An efficient and facile synthesis of N-Cbz-β-aminoalkanesulfonamides

Article abstract of DOI:10.1007/s11426-012-4607-9

An efficient method for the synthesis of N-Cbz-β- aminoalkanesulfonamides was described. N-Cbz-β-aminoalkanesulfona-mides were readily prepared in good yields from a variety of amino alcohols, including optically active ones, via N-Cbz protection with ben

Full text of DOI:10.1007/s11426-012-4607-9

SCIENCE CHINA
Chemistry
• ARTICLES •
doi: 10.1007/s11426-012-4607-9
doi: 10.1007/s11426-012-4607-9
An efficient and facile synthesis of
N-Cbz--aminoalkanesulfonamides
MENG FanHua, CHEN Ning & XU JiaXi*
State Key Laboratory of Chemical Resource Engineering; Department of Organic Chemistry, Faculty of Science,
Beijing University of Chemical Technology, Beijing 100029, China
Received February 25, 2012; accepted March 16, 2012
An efficient method for the synthesis of N-Cbz--aminoalkanesulfonamides was described. N-Cbz--aminoalkanesulfona-
mides were readily prepared in good yields from a variety of amino alcohols, including optically active ones, via N-Cbz pro-
tection with benzyl chloroformate, Mitsunobu esterification reaction with thiolacetic acid, N-chlorosuccinimide oxidation, and
ammonolysis process.
sulfonamides, amino alcohols, synthesis, Mitsunobu reaction, ammonolysis
direct reaction of aminoalkanesulfonyl chlorides with am-
1 Introduction
monia or amines [1416]. Aminoalkanesulfinyl chlorides
were generally prepared from naturally occurring amino
acids or amino alcohols via conversion of them into the
corresponding thiolacetates and subsequent treatment with
sulfuryl chloride in the presence of acetic anhydride [4, 11]
or chlorine in an aqueous solution [12, 13], or prepared
from cysteamine hydrochloride via the oxidation reaction
with iodine to the corresponding disulfide, followed by
treatment with chlorine in an aqueous solution [1315].
Aminoalkanesulfonyl chlorides can be prepared via oxida-
tion of thiols, thioacetates, or disulfides with phosgene [16,
17], triphosgene [18, 19], or chlorine in an aqueous solution
[15, 20], or via reaction of -aminoalkanesulfonic acids or
-aminoalkanesulfonates with phosgene [21, 22] or tri-
phosgene [23], thionyl chloride [9, 24, 25], or oxalyl chlo-
ride [9, 26]. Although aminoalkanesulfinyl chlorides show
higher reactivity than aminoalkanesulfonyl chlorides, the
oxidation step did not always result in high yields and was
difficult to optimize for use in solid phase synthesis. On the
other hand, toxic transition metal RuCl3 is necessary in the
oxidation. For preparation of aminoalkanesulfonyl chlorides
from thiols, thioacetates or disulfides, toxic gaseous rea-
Aminoalkanesulfonamides have been recognized as im-
portant building blocks in combinatorial chemistry. Alt-
hough -aminoalkanesulfonamides are close mimetics of
naturally occurring amino amides, few literature reported
-aminoalkanesulfonamides and their applications due to
their readily labile properties [1]. Inversely, there is still
growing interest in -aminoalkanesulfonamides due to the
fact that they can be considered as stable mimetics of tetra-
hedral transition states in hydrolysis and formation of esters
and amides [2]. Therefore, they have been widely used as
enzyme inhibitors [3, 4], antibacterial [57] and anticancer
agents [8]. Additionally, N-protected -aminoalkanesulfon-
amides as useful building blocks have been successfully
employed in the synthesis of sulfonopeptides [1] and hybrid
sulfonophosphinopeptides [9, 10]. Initially, -aminoalkane-
sulfonamides were synthesized via the reaction of aminoal-
kanesulfinyl chlorides with ammonia or amines and subse-
quent oxidation with sodium periodate under the catalysis of
RuCl3 [4, 1113]. Alternatively, they were prepared via the
*Corresponding author (email: jxxu@mail.buct.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2012
chem.scichina.com www.springerlink.com

2
Meng F H, et al. Sci China Chem January (2012) Vol.55 No.1
R
mL, 10.6 g, 60 mmol) at 0 °C, followed by Et3N (35 mL,
R
PPh3, DIAD, HSAc
CbzCl
Cbz
OH
OH
25.3 g, 250 mmol). The resulting mixture was stirred at
room temperature overnight. The resulting solution was
washed with brine (100 mL × 3) and dried over anhydrous
sodium sulfate. After concentration at reduced pressure, the
residue was crystallized from the mixture of ethyl acetate
and petroleum ether (60–90 °C) to give the corresponding
N-Cbz amino alcohols. If the desired product was oil, it was
purified by flash column chromatography on silica gel with
petroleum ether (60–90 °C): ethyl acetate = 1:5 to 1:1 (v/v)
as the eluent to afford the corresponding N-Cbz amino al-
cohol. Their analytic data are identical with those reported
previously [2733].
