Methanesulfinylation of Benzyl Halides with Dimethyl Sulfoxide

Article abstract of DOI:10.1021/acs.joc.9b03041

A phenyltrimethylammonium tribromide-mediated nucleophilic substitution/oxygen transformation reaction of benzyl halides with DMSO has been developed. In this transition-metal-free reaction, DMSO acts as not only a solvent but also a "S(O)Me" source, thus providing a convenient method for the efficient and direct synthesis of various benzyl methyl sulfoxides.

Full text of DOI:10.1021/acs.joc.9b03041

Subscriber access provided by BIU Pharmacie | Faculté de Pharmacie, Université Paris V
Note
Methanesulfinylation of benzyl halides with dimethyl sulfoxide
Duo Fu, Jun Dong, Hongguang Du, and Jiaxi Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03041 • Publication Date (Web): 24 Dec 2019
Downloaded from pubs.acs.org on December 25, 2019
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 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 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.
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 9
The Journal of Organic Chemistry
1
2
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
Methanesulfinylation of benzyl halides with
dimethyl sulfoxide
Duo Fu, Jun Dong, Hongguang Du and Jiaxi Xu*
State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry,
College of Chemistry, Beijing University of Chemical Technology, Beijing 100029, People’s
Republic of China
ABSTRACT: A phenyltrimethylammonium tribromide-mediated nucleophilic substitution/oxygen
transformation reaction of benzyl halides with DMSO has been developed. In this transition-metal-
free reaction, DMSO acts as not only a solvent, but also a “S(O)Me” source, thus providing a
convenient method for the efficient and direct synthesis of various benzyl methyl sulfoxides.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Sulfoxides represent an important class of compounds
Page 2 of 9
benzyl methyl sulfoxides from the corresponding benzyl
halides and dimethyl sulfoxide with the mediation of
phenyltrimethylammonium tribromide (PTAT) in one
step. The significance of the present protocol includes that
(1) DMSO is not only introduced as a common solvent, but
also as the source of the methylsulfinyl group. (2) The
chemistry provides a direct and experimentally simple
approach to synthesize methyl sulfoxides without the
generation of over oxidized product sulfones which
inevitably occurs with conventional oxidizing agents. (3)
The role of DMSO in the Kornblum reaction is changed
from the oxygen source to the S(O)Me source.
1
2
3
4
5
6
7
8
that have been widely employed as building blocks, chiral
ligands, and auxiliaries in transition-metal catalysis.1
Furthermore, the sulfur functional group is
pharmaceutically important cores or moieties of some
biological molecules and drugs, such as neurokinin
receptor antagonist YM-38336, anti-inflammatory drug
sulindac, proton pump inhibitor Omeprazole.2 Sulfoxides
have also been widely used as important intermediates in
organic synthesis for the preparation of sulfur-containing
compounds.3
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
Due to the importance of sulfoxides, significant effort has
been devoted to their preparation. The most popular
methods for the synthesis of sulfoxides include (1)
oxidation of sulfides with peroxyacids and common
organic or inorganic oxidants, organometallic catalytic
complexes;2b,4 (2) metal-catalyzed arylation of sulfenate
anions5 and metal-free alkylation of nucleophilic
sulfenate sources;6 (3) organometallic addition to
displacement of electrophilic sulfoxides derivatives.7
Despite the utility of these approaches, some deficiencies
have always existed, such as overoxidation to sulfones, the
production of large amount of toxic wastes, the use of
expensive catalysts. These methods also suffer from
limited functional group tolerance because either strong
oxidizing agents or reactive lithium- or magnesium-based
reagents are employed. During these approaches, pre-
existing sulfur functional groups in the molecules are
required. Among these sulfur-containing reagents, DMSO
as a cheap, safe, and low-toxic reagent has been widely
utilized as a one carbon source,8 and a sulfur source such
as S(O)Me,2a,9 S(O)Me2,10 S(O)2Me,11 and SMe12 for the
incorporation of functional groups into target molecules.
Scheme 1. DMSO as “S(O)Me” source to synthesize
sulfoxides
At the outset of this study, benzyl chloride (1a) and PTAT
were employed as the model substrates to optimize
reaction conditions in DMSO (Table 1). We first optimized
the reactant ratio (Table 1, entries 16). When the ratio of
1a:PTAT was increased from 1:0.10 to 1:0.25 to 1:0.50
(Table 1, entries 13), the yield of 2a increased from 25%
to 59% to 77%. Further increasing the ratio of 1a:PTAT to
1:1.00, product 2a was obtained in 81% and by-product
benzaldehyde (3a) was observed in 10% yield (Table 1,
entry 4). However, the yield decreased to 59% when the
ratio of 1a:PTAT was increased from 1:1.00 to 1:1.25
(Table 1, entry 5). No product 2a was observed and only
benzaldehyde 3a was received in 45% yield when the ratio
of 1a:PTAT was increased to 1:1.50 (Table 1, entry 6). The
other choices of brominium (Br+) precursors, such as NBS
and DBDMH (1,3-dibromo-5,5-dimethylhydantoin), were
also attempted and the product 2a was obtained in 64%
and 76% yields, respectively (Table 1, entries 7 and 8). It
was noteworthy mentioned that only 4% yield of product
2a was generated when NCS (N-chlorosuccinimide) was
used as a halogenium (X+) precursor instead of PTAT
(Table 1, entry 9). We further optimized the reaction time
(Table 1, entries 1012). When the reaction time was
shortened to 4 h, 83% yield of product 2a was obtained
(Table 1, entries 10). Next, the reaction time was
shortened to 2 h, product 2a was only obtained in 57%
yield (Table 1, entry 11). Further prolonging the reaction
time to 8 h resulted in the yield of 2a to decrease to 48%,
but 3a was obtained 24% yield (Table 1, entry 12). Then
we carried out further optimizations for 4 h at different
reaction temperatures and found that when the
temperature was decreased to 80 °C, the yield dropped
sharply to 3% (Table 1, entry 13). When the temperature
However, to the best of our knowledge, only two examples
of methylsulfoxidation utilizing DMSO as S(O)Me source
have been reported (Scheme 1). In 2016, Rastogi’s group
reported the synthesis of (hetero)aryl methyl sulfoxides
from DMSO and (hetero)aryl diazonium salts via mild
2a
photoredox catalysis with ruthenium complexes. Wu
and Zhang’s group obtained the antifungal active
methylsulfinyl-1H-tetrazole
derivatives
through
methylsulfoxidation of tetrazole-amines in neat DMSO
under the mediation of tert-butyl nitrite.9c Both of two
strategies undergo the generation of hetero-aryl or aryl
radical intermediates which are trapped by DMSO to
produce sulfinyl radicals. The generated sulfinyl radicals
are oxidized into sulfoxide cations and attacked by the
weakly nucleophilic DMSO to produce the final products.
However, only (hetero)aryl methly sulfoxides can be
obtained with the two reported methods. It is worthwhile
to realize the synthesis of alkyl methyl sulfoxides with
DMSO as S(O)Me source.
