Silver-mediated fluorination of potassium aryltrifluoroborates with Selectfluor Dedicated to Professor Andrea Vasella on the occasion of his 71st birthday

Article abstract of DOI:10.1016/j.tet.2014.10.055

A simple and practical procedure for the silver-mediated fluorination of aryl- and heteroaryltrifluoroborates with electrophilic fluorine from Selectfluor and LiOH·H₂O is presented. The reaction procedure is simple and easy to set up, the process produces fluorinated arenes and heteroarenes in good to excellent yields and a wide range of electronically and structurally diverse substrates are tolerated.

Full text of DOI:10.1016/j.tet.2014.10.055

Tetrahedron 70 (2014) 9676e9681
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Silver-mediated fluorination of potassium aryltrifluoroborates with
SelectfluorÒ
*
Srinivas Reddy Dubbaka , Venkateswara Reddy Narreddula, Satyanarayana Gadde,
Thresen Mathew
Department of Medicinal Chemistry, Albany Molecular Research Singapore Research Centre, Pte. Ltd., 61 Science Park Road, #05-01 Galen,
Science Park II, Singapore 117525, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 August 2014
Received in revised form 14 October 2014
Accepted 27 October 2014
Available online 30 October 2014
A simple and practical procedure for the silver-mediated fluorination of aryl- and heteroaryltri-
fluoroborates with electrophilic fluorine from SelectfluorÒ and LiOH$H2O is presented. The reaction
procedure is simple and easy to set up, the process produces fluorinated arenes and heteroarenes in good
to excellent yields and a wide range of electronically and structurally diverse substrates are tolerated.
Ó 2014 Elsevier Ltd. All rights reserved.
Dedicated to Professor Andrea Vasella on
the occasion of his 71st birthday
Keywords:
Fluoroarenes
Fluorination
Potassium aryltrifluoroborates
Silver
SelectfluorÒ
1. Introduction
fluorination of aromatics, but selectivity is not achieved.7,8 Nucle-
ophilic substitution of an aromatic halogen by fluorine is severely
Functionalized aryl fluorides are extremely important motifs
because of their biological, chemical and physical properties.
Fluorinated aromatic molecules are used as pharmaceuticals,
agrochemicals, materials, and as tracers for positron emission to-
mography (PET).1,2 A fluorine atom on an aromatic compound can
significantly enhance its pharmacological properties such as solu-
bility, bioavailability, and metabolic stability. As a result, the de-
velopment of efficient and practical procedures for the construction
of the aryldfluorine bond is of high demand in current organic
synthesis.3 Classical methods for aryldF bond construction usually
require harsh conditions that are incompatible with many sub-
stituents. Such traditional arene fluorination reactions include
nucleophilic substitution of electron-poor bromo- or chloroarenes
with KF (Halex reaction) via SNAr pathways,4 the conversion of
amines via the aryldiazonium salt with tetrafluoroborate (Balz-
Schiemann reaction)5 as well as the transformation of aryl iodides
with CuF2.6 Electrolysis is employed as a method for the direct
limited to electron-poor aromatics.9 Recently, several research
groups proposed alternatives to these methods starting from
aryltriflates,10 aryl halides,11 diaryliodonium salts,12 aryl Grignard
reagents,13 arylsilver-,14 arylpalladium-,15a and arylnickel11a com-
plexes, directed group assisted CeH bonds,16 and phenols.17
Recently arylboron reagents have been increasingly employed
as starting materials for fluorinations, owing to their ready syn-
thetic feasibility, nontoxicity, and stability.18 A direct conversion of
electron-rich arylboronic acids/trifluoroborates into the fluoroar-
enes is reported.19,20 Soon after, Ritter and Furuya came up with
a silver-mediated fluorination of various aryl and alkenyl boronic
acids.21 Recently, Rozen et al. reported fluorination of aryl boronic
acids using in situ generated acetyl hypofluorite. Under these
conditions, aryl boronic acid containing an electron-withdrawing
group (EWG) at the para position provides ortho and para
substituted fluoro compounds.22
More recently, several research groups showed that potassium
organotrifluoroborates can be used for fluorination, and these
transformations are either mediated by Cu or catalyzed by Pd
complexes. In 2013, the groups of Hartwig23 and Sanford24 reported
copper-mediated fluorinations of arylboronate esters and
* Corresponding author. Tel.: þ65 63950975; fax: þ65 63985511; e-mail address:
dubbaka.srinivasreddy@amriglobal.com (S.R. Dubbaka).
http://dx.doi.org/10.1016/j.tet.2014.10.055
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

S.R. Dubbaka et al. / Tetrahedron 70 (2014) 9676e9681
9677
potassium aryltrifluoroborates, respectively under electrophilic
fluorination reaction conditions. Later Ritter et al. reported Pd(III)-
catalyzed fluorination of arylboronate esters and potassium
aryltrifluoroborates.25 Recently Gouverneur et al. reported that
nucleophilic fluorination of arylboronic esters derived from pinacol
in the presence of Cu(II).26 Very recently, we have reported an
environmentally friendly version, where FeCl3 was employed to
mediate the fluorination of potassium aryltrifluoroborates with
SelectfluorÒ and KF. However, these conditions resulted in iso-
merized, more stable ortho and para-fluorinated products and no
meta-fluorinated products were formed.27 To the best of our
knowledge, there has been no report of the fluorination of potas-
sium aryltrifluoroborates under silver-mediated conditions. In this
paper, we report a general method for the synthesis of fluorinated
arenes, and heteroarenes in good yields by the reaction of potas-
sium aryl and heteroaryltrifluoroborates with SelectfluorÒ and
LiOH$H2O, mediated by silver triflate (Scheme 1). Advantages of
this method include the use of stable and easily accessible tri-
fluoroborates rather than their corresponding boronic acids, toler-
ance to several functional groups and a simple reaction set up.
fluorinated product, except those with acidic salts. We extended
our investigation for activators of trifluoroborate into fluoride
sources with various polarizability and size (NaF, KF, and AgF). KF
was found to be the best fluoride activator for trifluoroborate under
our reaction conditions.
