Palladium-Catalyzed α-Arylation of Methyl Sulfonamides with Aryl Chlorides

Article abstract of DOI:10.1002/adsc.201600090

A palladium-catalyzed α-arylation of sulfonamides with aryl chlorides is presented. A Buchwald-type pre-catalyst formed with Kwong’s indole-based ligand enabled this transformation to be compatible with a large variety of methyl sulfonamides and aryl chlorides in good to excellent yields. Importantly, under the optimized reaction conditions, only mono-arylated products were observed. This method has been applied to the efficient synthesis of sumatriptan, which is used to treat migraines. (Figure presented.) .

Full text of DOI:10.1002/adsc.201600090

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DOI: 10.1002/adsc.201600090
Palladium-Catalyzed a-Arylation of Methyl Sulfonamides with
Aryl Chlorides
a,b,
b
a
b,c
b,
Bing Zheng, * Minyan Li, Gui Gao, Yuying He, and Patrick J. Walsh *
a
Department of Applied Chemistry, China Agricultural University, Beijing 100193, Peopleꢀs Republic of China
E-mail: 2014026@cau.edu.cn
b
Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of
Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, USA
Fax : (+1)-215-573-6743; e-mail: pwalsh@sas.upenn.edu
Department of Chemistry, University of Pierre and Marie Curie, Paris 75005, France
c
Received: January 21, 2016; Revised: April 11, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600090.
Abstract:
A palladium-catalyzed a-arylation of only mono-arylated products were observed. This
sulfonamides with aryl chlorides is presented. A method has been applied to the efficient synthesis of
ACHTUNGTRENNUNG
Buchwald-type pre-catalyst formed with Kwongꢀs sumatriptan, which is used to treat migraines.
indole-based ligand enabled this transformation to
be compatible with a large variety of methyl sulfona-
mides and aryl chlorides in good to excellent yields. Keywords: aryl chlorides; arylation; palladium-cata-
Importantly, under the optimized reaction conditions, lyzed reaction; sulfonamides; sumatriptan
Introduction
CÀC bonds is an attractive route to these important
compounds, such transformations have met with limit-
Sulfonamides are widely occurring in synthetic inter- ed success.
[
1]
mediates and bioactive compounds. They are also
important structural motifs in drugs such as Almotrip-
A viable approach to the a-arylation of sulfon-
AHCTUNGTREGUNaNN mides is that used in the arylation of ketones and
[2]
[3]
[4]
[9]
tan, Avitriptan and Sumatriptan (Figure 1). Pre- esters. Due to the synthetic utility of a-arylated car-
vious methods to access sulfonamides range from bonyl compounds, the arylation of these substrates
[
5]
simple NÀS bond formation, to tandem reactions has been investigated by numerous research groups.
[
6]
[7]
that also include S=O, CÀS, and CÀN bond-form-
Despite similarities between a-arylation of ketones
[8]
ing reactions. Although a-arylation of unfunctional- and a-arylation of sulfonamides, the pK values of the
a
ized methyl sulfonamides with aryl halides to form a-hydrogens of sulfonamides, such as CH SO NR ,
3
2
2
[
10,11]
are estimated to be in the range of 32–35.
This
high pK value is approaching those of the a-hydro-
a
gens of acetamides, CH CONR , which have proved
3
2
to be very challenging substrates in arylation reac-
[
10]
tions.
Early studies on the a-arylation of methyl sulfon-
[
11]
AHCTUNGTRENNUNG
2
3
mides and gave moderate yields (average yield with
Ph-Br of 44%). The dominant by-products in these
reactions were derived from deprotonation of the
more acidic monoarylation product and subsequent
arylation to provide diarylated products. Recently,
Renꢁ and co-workers explored the arylation of cyclic
[
12]
sulfonamides (sultams). They noted that the aryla-
tion did not provide any product in the presence of
LiN(SiMe ) , KN(SiMe ) , NaO-t-Bu, or TMP-
Figure 1. Sulfonamide motifs in drugs.
3
2
3 2
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the zinc salts increases the cost and lowers the overall
atom economy.
Despite these efforts, a general direct intermolecu-
lar CÀH a-arylation of methyl sulfonamides with
more economical and abundant aryl chlorides is
scarcely reported. Herein, we report the first chemo-
selective mono-arylation of methyl sulfonamides with
aryl chlorides (Scheme 1, D). A Buchwald-type pre-
[
15]
catalyst
formed with Kwongꢀs indole-based
[
16]
ligand and alkoxide base led to formation of mono-
arylation products, with no diarylation observed. This
method has been applied to the efficient synthesis of
the marketed medication sumatriptan.
