Palladium-catalyzed coupling of arene C-H bonds with methyl- and arylboron reagents assisted by the removable 2-pyridylsulfinyl group

Article abstract of DOI:10.1021/jo2018137

The Pd^II-catalyzed direct coupling of arene C-H bonds with organoboron reagents assisted by the 2-pyridylsulfinyl group is reported. Methylboronic acid and arylboronic acid neopentyl esters proved to be efficient coupling partners, furnishing methylated arenes and biaryl products in moderate to good yields. The 2-pyridylsulfinyl group can be easily removed to provide the free biaryls. The essential role of the 2-pyridyl unit in stabilizing the cyclopalladation complex was demonstrated by X-ray diffraction analysis of the palladacycle intermediate.

Full text of DOI:10.1021/jo2018137

Note
pubs.acs.org/joc
Palladium-Catalyzed Coupling of Arene C−H Bonds with Methyl- and
Arylboron Reagents Assisted by the Removable 2-Pyridylsulfinyl
Group
́
́
Jose A. Romero-Revilla, Alfonso Garcıa-Rubia, Ramon Gomez Arrayas,* M. Angeles Fernandez-Ibanez,*
́
́
́
́
́
́
̃
and Juan C. Carretero*
́
́ ́noma de Madrid, Facultad de Ciencias, Cantoblanco, 28049 Madrid, Spain
Departamento de Quımica Organica, Universidad Auto
S
* Supporting Information
ABSTRACT: The PdII-catalyzed direct coupling of arene
C−H bonds with organoboron reagents assisted by the
2-pyridylsulfinyl group is reported. Methylboronic acid and
arylboronic acid neopentyl esters proved to be efficient coupling
partners, furnishing methylated arenes and biaryl products in
moderate to good yields. The 2-pyridylsulfinyl group can be
easily removed to provide the free biaryls. The essential role of
the 2-pyridyl unit in stabilizing the cyclopalladation complex was
demonstrated by X-ray diffraction analysis of the palladacycle intermediate.
he Suzuki−Miyaura cross-coupling reaction is one of
the most powerful and reliable tools for C−C bond
under aerobic conditions (air atmosphere) led us to find the
T
key role of p-benzoquinone (BQ), likely for promoting the
reductive elimination step as previously pointed out in seminal
reports.4b,17 As shown in Table 1, while the methylated product
construction for the synthesis of complex products.1 In recent
years, extensive efforts have been devoted to develop transition-
metal-catalyzed direct coupling of arene C−H bonds with
organoboron reagents. In comparison with the oxidative
addition of a low-valent transition-metal complex to Ar-X
(X = halide or pseudohalide), this strategy offers a more atom
economical and environmentally benign alternative route to
Ar-M (M = metal) intermediates.2−13 Consequently, this PdII-
catalyzed oxidative cross-coupling nicely complements the
Pd0-catalyzed direct C−H functionalization with aryl or alkyl
halides/pseudohalides.3 As in the majority of examples of C−H
functionalization, a directing group has been mostly applied as a
means of tuning the reactivity and achieving regiocontrol in the
metal-catalyzed C−H coupling with organoboron reagents.
Thus, a 2-pyridyl unit,4 imines,5 oxymes,6 carboxylic acids,7
and N-acetyl8 or N-carbamoyl9 anilines have been successfully
used for this purpose under Pd catalysis, whereas a ketone
directing group proved to be efficient under Ru catalysis.10−13
However, despite their versatility, frequently these directing
groups are not easily removed from the resulting products,
thus compromising the generality of the reaction. Therefore,
the development of novel directing groups, not only chemically
versatile but also readily attachable and removable, is highly
desirable. Recently, we14 and others15 have described the use
of the 2-pyridyl sulfoxide as a chemically versatile and
removable directing group in PdII-catalyzed C−H functional-
ization.16 Herein, we report the extension of this concept to
the oxidative cross-coupling of arenes with organoboron
reagents.
Table 1. Optimization of the Reaction Parameters
a
entry
x/y
AgI (equiv)
solvent
conv (%)
1
2
100/0
100/1
10/1
DCE
0
DCE
>98
25
16
10
47
54
67
82
73
68
3
Ag2O (2)
Ag2O (2)
Ag2O (2)
Ag2O (2)
Ag2O (2)
Ag2O (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
DCE
4
10/1
toluene
DMF
5
10/1
6
10/1
THF
7
10/1
AcOEt
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
8
10/1
9
10/0.5
10/0.2
5/0.5
10/0.5
10
11
12
b
AgOAc (3)
91 (74)
a
b
1
Conversion determined by H NMR and/or GC. Isolated yield.
2a was not formed in the absence of BQ (entry 1), complete
conversion was observed in the presence of BQ (1 equiv,
The model reaction of phenyl 2-pyridyl sufoxide (1a) with
methyl boronic acid (2 equiv) under a stoichiometric amount
of Pd(OAc)2 (1 equiv) in 1,2-dichloroethane (DCE) at 100 °C
Received: September 2, 2011
Published: September 30, 2011
© 2011 American Chemical Society
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Note
entry 2). To achieve effective catalytic turnover we focused on
the choice of the optimal oxidant/base combination to facilitate
transmetalation/catalyst regeneration. In this regard, Ag2O has
been reported to induce Suzuki−Miyaura cross-coupling,
presumably by accelerating the B-to-Pd transfer step.18 The
model reaction using catalytic Pd(OAc)2 (10 mol %) in the
presence of BQ (1 equiv) and Ag2O (2 equiv) in DCE at
100 °C for 20 h under air gave the methylated product 2a in
25% conversion (entry 3). Screening of solvents (entries 4−8)
allowed an increase in the conversion value to 67% using tert-
amyl alcohol. Then, several silver salts were tested in our
reaction system, among which AgOAc was found to be the
most efficient, providing 2a with 82% conversion and allowing
the use of substoichiometric amount of BQ (0.5 equiv, entry 9).
