Synthesis of enantiomerically pure aryl, hetero aryl and alkyl sulfinimides catalyzed by recyclable tungstophosphoric acid

Article abstract of DOI:10.1016/j.mcat.2017.06.035

A simple and efficient procedure was developed for the preparation of a variety of aryl, hetero aryl and alkyl N-sulfinylimines (2b-2u) with excellent yields (85–94%) using tungstophosphoric acid as catalyst. Also, this new synthetic protocol features hig

Full text of DOI:10.1016/j.mcat.2017.06.035

Molecular Catalysis 443 (2017) 294–300
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Editor’s choice paper
Synthesis of enantiomerically pure aryl, hetero aryl and alkyl
sulfinimides catalyzed by recyclable tungstophosphoric acid
S. Srinatha, S. Ramua, S. Elavarasanb, D. Paradesia, R. Mohan Kumarc,
K. Ilangoc,d,∗∗, B. Baskara,∗
a Department of Chemistry, SRM University, Kattankulathur 603 203, Kancheepuram (Dt), Tamilnadu, India
b Research Institute, SRM University, Kattankulathur 603 203, Kancheepuram (Dt), Tamilnadu, India
c Interdisciplinary Institute of Indian System of Medicine (IIISM), SRM University, Kattankulathur 603 203, Kancheepuram (Dt), Tamilnadu, India
d Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRM University, Kattankulathur 603 203, Kancheepuram (Dt), Tamilnadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient procedure was developed for the preparation of a variety of aryl, hetero aryl and
alkyl N-sulfinylimines (2b-2u) with excellent yields (85–94%) using tungstophosphoric acid as catalyst.
Also, this new synthetic protocol features high conversion, shorter reaction time, a straight forward and
simple work up procedure. Catalyst was recycled for 10 times without much loss in activity and also
scaled up in gram level with high yield. Hence, it is highly applicable for the industrial scale up process.
© 2017 Elsevier B.V. All rights reserved.
Received 24 March 2017
Received in revised form 26 June 2017
Accepted 27 June 2017
Keywords:
Tungstophosphoric acid
Silicotungstic acid
(S)-2-methyl-2-propanesulfinamide
Poly (ether sulfone) supported TPA
Poly (ether sulfone) supported TSA
Chiral aldsulfinimide
1. Introduction
Chemical and pharmaceutical industries are forced to reduce the
overall manufacturing cost in addition to environmentally benign
Enantiomerically pure aldsulfinimides are important build-
ing blocks for the synthesis of a number of biologically active
molecules [1,2], chiral amines [3–7], aziridines [8–10] and ␣- and
␤-aminophosphonic acids [11,12]. Though there are reports on the
synthesis of aldimines [13–16], most of them have their own disad-
vantages such as use of stoichiometric, expensive reagents, harsh
conditions, less yield and longer reaction time. Furthermore, tita-
nium tetraethoxide mediated imine formation is the choice of most
of the reactions reported so far. But the drawback of this particu-
lar reagent is the removal of titanium salt during the work up and
also stoichiometric quantity used [13]. Yet, other reagents are also
used for the aldimine formation such as metal based reagents or
catalysts [14,15]. Recently, an effective method was developed by
Reeves et al., wherein they use tris (2, 2, 2-trifluoroethyl) borate as
reagent [16] for both aldimines and ketimines. But, it requires the
use of very expensive and stoichiometric amount of reagent.
synthetic procedure due to global competitiveness and stringent
regulations enforced by the Environmental Protection Agencies
(EPA’s). Heteropoly acids (HPAs) are solid acids which are employed
as homogenous and heterogeneous catalyst [17]. Interestingly,
HPAs in solution are found to be stronger than the mineral acids
such as H2SO4, HCl, HNO3, etc., [18]. Furthermore, HPAs have sig-
nificant properties like less toxic, suitable to handle in any quantity,
environmentally benign character, cost effectiveness and commer-
cial availability [19]. Among the many available acids, keggin’s
HPAs are more stable and readily employable (tungstophosphoric
acid (TPA), phosphomolybdic acid (PMA), silicotungstic acid (STA))
[20,21].
Furthermore, a clean, high yielding, recyclable, optically pure
and scalable method would offer many advantages such as opera-
tional simplicity and less wastage generation. Usage of recyclable
catalyst is more favored in industries due to its economic viability,
easy separation and less wastage generation. Hence, we herein wish
to report a simple and efficient process for the preparation of aryl,
hetero aryl and aliphatic aldimines in the presence of tungstophos-
phoric acid as catalyst. To the best of our knowledge, the use of
the TPA as catalyst for synthesis of aldsulfinyl imines has not been
reported so far.
∗
Corresponding author.
