Improved Process for Preparation of tert-Butanesulfinyl Ketimines of Hindered Ketones under Nitrogen Flow

Article abstract of DOI:10.1021/acs.oprd.6b00188

An improved process for tert-butanesulfinyl ketimines formation using titanium(IV) alkoxides is described. This new protocol gives better results especially for sterically hindered ketones compared to classical conditions where titanium(IV) isopropoxide i

Full text of DOI:10.1021/acs.oprd.6b00188

Subscriber access provided by Weizmann Institute of Science
Communication
Improved process for preparation of tert-butanesulfinyl
ketimines of hindered ketones under nitrogen flow
Samuel Tabet, Nicolas Rodeville, Jean-Guy Boiteau, and Isabelle Cardinaud
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00188 • Publication Date (Web): 22 Jun 2016
Downloaded from http://pubs.acs.org on June 23, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Organic Process Research & Development is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Improved process for preparation of tertꢀ
butanesulfinyl ketimines of hindered ketones under
nitrogen flow
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Samuel Tabet, Nicolas Rodeville*, Jean-Guy Boiteau*, Isabelle Cardinaud
Galderma R&D Les Templiers, 2400 Route des colles BP 87, 06902 SophiaꢀAntipolis CEDEX,
France
ACS Paragon Plus Environment
1

Organic Process Research & Development
Page 2 of 17
1
2
3
4
TABLE OF CONTENTS GRAPHIC
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
2

Page 3 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
ABSTRACT An improved process for tertꢀbutanesulfinyl ketimines formation using
titanium(IV) alkoxides is described. This new protocol gives better results especially for
sterically hindered ketones compared to classical conditions where titanium(IV) isopropoxide is
found to be only moderately effective. We found that removal of isopropanol or ethanol from
the reaction mixture either under a nitrogen flow or under vacuum dramatically increased
reaction rate, extent of conversion and yield of the reaction. This methodology has been
exemplified on several substrates reported in the literature to be difficult.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
KEYWORDS : sulfinyl ketimines, hindered ketones, improved process, nitrogen flow.
tertꢀButanesulfinyl ketimines are very versatile substrates providing access to a large variety of
chiral secondary and tertiary amines used in chemical synthesis.1 Indeed the chiral and electron
withdrawing tertꢀbutanesulfinyl group directs the addition of nucleophiles by chiral induction to
the imine and can be easily cleaved under mild acidic conditions providing chiral amines. Access
to tertꢀbutanesulfinyl ketimines has been widely described by the Elman group and is based on
the direct condensation of ketones with chiral tertꢀbutanesulfinamide using titanium(IV) alkoxide
as Lewis acid and water scavenger.2 It has been determined that titanium(IV) ethoxide is usually
more effective than titanium(IV) isopropoxide and elevated temperature are usually required, for
hindered substrates, or for less reactive ketones. The standard procedure is to heat the mixture of
ketone, chiral tertꢀbutanesulfinamide and titanium(IV) ethoxide in an aprotic solvent (eg. THF or
toluene) to 60 °C and increase, if necessary, the temperature until completion of the reaction.
We found that titanium(IV) isopropoxide can be as efficient as titanium(IV) ethoxide for
sulfonamide condensation with ketones under specific experimental conditions. During some
ACS Paragon Plus Environment
3

