Investigation of steric and electronic effects in the copper-catalysed asymmetric oxidation of sulfides

Article abstract of DOI:10.1016/j.tet.2013.08.063

Steric and electronic effects in the copper-catalysed asymmetric oxidation of aryl benzyl, aryl alkyl and alkyl benzyl sulfides have been investigated. The presence of an aryl group directly attached to the sulfur is essential to afford sulfoxides with high enantioselectivities, with up to 97% ee for 2-naphthyl benzyl sulfoxide, the highest enantioselectivity achieved to date for copper-catalysed asymmetric sulfoxidation. In contrast, the benzyl substituent can be replaced by sterically comparable groups with no effect on enantioselectivity. Copper-mediated oxidation of substituted aryl benzyl sulfides display modest steric and electronic effects resulting in comparable or lower enantioselectivities to those obtained with the unsubstituted benzyl phenyl sulfide.

Full text of DOI:10.1016/j.tet.2013.08.063

Tetrahedron 69 (2013) 10168e10184
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Investigation of steric and electronic effects in the copper-catalysed
asymmetric oxidation of sulfides
Graham E. O’Mahony a, Kevin S. Eccles a, Robin E. Morrison a, Alan Ford a,
,
Simon E. Lawrence a, Anita R. Maguire b
*
a Department of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
b Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 May 2013
Received in revised form 15 August 2013
Accepted 23 August 2013
Available online 24 September 2013
Steric and electronic effects in the copper-catalysed asymmetric oxidation of aryl benzyl, aryl alkyl and
alkyl benzyl sulfides have been investigated. The presence of an aryl group directly attached to the sulfur
is essential to afford sulfoxides with high enantioselectivities, with up to 97% ee for 2-naphthyl benzyl
sulfoxide, the highest enantioselectivity achieved to date for copper-catalysed asymmetric sulfoxidation.
In contrast, the benzyl substituent can be replaced by sterically comparable groups with no effect on
enantioselectivity. Copper-mediated oxidation of substituted aryl benzyl sulfides display modest steric
and electronic effects resulting in comparable or lower enantioselectivities to those obtained with the
unsubstituted benzyl phenyl sulfide.
Keywords:
Sulfoxides
Enantioselective sulfur oxidation
Asymmetric oxidation
Copper catalysis
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
However, the majority of asymmetric sulfide oxidation methods
involve the use of a metal catalyst. Metal-catalysed asymmetric
The development of new methods to prepare enantiopure
sulfoxides has attracted a great deal of interest over the past two
decades. Enantiopure sulfoxides are extremely useful as chiral
auxiliaries in asymmetric synthesis,1,2 and are also important as
pharmaceutical agents.3 The two main methods for the preparation
of enantiopure sulfoxides are the Andersen synthesis and asym-
metric sulfide oxidation.4e6
sulfide oxidation has developed rapidly as a route to enantioen-
riched sulfoxides since the initial breakthrough of Kagan22,23 and
Modena24 in the 1980s, who independently reported a titanium-
mediated sulfide oxidation based on the Sharpless asymmetric
epoxidation procedure.25 In 1995, Bolm reported a vanadium-
catalysed asymmetric sulfide oxidation under very mild condi-
tions.26 Bolm’s procedure was later developed extensively by Ell-
man et al.27,28 Other metals, such as iron,29e31 manganese,32
aluminium,33 niobium,34 zirconium,35 tungsten,36 molybdenum37
and osmium38 have also been used to oxidise sulfides
asymmetrically.
However, there have been very limited reports of the use of
copper in asymmetric sulfide oxidation. Although the research
groups of Cross,39 Zhu40 and Alcon41 have successfully used copper
in the asymmetric oxidation of sulfides, the results reported were
extremely poor (enantioselectivities of 0e30% ee). The use of cop-
per is advantageous over other methods since it is relatively cheap
and environmentally benign. The Kagan system uses a complex and
expensive catalytic system and is sensitive to atmospheric mois-
ture.42 The Bolm system uses vanadium, which is known to exert
toxic, mutagenic and genotoxic effects on a variety of biological
systems.43
The Andersen synthesis,6 which involves the nucleophilic dis-
placement of a leaving group from a diastereopure sulfinate ester, is
limited by the fact that only one diastereopure sulfinate ester is
readily available and the preparation of other diastereopure esters
is challenging. However, the development of chiral precursors that
possess two leaving groups has extended the scope of this
methodology.7e13
The major alternative to the Andersen method is asymmetric
oxidation of sulfides, which is widely exploited for the synthesis of
enantioenriched sulfoxides.4,5,14e17 A number of biological sulfide
oxidations using both isolated enzymes and whole cell systems
have been reported,18,19 and a range of chiral oxaziridines20 and
hydroperoxides21 have been used as asymmetric oxidants under
metal-free conditions.
Previous investigations by a number of research groups have
demonstrated that sulfide substituents can have a large influence
* Corresponding author. E-mail address: a.maguire@ucc.ie (A.R. Maguire).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.063

G.E. O’Mahony et al. / Tetrahedron 69 (2013) 10168e10184
10169
on both the selectivity and enantioselectivity of the oxidation. Gao
et al. reported that the presence of substituents, such as the nitro
group on the phenyl ring of aryl alkyl sulfides resulted in a decline
in both yield and enantioselectivity in vanadium-catalysed oxida-
tions.44 Substituents, such as bromine had the opposite effect. This
trend has been observed in other investigations,26,45e47 although to
a lesser extent. Bryliakov and Talsi reported a titanium-mediated
oxidation that was best suited to oxidise bulky sulfides, such as
aryl benzyl sulfides; poorer results were obtained for the oxidation
of aryl alkyl sulfides.48
While asymmetric sulfide oxidation has been investigated for
almost three decades with considerable success in enantioselective
oxidation of aryl methyl sulfides and, to a lesser extent, aryl benzyl
sulfides, generalisation to other sulfides has proved elusive.
Recently, we reported the copper-catalysed asymmetric oxida-
tion of aryl benzyl and aryl alkyl sulfides, producing sulfoxides in
excellent yields and enantioselectivities (up to 93% ee).49 A direct
relationship between the steric bulk of the sulfide substituents and
the enantioselectivity of the oxidation was observed (Scheme 1).49
This was the first report of the influence of sulfide substituents in
copper-catalysed asymmetric sulfide oxidation. Herein, we wish to
describe the expansion of this investigation and explore the
mechanistic implications of the results.
copper-mediated oxidation a synthetically useful process.49 In-
terestingly, while the majority of metal-catalysed sulfur oxidations
are reported to give the best results in chlorinated solvents, such as
chloroform,4,45,47,50 an added benefit of our system is the use of
a more environmentally attractive solvent medium (mixed solvent
systems composed of hexane, cyclohexane or toluene with ethanol
or methanol can be used).49
A series of salicylaldehyde derived ligands (4e11) has been ex-
plored in this research programme. A series of sulfides (1aeo) was
selected for investigation to enable exploration of both the steric
and electronic effects of the R substituent on the outcome of the
copper-mediated oxidation, and in particular, to establish if the aryl
ring is critical for efficient enantioselective oxidation (Fig. 1).
As summarised in Table 1 and Scheme 2, replacement of an aryl
ring with alkyl substituents resulted in a dramatic decrease in
enantioselectivity even with the most sterically demanding tert-
butyl group (37% cf. 79% for benzyl phenyl sulfide under the same
conditions, entries 1e3, Table 1 and Scheme 2), thus the presence of
the aryl ring is a critical feature in enabling effective enantiose-
lective sulfide oxidation using this copper system. Interestingly,
a steric effect is evident, with enhanced enantioselectivity as the
steric demand of the R group increases from methyl to isobutyl to
cyclohexyl to isopropyl to tert-butyl, albeit at modest levels in all
Scheme 1.
2. Results and discussion
cases (entries 1e13, Table 1 and sulfoxides 2aee, Scheme 2). Sim-
ilarly, oxidation of 1j and 1k, which contain long alkyl chains result
in modest enantioselectivity (entries 20e25, Table 1 and sulfoxides
2j, 2k Scheme 2). In contrast, oxidation of the phenyl sulfides 1l and
1m proceed with improved enantioselectivity (57e58% ee using
ligand 5), highlighting the importance of direct attachment of the
sulfur to the aryl ring (entries 26e30, Table 1 and sulfoxides 2l, 2m
Scheme 2). Oxidation of the allyl benzyl and allyl phenyl sulfides 1n
and 1o follow the same pattern with enhanced enantioselectivity
with the phenyl sulfide 1o, albeit with modest enantioselectivities
(entries 30e34, Table 1 and sulfoxides 2n, 2o Scheme 2). Having
Based on our original discovery17 that aryl benzyl sulfides were
effectively oxidised by copper catalysis with good asymmetric in-
duction, a comprehensive programme to explore the scope and
synthetic utility of this process was undertaken. We have recently
reported the impact of variation of the benzyl substituent49 and in
this work we now focus on the effect of variation of the aryl sub-
stituent on the enantioselective copper-mediated oxidation. While
in the original study17 we reported poor efficiencies, use of mixed
solvent systems has overcome this problem and has rendered the

10170
G.E. O’Mahony et al. / Tetrahedron 69 (2013) 10168e10184
Fig. 1. Investigation of steric and electronic effect of phenyl substituent.
Table 1
Influence of steric and electronic effects
Entry
Sulfide
R
R0
Ligand
1:2:3a
Yield%b
%eec
Sulfoxide
2
(R) 2
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
1d
1e
1f
t-Bu
t-Bu
t-Bu
i-Bu
i-Bu
i-Bu
i-Pr
i-Pr
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4
5
6
4
5
6
4
5
6
4
5
6
4
4
5
4
5
4
4
4
5
6
4
5
6
4
5
4
5
4
5
4
5
4
7
8
4
7
8
2:97:1
1:98:1
11:88:1
4:94:2
2:97:1
10:90:0
0:97:3
1:96:3
0:98:2
3:94:3
4:93:3
5:93:2
5:94:1
48:52:0
56:44:0
62:38:0
58:42:0
65:35:0
23:75:2
9:85:6
10:84:6
19:76:5
2:93:5
9:86:5
6:88:6
32:62:6
31:63:6
29:65:6
27:65:8
6:94:0
6:94:0
26:74:0
21:79:0
1:98:1
15:83:2
61:39:0
1:98:1
52:48:0
75:25:0
88
90
82
87
89
80
86
88
82
88
85
82
85
46e
37e
32e
38e
28e
67e
77
77
65
88
79
78
55
55
60
57
87
85
67
72
90
72
30
91
45
17
37
40
16
11
19
8
27
36
13
27
33
21
4
75
77
97
95
71
90
22
21
10
21
26
22
36
58
57
57
11d
13d
29
24
79
38
5
2a
2a
2a
2b
2b
2b
2cd
2cd
2cd
2dd
2dd
2dd
2ef
2f
9
i-Pr
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
Cyclohexyl
Cyclohexyl
Cyclohexyl
CH3
1-Naphthyl
1-Naphthyl
2-Naphthyl
2-Naphthyl
1-Naphthyl
2-Naphthyl
CH3(CH2)6CH2
CH3(CH2)6CH2
CH3(CH2)6CH2
CH3(CH2)10CH2
CH3(CH2)10CH2
CH3(CH2)10CH2
Ph
1f
2f
1g
1g
1h
1i
1j
1j
2g
2g
2h
2i
2j
2j
Ph
40-ClC6H4
40-ClC6H4
Ph
Ph
Ph
Ph
Ph
Ph
1j
2j
1k
1k
1k
1l
2k
2k
2k
2l
CH2(CH2)5CH3
CH2(CH2)5CH3
CH2(CH2)9CH3
CH2(CH2)9CH3
Ph
Ph
CH]CH2
CH]CH2
Ph
Ph
Ph
Ph
Ph
1l
Ph
Ph
Ph
2l
1m
1m
1n
1n
1o
1o
1p
1p
1p
1q
1q
1q
2m
2m
2nd
2nd
2o
2o
A
A
A
2q
2q
2q
CH2]CHCH2
CH2]CHCH2
Ph
Ph
Ph
Ph
Ph
o-Tolyl
o-Tolyl
o-Tolyl
64
34
6
Ph

G.E. O’Mahony et al. / Tetrahedron 69 (2013) 10168e10184
10171
Table 1 (continued )
Entry
Sulfide
R
R0
Ligand
1:2:3a
Yield%b
%eec
Sulfoxide
2
(R) 2
40
41
42
1r
1r
1r
m-Tolyl
m-Tolyl
m-Tolyl
Ph
Ph
Ph
4
7
8
11:89:0
37:60:3
67:33:0
84
52
27
54
29
3
2r
2r
2r
a
Ratio of 1:2:3 determined by 1H NMR analysis of the crude product.
Yield of 2 after purification by column chromatography.
Determined by HPLC analysis on chiral column (Chiracel OD-H for 2a, 2e, 2g, 2h, 2i, A, 2q, 2r; Chiracel AS-H for 2b, 2c, 2f, 2j, 2k, 2m, 2n; Chiracel OJ-H for 2o; Phenomenex
b
c
Lux Cellulose-4 for 2e, 2l; Phenomenex Lux Amylose-for 2b, 2c, 2f, 2j, 2k, 2m, 2n; Chiracel OJ-H for 2o; Phenomenex Lux Cellulose-4 for 2e, 2l; Phenomenex Lux Amylose-2 for
2d); 2e enantiomers were separated using both OD-H and Phenomenex Lux Cellulose-4 columns, resolution was better using Phenomenex Lux Cellulose-4 column; absolute
configuration determined by comparison of rotation values for 2a, 2b, 2o, 2r, A to known literature values; for 2f and 2g absolute configuration was determined by single
crystal X-ray diffraction on a crystalline sample recrystallised from CH2Cl2, 2h, 2i, 2q, 2r proposed configuration based on HPLC elution order and direction of specific rotations,
2j and 2k proposed configuration based on comparison of optical rotation to known literature values for (R)-decyl phenyl sulfoxide51 and (R)-butyl phenyl sulfoxide,52 2l and
2m proposed configuration based on comparison of optical rotation to known literature value for (R)-decyl benzyl sulfoxide.53
d
Configuration of 2c, 2d, 2n not determined.
These oxidations were carried out in 9:1 toluene/MeOH.
Sulfoxide 2e was essentially racemic.
e
f
Scheme 2.

