Improved synthesis of 1-benzenesulfinyl piperidine and analogs for the activation of thioglycosides in conjunction with trifluoromethanesulfonic anhydride

Article abstract of DOI:10.1081/CAR-200066978

An improved protocol for the large-scale production of 1-benzenesulfinyl piperidine and other sulfinamides is described. It is demonstrated that 1-benzenesulfinyl pyrrolidine and N,N-diethyl benzenesulfinamide function analogously to 1-benzenesulfinyl pip

Full text of DOI:10.1081/CAR-200066978

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Improved Synthesis of 1‐Benzenesulfinyl
Piperidine and Analogs for the Activation
of Thioglycosides in Conjunction with
Trifluoromethanesulfonic Anhydride
a
a
a
a
David Crich , Abhisek Banerjee , Wenju Li & Qingjia Yao
a
Department of Chemistry, University of Illinois at Chicago,
Chicago, Illinois, USA
Published online: 16 Aug 2006.
To cite this article: David Crich , Abhisek Banerjee , Wenju Li & Qingjia Yao (2005): Improved
Synthesis of 1‐Benzenesulfinyl Piperidine and Analogs for the Activation of Thioglycosides in
Conjunction with Trifluoromethanesulfonic Anhydride , Journal of Carbohydrate Chemistry, 24:4-6,
15-424
4
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Journal of Carbohydrate Chemistry, 24:415–424, 2005
Copyright # Taylor & Francis, Inc.
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1081/CAR-200066978
Improved Synthesis of
1
-Benzenesulfinyl Piperidine
and Analogs for the
Activation of Thioglycosides
in Conjunction with
Trifluoromethanesulfonic
Anhydride
David Crich, Abhisek Banerjee, Wenju Li, and Qingjia Yao
Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA
An improved protocol for the large-scale production of 1-benzenesulfinyl piperidine and
other sulfinamides is described. It is demonstrated that 1-benzenesulfinyl pyrrolidine
and N,N-diethyl benzenesulfinamide function analogously to 1-benzenesulfinyl piper-
idine in the trifluoromethanesulfonic anhydride-mediated activation of thioglycosides,
and that their less crystalline nature enables them to be used at 2788C as opposed to
the 2608C required to keep 1-benzenesulfinyl piperidine in solution. N,N-Dicyclohexyl
benzenesulfinamide does not activate thioglycosides in combination with trifluoro-
methanesulfonic anhydride, which is attributed to its greater steric bulk.
Keywords Glycosylation, Sulfinamide, Thioglycoside, Trifluoromethanesulfonate
INTRODUCTION
We recently introduced the combination of 1-benzenesulfinyl piperidine (BSP, 1)
and trifluoromethanesulfonic anhydride (Tf O) as a powerful means of activation
2
[1,2]
of both armed and disarmed thioglycosides.
In designing the sulfinamide
Received and accepted February 21, 2005.
Dedicated with respect to the memory of Professor Jacques H. Van Boom.
Address correspondence to David Crich, Department of Chemistry, University of
Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, USA.
E-mail: dcrich@uic.edu
415

