Mechanochemical synthesis of N-tert-butanesulfinyl imines under metal-free conditions

Article abstract of DOI:10.1016/j.tet.2017.11.028

A simple and convenient mechanochemical method for the condensation of aldehydes with tert-butanesulfinamide using catalytic amounts of iodine under metal- and solvent-free conditions is described.

Full text of DOI:10.1016/j.tet.2017.11.028

Accepted Manuscript
Mechanochemical synthesis of N-tert-butanesulfinyl imines under metal-free
conditions
Mohamed Elsherbini, Thomas Wirth
PII:
S0040-4020(17)31176-6
10.1016/j.tet.2017.11.028
TET 29108
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 September 2017
Revised Date: 6 November 2017
Accepted Date: 10 November 2017
Please cite this article as: Elsherbini M, Wirth T, Mechanochemical synthesis of N-tert-butanesulfinyl
imines under metal-free conditions, Tetrahedron (2017), doi: 10.1016/j.tet.2017.11.028.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Mechanochemical Synthesis of N-tert-
Butanesulfinyl Imines Under Metal-Free
Conditions
Leave this area blank for abstract info.
Mohamed Elsherbini and Thomas Wirth
School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK

ACCEPTED MANUSCRIPT
Graphical Abstract
Mechanochemical Synthesis of N-tert-
Butanesulfinyl Imines Under Metal-Free
Conditions
Leave this area blank for abstract info.
Mohamed Elsherbini and Thomas Wirth
School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Mechanochemical Synthesis of N-tert-Butanesulfinyl Imines Under Metal-Free
Conditions
Mohamed Elsherbinia and Thomas Wirtha,
a School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and convenient mechanochemical method for the condensation of aldehydes with tert-
butanesulfinamide using catalytic amounts of iodine under metal- and solvent-free conditions is
described.
2009 Elsevier Ltd. All rights reserved
.
Available online
Keywords:
Mechanochemistry
Sulfinylimines
Iodine
Sulfinamides
Ball mill
———
Corresponding author. Tel.: +44-2920-876-968; e-mail: wirth@cf.ac.uk

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
Table 1. Optimization of the reaction conditions
Chiral N-sulfinyl imines are valuable synthetic intermediates
that undergo diverse transformations with a high degree of
stereoselectivity. Some examples are the palladium-catalyzed α-
allylation of ketones,1 asymmetric fluoroalkylation,2 diastereo-
selective alkylation,3,4 asymmetric Strecker synthesis,5 and
asymmetric synthesis of amine derivatives such as α- and β-
aminophosphonic acids,6 α- and β-amino acids,7 α-branched
amines,8,9 and aziridines.10 They also find applications in the total
synthesis of natural products and biologically active molecules.11-
O
O
S
catalyst
CHO
S
+
R
H2N
R
N
ball mill
1
2
3
Noa
Catalyst
Catalyst
Time
[min]
Conversion
[%]b
[mol%]
-----
10
10
10
10
10
10
10
10
10
10
2
1c
2
------
I2
60
15
15
15
15
15
15
15
20
25
30
20
20
20
20
20
47
80
18
16
20
16
12
31
84
81
80
55
80
81
80
83
13
Chiral N-sulfinyl imines are the condensation products of
carbonyl compounds with commercially available chiral
sulfinamides such as p-toluenesulfinamide and tert-
butanesulfinamide. However, such condensations typically
require the utilization of excess amounts (2-5 equivalents) of
metal reagents such as Ti(IV) derivatives and CuSO4 that act as
Lewis acids and dehydrating agents at the same time.14-16
3
CuBr
CuI
4
5
ZnCl2
ZnF2
6
7
Cu(OAc)2
Lately, mechanochemistry is gaining increased attention of
synthetic chemists and is becoming a useful tool in some
laboratories rather than being a side-line in organic synthesis.
Mechanochemistry typically provides a solvent-free and, hence,
green alternative to the conventional solution-based chemistry.
Mechanochemical reactions are often cleaner, rapid and the
workup is usually simple.17-28 These advantages of
mechanochemistry promoted us to investigate the condensation
of tert-butanesulfinamide with carbonyl compounds under
grinding conditions as a metal-free, solvent-free and greener
approach for accessing the synthetically valuable tert-
butanesulfinyl imines.
8
Cu(OTf)2
9
I2
I2
I2
I2
I2
I2
I2
I2
10
11
12
13
14
15
16d
5
12
15
10
2. Results and Discussion
a PhCHO (0.5 mmol), t-Bu-sulfinamide (0.5 mmol), Retsch MM400 ball mill,
We initially examined the condensation of 2-
iodobenzaldehyde with (R)-(+)-2-methyl-2-propanesulfinamide
[(R)-(+)-tert-butanesulfinamide] under solvent free conditions
using agate mortar and pestle without any additives. Under these
conditions, there was no reaction observed even after grinding for
one hour. Repeating the reaction in presence of iodine (1
equivalent) lead to the formation of the desired sulfinylimine
5 mL stainless steel jar, one 10 mm stainless steel ball, 30 Hz; b Determined
1
c
by H NMR of the crude mixture; Performed with agate mortar and pestle:
0% conversion; d Na2SO4 (1 eq) was added.