In 1957, Kornblum and co-workers reported that
activated primary benzyl bromides were efficiently
oxidized to the corresponding aldehydes by simply
dissolving the substrates in DMSO.13 Subsequent studies
showed that DMSO can be used as an oxygen source and
solvent in these reactions. Therefore, expanding the
application range of DMSO in Kornblum oxidation
reaction is meaningful. Considering the development of
DMSO in organic transformation during the recent years14
and the importance to synthesize sulfoxide compounds,
we report a novel and efficient method to synthesize
ACS Paragon Plus Environment

Page 3 of 9
The Journal of Organic Chemistry
was increased to 100 °C, the yield of 2a was 78% (Table 1,
entry 14). The results indicated that the temperature had
an important impact on the reaction yield. And then, the
yield of 2a was only detected in 35% when the solvent
DMSO was used without waterless treatment (Table 1,
entry 15). At last, the product 2a was obtained in 78%
yield when the reaction was conducted at 90 °C for 30 min.
under microwave irradiation (Table 1, entry 16).
with naphthyl, the corresponding products 2q and 2r
were obtained in 75% and 79% yields, respectively. To our
delight, the heteroarylmethyl halides 1s and 1t can also
produce the corresponding sulfoxides 2s and 2t in 49%
and 83% yields, respectively. The reaction also worked
well with deuterated DMSO since methylsulfoxidation of
substrate 1a using deuterated DMSO was carried out
smoothly, yielding deuterated methylsulfoxide 2a-d3 in
73% yield. Because 4-(chloromethyl)phenol and 4-
(chloromethyl)aniline are too active and can react
themselves intermolecularly, 4-methoxybenzyl chloride
(1u) and tert-butyl (4-(chloromethyl)phenyl) carbonate
(1v) were attempted, affording the corresponding
products in low yields (2u in 34% and 2v in 13%),
respectively. The reaction of benzyl chloride with 4-
methylphenol (1 eq.) as an additive was also performed,
affording benzyl methyl sulfoxide (2a) in 32% yield,
revealing that the phenolic hydroxy group is tolerance in
the reaction system, but inhibited the reaction. However,
1
2
3
4
5
6
7
8
Table 1. Optimization of the reaction conditionsa)
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
Entry
PTAT (equiv)
t (h) Yield (%)
2ai
3ai
1
1
0.10
0.25
0.50
1.00
1.25
6
6
6
6
6
6
6
6
6
4
2
25
59
77
2
3
neither
of
reactions
of
tert-butyl
(4-
3
5
(chloromethyl)phenyl)carbamate (1w) and benzyl
chloride with 4-methylaniline (1 eq.) as an additive
worked. Two C=C double bond containing substrates (1-
allyloxy-4-chloromethylbenzene
chloromethyl-4-vinylbenzene (1y)) were tested as well.
4
81
59
0
10
16
45
2
5
(1x)
and
1-
6
1.50
1.00b
1.00c
1.00d
1.00
1.00
1.00
1.00
1.00
1.00
1.00
7
64
76
4
However, no desired products were observed.
8
3
More practically, this reaction can be performed at a 7.90
mmol scale, which clearly showing the potential
application in a large scale preparation (Scheme 3). For
example, 7.90 mmol (1.00 g) of benzyl chloride and 7.90
mmol (2.97 g) of PTAT were heated in 60 mL of DMSO at
90 °C for 2 h to afford 2a in 53 % yield (640 mg) by flash
column chromatograph on silica gel.
9
trace
6
10
11
12
13e
14f
15g
16h
83(68)
57
48
3
trace
24
1
8
4
4
4
0.5
78
35
78
5
Scheme 2. Scope of benzyl halides and sulfonates
7
10
a)Reactions were conducted on a 0.125 mmol scale of 1a
(0.125 mmol) in 1.25 mL of anhydrous DMSO. b)NBS
instead
of
PTAT.
c)DBDMH
(1,3-dibromo-5,5-
dimethylhydantoin). d)NCS instead of PTAT. e)At 80 °C.
f)At 100 °C. g)Reaction was conducted in commercial
DMSO (without waterless treatment). h)Reaction was
carried out under microwave irradiation at 90 °C for 30
i)
min. NMR yield of the crude products 2a and 3a using
1,3,5-trimethoxybenzene as an internal standard except
for the yield in brackets in entry 10.
With the optimized reaction conditions in hand (Table 1,
entry 10), we subsequently investigated the substrate
scope of this transformation (Scheme 2). Benzyl chloride
bearing neutral, electron-donating, and electron-
withdrawing substituents at the o, m, p-positions of the
aromatic ring reacted smoothly under the optimized
reaction conditions, affording the corresponding products
2 in high yields in most of the cases (Scheme 2). Besides
benzyl chlorides, other benzyl bromide derivatives like
benzyl bromide (4a), 4-nitrobenzyl bromide (4i), and 4-
methylbenzyl bromide (4l) can also generate the
corresponding products 2 in moderate yields from
5865%. Moreover, the reaction also tolerated several
functional groups, such as nitrile for 2j, ester for 2m,
aldehyde for 2n on aryl. After replacing the phenyl group
a)Benzyl bromide (4a) was used instead of benzyl chloride
(1a). a)Benzyl tosylate was used instead of benzyl chloride
(1a). c)4-Nitrobenzyl bromide (4i) was used instead of 4-
nitrobenzyl chloride (1i). d)4-Methylbenzyl bromide (4l)
was used instead of 4-methylbenzyl chloride (1l).
f)
e)Reaction time is 100 min. Product 2v was verified by
GC-MS and 1H NMR, but cannot be purified due to
impurity with very close polarity. g)4-Methylphenol (1 eq.)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Based on the preceding literature reports15 and the above-
Page 4 of 9
was added as an additive.
1
2
3
4
5
6
7
8
mentioned control experiments, we proposed the reaction
mechanism as depicted in Scheme 5. Initially, dimethyl
sulfide is generated through the decomposition of
dimethyl sulfoxide with the aid of PTAT under heating.
Subsequently, benzyl chloride (1a) is attacked by
dimethyl sulfide to furnish benzylchlorodimethyl-λ4-
sulfane (A’).16 Subsequently, the generated intermediate
A’ is nucleophilically attacked by a halide (Cl- or Br-) in
the reaction system to produce phenyl(methyl)sulfane (A).
Phenyl(methyl)sulfane (A) further serves as a nucleophile
to attack PTAT to afford benzylbromo(methyl)sulfonium
(B). Finally, dimethyl sulfoxide as the oxygen source
attacks benzyl (methyl)sulfonium bromide (B) to form
intermediate C, which undergoes an elimination to get the
To gain insight into the reaction mechanism, a number of
control experiments were conducted as shown in Scheme
4. First, when DMSO-d6 was used to replace DMSO, the
deuterated product 2a-d3 was formed in 73% yield under
our optimized conditions (eq. a). H and 13C{1H} NMR
1
analyses confirm the complete deuterated incorporation
at the “CH3” moiety, which reveals that DMSO is not only
as the solvent, but also as the “SMe” source. To further
investigate the reaction mechanism, other designed
experiments were performed. When the reaction of
substrate 1a was performed under standard conditions
and N2 atmosphere, product 2a was received in 63% yield,
confirming that the oxygen of 2a comes from DMSO
rather than oxygen in air (eq. b). No product 2a was
detected when PTAT was not used (eq. c). Moreover, the
formation of dimethyl sulfide and 1,3,5-trioxane was
observed in gas chromatography-mass spectrometric
(GC-MS) analysis, under the standard conditions without
the addition of benzyl chloride (1a) (eq. d). When we
carried out this reaction under standard conditions for 2
h (eq. e), side product benzyl(methyl)sulfane (A) was
obtained in 2% yield. In our reaction system,
benzyl(methyl)sulfane (A) potentially generated from
benzyl chloride. When we employed A as the substrate,
product 2a was obtained in 73% yield under our
optimized reaction conditions (eq. f), which implied that
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
product
benzyl
methyl
sulfoxide
(2a)
and
dimethylsulfonium bromide.
Scheme 5. Proposed mechanism
A
generated from benzyl chloride under standard
conditions.
Scheme 3. Gram-scale synthesis of product 2a
To further extend application of the synthetic method, we
tested other sulfoxides, including methyl phenyl sulfoxide
(in DMF or HMPT as solvent), dodecyl methyl sulfoxide,
and tetrahydrothiophene 1-oxide, in the reaction with
benzyl chloride under the optimal reaction conditions.