D. Crich et al.
4
16
activating system we set several criteria, the most important of which was the
need for a stable, crystalline reagent capable, in combination with triflic anhy-
dride, of rapidly activating a wide range of armed and disarmed thioglycosides
[
1]
at low temperature. BSP met these criteria admirably and activates most thio-
glycosides for coupling in a matter of minutes at 2608C as demonstrated in a
[
3–7]
series of subsequent synthetic endeavors from this
and other labora-
[8–13]
tories.
The highly crystalline nature of BSP, however, limits its solubility
below 2608C, which explains the choice of this temperaturefor coupling reactions
as opposed to the more convenient 2788C achieved with dry ice/acetone cooling
baths. This minor inconvenience and, more importantly, the recognition that
liquid analogs of BSP might ultimately prove preferable in automated oligosac-
charide synthesis applications requiring robotic dispensation prompted the
synthesis and evaluation of other sulfinamides as described here.
We began with a refinement to our synthesis of BSP, the original version of
which was based on the production of benzenesulfinyl chloride from diphenyl
[1]
disulfide, sulfuryl chloride, and acetic anhydride, which itself is a more con-
venient version of the protocol of Douglass and Norton employing sulfuryl
[
14]
chloride instead of chlorine gas.
Though adequate, this protocol requires
careful control of temperature in the evaporation of the byproduct, acetyl
chloride, if a high-quality sulfinyl chloride is to be obtained. The use of lower-
quality sulfinyl chloride results in lower yields of BSP due to the formation of con-
taminants that hinder the direct isolation by crystallization. We have now found
[15,16]
that a modification of a protocol described by Craig
affords higher-quality
benzenesulfinyl chloride and thereby facilitates the isolation of the ensuing sulfi-
namides. In this method sodium benzenesulfinate is suspended in toluene in the
presence of catalytic tetrabutylammonium bromide and is treated with thionyl
chloride. Removal of the volatiles below 258C then affords crude benzenesulfinyl
chloride in admixture with sodium chloride. This mixture is used immediately in
the derivatization of secondary amines. In this manner we were able to prepare
high quality benzenesulfinyl piperidine in 86% yield on a 55 g scale. Similarly
[17]
prepared on multigram scales were 1-benzenesulfinyl pyrrolidine (2),
N,N-
and N,N-dicyclohexyl benzenesulfinamide
4). Two of these sulfinamides (2 and 4) were crystalline, with melting points
[
18]
diethyl benzenesulfinamide (3),
(
bracketing that of BSP, while a third (3) was a free- flowing, distillable liquid.
All were found to be soluble in dichloromethane at 2788C.

Activation of Thioglycosides
417
All three compounds (2–4) were assayed for their ability to activate to a
[
19]
standard mannosyl donor 6,
in combination with triflic anhydride and the
[20]
hindered base 2,4,6-tri-tert-butylpyrimidine (TTBP),
and to effect its
coupling to 1,2;5,6-diacetone glucofuranose 5. As reported in Table 1, with 2
and 3 the results were qualitatively the same as those previously obtained with
[
1]
BSP originally at –608C. Reagent 4, on the other hand, did not effect activation
of 6 under these conditions. We attribute this failure to the greater steric bulk in
the 4-Tf O adduct effectively preventing approach to the thioglycoside, and
2
elected not to pursue this particular sulfinamide further. A number of other coup-
lings were conducted by means of thioglycoside activation with 2 and/or 3 in com-
bination with Tf O, each of which demonstrated comparable results to those
2
obtained with BSP (Table 1).
Following the work of Gin on the activation of 1-hydroxy sugars (hemiace-
[
2,21]
tals),
van Boom and coworkers introduced the combination of diphenyl
sulfoxide and triflic anhydride for the activation of thioglycosides and found
this reagent combination to be somewhat comparable to the BSP/Tf O
2
[
2,10,22,23]
couple.
While no actual comparisons between the BSP and Ph SO
2
methods of thioglycoside activation have been carried out in this study, other
work from our laboratory leads us to agree with the conclusion of van Boom
[
24–27]
and coworkers.
We anticipate that between BSP, its analogs introduced
[
28]
here, the recent modification of Wong (23),
and diphenyl sulfoxide, a reagent
will be found to activate almost all classes of thioglycoside, in conjunction with
trifluoromethanesulfonic anhydride, under milder conditions than have
[
29–31]
hitherto been possible.
EXPERIMENTAL
General Methods
1
13
Unless otherwise stated H (300 MHz) and C (75 MHz) NMR spectra were
recorded in CDCl solution. Optical rotations were recorded in CHCl solution,
3
3
unless otherwise stated. All solvents were dried and distilled by standard pro-
tocols. All reactions were conducted under a blanket of dry nitrogen. All organic
extracts were dried over sodium sulfate and concentrated under aspirator
vacuum. Chromatographic purifications were carried out over silica gel. All
glycosyl donors and acceptors were prepared by the literature methods or

