Sulfur-Based Chiral Iodoarenes: An Underexplored Class of Chiral Hypervalent Iodine Reagents

Article abstract of DOI:10.1055/a-1508-9593

Chiral hypervalent iodine reagents are active players in modern stereoselective organic synthesis. Structurally diverse chiral hypervalent iodine reagents have been synthesised and extensively studied, but hypervalent iodine reagents containing chiral sul

Full text of DOI:10.1055/a-1508-9593

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–H
special topic
A
Special Issue dedicated to Prof. Alain Krief
M. Elsherbini et al.
Special Topic
Synthesis
Sulfur-Based Chiral Iodoarenes: An Underexplored Class of Chiral
Hypervalent Iodine Reagents
Mohamed Elsherbinia,b
Arnaud Osia
Haifa Alharbia
Fatemah Karama
Thomas Wirth*a
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a School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK
wirth@cf.ac.uk
b New address: Department of Chemistry, University of Huddersfield,
Queensgate, Huddersfield HD1 3DH, UK
M.Elsherbini@hud.ac.uk
Dedicated to Prof. Alain Krief on the occasion of his 80th birthday
Published as part of the
Special Issue dedicated to Prof. Alain Krief
Corresponding Author
Received: 01.04.2021
Accepted after revision: 14.05.2021
Published online: 14.05.2021
1). Using chiral ligands to the iodine is another strategy,
even though limited.25–27 The vast majority of chiral hyper-
valent iodine reagent are synthesised by the oxidation of
chiral iodoarenes containing chiral tetrahedral carbon cen-
tres I, II or C–C axis of chirality III. C–N axially chiral hyper-
valent iodine reagents of type IV are also gaining interest
lately.28,29 On the other hand, the synthesis of hypervalent
iodine reagents with chiral sulfur moieties is scarcely devel-
oped, even though there are a few examples known.30,31 To
the best of our knowledge only one report on the synthesis
and reactions of diaryliodonium salts containing chiral sulf-
oxide moiety has been published.32 Herein, we report our
efforts towards the synthesis of this challenging class of chi-
ral hypervalent iodine reagents from precursors of types V
and VI (Figure 1).
DOI: 10.1055/a-1508-9593; Art ID: ss-2021-t0190-op
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© 2021. The Author(s). This is an open access article published by Thieme under the
terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License,
permitting copying and reproduction so long as the original work is given appropriate
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Abstract Chiral hypervalent iodine reagents are active players in
modern stereoselective organic synthesis. Structurally diverse chiral hy-
pervalent iodine reagents have been synthesised and extensively stud-
ied, but hypervalent iodine reagents containing chiral sulfur stereogen-
ic centre are scarce and their synthesis is challenging. A small library of
iodoarenes containing chiral sulfinamide and chiral sulfoximine moi-
eties has been synthesised using commercially available reagents. The
oxidation of the chiral iodoarene precursors to iodine(III) reagents was
cumbersome due to facile overoxidation of the sulfoxide moiety and
hence loss of chirality under various oxidation conditions. Oxidation of
chiral sulfonimidoyl derivatives to the corresponding hypervalent iodine
reagents was successful and led to novel sulfur-based chiral iodine(III)
reagents.
I
I
N
I
R*
R*
R*
I
R
Key words hypervalent iodine, oxidation, stereoselective synthesis,
sulfoximines, sulfur derivatives
I
II
III
IV
central chirality - carbon
axial chirality
Chiral hypervalent iodine reagents are widely used as
active reagents in stereoselective synthesis.1–4 They are ex-
tensively studied in a wide range of stereoselective trans-
formations under stoichiometric and catalytic conditions.
Stereoselective synthesis of chiral sulfur compounds,5,6 oxi-
dative phenol dearomatisation,7–11 -functionalisation of
carbonyl compounds,12–15 difunctionalisation of alkenes,16–
20 and oxidative rearrangement reactions21–24 are efficiently
achieved with high degree of stereochemical control using
diverse chiral hypervalent iodine reagents.
This work
I
I
R
S
X
X
R
S
O
NR'
O
V
VI
central chirality - sulfur
Figure 1 Strategies of introducing chirality into iodoarene scaffolds
The incorporation of chirality into hypervalent iodine
reagents is typically achieved through substituents of the
iodoarene moiety containing a stereogenic centre (Figure
The main challenge of synthesis of hypervalent iodine
reagents with chiral sulfoxide moiety is the loss of chirality
due to the possible oxidation of sulfoxides to sulfones under
© 2021. The Author(s). Synthesis 2021, 53, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Elsherbini et al.
Special Topic
Synthesis
the oxidation conditions to prepare iodine(III) reagents.32
We envisaged that the introduction of a chiral sulfinamide
(type V) or sulfoximine (type VI) and adjusting the substi-
tution pattern around the central sulfur could alleviate this
problem.
borate in acetic acid led to the achiral cyclic hypervalent io-
dine reagent 8 in 85% yield. The chemical constitution of
compound 8 was additionally confirmed by X-ray crystal-
lography.38 Oxidation of precursors 4 and 5 with sodium
perborate led to the corresponding achiral sulfones 938 and
10 with the iodine centre untouched, which could not be
further oxidised using perborate or Koser’s reagent, while
with Oxone in the presence of trifluoroacetic acid the tert-
butanesulfoxide moiety was cleaved to form 11. Similarly,
the oxidation of precursor 6 with perborate led to sulfone
12 in 95% yield in 2.5 hours. Extended reaction times (12 h)
or further oxidation of 12 formed the cyclic iodine(III) com-
pound 13, which is chiral, but does no longer have a stereo-
genic sulfur centre. On the other hand, attempted oxidation
of 7 via iodine metathesis41,42 using Koser’s reagent led to
the cleavage of the tert-butanesulfoxide moiety and formed
salt 14.
