Regioselective alkylation of saccharin with alcohols under Mitsunobu conditions

Article abstract of DOI:10.3184/174751913X13716447161975

The regioselective Mitsunobu alkylation of saccharin with various alcohols has been examined. The N/O-alkylation is dependent on the steric hindrance of the alcohols, that is, less sterically hindered alcohol preferentially afford N-alkylated saccharin an

Full text of DOI:10.3184/174751913X13716447161975

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 417
JULY, 417–419
Regioselective alkylation of saccharin with alcohols under Mitsunobu
conditions
Xiaolong Wang,* Yanying Ma and Tingting Ju
The School of Chemical and Biological Engineering, Lanzhou Jiaotong University, 88 West Anning Road, Lanzhou 730070, P. R. China
The regioselective Mitsunobu alkylation of saccharin with various alcohols has been examined. The N/O-alkylation
is dependent on the steric hindrance of the alcohols, that is, less sterically hindered alcohol preferentially afford
N-alkylated saccharin and vice versa.
Keywords: saccharin, Mitsunobu reaction, alkylation, steric effect, regioselectivity
Saccharin is a well-known heterocyclic compound and has
been used as a sweetener in the form of its sodium salt. It is
also found as a key structural element in various biologically
active compounds, such as human leukocyte elastase (HLE)
inhibitors, analgesics and tyrosinase inhibitors.1 The N-alkyl
derivatives of saccharin, normally prepared by the reaction
of sodium saccharin with alkyl halides, have been used as
important intermediates in the preparation of bioactive
molecules.2 Since saccharin is an organic acid, we reasoned
that the N-alkylation of saccharin could be achieved by the
Mitsunobu reaction3,4 using readily available alcohols as
alkylating agents, as opposed to alkyl halides that may not be
commercially available.
A survey of the literature revealed that a rare case of Mitsu-
nobu reaction of saccharin has been examined by Robinson
and coworkers.5 However, only two alcohols (benzyl alcohol
and 2-bromoethanol) were investigated in this work and the
regiochemistry was reported to favour the corresponding
O-alkylation product. This regiochemical result seemed to be
atypical and one-sided. In connection with our ongoing studies
on the regioselective Mitsunobu reaction, herein we wish to
present a systematic investigation of the Mitsunobu alkylation
of saccharin with a series of alcohols.
Initially, under the same Mitsunobu conditions used in our
previous research,6 we employed methanol to attempt the regi-
oselective alkylation of saccharin with a molar ratio of alcohol/
saccharin/DIAD/Ph3P of 1:1:1.5:1.5 equiv. To our surprise,
this reaction proceeded in a completely regioselective manner
to provide the N-methylated saccharin in 92% yield. No trace
of the O-methylated isomer could be detected on TLC and by
NMR spectroscopy (Scheme 1). Evidently, the regioselectivity
observed in this case was quite different from that reported by
Robinson and coworkers.5 Next, when the same reaction was
performed with allyl alcohol instead of methanol, both N- and
O-allylated isomers were obtained and could be easily isolated
by column chromatography in 54% and 32% yields, respec-
tively (Scheme1). The structures of these products were conve-
niently confirmed by comparing their melting points and NMR
data with the literature values.7,8
Thus, we reasoned that steric effects could play an impor-
tant role on the N/O selectivity in the Mitsunobu alkylation of
saccharin. In order to further determine the regioselectivity of
this methodology, other commercially available alcohols were
subjected to the protocol using the same reaction conditions
noted above. The starting materials, products, and data obtained
are summarised in Table 1. As expected, the Mitsunobu alkyla-
tion of saccharin with ethanol showed high regioselectivity
for the NH group, providing the N-ethylated isomer as the
major product in 89% yield along with a trace amount of
O-regioisomer (Table 1, entry 3). The alkylation with 2-phenyl-
ethanol proceeded similarly well wherein the N-alkylated
derivative was also favoured over the O-isomers (Table 1, entry
4). In the cases of 1-butanol and 1-octanol, however, the
coupling reactions provided approximately equal amounts of
N- and O-alkylated isomers (Table 1, entries 5 and 6). The
alkylations of saccharin with 1-dodecanol, benzyl alcohol
and 2-methyl-1-propanol showed a slight preference for the
O-regioisomers (Table 1, entries 7–9). As anticipated, when
more sterically hindered alcohols such as 2-propanol,
2-butanol, 1-phenylethanol and cyclohexanol were used, the
Mitsunobu coupling reactions were clearly regioselective in
favour of O-alkylated derivatives (Table 1, entries 10–13).