Table 1
Screening for activator in fluorinationa,b
Entry
Activator
%Yield (2a)b
1
2
3
4
5
6
7
8
LiOH$H2O
NaOH
K2CO3
70
46
47
12
39
33
23c
50
55
49c
23
50
61
32
(NH4)2CO3
NaOAc
KOAc
NH4OAc
NaHCO3
KHCO3
NH4HCO3
pyridine
NaF
9
10
11
12
13
14
KF
AgF
a
Reaction Conditions: 1a (1.0 equiv, 0.10 mmol), AgOTf (3.0 equiv), SelectfluorÔ
(1.2 equiv), activator (1.2 equiv), EtOAc, 55 ꢀC, 15 h.
b
Yield determined by 19F NMR with 4-fluorobenzonitrile as an internal standard
added after the reaction.
c
2e10% of isomerized ortho product (2-fluoroanisole) was formed.
We then went on to examine various commercial electrophilic
fluorinating reagents (Fig. 1) with different reactivity, solubility and
stability. Only poor yield was obtained upon reaction of 1a with
electrondeficientFþ reagent (N-fluorobenzenesulfonimide, NFSI), or
with electron rich Fþ reagent (1-fluoro-2,4,6-trimethylpyridinium,
Me3pyFþ).
Scheme 1. Fluorination of organoboron derivatives.
2. Results and discussion
In our first search for a general reaction protocol, investigations
were done under the previously reported conditions for boronic
acids: substrate (1.0 equiv), NaOH (1.2 equiv), and AgOTf (3.0 equiv)
were reacted in MeOH at 0 ꢀC for 15 min; solvents were evaporated,
then co-evaporated with acetone to form arylsilver complexes. The
obtained arylsilver complexes were dissolved in acetone containing
Ò
ꢀ
3 A molecular sieves and treated with Selectfluor at room tem-
perature.21 Under these conditions, the fluorination of potassium 4-
methoxyphenyltrifluoroborate (1a) gave only 20% yield of 4-
fluoroanisole (2a, by 19F NMR). We explored the use of bases
(LiOH$H2O, Na2CO3, Cs2CO3, NaHCO3, NaOAc, K3PO4, Et3N, and
pyridine) with trifluoroborate 1a using the above procedure.
LiOH$H2O gave 25% yield of the desired 4-fluoroanisole (2a) at best.
In order to find a simpler and more practical procedure for the
fluorination of potassium organotrifluoroborates, we mixed all re-
agents (substrate (1.0 equiv), LiOH$H2O (1.2 equiv), AgOTf
(3.0 equiv), SelectfluorÒ (1.2 equiv)) in one pot in various polar and
non-polar solvents (THF, CH3CN, acetone, DME, iPrOAc, EtOAc, THF/
H2O, MeOH) and stirred at 55 ꢀC overnight. To our delight EtOAc at
55 ꢀC gave 4-fluoroanisole (2a) in 70% yield. When we used CH3CN
or MeOH in the reaction, it resulted in about 20e30% isomerized
ortho product (2-fluoroanisole) together with the desired ipso
substituted product (4-fluoroanisole).
We then explored the use of inorganic and organic bases for the
activation of the trifluoroborate, such as NaOH, K2CO3, (NH4)2CO3,
NaOAc, NH4OAc, NaHCO3, KHCO3, NH4HCO3, and pyridine. From the
various inorganic bases tested, we did not find an activator better
than LiOH$H2O for trifluoroborate, whereas the organic base gave
a reduced yield (Table 1, entries 1e10 vs 11). Under our reaction
conditions, most of the bases only gave the ipso substituted
Fig. 1. Electrophilic fluorine (Fþ) reagents.
We then tested a few silver salts (Table 2, entries 2e6) under our
reaction conditions in comparison with AgOTf (entry 1). Only 16%
yield was obtained with AgPF6 (entry 2), whereas AgBF4 (entry 3)
gave no product. Other insoluble silver salts AgF, Ag2O and Ag2CO3
provided the desired product with moderate yield along with
2e10% of the isomerized ortho product (2-fluoroanisole).
Even though we examined other ratios of AgOTf with LiOH$H2O
for the fluorination reaction, it was found that a super stoichiometric
amount of AgOTf (3.0 equiv) was required to achieve high yields for
fluorination. This is in agreement with previously reported reactions
of boronic acids.21 Lastly, a series of p-OMeC6H4BXn derivatives were
investigated under the above optimized reaction conditions (Table 3).
The corresponding pinacol ester (1a-Pin, entry 2), boronic acid (1a-
BA, entry 3), and MIDA ester (1a-MIDA, entry 4) afforded low yields
under these conditions in comparison with trifluoroborate (1a, entry
1). Low yield is attributed to the formation of by products such as
anisole from protodeboronation or unreacted starting material. Op-
timized reaction conditions were finalized for this transformation:

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S.R. Dubbaka et al. / Tetrahedron 70 (2014) 9676e9681
Table 2
Table 4
Screening for Ag salts in fluorinationa,b
Substrate scope for silver mediated fluorination of potassium aryl and heteroaryl
trifluoroboratesa
Entry
Ag salts
%Yield (2a)b
1
2
3
4
5
6
AgOTf
AgPF6
AgBF4
AgF
Ag2O
Ag2CO3
70
16
0
38c
35c
48c
a
Reaction Conditions: 1a (1.0 equiv, 0.10 mmol), Ag salts (3.0 equiv), SelectfluorÔ
(1.2 equiv), LiOH$H2O (1.2 equiv), EtOAc, 55 ꢀC, 15 h.
b
Yield determined by 19F NMR with 4-fluorobenzonitrile as an internal standard
added after the reaction.
c
2e10% of isomerized ortho product (2-fluoroanisole) was formed.