N
H
H2N
CH2Cl2 /Et3N
1
R
R
R
O
O
NH3(aq)
O
NCS
O
SAc
CbzHN
S
S
CbzHN
Cl
CbzHN
NH2
2
3
4
Scheme 1 Preparation of N-Cbz--aminoalkanesulfonamides.
gents, such as phosgene and chlorine, are generally used
with difficulty to control the stoichometry and dangerous
handle. In the methods with -aminoalkanesulfonic acids or
-aminoalkanesulfonates as starting materials, it is general-
ly difficult in the product isolation and purification in the
preparation of -aminoalkanesulfonic acids and -amino-
alkanesulfonates due to their strong polarity and solubility
in water. They also showed poor solubility in the chlorida-
tion step and unsatisfactory reproducibility on a large scale,
low yields sometimes. Therefore, it is worthy to develop a
new efficient method for the preparation of this type of im-
portant sulfonamides. Herein, we present a convenient and
facile synthetic method for the preparation of N-Cbz--
aminoalkanesulfonamides in high yields by using mild rea-
gents and reaction conditions (Scheme 1).
2.3 General procedure for synthesis of N-benzyloxy-
carbonylaminoalkyl thiolacetates 2a–g
To an efficiently stirred solution of triphenylphosphine
(10.48 g, 40 mmol) in anhydrous THF (48 mL) was added
dropwise a solution of diisopropyl azodicarboxylate (DIAD,
8.0 g, 40 mmol) in anhydrous THF (24 mL) at 10 °C over
30 min. The resulting mixture was stirred at 10 °C for an-
other 0.5 h. A white precipitate appeared. A solution of
Cbz-amino alcohol 1 (20 mmol) and thiolacetic acid (3.04 g,
40 mmol) in anhydrous THF (48 mL) was added dropwise
over 45 min, and the reaction mixture was stirred overnight
at 10 °C. After concentrated under reduced pressure, tri-
phenylphosphine oxide was crystallized upon the addition
of a mixture of ethyl acetate and petroleum ether (60–90 °C)
in fridge. After filtration, the combined filtrate was concen-
trated in vacuo and subjected to silica gel column chroma-
tography with petroleum ether (60–90 °C) (PE) : ethyl ace-
tate (EA) = 20:1 to 5:1 (v/v) as the eluent to afford thio-
lacetate 2.
2 Experiments
2.1 Materials and measurements
Amino alcohols were purchased commercially. Dichloro-
methane was refluxed with calcium hydride and freshly
distilled prior to use. Tetrahydrofuran was refluxed with
sodium and diphenyl ketone until the color of system be-
came blue and freshly distilled prior to use. TLC analysis
was performed on glass pre-coated silica gel YT257-85
(1040 m) plate. Spots were visualized with UV light or
iodine. Column chromatography was performed on silica
gel zcx.II (200300 mesh). Melting points were measured
2-Benzyloxycarbonylaminoethyl thiolacetate (2a)
o
Colorless needle crystals; yield: 82%; m.p. 36−37 C; Rf =
0.29 (silica gel plate, PE: EA = 6:1, v/v). IR v (cm1): 3340
(NH), 1724 (C=O), 1692 (C=O), 1135 (S-CO). 1H NMR
(400 MHz, CDCl3) : 2.33 (s, 3H, CH3), 3.02 (t, J = 6.4 Hz,
SCH2), 3.36 (dt, J = 6.3, 6.4 Hz, 2H, NCH2), 5.09 (s, 3H,
OCH2 & NH), 7.297.35 (m, 5H, ArH). 13C NMR (100.6
MHz, CDCl3) : 29.1, 30.5, 40.7, 66.7, 128.06, 128.1, 128.5,
136.4, 156.3, 195.7. HRMS (ESI) Calcd. for C12H16NO3S
[M+H]+ m/z: 254.0845; Found 254.0841.
on a Yanaco MP-500 melting point apparatus. H and 13C
1
NMR spectra of all compounds were recorded on a Brucker
400 NMR or Varian 300 plus spectrometer in CDCl3 or
DMSO-d6 with TMS as the internal standard. HRMS data
was carried out on an Agilent LC/MSD TOF mass spec-
trometer. IR spectra were determined on a Nicolet
AVATAR 330 FT-IR spectrometer. Optical rotations were
measured on a PerkinElmer Model 341 polarimeter with a
thermally jacketed 10 cm cell (concentration c expressed as
g/100 mL).
(S)-2-Benzyloxycarbonylaminopropyl thiolacetate (2b)
o
Colorless needle crystals; yield: 68%; m.p. 66−67 C; Rf =
0.31 (silica gel plate, PE:EA = 6:1, v/v); []20 = 30.8 (c,
D
1.0, MeOH). IR v (cm1): 3317 (NH), 1695 (C=O), 1135 &
1
1105 (S-CO); H NMR (200 MHz, CDCl3) : 1.20 (d, J =
2.2 General procedure for synthesis of N-Cbz protect-
ed amino alcohols 1ag
6.7 Hz, 3H, CH3), 2.33 (s, 3H, CH3), 3.05 (d, J = 5.6 Hz, 2H,
CH2S), 3.844.00 (m, 1H, CHN), 4.81 (br s, 1H, NH), 5.09
(s, 2H, OCH2), 7.267.35 (m, 5H, ArH). 13C NMR (100.6
MHz, CDCl3) : 20.0, 30.5, 34.9, 47.1, 66.5, 77.4, 128.0
To a solution of an amino alcohol (50 mmol) in CH2Cl2
(165 mL) was added dropwise benzyl chloroformate (8.6

Meng F H, et al. Sci China Chem January (2012) Vol.55 No.1
3
1
(para and meta ArC), 128.5, 136.6, 155.7, 195.6. HRMS
(ESI) Calcd. for C13H18NO3S [M+H]+ m/z: 268.1002; Found
268.0996.
