The N-alkylation of sulfonamides with alcohols in water catalyzed by the water-soluble iridium complex {Cp*[6,6'-(OH)2bpy](H 2O)}[OTf]2

Article abstract of DOI:10.1002/adsc.201300711

The water-soluble iridium complex {Cp*[6,6'-(OH)₂bpy] (H₂O)}[OTf]₂ (Cp=ν5-pentamethylcyclopentadienyl, bpy=2,2'-bipyridine) was found to be a general and highly efficient catalyst for the Nalkylation of the poor nucleophilic sulfonamides with alcohols as alkylating agents in water. The presence of OH units in the bpy ligand is crucially important for the catalytic activity of the iridium complex. Mechanistic investigations revealed that the catalytically active species is a ligand-metal bifunctional iridium complex bearing an N,N'-chelated 2,2'-bipyridinated ligand and an aqua ligand. Notably, the present catalytic system and the proposed mechanism provide a new horizon and scope for the development of "hydrogen autotransfer (or hydrogen-borrowing) processes".

Full text of DOI:10.1002/adsc.201300711

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DOI: 10.1002/adsc.201300711
The N-Alkylation of Sulfonamides with Alcohols in
Water Catalyzed by the Water-Soluble Iridium Complex
A
E
G
U
Panpan Qu,a Chunlou Sun,a Juan Ma,a and Feng Lia,*
a
Key Laboratory for Soft Chemistry and Functional Materials, Ministry of Education, Nanjing University of Science and
Technology, Nanjing 210094, Peopleꢀs Republic of China
Fax : (+86)-25-8443-1939; e-mail: fengli@njust.edu.cn
Received: August 7, 2013; Revised: October 13, 2013; Published online: January 13, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300711.
Abstract: The water-soluble iridium complex {Cp*Ir- dium complex bearing an N,N’-chelated 2,2’-bipyridi-
[OTf]2 (Cp*=h5-pentamethyl- nated ligand and an aqua ligand. Notably, the pres-
ACHTUNGTRENNUNG[6,6’-(OH)2bpy]ACHTUNGTRENNUNG(H2O)}ACHTNUGTRENNGUN
cyclopentadienyl, bpy=2,2’-bipyridine) was found to ent catalytic system and the proposed mechanism
be a general and highly efficient catalyst for the N- provide a new horizon and scope for the develop-
alkylation of the poor nucleophilic sulfonamides with ment of “hydrogen autotransfer (or hydrogen-bor-
alcohols as alkylating agents in water. The presence rowing) processes”.
of OH units in the bpy ligand is crucially important
for the catalytic activity of the iridium complex. Keywords: alcohols; N-alkylation; hydrogen auto-
Mechanistic investigations revealed that the catalyti- transfer; iridium; sulfonamides; water-soluble cata-
cally active species is a ligand-metal bifunctional iri- lyst
Introduction
thromboxane receptor antagonists (B),[2b] inhibitors of
Mycobacterium tuberculosis (C),[2c] hypoxia-activated
Sulfonamide derivatives represent an important class prodrugs for cancer therapy (D),[2d] potential antitry-
of nitrogen-containing compounds.[1] In particular, N- panosomal agents (E)[2e] and specific c.met/ron dual
alkylsulfonamides display a large range of biological kinase inhibitors (F)[2f] (Scheme 1). The traditional
activities.[2] Recent examples include secreted frizzled method for the synthesis of N-alkylsulfonamides in-
related protein-1 (sFRP-1) inhibitors (A),[2a] potent volves the reaction of sulfonyl halides with N-alkylat-
Scheme 1. Biologically active N-alkylsulfonamides.
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Panpan Qu et al.
ed amines.[3] However, sulfonyl halides are highly Results and Discussion
toxic reagents, and are not suitable for long-term stor-
age. Reactions of activated sulfonate esters[4] or sul- Initially, the N-alkylation of p-methylbenzenesulfona-
fonic acids[5] with N-alkylamines have been developed mide 1a with benzyl alcohol 2a in water was selected
for the preparation of N-alkylsulfonamides. These as a model to explore the feasibility of reaction. A
procedures suffer from the generation of at least stoi- range of water-soluble Cp*Ir complexes, including
chiometric amounts of harmful waste by-products.
In recent years, much attention has been paid to 1),[18] Cp*Ir complex bearing one or more aqua li-
the N-alkylation of amines with alcohols as alkylating gands [Cp*Ir(H2O)3] (bpy)-
[OTf]2 (cat. 2),[19] [Cp*Ir
[OTf]2 (cat. 3)[20] and [Cp*Ir
(6,6’-(OH)2bpy)-
[OTf]2 (6,6’-(OH)2bpy=6,6’-dihydro-2,2’-bipyr-
cationic [Cp*IrACTHNGUTERNNU(G bpy)Cl]Cl (bpy=2,2’-bipyridine) (cat.
