Metal-free chlorodeboronation of organotrifluoroborates

Article abstract of DOI:10.1021/jo201313a

A mild and metal-free method for the chlorodeboronation of organotrifluoroborates using trichloroisocyanuric acid (TCICA) was developed. Aryl-, heteroaryl-, alkenyl-, alkynyl-, and alkyltrifluoroborates were converted into the corresponding chlorinated products in good yields. This method proved to be tolerant of a broad range of functional groups.

Full text of DOI:10.1021/jo201313a

ARTICLE
pubs.acs.org/joc
Metal-Free Chlorodeboronation of Organotrifluoroborates
Gary A. Molander* and Livia N. Cavalcanti
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States
S Supporting Information
b
ABSTRACT: A mild and metal-free method for the chlorodeboronation of organotri-
fluoroborates using trichloroisocyanuric acid (TCICA) was developed. Aryl-, hetero-
aryl-, alkenyl-, alkynyl-, and alkyltrifluoroborates were converted into the corresponding
chlorinated products in good yields. This method proved to be tolerant of a broad
range of functional groups.
’ INTRODUCTION
’ RESULTS AND DISCUSSION
Aryl chlorides are found in many pharmaceuticals and natural
products and have been employed as important synthetic intermedi-
ates in carbonÀcarbon bond-forming reactions, such as SuzukiÀ
Miyaura cross-couplings.1 Among the methods utilized for the
synthesis of chlorinated arenes, the Sandmeyer2 reaction and
direct electrophilic aromatic substitution3 are the most utilized.
The direct halogenation of aromatics with electrophilic halogen-
ating agents via electrophilic aromatic substitution is the classic
way to introduce chlorine into aromatic and heteroaromatic
substrates.4 However, this method has obvious limitations in terms
of both chemoselectivity and regioselectivity. In particular, the
site selectivity of these chlorinations relies on directing functional
groups in the substrate, and certain regioisomers are often unattain-
able. The halogenation of boron compounds, particularly those
synthesized by complementary methods such as CÀH activation5
and ortho metalation,6 has emerged as an alternative to circum-
vent this problem.7 Specifically, the chlorodeboronation of
boronic acids and boronate esters has been described.8 In the
absence of a metal-based catalyst or promoter, the scope of these
reactions appears limited, and moderate yields have been de-
scribed for electron-deficient aryl substrates.8d The use of transition
metal complexes, such as copper salts, as catalysts for the chlorina-
tion of aromatic boronic acids and boronate esters improved
the yield for electron-poor aromatic systems.8a Although many
boronic acids and boronate esters are commercially available,
their susceptibility to protodeboronation as well as their ability to
react with commonly employed organic reagents, such as bases,
nucleophiles, and oxidants, make them prone to undesirable side
reactions. Over the past years, organotrifluoroborates have
emerged as an alternative to other organoboron species.9 The
stability of this boron functional group allows molecular complex-
ity to be built into a molecule while leaving the carbonÀboron bond
intact.10 Thus, the use of organotrifluoroborates would allow
extensive elaboration of a simple substructure, with subsequent
late stage chlorination. To the best of our knowledge, no
chlorodeboronation of organotrifluoroborates has been re-
ported; consequently, we were prompted to investigate a mild
and convenient method for the synthesis of aryl chlorides. Herein
we report a metal-free chlorodeboronation of organotrifluoro-
borates using trichloroisocyanuric acid (TCICA).
Electrophilic chlorinating agents have been reported as effi-
cient reagents for the chlorination of boronic acids and boronate
esters.8 Our investigations were initiated by exploring the
chlorodeboronation of potassium naphthalen-1-yltrifluoroborate
with sodium hypochlorite (NaOCl, 6.15%, Clorox), because this
is a widely available and inexpensive chlorinating agent. A
screening of common solvents revealed that EtOAc:H2O (1:1)
was a good solvent system. Thus, the reaction of 1a and 1.2 equiv
of NaOCl provided the desired product in 92% yield (Table 1)
after 30 min (monitored by 11B NMR). The scope of the reaction
for various aryltrifluoroborates was investigated (Table 1).
The reaction with electron-rich aryltrifluoroborates pro-
ceeded in good yields, and most transformations were complete
in 40 min or 1 h (entries 1À7). Halogen-containing aryltrifluor-
oborates also underwent chlorodeboronation to afford the
desired aryl chlorides in modest yields (entries 8 and 9).
Unfortunately, electron-deficient aryltrifluoroborates were not
reactive under these conditions, and the starting material was
completely recovered. In an attempt to obtain complete reaction
conversion, an excess of NaOCl was utilized (5 equiv); however,
the use of a large amount of this reagent afforded a mixture of the
desired chlorinated product (2a) along with protodeboronation,
dichlorination, and boronic acid side products (eq 1). All efforts
to optimize the conditions for aryltrifluoroborates containing
electron-withdrawing groups (e.g., ester, ketone, or nitro) with
NaOCl were unsuccessful.
Next we investigated the use of Chloramine-T as the chlor-
inating reagent, because it has been used as an oxidant for the
Received: June 22, 2011
Published: August 03, 2011
r
2011 American Chemical Society
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Table 1. Chlorination of Potassium Aryltrifluoroborates
Using Sodium Hypochlorite
Table 2. Chlorination of Potassium Aryltrifluoroborates
Using Chloramine-T
bromination5c and iodination5d of aryltrifluoroborates. After
extensive optimization, we determined that the reaction of potas-
sium naphthalen-1-yltrifluoroborate with 1.1 equiv of Chlora-
mine-T and 0.5 equiv of NaCl in EtOAc:H2O at rt (condition A)
afforded the desired chlorinated product (1a) in 94% yield
(Table 2). Importantly, the reactions with 0.3 equiv of Chlor-
amine-T and 1.5 equiv of NaCl in EtOAc:H2O at 60 °C
(condition B) also afforded the desired chlorinated product
(1a) in 83% yield and 100% conversion.