With the optimized reaction conditions we studied the scope
of the reaction using different aldehydes by varying electronic
and steric properties (Table 2). Aromatic, heteroaromatic and
aliphatic aldehydes afforded the corresponding sulfinylimines in
moderate to excellent yields, while paraformaldehyde showed no
reactivity at all. Under the same conditions neither acetophenone
nor 2,2,2-trifluoroacetophene were converted to the
corresponding sulfinylimines indicating that ketones are
unreactive under these conditions. This could be considered as a
limitation of this methodology, but shows that the reaction is
selective for aldehydes, which is beneficial especially with
complex molecules having different carbonyl functionalities.
Most of the aldehyde substrates were used without purification
but the purification of the aldehydes prior to the reaction had a
great impact on the reaction yield as expected, where the yields
of the products 3k, 3q, 3t, and 3u for example is significantly
increased upon purification of the starting materials. We noticed
that electronic factors affect the reaction outcome more than
steric factors. Aromatic aldehydes with an electron-withdrawing
group such as 4-nitrobenzaldehyde and 4-cyanobenzaldehyde
gave the corresponding products in low yields. This could be
attributed to the reactivity of the formed sulfinylimines and that
iodine also can catalyze the backward reaction. To test this
hypothesis, we performed the reaction of 4-cyanobenzaldehyde
and 4-nitrobenzaldehyde under the optimized condition
conditions but reducing the reaction time from 20 to 10 minutes.
This reduction in the reaction time showed an increase in the
yield of 4-cyanobenzaldehyde (49% to 76%), while no effect was
observed with 4-nitrobenzaldehyde. By reducing the reaction
1
(80% H NMR conversion) in 20 minutes. After finding that this
condensation is possible mechanochemically without a metal
catalyst, we started a systematic study of the reaction with
benzaldehyde and racemic tert-butanesulfinamide using a ball
mill (Retsch MM400 ball mill at 30 Hz). We found that in
contrast to grinding using a mortar and pestle, the reaction
proceeds without any catalyst in the ball mill (table 1, entry 1).
Addition of 10 mol% of iodine enhanced the reaction (80%
conversion) in 15 minutes (Table 1, entry 2). We examined
different copper and zinc salts as catalysts for this reaction (Table
1, entries 3-8), but none of these catalysts was as efficient as
iodine. Increasing the reaction time from 15 to 20 minutes lead to
a slight enhancement of the yield, but any further increase of the
reaction time (> 20 min) led to a slight decrease in the reaction
yield (Table 1, entries 9-11). Decreasing the iodine loading from
10 mol% to 2 mol% lead to a significant decrease in the
conversion of benzaldehyde to the desired sulfinylimine, while
increasing the catalyst loading over 10% showed no significant
effect on the reaction outcome (Table 1, entries 12-15). Addition
of anhydrous sodium sulfate (1 equivalent) had no impact on the
reaction outcome (Table 1, entry 16). From these results, we
conclude that the optimum reaction conditions are milling the
substrates in the presence of 10 mol% of iodine as a catalyst for
20 minutes.

3
time in the case of 4-nitrobenzaldehyde to only two minutes, the
yield of the product 3p increased from 40% (20 min reaction
time) to 53% proving our hypothesis.
sulfinylimine products 3z-1 and 3z-2 in a 1:1 ratio as indicated
ACCEPTED MANUSCRIPT
by the 1H NMR of the crude mixture. The two isomeric products
were isolated by flash column chromatography (10% EtOAc/n-
hexane). The compound of the lower Rf (0.25) (3z-2) was
characterized as the product of the trans-citral as its NOESY
spectrum showed a NOE signal between the azomethine proton
and the nearby methyl group. This NOE signal is absent in the
NOESY spectrum of the product with the higher Rf (0.31)
indicating that the product 3z-1 has the Z-configuration.
