Palladium-catalyzed electrophilic C–H fluorination of arenes using oxazoline as a removable directing group

Article abstract of DOI:10.1016/j.tetlet.2016.10.079

Dimethyloxazoline was rationally designed to act as a removable ortho-directing group (DG) for the palladium-catalyzed C–H electrophilic fluorination of arenes. Using NFSI as the fluorinating agent, and Pd(II), Ag(I) catalytic system, electrophilic C(sp²–H) ortho-fluorination took place on a variety of aryl substrates to afford the corresponding mono- and di-fluorinated products.

Full text of DOI:10.1016/j.tetlet.2016.10.079

Accepted Manuscript
Palladium-catalyzed electrophilic C–H fluorination of arenes using oxazoline
as a removable directing group
David A. Gutierrez, Wan-Chen Cindy Lee, Yuning Shen, Jie Jack Li
PII:
S0040-4039(16)31400-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.079
TETL 48249
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
27 September 2016
20 October 2016
Please cite this article as: Gutierrez, D.A., Cindy Lee, W-C., Shen, Y., Jack Li, J., Palladium-catalyzed electrophilic
C–H fluorination of arenes using oxazoline as a removable directing group, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.10.079
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Palladium-catalyzed Electrophilic C–H Fluorination
of Arenes Using Oxazoline as a Removable Directing
Group
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David A. Gutierrez, Wan-Chen Cindy Lee, Yuning Shen, and Jie Jack Li*

1
Tetrahedron Letters
Palladium-catalyzed electrophilic C–H fluorination of arenes using oxazoline as a removable directing
group
David A. Gutierrez, Wan-Chen Cindy Lee, Yuning Shen, and Jie Jack Li*
Department of Chemistry, University of San Francisco, 2130 Fulton Street, San Francisco, CA 94117, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Dimethyloxazoline was rationally designed to act as a removable ortho-directing group (DG) for
the palladium-catalyzed C–H electrophilic fluorination of arenes. Using NFSI as the fluorinating
agent, and Pd(II), Ag(I) catalytic system, electrophilic C(sp2–H) ortho-fluorination took place on
a variety of aryl substrates to afford the corresponding mono- and di-fluorinated products.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
C-H fluorination
removable directing group
electrophilic substitution
oxazolines
The introduction of fluorine has been widely used in
medicinal chemistry, to boost potency, increase membrane
permeability, modulate pKa, and block metabolic sites on
potential drug molecules.1 In addition, 18F-Labeled compounds
are indispensable as radionuclides in radiotracers for positron
emission tomography (PET). These unique properties make the
introduction of fluorine to bioactive molecules intriguing. The
construction of C–F bonds is very challenging,2 particularly in a
selective late-stage manner. However, recently there have been
advances in ortho-directed palladium-catalyzed electrophilic
fluorination of arenes via C–H activation.2 In 2006 Sanford used
8-methylquinolines and phenyl-pyridines to accomplish this
transformation in acceptable yields and under microwave
conditions.3 The Xu group has also shown that a wide variety of
N-heterocyclic DGs such as quinoxaline, pyrazole and
benzo[d]oxazole can promote selective mono-ortho-fluorination
using trifluoroacetic acid as an additive.4 A more expansive
investigation into the electrophilic fluorination of aryls using
benzo[d]oxazole and pyrazole as DGs has also been
established.5,6 Experimental studies of the electrophilic
fluorination of arylpyrazoles has shown evidence of an
alternative mechanism to the standard Pd(II)/Pd(IV) process,
amide and triflamides have also been shown to be suitable DGs
for selective mono ortho-fluorination.9 These DGs are labile and
their removal makes the aryls amenable for further synthetic
transformations but most of the benzamides suffer from their
large size and poor atom economy.
We have developed ortho-directed palladium-catalyzed
electrophilic fluorination using dimethyl oxazoline as DG. The
oxazoline is an N-heterocycle which can be employed for ortho-
C–H activation and is also labile and be unmasked to the
carbocylic acid (Scheme 1). Aryloxazolines have been shown to
be suitable DGs for C–C bond formation via C–H activation10
and aryl-oxazolines have been fluorinated via ortho-metalation
using magnesate bases and by lithiation.11,12 Thus the
development of a palladium catalyzed oxazoline ortho-directed
electrophilic fluorination takes advantage of the heterocyclic
moiety to direct fluorination for late stage synthesis and can be
hydrolyzed for other synthetic transformations.
suggesting
a
possible
oxidative
addition
of
N-
fluorobenzenesulfonimide (NFSI) to Pd(II).6
Scheme 1. Oxazoline directed C–H bond fluorination and hydrolysis
Despite these recent advances in ortho-directed palladium-
catalyzed electrophilic fluorination via C–H activation many of
the initial DGs were heteroaryls thus not easily removable thus
limiting their synthetic utility. A set of removable non-heteroaryl
DGs have since been developed. The Xu group was able to
demonstrate that O-methyloxime as a DG for ortho-fluorination
of arenes at moderate temperatures.7 They also demonstrated the
selective ortho-mono-fluorination of 2-phenoxylpyridines via a
six-membered cyclopalladation step. Yu has reported the
fluorination of arenes using the –C(O)NHC6F4CF3 amide-DG and
was able to achieve selective mono-fluorination by increasing the
acidity of the benzamide DG.8 Other benzamides such as oxalyl
We began our investigation into fluorination using 4,4-
dimethyl-2-phenyl-2-oxazoline because we have previously
shown that ring opening occurred on 2-phenyl-oxazoline, 1,
when N-fluorobenzenesulfonimide (NFSI) was used as the
electrophilic fluorine source and produced the corresponding
sulfonimides, 2, as the predominate product13 (Scheme 2). The
dimethyl substituents add steric bulk to the oxazline in order to
hinder the ring opening reaction and promote fluorination.
The 4,4-dimethyl oxazoline derivatives were prepared using
standard procedures (Scheme 3). The corresponding benzoic acid