A first set of sulfinamide-based precursors was easily
obtained from 2-iodobenzaldehyde (1) and (R)-tert-butane-
sulfinamide (2) (Scheme 1). Condensation of 1 and 2 in the
presence of excess Lewis acids such as titanium(IV) alkox-
ides33,34 or under iodine-catalysed solvent-free mechano-
chemical conditions35 provided imine 3 in high yields (95%
and 73%). Reduction of imine 3 with NaBH4 led to sulfin-
amide 4 in 93% yield,36 which was then converted into the
N-methyl derivative 5 upon treatment with NaH and io-
domethane. Addition of phenylmagnesium bromide to the
chiral imine 3 proceeded smoothly with a high degree of
stereochemical control delivering 6 as a single diastereomer
(dr >20:1) in 85% yield.37 The absolute configuration of
compound 6 was determined by X-ray crystallography.38
Treatment of 6 with NaH/MeI led to the N-methyl derivative
7 in 82% yield.
O
O
NaBO3•4H2O
O
N
S
3
I
t-Bu
AcO
8
CHO
O
O
S
Oxone
t-Bu
TFA
O
S
a) 5 equiv Ti(OEt)4
CH2Cl2, rt, 20 h
or
I
N
NaBO3•4H2O
NH
R
1
+
4, 5
R
N
t-Bu
I
I
I
O
S
b) ball mill (30 Hz)
11 R = Me, 70%
9
R = H, 90%
I2 (10 mol%)
3 a) 95%
b) 73%
10 R = Me, 86%
H2N
t-Bu
20 min
NaBH4
rt, 1 h
2
Ph
PhMgBr, CH2Cl2
–48 °C to rt
Ph
O
O
NaBO3
•4H2O
NaBO3
•4H2O
O
O
S
6
N
S
N
t-Bu
H
I
Ph
O
S
t-Bu
O
S
I
AcO
13 82%
N
R
t-Bu
N
R
t-Bu
12 95%
Ph
I
I
I
6 R = H, 85%
d.r. >20:1
4 R = H, 93%
PHI(OH)OTs
NH
Me
1.8 equiv NaH
5.7 equiv MeI
rt, 1 h
TsOH
7
5 R = Me, 84%
7 R = Me, 82%
14 83%
Scheme 1 Synthesis of sulfinamide-based chiral iodoarenes
Scheme 2 Oxidation of sulfinamide-based iodoarenes 3–7
To probe the potential of selective oxidation of the io-
dine centre without affecting the sensitive sulfoxide moi-
ety, precursors 3–7 were subjected to oxidation using vari-
ous oxidants and conditions. It is not surprising that the la-
bile sulfoxide group was not tolerated under most of the
oxidation protocols. Many oxidants typical for preparing io-
dine(III) compounds such as Selectfluor, Oxone, perborates,
and Koser’s reagent [PhI(OH)OTs] were investigated; in ad-
dition, anodic oxidation was also attempted.39,40 The iodine
precursors 3–7 were not reactive under many reaction con-
ditions, only sodium perborate oxidation was productive
(Scheme 2). Generally, the selective oxidation of the iodine
centre was not possible under the reaction conditions in-
vestigated and is either oxidised along with the sulfoxide
moiety or the latter is solely oxidised and hence the chirali-
ty is lost. Oxidation of the chiral imine 3 with sodium per-
In view of these results, we envisaged that a replace-
ment of the chiral sulfinamide moiety with a chiral sulfoxi-
mine would lead to chiral sulfur-based iodoarene deriva-
tives that could be oxidised to the corresponding hyperva-
lent iodine reagents without loss of chirality. Initially,
oxidation of compounds 3, 4, and 5 to the corresponding
sulfoximines was attempted. However, oxidations using
typical procedures such as [Rh2(OAc)4] and (diacetoxyio-
do)benzene43 or t-BuOCl44 in the presence of an amine were
unsuccessful and led to complex reaction mixtures. The 1H
NMR spectra of the crude reaction mixtures showed the ab-
sence of the t-Bu moiety suggesting that it cleaved under
these conditions. Also, the oxidation of (R)-N,2-dimethyl-
propane-2-sulfinamide with tBuOCl in the presence of ani-
line resulted in the formation of N-methyl-N-phenyl-sulf-
Synthesis 2021, 53, A–H

C
M. Elsherbini et al.
Special Topic
Synthesis
amide proved that the t-Bu group is not tolerated under the
reaction conditions used to convert sulfinamides into sulf-
oximines.
Me
O
O
Me
(S)-18
(S)-21
(S)-22
S
I
S
I
NaBO3•4H2O
NH
OAc
+
N
To avoid the difficulties encountered during the oxida-
tion of the above compounds, the synthesis of different
sulfoximine containing chiral iodoarenes was attempted
(Scheme 3). Relying on the oxidation of thioanisole (15) and
2-iodothioanisole (16) to sulfoximines 17 and 18 followed
by chiral resolution with (+)-camphorsulfonic acid (CSA),
the chiral sulfoximine derivatives (S)-17 and (S)-18 were
obtained and converted into the N-substituted derivatives
20–22 in high yields.
AcO
AcO
(S)-23
(S)-24
up to 81%
minor product
18, 22:
21:
Scheme 4 Oxidation of chiral sulfoximine-based iodoarenes 18, 21,
and 22
ray crystallography (Figure 2). Analysis of the X-ray data of
compound 24 showed a strong interaction (2.100 Å) be-
tween the sulfoximine nitrogen [(N(1)] and the iodine cen-
tre [I(1)], which is shorter than the iodine–oxygen bond
[I(1)–O(2), 2.249 Å]. The observed angle [N(1)–I(1)–O(2)] of
compound 24 (167.15°) is in the range of the distorted T-
shaped geometry characteristic to 3-iodanes.30,46
O
NH
0.5 equiv
(+)-CSA
2.3 equiv PhI(OAc)2
1.5 equiv (NH4)2CO3
S
R
S
R
Me
Me
MeOH
15 R = H
16 R = I
17 R = H, 92%
18 R = I, 68%
Br
O
NH
O
I
N
S
S
KOH
Me
Me
+
I
(S)-17
19
(S)-20 66%
O
S
NH
Me
O
N
R
KOH, EtBr
or
AcCl, Py
S
I
Me
I
(S)-21 R = Et, 81%
(S)-22 R = Ac, quant.