Results and Discussion
Two important variables in the development of aryla-
3
tion of weakly acidic C(sp )ÀHꢀs are (i) identification
of a suitable ligand and (ii) choice of a palladium pre-
cursor that will efficiently generate the catalyst.
Based on our previous experience in the palladium-
[
17]
[18]
catalyzed a-arylation of sulfoxides, sulfones, and
amides,
[
19]
we initiated studies of the coupling be-
tween 1-(methylsulfonyl)piperidine 1a and aryl chlor-
ides employing Buchwaldꢀs palladium pre-catalysts
(
see Table 1 for structures).
Using microscale (10 umol) high throughput experi-
[
20]
mentation (HTE) techniques we examined the cou-
pling between 1-(methylsulfonyl)piperidine 1a and 4-
tert-butyl-1-chlorobenzene 2b by screening ligands
(
Scheme 2) known to perform well in many coupling
reactions. A total of 37 electronically diverse mono-
and bidentate phosphines were examined using Buch-
waldꢀs 2 generation palladium dimer, LiO-t-Bu as
Scheme 1. Palladium-catalyzed a-arylation of sulfonamides.
nd
base, toluene as solvent at 1108C for 24 h (see the
Supporting Information for details). In the ligand
MgCl·LiCl bases. Arylation of sultams was observed screen, the reaction using Kwongꢀs indole-based
with TMP-ZnCl·LiCl, aryl iodides, and 10 mol% of ligand exhibited the highest assay yield based on the
a Pd(RuPhos)-based catalyst (Scheme 1, B). One ex- product/internal standard ratio (2.05) (determined by
ample with chlorobenzene was presented in this study integration of the product against the biphenyl inter-
that gave 39% yield. The results from these two nal standard by HPLC (UV/vis, see the Supporting
groups suggest that the direct CÀH arylation of Information for details). Other ligands that showed
sulfonamides is a challenging reaction.
good HPLC assay yields were cataCXium ABn
The Zhou group also reported difficulties in the (1.83), JosiPhos (1.75), P(t-Bu)3 (1.42), DavePhos
[13]
direct CÀH functionalization of sulfonamides. They (1.36), MePhos (1.33).
found that the reaction of 1-(methylsulfonyl)piperi-
With the best ligand hit, we next conducted
dine, bromobenzene, and LiN(SiMe ) in the presence a second microscale screen (0.01 mmol) focusing
3
2
of a palladium catalyst failed to give coupling prod- on six bases [LiO-t-Bu, NaO-t-Bu, KO-t-Bu,
uct. Switching to a Negishi coupling with intermediate LiN(SiMe ) , NaN(SiMe ) , and KN(SiMe ) ] and four
3
2
3
2
3 2
transmetallation to zinc, they discovered that the solvents [THF, CPME, DME, toluene] with Buch-
nd
rd
combination of 1.25 equiv. LiN(SiMe ) and 1.5 equiv. waldꢀs 2 and 3 generation palladium dimers (see
3
2
of ZnCl2 with methyl sulfonamides and a Pd(X- the Supporting Information for details). The most
Phos)-based catalyst resulted in cross-coupling to fur- promising hit from this screen was LiO-t-Bu, Buch-
nd
nish the arylation product in good to excellent yields wald-type 2 generation palladium dimer in toluene
[14]
(
Scheme 1, C).
Although the transmetallation to at 1108C. On a laboratory scale (0.1 mmol), such con-
zinc facilitated the coupling process, introduction of ditions led to the desired arylation product in 96%
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Table 1. Optimization of a-arylation of sulfonamide 1a with
[a,b]
Ar-Cl 2b.
Entry Dimer/L
mol%]
Conc.
[M]
Temp.
[ C]
Assay yield
[%]
o
[
1
2
3
4
5
6
5/20
5/20
5/20
5/20
2.5/10
1.25/5
0.2
0.1
0.05
0.2
0.2
0.2
110
110
110
80
110
110
96
88
80
66
87 (85)
75
[c]
[
[
[
a]
Reactions conducted on a 0.1 mmol scale using 1 equiv.
of 1a, 3 equiv. of LiO-t-Bu, and 2 equiv. of ArCl.
b]
c]
1
Yields determined by H NMR spectroscopy of the crude
reaction mixtures on a 0.1 mmol scale.
Isolated yield after chromatographic purification.
yield. Electron poor 4-chlorobenzophenone afforded
ae in 57% yield at 10 mol% Pd loading in CPME.