Table 1: Glycosidic bond forming reactions.
Activator
2
1
(BSP)
a : b
3
Yield
(%)
Yield
a : b
Yield
(%)
a : b
Acceptor
Donor
Product
ratio
(%)
ratio
ratio
7
7
1 : . 9
90
1 : . 9
87
1 : . 9
—
—
1 : . 9
—
91
88
94
89
1 : . 9
1 : . 9
1 : . 9
8.3 : 1
89
—
99
82
1 : . 9
8
8
—
—
1 : . 9
7.3 : 1
7
4
.9 : 1

a
a
7
7
2
8
.9 : 1
91
7.0 : 1
1 : 3.0
86
6.2 : 1
1 : 3.9
1 : 1
87
87
—
—
83
85
1 : . 9
1 : . 9
—
—
b
7
7
8
0
1 : . 9
80
1 : . 9
b
b
b
1 : . 9
76
1 : . 9
73
1 : . 9
a
b
Reaction was performed under dilute conditions (0.01 M donor in dichloromethane) as this led to enhanced a : b ratio.
Reaction was conducted at –408C to achieve rapid activation of this disarmed donor.

D. Crich et al.
4
20
were commercial samples. With the exception of the compounds reported
below, all disaccharide physical characteristics and spectral data are consistent
[
1]
with the literature.
1
-Benzenesulfinyl piperidine (1). To an ice-cooled suspension of PhSO Na
2
(
50.0 g, 0.31 mol) and Bu NBr (4.90 g, 15.2 mmol) in dry toluene (200 mL) was
4
added thionyl chloride (89.6 mL, 1.2 mol) dropwise over 30 min. After the
addition, the reaction mixture was stirred at 08C for 30 min, then warmed up
to rt and stirred for a further 2 hr. The reaction mixture was then concentrated
under reduced pressure keeping the temperature of the water bath below 258C
after which the residue was diluted with dry toluene (500 mL) and then treated
with pyridine (24.6 mL, 0.31 mol) in one portion. The reaction mixture was
cooled to 08C, followed by dropwise addition of piperidine (60.8 mL, 0.61 mol)
over 1 hr. After the addition, the reaction mixture was stirred in an ice bath
for 2 hr, and then warmed up to rt and stirred for a further 1 hr. The reaction
mixture was poured into a vigorously stirred mixture of ice and water (1 L)
and NaHCO (100 g, 1.2 mol). The organic layer was separated and washed
3
with brine (500 mL), and then the aqueous layer was extracted with toluene
(
2 ꢀ 200 mL). The combined organic layer was dried and then concentrated.
The residue was purified by recrystallization from ethanol to provide 1 as
white crystals (55.0 g, 86%). mp: 83–848C, lit. mp 83–848C;
[32] 1
H NMR d:
7
1
.62–7.65 (m, 2H), 7.43–7.50 (m, 3H), 3.05–3.12 (m, 2H), 2.88–2.95 (m, 2H),
.47–1.62 (m, 6H); C NMR d: 143.3, 130.6, 128.7, 126.1, 46.9, 26.1, and 23.8.
1
3
[17]
1
-Benzenesulfinyl pyrrolidine (2).
This compound was prepared analo-
gously to 1 in 73% yield on a scale of 60 g. Colorless crystals were obtained
1
by recrystallization from hexane and ethyl acetate. mp: 33–348C, H NMR d:
13
7.66 (m, 2H), 7.49 (m, 3H), 3.33 (m, 2H), 3.00 (m, 2H), 1.83 (m, 4H).
C
NMR d: 130.6, 128.9, 125.9, 46.2, 26.1.
[18]
N,N-Diethyl benzenesulfinamide (3).
This compound was prepared ana-
logously to 1 in 78% on a 55 g scale. The crude reaction mixture was purified by
distillation under reduced pressure (1108C, 0.1 mm Hg) to yield the sulfinamide
1
as colorless oil. H NMR d: 7.61 (dd, J ¼ 8.1, 2.4 Hz, 2H), 7.42 (m, 3H), 3.07
[13]
(
4
q, J ¼ 7.5 Hz, 4H) 1.11 (t, J ¼ 7.2 Hz, 6H);
C NMR d: 130.7, 128.8, 126.4,
2.1, 14.5.
N,N-Dicyclohexyl benzenesulfinamide (4). This compound was prepared
analogously to 1 in 78% on a 16 g scale. Recrystallization from ethyl acetate
1
and hexane gave the sulfonamide as colorless crystals. mp 938C; H NMR d:
7
.67–7.64 (m, 2H), 7.49–7.41 (m, 3H), 3.11–3.02 (m, 2H), 2.08–2.03 (m, 2H),
1
3
1.81–1.44 (m, 12H), 1.30–1.04 (m, 6H); C NMR d: 145.0, 130.2, 128.6,
1
26.7, 55.5, 34.9, 26.4, 25.5. Anal. calcd. for C H NOS: C, 70.77; H, 8.91.
1
8
27
Found: C, 70.81; H, 8.98.

