pubs.acs.

org/OrgLett Letter

Photoinduced Cascade C−N/CO Bond Formation from

Bromodifluoroalkyl Reagents, Amines, and H2O via a Triple-
Cleavage Process
Xiaohui Zhuang, Lan Ling, Yingying Wang, Bingqian Li, Bin Sun,* Weike Su,* and Can Jin*
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ABSTRACT: A green, sustainable, and straightforward method for

the synthesis of unsymmetrical oxalamides via photoinduced C−N/
CO bond formation of bromodifluoroacetamide, amine, and H2O
through a triple-cleavage process has been developed. In addition,
this approach also provides access to the known bioactive
compounds, and a feasible reaction mechanism is proposed.
Moreover, the advantages of this transformation, including mild
reaction conditions, a broad substrate scope, and operational simplicity, make this protocol attractive for further applications.

O xalamide derivatives, which exhibit self-complementary

hydrogen bonding ability, have attracted a great deal of
attention from researchers and exhibited excellent bioactivities
Scheme 1. Motivation and Synthetic Strategy

such as antimalarial,1 anticoagulant,2 IDO1 inhibitor,3 tubulin

polymerization inhibitor,4 and HIV entry inhibitor activities.5
Additionally, oxalamides are also widely employed as a ligand
in transition-metal-catalyzed cross coupling reactions (espe-
cially Ullmann reactions).6 Because of the extensive application
of oxalamides, developing a novel, mild, and efficient protocol
for preparing these useful derivatives would be significant.
To date, synthesis of symmetrical oxalamides derivatives has
been extensively investigated, but the protocol for constructing
unsymmetrical oxalamides has been less explored. The
conventional methods for the synthesis of unsymmetrical
oxalamides are as follows: two-step treatments of ethyl oxalyl
monochloride or ethylene glycol with amines,3,7 trapping of
carbamoyl lithiums with isocyanates,8 treating isocyanides with
trichloroacetic acid anhydride to form a trichloropyruvamide
skeleton followed by addition with amine in TMSCl/NEt3,9
etc. However, these known methods still exhibited drawbacks,
such as a low atom economy, harsh conditions, and a
cumbersome operation. Recently, the selective amidation of
1,3-ketoamide with amine under CuI catalysis to form
unsymmetrical oxalamides has been developed.10 For example,
in 2020, Tikhonova’s group11 achieved thioamidation/cyclo-
different cleavages in thermochemistry or photochemistry
condensation/hydrolysis of 2,2′-biphenyl diamines with 2-
(Scheme 1b). Despite the continuing development of
chloroacetamides and water in one pot, but this protocol was
suitable for only substituted aromatic amines (Scheme 1a).
Despite these achievements, developing additional mild and Received: January 21, 2022
environmental protocols for synthesizing unsymmetrical Published: February 22, 2022
oxalamides is still in high demand.
Currently, halodifluoromethyl compounds have been largely
employed as sources of difluoromethyl,12 monofluoromethyl,13
difluorocarbene,14 carbonyl synthon,15 C2,16 or C1,17 via

© 2022 American Chemical Society https://doi.org/10.1021/acs.orglett.2c00233

1668 Org. Lett. 2022, 24, 1668−1672
Organic Letters pubs.acs.org/OrgLett Letter

halodifluoromethyl compounds, halodifluoroacetamide was Scheme 2. Substrate Scope of Bromodifluoroalkyl