1141 (SCO). H NMR (400 MHz, CDCl3) : 2.31 (s, 3H,
CH3), 3.21 (dd, J = 4.5, 13.8 Hz, 1H in CH2S), 3.31 (dd, J =
9.0, 13.8 Hz, 1H in CH2S), 4.88 (br s, 1H, NH), 5.04 (d, J =
12.3 Hz, 1H in OCH2), 5.10 (d, J = 12.3 Hz, 1H in OCH2),
5.35-5.51 (m, 1H, PhCH), 7.237.36 (m, 10H, ArH). 13C
NMR (100.6 MHz, CDCl3) : 30.5, 34.9, 55.5, 66.8, 126.2,
127.9, 128.1, 128.4, 128.7 (2 carbons overlap), 136.4, 140.8,
155.7, 196.1. HRMS (ESI) Calcd. for C18H20NO3S [M+H]+
m/z: 330.1158; Found 330.1148.
(S)-2-Benzyloxycarbonylamino-3-methylbutyl thiolacetate (2c)
Colorless crystals; yield: 57%; m.p. 89−90 oC; Rf = 0.3 (sil-
ica gel plate, PE:EA = 6:1, v/v); []20 = 94.9 (c, 1.0,
D
MeOH). IR v (cm1): 3312 (NH), 1695 (C=O), 1130 & 1102
(S-CO). 1H NMR (300 MHz, CDCl3) : 0.93 (d, J = 6.9 Hz,
3H, CH3), 0.96 (d, J = 6.9 Hz, 3H, CH3), 1.751.86 (m, 1H,
CH), 2.28 (s, 3H, CH3), 2.943.09 (m, 2H, CH2S),
3.603.70 (m, 1H, CHN), 4.80 (d, J = 9.4 Hz, 1H, NH),
5.05 (d, J = 12.3 Hz, 1H in OCH2), 5.13 (d, J = 12.3 Hz, 1H
in OCH2), 7.257.41 (m, 5H, ArH); 13C NMR (75 MHz,
CDCl3) : 17.9, 19.1, 30.4, 31.7, 32.0, 56.5, 66.5, 127.91,
127.96, 128.4, 136.6, 156.3, 196.0. HRMS (ESI) Calcd. for
C15H22NO3S [M+H]+ m/z: 296.1315; Found 296.1318.
(S)-1-Benzyloxycarbonylpyrrolidine-2-methyl thiolacetate (2g)
Viscous oil; yield: 80%; Rf =0.44 (silica gel plate, PE:EA =
6:1, v/v); []20 = 52.5 (c, 1.0, CHCl3). IR v (cm1): 1698
D
(C=O), 1133 & 1108 (S-CO). 1H NMR (400 MHz, CDCl3) :
1.661.76 (m, 1H in CH2), 1.771.85 (m, 1H in CH2),
1.882.04 (m, 2H, CH2), 2.30 (Rotamer), 2.34 (Rotamer) (s,
3H, CH3), 3.013.29 (m, 2H, CH2S), 3.44 (t, J = 6.4 Hz, 2H,
NCH2), 3.964.08 (m, 1H, NCH), 5.10-5.20 (m, 2H, OCH2),
7.307.40 (m, 5H, ArH). 13C NMR (100.6 MHz, CDCl3) :
22.6, 23.4 (Rotamer), 28.8, 29.9 (Rotamer), 30.2, 31.0, 32.0
(Rotamer), 46.5, 46.9 (Rotamer), 56.2, 57.0 (Rotamer), 66.3,
66.6 (Rotamer), 127.5, 127.6, 127.7, 128.1, 136.5, 136.6,
154.5, 194.4, 194.8. HRMS (ESI) Calcd. for C15H20NO3S
[M+H]+ m/z: 294.1158; Found 294.1156.
(S)-2-Benzyloxycarbonylamino-4-methylpentyl thiolacetate (2d)
o
Colorless crystals; yield: 77%; m.p. 62−62.5 C; Rf =0.4
(silica gel plate, PE:EA = 6:1, v/v); []20 = 29.4 (c, 1.0,
D
MeOH). IR v (cm1): 3340 (NH), 1718 (C=O), 1696 (C=O),
1
1105 & 1027 (S-CO); H NMR (300 MHz, CDCl3) : 0.91
(d, J = 6.5 Hz, 6H, 2CH3), 1.241.43 (m, 2H, CHCH2),
1.591.70 (m, 1H, CH(CH3)2), 2.29 (s, 3H, COCH3), 2.96
(dd, J = 7.2, 13.8 Hz, 1H in CH2S), 3.11 (dd, J = 4.7, 13.8
Hz, 1H in CH2S), 3.90 (br s, 1H, CHN), 4.81 (d, J = 8.8 Hz,
1H, NH), 5.05 (d, J = 12.3 Hz, 1H in OCH2), 5.11 (d, J =
12.3 Hz, 1H in OCH2), 7.297.40 (m, 5H, ArH). 13C NMR
(75 MHz, CDCl3) : 22.0, 22.9, 24.7, 30.4, 34.1, 43.4, 49.2,
66.5, 127.89, 127.9, 128.3, 136.5, 155.9, 195.5. HRMS (ESI)
Calcd. for C16H24NO3S [M+H]+ m/z: 310.1417; Found
310.1473.
2.4 General procedure for synthesis of 2-benzyloxy-
carbonylaminoalkanesulfonamides 4ag
NCS (16 g, 120 mmol) was dissolved to a mixture of 2 M
HCl (8 mL) and MeCN (40 mL). The resulting solution was
cooled to 10 °C. A solution of thiolacetate 2 (30 mmol) in
MeCN (8 mL) was added dropwise to the cooled solution at
below 20 °C. The resulting solution was stirred at the same
temperature for 30 min, and then diluted with isopropyl
ether (156 mL). The organic layer was washed with aq.
