Palladium-Catalyzed Intermolecular Coupling of Aryl Chlorides and Sulfonamides under Microwave Irradiation

Article abstract of DOI:10.1021/ol035655u

(Equation presented) An efficient intermolecular N-arylation of sulfonamides with aryl chlorides is realized using palladium catalysis. The reaction proceeds under microwave irradiation at 180-200°C for 10 min with 2-10 mol % of Pd catalyst in 32-85% isol

Full text of DOI:10.1021/ol035655u

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4373-4376
Palladium-Catalyzed Intermolecular
Coupling of Aryl Chlorides and
Sulfonamides under Microwave
Irradiation
,†
George Burton,† Ping Cao,* Gang Li,† and Ralph Rivero‡
GlaxoSmithKline, DiscoVery Research, High-throughput Chemistry, 1250 South
CollegeVille Road, CollegeVille, PennsylVania 19426, and GlaxoSmithKline,
DiscoVery Research, High-throughput Chemistry, 709 Swedeland Road,
King of Prussia, PennsylVania 19406
ping_2_cao@gsk.com
Received August 29, 2003
ABSTRACT
An efficient intermolecular N-arylation of sulfonamides with aryl chlorides is realized using palladium catalysis. The reaction proceeds under
microwave irradiation at 180−200 °C for 10 min with 2−10 mol % of Pd catalyst in 32−85% isolated yields.
N-Arylsulfonamides constitute an important class of thera-
peutic agents in medicinal chemistry.1 Over 30 drugs
containing this moiety are in clinical use in the areas of
antibacterials,2 non-nucleotide reverse transcriptase inhibi-
tors,3 antitumor agents,4 and HIV-1 protease inhibitors.5
Traditional preparation of sulfonamides involves reaction
of sulfonyl chlorides with amines, but the sulfonylation of
weakly nucleophilic amines (e.g., 4-aminoquinoline) is
difficult. Transition-metal-catalyzed C-N bond-forming
reactions are extensively utilized in industrial chemistry and
academic laboratories.6 Transition-metal-catalyzed N-aryla-
tion of sulfonamides offers a straightforward method for the
preparation of N-arylsulfonamides. Despite significant ad-
vances in the palladium-catalyzed N-arylation of amines and
amides, there are very few reports describing the use of
sulfonamides as the nitrogen nucleophile. To our knowledge,
the first report of the synthesis of N-arylsulfonamides by
C-N bond formation was through the copper-catalyzed
coupling of sulfonamides with arylboronic acids.7 More
recently, Buchwald and co-workers8,9 reported the palladium-
catalyzed coupling of aryl bromides with several sulfona-
mides. During the preparation of this manuscript, Wu et al.10
described the copper-catalyzed N-arylation of a sulfona-
† GlaxoSmithKline, Collegeville.
‡ GlaxoSmithKline, King of Prussia.
(1) Casini,; A. Scozzafava, A.; Supuran, C. T. Expert Opin. Ther. Pat.
2002, 12, 1307-1327. (b) Scozzafava, A.; Owa, T.; Mastrolorenzo, A.;
Supuran, C. T. Curr. Med. Chem. 2003, 10, 925-953.
(2) Hansch, C.; Sammes, P. G.; Taylor, J. B. ComprehensiVe Medicinal
Chemistry; Pergamon Press: Oxford, 1990; Vol. 2, Chapter 7, pp 255-
277.
(6) (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131-
209. (b) Hartwig, J. F. Handb. Organopalladium Chem. Org. Synth. 2002,
1, 1097-1106.
(7) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933-2936. (b) Combs, A. P.; Rafalski, M. J.
Comb. Chem. 2000, 2, 29-32. (c) Lam, P. Y. S.; Vincent, G.; Clark, C.
G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415-3418.
(8) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101-1104.
(9) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043-6048.
(10) He, H.; Wu, Y.-J. Tetrahedron Lett. 2003, 44, 3385-3386.
(3) Drew, J. Science 2000, 287, 1960-1964.
(4) Owat, N. T. Expert Opin. Ther. Pat. 2000, 10, 1725-1740.
(5) Turner, S. R.; Strohbach, J. W.; Tommasi, R. A.; Aristoff, P. A.;
Johnson, P. D.; Skulnick, H. I.; Dolak, L. A.; Seest, E. P.; Tomich, P. K.;
Bohanon, M. J.; Horng, M. M.; Lynn, J. C.; Chong, K.-T.; Hinshaw, R. R.;
Watenpaugh, K. D.; Janakiraman, M. N.; Thaisrivongs, S. J. Med. Chem.
1998, 41, 3467-3476.
10.1021/ol035655u CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/24/2003

