Synthesis of N-arylated sultams: Palladium- and copper-catalyzed cross coupling of aryl halides with 1,4-butane and 1,3-propanesultams

Article abstract of DOI:10.1016/j.tetlet.2004.02.081

Palladium-catalyzed cross coupling of 1,4-butanesultam and 1,3-propanesultam with a variety of aryl halides was found to provide the desired products in 62-93% isolated yield using Xantphos as ligand. The Pd-catalyzed reaction was found to be superior to the analogous Cu-catalyzed reaction based on product yields, reaction rates, and substrate scope.

Full text of DOI:10.1016/j.tetlet.2004.02.081

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3305–3307
Synthesis of N-arylated sultams: palladium- and copper-catalyzed
cross coupling of aryl halides with 1,4-butane
and 1,3-propanesultams
Dietrich Steinhuebel,* Michael Palucki, David Askin and Ulf Dolling
Department of Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 26 November 2003; revised 10 February 2004; accepted 16 February 2004
Abstract—Palladium-catalyzed cross coupling of 1,4-butanesultam and 1,3-propanesultam with a variety of aryl halides was found
to provide the desired products in 62–93% isolated yield using Xantphos as ligand. The Pd-catalyzed reaction was found to be
superior to the analogous Cu-catalyzed reaction based on product yields, reaction rates, and substrate scope.
Ó 2004 Elsevier Ltd. All rights reserved.
The transition metal-catalyzed coupling of sulfonamides
with aryl halides has recently received considerable
attention.1 This is due, in part, to the fact that a large
number of biologically active and important compounds
contain an aryl sulfonamide, and to the realization that
the coupling strategy to form the aryl–N bond provides
a new and unique vantage point for diversity-orientated
synthesis as well as total synthesis.
of five and six-membered N-aryl sultams from readily
accessible starting materials (Scheme 1).6
The Ullmann coupling is the classic method to perform
this reaction.7 Attempts to apply standard Ullmann
coupling conditions (Cu2O, 2,20-bipyridine, K3PO4,
NMP, 120 °C, 12–24 h) with a variety of aryl halides and
the 1,4-butanesultam afforded the coupled product in
low to moderate assay yields (Table 1). These reactions
typically show low rates of conversion to product, even
at 120 °C, while exhibiting poor reaction profiles as
determined by HPLC. The only substrate exhibiting
clean coupling is 2-bromopyridine. Control experiments
wherein the copper was omitted resulted in only trace
product.8
N-substituted 1,4-butanesultams and 1,3-propanesul-
tams are a class of cyclic sulfonamides that have been
known for years.2 Compounds containing the sultam
moiety have been found to possess pharmacological
activity and therefore the synthesis of families of these
compounds has been of interest.3 The most common
preparation of N-substituted sultams involves reaction
of 4-chloro-butane sulfuryl chloride, which must be
prepared, with the appropriate amine followed by
dehalogenative ring closure.4
We therefore screened palladium based systems and
found that the conditions recently reported by Buch-
wald for the coupling of amides and sulfonamides with
aryl halides utilizing the Xantphos ligand were the most
efficient.9;10 We have found that this protocol works well
when applied to both the 1,4-butane and 1,3-propane-
sultams. Our results for the 1,4-butane sultam are shown
in Table 2.
Recently, a convenient preparation of both N–H 1,4-
butanesultam and 1,3-propanesultam from commer-
cially available starting materials has been disclosed.5
With these sultams readily available, a transition metal-
catalyzed cross coupling protocol would represent a new
and rapid method for the preparation of a wide variety
Pd or Cu
SO2Cl
Cl
ArX
Ar
N
O2S
H
N
O2S
+
+
Keywords: Sultam; Palladium.
* Corresponding author. Tel.: +1-732-594-0087; fax: +1-732-594-1499;
e-mail: dietrich_steinheubel@merck.com
ArNH2
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.081

