Palladium Catalyzed Monoselective α-Arylation of Sulfones and Sulfonamides with 2,2,6,6-Tetramethylpiperidine·ZnCl·LiCl Base and Aryl Bromides

Article abstract of DOI:10.1021/acs.joc.6b01062

A palladium catalyzed Negishi-type α-arylation of sulfones and sulfonamides with a broad range of aryl bromides has been developed. The substrates are selectively metalated in situ with tmp·ZnCl·LiCl base (tmp: 2,2,6,6-tetramethylpiperidine) and cross-coupled in the presence of a catalyst system that is generated from Pd(dba)₂ and XPhos. Electron-deficient, electron-rich, and heterocyclic aryl bromides have been successfully cross-coupled, and sensitive functional groups are well tolerated. Simple aryl bromides are converted overnight at 60 °C in THF while heteroaryl bromides are efficiently coupled within 2 h at 130 °C in a microwave reactor. The desired monoarylated α-branched benzyl sulfones and sulfonamides were obtained in good yields, and overarylation was not detected. The procedure is ideal for late stage functionalization in parallel medicinal chemistry.

Full text of DOI:10.1021/acs.joc.6b01062

Article
pubs.acs.org/joc
Palladium Catalyzed Monoselective α‑Arylation of Sulfones and
Sulfonamides with 2,2,6,6-Tetramethylpiperidine·ZnCl·LiCl Base and
Aryl Bromides
Thomas Knauber* and Joseph Tucker
Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: A palladium catalyzed Negishi-type α-arylation of
sulfones and sulfonamides with a broad range of aryl bromides has
been developed. The substrates are selectively metalated in situ
with tmp·ZnCl·LiCl base (tmp: 2,2,6,6-tetramethylpiperidine) and
cross-coupled in the presence of a catalyst system that is generated
from Pd(dba)2 and XPhos. Electron-deficient, electron-rich, and heterocyclic aryl bromides have been successfully cross-coupled,
and sensitive functional groups are well tolerated. Simple aryl bromides are converted overnight at 60 °C in THF while
heteroaryl bromides are efficiently coupled within 2 h at 130 °C in a microwave reactor. The desired monoarylated α-branched
benzyl sulfones and sulfonamides were obtained in good yields, and overarylation was not detected. The procedure is ideal for
late stage functionalization in parallel medicinal chemistry.
decompose upon storage.11 Activations for the reaction with
INTRODUCTION
■
amines by the use of milder leaving groups such as electron-
Sulfones and sulfonamides are important structural motifs in
deficient phenolates12 or in situ activation with Ph3PO/
biologically active compounds.1 In one of our medicinal
13
(TfO)2 also failed, and rearrangement to the corresponding
chemistry projects, we set out to explore the structure−activity
relationships (SAR)2 of a series of α-branched heterocyclic
olefinic sulfonamide was observed.
Significant research by the Willis group14 and others15
benzyl sulfone and sulfonamide motifs on a heteroaromatic
core (Scheme 1).
We aimed for the structural diversification to be performed in
one high-yielding late step with a diverse set of starting
introduced sulfur dioxide adduct reagents for the synthesis of
sulfones and sulfonamides, but general applicable syntheses of
α-branched heterocyclic derivatives in compound libraries are
still scarce.
materials and for the method to be transferable to the parallel
Palladium-catalyzed α-arylations of easily accessible sulfones
syntheses of compound libraries. Traditional methods including
alkylations,3 Cu-catalyzed arylations,4 Chan−Lam type aryla-
and sulfonamides caught our interest upon reviewing the
chemical literature.16 In general, the α-arylations (Scheme 3)
tions,5 and aminations with N-electrophiles rely on the use of
start with deprotonation of the sulfone or sulfonamide substrate
sulfinate salts as key intermediates which often have to be
custom-made following alkylation6 or oxidation7 procedures.
by a strong base (pKa = 29 in DMSO for methyl phenyl
sulfone).17 The in situ generated C-nucleophile coordinates to a
Initially, we accessed our target molecules by following the
traditional sequence depicted in Scheme 1. Heterocyclic benzyl
alcohols were transferred into the corresponding sodium
sulfinates by an Appel reaction, alkylation with sodium 1-
PdII−aryl complex, formed by oxidative addition of a Pd0-
complex to an aryl halide. Reductive elimination liberates the
desired product and closes the catalytic cycle.
The method was pioneered by the group of Beletskaya in
methyl 3-sulfinopropanoate (SMOPS), and elimination with
2002.16a Subsequently, the groups of Koning16b and Oshima16d
focused on the coupling of sulfones while the group of
Northrup16c reported on the arylation of activated sulfamoyl
acetates with subsequent multistep diversification of the
coupling products. The group of Walsh developed an efficient
arylation of alkyl aryl sulfones in the presence of Pd(OAc)2 and
the N-(dicyclohexylphosphino)-2-(2′-tolyl)-indole ligand.16g,h
This phosphine is commercially available, but we observed slow
oxidation and hydrolysis of the labile P−N bond over time.
Consequently, we stepped back from pursuing this procedure.
A Pd(OAc)2/XPhos catalyzed arylation of phenyl methyl
sodium methoxide.6 The sulfinate was reacted with hydroxyl-
amine-O-sulfonic acid,6 and the corresponding sulfonamide was
coupled with the heteroaromatic core.8 As a consequence, the
overall yields are relatively low, and the processes are too step-
intensive for library syntheses and thus did not meet our initial
requirements. In particular, the synthesis of α-branched
heterocyclic benzyl sulfonamides proved to be challenging, as
the corresponding sulfonyl chlorides readily decompose into
the corresponding benzyl chlorides with extrusion of sulfur
dioxide (Scheme 2).9 We observed decomposition of substrate
1 upon activation with thionyl chloride followed by an oxidative
rearrangement.10 The corresponding unsaturated side product
3 was obtained exclusively (Scheme 2).9 In addition, free α-
branched benzyl sulfonic acids are sensitive and gradually
Received: May 6, 2016
© XXXX American Chemical Society
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Scheme 1. Synthetic Strategies to α-Branched Heterocyclic Benzyl Sulfones and Sulfonamides
Scheme 2. Decomposition of Aliphatic Sulfonyl Chlorides
Scheme 3. Mechanistic Concept
Scheme 4. Selective α-Arylation of Sultams
Negishi coupling chemistry by an operationally simple means
without requiring prolonged deprotonation and salt metathesis
steps at cryogenic temperatures, which substantially increase
the operational difficulty when applied to parallel synthesis.
With this in mind, we envisaged that a general Pd-catalyzed
Negishi-type α-arylation procedure would enable the late stage
diversification of acyclic α-branched sulfones and sulfonamides.
The use of tmp·ZnCl·LiCl promises high monoselectivity for
the arylation, relative to previous methods, and would allow a
method suited for compound library syntheses in parallel. We
also aimed to broaden the scope to aryl and heteroaryl
bromides which are available in considerably broader structural
diversity than aryl iodides.
sulfone was developed by Nambo and Crudden as the first step
in their modular synthesis of triarylmethanes.16i Overarylation
was successful minimized to less than 1% by using 3 equiv of
the sulfone, LiOtBu base, and cyclopentyl methyl ether
as solvent. Zhou and co-workers reported the first method ap-
plicable to the arylation of both sulfones and sulfonamides.16e,f
The method exhibits a broad scope, but overarylation was
reported in some cases. The substrates are deprotonated,
converted into the corresponding Negishi reagents at cryogenic
temperatures, and subsequently cross-coupled with aryl halides.
Overall, the procedure did not fully meet our requirements for
applications in parallel medicinal chemistry, and we finally
stopped pursuing this method after we were unable to
reproduce the reaction with our target compounds. Recently,
RESULTS AND DISCUSSION
■
We chose phenyl methyl sulfone (4a) and 4-bromotoluene
(5a) as model substrates, which were reacted in the presence of
tmp·ZnCl·LiCl and Pd(dba)2 in anhydrous THF at 60 °C
(Table 1). The base is commercially available or can be
prepared following the literature procedures.20 The desired
cross-coupling product 6aa was not detected with triphenyl-
phosphine (Table 1, entry 1), with tri(2-furyl)phosphine
(Table 1, entry 2), or in the absence of a ligand. Further
experiments demonstrated that bulky, electron-rich, mono-
dentate phosphines (Table 1, entries 1−6) are competent
ligands for the arylation. The use of DavePhos (Table 1, entry
3) and RuPhos (Table 1, entry 4), which is highly efficient in
́
Rene and colleagues developed the α-arylation of cyclic
sulfonamides (sultams) with aryl iodides in the presence of a
Pd/RuPhos catalyst and Knochel’s tmp·ZnCl·LiCl18 base (tmp:
2,2,6,6-tetramethylpiperidine) (Scheme 4) which gave high
selectivity for the monoarylated products.19
Unfortunately for our purpose, the group focused their study
exclusively on sultams and aryl iodides as starting materials.
However, they demonstrated that the use of tmp·ZnCl·LiCl
could afford a competent organozinc species to engage in
Rene’
́
s procedure,19 resulted in moderate conversion of a 38%
and 45% yield, respectively. Full conversion of the starting
materials was detected with XPhos (Table 1, entry 5) and
BrettPhos (Table 1, entry 6).21 We decided to carry on with the
B
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a
Table 1. Optimization of the Reaction Conditions
a
a
Ar
P-ligand [mol %]
Base
T [°C]
60
t [h]
6 [%]
7 [%]
1
4-Tol
4-Tol
4-Tol
4-Tol
4-Tol
4-Tol
4-Tol
4-Tol
4-Tol
4-Tol
4-Tol
4-Tol
4-Tol
4-Tol
3-Py
PPh3 (2)
tmp·ZnCl·LiCl
tmp·ZnCl·LiCl
tmp·ZnCl·LiCl
tmp·ZnCl·LiCl
tmp·ZnCl·LiCl
tmp·ZnCl·LiCl
tmp·ZnCl·LiCl
tmp·ZnCl·LiCl
LiOtBu
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
96
16
2
0
0
0
2
P(2-furyl)3 (2)
DavePhos (2)
RuPhos (2)
XPhos (2)
60
0
3
60
38
45
0
4
5a
60
0
60
99 (isol.)
0
0
6
BrettPhos (2)
Xantphos (2)
rac. BINAP (2)
XPhos (2)
60
99
7
60
36
0
8
60
0
0
9
60
0
0
b
b
b
b
b
10
11
12
13
14
15
16
17
18
19
20
XPhos (10)
XPhos (10)
XPhos (10)
XPhos (10)
XPhos (10)
XPhos (2)
LiOtBu
60
26
10
3
NaOtBu
60
11
KOtBu
60
0
0
LiHMDS
60
0
0
LiOtBu
120
29
12
0
tmp·ZnCl·LiCl
tmp·ZnCl·LiCl
tmp·ZnCl·LiCl
tmp·ZnCl·LiCl
tmp·ZnCl·LiCl
tmp·ZnCl·LiCl
60
traces
traces
55
3-Py
XPhos (2)
60
0
3-Py
XPhos (2)
80
0
3-Py
XPhos (2)
130 (μW)
130 (μW)
150 (μW)
24
0
3-Py
XPhos (10)
XPhos (10)
2
72 (isol.)
34
0
3-Py
1
0
a
Methyl-(4-tolyl)-sulfone (4a) (0.25 mmol, 1.0 equiv), 4-bromotoluene (5a) (0.275 mmol, 1.1 equiv) or 3-bromopyridine (5b) (0.275 mmol, 1.1
equiv), base (0.625 mmol, 2.5 equiv), Pd(dba)2 (equimolar to the ligand), phosphine ligand, anhydrous THF (0.07 M). Yields were determined by
b
1H NMR with mesitylene as internal standard unless noted otherwise. Anhydrous 1,4-dioxane (0.07 M) was used as solvent. DavePhos: 2-
dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl. RuPhos: 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl. XPhos: 2-dicyclohexyl-
phosphino-2′,4′,6′-triisopropylbiphenyl. BrettPhos: 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl. Xanthphos: 4,5-
bis(diphenylphosphino)-9,9-dimethyl-xanthene. BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene.
somewhat cheaper and more common XPhos ligand. The
addition of bidentate ligands such as Xantphos (Table 1, entry
7) and racemic BINAP (Table 1, entry 8) reduced the yield of
the desired coupling product to 36% and 0%, respectively.
As anticipated, the reactions were highly monoselective and
the overarylated side product 7aa was not detected (Table 1
entries 1−8). Having identified an ideal procedure for the
coupling of the model substrates we set out to benchmark the
conditions against more commonly used bases, and we chose
lithium, sodium, and potassium tert-butylate as well as lithium
hexamethyldisilazane which have been successfully employed
earlier.16 However, the desired product 6aa was not detected
with these bases in tetrahydrofuran (Table 1, entry 9) even with
10 mol % of the catalyst system. Low quantities of 6aa along
with diarylated side product 7aa were obtained in 1,4-dioxane
(Table 1, entries 10 and 11) with LiOtBu giving the best result
of 26% of the desired product 6aa along with 10% of the side
product 7aa (Table 1, entry 10). Sodium tert-butylate gave
product 6aa in 11% yield along with 3% side product (Table 1,
entry 11), while no conversion was observed with potassium
tert-butylate (Table 1, entry 12) and the use of LiHMDS
resulted in decomposition of the substrates (Table 1, entry 13).