Table 3
Scope of fluorination of aryl boronic acid derivatives with AgOTf, SelectfluorÒ and
LiOH$H2Oa,b
Entry
p-OMeC6H4BXn
%Yield (2a)b
1
70
2
19
3
16c
4
4c
a
Reaction Conditions: 1 (1.0 equiv, 0.10 mmol), AgOTf (3.0 equiv), SelectfluorÔ
(1.2 equiv), LiOH$H2O (1.2 equiv), EtOAc, 55 ꢀC, 15 h.
b
Yield determined by 19F NMR with 4-fluorobenzonitrile as an internal standard
added after the reaction.
c
2e10% of isomerized ortho product (2-fluoroanisole) was formed.
trifluoroborate (1.0 equiv, 0.50 mmol), AgOTf (3.0 equiv), SelectfluorÒ
(1.2 equiv), LiOH$H2O (1.2 equiv) in EtOAc at 55 ꢀC for 15 h.
a
Reaction conditions: Potassium trifluoroborate (1.0 equiv, 0.5
With the optimized reaction condition in hand, the substrate
scope was then investigated. A wide range of electronically and
structurally diverse aryl- and heteroaryltrifluoroborates was se-
lected. We found that electron-rich, electron-neutral, and electron-
deficient substrates gave good to moderate yields (Table 4). Sub-
strates containing meta, ortho-substituent and di- and tri-
substituents also underwent efficient fluorination under these opti-
mized conditions. Aryltrifluoroborates with electron-donating para-
substituents (methoxy, ethoxy, butoxy, benzyolxy, methyl, hexyl,
tert-butyl, phenyl) underwent trifluoromethylation in good yields
(Table 4; 2a, 70%; 2b, 72%; 2c, 81%; 2d, 61%; 2e, 70%; 2f, 78%; 2g, 75%;
2h, 91%). Under our reaction condition, potassium phenyl-
trifluoroborate gave fluorobenzene (2i) in only 51% yield, due to
the formation of the protodeboronation product (benzene).
1-Naphthyltrifluoroborate was converted into the corresponding 1-
fluoronaphthalene (2j) in 68% yield. Interestingly, 2-
naphthyltrifluoroborate gave 2-fluoronaphthalene (2k) in an
mmol), AgOTf (3.0 equiv), Selectfluor® (1.2 equiv), LiOH•H2O
(1.2 equiv), EtOAc, 55 °C, 5-15 h. Low boiling and low yielding
b
compounds were not isolated. Yield determined by 19F NMR
with 4-fluorobenzonitrile as an internal standard added after the
reaction. c Isolated yield; some of the isolated compound contains
2-5% of protodeboronation product. d 5-15% of protodeboronation
product was detected in crude 1H NMR. e Yield determined by 19
F
NMR with 3-fluorotoluene as an internal standard added after the
f
reaction. 2-5% Of isomerized ortho and para products were
formed.
acceptable yield of 66%. Fluorination of week electron-withdrawing
substrates (fluoro-, chloro- and bromo) gave the desired fluori-
nated products in good yields (Table 4; 2l, 72%; 2m, 65%). Surpris-
ingly, (4-bromophenyl)trifluoroborate gave exclusively 4-
fluorobromobenzene indicating an inert CeBr linkage under the

S.R. Dubbaka et al. / Tetrahedron 70 (2014) 9676e9681
9679
explored reaction conditions (Table 3, 2n, 63%). Aryltrifluoroborates
with electron-withdrawing para-substituents (ketone, ester, tri-
fluoromethyl, cyano) afforded fluorination in excellent to moderate
yields (Table 4; 2o, 81%; 2p, 90%; 2q, 68%; 2r, 40%). Aryltri-
fluoroborates with either electron-donating or withdrawing groups
at meta-position (methoxy, ethoxy, benzyloxy, methyl, iso-propyl,
acetyl, ester, trifluoromethyl) provided fluorination in moderate to
acceptableyields(Table 4; 2s, 42%; 2t, 45%; 2u, 58%; 2v, 75%; 2w, 68%;
2x, 72%; 2y, 74%; 2z, 45%). In some cases, 2e5% of isomerized ortho-
and para-fluorination products were observed. Our protocol also
accommodates ortho-substituted trifluoroborates, affording good to
excellent yields (Table 4; 2aa, 40%; 2ab, 80%; 2ac, 70%). Di- and tri-
substituted aryltrifluoroborates provided the desired fluorinated
compounds (Table 4; 2ad, 90%; 2ae, 60%; 2af, 77%; 2ag, 82%; 2ah,
35%). Furthermore, when we employed heteroaryltrifluoroborates
they afforded in moderate yields the corresponding fluorinated
products (Table 4; 2ai, 40%; 2aj, 42%).
hexane (5 mL) and H2O (3.0 mL). The layers were separated and an
an aliquote of the organic phase was withdrawn for the 19F NMR
measurement in CDCl3.
4.2.1. 1-Fluoro-4-methoxybenzene (2a).28 Compound 2a was iso-
lated in 65% yield (40.9 mg) and 70% yield was determined by 19F
NMR. 1H NMR (CDCl3, 300 MHz):
3H); 19F NMR (CDCl3, 282 MHz)
d
ppm 6.51e6.92 (m, 4H), 3.73 (s,
ppm ꢂ125.66; GCeMS m/z 126
d
(Mþ). The 19F NMR spectral data correspond to previously reported
data.