Activation of Thioglycosides
421
Typical glycosylation protocol. A stirred solution of substrate, BSP (1.1
˚
equiv.), TTBP (2.0 equiv.) and 3 A sieves in CH Cl (0.03 M in substrate) was
2
2
kept at –788C for 15 min. Then Tf O (1.2 equiv.) was added and after 5 min.
2
the acceptor (1.5 equiv.) in CH Cl (2.0 M) was added. Stirring was continued
2
2
at –788C for 0.5 hr and then the reaction mixture was allowed to warm to rt
over a period of 2 hr before it was filtered, washed with a saturated solution
of NaHCO and brine, dried, and concentrated. Chromatographic purification
3
(
eluting with mixtures of ethyl acetate in hexane) afforded the coupled
products.
Methyl 2,3,6-tri-O-benzyl-4-O-(2,3-di-O-dibenzyl-b-D-mannopyranosyl)-
a-D-glucopyranoside (18). This compound was prepared by the standard
2
0
1
protocol and had the following characteristics: [a] –17.1 (c, 0.75); H NMR
D
(
(
(
500 MHz) d: 7.50–7.48 (m, 2H), 7.42–7.17 (m, 28H), 5.52 (s, 1H), 5.08–5.04
d, J ¼ 11.0 Hz, 1H), 4.86–4.79 (m, 3H), 4.77 (s, 1H), 4.73 (s, 1H), 4.66–4.56
m, 4H), 4.36 (s, 1H), 4.30–4.26 (d, J ¼ 12.0 Hz, 1H), 4.14–4.02 (m, 2H),
3
.93–3.83 (m, 2H), 3.64–3.58 (m, 2H), 3.54–3.47 (m, 3H), 3.44–3.43
(
d, J ¼ 3.0 Hz, 1H), 3.41 (s, 3H), 3.45–3.31 (dd, J ¼ 3.3, 9.6 Hz, 1H), 3.09–
13
3
1
1
7
9
.01 (m, 1H); C NMR (125 MHz) d: 139.9, 139.1, 139.0, 138.8, 138.1, 138.0,
29.3, 129.0, 128.8, 128.7, 128.6, 128.5, 128.2, 128.1, 128.0, 127.9, 127.8,
26.7, 101.9, 101.7, 98.8, 80.7, 79.4, 79.1, 78.7, 78.1, 75.7, 75.4, 74.1, 72.5,
þ
0.0, 69.0, 68.8, 67.7, 55.8; ESI-HRMS calcd. for C H O Na [M þ Na] :
55
58 11
17.3877. Found 917.3871.
1
,2:3,4-Di-O-isopropylidene-3-O-(2,3,4,6-tetra-O-benzoyl-b-D-b-galacto-
pyranosyl)-a-D-galactopyranose (21). This compound was prepared by the
2
6
standard protocol and had the following characteristics: [a] þ 34.78 (c, 3.0),
D
[
33]
1
lit.
[a] ¼ þ 458 (CHCl ); H NMR (500 MHz) d: 8.09 (d, J ¼ 7.6 Hz, 2H),
D
3
8
7
.03 (d, J ¼ 7.7 Hz, 2H), 7.98 (d, J ¼ 7.7 Hz, 2H), 7.79 (d, J ¼ 7.7 Hz, 2H),
.23–7.49 (m, 12H), 6.00 (d, J ¼ 2.8 Hz, 1H), 5.82 (t, J ¼ 10.0 Hz, 1H), 5.62
(
dd, J ¼ 3.2, 10.4 Hz, 1H), 5.42 (d, J ¼ 4.9 Hz, 1H), 5.03 (d, J ¼ 8.0 Hz, 1H),
4
4
1
1
1
7
.68 (dd, J ¼ 6.6, 11.2 Hz, 1H), 4.41–4.45 (m, 2H), 4.35 (t, J ¼ 6.5 Hz, 1H),
.22 (d, J ¼ 2.7 Hz, 1H), 4.05–4.12 (m, 2H), 3.90–3.93 (m, 2H), 1.40 (s, 3H),
1
3
.24 (s, 3H), 1.22 (s, 3H), 1.20 (s, 3H); C NMR (125 MHz) d: 166.0, 165.6,
65.3, 133.6, 133.2, 133.0, 130.02, 129.98, 129.79, 129.4, 129.3, 129.0, 128.8,
28.6, 128.4, 128.3, 128.2, 124.8, 109.3, 108.4, 101.7, 96.2, 71.8, 71.3, 71.0,
0.5, 70.3, 69.7, 68.4, 68.2, 67.4, 62.4, 62.0, 25.9, 25.7, 24.8, 24.2.
1
,2:5,6-Di-O-isopropylidene-3-O-(2,3,4,6-tetra-O-benzoyl-b-D-b-galacto-
[
34]
pyranosyl)-a-D-glucofuranose (22).
This compound was prepared by the
[
24]
standard protocol and had the following characterisitcs: [a]
þ46.1 (c, 1.8);
D
1
H NMR (500 MHz) d: 8.10–8.08 (d, J ¼ 7.5 Hz, 2H), 8.04–8.02 (d, J ¼ 8.0 Hz,
2
H), 8.00–7.94 (d, J ¼ 8.0 Hz, 2H), 7.79–7.77 (d, J ¼ 7.5 Hz, 2H), 7.63–7.60
(
t, J ¼ 7.5 Hz, 1H), 7.58–7.55 (t, J ¼ 7.5 Hz, 1H), 7.51–7.41 (m, 6H),