A slight step-up in yield was observed at 120 °C with LiOtBu
which produced 20% of 6aa along with 12% of the undesired
side product 7aa (Table 1, entry 14). These results clearly
demonstrate the synthetic benefits of using the more elaborate
tmp·ZnCl·LiCl over commonly used bases which allows
relatively mild reaction conditions and excellent monoselectiv-
ity.
Encouraged, we turned our attention to the pharmaceutically
relevant coupling of nitrogen containing heteroaryl bromides
which are often challenging to convert because of coordination
of the nitrogen atom to the palladium catalyst.22 We chose 3-
bromopyridine (5b) as a model substrate, which gave traces of
the desired coupling product 6ab under the previously
optimized reaction conditions (Table 1, entry 15).
Extending the reaction time to 96 h did not improve the
yield (Table 1, entry 16). However, a boost in yield (55%) was
obtained by heating the reaction mixture in a sealed vial at 80
°C (Table 1, entry 17). We opted to conduct the coupling
reactions in a microwave reactor which offers safer heating and
emergency shut-off prevents dangerous overpressurization of
the vessel. In our first microwave experiment, the desired
product was detected in 24% yield after 2 h of irradiation at 130
°C (Table 1, entry 18). The starting materials were recovered,
and we hypothesized that the active palladium catalyst might
have decomposed prematurely. Increasing the Pd(dba)2/XPhos
loading to 10 mol % resulted in the isolation of the desired
product in 72% yield (Table 1, entry 19). Further increasing the
reaction temperatures resulted in significant decomposition,
and the desired product was detected in only 34% at 150 °C
along with undefined side products (Table 1, entry 20).
With the optimized procedures, using both conventional and
microwave heating, in hand, we set out to investigate the scope
of the α-arylation of sulfones with aryl bromides (Scheme 5). In
general, higher yields were obtained with the microwave
protocol in comparison to the thermal procedure. Electron-rich
(5c and 5d), electron-deficient (5i, 5j, and 5k), and sterically
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a
Scheme 5. Coupling of Sulfones with Aryl Bromides
a
Sulfone (0.5 mmol, 1.0 equiv), aryl bromide (0.55 mmol, 1.1 equiv), tmp·ZnCl·LiCl-solution (0.25 M in THF, 5 mL, 2.5 equiv) (tmp: 2,2,6,6-
tetramethylpiperidine), anhydrous tetrahydrofuran (2 mL). Thermal heating: Pd(dba)2 (2 mol %), XPhos (2 mol %), 60 °C, 16 h. Microwave
1
protocol: Pd(dba)2 (10 mol %), XPhos (10 mol %), 130 °C, 2 h. Yields in parentheses are determined by H NMR with mesitylene as internal
standard. XPhos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.
demanding aryl bromides (5f and 5g) were smoothly converted
to give the desired monocoupled products (6). Furthermore,
functional groups such as ester (5i), nitrile (5j), nitro (5k), and
even formyl (5l) groups were well tolerated.
1-Bromo-4-chlorobenzene (5h) was selectively function-
alized at the C−Br bond which leaves the C−Cl bond as an
anchor for further functionalization. The result also excludes
aryl chlorides as substrates. A broad range of pharmaceutically
relevant heterocyclic aryl bromides (5m−5x) was successfully
cross-coupled with the optimized procedure. High yields were
obtained for most 3-bromopyridines (5b and 5o−5s) or
azaindoles (5v). The five-membered heterocycles 3-bromofur-
ane (5m) and 2-bromothiophene (5n) were converted in
moderate yields of 51% and 31% respectively. We were pleased
that even highly challenging but pharmaceutically impactful
heterocycles were successfully converted albeit in lower yields.
However, the method provides broad structural diversity in
compound libraries which is crucial for the elucidation of
structure−activity relationships within the drug discovery
process. 2-Bromopyridines (5t and 5u) were converted, and
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a
Scheme 6. α-Arylation of Sulfonamides
a
Sulfonamide (0.5 mmol, 1.0 equiv), aryl bromide (0.55 mmol, 1.1 equiv), Pd(dba)2 (10 mol %), XPhos (10 mol %), tmp·ZnCl·LiCl-solution (0.25
M in THF, 5 mL, 2.5 equiv) (tmp: 2,2,6,6-tetramethylpiperidine), anhydrous tetrahydrofuran (2 mL), 130 °C in microwave reactor, 2 h. XPhos: 2-
dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.
the corresponding products 6at and 6au were obtained in 18%
and 24%. 5-Bromopyrimidine (5w) yielded the desired product
6aw in 10% yield, and even 4-bromo-N-methylpyrazole (5x)
gave the corresponding product in 21% yield.
reacted with 4-bromotoluene (9a). The N−H bond of 8c was
protected with an SEM group to prevent deprotonation by
tmp·ZnCl·LiCl, and product 10ca was obtained in 65% yield.
Product 10da was isolated in moderate 32% yield, but no side
products were detected in the reaction mixture.
We then turned our attention to the sulfone coupling
partners. Electron-rich (4b) and electron-deficient (4d) aryl
methyl sulfones were successfully coupled with 4-bromotoluene
(4a). Dimethyl sulfone (4g) was exclusively monoarylated, and
the product 6ga was isolated in near quantitative yield.
Furthermore, tolyl ethyl sulfone (4e) was coupled in 81%
yield. Products that could arise from β-hydride elimination were
not detected, and the crude reaction mixture consisted of the
desired product and traces of both substrates. Increasing the
steric bulk on the sulfone shut down the cross-coupling
completely, and p-tolyl isopropyl sulfone (4f) was fully
recovered. We hypothesize that this steric sensitivity is likely
the reason for the high monoselectivity of the process, and the
corresponding monoarylated products were obtained exclu-
sively for all tested substrates.
CONCLUSION
■
A Pd/XPhos-catalyzed Negishi-type α-arylation of easily
accessible acyclic sulfones and sulfonamides with aryl bromides
in the presence of tmp·ZnCl·LiCl has been developed. The
arylation reaction has a broad scope, and the desired α-
branched products have been obtained in good yields and
excellent monoselectivities. This procedure marks an effective
strategy to access α-substitued benzylic sulfonamides, for which
the corresponding sulfonyl chlorides are unstable. The
operationally simple procedure is ideal for the execution of
compound libraries and enabled us to explore structure−
activity relationships rapidly which were otherwise inaccessible
in ongoing drug discovery projects.
Having established an efficient procedure for the α-
functionalization of sulfones, we continued our investigation
with the arylation of sulfonamides (Scheme 6). The substrates
(8a−8d) were prepared by sulfonylation of the corresponding
amines with inexpensive methanesulfonyl chloride or ethane-
sulfonyl chloride. The sulfonamides (8a−d) were successfully
cross-coupled with a set of aryl bromides (9a−g). These results
illustrate our alternate synthetic strategy to access α-branched
benzylic sulfonamides which circumvents the chemical
instability observed with the corresponding sulfonyl chlorides.
The cross-couplings were performed in a microwave reactor,
and the desired α-branched products (10) were obtained in
good yields. Electron-rich (9b), electron deficient (9c−d), and
heterocyclic aryl bromides (9e−g) were smoothly converted,
and the reaction has a similar scope to the arylation of sulfones
(Scheme 5). Finally, we turned our attention to the
sulfonamide coupling partner. The amides of aliphatic (8a
and 8b) and aromatic amines (8c and 8d) were successfully
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all reagents were
obtained from commercial suppliers and used without further
purification. Anhydrous solvents were purchased from Acros
(AcroSeal) or EMD Chemicals (DriSolv) and used as received. Zinc
chloride solution (0.5 M) in tetrahydrofuran, p-tolyl sulfinate, and n-
butyl lithium solution (2.5 M in hexanes) were purchased from Aldrich
and used as received. 2,2,6,6-Tetramethylpiperidinylzinc chloride
lithium chloride complex (tmp·ZnCl·LiCl) is commercially available
from Rockwood Lithium Inc. or can be prepared following the
literature-known procedures.18 Reactions were performed in regular
glassware under a nitrogen atmosphere. Solid materials were added
under air, and the reaction vessel was closed, evacuated for 5 min, and
refilled with dry nitrogen (3 purge cycles). Analytical thin-layer
chromatography was performed with precoated silica gel 60 F254 glass
plates with a 250 μm layer thickness. The spots were visualized under
UV irradiation (λ = 254 nM) and KMnO4 stains. Reactions under
microwave irradiation were performed in a Biotage Initiator microwave
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reactor using designated glassware and crimp-top septa. The
temperature was measured with an IR-sensor on the outside of the
reaction vial. Isolations and purifications were accomplished by
medium performance liquid chromatography (MPLC) with heptane
and ethyl acetate eluents and prepacked silica gel cartridges (12 g silica
and 24 g silica). Proton (1H NMR), fluorine (19F NMR), and carbon
(13C{1H}NMR) nuclear magnetic spectroscopy data were recorded
on 300 or 400 MHz spectrometers. Carbon spectra are proton
decoupled. Chemical shifts are reported in ppm (δ) and referenced to
the deuterated solvent residual peak. The obtained data are reported
with s = singlet, d = doublet, t = triplet, q = quartet, m = multiple and
br = broad signal. Coupling constants are given in Hz. GC-MS data
were acquired with scanning from 50 to 550 Da. An HP-1 column (12
m × 0.2 mm × 0.33 μm) with helium carrier gas was used. Samples for
high resolution mass spectrometry (HRMS) were separated on a
UPLC system and analyzed by TOF mass spectrometery in positive
electrospray mode. The recorded spectra were automatically lockmass
corrected, and the mass accuracy for all observed isotopes was
calculated against the theoretical ion mass derived from the chemical
formula. IR spectra of neat liquid and solid samples were recorded on
an FTIR spectrometer with a diamond ATR scanning from 4000 to
500 nm. Frequencies are reported in cm−1.
General Procedure for the Negishi Arylation of Sulfones
and Sulfonamides (Method A). The corresponding sulfone or
sulfonamide (1.00 equiv), the aryl bromide (1.10 equiv, if solid),
bis(dibenzylideneacetone)palladium (2.00 mol %), and 2-dicyclohexyl-
phosphino-2′,4′,6′-triiso-propylbiphenyl (XPhos, 2.0 mol %) were
weighed in a reaction vial, capped, evacuated, and refilled with nitrogen
(3 purge cycles, 5 min each). Anhydrous tetrahydrofuran (4 mL/
mmol) and the aryl bromide (1.10 equiv, if liquid) were added, and the
resulting dark solution was stirred for 10 min at room temperature. A
solution of 2,2,6,6-tetramethylpiperidinylzinc chloride lithium chloride
complex (tmp·ZnCl·LiCl, 0.25 M in tetrahydrofuran, 2.50 equiv) was
added, and the resulting bright orange-brown solution was heated at
60 °C for 16 h. After cooling to room temperature, the brown reaction
mixture was quenched with diluted sodium bicarbonate solution and
extracted with ethyl acetate (3 × 20 mL). The combined organic
extracts were washed with brine, dried with sodium sulfate, filtered,
and concentrated. The remaining crude mixture purified by column
chromatography (silica gel, heptane/ethyl acetate gradient).
General Procedure for the Negishi Arylation under Micro-
wave Irradiation (Method B). The corresponding sulfone or
sulfonamide (1.00 equiv), the aryl bromide (1.2 equiv, if solid),
bis(dibenzylideneacetone)palladium (10.0 mol %), and 2-dicyclohexyl-
phosphino-2′,4′,6′-triiso-propylbiphenyl (XPhos, 10.0 mol %) were
weighed in a microwave reaction vial, capped, evacuated, and refilled
with nitrogen (3 purge cyles, 5 min each). Anhydrous tetrahydrofuran
(4 mL/mmol) and the aryl bromide (1.20 equiv, if liquid) were added,
and the resulting dark solution was stirred for 10 min at room
temperature. A solution 2,2,6,6-tetramethylpiperdinylzinc chloride
lithium chloride complex (tmp·ZnCl·LiCl, 0.25 M in tetrahydrofuran,
2.50 equiv) was added, and the crimp cap was replaced under a stream
of nitrogen. The bright orange-brown reaction mixture was placed in
the microwave reactor, prestirred for 5 s, and heated at 130 °C for 2 h.
After cooling to room temperature, the brown reaction mixture was
quenched with diluted sodium bicarbonate solution and extracted with
ethyl acetate (3 × 20 mL). The combined organic extracts were
washed with brine, dried with sodium sulfate, filtered, and
concentrated. The remaining crude mixture was purified by column
chromatography (silica gel, heptane/ethyl acetate gradient).
Preparation of Starting Materials. 5-Bromo-N-methyl-7-
azaindole (5v and 9g) [CAS: 183208-22-2]. 5-Bromo-7-azaindole
(1.00 g, 5.08 mmol) and sodium hydride (60% dispersion in mineral
oil, 244 mg, 5.58 mmol) were weighed in a 100 mL round-bottom
flask with septa, evacuated, and refilled with nitrogen (3 purge cycles).