A
R
ACHTUNGTRENNUNG
agents based on the “hydrogen autotransfer (or hy-
drogen-borrowing) process”,[6] using ruthenium,[7] iri-
N
G
ACHTUNGTRENNUNG
dium[8] or other transition metal catalysts.[9] In this idine) (cat. 4),[21] were assayed for their ability to cata-
process, alcohols are first dehydrogenated to form al- lyze the selected model reaction. In the presence of
dehydes, followed by the condensation of the result- catalyst (1 mol%) and Cs2CO3 (0.1 equiv,), the reac-
ing aldehydes with amines to afford imine intermedi- tion of 1a with 2a was carried out at 1208C in water
ates, which are hydrogenated to give the final N-alky- (1 mL) for 15 h. As shown in Table 1, no reaction oc-
lated products. This methodology is attractive because curred when cat. 1 and cat. 3 were used as the catalyst
of high atom efficiency and the formation of water as (Table 1, entry 1 and entry 3). The N-alkylated prod-
the only by-product. Williams,[10a] Beller,[10b,c] Ramꢂn uct 3aa was obtained with 11% yield in the presence
and Yus,[10d,e] Fujita and Yamaguchi,[10f] Xu[10g,h] and of cat. 2 (Table 1, entry 2). To our surprise, cat. 4,
their co-workers, have demonstrated the synthesis of which was originally developed by Fujita and Yama-
N-alkylsulfonamides via the N-alkylation of sulfona- guchiꢀs group for the dehydrogenative oxidation of al-
mides with alcohols as alkylating agents using ruthe- cohols in water,[21] exhibited excellent activity for this
nium,[10a,b,e] copper,[10c,d] iridium[10f,i] and other transi- reaction and the N-alkylated product 3aa could be ob-
tion metal catalysts.[10g,h] However, these procedures tained with 92% yield (Table 1, entry 4). The cat. 4
have to be performed using several equivalents of al- was chosen as the catalyst for further research. Using
cohols as solvents or in organic solvents such as tolu- NaOH, KOH or KO-t-Bu as the alternative base, re-
ene. From the standpoint of sustainable chemistry, the actions afforded the product 3aa with high yields as
development of organic synthesis in water is becom- well (Table 1, entries 5–7). In the presence of a rela-
ing increasingly important because water is cheap, tively weak base, such as Na2CO3, K2CO3 or
safe and environmentally benign.[11] Fujita and Yama- NaHCO3, decreases in the yield were observed
guchiꢀs group, and Williamsꢀs group have demonstrat- (Table 1, entries 8–10). Attempts to reduce the reac-
ed that water-soluble [Cp*IrACHTNUGRTNEUNG
(NH3)3]I2 (Cp*=h5-pen- tion temperature resulted in relatively low yields
tamethylcyclopentadienyl)[12] and [Cp*IrI2]2[13] are effi- (Table 1, entries 11 and 12). It was also found that no
cient catalysts for the N-alkylation of ammonia as reaction took place in the individual presence of cat.
well as aromatic and aliphatic amines with alcohols in 4 or Cs2CO3 (Table 1, entries 13 and 14).
water. However, the N-alkylation of poor nucleophilic
Having established the optimal reaction conditions
amines, such as sulfonamides, with alcohols in water (Table 1, entry 4), the N-alkylation of 1a with a variety
is still extremely challenging.[14] Therefore, the devel- of alcohols 2 was investigated. As shown in Table 2,
opment of new typed of water-soluble catalysts for the transformation of benzylic alcohols bearing one
the N-alkylation reaction in water is highly desirable. or two electron-donating groups, such as methyl 2b,
Recently, we reported the transition metal-cata- isopropyl 2c, methoxy 2d, 2e and dimethoxy 2f, af-
lyzed regioselective N-alkylation with alcohols for the forded the corresponding products 3ab–3af with 81–
preparation of 2-(N-alkylamino)azoles,[15a–d] 2-(N-alky- 91% yields (Table 2, entries 1–5). Reactions with ben-
lamino)quinazolines,[15e] N,N’-alkylarylureas and N,N’- zylic alcohols bearing one or two halide atoms, such
dialkylureas.[15f] We also demonstrated the synthesis as fluoro 2g, chloro 2h, 2i, dichloro 2j and bromo 2k,
of N-alkylated amides from aldoximes and alcohols gave the desired products 3ag–3ak with 80–94%
via a tandem rearrangement/N-alkylation reaction yields (Table 2, entries 6–10). Furthermore, benzylic
using Ru/Ir dual catalyst system[16] and Ir-catalyzed alcohols bearing an electron-withdrawing group, such
direct coupling of indoles with methanol to 3,3’-bisin- as trifluoromethyl 2l and trifluoromethoxy 2m, were
doles (3,3’-BIMs).[17] As part of a continuing interest utilized as alkylating agents and the corresponding
in exploring Ir-catalyzed reactions, herein we wish to products 3al and 3am were obtained with 84% and
describe our efforts towards the development of a gen- 90% yields, respectively (Table 2, entries 11 and 12).
eral and efficient catalyst for the N-alkylation of sul- High catalytic activity was found for the N-alkylation
fonamides with alcohols in water. Furthermore, mech- with 2-naphthalenemethanol 2n, 2-pyridylmethanol 2o
anistic studies are also presented.
and ferrocenemethanol 2p (Table 2, entries 13–15).
Apart from benzylic-type alcohols, the linear aliphatic
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The N-Alkylation of Sulfonamides with Alcohols in Water
Table 1. N-Alkylation of p-methylbenzenesulfonamide 1a with benzyl alcohol 2a under vari-
ous conditions.[a]
[a]
Reactions conditions: 1a (1 mmol), alcohol (1.2 mmol), cat. (1 mol%), water (1 mL),
1208C, 15 h.
Isolated yield.
[b]
alcohols, such as 1-butanol 2q and 1-hexanol 2r, were the corresponding products 3da–3ga with 84–94%
also successfully converted into the desired products yields (Table 3, entries 3–6). Differing from the previ-
3as and 3at with 83% and 81% yields, respectively ous report,[8b] benzenesulfomamides bearing a strong
(Table 2, entries 16 and 17). Similarly, reactions with electron-withdrawing substituent, such as nitro 1h, tri-
the branched alcohol 2s and cyclic alcohol 2t gave the fluoromethyl 1i and trifluoromethoxy 1j, were proven
corresponding products 3as and 3at with 78% and to be suitable substrates and the desired products
85% yields, respectively (Table 2, entries 18 and 19). 3ha–3ja were obtained with 85–91% yields (Table 3,
When secondary alcohols with high steric hindrance, entries 7–9). In the case of benzenesulfonamide 1k
such as 1-cyclopentanol and 1-cyclophenanol, were and naphthalenesulfonamide 1l, the corresponding
used as substrates, none of N-alkylated products were products 3ka and 3la were obtained with 88% and
found.
92% yields, respectively (Table 3, enties 10 and 11).
