Metal-free direct N-benzylation of sulfonamides with benzyl alcohols by employing boron trifluoride-diethyl ether complex

Article abstract of DOI:10.1055/s-0034-1380129

N-Benzylation of sulfonamides with both primary and secondary benzyl alcohols by employing boron trifluoride-diethyl ether complex under mild reaction conditions has been developed, which is an environmentally benign and facile protocol for assembling a series of primary and secondary benzyl sulfonamides in yields up to 83%. In this coupling reaction, the beneficial role of water has been clarified in detail through control experiments.

Full text of DOI:10.1055/s-0034-1380129

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1101–1108
paper
1101
J. Pan et al.
Paper
Synthesis
Metal-Free Direct N-Benzylation of Sulfonamides with Benzyl
Alcohols by Employing Boron Trifluoride–Diethyl Ether Complex
Jing Pana
Jia-qiang Lia
Ruo-feng Huanga
Xiao-hui Zhanga
Hang Shena
R1
R1
BF3•OEt2
NH-O2SR
OH
+
RSO2-NH2
14 examples, yields up to 83%
Yan Xiong*a,b
Xiang-ming Zhuc
a School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, P. R. of China
xiong@cqu.edu.cn
b Chongqing Key Laboratory of Chemical Process for Clean Energy and Resource Utilization, Chongqing University, Chongqing 400044, P. R. of China
c UCD School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
Received: 10.11.2014
Accepted after revision: 30.12.2014
Published online: 10.02.2015
ever the utilization of a noble metal/transition metal [such
as Ag–Mo,5a RhCl(PPh3)3,5b,c Ru–Fe3O4,6a Ir(II),6b Cu(OAc)2,6c
Fe(II)6d] and harsh reaction conditions (high temperature,
long reaction time, air-sensitive) are inevitable; with Lewis
acid [including Bi(OTf)3,7a MoCl5,7b FeCl3,7c NaAuCl4,7d
AgOTf7e] and Brønsted acid (p-toluenesulfonic acid mono-
hydrate)7f mediated direct amination, the substrate scope is
limited to only either primary or secondary benzyl alco-
hols. As a result, the development of a metal-free N-ben-
zylation of sulfonamides with benzyl alcohols under mild
reaction conditions is still an important need in the prepa-
ration of N-benzylated sulfonamides.
DOI: 10.1055/s-0034-1380129; Art ID: ss-2014-h0688-op
Abstract N-Benzylation of sulfonamides with both primary and sec-
ondary benzyl alcohols by employing boron trifluoride–diethyl ether
complex under mild reaction conditions has been developed, which is
an environmentally benign and facile protocol for assembling a series of
primary and secondary benzyl sulfonamides in yields up to 83%. In this
coupling reaction, the beneficial role of water has been clarified in de-
tail through control experiments.
Key words N-benzylation, sulfonamides, benzyl alcohols, boron tri-
fluoride–diethyl ether complex, water
Boron trifluoride–diethyl ether complex (BF3·OEt2) is a
versatile Lewis acid, the use of which has been successful in
various synthetic procedures such as alkylation,9a,b cycliza-
tion,9c–f rearrangement9g and coupling reactions.9h Nowa-
days, more and more attention is being paid to its use in in-
dustrial applications due to its convenient operation and
simple workup after reaction. BF3·OEt2 is an adduct of bo-
ron trifluoride and diethyl ether through donor–acceptor
bonding;10 upon exposure to water, ligand exchange be-
tween diethyl ether and water has been detected and the
highly effective acid BF3·H2O is generated owing to its
stronger interaction.11 Recently, we have found an effective
transformation of structurally diverse diarylmethanes pro-
moted by the superacid BF3·H2O, which is formed through
coordination of BF3·OEt2 with water,12 and interestingly, the
successively generated byproduct water has been utilized in
the in situ preparation of BF3·H2O. As an extension of this
research, herein we would like to report a direct N-benzyla-
tion of sulfonamides with both primary and secondary
benzyl alcohols by employing BF3·OEt2 under mild reaction
conditions.
Sulfonamides and their derivatives have attracted in-
creased attention in the past decade due to their biological
and pharmaceutical activities, such as antibacterial, anti-
cancer and HIV protease inhibition activities.1 For the syn-
thesis of various N-substituted sulfonamides, many strate-
gies have been exploited, including reactions of amines
with sulfonyl halides2 and cross-coupling of sulfonamides
with organic halides,3 which are regarded as the classical
methods. A few novel protocols have been reported in re-
cent years,4–8 such as noble metal catalytic intermolecular
amidation4a–c and hydroamination,4d,e nucleophilic addi-
tion–elimination of sulfonic acids or sulfonates with
amines,4f,g N-benzylation of sulfonamides with benzyl alco-
hols,5–7 and Lewis acid mediated hydroamination of
sulfenamides.8
Of these aforementioned strategies, N-benzylation of
sulfonamides with benzyl alcohols appears to be most at-
tractive due to the ready availability of materials and the
low cost, and the fact that only environment-friendly water
is obtained as byproduct. Significant advances have been
achieved in N-benzylation through borrowing hydrogen,
hydrogen autotransfer strategies or direct amination, how-
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Table 1 Optimization of the Reaction Conditionsa
1,2-dichloroethane or dichloromethane, the same level of
activity was observed with yields of 38% and 39%, respec-
tively (Table 1, entries 3 and 4). With chloroform as solvent,
the N-benzylated sulfonamide was afforded in better yield
(Table 1, entry 5). The ratio of 1a to 2a significantly influ-
enced the yield of the desired product (Table 1, entries 6–
10). Increasing the amount of 1a led to a continued im-
proved reactivity in this N-benzylation (Table 1, entries 6–
9) and an amount of 1.8 equivalents of 1a in chloroform
provided the best results, giving the mono- and di-N-ben-
zylated products in yields of up to 83% and 14%, respective-
ly (Table 1, entry 9). The effects of the loading of BF3·OEt2
and the temperature on this N-benzylation were next stud-
ied. In the presence of 0.2 equivalents of BF3·OEt2, only 12%
of the monobenzylated sulfonamide was detected (Table 1,
entry 11). Then, 1.0 and 1.4 equivalents of BF3·OEt2 were in-
vestigated, which provided a slightly lower yield than the
use of 1.2 equivalents of BF3·OEt2 (Table 1, entries 12 and 13
vs entry 9). Under a lower temperature of 60 °C, a similarly
decreased yield of N-benzylated sulfonamide was obtained
(Table 1, entry 14) and no reaction occurred at room tem-
perature (Table 1, entry 15), which is significantly different
to the results obtained by Prim, Campagne and co-workers
with secondary alcohols.7d Subsequently, a different vol-
ume of solvent was investigated. As a result, in 1.0 mL of
chloroform, 69% of N-benzylated sulfonamide was ob-
tained, due to the decreased solubility of 1a (Table 1, entry
16), and there was a slightly decreased isolated yield of the
desired product in 3.0 mL of chloroform (Table 1, entry 17).