Corresponding author at: Interdisciplinary Institute of Indian System of Medicine
∗∗
(IIISM), SRM University, Kattankulathur 603 203, Kancheepuram (Dt), Tamilnadu,
India.
E-mail addresses: ilangok67@gmail.com (K. Ilango), bbaskar10@gmail.com (B.
Baskar).
http://dx.doi.org/10.1016/j.mcat.2017.06.035
2468-8231/© 2017 Elsevier B.V. All rights reserved.

S. Srinath et al. / Molecular Catalysis 443 (2017) 294–300
295
Table 1
Effect of amounts of TPA and other catalysts on the synthesis of (S)-2a by the reaction of benzaldehyde (1a), with (S)-t-butylsulfinamide ((S)-3).
Entries
Catalyst
Substrate/Amine /Cat. (Equiv.)
Time (h)
Temp (◦C)
Isolated yield (%)c
1
2
3
4
5
6
7
8
9
SPEEK/TPA (A)a
1:1.2:40b
1:1.2:40b
1:1.2:0.2
1:1.2:0.2
1:1.2:0.1
1:1.2:0.01
1:1:20b
24
24
20
12
1
2
2
2
2
rt
rt
rt
rt
60
60
60
60
60
60
90
87
80
93
93
92
60
75
70
48
SPEEK/TSA (B)a
H4SiW12O40nH2O (C)
H3PW12O40 (D)
H3PW12O40 (D)
H3PW12O40 (D)
Zeolite ZSM-5 (E)
Amberlite® IR120 hydrogen form (F)
Montmorillonite (G)
Aluminium silicate (H)
1:1:20b
1:1:20b
10
1:1:20b
2
a
SPEEK − Sulfonylated poly (ether ether ketone).
b
c
40 and 20 represent the wt% with the starting material.
The products were purified by column chromatography on silica gel (230–400 mesh, EtOAc – petroleum ether, 9:1).
2. Experimental section
icotungstic acid and phosphotungstic acid) was added, stirred well
and heated up to 60 ◦C for 6 h. After that the viscous polymer solu-
tion was cast onto a flat glass plate using a thin glass rod and
was kept in a closed chamber for 24 h. The cast membranes were
dried at 60 ◦C for 6 h, 90 ◦C for 8 h and 140 ◦C for 3 h. The resultant
dried films were soaked in de-ionized water overnight to release
the membranes from the glass plates. Then the composite mem-
branes were carefully washed with de-ionized water and dried in a
vacuum oven at 100 ◦C for 12 h. The infra-red absorption bands of
W-O-W and W = O vibrations for HPA were obtained at 895 cm−1
and 980 cm−1 respectively. These characteristic absorptions con-
firm the successful incorporation of the tungstic acid in to the SPEEK
polymer.
Unless otherwise stated, all reactions were performed in
flame-dried glassware under an atmosphere of N2. All chem-
icals and reagents such as aldehydes, (S)-t-BuSONH2, (RS)-t-
BuSONH2, phosphotungstic acid, tungstosilisic acid, zeolite ZSM-5
(SiO2:Al2O3 = 50:1), amberlite® IR120 hydrogen form, montmoril-
lonite K10 and aluminium silicate (3Al2O3 · 2SiO2) were purchased
from Aldrich and Alfa Aesar suppliers and used without further
purification. Flash column chromatography was performed with
silica gel (230−400 mesh size). Thin layer chromatography (TLC)
was performed on precoated silica gel plates (Merck 60, F254,
0.25 mm); detection was accomplished using a UV254 light and
staining with phosphomolybdic acid staining solution; NMR data
was recorded on a Bruker 500 MHz spectrometer, operating at
500 MHz for 1H acquisitions in the indicated deuterated solvent.
Chemical shifts (␦) are reported in parts per million (ppm) and rela-
tive to TMS at 0 ppm. The data is reported as (s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet or unresolved, br = broad sig-
nal, coupling constant(s) in Hz). HPLC analysis was performed on a
Shimadzu prominence UFLC binary gradient HPLC system. Conver-
sion was determined by the HPLC using analytical C18 column. The
enantiomeric purities (% e.e.) of 2b and 2 l were determined by chi-
ral HPLC analysis in comparison with racemates. The column used
was Chiralpak® AD-H LC column 250 × 4.6 mm. The mobile phase
was hexane − isopropanol at a flow rate of 0.4 mL min−1 and the
absorbance was monitored using a UV detector at 254 nm.