To evaluate further the scope of the reaction, the The coupling was also applied to aliphatic sulfona-
N-alkylation of a series of sulfonamides 1 with 2a was mides, such as methyl 1m, cyclopropyl 1n and phenyl-
examined and the results are outlined in Table 3. Sim- methyl 1o, affording the desired products 3ma–3oa
ilar to the case of 1a, reactions of benzenesulfona- with 80–86% yields (Table 3, entries 12–14).
mides bearing an electron-donating substituent, such
Realizing the importance of the presence of OH
as methyl 1b and methoxy 1c, afforded the desired units in the bpy ligand for the catalytic activity of the
products 3ba and 3ca with 83% and 87% yields, re- iridium complex, a possible mechanism was proposed
spectively (Table 3, entries 1 and 2). The N-alkylation and is shown in Scheme 2. The initial step of the reac-
of benzenesulfonamides containing a halide atom, tion involved the formation of neutral iridium species
such as fluoro 1d, chloro 1e, 1f and bromo 1g, gave A bearing an N,N-chelated 2,2’-bipyridonated ligand
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Table 2. N-Alkylation of p-methylbenzenesulfonamide 1a with a variety of alco-
hols 2 in water.[a]
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The N-Alkylation of Sulfonamides with Alcohols in Water
Table 2. (Continued)
[a]
Reactions conditions: 1a (1 mmol), 2 (1.2 mmol), cat. 4 (1 mol%), Cs2CO3
(0.1 equiv.), water (1 mL), 1208C, 15 h.
Isolated yield.
[b]
[c]
2 (2 mmol), Cs2CO3 (0.2 equiv.).
and an aqua ligand by the reaction of dicationic cat. 4 from B occurred to give iridium hydride species C
with base in water.[22] The bipyridonate ligand accept- and aldehydes, which are condensed with sulfona-
ed a proton in the step of the activation of alcohols, mides to form unsaturated sulfonimine intermediates.
resulting in the generation of alkoxy iridium species The simultaneous transfer of the hydride on iridium
B, and the process could be stimulated by the addition and the hydroxy proton on the bpy ligand of species
of a base.[21] Furthermore, b-hydrogen elimination C to the C=N bond of sulfonimine intermediates took
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Table 3. N-Alkylation of a series of sulfonamides 1 with benzyl alcohol 2a in water.[a]
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Table 3. (Continued)
[a]
[b]
Reactions conditions: 1 (1 mmol), 2a (1.2 mmol), cat. 4 (1 mol%), Cs2CO3 (0.1 equiv.), water
(1 mL), 1208C, 15 h.
Isolated yield.
place, and thus the N-alkylated products were re-
It should be noted that, apart from the desired
leased and the catalytic species A were regenerated. products N-monoalkylsulfonamides, none of the over-
A similar mechanism for the simultaneous delivery of alkylated N,N-dialkylsulfonamides were found in all
hydride and proton to ketones or sulfonamides is pro- cases. In addition, in most cases, it is very easy to iso-
posed in metal-ligand bifunctional catalysts, such as late N-alkylsulfonamides from water by simple filtra-
Shvoꢀs catalyst,[23] and Ru-TsDPEN systems.[24]
tion when the crude mixtures were cooled to room
To support the above mechanism, the proposed cat- temperature (see Figure S1 in the Supporting Infor-
alytically active species A was synthesized by the re- mation).
action of the dicationic complex with base.[22] Treat-
ment of cat. 4 with 1 equiv. of Cs2CO3 in water afford-
ed the neutral species A with 70% yield. In the pres- Conclusions
ence of species A (1% mol) and Cs2CO3 (0.1 equiv.),
the reaction of 1a with 2a was carried out in water at In summary, we have demonstrated that the water-
1208C for 15 h to give the N-alkylated product 3aa soluble [Cp*IrACTHUGNTERN(NNUG 6,6’-(OH)2bpy)ACHTNUTRGEG(NUNN H2O)]ACHTNUGTERN[NUGN OTf]2 is a gener-
with 93% yield (Scheme 3). Apparently, the species A al and highly efficient catalyst for the N-alkylation of
exhibited catalytic activity comparable to that of cat. poor nucleophilic sulfonamides with alcohols as alky-
4, indicating its importance as a catalytically active lating agents in water. The presence of OH units in
species.
the bpy ligand is crucially important for the catalytic
The catalytic hydrogen transfer between sulfoni- activity of the iridium complex. Mechanistic investiga-
mine with alcohol in water was investigated. The reac- tions revealed that the catalytically active species is
tion of (E)-N-benzylidene-4-methylbenzenesulfona- ligand-metal bifunctional iridium complex bearing an
mide 4, which is prepared by the condensation be- N,N’-chelated 2,2’-bipyridonated ligand and an aqua
tween p-methylbenzenesulfonamide and benzyl alde- ligand. Notably, the present catalytic system and the
hyde, with benzyl alcohol 2a as the hydrogen source proposed mechanism provide new horizons and scope
in the presence of cat. 3 (1 mol%) and Cs2CO3 for the development of “hydrogen autotransfer (or
(0.1 equiv.) proceeded for 15 h, and none of N-benzyl- hydrogen-borrowing) process”.
4-methylbenzenesulfonamide 3aa was observed and
all starting material was hydrated into p-methylbenze-
nefulfonamide. When cat. 4 or the species A was
used, the reactions afforded the product 3aa with
Experimental Section
65% and 63% yields, respectively, although the hydra-
tion of a part of starting material occurred as well
General Experimental Details
(Scheme 4). These results support the proposed mech-
anism.
High-resolution mass spectra (HR-MS) were obtained on an
HPLC-Q-Tof MS(Micro) spectrometer and are reported as
AHCTUNGTRENNUNG
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on a X-6 micro-melting apparatus. Proton nuclear magnetic
resonance (1H NMR) spectra were recorded at 500 MHz
using a Bruker Avance 500 spectrometer. Chemical shifts
are reported in delta (d) units, parts per million (ppm)
downfield from trimethylsilane or ppm relative to the center
of the singlet at 7.26 ppm for CDCl3 and 2.50 ppm for
DMSO-d6. Coupling constants J values are reported in
Hertz (Hz), and the splitting patterns were designated as
follows: s, singlet; d, doublet; t, triplet; m, multiplet; b,
broad. Carbon-13 nuclear magnetic resonance (13C NMR)
spectra were recorded at 125 MHz using a Bruker Avance
500 spectrometer. Chemical shifts are reported in delta (d)
units, ppm relative to the center of the triplet at 77.0 ppm
for CDCl3 and 39.5 ppm for DMSO-d6. 13C NMR spectra
were routinely run with broadband decoupling. All reactions
were run under an atmosphere of nitrogen, unless otherwise
indicated. Analytical thin-layer chromatography (TLC) was
carried out using 0.2 mm commercial silica gel plates.