Organic Process Research & Development
Page 4 of 17
1
2
3
4
5
6
7
8
9
laboratory experiments using titanium(IV) isopropoxide and hindered ketone we noted how
different extents of conversion for our substrate between a sealed tube (conv 50%) and a flask
under a nitrogen flow (full conversion).3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We hypothesized that removal of a volatile sideꢀproduct could be implicated and decided to
evaluate the importance of nitrogen flow and vacuum with reported literature results and
conditions. Preliminary investigations were carried out with racemic tetralone 1 as a model
compound which is reported to react poorly with chiral tertꢀbutanesulfinamide and titanium(IV)
isopropoxide (conversion <50%, Table 1, entry1).4 When toluene was used as the unique solvent
with titanium(IV) isopropoxide at 70 °C in a sealed tube only 33% conversion was obtained after
24 hours which was comparable with the reported conversion (entry 2).4a With the same reaction
conditions, but in an open tube under a nitrogen flow (4 liters per minute), the reaction proceeded
to 99% completion in 5 hours (entry 3). In this case, due to evaporation, toluene was added
regularly to the reaction mixture to keep a constant volume. The same comparison was done
replacing titanium(IV) isopropoxide by titanium(IV) ethoxide. In this case reaction completion
was observed in 3 hours (entry 5), whereas literature data indicated a conversion inferior to 70%
(entry 4). For practical reasons, we investigated reaction with neat titanium(IV) isopropoxide to
avoid the need to recharge toluene and facilitate titanium dioxide precipitation during work up.
In a sealed tube, a 70% conversion was obtained in 24 hours (entry 6) while in an open tube at
the same temperature under nitrogen flow a 99% conversion was reached in just 4 hours (entry
7). We also performed the same experiment under vacuum (10 mbar) at 70 °C and after 15 hours,
full conversion was also obtained (entry 8). To complete this evaluation a kinetic study was
realized with the experimental conditions of entry 2 and entry 3 (Figure 1a). During the first 3
hours a first order reaction was observed that allowed us the calculation of the rate constants for
ACS Paragon Plus Environment
4

Page 5 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
both reactions (figure 1b). When a nitrogen flow was used the reaction rate was 22 times faster
than operation in a sealed tube (kentry3/kentry2= 22) during this early phase of the reaction.
Table 1. Condensation of racemic tetralone 1 mediated by Ti(IV) alkoxides
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry
Solvent/ T °C
Reaction
conditions
Nitrogen
flow
Time
Conv (a%
UPLC)a
Isolated
Yield
Ti(OiPr)4/ THF / 75 °C
ꢀ
ꢀ
ꢀ
<50%4a
33%
ꢀ
ꢀ
1b
2
Ti(OiPr)4/ Toluene/ 70 °C
Sealed
Tube
No
24h
Ti(OiPr)4/ Toluene /70 °C
Ti(OEt)4/ THF Toluene /90 °C
Ti(OEt)4/ Toluene / 70 °C
Ti(OiPr)4/ Neat/ 70 °C
Open Tube
ꢀ
Yes
ꢀ
5h
ꢀ
99%
<70%4a
99%
94%
3
4b
5
ꢀ
95%
ꢀ
Open Tube
Yes
No
3h
18h
Sealed
Tube
70%
6
Ti(OiPr)4/ Neat / 70 °C
Ti(OiPr)4/ Neat / 70 °C
Open Tube
Yes
No
4h
99%
99%
95%
96%
7
8
Tube under
Vacuum
15h
aBased on disappearance of ketone
b
Data from literature4a
ACS Paragon Plus Environment
5

Organic Process Research & Development
Page 6 of 17
1
2
3
4
Figure 1. Reaction rate kinetics for entry 2and entry 3 (Table 1):
5
6
7
a)UPLC formation of compound 2a during 24 hours.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
100
90
80
70
60
50
40
30
20
10
0
Entry 3
Entry 2
0
10
20
Time (Hours)
b) Ln(% residual tetralon 1) vs time
5
4.5
4
y = -0,0531x + 4,5812
R² = 0,9149
3.5
3
2.5
Entry 3
Entry 2
y = -1.1924x + 4.631
R² = 0.9993
2
1.5
1
0.5
0
0
1
2
3
Time (hours)
For tertꢀbutanesulfinyl ketimines condensation, titanium(IV) alkoxides are known to act as
Lewis acids and also as water scavengers. We postulated that the first step of the mechanism
with titanium(IV) isopropoxide is displacement of one molecule of isopropanol from titanium
ACS Paragon Plus Environment
6