2.3. Synthesis of
(E)-N-benzylidene-2-methylpropane-2-sulfinamide (2b) using
SPEEK/heteropoly acids (HPA or STA) or STA or TPA
To a stirred solution of benzaldehyde 1 (2 mmol) in toluene
(5 mL) was added 2-methyl-2-propanesulfinamide (3; 2.4 mmol)
under inert conditions. Catalysts A or B (40 wt%) and catalysts C or
D (as mentioned in Table 1) was added and the reaction mixture
was heated to 60 ◦C for 2–4 h. Progress of the reaction was moni-
tored by TLC. After the reaction was complete, the reaction mixture
was allowed to room temperature. Crude reaction mixture was fil-
tered and then washed with toluene. The solvent was evaporated
under reduced pressure to obtain a crude mass, which was puri-
fied by flash chromatography on silica gel using hexanes-EtOAc as
eluent to afford pure compound 2a.
2.1. Synthesis of sulfonated poly (ether ether ketone) (SPEEK)
The sulfonation of poly (ether ether ketone) (PEEK) was per-
formed according to the reported literature [25,26]. The powdered
form of PEEK was first dried in a vacuum oven at 100 ◦C for 24 h. A
volume of 100 mL of conc. sulfuric acid was taken in a round bot-
tom flask and heated up to 40 ◦C in a water bath fitted in a magnetic
stirrer. A quantity of 2.0 g of dried PEEK was slowly transferred to
the acid for the period of 1 h. The reaction mass was constantly
stirred and maintained at 50 ◦C for 5 h. The obtained viscous solu-
tion was slowly transferred to the beaker containing large excess of
ice-water. The resultant pink colored solid was filtered and washed
thoroughly with de-ionized water until the neutral pH reached. The
resulted sulfonated PEEK was dried at 100 ◦C for 12 h in a vacuum
oven.
2.4. Recyclability test on PTA for the synthesis of
(E)-N-benzylidene-2-methylpropane-2-sulfinamide (2b)
To a stirred solution of benzaldehyde 1a (2 mmol) in toluene
(5 mL) was added 2-methyl-2-propanesulfinamide (3; 2.4 mmol)
under inert conditions in a 10 mL screw capped vial. TPA (1 mol%)
was added and the reaction mixture was heated to 60 ◦C for 2–6 h.
Progress of the reaction was monitored by TLC. The reaction mix-
ture was allowed to room temperature and then filtered through a
sintered crucible and washed with toluene (2 × 2 mL). The solvent
was evaporated under reduced pressure to obtain a crude com-
pound, which was purified by flash chromatography on silica gel
using hexanes–EtOAc as eluent to obtain compound 2a. Recovered
catalyst was reused by following the same procedure. The reaction
was repeated using recovered catalyst for 10 subsequent cycles.
Yields ranged from 90 to 92%.
2.2. Preparation of SPEEK − Heteropoly acids (HPA) composite
membranes
The acid form of 5 wt% SPEEK polymer was dissolved in N, N-
dimethylacetamide with constant stirring using a magnetic stirrer.
After the whole dissolution of SPEEK, 20 wt% heteropoly acids (sil-

296
S. Srinath et al. / Molecular Catalysis 443 (2017) 294–300
1.25 (s, 9H); 13C NMR (CDCl3, 125 MHz) (␦, ppm) 157.46, 153.31,
151.75, 131.08, 125.56, 125.22, 119.53, 119.18, 117.72, 114.52,
113.96, 53.17, 17.90.
2.5. Synthesis of enantiomerically pure N-(tert-Butylsulfinyl)
imines (2a to 2u) using PTA; General procedure
To
a dry 10 mL conical vial were added aldehyde, 1a
to 1 u (2.0 mmol, 1.0equiv), (S)-tert-butanesulfinamide (291 mg,
2.4 mmol, 1.2 equiv) and toluene (5.0 mL) under nitrogen atmo-
sphere. To this solution was added TPA (1 mol%) and the solution
was stirred at 60 ◦C for 2–4 h. Reaction progress was monitored
by TLC and HPLC. After completion of the reaction, the reaction
mixture was allowed to room temperature and then catalyst was
filtered through filter paper and washed with toluene (2 × 2 mL).
The solvent was evaporated under reduced pressure to obtain a
crude compound, which was purified by flash chromatography on
silica gel using eluant hexanes–EtOAc to obtain enantiomerically
pure aldsulfinimides, 2a to 2u.
7. (S)-(E)-2-methyl-N-(naphthalen-1-ylmethylene)propane-
2-sulfinamide (2 g): Yield: 94%, 1H NMR (CDCl3, 500 MHz) (␦, ppm)
9.05 (s, 1H), 8.93 (d, J = 8.5 Hz, 1H), 7.93 (m, 2H), 7.81 (d, J = 8.0 Hz,
1H), 7.53-7.45(4H, m), 1.22 (9H, s). 13C NMR (CDCl3, 125 MHz)
(␦, ppm) 161.46, 132.84, 132.27, 130.97, 130.17, 128.31, 127.80,
127.00, 125.45, 124.18, 123.31, 56.65, 21.59.