As illustrated in Table 2, the reaction of electron-rich aryltri-
fluoroborates with Chloramine-T afforded the desired chlorinated
products in good yield (entries 1À7). However, the chlorodebor-
onation of halogen-containing aryltrifluoroborates proceeded in low
yields (entries 8 and 9). Once more, the chlorination of aryltri-
fluoroborates bearing electron-withdrawing groups (e.g., ester,
ketone, or nitro) did not afford the desired product in good yield.
To improve the yield of this reaction for electron-withdrawing
groups, other chlorinating agents were tested (Table 3). The
chlorodeboronation of potassium (3-methoxycarbonyl)phenyl-
trifluoroborate with N-chlorosuccinimide (NCS) afforded the
desired chlorinated product (3a) in only 21% yield. Chloramine-T
improved the yield to only 30% after 24 h in a mixture with
protodeboronation product, whereas 1,3-dichloro-5,5-dimethylhy-
dantoin (DCDMH) and sodium hypochlorite (NaOCl) were
inefficient in this transformation. However, when 1.0 equiv of
trichloroisocyanuric acid (TCICA) was utilized, we were pleased to
find that methyl 3-chlorobenzoate (3a) was obtained in 92% yield in
only 1 h at room temperature. Because TCICA is a widely available
and inexpensive material ($11.00/mol catalog price), all subsequent
reactions were carried out using this electrophilic chlorinating agent.
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Table 3. Chlorination of Potassium (3-methoxycarbonyl)-
phenyltrifluoroborate Using Various Chlorinating Agents
Table 4. Chlorodeboronation of Electron-Poor Potassium
Aryltrifluoroborates with TCICA
entry
oxidant
NCS
(mmol) reaction time, h
yield (%)
1
2
3
4
5
1.2
1.2
1.2
1.2
1.0
24
24
24
2
21
36
Chloramine-T
DCDMH
NaOCI
only S.M. recovered
15
92
TCICA
1
With optimized conditions in hand, the scope of the reaction
for aryltrifluoroborates containing electron-withdrawing groups
was investigated (Table 4).
The reaction with a variety of available electron-poor aryltri-
fluoroborates proceeded in good yields with 1 equiv of TCICA.
1-Chloro-3-nitrobenzene (2e, entry 5) and 3-chlorobenzamide
(2f, entry 6) were obtained in high yields, although heating to
80 °C was required. Furthermore, 2f was obtained in 89% yield
with no observed chlorination at the nitrogen of the amide.11
Importantly, the reaction with potassium (4-methoxycarbonyl)-
phenyltrifluoroborate afforded 2b (entry 2) in 87% yield. This
regiochemistry was previously unattainable by the chlorination of
simple arenes.4
Next, TCICA was applied as the chlorinating agent in the
reaction with electron-rich aryltrifluoroborates (Table 5).
The reaction with electron-rich aryltrifluoroborates pro-
ceeded in good yields using only 0.33 equiv of TCICA at rt
(condition A) or 0.16 equiv of TCICA and 1.5 equiv of NaCl at
60 °C (condition B), and all were complete in 1 h or less (entries
1À7). It is important to mention that the reaction with electron-
donating groups in the para position (e.g., compounds 1bÀe and
1g) can be run at higher concentrations (e.g., 0.33 M). However,
for compounds such as 1a and 1hÀj, higher concentrations lead
to a mixture of regioisomers. Nonetheless, the reaction with
potassium biphenyl-4-yltrifluoroborate was carried out on a 5
mmol scale (1.3 g) with 0.33 equiv of TCICA and 15 mL of
solvent (0.33 M), providing product 1b in 81% yield (entry 2).
Halogen-containing aryltrifluoroborates also underwent chloro-
deboronation to afford the desired aryl chloride in moderate
to good yields (entries 8 and 9), depending on the condition
utilized. Unfortunately, this method was unsuccessful for the
chlorodeboronation of meta-substituted electron-rich aryl
systems. Inexplicably, only starting material or protodebor-
onation products were obtained for the reactions of TCICA
with potassium 3-methoxyphenyltrifluoroborate, potassium
3-(benzyloxy)phenyltrifluoroborate, and potassium 3,5-diiso-
propylphenyltrifluoroborate.
a Reaction run at 80 °C.
However, no cyclization product was observed, and the reaction
afforded only the ortho-substituted chlorinated product in 84%
or 76% yield, respectively. Therefore, it seems unlikely that the
reaction proceeds by a radical mechanism,13 and perhaps an
electrophilic aromatic substitution with ipso attack is more likely
(Scheme 2).14
Moving forward, the scope of the reaction for heteroaryl
systems was also examined. To the best of our knowledge, the
chlorodeboronation of heteroarylboron compounds in the lit-
erature is limited to one example using stoichiometric copper(II)
chloride as the chlorinating agent.8b Hence, diverse heteroaryl-
trifluoroborates were examined under two different reaction
conditions with TCICA (Table 6).
The majority of the heteroaryl chlorides obtained were not
commercially available or had limited commercial availability.