(S)-18
Figure 2 3D structure and absolute configuration the cyclic chiral sulf-
oximine-based hypervalent iodine reagent (S)-24
Scheme 3 Synthesis of iodoarene scaffolds with chiral sulfoximine
moieties
The oxidation of (S)-20 to the corresponding chiral hy-
pervalent iodine reagent using Selectfluor in the presence
of acetic acid was unsuccessful, leaving the starting materi-
al unreacted. Sodium perborate as oxidant or aerobic oxida-
tion in the presence of a CoCl2 catalyst45 led to complex re-
action mixtures with 2-iodobenzoic acid identified as one
of the products. Similar outcomes were obtained upon oxi-
dation of compounds (S)-18, (S)-21, and (S)-22 using Select-
fluor or the CoCl2-catalysed aerobic oxidation protocol.
With sodium perborate the formation of a cyclic chiral
hypervalent iodine reagent (S)-24 was observed as a major
product in the case of precursors (S)-18 and (S)-22 and as a
minor product in the case of precursor (S)-21 (Scheme 4).
The 1H NMR analysis of the crude reaction mixture showed
the formation of the hypervalent iodine reagent (S)-23
along with the cyclic product (S)-24 that is formed most
likely through cyclization of (S)-23.
In conclusion, various sulfur-based chiral iodoarenes
were synthesised starting with readily available chemicals.
Chiral iodoarenes containing sulfinamide units and com-
pounds containing sulfoximine unit have been prepared.
Oxidation of both categories to the corresponding chiral hy-
pervalent iodine reagents was cumbersome. All sulfin-
amide derivatives underwent overoxidation and, hence, the
chirality is lost. Chiral sulfoximine units are more robust
and cannot undergo further oxidation. However, the oxida-
tion of the sulfoximines to the corresponding chiral hyper-
valent iodine reagents was not easy due to the degradation
of some precursors. Only the oxidation of chiral 1-iodo-2-
(S-methylsulfonimidoyl)benzene derivatives was successful
and led to a cyclic chiral-at-sulfur iodine(III) reagent. Appli-
cations of sulfur-based chiral hypervalent iodine reagents
in stereoselective oxidative transformations are ongoing in
our laboratory.
The ratio of 23:24 varies with the reaction time and the
equivalents of sodium perborate, but 24 was the major
product in all cases. The non-cyclic product 23 was only de-
tected in the crude reaction mixture, but could not be iso-
lated, while the cyclic product 24 was isolated and crystal-
lised. The structure of (S)-24 was proven by single crystal X-
All starting materials were purchased from commercial suppliers and
used without further purification and all solvents used were dried
and purified by standard techniques. Reactions requiring the exclu-
sion of moisture were carried out under an atmosphere of argon or N2
Synthesis 2021, 53, A–H

D
M. Elsherbini et al.
Special Topic
Synthesis
in oven-dried glassware. Flash chromatography was carried out using
Merck silica gel (35–70 m) or on a Biotage Isolera Four platform us-
ing SNAP Ultra (25 m) cartridges. Melting points were recorded on a
Gallenkamp MPD350 apparatus. IR measurements were taken using a
PerkinElmer 1600 FTIR spectrometer. NMR spectra were recorded on
Bruker DPX 300, Bruker DPX 400, or Bruker DPX 500. 1H NMR spectra
were measured at 300, 400, and 500 MHz. 13C {1H} NMR spectra were
recorded at 75, 100, and 125 MHz using CDCl3 as the solvent and in-
ternal reference. Coupling constants J are given in hertz (Hz). Stan-
dard abbreviations were used for denoting multiplicity. High-resolu-
tion mass spectrometry (HRMS) was carried out using a Waters LCT
Premier XE mass spectrometer using electrospray ionisation (ESI).
Optical rotations were measured with a UniPol L polarimeter at 20 °C.
High-performance liquid chromatography (HPLC) analysis was con-
ducted using Shimadzu LC-10 AD coupled diode array-detector SPD-
MA-10A-VP.
(R)-N-(2-Iodobenzyl)-2-methylpropane-2-sulfinamide (4)
Sulfinamide 3 (1.71 g, 5.1 mmol) was dissolved in 98:2 THF:H2O (15
mL) and cooled down to 0 °C. NaBH4 (0.579 g, 15.32 mmol, 3 equiv)
was added and the resulting solution was warmed to rt and moni-
tored by TLC (7:3 hexane:EtOAc). After 1 h, the TLC showed the con-
sumption of the starting material. Then, H2O (20 mL) was added, and
the mixture was stirred at rt for 5 min. THF was evaporated off before
extracting with CH2Cl2 (3 × 10 mL). The combined CH2Cl2 layers were
dried (anhyd MgSO4) and evaporated off to give the crude product,
which was purified by flash chromatography (silica gel, 9:1 hex-
ane:EtOAc) to give the pure reduced imine 4 as a white solid; yield:
1.61 g (4.77 mmol, 93%); mp 134.6 °C; []D –15.45 (c 1.03, CHCl3).
IR (neat): 3194, 3059, 2976, 2360, 1583, 1564, 1436, 1363, 1074,
1040, 744, 428 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.85 (dd, J =7.9, 1.2 Hz, 1 H), 7.39 (dd,
J = 7.6, 1.8 Hz, 1 H), 7.34 (td, J = 7.4, 1.2 Hz, 1 H), 7.00 (td, J = 7.6, 1.8
Hz, 1 H), 4.42 (dd, J = 14.2, 5.4 Hz, 1 H), 4.29 (dd, J = 14.2, 7.7 Hz, 1 H),
3.58 (t, J = 5.6 Hz, 1 H), 1.24 (s, 9 H).