Based on an understanding of the crucial role of water
in the transformation of diarylmethanes,12b the optimal
conditions were then applied in an examination of the in-
fluence of water on the N-benzylation of sulfonamide 1a,
with the results shown in Table 2. In the absence of water
under argon atmosphere, BF3·OEt2 performed with a mod-
erate activity and the benzylated products 3a and 4a were
obtained in yields of 60% and 12%, respectively (Table 2, en-
try 1). When 0.1 equivalent of water was added, the yield of
the desired N-benzylated product increased to 72% (Table 2,
entry 2). Compared with the reaction performed under
open-flask conditions (Table 1, entry 9), an equally excel-
lent isolated yield was obtained upon the addition of 0.2
equivalents of water (Table 2, entry 3). An increase in the
amount of water to 0.3 equivalents resulted in a diminished
yield (73%) of the monosubstituted product 3a (Table 2, en-
try 4), and a further decreased yield (39%) was detected in
the presence of 0.4 equivalents of water (Table 2, entry 5),
both of which indicated that excessive hydration of BF3·OEt2
is detrimental to this transformation. Then, 1.2 equivalents
of potassium carbonate were added to this model reaction
under open-flask and reflux conditions; no desired product
was detected, as BF3·OEt2 or BF3·H2O was neutralized by the
potassium carbonate (Table 2, entry 6). The influence of
molecular sieves on trace water amounts has been explored
O
O
O
S
S
Bn
Bn
N
O
O
H
S
H
N
BF3•OEt2
OH
+
3a
H
solvent
2 h
O
N
1a
2a
Bn
4a
Entry
Solvent
Et2O
Ratio
(1a/2a)
BF3·OEt2
(equiv)
Temp
(°C)
Yieldb
(%)
1
2
1.0:1.0
1.0:1.0
1.0:1.0
1.0:1.0
1.0:1.0
1.0:1.2
1.2:1.0
1.5:1.0
1.8:1.0
2.0:1.0
1.8:1.0
1.8:1.0
1.8:1.0
1.8:1.0
1.8:1.0
1.8:1.0
1.8:1.0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
0.2
1.0
1.4
1.2
1.2
1.2
1.2
reflux
NRc
toluene
DCE
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
60
19
3
38
4
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
39
5
58
6
51
7
62
8
70
9
83 (14)d
77
10
11
12
13
14
15
16
17
12
73 (12)d
76 (12)d
72
25
n.r.c
reflux
reflux
69 (8)d,e
77 (10)d,f
a Reaction conditions: BnOH (2a), p-TolSO2NH2 (1a), BF3·OEt2, undistilled sol-
vent (2.0 mL), in air, heat, 2 h.
b Yield of 3a determined by 1H NMR spectroscopy using 1,3,5-trimethylben-
zene as an internal standard.
c No reaction.
d Isolated yields of 3a and 4a (4a in parentheses).
e Undistilled CHCl3 (1.0 mL) was used.
f Undistilled CHCl3 (3.0 mL) was used.
Our investigation was firstly concentrated on the opti-
mization of the reaction conditions for N-benzylation based
on the model reaction of p-toluenesulfonamide (1a) with
benzyl alcohol (2a) under open-flask conditions, with the
results shown in Table 1. In this coupling reaction, both the
mono- and di-N-benzylated sulfonamides 3a and 4a were
observed, and could be readily separated by silica gel col-
umn chromatography. Various solvents were initially
screened, under reflux conditions (Table 1, entries 1–5); as
a result, no desired product was detected in diethyl ether
(entry 1), while 19% of N-benzylated sulfonamide was ob-
tained with toluene as solvent (entry 2). Upon exposure to
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1101–1108

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J. Pan et al.
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Synthesis
as well (Table 2, entries 7–9); slightly decreased yields of N-
benzylated product were obtained upon the addition of dif-
ferent types of molecular sieves.
