Slicing and Splicing of Bromodifluoro-N-arylacetamides: Dearomatization and Difunctionalization of Pyridines

Article abstract of DOI:10.1021/acs.orglett.0c02368

Copper-catalyzed dearomatization and difunctionalization of pyridines have been disclosed, in which bromodifluoro-N-arylacetamide was sliced into five fragments and three or four of them were transferred to pyridine partners. Through this reaction, novel N-difluoromethyl-2-imine dihydropyridine derivatives can be conveniently accessed from commercially available 4-amino substituted pyridines. This strategy demonstrates a novel fluorination method featuring high atom economy, environmental friendliness, an easily available catalyst, and simple operation.

Full text of DOI:10.1021/acs.orglett.0c02368

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Letter
Slicing and Splicing of Bromodifluoro‑N‑arylacetamides:
Dearomatization and Difunctionalization of Pyridines
Hongtai Chen, Yanyan Yang, Lianxin Wang, Yuxiang Niu, Minjie Guo, Xiangwei Ren, Wentao Zhao,
Xiangyang Tang, and Guangwei Wang*
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ABSTRACT: Copper-catalyzed dearomatization and difunction-
alization of pyridines have been disclosed, in which bromodifluoro-
N-arylacetamide was sliced into five fragments and three or four of
them were transferred to pyridine partners. Through this reaction,
novel N-difluoromethyl-2-imine dihydropyridine derivatives can be
conveniently accessed from commercially available 4-amino
substituted pyridines. This strategy demonstrates a novel fluorination method featuring high atom economy, environmental
friendliness, an easily available catalyst, and simple operation.
he exploitation of new modes of cleavage and formation
of chemical bonds is an important and urgent goal that
Scheme 1. Difluoromethylation Strategies
T
promises to expand the palette of synthetic methods available
for the streamlined preparation of complex molecules.1
Constructing two or more new bonds in a single step has
been well established in concerted cycloaddition reactions2 and
multicomponent cascade reactions.3 However, breaking a
molecule into three or more fragments, which then reassemble
or serve as molecular building blocks installed onto a reaction
partner to afford a new multifunctionalized product in a single
step, is very rare. Here, we disclose a novel derivatization of 4-
N-dialkylamino pyridine by fragmenting the common N-
phenyl bromodifluoroacetamide.
Introduction of the fluorine atom in organic molecules is an
important strategy to alter the physical, chemical, and
biological properties of parent molecules.4 The difluoromethyl
group is a very useful structural moiety that has received much
attention in organic synthesis and pharmaceutical industry.5
To date, various stable and convenient difluoromethylation
reagents have been developed.6 As shown in Scheme 1, there
are mainly three types of difluoromethylation strategies:
nucleophilic difluoromethylation, electrophilic difluoromethy-
lation, and radical difluoromethylation.7 Difluoromethylcad-
mium, zinc, copper, and TMSCF2H usually serve as
nucleophilic difluoromethyl reagents (Scheme 1a).8 Difluor-
omethylation of nucleophiles, such as oxygen, phosphorus,
sulfur, nitrogen, or carbon nucleophiles, generally involves
electrophilic difluoromethylation reagents (Scheme 1b).9
Electrophilic difluoromethylation reagents include electrophilic
difluorocarbene reagents (such as CHClF2, ClCF2CO2Na,
PhCOCF2Cl, PhSO2CF2Cl, BrCF2PO(OEt)2), sulfonium salt,
sulfonium ylide, and iodonium salt. Radical difluoromethyla-
tion has also been investigated by using HCF2I, CF2Br2,
CF2BrCl, and PhSO2CF2I that have a readily cleavable C−Br
or C−I bond (Scheme 1c).10 It is noteworthy that most above-
mentioned difluoroalkylations are accompanied by generation
of a large amount of waste fragments. There has been a strong
demand to develop a green difluoromethylation strategy with less
waste or with all the fragments being fully utilized.
Received: July 17, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02368
© XXXX American Chemical Society
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A

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a
For the difluoromethylation of nitrogen-containing hetero-
arenes, which are among the most significant structural
components of natural products, difluoromethylation can
occur at the C- or N-atom depending on both the conditions
and the types of heteroarenes.11 For example, difluoromethy-
lation of heteroarenes by zinc sulfinate generally leads to C−H
functionalization.12 However, the electron-rich N-atoms in
oxazole, azole, or triazole can be selectively difluoromethylated
by electrophilic difluoromethylation reagents.13 In 2016,
Zafrani disclosed an N-difluoromethylation of pyridine by
bromodifluoromethylphosphonate, leading to corresponding
difluoromethyl pyridium salts.14 Since pyridium salt could
serve as activated pyridine for functionalization,15 we expect
further reaction on in situ formed difluoromethylated pyridium
will result in dearomatization of pyridine leading to N-
difluoromethylated dihydropyridine derivatives. This strategy
will provide a novel class of difluoromethylated dihydropyr-
idine compounds with potential biological activities16 (Scheme
1d).