The mixture was suspended in anhydrous tetrahydrofuran and stirred
at room temperature for 2 h. Iodomethane (792 mg, 5.58 mmol, 348
μL) was added, and the resulting mixture was stirred for 16 h at room
temperature. The reaction mixture was quenched with methanol (2
mL) and concentrated. The remaining residue was dissolved in ethyl
acetate (30 mL) and washed with saturated aqueous sodium
bicarbonate solution (20 mL).The aqueous layer was re-extracted
with ethyl acetate (2 × 20 mL). The combined organic layers were
washed with brine, dried with sodium sulfate, filtered, and
concentrated. The remaining crude was purified by flash chromatog-
raphy (silica gel, n-heptane/ethyl acetate gradient). The desired
product (898 mg, 4.25 mmol, 84%) was obtained as a colorless solid.
1H NMR (400 MHz, CDCl3) δ = 3.88 (s, 3 H), 6.40 (d, J = 3.51 Hz, 1
H), 7.19 (d, J = 3.51 Hz, 1 H), 8.02 (d, J = 2.34 Hz, 1 H), 8.35 (d, J =
2.34 Hz, 1 H) ppm; 13C{1H}NMR (100 MHz, CDCl3) δ = 31.4, 98.9,
111.5, 122.0, 130.4, 130. 7, 143.3, 146.2 ppm; MS (EI): m/z (%) =
211 [M]+ (100), 184 (5), 157 (2), 130 (35), 103 (20), 84 (15); IR: υ
= 2920 (w), 1512 (s), 1469 (s), 1399 (s), 1344 (m), 1268 (s), 1238
(w), 1125 (w), 1075 (m), 880 (m), 719 (s) cm−1. The obtained data
match those reported in the literature.23
p-Tolyl Ethyl Sulfone (4e) [CAS: 7569-34-8]. The sodium tolyl
sulfinate (649 mg, 4.00 mmol) was dissolved in dimethyl sulfoxide (5
mL), and ethyl iodide (936 mg, 6.00 mmol, 482 μL) was added. The
colorless suspension was stirred at room temperature over the
weekend. The reaction mixture was diluted ethyl acetate (30 mL) and
washed with saturated aqueous sodium bicarbonate solution (50 mL).
The aqueous layer was re-extracted with ethyl acetate (2 × 20 mL).
The combined organic layers were washed with brine, dried with
sodium sulfate, filtered, and concentrated. The brown crude was
purified by column chromatography, and p-tolyl ethyl sulfone (4e)
(274 mg, 1.49 mmol, 37%) was obtained as a colorless solid after
recrystallization from ethyl acetate/heptane. 1H NMR (400 MHz,
CDCl3) δ = 1.27 (t, J = 7.41 Hz, 3 H), 2.46 (s, 3 H), 3.10 (q, J = 7.41
Hz, 2 H), 7.37 (d, J = 8.20 Hz, 2 H), 7.73−7.83 (m, 2 H);
13C{1H}NMR (100 MHz, CDCl3) δ = 7.5, 21.6, 50.6, 128.2, 129.8,
135.6, 144.6 ppm, MS (EI): m/z (%) = 184 [M]+ (50), 155 (55), 139
(20), 91 (100), 65 (40); IR: υ = 2923 (w), 1591 (m), 1453 (w), 1406
(w), 1313 (m), 1294 (m), 1142 (s), 1084 (m), 813 (m), 775 (m), 728
(s) cm−1. The obtained data match those reported in the literature.24
1-(Ethylsulfonyl)-1,2,3,4-tetrahydroquinoline (8a) [CAS: 544456-
91-9].25 A 500 mL three necked flask equipped with a reflux condenser
was evacuated and refilled with nitrogen (3 purge cycles). Anhydrous
chloroform (200 mL), 1,2,3,4-tetrahydroquinoline (9.99 g, 75.9 mmol,
9.40 mL), and anhydrous pyridine (7.91 g, 100 mmol, 8.00 mL) were
added. The mixture was cooled to 0 °C, and ethyl sulfonyl chloride
(6.43 g, 50.0 mmol, 4.72 mL) was added dropwise within 30 min.
After complete addition, the reaction mixture was heated to reflux for
4 h. The reaction mixture was cooled to room temperature and washed
with ammonium hydroxide solution (12%, 150 mL). The aqueous
layer was re-extracted with dichloromethane (2 × 100 mL). The
combined organic layers were washed with brine (50 mL), dried with
sodium sulfate, filtered, and concentrated. The crude orange oil was
purified by flash column chromatography (silica gel, n-heptane/ethyl
acetate gradient). A brownish oil was obtained that was further purified
by distillation under reduced pressure (heating block: 180 °C, bp: 145
°C). The desired product was obtained as a light yellow oil (8.52 g,
1
37.8 mmol, 76%). H NMR (400 MHz, CDCl3) δ = 1.34 (t, J = 7.41
Hz, 3 H), 1.95−2.06 (m, 2 H), 2.85 (t, J = 6.63 Hz, 2 H), 3.12 (q, J =
7.41 Hz, 2 H), 3.76−3.84 (m, 2 H), 6.98−7.07 (m, 1 H), 7.08−7.18
(m, 2 H), 7.64 (dd, J = 8.39 Hz, J = 0.98 Hz, 1 H) ppm;
13C{1H}NMR (100 MHz, CDCl3) δ = 7.9, 22.6, 27.0, 46.3, 46.4,
121.8, 123.9, 126.6, 128.6, 129.6, 137.0 ppm; MS (EI): m/z (%) = 225
[M]+ (40), 181 (1), 160 (1), 132 (100), 105 (10), 77 (10); IR: υ =
2940 (w), 1488 (m), 1453 (m), 1331 (s), 1253 (m), 1143 (s), 1086
(m), 1041 (m), 973 (m), 846 (m), 754 (s) cm−1. The obtained data
match those reported in the literature for 1-(methylsulfonyl)-1,2,3,4-
tetrahydroquinoline.26
3-(Ethylsulfonyl)-2,3,4,5-tetrahydrobenzoazepine (8b) [CAS:
1484866-61-6]. A 50 mL round-bottom flask was charged with
2,3,4,5-tetrahydrobenzoazepinium hydrochloride. Dichloromethane
(25 mL) and trimethylamine (1.13 g, 11.2 mmol, 1.56 mL) were
added. The mixture was stirred until a clear homogeneous solution was
obtained. Ethyl sulfonyl chloride (1.43 g, 11.2 mmol, 1.06 mL) was
added dropwise, and the mixture was stirred for 15 min at room
temperature. The reaction mixture was washed with water (100 mL),
F
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The Journal of Organic Chemistry
Article
and the aqueous layer was re-extracted with dichloromethane (20 mL).
The combined organic layers were dried with sodium sulfate, filtered,
and concentrated. The remaining brownish oil was purified by flah
column chromatography (silica gel, n-heptane/ethyl acetate gradient).
The desired product was obtained as a colorless solid (240 mg, 1.00
mmol, 27%). 1H NMR (400 MHz, CDCl3) δ = 1.32 (t, J = 7.41 Hz, 3
H), 2.95 (q, J = 7.41 Hz, 2 H), 2.98−3.04 (m, 4 H), 3.41−3.52 (m, 4
H), 7.09−7.19 (m, 4 H) ppm; 13C{1H}NMR (100 MHz, CDCl3) δ =
7.7, 38.1, 45.2, 48.0, 126.5, 129.3, 140.3 ppm; MS (EI): m/z (%) = 239
[M]+ (50), 213 (1), 194 (1), 146 (100), 117 (75), 91 (25); IR: υ =
2903 (w), 1497 (w), 1451 (w), 1321 (s), 1281 (m), 1133 (s), 1081
(s), 1032 (m), 937 (m), 895 (s), 771 (s), 737 (s) cm−1.
N-(2-Methoxypyridin-3-yl)ethanesulfonamide [CAS: 1341535-24-
7]. A 20 mL screw cap vial with PTFE septa was charged with 3-
amino-2-methoxy pyridine (621 mg, 5.00 mmol), evacuated, and
refilled with nitrogen (3 purge cycles). Anhydrous dichloromethane (5
mL), triethylamine (759 mg, 7.50 mmol, 1.05 mL), and ethane
sulfonyl chloride (707 mg, 5.50 mmol, 520 μL) were added. The
reaction mixture was stirred 16 h at room temperature. The reaction
mixture was diluted with dichloromethane (20 mL) and washed with
saturated sodium bicarbonate solution (50 mL). The aqueous layer
was re-extracted with dichloromethane (2 × 20 mL). The combined
organic layers were washed with brine (50 mL), dried with sodium
sulfate, filtered, and concentrated. The crude product was concen-
trated and purified by flash chromatography (silica gel, n-heptane/
ethyl acetate gradient). The desired product was obtained as a light
yellow oil (710 mg, 3.28 mmol, 66%). 1H NMR (400 MHz, CDCl3) δ
= 1.36 (t, J = 7.43 Hz, 3 H), 3.04−3.13 (m, 2 H), 4.01 (s, 3 H), 6.72
(sbr, 1 H), 6.90 (dd, J = 7.73 Hz, J = 4.99 Hz, 1 H), 7.78 (dd, J = 7.73
Hz, J = 1.66 Hz, 1 H), 7.88−7.96 (m, 1 H) ppm; 13C{1H}NMR (101
MHz, CDCl3) δ = 8.1, 46.1, 53.9, 117.4, 121.4, 127.0, 141.8, 154.0
ppm; MS (EI): m/z (%) = 216 [M]+ (65), 187 (2), 151 (2), 123 (99),
93 (100), 72 (20); IR: υ = 3075 (br., w), 2929 (w), 1596 (m), 1476
(s), 1437 (s), 1408 (s), 1323 (s), 1196 (m), 1141 (s), 1109 (s), 1009
(m), 922 (m), 851 (m), 763 (s) cm−1; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C8H12N2NaO3S: 239.0458; found: 239.0461. The
obtained data match those reported in the literature for N-(2-
methoxypyridin-3-yl)methanesulfonamide.27
N-(2-Methoxypyridin-3-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-
ethanesulfonamide (9c). Sodium hydride (60% in mineral oil, 128
mg, 3.19 mmol) and N-(2-methoxypyridin-3-yl)-ethanesulfonamide
(575 mg, 2.66 mmol) were weighed in a 25 mL round-bottom flask,
evacuated, and refilled with nitrogen (3 purge cycles). Anhydrous N,N-
dimethylformamide (5 mL) was added, and the resulting mixture was
stirred for 1 h at room temperature. 2-(Trimethylsilyl)ethoxymethyl
chloride (493 mg, 2.66 mmol, 534 μL) was added, and the mixture was
stirred for 30 min at room temperature. The reaction mixture was
quenched with water and extracted with dichloromethane (3 × 30
mL). The combined organic layers were dried with sodium sulfate,
filtered, and concentrated. The remaining yellow oil was purified by
flash chromatography (silica gel, n-heptane/ethyl acetate gradient).
The title compound was obtained as a colorless oil (864 mg, 2.49
mmol, 94%). 1H NMR (400 MHz, CDCl3) δ = −0.02 (s, 9 H), 0.84−
0.90 (m, 2 H), 1.35 (t, J = 7.41 Hz, 3 H), 3.01 (q, J = 7.28 Hz, 2 H),
3.64−3.71 (m, 2 H), 3.96 (s, 3 H), 4.99 (s, 2 H), 6.92 (dd, J = 7.61 Hz,
J = 4.88 Hz, 1 H), 7.64 (dd, J = 7.61 Hz, J = 1.76 Hz, 1 H), 8.11−8.14
(m, 1 H) ppm; 13C{1H}NMR (100 MHz, CDCl3) δ = −1.5, 7.7, 17.6,
47.7, 53.5, 65.1, 79.1, 117.3, 121.0, 142.2, 146.9, 159.8 ppm; MS (EI):
m/z (%) = 346 [M]+ (1), 317 (1), 288 (100), 259 (5), 229 (55), 180
(20), 136 (60), 107 (30), 73 (80); IR: υ = 2952 (w), 1469 (s), 1408
(s), 1339 (s), 1247 (m), 1215 (m), 1156 (s), 1078 (s), 1013 (s), 857
(s), 833 (s), 771 (s) cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C14H26N2NaO4SSi: 369.1278; found: 369.1275.
3.20 mL) was added dropwise within 5 min. The resulting light yellow
solution was stirred at the given temperature for an additional 5 min
and was allowed to warm to room temperature. The solvent was
removed in vacuo, and the resulting light yellow solid was dissolved in
tetrahydrofuran (16 mL). (Note: 2,2,6,6-tetramethylpiperidinyl
lithium turns into an orange gum when exposed to traces of air.
The resulting material is only moderately soluble in tetrahydrofuran).
A solution of zinc chloride in tetrahydrofuran (0.5 M, 8.00 mmol, 16
mL) was added. The reaction is slightly exothermal. The resulting light
yellow solution (0.25 M) was used as received and is stable upon
storage when kept under a protective atmosphere.
