A useful Pd-catalyzed Negishi coupling approach to benzylic sulfonamide derivatives

Article abstract of DOI:10.1021/ol800785g

(Chemical Equation Presented) A mild catalytic system to access diversely functionalized benzylic sulfonamides has been developed. Palladium-catalyzed α-arylation by Negishi cross-coupling of sulfonamide-stabilized anions and a wide range of aryl iodides, bromides, and triflates constitutes a practical strategy for the synthesis of various benzylic sulfonamides.

Full text of DOI:10.1021/ol800785g

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2517-2520
A Useful Pd-Catalyzed Negishi Coupling
Approach to Benzylic Sulfonamide
Derivatives
Gang Zhou,* Pauline Ting, Robert Aslanian, and John J. Piwinski
Department of Medicinal Chemistry, Schering-Plough Research Institute,
Kenilworth, New Jersey 07033
gang.zhou@spcorp.com
Received April 8, 2008
ABSTRACT
A mild catalytic system to access diversely functionalized benzylic sulfonamides has been developed. Palladium-catalyzed r-arylation by
Negishi cross-coupling of sulfonamide-stabilized anions and a wide range of aryl iodides, bromides, and triflates constitutes a practical strategy
for the synthesis of various benzylic sulfonamides.
The sulfonamide is an important functional group that is
widely found in both natural products and medicines such
as Axert for migraine1 and Zonisamide for seizure.2 Several
conventional approaches have been used to prepare benzylic
sulfonamides which include using unstable sulfonyl chloride
intermediates, free-radical processes, vicarious nucleophilic
substitution, or harsh oxidation conditions.3 However, sub-
strate dependency and operational practicality have limited
the use of these approaches in sulfonamide synthesis. In
conjunction with our interest in readily accessing diversified
benzylic sulfonamides, we needed to develop an effective
method for the construction of benzylic sulfonamides.
Since the pioneering efforts of Buchwald, Hartwig, and
Miura in 1997,4 Pd-catalyzed arylation of ketones has opened
a new path to a reliable construction of molecules that were
traditionally difficult to synthesize. The scope of arylation
reaction has been expanded to include a variety of nucleo-
philic coupling partners including ketones, esters, amides,
nitriles, aldehydes, nitroalkanes, sulfones, and sulfoximines
in recent years.5
While many reports have appeared detailing arylation of
ketone and amide substrates, there are few reports concerning
C-arylations of alkanesulfonamide derivatives. In most cases,
the nucleophilic component is generally limited to sulfona-
mides in which the R-H acidity is enhanced by activating
groups (e.g., NO2, CN, CO2R) that need to be removed if
R-unsubstituted sulfonamide was desired (Scheme 1).6 To
Scheme 1. General Strategy for Sulfonamide C-Arylations
(1) Bosch, J.; Roca, T; Armengol, M.; Fernandaz-Forner, D. Tetrahedron
2001, 57, 1041.
(2) Uno, H.; Kurokawa, M.; Masuda, Y.; Nishimura, H. J. Med. Chem.
1979, 22, 180.
(3) (a) Anderson, K. K. In ComprehensiVe Organic Chemistry; Jones,
D. N., Ed.; Pergamon Press: Oxford, 1979; Vol. 3, p 345. (b) Lee, I.; Kang,
H. K.; Lee, H. W. J. Am. Chem. Soc. 1987, 109, 7472. (c) Wininarski, J.;
Makosza, M. Acc. Chem. Res. 1987, 20, 282.
our knowledge, only a single literature example exists in
which simple methanesulfonamide derivatives lacking such
an activating group are converted to a mixture of mono- and
bisarylated products.7
(4) (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.
(b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382. (c)
Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1740.
10.1021/ol800785g CCC: $40.75
Published on Web 05/21/2008
2008 American Chemical Society