[Cp*Ir
2),[19a] [Cp*Ir
(OH)2bpy)(H2O)]ACHTUNGTRENNUNG
G
ACHUTGTNREN(NUG H2O)3]ACHTNUGTRENNNUG
E
E
N
ACHTUNGTRENNUNG
U
ing to the previous reports.
General Procedure for the N-Alkylation of
Sulfonamides with Alcohols in Water Catalyzed by
Water-Soluble Cp*Ir Complex
Under a nitrogen atmosphere, to a 25-mL Schlenk tube
were added water-soluble Cp*Ir complex (0.01 mmol,
1 mol%), sulfonamide (1 mmol), alcohol (1.2 mmol),
Cs2CO3 (0.1 equiv.) and water (1 mL). The mixture was
heated at 1208C for 15 h and allowed to cool to ambient
temperature. In the case of N-alkylation of 1a with 2q–t, the
mixture was concentrated under vacuum and purified by
flash column chromatography with hexane/ethyl acetrate to
afford the corresponding product. In the other cases, the re-
action mixture became clear and a large amount of precipi-
tation appeared after about 1 hour. The precipitation was
isolated by simple filtration, washed with water three times
and dried under vacuum to afford the desired N-alkylated
product.
Scheme 2. The proposed reaction mechanism.
N-Benzyl-4-methylbenzenesulfonamide (3aa):[10b] mp 113–
1
1148C; H NMR (500 MHz, CDCl3): d=7.74 (d, J=8.4 Hz,
m/z (relative intensity). Accurate masses are reported for
the molecular ion [M+Na]+. Melting points were measured
2H, ArH), 7.29–7.23 (m, 5H, ArH), 7.19–7.17 (m, 2H,
ArH), 4.99 (br s, 1H, NH), 4.09 (d, J=6.0 Hz, 2H,
Scheme 3. The synthesis of species A and its application for the N-alkylation of 1a with 2a.
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Scheme 4. The hydrogen transfer between sulfonimine and alcohol.
CH2NH); 13C NMR (125 MHz, CDCl3): d=143.4, 136.8,
136.3, 129.7, 128.6, 127.81, 127.78, 127.1, 47.2, 21.4.
N-(4-Methylbenzyl)-4-methylbenzenesulfonamide
NH), 4.09 (d, J=5.5 Hz, 2H, CH2NH), 2.44 (s, 3H, CH3);
13C NMR (125 MHz, CDCl3): d=162.3 (d, JC,F =245.3 Hz),
143.6, 136.9, 132.1, 129.7, 129.6 (d, JC,F =7.6 Hz), 127.1, 115.5
(d, JC,F =21.0 Hz), 46.5, 21.5; HR-MS-EI (70 eV): m/z=
344.0628, calcd. for C14H14FNO2SNa [M+Na]+: 302.0627.
N-(2-Chlorobenzyl)-4-methylbenzenesulfonamide
1
(3ab):[26] mp 90–918C; H NMR (500 MHz, CDCl3): d=7.74
(d, J=8.2 Hz, 2H, ArH), 7.29 (d, J=8.2 Hz, 2H, ArH), 7.06
(s, 4H, ArH), 4.83 (br s, 1H, NH), 4.05 (d, J=5.4 Hz, 2H,
CH2NH), 2.43 (s, 3H, CH3), 2.30 (s, 3H, CH3); 13C NMR
(125 MHz, CDCl3); d=143.4, 137.6, 136.8, 133.2, 129.7,
129.3, 127.8, 127.1, 47.0, 21.5, 21.0.
1
(3ah):[10d] mp 66–678C; H NMR (500 MHz, CDCl3): d=7.71
(d, J=7.9 Hz, 2H, ArH), 7.35–7.23 (m, 4H, ArH), 7.22–7.14
(m, 2H, ArH), 4.87 (br s, 1H, NH), 4.25 (d, J=6.5 Hz, 2H,
CH2NH), 2.41 (s, 3H, CH3); 13C NMR (125 MHz, CDCl3):
d=143.4, 136.9, 133.9, 133.3, 130.2, 129.6, 129.4, 129.2, 127.0,
45.1, 21.5.
N-(4-Chlorobenzyl)-4-methylbenzenesulfonamide
(3ai):[10b] mp 103–1058C; 1H NMR (500 MHz, CDCl3): d=
7.72 (d, J=7.8 Hz, 2H, ArH), 7.28 (d, J=8.0 Hz, 2H, ArH),
7.23–7.20 (m, 2H, ArH), 7.12 (d, J=8.3 Hz, 2H, ArH), 5.03
(br s, 1H, NH), 4.08 (d, J=6.3 Hz, 2H, CH2NH), 2.43 (s,
3H, CH3); 13C NMR (125 MHz, CDCl3): d=143.7, 136.8,
134.8, 133.8, 129.8, 129.2, 128.8, 127.1, 46.6, 21.5.
N-(4-Isopropylbenzyl)-4-methylbenzenesulfonamide
1
(3ac):[10b] mp 113–1148C; H NMR (500 MHz, CDCl3): d=
7.75 (d, J=8.2 Hz, 2H, ArH), 7.30 (d, J=8.1 Hz, 2H, ArH),
7.12 (quart, J=8.0 Hz, 4H, ArH), 4.56 (br s, 1H, NH), 4.09
(t, J=2.9 Hz, 2H, CH2NH), 2.91–2.82 (heptet, J=6.9 Hz,
1H, CH), 2.44 (s, 3H, CH3), 1.21 (d, J=7.0 Hz, 6H, 2xCH3);
13C NMR (125 MHz, CDCl3): d=148.7, 143.4, 137.0, 133.6,
129.7, 128.0, 127.2, 126.7, 47.1, 33.8, 23.9, 21.5.
N-(3-Methoxybenzyl)-4-methylbenzenesulfonamide
1
(3ad):[10b] mp 83–848C; H NMR (500 MHz, CDCl3): d=7.76
(d, J=8.1 Hz, 2H, ArH), 7.31 (d, J=7.8 Hz, 2H, ArH), 7.19
(t, J=7.8 Hz, 1H, ArH), 76.77 (t, J=8.4 Hz, 2H, ArH), 6.72
(s, 1H, ArH), 4.67 (br s, 1H, NH), 4.10 (d, J=6.1 Hz, 2H,
CH2NH), 3.75 (s, 3H, OCH3), 2.44 (s, 3H, CH3); 13C NMR
(125 MHz, CDCl3): d=159.8, 143.5, 137.8, 136.8, 129.7,
129.6, 127.1, 120.0, 113.6, 113.1, 55.1, 47.1, 21.5.