1.
(S)-(E)-N-benzylidene-2-methylpropane-2-sulfinamide
(2a): Yield: 92%, 1H NMR (CDCl3, 500 MHz) (␦, ppm) 8.50 (s, 1H),
7.77 (m, 2H), 7.38 (m, 2H), 1.17(s, 9H). 13C NMR (CDCl3, 125 MHz)
(␦, ppm) 161.82, 132.02, 131.43, 128.36, 127.92, 56.76, 21.58.
8.(S)-(E)-N-(anthracen-9-ylmethylene)-2-methylpropane-2-
sulfinamide (2 h): Yield: 90%, 1H NMR (CDCl3, 500 MHz) (␦, ppm)
9.79 (s, 1H), 8.76 (d, J = 8.0 Hz, 2H), 8.43 (s, 1H), 7.90 (d, J = 8.5 Hz,
2H), 7.49–7.47 (m, 2H), 7.41–7.40 (m, 2H), 1.27 (s, 9H). 13C NMR
(CDCl3, 125 MHz) (␦, ppm) 61.88, 132.62, 131.20, 129.23, 128.3,
128.00, 125.55, 124.23, 57.65, 22.73.
2. (S)-(E)-N-(3,4-dimethoxybenzylidene)-2-methylpropane-
2-sulfinamide (2b): Yield: 91%, 1H NMR (CDCl3, 500 MHz) (␦, ppm)
8.49 (s, 1H), 7.45 (S, 1H), 7.38 (d, J = 8.0 Hz, 1H, ArH), 6.95 (d,
J = 8.50 Hz, 1H), 3.95 (s, 6H), 1.26 (s, 9H); 13C NMR (CDCl3, 125 MHz)
(␦, ppm) 162.0, 152.9, 149.4, 127.4, 125.0, 110.7, 109.9, 57.5, 56.0,
55.9, 22.5
9. (S)-(E)-N-(4-isopropylbenzylidene)-2-methylpropane-2-
sulfinamide (2i): Yield: 90%, 1
H
NMR (CDCl3, 500 MHz) (␦, ppm)
8.48 (s, 1H), 7.71-7.69 (d, J = 8 Hz, 2H), 7.26-7.24 (d, J = 8 Hz, 2H),
2.88 (m, 1H), 1.20 −1.17 (m, 15H). 13C NMR (CDCl3, 125 MHz) (␦,
ppm) 157.78, 149.24, 127.28, 124.83, 122.34, 52.94, 29.59, 18.98,
17.87.
3.
(S)-(E)-N-(4-hydroxybenzylidene)-2-methylpropane-2-
sulfinamide (2c): Yield: 86%, 1H NMR (CDCl3, 500 MHz) (␦, ppm)
10.37(bs, 1H); 8.41 (s, 1H), 7.80 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.5 Hz,
2H), 1.16 (s, 9H); 13C NMR (CDCl3, 125 MHz) (␦, ppm) = 162.24,
162.16, 132.00, 125.86, 116.40, 57.33, 22.48.
10.
(S)-(E)-N-(4-(dimethylamino)benzylidene)-2-
methylpropane-2-sulfinamide (2j): Yield: 89%, 1H NMR (CDCl3,
500 MHz) (␦, ppm) 8.31 (s, 1H), 7.60-8.58 (d, J = 8 Hz, 2H), 6.56-6.54
(d, J = 8 Hz, 2H), 2.89(s, 6H), 1.12 (s, 9H); 13C NMR (CDCl3, 125 MHz)
(␦, ppm) 161.56, 153.01, 131.16, 122.27, 111.33, 57.23, 40.00,
22.49.
4.
(S)-(E)-N-(4-Methoxybenzylidene)-2-methylpropane-2-
sulfinamide (2d): Yield: 93%, 1H NMR (CDCl3, 500 MHz) (␦, ppm)
8.42 (s, 1H), 7.72- 7.70 (d, J = 8 Hz, 2H), 6.88-6.87 (d, J = 8 Hz, 2H).
3.78 (s, 3H), 1.16 (s, 9H); 13C NMR (CDCl3, 125 MHz) (␦, ppm) 163.1,
161.8, 131.3, 127.3, 114.4, 57.6, 55.5, 22.6.
11. (S)-(E)-2-methyl-N-((E)-3-phenylallylidene)propane-2-
sulfinamide (2k): Yield: 89%, 1H NMR (CDCl3, 500 MHz) (␦, ppm)
8.28 (d, J = 9.0 Hz, 1H), 7.43-7.40 (dd,J = 1.5; 8 Hz, 2H), 7.28-7.26 (m,
3H), 7.12 (d, J = 16.0 Hz, 2H), 7.00 (dd, J = 9.0, 15.5 Hz, 1H), 1.15 (s,
9H); 13C NMR (CDCl3, 125 MHz) (␦, ppm) 163.77, 146.38, 135.00,
130.24, 128.96, 127.90, 125.50, 57.53, 22.49.