Preparation of the Cross-Coupling Products. 1-Methyl-4-(4-
methylbenzylsulfonyl)benzene (6aa) [CAS: 21668-99-5]. The
compound was prepared according to method A from p-tolyl methyl
sulfone (85.1 mg, 0.50 mmol), 4-bromotoluene (94.1 mg, 0.55 mmol),
Pd(dba)2 (5.75 mg, 0.01 mmol), XPhos (4.77 mg, 0.01 mmol), and
tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired
product (129.8 mg, 0.50 mmol) was obtained after chromatography
(silica gel, heptane/ethyl acetate gradient) in 99% yield as a colorless
1
solid. H NMR (400 MHz, CDCl3) δ = 2.33 (s, 3 H), 2.43 (s, 3 H),
4.26 (s, 2 H), 6.95−7.01 (m, 2 H), 7.05−7.11 (m, 2 H), 7.25 (m, 2 H),
7.49−7.55 (m, 2H) ppm; 13C{1H}NMR (100 MHz, CDCl3) δ = 21.2,
21.6, 62.6, 125.1, 128.6, 129.2, 129.5, 130.7, 135.1, 138.6, 144.5 ppm;
MS (EI): m/z (%) = 260 [M]+ (5), 207 (1), 181 (3), 153 (1), 105
(100), 77 (10); IR: υ = 2923 (w), 1593 (w), 1415 (w), 1301 (s), 1286
(s), 1183 (s), 1143 (s), 1083 (m), 815 (s), 690 (s) cm−1. The obtained
data match those reported in the literature.28
3-(Tosylmethyl)pyridine (6ab) [CAS 106651-91-6]. The compound
was prepared according to method B from p-tolyl methyl sulfone (85.1
mg, 0.50 mmol), 3-bromopyridine (94.8 mg, 0.60 mmol, 58 μL),
Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and
tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired
product (79.0 mg, 0.32 mmol) was obtained after chromatography
(silica gel, heptane/ethyl acetate gradient) in 64% yield as a colorless
1
solid. H NMR (400 MHz, CDCl3) δ = 2.38 (s, 3 H), 4.27 (s, 2 H),
7.18−7.26 (m, 3 H), 7.43−7.52 (m, 2 H), 7.56 (dt, J = 7.80 Hz, J =
1.95 Hz, 1 H), 8.14 (d, J = 2.34 Hz, 1 H), 8.52 (dd, J = 5.07 Hz, J =
1.56 Hz, 1 H) ppm; 13C{1H}NMR (100 MHz, CDCl3) δ = 21.5, 59.9,
123.3, 124.6, 128.4, 129.7, 134.3, 138.1, 145.1, 149.8, 151.1 ppm; MS
(EI): m/z (%) = 247 [M]+ (30), 207 (4), 167 (5), 139 (1), 115 (1),
92 (100), 65 (30); IR: υ = 2981 (w), 1594 (m), 1479 (m), 1301 (s),
1288 (s), 1270 (s), 1193 (s), 1147 (s), 1084 (s), 1027 (m), 896 (w)
cm−1. The obtained data match those reported in the literature.29
1-Methoxy-4-(tosylmethyl)benzene (6ac) [CAS: 58680-51-6]. The
compound was prepared according to method B from p-tolyl methyl
sulfone (85.1 mg, 0.50 mmol), 4-bromoanisole (112 mg, 0.60 mmol,
75 μL), Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05
mmol), and tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The
desired product (136.4 mg, 0.49 mmol) was obtained after
chromatography (silica gel, heptane/ethyl acetate gradient) in 99%
1
yield as a colorless solid. H NMR (400 MHz, CDCl3) δ = 2.43 (s, 3
H), 3.80 (s, 3 H), 4.24 (s, 2 H), 6.76−6.83 (m, 2 H), 6.96−7.05 (m, 2
H), 7.25 (dd, J = 8.59 Hz, J = 0.78 Hz, 2 H), 7.49−7.55 (m, 2 H) ppm;
13C{1H}NMR (100 MHz, CDCl3) δ = 21.6, 55.3, 62.2, 113.9, 120.2,
128.6, 129.5, 132.0, 135.1, 144.5, 159.9 ppm; MS (EI): m/z (%) = 276
[M]+ (3), 228 (1), 197 (1), 164 (1), 121 (100), 91 (10); IR: υ = 2956
(w), 1607 (w), 1509 (m), 1288 (s), 1241 (s), 1178 (s), 1146 (s), 1085
(m), 1031 (m), 817 (s), 756 (s) cm−1. The obtained data match those
reported in the literature.30
N,N-Dimethyl-4-(tosylmethyl)aniline (6ad) [CAS: 3933-62-9]. The
compound was prepared according to method A from p-tolyl methyl
sulfone (85.1 mg, 0.50 mmol), 4-bromo-N,N-dimethylaniline (111 mg,
0.55 mmol), Pd(dba)2 (5.75 mg, 0.01 mmol), XPhos (4.77 mg, 0.01
mmol), and tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The
desired product (135.2 mg, 0.47 mmol) was obtained after
chromatography (silica gel, heptane/ethyl acetate gradient) in 93%
2,2,6,6-Tetramethylpiperidinylzinc Chloride Lithium Chloride
Complex (tmp·ZnCl·LiCl) [CAS: 1145881-09-9].18 A hot 100 mL
round-bottom flask with a new rubber septa was evacuated and refilled
with nitrogen (3 purge cycles). 2,2,6,6-Tetramethylpiperidine (1.13 g,
8.00 mmol, 1.36 mL) was added, dissolved in anhydrous
tetrahydrofuran (4 mL), and cooled to −78 °C in an acetone/dry
ice bath. A solution of n-butyl lithium in hexanes (2.6 M, 8.00 mmol,
1
yield as a colorless solid. H NMR (400 MHz, CDCl3) δ = 2.42 (s, 3
H), 2.94 (s, 6 H), 4.20 (s, 2 H), 6.55−6.62 (m, 2 H), 6.90−6.97 (m, 2
H), 7.24 (d, J = 8.20 Hz, 2 H), 7.49−7.58 (m, 2 H) ppm;
13C{1H}NMR (100 MHz, CDCl3) δ = 21.6, 40.3, 62.4, 112.0, 115.0,
G
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The Journal of Organic Chemistry
Article
127.3, 128.6, 129.3, 131.5, 135.3, 150.5 ppm; MS (EI): m/z (%) = 289
[M]+ (5), 224 (1), 194 (1), 178 (1), 165 (1), 134 (100), 118 (15), 91
(10); IR: υ = 2915 (s), 1617 (m), 1531 (m), 1367 (m), 1299 (m),
1287 (m), 1142 (s), 1084 (m), 946 (w), 804 (s), 729 (s) cm−1. The
obtained data match those reported in the literature.31
sulfone (85.1 mg, 0.50 mmol), ethyl 4-bromobenzoate (137 mg, 0.60
mmol, 98 μL), Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05
mmol), and tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The
desired product (158 mg, 0.44 mmol) was obtained after
chromatography (silica gel, heptane/ethyl acetate gradient) in 99%
yield as a colorless solid. 1H NMR (400 MHz, CDCl3) δ = 1.40 (t, J =
7.02 Hz, 3 H), 2.43 (s, 3 H), 4.35 (s, 2 H), 4.38 (q, J = 7.02 Hz, 2 H),
7.13−7.19 (m, 2 H), 7.25 (d, J = 8.20 Hz, 2 H), 7.47−7.54 (m, 2 H),
7.90−7.98 (m, 2 H) ppm; 13C{1H}NMR (100 MHz, CDCl3) δ =
14.2, 21.6, 61.1, 62.5, 128.5, 129. 6, 129.9, 130.6, 130.7, 133.1, 134.7,
144. 9, 166.0 ppm; MS (EI): m/z (%) = 318 [M]+ (5), 273 (5), 254
(1), 209 (2), 182 (1), 163 (100), 135 (20), 107 (20); IR: υ = 2916
(w), 1710 (s), 1276 (s), 1148 (s) 1113 (s) 1086 (m), 1020 (m), 820
(m), 777 (m), 708 (s) cm−1. The obtained data match those reported
in the literature.34
4-(Tosylmethyl)thioanisole (6ae). The title compound was
prepared according to method B from p-tolyl methyl sulfone (85.1
mg, 0.50 mmol), 4-bromothioanisole (122 mg, 0.60 mmol), Pd(dba)2
(28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and tmp·ZnCl·
LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired product (145.0
mg, 0.50 mmol) was obtained after chromatography (silica gel,
1
heptane/ethyl acetate gradient) in 99% yield as a colorless solid. H
NMR (400 MHz, CDCl3) δ = 2.42 (s, 3 H), 2.44−2.48 (m, 3 H), 4.24
(s, 2 H), 6.96−7.03 (m, 2 H), 7.09−7.15 (m, 2 H), 7.25 (d, J = 8.20
Hz, 2 H), 7.48−7.57 (m, 2 H); 13C{1H}NMR (100 MHz, CDCl3) δ =
15.3, 21.6, 62.3, 124.6, 126.0, 128.5, 129.5, 131.1, 134.9, 139.6, 144.6
ppm; MS (EI): m/z (%) = 292 [M]+ (5), 213 (1), 184 (1), 165 (2),
137 (100), 91 (5); IR: υ = 2980 (w), 1492 (m), 1300 (s), 1288 (s),
1146 (s), 1086 (s), 812 (s), 697 (s) cm−1; mp 151−153 °C. HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C15H16NaO2S2: 315.0484;
found: 315.0492.
4-(Tosylmethyl)benzonitrile (6aj) [CAS: 59475-60-4]. The com-
pound was prepared according to method B from p-tolyl methyl
sulfone (85.1 mg, 0.50 mmol), 4-bromobenzonitrile (109 mg, 0.60
mmol), Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05
mmol), and tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The
desired product (120.6 mg, 0.50 mmol) was obtained after
chromatography (silica gel, heptane/ethyl acetate gradient) in 89%
2-(Tosylmethyl)-m-xylene (6af). The compound was prepared
according to method A from p-tolyl methyl sulfone (85.1 mg, 0.50
mmol), 2-bromo-m-xylene (103 mg, 0.55 mmol, 74 μL), Pd(dba)2
(5.75 mg, 0.01 mmol), XPhos (4.77 mg, 0.01 mmol), and tmp·ZnCl·
LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired product (65.6
mg, 0.24 mmol) was obtained after chromatography (silica gel,
1
yield as a colorless solid. H NMR (400 MHz, CDCl3) δ = 2.45 (s, 3
H), 4.34 (s, 2 H), 7.21−7.26 (m, 2 H), 7.27−7.31 (m, 2 H), 7.49−7.55
(m, 2 H), 7.56−7.61 (m, 2 H) ppm; 13C{1H}NMR (100 MHz,
CDCl3) δ = 21.7, 62.5, 112.8, 118.2, 128.5, 129.8, 131.5, 132.2, 133.6,
134.6, 145.32 ppm; MS (EI): m/z (%) = 271 [M]+ (20), 192 (5) 155
(40) 116 (100), 91 (40), 65 (30); IR: υ = 2929 (w), 2227 (w), 1311
(s), 1291 (s), 1147 (s), 1085 (m), 819 (s) 736 (s) cm−1. The obtained
data match those reported in the literature.33
1-Nitro-4-(tosylmethyl)benzene (6ak) [CAS: 61081-32-1]. The
title compound was prepared according to method B from p-tolyl
methyl sulfone (85.1 mg, 0.50 mmol), 4-bromo-1-nitrobenzene (121
mg, 0.60 mmol), Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg,
0.05 mmol), and tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL).
The desired product (130 mg, 0.45 mmol) was obtained after
chromatography (silica gel, heptane/ethyl acetate gradient) in 89%
yield as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ = 2.45 (s,
3 H), 4.39 (s, 2 H), 7.28−7.34 (m, 4 H), 7.50−7.59 (m, 2 H), 8.09−
8.19 (m, 2 H) ppm; 13C{1H}NMR (100 MHz, CDCl3) δ = 21.7, 62.2,
123.7, 128.5, 129.9, 131.8, 134. 6, 135.5, 145.4, 148.1 ppm; MS (EI):
m/z (%) = 291 [M]+ (40), 261 (1), 227 (5), 197 (1), 178 (3), 155
(100), 136 (75), 111 (35), 91 (90), 65 (30); IR: υ = 2923 (w), 1596
(m), 1512 (s), 1340 (s), 1301 (s), 1289 (s), 1145 (s), 1085 (s), 857
(m), 699 (s) cm−1. The obtained data match those reported in the
literature.28
1
heptane/ethyl acetate gradient) in 48% yield as a colorless solid. H
NMR (400 MHz, CDCl3) δ = 2.22 (s, 6 H), 2.45 (s, 3 H), 4.50 (s, 2
H), 7.02 (d, J = 7.41 Hz, 1 H), 7.10−7.17 (m, 1 H), 7.30 (d, J = 8.20
Hz, 1 H), 7.60−7.66 (m, 1 H) ppm; 13C{1H}NMR (100 MHz,
CDCl3) δ = 20.3, 21.6, 57.4, 125.5, 128.4, 128.5, 128.6, 129.7, 136.6,
139.2, 144.7 ppm; MS (EI): m/z (%) = 274 [M]+ (5), 195 (1), 180
(1), 165 (2), 155 (1), 139 (1), 119 (100), 91 (20), 77 (10); IR: υ =
2926 (s), 1596 (2), 1449 (s), 1310 (m), 1143 (s), 1083 (s), 910 (w),
763 (s) cm−1; mp 113−115 °C. HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C16H18NaO2S: 297.0920; found: 297.0919.