NaCl (12%, 3 × 78 mL) and then dried over anhydrous
Na2SO4. After concentration in vacuo, the crude sulfonyl
chloride 3 was obtained as colorless solids or pale yellow
oil, and used directly without further purification. The sul-
fonyl chloride 3 was dissolved in dry dichloromethane (20
mL) and the resulting solution was added dropwise into
ammonia (100 mL) under stirring at 10 °C. After addition,
the resulting mixture was stirred for another 1 h at 10 °C.
The solution was concentrated in vacuo to afford the crude
product 4. Further recrystallization from ethanol gave rise to
N-Cbz--aminoalkanesulfonamide as colorless crystals.
(S)-2-Benzyloxycarbonylamino-3-phenylpropyl thiolacetate
(2e)
Colorless solids; yield: 42%; m.p. 92−93 °C; Rf =0.4 (silica
gel plate, PE:EA = 6:1, v/v); []20D = 20.6 (c, 1.0, MeOH).
IR v (cm1): 3327 (NH), 1689 (C=O), 1134 & 1082
(S-CO).1H NMR (400 MHz, CDCl3) : 2.31 (s, 3H, CH3),
2.80 (dd, J = 7.1, 13.6 Hz, 1H in CH2Ph), 2.92 (dd, J = 6.3,
13.6 Hz, 1H in CH2Ph), 2.97 (dd, J = 7.8, 14.1 Hz, 1H in
CH2S), 3.08 (dd, J = 4.7, 14.1 Hz, 1H in CH2S), 4.05 (m,
1H, CHN), 4.90 (d, J = 7.2 Hz, 1H, NH ), 5.06 (s, 2H,
OCH2), 7.167.36 (m, 10H, ArH). 13C NMR (100.6 MHz,
CDCl3) : 30.5, 32.6, 40.3, 52.5, 66.6, 126.7, 127.9, 128.0,
128.4, 128.6, 129.3, 136.5, 137.0, 155.7, 195.8. HRMS (ESI)
Calcd. for C19H22NO3S [M+H]+ m/z: 344.1315; Found
344.1320.
(S)-2-Benzyloxycarbonylaminopropanesulfonamide (4a)
Colorless needle crystals; yield: 81%; m.p. 142143 °C; Lit.
[9] m.p. 138.5140 °C; Rf = 0.26 (silica gel plate, PE:EA =
1:1, v/v). 1H NMR (400 MHz, DMSO-d6) : 3.12 (t, J = 7.0
Hz, 2H, CH2), 3.40 (dt, J = 6.8, 7.0 Hz, 2H, CH2), 5.02 (s,
2H, CH2), 6.90 (s, 2H, NH2), 7.307.39 (m, 6H, ArH, NH).
13C NMR (100.6 MHz, DMSO-d6) : 36.2, 54.4, 66.0, 128.2,
(S)-2-Benzyloxycarbonylaminophenylethyl thiolacetate (2f)
Colorless needle crystals; yield: 72%; m.p. 112−113 °C; Rf
= 0.49 (silica gel plate, PE:EA = 6:1, v/v); []20D = 38.1 (c,
1.0, CHCl3). IR v (cm1): 3331 (NH), 1686 (C=O), 1180 &

4
Meng F H, et al. Sci China Chem January (2012) Vol.55 No.1
11H, ArH & NH). 13C NMR (75 MHz, DMSO-d6) : 39.2,
128.3, 128.8, 137.4, 156.5.
48.7, 58.1, 65.0, 126.2, 127.3, 127.6, 128.1, 128.2, 129.2,
137.1, 138.0, 155.3. HRMS (ESI) Calcd. for C17H21N2O4S
[M+H]+ m/z: 349.1217; Found 349.1213.
(S)-2-Benzyloxycarbonylaminopropanesulfonamide (4b)
Colorless needle crystals; yield: 63%; m.p. 150−151 °C; Rf
= 0.57 (silica gel plate, PE:EA = 1:1, v/v); []20D = 10.8 (c,
1.0, MeOH). IR v (cm1): 1668 (C=O), 1342 & 1142 (SO2).
1H NMR (300 MHz, DMSO-d6) : 1.24 (d, J = 6.6 Hz, 3H,
CH3), 3.04 (dd, J = 7.5, 13.9 Hz, 1H in CH2S), 3.25 (dd, J =
5.3, 13.9 Hz, 1H in CH2S), 4.01(ddq, J = 5.3, 6.6, 7.5 Hz,
1H, CHN), 5.03 (s, 2H, OCH2), 6.90 (s, 2H, NH2),
7.287.42 (m, 6H, ArH & NH). 13C NMR (75 MHz,
DMSO-d6) : 20.4, 43.2, 59.8, 65.3, 127.7, 127.8, 128.3,
137.0, 155.2. HRMS (ESI) Calcd. for C11H17N2O4S [M+H]+
m/z: 273.0904; Found 273.0902.
(S)-2-Benzyloxycarbonylamino-2-phenylethanesulfonamide
(4f)
Colorless flaky crystals; yield: 69%; m.p. 150−150.5 °C; Rf
= 0.54 (silica gel plate, PE:EA = 1:1, v/v); []20D = +41.4 (c,
1.0, MeOH). IR v (cm1): 1701 (C=O), 1340 & 1142 (SO2).
