Simple and versatile catalytic system for N-alkylation of sulfonamides with various alcohols

Article abstract of DOI:10.1021/ol1002434

"Chemical Equation Presented" A simple and versatile catalytic system for N-alkylation of sulfonamides with various alcohols based on a catalytic hydrogen transfer reaction has been developed under a low catalyst loading of [Cp^*lrCl₂]₂ (0.050-1.5 mol %) in the presence of t-BuOK. A variety of N-alkylated sulfonamides were prepared In good to excellent yields. Mechanistic investigations revealed that the key catalytic species in the present system is a sulfonylimido-bridged unsaturated diirldium complex [(Cp^*lr)₂(μ-NTs)₂].

Full text of DOI:10.1021/ol1002434

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1336-1339
Simple and Versatile Catalytic System
for N-Alkylation of Sulfonamides with
Various Alcohols
Mingwen Zhu,† Ken-ichi Fujita,*,†,‡ and Ryohei Yamaguchi*,†
Graduate School of Human and EnVironmental Studies and Graduate School of Global
EnVironmental Studies, Kyoto UniVersity, Sakyo-ku, Kyoto 606-8501, Japan
fujitak@kagaku.mbox.media.kyoto-u.ac.jp; yama@kagaku.mbox.media.kyoto-u.ac.jp
Received January 30, 2010
ABSTRACT
A simple and versatile catalytic system for N-alkylation of sulfonamides with various alcohols based on a catalytic hydrogen transfer reaction
has been developed under a low catalyst loading of [Cp*IrCl2]2 (0.050-1.5 mol %) in the presence of t-BuOK. A variety of N-alkylated sulfonamides
were prepared in good to excellent yields. Mechanistic investigations revealed that the key catalytic species in the present system is a
sulfonylimido-bridged unsaturated diiridium complex [(Cp*Ir)2(µ-NTs)2].
Sulfonamides are a highly important class of compounds
because of their biological activities such as antibacterial
agents, anticancer agents, antiviral drugs, and antiviral HIV
protease inhibitors.1 The synthesis of sulfonamides having
a substituent on nitrogen usually has been carried out by the
reaction of primary or secondary amines with sulfonyl
halides2 or catalytic cross coupling of sulfonamides with
organic halides.3 Aminosulfonation of hydrocarbons has also
been reported very recently.4 However, these reactions have
drawbacks from environmental and atom economical points
of view, because they generate equimolar amounts of
wasteful byproducts such as hydrogen halides, metal halogen
salts, or organic halides.5
Meanwhile, much attention has been focused on the
catalytic N-alkylation reactions with alcohols as alkylating
agents based on hydrogen transfer, using iridium,6 ruthe-
nium,7 and other transition metal catalysts.8 Such methodolo-
gies with alcohols are apparently attractive because they do
not produce wasteful coproducts (only water is produced as
coproduct) and highly atom economical synthesis can be
(5) Catalytic hydroamination of alkenes with sulfonamides also affords
N-alkylated sulfonamides with high atom economy. However, these
reactions give Markovnikov products selectively, and terminally alkylated
sulfonamide cannot be obtained. (a) Karshtedt, D.; Bell, A. T.; Tilley, T. D.
J. Am. Chem. Soc. 2005, 127, 12640. (b) Zhang, J.; Yang, C.-G.; He, C.
J. Am. Chem. Soc. 2006, 128, 1798.
† Graduate School of Human and Environmental Studies.
‡ Graduate School of Global Environmental Studies.
(1) (a) Scozzafava, A.; Owa, T.; Mastrolorenzo, A.; Supuran, C. T. Curr.
Med. Chem. 2003, 10, 925, and references cited therein. (b) Drew, J. Science
2000, 287, 1960. (c) Scozzafava, A.; Supuran, C. T. J. Med. Chem. 2000,
43, 3677.
