TiCl4-mediated direct N-alkylation of sulfonamides with inactive ethers

Article abstract of DOI:10.1055/s-0031-1290332

A TiCl₄-mediated intermolecular or intramolecular direct N-alkylation reaction of sulfonamides with inactive ethers as alkylating agents was successfully achieved. This method provides a novel approach towards N-alkyl sulfonamides from inactive ethers via an easy workup procedure. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290332

LETTER
595
TiCl4-Mediated Direct N-Alkylation of Sulfonamides with Inactive Ethers
T
iCl4-Mediiated
D
a
irect N-Al
y
kylation of
S
a
ulfonamide
n
s
w
ithInactive
E
th
C
ers hen, Ling Dang, Qiang Li, Yong Ye, Shaomin Fu, Wei Zeng*
School of Chemistry and Chemical Engineering, South China University of Technology, 381 Wushan Road, Guangzhou 510641,
P. R. of China
Fax +86(20)22236337; E-mail: zengwei@scut.edu.cn
Received 18 November 2011
an ether via the coordination with the ether oxygen atom,
then enhance the nucleophilic attack of the amide nitrogen
at the ether carbon atoms to produce N-alkylating sulfon-
amides 3 (Scheme 1, c). In connection with our interest in
the development of N-acylation and N-alkylation of sul-
fonamide,10 we report herein a novel TiCl4-promoted N-
alkylation of sulfonamides using inactive ethers as alkyl-
ating reagents.
Abstract: A TiCl4-mediated intermolecular or intramolecular di-
rect N-alkylation reaction of sulfonamides with inactive ethers as
alkylating agents was successfully achieved. This method provides
a novel approach towards N-alkyl sulfonamides from inactive
ethers via an easy workup procedure.
Key words: N-alkylation, Lewis acid, N-alkyl sulfonamide, dialkyl
ether, titanium tetrachloride
a)
The development of new methodologies for the formation
of carbon–nitrogen bonds is a challenging area of organic
synthesis.1 In this context, N-alkylation reactions of sul-
fonamides have attracted significant attention, because N-
alkyl sulfonamides exhibit a wide range of biological ac-
tivities, such as antibacterial, anticancer and antiviral
functions, and they serve as antiviral HIV protease inhib-
itors.2 Generally, the classical method for the synthesis of
N-alkylated sulfonamides are performed by the reaction
of amines with sulfonyl halides,3 and transition-metal-
catalyzed cross-coupling of sulfonamides with organic
halides or olefins.4 Recently, N-alkylation of sulfonamide
using alcohol as alkylating agent has attracted particularly
interest due to the easy activation of the hydroxyl group
by transition metal salts or small organic molecules. For
example, Beller and Williams et al. found transition met-
als Ru(III) or Cu(II) could efficiently catalyze the N-alky-
lation of sulfonamide using borrowing hydrogen
methodology (Scheme 1, a).5 Of course, besides Fukuya-
ma–Mitsunobu N-alkylation,6 much progress on acid-cat-
alyzed direct N-alkylation with alcohol has also been
achieved. Various Lewis acids and Brønsted acids have
been employed to realize this transformation via a car-
bocation mechanism (Scheme 1, b).7 Considering the
widespread application of N-alkylated sulfonamide in the
synthesis of pharmaceuticals and agrochemicals, the ex-
ploration of new direct N-alkylation of sulfonamides us-
ing various alkylating agents under mild conditions is
always desirable.