4.2.2. 1-Ethoxy-4-fluorobenzene (2b).29 Compound 2b was isolated
in 65% yield (45.5 mg) and 72% yield was determined by 19F NMR.
1H NMR (CDCl3, 300 MHz):
d
ppm 6.96 (t, J¼6.9 Hz, 2H), 6.82 (dd,
J¼6.8 Hz, J¼6.9 Hz, 2H), 3.99 (q, J¼7.0 Hz, 2H), 1.39 (t, J¼7.2 Hz, 3H);
19F NMR (CDCl3, 282 MHz)
d
ppm ꢂ125.39; GCeMS m/z 140 (Mþ).
These spectroscopic data correspond to previously reported data.
3. Conclusions
4.2.3. 1-Butoxy-4-fluorobenzene (2c).30 Compound 2c was isolated
in 75% yield (63.0 mg) and 81% yield was determined by 19F NMR.
In conclusion, we report a convenient silver-mediated fluori-
nation of potassium aryl- and heteroaryl trifluoroborates with an
electrophilic fluorinating reagent (SelectfluorÒ) and LiOH$H2O. The
conditions previously reported for boronic acids are not suitable for
potassium trifluoroborates. The modified, robust, and simple pro-
tocol exhibits a broad substrate scope.
1H NMR (CDCl3, 300 MHz):
d
ppm 6.94 (dd, J¼9.0 Hz, J¼7.7 Hz, 2H),
6.82 (dd, J¼9.0 Hz, J¼8.9 Hz, 2H), 3.91 (t, J¼6.7 Hz, 2H), 1.79e1.71
(m, 2H), 1.56e1.44 (m, 2H), 0.97 (t, J¼6.7 Hz, 3H); 19F NMR (CDCl3,
282 MHz)
d
ppm ꢂ125.34; GCeMS m/z 168 (Mþ). These spectro-
scopic data correspond to previously reported data.
4.2.4. 1-(Benzyloxy)-4-fluorobenzene (2d).12a Compound 2d was
4. Experimental
isolated in 55% yield (55.5 mg) and 61% yield was determined by 19
F
NMR. 1H NMR (CDCl3, 300 MHz):
d ppm 7.32e7.46 (m, 5H),
4.1. General information
6.90e7.02 (m, 4H), 5.05 (s, 2H); 19F NMR (CDCl3, 282 MHz)
d ppm
ꢂ125.03; GCeMS m/z 202 (Mþ). These spectroscopic data corre-
1H NMR Spectra and 19F NMR were recorded on a Bruker400 MHz
or 300 MHz in the solvents indicated; chemical shifts are reported in
units (ppm) by assigning CDCl3 resonance in the 1H spectrum as
7.26 ppm.19F NMR chemical shifts were determined relative to CFCl3
as internal standard and are measured proton decoupled. All cou-
pling constants (J values) were reported in Hertz (Hz). GCeMS
spectra were measured on Shimadzu GSMS-QP2010S. Column
chromatography was performed on silica gel 200e300 mesh on
CombiflashÒ. If not specially mentioned, all the solventsandreagents
wereusedaspurchasedfromCombi-Blocks, Tokyochemicalindustry
(TCI), Fluorochem and Aldrich and without further purification.
spond to previously reported data.
4.2.5. 1-Fluoro-4-methylbenzene (2e). Compound 2e was isolated
in 63% yield (34.6 mg) and 70% yield was determined by 19F NMR.
1H NMR (CDCl3, 300 MHz):
d
ppm 7.11 (dd, J¼8.1 Hz, 5.4 Hz, 2H),
6.93 (t, J¼8.7 Hz, 2H), 2.32 (s, 3H); 19F NMR (CDCl3, 282 MHz)
d ppm
ꢂ118.82; GCeMS m/z 110 (Mþ). The 19F NMR spectral data corre-
spond to previously reported data.
4.2.6. 1-Fluoro-4-hexylbenzene (2f).24b The yield (78%) of 2f was
determined by 19F NMR. 19F NMR (CDCl3, 377 MHz)
d
ppm ꢂ118.71;
GCeMS m/z 180 (Mþ). The 19F NMR spectral data correspond to
4.2. General procedure for the silver-mediated fluorination of
potassium aryl and heteroaryl trifluoroborates with
SelectfluorÒ (Table 4)
previously reported data.
4.2.7. 1-(tert-Butyl)-4-fluorobenzene (2g).21 Compound 2g was
isolated in 70% yield (53.2 mg) and 75% yield was determined by 19
F
Trifluoroborate (0.50 mmol, 1.0 equiv), LiOH$H2O (25.2 mg,
0.60 mmol, 1.2 equiv), SelectfluorÒ (212 mg, 0.60 mmol, 1.2 equiv),
AgOTf (386 mg, 1.5 mmol, 3.0 equiv) were weighed into a 20 mL
microwave vial. EtOAc (5 mL) was added, and sealed with a mi-
crowave cap and the mixture was allowed to stir at 55 ꢀC for 5e15 h.
The resulting solution was cooled to room temperature.
For the compounds reported with isolated yields (2a, 2b, 2c, 2d,
2e, 2g, 2h, 2j, 2k, 2l, 2m, 2o, 2p, 2t, 2u, 2x, 2v, 2y, 2ab, 2ac, and 2ag)
the reaction mixture was diluted with MTBE or hexane (5 mL) and
H2O (4.0 mL). Then organic phase was separated, the aqueous phase
was extracted with MTBE (2ꢁ5 mL). The combined organic phases
were dried over anhydrous Na2SO4. The filtrate was concentrated in
rotavapor and the residue was purified by column chromatography
on Combiflash withhexanes/EtOActo affordthedesired compounds.