10172
G.E. O’Mahony et al. / Tetrahedron 69 (2013) 10168e10184
Table 2
established the importance of the aryl substituent on the sulfide,
the derivatives 1f and 1g bearing 1- and 2-naphthyl sulfides were
next explored. Replacement of phenyl substituents with naphthyl
substituents results in efficient asymmetric oxidation, with com-
parable levels of asymmetric induction in the 1-naphthyl system 2f
(75% ee cf. phenyl benzyl sulfoxide A, 79% ee) while enhanced levels
of enantioinduction were seen with the 2-naphthyl system 2g, up
to 97% ee (entries 14e17, Table 1 and sulfoxides 2f, 2g Scheme 2).
The oxidation of sulfides 1h and 1i affords sulfoxides 2h and 2i with
slightly lower enantioselectivities than their unsubstituted coun-
terparts (71 and 90% ee compared to 75 and 97% ee, entries 14, 16,
18 and 19, Table 1 and sulfoxides 2fei Scheme 2) demonstrating
that the presence of the para-chloro substituent on the phenyl ring
has a negative impact on enantioselectivity, although the reduction
is only marginal. The naphthyl sulfides were insoluble in hex-
aneemethanol and, as a result, tolueneemethanol was used as
solvent in these oxidations. In our previous study, we demonstrated
the use of tolueneeMeOH for asymmetric sulfide oxidation with
only a slight reduction in enantioselectivity relative to hex-
aneeMeOH.49 The results of the study described in Scheme 1 and
Table 1/Scheme 2 lead to two major conclusions: (1) An aryl moiety
must be directly attached to the sulfide to achieve good enantio-
selectivity, with the best result (97% ee) obtained when the aryl
moiety is a 2-naphthyl substituent. (2) The steric properties of the
second substituent have a strong influence on the enantiose-
lectivity of the oxidation, but this substituent does not have to be an
aryl or benzyl moiety.
Eight Schiff base ligands were investigated during this study. As
seen in our previous study,49 the optimum ligands for the asym-
metric oxidation were ligands 4 and 5; these significantly out-
performed the other ligands both in terms of yield and
enantioselectivity (Table 1). The results of the oxidations using li-
gands 7 and 8 demonstrate that the presence of a chloro sub-
stituent at the 30 position of the ligand is more important to the
yield and enantioselectivity than at the 50 position (entries 34e42,
Table 1). However, the presence of chloro substituents at both po-
sitions results in the highest yields and enantioselectivities. The
overall results of the asymmetric oxidations, in terms of enantio-
selectivities, are summarised in Scheme 2.
For most of the sulfoxides generated, the (R)-sulfoxide pre-
dominated with use of ligands derived from (S)-tert-leucinol, thus
the sense of the asymmetric induction was the same for the ma-
jority of the sulfides. Interestingly, the sample of benzyl methyl
sulfoxide 2e was essentially racemic. With the isobutyl derivative
1b and the long chain sulfides 1j and 1k, the (R)-sulfoxides again
predominated, but in this case correspond to the opposite sense of
oxygen approach to the prochiral sulfide, albeit at low levels of
enantioselectivity.
A number of substituted aryl benzyl sulfides were also syn-
thesised and oxidised by this system as shown in Fig. 2 and Table 2.
As summarised in Table 2, the outcome of the oxidation was
strongly ligand-dependent with the most efficient oxidation seen
with ligand 4 and 5 in line with our earlier observations. An in-
vestigation of the influence of substituents on the aryl and benzyl
moieties was undertaken. Of note, the 84% ee obtained in the
Copper catalysed oxidation of substituted aryl benzyl sulfides
Entry Sulfide Ar
Ar0
Ligand 1:2:3a Yield%b %eec Sulfoxide
2
(R) 2
149,e 1q
249,e 1q
2-MeC6H4 Ph
2-MeC6H4 Ph
2-MeC6H4 Ph
2-MeC6H4 Ph
2-MeC6H4 Ph
2-MeC6H4 Ph
3-MeC6H4 Ph
3-MeC6H4 Ph
3-MeC6H4 Ph
3-MeC6H4 Ph
3-MeC6H4 Ph
3-MeC6H4 Ph
4-MeC6H4 Ph
4-MeC6H4 Ph
4-MeC6H4 Ph
4-MeC6H4 Ph
4-MeC6H4 Ph
4-MeC6H4 Ph
4
5
6
9
10
11
4
5
6
1:98:1 91
6:94:0 88
40:60:0 51
79:21:0 16
70:30:0 24
88:12:0 10
11:89:0 84
10:88:2 83
15:85:0 77
83:17:0 16
49:51:0 45
76:24:0 17
2:97:1 91
4:96:0 90
2:98:0 90
81:19:0 12
33:67:0 60
71:29:0 23
13:85:2 80
19:81:0 74
23:76:1 69
64
71
55
11
60
9
65
69
49
16
34
3
81
84
59
6
66
1
48
46
45
3
47
3
52
46
54
13
32
5
57
51
46
6
42
5
48
52
26
5
59
54
55
39
4
52
52
38
48
7
44
32
19
6
42
37
36
19
1
2q
2q
2q
2q
2q
2q
2r
2r
2r
2r
2r
2r
2s
2s
2s
2s
2s
2s
3
4
5
6
7
1q
1q
1q
1q
1r
849,e 1r
9
1r
1r
1r
1r
10
11
12
9
10
11
4
5
6
1349,e 1s
1449,e 1s
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
1s
1s
1s
1s
1t
1t
1t
1t
9
10
11
4
5
6
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
20-MeC6H4
2td
2td
2td
2td
2td
2td
2u
2u
2u
2u
2u
2u
2v
2v
2v
2v
2v
2v
2w
2w
2w
2w
2x
2x
2x
2x
2x
2y
2y
2y
2y
2y
2z
2z
2z
2z
20-MeC6H4
20-MeC6H4
20-MeC6H4
9
87:13:0
9
1t
1t
20-MeC6H4 10
20-MeC6H4 11
55:45:0 40
72:28:0 21
9:90:1 81
4:95:1 90
7:92:1 83
81:19:0 15
56:44:0 36
78:22:0 17
1:97:2 89
24:75:1 68
14:85:1 80
1u
1u
1u
1u
1u
1u
1v
1v
1v
1v
1v
1v
1w
1w
1w
1w
1x
1x
1x
1x
1x
1y
1y
1y
1y
1y
1z
1z
1z
1z
30-MeC6H4
30-MeC6H4
30-MeC6H4
30-MeC6H4
4
5
6
9
30-MeC6H4 10
30-MeC6H4 11
40-MeC6H4
40-MeC6H4
40-MeC6H4
40-MeC6H4
4
5
6
9
91:9:0
5
Ph
Ph
40-MeC6H4 10
40-MeC6H4 11
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
20-ClC6H4
20-ClC6H4
20-ClC6H4
20-ClC6H4
30-ClC6H4
30-ClC6H4
30-ClC6H4
30-ClC6H4
30-ClC6H4
40-ClC6H4
66:34:0 28
75:25:0 16
67:32:1 26
47:51:2 46
73:26:1 21
2-ClC6H4
2-ClC6H4
2-ClC6H4
2-ClC6H4
3-ClC6H4
3-ClC6H4
3-ClC6H4
3-ClC6H4
3-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4
5
7
8
4
5
6
7
8
4
5
6
7
8
4
5
7
8
4
5
6
7
8
4
88:12:0
7
60:39:1 33
57:42:1 36
77:23:0 17
63:36:1 24
70:30:0 22
28:72:0 67
20:80:0 71
66:34:0 27
34:66:0 57
76:24:0 16
18:78:4 72
19:77:4 72
29:67:4 58
76:24:0 17
10:89:1 82
17:81:2 75
38:62:0 57
47:51:2 43
68:31:1 21
9:90:1 85
1
1
1
1
1
1
a
a
a
a
a
b
2
2
2
2
2
2
a
a
a
a
a
b
Ph
49
Fig. 2. Investigation of substituted aryl benzyl sulfides.

G.E. O’Mahony et al. / Tetrahedron 69 (2013) 10168e10184
10173
Table 2 (continued )
Entry Sulfide Ar
expected the enantioselectivities were very low, indicating poor
differentiation between the enantiotopic lone pairs of the sulfide
(Table 3 and Scheme 4). Interestingly, the efficiencies of oxidations
of the dibenzyl derivatives were high, but very poor efficiencies
were obtained with the diphenyl derivatives. The electronic prop-
erties of the diphenyl derivatives are significantly different to the
aryl benzyl sulfides and hence the poor yields obtained in the ox-
Ar0
Ligand 1:2:3a Yield%b %eec Sulfoxide
2
(R) 2
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
1
1
1
1
1
1
1
1ε
1ε
1ε
1
1
1
1
1
1
1
1
b
g
g
g
d
d
d
Ph
40-ClC6H4
5
4
5
6
4
5
6
4
5
6
4
5
6
4
5
6
4
5
12:87:1 80
28:69:3 62
29:69:2 64
47:52:1 47
17:81:2 76
21:78:1 70
54:46:0 40
19:80:1 75
24:75:1 71
46:54:0 48
19:80:1 74
25:74:1 65
57:43:0 39
24:75:1 70
23:76:1 68
38:61:1 55
13:87:0 81
63:37:0 32
62
32
28
35
52
49
43
70
69
65
37
37
42
61
69
62
69
65
2
2
2
2
2
2
2
2ε
2ε
2ε
2
2
2
2
2
2
2
2
b
4-MeC6H4 20-MeC6H4
4-MeC6H4 20-MeC6H4
4-MeC6H4 20-MeC6H4
4-MeC6H4 30-MeC6H4
4-MeC6H4 30-MeC6H4
4-MeC6H4 30-MeC6H4
2-MeOC6H4 20-ClC6H4
2-MeOC6H4 20-ClC6H4
2-MeOC6H4 20-ClC6H4
4-MeC6H4 20-ClC6H4
4-MeC6H4 20-ClC6H4
4-MeC6H4 20-ClC6H4
4-MeC6H4 30-ClC6H4
4-MeC6H4 30-ClC6H4
4-MeC6H4 30-ClC6H4
4-MeC6H4 40-ClC6H4
4-MeC6H4 40-ClC6H4
gd
gd
gd
d
idation of the diphenyl sulfides 1ses are perhaps due to poor co-
d
ordination of these sulfides to the copper complex. The poor
yields obtained for the diaryl sulfides are in contrast to a study
carried out by Islam et al. who obtained both aryl benzyl and diaryl
sulfoxides in good yields in a copper-catalysed racemic oxidation
procedure, indicating a different mode of action of the catalytically
active complex in this case.54 Interestingly, the efficiency of oxi-
dation in this series with the difluoro substituted ligand 10 was
notably lower than with the other ligands in line with our earlier
observations.49 Small amounts of sulfone (up to 12%) were evident
in the dibenzyl sulfide oxidations, in contrast to our earlier studies
where very little or no sulfone was detected in the crude products.
The production of an increased amount of sulfone did not result in
an increase in enantioselectivity (e.g., Table 3 entries 8 and 9, al-
though different ligands are employed), indicating that comple-
mentary kinetic resolution is not occurring at least in the oxidation
of the dibenzyl sulfides.
d
z
z
z
z
z
z
h
h
h
q
q
h
h
h
q
q
a
Ratio of 1:2:3 determined by 1H NMR analysis of the crude product.
Yield of 2 after purification by column chromatography.
Determined by HPLC analysis on chiral column (Chiracel OD-H for 2qes, 2u, 2v,
b
c
2y, 2
a
, 2 , 2 , 2 , Chiracel OJ-H for 2w, 2x, Chiracel AS-H for 2t, 2z, 2 , 2ε, 2 , 2 ); 2
b
d
q
g
z
h
d
enantiomers were separated using both OD-H and Phenomenex Lux Cellulose-4
columns, resolution was better using Phenomenex Lux Cellulose-4 column; abso-
lute configuration determined by comparison of rotation values for 2s, 2w, 2
known literature values; for 2q, 2r, 2u, 2v, 2x, 2y, 2z, 2 , 2 , 2 , 2ε, 2 , 2 proposed
configuration based on HPLC elution order and direction of specific rotations.
q to
Preliminary investigation has indicated that modafinil 12 can be
generated from the analogous sulfide using this copper-mediated
sulfide oxidation albeit with modest enantioselectivities.
a
b
d
z
h
d
Configuration of 2t and 2
g
not determined.
e
These results were reported in our previous publication.49
oxidation to form 2s is the highest achieved to date in the aryl
benzyl series (entry 14, Table 2). Overall, the enantioselectivities
obtained in the oxidation of the substituted derivatives proceeded
with comparable or lower enantioselectivities to those obtained
with benzyl phenyl sulfide. Interestingly, oxidation of 1ε containing
an ortho-methoxyphenyl substituent, in addition to an ortho-
chlorobenzyl substituent, proceeded with good enantiocontrol
(entries 68e70, Table 2 and sulfoxide 2ε, Scheme 3) in agreement
with our previous observations of the impact of an ortho-methoxy
substituent on a copper-mediated oxidation as shown in Scheme 1
(sulfoxides JeL).49 In terms of a methyl substituent on either the
aryl or benzyl ring the enantioselectivity increases slightly with
ligand 4 on going from ortho to meta to para substitution (entries
1,7,13 and entries 19, 25, 31, Table 2 and sulfoxides 2qev, Scheme 3).
A similar effect is seen with the chloro substituent on the benzyl
ring for the disubstituted sulfides (entries 71, 74 and 77, Table 2, and
The copper-catalysed asymmetric oxidation of
was next explored. -Keto sulfides have been successfully oxidised
by titanium-catalysed procedure, employing hydrobenzoin,
affording
b-keto sulfides
b
a
b
-keto sulfoxides in modest to excellent yields (57e90%)
and excellent enantioselectivities (in most cases >98% ee).55 Sulfide
13 was successfully oxidised using copper catalysis, affording
sulfoxide 14 in modest yield and enantioselectivity (Scheme 5). To
our knowledge, this represents the first reported preparation of an
enantioenenriched
b-keto sulfoxide through copper-catalysed
asymmetric sulfoxidation. The absolute configuration of 14 was
assigned as R based on the comparison of its optical rotation val-
ue¼þ42.1 (c 1.0, CHCl3) to literature value of (þ)-(R)-2-(phenyl-10-
sulfinyl)-acetophenone¼þ161.7 (CHCl3).56
sulfoxides 2
substituent on the phenyl ring of the benzyl moiety (sulfoxides
2tev, 2z, 2 and 2 , Scheme 3) results in a significant reduction in
x, 2h, 2q, Scheme 3). The presence of a chloro or methyl
a
b
enantioselectivity, but with similar yields relative to the oxidation
of benzyl phenyl sulfide. However, different trends are observed for
the substituents on the aryl moiety. While the presence of a chloro
substituent reduces the efficiency of the oxidation (sulfoxides
2wey, Scheme 3), the presence of a methyl substituent results in
similar yields to those obtained in the oxidation of benzyl phenyl
sulfide (sulfoxides 2qer, Scheme 3). Hence, for the aryl moiety
a clear electronic effect is evident with a decrease in both the ef-
ficiency and enantioselectivity on introduction of an electron
withdrawing chloro substituent, while the electron donating
methyl substituent has much less impact, leading in the case of
sulfoxide 2s to a slight increase in enantioselectivities when ligands
4 and 5 are employed. However, for the benzyl substituent only
a steric effect is evident with a decrease in enantioselectivity on
introduction of either a chloro or methyl substituent, with no vis-
ible impact on reaction efficiency.
2.1. Concluding remarks on the influence of nature of sulfide
and sulfide substituents on enantioselectivity, and its mech-
anistic significance
The results of these investigations of the steric and electronic
nature of the sulfide substituents leads to a number of conclusions:
(1) The sulfide must be attached to at least one aryl moiety to
obtain good enantioselectivity in the copper-catalysed oxida-
tion, with the highest enantioselectivity achieved when the
aryl moiety is a 2-naphthyl substituent (Fig. 3).
(2) The second sulfide substituent does not need to be an aryl or
benzyl moiety, but the steric properties of this substituent have
a strong influence on the enantioselectivity of the oxidation. It
is evident that good enantioselectivity is achieved when the
sulfide substituent is
(3) Electronic/steric modification of aryl and benzyl substituents.
b
-branched, i.e., R0¼i-Pr or larger (Fig. 4).
A
series of diphenyl and dibenzyl sulfides differentially
substituted on the two aryl rings was briefly explored and, as

