Selective C-H bond fluorination of phenols with a removable directing group: Late-stage fluorination of 2-phenoxyl nicotinate derivatives

Article abstract of DOI:10.1021/acscatal.5b00306

A facile and site-selective C-H bond fluorination of phenols using removable 2-pyridyloxy group as an auxiliary was developed. Alternatively, late-stage C-H bond fluorination of bioactive 2-phenoxyl nicotinate derivatives and diflufenican were also feasible under the present strategy.

Full text of DOI:10.1021/acscatal.5b00306

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Letter
Selective C-H Bond Fluorination of Phenols with a Removable Directing
Group: Late-Stage Fluorination of 2-Phenoxyl Nicotinate Derivatives
Shao-Jie Lou, Qi Chen, Yi-Feng Wang, Dan-Qian Xu, Xiao-
Hua Du, Jiang-Qi He, Yang-Jie Mao, and Zhen-Yuan Xu
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 30 Mar 2015
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Selective C-H Bond Fluorination of Phenols with a Removable
Directing Group: Late-Stage Fluorination of 2-Phenoxyl Nico-
tinate Derivatives
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Shao-Jie Lou, Qi Chen, Yi-Feng Wang, Dan-Qian Xu,* Xiao-Hua Du, Jiang-Qi He, Yang-Jie Mao and
Zhen-Yuan Xu*
Catalytic Hydrogenation Research Center, State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology,
Zhejiang University of Technology, Hangzhou 310014, P. R. China.
ABSTRACT: A facile and site-selective C-H bond fluorination of phenols using removable 2-pyridyloxy group as an auxiliary was
developed. Alternatively, late-stage C-H bond fluorination of bioactive 2-phenoxyl nicotinate derivatives and even more complicat-
ed Diflufenican were also feasible under the present strategy.
KEYWORDS : C-H bond fluorination, Phenols, Catalysis, Nicotinates, Late-stage fluorination
C-H bond fluorination has emerged as the most powerful
protocol to access C-F bond formation since it obviates the use
of pre-functionalized substrates.1 Nevertheless, despite the
recent advances, only handful of directing groups, e.g. am-
ides2a, 2b, 2c, aryl-N-heterocycles2d, 3b and oximes3a assisted or-
tho-fluorination of aromatic C-H bonds have been developed
and the substrates scope is still limited to 2-aryl N-heterocycls,
aromatic carboxylic acids, benzylic amines and aryl ketones so
far. More directing groups especially removable directing
groups are highly desirable to be developed for the directed
selective C-H bond fluorination of various synthetically rele-
vant substrates.
blocks construction for further formation of various pharma-
ceuticals, agrochemicals and materials.
Phenols are ubiquitous substructures found in various bioac-
tive nature products and materials.4 Moreover, as fundamental
raw materials, phenols are widely occurred in organic synthe-
sis as well. As a commonly used cross-coupling partner, phe-
nols and their derivatives, e.g. aryl -triflates, -pivalates and -
carbamates are widely involved in classic Ullman reactions,
Suzuki reactions, etc. and other latest-developed coupling
reactions.5 Moreover, phenols and their derivatives could also
undergo ipso-deoxylation functionalization to furnish corre-
sponding arenes6 and aryl fluorides.7 Given the synthetic and
economic potential of phenol derivatives, fluorination of phe-
nols is of great important in fluorine-containing building
Figure 1. C-H bond fluorination of phenols and bioactive 2-
phenoxyl nicotinates.
Up to date, phenols and several phenol derivatives, such as
phenol esters and phenol carbamates, etc. have successfully
been used as substrates for versatile C-H functionalizations.8
Among them, 2-phenoxypyridines were employed as efficient
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Table 2. C-H Fluorination of 2-aryloxyl pyridine.a
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Table 1. Condition Screening for the C-H Bond Fluorina-
tion of 2-Phenoxyl Pyridine.a
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2
3
4
5
6
7
8
9
Entry
[Pd]
Solvent
T
Yield of Yield of
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11
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13
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(oC) 2a (%)
2aa (%)
1b
2b
3b
4
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(TFA)2
PdCl2
CH3NO2
EtOAc
EtOAc
EtOAc
CH3CN
Toulene
DCE
80
80
60
80
80
80
80
80
80
80
80
80
80
80
80
19
84
49
84
10
72
13
12
80
47
47
40
86
44
0
3
6
2
5
5
2
6
3
7
1
8
n-hexane
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
0
9
3
10
11
12
13
14c
1
trace
5
Pd(PPh3)4
Pd(dba)2
Pd(dba)2
--
3
1
15
0
a
Conditions: 1a (0.1 mmol), [Pd] (5 mol%), NFSI (1.5 equiv.),
Solvent (1.0 mL), indicated temperature, under air, 2h, GC-MS
yields (unless otherwise noted); b 12h; c Pd(dba)2 (1 mol%), NFSI
(1.5 equiv.), under air, 6 h.
phenols surrogates to undergo ortho-silylation, -arylation, -
borylation, -alkenylation and acylation.9 However, C-H bond
fluorination of 2-phenoxypyridines has not been reported yet.