Organotrifluoroborate derivatives containing the dibenzofura-
nyl, quinolinyl, benzofuranyl, pyrimidinyl, and pyridinyl subunits
were successfully converted into the corresponding chlorinated
product in good yields. However, the use of only 0.33 equiv of
TCICA (method A) in the reaction with the pyridine and
benzofuran derivatives (entries 7À9) afforded mixtures of
mono- and dichlorinated compounds (1: 1). The use of less
than 0.33 equiv of TCICA with or without NaCl did not
improve the selectivity of the reaction. When method B (1 equiv
of TCICA) was applied to these substrates, only dichlorination
products were observed in good yields. Under the developed
conditions, heteroaryls such as thiophenes, furans, and indoles
afforded complex product mixtures of monochlorinated re-
gioisomers, as well as dichlorinated and protodeboronated
compounds.
The mechanism of these transformations is enigmatic, parti-
cularly in view of the fact that less than 1 equiv of electrophilic
chlorine can be employed along with NaCl in an oxygenated
atmosphere. We considered the possibility that the reaction
transpired via a version of the rare SON1 mechanism (Scheme 1),12
where the various chlorinating agents initially served as oxidants
of the trifluoroborate. To investigate the possibility of radical
intermediates, potassium [2-(allyloxy)phenyl]trifluoroborate
was subjected to both reaction conditions (Table 5, entry 10).
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Table 5. Chlorodeboronation of Electron-Rich and Halogen-
Scheme 2
Containing Potassium Aryltrifluoroborates with TCICA
To elucidate the source of these products, we examined the
possibility of a chlorodeboronation and subsequent chlorination
of the monochloride intermediate 3j (eq 2). Thus, we applied our
general method B (1 equiv of TCICA) in the reaction with
2-chlorobenzofuran (3j, eq 2). Surprisingly, none of the dichlori-
nated product was observed under these conditions, and only
starting material 3j was recovered. Although the developed protocol
is an efficient method for the synthesis of these dichlorinated
heterocycles, the mechanistic pathway for their formation is
again puzzling.
Encouraged by the results obtained with aryl- and heteroar-
yltrifluoroborates, we examined the feasibility of applying the
process to alkyl-, alkenyl-, and alkynyltrifluoroborates (Table 7).
The use of only 0.33 equiv of TCICA was sufficient to afford
the desired chlorinated products in good yields. Although
for many substrates the process worked very well, the protocol
is somewhat capricious, and thus attempts to promote the
chlorodeboronation of secondary alkyltrifluoroborates as well
as Z-alkenyltrifluoroborates were unsuccessful.
Finally, based on the work of Kabalka and co-workers7c where
the bromination of aryltrifluoroborates was described by using
Chloramine-T and sodium bromide, we demonstrated that the
use of 0.33 equiv of TCICA in the presence of 1 equiv of sodium
bromide afforded the desired brominated product (5a) in 94%
yield in only 30 min (eq 3).
a 5 mmol scale, 15 mL of solvent mixture.
In conclusion, we have developed the first metal-free method
for the chlorodeboronation of organotrifluoroborates utilizing
commercially available TCICA. Under our mild conditions, aryl-,
heteroaryl-, alkyl-, alkenyl-, and alkynyltrifluoroborates bearing a
variety of functional groups afforded the corresponding chlori-
nated product in good yields. The mechanism of these reactions
is unclear, leading to surprising and perplexing results in some
cases. We are attempting to elucidate the nature of these and
other reactions that transpire under oxidative conditions15 in our
continuing studies of the organotrifluoroborates.
Scheme 1
The formation of dichlorinated compounds from monotri-
fluoroborato heteroaryls represented an unexpected reactivity.
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Table 6. Chlorodeboronation of Potassium Heteroaryltrifluoroborates with TCICA
’ EXPERIMENTAL SECTION
Trace impurities were removed by column chromatography using Et2O/
pentanes to afford the desired pure product, compounds 1aÀi.
General Procedure for Chlorination of Organotrifluoro-
borates with Stoichiometric Chloramine-T. To a 50 mL round-
bottom flask containing a solution of potassium organotrifluoroborate
(1 mmol) in EtOAc:H2O (1:1, 10 mL, 0.1 M) were added NaCl (1 M in
General Procedure for Chlorination of Organotrifluoro-
borates with NaOCl. To a 50 mL round-bottom flask containing a
solution of potassium organotrifluoroborate (1 mmol) in EtOAc:H2O
(1:1, 10 mL, 0.1 M) was added NaOCl [1.5 mL of Clorox Ultra (6.15%
NaOCl), 1.2 mmol, 1.2 equiv] in one portion. The reaction was stirred
open to air at rt until 11B NMR indicated completion of the reaction. The
reaction was quenched with 10% aq Na2SO3 (10 mL). The aqueous
layer was extracted with Et2O (3 Â 10 mL). The combined organic
layers were washed with 1 N NaOH (3 Â 10 mL) to remove any
unreacted starting material. The Et2O layer was dried (Na2SO4), filtered,
concentrated, and dried in vacuo. In general, the product obtained was pure.
H2O, 0.5 mL, 0.5 mmol, 0.5 equiv) and Chloramine-T 3H2O (310 mg,
3
1.1 mmol, 1.1 equiv) in one portion. The reaction was stirred open to air
at rt until 11B NMR indicated completion of the reaction. The reaction
was quenched with 10% aq Na2SO3 (10 mL). The aqueous layer was
extracted with Et2O (3 Â 10 mL). The combined organic layers were
washed with 1 N NaOH (3 Â 10 mL) to remove any unreacted starting
material. The Et2Olayerwasdried(Na2SO4), filtered, concentrated, and the
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Table 7. Chlorodeboronation of Potassium Alkyl-, Alkenyl-,
and Alkynyltrifluoroborates with TCICA
NaOH (3 Â 10 mL) to remove any unreacted starting material. The
Et2O layer was dried (Na2SO4), filtered, concentrated, and the resulting
crude product was dried in vacuo. In general, the product obtained was
pure. Trace impurities were removed by column chromatography using
Et2O/pentanes to afford the desired pure product, compounds 1aÀj.