2
Tetrahedron Letters
Table 1. Optimization of palladium-catalyzed fluorination of aryl
4,4-dimethyloxazoline 3
was converted to the acyl chloride using oxalyl chloride and
catalytic DMF, followed by formation of the amide using 2-
amino-2-methyl-1-propanol. The corresponding alcohol was then
mesylated and then cyclized using NaOH in ethanol in high
yield.
F+
source
Yield
Entry
Pd cat.
promoter
solvent
(3:4)a
1b
2b
Pd(OAc)2
Pd(OAc)2
TFA
TFA
DMF
DMF
72:28
87:13
A
B
Scheme 2. Sulfonamidation via nucleophilic ring-opening of 2-
oxazolines with acidic sulfonimides
3b
4b
5b
6b
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Dioxane
NR
NR
NR
NR
C
D
E
F
Scheme 3. Procedures for formation of substituted aryl oxazolines
7b
8b
Pd(TFA)2
Pd(dba)2
71:29
90:10
A
A
With the oxazoline in hand we began treating our model
substrate 3 with several fluorinating agents (A, B, C, D, E, and
F) that have previously been shown to be successful (Table 1).
DMF was initially used as the solvent for the fluorination
reactions because this polar solvent was shown to retard the ring
opening of phenyl oxazolines.13 Pd(OAc)2 catalyst and TFA as an
additive was the catalytic system was first used based on Xu’s
positive results. NFSI (A) and Selectfluor (B) afforded the
fluorinated product 4 in 28% and 13%, respectively (Entries 1–
2). The four 1-fluoropyridinium-based fluorinating agents
including [PyF]BF4 (C), [Cl2PyF]OTf (D), complex E, and
[Me2PyF]BF4 (F) all failed to produce more than a trace amount
of the desired product (entries 3–6). NFSI was selected as the
fluorinating agent of choice and it was determined that five
equivalents of TFA was needed to promote the fluorination
reaction (See SI). A selection of Pd(II) and Pd(0) catalysts were
screened (entry 8–12). Pd(0) catalysts gave low conversion to the
fluorinated product (entry 8 and 11). Surprisingly Pd(TFA)2 did
not give a significant boost in conversion (entry 7). This is in
contrast to previously known reports which show that using TFA
along with Pd(TFA)2 leads to higher yields of fluorinated
product.4 Pd(NO3)2 gave the best conversion to 4 (entry 12). As a
result of this catalyst giving superior conversion, a series of
nitrates were screened as promoters but the use of KNO3 and
Ca(NO3)2 completely halted the reaction (entry 13–14). AgNO3
gave the best conversion of all the screened nitrates (entry 15).
Other silver salts were screened however none of them showed
any effectiveness at promoting the reaction (entry 16–17). No
trace of fluorinated product was detected when no additive was
used. It appears that that the silver nitrate salt is unique in its
ability to promote fluorination. Solvents that have promoted
other fluorination reactions were then screened. Trifluorotoluene,
1,2-dichloroethane, ethyl acetate, and dioxane all gave no
reaction. Nitromethane was able to give conversion to desired
product 4 but acetonitrile gave the full conversion to the
fluorinated product. It was also concluded that when using
acetonitrile as the solvent only 50 mol% of AgNO3 was needed to
give full conversion to the desired product. Using the optimized
reaction conditions (Table 2) ,the scope of the reaction was then
explored. Electron rich oxazolines showed moderate to good
yields of fluorinated products. The fluorination of 2-o-tolyl
substrate 4a and 2-o-methoxyl substrate 4b, gave moderate yields
of fluorinated product. When the electron rich 4-p-methoxyl 4i
was fluorinated the 2,6-difluorination product 5i was the major
product with trace amounts of the monofluorinated observed by
GCMS. Surprisingly 4-p-methyl 4h was only able to be
fluorinated once despite increasing the amount of fluorinating
agent used to 5 equivalents and increasing reaction time. Electron
deficient oxazolines were not able to be fluorinated as readily as
electron-rich oxazolines. The un-substituted oxazoline 4f gave
9b
PdCl2
NR
82:18
66:34
60:40
92:8
A
A
A
A
A
10b
11b
12b
13c
14c
15c
16c
17c
18d
19d
20d
21d
22d
23e
Pd(OTf)2
Pd(PPh3)4
Pd(NO3)2
Pd(NO3)2
Pd(NO3)2
Pd(NO3)2
Pd(NO3)2
Pd(NO3)2
Pd(NO3)2
Pd(NO3)2
Pd(NO3)2
Pd(NO3)2
Pd(NO3)2
Pd(NO3)2
TFA
KNO3
Ca(NO3)2
89:11
51:49
100:0
93:7
A
A
AgNO3
AgTFA
AgOAc
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
A
A
A
A
A
A
A
A
NR
NR
DCE
NR
PhCF3
73:27
NR
CH3NO2
EtOAc
CH3CN
0:100
Reaction conditions: Pd (20 mol %) aryloxazoline (0.1 mmol), NFSI (0.15
mmol), solvent (1 mL). aGCMS conversions using dodecane as an internal
standard. bTFA (0.5 mmol) 150 oC. cNitrate (0.5mmol) 150 oC. dAgNO3
(0.5mmol) 100 oC. eAgNO3 (50 mol%) 80 oC.
the monofluorinated product 4c in 46% yield, and the difluoro-
product, 5%. Similar results were observed when the reaction
was carried out in nitromethane. This experimental result is in
contrast with other fluorination reactions which show
nitromethane promotes fluorination and even promotes derivative
4c gave only 19% isolated yield of the desired difluoro-product
5c. The extremely deactivated 2-o-nitro-oxazoline 4k, was
completely unable to be fluorinated and 4-p-chloro substituted
aryloxazoline 4l, showed only 13% GCMS conversion to the
mono fluorinated product 5l, and no difluoro-product was
observed. The stark lack of reactivity observed for the