2-(Tosylmethyl)-o-toluene (6ag) [CAS: 98752-69-3]. The com-
pound was prepared according to method A from p-tolyl methyl
sulfone (85.1 mg, 0.50 mmol), 2-bromotoluene (94.1 mg, 0.55 mmol,
66 μL), Pd(dba)2 (5.75 mg, 0.01 mmol), XPhos (4.77 mg, 0.01
mmol), and tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The
desired product (117.8 mg, 0.45 mmol) was obtained after
chromatography (silica gel, heptane/ethyl acetate gradient) in 90%
yield as a light yellow solid. 1HNMR (400 MHz, CDCl3) δ = 2.12 (s, 3
H), 2.42 (s, 3 H), 4.36 (s, 2 H), 6.99−7.06 (m, 1 H), 7.07−7.16 (m, 2
H)- 7.18−7.29 (m, 3 H), 7.48−7.57 (m, 2 H) ppm; 13C{1H}NMR
(100 MHz, CDCl3) δ = 19.3, 21.5, 59.9, 125. 9, 126.6, 128.5, 128.8,
129.4, 130.5, 131.8, 135.4, 138.2, 144.6 ppm; MS (EI): m/z (%) = 260
[M]+ (5), 207 (1), 181 (2), 139 (1), 105 (100), 77 (10); IR: υ = 2923
(w), 1595 (w), 1451 (w), 1312 (s), 1288 (s), 1153 (s), 1132 (s), 1084
(s), 884 (w), 812 (s) cm−1. The obtained data match those reported in
the literature.32
4-(Tosylmethyl)benzaldehyde (6al). The compound was prepared
according to method B from p-tolyl methyl sulfone (85.1 mg, 0.50
mmol), 4-bromobenzaldehyde (111 mg, 0.60 mmol), Pd(dba)2 (28.8
mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and tmp·ZnCl·LiCl
solution (2.5 M, 1.25 mmol, 5.0 mL). The desired product (52.1 mg,
0.19 mmol) was obtained after chromatography (silica gel, heptane/
ethyl acetate gradient) in 38% yield as a colorless solid. 1H NMR (400
MHz, CDCl3) δ = 2.34 (s, 3 H), 4.28 (s, 2 H), 7.18 (t, J = 8.39 Hz, 4
H), 7.40−7.45 (m, 2 H), 7.65−7.72 (m, 2 H), 9.91 (s, 1 H) ppm;
13C{1H}NMR (100 MHz, CDCl3) δ = 21.6, 62.7, 128.5, 129.7, 131.5,
134.7, 134.8, 136.2, 145.1, 191.6 ppm; MS (EI): m/z (%) = 274 [M]+
(30), 195 (3), 165 (10), 139 (5), 119 (100), 91 (75), 65 (25); IR: υ =
2849 (w), 1691 (s), 1604 (m), 1303 (s) 1290 (s), 1205 (w), 1145 (s),
1083 (m), 817 (s), 740 (s) cm−1; mp 155−157 °C. HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C15H14NaO3S: 297.0556; found: 297.0554.
3-(Tosylmethyl)furan (6am) [CAS: 92631-12-4]. The compound
was prepared according to method B from p-tolyl methyl sulfone (85.1
mg, 0.50 mmol), 3-bromofuran (111 mg, 0.60 mmol, 54 μL),
Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and
tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired
product (60.6 mg, 0.26 mmol) was obtained after chromatography
(silica gel, heptane/ethyl acetate gradient) in 51% yield as a colorless
1-Chloro-4-(tosylmethyl)benzene (6ah) [CAS: 20025-49-4]. The
title compound was prepared according to method A from p-tolyl
methyl sulfone (85.1 mg, 0.50 mmol), 1-bromo-4-chlorobenzene (105
mg, 0.55 mmol), Pd(dba)2 (5.75 mg, 0.01 mmol), XPhos (4.77 mg,
0.01 mmol), and tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL).
The desired product (55.9 mg, 0.20 mmol) was obtained after
chromatography (silica gel, heptane/ethyl acetate gradient) in 40%
1
yield as a colorless solid. H NMR (400 MHz, CDCl3) δ = 2.39 (s, 3
H), 4.22 (s, 2 H), 6.96−7.03 (m, 2 H), 7.17−7.26 (m, 4 H), 7.46−7.52
(m, 2 H) ppm; 13C{1H}NMR (100 MHz, CDCl3) δ = 21.6, 62.1,
126.8, 128.6, 128.8, 129.6, 132.0, 134.7, 134.9, 144.9 ppm; MS (EI):
m/z (%) = 280 [M]+ (2), 201 (1), 165 (2), 125 (100), 89 (10). IR: υ
= 2932 (w), 1487 (w), 1303 (s), 1147 (s), 1085 (s), 1014 (m), 817
(s), 717 (s) cm−1. The obtained data match those reported in the
literature.33
1
Ethyl 4-(Tosylmethyl)benzoate (6ai) [CAS: 117687-58-8]. The
solid. H NMR (400 MHz, CDCl3) δ = 2.32 (s, 3 H), 4.06 (s, 2 H),
compound was prepared according to method B from p-tolyl methyl
6.19 (dd, J = 1.95 Hz, J = 0.78 Hz, 1 H), 7.11 (dd, J = 1.56 Hz, J = 0.78
H
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The Journal of Organic Chemistry
Article
Hz, 1 H), 7.15−7.21 (m, 2 H), 7.25 (t, J = 1.76 Hz, 1 H), 7.46−7.55
(m, 2 H) ppm; 13C{1H}NMR (100 MHz, CDCl3) δ = 21.6, 53.3,
111.5, 112.7, 128.5, 129.6, 134.8, 142.7, 143.3 ppm; MS (EI): m/z (%)
= 236 [M]+ (5), 190 (1), 172 (25), 147 (10), 128 (10), 101 (15), 81
(100); IR: υ = 2922 (w), 1594 (w), 1381 (w), 1308 (s), 1274 (s),
1235 (m), 1148 (s), 1124 (s), 1017 (s), 871 (s), 805 (s) cm−1. The
obtained data match those reported in the literature.35
[M]+ (60), 246 (1), 217 (5), 180 (1), 155 (40), 126 (100), 91 (50),
65 (20); IR: υ = 2916 (w), 1594 (w), 1424 (m), 1307 (s), 1258 (s),
1141 (s), 1121 (s), 1185 (m), 1021 (m), 893 (m), 755 (s), 713 (s)
cm−1; mp 123−125 °C. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C13H12ClNNaO2S: 304.0169; found: 304.0171.
2-(N-Boc-piperazinyl)-5-(tosylmethyl)piperidine (6ar). The title
compound was prepared according to method B from p-tolyl methyl
sulfone (85.1 mg, 0.50 mmol), 5-bromo-2-(N-boc-piperazinyl)pyridine
(205 mg, 0.60 mmol), Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1
mg, 0.05 mmol), and tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0
mL). The desired product (214 mg, 0.50 mmol) was obtained after
chromatography (silica gel, heptane/ethyl acetate gradient) in 99%
2-(Tosylmethyl)thiophene (6an) [CAS: 20895-79-8]. The com-
pound was prepared according to method B from p-tolyl methyl
sulfone (85.1 mg, 0.50 mmol), 2-bromothiophene (97.8 mg, 0.60
mmol, 58 μL), Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05
mmol), and tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The
desired product (38.8 mg, 0.15 mmol) was obtained after
chromatography (silica gel, heptane/ethyl acetate gradient) in 31%
1
yield as a colorless solid. H NMR (400 MHz, CDCl3) δ = 1.49 (s, 9
H), 2.42 (s, 3 H), 3.52 (s, 8 H), 4.15 (s, 2 H), 6.57 (d, J = 8.59 Hz, 1
H), 7.27 (d, J = 7.41 Hz, 2 H), 7.37 (dd, J = 8.78 Hz, J = 2.54 Hz, 1
H), 7.52−7.60 (m, 2 H), 7.74 (d, J = 2.34 Hz, 1 H) ppm;
13C{1H}NMR (100 MHz, CDCl3) δ = 21.6, 28.3, 44.7, 59.5, 79.9, 106.
6, 113.0, 128. 5, 129.6, 134.9, 139.6, 144.7, 149.6, 154.7, 158.9 ppm;
MS (EI): m/z (%) = 403 [M − CH3]+ (10), 386 (20), 345 (10), 263
(8), 176 (100), 134 (10), 91 (5); IR: υ = 2977 (w), 1691 (s), 1603 (s),
1496 (s), 1407 (s), 1238 (s), 1163 (s),1121 (s), 1083 (m), 934 (m),
811 (m), 769 (m) cm−1; mp 136−138 °C. HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C22H29N3NaO4S: 454.1771; found: 454.1780.
3-(Tosylmethyl)quinoline (6as). The compound was prepared
according to method B from p-tolyl methyl sulfone (85.1 mg, 0.50
mmol), 3-bromoquinoline (104 mg, 0.60 mmol, 68 μL), Pd(dba)2
(28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and tmp·ZnCl·
LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired product (105.9
mg, 0.36 mmol) was obtained after chromatography (silica gel,
1
yield as a colorless solid. H NMR (400 MHz, CDCl3) δ = 2.34 (s, 3
H), 4.42 (s, 2 H), 6.77 (d, J = 3.51 Hz, 1 H), 6.85 (dd, J = 5.27 Hz, J =
3.71 Hz, 1 H), 7.14−7.21 (m, 3 H), 7.46−7.52 (m, 2 H) ppm;
13C{1H}NMR (100 MHz, CDCl3) δ = 21.6, 57.3, 127.1, 127.4, 128.6,
128.7, 129.6, 130.1, 134.5, 144.9 ppm; MS (EI): m/z (%) = 252 [M]+
(5), 207 (1), 187 (5), 155 (3), 129 (5), 97 (100), 65 (10); IR: δ =
2969 (w), 1593 (w), 1403 (w), 1310 (s), 1303 (s), 1288 (s), 1144 (s),
1081 (m), 814 (m), 719 (s) cm−1. The obtained data match those
reported in the literature.36
2-Ethoxy-5-(tosylmethyl)pyridine (6ao). The compound was
prepared according to method B from p-tolyl methyl sulfone (85.1
mg, 0.50 mmol), 3-bromo-2-ethoxypyridine (121 mg, 0.60 mmol),
Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and
tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired
product (141.2 mg, 0.49 mmol) was obtained after chromatography
(silica gel, heptane/ethyl acetate gradient) in 97% yield as a colorless
solid. 1H NMR (400 MHz, CDCl3) δ = 1.35 (t, J = 7.02 Hz, 3 H), 2.40
(s, 3 H), 4.19 (s, 2 H), 4.29 (q, J = 7.02 Hz, 2 H), 6.64 (d, J = 8.59 Hz,
1 H), 7.20−7.28 (m, 2 H), 7.41 (dd, J = 8.59 Hz, J = 2.73 Hz, 1 H),
7.48−7.55 (m, 2 H), 7.69 (d, J = 2.34 Hz, 1 H) ppm; 13C{1H}NMR
(100 MHz, CDCl3) δ = 14.4, 21.6, 59.4, 61.9, 110.9, 116.9, 128.5,
129.6, 134.6, 140.5, 144.9, 148.6, 164.0 ppm; MS (EI): m/z (%) = 291
(3), 233 (1), 212 (1), 181 (1), 155 (2), 136 (100), 108 (75), 80 (20);
IR: υ = 2980 (w), 1732 (w), 1607 (w), 1476 (s), 1400 (w), 1379 (m),
1303 (s), 1287 (s), 1260 (m), 1144 (s), 925 (m), 818 (m), 728 (s)
cm−1; mp 115−117 °C. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C15H17NNaO3S: 314.0823; found: 314.0821.
1
heptane/ethyl acetate gradient) in 71% yield as a colorless solid. H
NMR (400 MHz, CDCl3) δ = 2.42 (s, 3 H), 4.48 (s, 2 H), 7.26 (d, J =
7.80 Hz, 2 H), 7.51−7.56 (m, 2 H), 7.56−7.62 (m, 1 H), 7.72−7.82
(m, 2 H), 8.05−8.11 (m, 2 H), 8.42 (d, J = 2.34 Hz, 1 H) ppm;
13C{1H}NMR (100 MHz, CDCl3) δ = 21.7, 60.2, 121.6, 127.2, 127.5,
127.9, 128.6, 129.3, 129.9, 130.3, 134.6, 138.3, 145.3, 147.7, 151.4
ppm; MS (EI): m/z (%) = 297 [M]+ (3), 256 (100), 227 (10), 200
(8), 163 (1), 142 (40), 115 (10), 88 (8); IR: υ = 2971 (w), 1739 (w),
1493 (m), 1300 (s), 1145 (s), 1084 (s), 908 (m), 818 (s), 742 (s), 699
(s) cm−1; mp 144−146 °C. HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C17H15NNaO2S: 320.0716; found: 320.0710.