tions of sulfonamides 1b and 1c with benzyl alcohol pro-
ceeded smoothly, with the N-benzylated products 3b and
3c accompanied by the N,N-dibenzylated sulfonamides 4b
and 4c in yields of 16% and 18%, respectively (Table 3, en-
tries 2 and 3). In the N-benzylation of the sulfonamide 1d
bearing a bromo substituent, a slightly lower yield of the
corresponding N-benzylated product 3d was obtained (Ta-
ble 3, entry 4). Moreover, the aliphatic sulfonamide 1e was
accepted in this coupling process, and a good isolated yield
of 3e was obtained (Table 3, entry 5). We then focused on
N-benzylation with various benzyl alcohols (Table 3, entries
6–14). A series of primary benzyl alcohols 2b–g was exam-
ined in the reaction with 1a. In the case of p-tolylmethanol
(2b), a moderate yield of the corresponding monobenzylat-
ed product 3f was obtained (Table 3, entry 6). Benzyl alco-
hols with a halogen substituent at the para-position pre-
sented appreciable activities, giving the N-benzylated prod-
ucts 3g–i in 68% to 81% yield (Table 3, entries 7–9); a 16%
yield of the N,N-dibenzylated sulfonamide 4i was obtained
in the case of p-bromo-substituted benzyl alcohol as the
substrate. A good yield of the corresponding N-benzylated
sulfonamide was also obtained for the bulky o-iodo-substi-
tuted benzyl alcohol (Table 3, entry 10). In this coupling re-
action, the benzyl alcohol 2g bearing two halo substituents,
at both the ortho- and para-positions, gave a moderate yield
of the target sulfonamide 3k after 12 hours (Table 3, entry
11). The N-benzylation of p-toluenesulfonamide (1a) was
also examined with a series of secondary benzyl alcohols;
as a result, somewhat sluggish activity was observed in the
case of the m-fluoro-substituted benzyl alcohol 2h (Table 3,
entry 12), while alcohol 2i with a m-chloro substituent per-
formed with good activity to provide the monobenzylated
product 3m in 80% yield (Table 3, entry 13). Only a 34%
yield of the N-benzhydryl-substituted sulfonamide 3n was
obtained from the reaction of sterically hindered diphenyl-
methanol (2j) with sulfonamide 1a (Table 3, entry 14),
which is opposite to the results presented in the aforemen-
tioned acid-mediated N-benzylation reactions where acti-
vated secondary and tertiary benzyl alcohols behaved bet-
ter than primary alcohols.7b–d,f
Table 2 Influence of Water and Molecular Sieves on N-Benzylationa
O
O
S
Bn
Bn
N
BF3•OEt2
(1.2 equiv)
H2O, additive
O
H
O
S
H
OH
N
+
3a
CHCl3
reflux, 2 h
H
O
O
S
N
1a
2a
Bn
4a
Entry
H2O (equiv) Atmosphere Additive
Yieldb (%)
1
2
3
4
5
6
7
8
9
0
argon
argon
argon
argon
argon
air
–
–
–
–
–
60 (12)
72 (14)
83 (14)
73 (14)
39 (22)c
NRd
0.1
0.2
0.3
0.4
–
K2CO3 (1.2 equiv)
3-Å MS (0.2 wt)
4-Å MS (0.2 wt)
5-Å MS (0.2 wt)
–
argon
argon
argon
67 (9)
–
71 (10)
65 (8)
–
a Reaction conditions: BnOH (2a, 1.0 mmol), p-TolSO2NH2 (1a, 1.8 mmol),
BF3·OEt2 (1.2 equiv), H2O (as specified), anhydrous CHCl3 (2.0 mL), reflux, 2
h.
b Isolated yields of 3a and 4a (4a in parentheses).
c Yield of 3a determined by 1H NMR spectroscopy using 1,3,5-trimethyl-
benzene as an internal standard (isolated yield of 3a in parentheses).
d No reaction.
With the optimized reaction conditions in hand (Table
1, entry 9), our interest was further focused on the N-ben-
zylation of different sulfonamides 1a–e with benzyl alco-
hols 2a–j under open-flask conditions using undistilled
chloroform as solvent, and the results are summarized in
Table 3. It was found that differently substituted sulfon-
amides were tolerated, resulting in the N-benzylated prod-
ucts 3a–e in good yields (65–83%) under the optimal reac-
tion conditions, along with a few separated N,N-dibenzylat-
In conclusion, an environmentally benign and facile
method for the direct N-benzylation of sulfonamides with
primary and secondary benzyl alcohols by employing bo-
ron trifluoride–diethyl ether complex has been developed.
The beneficial role of water has been illustrated, and vari-
ous primary and secondary benzyl sulfonamides have been
assembled effectively under these coupling conditions.
ed sulfonamides.
A
gram-scale reaction of p-
toluenesulfonamide (1a) with benzyl alcohol (2a) was car-
ried out which gave a similarly excellent yield to the 1-
mmol-scale reaction (Table 3, entry 1). The coupling reac-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1101–1108

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Synthesis
Table 3 N-Benzylation of Different Sulfonamides 1 with Benzyl Alcohols 2a
R2
R2
O
R2
O
O
O
R2
O
O
BF3•OEt2
S
S
S
H
N
Ar
+
N
Ar
R1
N
R1
Ar
OH
R1
CHCl3
reflux, 2 h
H
H
Ar
1a–e
2a–j
3a–n
4a–c,i
Entry
1, 2
Product, yieldb
O
O
O
O
S
N
Bn
S
Bn
N
H
1
4-TolSO2NH2 (1a), BnOH (2a)
Bn
3a, 83% (82%)c
4a, 14% (12%)c
O
O
O
O
S
Bn
S
Bn
N
N
H
2
3
2-TolSO2NH2 (1b), 2a
Bn
3b, 73%
4b, 16%
O
O
O
O
S
Bn
S
Bn
N
H
N
PhSO2NH2 (1c), 2a
Bn
3c, 69%
4c, 18%
O
O
S
Bn
N
4
4-BrC6H4SO2NH2 (1d), 2a
H
Br
3d, 65%
O
O
S
Bn
N
5
6
MeSO2NH2 (1e), 2a
1a, 4-TolCH2OH (2b)
Me
H
3e, 78%
O
O
S
N
H
3f, 51%
O
O
S
N
H
7
1a, 4-FC6H4CH2OH (2c)
F
3g, 81%
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Synthesis
Table 3 (continued)
Entry
1, 2
Product, yieldb
O
O
S
N
8
1a, 4-ClC6H4CH2OH (2d)
1a, 4-BrC6H4CH2OH (2e)
1a, 2-IC6H4CH2OH (2f)
H
Cl
3h, 81%
Br
O
O
S
N
O
9
S
H
N
Br
O
3i, 68%
Br
4i, 16%
I
O
O
S
N
10
H
3j, 69%
Cl
O
O
S
N
11
12
13
1a, 2,4-Cl2C6H3CH2OH (2g)
1a, 3-FC6H4CH(Me)OH (2h)
1a, 3-ClC6H4CH(Me)OH (2i)
H
Cl
F
3k, 42%d
O
O
S
N
H
3l, 44%
O
O
S
N
Cl
H
3m, 80%
O
O
S
N
14
1a, Ph2CHOH (2j)
H
3n, 34%
a Reaction conditions: sulfonamide 1 (1.8 mmol), benzyl alcohol 2 (1.0 mmol), BF3·OEt2 (1.2 equiv), undistilled CHCl3 (2.0 mL), in air, reflux, 2 h.