2-Iodobenzaldehyde (1)
Pyridinium chlorochromate (3.11 g, 14.45 mmol, 1.16 equiv) and
Celite (13.12 g, 21.84 mmol, 1.74 equiv) were dried under vacuum in
a 3-necked round-bottomed flask and then flushed with N2, and sus-
pended in anhyd CH2Cl2 (145 mL). A solution of 2-iodobenzyl alcohol
(2.92 g, 12.5 mmol) in anhyd CH2Cl2 (40 mL) was added dropwise at
rt. The reaction mixture turned from red to brown to black and is
stirred at rt overnight. After filtration through Celite, the solvent was
removed under reduced pressure. The crude product was purified by
flash chromatography (9:1 hexane:EtOAc); yield: 2.15 g (9.26 mmol,
74%); white solid; mp 37.3–37.4 °C (Lit.21 mp 37 °C).
13C NMR (101 MHz, CDCl3):  = 141.0, 139.9, 129.9, 129.6, 128.7, 99.5,
56.3, 54.1, 22.8.
The spectral data are in agreement with literature.45
(R)-N-(2-Iodobenzyl)-N,2-dimethylpropane-2-sulfinamide (5)
To a solution of the sulfinamide 4 (317 mg, 0.94 mmol) in anhyd THF
(5.5 mL) were added 60% NaH in mineral oil (68 mg, 1.69 mmol, 1.8
equiv) and MeI (760 mg, 0.33 mL, 5.36 mmol, 5.7 equiv). The reaction
mixture was stirred at rt under N2 for 1 h, and the solvent was re-
moved under reduced pressure. The residue was dissolved in Et2O (5
mL) and washed with H2O (5 mL). The aqueous phase was extracted
with Et2O (3 × 5 mL). The combined Et2O extracts were washed with
10% aq Na2S2O3 (5 mL) and H2O (5 mL), dried (MgSO4), filtered. The
filtrate was evaporated under vacuum to give methylated product 5 as
a pale-yellow oil; yield: 277 mg (0.79 mmol, 84%); []D +20.54 (c 0.73,
CHCl3).
1H NMR (400 MHz, CDCl3):  = 10.07 (s, 1 H), 7.96 (d, J = 7.9 Hz, 1 H),
7.89 (d, J = 7.7 Hz, 1 H), 7.47 (t, J = 7.5 Hz, 1 H), 7.29 (t, J = 7.6 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 196.0, 140.8, 135.6, 135.3, 130.4,
128.9, 100.9.
The spectral data are in agreement with literature.44
(R,E)-N-(2-Iodobenzylidene)-2-methylpropane-2-sulfinamide (3)
IR (neat): 2953, 2864, 2360, 2331, 1562, 1508, 1458, 1435, 1359,
A solution of 2-iodobenzaldehyde (1; 1.12 g, 4.82 mmol) and Ti(OEt)4
(5.05 mL) in anhyd CH2Cl2 (48 mL) was stirred for 5 min under N2.
Then, (R)-(+)-2-methyl-2-propanesulfinamide (2; 0.58 g, 4.82 mmol)
was added portionwise. The reaction mixture was stirred at rt for 20
h. Sat. aq NaHCO3 (30 mL) was added until white titanium salt
stopped precipitating. The suspension was filtered off a short pad of
Celite washing with small portions of EtOAc. The aqueous filtrate was
extracted with EtOAc and the combined organic layers were washed
with brine, dried (anhyd MgSO4), and concentrated in vacuo. The
crude product (yellow oil) was purified by flash chromatography (sili-
ca gel, 9:1 hexane:EtOAc) to give the pure sulfinamide 3 as a yellow
solid; yield: 1.53 g (4.58 mmol, 95%); mp 77.5–77.7 °C; []D –179.18
(c 1.23, CHCl3).
1068, 1012, 748, 432 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.81 (dd, J = 7.9, 1.1 Hz, 1 H), 7.39 (dd,
J = 7.7, 1.7 Hz, 1 H), 7.33 (td, J = 7.5, 1.2 Hz, 1 H), 6.95 (td, J = 7.8, 1.8
Hz, 1 H), 4.27 (d, J = 15.8 Hz, 1 H), 4.18 (d, J = 15.9 Hz, 1 H), 2.66 (s, 3
H), 1.18 (s, 9 H).
13C NMR (101 MHz, CDCl3):  = 139.8, 139.4, 129.2, 129.2, 128.5, 99.5,
77.4, 61.7, 58.8, 23.6.
HRMS (ESI+): m/z [M + H+] calcd for C12H19INOS: 352.0227; found:
352.0230.
(R)-N-[(S)-(2-Iodophenyl)(phenyl)methyl]-2-methylpropane-2-
sulfinamide (6)
IR (neat): 2956, 2360, 1577, 1554, 1460, 1074, 1012, 771, 740, 441
To a solution of the imine 3 (322 mg, 0.96 mmol) in CH2Cl2 (5.8 mL)
was added phenylmagnesium bromide (348 mg, 0.69 mL, 1.92 mmol,
2 equiv) at –48 °C. The reaction mixture was stirred at –48 °C for 6 h
and then allowed to warm to rt and stirred overnight. The mixture
was quenched with sat. aq NH4Cl (2 mL) and the aqueous layer was
extracted with EtOAc (3 × 3 mL). The combined organic layers were
dried (Na2SO4) and concentrated to provide the crude product, which
was purified by crystallization from hexane:CH2Cl2 (10:1) to give the
pure product 6 as colourless crystals; yield: 337 mg (0.82 mmol, 85%);
mp 145–146 °C; []D –68.14 (c 0.66, CHCl3).
cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.79 (s, 1 H), 7.99 (d, J = 7.8 Hz, 1 H),
7.94 (d, J = 7.9 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 1 H), 7.18 (t, J = 7.6 Hz, 1 H),
1.28 (s, 9 H).