Accordingly, the results obtained above indicated that the regi-
oselectivity for the N/O-alkylation of saccharin is generally
dependent on the steric hindrance of the alcohols, wherein
less sterically hindered alcohol should favourably afford
N-alkylated saccharin and vice versa. With an aim to prepare
Table 1 Regioselective alkylation of saccharin with alcohols
under Mitsunobu conditionsa
Entry
Alcohol
CH3OH
Yield
Yield
of N-isomer/%b of O-isomer/%b
1
2
92
54
0
32
3
4
5
6
7
8
CH3CH2OH
PhCH2CH2OH
CH3(CH2)3OH
CH3(CH2)7OH
CH3(CH2)11OH
PhCH2OH
89
52
46
42
48
41
trace
39
43
45
45
50
9
10
11
40
20
17
47
68
62
(CH3)2CHOH
12
24
58
13
22
56
Scheme 1
a Standard reaction conditions: saccharin (1 equiv.), ROH
(1 equiv.), Ph3P (1.5 equiv.), DIAD (1.5 equiv.), THF (25 mL).
b Isolated yield by column chromatography.
* Correspondent. E-mail: wangxl@mail.lzjtu.cn

418 JOURNAL OF CHEMICAL RESEARCH 2013
5H), 7.83 (m, 2H), 7.92 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 7.2 Hz,
1H). 13C NMR (100 MHz, CDCl3): δ 34.7, 40.4, 120.9, 125.1, 126.8,
127.3, 128.6, 128.9, 134.3, 134.7, 137.4, 137.7, 158.6.
the O-alkylated isomer exclusively, we also examined the
highly hindered t-butanol as alkylating agent. Unfortunately,
no product was observed perhaps due to the bulkiness of
t-butanol. In all the cases listed in Table 1, the products were
easily purified by column chromatography on silica gel and
were characterised on the basis of physical and spectroscopic
data and also by comparison with authentic samples.5,7–10
In conclusion, we have systematically examined the alkyla-
tion of saccharin with various alcohols under Mitsunobu con-
ditions. It was found for the first time that the regioselectivity
for the N/O-alkylation in this protocol is clearly determined by
steric effects wherein the less sterically hindered alcohols tend
to favour the N-alkylation and vice versa. This protocol has
several advantages, such as mild reaction conditions, good
product yields, simplicity in operation and easy availability
of the substrates. Thus, we believe that this methodology will
offer an important complement to the reported methods for
alkylation of saccharin and will further expand the utilities of
saccharin in the field of synthetic and medicinal chemistry.
3-(2-Phenylethyloxy)-1,2-benzisothiazole 1,1-dioxide: Colourless
1
oil; H NMR (400 MHz, CDCl3): δ 3.20 (t, J = 6.8 Hz, 2H), 4.78 (t,
J = 6.8 Hz, 2H), 7.29 (m, 5H), 7.73 (m, 3H), 7.86 (d, J = 7.2 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ 34.6, 72.1, 121.8, 123.2, 126.9, 127.0,
128.7, 128.9, 133.4, 134.0, 136.4, 143.5, 169.0; HRMS Calcd for
C15H14NO3S [M+H]+: 288.0689. Found: 288.0683.
2-Butyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide: Colourless solid,
m.p. 38–40 °C (lit.9 39–40 °C); 1H NMR (400 MHz, CDCl3): δ 0.91 (t,
J = 7.2 Hz, 3H), 1.37 (m, 2H), 1.77 (m, 2H), 3.71 (t, J = 7.6 Hz, 2H),
7.78 (m, 3H), 7.97 (dd, J = 6.8, 1.6 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 13.3, 19.8, 30.2, 38.9, 120.6, 124.8, 127.2, 134.1, 134.5,
137.5, 158.7.
3-Butyloxy-1,2-benzisothiazole 1,1-dioxide: Colourless solid, m.p.
1
94–96 °C; H NMR (400 MHz, CDCl3): δ 0.98 (t, J = 7.2 Hz, 3H),
1.48 (m, 2H), 1.86 (m, 2H), 4.58 (t, J = 6.8 Hz, 2H), 7.73 (m, 3H),
7.85 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 13.5, 18.9,
30.2, 72.0, 121.7, 123.2, 127.0, 133.4, 134.0, 143.5, 169.2; HRMS
Calcd for C11H14NO3S [M+H]+: 240.0689; found: 240.0695.