However, unfortunately, no corresponding desired
products sulfoxides were obtained. Thioanisole was
observed in the reaction of methyl methyl sulfoxide by
GC-MS analysis. No reactions occurred for other two
sulfoxides.
Scheme
4.
Control
experiments
In conclusion, we have developed an efficient and
convenient approach to synthesize benzyl methyl
sulfoxides under Kornblum-like conditions from benzyl
halides and DMSO. DMSO plays a vital role in this
transformation, not only as a solvent, but also as a
“S(O)Me” source.
Experimental Section
General Information. Unless otherwise noted, all
starting materials were purchased from commercial
suppliers. Anhydrous DMSO, DMF, and HMPT were
purchased from J & K chemical company. Acetonitrile was
refluxed over CaH2 and freshly distilled prior to use.
Chloroform was dried over anhydrous MgSO4 and freshly
distilled prior to use. Column chromatography was
performed using silica gel (normal phase, 200300 mesh)
from Branch of Qingdao Haiyang Chemical, with
dichloromethane and methanol as eluent. Reactions were
monitored by thin-layer chromatography on GF254 silica gel
ACS Paragon Plus Environment

Page 5 of 9
The Journal of Organic Chemistry
plates (0.2 mm) from Institute of Yantai Chemical Industry.
7.09(m, 2H), 4.06 (d, J = 14.0 Hz, 1H), 4.02 (d, J = 13.6 Hz,
1H), 2.48 (d, J = 0.8 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 161.0 (d, JF-C = 248.5 Hz), 132.4 (d, JF-C = 3.1 Hz, 1H), 130.4
(d, JF-C = 8.2 Hz), 124.6 (d, JF-C = 3.5 Hz), 117.0 (d, JF-C = 15.1
Hz), 115.6 (d, JF-C = 21.6 Hz), 52.7, 37.4. 19F NMR (377 MHz,
CDCl3) δ -116.8. HRMS (ESI) m/z [M+H]+ calcd for
C8H10FOS+: 173.0431, found: 173.0427.
The plates were visualized under UV light, as well as other
TLC stains (10% phosphomolybdic acid in ethanol; 1%
potassium permanganate in water; 10 g of iodine absorbed
1
2
3
4
5
6
7
8
1
on 30 g of silica gel). H and 13C{1H} NMR spectra were
recorded on a Bruker 400 MHz spectrometer, usually in
CDCl3 as an internal standard, and the chemical shifts (δ) are
reported in parts per million (ppm). And multiplicities are
indicated as s (singlet), d (doublet), t (triplet), q (quartet), dd
(double doublet), m (multiplet). Coupling constants (J) are
reported in Hertz (Hz). HRMS measurements were carried
out on an Agilent LC/MSD TOF mass spectrometer. Melting
points were obtained on a Yanaco MP-500 melting point
apparatus and are uncorrected.
1-Fluoro-3-((methylsulfinyl)methyl)benzene
(2f).Yellow oil, yield: 18 mg, 84%; Rf = 0.46 (DCM/MeOH
15:1, v/v). IR (KBr) 2917, 1617, 1589, 1488, 1448, 1033, 791,
9
1
705 cm-1. H NMR (400 MHz, CDCl3) δ 7.38–7.32 (m, 1H),
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
7.08–7.01 (m, 3H), 3.98 (d, J = 13.2 Hz, 1H), 3.92 (d, J = 12.8
Hz, 1H), 2.47 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.8
(d, JF-C = 248.4Hz), 132.0 (d, JF-C = 7.7 Hz, 1H), 130.4 (d, JF-
C = 8.4 Hz), 125.8 (d, JF-C = 2.6 Hz), 117.0 (d, JF-C = 22.0 Hz),
115.5 (d, JF-C = 21.0 Hz), 59.6, 37.5. 19F NMR (377 MHz,
CDCl3) δ -111.9. HRMS (ESI) m/z [M+H]+ calcd for
C8H10FOS+: 173.0431, found: 173.0437.
General procedure for the Synthesis of Benzyl
Methyl Sulfoxides 2. To a stirred suspension of PTAT
(phenyltrimethylammonium tribromide) (0.125 mmol, 47
mg) in anhydrous DMSO (1.25 mL) was added benzyl halides
1 or 3 (0.125 mmol). The reaction mixture was further stirred
at 90 oC in an oil-bath for 4 hours. After cooling and addition
of water, the mixture was extracted with DCM, and combined
organic layer was washed with brine, dried over anhydrous
sodium sulfate, and concentrated in vacuo. The resulting
residue was purified by silica gel column chromatography
with DCM and methanol (150/1 to 10/1, v/v) as eluent to
afford benzyl methyl sulfoxides 2.
1-Fluoro-4-((methylsulfinyl)methyl)benzene
(2g).17 Yellow oil, yield: 13 mg, 61%; Rf = 0.47 (DCM/MeOH
1
15:1, v/v). IR (KBr) 2920, 1604, 1510, 1028, 841 cm-1. H
NMR (400 MHz, CDCl3) δ 7.30–7.27 (m, 2H), 7.10–7.05 (m,
2H), 3.97 (d, J = 13.2 Hz, 1H), 3.93 (d, J = 13.2 Hz, 1H), 2.46
(s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.8 (d, JF-C
=
248.9 Hz), 131.7 (d, JF-C = 8.3 Hz), 125.5, 116.0 (d, JF-C = 21.8
Hz), 59.1, 37.2. 19F NMR (377 MHz, CDCl3) δ -113.1. HRMS
(ESI) m/z [M+H]+ calcd for C8H10FOS+: 173.0431, found:
173.0426.
((Methylsulfinyl)methyl)benzene (2a).17 Orange oil,
yield: 13 mg, 68%; Rf = 0.48 (DCM/MeOH 15:1, v/v). IR (KBr)
1
2915, 1604, 1496, 1455, 1028, 767, 700 cm-1. H NMR (400
1-Bromo-4-((methylsulfinyl)methyl)benzene
(2h).17 White solid, yield: 22 mg, 76%; M.p. 84–86 °C, Rf =
0.51 (DCM/MeOH 15:1, v/v). IR (KBr) 2915, 1590, 1487, 1033,
MHz, CDCl3) δ 7.40–7.34 (m, 3H), 7.29–7.27 (m, 2H), 4.05
(d, J = 12.8 Hz, 1H), 3.92 (d, J = 12.8 Hz, 1H), 2.45 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 130.0, 129.6, 128.9, 128.4,
60.3, 37.3. HRMS (ESI) m/z [M+H]+ calcd for C8H11OS+:
155.0525, found: 155.0526.
1
833 cm-1. H NMR (400 MHz, CDCl3) δ 7.53–7.49 (m, 2H),
7.17–7.15 (m, 2H), 3.93 (d, J = 13.6 Hz, 1H), 3.90 (d, J = 13.6
Hz, 1H), 2.45 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 132.1,
131.6, 128.6, 122.7, 59.2, 37.3. HRMS (ESI) m/z [M+H]+
calcd for C8H10BrOS+: 232.9630, found: 232.9624.
1-Chloro-2-((methylsulfinyl)methyl)benzene (2b).
Yellow oil, yield: 16 mg, 68%; Rf = 0.49 (DCM/MeOH 15:1,
v/v). IR (KBr) 2919, 1444, 1053, 763 cm-1. 1H NMR (400 MHz,
CDCl3) δ 7.45–7.42 (m, 1H), 7.40–7.37 (m, 1H), 7.30–7.28
(m, 2H), 4.17 (s, 2H), 2.52 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 134.5, 132.3, 129.9, 128.1, 127.3, 57.4, 37.6. HRMS
(ESI) m/z [M+H]+ calcd for C8H10ClOS+: 189.0135, found:
189.0131.