10174
G.E. O’Mahony et al. / Tetrahedron 69 (2013) 10168e10184
Scheme 3.
The presence of a methyl substituent on the phenyl ring of the
impacts deleteriously on the enantioselectivity of the oxidation
(Table 2, entries 19e36 and Scheme 3, sulfoxides 2tev).
The presence of substituents on the aryl and benzyl moieties has
differing effects on the efficiency and enantioselectivity of the ox-
idation. For the aryl moiety, a clear electronic effect is evident with
benzyl substituent affords sulfoxides with similar yields to benzyl
phenyl sulfoxide, but a significant reduction in enantioselectivity is
observed, in line with our results above which demonstrate that the
presence of a substituent on the phenyl ring of the benzyl moiety

G.E. O’Mahony et al. / Tetrahedron 69 (2013) 10168e10184
10175
Table 3
Interestingly, the presence of a chloro substituent on the phenyl
ring of the benzyl substituent in sulfides 1i and 1h afforded the
corresponding sulfoxides 2i and 2h in reduced enantioselectivity
relative to their unsubstituted counterparts, although the reduction
in enantioselectivity is not as significant in this case (Fig. 5). A large
increase in yield was observed in the synthesis of sulfoxide 2i rel-
ative to its unsubstituted counterpart 2g. However, the opposite
trend was observed with sulfoxides 2f and 2h, with sulfoxide 2h
afforded in lower yield than its unsubstituted counterpart 2f
(Fig. 5).
Copper catalysed oxidation of substituted dibenzyl and diphenyl sulfides
Entry Sulfide R
R0 Ligand 1:2:3a
Yield%b %eec Sulfoxide
2
2
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
i
2-Methylbenzyl Bn 4
2:91:7
3:92:5
83
83
2
3
1
1
4
0
3
1
2
1
2
4
2
2
2
1
2
10
9
10
4
3
2
1
1
13
13
4
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
i
i
2-Methylbenzyl Bn 5
2-Methylbenzyl Bn 6
2-Methylbenzyl Bn 7
2-Methylbenzyl Bn 8
2-Methylbenzyl Bn 10
3-Methylbenzyl Bn 4
3-Methylbenzyl Bn 5
3-Methylbenzyl Bn 6
3-Methylbenzyl Bn 7
3-Methylbenzyl Bn 10
4-Methylbenzyl Bn 4
4-Methylbenzyl Bn 5
4-Methylbenzyl Bn 6
4-Methylbenzyl Bn 7
4-Methylbenzyl Bn 8
4-Methylbenzyl Bn 10
i
i
12:87:1 79
10:87:3 80
19:79:2 71
24:73:3 67
1:89:10 82
1:88:11 80
23:75:2 65
9:80:11 70
44:55:1 48
2:89:9
3:89:8
5:90:5
26:72:2 66
10:78:12 74
35:62:3 54
i
The substituted diphenyl sulfoxides 2
s
, 2r
and 2s were obtained
i
i
from the corresponding sulfides 1 , 1
s
r
and 1s
in poor yields and
i
i
enantioselectivities (Table 3, entries 32e42 and Scheme 4), in
contrast to a study by Islam et al. who obtained both aryl benzyl
and diaryl sulfoxides in good yields in a copper-catalysed racemic
oxidation procedure, indicating a different catalytically active
complex in this case.54 While the poor enantioselectivities achieved
are likely due to poor differentiation between the enantiotopic lone
pairs of the sulfide, the poor yields are perhaps due to the poor co-
ordination of these diaryl sulfides to the copper complex. The
i
i
k
k
k
k
k
l
l
l
l
l
l
m
m
m
m
n
n
n
n
x
k
k
k
k
k
l
l
l
l
l
l
m
m
m
m
n
n
n
n
x
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
82
82
83
substituted dibenzyl sulfoxides 2
iex were obtained from the cor-
responding sulfides 1 in good yields but poor enantioselectiv-
iex
2-Chlorobenzyl
2-Chlorobenzyl
2-Chlorobenzyl
2-Chlorobenzyl
3-Chlorobenzyl
3-Chlorobenzyl
3-Chlorobenzyl
3-Chlorobenzyl
4-Chlorobenzyl
4-Chlorobenzyl
4-Chlorobenzyl
4-Chlorobenzyl
4-Chlorobenzyl
4-Chlorobenzyl
Bn 4
Bn 5
Bn 6
Bn 10
Bn 4
Bn 5
Bn 6
Bn 7
Bn 4
Bn 5
Bn 6
Bn 7
Bn 8
Bn 10
3:92:5
88
ities (Table 3, entries 1e31 and Scheme 4), again indicating poor
differentiation between the enantiotopic faces of these sulfides.
In terms of developing a mechanistic understanding of the
asymmetric sulfur oxidation employing the copper Schiff base
complex, the trends seen in this study are very helpful in providing
some insight. A review of the literature reveals very limited
knowledge of the mechanistic nature of copper mediated sulfur
oxidation and the intermediates involved.4,5,49,54,57 As Kelly’s ear-
lier work demonstrated optimum results using 2 equiv of the ligand
to the copper source in CCl4,58 this approach was used throughout
this study in the hexaneemethanol mixture used in this work.
Accordingly it is reasonable to assume a 2:1 Schiff base:copper
complex in solution, although the nature of the active enantiose-
lective catalyst cannot be inferred on the basis of this experimental
observation alone. Furthermore it is evident that a diverse range of
copper complexes can be envisaged as the catalytically active
species, including mononuclear and dinuclear copper complexes,
with peroxo, oxo or superoxo species.59,60
Accordingly while it is difficult to definitively propose a mech-
anistic model, the results to date indicate quite clearly both steric
and electronic factors are critical in determining the enantiose-
lectivity in the sulfur oxidation process (Fig. 6). It is possible to
envisage co-ordination of the sulfide to a copper complex of the
nature shown in Fig. 7 whereby the efficiency of the complexation
is directly influenced by the electronic properties of the sulfide with
optimum results with mono aryl sulfides, but noticeably decreased
efficiency with diaryl sulfides in contrast to Islam’s study.54 The
enantiofacial control in transfer of the oxygen to the sulfide is
strongly influenced in addition by steric factors, especially on the
second sulfur substituent.
There is direct evidence for sulfoxide inhibition of the oxidation.
Kelly demonstrated that the oxidation of benzyl phenyl sulfide,
using coppereSchiff base catalysis, in the presence of increasing
amounts of DMSO, proceeded with a corresponding reduction in
yield, indicating that the sulfoxide was perhaps competing with the
sulfide to bind to the copper complex.58 The improved efficiencies
obtained when the oxidation is carried out in the presence of NMO
or methanol further demonstrate that the sulfoxide binds to the
copper complex and can be displaced by the co-ordination of NMO
(partial) or methanol (more effective) to the copper complex,
thereby overcoming sulfoxide inhibition.49 In the absence of
methanol or another polar solvent the catalyst turnover is very
limited with typically only 15e30% yield with 2 mol % of the copper
complex. Thus, the efficiency of the oxidation in methanol is much
15:81:4 65
18:77:5 55
64:36:0 24
12:80:8 72
8:81:11 74
20:74:6 68
31:65:4 56
12:86:2 78
11:87:2 80
45:54:1 46
11:83:6 72
40:58:2 52
67:32:1 26
70:30:0 28
65:35:0 13
41:59:0 53
46:54:0 50
86:14:0 10
68:32:0 26
68:32:0 24
x
x
x
x
x
8
1
8
20
9
17
11
12
10
10
7
x
x
x
x
x
s
s
2-Methoxyphenyl Ph 4
2-Methoxyphenyl Ph 5
4-Methoxyphenyl Ph 4
4-Methoxyphenyl Ph 5
4-Methoxyphenyl Ph 6
4-Methylphenyl Ph 4
4-Methylphenyl Ph 5
4-Methylphenyl Ph 6
4-Methylphenyl Ph 7
4-Methylphenyl Ph 8
4-Methylphenyl Ph 10
s
s
r
r
r
s
s
s
s
s
s
r
r
r
s
s
s
s
s
s
91:9:0
79:21:0 16
93:7:0
93:10:0
6
8
4
6
5
6
a
Ratio of 1:2:3 determined by 1H NMR analysis of the crude product.
Yield of 2 after purification by column chromatography.
Enantioselectivities determined by HPLC analysis on chiral column (Chiracel
, 2 , 2 Chiracel OJ-H for 2 , 2 ; Chiracel AS-H for 2 , 2 ; Phenomenex
; absolute configuration of sulfoxides 2 were not
b
c
OD-H for 2
Lux Cellulose-4 for 2
i
l
x
m
s
k
s
n, 2
r
ies
determined.
a decrease in both efficiency and enantioselectivity on introduction
of an electron withdrawing chloro substituent (Table 2, entries
37e50 and Scheme 3, sulfoxides 2wey), while the inductively
electron donating methyl substituent has much less impact, leading
in the case of sulfoxide 2s to a very slight increase in enantiose-
lectivity (Scheme 3). In the case of the benzyl substituent only
a steric effect is evident with a general decrease in enantiose-
lectivity on introduction of either a chloro or methyl substituent,
with no visible impact on reaction efficiency (Table 2, entries 19e61
Scheme 3, sulfoxides 2tev and 2zeb). These results can perhaps be
rationalised on the basis of decreased efficiency of co-ordination of
the sulfide to the copper complex in the presence of the electro-
negative chloro substituent in sulfoxides 2wey compared to sulf-
oxide A.
However, naphthyl sulfoxides 2ze
enantioselectivity relative to benzyl phenyl sulfoxide (Scheme 3).
b were afforded with reduced

10176
G.E. O’Mahony et al. / Tetrahedron 69 (2013) 10168e10184
Scheme 4.
Scheme 5.
present in solution in this environment. Use of a mixed meth-
anolehexane solvent mixture enables balancing of the competing
effects, resulting in the optimum outcome in terms of efficiency and
enantioselectivity.
3. Conclusion
The scope of enantioselective copper mediated sulfur oxidation
has been established with enantioselectivities up to 97% ee, the
highest enantioselectivity reported to date for a copper-mediated
sulfur oxidation. Starting from aryl benzyl sulfide the substrate
scope has been investigated in detail. In the copper-mediated sul-
fide oxidation, the aryl ligand directly attached to the sulfide is
essential for high enantiocontrol, in contrast to our earlier study,
which demonstrated that the benzyl substituent could be replaced
by substituents with similar steric demands, without a detrimental
effect on enantiocontrol. In this work, it is clear that the aryl sub-
stituent is critically important, presumably via an electronic effect.
Significantly, use of naphthyl sulfides results in excellent enantio-
control with comparable enantioselectivities for the 1-naphthyl
benzyl sulfide 1f to phenyl benzyl sulfide but substantially en-
hanced asymmetric induction in the oxidation of the 2-naphthyl
benzyl sulfide 1g, presumably via a combination of steric and
electronic effects. In the copper-mediated enantioselective oxida-
tion of aryl benzyl sulfides the outcome is influenced, to a certain
extent, by the presence of substituents on each of the two aryl rings,
with both steric effects and electronic effects evident (Fig. 6).
Fig. 3. Investigation of steric and electronic effects of R group.
better than in the non-polar toluene, presumably reflecting
decomplexation of the sulfoxide from the copper catalyst post ox-
idation.49 On the other hand the dramatic decrease in enantiose-
lectivity with use of pure methanol as the solvent medium
indicates a dramatic alteration in the nature of the copper complex
Fig. 4. Investigation of steric and electronic effects of R0 group.