2-Octyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide: Colourless oil10;
1H NMR (400 MHz, CDCl3): δ 0.86 (t, J = 6.8 Hz, 3H), 1.35 (m,
10H), 1.84 (m, 2H), 3.75 (t, J = 7.2 Hz, 2H), 7.84 (m, 3H), 8.04 (d,
J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 14.0, 22.6, 26.8, 28.4,
28.9, 29.0, 31.7, 39.4, 120.8, 125.0, 127.4, 134.2, 134.6, 137.7, 158.9;
HRMS Calcd for C15H22NO3S [M+H]+: 296.1315; found: 296.1309.
3-Octyloxy-1,2-benzisothiazole 1,1-dioxide: Colourless oil; 1H NMR
(400 MHz, CDCl3): δ 0.84 (t, J = 6.8 Hz, 3H), 1.36 (m, 10H), 1.84 (m,
2H), 4.53 (t, J = 6.8 Hz, 2H), 7.69 (m, 3H), 7.81 (d, J = 7.2 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ 13.8, 22.4, 25.5, 28.1, 28.9, 31.5,
72.1, 121.5, 123.2, 126.8, 133.3, 133.9, 143.3, 169.0; HRMS Calcd
for C15H22NO3S [M+H]+: 296.1315; found: 296.1326.
Experimental
Reagents and solvents were all from commercial sources and were
used without further purification. 1H NMR and 13C NMR spectra were
recorded on a Mercury Plus 400 MHz spectrometer. Chemical shifts
were reported relative to internal tetramethylsilane (δ 0.00 ppm) or
CDCl3 (δ 7.26 ppm) for 1H and CDCl3 (δ 77.0 ppm) for 13C. Melting
points were measured on a Kofler apparatus and uncorrected. Column
chromatography was performed on 200–300 mesh silica gel. Analyti-
cal TLC was performed on silica gel GF254 plates. HRMS were recorded
on a Bruker Daltonics APEX II 47e spectrometer.
2-Dodecyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide: Colourless
Alkylation of saccharin under Mitsunobu conditions, general
procedure:
1
solid, m.p. 49–51 °C (lit.9 48–50 °C); H NMR (400 MHz, CDCl3):
δ 0.88 (t, J = 6.6 Hz, 3H), 1.34 (m, 18H), 1.85 (m, 2H), 3.77 (t, J =
7.6 Hz, 2H), 7.84 (m, 2H), 7.92 (d, J = 7.6 Hz, 1H), 8.05 (d, J =
7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 14.1, 22.6, 26.8, 28.4,
29.0, 29.3, 29.4, 29.5, 29.6, 31.9, 39.5, 120.8, 125.0, 127.5, 134.2,
134.6, 137.7, 158.9.
Diisopropyl azodicarboxylate (DIAD, 4.5 mmol) was placed in a
50 mL round-bottomed flask equipped with a stirring bar. Then triphe-
nylphosphine (Ph3P, 4.5 mmol) and dry tetrahydrofuran (THF, 20 mL)
were added and the solution was cooled in an ice bath. Then the alco-
hol (3.0 mmol) was added. The mixture was then stirred for 10 min
and a solution of saccharin (3.0 mmol) in dry THF (5 mL) was added
dropwise. After being stirred for 30 min, the flask was removed from
the ice bath and the solution was stirred at room temperature, and
monitored by TLC. When the reaction was judged to be complete, the
organic solvent was evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel using petroleum
ether/EtOAc (v/v = 10:1) as the eluent to give the products. All the
isolated products were characterised by physical and spectroscopic
data and also by comparison with authentic samples.5,7–10 The physical
and spectral data of the products are shown as follows.
3-Dodecyloxy-1,2-benzisothiazole 1,1-dioxide: Colourless solid,
1
m.p. 54–55 °C; H NMR (400 MHz, CDCl3): δ 0.88 (t, J = 6.4 Hz,
3H), 1.39 (m, 18H), 1.89 (m, 2H), 4.59 (t, J = 6.8 Hz, 2H), 7.73 (m,
3H), 7.88 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 14.0,
22.6, 25.6, 28.2, 29.1, 29.2, 29.4, 29.5, 29.6, 31.8, 72.3, 121.8, 123.2,
127.1, 133.3, 134.0, 143.5, 169.2; HRMS Calcd for C19H30NO3S
[M+H]+: 352.1941; found: 352.1933.
