalyst system containing the Ru-Phos ligand allows the
selective preparation of a variety of interesting functionalized
synthetic building blocks in good to high yields.
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Author contributions
5
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Huang, Ning Sun, Meng Hao were preparing the scope and the
experimental data. Helfried Neumann has corrected the article
and checked the NMR data and Matthias Beller wrote the
article.
2
2, 5109–5114; (f) N. J. Young, V. W. Pike and C. Taddei,
Conflicts of interest
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acsomega.0c02027; (g) X. Gao, Y.-L. Xiao, X. Wan and
X. Zhang, Angew. Chem., 2018, 130, 3241–3245; Angew.
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regarding the publication of this paper.
Acknowledgements
36–42.
We are grateful for the nancial support by the National Natural
Science Foundation of China (GZ1645), the Key Research &
Development Project in Shaanxi Province (2017ZDXM-GY-040),
and the Doctoral Scientic Research Foundation of Xi'an Poly-
technic University (107020336). In addition, we acknowledge
funding by the Federal Ministry BMBF, Germany and the state
of Mecklenburg-Western Pomerania.
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