13C NMR (101 MHz, CDCl3):  = 166.7, 140.5, 135.6, 133.5, 129.9,
128.6, 101.4, 58.2, 22.9.
The spectral data are in agreement with literature.34
IR (neat): 3213, 2981, 2962, 1560, 1494, 1465, 1448, 1357, 1033, 391
cm–1
.
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M. Elsherbini et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3):  = 7.85 (dd, J = 7.9, 1.2 Hz, 1 H), 7.56 (dd,
J = 7.8, 1.7 Hz, 1 H), 7.41–7.36 (m, 3 H), 7.33 (ddd, J = 7.4, 4.6, 1.4 Hz, 2
H), 7.30–7.26 (m, 1 H), 6.99 (td, J = 7.6, 1.7 Hz, 1 H), 5.97 (d, J = 2.8 Hz,
1 H), 3.73 (d, J = 2.4 Hz, 1 H), 1.25 (s, 9 H).
The combined organic layers were washed with brine (5 mL), dried
(anhyd MgSO4), filtered, and concentrated under pressure to give the
sulfonamide 9 as a pale-yellow solid; yield: 128 mg (0.36 mmol, 90%);
mp 77–78 °C.
13C NMR (101 MHz, CDCl3):  = 143.4, 141.2, 140.2, 129.5 (2 C), 129.0,
128.4, 128.2, 128.1, 100.1, 65.8, 56.2, 22.8.
IR (neat): 3277, 2976, 2879, 2360, 1683, 1456, 1436, 1398, 1300,
1112, 1010, 742, 511 cm–1
.
HRMS (ESI+): m/z [M + H+] calcd for C17H21INOS: 414.0383; found:
414.0382.
1H NMR (400 MHz, CDCl3):  = 7.83 (dd, J = 7.9, 1.2 Hz, 1 H), 7.47 (dd,
J = 7.7, 1.7 Hz, 1 H), 7.36 (td, J = 7.5, 1.2 Hz, 1 H), 7.01 (td, J = 7.6, 1.7
Hz, 1 H), 4.40 (d, J = 6.2 Hz, 2 H), 4.36–4.30 (m, 1 H), 1.41 (s, 9 H).
13C NMR (101 MHz, CDCl3):  = 140.3, 139.7, 130.1, 130.0, 129.0, 99.0,
(R)-N-[(S)-(2-Iodophenyl)(phenyl)methyl]-N,2-dimethylpropane-
2-sulfinamide (7)
60.3, 53.0, 24.5.
HRMS (ESI+): m/z [M + H+] calcd for C11H17INO2S: 354.0019; found:
354.0018.
To a solution of the sulfinamide 6 (413 mg, 1 mmol) in anhyd THF (6
mL) were added 60% NaH in mineral oil (72 mg, 1.8 mmol, 1.8 equiv)
and MeI (795 mg, 0.34 mL, 5.6 mmol, 5.6 equiv). The reaction mixture
was stirred at rt under N2 for 1 h, and the solvent was removed under
reduced pressure. The residue was dissolved in Et2O (5 mL) and
washed with H2O (5 mL). The aqueous phase was extracted with Et2O
(3 × 5 mL). The combined ether extracts were washed with 10% aq
Na2S2O3 (5 mL) and H2O (5 mL), dried (MgSO4), filtered, and the fil-
trate was evaporated under vacuum to give methylated product 7 as a
white solid; yield: 350 mg (0.82 mmol, 82%); mp 98–99 °C; []D
+88.11 (c 1.29, CHCl3).
N-(2-Iodobenzyl)-N,2-dimethylpropane-2-sulfonamide (10)
To a solution of sulfinamide 5 (140 mg, 0.4 mmol, 1 equiv) in glacial
AcOH (6 mL) was added NaBO3·4H2O (615 mg, 4 mmol, 10 equiv). The
reaction mixture was stirred at 40–45 °C. After 1 h, the TLC (hex-
ane:EtOAc 7:3) showed the consumption of the starting material. The
solvent was removed under reduced pressure and the white solid left
was partitioned between H2O (5 mL) and CH2Cl2 (5 mL). The two lay-
ers were separated, and the aqueous layer was extracted with CH2Cl2
(3 × 5 mL). The combined organic layers were washed with brine (5
mL) and dried (anhyd MgSO4), filtered, and concentrated under pres-
sure to give the sulfonamide 10 as a pale-yellow solid; yield: 126 mg
(0.34 mmol, 86%); mp 82–83 °C.
IR (neat): 2954, 2920, 1452, 1072, 565 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.87 (dd, J = 7.9, 1.2 Hz, 1 H), 7.56 (dd,
J = 7.8, 1.6 Hz, 1 H), 7.40 (td, J = 7.6, 1.2 Hz, 1 H), 7.31–7.25 (m, 3 H),
7.22–7.18 (m, 2 H), 6.99 (td, J = 7.6, 1.6 Hz, 1 H), 5.95 (s, 1 H), 2.60 (s, 3
H), 1.12 (s, 9 H).
IR (neat): 2360, 1695, 1581, 1436, 1317, 1261, 1120, 1016, 790, 511,
13C NMR (101 MHz, CDCl3):  = 142.4, 140.3, 138.7, 129.7, 129.6,
418 cm–1
.
129.4, 128.5, 128.5, 127.8, 101.2, 77.1, 59.1, 29.8, 24.2.
HRMS (ESI+): m/z [M + H+] calcd for C18H23INOS: 428.0540; found:
428.0535.
1H NMR (400 MHz, CDCl3):  = 7.82 (dd, J = 7.9, 1.2 Hz, 1 H), 7.55 (dd,
J = 7.8, 1.6 Hz, 1 H), 7.40 (td, J = 7.7, 1.2 Hz, 1 H), 6.99 (td, J = 7.8, 1.7
Hz, 1 H), 4.52 (s, 2 H), 2.90 (s, 3 H), 1.47 (s, 9 H).