2-(Tosylmethyl)pyridine (6at). The compound was prepared
according to method B from p-tolyl methyl sulfone (85.1 mg, 0.50
mmol), 2-bromopyridine (94.8 mg, 0.60 mmol, 57 μL), Pd(dba)2
(28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and tmp·ZnCl·
LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired product (22.8
mg, 0.09 mmol) was obtained after chromatography (silica gel,
2-Methyl-5-(tosylmethyl)pyridine (6ap). The compound was
prepared according to method B from p-tolyl methyl sulfone (85.1
mg, 0.50 mmol), 3-bromo-2-metylpyridine (103 mg, 0.60 mmol),
Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and
tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired
product (108.3 mg, 0.41 mmol) was obtained after chromatography
(silica gel, heptane/ethyl acetate gradient) in 83% yield as a colorless
1
heptane/ethyl acetate gradient) in 18% yield as a colorless solid. H
NMR (400 MHz, CDCl3) δ = 2.71 (s, 3 H), 4.82 (s, 2 H), 7.49−7.57
(m, 4 H), 7.76 (d, J = 7.81 Hz, 1 H), 7.80−7.86 (m, 2 H), 7.99 (td, J =
7.71 Hz, J = 1.76 Hz, 1 H), 8.72 (dd, J = 3.90 Hz, J = 0.78 Hz, 1 H)
ppm; 13C{1H}NMR (100 MHz, CDCl3) δ = 21.6, 64.7, 123.3, 125.8,
128.4, 129.6, 135.4, 136.7, 144. 8, 149.1, 149.6 ppm; MS (EI): m/z
(%) = 246 [M − H]+ (1), 220 (1), 201 (1), 182 (100), 158 (1), 139
(1), 92 (30), 65 (35); IR: υ = 2969 (w), 1585 (w), 1473 (w), 1434
(m), 1379 (m), 1298 (s), 1148 (s), 1084 (s), 792 (s), 726 (s) cm−1;
mp 131−133 °C. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C13H13NNaO2S: 270.0559; found: 270.0559.
5-Cyano-2-(tosylmethyl)pyridine (6au). The compound was
prepared according to method B from p-tolyl methyl sulfone (85.1
mg, 0.50 mmol), 2-bromo-5-cyanopyridine (110 mg, 0.60 mmol),
Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and
tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired
product was obtained along with nonconverted 2-bromo-5-cyanopyr-
idine which could not be separated by column chromatography (silica
gel, heptane/ethyl acetate gradient). The mixture contains the product
in 24% yield (32.6 mg, 0.12 mmol) by 1H NMR with mesitylene as an
internal standard. 1H NMR (400 MHz, CDCl3) δ = 2.43 (s, 3 H), 4.59
(s, 2 H), 7.26−7.31 (m, 2 H), 7.55 (d, J = 8.20 Hz, 2 H), 8.68 (m, 1
H) ppm; 13C{1H}NMR (100 MHz, CDCl3) δ = 21.6, 64.5, 109.6,
116.1, 125.6, 128.3, 129.8, 135.00, 139. 8, 145.4, 153.2, 154.3 ppm; MS
1
solid. H NMR (400 MHz, CDCl3) δ = 2.38 (s, 3 H), 2.50 (s, 3 H),
4.22 (s, 2 H), 7.08 (d, J = 8.20 Hz, 1 H), 7.23 (d, J = 7.81 Hz, 2 H),
7.45 (dd, J = 8.00 Hz, J = 2.15 Hz, 1 H), 7.50 (d, J = 8.20 Hz, 2 H),
8.00 (d, J = 2.34 Hz, 1 H) ppm; 13C{1H}NMR (100 MHz, CDCl3) δ
= 21.5, 24.1, 59.6, 121.4, 123.00, 128.4, 129.7, 134.5, 138.3, 145.0,
150.4, 158.8 ppm; MS (EI): m/z (%) = 261 [M]+ (10), 214 (1), 182
(3), 155 (1), 125 (1), 106 (100), 77 (25); IR: υ = 2923 (w), 1597 (m)
1488 (m), 1310 (s), 1258 (m), 1148 (s), 1085 (s), 1030 (m), 813 (s),
723 (s) cm−1; mp 97−99 °C. HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C14H15NNaO2S: 284.0716; found: 284.0717.
2-Chloro-5-(tosylmethyl)pyridine (6aq). The compound was
prepared according to method B from p-tolyl methyl sulfone (85.1
mg, 0.50 mmol), 3-bromo-5-chloropyridine (115 mg, 0.60 mmol),
Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and
tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired
product (50.0 mg, 0.18 mmol) was obtained after chromatography
(silica gel, heptane/ethyl acetate gradient) in 35% yield as a colorless
1
solid. H NMR (400 MHz, CDCl3) δ = 2.44 (s, 3 H), 4.26 (s, 2 H),
7.27−7.33 (m, 2 H), 7.51−7.57 (m, 2 H), 7.60 (t, J = 2.15 Hz, 1 H),
8.05 (d, J = 1.95 Hz, 1 H), 8.52 (d, J = 2.34 Hz, 1 H) ppm;
13C{1H}NMR (100 MHz, CDCl3) δ = 21.6, 59.3, 125.8, 128.5, 129.9,
131.9, 134.2, 137.7, 145.5, 148.9, 148.9 ppm; MS (EI): m/z (%) = 281
I
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(EI): m/z (%) = 272 [M]+ (1), 245 (1), 207 (100), 176 (1), 155 (5),
117 (10), 91 (65).
from p-chlorophenyl methyl sulfone (97.3 mg, 0.50 mmol), 4-
bromotoluene (103 mg, 0.60 mmol), Pd(dba)2 (5.75 mg, 0.01 mmol),
XPhos (4.77 mg, 0.01 mmol), and tmp·ZnCl·LiCl solution (2.5 M,
1.25 mmol, 5.0 mL). The desired product (73.9 mg, 0.26 mmol) was
obtained after chromatography (silica gel, heptane/ethyl acetate
gradient) in 53% yield as a colorless solid. 1H NMR (400 MHz,
CDCl3) δ = 2.33 (s, 3 H), 4.28 (s, 2 H), 6.97 (d, J = 8.02 Hz, 2 H),
7.09 (d, J = 7.83 Hz, 2 H), 7.38−7.45 (m, 2 H), 7.52−7.59 (m, 2 H)
ppm; 13C{1H}NMR (101 MHz, CDCl3) δ = 21.2, 62.5, 124.6, 129.1,
129.3, 130.1, 130.6, 136. 4, 138.8, 140.3 ppm; MS (EI): m/z (%) =
280 [M]+ (5), 215 (1), 201 (1), 178 (1), 165 (1) 142 (1), 105 (100),
89 (2), 77 (10); IR: υ = 2916 (w), 1511 (w), 1476 (w), 1393 (w),
1311 (m), 1274 (m), 1149 (s), 1086 (s), 1013 (m), 831 (s), 770 (s),
744 (m) cm−1. The obtained data match those reported in the
literature.37
N-Methyl-5-(tosylmethyl)-7-azaindole (6av). The compound was
prepared according to method B from p-tolyl methyl sulfone (85.1 mg,
0.50 mmol), 5-bromo-N-methyl-7-azaindole (127 mg, 0.60 mmol),
Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and
tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired
product (135 mg, 0.45 mmol) was obtained after chromatography
(silica gel, heptane/ethyl acetate gradient) in 90% yield as light brown
1
solid. H NMR (400 MHz, CDCl3) δ = 2.38 (s, 3 H), 3.83 (s, 3 H),
4.37 (s, 2 H), 6.40 (d, J = 3.51 Hz, 1 H), 7.18 (d, J = 3.51 Hz, 1 H),
7.20 (d, J = 7.80 Hz, 2 H), 7.45−7.52 (m, 2 H), 7.78 (d, J = 1.95 Hz, 1
H), 7.83 (d, J = 1.95 Hz, 1 H) ppm; 13C{1H}NMR (100 MHz,
CDCl3) δ = 21.5, 31.2, 60.5, 99.5, 115.6, 120.2, 128. 5, 129. 6, 130.0,
130.9, 134.7, 144.4, 144.7, 147.6 ppm; MS (EI): m/z (%) = 300 [M]+
(5), 281 (1), 235 (2), 206 (1), 164 (1), 145 (100), 117 (5), 91 (5), 65
(5); IR: υ = 2970 (w), 1597 (w), 1513 (m), 1400 (m), 1352 (m),
1308 (s), 1144 (s), 1082 (s), 818 (s), 721 (s) cm−1; mp 147−149 °C.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H16N2NaO2S:
323.0825; found: 323.0823.
5-(Tosylmethyl)pyrimidine (6aw). The compound was prepared
according to method B from p-tolyl methyl sulfone (85.1 mg, 0.50
mmol), 5-bromopyrimidine (95.4 mg, 0.60 mmol), Pd(dba)2 (28.8
mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and tmp·ZnCl·LiCl
solution (2.5 M, 1.25 mmol, 5.0 mL). The desired product (12.3 mg,
0.05 mmol) was obtained after chromatography (silica gel, heptane/
ethyl acetate gradient) in 10% yield as a colorless solid. 1H NMR (400
MHz, CDCl3) δ = 2.45 (s, 3 H), 4.28 (s, 2 H), 7.32 (d, J = 8.20 Hz, 2
H), 7.56 (d, J = 8.20 Hz, 2 H), 8.48 (s, 2 H), 9.18 (s, 1 H) ppm;
13C{1H}NMR (100 MHz, CDCl3) δ = 21.7, 57.6, 123.3, 128.5, 130.1,
134.1, 145.8, 158.2, 158.7 ppm; MS (EI): m/z (%) = 248 [M]+ (80),
207 (1), 183 (2), 155 (90), 91 (100), 66 (40); IR: υ = 2920 (w), 1587
(w), 1562 (s), 1439 (m), 1412 (s), 1307 (s), 1147 (s), 1084 (s), 922
(w), 881 (m), 752 (s), 729 (m) cm−1; mp 124−126 °C. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C12H12N2NaO2S: 271.0512; found:
270.0511.
N-Methyl-4-(tosylmethyl)pyrazole (6ax). The compound was
prepared according to method B from p-tolyl methyl sulfone (85.1
mg, 0.50 mmol), 4-bromo-N-methylpyrazole (96.6 mg, 0.60 mmol, 62
μL), Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol),
and tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired
product (26.3 mg, 0.11 mmol) was obtained after chromatography
(silica gel, heptane/ethyl acetate gradient) in 21% yield as a colorless
oil. 1H NMR (400 MHz, CDCl3) δ = 2.43 (s, 3 H), 3.86 (s, 3 H), 4.18
(s, 2 H), 7.10 (s, 1 H), 7.29 (d, J = 8.20 Hz, 2 H), 7.37 (s, 1 H), 7.55−
7.63 (m, 2 H) ppm; 13C{1H}NMR (100 MHz, CDCl3) δ = 21.6, 39.1,
53.0, 107.9, 128.5, 129.6, 131.1, 134.1, 140.1, 144.7 ppm; MS (EI): m/
z (%) = 250 [M]+ (2), 207 (2), 171 (1), 128 (1), 95 (100), 65 (5); IR:
υ = 2970 (w), 1378 (s), 1298 (s), 1254 (s), 1216 (m), 1151 (s), 1124
(s), 1085 (m), 890 (s), 759 (s) cm−1; mp 86−88 °C. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C12H14N2NaO2S: 273.0668; found:
273.0666.
1-Fluoro-4-(4-methylbenzylsulfonyl)benzene (6da) [CAS: 1494-
30-0]. The compound was prepared according to method A from p-
fluorophenyl methyl sulfone (87.1 mg, 0.50 mmol), 4-bromotoluene
(103 mg, 0.60 mmol), Pd(dba)2 (5.75 mg, 0.01 mmol), XPhos (4.77
mg, 0.01 mmol), and tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0
mL). The desired product (132 mg, 0.50 mmol) was obtained after
chromatography (silica gel, heptane/ethyl acetate gradient) in 99%
yield as a colorless solid. 1H NMR (400 MHz, CDCl3) δ = 2.27−2.37
(m, 3 H), 4.27 (s, 2 H), 6.92−6.99 (m, 2 H), 7.04−7.15 (m, 4 H),
7.59−7.67 (m, 2 H) ppm; 13C{1H}NMR (101 MHz, CDCl3) δ =
2
21.2, 62.7, 116.1 (d, JC−F = 22.50 Hz), 124.8, 129.3, 130.6, 131.5 (d,
3JC−F = 9.54 Hz), 133. 9, 138.8, 165.7 (d, 1JC−F = 256.80 Hz) ppm; 19
F
NMR (377 MHz, CDCl3) δ = −103.6 (m) ppm; MS (EI): m/z (%) =
264 [M]+ (2), 216 (1), 196 (1), 170 (1), 159 (1), 143 (1), 115 (1),
105 (100), 95 (10), 77 (15); IR: υ = 2922 (w), 1590 (s), 1494 (s),
1406 (w), 1314 (s), 1287 (s), 1232 (s), 1146 (s), 1085 (s), 842 (s),
820 (s), 760 (s) cm−1.