The volatile and low yielding products were not isolated and
their yields were determined only by 19F NMR of the reaction
mixture. For the compounds reported with 19F NMR yields, 4-
fluorobenzonitrile (0.50 mmol) was added as reference to the re-
action mixture, stirred for 5 min, and then diluted with MTBE or
NMR. 1H NMR (CDCl3, 300 MHz):
d
ppm 7.33 (dd, J¼9.0 Hz,
J¼8.8 Hz, 2H), 6.96 (t, J¼8.8 Hz, 2H), 1.31 (s, 9H); 19F NMR (CDCl3,
282 MHz)
d
ppm ꢂ119.19; GCeMS m/z 152 (Mþ). These spectro-
scopic data correspond to previously reported data.
4.2.8. 4-Fluoro-1,10-biphenyl (2h).21 Compound 2h was isolated in
85% yield (73.1 mg) and 91% yield was determined by 19F NMR. 1H
NMR (CDCl3, 300 MHz):
d ppm 7.58e7.52 (m, 4H), 7.46e7.41 (m,
2H), 7.33 (t, J¼7.5 Hz, 1H), 7.13 (dd, J¼8.0 Hz, 7.5 Hz, 2H); 19F NMR
(CDCl3, 282 MHz)
spectroscopic data correspond to previously reported data.
d
ppm ꢂ116.87; GCeMS m/z 172 (Mþ). These
4.2.9. Fluorobenzene (2i).24a The yield (51%) of 2i was determined
by 19F NMR. 19F NMR (CDCl3, 377 MHz)
d
ppm ꢂ113.62; GCeMS m/z
96 (Mþ). The 19F NMR spectral data correspond to previously re-
ported data.
4.2.10. 1-Fluoronaphthalene (2j).28 Compound 2j was isolated in
63% yield (45.9 mg) and 68% yield was determined by 19F NMR. 1H

9680
S.R. Dubbaka et al. / Tetrahedron 70 (2014) 9676e9681
NMR (CDCl3, 300 MHz):
d
ppm 8.14e8.09 (m, 1H), 7.89e7.84 (m,
19F NMR (CDCl3, 282 MHz)
These spectroscopic data correspond to previously reported data.
d
ppm ꢂ112.92; GCeMS m/z 140 (Mþ).
1H), 7.63 (d, J¼8.0 Hz, 1H), 7.58e7.52 (m, 2H), 7.40 (ddd, J¼8.8 Hz,
8.8 Hz, 4.8 Hz, 1H), 7.15 (dd, J¼11.2 Hz. 8.0 Hz, 1H); 19F NMR (CDCl3,
4.2.21. 1-(Benzyloxy)-3-fluorobenzene (2u).12a Compound 2u was
282 MHz)
d
ppm ꢂ123.96; GCeMS m/z 146 (Mþ). These spectro-
isolated in 52% yield (52.5 mg) and 58% yield was determined by 19
F
scopic data correspond to previously reported data.
NMR. NMR data were read by overlapping with those pure 2d and
2u compounds. 1H NMR (CDCl3, 300 MHz):
d
ppm 7.29e7.46 (m,
4.2.11. 2-Fluoronaphthalene (2k).12a,24b Compound 2k was isolated
5H), 6.86e7.12 (m, 4H), 5.14 (s, 2H); 19F NMR (CDCl3, 282 MHz)
d
in 60% yield (43.8 mg) and 66% yield was determined by 19F NMR.
ppm ꢂ112.81; GCeMS m/z 202 (Mþ). These spectroscopic data
1H NMR (CDCl3, 300 MHz):
d ppm 7.87e7.82 (m, 2H), 7.79 (dd,
correspond to previously reported data.
J¼8.4 Hz, 1.2 Hz,1H), 7.51 (ddd, J¼7.5 Hz, 7.5 Hz, 1.2 Hz, 1H),
7.46e7.45 (m, 2H), 7.27 (ddd, J¼10.5 Hz, 8.5 Hz,1.2 Hz, 1H); 19F NMR
4.2.22. 1-Fluoro-3-methylbenzene (2v).24b Compound 2v was iso-
(CDCl3, 282 MHz)
NMR spectral data correspond to previously reported data.
d
ppm ꢂ116.00; GCeMS m/z 146 (Mþ). The 19F
lated in 66% yield (36.3 mg) and 75% yield was determined by 19F
NMR. 1H NMR (CDCl3, 300 MHz):
d
ppm 7.21 (dd, J¼14.1 Hz, 7.8 Hz,
1H), 6.94 (brd, J¼7.5 Hz, 1H), 6.88e6.81 (m, 2H), 2.35 (s, 3H); 19F
4.2.12. 1,4-Difluorobenzene (2l).12a Compound 2l was isolated in
ppm ꢂ115.36; GCeMS m/z 110 (Mþ). The
65% yield (37.1 mg) and 72% yield was determined by 19F NMR. 1H
NMR (CDCl3, 282 MHz)
d
19F NMR spectral data correspond to previously reported data.
NMR (CDCl3, 300 MHz):
d
ppm 7.00 (t, J¼6.1 Hz, 4H); 19F NMR
(CDCl3, 282 MHz)
d
ppm ꢂ120.13; GCeMS m/z 114 (Mþ). These
4.2.23. 1-Fluoro-3-isopropylbenzene (2w).12a,24b The yield (68%) of
spectroscopic data correspond to previously reported data.
2w was determined by 19F NMR. 19F NMR (CDCl3, 282 MHz)
d ppm
ꢂ114.71; GCeMS m/z 138 (Mþ). The 19F NMR spectral data corre-
4.2.13. 1-Chloro-4-fluorobenzene (2m).24b Compound 2m was iso-
lated in 60% yield (39.0 mg) and 65% yield was determined by 19F
spond to previously reported data.