In case of the 1,3-isophthaldicarboxaldehyde the starting
material was quantitatively converted into products giving the
bissufinylimine 3r as major product (85%) in addition to 3s in
14%. The condensation of citral (cis/trans mixture) with (R)-1
lead to the formation of the two-corresponding isomeric
O
S
O
S
O
S
O
S
O
S
OH
O
S
HO
N
N
N
N
N
N
NO2
I
Br
(R)-3c, 86% (50%)c
3d, 40%b
3f, 68%
(R)-3a, 73%
(S)-3b, 57% (93%)a
3e, 46 (90%)a
O
O
O
S
O
O
S
S
N
MeO
S
F
S
O
O
N
N
N
N
MeO
3g, 33%b
(R)-3i, 73%b
(R)-3j, 51% (88%)a
(R)-3k, 81% (56%)b
3h, 54%b
O
S
O
O
S
O
S
O
S
N
S
N
N
N
N
O2N
MeS
Cl
NC
3l, 65%b
3m, 30%b
(R)-3n, 65%
(R)-3o, 49% (76%)c
(R)-3p, 40% (53%)d
O
O
S
O
S
O
S
O
S
O
S
N
OHC
S
O
N
N
N
N
N
(R)-3q, 85% (56%)b
(R)-3r, 85%
(R)-3s, 14%
(R)-3t, 93% (36%)b
(R)-3u, 56% (17%)b
O
O
O
S
N
O
S
O
S
S
S
S
N
N
N
MeS
N
(R)-(Z)-3z-1, 72%b
(R)-(E)-3z-2, 65%b
(rac)-3v, 30%b
(R)-3w, 40%b
(R)-3x, 70%b
(R)-3y, 84%b
Table 2. Substrate scope of the mechanochemical condensation of aldehydes and tert-butanesulfinamide.
a Yield calculated based on the recovered aldehyde; b Aldehyde used without purification; c reaction time 10 min; d reaction time 2 min.
Commercially available aldehydes were used in all reactions
without purification unless specifically indicated. The
mechanochemical reactions are performed in Retsch MM400
vibrating mill at a frequency of 30 Hz in a stainless steel 10 mL
vial with one steel ball of 10 mm diameter. Thin-layer
chromatography (TLC) was performed on pre-coated aluminium
sheets of Merck silica gel 60 F254 (0.20 mm) and visualized by
UV radiation (254 nm). Automated column chromatography was
performed on a Biotage® Isolera Four using Biotage® cartridges
SNAP Ultra 10 g. 1H NMR and 13C NMR spectra were measured
on Bruker DPX 300, 400 or 500 apparatus and were referenced to
the residual proton solvent peak (1H: CDCl3, δ 7.26 ppm) and
solvent 13C signal (CDCl3, δ 77.2 ppm). Chemical shifts δ were
reported in ppm, multiplicity of the signals was declared as
followed: s = singlet, d = doublet, t = triplet, q = quartet, quin =
quintet, sex = sextet, hep = septet, dd = doublet of doublets, m =
multiplet, b = broad; and coupling constants (J) in Hertz. Mass
spectrometric measurements were performed by the EPSRC
Mass Spectrometry Facility in Swansea University on a Waters
Xevo G2-S. Ions were generated by the Atmospheric Pressure
3. Conclusion
In summary, we have developed a simple, rapid, efficient, and
green method for the introduction of the valuable chiral auxiliary
tert-butansulfinamide into aldehydes under metal- and solvent-
free reaction conditions. The reaction is performed using a ball
mill and catalyzed by 10 mol% iodine. The reaction is applicable
to a wide range of aldehydes and shows good function group
tolerance.
Synthetic organic chemists should pay more attention to
mechanochemistry as a promising, efficient, simpler and greener
alternative to the conventional solution-based chemistry. There is
an urgent need for developing elegant engineering solutions to
make mechanochemistry more reliable and to open a window on
monitoring the reaction during its progress.
4. Experimental section
4.1. General

4
Tetrahedron
ACCEPTED MANUSCRIPT
Ionisation Techniques (APCI). The molecular ion peaks values
mg, 0.5 mmol) and iodine (13 mg, 0.05 mmol). The crude
product was purified by flash chromatography (17% EtOAc/n-
hexane) to give 3e (59 mg, 46%) as a yellow solid; δH (400 MHz,
CDCl3) 8.99 (s, 1H), 8.07 – 7.98 (m, 2H), 7.73 (ddd, J = 7.7, 1.3,
0.6 Hz, 1H), 7.66 (td, J = 7.8, 1.5 Hz, 1H), 1.30 (s, 9H).
quoted for molecular ion plus hydrogen [M+H]+. IR spectra were
recorded on
a
Shimadzu FTIR Affinity-1S apparatus.
Wavenumbers are quoted in cm–1. All compounds were measured
neat directly on the crystal of the IR machine.
4.2. Typical procedure for ball milling imine formation
4.8. N-(3-Hydroxybenzylidene)-2-methylpropane-2-sulfinamide
[3f]33
A mixture of 2-methyl-2-propanesulfinamide (0.5 mmol, 1
eq), the appropriate aldehyde (0.5 mmol, 1 eq), and elemental
iodine (10 mol%) was placed in a 5 mL grinding steel jar and
milled for 20 min at 30 Hz. The reaction mixture was dissolved
in dichloromethane (20 mL) and washed with a saturated solution
of Na2S2O8 (10 mL), then with brine (10 mL). The organic phase
was dried over anhydrous MgSO4, filtered and evaporated under
reduced pressure. The residue was purified by flash column
chromatography.