5.
(S)-(E)-N-(4-hydroxy-3-methoxybenzylidene)-2-
methylpropane-2-sulfinamide (2e): Yield: 92%, 1H NMR (CDCl3,
500 MHz) (␦, ppm) 8.47 (s, 1H), 7.42 (s, 1H), 7.36 (d, J = 7.0 Hz, 1H),
7.00 (d, J = 8 Hz, 1H), 6.41(bs, 1H), 3.96(s, 3H) 1.26 (s, 9H); 13C NMR
(CDCl3, 125 MHz) (␦, ppm)162.16, 150.00, 147.06, 127.10, 125.46,
114.66, 109.83, 57.65, 56.06, 22.60
12.
(S)-(E)-N-(2-bromobenzylidene)-2-methylpropane-2-
sulfinamide (2l): Yield: 92%, 1H NMR (CDCl3, 500 MHz) (␦, ppm)
8.90 (s, 1H), 7.97 (dd, J = 1.5; 7.5 Hz, 1H), 7.57 (dd, J = 1.0; 7.5 Hz,
1H), 7.31 (m, 2H), 1.20 (s, 9H). 13C NMR (CDCl3, 125 MHz) (␦, ppm)
162.17, 133.65, 133.36, 132.85, 129.64, 127.73, 126.41, 58.03,
22.72.
6.
(S)-(E)-2-methyl-N-(3-phenoxybenzylidene)propane-2-
sulfinamide (2f): Yield: 91%, 1H NMR (CDCl3, 500 MHz) (␦, ppm)
8.53 (m, 1H), 7.57 (d, J = 8 Hz, 1H), 7.50 (t, J = 2.5 Hz, 1H, 1H), 7.42 (t,
J = 8 Hz, 1H), 7.31 (t, J = 8 Hz, 1H), 7.15 (m, 2H), 7.05 (d, J = 8 Hz, 2H),

S. Srinath et al. / Molecular Catalysis 443 (2017) 294–300
297
20.
(S)-(E)-N-butylidene-2-methylpropane-2-sulfinamide
(2t): Yield: 85%, 1H NMR (CDCl3, 500 MHz) (␦, ppm) 7.99 (m, 1H),
2.43 (m, 2H), 1.60 (m, 2H), 1.12 (s, 9H), 0.92 (m, 3H); 13C NMR
(CDCl3, 125 MHz) (␦, ppm) 168.54, 55.41, 37.02, 21.31, 17.91, 12.79.
13.
(S)-(E)-2-methyl-N-(4-nitrobenzylidene)propane-2-
sulfinamide (2m): Yield: 93%, 1H NMR (CDCl3, 500 MHz) (␦, ppm)
8.60 (s, 1H), 8.27-8.25 (d, J = 8.5 Hz, 2H), 6.56-6.54 (d, J = 8.5 Hz,
2H), 1.22 (s, 9H); 13C NMR (CDCl3, 125 MHz) (␦, ppm) 160.7, 149.8,
138.9, 130.0, 124.2, 58.5, 22.7.
21.
(S)-(E)-2-methyl-N-(3-methylbutylidene)propane-2-
sulfinamide (2u): Yield: 87%, 1H NMR (CDCl3, 500 MHz) (␦, ppm)
8.05 (m, 1H), 2.41 (m, 2H), 2.08 (m, 1H), 1.20 (s, 9H), 1.01 (d,
J = 6.5 Hz, 6H); 13C NMR (CDCl3, 125 MHz) (␦, ppm) 169.42, 56.52,
44.94, 26.15, 22.62, 22.54, 22.36.
14.
(S)-(E)-N-((1H-pyrrol-2-yl)methylene)-2-
methylpropane-2-sulfinamide (2n): Yield: 92%, 1H NMR (CDCl3,
500 MHz) (␦, ppm) 9.72 (bs, 1H), 8.41 (s, 1H), 7.04 (s, 1H), 6.77 (s,
1H), 6.32(d, J = Hz, 1H) 1.22 (s, 9H); 13C NMR (CDCl3, 125 MHz) (␦,
ppm) 152.00, 129.34, 124.87, 118.40, 111.04, 57.50, 22.43.