O
+ TsNH2
H
– H2O
M
MH
RCH=NTs
RCH2NHTs
R
OH
R
– MH
transition-metal-catalyzed N-alkylation of sulfonamide with alcohol7
b)
Bronsted acid
R1
R1
OH or Lewis acid
R1
NH2Ts
R1
NHTs
TsNH2
– H+
R2
R2
R2
R2
acid-catalyzed N-alkylation of sulfonamide with alcohol8
c)
R
LA
Lewis acid (LA)
R
O
R
O
R
R
NHTs
2
3
NH2Ts
this work: Lewis acid catalyzed direct N-alkylation of sulfonamide with ether
Scheme 1 N-alkylation of sulfonamide
N-Alkylation of 4-toluene sulfonamide (0.5 mmol) with
ether was first succeeded with boron trifluoride diethyl
etherate (BF3·OEt2, 2.0 equiv) in dry toluene (1.0 mL) at
110 °C. It is believed that the coordination of the ether ox-
ygen to the boron atom activates the carbon–oxygen
bonds of ether for the nucleophilic attack. To our delight,
we found BF3 could promote the N-alkylation of sulfon-
amide with diethyl ether to form N-alkyl sulfonamide 3a
(38% yield) and N,N-dialkyl sulfonamide 3aa (11% yield,
Table 1, entry 1). Inspired by this positive result, we fur-
ther investigated other reaction conditions to define the re-
action parameters, and found that a reaction time of 48
hours and 6.0 equiv of BF3·OEt2 gave 3a and 3aa in a total
yield of 95% (Table 1, entry 6). Increasing the promoter
loading further did not improve the yields (Table 1, com-
pare entries 6, 7, and 8). When the reaction temperature
was lowered to 90 °C or increased to 130 °C, the yield de-
creased due to the incomplete reaction or tedious workup,
respectively (Table 1, compare entries 6 and 9, 10). The
effect of the solvent was also investigated, toluene and
ethyl acetate were the better solvents, with 1,1,2,2-tetra-
As we know, compared with alcohol alkylating agent, the
activation of sp3 C–O bond in aliphatic ether is much more
challenging which is arising from the high bond energy,8
and the N-alkylation of amides with ethers are rarely stud-
ied.9 Nevertheless, we think that a suitable catalyst could
also possibly activate the carbon–oxygen single bond of
SYNLETT 2012, 23, 595–600
x
x
.
x
x
.
2
0
1
2
Advanced online publication: 06.02.2012
DOI: 10.1055/s-0031-1290332; Art ID: W65411ST
© Georg Thieme Verlag Stuttgart · New York

596
J. Chen et al.
LETTER
chloroethane (TCE) being the best (Table 1, compare en- tion time (48 h) in order to further improve the yield of the
tries 6 and 11–15).
transformation, and finally the best yield of 3b (78%) was
achieved in the presence of TiCl4 (6.0 equiv) at 120 °C for
48 hours when the ratio of 2b/1a is 12:1(Table 1, compare
entries 12–14). Noteworthy, if the reaction time was fur-
ther extended to 72 hours, the yield of monoalkylation
product 3b would decrease to some degree due to the for-
mation of N,N-dialkylated product (Table 2, entry 14).
Unfortunately, when we attempted to extend this reaction
to other dialkyl ethers such as di-n-butyl ether using
BF3·OEt2 (6.0 equiv) as promoter, only 36% yield of N-
n-butyl p-toluene sulfonamide (3b) was obtained due to a
possible weak complexation between BF3 and di-n-butyl
ether (Table 2, entry 11), so we turned our efforts to
screen other Lewis acid promoters including AlCl3, FeCl3, Accordingly, the substrate scope for the mono-N-alkyla-
TiCl4, ZrCl4, MgO, etc. to get satisfying conversion, and tion of sulfonamides was further extended to various
the corresponding results are summarized in Table 2. As ethers using the optimized reaction conditions.11 As
shown in Table 2, among the tested Lewis acids, TiCl4 shown in Table 3, the alkylating reagents examined could