Page 7 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
(Scheme 1), and in the case of hindered ketones this step might be the limiting step in the
kinetics. Removing isopropanol under a nitrogen flow or with vacuum displaces this equilibrium
and drives the mechanism towards ketimine formation. The monohydroxy titanate obtained
reacts immediately with a second molecule of titanium(IV) isopropoxide to afford a dimeric
product and isopropanol.5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Postulated Mechanism
To confirm this hypothesis, condensation of tetralone 1 without solvent was repeated on a larger
1
scale to trap the solvent removed from the reaction mixture. Analysis by H NMR of the
distillate confirmed the presence of isopropanol removal from the reaction. The same result was
obtained repeating the experiment with titanium(IV) ethoxide and ethanol removal. In addition,
we repeated entry 2 experiment (Table 1) with 2 equivalents of extra isopropanol, that
considerably slowed down the kinetic of reaction and only a 3% conversion was obtained after
24 hours at 70 °C
To explore the scope of the reaction we decided to focus on titanium(IV) isopropoxide and how
its use can be extended to a large variety of ketones. Moreover, on larger scale, titanium(IV)
isopropoxide is easier to handle and cheaper than titanium(IV) ethoxide.
In the literature, the standard procedure is to heat reaction mixture to 60 °C, and increase the
temperature above 100 °C if the conversion is sluggish.1,2 The drawback of elevated temperatures
is that some ketimine compounds are susceptible to thermal decomposition and aldol
ACS Paragon Plus Environment
7

Organic Process Research & Development
Page 8 of 17
1
2
condensation.2 To overcome this issue we chose to operate at 50 °C under a nitrogen flow and
increased the temperature to 60ꢀ70 °C if the rate of the reaction was sluggish. When 95ꢀ99%
conversion was reached, the mixture was diluted with THF and quenched with a saturated
aqueous solution of sodium chloride. Titanium oxide was removed by filtration and after workꢀ
up the desired ketimine was isolated. A supplementary purification using silica gel
chromatography was sometimes necessary depending on the ketone substrate.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Because the protocol requires nitrogen flow and heating, we excluded volatile ketones from our
study (Table 2). For all the examples, a temperature below 60 °C was sufficient to provide a
complete conversion without degradation and in most cases silica gel purification was not
necessary. Where data was available our isolated yields were compared to those obtained with
titanium(IV) isopropoxide from the literature. Using acetophenone, 2b (60% yield using toluene
at 110 °C)2,6 a yield of 85% was obtained at just 50 °C. Even with sterically hindered ketone such
as pivalophenone 2d a 99% conversion and a 70% isolated yield were obtained.7 The same
difference was also observed with 2ꢀacetonaphthone 2g giving 80% yield compared to the 50%
yield in literature.10 Interestingly, for examples 2c and 2i, isolated yields of respectively 80% and
84%, were better than those obtained with titanium(IV) ethoxide at higher temperature.6a,7,12 For
entries, 2d, 2e and 2h, the yields obtained at 50ꢀ60 °C are comparable to those obtained with the
standard titanium(IV) ethoxide Lewis acid procedure.7,8,11 Finally, with entry 2f, a similar yield
was obtained with the titanium(IV) isopropoxide procedure compared to the microwave
procedure at 120 °C from literature.9 Examples 2h-i were all performed at 60 °C and the reaction
was complete in 4ꢀ6 hours compared to 15 hours at 50 °C using the literature protocol. The
isolated yield for ketone 2i was significantly improved (84%) compared to the 29% reported
yield.12 For the most hindered example 2j, titanium(IV) isopropoxide was not sufficient to
ACS Paragon Plus Environment
8

Page 9 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
provide complete conversion (12%) in 48 hours and 70 °C. However, when we replaced
titanium(IV) isopropoxide by titanium(IV) ethoxide a 60% conversion and 40% isolated yield
were obtained compared to the 5% literature yield with the same Lewis acid.13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In summary, we have developed an efficient and mild procedure for the preparation of tertꢀ
butanesulfinyl ketimines with titanium(IV) isopropoxide using vacuum or under a nitrogen flow
to remove isopropanol from the reaction mixture. We found that removing isopropanol displaces
the equilibrium of the reaction and leads to high conversions even with hindered ketones. This
protocol avoids the use of high temperatures and gives better purity profile compared to classical
conditions. For the most hindered ketones, when titanium(IV) isopropoxide was not efficient
enough, the more expensive titanium(IV) ethoxide can be used with satisfactory to excellent
results.
Table 2. Scope of the condensation of ketones mediated by titanium(IV) isopropoxide
(Methode A)
O
S
(S)-tert-butylsulfinamide
O
N
R1
R2
R1
R2
Ti(OiPr)4
50-60°C
(2 equiv)
Entry
Ketone
Reaction
T °C
Conv.
Reaction
Time
Isolated
Yield
Literature condition
(a% UPLC)a
50 °C
99%
15h
85%
60%/ Ti(OiPr)4/ Toluene/
110 °C2,6
2b
50 °C
99%
15h
80%
45%/ Ti(OEt)4/ 65 °C/ 24h6a,7
2c
ACS Paragon Plus Environment
9