13C NMR (101 MHz, CDCl3):  = 139.5, 138.3, 129.5, 129.1, 128.9, 98.8,
62.4, 59.8, 36.4, 25.2.
2-(tert-Butylsulfonyl)-3-oxo-2,3-dihydro-1H-13-benzo[d][1,2]-
iodazol-1-yl Acetate (8)
HRMS (ESI+): m/z [M + H+] calcd for C12H19INO2S: 368.0176; found:
To a solution of sulfinamide 3 (67 mg, 0.2 mmol) in glacial AcOH (4
mL) was added NaBO3·4H2O (312 mg, 2.0 mmol, 10 equiv). The reac-
tion mixture was stirred at 40–45 °C for 4 h. The solvent was removed
under reduced pressure and the white solid left was partitioned be-
tween H2O (5 mL) and CH2Cl2 (5 mL). The two layers were separated,
and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The com-
bined organic layers were washed with brine (5 mL) and dried (anhyd
MgSO4), filtered, and concentrated under pressure to give the crude
product 8 as a white solid, which was purified by recrystallisation
from hexane:AcOH (8:2) to obtain 8 as a white solid; yield: 73 mg
(0.17 mmol, 85%).
1H NMR (400 MHz, acetone-d6):  = 8.17 (dd, J = 7.6, 1.1 Hz, 1 H), 8.13
(d, J = 8.4 Hz, 1 H), 8.03 (t, J = 7.2 Hz, 1 H), 7.84 (t, J = 7.5 Hz, 1 H), 2.19
(s, 3 H), 1.54 (s, 9 H).
13C NMR (101 MHz, acetone-d6):  = 176.4, 163.2, 137.2, 134.5, 132.9,
132.0, 130.6, 117.8, 64.0, 25.1, 20.5.
368.0179.
1-(2-Iodophenyl)-N-methylmethanamine (11)
To a solution of 10 (43 mg, 0.12 mmol) in a mixture of trifluoroacetic
acid (1.2 mL) and CHCl3 (0.4 mL) was added Oxone (111 mg, 0.18
mmol, 1.5 equiv). The reaction mixture was stirred at rt and moni-
tored by TLC. After completion of reaction, the solvent was evaporat-
ed under vacuum and the residue was treated with CHCl3 (2 mL). The
insoluble residue of inorganic salts was collected by filtration, washed
with CHCl3 (2 mL), and discarded. Evaporation of combined CHCl3 lay-
ers under reduced pressure afforded amino compound 11 as a pale-
yellow oil; yield: 21 mg (0.0841 mmol, 70%).
IR (neat): 3014, 2818, 2742, 2358, 2331, 1778, 1670, 1176, 1138,
1014, 798, 756, 403 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.82 (dd, J = 8.0, 1.2 Hz, 1 H), 7.48 (dd,
J = 7.7, 1.6 Hz, 1 H), 7.33 (td, J = 7.6, 1.2 Hz, 1 H), 7.02 (td, J = 7.8, 1.6
Hz, 1 H), 3.79 (s, 2 H), 2.47 (s, 3 H).
N-(2-Iodobenzyl)-2-methylpropane-2-sulfonamide (9)
The spectral data are in agreement with literature.47
To a solution of sulfinamide 4 (135 mg, 0.4 mmol) in glacial AcOH (6
mL) was added NaBO3·4H2O (615 mg, 4 mmol, 10 equiv) and the reac-
tion mixture was stirred at 40–45 °C. After 1 h, the TLC (hexane:EtOAc
7:3) showed the consumption of the starting material. The solvent
was removed under reduced pressure and the white solid left was
treated with H2O (5 mL) and CH2Cl2 (5 mL). The two layers were sepa-
rated, and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL).
(S)-N-[(2-Iodophenyl)(phenyl)methyl]-2-methylpropane-2-sul-
fonamide (12)
To a solution of sulfinamide 6 (52 mg, 0.125 mmol) in glacial AcOH
(2.5 mL) was added NaBO3·4H2O (289 mg, 1.88 mmol, 15 equiv). The
reaction mixture was stirred at 40–45 °C. After 2.5 h, the TLC (hex-
Synthesis 2021, 53, A–H

F
M. Elsherbini et al.
Special Topic
Synthesis
ane:EtOAc 3:1) showed the consumption of the starting material. The
solvent was removed under reduced pressure and the white solid left
was treated with H2O (5 mL) and CH2Cl2 (5 mL). The two layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3 × 5
mL). The combined organic layers were washed with brine (5 mL) and
dried (anhyd MgSO4), filtered, and concentrated under pressure to
give the sulfonamide 12 as a white solid; yield: 51 mg (0.12 mmol,
95%).
1H NMR (300 MHz, CDCl3):  = 7.87 (dd, J = 7.9, 0.7 Hz, 1 H), 7.53–7.40
(m, 2 H), 7.36–7.19 (m, 5 H), 7.04 (ddd, J = 7.9, 6.7, 2.4 Hz, 1 H), 6.03
(d, J = 9.0 Hz, 1 H), 4.81 (d, J = 8.9 Hz, 1 H), 1.32 (s, 9 H).
1H NMR (400 MHz, CDCl3):  = 8.30 (d, J = 7.9 Hz, 1 H), 8.12 (d, J = 7.8
Hz, 1 H), 7.54 (t, J = 7.6 Hz, 1 H), 7.21 (t, J = 7.6 Hz, 1 H), 3.28 (s, 3 H),
2.75 (s, 1 H).
13C NMR (101 MHz, CDCl3):  = 145.6, 143.1, 133.9, 130.6, 129.0, 93.3,
42.6.
HRMS: m/z [M + H]+ calcd for [C7H9INOS]: 281.9444; found: 281.9452.