never used as a C2 source for the preparation of unsymmetrical Reagentsa,b
oxalamide derivatives. With our ongoing studies of the
photoredox reaction,18 herein, we have developed a novel
and efficient protocol for combining double aliphatic C−F
bond activation and simultaneous new C−N/CO bond
formation, under visible-light irradiation of bromodifluoroace-
tamides and amines, resulting in a variety of unsymmetrical
oxalamide derivatives (Scheme 1c).
We initiated our studies by choosing 2-bromo-2,2-difluoro-
N-phenylacetamide 2′ and diethyl amine 1a as model
substrates for the optimization of the reaction conditions
(Table S1). To our delight, the desired product 2a could be
obtained in 94% yields, when the reaction mixture was
irradiated with 3 W white LEDs for 10 h at room temperature
in DCE under an air atmosphere with methylene blue as the
photocatalyst (Table S1, entry 22), after screening different
photosensitizers, commonly used solvents, amine loadings,
light sources, and other conditions.
With the optimal condition in hand, we next investigated the
substrate scope of N-substituted bromodifluoroacetamides. As
shown in Scheme 2, a variety of 2-bromo-2,2-difluoro-N-
arylacetamides were tolerated well and gave the desired
products 2a−34a in moderate to excellent yields (56−94%).
First, the substrates bearing an electron-withdrawing group
(-Br, -F, -Cl, or -COOMe), an electron-donating group (-Me,
-OMe, -iPr, or -OPh), or an electron-neutral group (-Ph) at the
para positions of the phenyl ring all performed well in this
transformation, furnishing the corresponding products in 78−
92% yields. It seemed that the electron effect has no obvious
influence on this transformation. Moreover, both meta-
substituted (-CF3, -Cl, -Br, -Me, -OMe, or -CN) and ortho-
substituted (-Me, -OMe, or -Br) substrates also displayed good
tolerance for this transformation, and the corresponding
oxalamides (12a−20a) could be obtained in moderate to
good yields. Furthermore, substrates with two substituents on
the phenyl ring were tested, and the result revealed that
disubstituted derivatives (21′−24′) could undergo this
photoinduced triple-bond cleavage process well to give the
desired products 21a−24a, respectively, in 72−83% yields. In
addition, the optimal conditions were also suitable for N-
naphthalene ring-substituted bromodifluoroacetamides and
afforded the desired products 25a−27a in 82−94% yields. In
addition, it should be mentioned that N-hetero-aromatic cyclic
substituted derivatives such as quinoline and pyridine were also
tolerated well in this reaction, as certified by 28a−34a.
Notably, N,N′-[oxybis(4,1-phenylene)]bis(2-bromo-2,2-di-
fluoroacetamide) 35′ was also amenable to the transformation
via undergoing a double triple-bond cleavage process, giving
the corresponding product 35a in 70% yield.
Next, the scope of bromodifluoroacetamides with various N-
a
Unless otherwise noted, all reactions were performed with n′ (0.1
alkyl moieties was further examined. The experimental results mmol), a catalyst (0.001 mmol), 1a (1 mL), and DCE (1 mL) under
indicated that various N-alkyl bromodifluoroacetamides were irradiation with 3 W white LEDs at room temperature under an air
also suitable for this protocol with diethyl amine, giving a series atmosphere for 10 h. bIsolated yields.
of oxalamide derivatives 36a−45a in 66−87% yields. For
example, substrates with benzyl or benzhydryl groups attached products in 66−78% yields. In addition, to showcase the
to nitrogen could undergo this process well and furnished the robustness and utility of this method, ethyl (2-bromo-2,2-
desired products 36a and 37a in 73% and 87% yields, difluoroacetyl)-L-phenyl- alaninate 45′, which was synthesized
respectively. Expectedly, the transformation succeeded in from a natural molecule, was also converted into the
providing the target products 38a−40a in good yields when corresponding product 45a under the optimal reaction
we extended the alkyl to phenylethyl, phenylpropyl, or conditions for 15 h.
phenylbutyl. In addition, substrates with multiple substituents, We then investigated the reactivity of different brominated
such as 41′−44′, could also be converted to the homologous difluoro reagents with organoamine. However, ethyl bromodi-
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Org. Lett. 2022, 24, 1668−1672
Organic Letters pubs.acs.org/OrgLett Letter

fluoroacetate failed to give the desired products, whereas 2- strategy, two known bioactive compounds, 51n and 5o,
bromo-2,2-difluoro-1-arylethan-1-one could undergo this which were potential antimalarial agents or IDO1 inhibitors,
transformation well. As shown in Scheme 2, 2-bromo-2,2- were prepared by employing this strategy (Scheme 4). For
difluoro-1-arylethan-1-one bearing an electron-withdrawing (-F
or -Cl) or an electron-donating (-Me or OMe) substituent at Scheme 4. Synthesis of the Drug Molecule
the para position of the phenyl ring showed moderate
reactivity, giving the desired products 46a−50a in 49−52%
yields.
After exploring the scope of bromodifluoroalkyl reagents, we
investigated a variety of organoamines in this process with 3′
under the optimized reaction conditions. As shown in Scheme
3, this method was found to be applicable to both secondary

Scheme 3. Substrate Scope of Aminea,b

intermediate 51′, which was prepared by cyclization, nitro
reduction and bromodifluoro acetamidation could afford the
desired product 51n under the optimized reaction conditions
in 77% yields. Moreover, 2-bromo-N-(4-chlorophenyl)-2,2-
difluoroacetamide was also converted into corresponding
product 5o in 82% yield. To our delight, the gram-scale
reaction (for details, see the Supporting Information) could
perform well between 2′ and 1a, and the desired product 2a
was finally isolated in 68% yield.
To investigate the feasible reaction mechanism, we
performed several control experiments (Scheme 5). The