1-((Methylsulfinyl)methyl)-4-nitrobenzene (2i).17
White solid, yield: 12 mg, 44%; 16 mg, 65%; M.p. 99–100 °C ,
Rf = 0.49 (DCM/MeOH 15:1, v/v). IR (KBr) 2922, 1604, 1519,
1028, 860 cm-1. 1H NMR (400 MHz, CDCl3) δ 8.27–8.24 (m,
2H), 7.50–7.48 (m, 2H), 4.09 (d, J = 13.2 Hz, 1H), 3.98 (d, J
= 12.8 Hz, 1H), 2.52 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 148.0, 137.1, 131.1, 124.0, 59.0, 37.8. HRMS (ESI) m/z
[M+H]+ calcd for C8H10NO3S+: 200.0376, found: 200.0372.
1-Chloro-3-((methylsulfinyl)methyl)benzene (2c).
Orange oil, yield: 17 mg, 72%; Rf = 0.47 (DCM/MeOH 15:1,
v/v). IR (KBr) 2917, 1598, 1573, 1430, 1043, 791, 705 cm-1. 1H
NMR (400 MHz, CDCl3) δ 7.34–7.29 (m, 3H), 7.20–7.17 (m,
1H), 3.96 (d, J = 13.2 Hz, 1H), 3.90 (d, J = 12.8 Hz, 1H), 2.47
(s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 134.8, 131.7, 130.2,
130.0, 128.6, 128.2, 59.4, 37.5. HRMS (ESI) m/z [M+H]+
calcd for C8H10ClOS+: 189.0135, found: 189.0131.
4-((Methylsulfinyl)methyl)benzonitrile
(2j).17
White solid, yield: 13 mg, 58%; M.p. 74–76 °C , Rf = 0.32
(DCM/MeOH 15:1, v/v). IR (KBr) 2919, 2227, 1606, 1504,
1025, 844 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.2
Hz 2H), 7.42 (d, J = 8.2 Hz 2H), 4.03 (d, J = 12.8 Hz, 1H),
3.94 (d, J = 12.8 Hz, 1H), 2.50 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 135.1, 132.5, 130.9, 118.3, 112.4, 59.3, 37.7.
HRMS (ESI) m/z [M+H]+ calcd for C9H10NOS+: 180.0478,
found: 180.0471.
1-Chloro-4-((methylsulfinyl)methyl)benzene
(2d).17 Yellow oil, yield: 14 mg, 59%; Rf = 0.40 (DCM/MeOH
15:1, v/v). IR (KBr) 2921, 1595, 1492, 1045, 836 cm-1. 1H NMR
(400 MHz, CDCl3) δ 7.38–7.34 (m, 2H), 7.25–7.21 (m, 2H),
3.95 (d, J = 13.2 Hz, 1H), 3.91 (d, J = 12.8 Hz, 1H), 2.45 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 134.6, 131.3, 129.1,
128.1, 59.2, 37.3. HRMS (ESI) m/z [M+H]+ calcd for
C8H10ClOS+: 189.0135, found: 189.0130.
1-((Methylsulfinyl)methyl)-4-
(trifluoromethyl)benzene (2k).17 White solid, yield: 18
mg, 65%; M.p. 80–82 °C , Rf = 0.37 (DCM/MeOH 15:1, v/v).
IR (KBr) 2916, 1034, 849 cm-1. 1H NMR (400 MHz, CDCl3) δ
7.65 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 4.02 (d, J
= 12.8 Hz, 1H), 3.99 (d, J = 12.8 Hz, 1H), 2.48 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 133.7, 130.7 (q, JF-C = 32.5 Hz),
130.4, 125.8 (q, JF-C = 3.6 Hz), 123.9 (q, JF-C = 272.0 Hz), 59.3,
1-Fluoro-2-((methylsulfinyl)methyl)benzene (2e).
Orange oil, yield: 14 mg, 84%; Rf = 0.48 (DCM/MeOH 15:1,
v/v). IR (KBr) 2926, 1618, 1586, 1492, 1455, 1049, 761 cm-1.
1H NMR (400 MHz, CDCl3) δ 7.37–7.31 (m, 2H), 7.19–
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 9
37.5. 19F NMR (377 MHz, CDCl3) δ -62.7. HRMS (ESI) m/z
13C{1H} NMR (101 MHz, CDCl3) δ 133.3, 133.0, 129.2, 128.8,
127.8, 127.7, 127.3, 127.1, 126.55, 126.47, 60.6, 37.4. HRMS
(ESI) m/z [M+H]+ calcd for C12H13OS+: 205.0682, found:
205.0678.
[M+H]+ calcd for C9H10F3OS+: 223.0399, found: 223.0394.
1
2
3
4
5
6
7
8
1-Methyl-4-((methylsulfinyl)methyl)benzene
(2l).17 Orange oil, yield: 12 mg, 58%; 14 mg, 66%; Rf = 0.31
(DCM/MeOH 15:1, v/v). IR (KBr) 2918, 1515, 1030, 820 cm-
1. 1H NMR (400 MHz, CDCl3) δ 7.20–7.15 (m, 4H), 4.04 (d, J
= 12.8 Hz, 1H), 3.89 (d, J = 12.8 Hz, 1H), 2.44 (s, 3H), 2.35
(s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 138.3, 129.9, 129.7,
126.5, 60.1, 37.2, 21.2. HRMS (ESI) m/z [M+H]+ calcd for
C9H13OS+: 169.0682, found: 169.0678.
Ethyl
5-((methylsulfinyl)methyl)furan-2-
carboxylate (2s). Yellow oil, yield: 13 mg, 49%; Rf = 0.29
(DCM/MeOH 15:1, v/v). IR (KBr) 2983, 2922, 1717, 1594,
1020 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 3.6 Hz,
1H), 6.54 (d, J = 3.6 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 4.10 (d,
J = 14.0 Hz, 1H), 4.06 (d, J = 14.0 Hz, 1H), 2.56 (s, 3H), 1.36
(t, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.3,
148.1, 145.4, 118.9, 113.3, 61.1, 52.3, 38.2, 14.3. HRMS (ESI)
m/z [M+H]+ calcd for C9H13O4S+: 217.0529, found: 217.0527.
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
Methyl
4-((methylsulfinyl)methyl)benzoate
(2m).17 White solid, yield: 18 mg, 68%; M.p. 74–76 °C , Rf =
0.27 (DCM/MeOH 15:1, v/v). IR (KBr) 2920, 1719, 1611, 1575,
1509, 1284, 864 cm-1. 1H NMR (400 MHz, CDCl3) δ 8.04 (d,
J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 4.03 (d, J = 12.8 Hz,
1H), 3.99 (d, J = 12.8 Hz, 1H), 3.91 (s, 3H), 2.46 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 166.5,134.7, 130.2, 130.19,
130.09, 59.8, 52.2, 37.5. HRMS (ESI) m/z [M+H]+ calcd for
C10H13O3S+: 213.0580, found: 213.0576.
2-Chloro-5-((methylsulfinyl)methyl)thiophene
(2t). Yellow oil, yield: 20 mg, 83%; Rf = 0.42 (DCM/MeOH
15:1, v/v). IR (KBr) 2921, 1656, 1033 cm-1. 1H NMR (400 MHz,
CDCl3) δ 6.85 (d, J = 4.0 Hz, 1H), 6.82 (d, J = 4.0 Hz, 1H),
4.08 (d, J = 14.0 Hz, 1H), 4.02 (d, J = 14.0 Hz, 1H), 2.49 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 131.1, 128.8, 128.3,
126.5, 54.1, 37.2. HRMS (ESI) m/z [M+H]+ calcd for
C6H8ClOS2+: 194.9700, found: 194.9696.
4-((Methylsulfinyl)methyl)benzaldehyde
(2n).