General Procedure C. To a 50 mL round-bottom flask containing a
solution of potassium organotrifluoroborate (1 mmol) in EtOAc:H2O
(1:1, 10 mL, 0.1 M) was added trichloroisocyanuric acid (232.4 mg,
1 mmol, 1 equiv) in one portion. The reaction was stirred open to air at rt
until 11B NMR indicated completion of the reaction. The reaction was
quenched with 10% aq Na2SO3 (10 mL). The aqueous layer was extracted
with Et2O (3 Â 10 mL). The combined organic layers were washed with
1 N NaOH (3 Â 10 mL) to remove any unreacted starting material. The
Et2O layer was dried (Na2SO4), filtered, concentrated, and the resulting
crude product was dried in vacuo. In general, the product obtained was pure.
Trace impurities were removed by column chromatography using Et2O/
pentanes to afford the desired pure product, compounds 2aÀf and 3gÀ i.
1-Chloronaphthalene (1a).16 General procedure A was employed
using potassium naphthalen-1-yltrifluoroborate (0.23 g, 1 mmol), and
the reaction was complete in 40 min. The desired pure product was
obtained in 95% yield (0.15 g, 0.94 mmol) as a colorless oil. 1H NMR
(500 MHz, CDCl3) δ 8.24 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H),
7.69 (d, J = 8.0 Hz, 1H), 7.56À7.52 (m, 2H), 7.48 (m, 1H), 7.31 (t, J =
8.0 Hz, 1H). 13C NMR (125.8 MHz, CDCl3) δ 134.8, 132.1, 131.0,
128.4, 127.4, 127.2, 126.9, 126.4, 125.9, 124.6.
resulting crude product was dried in vacuo. In general, the product obtained
was pure. Trace impurities were removed by column chromatography using
Et2O/pentanes to afford the desired pure product, compounds 1aÀi.
General Procedure for Chlorination of Organotrifluoro-
borates with Substoichiometric Chloramine-T. To a 50 mL
round-bottom flask containing a solution of potassium organotrifluorobo-
rate (1 mmol) in EtOAc:H2O (1:1, 10 mL, 0.1 M) were added NaCl (1 M
4-Chlorobiphenyl (1b).17 General procedure A was employed using
potassium biphenyl-4-yltrifluoroborate (1.3 g, 5 mmol) and 15 mL of
the solvent mixture, and the reaction was complete in 40 min. The
desired pure product was obtained in 81% yield (0.76 g, 4.05 mmol)
1
as a white solid, mp 75À77 °C (lit.11 76À78 °C). H NMR (500
MHz, CDCl3) δ 7.54À7.52 (m, 2H), 7.49 (d, J = 8.5 Hz, 2H),
7.43À7.40 (m, 2H), 7.38 (d, J = 8.5 Hz, 2H), 7.34 (m, 1H). 13C NMR
(125.8 MHz, CDCl3) δ 140.2, 139.8, 133.6, 129.1, 129.0, 128.6,
127.8, 127.2.
in H2O, 1.5 mL, 1.5 mmol, 1.5 equiv) and Chloramine-T 3H2O (85 mg,
3
0.3 mmol, 0.3 equiv) in one portion. The reaction was stirred open to air at
rt until 11B NMR indicated completion of the reaction. The reaction was
quenched with 10% aq Na2SO3 (10 mL). The aqueous layer was extracted
with Et2O (3 Â 10 mL). The combined organic layers were washed with
1 N NaOH (3 Â 10 mL) to remove any unreacted starting material. The
Et2O layer was dried (Na2SO4), filtered, concentrated, and the resulting
crude product was dried in vacuo. In general, the product obtained was
pure. Trace impurities were removed by column chromatography using
Et2O/pentanes to afford the desired pure product, compounds 1aÀi.
General Procedure for Chlorination of Organotrifluoro-
borates with Trichloroisocyanuric Acid. General Procedure A.
To a 50 mL round-bottom flask containing a solution of potassium
organotrifluoroborate (1 mmol) in EtOAc:H2O (1:1, 10 mL, 0.1 M) was
added trichloroisocyanuric acid (76.7 mg, 0.33 mmol, 0.33 equiv) in
one portion. The reaction was stirred open to air at rt until 11B NMR
indicated completion of the reaction. The reaction was quenched with
10% aq Na2SO3 (10 mL). The aqueous layer was extracted with Et2O
(3 Â 10 mL). The combined organic layers were washed with 1 N NaOH
(3Â 10 mL) to remove any unreacted starting material. The Et2Olayerwas
dried (Na2SO4), filtered, concentrated, and the resulting crude product was
dried in vacuo. In general, the product obtained was pure. Trace impurities
were removed by column chromatography using Et2O/pentanes to afford
the desired pure product, compounds 1aÀj, 3aÀ f, and 4aÀd.
1-tert-Butyl-4-chlorobenzene (1c).18 General procedure A was
employed using potassium 4-tert-butylphenyltrifluoroborate (0.24 g, 1
mmol), and the reaction was complete in 1 h. The desired pure product
1
was obtained in 94% yield (0.16 g, 0.94 mmol) as a colorless oil. H
NMR (500 MHz, CDCl3) δ 7.33 (d, J = 9 Hz, 2H), 7.27 (d, J = 8.5 Hz,
2H), 1.32 (s, 9H). 13C NMR (125.8 MHz, CDCl3) δ 149.7, 131.3, 128.2,
126.9, 34.6, 31.4.