1-Methyl-4-(1-p-tolylethylsulfonyl)benzene (6ea) [CAS: 1244620-
48-1]. The compound was prepared according to method A from p-
tolyl ethyl sulfone (92.1 mg, 0.50 mmol), 4-bromotoluene (103 mg,
0.60 mmol), Pd(dba)2 (5.75 mg, 0.01 mmol), XPhos (4.77 mg, 0.01
mmol), and tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The
desired product (110 mg, 0.40 mmol) was obtained after
chromatography (silica gel, heptane/ethyl acetate gradient) in 81%
yield as a colorless solid. 1H NMR (400 MHz, CDCl3) δ = 1.72 (d, J =
7.02 Hz, 3 H), 2.33 (s, 3 H), 2.40 (s, 3 H), 4.19 (q, J = 7.02 Hz, 1 H),
7.01−7.09 (m, 4 H), 7.20 (d, J = 7.81 Hz, 2 H), 7.41−7.49 (m, 2 H)
ppm; 13C{1H}NMR (100 MHz, CDCl3) δ = 14.1, 21.1, 21.5, 65.6,
128.9, 129.2, 129.2, 129.2, 130.7, 133.9, 138.5, 144.3 ppm; MS (EI):
m/z (%) = 273 [M]+ (1), 195 (1), 165 (1), 139 (1), 119 (100), 91
(20), 65 (10); IR: υ = 2927 (w), 1512 (w), 1448 (w), 1378 (m), 1298
(s), 1140 (s), 1084 (m), 1042 (m), 816 (m), 144 (m) cm−1. The
obtained data match those reported in the literature.31
(p-Methyl-benzyl) Methyl Sulfoxide (6ga) [CAS: 5936-94-7]. The
title compound was prepared according to method B from dimethyl
sulfone (47.1 mg, 0.50 mmol), 4-bromotoluene (103 mg, 0.60 mmol),
Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and
tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired
product (90.3 mg, 0.49 mmol) was obtained after chromatography
(silica gel, heptane/ethyl acetate gradient) in 98% yield as a colorless
4-(4-Methylbenzylsulfonyl)anisole (6ba) [CAS: 108545-54-6]. The
compound was prepared according to method B from p-anisyl methyl
sulfone (93.1 mg, 0.50 mmol), 4-bromotoluene (103 mg, 0.60 mmol),
Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and
tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired
product (132 mg, 0.48 mmol) was obtained after chromatography
(silica gel, heptane/ethyl acetate gradient) in 95% yield as a colorless
1
solid. H NMR (400 MHz, CDCl3) δ = 2.38 (s, 3 H), 2.75 (s, 3 H),
4.22 (s, 2 H), 7.19−7.25 (m, 2 H), 7.28−7.33 (m, 2 H) ppm;
13C{1H}NMR (100 MHz, CDCl3) δ = 21.2, 38.82, 61.0, 125.2, 129. 8,
130.3, 139.2 ppm; MS (EI): m/z (%) = 184 [M]+ (5), 105 (100), 77
(15); IR: υ = 2923 (w), 1515 (w), 1452 (w), 1302 (s), 1258 (m), 1159
(m), 1120 (s), 975 (w), 888 (m), 821 (m), 758 (w) cm−1. The
obtained data match those reported in the literature.38
1
solid. H NMR (400 MHz, CDCl3) δ = 2.32 (s, 3 H), 3.85 (s, 3 H),
4.24 (s, 2 H), 6.86−6.93 (m, 2 H), 6.94−7.00 (m, 2 H), 7.07 (d, J =
8.20 Hz, 2 H), 7.50−7.57 (m, 2 H) ppm; 13C{1H}NMR (100 MHz,
CDCl3) δ = 21.1, 55.5, 62.7, 113.9, 125.2, 129.1, 129.5, 130.6, 130.7,
138.5, 163.6 ppm; MS (EI): m/z (%) = 276 [M+] (3), 233 (1), 212
(2), 178 (1), 155 (1), 126 (1), 105 (100), 77 (15); IR: υ = 2969 (w),
1592 (m), 1496 (m), 1296 (s), 1258 (s), 1135 (s), 1086 (s), 1017
(m), 817 (s), 665 (s) cm−1. The obtained data match those reported in
the literature.37
N-((1-(p-Tolyl)ethyl)sulfonyl)-1,2,3,4-tetrahydroquinoline (10aa).
The compound was prepared according to method B from N-
(ethylsulfonyl)-1,2,3,4-tetrahydroquinoline (113 mg, 0.50 mmol), 4-
bromotoluene (103 mg, 0.60 mmol), Pd(dba)2 (28.8 mg, 0.05 mmol),
XPhos (25.1 mg, 0.05 mmol), and tmp·ZnCl·LiCl solution (2.5 M,
1.25 mmol, 5.0 mL). The desired product (125 mg, 0.40 mmol) was
obtained after chromatography (silica gel, heptane/ethyl acetate
1-Chloro-4-(4-methylbenzylsulfonyl)benzene (6ca) [CAS:
108545-52-4]. The compound was prepared according to method A
1
gradient) in 79% yield as a light yellow oil. H NMR (400 MHz,
J
DOI: 10.1021/acs.joc.6b01062
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
CDCl3) δ = 1.43 (m, 1 H), 1.71 (m, 1 H), 1.83 (d, J = 7.02 Hz, 3 H),
2.36 (s, 3 H), 2.43−2.53 (m, 1 H), 2.63−2.73 (m, 1 H), 3.08−3.17
(m, 1 H), 3.42−3.53 (m, 1 H), 4.55 (q, J = 7.02 Hz, 1 H), 6.99−7.04
(m, 1 H), 7.05−7.09 (m, 1 H), 7.12 (s, 4 H), 7.14−7.20 (m, 1 H), 7.60
(d, J = 8.20 Hz, 1 H) ppm; 13C{1H}NMR (100 MHz, CDCl3) δ =
15.5, 21.1, 22.1, 27.1, 47.3, 62.0, 120.2, 123.1, 126.5, 128.0, 129.0,
129.1, 129.7, 131.3, 137.3, 138.7 ppm; MS (EI): m/z (%) = 315 [M]+
(1), 281 (1), 251 (20), 298 (1), 180 (1), 160 (1), 139 (55), 119 (100),
91 (10); IR: υ = 2937 (w), 1513 (w), 1489 (s), 1453 (m), 1331 (s),
1235 (m), 1145 (s), 1087 (m), 978 (m), 910 (m), 850 (s), 728 (s)
cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C18H21NNaO2S:
338.1185; found: 338.1186.
N-((1-(p-Anisyl)ethyl)sulfonyl)-1,2,3,4-tetrahydroquinoline
(10ab). The compound was prepared according to method B from N-
(ethylsulfonyl)-1,2,3,4-tetrahydroquinoline (113 mg, 0.50 mmol), 4-
bromoanisole (112 mg, 0.60 mmol), Pd(dba)2 (28.8 mg, 0.05 mmol),
XPhos (25.1 mg, 0.05 mmol), and tmp·ZnCl·LiCl solution (2.5 M,
1.25 mmol, 5.0 mL). The desired product (98.4 mg, 0.30 mmol) was
obtained after chromatography (silica gel, heptane/ethyl acetate
gradient) in 59% yield as a colorless oil. 1H NMR (400 MHz,
CDCl3) δ = 1.35−1.49 (m, 1 H), 1.71 (m, 1 H), 1.81 (d, J = 7.02 Hz, 3
H), 2.42−2.54 (m, 1 H), 2.61−2.74 (m, 1 H), 3.06−3.17 (m, 1 H),
3.41−3.52 (m, 1 H), 3.75−3.84 (m, 3 H), 4.52 (q, J = 7.02 Hz, 1 H),
6.79−6.86 (m, 2 H), 6.98−7.04 (m, 1 H), 7.04−7.09 (m, 1 H), 7.10−
7.19 (m, 3 H), 7.59 (d, J = 8.20 Hz, 1 H) ppm; 13C{1H}NMR (100
MHz, CDCl3) δ = 15.6, 22.2, 27.2, 47.3, 55.3, 61.7, 113.8, 120.2, 123.1,
126.3, 126.5, 128.0, 129.7, 130.4, 137.3, 159.9 ppm; MS (EI): m/z (%)
= 331 [M]+ (1), 267 (15), 238 (1), 217 (1), 194 (1), 154 (1), 135
(100), 105 (20), 77 (10); IR: υ = 2937 (w), 1609 (w), 1512 (s), 1488
(s), 1453 (s), 1330 (s), 1249 (s), 1179 (s), 1143 (s), 1086 (m), 1023
(s), 833 (s), 753 (s) cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C18H21NNaO3S: 354.1134; found: 354.1127.
[M]+ (25), 267 (65), 236 (5), 197 (2), 151 (50), 132 (100), 104 (30),
77 (28); IR: υ = 2941 (w), 1520 (s), 1488 (s), 1453 (m), 1339 (s),
1235 (m), 1145 (s), 1119 (m), 1042 (m), 978 (m), 853 (s), 755 (s),
695 (s) cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C17H18N2NaO4S: 369.0879; found: 369.0881.
N-(1-(6-Methylpyridin-3-yl)ethylsulfonyl)-1,2,3,4-tetrahydro-
quinoline (10ae). The compound was prepared according to method
B from N-(ethylsulfonyl)-1,2,3,4-tetrahydroquinoline (113 mg, 0.50
mmol), 5-bromo-2-methylpyridine (103 mg, 0.60 mmol), Pd(dba)2
(28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and tmp·ZnCl·
LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired product (19.6
mg, 0.06 mmol) was obtained after chromatography (silica gel,
heptane/ethyl acetate gradient) in 19% yield as a yellow oil. 1H NMR
(400 MHz, CDCl3) δ = 1.22−1.31 (m, 2 H), 1.42−1.46 (m, 2 H),
1.67−1.80 (m, 2 H), 1.82 (d, J = 7.02 Hz, 3 H), 2.55 (s, 3 H), 2.64−
2.75 (m, 1 H), 3.20−3.26 (m, 1 H), 3.47−3.57 (m, 1 H), 4.54 (q, J =
7.41 Hz, 1 H), 6.94−7.11 (m, 2 H), 7.11−7.18 (m, 2 H), 7.58 (d, J =
8.59 Hz, 1 H), 7.63 (dd, J = 8.20 Hz, J = 2.34 Hz, 1 H), 8.14 (d, J =
2.34 Hz, 1 H) ppm; 13C{1H}NMR (100 MHz, CDCl3) δ = 15.5, 22.3,
24.1, 27.1, 47.3, 59.6, 120.2, 120.4, 123.2, 123.6, 126.7, 128.3, 130.0,
136.6, 136.9, 149.7, 159.1 ppm; MS (EI): m/z (%) = 316 [M]+ (10),
280 (1), 252 (30), 196 (2), 160 (1), 138 (75), 120 (100), 96 (10), 77
(20); IR: υ = 2930 (w), 1600 (w), 1489 (s), 1452 (m), 1333 (s), 1235
(w), 1145 (s), 1086 (m), 1021 (m), 978 (m), 849 (s), 754 (s) cm−1;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H20N2NaO2S:
339.1138; found: 339.1135.
1-(1-(6-Isopropoxypyridin-3-yl)ethylsulfonyl)-1,2,3,4-tetrahydro-
quinoline (10af). The compound was prepared according to method
B from N-(ethylsulfonyl)-1,2,3,4-tetrahydro-quinoline (113 mg, 0.50
mmol), 5-bromo-2-isopropoxy pyridine (130 mg, 0.60 mmol, 94 μL),
Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and
tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired
product (73.4 mg, 0.20 mmol) was obtained after chromatography
(silica gel, heptane/ethyl acetate gradient) in 41% yield as a yellow oil.
1H NMR (400 MHz, CDCl3) δ = 1.33 (d, J = 6.24 Hz, 6 H), 1.41−
1.52 (m, 1 H), 1.71−1.78 (m, 1 H), 1.80 (d, J = 7.02 Hz, 3 H), 2.47−
2.59 (m, 1 H), 2.65−2.76 (m, 1 H), 3.25−3.30 (m, 1 H), 3.48−3.58
(m, 1 H), 4.49 (q, J = 7.02 Hz, 1 H), 5.25 (quin., J = 6.24 Hz, 1 H),
6.65 (d, J = 8.59 Hz, 1 H), 6.97−7.03 (m, 1 H), 7.04−7.09 (m, 1 H),
7.10−7.17 (m, 1 H), 7.53−7.61 (m, 2 H), 7.76 (d, J = 2.73 Hz, 1 H)
ppm; 13C{1H}NMR (100 MHz, CDCl3) δ = 15.4, 21.9, 22.3, 27.1,
47.3, 59.3, 68.3, 111.6, 120.3, 122.6, 123.5, 126.6, 128.1, 129.9, 137.1,
138.7, 147. 7, 163.7 ppm; MS (EI): m/z (%) = 369 [M]+ (1), 346 (1),
317 (1), 296 (15), 239 (1), 196 (91), 164 (45), 142 (30), 122 (100),
94 (15), 67 (5); IR: υ = 2977 (w), 2936 (w), 1604 (s), 1484 (s), 1333
(s), 1306 (s), 1281 (s), 1144 (s), 1105 (s), 1018 (m), 948 (m), 847
(s), 753 (s) cm−1. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C19H24N2NaO3S: 383.1400; found: 383.1401.