Despite the C-H bond fluorination of 2- phenylpyridines that
presented by Sanford group, less mono- / di-fluorination selec-
tivity was occurred with respect to the strong coordinating
ability of the pyridinyl directing group.2d We envisioned that
the oxy-bridge in 2-phenoxypyridines might alter the electron-
ic nature of the N-donor ligand and pave the way for selective
ortho-C-H bond mono-fluorination. Thus, in continuation of
our previous C-H fluorination studies,3 we developed herein a
palladium-catalyzed C-H fluorination via 6-membered cy-
clopalladation mode using a removable directing group (Fig-
ure 1, a).10 Notably, the present protocol could further be ap-
plied in the late-stage fluorination of bioactive 2-phenoxyl
nicotinate derivatives (Figure 1, b).
a Conditions: 1 (0.3 mmol), Pd(dba)2 (5 mol%), NFSI (1.5 equiv.),
EtOAc (3.0 mL), indicated temperature, under air, 2-6 h, isolated
yields (unless otherwise noted). b Pd(dba)2 (10 mol%), NFSI (2.0
equiv.), KNO3 (30 mol%), 6h.
the loading of catalyst to 1 mol% could also afford a moderate
yield along with a longer reaction time (entry 14). However,
omission of Pd catalyst led to a negative result (entry 15).
Encouraged by our initial results, we sought to explore the
scope and generality of our C-H fluorination protocol. Various
decorated phenols masked by 2-pyridyl directing group were
evaluated. In generally, both electron-donating and electron-
withdrawing functional groups were well tolerated by cau-
tiously adjusting the reaction temperatures (Table 2). Milder
condition was required with respect to the electron-rich aryl
rings in order to obviate the undesired di-fluorination. Howev-
er, more forcing conditions were beneficial for the fluorination
of electron-deficient aryl rings. Furthermore, in case that some
strong electron-withdrawing groups e.g. –CF3, -CN or –NO2
were tethered to the substrates (2i, 2j, 2r), catalytic amount of
a nitrate additive (30 mol%)3a were required to drive the trans-
formations. Mono-fluorination underwent smoothly even
when the bulky phenyl or bromo groups were substituted on
the ortho position (2k, 2m). Intriguingly, fluorination was
At the outset, we initialed our research by treating the pilot
substrate 2-phenoxypyridine (1a) with 5 mol% Pd2(dba)3 and
N- Fluorobenzenesulfonimide (NFSI) in various solvents at
different temperatures (Table 1, entries 1-8). 11 Gratefully, with
slightly modifying of solvents and reaction temperatures, 1a
was selectively converted to 2a in EtOAc solvent at 80 oC in a
short period of 2 hours (entry 4). Additionally, the mono-/di-
fluorination selectivity could slightly been enhanced with 5
mol% Pd(dba)2 in lieu of Pd2(dba)3 (entries 9-13). Reducing
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Table 3. C-H Bond Fluorination of 2-Phenoxyl Nicotinic
Acid Derivatives.a
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2
3
4
5
Scheme 1. Control experiments.
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Scheme 2. Removal of the Directing Group.
exclusively took place on the “inactive” ortho-C-H bond with
the more “reactive” ortho-C-X (Cl, Br) bond remaining intact
(2l, 2m).12 Steric effects adjacent to the reaction center had a
remarkable influence on the reaction as evidenced by the in-
vestigation of the meta-functionalized substrates, as shown in
Table 2, less congested C-H bonds at the para-position of the
functionalities were highly selectively fluorinated (2o-2u).
Notably, attempt to expand this chemistry to quinoline and a
more complex estrone structure were also proved viable albeit
with lower yields (2t, 2u).
a Conditions: 4 (0.3 mmol), Pd(dba)2 (5 mol%), NFSI (1.5 equiv.),
EtOAc (3.0 mL), indicated temperature, under air, 2 h, isolated
yields (unless otherwise noted). b Pd(dba)2 (10 mol%), NFSI (2.0
equiv.), KNO3 (30 mol%), 6h.