NMR. 1H NMR (CDCl3, 400 MHz):
d
ppm 7.29 (dd, J¼9.0 Hz, J¼9.1 Hz,
4.2.24. 3-Fluoroacetophenone (2x).12a Compound 2x was isolated in
2H), 6.96 (t, J¼9.0 Hz, 2H); 19F NMR (CDCl3, 377 MHz)
d ppm
65% yield (44.8 mg) and 72% yield was determined by 19F NMR. 1H
ꢂ115.94; GCeMS m/z 130 (Mþ). These spectroscopic data corre-
NMR (CDCl3, 300 MHz):
d
ppm 7.73 (dd, J¼8.7 Hz, J¼1.6 Hz, 1H),
spond to previously reported data.
7.65e7.61 (m,1H), 7.48e7.41 (m,1H), 7.30e7.23 (m,1H), 2.60 (s, 3H);
19F NMR (CDCl3, 282 MHz)
d
ppm ꢂ112.41; GCeMS m/z 138 (Mþ).
4.2.14. 1-Bromo-4-fluorobenzene (2n).12a The yield (63%) of 2n was
These spectroscopic data correspond to previously reported data.
determined by 19F NMR. 19F NMR (CDCl3, 282 MHz)
d
ppm ꢂ116.38;
GCeMS m/z 174 (Mþ). The 19F NMR spectral data correspond to
4.2.25. Methyl 3-fluorobenzoate (2y).12a Compound 2y was isolated
previously reported data.
in 67% yield (51.6 mg) and 74% yield was determined by 19F NMR. 1H
NMR (CDCl3, 300 MHz):
d
ppm 7.83 (dd, J¼7.8 Hz, 1.4 Hz, 1H),
4.2.15. 4-Fluoroacetophenone (2o).14c Compound 2o was isolated in
7.51e7.66 (m, 1H), 7.40 (ddd, J¼8.1 Hz, 5.2 Hz, 3.2 Hz, 1H), 7.31e7.17
75% yield (51.7 mg) and 81% yield was determined by 19F NMR. 1H
(m, 2H), 3.92 (brd, J¼1.5 Hz, 3H); 19F NMR (CDCl3, 282 MHz)
d ppm
NMR (CDCl3, 300 MHz):
d
ppm 7.98 (dd, J¼9.0 Hz, J¼9.1 Hz, 2H),
ꢂ113.01; GCeMS m/z 154 (Mþ). The 19F NMR spectral data corre-
7.31 (t, J¼9.0 Hz, 2H); 2.59 (s, 3H); 19F NMR (CDCl3, 376 MHz)
d ppm
spond to previously reported data.
ꢂ105.36; GCeMS m/z 138 (Mþ). These spectroscopic data corre-
spond to previously reported data.
4.2.26. 1-Fluoro-3-(trifluoromethyl)benzene (2z).21 The yield (45%)
of 2z was determined by 19F NMR. 19F NMR (CDCl3, 282 MHz)
d ppm
4.2.16. Methyl 4-fluorobenzoate (2p).21 Compound 2p was isolated
ꢂ111.71 & ꢂ64.12 (CF3); GCeMS m/z 164 (Mþ). The 19F NMR spectral
in 82% yield (63.2 mg) and 90% yield was determined by 19F NMR.
data correspond to previously reported data.
1H NMR (CDCl3, 300 MHz):
d
ppm 8.05 (dd, J¼8.8 Hz, 6.4 Hz, 2H),
7.11 (dd, J¼8.8 Hz, 8.8 Hz, 2H), 3.91 (s, 3H). 19F NMR (CDCl3,
4.2.27. 1-Fluoro-2-methoxybenzene (2aa).28 The yield (40%) of 2aa
282 MHz)
d
ppm ꢂ107.07; GCeMS m/z 154 (Mþ). These spectro-
was determined by 19F NMR. 19F NMR (CDCl3, 282 MHz)
d ppm
ꢂ136.40; GCeMS m/z 126 (Mþ). The 19F NMR spectral data corre-
scopic data correspond to previously reported data.
spond to previously reported data.
4.2.17. 1-Fluoro-4-(trifluoromethyl)benzene (2q).21 The yield (68%)
of 2q was determined by 19F NMR. 19F NMR (CDCl3, 282 MHz)
4.2.28. 1-Fluoro-2-methylbenzene (2ab).24b Compound 2ab was
d
ppme63.32 (CF3) & ꢂ108.69; GCeMS m/z 164 (Mþ). The 19F NMR
isolated in 71% yield (39.0 mg) and 80% yield was determined by 19
F
NMR. 1H NMR (CDCl3, 300 MHz):
d 7.20e7.10 (m, 2H), 7.04e6.96 (m,
spectral data correspond to previously reported data.
2H), 2.27 (brd, J¼2.1 Hz, 3H); 19F NMR (CDCl3, 282 MHz)
d ppm
ꢂ118.24; GCeMS m/z 110 (Mþ). The 19F NMR spectral data corre-
4.2.18. 4-Fluorobenzonitrile (2r). The yield (40%) of 2r was de-
termined by 19F NMR. 19F NMR (CDCl3, 282 MHz)
d
ppm ꢂ103.76;
spond to previously reported data.
GCeMS m/z 121 (Mþ). The 19F NMR spectral data The 19F NMR
spectral data matched that of an authentic sample (Aldrich,
ꢂ104.01 ppm).