A further decrease of the amount of BQ (entry 10) or reducing
the Pd-catalyst loading to 5 mol % (entry 11) led to lower
conversions, whereas increasing to 3 equiv the amount of
AgOAc provided the highest conversion (91%, 74% isolated
yield of 2a, entry 12).19 The silver salt may work as both
co-oxidant and base (promoter for transmetalation).4b
respectively), electron-deficient groups at the para-position had
a deleterious effect on the yield (products 2d and 2e, 45% and
39% yield, respectively). Acceptable yields for the major
regioisomer (37−47%) but poor regioselectivity (1.5:1−2:1)
in favor of the less hindered C−H bond were obtained with
meta-substituted substrates (products 2f, 2h, and 2i), except
for the case of a m-methoxy substituent that induced a high
regiocontrol (8:1) (product 2g). Substituents at the ortho-
position of the sulfoxide significantly compromised the reaction
(product 2j, 16% yield), indicating that the reaction is very
sensitive to steric effects.
Unfortunately, the use of butylboronic acid as the coupling
partner in the reaction with 1a under various conditions failed
to provide the desired alkylation product in practical yields
(a maximum of 36% conversion was achieved using 2,2,5,5-
tetramethyl-THF as solvent to minimize β-hydride elimination).13a
Driven by the wide range significance of biaryl systems as
structural units in biologically active molecules and functional
materials,20 we sought to extend this coupling reaction to
arylboronic acids. Unfortunately, the reaction of 1a with pheny-
lboronic acid (2 equiv) under the standard reaction conditions
failed to provide the desired product. Only homocoupling of
the organometallic reagent was observed, indicating that this
undesired reaction is faster than the C−H activation process.
To solve this problem, we tested other phenyl boron reagents
such as potassium phenyltrifluoroborate and the pinacol or
neopentyl phenylboronate esters under the optimized reaction
conditions. Among them, the phenylboronic acid neopentyl
ester provided the best result, affording the corresponding
biphenyl sulfoxide 3a in 79% conversion (59% isolated yield,
Table 3).
With the optimized reaction conditions in hand, the substrate
scope with regard to the arene was examined. As in the model
reaction, the conversions were never complete, and traces of
dimethylated product were detected for some substrates. As
shown in Table 2, this C−H alkylation process was amenable to
Table 2. PdII-Catalyzed C−H Methylation of Aryl 2-Pyridyl
Sulfoxides with Methylboronic Acid
Table 3. PdII-Catalyzed C−H Arylation of Aryl 2-Pyridyl
Sulfoxides with Arylboronates
a
Isolated yield.
a
b
c
1
Isolated yield. Conversion determined by H NMR. Regioisomer
d
methylation ratio. Isolated yield of the major regioisomer.
The study of the scope of this reaction with regard to the
organoboron reagent is shown in Table 3. In all these reactions,
complete selectivity was observed, but full conversions were not
achieved (50−80% conversion). The reaction was found to be
marginally affected by the electronic effect of the substituents
on the arylboronate, tolerating both electron-donating groups
different aryl 2-pyridyl sufoxides, yet the reaction was found
to be deeply impacted by the electronic and steric effects of
the substituents on the aryl sulfoxide. Thus, while electron-
donating groups at the para-position had no influence on the
methylation reaction (products 2b and 2c, 62% and 75% yield,
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Note
(products 4a, 5a, 7a, 47−72% isolated yield) and electron-
withdrawing groups (6a, 8a, 40−63% isolated yield) at the
para- or meta-positions. This biaryl coupling methodology
allowed for the efficient coupling of two electronically dissimilar
aromatic partners, as exemplified in the synthesis of 6c (65%
yield). In contrast, ortho-substituents at the boronate ester were
not tolerated under the reaction conditions and completely
suppressed the cross-coupling.21
Finally, to demostrate the synthetic potencial of this
methodology, the 2-pyridylsulfinyl directing group was easily
removed by sulfoxide/lithium exchange with n-BuLi in THF
at −98 °C to provide the free corresponding biaryl products
(Scheme 1).14a,15,22
Complex I underwent methylation upon treatment with
MeB(OH)2 in DCE at 100 °C23 to give full conversion to
the ortho-methylated product 2a in the presence of BQ.
Competitive experiments with electronically varied aryl
2-pyridyl sulfoxides in the reaction with methylboronic acid
revealed higher reactivity of electron-rich arenes (Scheme 3a,
2d/2c, kCl/kOMe = 0.19). On the other hand, a very low intra-
molecular kinetic isotope effect was observed using 2-
deuteriophenyl 2-pyridyl sulfoxide 1a-D in the ortho-methyl-
ation with MeB(OH)2 (Scheme 3b). These preliminary studies
suggest as the most likely reaction mechanism the initial
electrophilic C−H palladation of the arene with the assistance
of the 2-pyridylsulfinyl group, followed by transmetalation of
the boron reagent and subsequent reductive elimination to give
the methylated or arylated product.