mide with aryl bromides and iodides under microwave
irradiation. However, it required a prolonged reaction time
(2-4 h of microwave irradiation at 195 °C), and aryl
chlorides were inert under their conditions.
Scheme 1. Pd-catalyzed N-Arylation of Sulfonamide
Recent advances in microwave instrumentation have
increased the accessibility of this technique for organic
synthesis11 including more elegant applications such as
transition-metal-catalyzed transformations.12 Despite these
advances, very few microwave-assisted metal-catalyzed
N-arylations of sulfonamides have been reported.
Herein, we wish to report an efficient microwave-promoted
palladium-catalyzed coupling of aryl chlorides with sulfona-
mides.13
To optimize conditions for the sulfonamide coupling, we
undertook an intensive screening of a variety of ligands and
reaction variables using 4-chloroquinoline 1 and R-toluene-
sulfonamide 2 as well as benzenesulfonamide as representa-
tive substrates. In a typical experiment, a mixture of 1 equiv
of 1 and 1.5 equiv of 2 in 1,4-dioxane was microwaved for
10 min at 180 °C in the presence of 2 equiv of Cs2CO3 and
2 mol % of palladium catalyst (1mol % Pd2(dba)3). Reactions
were monitored by LC/MS, and the results are summarized
in Table 1. Ten commonly used Pd-phosphine catalysts were
was desired for efficient microwave heating. In addition to
Cs2CO3, NaO-t-Bu was identified as an alternative base
providing similar results for the C-N bond formation. In a
few reactions, the reduction product 4 was detected (Table
1, entry 5).
For comparison, the reaction in Scheme 1 was also
conducted using a preheated oil bath under otherwise
identical conditions as for the microwave reaction, i.e., Pd-
DPPF, 100 °C, 17 h. As expected, lower conversion (78%)
was observed under the thermal conditions as compared to
the microwave irradiation (100%). Without the Pd catalyst
no reaction occurs under microwave irradiation.
Table 1. Palladium-Catalyzed Amination of 4-Chloroquinoline
entry
Pd catalysta
conv, %b
byproduct 4%
The microwave conditions from entry 1 in Table 1 were
identified as the preferred reaction conditons16 and were
utilized for the synthesis of a diverse set of N-aryl sulfona-
mides. Analysis of the crude reaction mixtures by LC/MS
showed complete conversion in most cases. Following
preparative HPLC purification, satisfactory isolated yields
were obtained (Table 2). The coupling of 4-chloroquinoline
with various aryl sulfonamides is fairly general with a variety
of electronic and steric factors (e.g., 2-trifluoromethoxy
(Table 2, entry 5) and 2,4,6-triisopropyl (Table 2, entry 7)
well tolerated. In addition to arylsulfonamides, aliphatic
sulfonamides (Table 2, entries 12-17), the six-membered
1
2
3
4
5
6
8
9
10
Pd2(dba)3 + 5
100
100
86
100
60
0
50
50
40
0
0
0
0
10
N/A
0
0
0
Pd2(dba)3 + dppf
Pd2(dba)3 + Xantphos
Pd2(dba)3 + 6
Pd2(dba)3 + 717
Pd2(dba)3 + BINAP
Pd2(dba)3 + 817
Pd2(dba)3 + 917
Pd2(dba)3 + 1017
a The palladium catalysts were generated in situ from Pd2(dba)3 at room
temperature for 30 min. b The conversion was detected by LC/MS.
screened, and we found that the catalysts employing the
hemilabile N,P ligand 5, discovered by the Buchwald group
for amination of aryl chlorides,14 provide the most consistent
results. The less electron-rich chelating ligands DPPF,
Xantphos,8 and monodentate dihydroimidazoline carbene
ligand 615 could also be used for the transformation (Scheme
1). A high concentration of reactants in 1,4-dioxane (1.0 M)
(16) Typical Experimental Procedure. A Smith process vial (0.5-2
mL) was charged with 1 mol % Pd2(dba)3 (4.6 mg, 5 µmol), 3 mol % ligand
(6.0 mg, 15 µmol), and Cs2CO3(228 mg, 0.7 mmol). After sealing the cap
and twice purging with N2, the vial was charged with 100 µL of anhydrous
1,4-dioxane and stirred at room temperature for 10 min. A solution of 0.5
mmol of aryl chloride (4-chloroquinoline, 81 mg, 0.5 mmol) and 0.6 mmol
of sulfonamide (R-toluenesulfonamide, 103 mg, 0.6 mmol) in 400 µL of
anhydrous 1,4-dioxane was introduced via syringe. The resulting mixture
was stirred at room temperature for 30 min and then was irradiated at 180
°C for 10 min in the Smith Synthesizer. After irradiation, the sample was
cooled and purified by reversed-phase HPLC to afford 123 mg (60%) of
1-phenyl-N-quinolin-4-ylmethanesulfonamide (Table 1, entry 1) TFA salt
as a solid.
(11) For recent reviews, see: (a) Perreux, L.; Loupy, A. Tetrahedron
2001, 57, 9199. (b) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 9225-9283. (c) Lew, A.; Krutzik, P. O.; Hart, M. E.;
Chamberlin, A. R. J. Comb. Chem. 2002, 4, 95-105. (d) Santagada, V.;
Perissutti, E.; Caliendo, G. Curr. Med. Chem. 2002, 9, 1251-1283.
(12) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35,
717-727.
(17) Phosphine ligands used in Table 1: (a) Strem, www.strem.com;
(b) Combi-phos, www.combiphos.com; (c) Johnson Matthey, www.chemi-
cals.matthey.com.
(13) Internal communication from UK colleagues: Smooth N-arylations
occurred between the triflate of 4-hydroxyquinoline and R-toluenesulfona-
mide using a Pd-BINAP catalyst under microwave irradiation.
(14) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722-9723.
(15) Stuffer, S. R.; Lee, S.; Stambuli, J. P.; Hauck, S. I.; Hartwig, J. F.
Org. Lett. 2000, 2, 1423-1426.
4374
Org. Lett., Vol. 5, No. 23, 2003

