Nitrate-promoted Selective C-H Fluorination of Benzamides and Benzeneacetamides

Article abstract of DOI:10.1021/acs.orglett.8b00793

A versatile and site-selective nitrate-promoted C-H bond fluorination using various weak coordinating amides as intrinsic directing groups was developed. Diverse tertiary and secondary amides underwent selective aromatic C-H bond fluorination, which featu

Full text of DOI:10.1021/acs.orglett.8b00793

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nitrate-promoted Selective C−H Fluorination of Benzamides and
Benzeneacetamides
Xing-Qian Ning, Shao-Jie Lou,* Yang-Jie Mao, Zhen-Yuan Xu, and Dan-Qian Xu*
Catalytic Hydrogenation Research Center, State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang
University of Technology, Hangzhou 310014, P. R. China
S
* Supporting Information
ABSTRACT: A versatile and site-selective nitrate-promoted
C−H bond fluorination using various weak coordinating
amides as intrinsic directing groups was developed. Diverse
tertiary and secondary amides underwent selective aromatic
C−H bond fluorination, which features broad substrate scope,
good regioselectivity, and mild conditions. Moreover, the late-
stage C−H bond fluorination of the challenging benzeneace-
tamides via distal directing was reported for the first time.
mides such as benzamides and benzeneacetamides are
considered one of the most ubiquitous moieties among
of diverse substrates.5,6 Among which, amide groups are usually
used as auxiliaries for the C−H fluorination of carboxylic acids,
and the selective C−H fluorination of more general amides still
remains elusive (Figure 2). For instance, Yu’s group reported a
A
various pharmaceuticals, agrochemicals, and natural products.
Moreover, organofluorides have received increasing attention in
modern chemical society due to their unique properties in
lipophilicity, bioavailability, and metabolic stability.1 For
instance, several ortho-fluorinated benzamides such as Olaparib
and Xtandi serve as important antitumor drugs (Figure 1).2
Figure 2. Selective C−H fluorination of benzamides or benzeneaceta-
mides.
Figure 1. Representative examples of bioactive amides.
weak coordinating anionic auxiliary to access high mono/
difluorination selectivity.5e A copper-catalyzed C−H fluorination
of benzoic acids was developed by Daugulis’ group using 8-
aminoquinoline as a bidentate directing group.5d Despite the
advances of using these special amides as removable auxiliaries in
C−H fluorination, it would be highly desirable to develop a
selective C−H fluorination protocol using diverse amides as
intrinsic directing groups due to the wide application of amides in
organic chemistry. Nevertheless, there are two major obstacles
Thus, a general fluorination of various benzamides or
benzeneacetamides is in growing demand for the preparation
of fluorine-containing amide drugs or structure modification of
their nonfluorinated analogues, especially for the fluorination of
inert C−H bonds in amides.3 Given the successful application of
amides as powerful directing groups in C−H bond functionaliza-
tion,4 we envisioned that a selective C−H fluorination would be
feasible via a weak coordinating mode of a palladium catalyst and
the O-donor ligand of amide groups.
In several recent years, transition-metal catalyzed C−H bond
fluorination assisted by different directing groups has been
developed as a powerful method for the site-selective fluorination
Received: March 11, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00793
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
for developing C−H fluorination of amide substrates. First,
amides are usually considered a weak coordinating O-donor
ligand,4a,d which might be less efficient in the palladium catalysis,
especially for the C−H fluorination of distal weak coordinating
benzeneacetamides, which has not yet been achieved.7 Second,
benzamides are strong electron-withdrawing functional groups,
which significantly suppress the reactivity of the aromatic rings.
To address the above-mentioned issues, some in situ generated
cationic palladium catalysts with enhanced electrophilicity were
often used to accelerate the coordination and facilitate C−H
bond activation.8 Our group has developed a Pd−nitrate catalytic
system for the mild C−H fluorination of oximes,6b in which a
cationic palladium nitrate was proposed to promote the
transformation. We proposed that a similar strategy might also
promote the challenging C−H fluorination of general amides.
Herein, as part of our continuous interest in the C−H
fluorination of diverse general substrates,6 we reported a
nitrate-promoted selective and mild C−H bond fluorination of
diverse benzamides and benzeneacetamides.
2a was detected in the absence of AgNO3 (entry 13).9
A
comparable result was obtained with AgNO2 in lieu of AgNO3
(entry 14). However, other nitrate additives only gave moderate
yields, probably due to the slow interaction between nitrates with
palladium chloride, which indicated that the in situ generated
electrophilic palladium nitrate species might initiate the catalytic
cycle (entries 15−16).
With the optimized conditions in hand, we sought to explore
the scope and generality of this C−H fluorination protocol.