3. Results and discussion
Chiral aldsulfinimides are important building blocks for medic-
inal chemistry research [22,23]. We aimed to investigate for an
effective catalyst on the synthesis of chiral aldsulfinimides from
aldehydes and (S)-2-methyl-2-propanesulfinamide (3). Reported
methods on direct condensation of sulfinamide with aldehydes
using either molecular sieves or sodium sulfate were not effective
to obtain the aldsulfinimides in high yields. Also, use of magnesium
sulfate coupled with pyridium p-toluenesulfonate for the imine for-
mation has resulted in quantitative yield but process may not be
feasible for large scale production under stringent dry conditions
[24]. Hence, we envisaged to make use of polymer supported het-
eropoly acid (HPA) as catalyst for the formation of aldsulfinimides
by treating the benzaldehyde (1) as a model substrate. Employing
the polymer supported HPA’s would help the easy separation of
catalyst from the reaction mixture and its subsequent reuse. There-
fore, the preparation of the polymer supported HPA’s (entries 1
and 2; Table 1) was carried out based on the parallel procedure
reported in the literature [25,26]. The synthesized polymer sup-
ported catalysts (A and B, Table 1) were employed for the proposed
reaction (Scheme 1). Reaction was carried out in toluene using
40 wt% catalysts at rt for 24 h. Reaction proceeded smoothly and
gave isolated yields of 87% and 90% for polymer supported STA and
TPA respectively. Catalyst employed was recovered without any
loss and reused for another two cycles. However, its activity was
found to be diminishing after two cycles.
15. (S)-(E)-2-methyl-N-(pyridin-2-ylmethylene)propane-2-
sulfinamide (2o): Yield: 93%, 1H NMR (CDCl3, 500 MHz) (␦, ppm)
8.75 (m, 1H), 8.71 (s, 1H), 8.01 (d; J = 7.8, 1H), 7.82 (m, 1H), 7.40
(m, 1H), 1.29 (s, 9H); 13C NMR (CDCl3, 125 MHz) (␦, ppm) 163.7,
152.5, 150.2, 136.8, 125.9, 123.1, 58.5, 22.7
16. (S)(E)-2-methyl-N-(thiophen-2-ylmethylene) propane-2-
sulfinamide (2p): Yield: 92%, 1H NMR (CDCl3, 500 MHz) (␦, ppm)
8.68 (s, 1H), 7.59 (d, J = 5.0 Hz, 1H), 7.53 (dd, J = 3.6, 0.9 Hz, 1H), 7.12-
7.16 (m, 1H), 1.25 (s, 9H). 13C NMR (CDCl3, 125 MHz) (␦, ppm) 155.5,
140.5, 133.8, 132.3, 128.2, 57.97, 22.56
17.
(S)-(E)-N-(furan-2-ylmethylene)-2-methylpropane-2-
sulfinamide (2q): Yield: 91%, 1H NMR (CDCl3, 500 MHz) (␦, ppm)
8.31 (s, 1H), 7.57 (s, 1H), 6.95 (d, J = 3.5 Hz, 1H), 6.50(dd, J = 1.5;
3.5 Hz, 1H), 1.17 (s, 9H); 13C NMR (CDCl3, 125 MHz) (␦, ppm)
150.76, 149.83, 146.84, 118.73, 112.54, 57.80, 22.45.
This result has encouraged us to use the HPA’s without any
support or modification. To our delight, the reaction proceeded
to almost complete conversion using tungstophosphoric acid
(TPA) (20 mol%) at rt after 12 h, whereas silicotungstic acid (STA)
(20 mol%) gave only 85% conversion (entries 3 and 4, Table 1). After
the reaction, TPA was found to be in heterogeneous state at rt in
the reaction medium. Furthermore, TPA was taken for subsequent
optimization since high yield was obtained.
With the focus on catalyst loading, 10 and 1 mol% of catalyst
was employed under similar reaction conditions at rt. Both the
reactions were found to be slow. To overcome this drawback, tem-
perature of the reaction was increased to 60 ◦C and the reaction
was completed in 2 h. 10 and 1 mol% did not show any drastic
change in the yield obtained. Reaction mixture was allowed to rt
and catalyst was recovered by simple filtration. Concentration of
crude filtrate was found to be containing the benzaldsulfinimide
(2b) as the only product, without significant amounts of either
1a or 3. Yields ranged from 92 to 93% (entries 5 and 6, Table 1).
Also, time course of the reaction was studied for the formation
of 2b catalyzed by TPA as shown in Fig. 1. Furthermore, reaction
was carried out using other solid catalysts such as zeolite ZSM-5
(E), amberlite® IR120 hydrogen form (F), montmorillonite K10 (G)
and silica-alumina (H) for the synthesis of sulfinamide under opti-
18. (S)-(E)-2-methyl-N-(pyridin-3-ylmethylene)propane-2-
sulfinamide (2r): Yield: 92%, 1H NMR (CDCl3, 500 MHz) (␦, ppm)
8.97(s, 1H), 8.67(d, J = 5 Hz, 1H), 8.58(s, 1H), 8.12(d, J = 8 Hz, 1H),
7.37(m, 1H), 1.21(s, 9H). 13C NMR (CDCl3, 125 MHz) (␦, ppm)
160.43, 152.86, 150.94, 135.78, 129.70, 123.98, 58.16, 22.63.