D. Crich et al.
4
22
7
1
.38–7.35 (t, J ¼ 7.5 Hz, 2H), 7.26–7.22 (t, J ¼ 8.0 Hz, 2H), 5.99 (d, J ¼ 2.5 Hz,
H), 5.90 (d, J ¼ 3.5 Hz, 1H), 5.83–5.80 (t, J ¼ 8.0 Hz, 1H), 5.61-5.59 (dd,
J ¼ 3.5, 10.5 Hz, 1H), 4.93–4.92 (d, J ¼ 8.0 Hz, 1H), 4.69–4.65 (dd, J ¼ 6.5,
1
1.0 Hz, 1H), 4.50–4.49 (d, J ¼ 3.5 Hz, 1H), 4.44–4.41 (dd, J ¼ 6.5, 11.0 Hz,
1
H), 4.34–4.31 (t, J ¼ 6.5 Hz, 1H), 4.17–4.14 (m, 2H), 4.08–4.07
(d, J ¼ 3.5 Hz, 1H), 3.76–3.71 (m, 2H), 1.40 (s, 3H), 1.29 (s, 3H), 1.13 (s, 3H),
13
1.09 (s, 3H); C NMR (125 MHz) d: 166.5, 166.0, 165.9, 165.5, 134.0, 133.7,
133.6, 130.5, 130.3, 130.2, 129.85, 129.81, 129.4, 129.2, 129.0, 128.9, 128.7,
128.6, 112.6, 106.8, 102.6, 101.3, 84.4, 79.6, 75.3, 72.0, 71.7, 70.9, 70.1, 68.5,
6
8
þ
2.4, 27.5, 26.9, 24.1, 23.1; ESI-HRMS calcd. for C H O Na [M þ Na] :
46
46 15
61.2734. Found 861.2704.
ACKNOWLEDGMENTS
We thank the NIH (GM 62160) for support of this work.
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1
34] An erroneous data set was inadvertantly recorded previously for this compound.
The correct data are given here.