2-Benzyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide: Colourless
solid, m.p. 108–110 °C (lit.5 108–110 °C); 1H NMR (400 MHz,
CDCl3): δ 4.91 (s, 2H), 7.33 (m, 3H), 7.51 (d, J = 7.2 Hz, 2H), 7.84
(m, 2H), 7.93 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 6.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ 42.9, 121.3, 125.5, 127.5, 128.5, 128.9, 129.0,
134.6, 134.7, 135.0, 138.0, 159.1.
2-Methyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide: Colourless solid,
1
m.p. 132–133 °C (lit.7 129–130 °C); H NMR (400 MHz, CDCl3):
δ 3.26 (s, 3H), 7.83 (m, 2H), 7.93 (dd, J = 7.2, 1.6 Hz, 1H), 8.05 (dd,
J = 7.2, 1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 23.2, 120.9,
125.1, 127.5, 134.3, 134.6, 137.5, 158.6.
3-Benzyloxy-1,2-benzisothiazole 1,1-dioxide: Colourless solid,
1
m.p. 131–133 °C (lit.5 128–129 °C); H NMR (400 MHz, CDCl3):
δ 5.59 (s, 2H), 7.47 (m, 5H), 7.74 (m, 3H), 7.88 (d, J = 7.6 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ 73.5, 121.9, 123.4, 126.9, 128.8,
129.1, 129.3, 133.39, 133.43, 134.1, 143.6, 169.0.
2-Allyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide: Colourless solid,
1
m.p. 88–90 °C (lit. 77–82 °C8 or 89–90 °C9); H NMR (400 MHz,
CDCl3): δ 4.37 (d, J = 6.0 Hz, 2H), 5.30 (d, J = 10.0 Hz, 1H), 5.44 (d,
J = 17.2 Hz, 1H), 5.96 (m, 1H), 7.84 (m, 2H), 7.92 (d, J = 7.2 Hz,
1H), 8.05 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 41.2,
119.7, 120.9, 125.1, 127.3, 130.5, 134.3, 134.7, 137.8, 158.5.
3-Allyloxy-1,2-benzisothiazole 1,1-dioxide: Colourless solid, m.p.
2-Isobutyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide: Colourless
solid, m.p. 56–58 °C; H NMR (400 MHz, CDCl3): δ 1.02 (d, J =
1
6.4 Hz, 6H), 2.30 (m, 1H), 3.59 (d, J = 8.0 Hz, 2H), 7.85 (m, 2H), 7.93
(d, J = 7.2 Hz, 1H), 8.06 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 20.0, 27.6, 46.6, 120.8, 125.1, 127.3, 134.2, 134.6, 137.6,
159.2; HRMS Calcd for C11H14NO3S [M+H]+: 240.0689; found:
240.0697.
3-Isobutyloxy-1,2-benzisothiazole 1,1-dioxide: Colourless solid,
m.p. 101–102 °C; 1H NMR (400 MHz, CDCl3): δ 1.07 (d, J = 6.8 Hz,
6H), 2.23 (m, 1H), 4.37 (d, J = 6.8 Hz, 2H), 7.74 (m, 3H), 7.87 (d,
J = 6.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 18.8, 27.6, 77.8,
121.8, 123.2, 127.0, 133.4, 134.0, 143.5, 169.2; HRMS Calcd for
C11H14NO3S [M+H]+: 240.0689; found: 240.0693.
1
139–140 °C (lit.8 140 °C); H NMR (400 MHz, CDCl3): δ 5.06 (d,
J = 6.0 Hz, 2H), 5.43 (d, J = 10.4 Hz, 1H), 5.52 (d, J = 17.2 Hz, 1H),
6.10 (m, 1H), 7.74 (m, 3H), 7.87 (d, J = 8.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ 72.2, 121.3, 121.8, 123.3, 126.9, 129.9, 133.4,
134.1, 143.6, 168.9.
2-Ethyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide: Colourless solid,
1
m.p. 92–94 °C (lit.9 93.5–94.5 °C); H NMR (400 MHz, CDCl3):
δ 1.46 (t, J = 7.2 Hz, 3H), 3.86 (d, J = 7.2 Hz, 2H), 7.87 (m, 3H), 8.05
(d, J = 6.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 14.1, 34.7, 121.0,
125.2, 127.7, 134.4, 134.8, 138.0, 158.8.