19. (S)-(E)-N-((1H-indol-3-yl)methylene)-2-methylpropane-
2-sulfinamide (2s): Yield: 92%, 1H NMR (CDCl3, 500 MHz) (␦, ppm)
9.56 (bs, 1H), 8.78(s, 1H), 8.31 (dd, J = 2.5,7 Hz, 1H), 7.64(d, J = 3 Hz,
1H), 7.47 (dd, J = 1.5; 6.5 Hz, 2H), 7.33–7.27 (m, 2H), 1.31 (s, 9H).
13C NMR (CDCl3, 125 MHz) (␦, ppm) 156.37, 137.09, 132.70, 124.87,
124.04, 122.35, 122.18, 115.20, 111.74, 57.13, 22.50.

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S. Srinath et al. / Molecular Catalysis 443 (2017) 294–300
Scheme 1. Synthesis of (E)-N-benzylidene-2-methylpropane-2-sulfinamide (2a).
Table 2
TPA catalyzed synthesis of enantiomerically pure various substituted aryl, hetero
aryl and aliphatic aldsulfinimides ((S) − 2b-2u).
Substratesa
R1
Time (h)
Yield (%)b
1b
1c
1d
3,4-(MeO)2Ph—
4-OH Ph-
4-OMePh-
2
3
2
91
86
93
1e
2
92
1f
m-Pho- C6H4-
4
3
91
94
1g
1h
1i
3
2
90
90
p-iPrPh
Fig. 1. Time course for the formation of benzaldsulfinamide catalyzed by
TPA. Reaction conditions: TPA (1 mol%), benzaldehyde (2.0 mmol), 2-methyl-2-
propanesulfinamide (2.4 mmol), Toluene (5 mL), 60 ◦C, under N2 atm.
1j
2
3
89
1k
89
mized conditions. All of them led to the desired product with yields
ranging from 48 to 75%. The results obtained, as shown in Table 1
(entries 7, 8, 9 and 10), have clearly prompted us to proceed with
TPA as the choice of catalyst in order to further study the scope
of the reaction. Earlier, Sanaboina et al., had reported the synthe-
sis of N-(tert-butylsulfinyl)imines catalyzed by Amberlist-15 under
microwave conditions [27]. However, reaction requires 20 mol% of
the catalyst and THF as solvent.
1l
1m
2-Br Ph
4-NO2Ph
92
93
3
3
1n
1o
92
93
3
3
1p
92
The scope of the reaction was subsequently explored with
respect to various aromatic aldehydes, hetero aromatic aldehy-
des and aliphatic aldehydes (Scheme 2, Table 2, substrates 1b-1m,
1n −1s and 1t- 1u, respectively). Very good to excellent yields
were obtained for both electron withdrawing and electron donating
(1b-1m) aryl aldehydes. Progress of the reaction was analyzed by
TLC and HPLC except aliphatic aldehydes wherein NMR was used.
Maximum conversion was achieved in 2–4 h for all the substrates
(1b-1u, Table 2).
In order to study the electronic effects of the substituents, we
employed the aryl aldehydes with electron donating substituents
for the synthesis of aldsulfinimides (2b-2k, Table 2). All of them
resulted in high yields. Reaction with unreactive electron rich alde-
hyde, 4-methoxy benzaldehyde gave 2d in excellent yield (93%).
Furthermore, the substrate with larger substituent at m-position
(1f) was found to be desirable and afforded in 91% yield. Never-
theless, it is significant to note that, our results are very much
comparable with the work reported in the literature using stoi-
chiometric quantity of reagents such as Ti(OEt)4 and B(OCH2CF3)3
[14,16,28]. Imine formation for the substrates with electron with-
drawing substituents (1 l to 1m) proceeded smoothly and resulted
in high yields (90–92%). From the above experiments, it was evident
that, the method was tolerant to various functional groups such as
electron-rich as well as electron-deficient on aromatic rings under
the optimized conditions (Table 2).
1q
1r
3
4
91
92
1s
2
92
1t
1u
a
3
3
85
87
Substrates 1b-u and (S)-3 were used in 1:1.2 ratio unless otherwise mentioned.
Yield refers to isolated material. Products were characterized by 1H and 13C NMR
b
analyses.
noted by Liu and co-workers [14]. In contrast, our reaction required
only 2.0 equiv. of 3 to afford the desired product 2 s in 92% yield.