3
Sterically hindered 2-chlorotoluene (2f) delivered de-
sired product 3af in 70% yield. Aryl chlorides bearing
various substituents at the 3-position were good sub-
strates. For example, 3-chlorotoluene furnished the
product (3ag) in 75% yield, 3-chloro-N,N-dimethyl-
Scheme 2. Ligand screening.
1
assay yield (determined by H NMR analysis, Table 1,
ACHTUNGTRENNUNGa niline provided 3ah in 78% yield (10 mol% Pd in
entry 1). Changing the concentration from 0.2 to 0.1 CPME), 1-chloro-3,5-dimethoxybenzene led to 3ai in
and 0.05M resulted in decreased assay yields to 88% 79% yield (10 mol% Pd in CPME), and 1-chloro-3,5-
and 80%, respectively (entries 2 and 3). A significant difluorobenzene resulted in formation of 3aj in 60%
decrease in assay yield to 66% was observed when yield. Heteroaryl chlorides 3-chloropyridine and 5-
lowering the temperature to 808C (entry 4). Further chloroquinoline were coupled with 1a to afford 3ak
optimization of the catalyst loading indicated that the and 3al in 72% and 63% yield, respectively, after ex-
assay yield fell to 87% at 5 mol% Pd (entry 5) and tending reaction times to 48 h.
dropped to 75% at 2.5 mol% (entry 6). Using
.0 mol% palladium, the isolated yield was 85%
We next examined the substrate scope of sulfon-
5
ACHTUNGTRENNUNG
(
entry 5).
Starting from the optimized conditions (Table 1,
ACHTUNGTRENNGNUa mide (1b) was sluggish under the optimized condi-
entry 5), we explored the scope of the reaction tions, and required increasing Pd loading from 5 to
Table 2). In general, mono-arylated products were 10 mol% to afford product 3ba in 75% yield. Mor-
(
formed with very good yields. Chlorobenzene ren- pholine substituted sulfonamide 1c underwent cou-
dered product 3aa in 80% yield. Aryl chlorides bear- pling with chlorobenzene to give product 3ca in 69%
ing electron donating 4-t-Bu (2b) and 4-methoxy (2c) yield under the standard conditions. Acyclic sub-
groups provided products in excellent yields at 5 and strates N,N-dimethyl (1d) and N,N-diethyl (1e)
10 mol% Pd loading (85% and 79% yield, respective- methyl sulfonamides coupled with chlorobenzene to
ly, for 3ab and 3ac). 4-Fluoro-1-chlorobenzene was form the mono-arylated products 3da and 3ea in 78%
successfully coupled with 1a to afford 3ad in 69% and 63% yield, respectively. Extending the alkyl
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Table 2. Substrate scope of aryl chlorides in the a-arylation
of sulfonamide 1a with Kwongꢀs indole-based phosphine.
Table 3. Substrate scope of sulfonamides in the a-arylation
of aryl chloride 2a.
[a]
[a]
[
[
a]
b]
Reactions conducted on a 0.2 mmol scale using 1 equiv.
of sulfonamide, 3 equiv. of LiO-t-Bu, and 2 equiv. of
PhCl. Isolated yield after chromatographic purification.
1
0 mol% Pd loading.
[
a]
Reactions conducted on a 0.2 mmol scale using 1 equiv.
of 1a, 3 equiv. of LiO-t-Bu, and 2 equiv. of ArCl. Isolated
yields after chromatographic purification.
[
[
b]
c]
1
1
0 mol% Pd loading in CPME.
0 mol% Pd loading after 48 h.
group to N,N-diisopropyl rendered product 3fa in
0% yield. Furthermore, N-benzyl-N-methyl, N-
benzyl-N-isopropyl, and N-benzyl-N-phenyl-substitut-
8
ed sulfonamides led to satisfactory yields of arylation Scheme 3. Gram scale synthesis of 3fa.
products 3ga, 3ha, 3ia in 83, 70 and 70% yield, respec-
tively, without any arylation at the benzylic positions
[21]
observed.
thylamino)ethyl]-1H-indole-1-carboxylate (2m). The
We desired to evaluate the scalability of our coupling between 1g and 2m under standard condi-
method (Scheme 3). We conducted the arylation of tions followed by removal of the protecting group
N,N-diisopropylmethanesulfonamide 1f with chloro- gave rise to sumatriptan in 75% yield (Scheme 4).
benzene 2a on an 8 mmol scale with 5.0 mol% Pd
loading. The product 3fa was isolated in 82% yield
(
1.67 g).