4.2.29. 1,2-Difluorobenzene (2ac).24a The yield (70%) of 2ac was
determined by 19F NMR. 19F NMR (CDCl3, 377 MHz)
d
ppm ꢂ138.90;
GCeMS m/z 114 (Mþ). These spectroscopic data correspond to
4.2.19. 1-Fluoro-3-methoxybenzene (2s).12a The yield (42%) of 2s
previously reported data.
was determined by 19F NMR. 19F NMR (CDCl3, 282 MHz)
d ppm
ꢂ113.03; GCeMS m/z 126 (Mþ). The 19F NMR spectral data corre-
4.2.30. 1-Fluoro-2,3-dimethylbenzene (2ad).12a The yield (90%) of
2ad was determined by 19F NMR. 19F NMR (CDCl3, 282 MHz)
d ppm
spond to previously reported data.
ꢂ118.88; GCeMS m/z 124 (Mþ). The 19F NMR spectral data corre-
4.2.20. 1-Ethoxy-3-fluorobenzene (2t).12a,29 Compound 2t was iso-
spond to previously reported data.
lated in 42% yield (29.4 mg) and 45% yield was determined by 19F
4.2.31. 1,2-Difluoro-4-methoxybenzene (2ae).29b The yield (77%) of
NMR. 1H NMR (CDCl3, 300 MHz):
1H), 6.68e6.57 (m, 3H), 4.01 (q, J¼7.0 Hz, 2H); 1.41 (t, J¼7.0 Hz, 3H);
d
ppm 7.21 (dd, J¼8.0 Hz, J¼7.2 Hz,
2ad was determined by 19F NMR. 19F NMR (CDCl3, 377 MHz)
d ppm

S.R. Dubbaka et al. / Tetrahedron 70 (2014) 9676e9681
9681
ꢂ148.65; GCeMS m/z 144 (Mþ). The 19F NMR spectral data corre-
5. Finger, G. C.; Kruse, C. W. J. Am. Chem. Soc. 1956, 78, 6034.
6. Grushin, V. V. U.S. Patent 2007, 7,202,388.
7. (a) Sandford, G. J. Fluorine Chem. 2007, 128, 90; (b) Adams, D. J.; Clark, J. H. Chem.
Soc. Rev. 1999, 28, 225.
spond to previously reported data.
4.2.32. 2-Chloro-4-fluoro-1-methoxybenzene (2af).31 The yield
(77%) of 2af was determined by 19F NMR. 19F NMR (CDCl3, 377 MHz)
8. Dawood, K. M. Tetrahedron 2004, 60, 1435.
9. (a) Sun, H.; DiMagno, S. G. Chem. Commun. 2007, 528; b) Sun, H.; DiMagno, S. G.
Angew. Chem., Int. Ed. 2006, 45, 2720; (c) Sun, H.; DiMagno, S. G. J. Am. Chem.
Soc. 2005, 127, 2050.
10. (a) Watson, D. A.; Su, M. J.; Teverovskiy, G.; Zhang, Y.; Garcia-Fortanet, J.; Kinzel,
T.; Buchwald, S. L. Science 2009, 325, 1661; (b) Lee, H. G.; Milner, P. J.; Buchwald,
S. L. J. Am. Chem. Soc. 2014, 136, 3792.
11. (a) Lee, E.; Hooker, M. H.; Ritter, T. J. Am. Chem. Soc. 2012, 134, 17456; (b) Casitas,
A.; Canta, M.; Sola, M.; Costas, M.; Ribas, X. J. Am. Chem. Soc. 2011, 133, 19386.
12. (a) Ichiishi, N.; Canty, A. J.; Yates, B. F.; Sanford, M. S. Org. Lett. 2013, 15, 5134; (b)
Wang, B.; Qin, L.; Neumann, K. D.; Uppaluri, S.; Cerny, R. L.; DiMagno, S. G. Org.
Lett. 2010, 12, 3352; (c) Wang, B.; Cerny, R. L.; Uppaluri, S.; Kempinger, J. J.;
DiMagno, S. G. J. Fluorine Chem. 2010, 131, 1113; (d) German, L. S.; Delyagina, N.
I.; Vanchikov, A. N.; Tolstaya, T. P. Russ. Chem. Bull. 1989, 38, 174; (e) Grushin, V.
V.; Kantor, M. M.; Tolstoya, T. P.; Shcherbina, T. M. Russ. Chem. Bull. 1984, 33,
2130; (f) Van Der Puy, M. J. Fluorine Chem. 1982, 21, 385.
d
ppm ꢂ122.97; GCeMS m/z 160 (Mþ). The 19F NMR spectral data
correspond to previously reported data.
4.2.33. 1,2-Dichloro-4-fluorobenzene (2ag).13b Compound 2ag was
isolated in 75% yield (61.5 mg) and 82% yield was determined by 19
F
NMR. 1H NMR (CDCl3, 300 MHz):
d ppm 7.52e7.41 (m, 1H),
7.25e7.18 (m, 1H), 6.98e6.91 (m, 1H); 19F NMR (CDCl3, 282 MHz)
d
ppm ꢂ114.45; GCeMS m/z 164 (Mþ). These spectroscopic data
correspond to previously reported data.
4.2.34. 5-Fluoro-1,2,3-trimethoxybenzene (2ah).12a The yield (35%)
of 2ah was determined by 19F NMR. 19F NMR (CDCl3, 377 MHz)
13. (a) Yamada, S.; Gavryushin, A.; Knochel, P. Angew. Chem., Int. Ed. 2010, 49, 2215;
(b) Yamada, S.; Knochel, P. Synthesis 2010, 2490; (c) Anbarasan, P.; Neumann,
H.; Beller, M. Angew. Chem., Int. Ed. 2010, 49, 2219.
14. (a) Furuya, T.; Strom, A. E.; Ritter, T. J. Am. Chem. Soc. 2009, 131, 1662; (b) Tang, P.
P.; Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2010, 132, 12150; (c) Tang, P. P.; Ritter, T.