b Isolated yields.
c Isolated yields for a 5-mmol-scale reaction: BnOH (2a, 5.0 mmol), p-toluenesulfonamide (1a; 1.8 equiv), BF3·OEt2 (1.2 equiv), undistilled CHCl3 (10.0 mL).
d Reaction time: 12 h.
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NMR spectra were recorded on a Bruker Avance 500 MHz NMR spec-
trometer (1H, 500 MHz; 13C, 125 MHz) with CDCl3 as solvent at 20–
25 °C. H NMR data are reported in parts per million using TMS (δ =
0.00 ppm) as an internal standard, as follows: chemical shift, multi-
plicity (s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet,
m = multiplet), coupling constants (Hz) and integration. 13C NMR data
are reported in parts per million using the solvent (CDCl3, δ = 77.2
ppm) as internal standard. IR spectra were recorded on a Nicolet 550II
spectrophotometer. HRMS (ESI) data were measured on an Agilent
6510 Q-TOF mass spectrometer.
N-Benzyl-4-bromobenzenesulfonamide (3d)
White solid; yield: 212.0 mg (65%); mp 97.2–98.6 °C.
1
IR (KBr): 3282, 3027, 2921, 2853, 1600, 1589, 1474, 1460, 1440, 1325,
1154, 1090, 1056, 823, 756, 700, 535 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.79 (d, J = 8.5 Hz, 2 H), 7.47 (d, J = 8.0
Hz, 2 H), 7.29–7.28 (m, 3 H), 7.18 (dd, J1 = 7.5 Hz, J2 = 2.5 Hz, 2 H), 4.74
(br s, 1 H), 4.16 (d, J = 6.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 139.2, 135.9, 132.4, 129.4, 128.8,
128.6, 128.1, 127.9, 47.3.
HRMS (ESI): m/z [M + H]+ calcd for C13H13BrNO2S: 325.9844; found:
325.9842.
Mono- and Di-N-benzylated Sulfonamides 3 and 4; General Proce-
dure
In a round-bottom flask, a benzyl alcohol 2 (1.0 mmol), a sulfonamide
1 (1.8 mmol) and BF3·OEt2 (151 μL, 1.2 mmol) were dissolved in CHCl3
(2.0 mL). The mixture was stirred for 2 h under reflux in air atmo-
sphere, then the solvent was removed under reduced pressure using a
rotary evaporator. The product was isolated by column chromatogra-
phy of the residue on silica gel (EtOAc–PE, 1:10 to 1:2, v/v) to give the
desired mono- and di-N-benzylated products 3 and 4.
N-Benzylmethanesulfonamide (3e)
White solid; yield: 144.5 mg (78%); mp 59.9–60.6 °C.
IR (KBr): 3232, 3038, 2929, 2856, 1600, 1496, 1457, 1435, 1303, 1151,
1084, 1056, 765, 736, 700 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.35–7.15 (m, 5 H), 5.30–5.27 (m, 1 H),
4.25 (dd, J1 = 6.5 Hz, J2 = 2.0 Hz, 2 H), 2.78 (d, J = 2.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 136.9, 128.9, 128.02, 127.98, 47.1,
40.9.
N-Benzyl-4-methylbenzenesulfonamide (3a)
HRMS (ESI): m/z [M + H]+ calcd for C8H12NO2S: 186.0583; found:
White solid; yield: 217.0 mg (83%); mp 105.7–107.2 °C.
186.0587.
IR (KBr): 3265, 3030, 2915, 2870, 2845, 1603, 1491, 1454, 1421, 1325,
1160, 1093, 1056, 874, 812, 745, 694 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.75 (d, J = 8.5 Hz, 2 H), 7.30 (d, J = 8.0
Hz, 2 H), 7.27–7.24 (m, 3 H), 7.19 (d, J = 7.5 Hz, 2 H), 4.78 (t, J = 5.5 Hz,
1 H), 4.11 (d, J = 6.5 Hz, 2 H), 2.43 (s, 3 H).
4-Methyl-N-(4-methylbenzyl)benzenesulfonamide (3f)
White solid; yield: 140.4 mg (51%); mp 89.9–91.1 °C.
IR (KBr): 3268, 3030, 2971, 2918, 2865, 1597, 1491, 1451, 1429, 1325,
13C NMR (125 MHz, CDCl3): δ = 143.7, 137.0, 136.4, 129.9, 128.8,
1160, 1087, 1051, 877, 840, 804 cm–1
.
128.0, 127.3, 47.4, 21.7.
HRMS (ESI): m/z [M + H]+ calcd for C14H16NO2S: 262.0896; found:
262.0897.