Scheme 1. Removal of the 2-Pyridylsulfinyl Group
In conclusion, we have developed a PdII-catalyzed ortho
C−H methylation and arylation with organoboron reagents
directed by the removable 2-pyridylsulfinyl group. The origin of
the directing ability of the 2-pyridylsulfinyl group has been
attributed to the participation of the pyridinic nitrogen in the
stabilization of the PdII-cyclopalladation intermediate complex,
which has been evidenced by X-ray crystallographic study.
EXPERIMENTAL SECTION
■
To further understand this transformation, we carried out
some mechanistic studies. First, treatment of 1a with Pd(OAc)2
(1 equiv) in DCE at 100 °C for 1 h led to the quantitative
formation of the six-membered cyclopalladated complex I,
which was isolated as an air stable solid (Scheme 2). X-ray
General Information. Chromatography: silica gel (230−400
mesh). TLC: silica gel (0.25 mm). Visualization of the chromatograms
was performed by UV lamp and phosphomolybdic acid or potassium
permanganate or Seebach’s “magic” staining [a mixture of phos-
phomolybdic acid (25 g), cerium(IV) sulfate (7.5 g), H2O (500 mL),
and H2SO4 (25 mL)]. Mass spectra were recorded on a GC/EI or
ESI (LC/MSD TOF by electrospray ionization time-of-flight) mass
spectrometers. Progress and conversion of the reaction were
determined by 1H NMR (300 MHz) and GC. 1H and 13C NMR
were recorded with 1H at 300 MHz and 13C at 75.4 MHz, respectively,
using CDCl3 as solvent. Chemical shift values are reported in ppm
with the solvent resonance as the internal standard (CHCl3: δ 7.26
Scheme 2. Cyclopalladation and Methylation of 1a
for H, δ 77.0 for 13C). Data are reported as follows: chemical shifts,
1
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet), coupling constants (Hz), and integration. Melting points
were recorded on a melting point apparatus and are uncorrected.
2-Pyridyl aryl sulfoxides (1a−j)14a and boronic acid neopentyl esters24
were synthesized following procedures described in the literature.
p-Benzoquinone was purified by sublimation before use.
General Procedure for the Palladium(II)-Catalyzed C−H
Activation/Suzuki−Miyaura-Type Coupling. In a screw-capped
tube, the corresponding aryl 2-pyridyl sulfoxide (0.25 mmol), boronic
diffraction analysis of suitable crystals established the acetate-
bridged dimer structure of complex I, in which the PdII atom
coordinates to the pyridyl nitrogen of the directing group, proving
the directing ability of the 2-pyridylsulfinyl group in C−H
functionalization reactions (see the Supporting Information).
Scheme 3. Intermolecular Competition Experiment and Intramolecular Kinetic Isotopic Effect Studies
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Note
acid derivative (0.5 mmol, 2 equiv), Pd(OAc)2 (5.6 mg, 0.025 mmol,
10 mol %), p-benzoquinone (13.5 mg, 0.125 mmol, 0.5 equiv), and
AgOAc (125.2 mg, 0.75 mmol, 3 equiv) were dissolved in tert-amyl
alcohol (2.5 mL) under atmospheric air. The reaction mixture was
stirred at 100 °C for 20 h before it was allowed to reach room
temperature. The mixture was filtered through a pad of Celite (washed
with EtOAc), and the filtrate was concentrated under reduced
(ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 7.19−7.06 (m, 2H), 2.64 (s, 3H), 2.33
(s, 3H). 13C NMR δ: 166.5, 149.6, 142.4, 138.0, 136.8, 134.4, 131.9,
130.9, 124.6, 124.4, 119.0, 20.9, 18.9. MS (ESI) m/z: 232 (M+ + H)
(100), 254 (M+ + Na), 485 (2M+ + Na). HRMS: calcd for C13H14NOS
(M+ + H) 232.0790, found 232.0789.
2-[(5-Methoxy-2-methylphenyl)sulfinyl]pyridine (2g). Com-
pound 2g was obtained from 2-[(3-methoxyphenyl)sulfinyl]pyridine
and methylboronic acid following the general procedure, after
purification by flash chromatography (n-hexane−EtOAc 2:1), as a
1
pressure. The conversion was determined by H NMR of the crude
mixture before it was purified by flash column chromatography to give
the desired product.25
mixture 8:1 of regioisomers in favor of 2g (yield 50%). H NMR
1
2-[(2-Methylphenyl)sulfinyl]pyridine (2a).14a Compound 2a
was obtained from 2-(phenylsulfinyl)pyridine and methylboronic
acid following the general procedure, after purification by flash
chromatography (n-hexane−EtOAc 2:1), as a white solid (yield 74%).
Analytical data are in accordance with those from the literature.14a 1H
NMR δ: 8.51 (d, J = 4.3 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.88 (td,
J = 7.8, 1.7 Hz, 1H), 7.83−7.71 (m, 1H), 7.38−7.16 (m, 4H), 1.53
(s, 3H).