(6) (a) Fujita, K.; Yamaguchi, R. Synlett 2005, 560, and references cited
therein. (b) Fujita, K.; Yamaguchi, R. In Iridium Complexes in Organic
Synthesis; Oro, L. A., Claver, C., Eds.; Wiley-VCH Verlag GmbH & Co.
KGaA: Weinheim, Germany, 2009; Chapter 5, pp 107-143, and references
cited therein. (c) Fujita, K.; Enoki, Y.; Yamaguchi, R. Tetrahedron 2008,
64, 1943. (d) Yamaguchi, R.; Kawagoe, S.; Asai, C.; Fujita, K. Org. Lett.
2008, 10, 181. (e) Balcells, D.; Nova, A.; Clot, E.; Gnanamgari, D.; Crabtree,
R. H.; Eisenstein, O. Organometallics 2008, 27, 2529. (f) Blank, B.;
Madalska, M.; Kempe, R. AdV. Synth. Catal. 2008, 350, 749. (g) Fujita,
K.; Komatsubara, A.; Yamaguchi, R. Tetrahedron 2009, 65, 3624. (h) Blank,
B.; Michlik, S.; Kempe, R. Chem.sEur. J. 2009, 15, 3790.
(2) (a) March, J. AdVanced Organic Chemistry, 3rd ed.; Wiley: New
York, 1985; p 445. (b) Sridhar, R.; Srinivas, B.; Kumar, V. P.; Narender,
M.; Rao, K. R. AdV. Synth. Catal. 2007, 349, 1873.
(3) (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043. (b)
Burton, G.; Cao, P.; Li, G.; Rivero, R. Org. Lett. 2003, 5, 4373.
(4) Kalita, B.; Lamar, A. A.; Nicholas, K. M. Chem. Commun. 2008,
4291.
10.1021/ol1002434  2010 American Chemical Society
Published on Web 02/25/2010

Table 1. Cp*Ir-Catalyzed N-Alkylation of
p-Toluenesulfonamide (1a) with Benzyl Alcohol (2a) under
Various Conditionsa
Table 2. Cp*Ir-Catalyzed N-Alkylation of
p-Toluenesulfonamide (1a) with Various Primary Alcoholsa
entry
cat. (mol %)
base (mol %)
time (h)
yield (%)b
1
2
3
4
5
6
7
8
9
0.050
0.050
0.050
0.050
0.050
0.050
0.050
0.025
0.050
none
none
17
17
17
17
17
17
17
17
7
trace
17
80
92
97
99
100 (95)
82
89
0
Li2CO3 (1.0)
Na2CO3 (1.0)
K2CO3 (1.0)
Cs2CO3 (1.0)
MeOK (1.0)
t-BuOK (1.0)
t-BuOK (1.0)
t-BuOK (1.0)
t-BuOK (1.0)
10
17
a The reaction was carried out with 1a (2.0 mmol), 2a (2.2 mmol),
[Cp*IrCl2]2 (0.050 mol %), and base (1.0 mol %) in toluene (1 mL) under
reflux. b Determined by 1H NMR. The value in parentheses is isolated yield.
achieved. To date, several catalytic systems for the N-
alkylation of amines, ammonium salts, and carboxamides
with alcohols have been reported. In contrast, only a few
publications on the catalytic N-alkylation of sulfonamides
with alcohols have appeared,7d,9-11 in spite of the importance
of N-alkylated sulfonamides as mentioned above.12 More-
over, alcohols used in these catalytic systems are almost
limited to benzylic and allylic ones. We report here a simple
and versatile catalytic system for the N-alkylation of sul-
fonamides with various alcohols catalyzed by [Cp*IrCl2]2/
t-BuOK, which requires very small amounts of the iridium
catalyst (0.050-1.5 mol %). Mechanistic studies of this
catalytic system are also demonstrated.
a The reaction was carried out with 1a (2.0 mmol), primary alcohol
(2.2 mmol), [Cp*IrCl2]2 (0.050-1.5 mol %), and t-BuOK (1.0 - 30 mol
%) in toluene (1 mL) under reflux for 17 h. b Isolated yield.