1H NMR (500 MHz, CDCl3): δ = 7.76 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 8.0
Hz, 2 H), 7.08 (s, 4 H), 4.55 (t, J = 5.0 Hz, 1 H), 4.08 (d, J = 6.0 Hz, 2 H),
2.44 (s, 3 H), 2.31 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 143.5, 137.8, 136.9, 133.2, 129.8,
129.4, 127.9, 127.2, 47.1, 21.6, 21.1.
N-Benzyl-2-methylbenzenesulfonamide (3b)
HRMS (ESI): m/z [M + H]+ calcd for C15H18NO2S: 276.1052; found:
White solid; yield: 190.8 mg (73%); mp 101.2–102.5 °C.
276.1051.
IR (KBr): 3299, 3027, 2968, 2926, 2859, 1600, 1572, 1496, 1457, 1418,
1322, 1160, 1132, 1067, 756, 734, 697 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.99 (d, J = 8.0 Hz, 1 H), 7.46 (t, J = 7.5
Hz, 1 H), 7.33–7.29 (m, 2 H), 7.26–7.24 (m, 3 H), 7.15 (d, J = 8.0 Hz, 2
H), 4.78 (s, 1 H), 4.11 (d, J = 6.5 Hz, 2 H), 2.61 (s, 3 H).
N-(4-Fluorobenzyl)-4-methylbenzenesulfonamide (3g)
White solid; yield: 226.3 mg (81%); mp 108.2–109.1 °C.
IR (KBr): 3243, 3038, 2965, 2921, 2862, 1608, 1592, 1505, 1460, 1437,
13C NMR (125 MHz, CDCl3): δ = 137.9, 137.2, 136.5, 133.0, 132.7,
1314, 1224, 1151, 1093, 1065, 863, 835, 812 cm–1
.
129.8, 128.9, 128.13, 128.07, 126.4, 47.3, 20.5.
HRMS (ESI): m/z [M + H]+ calcd for C14H16NO2S: 262.0896; found:
262.0893.
1H NMR (500 MHz, CDCl3): δ = 7.73 (d, J = 8.0 Hz, 2 H), 7.29 (d, J = 8.0
Hz, 2 H), 7.16 (dd, J1 = 8.0 Hz, J2 = 5.5 Hz, 2 H), 6.93 (t, J = 8.0 Hz, 2 H),
5.08 (t, J = 6.0 Hz, 1 H), 4.07 (d, J = 6.0 Hz, 2 H), 2.43 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 143.7, 137.0, 129.9, 129.8, 129.7,
127.3, 115.7, 115.5, 46.7, 21.7.
N-Benzylbenzenesulfonamide (3c)
HRMS (ESI): m/z [M + H]+ calcd for C14H15FNO2S: 280.0802; found:
White solid; yield: 170.6 mg (69%); mp 67.3–68.5 °C.
280.0802.
IR (KBr): 3333, 3036, 2932, 1597, 1491, 1446, 1415, 1328, 1151, 1093,
1062, 751, 700, 689 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.86 (d, J = 7.5 Hz, 2 H), 7.57 (t, J = 7.5
Hz, 1 H), 7.50 (t, J = 7.5 Hz, 2 H), 7.26–7.23 (m, 3 H), 7.18 (d, J = 7.5 Hz,
2 H), 4.90 (s, 1 H), 4.14 (d, J = 6.0 Hz, 2 H).
N-(4-Chlorobenzyl)-4-methylbenzenesulfonamide (3h)
White solid; yield: 239.6 mg (81%); mp 100.4–101.4 °C.
IR (KBr): 3268, 3044, 2949, 2921, 2851, 1594, 1491, 1451, 1432, 1322,
13C NMR (125 MHz, CDCl3): δ = 140.1, 136.3, 132.9, 129.3, 128.9,
1157, 1100, 1067, 879, 835, 812 cm–1
.
128.1, 128.0, 127.3, 47.4.
HRMS (ESI): m/z [M + H]+ calcd for C13H14NO2S: 248.0739; found:
248.0737.
1H NMR (500 MHz, CDCl3): δ = 7.72 (d, J = 8.0 Hz, 2 H), 7.29 (d, J = 8.0
Hz, 2 H), 7.22 (d, J = 8.5 Hz, 2 H), 7.13 (d, J = 8.5 Hz, 2 H), 4.99 (t, J = 6.0
Hz, 1 H), 4.08 (d, J = 6.5 Hz, 2 H), 2.44 (s, 3 H).
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13C NMR (125 MHz, CDCl3): δ = 143.7, 136.8, 134.9, 133.7, 129.8,
129.2, 128.8, 127.2, 46.6, 21.6.
IR (KBr): 3291, 3041, 2979, 2921, 2865, 1594, 1572, 1495, 1435, 1336,
1317, 1160, 1121, 1087, 877, 818, 781, 697, 692, 666 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C14H15ClNO2S: 296.0506; found:
296.0505.
1H NMR (500 MHz, CDCl3): δ = 7.59 (d, J = 8.5 Hz, 2 H), 7.16 (d, J = 8.5
Hz, 2 H), 7.11–7.09 (m, 2 H), 7.04–7.01 (m, 1 H), 6.98 (s, 1 H), 5.55 (d,
J = 7.0 Hz, 1 H), 4.43 (quin, J = 7.0 Hz, 1 H), 2.38 (s, 3 H), 1.37 (d, J = 7.0
Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 144.2, 143.5, 137.5, 134.3, 129.9,
129.6, 127.5, 127.2, 126.6, 124.5, 53.3, 23.6, 21.6.
N-(4-Bromobenzyl)-4-methylbenzenesulfonamide (3i)
White solid; yield: 231.4 mg (68%); mp 112.9–113.4 °C.
IR (KBr): 3265, 3044, 2921, 2856, 1592, 1488, 1454, 1432, 1317, 1154,
HRMS (ESI): m/z [M + H]+ calcd for C15H17ClNO2S: 310.0663; found:
1090, 1073, 877, 812, 540 cm–1
.
310.0666.