To verify our idea, we chose 2-bromo-2,2-difluoro-N-
phenylacetamide (BrCF2CONHPh, 1a) as a difluoromethyla-
tion source.17 We envision the aniline fragment could serve as
a nucleophile toward activated pyridium. First, we tried
pyridine as a substrate with CuI as catalyst and no reaction
occurred. When 4-dimethylaminopyridine (DMAP, 2a) was
used as a substrate together with 1a, a dearomatized N-
difluoromethyl product 3aa was isolated with 59% yield. In this
reaction, the BrCF2CONHPh is sliced into five parts, among
which three fragments are installed onto the pyridine
substrates. Encouraged by this result, various reaction
parameters were screened for reaction optimization. First, a
series of nitrogen-containing ligands were tested (Table 1,
entries 2−7). We found that in the presence of bidentate
ligand (such as bpy and phen) the yield decreased
dramatically, and with a tridentate ligand (such as tpy and
PMDETA), no product (3aa) resulted. However, the highest
yield was observed with pyridine as ligand (entry 7). We
suggest that the ligand can have an influence on the further
binding of the alkene bond for aza-Michael addition. Too
strong binding of ligands on copper will render the activation
of substrate through binding unfavorable. Then, other copper
salts, including CuCl, CuBr, CuBr2, and Cu(OTf)2 were
employed, and no higher yields were obtained (entries 8−11).
Subsequently, we screened various solvents. A nonpolar
solvent such as toluene or CH3CN leads to poor yields.
Polar DMF leads to a higher yield than toluene and
acetonitrile, however still quite lower than in the case of
DMSO as solvent (entries 12−14). When we attempted to
lower the temperature from 110 to 80 °C, the yield 3aa
dropped to 41% with 55% of substrate 1a being recovered.
Based on the above screening results, we chose the following
reaction parameters as the optimized conditions: 0.1 equiv of
CuI as catalyst, 0.2 equiv of pyridine as ligand, and DMSO as
solvent at 110 °C.
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuBr
CuBr2
Cu(OTf)2
CuI
CuI
CuI
CuI
ligand
solvent
yield (%)
1
2
3
4
5
6
7
8
−
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Tol
71(59)
24
33
31
n.d.
5
83(72)
14
44
22
33
phen
bipy
TMEDA
TPY
PMDETA
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
9
10
11
12
13
14
6
12
35
41
CH3CN
DMF
DMSO
c
15
a
Reaction conditions: Unless otherwise noted, all reactions were
performed with 1a (0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 1.5 equiv),
catalyst (0.02 mmol, 0.1 equiv), and ligand (0.04 mmol, 0.2 equiv) in
solvent (0.5 mL) at 110 °C under Ar for 12 h. TPY = 2,2′,2′′-
terpyridine; PMDETA = pentamethyldiethylenetriamine; TMEDA =
tetramethylethylenediamine Yields were determined by GC analysis.
The values in parentheses are isolated yields. The reaction was run at
b
c
80 °C.
influence on this reaction. For example, both meta-substituted
and ortho-substituted substrates proceeded well, providing the
desired products in good yields (3ka−3oa). Substrates with
multisubstituents on the phenyl ring can also be converted into
the corresponding products in good yields (3pa−3qa). Then
N-aryl chlorodifluoroacetamide was also investigated instead of
1a, the reaction cannot occur and the starting materials are
completely recovered.
The scope of the pyridin-4-amine was also explored with the
representative examples shown in Scheme 2. It was noted that
4-substituted pyridines were tolerated to give desired products
in moderate yields (3ab−3ai). Other nitrogen-containing
heteroarenes have also been subjected to the above conditions,
and no expected products resulted. For example, when 4-
methoxy pyridine and N,N-dimethylquinolin-4-amine were
subject to the optimized reaction conditions, no desired
product was observed (see Supporting Information (SI) for
details).
Distinguished from former difuoromethylation reagents, less
waste resulted for N-aryl bromodifluoroacetamide. The
difluoromethylation is accompanied by migration of aniline
part to 2-postion of pyridine. However, we still did not achieve
complete utilization due to the loss of CO and HBr. If the
bromide ion were oxidized in situ, it could attack the aniline
ring in an electrophilic manner to build the C−Br bond, which
might serve as a precursor for further derivatization. Here, we
focus on the screening of suitable oxidants for in situ
preparation of an active bromination species.18 Various
oxidants were tested, and K2S2O8, DDQ, TBHP, Ag2O, m-
CPBA, PhI(OAc)2, and Dess-Martin periodinane were found
to be not effective for this transformation (see Table S1 in SI).