Organic Process Research & Development
Page 10 of 17
1
2
69%/ Ti(OEt)4/ 85 °C/ 21h7
3
4
50 °C
99%
15h
70%
2d
5
6
7
8
9
50 °C
50 °C
99%
99%
15h
5h
89%
88%
75%/ Ti(OEt)4/ CH2Cl2/
reflux8
2e
2f
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
89%/ Ti(OEt)4 / THF/
MW(160W)/ 120 °C9
60 °C
60 °C
96%
95%
15h
6h
80%
66%
50%/ Ti(OiPr)4/ THF/ reflux10
61%/ Ti(OEt)4/ THF/ reflux 11
2g
2h
60 °C
99%
4h
84%
29%/ Ti(OEt)4/ DCM/
reflux/ 2d12
2i
2j
70 °C
12%
60%
48h
48h
Not isolated
40%
5%/ Ti(OEt)4 / THF/ reflux/
2d13
70 °Cb
a Based on disappearance of ketone
b Ti(OEt)4 was used
EXPERIMENTAL SECTION
General Information. All Ketones, except for example 2j13, were obtained from commercial
suppliers and used without further purification. Only anhydrous solvents were used for reaction
and were purchased from Carlo Erba without further purification. Lewis acids were obtained
from Sigma Aldrich , Ti(OEt)4 99% and Ti(OiPr)4 97%, and were used without purification from
1
new bottles. (S)ꢀ(ꢀ)ꢀ2ꢀmethylꢀ2ꢀpropanesulfinamide 99% was obtained from AK Scientific. H
NMR and 13C NMR were recorded on a 400 MHz nuclear magnetic resonance spectrometer
Bruker Avance (400 MHz for 1H NMR and 100 MHz for 13C NMR). The chemical shifts (δ) and
ACS Paragon Plus Environment
10

Page 11 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
coupling constants (J) were expressed in parts per million and hertz, respectively. Conversion
were measured on a Waters UPLC Acquity system Acquity CSH C18 1.7 µm 2.1*50 mm
Column, mobile phase (Acetonitrile + 0.1% formic acid) / (Water + 0.1% formic acid), flow rate
0.8 mL/min, with photodiode array detector and the following gradient: 10% to 98% acetonitrile
0 to 0.8 min, 98% acetonitrile from 0.8 min to 1.5 min and 98% to 10% acetonitrile from 1.5 to
2.0 min. HRMS (ESI) data were recorded on Thermo orbitrap QExactive. General method A, B
or C were conducted on 2 g scale of the corresponding ketone.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Method A. General solvent free procedure for the Synthesis of tertꢀbutanesulfinyl ketimines
with titanium alkoxide (Ti(OiPr)4 or Ti(OEt)4) neat under nitrogen flow. A solution or a
suspension of ketone (1 equiv) in titanium alkoxide (2 equiv) was prepared under a nitrogen flow
(4 liters per minute) without vapor condenser. Then (S)ꢀ(ꢀ)ꢀ2ꢀmethylꢀ2ꢀpropanesulfinamide (1.05
equiv) was added and the reaction mixture was heated to 50ꢀ70 °C. Conversion was followed by
UPLCꢀMS. Immediately upon completion the mixture was cooled to room temperature, diluted
with THF (25 vol) and treated with a solution of 24 wt % aq NaCl (0.5 vol). The resulting
titanium oxide suspension was filtered through a plug of Celite, and the filter cake was washed
with THF. The filtrate was concentrated under reduce pressure, diluted with ethyl acetate and
transferred to a separatory funnel. The organic layer was washed with water and the aqueous
phase was extracted once with ethyl acetate. The combined organic portions were dried on
Na2SO4, filtered and concentrated under reduce pressure. When necessary the sulfinyl ketimines
were purified through a pad of silica.
Method B. General procedure for the Synthesis of tertꢀbutanesulfinyl ketimines with titanium
alkoxide (Ti(OiPr)4 or Ti(OEt)4) with toluene and nitrogen flow. A solution of ketone (1 equiv)
and titanium alkoxide (2 equiv) in toluene (0.35M) was prepared under a nitrogen flow (4 liters
ACS Paragon Plus Environment
11