Encouraged by the remarkable compatibility of nicotinate
directing group with the present fluorination protocol, we then
turned our attention to more challenging late-stage fluorination
of diflufenican, a widely used commercial-available herbicide
in winter wheat and bar ley.17 The great problem needed to be
overcome in this case is the site-selective C-Ha bond fluorina-
tion in the presence of multiple potentially reactive C-H bonds.
For instance, C-Hb bond could be cleaved directed by the same
nicotinate group in competition with C-Ha bond. C-Hc and C-
Hd bonds are also reactive enough to be fluorinated assisted by
the amide directing group. Pleasingly, mono-fluorinated prod-
uct was exclusively yielded from the 2-pyridyloxy-directed
activation at the less sterically hindered C-Ha bond (Scheme 3).
Late-stage fluorination of C-H bonds without touching the
other functional groups is the most efficient way to introduce
fluorine into complicated molecules and enrich the strategies
of building the highly important fluorine-contained struc-
tures.18
The 2-pyridyl directing group was essential to the reaction
profile as evidenced by the parallel tests of 2-phenoxy benzene
and 3-phenoxy pyridine, which did not give the target fluori-
nated product (Scheme 1). In addition, the 2-pyridyl group can
readily be removed to deliver the 2-fluorinated phenols using
the previous reported method (Scheme 2).9 Very recently, a
Rh-catalyzed C-O bond cleavage borylation of pyridyl ethers
extended the further application of our fluorination strategy.13
Though the readily removable 2-pyridyloxy directing group
could sever as a practical auxiliary for the C-H fluorination of
phenols, the 2-phenoxy pyridine substructures are also widely
found in various agrochemicals.14 Among them, 2-phenoxy
nicotinate derivatives are frequently appeared in pesticide
industry, selective and late-stage fluorination of these bioac-
tive structures are of great important for the modification of
their lipophilicity, bioavailability and metabolic stability.15
Substituted methyl 2-phenoxy nicotinates, which can facile-
ly be prepared via the coupling of 2-chloronicotinate and phe-
nols, were employed to evaluate the application prospect of
the present fluorination protocol. To our delight, diverse func-
tionalized methyl 2-phenoxy nicotinates were mono-
fluorinated in good yields under the indicated conditions (Ta-
ble 3, 5a-5g). Notably, C-H bond fluorination of other nico-
tinates including cyclohexyl, phenyl nicotinates and N, N-
diethyl nicotinamide also proceeded smoothly in good yields
(5h-5j). It seemed that the carboxylate tethered at the C-3 po-
sition did not hamper the C-H bond activation directed by
pyridine group, which provided an efficient route for the new
pesticides discovery via the late-stage replacement of inert C-
H bonds of these bioactive 2-phenoxy nicotinate analogues.16
Scheme 3. Regio-selective Late-Stage C-H bond Fluorina-
tion of Diflufenican.
In conclusion, we have developed a facile and site-selective
C-H bond fluorination of phenols using 2-pyridyloxy group as
an auxiliary. The methodology has a broad substrate scope
with high functional group tolerance. Furthermore, late-stage
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Mehta, V. P. Chem. Eur. J. 2012, 18, 10230-10233; (j) Song, W.;
C-H bond fluorination of bioactive 2-phenoxyl nicotinate de-
rivatives such as diflufenican were also implemented success-
fully under the present conditions. Attempt to apply this late-
stage diversification to more useful and bioactive compounds
with complex structures are still ongoing in our lab.
Ackermann, L. Angew. Chem., Int. Ed. 2012, 51, 8251-8254.
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ASSOCIATED CONTENT
Supporting Information. General experimental procedures,
characterization details and spectra copies.
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AUTHOR INFORMATION
Corresponding Author
*E-mail for D.-Q. Xu: chrc@zjut.edu.cn
*E-mail for Z.-Y. Xu: greenchem@zjut.edu.cn
Funding Sources
National Nature Science Foundation of China (No.
21361130021), China Postdoctoral Science Foundation (No.
2014M560494) and the Postdoctoral Science Foundation of
Zhejiang Province.
Notes
The authors declare no competing financial interest.
(10) Zhang, F.; Spring, D. R. Chem. Soc. Rev. 2014, 43, 6906-
6919.
ACKNOWLEDGMENT
(11) For detail information, see the Supporting Information.
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(13) Kinuta, H.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2015,
137, 1593-1600.
The authors acknowledge the National Nature Science Foundation
of China (No. 21361130021), China Postdoctoral Science Foun-
dation (No. 2014M560494) and the Postdoctoral Science Founda-
tion of Zhejiang Province for financial support.
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