N-(4-Methoxybenzyl)-4-methylbenzenesulfonamide
(3ae):[27] mp 121–1228C; 1H NMR (500 MHz, CDCl3): d=
7.75 (d, J=7.9 Hz, 2H, ArH), 7.30 (d, J=7.9 Hz, 2H, ArH),
7.10 (d, J=8.4 Hz, 2H, ArH), 6.79 (d, J=8.3 Hz, 2H, ArH),
4.69 (br s, 1H, NH), 4.04 (d, J=5.9 Hz, 2H, CH2NH), 3.77
(s, 3H, OCH3), 2.44 (s, 3H, CH3); 13C NMR (125 MHz,
CDCl3): d=159.3, 143.4, 136.9, 129.7, 129.2, 128.2, 127.2,
114.0, 55.3, 46.8, 21.5.
N-(3,4-Dichlorobenzyl)-4-methylbenzenesulfonamide
(3aj): mp 105–1068C; H NMR (500 MHz, CDCl3): d=7.71
1
(d, J=8.2 Hz, 2H, ArH), 7.33 (d, J=8.3 Hz, 1H, ArH), 7.29
(d, J=8.1 Hz, 2H, ArH), 7.23 (d, J=1.6 Hz, 1H, ArH), 7.05
(dd, J=8.2 Hz and 1.5 Hz, 1H, ArH), 4.87 (br s, 1H, NH),
4.09 (d, J=6.4 Hz, 2H, CH2NH), 2.44 (s, 3H, CH3);
13C NMR (125 MHz, CDCl3): d=143.9, 136.7, 136.6, 132.6,
131.9, 130.5, 129.8, 129.7, 127.10, 127.07, 46.0, 21.5; HR-MS-
EI (70 eV): m/z=351.9951, calcd. for C14H13NO2SCl2Na
[M+Na]+: 351.9942.
N-(4-Bromobenzyl)-4-methylbenzenesulfonamide
1
(3ak):[10d] mp 117–1188C; H NMR (500 MHz, CDCl3): d=
7.72 (d, J=8.1 Hz, 2H, ArH), 7.38 (d, J=8.2 Hz, 2H, ArH),
7.29 (d, J=8.0 Hz, 2H, ArH), 7.07 (d, J=8.2 Hz, 2H, ArH),
4.85 (br s, 1H, NH), 4.07 (d, J=6.3 Hz, 2H, CH2NH), 2.44
(s, 3H, CH3); 13C NMR (125 MHz, CDCl3): d=143.7, 136.8,
135.4, 131.7, 129.7, 129.5, 127.1, 121.8, 46.6, 21.5.
N-(3,4-Dimethoxybenzyl)-4-methylbenzenesulfonamide
1
(3af): mp 123–1248C; H NMR (500 MHz, CDCl3): d=7.76
(d, J=7.3 Hz, 2H, ArH), 7.32 (d, J=7.3 Hz, 2H, ArH),
6.76–6.68 (m, 3H, ArH), 4.63 (br s, 1H, NH), 4.07 (d, J=
5.4 Hz, 2H, CH2NH), 3.84 (s, 3H, OCH3), 3.80 (s, 3H,
OCH3), 2.44 (s, 3H, CH3); 13C NMR (125 MHz, CDCl3): d=
149.1, 148.6, 143.4, 137.0, 129.7, 128.7, 127.1, 120.1, 110.9,
55.9, 55.7, 47.1, 21.5; HR-MS-EI (70 eV): m/z=344.0943,
calcd. for C16H19NO4SNa [M+Na]+: 344.0932.
N-[4-(Trifluoromethyl)benzyl]-4-methylbenzenesulfona-
1
mide (3al):[10h] mp 136–1378C; H NMR (500 MHz,CDCl3):
d=7.72 (d, J=8.3 Hz, 2H, ArH), 7.52 (d, J=8.1 Hz, 2H,
ArH), 7.33 (d, J=7.9 Hz, 2H, ArH), 7.29 (d, J=8.0 Hz, 2H,
ArH), 4.81 (br s, 1H, NH), 4.20 (d, J=6.4 Hz, 2H,
CH2NH), 2.43 (s, 3H, CH3); 13C NMR (125 MHz, CDCl3):
d=143.7, 140.5, 136.8, 130.0 (q, JC,F =32.2 Hz), 128.0, 127.2,
127.1, 125.5, 123.9 (q, JC,F =270.0 Hz), 46.6, 21.4; HR-MS-EI
(70 eV): m/z=352.0599, calcd. for C15H14F3NO2SNa [M+
Na]+: 352.0595.
N-(4-Fluorobenzyl)-4-methylbenzenesulfonamide (3ag):[28]
1
mp 93–948C; H NMR (500 MHz, CDCl3): d=7.75 (d, J=
7.4 Hz, 2H, ArH), 7.31 (d, J=7.5 Hz, 2H, ArH), 7.17 (s,
2H, ArH), 6.96 (t, J=8.2 Hz, 2H, ArH), 4.68 (br s, 1H,
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455

FULL PAPERS
Panpan Qu et al.
N-[4-(Trifluoromethoxy)benzyl]-4-methylbenzenesulfona-
mide (3am): mp 85–868C; H NMR (500 MHz, CDCl3): d=
7.73 (d, J=8.3 Hz, 2H, ArH), 7.30 (d, J=8.1 Hz, 2H, ArH),
7.23 (d, J=8.4 Hz, 2H, ArH), 7.11 (d, J=8.3 Hz, 2H, ArH),
4.71 (br s, 1H, NH), 4.15 (d, J=6.3 Hz, 2H, CH2NH), 2.43
(s, 3H, CH3); 13C NMR (125 MHz, CDCl3): d=148.7, 143.7,
CH3), 1.68–1.66 (m, 5H, 2CH2, CH), 1.41–1.38 (m, 1H,
CH), 1.21–1.06 (m, 3H, CH2, CH), 0,88–0.81 (m, 2H, CH2);
13C NMR (125 MHz, CDCl3): d=143.2, 137.1, 129.6, 127.0,
49.3, 37.7, 30.5, 26.2, 25.6, 21.5.