2-Isopropyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide: Colourless
1
solid, m.p. 65–66 °C (lit.5 63–64 °C); H NMR (400 MHz, CDCl3):
2-(2-Phenylethyl)-1,2-benzisothiazol-3(2H)-one1,1-dioxide:Colour-
δ 1.62 (d, J = 7.2 Hz, 6H), 4.53 (m, 1H), 7.84 (m, 3H), 8.02 (d, J =
7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 20.3, 47.1, 120.5, 124.8,
127.4, 134.1, 134.5, 137.9, 158.7.
1
less solid, m.p. 138–139 °C (lit.9 138–139 °C); H NMR (400 MHz,
CDCl3): δ 3.15 (t, J = 8.2 Hz, 2H), 4.00 (t, J = 8.2 Hz, 2H), 7.28 (m,

JOURNAL OF CHEMICAL RESEARCH 2013 419
3-Isopropyloxy-1,2-benzisothiazole 1,1-dioxide: Colourless solid,
m.p. 139–140 °C; 1H NMR (400 MHz, CDCl3): δ 1.48 (d, J = 6.4 Hz,
6H), 5.40 (m, 1H), 7.74 (m, 3H), 7.84 (d, J = 7.2 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ 21.4, 76.9, 121.6, 123.3, 127.4, 133.3, 133.9,
143.2, 168.3; HRMS Calcd for C10H12NO3S [M+H]+: 226.0532; found:
226.0525.
3-Cyclohexyloxy-1,2-benzisothiazole 1,1-dioxide: Colourless solid,
m.p. 102–104 °C; 1H NMR (400 MHz, CDCl3): δ 1.33–2.09 (m,
10H), 5.20 (m, 1H), 7.74 (m, 3H), 7.87 (d, J = 8.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ 23.4, 25.0, 31.0, 81.5, 121.6, 123.3, 127.5,
133.3, 133.9, 143.3, 168.3; HRMS Calcd for C13H16NO3S [M+H]+:
266.0845; found: 266.0848.
2-Sec-butyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide: Colourless
1
solid, m.p. 83–84 °C (lit.9 80–81 °C); H NMR (400 MHz, CDCl3):
We are grateful for financial support from the Natural Science
Foundation of Gansu Province (1007RJYA011) and the ‘Qing
Lan’ talent engineering funds (QL-06-01A) of the Lanzhou
Jiaotong University.
δ 0.98 (t, J = 7.2 Hz, 3H), 1.57 (d, J = 6.8 Hz, 3H), 1.87 (m, 1H), 2.15
(m, 1H), 4.20 (m, 1H), 7.83 (m, 3H), 8.01 (d, J = 6.8 Hz, 1H). 13C
NMR (100 MHz, CDCl3): δ 11.3, 18.4, 27.1, 52.9, 120.6, 124.9, 127.4,
134.1, 134.5, 137.7, 158.8.
1
3-Sec-butyloxy-1,2-benzisothiazole 1,1-dioxide: Colourless oil; H
NMR (400 MHz, CDCl3): δ 0.97 (t, J = 7.6 Hz, 3H), 1.44 (d, J =
6.0 Hz, 3H), 1.78 (m, 2H), 5.21 (m, 1H), 7.71 (m, 3H), 7.83 (d, J =
7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 9.3, 18.8, 28.4, 81.4,
121.5, 123.2, 127.3, 133.3, 133.9, 143.2, 168.5; HRMS Calcd for
C11H14NO3S [M+H]+: 240.0689; found: 240.0684.
Received 30 March 2013; accepted 25 April 2013
Paper 1301870 doi: 10.3184/174751913X13716447161975
Published online: 18 July 2013
2-(1-Phenylethyl)-1,2-benzisothiazol-3(2H)-one1,1-dioxide:Colour-
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1
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5
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(m, 10H), 4.15 (m, 1H), 7.83 (m, 3H), 8.02 (d, J = 7.2 Hz, 1H). 13C
NMR (100 MHz, CDCl3): δ 25.0, 26.0, 30.3, 54.8, 120.5, 124.9, 127.4,
134.1, 134.4, 137.8, 158.6; HRMS Calcd for C13H16NO3S [M+H]+:
266.0845; found: 266.0852.
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7
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