Orange oil, yield: 16 mg, 71%; Rf = 0.28 (DCM/MeOH 15:1,
1
v/v). IR (KBr) 2920, 1719, 1611, 1436, 1284 cm-1. H NMR
(((Trideuteromethyl)sulfinyl)methyl)benzene
(2a-d3). Colorless oil, yield: 14 mg, 73%; Rf = 0.35 (DCM
/MeOH 20:1, v/v). IR (KBr) 1603, 1496, 1455, 1025 cm-1. 1H
NMR (400 MHz, CDCl3) δ 7.41–7.33 (m, 3H, ArH), 7.32–
7.25 (m, 2H, ArH), 4.05 (d, J = 12.8 Hz, 1H), 3.92 (d, J = 12.8
Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 129.9, 129.6, 128.9,
128.4, 59.9, 36.4 (hept, JD-C = 20.9 Hz). HRMS (ESI) m/z
[M+H]+ calcd for C8H8D3OS+: 158.0713, found: 158.0713.
(400 MHz, CDCl3) δ 10.02 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H),
7.47 (d, J = 8.4 Hz 2H), 4.05 (d, J =12.8 Hz, 1H), 4.02 (d, J =
12.8 Hz, 1H), 2.49 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
191.6, 136.4, 136.2, 130.8, 130.1, 59.7, 37.6. HRMS (ESI) m/z
[M+H]+ calcd for C9H11O2S+: 183.0474, found: 183.0471.
2,4-Dichloro-1-((methylsulfinyl)methyl)benzene
(2o). Orange oil, yield: 14 mg, 65%; Rf = 0.56 (DCM/MeOH
15:1, v/v). IR (KBr) 2925, 1626, 1588, 1052, 867, 826 cm-1. 1H
NMR (400 MHz, CDCl3) δ 7.46 (d, J =2.0 Hz, 1H), 7.33 (d, J
=8.0 Hz, 1H), 7.28 (dd, J =8.0, 2.0 Hz, 1H), 4.14 (d, J = 12.8
Hz, 1H), 4.08 (d, J = 12.8 Hz, 1H), 2.52 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 136.2, 135.1, 133.1, 129.7, 127.6, 126.7,
56.5, 37.7. HRMS (ESI) m/z [M+H]+ calcd for C8H19Cl2OS+:
222.9746, found: 222.9740.
1-Methoxy-4-((methylsulfinyl)methyl)benzene
(2u).17 Collorless crystals; M.p. 55–56 °C, yield: 23 mg, 34%;
Rf = 0.68 (DCM/MeOH 10:1, v/v). 1H NMR (400 MHz, CDCl3)
δ 7.21 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.01 (d, J
= 12.8 Hz, 1H), 3.90 (d, J = 12.8 Hz, 1H), 3.81 (s, 3H), 2.44 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.7, 131.2, 121.4,
114.4, 59.5, 55.2, 37.0.
1,4-Dimethyl-2-((methylsulfinyl)methyl)benzene
(2p). White solid, yield: 15 mg, 66%; M.p. 84–86 °C , Rf =
0.36 (DCM/MeOH 15:1, v/v). IR (KBr) 2917, 1505, 1382,
1023, 823 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.10–7.02 (m,
3H), 4.17 (d, J = 12.8 Hz, 1H), 3.90 (d, J = 12.4 Hz, 1H), 2.51
(s, 3H), 2.36 (s, 3H), 2.30 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 136.0, 134.0, 131.5, 130.7, 129.4, 128.3, 59.1, 37.7,
20.8, 19.3. HRMS (ESI) m/z [M+H]+ calcd for C10H15OS+:
183.0838, found: 183.0835.
Large scale synthesis of benzyl methyl sulfoxide
(2a). To a stirring suspension of PTAT (7.90 mmol, 2.97 g)
in anhydrous DMSO (60 mL) (Caution: with 480 mL
pressure tube) was added benzyl chloride (1a) (7.90 mmol, 1
o
g). The reaction mixture was further stirred at 90 C for 160
minutes. After cooling and addition of water, the mixture was
extracted with DCM, and the combined organic layer was
washed with brine, dried over anhydrous sodium sulfate, and
concentrated in vacuo. The resulting residue was purified
by silica gel column chromatography with DCM and
methanol (150:1 to 10/1, v/v) as eluent to afford 0.64 g (53%)
of benzyl methyl sulfoxide (2a) as an orange oil.
1-((Methylsulfinyl)methyl)naphthalene
(2q).
Light yellow solid, yield: 19 mg, 75%; M.p. 68–70 °C , Rf =
0.38 (DCM/MeOH 15:1, v/v). IR (KBr) 2920, 1627, 1595,
1
1400, 1028 cm-1. H NMR (400 MHz, CDCl3) δ 8.08 (d, J =
Synthesis of benzyl 4-methylbenzenesulfonate.18
To a stirring solution of benzyl alcohol (270 mg, 2.5 mmol),
triethylamine (0.55 ml, 3.75 mmol), and DMAP (75 mg, 0.5
mmol) in anhydrous DCM (10 mL) in a 50 mL round bottom
flask in an ice-water bath was added dropwise a solution of
4-methylbenzenesulfonyl chloride (715 mg, 3.75 mmol) in
dried DCM (10 mL). After addition, the reaction mixture was
further stirred at 0 oC for 2 hours. After addition of water (10
mL), stirring, and separation, the organic phase was washed
with saturated aqueous sodium bicarbonate solution (20 mL
x 2), saturated brine (20 mL), and dried over anhydrous
sodium sulfate. After concentrated in vacuo, the resulting
residue was purified by silica gel column chromatography
with petroleum ether (60 – 90 oC) and ethyl acetate (10:1, v/v)
8.4 Hz, 1H), 7.90–7.84 (m, 2H), 7.59 (ddd, J = 8.4, 6.8, 1.2
Hz, 2H), 7.54 (ddd, J = 8.4, 6.8, 1.2 Hz, 2H), 4.68 (d, J = 13.2
Hz, 1H), 4.33 (d, J = 13.2 Hz, 1H), 2.48 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 133.9, 131.8, 129.4, 129.0, 128.9, 126.8,
126.34, 126.27, 125.4, 123.5, 58.8, 38.0. HRMS (ESI) m/z
[M+H]+ calcd for C12H13OS+: 205.0682, found: 205.0678.
2-((Methylsulfinyl)methyl)naphthalene
(2r).
Colorless solid, yield: 20 mg, 79%; M.p. 104–106 °C , Rf =
0.36 (DCM/MeOH 15:1, v/v). IR (KBr) 2910, 1597, 1026 cm-
1
1. H NMR (400 MHz, CDCl3) δ 7.87–7.82 (m, 3H), 7.77 (s,
1H), 7.52–7.49 (m, 2H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 4.23
(d, J = 12.8 Hz, 1H), 4.08 (d, J = 12.8 Hz, 1H), 2.48 (s, 3H).
ACS Paragon Plus Environment

Page 7 of 9
The Journal of Organic Chemistry
as eluent to afford 190 mg (29%) of benzyl 4-
1-(Allyloxy)-4-(chloromethyl)benzene
(1x).24
methylbenzenesulfonate as colorless crystals, M.p. 48–50 oC,
Rf = 0.18 (PE:EA 10:1, v/v). 1H NMR (400 MHz,CDCl3) δ 7.78
(d, J = 8.0 Hz, 2H), 7.32–7.27 (m, 5H), 7.26–7.20 (m, 2H),
5.03 (s, 2H), 2.41 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
144.7, 133.14, 133.06, 129.7, 128.9, 128.5, 128.4, 127.8, 71.8,
21.5.