1-Chloro-4-methoxybenzene (1d).19 General procedure A was
employed using potassium 4-methoxyphenyltrifluoroborate (0.21 g, 1
mmol), and the reaction was complete in 40 min. The desired pure
product was obtained in 98% yield (0.14 g, 0.98 mmol) as a light yellow
oil. 1H NMR (500 MHz, CDCl3) δ 7.22 (d, J = 9.0 Hz, 2H), 6.81 (d, J =
9.0 Hz, 2H), 3.77 (s, 3H). 13C NMR (125.8 MHz, CDCl3) δ 158.3,
129.4, 125.7, 115.3, 55.6.
1-(Benzyloxy)-4-chlorobenzene (1e).20 General procedure A was
employed using potassium 4-(benzyloxy)phenyltrifluoroborate (0.25 g,
1 mmol), and the reaction was complete in 40 min. The desired pure
product was obtained in 92% yield (0.20 g, 0.92 mmol) as a light yellow
solid, mp 65À67 °C (lit.21 65À67 °C). 1H NMR (500 MHz, CDCl3) δ
7.37À7.33 (m, 4H), 7.31 (m, 1H), 7.19 (d, J = 9 Hz, 2H) 6.85 (d, J = 9.0
Hz, 2H), 4.98 (s, 2H). 13C NMR (125.8 MHz, CDCl3) δ 157.3, 136.6,
129.3, 128.6, 128.1, 127.4, 125.8, 116.1, 70.2.
General Procedure B. To a 50 mL round-bottom flask containing a
solution of potassium organotrifluoroborate (1 mmol) in EtOAc:H2O
(1:1, 10 mL, 0.1 M) were added NaCl (1 M in H2O, 1.5 mL, 1.5 mmol,
1.5 equiv) and trichloroisocyanuric acid (37 mg, 0.16 mmol, 0.16 equiv)
in one portion. The reaction was stirred open to air at rt until 11B NMR
indicated completion of the reaction. The reaction was quenched with
10% aq Na2SO3 (10 mL). The aqueous layer was extracted with Et2O
(3 Â 10 mL). The combined organic layers were washed with 1 N
1-(Benzyloxy)-2-chlorobenzene (1f).20 General procedure A was
employed using potassium 2-(benzyloxy)phenyltrifluoroborate (0.25 g,
1 mmol), and the reaction was complete in 1 h. The desired pure product
was obtained in 94% yield (0.21 g, 0.94 mmol) as a yellow oil. 1H NMR
(500 MHz, CDCl3) δ 7.37À7.33 (m, 4H), 7.31 (m, 1H), 7.19 (d, J = 9
Hz, 2H) 6.85 (d, J = 9.0 Hz, 2H), 4.98 (s, 2H). 13C NMR (125.8 MHz,
CDCl3) δ 154.3, 136.6, 130.4, 128.7, 128.0, 127.8, 127.1, 123.3, 121.7,
114.1, 70.8.
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5-(Benzyloxy)-2-chlorobenzaldehyde (1g). General procedure A
was employed using potassium (4-(benzyloxy)-2-formylphenyl)trifluor-
oborate (0.32 g, 1 mmol), and the reaction was complete in 40 min. The
desired pure product was obtained in 91% yield (0.22 g, 0.91 mmol) as a
light yellow solid, mp 55À57 °C. 1H NMR (500 MHz, CDCl3) δ 10.43
(s, 1H), 7.49 (d, J = 3 Hz, 1H), 7.43À7.38 (m, 4H), 7.39À7.34 (m, 2H),
7.16 (m, 1H) 5.09 (s, 2H). 13C NMR (125.8 MHz, CDCl3) δ 189.7,
157.7, 135.9, 132.9, 131.5, 129.9, 128.7, 128.3, 127.5, 123.4, 113.0, 70.5.
FT-IR (neat) 1696, 1230, 1004, 748 cmÀ1. HRMS (ESI) m/z calcd for
C14H11O2NaCl (M + Na)+ 269.0345, found 269.0347.
the reaction was run at 80 °C, and it was complete in 4 h. The desired
pure product was obtained in 85% yield (0.13 g, 0.85 mmol) as a yellow
1
oil. H NMR (500 MHz, CDCl3) δ 8.22 (t, J = 2.1 Hz, 1H), 8.14
(m, 1H), 7.69 (m, 1H), 7.52 (t, J = 8.1 Hz, 1H). 13C NMR (125.8 MHz,
CDCl3) δ 148.7, 135.3, 134.6, 130.3, 123.8, 121.6.
3-Chlorobenzamide (2f).8a General procedure C was employed
using potassium (3-carbamoylphenyl)trifluoroborate (0.23 g, 1 mmol),
the reaction was run at 80 °C, and it was complete in 6 h. The desired
pure product was obtained in 89% yield (0.14 g, 0.89 mmol) as a white
1
solid, mp 125À127 °C (lit.17 125À128 °C). H NMR (500 MHz,
1-Bromo-4-chlorobenzene (1h).7b General procedure A was em-
ployed using potassium (4-bromophenyl)trifluoroborate (0.26 g, 1 mmol),
and the reaction was complete in 1 h. The desired pure product was
obtained in 81% yield (0.15 g, 0.81 mmol) as a colorless solid, mp
64À66 °C (lit.22 65À66 °C). 1H NMR (500 MHz, CDCl3) δ 7.41 (d, J =
8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H). 13C NMR (125.8 MHz, CDCl3) δ
133.2, 132.7, 130.2, 120.2.
CDCl3) δ 7.81 (t, J = 2.0 Hz, 1H), 7.68 (m, 1H), 7.51 (m, 1H), 7.39
(t, J = 8.0 Hz, 1H), 6.02 (brs, 2H). 13C NMR (125.8 MHz, CDCl3) δ
167.9, 135.1, 134.9, 132.0, 129.9, 127.7, 125.4.