(7) (a) Naota, T.; Takaya, H.; Murahashi, S.-I. Chem. ReV. 1998, 98,
2599, and references cited therein. (b) Hollmann, D.; Tillack, A.; Michalik,
D.; Jackstell, R.; Beller, M. Chem. Asian J. 2007, 2, 403. (c) Tillack, A.;
Hollmann, D.; Mevius, K.; Michalik, D.; Ba¨hn, S.; Beller, M. Eur. J. Org.
Chem. 2008, 4745. (d) Hamid, M. H. S. A.; Allen, C. L.; Lamb, G. W.;
Maxwell, A. C.; Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J. J. Am.
At first, we examined the reaction of p-toluenesulfonamide
(1a) with benzyl alcohol (2a) under various conditions. The
results are summarized in Table 1. When the reaction of 1a
with 2a was carried out in the presence of [Cp*IrCl2]2 (0.050
mol %) under reflux in toluene for 17 h, only a trace amount
of N-benzyl-p-toluenesulfonamide 3a was formed (entry 1).
The reaction was considerably accelerated by the addition
of a base (entries 2-5). When the reactions were carried
out in the presence of Na2CO3, K2CO3, and Cs2CO3 (1.0 mol
%, respectively), the yields of 3a were improved up to 80%,
92%, and 97%, respectively (entries 3-5). Stronger base
(MeOK and t-BuOK) was more effective, giving a quantita-
tive yield of 3a (entries 6 and 7). With a lower amount of
the iridium catalyst (0.025 mol % Ir), 3a was formed in a
lower yield (entry 8). The optimum reaction time was 17 h,
since the reaction for 7 h resulted in a slightly lower yield
(entry 9). The reaction with t-BuOK as a base in the absence
of iridium catalyst gave no product (entry 10), indicating
that a combination of the iridium catalyst and base is
indispensable to afford 3a.
Chem. Soc. 2009, 131, 1766
(8) Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpenyai, N.
J. Chem. Soc., Chem. Commun. 1981, 611
.
.
(9) (a) Shi, F.; Tse, M. K.; Zhou, S.; Pohl, M.-M.; Radnik, J.; Hu¨bner,
S.; Ja¨hnisch, K.; Bru¨ckner, A.; Beller, M. J. Am. Chem. Soc. 2009, 131,
1775. (b) Shi, F.; Tse, M. K.; Cui, X.; Go¨rdes, D.; Michalik, D.; Thurow,
K.; Deng, Y.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, 5912
.
(10) Eisenstein and Crabtree have reported the N-alkylation of p-
toluenesulfonamide with benzyl alcohol catalyzed by the [Cp*IrCl2]2/K2CO3
system in their mechanistic study on Cp*Ir-catalyzed N-alkylation of amines
(ref 6e). However, only one example was presented for the N-alkylation of
sulfonamide, and the yield of the product was moderate (53%) although a
relatively large amount of the catalyst (2.5 mol %) was employed.
(11) Some publications on Lewis acid-catalyzed amidation of alcohols
with sulfonamides via stabilized carbocation intermediates have also
appeared. (a) Terrasson, V.; Marque, S.; Georgy, M.; Campagne, J.-M.;
Prim, D. AdV. Synth. Catal. 2006, 348, 2063. (b) Reddy, C. R.; Madhavi,
P. P.; Reddy, A. S. Tetrahedron Lett. 2007, 48, 7169. (c) Sreedhar, B.;
Reddy, P. S.; Reddy, M. A.; Neelima, B.; Arundhathi, R. Tetrahedron Lett.
2007, 48, 8174. (d) Qin, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M.
Angew. Chem., Int. Ed. 2007, 46, 409
.
(12) N-Alkylation of sulfonamides is also important as an alternative
to the direct alkylation of ammonia, since N-alkylated sulfonamides can
be easily converted to primary amines by deprotection.