1H NMR (400 MHz, DMSO-d6) : 3.26 (dd, J = 3.3, 14.2
Hz, 1H in SCH2), 3.55 (dd, J = 9.0, 14.2 Hz, 1H in SCH2),
4.98 (d, J = 12.7 Hz, 1H in OCH2), 5.03 (d, J = 12.7 Hz, 1H
in OCH2), 5.11 (ddd, J = 3.3, 8.2, 9.0 Hz, 1H, CHN), 6.92 (s,
2H, NH2), 7.207.40 (m, 10H, ArH), 8.02 (d, J = 8.2 Hz,
1H, NH). 13C NMR (75 MHz, DMSO-d6) : 50.9, 59.8, 65.3,
126.2, 127.2, 127.6, 127.7, 128.2, 128.4, 136.9, 142.1,
155.1. HRMS (ESI) Calcd. for C16H18N2NaO4S [M+Na]+
m/z: 357.0879; Found 357.0873.
(S)-2-Benzyloxycarbonylamino-3-methylbutanesulfonamide
(4c)
Colorless solids; yield: 80%; m.p. 113−114 °C; Rf = 0.66
(silica gel plate, PE:EA = 1:1, v/v); []20 = 17.2 (c, 1.0,
D
MeOH). IR v (cm1): 1696 (C=O), 1327 & 1143 (SO2). H
1
NMR (300 MHz, DMSO-d6) : 0.81 (d, J = 6.6 Hz, 6H,
2CH3), 0.82 (d, J = 6.6 Hz, 6H, 2CH3), 1.85 (dhept, J = 5.3,
6.6 Hz, 1H, CH), 3.10 (d, J = 6.0 Hz, 2H, CH2S), 3.853.94
(m, 1H, CHN), 5.03 (s, 2H, OCH2), 6.81 (s, 2H, NH2),
7.307.36 (m, 6H, ArH & NH). 13C NMR (75 MHz,
DMSO-d6) : 17.3, 18.6, 31.6, 51.9, 56.0, 65.1, 127.5, 127.6,
128.3, 137.2, 155.8. HRMS (ESI, m/z) Calcd. for
C13H21N2O4S [M+H]+ m/z: 301.1217; Found 301.1214.
(S)-1-Benzyloxycarbonylpyrrolidine-2-methanesulfonamide
(4g)
Viscous oil; yield: 60%; Rf = 0.49 (silica gel plate, PE:EA =
1:1, v/v); []20 = 21.6 (c, 1.0, CHCl3). IR v (cm1): 1686
D
(C=O), 1358 & 1158 (SO2). 1H NMR (400 MHz, CDCl3) :
1.871.97 (m, 2H, CH2), 2.022.14 (m, 2H, CH2), 3.08 (dd,
J = 8.1, 14.0 Hz, 1H in SCH2), 3.403.48 (m, 2H, NCH2),
3.57 (dd, J = 4.6, 14.0 Hz, 1H in SCH2), 4.384.46 (m, 1H,
CH), 5.12 (s, 2H, OCH2), 5.45 (s, 2H, NH2), 7.297.40 (m,
5H, ArH). 13C NMR (75 MHz, CDCl3) : 23.5, 30.7, 46.1,
54.0, 57.7, 67.2, 127.7, 128.1, 128.5, 136.4, 155.4. HRMS
(ESI) Calcd. for C13H19N2O4S [M+H]+ m/z: 299.1060;
Found 299.1054.
(S)-2-Benzyloxycarbonylamino-4-methylpentanesulfonamid
e (4d)
Colorless solids; yield: 70%; m.p. 128−129 °C; Rf = 0.77
(silica gel plate, PE:EA = 1:1, v/v); []20 = 7.5 (c, 1.0,
D
MeOH). IR v (cm1): 1683 (C=O), 1326 & 1152 (SO2). H
1
NMR (300 MHz, DMSO-d6) : 0.86 (d, J = 6.3 Hz, 6H,
2CH3), 1.421.48 (m, 2H, CH2), 1.561.65 (m, 1H, CH),
3.04 (dd, J = 6.0, 13.8 Hz, 1H in CH2S), 3.22 (dd, J = 6.3,
13.8 Hz, 1H in CH2S), 3.94-4.05 (m, 1H, CHN), 5.02 (s, 2H,
CH2), 6.81 (s, 2H, NH2), 7.29-7.36 (m, 6H, ArH & NH). 13C
NMR (75 MHz, DMSO-d6) : 21.4, 23.1, 24.1, 42.7, 45.4,
59.2, 65.1, 127.5, 127.7, 128.2, 137.1, 155.5. HRMS (ESI)
Calcd. for C14H22N2O4S [M+H]+ m/z: 315.1373; Found
315.1370.
3 Results and discussion
Commercially available -amino alcohols first were pro-
tected their amino group with benzyl chloroformate (CbzCl)
to give the corresponding N-Cbz--amino alcohols 1ag in
satisfactory to perfect yields from 48% to 98% by referring
the method described by Veitia et al. (Table 1, column 3)
[34]. The workup procedure was modified. The reaction
solution was first washed with brine to remove water solu-
ble byproducts. After being dried over sodium sulfate and
concentrated under reduced pressure, the crude residue was
crystallized conveniently from the mixture of ethyl acetate
and hexanes instead of the reported column chromato-
graphic purification to afford the corresponding N-Cbz
amino alcohols 1af except for 1g due to its oily property.