With the optimized conditions in hand, the scope of the N-
aryl bromodifluoroacetamide was explored with the represen-
tative examples shown in Scheme 2. The N-aryl bromo-
difluoroacetamide was obtained either from a commercial
source or via a one-step synthesis according to literature
procedures. Various functional groups, such as halogen, ester,
nitrile, and trifluoromethyl, were well tolerated to give desired
products in moderate yields (3aa−3ja). Furthermore, the
position of the substituents on the phenyl ring had no obvious
B
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Scheme 2. Copper Catalyzed N-Difluoromethylation/β-
Imidization of 4-Aminopyridines
Scheme 3. Copper Catalyzed N-Difluoromethylation/β-
a
a
Imidization/Electrophilic Bromination Cascade
a
Reaction conditions: 1 (0.5 mmol, 1.0 equiv), 2 (0.75 mmol, 1.5
equiv), CuI (0.05 mmol, 0.1 equiv), pyridine (0.1 mmol, 0.2 equiv),
DMSO (1.0 mL) under O2 (balloon) at 110 °C for 24 h. Isolated
yield.
conducted. In the absence of copper catalyst, no 3aa resulted
and the intermediate 5 was separated with a 72% yield.
However, when we subjected it to standard conditions, the
desired product 3aa was afforded in 92% yield, indicating that
pyridinium salts 5 might be a key intermediate in the reaction.
In the absence of CuI or DMAP, no reaction occurred
(Scheme 4, eq 1). We also synthesized difluoromethyl
pyridium salt 6 and tested the reaction of 6 with aniline or
phenyl isocyanate, yet no 3aa formed (Scheme 4, eq 2). This
excludes the possibility of 5 fragmenting into 6 followed by
attack of aniline. When 4-fluoroaniline was added in the
standard reaction, no cross product 3ab was produced
(Scheme 4, eq 3), suggesting that the pyridinium salts 5 may
undergo an intramolecular nucleophilic attack to form a C−N
bond. To trace the source of hydrogen in the CF2−H of
product, a series of deuterium-labeling experiments were
conducted. When the reaction was carried out in deuterated
solvent (DMSO-d6), no deuterium was incorporated into the
product (Scheme 4, eq 4). When 2a-d2 (with deuterium atom
on both α position) used instead of 2a, α-D-3aa was obtained
with no deuterium installed on the difluoromethyl group
(Scheme 4, eq 5). In contrast, reaction of N-deuterated bromo-
2,2-difluoro-N-phenylacetamide 1a-d1 gave CF2D-3aa with
60% of difluoromethyl deuterated (Scheme 4, eq 6).
Considering the acidity of amide N−H (which can exchange
with water in the reaction), D2O (2.0 equiv) was added into
the reaction mixture, and CF2D-3aa was obtained with a
similar deuterated ratio as 1a-d1 (Scheme 4, eq 7). These data
provide strong support that the hydrogen source of N−CF2H
originates from N−H of 2-bromo-2,2-difluoro-N-phenylaceta-
mide.
a
Reaction conditions: 1 (0.5 mmol, 1.0 equiv), 2 (0.75 mmol, 1.5
equiv), CuI (0.05 mmol, 0.1 equiv), pyridine (0.1 mmol, 0.2 equiv),
DMSO (1.0 mL), under Ar at 110 °C for 12 h. Isolated yield. 1.0
mmol scale.
b
While using aqueous hydrogen peroxide (30%) as an oxidizing
agent, the bromination product (3da) was produced in 44%
yield. When we operated the reaction under O2, 3da was
obtained in 59% yield. Therefore, we chose O2, which is cheap
and clean, as the optimal oxidant.
With these conditions in hand, the scope of bromodifluoro-
acetamides and pyridin-4-amines were explored (Scheme 3).
Bromination sites depend on the existing substitution mode of
phenyl ring. Bromodifluoroacetamides with para-bromo,
methyl, tert-butyl, pentyl, and methoxy substitution on N-aryl
can proceed with moderated yields, leading to C-2 brominated
products (4b, 4c, 4d, 4e, 4f). When para-position is available,
C-4 bromination products will form. For example, meta or
ortho substituted N-aryl bromodifluoroacetamides afforded the
C-4 bromination products (4g, 4h, 4i, 4j). Other 4-
dialkylamino-pyridins such as 4-diethylamino pyridine and 4-
piperidin-1-yl pyridine were also explored and good yields were
obtained (4k and 4l), which highlight the practicability of this
method.