showed the most effective promotion of mono-N-alkyla- be performed smoothly in moderate to good yields. Anal-
tion of sulfonamide with di-n-butyl ether in 60% yield ysis of the efficiency in which our substrates are N-alkyl-
(Table 2, entry 5), and basically other Lewis acids could ated indicates that both electronic and steric effects
not afford good yields of the desired product 3b (Table 2, govern the N-alkylation system. Increasing the electronic
entries 1–11). We tried to use an excess amount of dialkyl density of the sulfonamide nitrogen enhance the N-alkyla-
ether with respect to sulfonamide and extended the reac- tion performance (Table 3, entries 1–5), while electronic-
Table 1 BF3-Promoted N-Alkylation of p-Toluenesulfonamide (1a) with Diethyl Ether as Alkylating Agenta
O
O
solvent, 90–130 °C
Me
S
N
+
Me
SO2NH2
BF3⋅OEt2
+
Me
S
NH
O
3aa
2a
O
3a
1a
Entry
BF3·OEt2 (equiv) Temp (°C)
Solvent
Product (%)b
3a
3aa
Total yield
1
2
2
3
4
6
6
6
7
8
6
6
6
6
6
6
6
110
110
110
110
110
110
110
110
90
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
TCE
38
40
40
45
54c
39d
48
44
40
46
38
41
54
–
11
37
36
46
34c
56d
31
40
7
49
77
76
91
88
95
79
84
47
87
94
77
64
–
3
4
5
6
7
8
9
10
11
12
13
14
15
130
120
80
41
56
36
10
–
EtOAc
DCE
90
150
110
DMSO
MeCN
trace
trace
trace
a Reaction conditions: all reactions were carried out under an Ar atmosphere in a sealed tube, sulfonamide (0.5 mmol), solvent (1.0 mL), 24 h.
b Isolated yield after purification.
c Reaction time: 18 h.
d Reaction time: 48 h.
Synlett 2012, 23, 595–600
© Thieme Stuttgart · New York

LETTER
TiCl4-Mediated Direct N-Alkylation of Sulfonamides with Inactive Ethers
597
in product yield, while decreasing the steric hindrance at
Ca leads to an improved N-alkylating yield (Table 3, com-
pare entries 1 and 11, 12), but for the N-substituted sul-
fonamide 1g, no significant steric effect was observed
(Table 3, compare entries 1 and 15). It is interesting to
note that when we employed diethyl ether as alkylating
agent using BF3·OEt2 as promoter, the N-alkylation prod-
uct of N-phenyl-p-toluene sulfonamide (1h) is toluene-4-
sulfonic acid ethyl ester (3p, 69% yield) instead of N-eth-
yl-N-phenyl-4-methyl-benzenesulfonamide (Table 3, en-
try 16), possibly due to the large steric hindrance effect
from N-substituted amide that favors esterlysis of sulfon-
amide. Changing the substrate from an aryl sulfonamide
to an alkyl sulfonamide, such as methanesulfonamide,
also gave the desired alkylated product 3q in 56% yield
(Table 3, entry 17). Moreover, if p-toulene sulfonamide
(1a) was treated upon the unsymmetrical ether meth-
oxymethylbenzene (2f), the alkylation reaction would
only afford N-benzyl-4-methyl-benzensulfonamide (3h,
40% yield) without detectable byproducts N-methyl-4-
methyl-benzensulfonamide (Table 3, entry 10). Although
TiCl4 could promote 2-(ethoxymethyl) benzenesulfon-
amide to form 2,3-dihydro-benzo[d]isothiazole 1,1-diox-
ide (3r) via intramolecular N-alkylation, the
corresponding yield is poor (Table 3, entry 18).
Table 2 Catalyst Screening for Mono-N-alkylation of p-Toluene
Sulfonamide with Di-n-butyl Ether as Alkylating Agenta
Me
SO2NH2
1a
Lewis acid
TCE
O
S
H
+
Me
N
n-Bu
120 °C, 24 h
O
3b
O
2b
Entry
1
Catalyst
AlCl3
FeCl3
Fe2O3
ZrCl4
TiCl4
Reaction time (h) Yield (%)b,c
24
24
24
24
24
24
24
24
24
24
24
24
48
72
24
2
23
3
n.r.
9
4
5
60
6
MgO
n.r.
n.r.
n.r.
n.r.
n.r.