After synthesizing the N-Cbz-amino alcohols 1, we next
focused on the conversion of the N-Cbz-amino alcohols 1 to
their thiolacetates 2. To the best of our knowledge, there are
two main approaches for the conversion. The first one is an
(S)-2-Benzyloxycarbonylamino-3-phenylpropanesulfonamid
e (4e)
Colorless solids; yield: 74%; m.p. 168−169 oC; Rf = 0.57
(silica gel plate, PE:EA = 1:1, v/v); []20 = 14.4 (c, 1.0,
D
MeOH). IR v (cm1): 1683 (C=O), 1326 & 1152 (SO2). H
1
NMR (400 MHz, DMSO-d6) : 2.81 (dd, J = 9.0, 13.5 Hz,
1H in CH2), 3.02 (dd, J = 5.1, 13.5 Hz, 1H in CH2), 3.14 (dd,
J = 6.0, 14.0 Hz, 1H in CH2S), 3.25 (dd, J = 6.4, 14.0 Hz,
1H in CH2S), 4.15 (dddd, J = 5.1, 6.0, 6.4, 9.0 Hz, 1H,
NCH), 5.0 (s, 2H, OCH2), 6.90 (s, 2H, NH2), 7.207.40 (m,

Meng F H, et al. Sci China Chem January (2012) Vol.55 No.1
5
indirect method. The N-Cbz-amino alcohols 1 were first
converted to their mesylates via reaction with methanesul-
fonyl chloride, and then the mesylates were further dis-
placed with sodium or potassium thiolacetate. In the second
approach, the thiolacetates were synthesized directly from
N-Cbz-amino alcohols 1 and thiolacetic acid via the
Mitsunobu reaction. Liskamp’s group had attempted the two
approaches previously [17] and found that the Mitsunobu
reaction is more efficient than the indirect one. However,
the purification process in the Mitsunobu reaction was usu-
ally very tedious and not reproducible on a larger scale (>
10 mmol). Additionally, the yields were unsatisfactory due
to the formation of the Michael adduct of thiolacetic acid to
DEAD (diethyl azodicarboxylate). Our group modified the
method to avoid the formation of the Michael adduct. In our
procedure, DEAD and triphenylphosphine were mixed first
to form a white precipitate of the active intermediate, the
adduct of DEAD and triphenylphosphine, and subsequently
a solution of an N-Cbz-amino alcohol and thiolacetic acid
was added slowly into the reaction mixture [35, 36]. Fol-
lowing our modified procedure, a series of thiolacetates
2ag were prepared in satisfactory to good yields from 42%
to 82% (Table 1).
disappeared (vide post product 4g), revealing that the steric
hindrance between Cbz and methanesulfonamide groups is
less than that between Cbz and acetylthiomethyl groups.
The crucial step is the preparation of N-Cbz--amino-
alkanesulfonyl chlorides, which were mainly prepared pre-
viously via chlorination of the corresponding sulfonic acid
with thionyl chloride [9, 24, 25], or oxalyl chloride [9, 26],
or oxidation of thioacetates or disulfides via phosgene [16,
17], triphosgene [18, 19], or chlorine in an aqueous solution
[15, 20]. Recently, Nishiguchi and his coworkers described
a new and very useful reaction for the conversion of thiols,
disulfides, thioacetates, and thiocarbamates to the cor-
responding sulfonyl chlorides in good yields via N-chloro-
succinimide (NCS) oxidation in dilute hydrochloric acid [37,
38]. However, aliphatic thiols and disulfides, electron-
rich 4-methoxybenzyl and allyl thioacetates gave rise to the
corresponding sulfonyl chlorides in relatively low yields,
even without the desired products in the method. We envi-
sioned that the above method could be applied in the prepa-
ration of functionalized N-Cbz--aminoalkanesulfonyl
chlorides. As an attempt, the thioacetate 2a was converted
to N-Cbz--aminoethanesulfonyl chloride (3a) completely
on TLC monitoring. The sulfonyl chloride 3a was then sub-
ject to ammonolysis without further purification to afford
the desired product N-Cbz--aminoethanesulfonamide (4a)
in 81% overall yield of two steps. We also attempted to use
NBS (N-bromosuccinimide) instead of NCS in the oxidation.
However, no desired reaction occurred. With the successful
method in hand, a series of N-Cbz--aminoalkanesulfon-
amides 4 were synthesized in satisfactory to good overall
yields (Table 1). The approach for the preparation of
N-Cbz--aminoalkanesulfonyl chlorides via the oxidation of
the N-Cbz-aminoalkyl thiolacetates with NCS not only im-
proves the reaction rate and product yields, but also uses a
nontoxic and solid reagent NCS, convenient to control stoi-
chiometry of the oxidizing agent. Compared with the chlo-
rine oxidation method, the current method is more conven-
ient, practical, and simple in controlling stoichiometry of
the chlorinating reagents in the laboratory preparation. Ad-
ditionally, except for 2-aminoethanol (1a), all of the other
amino alcohols are optically active and their configuration
is retained during the Mitsunobu substitution, NCS oxida-
tion, and ammonolysis process without racemization be-
cause all reactions do not affect the chiral carbon atom. To
the best of our knowledge, the current method is the best to
synthesize N-Cbz--aminoalkanesulfonamides.