N-((1-(4-Trifluoromethylphenyl)ethyl)sulfonyl)-1,2,3,4-tetrhydro-
quinoline (10ac). The compound was prepared according to method
B from N-(ethylsulfonyl)-1,2,3,4-tetrahydro-quinoline (113 mg, 0.50
mmol), 4-bromobenzotrifluoride (135 mg, 0.60 mmol, 84 μL),
Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and
tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired
product (126 mg, 0.34 mmol) was obtained after chromatography
(silica gel, heptane/ethyl acetate gradient) in 68% yield as a colorless
solid that crystallized slowly. 1H NMR (400 MHz, CDCl3) δ = 1.37−
1.50 (m, 1 H), 1.69−1.81 (m, 1 H), 1.85 (d, J = 7.02 Hz, 3 H), 2.42−
2.50 (m, 1 H), 2.65−2.73 (m, 1 H), 3.19−3.25 (m, 1 H), 3.47−3.57
(m, 1 H), 4.63 (q, J = 7.28 Hz, 1 H), 6.99−7.09 (m, 2 H), 7.16 (m, 1
H), 7.37 (d, J = 8.20 Hz, 2 H), 7.52−7.60 (m, 3 H) ppm;
13C{1H}NMR (100 MHz, CDCl3) δ = 15.7, 22.3, 27.1, 47.4, 62.0,
120.4, 123.7, 123.8 (q, 1JC−F = 272.16 Hz), 125.4 (q, 3JC−F = 3.91 Hz),
2
126.7, 128.2, 129.7, 129.9, 131.0 (q, JC−F = 32.28 Hz), 137.0, 138.5
(q, 4JC−F = 1.47 Hz) ppm; 19F NMR (377 MHz, CDCl3) δ = −62.8 (s)
ppm; MS (EI): m/z (%) = 369 [M]+ (15), 290 (50), 262 (2), 197 (2),
173 (85), 153 (40), 133 (100), 103 (20) 77 (25); IR: υ = 2940 (w),
1489 (m), 1454 (w), 1418 (w), 1322 (s), 1146 (s), 1116 (s), 1087 (s),
1068 (s), 1018 (m), 978 (m), 845 (s), 753 (s) cm−1; mp 64−66 °C.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C18H18F3NNaO2S:
392.0903; found: 392.0899.
N-(1-(N-Methyl-7-azaindol-5-yl)ethylsulfonyl)-1,2,3,4-tetrahydro-
quinoline (10ag). The compound was prepared according to method
B from N-(ethylsulfonyl)-1,2,3,4-tetrahydro-quinoline (113 mg, 0.50
mmol), N-methyl-5-bromo-7-azaindole (127 mg, 0.60 mmol), Pd-
(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and tmp·
ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The desired product
(93.1 mg, 0.26 mmol) was obtained after chromatography (silica gel,
heptane/ethyl acetate gradient) in 52% yield as a yellow oil. 1H NMR
(400 MHz, CDCl3) δ = 1.26−1.32 (m, 1 H), 1.58−1.70 (m, 1 H), 1.89
(d, J = 7.02 Hz, 3 H), 2.33−2.47 (m, 1 H), 2.56−2.68 (m, 1 H), 3.01−
3,07 (m, 1 H), 3.38−3.48 (m, 1 H), 3.82−3.89 (m, 3 H), 4.69 (q, J =
7.28 Hz, 1 H), 6.43 (d, J = 3.51 Hz, 1 H), 6.95−7.02 (m, 1 H), 7.02−
7.08 (m, 1 H), 7.11−7.17 (m, 1 H), 7.20 (d, J = 3.51 Hz, 1 H), 7.63
(d, J = 8.20 Hz, 1 H), 7.89 (d, J = 1.95 Hz, 1 H), 8.01 (d, J = 1.95 Hz,
1 H) ppm; 13C{1H}NMR (100 MHz, CDCl3) δ = 15.9, 22.2, 27.0,
31.3, 47.2, 60.3, 99.6, 120.1, 120.2, 121.8, 123.3, 126.5, 128.1, 129.0,
129.8, 130.1, 137.1, 143.8, 147.8 ppm; MS (EI): m/z (%) = 355 [M]+
(2), 291 (10), 243 (1), 191 (1), 159 (100), 133 (20), 103 (10), 77
(5); IR: υ = 2939 (w), 1515 (w), 1489 (m), 1453 (w). 1329 (s), 1234
(m), 1329 (s), 1234 (m), 1144 (s), 1085 (m), 979 (m), 906 (s), 850
(m), 720 (s) cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C19H22N3O2S: 356.1427; found: 356.1423.
N-((1-(4-Nitrophenyl)ethyl)sulfonyl)-1,2,3,4-tetrahydroquinoline
(10ad). The compound was prepared according to method B from N-
(ethylsulfonyl)-1,2,3,4-tetrahydroquinoline (113 mg, 0.50 mmol), 4-
bromo-1-nitrobenzene (121 mg, 0.60 mmol), Pd(dba)2 (28.8 mg, 0.05
mmol), XPhos (25.1 mg, 0.05 mmol), and tmp·ZnCl·LiCl solution
(2.5 M, 1.25 mmol, 5.0 mL). The desired product (133 mg, 0.38
mmol) was obtained after chromatography (silica gel, heptane/ethyl
1
acetate gradient) in 77% yield as a yellow oil. H NMR (400 MHz,
CDCl3) δ = 1.48−1.54 (m, 1 H), 1.73−1.83 (m, 1 H), 1.85 (d, J =
7.02 Hz, 3 H), 2.46−2.54 (m, 1 H), 2.68−2.75 (m, 1 H), 3.21−3.27
(m, 1 H), 3.52−3.61 (m, 1 H), 4.67 (q, J = 7.28 Hz, 1 H), 7.00−7.11
(m, 2 H), 7.14−7.20 (m, 1 H), 7.41−7.47 (m, 2 H), 7.57 (d, J = 8.20
Hz, 1 H), 8.12−8.20 (m, 2 H) ppm; 13C{1H}NMR (100 MHz,
CDCl3) δ = 15.7, 22.4, 27.1, 47.4, 61.8, 120.4, 123.6, 123.8, 126. 8,
128.2, 129.9, 130.2, 136.8, 141.6, 148.0 ppm; MS (EI): m/z (%) = 346
K
DOI: 10.1021/acs.joc.6b01062
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The Journal of Organic Chemistry
Article
N-(1-p-Tolylethylsulfonyl)-2,3,4,5-tetrahydrobenzoazepine
(10ba). The compound was prepared according to method B from N-
(ethylsulfonyl)-2,3,4,5-tetrahydrobenzoazepine (120 mg, 0.50 mmol),
4-bromotoluene (103 mg, 0.60 mmol), Pd(dba)2 (28.8 mg, 0.05
mmol), XPhos (25.1 mg, 0.05 mmol), and tmp·ZnCl·LiCl solution
(2.5 M, 1.25 mmol, 5.0 mL). The desired product (153 mg, 0.46
mmol) was obtained after chromatography (silica gel, heptane/ethyl
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Chris Helal and Dr. Kevin Hesp along with
Matthew Reese for fruitful discussion and Dr. Anabella
Villalobos for support.
1
acetate gradient) in 93% yield as a light yellow oil. H NMR (400
MHz, CDCl3) δ = 1.77 (d, J = 7.02 Hz, 3 H), 2.34 (s, 3 H), 2.76−2.94
(m, 4 H), 2.96−3.24 (m, 4 H), 4.18 (q, J = 7.28 Hz, 1 H), 7.02−7.09
(m, 2 H), 7.10−7.17 (m, 4 H), 7.26 (d, J = 8.20 Hz, 2 H) ppm;
13C{1H}NMR (100 MHz, CDCl3) δ = 16.0, 21.2, 39.1, 48.8, 62.9,
126.5, 128.8, 129.3, 129.6, 132.0, 134.3, 138.6, 140.8 ppm; MS (EI):
m/z (%) = 329 [M]+ (1), 250 (60), 174 (5), 147 (15), 119 (100), 91
(20); IR: υ = 2913 (w), 1514 (w), 1450 (w), 1357 (w), 1322 (s), 1307
(s), 1140 (s), 1083 (m), 1032 (m), 937 (w), 893 (s), 822 (s), 728 (s)
cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C19H23NNaO2S:
352.1342; found: 352.1338.
N-(2-Methoxypyridin-3-yl)-1-p-tolyl-N-((2-(trimethylsilyl)ethoxy)-
methyl)ethanesulfonamide (10ca). The compound was prepared
according to method B from N-(2-methoxypyridin-3-yl)-N-((2-
(trimethylsilyl)ethoxy)methyl)ethanesulfonamide (173 mg, 0.50
mmol), 4-bromotoluene (103 mg, 0.60 mmol), Pd(dba)2 (28.8 mg,
0.05 mmol), XPhos (25.1 mg, 0.05 mmol), and tmp·ZnCl·LiCl
solution (2.5 M, 1.25 mmol, 5.0 mL). The desired product (142 mg,
0.33 mmol) was obtained after chromatography (silica gel, heptane/
ethyl acetate gradient) in 65% yield as a light yellow oil. 1H NMR (400
MHz, CDCl3) δ = −0.01 (s, 9 H), 0.78−0.88 (m, 2 H), 1.77 (d, J =
7.41 Hz, 3 H), 2.36 (s, 3 H), 3.63 (t, J = 8.39 Hz, 2 H), 4.05 (s, 3 H),
4.21 (d, J = 7.41 Hz, 1 H), 4.61−4.80 (m, 2 H), 6.91 (dd, J = 7.61 Hz,
J = 4.88 Hz, 1 H), 7.18 (d, J = 7.80 Hz, 2 H), 7.37 (d, J = 8.20 Hz, 2
H), 7.47−7.55 (m, 1 H), 8.14 (dd, J = 4.88 Hz, J = 1.76 Hz, 1 H) ppm;
13C{1H}NMR (100 MHz, CDCl3) δ = −1. 5, 21.2, 22.7, 31.9, 53.6,
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64.2, 65.2, 79.4, 117.3, 121.3, 129.1, 129.3, 131.6, 138.6, 142.2, 146.6,
159.8 ppm; MS (EI): m/z (%) = 436 [M]+ (1), 407 (1), 378 (5), 343
(2), 299 (2), 260 (20), 241 (40), 196 (10), 165 (2), 138 (20), 119
(100), 93 (10), 73 (40); IR: υ = 2052 (w), 1586 (w), 1469 (s), 1409
(s), 1340 (s) 1300 (m), 1248 (m), 1214 (m), 1157 (s), 1079 (s), 1014
(s), 908 (s), 822 (s), 728 (s), cm−1; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C21H32N2NaO4SSi: 459.1744; found: 459.1745.
N,N-Diphenyl-1-p-tolylmethanesulfonamide (10da). The com-
pound was prepared according to method B from N,N-diphenyl-
methanesulfonamide (124 mg, 0.50 mmol), 4-bromotoluene (103 mg,
0.60 mmol), Pd(dba)2 (28.8 mg, 0.05 mmol), XPhos (25.1 mg, 0.05
mmol), and tmp·ZnCl·LiCl solution (2.5 M, 1.25 mmol, 5.0 mL). The
desired product (54.6 mg, 0.16 mmol) was obtained after
chromatography (silica gel, heptane/ethyl acetate gradient) in 32%
yield as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ = 2.36 (s,
3 H); 4.40 (s, 2 H); 7.06−7.12 (m, 4 H), 7.15−7.28 (m, 10 H) ppm;
13C{1H}NMR (100 MHz, CDCl3) δ = 21.2, 57.6, 125.4, 126.8, 127.5,
129.2, 129.5, 131.0, 138. 9, 141.2 ppm, MS (EI): m/z (%) = 337 [M]+
(3), 295 (1), 273 (50), 243 (1), 222 (1), 190 (2), 167 (20), 139 (5),
105 (100), 77 (20) cm−1; IR: υ = 2971 (w), 1588 (w), 1486 (s), 1338
(s), 1251 (m), 1156 (s), 1130 (s), 1028 (m), 962 (s), 903 (m), 866
(m), 828 (m), 756 (s) cm−1; mp 103−105 °C. HRMS (ESI-TOF) m/
z: [M + Na]+ calcd for C20H19NNaO2S: 360.1029; found: 360.1031.
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ASSOCIATED CONTENT
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* Supporting Information
(15) (a) Shavnya, A.; Coffey, S. B.; Smith, A. C.; Mascitti, V. Org.
Lett. 2013, 15, 6226−6229. (b) Rocke, B. N.; Bahnck, K. B.; Herr, M.;
Lavergne, S.; Mascitti, V.; Perreault, C.; Polivkova, J.; Shavnya, A. Org.
Lett. 2014, 16, 154−157. (c) Shavnya, A.; Hesp, K. D.; Mascitti, V.;
Smith, A. C. Angew. Chem., Int. Ed. 2015, 54, 13571−13575. (d) Tsai,
A. S.; Curto, J. M.; Rocke, B. N.; Dechert-Schmitt, A.-M. R.; Ingle, G.
K.; Mascitti, V. Org. Lett. 2016, 18, 508−511.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01062.
1H, 13C, and 19F NMR spectral data of all compounds are
reported (PDF)
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: thomas.knauber@pfizer.com.
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DOI: 10.1021/acs.joc.6b01062
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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