Org. Lett., Vol. 12, No. 6, 2010
1337

Table 3. Cp*Ir-Catalyzed N-Alkylation of
Table 4. Cp*Ir-Catalyzed N-Alkylation of Various
Sulfonamides (1b-f) with Benzyl Alcohol (2a)a
p-Toluenesulfonamide (1a) with Secondary Alcoholsa
a The reaction was carried out with 1a (1.0 mmol), secondary alcohol
(1.5 mmol), [Cp*IrCl2]2 (0.50 mol %), and t-BuOK (10 mol %) in p-xylene
(1 mL) under reflux for 17 h. b Isolated yield.
a The reaction was carried out with 1b-f (2.0 mmol), 2a (2.2 mmol),
[Cp*IrCl2]2 (0.050-1.0 mol %), and t-BuOK (1.0-20 mol %) in toluene
(1 mL) under reflux for 17 h. b Isolated yield.
The N-alkylation reactions of 1a with various primary
alcohols were conducted under the optimized reaction condi-
tions. The results are summarized in Table 2. The reactions with
benzylic alcohols bearing electron-donating (methyl and meth-
oxy groups) and electron-withdrawing substituents (chloro,
bromo, trifluoromethyl, and methoxycarbonyl groups) at the
aromatic ring proceeded to give the corresponding N-alkylated
products in good to excellent yields (entries 2-12). Chloro and
bromo substituents were tolerant in this catalytic system,
indicating that the N-alkylated p-toluenesulfonamides thus
produced can be subjected to further transformation such as
transition metal-catalyzed coupling reactions (entries 5-10). The
reactions of sterically demanding 2-chloro- and 2-bromobenzyl
alcohols proceeded smoothly to give the corresponding products
in high yields (entries 5 and 8). The N-alkylation with
2-naphthalenemethanol took place in high yield (entry 13).
However, the reaction with 4-pyridylmethanol required rela-
tively higher catalyst loading (1.5 mol %) in order to obtain
good yield (entry 14), probably due to the coordinating ability
of the pyridine ring. The reactions of 1a with a variety of
aliphatic primary alcohols also proceeded to give the corre-
sponding N-alkylated p-toluenesulfonamides in good to excel-
lent yields by using [Cp*IrCl2]2 (0.25 to 1.0 mol % Ir) and
t-BuOK (5.0 to 20 mol %) (entries 15-21), demonstrating the
versatility of the present catalytic system. In any of the reactions
in Table 2, no formation of dialkylated product was observed.
We next investigated the N-alkylation of 1a with second-
ary alcohols. The reactions with secondary alcohols were
conducted under reflux in p-xylene. The results are sum-
marized in Table 3. The reactions with cyclic secondary
alcohols using 0.50 mol % of the iridium catalyst and 10
mol % of base gave N-alkylated products in good to high
yields (entries 1-3). However, the reaction with 1-phenyle-
thanol resulted in moderate yield of the product (entry 4).
We also examined the reactions of sulfonamides bearing
various functional groups on the aromatic ring (Table 4).
The reactions of electron-deficient sulfonamides proceeded
to give good to excellent yields with a smaller amount of
the iridium catalyst (0.050 to 0.10 mol %) (entries 1, 3, and
4), while a higher catalyst loading (1.0 mol %) was necessary
in the case of an electron-rich sulfonamide (entry 2).
Methanesulfonamide could be also used as a good substrate
(entry 5).
To isolate and characterize the catalytically active species,
a
stoichiometric reaction of the catalyst precursor,
[Cp*IrCl2]2, with p-toluenesulfonamide under basic condition
was carried out. When the suspension of [Cp*IrCl2]2 (0.5
mmol), 1a (1.0 mmol), and t-BuOK (1.0 mmol) in toluene
was stirred at room temperature for 5 min, a dinuclear
complex, [(Cp*Ir)2(µ-NTs)2] (12), having bridging imido
ligands was formed quantitatively (eq 1).13 The complex 12
exhibited high catalytic activity comparable to that of the
[Cp*IrCl2]2 catalyst for the reaction of 1a with 2a (eq 2),
suggesting its importance as a catalytically active species.