1H NMR (500 MHz, CDCl3): δ = 7.69 (d, J = 8.5 Hz, 2 H), 7.34 (d, J = 8.0
Hz, 2 H), 7.26 (d, J = 8.0 Hz, 2 H), 7.05 (d, J = 8.5 Hz, 2 H), 5.30 (t, J = 6.5
Hz, 1 H), 4.04 (d, J = 5.5 Hz, 2 H), 2.42 (s, 3 H).
N-Benzhydryl-4-methylbenzenesulfonamide (3n)
White solid; yield: 114.7 mg (34%); mp 149.0–150.6 °C.
13C NMR (125 MHz, CDCl3): δ = 143.7, 136.9, 135.6, 131.8, 129.9,
129.7, 127.2, 121.8, 46.6, 21.7.
HRMS (ESI): m/z [M + H]+ calcd for C14H15BrNO2S: 340.0001; found:
339.9994.
IR (KBr): 3251, 3024, 2918, 1597, 1496, 1451, 1314, 1157, 1084, 1056,
861, 804, 753, 697 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.55 (d, J = 8.5 Hz, 2 H), 7.22–7.18 (m, 6
H), 7.13–7.09 (m, 6 H), 5.56 (d, J = 7.5 Hz, 1 H), 5.23 (d, J = 6.5 Hz, 1 H),
2.37 (s, 3 H).
N-(2-Iodobenzyl)-4-methylbenzenesulfonamide (3j)
White solid; yield: 267.2 mg (69%); mp 95.0–95.4 °C.
13C NMR (125 MHz, CDCl3): δ = 143.3, 140.7, 137.5, 129.5, 128.7,
127.7, 127.5, 127.4, 61.5, 21.6.
HRMS (ESI): m/z [M – H]– calcd for C20H18NO2S: 336.1063; found:
IR (KBr): 3274, 3044, 2971, 2918, 2867, 1603, 1558, 1463, 1432, 1322,
1160, 1090, 1039, 885, 804, 756, 529 cm–1
.
336.1055.
1H NMR (500 MHz, CDCl3): δ = 7.73–7.71 (m, 3 H), 7.31–7.23 (m, 4 H),
6.93 (t, J = 7.5 Hz, 1 H), 5.09 (s, 1 H), 4.17 (d, J = 6.5 Hz, 2 H), 2.41 (s, 3
H).
N,N-Dibenzyl-4-methylbenzenesulfonamide (4a)
White solid; yield: 24.6 mg (14%); mp 68.9–70.1 °C.
13C NMR (125 MHz, CDCl3): δ = 143.6, 139.6, 138.7, 137.0, 130.2,
129.8, 129.7, 128.7, 127.3, 98.9, 51.9, 21.7.
HRMS (ESI): m/z [M + H]+ calcd for C14H15INO2S: 387.9862; found:
387.9866.
IR (KBr): 3030, 2918, 2851, 1597, 1496, 1457, 1440, 1359, 1339, 1317,
1151, 1095, 1056, 888, 818, 776, 742, 728, 697 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.73 (d, J = 8.5 Hz, 2 H), 7.30 (d, J = 9.0
Hz, 2 H), 7.21–7.20 (m, 6 H), 7.06–7.04 (m, 4 H), 4.31 (s, 4 H), 2.45 (s, 3
H).
13C NMR (125 MHz, CDCl3): δ = 143.4, 137.8, 135.8, 129.9, 128.7,
N-(2,4-Dichlorobenzyl)-4-methylbenzenesulfonamide (3k)
White solid; yield: 138.7 mg (42%); mp 114.2–115.0 °C.
128.5, 127.8, 127.4, 50.6, 21.7.
HRMS (ESI): m/z [M + H]+ calcd for C21H22NO2S: 352.1365; found:
IR (KBr): 3291, 3030, 2921, 2848, 1600, 1586, 1474, 1429, 1387, 1334,
1160, 1093, 1039, 857, 826, 818, 664 cm–1
.
352.1369.
1H NMR (500 MHz, CDCl3): δ = 7.68 (d, J = 8.0 Hz, 2 H), 7.25–7.22 (m, 4
H), 7.10 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1 H), 5.45 (t, J = 6.5 Hz, 1 H), 4.18
(d, J = 6.5 Hz, 2 H), 2.41 (s, 3 H).
N,N-Dibenzyl-2-methylbenzenesulfonamide (4b)
White solid; yield: 28.1 mg (16%); mp 65.1–67.0 °C.
13C NMR (125 MHz, CDCl3): δ = 143.7, 136.9, 134.4, 134.0, 132.8,
131.1, 129.8, 129.3, 127.3, 127.1, 44.5, 21.6.
HRMS (ESI): m/z [M + H]+ calcd for C14H14Cl2NO2S: 330.0116; found:
330.0107.
IR (KBr): 3027, 2963, 2923, 2856, 1603, 1494, 1457, 1322, 1156, 1132,
1062, 779, 748, 725, 697 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.01 (d, J = 7.5 Hz, 1 H), 7.49 (t, J = 7.5
Hz, 1 H), 7.35 (d, J = 7.5 Hz, 1 H), 7.31 (t, J = 7.5 Hz, 1 H), 7.27–7.25 (m,
6 H), 7.03–7.02 (m, 4 H), 4.32 (s, 4 H), 2.61 (s, 3 H).
N-(1-(3-Fluorophenyl)ethyl)-4-methylbenzenesulfonamide (3l)
White solid; yield: 129.1 mg (44%); mp 109.4–110.7 °C.
13C NMR (125 MHz, CDCl3): δ = 138.7, 138.0, 135.7, 133.0, 132.9,
130.3, 128.9, 128.7, 128.0, 126.4, 49.6, 20.6.