4-Chlorodibenzo[b,d]furan (3a). General procedure A was em-
ployed using potassium dibenzo[b,d]furan-4-yltrifluoroborate (0.27 g,
1 mmol), and the reaction was complete in 2 h. The desired pure product
was obtained in 95% yield (0.19 g, 0.95 mmol) as a white solid, mp
64À66 °C. 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 7.7 Hz, 1H), 7.82
(d, J = 7.7 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.45
(d, J = 7.9 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H). 13C
NMR (125.8 MHz, CDCl3) δ 156.1, 151.9, 127.8, 127.1, 125.9, 124.0,
123.6, 123.2, 120.9, 119.0, 117.1, 112.1. FT-IR (neat) 1420, 1197, 1040,
870, 744, 683 cmÀ1. HRMS (ESI) m/z calcd for C12H8OCl (M + H)+
203.0264, found 203.0263.
2,3-Dichloroquinoline (3b). General procedure A was employed
using potassium (2-chloroquinolin-3-yl)trifluoroborate (0.27 g, 1 mmol),
and the reaction was complete in 6 h. The desired pure product was
obtained in 80% yield (0.16 g, 0.80 mmol) as a white solid, mp
97À99 °C. 1H NMR (500 MHz, CDCl3) δ 8.22 (s, 1H), 8.00
(m, 1H), 7.75À7.71 (m, 2H), 7.59 (m, 1H). 13C NMR (125.8 MHz,
CDCl3) δ 148.2, 145.8, 137.2, 130.6, 128.5, 127.9, 127.6, 127.1, 126.6.
FT-IR (neat) 1150, 975, 757, 655 cmÀ1. HRMS (ESI) m/z calcd for
C9H5NCl2 (M)+ 196.9799, found 196.9799.
5-Chloro-2,4-dimethoxypyrimidine (3c). General procedure A was
employed using potassium (2,4-dimethoxypyrimidin-5-yl)trifluorobo-
rate (0.25 g, 1 mmol), and the reaction was complete in 2 h. The desired
pure product was obtained in 91% yield (0.16 g, 0.91 mmol) as a white
solid, mp 70À72 °C (lit.29 72À73 °C). 1H NMR (500 MHz, CDCl3) δ
8.20 (s, 1H), 4.07 (s, 3H), 3.99 (s, 3H). 13C NMR (125.8 MHz, CDCl3)
δ 166.0, 163.4, 156.4, 110.3, 55.2, 54.7. FT-IR (neat) 1560, 1400, 1275,
1004, 780, 690 cmÀ1. HRMS (ESI) m/z calcd for C6H8N2O2Cl (M +
H)+ 175.0274, found 175.0281.
1,4-Dichlorobenzene (1i).23 General procedure A was employed
using potassium (4-chlorophenyl)trifluoroborate (0.22 g, 1 mmol), and
the reaction was complete in 1 h. The desired pure product was obtained
in 86% yield (0.13 g, 0.86 mmol) as a colorless solid, mp 47À50 °C (lit.24
1
46À49 °C). H NMR (500 MHz, CDCl3) δ 7.27 (s, 4H). 13C NMR
(125.8 MHz, CDCl3) δ 132.5, 129.8.
1-(Allyloxy)-2-chlorobenzene (1j).25 General procedure A was
employed using potassium (2-(allyloxy)phenyl)trifluoroborate (0.24 g,
1 mmol), and the reaction was complete in 1 h. The desired pure product
1
was obtained in 84% yield (0.14 g, 0.84 mmol) as a colorless oil. H
NMR (500 MHz, CDCl3) δ 7.37 (m, 1H), 7.19 (m, 1H), 6.93À6.88 (m,
2H), 6.08 (m, 1H), 5.47 (m, 1H), 5.31 (m, 1H), 4.63À4.61 (m, 2H). 13C
NMR (125.8 MHz, CDCl3) δ 154.1, 132.7, 130.3, 127.6, 123.1, 121.5,
117.8, 113.8, 69.7.
Methyl 4-Chlorobenzoate (2a).26 General procedure C was em-
ployed using potassium (4-methoxycarbonyl)phenyltrifluoroborate
(0.24 g, 1 mmol), and the reaction was complete in 2 h. The desired
pure product was obtained in 87% yield (0.15 g, 0.87 mmol) as a light
1
yellow solid mp 40À43 °C (lit.10 40À42 °C). H NMR (500 MHz,
CDCl3) δ 7.98 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 3.92 (s, 3H).
13C NMR (125.8 MHz, CDCl3) δ 166.2, 139.4, 131.0, 128.7, 128.6, 52.3.
Methyl 3-Chlorobenzoate (2b).27 General procedure C was em-
ployed using potassium (3-methoxycarbonyl)phenyltrifluoroborate
(0.24 g, 1 mmol), and the reaction was complete in 1 h. The desired
pure product was obtained in 92% yield (0.16 g, 0.92 mmol) as a
1
colorless oil. H NMR (500 MHz, CDCl3) δ 8.01 (m, 1H), 7.92 (m,
5-Chloro-2-(piperidin-1-yl)pyrimidine (3d). General procedure A
was employed using potassium 2-(piperidin-1-yl)pyrimidin-5-yltrifluor-
oborate (0.27 g, 1 mmol), and the reaction was complete in 2 h. The
desired pure product was obtained in 90% yield (0.18 g, 0.90 mmol) as a
white solid, mp 45À47 °C. 1H NMR (500 MHz, CDCl3) δ 8.19 (s, 2H),
1H), 7.52 (m, 1H), 7.38 (m, 1H), 3.92 (s, 3H). 13C NMR (125.8 MHz,
CDCl3) δ 165.8, 134.5, 132.9, 131.8, 129.6, 129.6, 127.6, 52.3.