Table 2. Palladium Catalyzed N-Arylation of Aryl Chlorides with Sulfonamidesa
a Reaction conditions: 1.0 equiv of aryl chloride, 1.2 equiv of sulfonamide, 5/Pd2(dba)3 ) 3/1 (L/Pd ) 1.5/1), 2 mol % Pd refers to 1 mol % Pd2(dba)3
1.4 equiv of Cs2CO3, 1,4-dioxane, 180 °C, 10 min. Personal Chemistry Smith Synthesizer. b Purified yield after reversed-phase HPLC. c 5 mol % Pd2(dba)3,
15 mol % ligand 5, 200 °C, 20 min. d Small amount of halide reduction product (10-15%) also formed.
ring sultam (Table 2, entry 9), and secondary aryl sulfona-
mides (Table 2, entry 10) are also effective nucleophiles.
Arylsulfonamides with a strong electron-withdrawing group
at the para-position (Table 2, entry 11) were unreactive even
when using 10 mol % Pd-catalyst. R-Toluenesulfonamide 2
reacted efficiently with a variety of aryl chlorides with
electron-withdrawing groups (Table 2, entries 12-16) under
typical reaction conditions. For less reactive aryl chlorides,
e.g., 1-chloronaphthalene (Table 2, entries 17-19), satisfac-
tory coupling with R-toluenesulfonamide 2, 4-methoxy-
Org. Lett., Vol. 5, No. 23, 2003
4375

benzenesulfonamide, and benzenesulfonamide was achieved
with the higher catalyst loading, 10 mol %. The N-arylation
of electron-rich aryl chlorides (e.g., 4-chloroanisole, Table
2, entry 21) did not proceed under similar conditions.
Surprisingly, in contrast to the results obtained with 2-chlo-
roquinoline and 1-chloroisoquinoline (Table 2, entries 16 and
15, respectively), 2-chloropyridine and 3-chloropyridine
(Table 2, entries 20 and 22) provided little or no desired
product.
sulfonamides in good to excellent yields. The results
presented in this paper represent a significant improvement
in the scope of the aryl halides over the previous reports by
the application of microwave heating. Further study to
expand the reaction scope and application to parallel library
synthesis is under investigation.
Acknowledgment. We thank Victoria Magaard, Walter
Johnson, Bing Wang, and Stone Shi for analytical support.
In conclusion, the use of N,P phosphine 5 as the ligand,
1,4-dioxane as solvent, Cs2CO3 as the base with microwave
irradiation as heating source allows for an efficient inter-
molecular C-N bond-forming reaction between aryl halides
and sulfonamides. This N-arylation proceeds efficiently at
180-200 °C with 2-10 mol % of Pd catalyst to form N-aryl
Supporting Information Available: Experimental pro-
cedures and characterization data for N-arylation products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL035655U
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Org. Lett., Vol. 5, No. 23, 2003