HRMS (ESI): m/z [M + H]+ calcd for C21H22NO2S: 352.1365; found:
IR (KBr): 3257, 3044, 2968, 2923, 2870, 1600, 1510, 1460, 1435, 1325,
1224, 1154, 1090, 840, 804, 736, 675 cm–1
.
352.1366.
1H NMR (500 MHz, CDCl3): δ = 7.60 (d, J = 8.5 Hz, 2 H), 7.19 (d, J = 8.5
Hz, 2 H), 7.09–7.06 (m, 2 H), 6.89–6.85 (m, 2 H), 4.73 (d, J = 6.0 Hz, 1
H), 4.46 (quin, J = 7.0 Hz, 1 H), 2.39 (s, 3 H), 1.40 (d, J = 7.0 Hz, 3 H).
N,N-Dibenzylbenzenesulfonamide (4c)
White solid; yield: 30.4 mg (18%); mp 67.2–69.2 °C.
13C NMR (125 MHz, CDCl3): δ = 142.5, 137.0, 136.8, 128.7, 127.1,
127.0, 126.3, 114.6, 114.5, 52.2, 22.8, 20.7.
HRMS (ESI): m/z [M + H]+ calcd for C15H17FNO2S: 294.0958; found:
294.0959.
IR (KBr): 3022, 2957, 2921, 2853, 1606, 1580, 1496, 1457, 1446, 1336,
1160, 1087, 1051, 776, 753, 734, 697 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.85 (d, J = 8.0 Hz, 2 H), 7.59 (t, J = 7.0
Hz, 1 H), 7.51 (t, J = 7.5 Hz, 2 H), 7.22–7.21 (m, 6 H), 7.05–7.03 (m, 4
H), 4.34 (s, 4 H).
N-(1-(3-Chlorophenyl)ethyl)-4-methylbenzenesulfonamide (3m)
13C NMR (125 MHz, CDCl3): δ = 141.0, 135.7, 132.7, 129.3, 128.7,
White solid; yield: 247.8 mg (80%); mp 66.6–67.8 °C.
128.6, 127.9, 127.3, 50.6.
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HRMS (ESI): m/z [M + H]+ calcd for C20H20NO2S: 338.1209; found:
338.1195.
2011, 76, 4158. (d) Karshtedt, D.; Bell, A. T.; Tilley, T. D. J. Am.
Chem. Soc. 2005, 127, 12640. (e) Zhang, J. L.; Yang, C. G.; He, C.
J. Am. Chem. Soc. 2006, 128, 1798. (f) Caddick, S.; Wilden, J. D.;
Judd, D. B. J. Am. Chem. Soc. 2004, 126, 1024. (g) Caddick, S.;
Wilden, J. D.; Bush, H. D.; Wadman, S. N.; Judd, D. B. Org. Lett.
2002, 4, 2549.
N,N-Bis(4-bromobenzyl)-4-methylbenzenesulfonamide (4i)
White solid; yield: 40.7 mg (16%); mp 124.9–125.9 °C.
IR (KBr): 3041, 2923, 2853, 1614, 1589, 1485, 1462, 1450, 1322, 1154,
(5) (a) Cui, X. J.; Zhang, Y.; Shi, F.; Deng, Y. Q. Chem. Eur. J. 2011, 17,
1021. (b) Liu, C. Z.; Liao, S. H.; Li, Q.; Feng, S. L.; Sun, Q.; Yu, X. C.;
Xu, Q. J. Org. Chem. 2011, 76, 5759. (c) Feng, S. L.; Liu, C. Z.; Li, Q.;
Yu, X. C.; Xu, Q. Chin. Chem. Lett. 2011, 22, 1021.
1084, 1067, 809, 790, 554 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.73 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.0
Hz, 6 H), 6.90 (d, J = 7.5 Hz, 4 H), 4.23 (s, 4 H), 2.47 (s, 3 H).
(6) (a) Shi, F.; Tse, M. K.; Zhou, S. L.; Pohl, M. M.; Radnik, J.; Hübner,
S.; Jähnisch, K.; Brückner, A.; Beller, M. J. Am. Chem. Soc. 2009,
131, 1775. (b) Zhu, M. W.; Fujita, K. I.; Yamaguchi, R. Org. Lett.
2010, 12, 1336. (c) Li, Q.; Fan, S. J.; Sun, Q.; Tian, H. W.; Yu, X. C.;
Xu, Q. Org. Biomol. Chem. 2012, 10, 2966. (d) Cui, X. J.; Shi, F.;
Zhang, Y.; Deng, Y. Q. Tetrahedron Lett. 2010, 51, 2048.
13C NMR (125 MHz, CDCl3): δ = 143.9, 137.4, 134.8, 131.8, 130.4,
130.1, 127.4, 122.0, 50.5, 21.8.
HRMS (ESI): m/z [M + H]+ calcd for C21H20Br2NO2S: 507.9576; found:
507.9573.
(7) (a) Qin, H. B.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew.
Chem. Int. Ed. 2007, 46, 409. (b) Reddy, C. R.; Madhavi, P. P.;
Reddy, A. S. Tetrahedron Lett. 2007, 48, 7169. (c) Jana, U.; Maiti,
S.; Biswas, S. Tetrahedron Lett. 2008, 49, 858. (d) Terrasson, V.;
Marque, S.; Georgy, M.; Campagne, J. M.; Prim, D. Adv. Synth.
Catal. 2006, 348, 2063. (e) Sreedhar, B.; Reddy, P. S.; Reddy, M.
A.; Neelima, B.; Arundhathi, R. Tetrahedron Lett. 2007, 48, 8174.
(f) Sanz, R.; Martínez, A.; Álvarez-Gutiérrez, J. M.; Rodríguez, F.
Eur. J. Org. Chem. 2006, 1383. (g) Sanz, R.; Martínez, A.; Miguel,
D.; Álvarez-Gutiérrez, J. M.; Rodríguez, F. Adv. Synth. Catal. 2006,
348, 1841.