(+)-(S)-S-Methyl-S-phenylsulfoximine [(S)-17]
To a solution of racemic S-methyl-S-phenylsulfoximine (rac-17; 1.43
g, 9.2 mmol) in acetone (6 mL) was added a solution of (+)-camphor-
sulfonic acid (1.2 g, 5.1 mmol 0.55 equiv) in acetone (14 mL). The re-
action mixture was stirred at rt overnight. The formed precipitate
was collected by filtration and washed thoroughly with acetone. The
obtained solid was then suspended in CH2Cl2 (30 mL). Sat. aq K2CO3
(30 mL) was added with stirring. Stirring was continued at rt for 1 h.
The organic phase was separated, and the aqueous phase was extract-
ed with CH2Cl2 (3 × 10 mL). The combined organic layers were dried
(anhyd MgSO4) and evaporated to dryness affording pure (S)-17 as a
colourless oil that solidified after a few days; yield: 0.46 g (2.95 mmol,
32%).
(S)-2-(tert-Butylsulfonyl)-3-phenyl-2,3-dihydro-1H-13-benzo-
[d][1,2]iodazol-1-yl Acetate (13)
Compound 13 was prepared following the above procedure (for com-
pound 12) starting with 6 or 12 but using 12 h as reaction time lead-
ing to 13 as a white solid; yield: 40 mg (0.082 mmol, 82%); mp 144–
146 °C; []D +29.67 (c 0.4, CHCl3).
1H NMR (300 MHz, CDCl3):  = 7.90 (d, J = 9.4 Hz, 1 H), 7.50–7.46 (m, 1
H), 7.46–7.43 (m, 1 H), 7.42–7.38 (m, 1 H), 7.37–7.29 (m, 5 H), 6.23 (s,
1 H), 2.13 (s, 3 H), 1.26 (s, 9 H).
1H NMR (400 MHz, CDCl3):  = 8.04–7.99 (m, 1 H), 7.65–7.60 (m, 1 H),
7.58–7.53 (m, 1 H), 3.11 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 143.7, 140.7, 140.4, 129.6, 129.0,
128.9, 128.8, 128.00, 127.97, 99.1, 65.3, 60.3, 24.3.
(+)-(S)-S-Methyl-S-2-iodophenylsulfoximine [(S)-18]
(S)-1-(2-Iodophenyl)-N-methyl-1-phenylmethanamine 4-Methyl-
benzenesulfonate (14)
Obtained following the above procedure [for (S)-17], starting with ra-
cemic S-methyl-S-2-iodophenylsulfoximine (rac-18; 0.764 g, 2.72
mmol) and (+)-camphorsulfonic acid (0.32 g, 1.36 mmol 0.5 equiv).
Compound (S)-18 was obtained as a colourless oil that solidified after
a few days; yield: 0.36 mg (1.28 mmol, 47%); mp 63–65 °C; []D +30 (c
2.6, CHCl3).
1H NMR (400 MHz, CDCl3):  = 8.30 (d, J = 7.9 Hz, 1 H), 8.12 (d, J = 7.8
Hz, 1 H), 7.54 (t, J = 7.6 Hz, 1 H), 7.21 (t, J = 7.6 Hz, 1 H), 3.28 (s, 3 H),
2.75 (s, 1 H).
Koser’s reagent (42 mg, 0.11 mmol) was added to a stirred solution of
12 (50 mg, 0.12 mmol, 1.1 equiv) in anhyd CH2Cl2 (1 mL) at rt. The
reaction was stirred and monitored by TLC. After the completion of
the reaction, the solvent was removed under reduced pressure and
the solid residue was filtered and washed with Et2O several times,
then dried in vacuum to give 14 as a white solid; yield: 48 mg (0.114
mmol, 83%).
1H NMR (300 MHz, CD3OD):  = 8.02 (d, J = 7.80 Hz, 1 H), 7.70 (d, J =
8.02 Hz, 2 H), 7.66–7.57 (m, 1 H), 7.53–7.39 (m, 5 H), 7.23 (d, J = 7.78
Hz, 2 H), 7.20–7.13 (m, 1 H), 5.71 (s, 1 H), 2.72 (s, 3 H), 2.37 (s, 3 H),
1.15 (s, 1 H).
13C NMR (101 MHz, CDCl3):  = 145.6, 143.1, 133.9, 130.6, 129.0, 93.3,
42.6.
(S)-N-2-Iodobenzyl-S-methyl-S-phenylsulfoximine [(S)-20]
To a solution of (S)-S-methyl-S-phenylsulfoximine [(S)-17; 0.459 g,
2.95 mmol) in DMSO (1.5 mL) was added KOH (0.33 g, 5.9 mmol, 2.0
equiv). The reaction was stirred at rt under argon for 5 min. 2-Iodo-
benzyl bromide (19; 1.31 g, 4.42 mmol, 1.5 equiv) was added and stir-
ring was continued at rt overnight. The reaction was quenched by the
addition of H2O (5 mL) and the aqueous phase was extracted with
CH2Cl2 (3 × 5 mL). The organic layers were combined, dried (anhyd
MgSO4) and evaporated under reduced pressure. The crude product
was purified by column chromatography (hexane:EtOAc 9:1) afford-
ing pure (S)-20 as a dark yellow oil; yield: 0.73 g (1.95 mmol, 66%);
[]D +1.23 (c 0.6, CHCl3)
rac-S-Methyl-S-phenylsulfoximine (17)
To a solution of thioanisole 15 (1.24 g, 10.0 mmol) in MeOH (100 mL)
was added (NH4)2CO3 (1.50 g, 15.6 mmol, 1.5 equiv). After the dissolu-
tion of (NH4)2CO3, (diacetoxyiodo)benzene (7.43 g, 23.1 mmol, 2.3
equiv) was added. The reaction mixture was stirred at rt overnight,
then evaporated to dryness and purified by column chromatography
(hexane:EtOAc 1:1) affording pure 17 as a yellow oil that solidified af-
ter few days; yield: 1.43 g (9.20 mmol, 92%); mp 33–34 °C (Lit.48 mp
34–35 °C).