G.E. O’Mahony et al. / Tetrahedron 69 (2013) 10168e10184
10177
Fig. 5. Reduction in enantioselectivity with chloro-substituted naphthyl benzyl sulfoxides.
on HPLC elution order and direction of specific rotations. Absolute
configurations for 2j and 2k are the proposed configurations based
on comparison of optical rotation to known literature values for
(R)-decyl phenyl sulfoxide51 and (R)-butyl phenyl sulfoxide.52 Ab-
solute configurations for 2l and 2m are the proposed configurations
based on comparison of optical rotation to known literature value
for (R)-decyl benzyl sulfoxide.53 High resolution precise mass
spectra (HRMS) were recorded on a TOF LCeMS instrument in
electrospray ionisation (ESI) mode, using 50% acetonitrileewater
containing 0.1% formic acid as eluent, samples were made up in
acetonitrile.
Fig. 6. Influence of steric and electronic effects of aryl and benzyl moieties on asym-
metric oxidation.
Racemic sulfoxides were prepared by treatment of the sulfide
with 0.6 equiv of OxoneÒ in acetone at 0 ꢀC. All reactions are carried
out at room temperature unless otherwise indicated. Sulfoxides
2a,61 2b,62 2e,63 2o,64 2p,49 2q,49 2r,49 2s,49 2t,49 2u,49 2v,49 2w,65
2 , 2 , 2
q 15 z 66 s67 and 2s68 have been reported in enantioenriched
form. Sulfoxides 2c,69 2d,70 2g,71 2j,72 2k72, 2l,73 2m,73 2n,74 2x,75
2y,76 a 76 b 76 and 2d 76 l 77 x 78 r79 have been reported in
racemic form only. Sulfoxides 2f, 2h, 2i, 2z, 2 , 2ε, 2 , 2 , 2 , 2 and
have not been previously reported.
2
,
2
,
,
2
,
2
,
2
g
h
i
k
n
2m
Single crystal X-ray diffraction data were collected as described
previously.80 All calculations and refinement were made using the
APEX software.81,82
4.2. Experimental procedure for asymmetric sulfide
oxidation
Fig. 7. Co-ordination of sulfide to copper Schiff base complex.
Copper (II) acetylacetonate (5.2 mg, 2.0 mol %) was added to
a round-bottomed flask containing Schiff base ligand 4 (11.6 mg,
4.0 mol %), and 9:1 hexane/MeOH (1 mL). The resulting solution
was stirred at room temperature for 5 min, and then a solution of
sulfide (1 mmol) in 9:1 hexane/MeOH (1 mL) was added. After
5 min stirring at room temperature. H2O2 (0.130 mL, 30%, 1.1 mmol)
was added in one portion, dropwise to the solution. The reaction
mixture was stirred at room temperature for a further 16 h. Then
H2O (1 mL) and CH2Cl2 (1 mL) were added and the phases sepa-
rated; the organic layer was washed with water (2ꢁ5 mL) and brine
(5 mL), dried and concentrated under reduced pressure to give the
crude product. The ratio of sulfideesulfoxideesulfone in the crude
product was determined by 1H NMR. The product was purified by
column chromatography on silica gel (6:4 hexane/ethyl acetate).
Schiff base ligand can be recovered after chromatography and can
be re-used.
4. Experimental section
4.1. General
Sulfides 1e and 1o were commercially available. For thin-layer
chromatography (TLC), silica gel plates were used and com-
pounds were visualised using UV. Solvents were distilled prior to
use. 1H (300 MHz), 1H (400 MHz) and 13C NMR (75 MHz) were
recorded with spectrometers at 20 ꢀC using CDCl3 as solvent.
Chemical shifts are given in parts per million relative to TMS as the
internal standard. Coupling constants (J) are reported in Hertz.
Chiral HPLC was performed using Chiralpak OD-H, OJ-H, AS-H,
Phenomenex Lux Cellulose-4 and Amylose-2 columns; eluting
with n-hexane and 2-propanol. Specific rotations were recorded at
20 ꢀC in the solvents indicated. The Sodium D line (589 nm) was
used unless otherwise indicated. Samples were analysed in a 1 mL
dual-walled thermostated glass cell of pathlength 10 cm. Sample
temperature control was maintained using an immersion circula-
tor. Absolute configurations were assigned by comparison of the
Sulfoxides A, 2qev were fully characterised in our previous
publication.49
4.2.1. (R)-(ꢂ)-tert-Butyl
benzyl
sulfoxide
(2a,
Table
1,
entry 23).61,70 Crude product contained a mixture of sulfide, sulf-
oxide and sulfone (2:97:1). Purification by chromatography affor-
ded the product as a white solid (173 mg, 88%, 37% ee).
specific rotations with the literature data for 2a, 2b, 2o, 2s, 2w, 2
q
and A. Absolute configurations for 2f and 2g were determined by
single crystal X-ray diffraction on samples recrystallised from
CH2Cl2. Absolute configurations for 2h, 2i, 2q, 2r, 2t, 2u, 2v, 2x, 2y,
Mp 73e75 ꢀC, (lit.70 mp 74e75 ꢀC, racemic); 1H NMR dH
(300 MHz) 1.32 (9H, s), 3.63 (1H, d, A of AB system, J 12.9 Hz), 3.83
(1H, d, B of AB system, J 12.9 Hz), 7.28e7.41 (5H, m); 13C NMR dC
2z, 2a, 2b, 2d, 2z, 2h and 2ε are the proposed configurations based

10178
G.E. O’Mahony et al. / Tetrahedron 69 (2013) 10168e10184
(75 MHz) 23.1, 53.0, 53.7, 128.0, 128.9, 130.0, 132.1; IR (KBr): nmax
/
125.4, 126.5, 127.2, 128.2, 128.3, 129.0, 129.2, 129.5, 130.3, 131.2, 133.2,
138.6; IR (KBr): nmax/cmꢂ1 3058, 1506, 1454, 1049, 770, 698; HRMS
(ESI): Exact mass calculated for C17H15OS [(MþH)þ] 267.0844, found
267.0838; (found: C, 76.38; H, 5.24. C17H14OS requires C, 76.66; H,
5.30);HPLC:tR (S)¼21.6 min, tR (R)¼42.2min[Chiracel AS-H;flow rate
1mLminꢂ1;hexanee2-PrOH(90:10);20ꢀC];¼þ335.8 (c1.03, CHCl3).
Crystal data: C17H14OS, M¼266.34, orthorhombic, space group
cmꢂ1 2962, 1456, 1366, 1034, 700; HPLC: tR (R)¼14.3 min, tR (S)¼
19.0 min [Chiracel OD-H; flow rate 1 mL minꢂ1; hexanee2-PrOH
(90:10); 20 ꢀC]; ¼ꢂ83.6 (c 0.92, CHCl3), ¼ꢂ48.6 (c 1.01, ethanol);
{¼þ140 (c 1.1, EtOH) for (S) >99% ee}.61
4.2.2. (R)-(þ)-Isobutyl benzyl sulfoxide (2b, Table 1, entry
4).62 Crude product contained a mixture of sulfide, sulfoxide and
sulfone (4:94:2). Purification by chromatography afforded the
product as a white solid (171 mg, 87%, 11% ee).
3
ꢀ
ꢀ
P212121, a¼5.6554(8), b¼14.536(2), c¼16.378(2) A, ¼1346.4(3) A ,
n
Z¼4, Dcalcd¼1.314 g cmꢂ3, F000¼560, Mo K
a
radiation,
l
¼0.7107 A,
ꢀ
T¼300(2) K, 2qmax¼26.58ꢀ,
m
¼0.228 mmꢂ1, 25,499 reflections col-
Mp 66e68 ꢀC; 1H NMR dH (300 MHz) 1.04 (6H, 2 overlapping d, J
6.6HzandJ6.6Hz), 2.09e2.27(1H, m, CofABCsystem),2.33(1H, dd,A
of ABC system, J 12.6 Hz and 9.3 Hz), 2.57 (1H, dd, B of ABC system, J
12.6Hzand4.8Hz), 3.92(1H, d,AofABsystem, J12.9Hz),4.03(1H, d,B
of AB system, J 12.9 Hz), 7.22e7.43 (5H, m); 13C NMR dC (75 MHz) 21.6,
22.9, 23.8, 59.0, 60.6, 128.3, 128.9, 130.0; IR (KBr): nmax/cmꢂ1 2960,
1455,1076,1028,699;HPLC:tR (S)¼43.1min, tR (R)¼47.7min[Chiracel
AS-H; flow rate 1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC]; ¼þ15.9
(c 1.0, CHCl3), {Ref. 62¼ꢂ110 (c 0.9, CHCl3) for (S) >99% ee}.
lected, 2764 unique (Rint¼0.073). Final GooF¼1.02, R1¼0.040, [2122
obs. data: I>2s(I)]; wR2¼0.088 (all data). CCDC 891524.
4.2.7. (R)-(þ)-2-Naphthyl benzyl sulfoxide (2g, Table 1,
entry 16).71 Crude product contained a mixture of sulfide, sulfoxide
and sulfone (62:38:0). Purification by chromatography afforded the
product as a white solid (85 mg, 32%, 97% ee).
Mp 155e157 ꢀC, (lit. mp 189e190 ꢀC, racemic).71 1H NMR dH
(300 MHz) 4.08 (1H, d, A of AB system, J 12.6 Hz), 4.16 (1H, d, B of AB
system, J 12.6 Hz), 6.90e7.07 (2H, m), 7.12e7.34 (3H, m), 7.36e7.47
(1H, m), 7.49e7.62 (2H, m), 7.74e7.99 (4H, m); 13C NMR dC (75 MHz)
63.4,120.2,125.3,127.2,127.8,128.0,128.3,128.5,129.0,129.2,130.4,
132.7, 134.5, 139.9; IR (KBr): nmax/cmꢂ1 2955, 1452, 1076, 1039, 695;
HPLC: tR (þ)¼27.0 min, tR (ꢂ)¼38.1 min [Chiracel OD-H; flow rate
1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC]; ¼þ63.7 (c 1.02,
CHCl3). Crystal data: C17H14OS, M¼266.34, triclinic, space group P1,
4.2.3. (ꢂ)-Isopropyl benzyl sulfoxide (2c, Table 1, entry 7).69 Crude
product contained a mixture of sulfide, sulfoxide and sulfone
(0:97:3). Purification by chromatography afforded the product as
a clear oil (157 mg, 86%, 27% ee).
1H NMR dH (300 MHz) 1.29 (3H, d, J 7.2 Hz), 1.33 (3H, d, J 6.6 Hz),
2.59e2.76 (1H, m), 3.91 (2H, s), 7.22e7.43 (5H, m); 13C NMR dC
(75 MHz) 13.8, 16.7, 48.2, 54.9, 128.2, 129.0, 129.9, 130.5; IR (film):
nmax/cmꢂ1 2968, 1497, 1455, 1051, 1020, 700; HPLC: tR (þ)¼
3
ꢀ
ꢀ
a¼5.7020(9), b¼8.4251(13), c¼14.510(2) A, ¼675.96(18) A , Z¼2,
n
Dcalcd¼1.309 g cmꢂ3, F000¼280, Mo K
a
radiation,
l
¼0.7107 A,
ꢀ
36.4 min, tR (ꢂ)¼63.6 min [Chiracel AS-H; flow rate 1 mL minꢂ1
hexanee2-PrOH (90:10); 20 ꢀC]; ¼ꢂ11.1 (c 1.27, CHCl3).
;
T¼296(2) K, 2qmax¼25.78ꢀ,
m
¼0.227 mmꢂ1 13,658 reflections col-
lected, 4784 unique (Rint¼0.068). Final GooF¼0.90, R1¼0.043, [3208
obs. data: I>2
s
(I)]; wR2¼0.094 (all data). CCDC 891525.
4.2.4. (þ)-Cyclohexyl benzyl sulfoxide (2d, Table 1, entry
10).70 Crude product contained a mixture of sulfide, sulfoxide and
sulfone (3:94:3). Purification by chromatography afforded the
product as a clear oil (196 mg, 88%, 27% ee).
4.2.8. (R)-(þ)-1-Naphthyl 4-chlorobenzyl sulfoxide (2h, Table 1, entry
18). Crude product contained a mixture of sulfide, sulfoxide and
sulfone (65:35:0). Purification by chromatography afforded the
product as a white solid (84 mg, 28%, 71% ee).
1H NMR dH (300 MHz) 1.17e1.76 (5H, m), 1.77e2.01 (4H, m),
2.02e2.19 (1H, m), 2.38e2.54 (1H, m) 3.90 (1H, d, A of AB system, J
12.9 Hz), 3.99 (1H, d, B of AB system, J 12.9 Hz), 7.20e7.45 (5H, m);
13C NMR dC (75 MHz) 24.0, 25.2, 25.48, 25.50, 26.9, 54.8, 56.9, 128.2,
128.9, 130.0, 130.7; IR (film): nmax/cmꢂ1 2929, 1453, 1028, 698;
HPLC: tR (ꢂ)¼32.4 min, tR (þ)¼39.7 min [Phenomenex Lux
Amylose-2; flow rate 1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC];
¼þ4.7 (c 1.0, CHCl3).
Mp 123e125 ꢀC; 1H NMR dH (300 MHz) 4.00 (1H, d, A of AB
system, J 12.9 Hz), 4.25 (1H, d, B of AB system, J 12.9 Hz), 6.68e6.82
(2H, m), 7.07e7.20 (2H, m), 7.45e7.72 (4H, m), 7.86e8.01 (3H, m);
13C NMR dC (75 MHz) 60.1, 121.3, 123.9, 125.4, 126.6, 127.3, 127.6,
128.3, 129.0, 129.1, 131.4, 131.6, 133.2, 134.4, 137.8; IR (KBr): nmax
/
cmꢂ1 3056, 1491, 1051, 801, 770; HRMS (ESI): Exact mass calculated
for C17H14ClOS [(MþH)þ] 301.0454, found 301.0450; HPLC: tR (ꢂ)¼
21.2 min, tR (þ)¼53.3 min [Chiracel OD-H; flow rate 1 mL minꢂ1
hexanee2-PrOH (90:10); 20 ꢀC]; ¼þ355.4 (c 1.06, CHCl3).
;
4.2.5. Benzyl methyl sulfoxide (2e, Table 1, entry 13).63 Crude
product contained a mixture of sulfide, sulfoxide and sulfone
(5:94:1). Purification by chromatography afforded the product as
a clear oil (134 mg, 87%, 4% ee).
4.2.9. (R)-(þ)-2-Naphthyl 4-chlorobenzyl sulfoxide (2i, Table 1, entry
19). Crude product contained a mixture of sulfide, sulfoxide and
sulfone (23:75:2). Purification by chromatography afforded the
product as a white solid (202 mg, 67%, 90% ee).
1H NMR dH (300 MHz) 2.46 (3H, s), 3.93 (1H, d, A of AB system, J
12.6 Hz), 4.07 (1H, d, B of AB system, J 12.6 Hz), 7.20e7.43 (5H, m);
13C NMR dC (75 MHz) 37.3, 60.3, 128.5, 129.0, 129.7, 130.0; IR (film):
nmax/cmꢂ1 3032, 2150, 1497, 1455, 1028, 700; HPLC: tR¼53.4 min,
Mp 196e198 ꢀC; 1H NMR dH (300 MHz) 4.05 (1H, d, A of AB system,
J 12.6 Hz), 4.11 (1H, d, B of AB system, J 12.9 Hz), 6.90 (2H, d, J 8.1 Hz),
7.09e7.31 (2H, m), 7.41 (1H, dd, J 8.4 Hz and J 1.5 Hz), 7.49e7.68 (2H,
m), 7.74e8.01 (4H, m); 13C NMR dC (75 MHz) 62.2, 120.1, 125.2, 127.4,
127.5,127.9,128.1,128.5,128.6,129.2,131.7,132.7,134.47,134.54,139.5;
IR (KBr): nmax/cmꢂ1 2958, 1490, 1038, 823, 749; HRMS (ESI): Exact
mass calculated for C17H14ClOS [(MþH)þ] 301.0454, found 301.0445;
HPLC: tR (þ)¼33.0 min, tR (ꢂ)¼49.4 min [Chiracel OD-H; flow rate
1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC]; ¼þ117.0 (c 1.0, CHCl3).
tR¼60.0 min, 4% ee, [Chiracel OD-H; flow rate 1 mL minꢂ1
;
hexanee2-PrOH (95:5); 20 ꢀC], tR¼50.7 min, tR¼63.1 min, 2% ee,
[Phenomenex Lux Cellulose-4; flow rate 1 mL minꢂ1; hexanee2-
PrOH (90:10); 20 ꢀC], better resolution was obtained using Phe-
nomenex Lux Cellulose-4 column; w0 (c 1.0, CHCl3).
4.2.6. (R)-(þ)-1-Naphthyl benzyl sulfoxide (2f, Table 1, entry
14). Crude product contained a mixture of sulfide, sulfoxide and
sulfone (48:52:0). Purification by chromatography afforded the
product as a white solid (123 mg, 46%, 75% ee).
4.2.10. (R)-(þ)-Octyl phenyl sulfoxide (2j, Table 1, entry 20).72 Crude
product contained a mixture of sulfide, sulfoxide and sulfone
(32:62:6). Purification by chromatography afforded the product as
a clear oil (122 mg, 55%, 36% ee).
Mp104e106 ꢀC; 1H NMR dH (300 MHz) 4.06 (1H, d, A of AB system,
J 12.6 Hz), 4.26 (1H, d, B of AB system, J 12.6 Hz), 6.81e6.97 (2H, m),
7.10e7.32 (3H, m), 7.43e7.62 (3H, m), 7.77 (1H, dd, J 8.6 Hz and J
1.6 Hz), 7.84e8.01 (3H, m); 13C NMR dC (75 MHz) 61.7, 121.5, 123.8,
1H NMR dH (300 MHz) 0.87 (3H, t, J 6.6 Hz), 1.12e1.83 (12H, m),
2.70e2.86 (2H, m), 7.43e7.68 (5H, m); 13C NMR dC (75.5 MHz) 14.0,