Acknowledgment
We gratefully acknowledge funding from the National Natural Science
Foundation of China (No. 21372265 and No. 61271059), the Scientific
Research Fundings of the Scientific Research Foundation for the Re-
turned Overseas Chinese Scholars, State Education Ministry, the Nat-
ural Science Foundation Project of CQ CSTC (No. cstc2013jcyjA10037),
and the Fundamental Research Funds for the Central Universities (No.
CDJZR14225502 and No. CQDXWL-2013-Z012).
(8) (a) Chase, P. A.; Jurca, T.; Stephan, D. W. Chem. Commun. 2008,
1701. (b) Shaabani, A.; Soleimani, E.; Rezayan, A. H. Tetrahedron
Lett. 2007, 48, 2185.
Supporting Information
Supporting information for this article is available online at
(9) (a) Schäfer, G.; Bode, J. W. Angew. Chem. Int. Ed. 2011, 50, 10913.
(b) Xu, X. F.; Xiong, Y.; Ling, X. G.; Xie, X. M.; Yuan, J.; Zhang, S.
T.; Song, Z. R. Chin. Chem. Lett. 2014, 25, 406. (c) Fang, Z. X.; Liu,
J. Q.; Liu, Q.; Bi, X. H. Angew. Chem. Int. Ed. 2014, 53, 7209.
(d) Onyango, E. O.; Fu, L. F.; Gribble, G. W. Org. Lett. 2014, 16,
322. (e) Fang, X. Q.; Liu, K.; Li, C. Z. J. Am. Chem. Soc. 2010, 132,
2274. (f) Xiao, D. J.; Wang, L. J.; Feng, X. M. Synlett 2005, 1531.
(g) Shao, L. X.; Zhang, Y. P.; Qi, M. H.; Shi, M. Org. Lett. 2007, 9,
117. (h) Shi, L.; Tu, Y. Q.; Wang, M.; Zhang, F. M.; Fan, C. A.; Zhao,
Y. M.; Xia, W. J. J. Am. Chem. Soc. 2005, 127, 10836.
(10) Laubengayer, A. W.; Finlay, G. R. J. Am. Chem. Soc. 1943, 65, 884.
(11) (a) Prakash, G. K. S.; Paknia, F.; Mathew, T.; Mlostoń, G.; Joschek,
J. P.; Olah, G. A. Org. Lett. 2011, 13, 4128. (b) Prakash, G. K. S.;
Mathew, T.; Hoole, D.; Esteves, P. M.; Wang, Q.; Rasul, G.; Olah,
G. A. J. Am. Chem. Soc. 2004, 126, 15770. (c) Prakash, G. K. S.;
Panja, C.; Shakhmin, A.; Shah, E.; Mathew, T.; Olah, G. A. J. Org.
Chem. 2009, 74, 8659. (d) Yu, H.; Li, C. Z. J. Org. Chem. 2004, 69,
142. (e) Liu, L.; Wang, X.; Li, C. Z. Org. Lett. 2003, 5, 361.
(12) (a) Li, Y.; Xiong, Y.; Li, X. M.; Ling, X. G.; Huang, R. F.; Zhang, X.
H.; Yang, J. C. Green Chem. 2014, 16, 2976. (b) Zhang, S. T.;
Zhang, X. H.; Ling, X. G.; He, C.; Huang, R. F.; Pan, J.; Li, J. Q.;
Xiong, Y. RSC Adv. 2014, 4, 30768. (c) Huang, R. F.; Zhang, X. H.;
Pan, J.; Li, J. Q.; Shen, H.; Ling, X. G.; Xiong, Y. Tetrahedron 2015,
in press; DOI: 10.1016/j.tet.2015.01.037.
http://dx.doi.org/10.1055/s-34-1380129.
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References
(1) (a) Cole, D. C.; Lennox, W. J.; Lombardi, S.; Ellingboe, J. W.;
Bernotas, R. C.; Tawa, G. J.; Mazandarani, H.; Smith, D. L.; Zhang,
G.; Coupet, J.; Schechter, L. E. J. Med. Chem. 2005, 48, 353.
(b) Natarajan, A.; Guo, Y.; Harbinski, F.; Fan, Y. H.; Chen, H.;
Luus, L.; Diercks, J.; Aktas, H.; Chorev, M.; Halperin, J. A. J. Med.
Chem. 2004, 47, 4979. (c) Banerjee, M.; Poddar, A.; Mitra, G.;
Surolia, A.; Owa, T.; Bhattacharyya, B. J. Med. Chem. 2005, 48,
547.
(2) (a) Sridhar, R.; Srinivas, B.; Pavan Kumar, V.; Narender, M.;
Rama Rao, K. Adv. Synth. Catal. 2007, 349, 1873. (b) Rattanaburi,
P.; Khumraksa, B.; Pattarawarapan, M. Tetrahedron Lett. 2012,
53, 2689.
(3) (a) Yin, J. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043.
(b) Deng, W.; Liu, L.; Zhang, C.; Liu, M.; Guo, Q. X. Tetrahedron
Lett. 2005, 46, 7295. (c) Burton, G.; Cao, P.; Li, G.; Rivero, R. Org.
Lett. 2003, 5, 4373. (d) Steinhuebel, D.; Palucki, M.; Askin, D.;
Dolling, U. Tetrahedron Lett. 2004, 45, 3305.
(4) (a) Xiao, B.; Gong, T. J.; Xu, J.; Liu, Z. J.; Liu, L. J. Am. Chem. Soc.
2011, 133, 1466. (b) Thu, H. Y.; Yu, W. Y.; Che, C. M. J. Am. Chem.
Soc. 2006, 128, 9048. (c) John, A.; Nicholas, K. M. J. Org. Chem.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1101–1108