In our research program, existing methods were found to
be inappropriate due to the harsh reaction conditions. It was
necessary for us to develop a novel sulfonamide C-arylation
protocol that uses mild reaction conditions and is compatible
with a variety of functional groups. After several preliminary
attempts, we found that use of zinc anions instead of alkali
metal anions led to greater functional group compatibility
in the R-arylation of sulfonamide reactions.
Herein, we report a mild palladium-catalyzed arylation
reaction with sulfonamide zinc reagents prepared in situ.
LHMDS was used as base to generate a sulfonamide anion,
and the sulfonamide zinc reagent was prepared by the
reaction of the anion with ZnCl2. The ligand usually plays a
critical role in the success of this type of reaction. Accord-
ingly, the effect of sterically and electronically varied
phosphine ligands on the model reaction of 5 with bro-
mobenzene was studied, and the reaction conditions were
optimized. A set of small ligands and a few sterically
hindered and electron-rich monophosphines as well as
bisphosphines (Figure 1) were selected for study.8
Table 1. Effect of Ligand Structure on the Arylation
yield (%)a b
,
entry
Pd source
Pd(PPh3)4
ligand
1
2
3
n/a
n/a
n/a
<5
<5
<5
19
<5
<5
15
<5
<5
<5
81
<5
55
[Pd(Pt-Bu3)Br]2
Pd(Pt-Bu3)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(dba)2
4
5
6
7
n-Bu3P•HBF4
t-Bu3P•HBF4
Cy3P•HBF4
Ph3P
8
9
BINAP
DBPF
10
11
12
13
14
15
16
17
18
DPPF
Q-Phos
1
2
Dave-Phos 3
4
S-Phos
X-Phos
X-Phos
95
<5
82
99
85
a Isolated yields based on the bromobenzene. b Reactions were conducted
with bromobenzene (0.8 mmol), 1-(methanesulfonyl)piperidine (1.0 mmol),
LHMDS (1.0 mmol), ZnCl2 (1.2 mmol), Pd reagent (0.012 mmol), ligand
(0.024 mmol) in THF (2 mL) at 65 °C for 10 h.
ried out under mild conditions and required low quantities
of catalyst (1.5 mol %).
Several ligands were found to be effective and provided
55-99% yields of the coupled product 6 (Table 1, entries
11, 13, 14, and 16-18). The reactions catalyzed by bulky,
electron-rich X-Phos or Dave-Phos afforded the highest yield
with Pd(OAc)2 (Table 1, entries 14 and 17), although reaction
with S-Phos or Q-Phos also provided a reasonable yield.
Interestingly, some ligands such as DBPF and DPPF that
have been successfully used in Pd-catalyzed couplings,
including arylations of ketones, were less effective for the
arylation of sulfonamide 5 (Table 1, entries 9 and 10).
Pd(OAc)2 is a better palladium source than Pd(dba)2 is in
terms of yield (Table 1, entry 18).8d
With the optimal Pd and ligand combination identified,
the effects of zinc salt, base, and solvent were examined next
(Table 2). A little excess of the organozinc reagent9 of
sulfonamide 5 (1.0 equiv) to bromobenzene (0.8 equiv)
apparently gave better conversion, better yield, and reduced
bisarylation side product. The zinc salt was also critical. If
the alkylzinc reagents were prepared from the corresponding
sulfonamide anions and ZnBr2, the coupling reaction became
much slower and led to lower yield (Table 2, entries 1 and
Figure 1. Selected ligand structures.
As shown in Table 1, reactions catalyzed by Pd(0)/ligand
combinations or preformed palladium complexes were car-
(5) (a) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
7996. (b) Jørgensen, M.; Lee, S.; Wolkowski, J. P.; Hartwig, J. F. J. Am.
Chem. Soc. 2002, 124, 12557.
(6) (a) Grimm, J. B.; Katcher, M. H.; Witter, D. J.; Northrup, A. B. J.
Org. Chem. 2007, 72, 8135. (b) Middleton, D. S.; Stobie, A. Patent WO
00/51972; Pfizer Ltd., 2000. (c) Waite, D. C. Patent WO 99/02493; Pfizer
Ltd., 1999. (d) Kashin, A. N.; Mitin, A. V.; Beletskaya, I. P.; Wife, R.
Tetrahedron Lett. 2002, 43, 2539.
(7) Zeevaart, J. G.; Parkinson, C. J.; de Koning, C. B. Tetrahedron Lett.
2005, 46, 1597.
(8) The chosen catalysts have been shown successful in other arylation
reactions; see: (a) Viciu, M. S.; Germaneau, R. F.; Nolan, S. P. Org. Lett.
2002, 4, 4053. (b) Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem.
Soc. 2006, 128, 4976. (c) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 6043. (d) Wu, L.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15824.
(e) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998,
63, 6546. (f) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.;
Chen, C. J. Am. Chem. Soc. 2006, 128, 3538.
(9) The (sulfonamido)methylzinc chloride could also be generated by
reacting of (chloromethanesulfonyl)piperidine with activated zinc powder
and LiCl by Knochel’s method, which resulted in the arylation product 6
in 30% yield under our Pd-catalyzed coupling conditions; see: (a) Metzger,
A.; Schade, M. A.; Knochel, P. Org. Lett. 2008, 10, 1107. (b) Krasovskiy,
A.; Knochel, P. Synthesis 2006, 5, 890.
2518
Org. Lett., Vol. 10, No. 12, 2008