The
general
procedure
was
followed
using
3-
hydroxybenzaldehyde (61 mg, 0.5 mmol), (rac)-2-methyl-2-
propanesulfinamide (61 mg, 0.5 mmol), and iodine (13 mg, 0.05
mmol). The crude product was purified by flash chromatography
(20% EtOAc/n-hexane) to give 3f (77 mg, 63%) as a white solid;
δH (400 MHz, CDCl3) 8.59 (s, 1H), 7.46 (dt, J = 7.6, 1.1 Hz, 1H),
7.41 (dd, J = 2.5, 1.5 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.05 (ddd,
J = 8.1, 2.6, 1.0 Hz, 1H), 1.28 (s, 9H).
4.9. N-(3-Methoxybenzylidene)-2-methylpropane-2-sulfinamide
4.3. (R)-(–)-N-(Benzylidene)-2-methylpropane-2-sulfinamide
[3g]34
[(R)-3a]14,15,29
The general procedure was followed using m-anisaldehyde (68
mg, 61 ꢀL, 0.5 mmol), (rac)-2-methyl-2-propanesulfinamide (61
mg, 0.5 mmol) and iodine (13 mg, 0.05 mmol). The crude
product was purified by flash chromatography (17% EtOAc/n-
hexane) to give 3g (40 mg, 33%) as a colourless oil; δH (400
MHz, CDCl3) 8.55 (s, 1H), 7.44 – 7.34 (m, 3H), 7.10 – 7.03 (m,
1H), 3.86 (s, 3H), 1.26 (s, 9H).
The general procedure was followed using benzaldehyde (53.1
mg, 51 ꢀL, 0.5 mmol), (R)-(+)-2-methyl-2-propanesulfinamide
(61 mg, 0.5 mmol) and iodine (13 mg, 0.05 mmol). The crude
product was purified by flash chromatography (17% EtOAc/n-
hexane) to give (R)-3a (77 mg, 73%) as a colourless solid; [α]D
= –213 (c 0.67, CHCl3); δH (400 MHz, CDCl3) 8.59 (s, 1H), 7.89
20
– 7.79 (m, 2H), 7.55 – 7.43 (m, 3H), 1.27 (s, 9H).
4.10. N-(3-Methylbenzylidene)-2-methylpropane-2-sulfinamide
4.4. (R)-(+)-N-(2-Iodobenzylidene)-2-methylpropane-2-
[3h]35
sulfinamide [(S)-3b]2
The general procedure was followed using m-tolualdehyde (60
mg, 59 ꢀL, 0.5 mmol), (rac)-2-methyl-2-propanesulfinamide (61
mg, 0.5 mmol) and iodine (13 mg, 0.05 mmol). The crude
product was purified by flash chromatography (14% EtOAc/n-
hexane) to give 3h (60 mg, 54%) as a colourless oil; δH (400
MHz, CDCl3) 8.56 (s, 1H), 7.67 (s, 1H), 7.64 (d, J = 7.2 Hz, 1H),
7.36 (dd, J = 9.1, 5.7 Hz, 1H), 7.34 – 7.31 (m, 1H), 2.41 (s, 3H),
1.27 (s, 9H).
The general procedure was followed using 2-iodobenzaldehyde
(116 mg, 0.5 mmol), (S)-(-)-2-methyl-2-propanesulfinamide (61
mg, 0.5 mmol) and iodine (13 mg, 0.05 mmol). The crude
product was purified by flash chromatography (10% EtOAc/n-
20
hexane) to give (S)-3b (96 mg, 57%) as a yellowish solid; [α]D
= 164 (c 0.77, CHCl3); δH (400 MHz, CDCl3) 8.78 (s, 1H), 7.99
(dd, J = 7.8, 1.7 Hz, 1H), 7.94 (dd, J = 8.0, 1.1 Hz, 1H), 7.47 –
7.37 (m, 1H), 7.18 (ddd, J = 7.9, 7.4, 1.8 Hz, 1H), 1.28 (s, 9H).
4.11. (R)-(–)-N-(3-Fluorobenzylidene)-2-methylpropane-2-
4.5. (R)-(–)-N-(2-Bromobenzylidene)-2-methylpropane-2-
sulfinamide [(R)-3i]36
sulfinamide [(R)-3c]29,30
The general procedure was followed using 3-fluorobenzaldehyde
(62 mg, 53 ꢀL, 0.5 mmol), (R)-(+)-2-methyl-2-propanesulfin-
amide (61 mg, 0.5 mmol) and iodine (13 mg, 0.05 mmol). The
crude product was purified by flash chromatography (11%
EtOAc/n-hexane) to give (R)-3i (83 mg, 73%) as a colourless oil;
[α]D20 = –4 (c 0.5, CHCl3); δH (400 MHz, CDCl3) 8.56 (d, J = 1.3
Hz, 1H), 7.63 – 7.55 (m, 2H), 7.46 (ddd, J = 11.2, 6.7, 3.1 Hz,
1H), 7.25 – 7.18 (m, 1H), 1.27 (s, 9H).