Tetrahedron Lett. 2011, 67, 4449.
d
ppm ꢂ139.73; GCeMS m/z 186 (Mþ). The 19F NMR spectral data
correspond to previously reported data.
15. (a) Furuya, T.; Kaiser, H. M.; Ritter, T. Angew. Chem., Int. Ed. 2008, 47, 5993.
16. (a) Lou, S. J.; Xu, D. Q.; Xia, A. B.; Wang, X. F.; Liu, Y. K.; Du, X. H.; Xu, Z. Y. Chem.
Commun. 2013, 6218; (b) Truong, T.; Klimovica, K.; Daugulis, O. J. Am. Chem. Soc.
2013, 135, 9342; (c) Yao, B.; Wang, Z.-L.; Zhang, H.; Wang, D.-X.; Zhao, L.; Wang,
M.-X. J. Org. Chem. 2012, 77, 3336; (d) Wang, X.; Mei, T. S.; Yu, J.-Q. J. Am. Chem.
Soc. 2009, 131, 7520; (e) Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc.
2006, 128, 7134.
4.2.35. 3-Fluoro-2-methoxypyridine (2ai). The yield (40%) of 2ai
was determined by 19F NMR. 19F NMR (CDCl3, 377 MHz)
d ppm
ꢂ140.38; GCeMS m/z 146 (Mþ). The 19F NMR spectral data matched
that of an authentic sample (Matrix Scientific, ꢂ139.67 ppm).
4.2.36. N-Boc-5-fluoroindole (2aj).21 The yield (42%) of 2aj was
17. Tang, P. P.; Wang, W. K.; Ritter, T. J. Am. Chem. Soc. 2011, 133, 11482.
18. (a) Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine,
2nd ed.; Hall, D. G., Ed.; Wiley-VCH: Weinheim, Germany, 2005; (b) Darses, S.;
determined by 19F NMR. 19F NMR (CDCl3, 377 MHz)
d
ppm ꢂ121.38;
GCeMS m/z 135 (MþꢂBoc). The 19F NMR spectral data correspond
^
Genet, J.-P. Chem. Rev. 2008, 108, 288; (c) Molander, G. A.; Sandrock, D. L. Curr.
to previously reported data.
Opin. Drug Discov. Dev. 2009, 12, 811.
19. Petasis, N. A.; Yudin, A. K.; Zavialov, I. A.; Prakash, G. K. S.; Olah, G. A. Synlett
1997, 606.
Acknowledgements
ꢁ
20. Cazorla, C.; Metay, E.; Andrioletti, B.; Lemaire, M. Tetrahedron Lett. 2009, 50,
3936.
21. Furuya, T.; Ritter, T. Org. Lett. 2009, 11, 2860.
We thank Dr. Sergei Belyakov for his support and also Ramesh
Neelakandan for some initial experiments done towards this
manuscript.
22. Vints, I.; Gatenyo, J.; Rozen, S. J. Org. Chem. 2013, 78, 11794.
23. Fier, P. S.; Luo, J.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 2552.
24. (a) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc. 2013, 135, 4648; (b) Cu-mediated
nucleophilic fluorination: Ye, Y.; Schimler, S. D.; Hanley, P. S.; Sanford, M. S. J.
Am. Chem. Soc. 2013, 135, 16292.
References and notes
25. Mazzotti, A. R.; Campbell, M. G.; Tang, P. P.; Murphy, J. M.; Ritter, T. J. Am. Chem.
Soc. 2013, 135, 14012.
€
1. (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881; (b) Hagmann, W. K.
26. Tredwell, M.; Preshlock, S. M.; Taylor, N. J.; Gruber, S.; Huiban, M.; Passchier, J.;
J. Med. Chem. 2008, 51, 4359; (c) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305;
(d) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320; (e) Jeschke, P. ChemBioChem 2004, 5, 570; (f) Jeschke, P. Pest Manag. Sci.
2010, 66, 10; (g) Thayer, A. M. Chem. Eng. News 2006, 84, 15.
2. (a) Phelps, M. E. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 9226; (b) Ametamey, S. M.;
Honer, M.; Schubiger, P. A. Chem. Rev. 2008, 108, 1501.
3. (a) Mu, X.; Liu, G. Org. Chem. Front. 2014, 1, 430; (b) Lin, A.; Huehls, B.; Yang, J.
Org. Chem. Front. 2014, 1, 434; (c) Liang, T.; Neumann, C. N.; Ritter, T. Angew.
Chem., Int. Ed. 2013, 52, 8214; (d) Fier, P. S.; Hartwig, J. F. Science 2013, 342,
956.
ꢁ
Mercier, J.; Genicot, C.; Gouverneur, V. Angew. Chem., Int. Ed. 2014, 53, 7751.
27. Dubbaka, S. R.; Gadde, S.; Narreddula, V. R. Manuscript submitted.
28. Laali, K. K. G.; Borodkin, I. J. Chem. Soc., Perkin Trans. 2 2002, 953.
29. (a) Stojan, S.; Zupan, M. J. Org. Chem. 1983, 50, 3609; (b) Stojan, S.; Zupan, M. J.
Org. Chem. 1991, 56, 7347.
30. (a) Kovac, M.; Anderluh, M.; Vercouillie, J.; Guilloteau, D.; Emond, P.; Mavel, S. J.
Fluorine Chem. 2013, 147, 5; (b) Stojan, S.; Zupan, M. J. Chem. Soc., Chem. Com-
mun. 1981, 148.
31. Syvret, R. G.; Butt, K. M.; Nguyen, T. P.; Bulleck, V. L.; Rieth, R. D. J. Org. Chem.
2002, 67, 4487.
4. Balz, G.; Schiemann, G. Ber. Dtsch. Chem. Ges. 1927, 60, 1186.