Table 2. Base and Zinc Source Effect on the R-Arylation of 5
Table 3. Substrate Scope for R-Arylation of Sulfonamide 5
yield (%)a b
,
entry
base
zinc source
1
2
3
4
5
6
7
8
9
LHMDS
LHMDS
LHMDS
KHMDS
NaHMDS
n-BuLi
sec-BuLi
NaOtBu
t-BuLi
without Zn salt
ZnBr2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
0
34
99
72
86
46
85
48
<5
a Isolated yield calculated from bromobenzene. b For conditions, see
Table 1.
2). With X-Phos as the ligand and THF as the solvent,
reactions carried out with LHMDS, NaHMDS, or sec-BuLi
as the base gave the best results (Table 2, entries 3, 5, and
7), while reactions with NaOtBu, BuLi, and t-BuLi led to
lower conversions. With LHMDS as base, reactions in THF,
dioxane, or THF-NMP (1:1) proceeded smoothly, while
reactions in toluene, MTBE, or diethyl ether were rather
sluggish.
Having identified the optimal conditions, we then exam-
ined the scope of this sulfonamide arylation by coupling a
variety of aryl halides and triflates with 5 (Table 3). Aryl
bromides, iodides, or triflates were employed as the elec-
trophilic partner. Reactions of aryl iodides or triflates gave
comparable yields to aryl bromides (Table 3, entry 1).
Furthermore, couplings of chloro- and iodo-substituted aryl
bromides were highly halogen-selective, providing exclu-
sively chlorophenylated and bromophenylated products,
respectively (Table 3, entries 2 and 3). The sterically
challenging 2,6-disubstituted aryl bromide also coupled
smoothly to give the desired product in 94% yield (Table 3,
entry 4).
The electronic properties of the reactants affected the
reactions to some extent. Electron-rich aryl bromides proved
to be good substrates under our coupling condition, as
exemplified by 4-bromo-2-methylanisole and 6-bromo-2-
methoxylnaphthalene (Table 3, entries 5 and 6). However,
a number of other aryl bromide components with electron-
withdrawing groups were also coupled with substrate 5 and
resulted in monoarylated product with moderate yields (Table
3, entries 7-10). The arylation reaction with substrates
bearing an acidic proton such as 4-bromoaniline did not
proceed under our optimized conditions. Alternatively, the
nitro-substituted aryl bromide reacted smoothly to provide
the product in 77% yield. The product was easily converted
to an amino product under hydrogenation conditions (H2,
10% Pd-C in MeOH, 10 h) in quantitative yield (Table 3,
entry 10). Heterocyclic halides such as 3- or 4-bromopyridine
were also tolerated in this system (Table 3, entries 11 and
12).
a Isolated yields based on the aryl halides or triflates. b Reactions were
conducted with aryl halides or triflates (0.8 mmol), 5 (1.0 mmol), LHMDS
(1.0 mmol), ZnCl2 (1.2 mmol), Pd(OAc)2 (0.012 mmol), X-Phos (0.024
mmol) in THF (2 mL) at 65 °C for 10 h.
Generally, only monoarylated sulfonamides were obtained
as single products for substrates in Table 3. For some
substrates, further arylation to form an bisarylated benzylic
sulfonamide was observed. The bisarylated benzylic sul-
fonamides 7-9 (Figure 2) were formed along with the
monoarylated benzylic sulfonamides (Table 3, entries 7-9).
Bisarylated product 7 was formed in trace amount (<5%),
while the bromobenzenes with electron-withdrawing sub-
stituents at the para position, such as p-NCC6H4Br and
p-MeO2CC6H4Br (Table 3, entries 8 and 9), gave more
bisarylated products (12 and 15% yield, respectively).
Org. Lett., Vol. 10, No. 12, 2008
2519