36
7
Cu(OAc)2·H2O
FeCl2·4H2O
CdCl2·2.5H2O
NiCl2·6H2O
BF3·OEt2
TiCl4
8
9
10
11
12
13
14
To our satisfaction, TiCl4 could enhance 2-sulfamonyl-
benzoic acid ethyl ester (1k) to form unexpected cyclic N-
alkylation product 2-n-butyl-1,1-dioxo-1,2-dihydro-1l6-
benzo[d] isothiazo-3-one (3s) and 2-benzyl-1,1-dioxo-
1,2-dihydro-1l6-benzo[d] isothiazo-3-one (3t) in good
yield (Table 3, entries 19 and 20). A possible reaction
pathway for 3s is depicted in Scheme 2. The ester carbon-
yl group was activated by an initial coordination of the
carbonyl oxygen with Ti(IV), and suffered an intramolec-
ular nucleophilic attack from sulfonamide nitrogen to
generate the N-acylation product 3u,10 and the corre-
sponding amide nitrogen continued to attack the ether–
oxygen bond activated by Ti(IV) via SN2 displacement,
and led to the formation of N-alkylation product 3s. Dur-
ing the N-alkylation reaction of 1k, the rearranged prod-
uct 3v was not detected using GC–MS method, so the SN1
transformation pathway was excluded.
69d
78d
70e
TiCl4
TiCl4
a Reaction conditions: p-toluene sulfonamide (0.5 mmol), di-n-butyl
ether (6.0 equiv, 3.0 mmol), Lewis acid (6.0 equiv), TCE (1.0 mL),
the reaction was carried out at 120 °C at the given reaction time in
sealed tube.
b Isolated yield after purification.
c n.r. = no reaction
d Conditions: 12.0 equiv of di-n-butyl ether were used.
e Conditions: 24.0 equiv of di-n-butyl ether were used.
deficient substrates leads to decreased product yield
(Table 3, entry 6), and the similar electronic effect of sub-
stituents on the dibenzyl ethers was also observed
(Table 3, entries 7–9). Steric-hindrance effects also play a
key role in this reaction system, as increasing the steric
hindrance of the ether at Ca leads to a substantial decrease
In conclusion, we have demonstrated that the direct inter-
molecular or intramolecular N-alkylation of sulfonamides
with inactive esters is possible using TiCl4 as promoter for
O2
S
N
SN2
O
O
O2
S
O
S
3s
NH2
Et
NH
Ti(IV)
– EtOH
O
O
O
A
B
O
O2
S
N
O2
3u
Ti(IV)
S
NH
SN1
O
O
3v
3u
Scheme 2 Mechanistic proposal for the TiCl4-promoted cascade N-acylation/N-alkylation of sulfonamide 1k
© Thieme Stuttgart · New York
Synlett 2012, 23, 595–600

598
J. Chen et al.
LETTER
the first time. This transformation may be of interest in the Supporting Information for this article is available online at
synthesis of complex cyclic polyfunctionalized sulfon- http://www.thieme-connect.com/ejournals/toc/synlett.
amides.