G.E. O’Mahony et al. / Tetrahedron 69 (2013) 10168e10184
10179
22.2, 22.6, 28.7, 29.0, 29.1, 31.7, 57.4,124.0,129.2,130.9,144.1; IR (KBr):
nmax/cmꢂ1 2927,1443, 1088,1046, 748, 693; HPLC: tR (S)¼18.8 min, tR
(R)¼23.4 min [Chiracel AS-H; flow rate 1 mL minꢂ1; hexanee2-PrOH
(90:10); 20 ꢀC]; ¼þ65.1 (c 1.0, CHCl3), ¼þ57.5 (c 1.03, acetone),
¼þ61.2 (c 1.00, ethanol); absolute configuration determined by
comparison of optical rotation to literature value of (R)-decyl phenyl
sulfoxide¼þ140 (acetone) for (R) >98% ee51 and (R)-butyl phenyl
sulfoxide¼þ181 (c 9.42, ethanol) for (R) >99% ee.52
HPLC: tR (ꢂ)¼81.8 min, tR (þ)¼112.9 min [Chiracel AS-H; flow rate
1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC]; ¼þ2.3 (c 1.0, CHCl3).
4.2.15. (R)-(þ)-Allyl phenyl sulfoxide (2o, Table 1, entry 31).31 Crude
product contained a mixture of sulfide, sulfoxide and sulfone
(26:74:0). Purification by chromatography afforded the product as
a clear oil (111 mg, 67%, 29% ee).
1H NMR dH (300 MHz) 3.43e3.65 (2H, m), 5.20 (1H, d, J 16.4 Hz),
5.39 (1H, d, J 10.5 Hz), 5.57e5.75 (1H, m), 7.42e7.69 (5H, m); 13C
NMR dC (75 MHz) 60.9, 123.9, 124.4, 125.3, 129.0, 131.0, 143.0; IR
(film): nmax/cmꢂ1 3058, 1635, 1444, 1090, 1042, 692; HPLC: tR (R)¼
4.2.11. (R)-(þ)-Dodecyl
phenyl
sulfoxide
(2k,
Table
1,
entry 23).72 Crude product contained a mixture of sulfide, sulfoxide
and sulfone (29:65:6). Purification by chromatography afforded the
product as a white solid (167 mg, 60%, 57% ee).
11.3 min, tR (S)¼14.1 min [Chiracel OJ-H; flow rate 1 mL minꢂ1
;
hexanee2-PrOH (90:10); 20 ꢀC]; ¼þ24.2 (c 1.0, CHCl3),
{Ref. 64¼ꢂ160.2 (c 0.9, CHCl3) for (S) >97% ee}.
Mp 50e53 ꢀC; 1H NMR dH (300 MHz) 0.88 (3H, t, J 6.3 Hz),
1.16e1.84 (20H, m), 2.70e2.84 (2H, m), 7.43e7.67 (5H, m); 13C NMR
dC (75.5 MHz) 14.1, 22.2, 22.7, 28.7, 29.2, 29.3, 29.5, 29.6, 31.9, 57.4,
124.0, 129.2, 130.9, 144.2; IR (KBr): nmax/cmꢂ1 2918, 1442, 1036,
1022, 687; HPLC: tR (S)¼27.5 min, tR (R)¼34.8 min [Chiracel AS-H;
flow rate 1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC]; ¼þ69.5 (c
1.26, CHCl3), ¼þ76.4 (c 1.36, acetone), ¼þ88.4 (c 1.00, ethanol);
absolute configuration determined by comparison of optical rota-
tion to literature value of (R)-decyl phenyl sulfoxide¼þ140 (ace-
tone) for (R) >98% ee51 and (R)-butyl phenyl sulfoxide¼þ181 (c
9.42, ethanol) for (R) >99% ee.52
4.2.16. (R)-(þ)-Benzyl 2-chlorophenyl sulfoxide (2w, Table 2, entry
37).65 Crude product contained a mixture of sulfide, sulfoxide and
sulfone (67:32:1). Purification by chromatography afforded the
product as a white solid (65 mg, 26%, 48% ee).
Mp 59e61 ꢀC, (lit.83 60 ꢀC, racemic) 1H NMR dH (300 MHz) 3.96
(1H, d, A of AB system, J 12.9 Hz), 4.01 (1H, d, B of AB system, J
12.6 Hz), 6.84e6.93 (2H, m), 7.18e7.33 (5H, m), 7.36e7.48 (2H, m);
13C NMR dC (75 MHz) 62.3, 125.8, 128.7, 129.3, 131.7, 134.6, 137.6,
140.9; IR (KBr) nmax/cmꢂ1 2963, 1476, 1408, 1390, 1097, 1037, 1013,
824; HPLC: tR (S)¼27.1 min, tR (R)¼32.2 min [Chiracel OJ-H; flow
rate 1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC]; ¼þ162.6 (c 1.05,
CHCl3), {Ref. 65¼þ397.1 (c 1.0, CHCl3) for (R)¼95% ee}.
4.2.12. (R)-(þ)-Octyl benzyl sulfoxide (2l, Table 1, entry 25).73 Crude
product contained a mixture of sulfide, sulfoxide and sulfone
(7:85:8). Purification by chromatography afforded the product as
a white solid (192 mg, 76%, 22% ee).
4.2.17. (R)-(þ)-Benzyl 3-chlorophenyl sulfoxide (2x, Table 2, entry
41).75 Crude product contained a mixture of sulfide, sulfoxide and
sulfone (60:39:1). Purification by chromatography afforded the
product as white solid (83 mg, 33%, 59% ee).
Mp 72e74 ꢀC, (lit.73 mp 71e71.5 ꢀC, racemic); 1H NMR dH
(300 MHz) 0.87 (3H, t, J 6.3 Hz), 1.12e1.53 (10H, m), 1.60e1.86 (2H,
m), 2.56 (2H, t, J 7.8 Hz), 3.93 (1H, d, A of AB system, J 12.9 Hz), 4.02
(1H, d, B of AB system, J 12.9 Hz), 7.20e7.52 (5H, m); 13C NMR dC
(75.5 MHz) 14.1, 22.4, 22.6, 28.8, 29.0, 29.1, 31.7, 51.0, 58.3, 128.3,
128.9,129.9,130.0; IR (KBr): nmax/cmꢂ1 2918,1455,1026, 698; HPLC:
tR (S)¼24.1 min, tR (R)¼34.8 min [Phenomenex Lux Cellulose-4;
flow rate 1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC]; ¼þ9.4 (c
1.0, CHCl3); absolute configuration determined by comparison of
optical rotation to literature value of (R)-decyl benzyl
sulfoxide¼þ76.9 (c 1.9, CHCl3) for (R) >99% ee.53
Mp 106e108 ꢀC, (lit.75 106e107 ꢀC, racemic); 1H NMR dH
(300 MHz) 4.00 (1H, d, A of AB system, J 12.6 Hz), 4.10 (1H, d, B of AB
system, J 12.6 Hz), 6.90e7.05 (2H, m), 7.14e7.50 (7H, m); 13C NMR dC
(75 MHz) 63.6, 122.6, 124.5, 128.53, 128.56, 128.6, 130.0, 130.4, 131.3,
135.3, 144.9; IR (KBr) nmax/cmꢂ1 2957, 1455, 1409, 1073, 1039, 695;
HPLC: tR (S)¼15.9 min, tR (R)¼22.3 min [Chiracel OJ-H; flow rate
1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC]; ¼þ142.0 (c 1.0, CHCl3).
4.2.18. (R)-(þ)-Benzyl 4-chlorophenyl sulfoxide (2y, Table 2, entry
46).76 Crude product contained a mixture of sulfide, sulfoxide and
sulfone (28:72:0). Purification by chromatography afforded the
product as white solid (168 mg, 67%, 52% ee).
4.2.13. (R)-(þ)-Dodecyl benzyl sulfoxide (2m, Table 1, entry
27).73 Crude product contained a mixture of sulfide, sulfoxide and
sulfone (5:89:6). Purification by chromatography afforded the
product as a white solid (259 mg, 84%, 21% ee).
Mp 126e129 ꢀC, (lit.84 120e122 ꢀC, racemic); 1H NMR dH
(400 MHz) 3.90 (1H, d, A of AB system, J 12.8 Hz), 4.02 (1H, d, B of
AB system, J 12.8 Hz), 6.81e6.95 (2H, m), 7.12e7.36 (7H, m); IR (KBr)
nmax/cmꢂ1 2966, 1474, 1454, 1389, 1035, 698; HPLC: tR (R)¼41.2 min,
tR (S)¼46.3 min [Chiracel OD-H; flow rate 1 mL minꢂ1; hexanee2-
PrOH (95:5); 20 ꢀC]; ¼þ131.5 (c 1.0, CHCl3).
Mp 77e79 ꢀC, (lit.73 mp 80e80.5 ꢀC, racemic); 1H NMR dH
(300 MHz) 0.88 (3H, t, J 6.6 Hz), 1.15e1.51 (18H, m), 1.62e1.86 (2H,
m), 2.56 (2H, t, J 7.5 Hz), 3.93 (1H, d, A of AB system, J 12.9 Hz), 4.02
(1H, d, B of AB system, J 12.9 Hz), 7.21e7.52 (5H, m); 13C NMR dC
(75.5 MHz) 14.1, 22.4, 22.7, 28.8, 29.2, 29.3, 29.5, 29.6, 31.9, 51.0,
58.3,128.3,128.9,129.9,130.0; IR (KBr): nmax/cmꢂ1 2916,1454,1020,
698; HPLC: tR (S)¼48.3 min, tR (R)¼66.0 min [Chiracel AS-H; flow
rate 1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC]; ¼þ13.1 (c 1.0,
CHCl3); absolute configuration determined by comparison of opti-
cal rotation to literature value of (R)-decyl benzyl sulfoxide¼þ76.9
(c 1.9, CHCl3) for (R) >99% ee.53
4.2.19. (R)-(þ)-2-Chlorobenzyl phenyl sulfoxide (2z, Table 2, entry
51). Crude product contained a mixture of sulfide, sulfoxide and
sulfone (18:78:4). Purification by chromatography afforded the
product as white solid (111 mg, 67%, 29% ee).
Mp 62e64 ꢀC; 1H NMR dH (300 MHz) 4.17 (1H, d, A of AB system,
J 12.6 Hz), 4.25 (1H, d, B of AB system, J 12.6 Hz), 7.03e7.30 (3H, m),
7.32e7.53 (6H, m); 13C NMR dC (75 MHz) 61.8, 124.3, 126.9, 128.1,
129.0, 129.6, 129.8, 131.4, 132.7, 134.9, 143.2; IR (KBr) nmax/cmꢂ1
3056, 1474, 1444, 1047, 748; (found: C, 62.35; H, 4.35. C13H11ClOS
requires C, 62.27; H, 4.42); HPLC: tR (S)¼64.4 min, tR (R)¼71.3 min
[Chiracel AS-H; flow rate 1 mL minꢂ1; hexanee2-PrOH (90:10);
20 ꢀC]; ¼þ23.8 (c 1.0, CHCl3).
4.2.14. (þ)-Allyl benzyl sulfoxide (2n, Table 1, entry 29).74 Crude
product contained a mixture of sulfide, sulfoxide and sulfone
(6:94:0). Purification by chromatography afforded the product as
a clear oil (157 mg, 87%, 11% ee).
1H NMR dH (300 MHz) 3.20e3.33 (1H, m), 3.36e3.50 (1H, m),
3.96 (1H, d, A of AB system, J 12.9 Hz), 4.01 (1H, d, B of AB system, J
13.2 Hz), 5.39 (1H, d, J 17 Hz), 5.49 (1H, d, J 10.2 Hz), 5.82e6.02 (1H,
m), 7.21e7.43 (5H, m); 13C NMR dC (75 MHz) 54.2, 56.9, 123.7, 125.8,
128.4, 129.0, 129.9, 130.1; IR (KBr): nmax/cmꢂ1 2963, 1455, 1031, 700;
4.2.20. (R)-(þ)-3-Chlorobenzyl phenyl sulfoxide (2
a, Table 2, entry
55).76 Crude product contained a mixture of sulfide, sulfoxide and