1H NMR (400 MHz, CDCl3):  = 8.05–8.00 (m, 2 H), 7.66–7.60 (m, 1 H),
7.59–7.53 (m, 2 H), 3.13 (s, 3 H).
The spectral data are in agreement with literature.49
IR (neat): 1445, 1221, 1140, 1011, 741, 689, 513 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.95 (d, J = 7.6 Hz, 2 H), 7.75 (d, J = 7.8
Hz, 1H), 7.67 (d, J = 7.6 Hz, 1 H), 7.62 (t, J = 7.2 Hz, 1 H), 7.56 (t, J = 7.5
Hz, 2 H), 7.33 (t, J = 7.4 Hz, 1 H), 6.91 (d, J = 7.5 Hz, 1 H), 4.15 (d, J =
15.5 Hz, 1 H), 4.05 (d, J = 15.5 Hz, 1 H), 3.20 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 143.0, 139.3, 139.1, 133.3, 129.7,
129.3, 128.8, 128.5, 128.4, 98.8, 52.4, 45.4.
rac-S-Methyl-S-2-iodophenylsulfoximine (18)
Prepared following the above procedure (for 17), starting with 2-io-
dothioanisole (16; 1.0 g, 4.0 mmol). Compound 18 was obtained as a
yellow oil that solidified after a few days; yield: 0.765 g (2.72 mmol,
68%); mp 64–66 °C.
HRMS: m/z calcd [M + H]+ for [C14H15INOS]: 371.9914; found:
371.9916.
IR (neat): 3287, 1564, 1422, 1314, 1204, 1080, 986, 932, 754, 700, 509
cm–1
.
Synthesis 2021, 53, A–H

G
M. Elsherbini et al.
Special Topic
Synthesis
(S)-N-Ethyl-S-methyl-S-2-iodophenylsulfoximine [(S)-21]
IR (neat): 3001, 2365, 1717, 1603, 1312, 1208, 991, 754 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.35 (d, J = 7.6 Hz, 1 H), 7.90 (dd, J = 7.0,
1.9 Hz, 1 H), 7.86–7.80 (m, 2 H), 3.40 (s, 3 H), 2.11 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 178.1, 134.4, 133.9, 132.3, 131.3,
128.2, 117.5, 47.7, 22.2.
To a solution of (S)-S-methyl-S-2-iodophenylsulfoximine [(S)-18;
0.168 g, 0.6 mmol] in DMSO (1.5 mL) was added KOH (90 mg, 1.6
mmol, 2.2 equiv). The reaction was stirred at rt under argon for 5 min.
EtBr (0.10 mL, 1.34 mmol, 2.1 equiv) was added and stirring was con-
tinued at rt overnight. The reaction was quenched by the addition of
H2O (5 mL) and the aqueous phase was extracted with CH2Cl2 (3 × 5
mL). The organic layers were combined, dried (anhyd MgSO4) and
evaporated under reduced pressure. The crude product was purified
by column chromatography (hexane:EtOAc 9:1) affording pure (S)-21
as a white solid; yield: 0.151 g (0.49 mmol, 81%); mp 53–55 °C; []D
+160 (c 5.9, CHCl3).
Conflict of Interest
The authors declare no conflict of interest
Funding Information
IR (neat): 2967, 2843, 2359, 1740, 1558, 1217, 1144, 1080, 1013, 750,
517 cm–1
.
We are grateful to the Erasmus program for the financial support and
a scholarship to A.O. We thank the government of Saudi Arabia and
the Northern Borders University, KSA, for the financial support and
scholarship to H.A. The authors are grateful to School of Chemistry,
1H NMR (400 MHz, CDCl3):  = 8.29 (dd, J = 7.9, 1.7 Hz, 1 H), 8.12 (dd,
J = 7.8, 1.2 Hz, 1 H), 7.56 (ddd, J = 7.9, 7.4, 1.2 Hz, 1 H), 7.24–7.20 (m, 1
H), 3.26 (s, 3 H), 2.94 (dq, J = 12.2, 7.2 Hz, 1 H), 2.78 (dq, J = 12.2, 7.2
Hz, 1 H), 1.21 (t, J = 7.2 Hz, 3 H).
Cardiff University, for the financial support and facilities.Erasmus+()Northern
B
orders
U
n
iversity()Sch
o
ol
o
f
C
h
emitsry, Card
i
f
U
n
iversiyt()
13C NMR (101 MHz, CDCl3):  = 143.1, 141.5, 133.8, 133.0, 129.2, 93.8,
42.1, 38.9, 18.0.
Acknowledgment
HRMS: m/z [M
+
H]+ calcd for [C9H13INOS]: 309.9757; found:
309.9751.
The authors are grateful to Dr Benson Kariuki, School of Chemistry,
Cardiff University, for X-ray crystallographic measurements.
(S)-N-Acetyl-S-methyl-S-2-iodophenylsulfoximine [(S)-22]
To a solution of (S)-S-methyl-S-2-iodophenylsulfoximine [(S)-18; 309
mg, 1.09 mmol] in CH2Cl2 (8 mL) at 0 °C was added pyridine (0.12 mL,
0.14 mmol, 1.3 equiv) followed by AcCl (77 L, 1.09 mmol). The reac-
tion mixture was stirred at 0 °C for 1 h, then allowed to warm to rt
and stirring was continued overnight. The reaction was quenched
with ice cold water (10 mL). The organic phase was separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were dried (anhyd MgSO4) and evaporated. The crude
product was purified by column chromatography (hexane:EtOAc 1:1)
affording pure (S)-22 as white crystals; yield: 348 mg (1.08 mmol,
99%); mp 137–139 °C; []D +11.5 (c 0.59 in CHCl3).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1508-9593. Su
p
p
ortingInformationS
u
p
p
ortingI
n
formati
o
n
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