Table 3 TiCl4-Catalyzed N-Alkylation of Sulfonamides with Ethers
O
O
TiCl4 (6.0 equiv), TCE
120 °C
R1 SO2NH2
R2
O
R3
R4
+
S
R1
N
1
2
3
H
Entry Sulfonamide
Ether
Time (h) Product
Yield (%)a,b
78
O
S
O
O
O
O
O
O
O
Me
N
Me
S
NH2
NH2
NH2
1
2
3
4
5
6
48
H
O
O
2b
1a
3b
O
O
Cl
1b
Br
S
Cl
S
N
24
73
75
79
80
39
H
O
O
2b
2b
2b
2b
2b
3c
O
S
O
S
Br
N
H
48
72
48
48
O
O
1c
3d
O
S
O
S
MeO
NH2
MeO
N
H
O
O
1d
3e
O
S
O
S
NH2
N
H
O
O
3f
1e
O
O
O2N
S
NH2
O2N
S
N
H
O
O
1f
3g
O
O
S
Me
S
NH2
7
8
48
24
69
49
Me
NH
NH
O
O
O
2c
1a
3h
O
S
Cl
Cl
O
Cl
Me
NH2
Me
S
O
O
O
2d
1a
3i
O
S
O2N
NO2
O
S
NO2
Me
NH2
9
48
48
–
Me
NH
NH
O
O
O
2e
2f
1a
3j
O
S
O
OMe
Me
NH2
10
40
Me
S
O
O
1a
3h
O
S
O
H
N
O
Me
NH2
Me
S
11
48
40
O
O
2g
1a
Synlett 2012, 23, 595–600
3k
© Thieme Stuttgart · New York

LETTER
TiCl4-Mediated Direct N-Alkylation of Sulfonamides with Inactive Ethers
599
Table 3 TiCl4-Catalyzed N-Alkylation of Sulfonamides with Ethers (continued)
O
O
TiCl4 (6.0 equiv), TCE
120 °C
R1 SO2NH2
R2
O
R3
R4
+
S
R1
N
1
2
3
H
Entry Sulfonamide
Ether
Time (h) Product
Yield (%)a,b
33
O
O
S
O
H
N
Me
S
NH2
12
48
Me
O
O
2h
1a
3l
O
S
O
S
Me
NH2
13
O
48
61
Me
NH
O
O
2i
1a
3m
O
S
O
3
O
Me
NH2
14
48
48
79
77
3
3
Me
S
NH
N
O
O
2j
1a
3a
O
S
O
S
O
Me
Me
NH Me
15
Me
O
O
2b
2k
1g
3o
O
S
O
S
16
17
18
48
48
48
69c
56d
18e
Me
NH
Me
OEt
O
O
O
1h
3p
O
S
MeSO2NH2
Me
NHBn
NH
O
O
1i
2c
3q
3r
O
–
S
SO2NH2
O2
1j
O
O
S
SO2NH2
O
N
19
20
48
24
64
69
CO2Et
2b
2c
O
1k
3s
3t
O
O
S
N
SO2NH2
CO2Et
O
O
1k
a Isolated yields, average of 2 runs.
b Reaction conditions: p-toluene sulfonamide (0.5 mmol), ether (12.0 equiv, 6.0 mmol), Lewis acid (6.0 equiv, 3.0 mmol), TCE (2.0 mL), the
reaction was carried out at 120 °C at the given reaction time in sealed tube.
c BF3·OEt2 (6.0 equiv) was used.
d The reaction was carried out at 90 °C.
e Lowering the reaction temperature (≤120 °C) or increasing the reaction temperature (≥120 °C) resulted in poorer yield.
© Thieme Stuttgart · New York
Synlett 2012, 23, 595–600

600
J. Chen et al.
LETTER
351, 2949. (d) Xu, C. P.; Xia, Z. H.; Zhuo, B. Q.; Wang, Y.
H.; Huang, P. Q. Chem. Commun. 2010, 46, 7834. (e) Zhu,
M.; Fujita, K.; Yamaguchi, R. Org. Lett. 2010, 12, 1336.
(6) For selected examples, see: (a) Fukuyama, T.; Jow, C. K.;
Cheung, M. Tetrahedron Lett. 1995, 36, 6373. (b) Kan, T.;
Fukuyama, T. Chem. Commun. 2004, 353.
(7) For selected examples, see: (a) Noji, M.; Ohno, T.; Fuji, K.;
Futaba, N.; Tajim, H.; Ishii, K. J. Org. Chem. 2003, 68,
9340. (b) Terrasson, V.; Marque, S.; Georgy, M.; Campagn,
J. M.; Prim, D. Adv. Synth. Catal. 2006, 348, 2063. (c) Qin,
H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew.
Chem. Int. Ed. 2007, 46, 409. (d) Wang, G. W.; Shen, Y. B.;
Wu, X. L. Eur. J. Org. Chem. 2008, 4367.