Various benzamides bearing diverse functional groups were
evaluated. In general, both electron-donating and electron-
withdrawing functional groups proved well tolerated (Scheme
1). Different functional groups such as alkyl, aryl, alkyoxyl,
a
Scheme 1. Scope of Substituted Benzamides
Benzamide 1a was selected as the pilot substrate for the initial
exploration (Table 1). Monofluorinated product 2a and
Table 1. Condition Screening for C−H Bond Fluorination of
a
Benzamides
additive (40
mol %)
yield of 2a yield of 2aa
entry
[Pd]
solvent
(%)
(%)
1
2
3
4
5
6
7
8
9
10
Pd(OAc)2
Pd(dba)2
Pd(PPh3)4
Pd(TFA)2
PdCl2
DCE
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
−
65
74
76
64
91
49
37
28
25
53
45
0
24
2
2
0
5
0
0
0
0
0
0
0
0
2
0
0
DCE
DCE
DCE
DCE
PdCl2
CHCl3
PhMe
hexane
EtOAc
MeNO2
DCE
PdCl2
PdCl2
PdCl2
PdCl2
b
11
PdCl2
12
13
14
15
16
−
PdCl2
DCE
DCE
34
84
43
48
PdCl2
DCE
AgNO2
PdCl2
DCE
KNO3
PdCl2
DCE
Ba(NO3)2
a
Conditions: 1a (0.1 mmol), [Pd] (10 mol %), NFSI (2.0 equiv),
additive (40 mol %), solvent (1.0 mL), 60 °C, under air, 24 h, GC−
a
b
Conditions: 1 (0.2 mmol), PdCl2 (10 mol %), NFSI (2.0 equiv),
MS yields DCE = 1,2-dichloroethane. PdCl2 (5 mol %) was used.
AgNO3 (40 mol %), DCE (2.0 mL), indicated temperatures, under air,
24 h, isolated yields.
difluorinated product 2aa were both detected when using
Pd(OAc)2 as catalyst in the presence of additive AgNO3, albeit in
poor selectivity (2a/2aa = 65/24, entry 1). Gratefully, PdCl2
exhibited superior performance among the Pd catalysts screened,
which gave 91% yield of 2a with good mono/difluorination
selectivity (2a/2aa = 91/5, entry 5). Fluorinations in several
other solvents were also investigated, and only moderate results
were obtained (entries 6−10). Reducing the loading of catalyst to
5 mol % could also afford the desired product 2a in moderate
yield; however, omission of Pd catalyst led to a negative result
(entries 11−12). As anticipated, nitrate additives played an
indispensable role in this transformation, and only 34% yield of
trifluoromethoxyl, and aryloxyl were compatible in the present
fluorination condition (2a−2g). Moreover, substrates bearing
sensitive functional groups, e.g., benzyloxyl or chloromethyl, also
underwent fluorination smoothly (2h, 2i). Halo groups
remained intact during the Pd-catalyzed C−H fluorination
(2j−2m). Relatively lower yields were obtained when strong
trifluoromethyl or acetyl electron-withdrawing groups were
tethered to the substrates (2n, 2o). C−H fluorination of meta-
functionalized benzamides showed remarkable steric effects, the
less congested C−H sites at the para-position of the
B
DOI: 10.1021/acs.orglett.8b00793
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Organic Letters
Letter
a
functionalities were highly selectively fluorinated (2p−2s).
However, fluorination of sterically congested C−H bonds of
meta-dimethyl benzamide also proceeded smoothly in good yield
(2t). Notably, attempts to expand this chemistry to other
aromatics such as naphthalene, thiophene, and benzothiophene
were also successful (2u−2w). In addition, ortho-fluorination
selectivity was further confirmed by the X-ray crystal structure of
product 2g.10
Scheme 3. Scope of Substituted Benzeneacetamides
The versatile Pd-catalyzed C−H fluorination was not limited
to the pyrrolidine masked benzamides. To our delight, diverse
amine masked secondary and tertiary benzamides were also well
tolerated, giving the monofluorinated products in moderate to
excellent yields (Scheme 2). The remarkable compatibility
showed a potential application prospect of the present
fluorination protocol using various amides as intrinsic directing
groups.
a
Scheme 2. Scope of Other Benzamides
a
Conditions: 4 (0.2 mmol), PdCl2 (10 mol %), NFSI (2.0 equiv),
AgNO3 (40 mol %), DCE (2.0 mL), indicated temperatures, under air,
24 h, isolated yields.
Scheme 4. Transformation of Ibuprofen Derivatives
a
Conditions: 1 (0.2 mmol), PdCl2 (10 mol %), NFSI (2.0 equiv),
AgNO3 (40 mol %), DCE (2.0 mL), indicated temperatures, under air,
24 h, isolated yields.
Having the C−H fluorination of benzamides established, we
turned our attention to the more challenging distal O-
coordinating benzeneacetamides. We were pleased to find that
the optimized conditions for fluorination of benzamides were
also viable in the case of benzeneacetamides, giving the
monofluorinated products in good yields, even at room
temperature in some cases (Scheme 3). Notably, benzeneace-
tamides derived from commercially available phenylacetic acid
drugs, e.g., ibuprofen, flurbiprofen, and ketoprofen, were
identified as feasible substrates, which might provide great
opportunities for the late-stage fluorinating modification of
complex amide drugs.11 To the best of our knowledge, it is the
first example of C−H fluorination of various benzeneacetamides.