1
N-Benzyl-2-methylbenzenesulfonamide (3ba):[10j] mp 57–
588C; 1H NMR (500 MHz, CDCl3): d=7.99 (d, J=7.6 Hz,
1H, ArH), 7.46 (t, J=7.3 Hz, 1H, ArH), 7.34–7.24 (m, 5H,
ArH), 7.16 (d, J=6.4 Hz, 2H, ArH), 4.76 (br s, 1H, NH),
4.11 (d, J=5.9 Hz, 2H, CH2NH), 2.62 (s, 3H, CH3);
13C NMR (125 MHz, CDCl3): d=137.7, 137.0, 136.2, 132.8,
132.5, 129.6, 128.6, 127.8, 126.1, 47.1, 20.2; HR-MS-EI
(70 eV): m/z=284.0722, calcd. for C12H19NO2SNa [M+
Na]+: 264.1034.
136.9, 135.2, 129.7, 129.3, 127.1, 123.4, 121.1, 120.4 (q, JCÀF
=
255.8 Hz), 46.4, 21.5; HR-MS-EI (70 eV): m/z=368.0538,
calcd, for C15H14NO3F3SNa [M+Na]+: 368.0544.
4-Methyl-N-(naphthalen-2-ylmethyl)benzenesulfonamide
(3an):[10a] mp 131–1328C; 1H NMR (500 MHz,CDCl3): d=
7.80–7.71 (m, 5H, ArH), 7.60 (s, 1H, ArH), 7.47–7.46 (m,
2H, ArH), 7.31–7.27 (m, 3H, ArH), 4.78 (br s, 1H, NH),
4.29 (d, J=5.9 Hz, 2H, CH2NH), 2.41(d, J=3.7 Hz, 3H,
CH3); 13C NMR (125 MHz, CDCl3): d=143.5, 136.9, 133.6,
133.2, 132.9, 129.7, 128.5, 127.7. 127.6, 127.2, 126.7, 126.3,
126.1, 125.6, 47.4, 21.5.
4-Methyl-N-(thiophen-2-ylmethyl)benzenesulfonamide
(3ao):[10b] mp 111–1128C; 1H NMR (500 MHz,CDCl3): d=
7.76 (d, J=8.0 Hz, 2H, ArH), 7.31 (d, J=7.9 Hz, 2H, ArH),
7.20 (d, J=5.1 Hz, 1H, ArH), 6.89 (t, J=4.2 Hz, 1H, ArH),
6.86 (s, 1H, ArH), 4.67 (br s, 1H, NH), 4.33 (s, 2H,
CH2NH), 2.44 (s, 3H, CH3); 13C NMR (125 MHz, CDCl3):
d=143.6, 138.9, 136.7, 129.7, 127.2, 126.8, 126.5, 125.8, 42.6,
21.5.
N-Benzyl-4-methoxybenzenesulfonamide (3ca):[7j] mp
106–1078C; 1H NMR (500 MHz, CDCl3): d=7.80 (d, J=
8.8 Hz, 2H, ArH), 7.30–7.24 (m, 3H, ArH), 7.19 (d, J=
7.9 Hz, 2H, ArH), 6.99–6.95 (m, 2H, ArH), 4.68 (br s, 1H,
NH), 4.11 (d, J=6.2 Hz, 2H, CH2NH), 3.88 (s, 3H, OCH3);
13C NMR (125 MHz, CDCl3): d=162.9, 136.3, 131.4, 129.2,
128.6, 127.81, 127.78, 114.2, 55.6, 47.2.
N-Benzyl-4-fluorobenzenesulfonamide (3da):[10b] mp 96–
1
978C; H NMR (500 MHz, CDCl3): d=7.86 (dd, J=8.8 Hz
and 4.7 Hz, 2H, ArH), 7.30–7.25 (m, 3H, ArH), 7.20–7.14
(m, 4H, ArH), 4.82 (br s, 1H, NH), 4.15 (s, 2H, CH2NH);
13C NMR (125 MHz, CDCl3): d=165.0 (d, JC,F =253.7 Hz),
136.02, 135.97, 129.8 (d, JC,F =9.9 Hz), 128.7, 127.9, 127.8,
116.2 (d, JC,F =22.2 Hz), 47.2.
N-Ferrocenemethyl-4-methylbenzenesulfonamide (3ap):
1
mp 121–1228C; H NMR (500 MHz, CDCl3) d 7.77 (d, J=
8.0 Hz, 2H, ArH), 7.33 (d, J=8.0 Hz, 2H, ArH), 4.44 (br s,
1H, NH), 4.20–4.08 (m, 9H, ferrocene H), 3.80(d, J=8.0 Hz,
2H, CH2NH), 2.45 (s, 3H, CH3); 13C NMR (125 MHz,
CDCl3): d=143.4, 136.9, 129.7, 127.1, 83.6, 68.6, 68.3, 67.9,
42.5, 21.5; HR-MS-EI (70 eV): m/z=392.0389, calcd. for
C18H19NO2SFeNa [M+Na]+: 392.0384.
N-Benzyl-2-chlorobenzenesulfonamide (3ea):[10b] mp 88–
908C; 1H NMR (500 MHz,CDCl3): d=8.08 (d, J=7.4 Hz,
1H, ArH), 7.51–7.46 (m, 2H, ArH), 7.41–7.38 (m, 1H,
ArH), 7.28–7.21 (m, 3H, ArH), 7.20–7.16 (m, 2H, ArH),
5.29 (br s, 1H, NH), 4.12 (s, 2H, CH2NH); 13C NMR
(125 MHz, CDCl3): d=137.2, 135.7, 133.7, 131.5, 131.33,
131.28, 128.6, 128.0, 127.9, 127.2, 47.5.
N-Butyl-4-methylbenzenesulfonamide (3aq):[7j] mp 38–
398C; 1H NMR (500 MHz, CDCl3): d=7.75 (d, J=8.0 Hz,
2H, ArH), 7.31 (d, J=8.0 Hz, 2H, ArH), 4.54 (br s, 1H,
NH), 2.93 (quart, J=6.7 Hz, 2H, CH2N), 2.43 (s, 3H, CH3),
1.44 (quint, J=7.3 Hz, 2H, CH2), 1.29 (sext, J=7.5 Hz, 2H,
CH2), 0.85 (t, J=7.3 Hz, 3H, CH3); 13C NMR (125 MHz,
CDCl3): d=143.2, 136.9, 129.6, 127.0, 42.9, 31.5, 21.4, 19.6,
13.5.