Scheme 5. Control Experiment

a
Unless otherwise noted, all reactions were performed with 3′ (0.1
mmol), a catalyst (0.001 mmol), 1 (1 mL), and DCE (1 mL) under standard reaction was markedly inhibited when 3.0 equiv of
irradiation with 3 W white LEDs at room temperature under an air 1,1-diphenylethylene, a commonly used radical scavenger, was
atmosphere for 10 h. bIsolated yields. added to the reaction system. It was pleasing to observe that
the reaction was also completely suppressed when TEMPO,
linear amines and secondary cyclic amines, giving the another radical inhibitor, was employed, and moreover, the
corresponding products 3b−3i in moderate to good yields. adduct of the difluoroalkyl radical with TEMPO could be
For example, a visible-light-mediated cascade reaction between isolated in 65% yield. In addition, the 18O isotope labeling
a series of dialkyl amines and 2-bromo-N-(4-bromophenyl)- experiment,18 which was conducted under the standard
2,2-difluoroacetamide 3′ could proceed well, affording the conditions with three drops of H2O18, indicated that the
desired products 3b−3f in 37−83% yields. In addition, oxygen atom in the newly constructed carbonyl group
secondary cyclic amines also displayed good reactivities; in originated from H2O. Furthermore, a series of Stern−Volmer
particular, when morpholine was used as the organoamine, the experiments (for details, see the Supporting Information)
corresponding product 3h was obtained in excellent yield in revealed that the photocatalyst methylene blue was effectively
only 2 h (95%). To our delight, a primary amine and a tertiary quenched by 2-bromo-2,2-difluoro-N-phenylacetamide 2′.
amine are also suitable for this transformation. For example, On the basis of the previous reports and observations
benzyl amine and isobutyl amine could furnish the desired mentioned above,15,19 a possible mechanism is illustrated in
products 3j and 3k, respectively, in good yields. In addition, Scheme 6. We assumed that the photosensitive methylene blue
when the reaction was carried out between PMDETA (1l) or was initially irradiated by visible light to afford the excited
N-methylmorpholine (1m) and 3′, the structure of the target photocatalyst, which was oxidized by 2′ to give [MB]•+,
molecule was confirmed as 3b or 3h with a yield of 71% or accompanied by the formation of the difluoroalkyl radical.
35%, respectively, which was the same as the product afforded Amine was transformed into the nitrogen radical cation
by using dimethyl amine or morpholine as the organoamine. [NR1R2R3]•+ via a single-electron transfer (SET) process
Subsequently, to evaluate the utility of this photoinduced with an oxidized state photocatalyst. Subsequently, a radical
triple-cleavage cascade C−N and CO bond formation coupling between the difluoroalkyl radical and nitrogen radical
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Org. Lett. 2022, 24, 1668−1672
Organic Letters pubs.acs.org/OrgLett Letter

Scheme 6. Proposed Mechanism Technology, Hangzhou 310014, P. R. China;

Email: [email protected]
Authors
Xiaohui Zhuang − Collaborative Innovation Center of Yangtze
River Delta Region Green Pharmaceuticals, Zhejiang
University of Technology, Hangzhou 310014, P. R. China
Lan Ling − College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou 310014, P. R. China
Yingying Wang − Collaborative Innovation Center of Yangtze
River Delta Region Green Pharmaceuticals, Zhejiang
University of Technology, Hangzhou 310014, P. R. China
Bingqian Li − College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou 310014, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.2c00233

Notes
The authors declare no competing financial interest.

cation generated nitrogen cation intermediate A, which

underwent dehydrofluorination to give intermediate B.
Iminium ion B might participate in an SNAr-like substitution
■ ACKNOWLEDGMENTS
This work was supported by the National Natural Science
or nucleophilic addition with the H2O, leading to secondary Foundation of China (22078299 and 22108250), the Zhejiang
defluorination to afford the target product. However, for the Provincial Natural Science Foundation of China
tertiary amine, a possible mechanism involving dealkylation is (LY21B060005 and LQ20B060007), the Opening Project of
introduced in Scheme S1. Zhejiang Engineering Research Center of Fat-soluble Vitamin
In conclusion, we have developed a photoinduced C−N/ (202101), and the Research Project of Zhejiang Provincial
CO bond formation of N-substituted bromodifluoroaceta- Department of Education (Y201840109). The authors are also
mides with a secondary amine to form unsymmetrical grateful to the College of Pharmaceutical Sciences, Zhejiang
oxalamide derivatives via triple cleavage of bromodifluoroace- University of Technology, and the Collaborative Innovation
tamides, including double stable C−F bonds and a single C− Center of Yangtze River Delta Region Green Pharmaceuticals
Br bond. In addition, this protocol is also suitable for some for financial support.

■
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