2-[(2,4-Dimethylphenyl)sulfinyl]pyridine (2b). Compound 2b
was obtained from 2-(p-tolylsulfinyl)pyridine and methylboronic acid
following the general procedure, after purification by flash
chromatography (n-hexane−EtOAc 2:1), as a white solid (yield
62%). Mp: 56−58 °C. 1H NMR δ: 8.42 (ddd, J = 4.7, 1.7, 0.8 Hz, 1H),
7.97 (dt, J = 7.9, 1.0 Hz, 1H), 7.79 (td, J = 7.8, 1.8 Hz, 1H), 7.55 (d,
J = 8.0 Hz, 1H), 7.19 (ddd, J = 7.5, 4.7, 1.2 Hz, 1H), 7.02 (d, J =
8.6 Hz, 1H), 6.95 (s, 1H), 2.54 (s, 3H), 2.23 (s, 3H). 13C NMR
δ: 166.5, 149.6, 141.5, 139.7, 137.9, 137.4, 131.7, 127.7, 124.9, 124.3,
119.0, 21.2, 19.2. MS (ESI) m/z: 126 (M+ − 105), 232 (M+ + H)
(100), 254 (M+ + Na), 485 (2M+ + Na). HRMS: calcd for C13H14NOS
(M+ + H) 232.0790, found 232.0784.
δ: 8.44 (ddd, J = 4.7, 1.7, 0.8 Hz, 1H), 7.93 (dd, J = 7.9, 0.8 Hz, 1H),
7.79 (td, J = 7.7, 1.8 Hz, 1H), 7.27 (d, J = 2.8 Hz, 1H), 7.24−7.18
(m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.79 (dd, J = 8.4, 2.8 Hz, 1H), 3.71
(s, 3H), 2.50 (s, 3H). 13C NMR δ: 166.4, 158.6, 149.6, 143.5, 138.0,
132.0, 129.2, 124.6, 118.9, 117.9, 108.2, 55.5, 18.4. MS (ESI) m/z: 248
(M+ + H) (100), 270 (M+ + Na), 517 (2M+ + Na). HRMS: calcd for
C13H14NO2S (M+ + H) 248.0739, found 248.0741.
2-[(5-Chloro-2-methylphenyl)sulfinyl]pyridine (2h). Com-
pound 2h was obtained from 2-[(3-chlorophenyl)sulfinyl]pyridine
and methylboronic acid following the general procedure, after purifi-
cation by flash chromatography (n-hexane−EtOAc 2:1), as a yellow
solid (yield 37%). Mp: 114−116 °C. 1H NMR δ: 8.43 (d, J = 4.7 Hz,
1H), 7.96 (d, J = 7.9 Hz, 1H), 7.83 (td, J = 7.7, 1.8 Hz, 1H), 7.69 (d,
J = 2.2 Hz, 1H), 7.32−7.13 (m, 2H), 7.07 (d, J = 8.2 Hz, 1H), 2.59
(s, 3H). 13C NMR δ: 166.0, 149.6, 144.8, 138.3, 135.7, 133.0, 132.3,
131.1, 124.8, 124.1, 118.9, 19.0. MS (ESI) m/z: 252 (M+ + H) (100),
274 (M+ + Na), 525 (2M+ + Na). HRMS: calcd for C12H11ClNOS
(M+ + H) 252.0244, found 252.0251.
2-(3-Methylnaphthalene-2-ylsulfinyl)pyridine (2i). Com-
pound 2i was obtained from 2-(naphthalen-2-ylsulfinyl)pyridine and
methylboronic acid following the general procedure, after purification
by flash chromatography (n-hexane−EtOAc 2:1), as a white solid
2-[(4-Methoxy-2-methylphenyl)sulfinyl]pyridine (2c). Com-
pound 2c was obtained from 2-[(4-methoxyphenyl)sulfinyl]pyridine
and methylboronic acid following the general procedure, after
purification by flash chromatography (n-hexane−EtOAc 2:1), as a
1
(yield 40%). Mp: 172−174 °C. H NMR δ: 8.49 (dd, J = 4.7, 0.8 Hz,
1H), 8.39 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.92−7.81 (m, 2H), 7.75
(d, J = 7.9 Hz, 1H), 7.63 (s, 1H), 7.54−7.41 (m, 2H), 7.30−7.23 (m,
1H), 2.74 (s, 3H). 13C NMR δ: 166.4, 149.5, 141.6, 138.2, 134.6,
133.2, 131.6, 129.4, 128.4, 127.8, 127.0, 126.1, 125.4, 124.6, 119.2,
19.6. MS (EI) m/z: 267 (M+), 251 (M+ − 16), 236 (M+ − 31), 218
(M+ − 49) (100). HRMS: calcd for C16H13NOS (M+) 267.0718,
found 267.0722.
1
white solid (yield 75%). Mp: 85−87 °C. H NMR δ: 8.43 (ddd, J =
4.7, 1.7, 0.8, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.81 (td, J = 7.7, 1.7 Hz,
1H), 7.55 (d, J = 8.7 Hz, 1H), 7.21 (ddd, J = 7.5, 4.7, 1.2 Hz, 1H), 6.73
(dd, J = 8.7, 2.6 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 3.72 (s, 3H), 2.56
(s, 3H). 13C NMR δ: 166.5, 161.8, 149.6, 139.8, 137.9, 134.2, 127.3,
124.3, 119.0, 116.2, 112.6, 55.3, 19.4. MS (ESI) m/z: 122 (M+ − 126)
(100), 248 (M+ + H), 270 (M+ + Na), 571 (2M+ + Na). HRMS: calcd
for C13H14NO2S (M+ + H) 248.0739, found 248.0742.