Organic Process Research & Development
Page 12 of 17
1
2
3
4
5
6
7
8
9
per minute) without vapor condenser. Then (S)ꢀ(ꢀ)ꢀ2ꢀmethylꢀ2ꢀpropanesulfinamide (1.05 equiv)
was added and the reaction mixture was heated to 50ꢀ70 °C. The toluene and the isopropanol
from the reaction are removed with the nitrogen flow. Due to evaporation toluene was added
regularly to the reaction mixture to keep a constant volume. Conversion was followed by UPLCꢀ
MS. Immediately upon completion the mixture was cooled to room temperature and workꢀup
conducted as described in Method A.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Method C. General procedure for the Synthesis of tertꢀbutanesulfinyl ketimines with titanium
alkoxide (Ti(OiPr)4 or Ti(OEt)4) under vacuum (10 mbar) . A solution or a suspension of ketone
(1 equiv) in titanium alkoxide (2 equiv) was prepared vacuum under without vapor condenser.
Then (S)ꢀ2ꢀmethylꢀ2ꢀpropanesulfinamide (1.05 equiv) was added and the reaction mixture was
heated to 50ꢀ70 °C. Conversion was followed by UPLCꢀMS. Immediately upon completion the
mixture was cooled to room temperature and workꢀup conducted as described in Method A.
(S)-N-(4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1(2H)-ylidene)-2-methylpropane-2-
sulfinamide (2a). Method A. Pure 2a was obtained (1.3g, 95%) as a yellow solid without
purification (diastereoisiomeric mixture). Method B. Pure 2a was obtained (1.28g, 94%) as a
yellow solid without purification (diastereoisiomeric mixture). Method C. Pure 2a was obtained
1
(1.32g, 96%) as a yellow solid without purification (diastereoisiomeric mixture). H NMR (400
MHz, DMSOꢀd6) δ 8.15 (dd, J = 7.9, 1.5 Hz, 1H), 7.60 (dd, J = 8.3, 1.8 Hz, 1H), 7.53 – 7.33 (m,
3H), 7.10 (ddd, J = 15.5, 8.3, 2.1 Hz, 1H), 6.94 (d, J = 7.5 Hz, 0.5H), 6.87 (d, J = 7.5 Hz, 0.5H),
4.45 – 4.31 (m, 1H), 3.22 (m, 1H), 3.16 – 3.01 (m, 1H), 2.29 – 2.09 (m, 2H), 1.24 (d, J = 1.8 Hz,
13
9H). C NMR (101 MHz, DMSOꢀd6) δ 175.7, 175.5, 145.3, 145.1, 143.5, 143.2, 132.8, 132.8,
132.6, 132.6, 131.3, 130.8, 130.7, 130.6, 130.5, 129.4, 129.4, 129.3, 129.3, 128.9, 128.8, 127.4,
ACS Paragon Plus Environment
12