1338
Org. Lett., Vol. 12, No. 6, 2010

According to our previous studies on the N-alkylation of
amines, carbamates, and carboxamides catalyzed by Cp*Ir
complexes,6a-d,g the mechanism for the present N-alkylation
of sulfonamides would be based on a “hydrogen-transfer
mechanism”, i.e., (1) hydrogen transfer oxidation of an
alcohol to an aldehyde, (2) formation of an iminic intermedi-
ate by condensation, and (3) transfer hydrogenation of the
iminic intermediate with the transient iridium hydride species
generated in step 1 to give the product. To confirm the
proposed mechanism, the catalytic reaction was monitored
intermediate.15 Addition of the iridium hydride to the iminic
intermediate followed by the reaction with the alcohol would
occur to give the product and regenerate the catalytically
active species.
Scheme 1. Plausible Mechanism for the Cp*Ir-Catalyzed
N-Alkylation of Sulfonamides with Alcohols
1
by H NMR. The reaction of 1a with 2a in the presence of
[Cp*IrCl2]2 (10 mol %) and t-BuOK (40 mol %) in toluene-
d8 was conducted in an NMR tube. After the reaction at 100
°C for 1 h, the formation of benzaldehyde (5%) and the
iminic intermediate 13 (1%), in addition to the product 3a
(19%), was observed (eq 3), supporting the hydrogen-transfer
mechanism. Additionally, the reaction of separately prepared
13 with benzyl alcohol 2a in the presence of catalytic
amounts of 12 and t-BuOK gave 3a (98%) and benzaldehyde
(98%) via transfer hydrogenation of the iminic CdN bond,
also supporting the hydrogen-transfer mechanism.
In summary, a simple and versatile catalytic system for
N-alkylation of sulfonamides with various alcohols based
on hydrogen transfer methodology has been developed. With
a low catalyst loading of Cp*Ir complex (0.050-1.5 mol
%), a variety of N-alkylated sulfonamides were synthe-
sized in good to high yields. Mechanistic investigations
revealed that the key catalytic species in the present system
is a sulfonylimido-bridged unsaturated diiridium complex
[(Cp*Ir)2(µ-NTs)2].
On the basis of these experimental results, a possible
mechanism for the Cp*Ir-catalyzed N-alkylation of sulfona-
mides with alcohols is illustrated in Scheme 1. The first step
of the reaction would involve the formation of the catalytic
species 12. Then, the hydrogen transfer oxidation of a
primary alcohol to an aldehyde would occur through an
alkoxo species accompanied by the formation of an iridium
hydride species.14 Next, the condensation of the aldehyde
with a sulfonamide would proceed to afford an iminic
Acknowledgment. We thank Johnson Matthey, Inc., for
a generous loan of iridium trichloride.
Supporting Information Available: General experimental
procedure and characterization data of the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Preparation of the complex 12 by the reaction of [Cp*IrCl2]2 with
1a in the presence of base (KOH) has been previously reported by Kuwata
and Ikariya. However, catalytic activity of 12 has never been investigated.
Ishiwata, K.; Kuwata, S.; Ikariya, T. Organometallics 2006, 25, 5847.
(14) We have also monitored the stoichiometric reaction of 12 with 2a
in the presence of t-BuOK at 100 °C in NMR tube (toluene-d8), which
indicated the formation of benzaldehyde, although the iridium species
formed in the reaction has not been characterized yet.
OL1002434
(15) The condensation of an aldehyde and a sulfonamide affording an
iminic intermediate was accelerated under basic conditions: The reaction
of 1a with benzaldehyde under toluene reflux for 1 h in the presence of
t-BuOK (1 mol %) gave the imine 13 in 56% yield, while the reaction in
the absence of base resulted in 13% yield.
Org. Lett., Vol. 12, No. 6, 2010
1339