2-[(2-Methoxy-6-methylphenyl)sulfinyl]pyridine (2j). Com-
pound 2j was obtained from 2-[(2-methoxyphenyl)sulfinyl]pyridine
and methylboronic acid following the general procedure, after purifi-
cation by flash chromatography (n-hexane−EtOAc 2:1), as a white
solid (yield 16%). Mp: 108−110 °C. 1H NMR δ: 8.48 (d, J = 4.7 Hz,
1H), 8.16 (d, J = 8.0 Hz, 1H), 7.88 (td, J = 7.7, 1.7 Hz, 1H), 7.32
(t, J = 8.0 Hz, 1H), 7.29−7.23 (m, 1H), 6.84 (d, J = 7.7 Hz, 1H), 6.74
(d, J = 8.4 Hz, 1H), 3.59 (s, 3H), 2.64 (s, 3H). 13C NMR δ: 165.3,
159.0, 149.2, 142.2, 136.7, 133.4, 129.7, 123.8, 123.5, 121.1, 110.3,
55.8, 19.7. MS (ESI) m/z: 122 (M+ − 126) (100), 248 (M+ + H), 280
(M+ + Na), 517 (2M+ + Na). HRMS: calcd for C13H14NO2S (M+ + H)
248.0739, found 248.0744.
2-(Biphenyl-2-ylsulfinyl)pyridine (3a). Compound 3a was
obtained from 2-(phenylsulfinyl)pyridine and phenylboronic acid
neopentylglycol ester following the general procedure, after purifi-
cation by flash chromatography (n-hexane−EtOAc 2:1), as a white
solid (yield 59%). Mp: 112−115 °C. 1H NMR δ: 8.50 (d, J = 4.5 Hz,
1H), 7.88−7.76 (m, 3H), 7.64−7.56 (m, 2H), 7.52−7.36 (m, 6H),
7.30−7.22 (m, 1H). 13C NMR δ: 165.7, 149.8, 143.1, 142.7, 138.2,
137.6, 131.2, 130.5, 130.4, 128.6, 128.1, 128.0, 126.4, 124.3, 120.1. MS
(EI) m/z: 279 (M+), 262 (M+ − 17) (100), 230 (M+ − 49), 186 (M+
− 93). HRMS: calcd for C17H13NOS (M+) 279.0718, found 279.0728.
2-[(4′-Methylbiphenyl-2-yl)sulfinyl]pyridine (4a). Compound
4a was obtained from 2-(phenylsulfinyl)pyridine and 5,5-dimethyl-2-
(p-tolyl)-1,3,2-dioxaborinane following the general procedure, after
purification by flash chromatography (n-hexane−EtOAc 2:1), as a
yellow solid (yield 72%). Mp: 74−76 °C. 1H NMR δ: 8.43 (d, J = 4.6,
1H), 7.79−7.67 (m, 3H), 7.47−7.07 (m, 8H), 2.32 (s, 3H). 13C NMR
δ: 165.7, 149.8, 143.0, 142.8, 138.2, 137.81, 137.6, 131.1, 130.9,
130.43, 128.7, 128.5, 128.0, 127.5, 126.4, 124.3, 120.3, 21.4. MS (EI)
2-[(4-Chloro-2-methylphenyl)sulfinyl]pyridine (2d). Com-
pound 2d was obtained from 2-[(4-chlorophenyl)sulfinyl]pyridine
and methylboronic acid following the general procedure, after
purification by flash chromatography (n-hexane−EtOAc 2:1), as a
1
white solid (yield 45%). Mp: 76−78 °C. H NMR δ: 8.49 (ddd, J =
4.7, 1.7, 0.9 Hz, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.89 (td, J = 7.7, 1.8 Hz,
1H), 7.71 (d, J = 8.4 Hz, 1H), 7.33−7.25 (m, 2H), 7.21 (d, J = 1.7 Hz,
1H), 2.65 (s, 3H). 13C NMR δ: 166.2, 149.7, 141.6, 139.3, 138.2,
137.1, 130.8, 127.2, 126.0, 124.6, 118.9, 19.3. MS (ESI) m/z: 126
(M+ − 125), 252 (M+ + H) (100), 274 (M+ + Na), 527 (2M+ + Na).
HRMS: calcd for C12H11ClNOS (M+ + H) 252.0244, found 252.0241.
Methyl 3-Methyl-4-[(2-pyridyl)sulfinyl]benzoate (2e). Com-
pound 2e was obtained from methyl 4-[(2-pyridyl)sulfinyl]benzoate
and methylboronic acid following the general procedure, after purifi-
cation by flash chromatography (n-hexane−EtOAc 2:1), as a white
1
solid (yield 39%). Mp: 118−120 °C. H NMR δ: 8.49 (ddd, J = 4.7,
1.7, 0.9 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.90−7.60 (m, 4H), 7.22
(ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 3.85 (s, 3H), 2.65 (s, 3H). 13C NMR δ:
166.2, 166.0, 149.6, 147.9, 138.2, 137.5, 132.3, 132.0, 127.8, 124.7,
124.3, 119.0, 52.3, 19.4. MS (ESI) m/z: 276 (M+ + H) (100), 298
(M+ + Na), 573 (2M+ + Na). HRMS: calcd for C14H14NO3S
(M+ + H) 276.0688, found 276.0699.