Page 13 of 17
Organic Process Research & Development
1
2
127.3, 126.5, 56.9, 56.9, 43.1, 42.9, 30.2, 30.0, 30.0, 29.1, 22.1. HRMS calcd for C20H22Cl2NOS+
[M + H]+ m/z 394.0799, found m/z 394.0787.
3
4
5
6
7
8
9
(S)-2-methyl-N-(1-phenylethylidene)propane-2-sulfinamide (2b). Method A. Pure 2b was
obtained (3.16 g, 85%) as a yellow solid from silica pad purification (4:1 heptane / ethyl acetate).
1H NMR (400 MHz, DMSOꢀd6) δ 7.96 – 7.89 (m, 2H), 7.60 – 7.46 (m, 3H), 2.73 (s, 3H), 1.23 (s,
9H).13C NMR (101 MHz, DMSOꢀd6) δ 176.6, 138.4, 131.9, 128. 7, 127.2, 56.8, 40.0, 22.1, 19.7.
HRMS calcd for C12H18NOS+ [M + H]+ m/z 224.1109, found m/z 224.1104.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)-2-methyl-N-(2-methyl-1-phenylpropylidene)propane-2-sulfinamide (2c). Method A. Pure 2c
was obtained (2.73 g, 80%) as a yellow solid from silica pad purification (4:1 heptane / ethyl
acetate).1H NMR (400 MHz, DMSOꢀd6) δ 7.45 (m, 3H), 7.39 – 7.30 (m, 2H), 3.08 (s, 1H), 1.12
(m, 15H).13C NMR (101 MHz, DMSOꢀd6) δ 189.5, 137.7, 129.4, 128.2, 126.7, 55.5, 40.0, 21.7,
19.9, 19.6. HRMS calcd for C14H22NOS+ [M + H]+ m/z 252.1422, found m/z 252.1416.
(S)-N-(2,2-dimethyl-1-phenylpropylidene)-2-methylpropane-2-sulfinamide (2d). Method A. Pure
1
2d was obtained (2.30 g, 70%) as a white solid from heptane trituration. H NMR (400 MHz,
DMSOꢀd6) δ 7.53 – 7.32 (m, 3H), 7.18 – 7.03 (m, 2H), 1.17 (s, 9H), 1.10 (s, 9H). 13C NMR (101
MHz, DMSOꢀd6) δ 192.1, 136.6, 128.4, 127.8, 126.4, 55.1, 42.0, 27.8, 21.7. HRMS calcd for
C15H24NOS+ [M + H]+ m/z 265.1579, found m/z 266.1573
(S)-N-(diphenylmethylene)-2-methylpropane-2-sulfinamide (2e). Method A. Pure 2e was
obtained (2.80 g, 89%) as a white solid from heptane trituration. 1H NMR (400 MHz, DMSOꢀd6)
δ 7.83 – 7.18 (m, 10H), 1.20 (s, 9H). 13C NMR (101 MHz, DMSOꢀd6) δ 179.0, 132.6, 128.5,
56.1, 21.9. HRMS calcd for C17H20NOS+ [M + H]+ m/z 285.1266, found m/z 286.1260
ACS Paragon Plus Environment
13