10180
G.E. O’Mahony et al. / Tetrahedron 69 (2013) 10168e10184
sulfone (10:89:1). Purification by chromatography afforded the
product as white solid (206 mg, 82%, 42% ee).
4.2.25. (R)-(þ)-2-Chlorobenzyl 4-methylphenyl sulfoxide (2
z, Table
2, entry 71). Crude product contained a mixture of sulfide, sulfox-
ide and sulfone (19:80:1). Purification by chromatography afforded
the product as a clear oil (196 mg, 74%, 37% ee).
Mp 79e82 ꢀC; 1H NMR dH (300 MHz) 3.98 (2H, s), 6.84e6.94 (2H,
m), 7.13e7.31 (2H, m), 7.34e7.52 (5H, m); 13C NMR dC (75 MHz)
62.8, 124.3, 128.4, 128.6, 129.0, 129.6, 130.3, 131.1, 131.4, 134.2, 142.4;
IR (KBr) nmax/cmꢂ1 2970, 1472, 1444, 1428, 1086, 1039, 704; HPLC: tR
(R)¼18.0 min, tR (S)¼22.8 min [Chiracel OD-H; flow rate
1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC]; ¼þ24.1 (c 1.2, CHCl3).
1H NMR dH (300 MHz) 2.41 (3H, s), 4.15 (1H, d, A of AB system,
J 12.6 Hz), 4.24 (1H, d, B of AB system, J 12.6 Hz), 7.02e7.44 (8H,
m, AreH); 13C NMR dC (75 MHz) 21.5, 61.9, 124.3, 126.9, 128.3,
129.6, 129.7, 129.8, 132.7, 134.9, 140.0, 141.8; IR (film): nmax/cmꢂ1
2923, 1474, 1084, 1054, 808, 762; HRMS (ESI): Exact mass calcu-
ClOS [(MþH)þ] 265.0454, found 265.0448;
35
4.2.21. (R)-(þ)-4-Chlorobenzyl phenyl sulfoxide (2
b
, Table 2, entry
lated for
C
H
14 14
60).76 Crude product contained a mixture of sulfide, sulfoxide and
sulfone (9:90:1). Purification by chromatography afforded the
product as a white solid (213 mg, 85%, 49% ee).
(found: C, 63.44; H, 5.03. C14H13ClOS requires C, 63.51; H, 4.95);
HPLC: tR (S)¼51.5 min, tR (R)¼60.3 min [Chiracel AS-H; flow rate
1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC]; ¼þ29.0 (c 1.1,
CHCl3).
Mp 167e169 ꢀC, (lit.85 173 ꢀC, racemic); 1H NMR dH (400 MHz)
3.99 (1H, d, A of AB system, J 12.8 Hz), 4.08 (1H, d, B of AB system, J
12.6 Hz), 6.92e7.05 (2H, m), 7.18e7.52 (7H, m); IR (KBr) nmax/cmꢂ1
2962, 1455, 1442, 1034, 745; HPLC: tR (R)¼15.9 min, tR (S)¼19.4 min
[Chiracel OD-H; flow rate 1 mL minꢂ1; hexanee2-PrOH (90:10);
20 ꢀC]; ¼þ52.7 (c 1.2, CHCl3).
4.2.26. (R)-(þ)-3-Chlorobenzyl 4-methylphenyl sulfoxide (2
h, Table
2, entry 74).66 Crude product contained a mixture of sulfide, sulf-
oxide and sulfone (24:75:1). Purification by chromatography
afforded the product as a white solid (185 mg, 70%, 61% ee).
Mp 90e93 ꢀC [lit. mp 88e88.5 ꢀC, (þ)-enantiomer, enantio-
4.2.22. (ꢂ)-2-Methylbenzyl 4-methylphenyl sulfoxide (2
g
, Table 2,
pure]66 1H NMR dH (300 MHz) 2.40 (3H, s), 3.94 (1H, d, A of AB
;
entry 62). Crude product contained a mixture of sulfide, sulfoxide
and sulfone (28:69:3). Purification by chromatography afforded the
product as a white solid (151 mg, 62%, 32% ee).
system, J 12.6 Hz), 3.99 (1H, d, B of AB system, J 12.9 Hz), 6.84e6.95
(2H, m), 7.13e7.33 (6H, m); 13C NMR dC (75 MHz) 21.5 (AreCH3),
62.9,124.4,128.3,128.6,129.6,129.7,130.3,131.3,134.2,139.2,142.0;
IR (KBr): nmax/cmꢂ1 2917, 1431, 1085, 1034, 817, 789; HPLC: tR (R)¼
1H NMR dH (300 MHz) 2.19 (3H, s), 2.40 (3H, s), 3.97 (1H, d, A of
AB system, J 12.6 Hz), 4.25 (1H, d, B of AB system, J 12.6 Hz), 6.86
(1H, d, J 7.5 Hz), 7.01e7.42 (7H, m); 13C NMR dC (75 MHz) 19.5, 21.5,
62.1, 124.5, 126.1, 128.1, 128.5, 129.6, 130.5, 131.5, 137.7, 139.9, 141.7;
IR (film): nmax/cmꢂ1 2922, 1494, 1083, 1045, 809, 771; HRMS (ESI):
Exact mass calculated for C15H17OS [(MþH)þ] 245.1000, found
245.0988; (found: C, 73.54; H, 6.66. C15H16OS requires C, 73.73; H,
6.60); HPLC: tR (þ)¼27.1 min, tR (ꢂ)¼32.2 min [Chiracel OJ-H; flow
rate 1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC]; HPLC: tR (þ)¼
46.8 min, tR (S)¼61.9 min [Chiracel AS-H; flow rate 1 mL minꢂ1
;
hexanee2-PrOH (90:10); 20 ꢀC]; ¼þ72.0 (c 1.0, CHCl3), ¼þ135.1 (c
1.0, acetone) {Ref. 66¼þ295 (acetone) for (þ) >99% ee}.
4.2.27. (R)-(þ)-4-Chlorobenzyl 4-methylphenyl sulfoxide (2
q, Table
2, entry 77).15 Crude product contained a mixture of sulfide, sulf-
oxide and sulfone (13:87:0). Purification by chromatography
afforded the product as a white solid (214 mg, 81%, 69% ee).
Mp155e157 ꢀC; 1HNMRdH (300MHz) 2.40(3H, s), 3.97 (2H, s), 6.90
(2H, d, J 8.4 Hz), 7.16e7.33 (6H, m); 13C NMR dC (75 MHz) 21.5, 62.5,
124.4, 127.7, 128.6, 129.7, 131.7, 134.3, 139.2, 141.8; IR (KBr): nmax/cmꢂ1
2966,1493,1034, 812; HPLC: tR (R)¼28.8 min, tR (S)¼33.0 min [Chiracel
OD-H; flow rate 1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC]; ¼þ83.5
(c 1.0, CHCl3), {Ref. 15¼ꢂ140 (c 0.5, CHCl3) for (S)¼98% ee}.
48.2 min, tR (ꢂ)¼63.0 min [Chiracel AS-H; flow rate 1 mL minꢂ1
hexanee2-PrOH (90:10); 20 ꢀC]; ¼ꢂ3.7 (c 1.65, CHCl3).
;
4.2.23. (R)-(þ)-3-Methylbenzyl 4-methylphenyl sulfoxide (2
d, Table
2, entry 65).76 Crude product contained a mixture of sulfide, sulf-
oxide and sulfone (17:81:2). Purification by chromatography
afforded the product as a white solid (185 mg, 76%, 52% ee).
Mp 65e68 ꢀC; 1H NMR dH (300 MHz) 2.27 (3H, s), 2.40 (3H, s), 3.91
(1H, d, A of AB system, J 12.3 Hz), 4.06 (1H, d, B of AB system, J 12.6 Hz),
6.74e6.85 (2H, m), 7.03e7.33 (6H, m); 13C NMR dC (75 MHz) 21.3, 21.5,
64.0,124.5,127.4,128.4,129.0,129.3,129.5,131.1,138.2,139.8,141.6; IR
(KBr): nmax/cmꢂ1 2919,1493,1085,1044, 789; HPLC: tR (R)¼25.9 min,
4.2.28. Benzyl 2-methylbenzyl sulfoxide (2i, Table 3, entry 1). Crude
product contained a mixture of sulfide, sulfoxide and sulfone
(2:91:7). Purification by chromatography afforded the product as
a white solid (203 mg, 83%, 2% ee).
Mp 107e109 ꢀC; 1H NMR dH (300 MHz) 2.26 (3H, s), 3.90e4.08
(4H, m), 7.13e7.43 (9H, m); 13C NMR dC (75 MHz) 19.7, 56.4, 58.3,
126.5, 128.4, 128.6, 129.0, 129.1, 130.1, 130.4, 130.8, 131.1, 137.4; IR
(KBr) nmax/cmꢂ1 2971, 1495, 1455, 1029, 1012, 698; (found: C, 73.64;
H, 6.81. C15H16OS requires C, 73.73; H, 6.60); HPLC: tR¼49.6 min,
tR¼56.4 min [Chiracel OD-H; flow rate 1 mL minꢂ1; hexanee2-
PrOH (90:10); 20 ꢀC].
tR (S)¼29.8 min, 51% ee, [Chiracel OD-H; flow rate 1 mL minꢂ1
;
hexanee2-PrOH (90:10); 20ꢀC], tR (S)¼45.3 min, tR (R)¼60.0 min, 52%
ee, [Phenomenex Lux Cellulose-4; flow rate 1 mL minꢂ1; hexanee2-
PrOH (95:5); 20 ꢀC], better resolution was achieved using Phenom-
enex Lux Cellulose-4 column; ¼þ45.6 (c 1.0, CHCl3).
4.2.24. (R)-(þ)-2-Chlorobenzyl 2-methoxyphenyl sulfoxide (2ε, Table
2, entry 68). Crude product contained a mixture of sulfide, sulfox-
ide and sulfone (19:80:1). Purification by chromatography afforded
the product as a white solid (211 mg, 75%, 70% ee).
4.2.29. Benzyl 3-methylbenzyl sulfoxide (2k, Table 3, entry 7). Crude
product contained a mixture of sulfide, sulfoxide and sulfone
(1:89:10). Purification by chromatography afforded the product as
a white solid (200 mg, 82%, 3% ee).
Mp 71e73 ꢀC; 1H NMR dH (300 MHz) 3.83 (3H, s), 4.13 (1H, d, A of
AB system, J 12.6 Hz), 4.53 (1H, d, B of AB system, J 12.6 Hz), 6.88
(1H, d, J 8.4 Hz), 7.03e7.15 (1H, m), 7.16e7.37 (4H, m), 7.38e7.50
(1H, m), 7.59 (1H, dd, J 7.8 Hz and J 1.5 Hz); 13C NMR dC (75 MHz)
55.6, 57.8, 110.3, 121.4, 125.4, 126.6, 128.8, 129.4, 129.5, 130.6, 132.2,
Mp 83e85 ꢀC; 1H NMR dH (300 MHz) 2.35 (3H, m), 3.79e3.99
(4H, m), 7.03e7.43 (9H, m); 13C NMR dC (75 MHz) 21.4, 57.4, 57.5,
127.1, 128.3, 128.8, 128.9, 129.2, 130.1, 130.15, 130.23, 130.8, 138.7; IR
(KBr) nmax/cmꢂ1 2916, 1495, 1454, 1029, 699; (found: C, 73.82; H,
6.74. C15H16OS requires C, 73.73; H, 6.60); HPLC: tR¼94.4 min,
tR¼112.9 min [Chiracel AS-H; flow rate 1 mL minꢂ1; hexanee2-
PrOH (90:10); 20 ꢀC].
132.9, 134.9, 155.5; IR (KBr): nmax/cmꢂ1 2938, 1477, 1274, 1040, 757;
35
HRMS (ESI): Exact mass calculated for C
H
14 14
ClO2S [(MþH)þ]
281.0403, found 281.0402; (found: C, 59.79; H, 4.71. C14H13ClO2S
requires C, 59.89; H, 4.67); HPLC: tR (S)¼39.6 min, tR (R)¼61.3 min
[Chiracel AS-H; flow rate 1 mL minꢂ1; hexanee2-PrOH (90:10);
20 ꢀC]; ¼þ228.3 (c 1.0, CHCl3).
4.2.30. Benzyl 4-methylbenzyl sulfoxide (2
l,
Table 3, entry
12).77 Crude product contained a mixture of sulfide, sulfoxide and