2-[(2,6-Dimethylphenyl)sulfinyl]pyridine (2f). Compound 2f
was obtained from 2-(m-tolylsulfinyl)pyridine and methylboronic acid
following the general procedure, after purification by flash chromato-
graphy (n-hexane−EtOAc 2:1), as a white solid (yield 47%). Mp:
1
72−74 °C. H NMR δ: 8.53 (ddd, J = 4.7, 1.7, 0.8 Hz, 1H), 8.06
(d, J = 7.9 Hz, 1H), 7.90 (td, J = 7.7, 1.7 Hz, 1H), 7.60 (s, 1H), 7.30
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The Journal of Organic Chemistry
Note
m/z: 293 (M+), 276 (M+ − 17) (100), 244 (M+ − 49), 186 (M+ −
107). HRMS: calcd for C18H15NOS (M+) 293.0874, found 293.0876
2-[(4′-Methoxybiphenyl-2-yl)sulfinyl]pyridine (5a). Com-
pound 5a was obtained from 2-(phenylsulfinyl)pyridine and 2-(4-
methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaborinane following the gen-
eral procedure, after purification by flash chromatography (n-hexane−
EtOAc 2:1), as a yellow solid (yield 47%). Mp: 162−165 °C. 1H NMR
δ: 8.50 (d, J = 4.5 Hz, 1H), 7.97−7.78 (m, 2H), 7.74 (d, J = 7.4, 1H),
7.54 (d, J = 8.6 Hz, 2H), 7.50−7.39 (m, 2H), 7.35 (d, J = 7.2, 1H),
7.30−7.22 (m, 1H), 6.97 (d, J = 8.6 Hz, 2H), 3.86 (s, 3H). 13C NMR
δ: 165.9, 159.6, 149.8, 143.1, 142.5, 137.7, 131.6, 131.2, 130.5, 128.3,
126.5, 124.3, 120.1, 113.6, 55.3. MS (EI) m/z: 309 (M+), 292 (M+ − 17)
(100), 260 (M+ − 49), 186 (M+ − 124). HRMS: calcd for C18H15NO2S
(M+) 309.3824, found 309.0830.
4′-Fluoro-3-methoxy-1,1′-biphenyl (9c).26 Compound 9c was
obtained from 2-[(4′-fluoro-5-methoxybiphenyl-2-yl)sulfinyl]pyridine
6c following the general procedure, after purification by flash
chromatography (n-hexane−EtOAc 3:1), as a yellow oil (yield 63%).
Analytical data are in accordance with those reported in the
literature.26 1H NMR δ: 7.58−7.53 (m, 2H), 7.41 (t, J = 7.6 Hz,
1H), 7.22−7.16 (m, 4H), 7.05 (dt, J = 7.5, 1.4 Hz, 1H), 3.81 (s, 3H).
3-Methylbiphenyl (10a).27 Compound 10a was obtained from
2-[(3′-methylbiphenyl]-2-yl)sulfinyl]pyridine 7a following the general
procedure, after purification by flash chromatography (n-hexane−
EtOAc 3:1), as a colorless oil (yield 91%). Analytical data are in
accordance with those from the literature.27 1H NMR δ: 7.52 (d, J =
7.3 Hz, 2H), 7.45−7.33 (m, 4H), 7.21−7.11 (m, 3H), 2.35 (s, 3H).
Synthesis of the Palladacycle (I). A mixture of substrate 1a
(406.0 mg, 2 mmol) and Pd(OAc)2 (448.0 mg, 2 mmol) in 1,2-
dichloroethane (2 mL) was stirred at 100 °C for 30 min before the
mixture was cooled down to room temperature. The reaction mixture
was filtered through a pad of Celite (washed with EtOAc), and the
filtrate was concentrated under reduced pressure. The residue was
crystallized from a mixture DCE/heptane to give the palladacycle I as a
yellow solid. Yield: 96%.
2-[(4′-Fluorobiphenyl-2-yl)sulfinyl]pyridine (6a). Compound
6a was obtained from 2-(phenylsulfinyl)pyridine and 2-(4-fluoro-
phenyl)-5,5-dimethyl-1,3,2-dioxaborinane following the general proce-
dure, after purification by flash chromatography (n-hexane−EtOAc
2:1), as a white solid (yield 62%). Mp: 107−109 °C. 1H NMR δ: 8.49
(d, J = 4.1 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.85 (td, J = 7.7, 1.6 Hz,
1H), 7.84−7.74 (m, 1H), 7.64−7.55 (m, 2H), 7.52−7.42 (m, 2H),
7.40−7.30 (m, 1H), 7.35−7.27 (m, 1H), 7.12 (t, J = 8.7 Hz, 2H). 13
C
Reaction of the Palladacycle (I) with MeB(OH)2. In a screw-
capped tube, dimeric palladacycle I (73.5 mg, 0.1 mmol), methyl-
boronic acid (23.8 mg, 0.4 mmol, 2 equiv according to Pd), and
p-benzoquinone (10.8 mg, 0.1 mmol, 0.5 equiv according to Pd)
were dissolved in tert-amyl alcohol (1 mL) under atmospheric air.
The reaction mixture was stirred at 100 °C for 20 h before it was
filtered through a pad of Celite (washed several times with EtOAc).
The filtrate was concentrated under reduced pressure, and the
NMR δ: 165.7, 149.8, 143.1, 141.7, 137.8, 132.3, 132.1, 131.3, 130.5,
128.8, 126.6, 124.4, 119.9, 115.3, 114.9. MS (EI) m/z: 297 (M+), 280
(M+ − 17) (100), 248 (M+ − 49), 186 (M+ − 111). HRMS calcd for
C17H12FNOS (M+) 297.0624, found 297.0612.