Organic Process Research & Development
Page 14 of 17
1
2
3
4
(S)-N-((2-aminophenyl)(phenyl)methylene)-2-methylpropane-2-sulfinamide (2f). Method A.
5
6
1
Pure 2f was obtained (2.7 g, 88%) as a yellow solid from diisopropyl ether trituration. H NMR
7
8
9
(400 MHz, MeOD) δ 7.77 (d, J = 35.4 Hz, 0.3 H), 7.53 (d, J = 4.3 Hz, 3H), 7.23 (dd, J = 15.4,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
7.2 Hz, 2.7H), 6.92 – 6.74 (m, 2H), 6.42 (t, J = 7.7 Hz, 1H), 1.26 (s, 9H). C NMR (101 MHz,
MeOD) δ 184.7, 152.2, 137.3, 134.7, 134.0, 128.9, 128.1, 127.5, 116.7, 115.9, 114.8, 55.1, 21.1.
HRMS calcd for C17H21N2OS+ [M + H]+ m/z 301.1375, found m/z 301.1372
(S)-2-methyl-N-(1-(naphthalen-2-yl)ethylidene)propane-2-sulfinamide (2g). Method A. Pure 2g
was obtained (2.6 g, 80%) as a yellow oil from silica pad purification (4:1 heptane / ethyl
acetate): Z/E isomers mixture. 1H NMR (400 MHz, DMSOꢀd6) δ 8.29 – 8.11 (m, 0.66H), 8.09 –
7.91 (m, 2H), 7.75 – 7.48 (m, 4H), 7.37 (dd, J = 18.2, 7.0 Hz, 0.39H), 2.82 (s, 2H), 2.59 (s, 1H),
1.22 (s, 6H), 1.09 (s, 3H).13C NMR (101 MHz, DMSOꢀd6) δ 181.3, 138.6, 133.4, 132.8, 130.1,
128.9, 128.8, 128.7, 128.6, 127.0, 126.5, 126.3, 125.5, 125.2, 125.1, 124.9, 124.6, 124.2, 123.7,
123.3, 56.3, 54.5, 24.8, 22.0, 21.6. HRMS calcd for C16H20NOS+ [M + H]+ m/z 274.1266, found
m/z 274.1250
(S)-2-methyl-N-(2-phenylcyclohexylidene)propane-2-sulfinamide (2h). Method A. Pure 2h was
obtained (2.1 g, 66%) as a yellow oil from silica pad purification (4:1 heptane / ethyl acetate) :
1
diasteroisomers mixture. H NMR (400 MHz, DMSOꢀd6) δ 7.29 (m, 2H), 7.23 – 7.13 (m, 3H),
3.77 (m, 1H), 3.49 (dt, J = 13.3, 4.3 Hz, 0.5H), 3.35 (m, 0.5H), 2.59 – 2.44 (m, 0.5H), 2.34 (td, J
= 12.7, 5.0 Hz, 0.5H), 2.16 – 1.92 (m, 3H), 1.87 (m, 1H), 1.80 – 1.51 (m, 2H), 0.94 (s, 4.5H),
0.91 (s, 4.5H). 13C NMR (101 MHz, DMSOꢀd6) δ 188.3, 188.1, 140.6, 140.5, 128.8, 128.7,
128.5, 127.9, 127.7, 126.3, 56.2, 55.8, 54.5, 54.5, 34.5, 34.3, 33.7, 33.3, 27.8, 27.2, 24.9, 24.8,
21.7, 21.6. HRMS calcd for C16H24NOS+ [M + H]+ m/z 278.1579, found m/z 278.1573
ACS Paragon Plus Environment
14

Page 15 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
(S)-N-(1-(2-chlorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (2i). Method A. Pure 2i
was obtained (2.8 g ,84%) as a yellow oil from silica pad purification (4:1 heptane / ethyl
acetate) : Z/E isomers mixture (M major and m minor). 1H NMR (400 MHz, DMSOꢀd6) δ 7.57 –
7.28 (m, 4H), 2.65 (s, 2H), 2.44 (s, 1H), 1.22 (s, 6H), 1.13 (s, 3H). 13C NMR (101 MHz, DMSOꢀ
d6) δ 178.8(M+m), 140.3(M+m), 131.0 (M), 130.4(m), 130.0(M), 129.3 (M+m), 129.1(m),
128.9(M), 127.8(m), 127.6(M), 127.0(m), 56.9(M+m), 23.9(M+m), 22.0(M), 21.8(m) HRMS
calcd for C12H17ClNOS+ [M + H]+ m/z 258.0719, found m/z 258.0715
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)-N-(1-(1-(4-chlorophenyl)cyclobutyl)-3-methylbutylidene)-2-methylpropane-2-sulfinamide
(2j). Method A with titanium ethoxide instead of titanium isopropoxide. Pure 2j was obtained
1
(1.2 g ,42%) as a yellow oil from silica pad purification (4:1 heptane / ethyl acetate). H NMR
(400 MHz, DMSOꢀd6) δ 7.49 – 7.41 (m, 2H), 7.38 (d, J = 8.3 Hz, 2H), 2.82 – 2.58 (m, 3H), 2.51
– 2.32 (m, 2H), 2.22 (dd, J = 13.5, 8.1 Hz, 1H), 1.92 – 1.66 (m, 3H), 1.22 (s, 9H), 0.70 (d, J =
13
6.6 Hz, 3H), 0.55 (d, J = 6.7 Hz, 3H). C NMR (101 MHz, DMSOꢀd6) δ 187.0, 142.6, 131.4,
128.8, 128.4, 57.2, 56.5, 40.3, 40.2, 40.1, 40.0, 32.2, 32.1, 25.8, 22.5, 22.1, 22.1, 15.5. HRMS
calcd for C19H29ClNOS+ [M + H]+ m/z 354.1658, found m/z 354.1655
ASSOCIATED CONTENT
Supporting Information.
Copies of 1H NMR, 13C NMR of all compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
Email: nicolas.rodeville@galderma.com ; Email : JeanꢀGuy.Boiteau@galderma.com.
ACS Paragon Plus Environment
15