N-Benzyl-3-chlorobenzenesulfonamide (3fa): mp 79–
1
808C; H NMR (500 MHz, CDCl3): d=7.83 (s, 1H, ArH),
7.74 (d, J=7.9 Hz, 1H, ArH), 7.54 (d, J=7.9 Hz, 1H, ArH),
7.44 (t, J=7.9 Hz, 1H, ArH), 7.31–7.26 (m, 3H, ArH), 7.20
(d, J=6.7 Hz, 2H, ArH), 4.76 (br s, 1H, NH), 4.18 (d, J=
6.1 Hz, 2H, CH2NH); 13C NMR (125 MHz, CDCl3): d=
141.7, 135.8, 135.2, 132.8, 130.4, 128.7, 128.1, 127.9, 127.2,
125.1, 47.3; HR-MS-EI (70 eV): m/z=304.0173, calcd. for
C13H12NO2SClNa [M+Na]+: 304.0175.
N-Hexyl-4-methylbenzenesulfonamide (3ar):[10b] mp 61–
628C; 1H NMR (500 MHz, CDCl3): d=7.74 (d, J=8.3 Hz,
2H, ArH), 7.31 (d, J=7.9 Hz, 2H, ArH), 4.33 (br s, 1H,
NH), 2.93 (quart, J=6.8 Hz, 2H, CH2N), 2.43 (s, 3H, CH3),
1.44 (quint, J=7.1 Hz, 2H, CH2), 1.28–1.16 (m, 6H, 3xCH2),
0.85 (t, J=6.9 Hz, 3H, CH3); 13C NMR (125 MHz, CDCl3):
d=143.3, 137.0, 129.6, 127.1, 43.2, 31.2, 29.5, 26.1, 22.4, 21.5,
13.9.
N-Benzyl-4-bromobenzenesulfonamide (3ga):[10b] mp 119–
1208C; 1H NMR (500 MHz,CDCl3): d=7.71 (d, J=6.6 Hz,
2H, ArH), 7.64 (d, J=6.7 Hz, 2H, ArH), 7.28 (s, 3H, ArH),
7.19 (s, 2H, ArH), 4.76 (br s, 1H, NH), 4.16 (s, 2H,
CH2NH); 13C NMR (125 MHz, CDCl3): d=139.0, 135.9,
132.3, 128.7, 128.6, 128.0, 127.8, 127.6, 47.2.
N-Isopentyl-4-methylbenzenesulfonamide (3as):[29] oil;
1H NMR (500 MHz, CDCl3): d=7.75 (d, J=8.3 Hz, 2H,
ArH), 7.31(d, J=8.3 Hz, 2H, ArH), 4.47 (br s, 1H, NH),
2.94 (quart, J=7.0 Hz, 2H, NCH2), 2.43 (s, 3H, CH3), 1.58
(heptet, J=6.8 Hz, 1H, CH), 1.33 (quart, J=7.2 Hz, 2H,
CH2), 0.83 (d, J=6.7 Hz, 6H, 2CH3); 13C NMR (125 MHz,
CDCl3): d=143.3, 136.9, 129.7, 127.1, 41.4, 38.3, 25.4, 22.2,
21.5; HR-MS-EI (70 eV): m/z=264.1040, calcd. for
C12H19NO2SNa [M+Na]+ 264.1034.
N-Benzyl-4-nitrobenzenesulfonamide (3ha):[13b] mp 124–
1
1258C; H NMR (500 MHz, CDCl3): d=8.30 (d, J=8.7 Hz,
2H, ArH), 7.99 (d, J=8.6 Hz, 2H, ArH), 7.28–7.25 (m, 3H,
ArH), 7.18–7.15 (m, 2H, ArH), 4.99 (br s, 1H, NH), 4.23 (d,
J=6.0 Hz, 2H, CH2NH); 13C NMR (125 MHz, CDCl3): d=
149.9, 146.0, 135.5, 128.8, 128.3, 128.2, 127.9, 124.3, 47.3.
N-Benzyl-4-(trifluoromethyl)benzenesulfonamide (3ia):[30]
1
mp 114–1158C; H NMR (500 MHz, CDCl3): d=7.95 (d, J=
7.9 Hz, 2H, ArH), 7.74 (d, J=8.0 Hz, 2H, ArH), 7.27–7.17
(m, 5H, ArH), 7.18 (d, J=7.2 Hz, 2H, ArH), 4.91 (br s, 1H,
NH), 4.20 (d, J=4.8 Hz, 2H, CH2NH); 13C NMR (125 MHz,
CDCl3): d=143.7, 135.6, 134.3 (q, JC,F =33.0 Hz), 128.8,
128.1, 127.9, 127.6, 126.2, 123.2 (q, JC,F =271.4 Hz), 47.3;
N-(Cyclohexylmethyl)-4-methylbenzenesulfonamide
1
(3at):[10a] mp 80–818C; H NMR (500 MHz, CDCl3): d=7.74
(d, J=8.1 Hz, 2H, ArH), 7.31 (d, J=7.9 Hz, 2H, ArH), 4.40
(br s, 1H, NH), 2.76 (t, J=6.6 Hz, 2H, CH2N), 2.43 (s, 3H,
456
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FULL PAPERS
The N-Alkylation of Sulfonamides with Alcohols in Water
HR-MS-EI
(70 eV):
m/z=338.0436,
calcd
for
(1 mL). The mixture was heated at 1208C for 15 h and al-
lowed to cool to ambient temperature. The reaction mixture
became clear and a large amount of precipitation appeared
after about 1 hour. The precipitation was isolated by simple
filtration, washed with water three times and dried under
vacuum to afford the desired product.
C14H12F3NO2SNa [M+Na]+ 338.0439.