Importantly, the sterically hindered n-propanesulfonamide
underwent a smooth cross-coupling reaction with bromoben-
zene to afford the arylated sulfonamide in 66% yield,
although an extended reaction time was required (24 h, Table
4, entry 8). Furthermore, a mild procedure for the generation
of primary sulfonamides was also developed and afforded
products in good yield. As shown in Scheme 2, p-methoxy-
Figure 2. Bisarylation products.
Scheme 2. Protocol to Generate Primary Sulfonamide 12
While the arylation reactions described in Table 3 em-
ployed various substituted aryl halides with 1-(methane-
sulfonyl)piperidine 5, additional unactivated sulfonamides
can be arylated under our optimized reaction conditions
(Table 4). Reactions of a spectrum of sulfonamides with
benzyl (PMB)-protected sulfonamide 10 was converted to
the corresponding benzyl sulfonamide 11 under our arylation
conditions in 90% yield. Deprotection of PMB group in 11
was readily achieved in the presence of TFA in dichlo-
romethane at room temperature to give the primary sulfona-
mide 12 in 85% yield.10
Table 4. Arylation of Various Sulfonamides
This protocol has been successfully applied to our
medicinal chemistry program. A series of functionalized
benzylic sulfonamides, which were difficult to access with
other methods, have been synthesized using our method.11
In conclusion, we have developed an efficient method for
the synthesis of functionalized benzylic sulfonamides, using
the palladium-catalyzed Negishi coupling reaction of unac-
tivated methanesulfonamides and aryl halides. This protocol
has the advantage of using readily available starting materials,
mild conditions, low catalyst loading, high yields, and good
functional group tolerance while providing important syn-
thetic potential for generating a variety of benzylic sulfona-
mides. Further studies on the enantioselective R-arylation
of sulfonamides, such as ethanesulfonamide derivatives,
using chiral ligands under our optimal conditions are in
progress.
Acknowledgment. Dedicated to Professor Elias J. Corey
on the occasion of his 80th birthday. We would like to thank
our colleagues at Schering-Plough Co., Mr. Ibrahim Daaro
for mass spectrometry assistance, Drs. Jared Cumming and
George Sun for helpful discussion, Drs. Michael Wong and
Xiaolei Gao for proofreading, and Dr. John Piwinski for
strong support of the program.
a Isolated yield based on bromobenzene. b Reactions were carried out
with sulfonamide (1.0 mmol), bromobenzene (0.8 mmol), LHMDS (1.0
mmol), ZnCl2 (1.2 mmol), Pd(OAc)2 (0.012 mmol), X-Phos (0.024 mmol)
in THF (2 mL) at 65 °C for 10 h. c Reaction was conducted at 70 °C for
24 h.
Supporting Information Available: Experimental details
and spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL800785G
bromobenzene were generally complete within 10 h at 67 °C
and consistently afforded monoarylated products in good to
excellent yields (Table 4, entries 1-8, 66-98%) under the
described condition.
(10) Hill, B.; Liu, Y.; Taylor, S. D. Org. Lett. 2004, 6, 4285.
(11) Ting, P.; Aslanian, R.; Cao, J.; Kim, D.; Kuang, R.; Zhou, G.; Zorn,
N.; Wu, H.; Jason, R.; Zych, A.; Yang, J. Schering-Plough Co. Patent
submitted.
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Org. Lett., Vol. 10, No. 12, 2008