Interestingly, even the less active aldehyde, furfural (1q) was also
effectively converted to their corresponding imine product (2q) in
quantitative yield.
Also, we were very much interested in employing the enoliz-
able aliphatic aldehydes 1 t and 1 u containing alkyl chains such as
isobutyl (1t) and n-propyl (1u). The previous reports on aliphatic
aldehydes have shown the decrease [14] or equal [16] in yield when
compared to our yields. Gratifyingly, reaction of aliphatic alde-
hydes using TPA resulted in good yields ranged from 85 to 87%
(Table 2). Another important observation is that, all the prepara-
tion of aldimines 2b-2u, was pure enough and can be taken for
next stage since the catalyst was simply filtered it off.
Heterocyclic aldehydes such as pyridine, pyrrole, indole, furan
and thiophene, (1n-1s) were also converted into their correspond-
ing imines in high yields ranging from 90 to 93% (Table 2). It
was observed that, pyridine-3-carboxaldehyde does not give the
expected product in the presence of CuSO4 since it is ineffective as

S. Srinath et al. / Molecular Catalysis 443 (2017) 294–300
299
Scheme 2. Synthesis of various aldsulfinamides (2b-2u).
Scheme 3. Synthesis of (S)-(E)-2-methyl-N-(1-phenylethylidene)propane-2-sulfinamide (5) using TPA.
Fig. 2. Recyclability of TPA for the synthesis of (E)-N-benzylidene-2-methylpropane-2-sulfinamide (2a) at 60 ◦C (t = 2–6 h).
Also, we have extended the reaction to check the recyclability of
the catalyst under the same reaction conditions. Recyclability was
tested in 2 mmol scale for 10 cycles. The conversion was found to
be same even after 10th cycle as shown in Fig. 2. Catalytic activity
almost remained as same as that of the 1st cycle. Yield of the reac-
tion at the 10th cycle was 91%. Besides the recyclability, study was
also carried out for the scale up viability. Reaction was performed
in 1 g scale by treating the benzaldehyde (1a; 1 g, 9.4 mmol) with
2-methyl-2-propanesulfinamide (3; 1.36 g, 11.28 mmol) under the
optimized conditions. Reaction gave rise to the desired product
(2a) in quantitative yield (1.82 g, 93%). Recyclability coupled with
scalability, the process can be employed for the preparation of ald-
sulfinimides on commercial scale.
Enantiomeric purity of selective products (2a and 2l) was ana-
lyzed by chiral HPLC. Gratifyingly, enantiomeric excess (e.e.) of the
products formed were found to be as same as that of the e.e., of
starting material (3a) (supplementary data). There was no racem-
ization during the reaction. Hence, this method shows that, it is
suitable for the synthesis of enantiomerically pure aldsulfinimides.
Also, it is imperative to note that the first asymmetric synthesis of
aldsulfinimides was reported by Liu and co-workers [14].
To study the scope of the methodology, reaction was also
extended to the ketone moieties. As a result, acetophenone (4) was
treated with methyl-2-propanesulfinamide (3) under the standard
conditions (Scheme 3). Though the reaction gave the desired prod-
uct, ketosulfinimide (5) in lower conversion (∼35 to 40%), but it did
not generate any side product. Even increasing the temperature to
reflux as well as extending the reaction time to 24 h did not show
any improvement in the conversion of product.
4. Conclusion
A simple, efficient, scalable and environmentally benign pro-
cedure was developed for the synthesis of enantiomerically pure
aldsulfinimides (2a-2u) using tungstophosphoric acid as catalyst.
The efficiency of the catalyst on recyclability and scalability was
effectively demonstrated. Also, the method was very effective for
the synthesis of aryl, heteroaryl and aliphatic aldsulfinamides in
good yields and shorter reaction times with simple work up pro-
cedure. Developed method can be easily employed on commercial
scale in industries.

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S. Srinath et al. / Molecular Catalysis 443 (2017) 294–300
[6] D.A. Cogan, J.A. Ellman, J. Am. Chem. Soc. 121 (1999) 268.
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Dr BB thanks Department of Science and Technology − SERB
Young Scientist Project, Government of India for financial sup-
port (SB/FT/CS-082/2014) to carry out this work. The authors thank
Prof. K. K. Balasubramanian, INSA Senior Scientist, Department of
Biotechnology, Indian Institute of Technology Madras, Chennai for
his help and valuable suggestions. Dr. BB thanks Prof. M. Sasidharan,
Professor (HOD, Research), Department of Chemistry, SRM Univer-
sity for his support and encouragement. SS thanks SRM University
for Junior Research Fellowship (JRF).
Appendix A. Supplementary data
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