1-(4-Chlorophenyl)ethanone (2c).28 General procedure C was
employed using potassium (4-acetylphenyl)trifluoroborate (0.23 g, 1 mmol),
and the reaction was complete in 30 min. The desired pure product was
obtained in 82% yield (0.13 g, 0.82 mmol) as a colorless oil. 1H NMR
(500 MHz, CDCl3) δ 7.86 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H),
2.56 (s, 3H). 13C NMR (125.8 MHz, CDCl3) δ 196.7, 139.5, 135.4,
129.6, 128.8, 26.5.
3.75 (t, J = 5.5 Hz, 4H), 1.67À1.66 (m, 2H), 1.61À1.58 (m, 4H). 13
C
NMR (125.8 MHz, CDCl3) δ 159.9, 155.7, 117.3, 45.1, 25.6, 24.7. FT-
IR (neat) 1584, 1508, 1441 1256, 782 cmÀ1. HRMS (ESI) m/z calcd for
C9H13N3Cl (M + H)+ 198.0798, found 198.0792.
4-(5-Chloropyrimidin-2-yl)morpholine (3e). General procedure A
was employed using potassium 2-morpholinopyrimidin-5-yltrifluorobo-
rate (0.27 g, 1 mmol), and the reaction was complete in 2 h. The desired
pure product was obtained in 89% yield (0.18 g, 0.89 mmol) as a white
3-Chloro-4-fluorobenzaldehyde (2d). General procedure A was
employed using potassium 2-fluoro-5-formylphenyltrifluoroborate (0.23 g,
1 mmol), and the reaction was complete in 40 min. The desired pure
product was obtained in 80% yield (0.13 g, 0.80 mmol) as a colorless
solid, mp 83À85 °C. 1H NMR (500 MHz, CDCl3) δ 9.94 (s, 1H), 7.97
(m, 1H), 7.81 (m, 1H), 7.32 (t, J = 8.5 Hz, 1H). 13C NMR (125.8 MHz,
CDCl3) δ 189.3, 161.8 (d, J = 7.3 Hz), 133.5, 132.1, 130.0 (d, J = 8.9 Hz),
122.7 (d, J = 18.9 Hz), 117.4 (d, J = 22.1 Hz). 19F NMR (470.8 MHz,
CDCl3) δ À104.7. FT-IR (neat) 1698, 1264, 1058, 708 cmÀ1. HRMS
(ESI) m/z calcd for C7H4OFCl (M)+ 157.9935, found 157.9941.
1-Chloro-3-nitrobenzene (2e).8a General procedure C was em-
ployed using potassium 3-nitrophenyltrifluoroborate (0.23 g, 1 mmol),
1
solid, mp 70À72 °C. H NMR (500 MHz, CDCl3) δ 8.24 (s, 2H),
3.76À3.75 (m, 8H). 13C NMR (125.8 MHz, CDCl3) δ 160.0, 155.9,
118.6, 66.7, 44.4. FT-IR (neat) 2922, 1585, 1494, 1253, 1112, 953, 787,
667 cmÀ1. HRMS (ESI) m/z calcd for C8H11N3OCl (M + H)+
200.0591, found 200.0589.
tert-Butyl 4-(5-Chloropyrimidin-2-yl)piperazine-1-carboxylate
(3f). General procedure A was employed using potassium (2-(4-(tert-
butoxycarbonyl)piperazin-1-yl)pyrimidin-5-yl)trifluoroborate (0.37 g,
1 mmol), and the reaction was complete in 2 h. The desired pure
7201
dx.doi.org/10.1021/jo201313a |J. Org. Chem. 2011, 76, 7195–7203

The Journal of Organic Chemistry
ARTICLE
product was obtained in 95% yield (0.28 g, 0.95 mmol) as a white solid,
7.45À7.42 (m, 2H), 4.32 (t, J = 6.5 Hz, 2H), 3.65 (t, J = 6.5 Hz, 2H),
1.81À1.76 (m, 2H), 1.63À1.59 (m, 2H), 1.49À1.43 (m, 4H). 13C NMR
(125.8 MHz, CDCl3) δ 166.9, 133.0, 130.6, 129.7, 128.5, 65.1, 62.9,
32.7, 28.9, 26.0, 25.6.
1
mp 102À105 °C. H NMR (500 MHz, CDCl3) δ 8.24 (s, 2H), 3.77
(t, J = 5.0 Hz, 4H), 3.49 (t, J = 5.0 Hz, 4H), 1.49 (s, 9H). 13C NMR
(125.8 MHz, CDCl3) δ 159.9, 156.0, 118.7, 80.2, 44.0, 28.6. FT-IR
(neat) 1677, 1585, 1514, 1249, 1131, 993, 784 cmÀ1. HRMS (ESI) m/z
calcd for C13H19N4O2NaCl (M + Na)+ 321.1094, found 321.1099.
3,5-Dichloro-N,N-dimethylpyridin-2-amine (3g). General proce-
dure C was employed using potassium (6-(dimethylamino)pyridin-3-
yl)trifluoroborate (0.23 g, 1 mmol), and the reaction was complete in
1 h. The desired pure product was obtained in 88% yield (0.17 g, 0.88
mmol) as a white solid, mp 24À26 °C. 1H NMR (500 MHz, CDCl3) δ
8.07 (d, J = 2 Hz, 1H), 7.54 (d, J = 2 Hz, 1H), 2.98 (s, 6H). 13C NMR
(125.8 MHz, CDCl3) δ 157.5, 143.9, 138.3, 122.7, 120.9, 41.5. FT-IR
(neat) 1491, 1414, 1176, 1049, 837, 753 cmÀ1. HRMS (ESI) m/z calcd
for C7H10N2Cl (M + H)+ 157.0533, found 157.0533.