The general procedure was followed using purified 2-
bromobenzaldehyde (93 mg, 59 ꢀL, 0.5 mmol), (R)-(+)-2-
methyl-2-propanesulfinamide (61 mg, 0.5 mmol) and iodine (13
mg, 0.05 mmol). The crude product was purified by flash
chromatography (14% EtOAc/n-hexane) to give (R)-3c (124 mg,
86%) as a colourless oil; [α]D20-227 (c 0.7, CHCl3); δH (500 MHz,
CDCl3) 8.98 (s, 1H), 8.04 (dd, J = 7.7, 1.9 Hz, 1H), 7.65 (dd, J =
7.7, 1.9 Hz, 1H), 7.43 – 7.30 (m, 2H), 1.28 (s, 9H).
4.12. (R)-(–)-N-(Benzo[d][1,3]dioxol-5-ylmethylene)-2-
4.6. N-(2-Hydroxybenzylidene)-2-methylpropane-2-sulfinamide
methylpropane-2-sulfinamide [(R)-3j]36
[3d]31
The general procedure was followed using piperonal (75 mg, 0.5
mmol), (R)-(+)-2-methyl-2-propanesulfinamide (61 mg, 0.5
mmol) and iodine (13 mg, 0.05 mmol). The crude product was
purified by flash chromatography (20% EtOAc/n-hexane) to give
The general procedure was followed using salicylaldehyde (61.1
mg, 53 ꢀL, 0.5 mmol), (rac)-2-methyl-2-propanesulfinamide (61
mg, 0.5 mmol) and iodine (13 mg, 0.05 mmol). The crude
product was purified by flash chromatography (20% EtOAc/n-
hexane) to give 3d (45 mg, 40%) as a white solid; δH (500 MHz,
CDCl3) 11.04 (s, 1H), 8.70 (s, 1H), 7.52 – 7.38 (m, 2H), 7.06 –
6.93 (m, 2H), 1.26 (s, 9H).
20
(R)-3j (65 mg, 51%) as a white solid; [α]D = –18 (c 0.66,
CHCl3); δH (400 MHz, CDCl3) 8.44 (s, 1H), 7.40 (d, J = 1.6 Hz,
1H), 7.28 (dd, J = 8.0, 1.6 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.05
(q, J = 1.3 Hz, 2H), 1.24 (s, 9H).
4.7. N-(2-Nitrobenzylidene)-2-methylpropane-2-sulfinamide
[3e]32
4.13. (R)-(–)-N-(4-Methoxybenzylidene)-2-methylpropane-2-
sulfinamide [(R)-3k]14,15
The general procedure was followed using 2-nitrobenzaldehyde
The general procedure was followed using purified p-
anisaldehyde (68 mg, 61 ꢀL, 0.5 mmol), (R)-(+)-2-methyl-2-
(76 mg, 0.5 mmol), (rac)-2-methyl-2-propanesulfinamide (61

5
20
propanesulfinamide (61 mg, 0.5 mmol) and iodine (13 mg, 0.05
mmol). The crude product was purified by flash chromatography
(20% EtOAc/n-hexane) to give (R)-3k (97 mg, 81%) as a white
yellow oil; [α]D = –6 (c 0.66, CHCl3); δH (400 MHz, CDCl3)
ACCEPTED MANUSCRIP
T
9.16 (s, 1H), 9.04 (d, J = 8.3 Hz, 1H), 8.08 – 7.99 (m, 2H), 7.93
(d, J = 7.6 Hz, 1H), 7.65 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H), 7.62 –
7.54 (m, 2H), 1.33 (s, 9H).
20
solid; [α]D = –68 (c 0.73, CHCl3); δH (400 MHz, CDCl3) 8.51
(s, 1H), 7.85 – 7.73 (m, 2H), 7.01 – 6.92 (m, 2H), 3.87 (s, 3H),
1.25 (s, 9H).
4.20. (R,R)-(–)-N,N’-Bis-(tert-butylsulfinyl)-isophthaldimine
[(R)-3r]40
4.14. N-(4-Isopropylbenzylidene)-2-methylpropane-2-sulfinamide
[3l]37
The general procedure was followed using isophthalaldehyde (34
mg, 0.25 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (61 mg,
0.5 mmol) and iodine (13 mg, 0.05 mmol). The crude product
was purified by flash chromatography (20% EtOAc/n-hexane) to
give (R)-3r (Rf = 0.24) (72 mg, 85%) as a white solid; [α]D20 = –
28 (c 0.50, CHCl3); δH (500 MHz, CDCl3) 8.65 (s, 2H), 8.31 (t, J
= 1.5 Hz, 1H), 8.00 (dd, J = 7.7, 1.7 Hz, 2H), 7.61 (dd, J = 9.5,
5.8 Hz, 1H), 1.29 (s, 18H).
The general procedure was followed using cuminaldehyde (74
mg, 76 ꢀL, 0.5 mmol), (rac)-2-methyl-2-propanesulfinamide (61
mg, 0.5 mmol) and iodine (13 mg, 0.05 mmol). The crude
product was purified by flash chromatography (14% EtOAc/n-
hexane) to give 3l (82 mg, 65%) as a colourless oil; δH (400
MHz, CDCl3) 8.56 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.33 (d, J =
8.3 Hz, 2H), 2.96 (hept, J = 6.9 Hz, 1H), 1.27 (s, J = 6.9 Hz, 6H),
1.26 (s, 9H).