Organic Process Research & Development
Page 16 of 17
1
2
3
4
ACKNOWLEDGMENT
5
6
7
8
9
We would like to thank Celine Mathieu for key analytical support, and Thibaud Gerfaud for
helpful discussion.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ABBREVIATIONS
REFERENCES
1) a) Robak, M. T.; Melissa Herbage, A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600–3740.
b) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984ꢀ995. c) Morton, D.;
Stockman, R. A. Tetrahedron, 2006, 62, 8869–8905.
2) Liu, G.; Cogan, D. A.; Owens, T.D.; Tang, T. P.; Ellman J. A. J. Org. Chem. 1999, 64,
1278ꢀ1284.
3) Unpublished results
4) a) Han, Z.; Koenig, S. G.; Zhao, H.; Su, X.; Singh, S. P.; Roger P. Bakale, R. P. Org.
Proc. Res. Dev. 2007, 11, 726ꢀ730. b) Jerussi, T. P.; Fang, Q. K.; Currie, M. Patent WO
2004/024669, 2004. c) Caron, J.; Wessel, T.; Lalji, K.; Varney, M.; Bakale, R. P.; Singh, S. P.;
Wilkinson, H. S.; Su, X.; Han, Z.; Koenig, S. G. Patent WO 2007/006003 A2, 2007.
5) a) Hanaor, D. A. H.; Chironi, I.; Karatchevtseva, I.; Triani, G. and Sorrell, C. C. Adv.
Appl Ceram. 2012, 111, 149ꢀ158. b) Park, J.ꢀK.; Myoung, J. J.; Kyong, J. B.; Kim, H.ꢀK. Bull.
Korean Chem. Soc. 2003, 24, 671ꢀ673.
6) a) Pablo, Ó.; Guijarro, D.; Yus, M. Eur. J. Org. Chem. 2014, 7034–7038. b) García
Ruano, J. L.; Alemán, J.; Cid, M. B.; Parra, A. Org. Lett. 2005, 7, 179ꢀ182. c) Cogan, D. A.;
ACS Paragon Plus Environment
16

Page 17 of 17
Organic Process Research & Development
1
2
3
4
5
6
Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268ꢀ269. c) Collados, J. F.; Toledano, E.; Guijarro,
D.; Yus, M. J. Org. Chem. 2012, 77, 5744ꢀ5750.
7
8
9
7) Reeves, J. T.; Tan, Z.; Herbage, M. A.; Han, Z. S.; Marsini, M. A.; Li, Z.; Li, G.; Xu,
Y.; Fandrick, K. R.; Gonnella, N. C.; Campbell, S.; Ma, S.; Grinberg, N.; Lee, H.; Lu, B. Z.;
Senanayake, C. H. J. Am. Chem. Soc. 2013, 135, 5565ꢀ5568.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8) García Ruano , J. L.; José Alemán, J.; Cid, M. B.; Parra, A. ; Org. Synth. 2007, 84, 129ꢀ
138.
9) Qin, J.; Huang, L.; Cao, Y.; Sun, Z. RSC Adv. 2015, 5, 7291– 7296.
10) Liu, J. F.; Imagire, J. patent WO 2008/122010, 2008
11) Chen, S.; Zhao, Y.; Wang, J. Synthesis 2006, 10, 1705–1710.
12) Zhao, Y.ꢀB.; Mariampillai, B.; Candito, D. A.; Laleu, B.; Li, M.; Lautens, M. Ang.
Chem. Int. Ed. 2009, 48, 1849–1852.
13) Han, Z.; Krishnamurthy, Z. D.; Senanayake, C. H. Org. Proc. Res. Dev. 2006, 10, 327ꢀ
333.
ACS Paragon Plus Environment
17