Conclusions
We next applied our method in the synthesis of
a marketed pharmaceutical. Sumatriptan is a 5-HT re- In summary, benzylic sulfonamides are an important
[22]
ceptor agonist used in the treatment of migraines. class of bioactive compounds and marketed pharma-
The synthesis of sumatriptan (3ja) was envisioned ceuticals. One can envision the rapid assembly of an
through the coupling of N-benzyl-N-methylmethane- array of such compounds from methyl sulfonamides
sulfonamide (1g) with tert-butyl 5-chloro-3-[2-(dime- and commercially available aryl halides, however, an
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General Experimental Procedure: High-Throughput
Experimentation Screening for Palladium-Catalyzed
a-Arylation of Methyl Sulfonamides with Aryl
Chlorides
(
1) Screening of ligand: Set up: Two 24-well plate experi-
ments were set up inside a glovebox under a nitrogen at-
mosphere. A 24-well aluminum block containing 1 mL glass
nd
vials was predosed with Buchwald-type 2 generation palla-
dium dimer (0.5 mmol) and the phosphine ligands (2 mmol
for monodentate ligands and 1 mmol for bidentate ligands)
in THF. The solvent was removed to dryness using a Gene-
Vac and LiO-t-Bu (30 mmol) in THF was added to the
ligand/catalyst mixture. The solvent was removed on the
GeneVac and a parylene stir bar was then added to each re-
action vial. 1-(Methylsulfonyl)piperidine 1a (10 mmol/reac-
tion) and 4-tert-butyl-1-chlorobenzene 2b (20 mmol) were
then dosed together into each reaction vial as a solution in
toluene (50 mL, 0.2M). The 24-well plate was then sealed
and stirred for 24 h at 1108C.
Scheme 4. Synthesis of sumatriptan (3ja).
a-arylation of methyl sulfonamides that avoids an in-
termediate transmetallation step remained elusive.
Herein, we advance the first general palladium-cata-
Work up: Upon opening the plate to air, 500 mL of a solu-
lyzed a-arylation of sulfonamides with aryl chlorides. tion of biphenyl (used as internal standard to measure
Under the optimized reaction conditions, good to ex- HPLC yields) in acetonitrile (0.002 mol/L) were added into
each vial. The plate was covered again and the vials stirred
cellent yields of mono-arylated methyl sulfonamides
for 10 min to ensure good homogenization. Into a separate
have been achieved.
9
6-well LC block were added 700 mL of acetonitrile, fol-
A significant finding of our research efforts into the
a-arylation of sulfonamides, sulfones, and sulfoxides
is that Kwongꢀs indole-based phosphine exhibits ex-
cellent selectivity with these challenging substrates.
Despite the increased acidity of the products over the
lowed by 25 mL of the diluted reaction mixtures. The LC
block was then sealed with a silicon-rubber storage mat and
mounted on an automated HPLC instrument for analysis.
(
2) Screening of Pd source, base and solvent: Set up: Ex-
periments were set up inside a glovebox under a nitrogen at-
starting materials by at lease 5 pK units, we observe mosphere. A 24-well aluminum block containing 1 mL glass
a
nd
mono-arylation with high selectivity. We hypothesize vials was predosed with 2 gen. Pd dimer (0.5 mmol) and
that the large size of Kwongꢀs ligand is responsible the N-(dicyclohexylphosphino)-2,2’-tolylindole (2 mmol) in
THF. The solvent was removed to dryness using a GeneVac
for the remarkable selectivity for the monoarylation
and
6 different bases [LiO-t-Bu, NaO-t-Bu, KO-t-Bu,
product in these reactions. We attribute the observed
selectivity to a slow rate of transmetallation of the de-
protonated benzyl sulfonamide with Pd(II) ligated to
Kwongꢀs bulky phosphine. It will be interesting to see
if our hypothesis above can be supported by success-
ful application of Kwongꢀs ligand to other systems
where diarylation is problematic.
LiN(SiMe ) , NaN(SiMe ) , KN(SiMe ) 30 mmol] in THF
3
2
3
2
3 2
were added to the ligand/catalyst mixture. The solvent was
removed on the GeneVac and a parylene stir bar was then
added to each reaction vial. 1-(Methylsulfonyl)piperidine 1a
(
10 mmol/reaction) and 4-tert-butyl-1-chlorobenzene 2b (20
mmol/reaction) were then dosed together into each reaction
vial as a solution in 4 different solvents (CPME, THF,
DME, toluene, 50 mL, 0.2M). The 24-well plate was then
sealed and stirred for 24 h at 1108C then cooled to room
temperature.