In order to gain some insight into the N-difluoromethylation
process, we conducted a series of control experiments. First, a
control experiment in the absence of copper salt was
Based on the above results, we propose a plausible
mechanism as shown in Scheme 5. The reaction of 2-bromo-
2,2-difluoro-N-phenylacetamide (1a) with 4-dimethyl-
C
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Scheme 4. Control Experiments for Mechanistic Studies
Scheme 5. Mechanistic Studies
methyl dihydropyridine imines. Beyond, this novel strategy will
also motivate us to design other slicing-splicing processes for
the efficient synthesis of valuable molecules.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02368.
Mechanistic studies, experimental procedures, com-
1
pound characterization data, copies of H, 19F, and 13C
NMR spectra for new compounds, X-ray crystal
structures of 3aa and 3da (PDF)
Accession Codes
CCDC 1877511 and 1880644 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
aminopyridine (2a) leads to pyridinium salt 5 or 5′, which can
undergo keto−enol tautomerism to afford intermediate A.
Then, Cu(I) catalyzed intramolecular aza-Michael addition19
was initiated by nucleophilic addition of DMSO toward
intermediate A, leading to intermediate B. The rearrangement
of B affords C, which fragments to molecular CO2, dimethyl
sulfide (DMS), and the desired product 3aa. The formation of
CO2 and DMS can be confirmed by GC analyses (see SI,
Figures S1 and S2). Under an oxygen atmosphere, the bromine
anion was oxidized to bromine or bromonium under assistance
of Cu(I), which further undergoes normal electrophilic
substitution with the aniline ring to afford the product 3da.
In conclusion, we have developed a copper-catalyzed
dearomatization and difunctionalization of pyridines with
high atom economy and environmental benignment. Prelimi-
nary mechanistic studies revealed a possible process of forming
pyridinium followed by intramolecular aza-Michael addition.
Formally, the N-aryl bromodifluoroacetamide is sliced into five
fragments with up to four of them being transferred on to 4-
amino substituted pyridine scaffold, leading to N-difluoro-
AUTHOR INFORMATION
Corresponding Author
■
Guangwei Wang − Tianjin Key Laboratory of Molecular
Optoelectronic Science, Department of Chemistry, School of
Science, Tianjin University, Tianjin 300072, P. R. China;
orcid.org/0000-0003-4466-9809; Email: wanggw@
tju.edu.cn
Authors
Hongtai Chen − Tianjin Key Laboratory of Molecular
Optoelectronic Science, Department of Chemistry, School of
Science, Tianjin University, Tianjin 300072, P. R. China;
orcid.org/0000-0002-7765-9781
D
https://dx.doi.org/10.1021/acs.orglett.0c02368
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1832−1844. (f) Liu, X.-Y.; Qin, Y. Indole Alkaloid Synthesis
Facilitated by Photoredox Catalytic Radical Cascade Reactions. Acc.
Chem. Res. 2019, 52, 1877−1891.
Yanyan Yang − Tianjin Key Laboratory of Molecular
Optoelectronic Science, Department of Chemistry, School of
Science, Tianjin University, Tianjin 300072, P. R. China
Lianxin Wang − Tianjin Key Laboratory of Molecular
Optoelectronic Science, Department of Chemistry, School of
Science, Tianjin University, Tianjin 300072, P. R. China
Yuxiang Niu − Tianjin Key Laboratory of Molecular
Optoelectronic Science, Department of Chemistry, School of
Science, Tianjin University, Tianjin 300072, P. R. China
Minjie Guo − Institute for Molecular Design and Synthesis,
School of Pharmaceutical Science and Technology, Tianjin
University, Tianjin 300072, P. R. China
Xiangwei Ren − Tianjin Key Laboratory of Molecular
Optoelectronic Science, Department of Chemistry, School of
Science, Tianjin University, Tianjin 300072, P. R. China
Wentao Zhao − Tianjin Key Laboratory of Molecular
Optoelectronic Science, Department of Chemistry, School of
Science, Tianjin University, Tianjin 300072, P. R. China
Xiangyang Tang − Tianjin Key Laboratory of Molecular
Optoelectronic Science, Department of Chemistry, School of
Science, Tianjin University, Tianjin 300072, P. R. China
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors are grateful for the financial support from Major
National Science and Technology Projects of water pollution
control and treatment (2017ZX07402003). We also thank the
Natural Science Foundation of Tianjin (No. 19JCYBJC20200)
and Tianjin University for support of this research.
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