4.21. (R)-(–)-N-(3-Formylbenzylidene)-2-methylpropane-2-
sulfinamide [(R)-3s]
4.15. N-(4-(Methylthio)benzylidene)-2-methylpropane-2-
sulfinamide [3m]38
Isolated as a colorless oil (8 mg, 14%) from the crude mixture of
the previous reaction (isophthalaldehyde reaction) by flash
chromatography (20% EtOAc/n-hexane) (Rf = 0.31); [α]D20 = –68
(c 0.50, CHCl3); IR (neat) νmax 3024, 2970, 1737, 1700, 1604,
1084 cm–1; δH (500 MHz, CDCl3) 10.09 (s, 1H), 8.66 (s, 1H),
8.35 (t, J = 1.5 Hz, 1H), 8.09 (dt, J = 7.7, 1.4 Hz, 1H), 8.06 –
7.99 (m, 1H), 7.67 (dd, J = 9.6, 5.7 Hz, 1H), 1.28 (m, 9H); δC
(126 MHz, CDCl3) 191.5, 161.7, 137.1, 135.1, 135.0, 132.8,
130.4, 129.9, 58.2, 22.8; HRMS (ASAP): MH+, found 238.0900.
C12H16NO2S requires 238.0902.
The
general
procedure
was
followed
using
4-
(methylthio)benzaldehyde (76 mg, 67 ꢀL, 0.5 mmol), (rac)-2-
methyl-2-propanesulfinamide (61 mg, 0.5 mmol) and iodine (13
mg, 0.05 mmol). The crude product was purified by flash
chromatography (14% EtOAc/n-hexane) to give 3m (38 mg,
30%) as a colourless oil; δH (400 MHz, CDCl3) 8.52 (s, 1H), 7.77
– 7.72 (m, 2H), 7.31 – 7.27 (m, 2H), 2.52 (s, 3H), 1.25 (s, 9H).
4.16. (R)-(–)-N-(4-Chlorobenzylidene)-2-methylpropane-2-
sulfinamide [(R)-3n]15,36
4.22. (R)-2-Methyl-N-((1E,2E)-3-phenylallylidene)propane-2-
sulfinamide [(R)-3t]15,39
The general procedure was followed using 4-chlorobenzaldehyde
(70 mg, 0.5 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (61
mg, 0.5 mmol) and iodine (13 mg, 0.05 mmol). The crude
product was purified by flash chromatography (10% EtOAc/n-
hexane) to give (R)-3n (79 mg, 65%) as a white solid; [α]D = –
68 (c 0.73, CHCl3); δH (400 MHz, CDCl3) 8.54 (s, 1H), 7.83 –
The general procedure was followed using trans-cinnamaldehyde
(66 mg, 63 ꢀL, 0.5 mmol), (R)-(+)-2-methyl-2-propanesulfin-
amide (61 mg, 0.5 mmol) and iodine (13 mg, 0.05 mmol). The
crude product was purified by flash chromatography (17%
EtOAc/n-hexane) to give (R)-3t (109 mg, 93%) as a yellow solid;
[α]D20 = –142 (c 0.70, CHCl3); δH (400 MHz, CDCl3) 8.38 (d, J =
9.2 Hz, 1H), 7.58 – 7.51 (m, 2H), 7.44 – 7.36 (m, 3H), 7.25 (t, J
= 7.9 Hz, 1H), 7.09 (dd, J = 15.9, 9.2 Hz, 1H), 1.24 (s, 9H).
20
7.74 (m, 2H), 7.49 – 7.40 (m, 2H), 1.26 (s, 9H).
4.17. (R)-(–)-N-(4-Cyanobenzylidene)-2-methylpropane-2-
sulfinamide [(R)-3o]38
4.23. (R)-N-(Furan-2-ylmethylene)-2-methylpropane-2-
sulfinamide [(R)-3u]14,15
The general procedure was followed using 4-cyanobenzaldehyde
(66 mg, 0.5 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (61
mg, 0.5 mmol) and iodine (13 mg, 0.05 mmol). The crude
product was purified by flash chromatography (17% EtOAc/n-
hexane) to give (R)-3o (57 mg, 49%) as a white solid; [α]D = –
70 (c 0.77, CHCl3); δH (400 MHz, CDCl3) 8.6 (s, 1H), 7.98 –
The general procedure was followed using purified furfural
(48 mg, 41
ꢀL, 0.5
mmol), (R)-(+)-2-methyl-2-
20
propanesulfinamide (61 mg, 0.5 mmol) and iodine (13 mg, 0.05
mmol). The crude product was purified by flash chromatography
(14% EtOAc/n-hexane) to give (R)-3u (62 mg, 62%) as a
7.91 (m, 2H), 7.80 – 7.72 (m, 2H), 1.26 (s, 9H).