3306
D. Steinhuebel et al. / Tetrahedron Letters 45 (2004) 3305–3307
Table 1. Copper catalyzed N-arylation of 1,4-butanesultam
A survey of various aryl bromides revealed that the rate
of reaction was significantly faster with aryl bromides
possessing strongly electron withdrawing groups such as
an ester (entries 2 and 3), nitrile (entry 5), or nitro group
(entry 6). Reactions using these substrates provided the
coupled product in 3–4 h in toluene at 90or 100 °C. On
the other hand, 4-bromo-1,2-dichlorobenzene requires
19 h to reach completion illustrating the weaker electron
withdrawing capabilities of a chlorine substituent. This
coupling method is tolerant of ortho substitution as
illustrated in entry 6. Clearly, electronic activation of the
aryl bromide is important since 2-bromotoluene shows
little conversion after 24 h at 100 °C. Similarly, 4-
bromotoluene shows minimal conversion. Bromobenz-
ene is a viable substrate (entry 1) but the 28 h reaction
time is the longest of any aryl halide. In general, aryl
halides with electron donating groups are not good
substrates for this coupling reaction.11
40 mol% Cu2O
40 mol% 2,2'-bipyridine
1.1 equiv K3PO4
ArX
+
Ar
N
O2S
HN
O2S
NMP
120 °C
Entry
ArX
Temperature Time
(°C)
Assay yield
(%)
(h)
1
2
1206
93
Br
N
NO2
I
12018
12048
44
Me
Br
3
50
O2N
Br
4
5
6
12024
12015
12036
35
63
35
Phenyl triflate does afford a small amount of coupled
product, but several byproducts are also observed by
HPLC. An aryl iodide, 1-iodo-2-nitrobenzene, is a via-
ble substrate (entry 7), and this example again illustrates
that ortho substitution is tolerated as long as the sub-
strate is electronically activated. This particular reaction
is a palladium catalyzed process since a control experi-
ment where Pd(OAc)2 was not added to the reaction
afforded ꢀ1% conversion after 3 h at 100 °C.12
NC
NC
Br
CN
Cl
N
2-Bromopyridine reacts rapidly to afford the coupled
product (entry 8) while 3-bromopyridine showed little
conversion. The greater reactivity of 2-bromopyridine
could be due to either the activating effect of a hetero-
atom alpha to a carbon–halogen bond or coordination
of the nitrogen atom to the metal. Aryl chlorides are
good substrates when activated by both an electron
withdrawing group and a heteroatom. Thus, 2-chloro-3-
cyanopyridine afforded product after 17 h (entry 9),
while 2-chloropyridine afforded no product after 17 h
at 100 °C.
Table 2. Palladium-catalyzed N-arylation of 1,4-butanesultam
10 mol% Pd(OAc)2,
Me
Me
15 mol% Xantphos
1.5 equiv Cs2CO3
ArX
+
Ar
N
O2S
HN
O2S
O
toluene
90 or 100 °C
PPh2
PPh2
Xantphos
Entry
ArX
Temperature Time
(°C)
Isolated
yield (%)
(h)
1
2
100
28
80
Br
100
100
3
4
89
83
MeO2C
PhOC
Br
Table 3. N-arylation of 1,3-propanesultam
10 mol% Pd(OAc)2,
15 mol% Xantphos
1.5 equiv Cs2CO3
3
4
Br
ArX
+
HN
N
Ar
Cl
Cl
Br
S
S
dioxane
85 or 90 °C
100
19
79
O2
O2
Entry
ArX
Temperature Time Isolated
(h)
Br
5
6
904
905
82
70
(°C)
yield (%)
NC
Me
Br
1
2
906
74
MeO2C
PhOC
Br
Br
O2N
85
85
18
18
93
88
NO2
7
903
70
Cl
Cl
Br
I
3
Br
8
9
100
100
6
62
80
Br
N
N
4
5
85
85
24
74
NC
NC
CN
17
1088
Br
Cl

D. Steinhuebel et al. / Tetrahedron Letters 45 (2004) 3305–3307
3307
Fisher, T. E.; Egbertson, M. S.; Payne, L. S.; Guare, J. P.;
Vacca, J. P.; Hazuda, D. J.; Felock, P. J.; Wolfe, A. L.;
Stillmock, K.; Witmer, M. V.; Moyer, G.; Scgleif, W.;
Gabryelski, L. J.; Leonard, Y. M.; Lynch, J. J., Jr.;
Michelson, S. R.; Young, S. D. J. Med. Chem. 2003, 453–
456.
1,3-Propanesultams are also effective as coupling part-
ners (Table 3). With this substrate class, dioxane was
found to be a superior solvent than toluene and the
reactions are in general slower than with the 1,4-
butanesultam. The only difference in substrate scope
between the two classes of sultams is that bromobenzene
was not an efficient coupling partner with the 1,3-pro-
panesultam.
4. Helferich, v. B.; Kleb, K. G. Liebigs Ann. Chem. 1960, 635,
91–96.
5. Lee, J.; Zhong, Y.-L.; Reamer, R. A.; Askin, D. Org. Lett.
2003, 5, 4175–4177.
In conclusion, a palladium based catalyst system affords
a wide range of N-arylated five and six membered ring
sultams directly from an easily accessible sultam and an
aryl halide under mild conditions.13 To the best of our
knowledge, this is the first use of a sultam in a cross-
coupling reaction and this approach offers a straight-
forward preparation of a family of N-arylated sultams.
6. Feichtinger, H.; Tummes, H. German Patent, DE 932676,
1955.
7. Lindley, J. Tetrahedron 1984, 40, 1435–1456.
8. He, H.; Wu, Y.-J. Tetrahedron Lett. 2003, 44, 3385–3386.
9. Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101–1104.
10. Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
6043–6048.
11. In the case of 2-(3-bromophenyl)-1,3-dioxalane the cou-
pling reaction with 1,4-butane sultam was not clean.
Attempted coupling of 2-bromo anisole with 1,4-butane
sultam resulted in low conversion. In a single experiment
we isolated ꢀ30–40% of the coupling product of 1,4-
butane sultam with 3-bromoanisole.
Acknowledgements
12. Under similar conditions, 1,4-butane sultam and phenyl
iodide afforded arylated product but the reaction suffers
from slow conversion and formation of unidentified
products.
We thank J. Yin for providing the Xantphos ligand and
R. Reamer for NMR assistance.
13. General procedure: A Schlenk flask was charged with 1,4-
butane-sultam (817 mg, 6.05 mmol), palladium acetate
(104 mg, 0.465 mmol), Xantphos (405 mg, 0.698 mmol)
and cesium carbonate (2.27 g, 6.98 mmol). Toluene
(4 mL) was added, followed by methyl 2-bromobenzoate
(1 g, 4.65 mmol). The flask was then capped with a septum.
The flask was evacuated and refilled with nitrogen, this
procedure was repeated a total of three times. The flask
was placed into a 100 °C oil bath for 3 h and then cooled to
room temperature and diluted with dichloromethane
(20mL). The slurry was filtered through a pad of solka-
floc and the pad washed with additional dichloromethane
(20mL). The volatiles were removed and the crude
material was chromatographed on silica gel (50:1 to 25:1
CH2Cl2/EtOAc) to afford the product as a white solid
(1.12 g, 89%).
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2. Feichtinger, H. Chem. Ber. 1963, 96, 3068–3075.
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