Encouraged by the remarkably mild conditions in mono-
fluorination of ibuprofen amide 4g, selective C−H difluorination
was carried out under an elevated temperature to give the desired
product 6 in excellent yield (Scheme 4a). Given the importance
of phenylacetic acid drugs, the removal of the amide auxiliary
took place smoothly to produce the fluorinated ibuprofen 7 in
good yield (Scheme 4b). Deuterated substrate [D1]-1a was
prepared in order to gain a better understanding of the nature of
the C−H cleavage step. A significant KIE value of 3.2 was
obtained, which indicated that the C−H activation might be
involved in the rate-determining step of the present fluorination
(Scheme 5).10 Based on the current results and previous reports,
a plausible mechanism involving a Pd (II/IV) catalytic cycle was
Scheme 5. Intramolecular KIE Experiment of 1a
depicted in Figure 3.12 Though the exact role of the nitrate is still
not clear so far, we believe that C−H activation should be
triggered by the in situ generated palladium nitrate species, which
is more electrophilic due to the nitrate anion.9a Pd(IV)
intermediate A was then formed by the oxidative addition of
fluorinating reagent NFSI. Notably, the ligand effect of poorly
nucleophilic nitrate additive (L = NO3) in the selective C−F
Figure 3. Proposed Mechanism.
C
DOI: 10.1021/acs.orglett.8b00793
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Organic Letters
Letter
bond reductive elimination could not be excluded in this case.9b
Final ligand exchange of Pd(II) intermediate B regenerated the
reactive palladium nitrate species and drove the catalytic cycle.
In conclusion, we have developed a site-selective C−H bond
fluorination of various amides via the weak coordination between
their intrinsic O-donor ligand and reactive palladium catalyst.
Diverse secondary and tertiary benzamides were well tolerated to
give the selective monofluorination products in moderate to
excellent yields. Notably, C−H fluorination of the more
challenging benzeneacetamide substrates was also achieved for
the first time. In addition, this reaction protocol was found to be
applicable to late-stage C−H bond fluorination of some bioactive
phenylacetic acid-derived amides. The present methodology has
a broad substrate scope with high functional group tolerance and
features mild conditions. Attempts to apply this late-stage
fluorination protocol in the preparation of more useful and
bioactive fluorine-containing amides are still ongoing in our
laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00793.
General experimental procedures, characterization details,
and spectra copies (PDF)
Accession Codes
(7) Selected examples on C−H functionalization of benzeneaceta-
mides: (a) Shen, P.-X.; Wang, X.-C.; Wang, P.; Zhu, R.-Y.; Yu, J.-Q. J.
Am. Chem. Soc. 2015, 137, 11574. (b) Li, G.; Wan, L.; Zhang, G.; Leow,
D.; Spangler, J.; Yu, J.-Q. J. Am. Chem. Soc. 2015, 137, 4391. (c) Deb, A.;
Bag, S.; Kancherla, R.; Maiti, D. J. Am. Chem. Soc. 2014, 136, 13602.
(d) Wang, X.-C.; Hu, Y.; Bonacorsi, S.; Hong, Y.; Burrell, R.; Yu, J.-Q. J.
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Commun. 2013, 49, 1654. (f) Yeung, C. S.; Zhao, X.; Borduas, N.; Dong,
V. M. Chem. Sci. 2010, 1, 331.
CCDC 1828843 contains 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.
AUTHOR INFORMATION
Corresponding Authors
■
(8) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev.
̈
2011, 40, 4740.
*E-mail: chrc@zjut.edu.cn.
*E-mail: loushaojie@zjut.edu.cn.
ORCID
(9) (a) Fairlamb, I. J. S. Angew. Chem., Int. Ed. 2015, 54, 10415.
(b) Camasso, N. M.; Perez-Temprano, M. H.; Sanford, M. S. J. Am.
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Chem. Soc. 2014, 136, 12771.
(10) For detailed information, see the Supporting Information.
(11) Reviews and selected examples on late-stage C−H bond
diversification: (a) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5,
369. (b) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int.
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Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7222. (d) Wang, D.-H.; Yu,
J.-Q. J. Am. Chem. Soc. 2011, 133, 5767.
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Ed. 2011, 50, 1478. (b) Xu, L.-M.; Li, B.-J.; Yang, Z.; Shi, Z.-J. Chem. Soc.
Rev. 2010, 39, 712.
Shao-Jie Lou: 0000-0003-3700-6812
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge the National Nature Science
Foundation of China (No. 21361130021), China Postdoctoral
Science Foundation (No. 2014M560494), and the Postdoctoral
Science Foundation of Zhejiang Province for financial support.
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DOI: 10.1021/acs.orglett.8b00793
Org. Lett. XXXX, XXX, XXX−XXX