20
colourless oil; [α]D = –228 (c 0.67, CHCl3); δH (400 MHz,
4.18. (R)-(–)-N-(4-Nitrobenzylidene)-2-methylpropane-2-
CDCl3) 8.40 (s, 1H), 7.64 (dd, J = 1.1, 0.6 Hz, 1H), 7.01 (dd, J =
3.5, 0.5 Hz, 1H), 6.57 (dd, J = 3.5, 1.8 Hz, 1H), 1.26 (s, 9H).
sulfinamide [(R)-3p]30
The general procedure was followed using 4-nitrobenzaldehyde
(76 mg, 0.5 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (61
mg, 0.5 mmol) and iodine (13 mg, 0.05 mmol). The crude
product was purified by flash chromatography (17% EtOAc/n-
hexane) to give (R)-3p (51 mg, 40%) as a yellow solid; [α]D20 = –
70 (c 0.77, CHCl3); δH (400 MHz, CDCl3) 8.67 (s, 1H), 8.37 –
8.29 (m, 2H), 8.06 – 7.99 (m, 2H), 1.29 (s, 9H).
4.24. 2-Methyl-N-(thiophen-2-ylmethylene)propane-2-
sulfinamide [(R)-3v]15
The general procedure was followed using purified 2-
thiophenecarboxaldehyde (56 mg, 47 ꢀL, 0.5 mmol), 2-methyl-2-
propanesulfinamide (61 mg, 0.5 mmol), and iodine (13 mg, 0.05
mmol). The crude product was purified by flash chromatography
(14% EtOAc/n-hexane) to give (R)-3v (32 mg, 30%) as a white
solid; δH (400 MHz, CDCl3) 8.67 (s, 1H), 7.59 (dt, J = 5.0, 1.1
Hz, 1H), 7.55 – 7.52 (m, 1H), 7.18 – 7.10 (m, 1H), 1.25 (s, 9H).
4.19. ((R)-(–)-2-Methyl-N-(naphthalen-1-ylmethylene)propane-2-
sulfinamide [(R)-3q]15,39
The general procedure was followed using purified 1-
naphthaldehyde (78 mg, 68 ꢀL, 0.5 mmol), (R)-(+)-2-methyl-2-
propanesulfinamide (61 mg, 0.5 mmol) and iodine (13 mg, 0.05
mmol). The crude product was purified by flash chromatography
(10% EtOAc/n-hexane) to give (R)-3q (110 mg, 85%) as a
4.25. (R)-N-(Cyclohexylmethylene)-2-methylpropane-2-
sulfinamide [(R)-3w]15,16
The
general
procedure
was
followed
using
cyclohexanecarboxaldehyde (56 mg, 61 ꢀL, 0.5 mmol), (R)-(+)-

6
Tetrahedron
ACCEPTED MANUSCRIPT
5. Acknowledgments
2-methyl-2-propanesulfinamide (61 mg, 0.5 mmol) and iodine
(13 mg, 0.05 mmol). The crude product was purified by flash
chromatography (10% EtOAc/n-hexane) to give (R)-3w (43 mg,
62%) as a colourless oil; [α]D = –180 (c 0.5, CHCl3); δH (400
MHz, CDCl3) 7.95 (d, J = 4.6 Hz, 1H), 2.54 – 2.33 (m, 1H), 1.96
– 1.60 (m, 6H), 1.32 (dt, J = 18.6, 4.8 Hz, 4H), 1.18 (s, 9H).
We gratefully acknowledge Dr. Duncan L. Browne (School of
Chemistry, Cardiff University) and his research group for
enabling the use of the ball mill and for fruitful discussions. We
also thank the EPSRC National Mass Spectrometry Facility,
Swansea, for mass spectrometric data.
20
4.26. (R)-2-Methyl-N-octylidenepropane-2-sulfinamide
[(R)-
3x]41
6. References and notes
1. Li, J.; Dawood, R. S.; Qin, S.; Liu, T.; Liu, S.; Stockman, R. A.;
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The general procedure was followed using octanal (64 mg, 78
ꢀL, 0.5 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (61 mg,
0.5 mmol) and iodine (13 mg, 0.05 mmol). The crude product
was purified by flash chromatography (10% EtOAc/n-hexane) to
20
give (R)-3x (81 mg, 70%) as a yellow oil; [α]D = –461 (c 0.77,
CHCl3); δH (500 MHz, CDCl3) 8.06 (t, J = 4.8 Hz, 1H), 2.51 (td,
J = 7.4, 4.8 Hz, 2H), 1.67 – 1.58 (m, 2H), 1.37 – 1.24 (m, 8H),
1.19 (s, 9H), 0.88 (t, J = 7.0 Hz, 3H).