4-Bromobiphenyl (5a).32 To a 50 mL round-bottom flask containing
a mixture of trichloroisocyanuric acid (76.7 mg, 0.33 mmol, 1 equiv) and
NaBr (103 mg, 1 mmol, 1 equiv) in EtOAc:H2O (1:1, 10 mL, 0.1 M) was
added potassium biphenyl-4-yltrifluoroborate (260 mg, 1 mmol) in one
portion. The reaction was stirred open to air at rt until 11B NMR
indicated completion of the reaction (30 min). The reaction was quenched
with 10% aq Na2SO3 (10 mL). The aqueous layer was extracted with
EtOAc (3 Â 10 mL). The combined organic layers were washed with
1 N NaOH (3 Â 10 mL) to remove any unreacted starting material.
The EtOAc layer was dried (Na2SO4), filtered, concentrated, and the
resulting crude product was dried in vacuo. The desired pure product
was obtained in 94% yield (0.84 g, 4.45 mmol) as a white solid, mp
88À90 °C (lit.25 89 °C). 1H NMR (500 MHz, CDCl3) δ 7.57À7.54 (m,
4H), 7.46À7.42 (m, 4H), 7.36 (m, 1H). 13C NMR (125.8 MHz, CDCl3)
δ 140.1, 140.0, 131.8, 128.9, 128.7, 127.6, 126.9, 121.5.
4-(3,5-Dichloropyridin-2-yl)morpholine (3h). General procedure C
was employed using potassium 6-morpholinopyridin-3-yltrifluoroborate
(0.27 g, 1 mmol), and the reaction was complete in 1 h. The desired pure
product was obtained in 91% yield (0.21 g, 0.91 mmol) as a white solid,
mp 83À85 °C. 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J = 2.5 Hz, 1H),
7.60 (d, J = 2.5 Hz, 1H), 3.85 (t, J = 5.0 Hz, 4H), 3.33 (t, J = 5.0 Hz, 4H).
13C NMR (125.8 MHz, CDCl3) δ 156.6, 144.3, 138.3, 124.5, 122.6, 66.8,
49.5. FT-IR (neat) 1435, 1243, 1111, 944, 823, 709 cmÀ1. HRMS (ESI)
m/z calcd for C9H11N2OCl2 (M + H)+ 233.0248, found 233.0257.
2,3-Dichlorobenzofuran (3i). General procedure C was employed
using potassium benzofuran-2-yltrifluoroborate (0.22 g, 1 mmol), and
the reaction was complete in 30 min. The desired pure product was
obtained in 86% yield (0.16 g, 0.86 mmol) as a white solid, mp
’ ASSOCIATED CONTENT
1
Supporting Information. Copies of H, 13C, and 19F
S
b
spectra for all compounds prepared by the method described.
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
1
25À27 °C. H NMR (500 MHz, CDCl3) δ 7.51 (m, 1H), 7.42 (m,
1H), 7.35À7.29 (m, 2H). 13C NMR (125.8 MHz, CDCl3) δ 152.3,
137.7, 126.5, 125.4, 123.9, 118.4, 111.3, 108.4. FT-IR (neat) 1449, 1155,
1034, 742 cmÀ1. HRMS (ESI) m/z calcd for C8H5OCl2 (M + H)+
186.9717, found 186.9721.
Corresponding Author
*E-mail: gmolandr@sas.upenn.edu.
(E)-(2-Chlorovinyl)benzene (4a).30 General procedure A was em-
ployed using potassium (E)-styryltrifluoroborate (0.21 g, 1 mmol), and
the reaction was complete in 40 min. The desired pure product was
obtained in 85% yield (0.12 g, 0.85 mmol) as a light yellow oil. 1H NMR
(500 MHz, CDCl3) δ 7.30À7.24 (m, 5H), 6.81 (d, J = 13.5 Hz, 1H),
6.61 (d, J = 13.5 Hz, 1H).13C NMR (125.8 MHz, CDCl3) δ 134.8, 133.2,
128.7, 128.1, 126.1, 118.6.
(E)-5-(2-Chlorovinyl)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (4b).
General procedure A was employed using potassium (E)-(2-(2,2-dimethyl-4-
oxo-4H-benzo[i][1,3]dioxin-5-yl)vinyl)trifluoroborate(0.18g,0.5mmol),and
the reaction was complete in 30 min. The desired pure product was obtained in
92% yield (0.11 g, 0.92 mmol) as a light yellow solid, mp 86À88 °C. 1H NMR
(500 MHz, CDCl3) δ 7.90 (d, J = 13.5, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.12
(d, J = 7.5 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 13.5 Hz, 1H), 1.71 (s,
6H). 13C NMR (125.8 MHz, CDCl3) δ 134.8, 133.2, 128.7, 128.1, 126.1,
118.6. FT-IR (neat) 1722, 1273, 1042, 924, 780, 691 cmÀ1. HRMS (ESI) m/z
calcd for C12H11O3NaCl (M + Na)+ 261.0294, found 261.0297.
’ ACKNOWLEDGMENT
This work was generously supported by the NIGMS (R01
GM086209, GM035249) and a Conselho Nacional de Desen-
volvimento Científico e Tecnolꢀogico (CNPq) Graduate Re-
search Fellowship to L.N.C. We also acknowledge Aldrich,
BoroChem, and Frontier Scientific for their donation of the
boronic acids used to prepare the organotrifluoroborates. Dr.
Rakesh Kohli (University of Pennsylvania) is acknowledged for
obtaining the HRMS data.
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1
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7202
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ARTICLE
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