Air Oxidative Radical Oxysulfurization of Alkynes Leading to α-Thioaldehydes

Article abstract of DOI:10.1021/acs.joc.5b00641

Air oxidative radical oxysulfurization of alkynes initiated by 0.5 mol % tert-butyl hydroperoxide with arylthiols is described. The reaction proceeded at room temperature in the presence of 5% mol water to afford selective α-thioaldehydes. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b00641

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Note
Air Oxidative Radical Oxysulfurization of
Alkynes Leading to alpha-Thioaldehydes
Shao-Fang Zhou, Xiang-Qiang Pan, Zhi-Hao Zhou, Adedamola Shoberu, Pei-Zhi Zhang, and Jian-Ping Zou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00641 • Publication Date (Web): 29 Apr 2015
Downloaded from http://pubs.acs.org on May 5, 2015
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Air Oxidative Radical Oxysulfurization of Alkynes
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Leading to α-Thioaldehydes
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ShaoꢀFang Zhou,a XiangꢀQiang Pan,*a ZhiꢀHao Zhou,a Adedamola Shoberu,a
PeiꢀZhi Zhang,a JianꢀPing Zou*a,b
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a Key Laboratory of Organic Synthesis of Jiangsu Province,,College of Chemistry and Chemical
Engineering, Soochow University, 199 Renai Street, Suzhou, Jiangsu 215123, China.
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China.
ABSTRACT: Air oxidative radical oxysulfurization of alkynes initiated by 0.5 mol % tertꢀbutyl
hydroperoxide with arylthiols is described. The reaction proceeded at room temperature in the presence of 5%
mol water to afford selective αꢀthioaldehydes.
Recently, difunctionalization of alkenes and alkynes has become a powerful tool in synthetic
organic chemistry.1 The radical difunctionalization having advantages such as mild reaction
conditions, high selectivity and convenient workup has made it more interesting.2 Thiol−oxygen
coꢀoxidation reactions (TOCO) provide attractive routes to functionalized valuable products with
studies focusing mainly on olefins,3 only a few have been on alkynes.3a, 4 The first example of
TOCO of alkynes appeared in the early 1960s when Griesbaum et al. 4b reported the reaction of
thiophenol with phenylacetylene in an oxygen atmosphere to give the phenylglyoxal
hemithioacetal. In 1993, the Isoe group found that the electroinitiated oxygenation of alkynes in
4c
the presence of thiophenol gave αꢀ(phenylthio) carbonyl compounds.
Also, Renaud et al.
reported that the reaction of terminal alkynes with thiophenol in the presence of AIBN afforded a
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4eꢀg
series of fiveꢀmembered cyclic compounds.
difunctionalization reactions,5
In continuation of our efforts on
herein, we report a new protocol, TBHP (tertꢀbutyl
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hydroperoxide)ꢀinitiated waterꢀcatalyzed difunctionalization of terminal alkynes with thiophenol
in air at room temperature to give αꢀthioaldehydes.
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We began our studies by exploring the reaction of thiophenol (1a) with tertꢀbutyl
2ꢀ(butꢀ3ꢀynꢀ1ꢀyloxy) acetate (2a) in DMF at 25oC, however, alkenyl sulfide 3a was obtained as
the sole product (Table 1, entry 1). After screening of solvents, we were pleased to observe a
mixture of products 3a and 4a in tertꢀbutanol and ethereal solvents such as 1,4ꢀdioxane,
tetrahydrofuran (THF), and 1,2ꢀdimethoxyethane (1,2ꢀDME) (Table 1, entries 5ꢀ8). Interestingly,
the addition of a catalytic amount of water into the reaction in THF slightly increased the yield of
4a (Table 1, entry 9). More interesting was the fact that no formation of 4a was observed in
anhydrous THF (Table 1, entry 10). To improve the selectivity and yield of reaction, 0.5% mol of
TBHP was added to the reaction and this led to a massive increase in the yield of 4a to 75%
(Table 1, entry 11). After screening the reaction time, temperature, amount of water and TBHP
(Table 1, entries 11ꢀ20), the optimum reaction conditions were determined to be: thiophenol (1a,
2.0 equiv) and tertꢀbutyl 2ꢀ(butꢀ3ꢀynꢀ1ꢀyloxy) acetate (2a, 1 equiv) in THF at 25oC for 48 h in the
presence of 0.5% mol TBHP and 5% mol H2O to afford the selective αꢀthioaldehyde 4a in good
yield (Table 1, entry 12).