4.27. (R)-2-Methyl-N-(3-(methylthio)propylidene)propane-2-
6. Mikołajczyk, M.; Łyżwa, P.; Drabowicz, J. Tetrahedron:
Asymmetry 1997, 8, 3991–3994.
sulfinamide [(R)-3y]42
7. Davis, F. A.; Zhou, P.; Chen, B.-C. Chem Soc. Rev. 1998, 27, 13–
18.
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The general procedure was followed using 3-
(methylthio)propionaldehyde (52 mg, 50 ꢀL, 0.5 mmol), (R)-(+)-
2-methyl-2-propanesulfinamide (61 mg, 0.5 mmol) and iodine
(13 mg, 0.05 mmol). The crude product was purified by flash
chromatography (20% EtOAc/n-hexane) to give (R)-3y (87 mg,
84%) as a yellow oil; [α]D20 = –292 (c 0.5, CHCl3); δH (500 MHz,
CDCl3) 8.08 (dt, J = 5.3, 4.0 Hz, 1H), 2.93 – 2.66 (m, 4H), 2.13
(s, 3H), 1.20 (s, 9H).
4.28. Condensation of citral (cis/trans mixture) with (R)-(+)-2-
methyl-2-propanesulfinamide
14. Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J.
Org. Chem. 1999, 68, 1278–1284.
15. Collados, J. F.; Toledano, E.; Guijarro, D.; Yus, M. J. Org. Chem.
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17. Stolle, A.; Ranu, B., Eds. Ball Milling Towards Green Synthesis:
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20. Wang G.-W. Chem. Soc. Rev. 2013, 42, 7668–7700.
21. Hernández, J. G.; Friscic, T. Tetrahedron Lett. 2015, 56, 4253–
4276.
The general procedure was followed using citral (mixture of cis-
and trans-isomers) (76 mg, 86 ꢀL, 0.25 mmol), (R)-(+)-2-methyl-
2-propanesulfinamide (61 mg, 0.5 mmol) and iodine (13 mg,
0.05 mmol). The crude product (1:1 mixture of E- and Z-isomers)
was purified and the two isomeric products were separated by
flash chromatography (10% EtOAc/n-hexane).
(R)-N-((1E,2Z)-3,7-Dimethylocta-2,6-dien-1-ylidene)-2-
methylpropane-2-sulfinamide [(R)-3z-1]
Rf = 0.31 (46 mg, 72%) as a colourless oil; [α]D20 = –530 (c 0.40,
CHCl3); IR (neat) νmax 2960, 2918, 2864, 1633, 1568, 1082 cm-1;
δH (500 MHz, CDCl3) 8.5 (d, J = 9.9 Hz, 1H), 6.24 (d, J = 9.9
Hz, 1H), 5.07 (tdd, J = 5.9, 2.8, 1.4 Hz, 1H), 2.47 (t, J = 7.5 Hz,
2H), 2.19 (td, J = 14.9, 6.2 Hz, 2H), 1.96 (d, J = 1.3 Hz, 3H),
1.65 (d, J = 0.8 Hz, 3H), 1.59 (s, 3H), 1.19 (s, 9H); δC (126 MHz,
CDCl3) 160.4, 157.2, 133.3, 124.7, 122.8, 57.2, 33.1, 27.0, 25.8,
24.9, 22.6, 17.9; HRMS (ASAP): MH+, found 256.1732.
C14H26NOS requires 256.1735.
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10.1002/chem.201703605.
23. Do, J.-L.; Friščić, T. Synlett 2017, 28, 2066–2092.
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Friščić, T.; Grepioni, F.; Harris, K. D. M.; Hyett, G.; Jones, W.;
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(R)-N-((1E,2E)-3,7-Dimethylocta-2,6-dien-1-ylidene)-2-
methylpropane-2-sulfinamide [(R)-3z-2]
20
Colourless oil; Rf = 0.25 (42 mg, 65%); [α]D = –303 (c 0.50,
CHCl3); IR (neat) νmax 2960, 2920, 2860, 1633, 1568, 1082 cm-1;
δH (500 MHz, CDCl3) 8.54 (d, J = 9.9 Hz, 1H), 6.23 (dd, J = 9.9,
1.0 Hz, 1H), 5.08 (dd, J = 8.9, 3.4 Hz, 1H), 2.29 – 2.12 (m, 4H),
2.04 (d, J = 1.0 Hz, 3H), 1.68 (s, 3H), 1.60 (s, 3H), 1.20 (s, 9H);
δC (126 MHz, CDCl3) 160.7, 157.3, 132.8, 123.6, 123.1, 57.2,
40.7, 28.3, 26.2, 25.8, 24.9, 22.6, 18.0, 17.9; HRMS (ASAP):
MH+, 256.1735. C14H26NOS requires 256.1735.
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7
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