2-[(4′-Fluoro-5-methoxybiphenyl-2-yl)sulfinyl]pyridine
(6c). Compound 6c was obtained from 2-[(4-methoxyphenyl)-
sulfinyl]pyridine and 2-(4-fluorophenyl)-5,5-dimethyl-1,3,2-dioxabor-
inane following the general procedure, after purification by flash
chromatography (n-hexane−EtOAc 2:1), as a yellow solid (yield
65%). Mp: 141−144 °C. 1H NMR δ: 8.51 (d, J = 4.6 Hz, 1H), 7.98 (d,
J = 7.9 Hz, 1H), 7.92−7.81 (m, 1H), 7.73−7.55 (m, 3H), 7.12 (t, J =
8.7 Hz, 2H), 6.95 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 2.6 Hz, 1H), 3.82
(s, 3H). 13C NMR δ: 166.1, 161.3, 149.7, 144.0, 137.7, 132.2, 132.0,
129.1, 127.3, 124.5, 124.2, 119.8, 118.5, 115.4, 115.2, 114.9, 114.7,
55.5. MS (ESI) m/z: 202 (M+ − 125), 310 (M+ − 17), 328 (M+ + H)
(100), 350 (M+ + Na), 677 (2M+ + Na). HRMS: calcd for
C18H15FNO2S (M+ + H) 328.0802, found 328.0802.
2-[(3′-Methyl-2-yl)sulfinyl]pyridine (7a). Compound 7a was
obtained from 2-(phenylsulfinyl)pyridine and 5,5-dimethyl-2-(m-
tolyl)-1,3,2-dioxaborinane following the general procedure, after
purification by flash chromatography (n-hexane−EtOAc 2:1), as a
yellow solid (yield 70%). Mp: 73−76 °C. 1H NMR δ: 8.50 (dt, J = 4.7,
1.4 Hz, 1H), 7.86−7.73 (m, 3H), 7.55−7.17 (m, 8H), 2.40 (s, 3H).
13C NMR δ: 165.7, 149.8, 143.0, 142.8, 138.2, 137.8, 137.5, 131.1,
1
conversion was determined to be >98% by H NMR on the crude
reaction mixture.
Intermolecular Competition Experiment. In a screw-capped
tube, 2-[(4-chlorophenyl]sulfinyl)pyridine 1d (11.8 mg, 0.05 mmol),
2-[(4-methoxyphenyl)sulfinyl]pyridine 1c (11.6 mg, 0.05 mmol),
methylboronic acid (11.9 mg, 0.2 mmol), Pd(OAc)2 (2.2 mg, 10 mol
%), p-benzoquinone (5.4 mg, 0.05 mmol), and AgOAc (49.9 mg,
0.3 mmol) were dissolved in tert-amyl alcohol (1 mL) under
atmospheric air. The reaction mixture was stirred at 100 °C for 2 h
before it was filtered through a pad of Celite (washed several times
with EtOAc). The filtrate was concentrated under reduced pressure,
and the residue was analyzed by 1H NMR. The corresponding
products 2d and 2c were obtained with 5% and 26% conversion,
respectively (kCl/kOMe= 0.19), along with the starting substrates.
Synthesis of 2-[(2-Deuteriophenyl)sulfinyl]pyridine (1a-D).
To a solution of 2-[(2-bromophenyl)thio]pyridine (115.0 mg, 0.41
mmol) in dry THF (2 mL), cooled to −78 °C and under nitrogen
atmosphere, was added dropwise a 1.6 M solution of BuLi in hexanes
(0.51 mL, 0.81 mmol). The reaction mixture was stirred at −78 °C for
1 h before it was quenched with MeOD (1 mL). The reaction was
allowed to reach room temperature and stirred for an extra 20 min.
The reaction mixture was then diluted with H2O (1 mL) and extracted
with EtOAc (3 × 5 mL). The combined organic phase was washed
with brine, dried (MgSO4) and concentrated under reduced pressure.
The residue was purified by flash chromatography (n-hexane−EtOAc
4:1) to give the deuterated product as a colorless oil. Yield: 92%. This
product was oxidized in the presence of m-chloroperbenzoic acid
(1 equiv) to give 2-[(2-deuterophenyl)sulfinyl]pyridine 1a-D.14a 1H
NMR δ: 8.55 (d, J = 4.1 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.87 (dt,
J = 7.8, 1.6 Hz, 1H), 7.83−7.77 (m, 1H), 7.50−7.38 (m, 3H), 7.29
(ddd, J = 7.4, 4.7, 0.9 Hz, 1H).
130.9, 130.4, 128.7, 128.5, 128.0, 127.5, 126.4, 124.3, 120.2, 21.4. MS
(EI) m/z: 293 (M+), 276 (M+ − 17) (100), 244 (M+ − 49), 186
(M+ − 107). HRMS: calcd for C18H15NOS (M+) 293.0874, found
293.0865.
2-[(3′-Chlorobiphenyl-2-yl)sulfinyl]pyridine (8a). Compound
8a was obtained from 2-(phenylsulfinyl)pyridine and 2-(3-chloro-
phenyl)-5,5-dimethyl-1,3,2-dioxaborinane following the general proce-
dure, after purification by flash chromatography (n-hexane−EtOAc
2:1), as a yellow oil (yield 40%). 1H NMR δ: 8.53 (d, J = 4.6 Hz, 1H),
7.98−7.79 (m, 3H), 7.64−7.22 (m, 8H). 13C NMR δ: 165.7, 149.8,
143.2, 141.2, 139.9, 137.8, 134.0, 131.3, 130.4, 129.3, 129.1, 128.7,
128.2, 126.5, 124.9, 124.4, 119.9. MS (EI) m/z: 313 (M+), 296 (M+ −
17). 264 (M+ − 49), 186 (M+ − 127) (100). HRMS: calcd for
C17H12ClNOS (M+) 313.0328, found 313.0319.