N-Benzyl-4-(trifluoromethoxy)benzenesulfonamide
(3ja):[10b] mp 110–1118C; 1H NMR (500 MHz, CDCl3): d=
7.88 (d, J=8.9 Hz, 2H, ArH), 7.30 (d, J=8.7 Hz, 2H, ArH),
7.28–7.25 (m, 3H, ArH), 7.19–7.15 (m, 2H, ArH), 4.78 (br s,
1H, NH), 4.19 (d, J=6.2 Hz, 2H, CH2NH); 13C NMR
(125 MHz, CDCl3): d=152.1, 138.5, 135.8, 129.2, 128.7,
128.1, 127.9, 121.0, 120.2 (q, JC,F =257.5 Hz), 47.3.
Hydrogen Transfer between 4 and 2a (Scheme 4)
N-Benzylbenzenesulfonamide (3ka):[10h] mp 85–868C;
1H NMR (500 MHz, CDCl3): d=7.87 (d, J=7.8 Hz, 2H,
ArH), 7.58 (t, J=7.1 Hz, 1H, ArH), 7.51 (t, J=7.9 Hz, 2H,
ArH), 7.26 (d, J=6.8 Hz, 3H, ArH), 7.18 (d, J=7.2 Hz, 2H,
ArH), 4.83 (br s, 1H, NH), 4.14 (s, 2H, CH2NH); 13C NMR
(125 MHz, CDCl3): d=139.9, 136.2, 132.6, 129.0, 128.6,
127.8, 127.0, 47.1.
To a 25-mL Schlenk tube were added (E)-N-benzylidene-4-
methylbenzenesulfonamide 4 (1 mmol), benzyl alcohol 2a
(1.2 mmol), Cs2CO3 (0.1 mmol, 0.1 equiv.), water (1 mL),
and cat. 4 or species A. The resulting mixture was then
heated at 1208C for 12 h, after which the reaction mixture
was allowed to cool to ambient temperature. The mixture
was concentrated under vacuum and the residue purified by
flash column chromatography with hexanes/ethyl acetate to
afford the product 3aa. When cat. 3 was used as the alterna-
tive catalyst, no trace of product 3aa was found.
N-Benzylnaphthalene-2-sulfonamide (3la):[10b] mp 105–
1
1068C; H NMR (500 MHz, CDCl3): d=8.45 (s, 1H, ArH),
8.02–7.90 (m, 3H, ArH), 7.84 (d, J=8.4 Hz, 1H, ArH),
7.70–7.60 (m, 2H, ArH), 7.28 À7.16 (m, 5H, ArH), 4.78 (br
s, 1H, NH), 4.18 (d, J=5.7 Hz, 2H, CH2NH); 13C NMR
(125 MHz, CDCl3): d=136.6, 136.1, 134.8, 132.1, 129.5,
129.2, 128.8, 128.62, 128.57, 127.9, 127.8, 127.5, 122.2, 47.3.
N-Benzylmethanesulfonamide (3ma):[10d] mp 58–598C;
1H NMR (500 MHz,CDCl3): d=7.39–7.31 (m, 5H, ArH),
4.77 (br s, 1H, NH), 4.32 (s, 2H, CH2NH), 2.86 (s, 3H,
CH3); 13C NMR (125 MHz, CDCl3): d=136.7, 128.8, 128.0,
127.8, 47.1, 40.9.
Acknowledgements
Financial support by National Natural Science Foundation of
China (No. 21272115) and Fundamental Research Funds for
the Central Universities (No. 30920130111005) is greatly ap-
preciated.
N-Benzylcyclopropanesulfonamide (3na):[10b] mp 54–558C;
1H NMR (500 MHz, CDCl3): d=7.37 (d, J=4.0 Hz, 4H,
ArH), 7.34–7.29 (m, 1H, ArH), 4.53 (br s, 1H, NH), 4.35 (d,
J=6.1 Hz, 2H, CH2NH), 2.38–2.32 (m, 1H, CH), 1.16 (d,
J=4.9 Hz, 2H, CH2), 0.94 (d, J=7.5 Hz, 2H, CH2);
13C NMR (125 MHz, CDCl3): d=137.1, 128.8, 127.9, 127.8,
47.3, 30.5, 5.4.
References
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fava, T. Owa, A. Mastrolorenzo, C. T. Supuran, Curr.
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Jones, Curr. Opin. Drug Discovery Dev. 2008, 11, 72–
79.
N-BenzylACHTUNGTRENNUNG
(phenyl)methanesulfonamide (3oa):[31] mp 147–
1
1488C; H NMR (500 MHz, CDCl3): d=7.39–7.25 (m, 10H,
ArH), 4.37 (br s, 1H, NH), 4.22 (s, 2H, CH2), 4.15 (d, J=
5.3 Hz, 2H, CH2NH); 13C NMR (125 MHz, CDCl3): d=
136.8, 130.6, 129.2, 128.8, 128.7, 128.1, 128.0, 59.3, 47.6; HR-
MS-EI (70 eV): m/z=284.0716, calcd. for C14H15NO2SNa
[M+Na]+: 284.0721.
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Synthesis of Catalytically Active Species A (Scheme
3)
To a flask were added cat. 4 (100 mg, 0.12 mmol), Cs2CO3
(1.0 equiv.), water (2 mL), and the mixture was stirred for
0.5 h at room temperature. The resulting suspension was fil-
tered and the residue was washed with water and dried
1
under vacuum to afford the species A; yield: 70%. H NMR
(500 MHz, CH3OD): d=7.40 (br s, 2H, ArH), 6.90 (br s,
2H, ArH), 6.41 (br s, 2H, ArH), 1.53 (s, 15H, Cp*H);
13C NMR (125 MHz, CH3OD): d=170.1, 156.4, 139.0, 117.3,
106.1, 87.0, 8.9.
N-Alkylation of 1a with 2a Catalyzed by Species A
(Scheme 3)
To a 25-mL Schlenk tube were added species A (0.01 mmol,
1 mol%), p-methylbenzenesulfonamide 1a (1 mmol), benzyl
alcohol 2a (1.2 mmol), Cs2CO3 (0.1 equiv.) and water
[3] a) J. March, Advanced Organic Chemistry, 3rd edn.,
Wiley, New York, 1985; b) R. Cremlyn, Organosulfur
Chemistry: An Introduction, John Wiley and Sons: New
Adv. Synth. Catal. 2014, 356, 447 – 459
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457

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