G.E. O’Mahony et al. / Tetrahedron 69 (2013) 10168e10184
10181
sulfone (2:89:9). Purification by chromatography afforded the
product as a white solid (200 mg, 82%, 4% ee).
HPLC: tR¼81.1 min, tR¼87.8 min [Phenomenex Lux Cellulose-4;
flow rate 1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC].
Mp 97e99 ꢀC (lit.77 mp 94 ꢀC); 1H NMR dH (300 MHz) 2.35 (3H,
m), 3.79e3.95 (4H, m), 7.18 (4H, s), 7.23e7.43 (5H, m); 13C NMR dC
(75 MHz) 21.2, 57.0, 57.2, 126.9, 128.3, 128.9, 129.7, 130.0, 130.2,
130.3, 138.3; IR (KBr) nmax/cmꢂ1 2957, 1495, 1454, 1036, 699; HPLC:
4.2.36. 4-Methylphenyl phenyl sulfoxide (2s
, entry 37).88 Crude
product contained a mixture of sulfide, sulfoxide and sulfone
(68:32:0). Purification by chromatography afforded the product as
a white solid (56 mg, 26%, 10% ee).
tR¼40.9 min, tR¼44.9 min [Chiracel OD-H; flow rate 1 mL minꢂ1
;
hexanee2-PrOH (90:10); 20 ꢀC].
Mp 73e76 ꢀC (lit.89 mp 78e82 ꢀC); 1H NMR dH (400 MHz) 2.47 (3H,
s), 7.22e7.29 (3H, m), 7.40e7.57 (4H, m), 7.60e7.66 (2H, m); IR (KBr)
nmax/cmꢂ1 2920, 1443, 1090, 1044; HPLC: tR¼60.2 min, tR¼87.8 min
[Chiracel AS-H; flow rate 1 mL minꢂ1;hexanee2-PrOH(90:10);20ꢀC].
4.2.31. Benzyl 2-chlorobenzyl sulfoxide (2m,
entry 18).86 Crude
product contained a mixture of sulfide, sulfoxide and sulfone
(3:92:5). Purification by chromatography afforded the product as
a white solid (233 mg, 88%, 10% ee).
4.2.37.
b-Keto sulfoxide 14. Crude product contained a mixture of
Mp 116e119 ꢀC (lit.86 mp 112e113 ꢀC); 1H NMR dH (300 MHz)
3.91 (1H, d, A of AB system 1, J 12.9 Hz), 3.98 (1H, d, A of AB system
2, J 12.9 Hz), 4.03 (1H, d, B of AB system 2, J 12.9 Hz), 4.23 (1H, d, B of
AB system 2, J 12.9 Hz), 7.19e7.46 (9H, m); 13C NMR dC (75 MHz)
55.8, 58.4, 127.3, 128.4, 128.9, 129.0, 129.8, 129.9, 130.1, 132.5, 134.5;
IR (KBr) nmax/cmꢂ1 3061, 1496, 1474, 1454, 1042, 699; HPLC:
sulfide, sulfoxide and sulfone (68:32:0). Purification by chroma-
tography afforded the product as a white solid (49 mg, 20%, 30% ee).
Mp 92e94 ꢀC; 1H NMR dH (400 MHz) 1.30 (3H, t, J 8.2 Hz, ArCH3),
2.60e2.72 (1H, A of ABX system, CH2CH3), 2.75e2.90 (1H, B of ABX
system, CH2CH3), 4.24 (1H, d, A of AB system, J 13.2 Hz, SOCH2), 4.45
(1H, d, B of AB system, J 13.2 Hz, SOCH2), 7.21e7.32 (1H, m, AreH),
7.35e7.63 (5H, m, AreH), 7.84e8.02 (3H, m, AreH); 13C NMR dC
(75.5 MHz) 15.1 (CH2CH3), 24.7 (CH2CH3), 62.3 (SOCH2),124.0 (CHAr),
127.5 (CHAr), 128.8 (CHAr), 128.9 (CHAr), 129.0 (CHAr), 131.6 (CHAr),
134.1 (CHAr), 136.2 (CAr(q)), 141.15 (CAr(q)), 141.20 (CAr(q)), 191.36
(CAr(q), C]O); (found C, 70.36; H, 6.11; C16H16O2S requires C, 70.56;
H, 5.92); HPLC: tR (R)¼25.6 min, tR (S)¼34.3 min [Chiracel OD-H;
flow rate 1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC]; ¼þ42.1 (c
1.0, CHCl3). Absolute configuration is the proposed configuration
based on comparison of optical rotation to literature value of
(þ)-(R)-2-(phenyl-10-sulfinyl)-acetophenone¼þ161.7 (CHCl3).56
tR¼24.6 min, tR¼30.7 min [Chiracel OJ-H; flow rate 1 mL minꢂ1
;
hexanee2-PrOH (90:10); 20 ꢀC].
4.2.32. Benzyl 3-chlorobenzyl sulfoxide (2n, entry 22). Crude prod-
uct contained a mixture of sulfide, sulfoxide and sulfone (12:80:8).
Purification by chromatography afforded the product as a white
solid (191 mg, 72%, 3% ee).
Mp 72e74 ꢀC; 1H NMR dH (400 MHz) 3.77 (1H, d, A of AB system,
J 12.9 Hz), 3.90 (1H, d, B of AB system, J 12.9 Hz), 3.97 (2H, s),
7.13e7.44 (9H, m); 13C NMR dC (75 MHz) 56.5, 57.7, 128.3, 128.5,
128.6, 129.1, 129.8, 130.09, 130.13, 132.3, 134.8; IR (KBr) nmax/cmꢂ1
2918, 1495, 1476, 1455, 1432, 1040, 699; (found: C, 63.37; H, 5.07.
C
14H13ClOS requires C, 63.51; H, 4.95); HPLC: tR¼33.9 min,
tR¼54.5 min [Phenomenex Lux Cellulose-4; flow rate 1 mL minꢂ1
;
4.3. Experimental procedure for Schiff base ligand synthesis
hexanee2-PrOH (80:20); 20 ꢀC].
Commercially available salicylaldehyde (1 mmol) and sodium
sulfate (0.5 g) were added to a solution of (S)-tert-leucinol (1 mmol)
4.2.33. Benzyl 4-chlorobenzyl sulfoxide (2
x,
entry 26).78 Crude
product contained a mixture of sulfide, sulfoxide and sulfone
(12:86:2). Purification by chromatography afforded the product as
a white solid (207 mg, 78%, 13% ee).
or L-valinol (1 mmol) in ethanol (20 mL). The reaction mixture was
stirred under reflux for 16 h, filtered and concentrated under re-
duced pressure. The reaction mixture was then dissolved in
dichloromethane (10 mL) and washed with water (3ꢁ10 mL) and
brine (15 mL). The organic layer was dried and concentrated under
reduced pressure to leave the crude product, which was purified by
column chromatography on silica gel (8:2 hexane/ethyl acetate) to
yield the pure ligand.
Mp 127e130 ꢀC; 1H NMR dH (300 MHz) 3.76 (1H, d, A of AB sys-
tem, J 13.2 Hz), 3.88 (1H, d, B of AB system, J 13.2 Hz), 3.91 (2H, s),
7.16e7.43 (9H, m); 13C NMR dC (75 MHz) 56.2, 57.6, 128.5, 128.8,
128.4,129.1,129.9,130.1, 131.5, 134.5; IR (KBr) nmax/cmꢂ1 2918,1496,
1474,1445,1043, 763, 698; HPLC: tR¼28.7 min, tR¼32.7 min [Chiracel
OD-H; flow rate 1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC].
Ligands 4, 5, 6, 9, 10 and 11 were fully characterised in our
previous publication.49
4.2.34. 2-Methoxyphenyl phenyl sulfoxide (2s
, entry 32).67 Crude
product contained a mixture of sulfide, sulfoxide and sulfone
(70:30:0). Purification by chromatography afforded the product as
a white solid (65 mg, 28%, 20% ee).
4.3.1. (S)-2-(N-30-Chlorosalicylidene)-amino-3,3-dimethyl-1-butanol
(7). Yellowsolid, 75%; mp 93e95 ꢀC; 1H NMR dH (300 MHz) 1.01 (9H,
s),1.62 (1H, brs), 2.83 (1H, brs), 3.05 (1H, dd, J 3.0Hz and 9.5Hz), 3.72
(1H, overlapping dd, J 11.1 Hz and 9.6 Hz), 3.99 (1H, dd, J 11.1 Hz and
2.4 Hz), 6.64 (1H, dd, appears as t, J 7.8 Hz and 7.8 Hz), 7.13 (1H, dd, J
Mp 96e98 ꢀC (lit.87 mp 98e99 ꢀC); 1H NMR dH (300 MHz) 3.82
(3H, s), 6.93e6.98 (1H, m), 7.14e7.19 (1H, m), 7.22e7.25 (1H, m),
7.35 (1H, t, J 7.6 Hz), 7.40e7.50 (3H, m), 7.61e7.69 (2H, m); 13C NMR
dC (75 MHz) 55.6, 109.1, 117.0, 117.4, 124.8, 129.3, 130.3, 131.1, 145.6,
147.0, 160.4; IR (KBr) nmax/cmꢂ1 2937, 1586, 1477, 1443, 1273, 1037,
751; HPLC: tR¼16.0 min, tR¼21.9 min [Chiracel OJ-H; flow rate
1 mL minꢂ1; hexanee2-PrOH (90:10); 20 ꢀC].
7.7 Hz and 1.8 Hz), 7.33 (1H, dd, J 7.8 Hz and 1.8 Hz), 8.25 (1H, s); 13
C
NMR dC (75.5 MHz) 26.9, 33.1, 62.0, 79.5, 117.3, 118.1, 122.7, 130.4,
35
133.3, 160.9, 165.6; (found: C, 60.80; H, 7.04; N, 5.38). C
H ClNO2
13 18
requires C, 61.05; H, 7.09; N, 5.48); ¼ꢂ60.8 (c 1.0, CHCl3).
4.3.2. (S)-2-(N-50-Chlorosalicylidene)-amino-3,3-dimethyl-1-
butanol (8). Yellow solid, 77%; mp 117e120 ꢀC; 1H NMR dH
(300 MHz) 0.97 (9H, s), 1.62 (1H, br s), 2.93 (1H, dd, J 9.0 Hz and
2.7 Hz), 3.71 (1H, overlapping dd, J 11.2 Hz and 9.8 Hz), 3.95 (1H, dd,
J 11.0 Hz and 2.1 Hz), 6.86e6.93 (1H, m), 7.20e7.31 (2H, m), 8.26
(1H, s); 13C NMR dC (75.5 MHz) 27.0, 33.2, 62.3, 81.1, 118.6, 119.3,
4.2.35. 4-Methoxyphenyl
phenyl
sulfoxide
(2
r
,
Table
3,
entry 34).79 Crude product contained a mixture of sulfide, sulfoxide
and sulfone (41:59:0). Purification by chromatography afforded the
product as a white solid (123 mg, 53%, 17% ee).
Mp 67e69 ꢀC (lit.87 mp 61e62 ꢀC); 1H NMR dH (400 MHz) 3.82
(3H, s), 6.91e7.00 (2H, m), 7.39e7.50 (3H, m), 7.53e7.65 (4H, m); 13
C
123.2, 130.7, 132.3, 160.0, 164.7; IR (KBr): nmax/cmꢂ1 3259, 2962,
35
NMR dC (75 MHz) 55.5, 114.8, 124.6, 127.3, 129.2, 130.7, 136.8, 145.9,
1634,1046; (found: C, 60.99; H, 6.80; N, 5.33). C H ClNO2 requires
13 18
162.1; IR (KBr) nmax/cmꢂ1 2838, 1594, 1496, 1255, 1090, 1042, 751;
C, 61.05; H, 7.09; N, 5.48); ¼ꢂ48.6 (c 1.0, CHCl3).