General Procedure for the Desulfinylation. To a solution of
aryl 2-sulfinylpyridine (0.1 mmol) in dry THF (1 mL), cooled to
−98 °C and under nitrogen atmosphere, was added a 1.6 M solution
of BuLi in hexanes (0.125 mL, 0.2 mmol). The reaction mixture was
stirred at −98 °C for 45 min before a saturated aqueous solution of
NH4Cl (5 mL) was added. The two phases were separated, and the
aqueous phase was extracted with AcOEt (×3). The combined organic
phase was dried (MgSO4), and the solvent was evaporated under
reduced pressure. The residue was purified by flash chromatography to
give the corresponding biaryl products.
Intramolecular Kinetic Isotope Effect. In a screw-capped tube,
2-[(2-deuterophenyl)sulfinyl]pyridine 1a-D (20.3 mg, 0.1 mmol),
Pd(OAc)2 (2.2 mg, 0.01 mmol), p-benzoquinone (5.3 mg, 0.05 mmol),
AgOAc (49.9 mg, 0.3 mmol), and methylboronic acid (11.9 mg,
0.2 mmol) were dissolved in tert-amyl alcohol (1 mL). The reaction
mixture was stirred at 100 °C for 2 h before it was filtered through
a pad of Celite (washed several times with EtOAc). The filtrate was
1
concentrated under reduced pressure, and H NMR analysis of the
crude mixture showed a kH/kD value of 1.1.
9529
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The Journal of Organic Chemistry
Note
Chem. Soc. 2008, 130, 7190. (b) Pastine, S. J.; Gribkov, D. V.;
Sames, D. J. Am. Chem. Soc. 2006, 128, 14220. For C−H arylation of
cyclic enamides with arylboronic acids, see: (c) Z, H.; Chung, W.-J.;
Xu, Y.-H.; Loh, T.-P. Chem. Commun. 2009, 3472.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13 C NMR spectra of new compounds and a
X-ray crystallographic view for complex I. This material is
available free of charge via the Internet at http://pubs.acs.org.
́
(14) For C−H olefination, see: (a) Garcıa-Rubia, A.; Fernan
́
dez-
́
Ibanez, M. A.; Go
mez Arrayas
́
, R.; Carretero, J. C. Chem.Eur. J.
̃
2011, 17, 3567. For the use of the related (2-pyridyl)sulfonyl group in
C−H functionalization of nitrogen-containing arenes and hetero-
AUTHOR INFORMATION
Corresponding Authors
*(R.G.A.) E-mail: ramon.gomez@uam.es.
*(M.A.F.-I.) E-mail: tati.fernandez@uam.es.
*(J.C.C.) E-mail: juancarlos.carretero@uam.es.
■
́
́
arenes, see: (b) Garcıa-Rubia, A.; Gómez Arrayas, R.; Carretero, J. C.
́
Angew. Chem., Int. Ed. 2009, 48, 6511. (c) Garcıa-Rubia, A.; Urones,
B.; Gomez Arrayas
́
́
, R.; Carretero, J. C. Chem.Eur. J. 2010, 16, 9676.
(15) For C−H acetoxylation, see: (a) Richter, H.; Beckendorf, S.;
́
Garcıa Mancheno, O. Adv. Synth. Catal. 2011, 353, 295. For C−H
̃
olefination and dehydrogenative arylation: (b) Yu, M.; Liang, Z.;
Wang, Y.; Zhang, Y. J. Org. Chem. 2011, 76, 4987.
(16) Recently, a PdII-catalyzed double C−H activation directed by a
sulfoxide has been reported: Samanta, R.; Antonchick, A. P. Angew.
Chem., Int. Ed. 2011, 50, 5217.
(17) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 9651.
(18) (a) Uenishi, J.-i.; Beau, J.-M.; Armstrong, R. W.; Kishi, Y. J. Am.
Chem. Soc. 1987, 109, 4756. (b) Zou, G.; Reddy, Y. K.; Falck, J. R.
Tetrahedron Lett. 2001, 42, 7213.
(19) Similar conversion was found after a longer reaction time (24 h
instead of 20 h).
́
(20) (a) Hassan, J.; Sevignon, M.; Cozzi, C.; Shulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359. (b) Corbet, J. P.; Mignani, G. Chem. Rev.
2006, 106, 2651.
ACKNOWLEDGMENTS
We thank the Ministerio de Ciencia e Innovacio
CTQ2009-07791) and the Consejerıa de Educacio
Comunidad de Madrid (programme AVANCAT, S2009/PPQ-
1634) for financial support. J.A.R, A.G.-R., and M.A.F.-I. thank
the MICINN for predoctoral fellowships (J.A.R, A.G.-R.) and a
Juan de la Cierva contract (M.A.F.-I.). Johnson Matthey PLC
is gratefully acknowledged for generous loans of PdCl2 and
Pd(OAc)2.
■
́
́
́
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9530
dx.doi.org/10.1021/jo2018137|J. Org. Chem. 2011, 76, 9525−9530