Colorless oil; yield: >98%, Rf = 0.64 (PE:EA 10:1, v/v). H
NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.8 Hz, 2H), 6.88 (d,
J = 8.4 Hz, 2H), 6.04 (ddt, J = 17.2, 10.8, 6.0 Hz 1H), 5.40
(dd, J = 17.2, 1.2 Hz, 1H), 5.28 (dd, J = 10.8, 1.2 Hz, 1H), 4.55
(s, 2H), 4.52 (dt, J = 5.6, 1.2 Hz, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 158.6, 133.01, 129.98, 129.8, 117.7, 114.9, 46.2.
1
1
2
3
4
5
6
7
8
9
Synthesis of tert-butyl (4-(hydroxymethyl)phenyl)
carbonate.19 Boc2O (879 mg, 4.03 mmol), carbon
ASSOCIATED CONTENT
Supporting Information
tetrachloride
(134
mg,
0.40
mmol),
and
4-
The Supporting Information is available free of charge on the
ACS Publications website.
hydroxymethylphenol (500 mg, 4.03 mmol) were stirred in
an oil bath at 75 °C for 2 hours. After addition of water (10
mL), the mixture was extracted with ethyl acetate (10 mL x
2). The combined organic phase was washed with saturated
brine (10 mL), and dried over anhydrous sodium sulfate.
After concentrated in vacuo, the resulting residue was
purified by silica gel column chromatography with petroleum
ether (60 – 90 oC) and ethyl acetate (50:1 and then 10:1, v/v)
as eluent to afford 630 mg (70%) of tert-butyl (4-
(hydroxymethyl)phenyl) carbonate as colorless oil, Rf = 0.32
(PE:EA 3:1, v/v).
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
Copies of 1H and 13C{H} NMR spectra of all products,
prepared starting materials, and GC-MS profiles on
mechanistic investigations (PDF file)
AUTHOR INFORMATION
Corresponding Author
*jxxu@mail.buct.edu.cn
Author Contributions
Synthesis
of
tert-butyl
(4-
4-
(hydroxymethyl)phenyl)carbamate.20
The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript.
(Aminophenyl)methanol (500 mg, 4.07 mmol) was dissolved
in a mixture of 1,4-dioxane (3 mL), water (3 mL), and 1 mol/L
NaOH (4 mL) at 0 oC in an ice-water bath. Boc2O (1.33 g, 6.09
mmol) was added under stirring in an oil bath at 0 °C. After
stirred for 10 min., the ice-water bath was removed. The
mixture was stirred at room temperature for 12 hours. After
addition of water (10 mL), the resulting mixture was
extracted with ethyl acetate (10 mL x 2). The combined
organic phase was washed with 1 mol/L HCl (20 mL x 2)
twice, saturated brine (10 mL), and dried over anhydrous
sodium sulfate. After concentrated in vacuo, the crude tert-
butyl (4-(hydroxymethyl)phenyl)carbamate was obtained
895 mg (98.7% yield) as yellow oil, Rf = 0.28 (PE:EA 2:1, v/v).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (Nos. 21572017, 21772010, and
21911530099) and the Fundamental Research Funds for the
Central Universities (XK1802-6).
REFERENCES
(1) Trost, B. M.; Rao, M. Development of Chiral Sulfoxide
Ligands for Asymmetric Catalysis. Angew. Chem. Int. Ed.
2015, 54, 5026-5043.
Synthesis of substituted benzyl chlorides via
chlorination with thionyl chloride (General
procedure).21 To a solution of thionyl chloride (1.01 g, 8.46
mmol) in chloroform (15 mL) in an ice-water bath was added
the above prepared substituted benzyl alcohol (2.82 mmol)
with a syringe during 30 min. After addition, the reaction
mixture was stirred at 0 oC for 2 hours. The mixture was
washed with water (10 mL x 3) and saturated brine (10 mL).
The organic phase was dried over anhydrous sodium sulfate.
After concentrated in vacuo, the resulting residue was
purified by silica gel column chromatography with petroleum
(2) (a) Pramanik, M. M. D.; Rastogi, N. Visible Light
Catalyzed Methylsulfoxidation of (Het)aryl diazonium Salts
Using DMSO. Chem. Commun. 2016, 52, 8557-8560.
Legros, J.; Dehli, J. R.; Bolm, C. Applications of Catalytic
Asymmetric Sulfide Oxidations to the Syntheses of
Biologically Active Sulfoxides. Adv. Synth. Catal. 2005, 347,
19-31.
(b)
o
ether (60 – 90 C) and ethyl acetate (50:1, v/v) as eluent to
(3) (a) Zhang, Z.; He, P.; Du, H.; Xu, J.; Li, P. Sulfur-
Mediated Electrophilic Cyclization of Aryl-Substituted
Internal Alkynes. J. Org. Chem. 2019, 84, 4517-4524.
afford substituted benzyl chloride.
(b)
tert-Butyl (4-(chloromethyl)phenyl) carbonate
(1v).22 Colorless oil, yield: 170 mg, 25%; Rf = 0.50 (PE:EA
10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.4 Hz,
2H), 7.16 (d, J = 8.4 Hz, 2H), 4.57 (s, 2H), 1.56 (s, 9H). 13C{1H}
NMR (101 MHz, CDCl3) δ 151.6, 150.9, 134.9, 129.7, 121.5,
83.7., 45.5, 27.6.
Kaiser, D.; Klose, I.; Oost, R.; Neuhaus, J.; Maulide, N. Bond-
Forming and -Breaking Reactions at Sulfur(IV): Sulfoxides,
Sulfonium Salts, Sulfur Ylides, and Sulfinate Salts. Chem.
Rev. 2019, 119, 8701-8780. (c) Smith, L. H. S.; Coote, S. C.;
Sneddon, H. F.; Procter, D. J. Beyond the Pummerer
Reaction: Recent Developments in Thionium Ion Chemistry.
Angew. Chem. Int. Ed. 2010, 49, 5832-5844. (d) Bur, S. K.;
Padwa, A. The Pummerer Reaction:ꢀ Methodology and
Strategy for the Synthesis of Heterocyclic Compounds. Chem.
Rev. 2004, 104, 2401-2432.
tert-Butyl
(4-(chloromethyl)phenyl)carbamate
(1w).23 White solid; yield: 160 mg, 18%; M.p. 95–96 °C, Rf =
0.64 (PE:EA 10:1, v/v). 1H NMR (400 MHz, CDCl3) δ 7.36–
7.26 (m, 4H), 6.55 (s, 1H), 4.55 (s, 2H), 1.52 (s, 9H). 13C{1H}
NMR (101 MHz, CDCl3) δ 152.6, 138.5, 131.9, 129.4, 118.5,
80.7, 46.1, 28.3.
(4) (a) Grogan, G. In Biocatalysis in Organic Synthesis;
2015 ed.; Faber, K., Fessner, W. D., Turner, N. J., Eds.;
Georg Thieme Verlag: Stuttgart, 2015, 3, 285-311. (b)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 9
Madesclaire, M. Synthesis of Sulfoxides by Oxidation of
Thioethers. Tetrahedron 1986, 42, 5459-5495.
X. Dimethyl Sulfoxide Serves as
a
Dual Synthon:
Construction of 5-Methyl Pyrimidine Derivatives via Four
Component Oxidative Annulation. Adv. Synth. Catal. 2018,
360, 2267-2271. (f) Liu, Y.-F.; Ji, P.-Y.; Xu, J.-W.; Hu, Y.-Q.;
Liu, Q.; Luo, W.-P.; Guo, C.-C. Transition Metal-Free α-
Csp3-H Methylenation of Ketones to Form C:C Bond Using
Dimethyl Sulfoxide as Carbon Source. J. Org. Chem. 2017,
82, 7159-7164. (g) Li, Z.; Cui, X.; Niu, L.; Ren, Y.; Bian, M.;
Yang, X.; Yang, B.; Yan, Q.; Zhao, J. An Iron(II) Chloride-
Promoted Radical Cascade Methylation or α-Chloro-β-
methylation of N-Arylacrylamides with Dimethyl Sulfoxide.