3
The differences in the reactivity of electron-rich and electron-
fluorination of electron-deficient aryloxazolines compared to
difluorination reactions.4 The fluorination of 2-o-fluoro- electron-
rich oxazolines has precedent in the literature.4
deficient oxazolines could be presumably attributed to the
basicity of the nitrogen on the oxazoline. The 4,4-dimethyl-2-
phenyl-2-oxazoline 4h has a pKa of 4.414 and the substituent
effect on the aryl can either increase or decrease the basicity of
the nitrogen. Electron-rich substituted aryls increase the basicity
of the oxazolines and increases its ability to facilitate the
fluorination reaction whereas electron-poor aryls have the
opposite effect. Other effects of substituted aryl oxazolines were
also investigated. ortho-Chloro- and ortho-bromo derivatives 4d
and 4e were tolerated in the reaction and gave good to moderate
yields respectively. The fluorination of 3-m-tolyl 4g was low
yielding and gave predominantly the less sterically hindered
product 5g. The naphthalene derivative 4j gave impressive yield
of the monofluorinated product 5j at the 2-position, 88% and 7%
conversion to the 2,8-difluorinated product 5k. However
increasing the amount of NFSI to 5 equivalents and prolonged
reaction time did not increase the amount of difluorinated product
5k. 5k is an interesting product because it represents a C–H
activation at the 8 position of the naphthalene resulting in a 6-
membered palladacyclic intermediate which then undergoes
fluorination.
Table 2. Palladium-catalyzed fluorination of aryl 4,4-
dimethyloxazolines substituted arenes
Entry
1
Substrate
Product
Yield
100b (65)
2
3
4
97b (42)
27b (19)
63b (68)
The oxazoline was converted to the corresponding acid using
a 2-step sequence.15 Treatment of 6a with methyl iodide followed
by basic hydrolysis using NaOH afforded 2-fluorobenzoic acid 8
in 77% in 2 steps (Scheme 4).
5
6
7
47b (37)
46b (48)
19b (12)
Scheme 4. Removal of the DG.
8
9
9
17bc (23)
100bc (92)
91b (88)
7b
Scheme 5. Proposed Mechanism
Mechanistic insight
for
palladium-catalyzed
electrophilic C–H fluorination has been forwarded by many
investigators.4,6 Based on the experimental results and compared
to the results other groups have reported a plausible mechanism
is proposed based on Hierso’s catalytic cycle, which has been
supported by experimental, and mass spectrometric analysis.6 As
shown in Scheme 4, C–H activation of substrate 4a by Pd(NO3)2
assembles Pd(II) complex I. Oxidative addition of NFSI to II
which undergoes reductive elimination to deliver fluorinated
product 5a. Based on the experimental results during the
optimization we propose that the Ag(I) assists in liberating the
palladium from the oxazline, giving complex 5a’. This
interaction between silver and phenyl oxazolines has precedent in
the literature.16,17 Similarly the proton from the trifluoroacetic
acid could have the same effect as the silver. This proposed
interaction could be why in the absence of an additive no reaction
10
11
0b
13b
aReaction conditions: Substrate 4 (0.5 mmol), NFSI (1.5 equiv),
Pd(NO3)2 (20 mol%), AgNO3 (50 mol%) in MeCN at 80 oC for 24 h.
bGCMS conversion using dodecane as internal standard. Percent of
isolated yields in parenthesis. c2.5 equivalents NFSI