Experimental Section
Work up: Upon opening the plate to air, 500 mL of a solu-
tion of biphenyl (used as internal standard to measure
HPLC yields) in acetonitrile (0.002 mol/L) were added into
each vial. The plate was covered again and the vials stirred
for 10 min to ensure good homogenization. Into a separate
General Information
All reactions were carried out under an atmosphere of dry
nitrogen. Anhydrous dioxane, CPME, and toluene were pur-
chased from Sigma–Aldrich and used without further purifi-
cation. THF was dried through activated alumina columns.
Unless otherwise stated, all reagents were commercially
available and used without further purification. Flash chro-
matography was performed with silica gel (300–400 mesh).
The NMR spectra were obtained using a Brꢃker 500 MHz
Fourier-transform NMR spectrometer. High-resolution mass
spectrometry (HR-MS) data were obtained on a Waters LC-
TOF mass spectrometer (model LCT-XE Premier) using
chemical ionization (CI) or electrospray ionization (ESI) in
positive or negative mode, depending on the analyte.
9
6-well LC block were added 700 mL of acetonitrile, fol-
lowed by 25 mL of the diluted reaction mixtures. The LC
block was then sealed with a silicon-rubber storage mat and
mounted on an automated HPLC instrument for analysis.
Procedures for the Pd-Catalyzed Arylation of
Sulfonamides
An oven-dried microwave vial equipped with a stir bar was
nd
charged with 2 generation Pd dimer (7.2 mg, 0.010 mmol)
and ligand L (16.2 mg, 0.040 mmol) under a nitrogen atmos-
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phere, followed by 1 mL dry toluene via syringe. After the
catalyst solution had been stirred for 120 min at 258C, LiO-
t-Bu (48.3 mg, 0.60 mmol, 3.0 equiv.) was added to the reac-
tion vial and 1-(methylsulfonyl) piperidine (32.6 mg,
J. Am. Chem. Soc. 2013, 135, 10638–10641; d) B.
Nguyen, E. J. Emmett, M. C. Willis, J. Am. Chem. Soc.
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Commun. 2012, 48, 7753–7755.
0
.20 mmol, 1.0 equiv.) was added dropwise. The microwave
vial was sealed and chlorobenzene (40.6 mL, 0.40 mmol,
.0 equiv.) was added by syringe while under a nitrogen at-
[6] a) J. L. Garciꢄ Ruano, A. Parra, F. Yuste, V. M. Mas-
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2
mosphere. The reaction was stirred at 1108C for the speci-
fied time then allowed to cool to room temperature. The re-
action mixture was quenched with H O (0.2 mL) and passed
through a short pad of silica gel and eluted with ethyl ace-
tate. The combined organics were dried over Na SO and
2
2
4
concentrated under vacuum. The crude residue was purified
by flash column chromatography to yield the monoarylated
sulfonamides derivatives 3.
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Synthesis of Sumatriptan 3ja
1
The reaction was performed following the general procedure
with 2m (128.9 mg, 0.40 mmol), LiO-t-Bu (48.3 mg,
0.60 mmol) and 1g (39.8 mg, 0.20 mmol). Then the crude
[
[
material was reacted in CF COOH for 12 h. After work-up
3
following the general procedure, the product was purified
by flash chromatography on silica gel (eluted with
MeOH:CH Cl =2:1) to give the product 3ja as a white
2
2
1
13
1
solid; yield: 44.2 mg (75%). The H and C{ H} NMR data
for this compound match the literature data.
5
3, 742–746.
Acknowledgements
[
[
[
12] O. Renꢁ, B. P. Fauber, S. Malhotra, H. Yajima, Org.
Lett. 2014, 16, 3468–3471.
13] G. Zhou, P. Ting, R. Aslanian, J. J. Piwinski, Org. Lett.
We thank the National Science Foundation (CHE-1464744)
and National Institutes of Health (NIGMS 104349) for finan-
cial support. BZ thanks the Chinese Universities Scientific
Fund (2015QC001) and Peking College Students Innovation
Training Program (2015bj127 and 2015bj145).
2
008, 10, 2517–2520.
14] In a reversed polarity approach, beginning with a-
bromo sulfonamides, Fu and co-workers performed
a beautiful stereoconvergent arylation with aryl zinc re-
agents to furnish enantioenriched sulfonamides: J.
Choi, P. Martin-Gago, G. C. Fu, J. Am. Chem. Soc.
2
014, 136, 12161–12165.
15] a) N. C. Bruno, M. T. Tudge, S. L. Buchwald, Chem. Sci.
013, 4, 916–920; b) T. Kinzel, Y. Zhang, S. L. Buch-
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