Adv. Synth. Catal. 2017, 359, 246-249.
(9) (a) Hazarika, H.; Neog, K.; Sharma, A.; Das, B.; Gogoi, P.
Three-Component Coupling Reactions of Aryne, DMSO, and
Activated Alkyne: Stereoselective Synthesis of 2-[(o-
Methylthio)aryloxy]-Substituted Dialkyl Maleates. J. Org.
Chem. 2019, 84, 5846-5854. (b) Du, K.-S.; Huang, J.-M.
Electrochemical Synthesis of Methyl Sulfoxides from
Thiophenols/thiols and Dimethyl Sulfoxide. Green Chem.
2018, 20, 1405-1411. (c) Dai, P.; Luo, K.; Yu, X.; Yang, W.-
C.; Wu, L.; Zhang, W.-H. Tert-Butyl Nitrite Mediated
Expeditious Methylsulfoxidation of Tetrazole-amines with
DMSO: Metal-free Synthesis of Antifungal Active
Methylsulfinyl-1H-tetrazole Derivatives. Adv. Synth. Catal.
2018, 360, 468-473.(d) Shao, A.; Gao, M.; Chen, S.; Wang,
T.; Lei, A. CO/O2 Assisted Oxidative Carbon-Carbon and
Carbon–Heteroatom Bond Cleavage for the Synthesis of
Oxosulfonates from DMSO and Olefins. Chem. Sci. 2017, 8,
2175-2178. (e) Gao, X.; Pan, X.; Gao, J.; Huang, H.; Yuan, G.;
Li, Y. Ammonium Iodide-Induced Sulfonylation of Alkenes
with DMSO and Water toward the Synthesis of Vinyl Methyl
Sulfones. Chem. Commun. 2015, 51, 210-212. (f) Jiang, Y.;
Loh, T.-P. Catalytic and Direct Methyl Sulfonylation of
Alkenes and Alkynes Using a Methyl Sulfonyl Radical
Generated from a DMSO, Dioxygen and Copper System.
1
2
3
4
5
6
7
8
(5) (a) Jia, T.; Zhang, M.; Sagamanova, I. K.; Wang, C. Y.;
Walsh, P. J. Palladium Catalyzed Diaryl Sulfoxide Generation
from Aryl Benzyl Sulfoxides and Aryl Chlorides. Org. Lett.
2015, 17, 1168-1171. (b) Jia, T.; Zhang, M.; Jiang, H.; Wang,
C. Y.; Walsh, P. J. Palladium-Catalyzed Arylation of Alkyl
Sulfenate Anions. J. Am. Chem. Soc. 2015, 137, 13887-13893.
(c) Gelat, F.; Lohier, J.-F.; Gaumont, A.-C.; Perrio, S. tert-
Butyl Sulfoxides: Key Precursors for Palladium-Catalyzed
Arylation of Sulfenate Salts. Adv. Synth. Catal. 2015, 357,
2011-2016. (d) Jia, T.; Bellomo, A.; Montel, S.; Zhang, M.; El
Baina, K.; Zheng, B.; Walsh, P. J. Diaryl Sulfoxides from Aryl
Benzyl Sulfoxides: A Single Palladium-Catalyzed Triple Relay
Process. Angew. Chem. Int. Ed. 2014, 53, 260-264. (e) Jia,
T.; Bellomo, A.; Baina, K. E. L.; Dreher, S. D.; Walsh, P. J.
Palladium-Catalyzed Direct Arylation of Methyl Sulfoxides
with Aryl Halides. J. Am. Chem. Soc. 2013, 135, 3740-3743.
(f) Bernoud, E.; Le Duc, G.; Bantreil, X.; Prestat, G.; Madec,
D.; Poli, G. Aryl Sulfoxides from Allyl Sulfoxides via [2,3]-
Sigmatropic Rearrangement and Domino Pd-Catalyzed
Generation/Arylation of Sulfenate Anions. Org. Lett. 2010,
12, 320-323.
(6) (a) Zong, L.; Ban, X.; Kee, C. W.; Tan, C.-H. Catalytic
Enantioselective Alkylation of Sulfenate Anions to Chiral
Heterocyclic Sulfoxides Using Halogenated Pentanidium
Salts. Angew. Chem. Int. Ed. 2014, 53, 11849-11853. (b)
Söderman, S. C.; Schwan, A. L. Sulfenate Substitution as a
Complement and Alternative to Sulfoxidation in the
Diastereoselective Preparation of Chiral β-Substituted β-
Amino Sulfoxides. J. Org. Chem. 2013, 78, 1638-1649. (c)
Foucoin, F.; Caupène, C.; Lohier, J.-F.; Sopkova de Oliveira
Santos, J.; Perrio, S.; Metzner, P. 2-(Trimethylsilyl)ethyl
Sulfoxides as a Convenient Source of Sulfenate Anions.
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
Synthesis 2007, 2007, 1315-1324.
(d)
Caupène,
C.;
Boudou, C.; Perrio, S.; Metzner, P. Remarkably Mild and
Simple Preparation of Sulfenate Anions from β-
Sulfinylesters:ꢀ A New Route to Enantioenriched Sulfoxides.
J. Org. Chem. 2005, 70, 2812-2815.
(7) (a) Wei, J.; Sun, Z. tert-Butyl Sulfoxide as a Starting Point
for the Synthesis of Sulfinyl Containing Compounds. Org.
Chem. Sci. 2014, 5, 4939-4943.
(g) Yuan, G.; Zheng, J.;
Gao, X.; Li, X.; Huang, L.; Chen, H.; Jiang, H. Copper-
Catalyzed Aerobic Oxidation and Cleavage/Formation of C-S
Bond: A Novel Synthesis of Aryl Methyl Sulfones from Aryl
Halides and DMSO. Chem. Commun. 2012, 48, 7513-7515.
(10) (a) Zhao, P.; Wu, X.; Geng, X.; Wang, C.; Zhou, Y.; Wu,
Y.-D.; Wu, A.-X. I2/PhI(OAc)2 Copromoted Amination
Reaction: Synthesis of α-Dicarbonylsulfoximine Derivatives
by Incorporating an Intact Dimethyl Sulfoxide. J. Org. Chem.
2019, 84, 8322-8329. (b) Xu, N.; Zhang, Y.; Chen, W.; Li, P.;
Wang, L. Photoinduced N-Methylation and N-Sulfonylation
of Azobenzenes with DMSO under Mild Reaction Conditions.
Adv. Synth. Catal. 2018, 360, 1199-1208. (c) Vaitla, J.;
Hopmann, K. H.; Bayer, A. Rhodium-Catalyzed Synthesis of
Sulfur Ylides via in Situ Generated Iodonium Ylides. Org.
Lett. 2017, 19, 6688-6691.
(11) (a) Rather, S. A.; Kumar, A.; Ahmed, Q. N. Iodine-
DMSO-Promoted Divergent Reactivities of Arylacetylenes.
Chem. Commun. 2019, 55, 4511-4514. (b) Zhang, J.; Cheng,
S.; Cai, Z.; Liu, P.; Sun, P. Radical Addition Cascade
Cyclization of 1,6-Enynes with DMSO To Access
Methylsulfonylated and Carbonylated Benzofurans under
Transition-Metal-Free Conditions. J. Org. Chem. 2018, 83,
9344-9352.
Lett. 2015, 17, 5396-5399.
(b) Han, Z.; Krishnamurthy,
D.; Grover, P.; Fang, Q. K.; Su, X.; Wilkinson, H. S.; Lu, Z.-
H.; Magiera, D.; Senanayake, C. H. Practical and Highly
Stereoselective Technology for Preparation of Enantiopure
Sulfoxides and Sulfinamides Utilizing Activated and
Functionally
Differentiated
N-Sulfonyl-1,2,3-
oxathiazolidine-2-oxide Derivatives. Tetrahedron 2005, 61,
6386-6408.