Under these conditions, reactions of a variety of terminal alkynes 2a-i with thiophenol (1a)
were carried out. The alkynes tertꢀbutyl 2ꢀ(butꢀ3ꢀynꢀ1ꢀyloxy) acetate (2a) and nꢀhexyne (2b)
gave exclusively αꢀthioaldehydes (4a and 4b) in excellent yields (Table 2, entries 1 and 2).
However, the reaction of other chain terminal alkynes 2c-2g gave majorly αꢀthioaldehydes 4c-4g
in moderate to good yields accompanied by alkenylsufides 3c-3g (Table 2, entries 3ꢀ7). In
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Table 1. Optimization of the Reaction Conditions
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Ratio
Temp Time
Yield(%)
Yield(%)
(4a)a
0
Entry
Solvent
(1a:2a)
(℃)
25
25
25
25
25
25
25
25
25
(h)
24
24
24
24
24
24
24
24
24
(3a)/(Z and E)a
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1
2
DMF
Toluene
CH2Cl2
CH3CN
tBuOH
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
37
2.2
29
0
0
0
3
4
0
5
11
17
15
14
20
25
28
29
21
38
0
6
1,4ꢀDioxane
THF
7
8
9b
1,2ꢀDME
THF
10c
11b,d,e
12b,d,e
13b,d,e
14b,e
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
25
25
25
25
0
24
24
48
72
48
48
48
48
48
48
48
0
25
2
75
98
90
0
9
0
15b,e
13
25
40
60
25
25
27
0
0
16b,e
77
25
1.4
70
0
17b,e
70
86
12
34
18b,e
19d,e, f
20b,d,g
aIsolated yield. Addition of 5% mol H2O (1 ꢀL). Anhydrous THF. Gas chromatography yield. Addition of
0.5% mol TBHP (1 ꢀL). fAddition of 4 ꢀL H2O. gAddition of 5% mol TBHP (10 ꢀL).
b
c
d
e
reactions involving the sterically hindered terminal alkynes such as tꢀbutylacetylene (2h) and
cyclopropyl acetylene (2i), low yields of αꢀthioaldehydes 4hꢀ4i were observed as the formation
of alkenylsufides 3hꢀ3i tends to predominate (Table 2, entries 8 and 9). The low yields of
αꢀthioaldehydes underline the effect of bulky group attached to the C≡C triple bond. It is worth
noting that the reaction of phenylacetylene (2j) with 1a led to formation of complicated mixtures
(Table 2, entry 10). This is probably due to the high reactivity of the conjugated alkenyl radical
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generated from the reaction of thiyl radical with 2j. Also, when alkyl group R = nꢀbutyl (2b) was
replaced with phenylethyl (2k) and phenylpropyl (2l), their reactions with 1a produced 4k and 4l
in low yields, 12% and 44% respectively (Table 2, entries 11 and 12), it was observed that most
of starting substrate 2k and 2l remained unreacted at the end of reaction. From the results
obtained, we reasoned that the yield of αꢀthioaldehydes depended mainly on the structure of the
terminal alkynes.
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Afterwards, the reactions of terminal alkynes having oxygen or nitrogenꢀcontaining substituent
groups were investigated. Alkynes bearing an ester group at αꢀ and βꢀpositions all reacted well
with 1a to give exclusively alkenylsufides 3mꢀ3n (Table 2, entries 13 and 14). Reactions
involving 5ꢀhydroxypentyne (2o) and 4ꢀhydroxybutyne (2p) also gave alkenylsufides 3o and 3p
as the sole products in 77% and 17% yield respectively (Table 2, entries 15 and 16). Interestingly,
the presence of the oxygen atom and COOtBu groups in tertꢀbutyl 2ꢀ(butꢀ3ꢀynꢀ1ꢀyloxy) acetate
(2a) led to formation of αꢀthioaldehyde, although the reason for this remained unknown.
Furthermore, no reactions were observed with
αꢀaminoalkynes (2qꢀ2s) (Table 2). We reasoned
that the amino group on the ꢀcarbon could probably be impeding the radical reaction.
α
To know the effect of substitution on phenyl ring, a series of arylthiols containing electronꢀ
donating and electronꢀwithdrawing groups were employed. In the reaction of 4ꢀmethyl
benzenethiol (1b) with terminal alkyne 2a, αꢀthioaldehyde (4ba) was obtained as the major
product in 59% yield and alkenylsulfide (3ba) as minor product in 32% yield (Table 3, entry 1).
On the contrary, the reaction of 2ꢀmethylbenzenethiol (1c) gave the alkenylsulfide (3ca) as major
product in 70% yield and αꢀthioaldehyde (4ca) as minor product in 23% yield (Table 3, entry 2).