Acknowledgment
The financial supports for this work from the Program for New Cen-
tury Excellent Talents in University by Ministry of Education (No.
NCET-10-0371), the FRFCU (No. 2009ZM0262), the NSFC (No.
21072063), RFDP (No. 20100172120020), and the FRFCU (No.
2009ZM0262, 2009ZM0126) are gratefully acknowledged.
References and Notes
(1) For selected reviews, see: (a) Severin, S.; Doye, S. Chem.
Soc. Rev. 2007, 36, 1407. (b) Hultzsch, K. C. Adv. Synth.
Catal. 2005, 347, 367. (c) Eilbracht, P.; Bärfacker, L.; Buss,
C.; Hollmann, C.; Kitsos-Rzychon, B. E.; Kranemann, C. L.;
Rische, T.; Roggenbuck, R.; Schmidt, A. Chem. Rev. 1999,
99, 3329. (d) Müller, T.; Beller, M. Chem. Rev. 1998, 98,
675.
(2) (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.
(8) Roberts, V. M.; Stein, V.; Reiner, T.; Lemonidou, A.; Li, X.;
Lercher, J. A. Chem. Eur. J. 2011, 17, 5939.
(9) (a) Albone, D. P.; Challenger, S.; Derrick, A. M.; Fillery, S.
M.; Irwin, J. C.; Parsons, C. M.; Takada, H.; Taylor, P. C.;
Wilson, D. J. Org. Biomol. Chem. 2005, 3, 107. (b) He, L.;
Yu, J.; Zhang, J.; Yu, X. Q. Org. Lett. 2007, 9, 2277.
(10) Fu, S.; Lian, X.; Ma, T.; Chen, W.; Zheng, M.; Zeng, W.
Tetrahedron Lett. 2010, 51, 5834.
(c) Scozzafava, A.; Supuran, C. T. J. Med. Chem. 2000, 43,
3677.
(11) General Procedure for the Transformation
Sulfonamide (0.50 mmol), ether (12.0 equiv, 6.0 mmol) and
Cl2CHCHCl2 (2.0 mL) were combined in a pressure tube
equipped with a stir bar, the mixture was stirred about 10
min, then TiCl4 (6.0 equiv, 3.0 mmol) was added, and the
reaction mixture was heated to 120 °C for the given time.
After the starting material has disappeared (monitored by
TLC), the reaction mixture was cooled to r.t. and treated with
H2O (5.0 mL) to decompose the exceed TiCl4, then filtered,
and the filtrate was extracted with EtOAc (3 × 10 mL).
The combined organic layers was dried over Na2SO4 and
concentrated in vacuo, the corresponding residue was
purified by flash column chromatography (silica gel) to
furnish the target product. All the products are known
compounds and are identified using 1H NMR, LRMS, and
IR by comparison with previously reported data (see
Supporting Information for complete details).
(3) For selected examples, see: (a) Caddick, S.; Wilden, J. D.;
Wadman, S. J.; Bush, H. D.; Judd, D. B. Org. Lett. 2002, 4,
2549. (b) Sridhar, R.; Srinivas, B.; Kumar, V. P.; Narender,
M.; Rao, K. R. Adv. Synth. Catal. 2007, 349, 1873.
(4) For selected examples, see: (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. (c) Sherman,
E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R. J. Org. Chem.
2007, 72, 3896. (d) Wu, T.; Yin, G.; Liu, G. J. Am. Chem.
Soc. 2009, 131, 16354.
(5) For selected examples, see: (a) Shi, F.; Tse, M. K.; Cui, X.;
Gordes, D.; Michalik, D.; Thurow, K.; Deng, Y.; Beller, M.
Angew. Chem. Int. Ed. 2009, 48, 5912. (b) 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. Chem. Soc.
2009, 131, 1766. (c) Cui, X.; Shi, F.; Tse, M. K.; Gördes, D.;
Thurow, K.; Beller, M.; Deng, Y. Adv. Synth. Catal. 2009,
Synlett 2012, 23, 595–600
© Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.