(8) (a) Zhang, P.; Yang, Y.; Chen, Z.; Xu, Z.; Xu, X.; Zhou, Z.;
Yu, X.; Yi, W. Cobalt(III)-Catalyzed, DMSO-Involved, and
TFA-Controlled Regioselective C-H Functionalization of
Anilines with Alkynes for Specific Assembly of 3-
Arylquinolines. Adv. Synth. Catal. 2019, 361, 3002-3007. (b)
Ebule, R.; Mudshinge, S.; Nantz, M. H.; Mashuta, M. S.;
Hammond, G. B.; Xu, B. A 5+1 Protic Acid Assisted Aza-
Pummerer Approach for Synthesis of 4-Chloropiperidines
from Homoallylic Amines. J. Org. Chem. 2019, 84, 3249-
3259. (c) Zhu, X.; Li, W.; Luo, X.; Deng, G.; Liang, Y.; Liu, J.
A Catalyst-free and Additive-free Method for the Synthesis of
Benzothiazolethiones from o-Iodoanilines, DMSO and
Potassium Sulfide. Green Chem. 2018, 20, 1970-1974. (d)
Zhang, R.; Yu, H.; Li, Z.; Yan, Q.; Li, P.; Wu, J.; Qi, J.; Jiang,
M.; Sun, L. Iron-Mediated Azidomethylation or
Azidotrideuteromethylation of Active Alkenes with
Azidotrimethylsilane and Dimethyl Sulfoxide. Adv. Synth.
Catal. 2018, 360, 1384-1388. (e) Xu, C.; Jiang, S.-F.; Wen,
X.-H.; Zhang, Q.; Zhou, Z.-W.; Wu, Y.-D.; Jia, F.-C.; Wu, A.-
(12) (a) Tan, H.-R.; Wang, L.; Zhu, J.-N.; Yang, Z.-H.; Zhao,
S.-Y. Iodine-Promoted C(sp2)-H Thiolation of Maleimides
with Dimethyl Sulfoxide and Thiols. Synthesis 2018, 50,
4113-4123. (b) Li, J.; Liu, G.; Shi, L.; Xing, Q.; Li, F. Cobalt
Modified N-Doped Carbon Nanotubes for Catalytic C=C
Bond Formation via Dehydrogenative Coupling of Benzyl
Alcohols and DMSO. Green Chem. 2017, 19, 5782-5788.
(c) Choudhary, R.; Bai, R.; Singh, P.; Sharma, M. C.; Badsara,
S. S. Metal-free, Regio- and Stereoselective S-
ACS Paragon Plus Environment

Page 9 of 9
The Journal of Organic Chemistry
Methylation/Phenylation of Allyl Halides Using Sulfoxides as
(18) Ding, R.; He, Y.; Wang, X.; Xu, J. L.; Chen, Y. R.; Feng,
M.; Qi, C. M. Treatment of Alcohols with Tosyl Chloride Does
Not always Lead to the Formation of Tosylates. Molecules
2011, 16, 5665-5673.
Sulfenylating Agent. Tetrahedron 2017, 73, 4323-4328.
(d) Chen, Z.; Cao, G.; Zhang, F.; Li, H.; Xu, J.; Miao, M.; Ren,
H. Metal-Free Mediated C-3 Methylsulfanylation of
1
2
3
4
5
6
7
8
9
Imidazo[1,2-a]-pyridines with Dimethyl Sulfoxide as
Methylsulfanylating Agent. Synlett 2017, 28, 1795-1800.
a
(19) Chankeshwara, S. V.; Chebolu R.; Chakraborti, A. K.
Organocatalytic Methods for Chemoselective O-tert-
Butoxycarbonylation of Phenols and Their Regeneration
from the O-t-Boc Derivatives. J. Org. Chem. 2008, 73, 8615-
8618.
(13) Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W.
J.; Larson, H. O.; Levand, O.; Weaver, W. M. A New and
Selective Method of Oxidation. J. Am. Chem. Soc. 1957, 79,
6562-6562.
(14) (a) Wu, X.-F.; Natte, K. The Applications of Dimethyl
Sulfoxide as Reagent in Organic Synthesis. Adv. Syn. Catal.
2016, 358, 336-352. (b) Jones-Mensah, E.; Karki, M.;
Magolan, J. Dimethyl Sulfoxide as a Synthon in Organic
Chemistry. Synthesis 2016, 48, 1421-1436.
(15) (a) Hull, C. M.; Bargar, T. W. Transfer of Oxygen to
Organic Sulfides with Dimethyl Sulfoxide Catalyzed by
Hydrogen Chloride. Preparation of Disulfoxides. J. Org.
Chem. 1975, 40, 3152-3154. (b) Harville, R.; Reed, S. F.
Sulfide Oxidation with N-Halosuccinimides. J. Org. Chem.
1968, 33, 3976-3977. (c) Traynelis, V. J.; Hergenrother, W.
L. Decomposition of Dimethyl Sulfoxide Aided by Ethylene
Glycol, Acetamide, and Related Compounds1. J. Org. Chem.
1964, 29, 221-222. (d) Searles, J. S.; Hays, H. Notes -
Oxidation of Organic Sulfides with Dimethyl Sulfoxide. J.
Org. Chem. 1958, 23, 2028-2029.
(16) Solladié-Cavallo, A.; Lupattelli, P.; Bonini, C. Regio- and
Stereoselective Ring Opening of 2,3-Diaryl Oxiranes by
LiBr/Amberlyst 15:ꢀ A New Stereocontrolled Access to 1,2-
Diaryl-2-bromo Alcohols. J. Org. Chem. 2005, 70, 1605-1611.
(17) Holland, H. L.; Brown, F. M.; Larsen, B. G.
Biotransformation of Organic Sulfides. Part 6. Formation of
(20) Rai, R.; Katzenellenbogen, J. A. Guanidinophenyl-
Substituted Enol Lactones as Selective, Mechanism-Based
Inhibitors of Trypsin-like Serine Proteases. J. Med. Chem.
1992, 35, 4150-4159.
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
(21) Wang, T.; Zhang, Y. H.; Kong, X.-W.; Lai, Y.-S.; Ji, H.;
Chen, Y. P.; Peng, S. X. Synthesis and Biological Evaluation
of Nitric Oxide-Donating Thalidomide Analogues as
Anticancer Agents. Chem. Biodiv. 2009, 6, 466-476.
(22) Beaulieu, P. L.; Fazal, G.; Gillard, J.; Kukolj, G.; Austel,
V. Preparation of Benzimidazolecarboxylates and Related
Compounds as Viral Polymerase Inhibitors. PCT Int. Appl.
(2002), WO 2002004425.
(23) Clancy, A. J.; Serginson, J. M.; Greenfield, J. L.; Shaffer,
M. S. P. Systematic Comparison of Single-Walled Carbon
Nanotube/Poly(vinylacetate) Graft-to Reactions. Polymer
2017, 133, 263-271.
(24) Podichetty, A. K.; Wagner, S.; Schroer, S.; Faust, A.;
Schafers, M.; Schober, O.; Kopka, K.; Haufe, G. Fluorinated
Isatin Derivatives. Part 2. New N-Substituted 5-
Pyrrolidinylsulfonyl Isatins as Potential Tools for Molecular
Imaging of Caspases in Apoptosis. J. Med. Chem. 2009, 52,
3484-3495.
Chiral para-Substituted
Benzyl
Methyl
Sulfoxides
by Helminthosporium Species NRRL 4671. Tetrahedron:
Asymmetry 1995, 6, 1561-1567.
ACS Paragon Plus Environment