The structures of all thiolacetates 2 were characterized by
1
IR, H NMR, 13C NMR, and HRMS spectrometries. As ob-
served generally, duplicated peaks appeared in the NMR
spectra of product 2g, indicating that it exists in two rota-
mers in its solution because the steric hindrance between
Cbz and acetylthiomethyl groups inhibits its single bond to
rotate freely. This is confirmed in the further reactions. Af-
ter further oxidation and aminolysis, the duplicated peaks
Table 1 Synthesis of compounds 1, 2 and 4
Yield (%)
Entry
Amino alcohol
1
2
4
OH
1
2
63
82
81
H2N
a
48
72
68
57
63
80
OH
H2N
b
3
4
OH
H2N
c
92
77
70
OH
Ph
OH
H2N
d
5
6
7
98
86
85
42
72
80
74
69
60
4 Conclusions
H2N
Ph
e
f
We developed a highly efficient and convenient method for
the synthesis of useful N-Cbz--aminoalkanesulfon- amides
from commercially available vicinal amino alcohols via the
N-Cbz protection, the Mitsunobu esterification, N-chloro-
succinimide oxidation, and ammonolysis process. The cur-
OH
OH
H2N
N
H
g

6
Meng F H, et al. Sci China Chem January (2012) Vol.55 No.1
1579–1584
rent method is an efficient, nontoxic, simple, and reproduci-
18 Gude M, Piarulli U, Potenza D, Salom B, Gennari C.A new method
for the solution and solid phase synthesis of chiral -sulfonopeptides
under mild conditions. Tetrahedron Lett, 1996, 37: 8589–8592
19 de Bont DBA, Dijkstra GDH, den Hartog JAJ, Liskamp RMJ.
Solid-phase synthesis of peptidosulfonamide containing peptides
derived from leu-enkephalin. Bioorg Med Chem Lett, 1996, 6:
3035–3040
ble route to synthesize N-Cbz--aminoalkanesulfonamides.
The authors express their thanks to the support from the National Natural
Science Foundation of China (20973013) and Beijing Natural Science
Foundation ( 2092022).
20 Luisi G, Calcagni A, Pinnen F. (SO2-NH) Transition state isosteres
of peptides. Synthesis of the glutathione disulfide analogue
[Glu-(SO2-NH)-Cys-Gly]2. Tetrahedron Lett, 1993, 34: 2391–2392
21 Brouwer AJ, Ceylan T, van der Linden, T, Liskamp, RMJ. Synthesis
of -aminoethanesulfonyl fluorides or 2-substituted taurine sulfonyl
fluorides as potential protease inhibitors. Tetrahedron Lett, 2009, 50:
3391–3393
22 Rijker DTS, Merkx R, Yim CB, Brouwer AJ, Liskamp RMJ.
‘Sulfo-click’ for ligation as well as for site-specific conjugation with
peptides, fluorophores, and metal chelators. J Pept Sci, 2010, 16: 1–5
23 Gude M, Piarulli U, Potenza D, Salom B, Gennari C. A new method
for the solution and solid phase synthesis of chiral -sulfonopeptides
under mild conditions. Tetrahedron Lett, 1996, 37: 8589–8592
24 Crowder MW, Sigdel TK, Golich F, Yang KW. Phosphinate, sul-
fonate, and sulfonamidate dipeptides as potential inhibitors of Esche-
richia coli aminopeptidase N. Bioorg Med Chem Lett, 2005, 15:
5150–5153
25 Carson KG, Schwender CF, Shroff HN, Cochran NA, Gallant DL,
Briskin MJ. Sulfonopeptide inhibitors of leukocyte adhesion. Bioorg
Med Chem Lett, 1997, 7: 711–714
26 Hara T, Durell SR, Myers MC, Appella DH. Probing the structural
requirements of peptoids that inhibit HDM2-P53 interactions. J Am
Chem Soc, 2006, 128: 1995–2004
27 Miller DJ, Surfraz MBU, Akhtar M, Gani D, Allemann RK. Removal
of the phosphate group in mechanism-based inhibitors of inositol
monophosphatase leads to unusual inhibitory activity. Org Biomol
Chem, 2004, 2: 671–688
28 Kung CH, Kwon CH. Carbamate derivatives of felbamate as poten-
tial anticonvulsant agents. Med Chem Res, 2010, 19: 498–513
29 Kumar GDK, Baskaran S. A facile, catalytic, and environmentally
benign method for selective deprotection of tert-butyldimethylsilyl
ether mediated by phosphomolybdic acid supported on silica gel. J
Org Chem, 2005, 70: 4520–4523
30 Correa A, Denis JN, Greene AE. A safe, simple, one-pot preparation
of N-derivatized -amino alcohols and oxazolidinones from amino
acids. Synth Commun, 1991, 21, 1–9
31 Kumar PS, Kumar GDK, Baskaran S. Truly catalytic and chemose-
lective cleavage of benzylidene acetal with phosphomolybdic acid
supported on silica gel. Eur J Org Chem, 2008, 36: 6063–6067
32 Wang YQ, Yu CB, Wang DW, Wang XB, Zhou YG. Enantioselec-
tive synthesis of cyclic sulfamidates via Pd-catalyzed hydrogenation.