10182
G.E. O’Mahony et al. / Tetrahedron 69 (2013) 10168e10184
4.4. Experimental procedure for synthesis of sulfides
m), 2.41 (2H, t, J 7.2 Hz), 3.70 (2H, s), 7.19e7.35 (5H, m); IR (film):
nmax/cmꢂ1¼2925, 1494, 1465, 1454, 767, 699.
The thiolate anion was first prepared by treatment of the thiol
with an excess of sodium ethoxide. The thiolate anion was then
treated with an equimolar amount of aryl or alkyl halide and stirred
for 16 h at room temperature. Water (20 mL) and dichloromethane
(20 mL) were added to the flask. The layers were separated and the
aqueous layer was extracted with dichloromethane (10 mL). The
combined organic layers were washed with aqueous sodium hy-
droxide (2 M, 3ꢁ20 mL) and brine (20 mL), dried, filtered and
concentrated under reduced pressure to give the sulfides, which
were purified by column chromatography (100% hexane).
Sulfides 2p, 2qer were characterised in our previous
publication.49
4.4.11. Octyl phenyl sulfide (1l).99 Clear oil, 84%; 1H NMR dH
(300MHz)0.88(3H, t, J6.6Hz),1.15e1.72(12H, m), 2.95(2H, t,J7.2Hz),
7.10e7.37 (5H, m); IR (film): nmax/cmꢂ1 2926, 1480, 1439, 737, 690.
4.4.12. Dodecyl phenyl sulfide (1m).100 Mp 29e32 ꢀC, (lit.100 mp
31e33 ꢀC); white solid, 78%; 1H NMR dH (300 MHz) 0.88 (3H, t, J
6.3 Hz), 1.15e1.72 (20H, m), 2.91 (2H, t, J 7.2 Hz), 7.10e7.36 (5H, m);
IR (film): nmax/cmꢂ1 2919, 1439, 730, 689.
4.4.13. Allyl benzyl sulfide (1n).101 Clear oil, 86%; 1H NMR dH
(300 MHz) 3.04 (2H, dt, J 7.1 Hz and J 1.0 Hz), 3.66 (2H, s), 5.02e5.20
(2H, m), 5.70e5.90 (1H, m), 7.18e7.38 (5H, m); IR (film): nmax/cmꢂ1
3029, 1494, 1453, 916, 701.
4.4.1. tert-Butyl benzyl sulfide (1a).90 Clear oil, 72%; 1H NMR dH
(300 MHz) 1.35 (9H, s), 3.77 (2H, s), 7.16e7.40 (5H, m); IR (film):
nmax/cmꢂ1 2941, 1495, 1455, 1364, 1168, 713, 696.
4.4.14. Benzyl 2-chlorophenyl sulfide (1w).102,103 Clear oil, 81%; 1H
NMR dH (300 MHz) 4.12 (2H, s), 7.07e7.19 (2H, m), 7.20e7.41 (7H,
m); IR (film) nmax/cmꢂ1 2918, 1490, 1477, 1390, 1097, 810.
4.4.2. Isobutyl benzyl sulfide (1b).91 Clear oil, 90%; 1H NMR dH
(300 MHz) 0.95 (6H, d, J 6.6 Hz), 1.69e1.86 (1H, symmetrical m),
2.31 (2H, d, J 6.9 Hz, SCH2), 3.69 (2H, s, SCH2eAr), 7.18e7.37 (5H, m,
AreH); IR (film): nmax/cmꢂ1 2957, 1494, 1453, 733, 700.
4.4.15. Benzyl 3-chlorophenyl sulfide (1x). White solid, 91%; mp
34e36 ꢀC; 1H NMR dH (300 MHz) 4.10 (2H, s), 7.08e7.34 (9H, m); 13
C
NMR dC (75.5 MHz) 38.7, 126.3, 127.38, 127.44, 128.6, 128.9, 129.0,
129.9,134.6,136.8, 138.7; IR (KBr) nmax/cmꢂ1 3030, 1578, 1495, 1454,
1406, 1072, 776; (found C, 66.32; H, 4.81; C13H11ClS requires C,
66.51; H, 4.72).
4.4.3. Isopropyl benzyl sulfide (1c).92 Clear oil, 91%; 1H NMR dH
(300 MHz) 1.25 (6H, d, J 6.7 Hz), 2.71e2.88 (1H, m), 3.74 (2H, s),
7.18e7.39 (5H, m); IR (film): nmax/cmꢂ1 2959, 1495, 1453, 1236, 703.
4.4.4. Cyclohexyl benzyl sulfide (1d).93 Clear oil, 88%; 1H NMR dH
(300 MHz) 1.13e1.43 (5H, m), 1.48e1.83 (3H, m), 1.86e2.02 (2H, m),
4.4.16. Benzyl 4-chlorophenyl sulfide (1y).104 White solid, 92%; mp
46e48 ꢀC, (lit.105 43e44 ꢀC); 1H NMR dH (300 MHz) 4.07 (2H, s),
7.11e7.32 (9H, m); IR (KBr) nmax/cmꢂ1 3059, 1598, 1575, 1479, 1438,
1089, 738, 690.
2.48e2.63 (1H, m) 3.74 (2H, s), 7.15e7.38 (5H, m); IR (film): nmax
/
cmꢂ1 2929, 1494, 1449, 1202, 700.
4.4.5. 1-Naphthyl benzyl sulfide (1f).94 White solid, 68%; mp
82e85 ꢀC, (lit.94 mp 84 ꢀC); 1H NMR dH (300 MHz) 4.14 (2H, s),
7.12e7.39 (6H, m), 7.41e7.60 (3H, m), 7.72 (1H, d, J 8.1 Hz), 7.83 (1H,
dd, J 7.2 Hz and 2.7 Hz), 8.42 (1H, dd, J 7.8 Hz and J 1.5 Hz); IR (KBr):
4.4.17. 2-Chlorobenzyl phenyl sulfide (1z).106 Clear oil, 84%; 1H NMR
dH (300 MHz) 4.21 (2H, s), 7.09e7.40 (9H, m); 13C NMR dC
(75.5 MHz) 37.0, 126.8, 128.6, 128.9, 129.7, 130.7, 134.1, 135.2, 135.7;
IR (film) nmax/cmꢂ1 3059, 1582, 1480, 1473, 1439, 1052, 736, 690.
nmax/cmꢂ1 2924, 1455, 785, 765; (found: C, 81.33; H, 5.74. C17H14
S
requires C, 81.56; H, 5.64).
4.4.18. 3-Chlorobenzyl phenyl sulfide (1a
).107 Clear oil, 93%; 1H NMR
dH (300 MHz) 4.06 (2H, s), 7.10e7.34 (9H, m); IR (film) nmax/cmꢂ1
4.4.6. 2-Naphthyl benzyl sulfide (1g).95 White solid, 73%; mp
89e91 ꢀC, (lit.96 mp 88 ꢀC); 1HNMRdH (300 MHz) 4.22 (2H, s), 7.18e7.51
(8H, m), 7.63e7.83 (4H, m); IR (KBr): nmax/cmꢂ1 2923, 1582, 814, 738.
3059, 1597, 1574, 1479, 1438, 1089, 1072, 739, 690.
4.4.19. 4-Chlorobenzyl phenyl sulfide (1b
).108 White solid, 89%; mp
75e77 ꢀC, (lit.105 78e78.5 ꢀC); 1H NMR dH (300 MHz) 4.05 (2H, s),
7.12e7.33(9H, m);IR(KBr)nmax/cmꢂ12917,1576,1437,1405,1090,734.
4.4.7. 1-Naphthyl 4-chlorobenzyl sulfide (1h). White solid, 65%; mp
79e81 ꢀC; 1H NMR dH (300 MHz) 4.07 (2H, s), 7.02e7.60 (8H, m),
7.74 (1H, d, J 8.1 Hz), 7.84 (1H, dd, J 8.1 Hz and 2.4 Hz), 8.34e8.46
(1H, m); 13C NMR dC (75 MHz) 38.8, 125.1, 125.5, 126.3, 126.6,
128.1, 128.5, 128.7, 130.0, 130.2, 132.5, 132.9, 133.2, 134.0, 136.1; IR
(KBr): nmax/cmꢂ1 3051, 1490, 1405, 788, 767; (found: C, 71.33; H,
4.52. C17H13ClS requires C, 71.69; H, 4.60).
4.4.20. 2-Methylbenzyl 4-methylphenyl sulfide (1g
).109 Clear oil,
88%; 1H NMR dH (300 MHz) 2.32 (3H, s), 2.38 (3H, s), 4.06 (2H, s),
7.00e7.28 (8H, m); IR (film): nmax/cmꢂ1 2921, 1493, 1091, 807.
4.4.21. 3-Methylbenzyl 4-methylphenyl sulfide (1d). Clear oil, 91%;
1H NMR dH (300 MHz) 2.31 (6H, 2 overlapping s), 4.04 (2H, s),
6.99e7.29 (8H, m); 13C NMR dC (75 MHz) 21.1, 21.4, 39.7, 125.9,
127.9, 128.3, 129.6, 130.5, 132.7, 136.5, 137.6, 138.1; IR (film):
nmax/cmꢂ1 2920, 1608, 1492, 1091, 802; HRMS (ESI): Exact
4.4.8. 2-Naphthyl 4-chlorobenzyl sulfide (1i). White solid, 75%; mp
77e79 ꢀC; 1H NMR dH (300 MHz) 4.16 (2H, s), 7.14e7.29 (4H, m),
7.32e7.52 (3H, m), 7.64e7.83 (4H, m); 13C NMR dC (75 MHz) 38.4,
126.0, 126.6, 127.2, 127.7, 127.9, 128.3, 128.5, 128.7, 130.2, 132.0,
133.0, 133.2, 133.7, 136.0; IR (KBr): nmax/cmꢂ1 2904, 1491, 1405, 818,
741; (found: C, 71.40; H, 4.68. C17H13ClS requires C, 71.69; H, 4.60).
mass calculated for
245.0994; (found: C, 78.71; H, 7.14. C15H16S requires C, 78.90;
H, 7.06).
C
15H17SO [(MþOH)þ] 245.1000, found
4.4.9. Octyl benzyl sulfide (1j).97 Clear oil, 83%; 1H NMR dH
(300 MHz) 0.88 (3H, t, J 7.3 Hz), 1.13e1.41 (10H, m), 1.47e1.63 (2H,
m), 2.41 (2H, t, J 7.2 Hz), 3.70 (2H, s), 7.17e7.38 (5H, m); IR (film):
nmax/cmꢂ1 2854, 1494, 1454, 767, 699.
4.4.22. 2-Chlorobenzyl 2-methoxyphenyl sulfide (1ε). White solid,
73%; mp 44e46 ꢀC; 1H NMR dH (300 MHz) 3.89 (3H, s), 4.19 (2H, s),
6.80e6.90 (2H, m), 7.07e7.28 (5H, m), 7.30e7.40 (1H, m); 13C NMR
dC (75 MHz) 35.0, 55.8, 110.5, 121.0, 123.6, 126.7, 128.2, 128.4, 129.5,
130.8, 131.5, 134.1, 135.3, 158.0; IR (film): nmax/cmꢂ1 2854, 1579,
1463, 1247, 1027, 743; HRMS (ESI): Exact mass calculated for
4.4.10. Dodecyl benzyl sulfide (1k).98 Clear oil, 88%; 1H NMR dH
(300 MHz) 0.88 (3H, t, J 6.9 Hz), 1.15e1.41 (18H, m), 1.48e1.63 (2H,

G.E. O’Mahony et al. / Tetrahedron 69 (2013) 10168e10184
10183
35
C14
H
ClO2S [(MþOH)þ] 281.0403, found 281.0391; (found: C,
Supplementary data
14
63.64; H, 4.99. C14H13ClOS requires C, 63.51; H, 4.95).
1H NMR spectra are available for compounds 1h, 1i, 1x, 1
d, 1ε, 1h,
4.4.23. 3-Chlorobenzyl 4-methylphenyl sulfide (1
z
).110 White solid,
1
m
, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2w, 2x, 2y,
2z, 2 , 2 , 2 , 2 , 2ε, 2 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 7
and 8. 13C NMR spectra are available for compounds 1h, 1i, 1
, 1ε,
, 2f, 2h, 2i, 2z, 2 , 2ε, 2 , 2 , 2 , 4, 5, 7, 8, 10 and 11. HPLC data are
available for sulfoxides 2f, 2g, 2h, 2i, 2z, 2 , 2 and 2 . Crystallo-
1
81%; mp 35e36 ꢀC; H NMR dH (300 MHz) 2.31 (3H, s), 4.00 (2H, s),
7.00e7.28 (8H, m); IR (film): nmax/cmꢂ1 2921,1597,1492,1201,1091, 806.
a
b
g
d
z
h
q
i
k
l
m
n
x
s
r
s
d
1h
g
z
i
k
4.4.24. 2-Chlorobenzyl 4-methylphenyl sulfide (1
h). Clear oil, 83%;
g
z
k
1H NMR dH (300 MHz) 2.31 (3H, s), 4.16 (2H, s), 7.00e7.28 (7H, m),
graphic data is available for sulfoxides 2f and 2g. Supplementary
data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.08.063.
7.30e7.41 (1H, m); 13C NMR dC (75 MHz) 21.1, 37.7, 126.7, 128.5,
129.6, 129.7, 130.7, 131.5, 131.9, 134.0, 135.5, 137.0; IR (film): nmax
/
cmꢂ1 2921, 1492, 1444, 1052, 807; HRMS (ESI): Exact mass calcu-
35
lated for
C
H
ClSO [(MþOH)þ] 266.0532, found 266.0532;
14 15
References and notes
(found: C, 67.76; H, 5.30. C14H13ClS requires C, 67.59; H, 5.27).
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4.4.25. 4-Chlorobenzyl 4-methylphenyl sulfide (1q
).104 White solid,
78%; mp 66e68 ꢀC, (lit.104 mp 64e65 ꢀC); 1H NMR dH (300 MHz)
2.30 (3H, s), 3.99 (2H, s), 7.00e7.29 (8H, m); IR (KBr): nmax/cmꢂ1
2926, 1490, 1405, 1090, 803.
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4303.
4.4.26. Benzyl 2-methylbenzyl sulfide (1i
).111 White solid 84%; mp
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75.
31e32 ꢀC, (lit.111 mp 31e32 ꢀC); 1H NMR dH (300 MHz) 2.30 (3H, s),
3.61 (2H, s), 3.66 (2H, s), 7.09e7.38 (9H, m); IR (film) nmax/cmꢂ1
2916, 1608, 1493, 1453, 1228, 716, 702.
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dH (300 MHz) 2.34 (3H, s), 3.57 (2H, s), 3.61 (2H, s), 7.00e7.13 (3H, m),
7.15e7.37 (6H, m); IR (film) nmax/cmꢂ13028,1608,1493,1453, 716, 702.
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4.4.28. Benzyl 4-methylbenzyl sulfide (1l
).111 White solid 80%; mp
29e30 ꢀC, (lit.111 mp 29e31 ꢀC); 1H NMR dH (300 MHz) 2.33 (3H, s),
3.56 (2H, s), 3.59 (2H, s), 7.07e7.36 (9H, m); IR (KBr) nmax/cmꢂ1
2917, 1616, 1511, 1454, 697.
4.4.29. Benzyl 2-chlorobenzyl sulfide (1m
). Clear oil 87%; 1H NMR dH
(300 MHz) 3.69 (2H, s), 3.74 (2H, s), 7.12e7.40 (9H, m); 13C NMR dC
(75.5 MHz) 33.4, 36.2,126.7,127.1,128.4,128.5,129.0,129.8,130.7,134.2,
135.9,137.9; IR (film) nmax/cmꢂ13028,1494,1472,1453,1444,1052, 739,
698; (found: C, 67.50; H, 5.47. C14H13ClS requires C, 67.59; H, 5.27).
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dH (300 MHz) 3.55 (2H, s), 3.60 (2H, s), 7.10e7.38 (9H, m); IR (film)
nmax/cmꢂ1 3028, 1598, 1494, 1475, 1453, 1431, 1076, 724, 702.
4.4.31. Benzyl 4-chlorobenzyl sulfide (1x
).111 Clear oil 81%; 1H NMR
dH (300 MHz) 3.55 (2H, s), 3.60 (2H, s), 7.15e7.38 (9H, m); IR (film)
nmax/cmꢂ1 3028, 1490, 1453, 1092, 1015, 705.
4.4.32. 2-Methoxyphenyl phenyl sulfide (1s
).112 Clear oil 71%; 1H
NMR dH (300 MHz) 3.75(3H, s), 6.73e6.81(1H, m), 6.84e6.95(2H, m),
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(3H, s), 6.84e6.93 (2H, m), 7.09e7.28 (5H, m), 7.37e7.45 (2H, m); IR
(KBr) nmax/cmꢂ1 2835, 1592, 1493, 1478, 1439, 1246, 1031, 739, 689.
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We are grateful to IRCSET Embark initiative for funding. We
would also like to thank the following students for their assistance:
Cormac Tobin and Aoife Ring.

10184
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