4
Tetrahedron Letters
(8)
Chan, K. S. L.; Wasa, M.; Wang, X.; Yu, J.-Q. Angew. Chem. Int.
Edit. 2011, 50, 9081.
occurs. Complex III undergoes ligand exchange with nitrate to
regenerate the catalyst, complex IV.
(9)
Chen, C.; Wang, C.; Zhang, J.; Zhao, Y. J. Org. Chem 2015, 80,
942.
In summary we have reported an ortho-directed palladium-
catalyzed electrophilic fluorination reaction using oxazoline as a
removable DG. The aryl substituents can efficiently promote the
fluorination reaction and the reaction conditions are tolerant to
chloro- and bromo-substituents. The reaction conditions can be
used for late stage fluorination and the dimethyloxazoline DG
may be hydrolyzed to give the corresponding acid. While the
scope of substrates for this removable DG is narrower in
comparison to O-methyloxime7 and the –C(O)NHC6F4CF3
amide9 DGs, we have demonstrated that dimethyloxazoline is a
viable alternative as a removable directing in palladium-catalyzed
electrophilic fluorination.
(10)
(11)
(12)
(13)
Ackermann, L.; Barfüsser, S.; Kornhaass, C.; Kapdi, A. R. Org.
Lett. 2011, 13, 3082.
Snieckus, V.; Beaulieu, F.; Mohri, K.; Han, W.; Murphy, C. K.;
Davis, F. A. Tetrahedron Lett. 1994, 35, 3465.
Bellamy, E.; Bayh, O.; Hoarau, C.; Trecourt, F.; Queguiner, G.;
Marsais, F. Chem. Commun. 2010, 46, 7043.
Gutierrez, D. A.; Dean, D.; Laxamana, C. M.; Migliozzi-Smith,
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Decken, A.; Eisnor, C. R.; Gossage, R. A.; Jackson, S. M. Inorg.
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Anquetin, G.; Greiner, J.; Vierling, P. Tetrahedron 2005, 61,
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Supplementary material will be inserted here,
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Sidduri, A.; Tilley, J. W.; Lou, J. P.; Chen, L.; Kaplan, G.;
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(a) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96,
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10330

Highlights
For the first time, the old directing group dimethyloxazoline, which was used to direct ortho-
lithiation has now been applied in palladium-catalyzed C-H fluorination. The removable
directing group may be unmasked readily via hydrolysis.