Org Lett, 2008, 10: 2071–2074
33 Denmark SE, Edwards JP, Weber T, Piotrowski DW. Organocerium
additions to proline-derived hydrazones: Synthesis of enantiomeri-
cally enriched amines. Tetrahedron: Asymmetry, 2010, 21,
1278–1302
34 Veitia MS, Brun PL, Jorda P, Falguieres A, Ferroud C. Synthesis of
novel N-protected 3-amino nitriles: Study of their hydrolysis in-
volving a nitrilase-catalyzed step. Tetrahedron: Asymmetry, 2009, 20,
2077–2089
35 Xu JX, Xu S. A general route to the synthesis of N-protected
1-substituted and 1,2-disubstituted taurines. Synthesis, 2004: 276–282
36 Wang BY, Zhang W, Zhang LL, Du DM, Liu G, Xu JX. Versatile
synthesis of free and N-benzyloxycarbonyl-protected 2,2-disub-
stituted taurines. Eur J Org Chem, 2008, 2: 350–355
37 Nishiguchi A, Maeda K, Miki S. Sulfonyl chloride formation from
thiol derivatives by N-chlorosuccinimide mediated oxidation.
Synthesis, 2006: 4131–4134
1
2
Xu JX. Synthesis of hydroxyalkanesulfonic acids, aminoalkan-
esulfonic acids and sulfonopeptides. Chin J Org Chem, 2003, 23: 1–9
Moree WJ, van der Marel GA, van Boom JH, Liskamp RMJ. Pep-
tides containing the novel methylphosphinamide transition-state
isostere. Tetrahedron, 1993, 49: 11055–11064
Piscitelli F, Coluccia A, Brancale A, Regina GL, Sansone A,
Giordano C, Balzarini J, Maga G, Zanoli S, Samuele A, Cirilli R,
Torre FL, Lavecchia A, Novellino E, Silvestri R. Indolylarylsulfones
bearing natural and unnatural amino acids. Discovery of potent inhib-
itors of HIV-1 non-nucleoside wild type and resistant mutant strains
reverse transcriptase and coxsackie B4 virus. J Med Chem, 2009, 52:
1922–1934
Lowik DWPM, Liskamp RMJ. Synthesis of - and -substituted
aminoethane sulfonamide arginine-glycine mimics. Eur J Org Chem,
2000: 1219–1228
Hanna NB, Dimitrijevich SD, Larson SB, Robins RK, Revankar GR.
Synthesis and single-crystal X-ray diffraction studies of 1--D- ribo-
furanosyl-1,2,4-triazole-3-sulfonamide and certain related nucleo-
sides. J Heterocyclic Chem, 1988, 25: 1857–1868
Bonina L, Orzalesi G, Merendino R, Arena A, Mastroeni P. Struc-
ture- activity relationships of new antiviral compounds. Antimicrob
Agents Chemother, 1982, 22: 1067–1069
Ohnishi H, Yamaguchi K, Shinada S, Himuro S, Suzuki Y. Antiviral
activity of sodium 5-aminosulfonyl-2,4-dichlorobenzoate (M12325)
Antimicrob Agents Chemother, 1982, 22: 250–254
Ramasamy K, Imamura N, Hanna NB, Finch RA, Avery TL, Robins
RK, Revankar GR. Synthesis and antitumor evaluation in mice of
certain 7-deazapurine (pyrrolo[2,3-d]pyrimidine) and 3-deazapurine
(imidazo[4,5-c]pyridine) nucleosides structurally related to sulfeno-
sine, sulfinosine, and sulfonosine. J Med Chem, 1990, 33: 1220–1225
He FD, Meng FH, Song XQ, Hu WX, Xu JX. First and convergent
synthesis of hybrid sulfonophosphinopeptides. Org Lett, 2009, 11:
3922–3925
3
4
5
6
7
8
9
10 Meng FH, He FD, Song XQ, Zhang LL, Hu WX, Liu G, Xu JX. Fac-
ile synthesis of hybrid sulfonophosphinodipeptides composing of
taurines and 1-aminoalkylphosphinic acids. Amino Acids, 2012,
online published. (DOI: 10.1007/s00726-011-1098-5)
11 Moree WJ, van der Marel GA, Liskamp RJ. Synthesis of
peptidosulfinamides and peptidosulfonamides: Peptidomimetics
containing the sulfinamide or sulfonamide transition-state isostere. J
Org Chem, 1995, 60: 5157–5169
12 Moree WJ, van der Marel GA, Liskamp RMJ. Synthesis of peptides
containing the -substituted aminoethane sulfinamide or sulfonamide
transition-state isostere derived from amino acids. Tetrahedron Lett,
1992, 33: 6389–6392
13 de Bont DBA, Moree WJ, Liskamp RMJ. Molecular diversity of pep-
tidomimetics: Approaches to the solid-phase synthesis of peptidosul-
fonamides. Bioorg Med Chem, 1996, 4: 667–672
14 Moree WJ, van Gent LC, van der Marel GA, Liskamp RMJ.
Synthesis of peptides containing a sulfinamide or a sulfonamide
transition-state isostere. Tetrahedron, 1993, 49: 1133–1150
15 Moree WJ, van der Marel GA, Liskamp RMJ. Peptides containing a
sulfinamide or a sulfonamide moiety : New transition-state analogues
Tetrahedron Lett, 1991, 32: 409–412
16 Brouwer AJ, Merkx R, Dabrowska K, Rijkers DTS, Liskamp RMJ.
Synthesis and applications of -aminoethanesulfonyl azides.
Synthesis, 2006: 455–460
17 Brouwer AJ, Monnee MCF, Liskamp RMJ. An efficient synthesis of
N-protected -aminoethanesulfonyl chlorides: Versatile building
blocks for the synthesis of oligopeptidosulfonamides. Synthesis, 2000:
38 Liu J, Hou SL, Xu JX. Diverse reactions of sulfonyl chlorides and
cyclic imines. Phosphorus Sulfur Silicon Relat Elem, 2011, 186:
2377–2391