In addition, the reaction of 2,6ꢀdimethylbenzenethiol (1d) with 2a gave alkenylsulfide (3da) as
sole product in 84% yield (Table 3, entry 3). These results show that hindered arylthiyl radicals
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Table 2. Reactions of Thiophenol (1a) with Terminal Alkynes 2a-sa
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favor formation of the less hindered alkenylsulfides 3. 4ꢀMethoxybenzenethiol (1e) and
2ꢀaminobenzenethiol (1f) did not give desired compounds due to selfꢀcoupling of the
electronꢀrich arylthiyl radicals generated from 1e and 1f leading to diaryldisulfides (Table 3,
entries 4 and 5). Arylthiols bearing F and Cl groups reacted with 2a to form αꢀthioaldehydes (4ga,
4ha, 4ia and 4ja) as major product in moderate to excellent yields (Table 3, entries 6ꢀ9). No
reactions were observed with 4ꢀnitrobenzenethiol 1k, pyridylthiol 1l and furylthiol 1m (Table 3,
entries 10ꢀ12). This is because the corresponding thiyl radicals could not formed under the
reaction condition.
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Table 3. Reactions of Arylthiols 1 with Terminal Alkyne 2aa
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As mentioned earlier, the reaction of tertꢀbutyl 2ꢀ(butꢀ3ꢀynꢀ1ꢀyloxy) acetate (2a) with
thiophenol (1a) did not take place in anhydrous THF. Further experiment also showed that the
same reaction did not take place when conducted in a nitrogen atmosphere, thus indicating that
oxygen is necessary for reaction to occur. To understand how the reaction proceeds, a
mechanistic study was done. An experiment using deuteriumꢀlabeled thiophenol (1a’) with
nꢀhexyne (2b) was carried out and the unlabeled αꢀthioaldehyde (4b) was isolated as the product
(Scheme 1, eq 1). However, the reaction of thiophenol (1a) with deuteriumꢀlabeled nꢀhexyne (2b’)
gave the deuterated αꢀthioaldehyde (4b’) (Scheme 1, eq 2) thus indicating that the aldehydic
proton originated from nꢀhexyne (2b). To know if the reaction proceeds via a radical pathway, the
reaction of tertꢀbutyl 2ꢀ(butꢀ3ꢀynꢀ1ꢀyloxy) acetate (2a) with thiophenol (1a) was carried out in
the presence of the radical inhibitor, TEMPO (2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy) (5), and only
2,2,6,6ꢀtetramethylꢀ1ꢀ((phenylthio)oxy)piperidine (6) and diphenyl disulfide (7) were isolated,
with no detectable sign of αꢀthioaldehyde (4a). Further experiment showed that TEMPO did not
react with 2a.
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Scheme 1. Mechanistic Study
On the basis of above findings, a plausible mechanism is proposed in Scheme 2. The
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thiophenyl radical 8 initiated by TBHP coordinates with terminal alkyne 2a to form flexible
radical 9, followed by addition of H2O to give radical 10 which then reacts with O2 (air) to give
peroxy radical 11, this decomposes to form αꢀthioaldehyde 4a and hydroperoxy radical 12, which
reacts with thiophenol (1a) to liberate thiophenyl radical 8, for further propagation of the reaction
cycle.
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Scheme 2. Proposed Mechanism for the Reaction of Terminal Alkyne 2a with Thiophenol (1a)
In conclusion, a new protocol for the oxysulfurization of alkynes via the reaction of arylthiols
with alkynes has been developed. The reaction was initiated by 0.5 mol % TBHP at room
temperature in the presence of 5 mol % water, with air (O2) as sole oxidant to afford the selective
αꢀthioaldehydes in moderate to good yields. This method is straightforward, requires no other
oxidant or additive, and involves simple manipulations. The αꢀthioaldehydes obtained can be
directly applied in syntheses of organic, medicinal and other functional compounds.
EXPERIMENTAL SECTION
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General Methods. H NMR (400 MHz) and C NMR (101 MHz) spectra were determined
with CDCl3 or DMSOꢀd6 as solvent and tetramethylsilane (TMS) as internal standard. Chemical
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shifts were reported in parts per million (ppm) from internal TMS (δ); all coupling constants (J
values) were reported in hertz (Hz). Highꢀresolution mass spectra were recorded on a TOF
machine (ESI). Column chromatography was performed with 300−400 mesh silica gel using
flash column techniques. All of the reagents were used directly as obtained commercially unless
otherwise noted.
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Preparation of 2-(Arylthio) aldehydes 4. Typical procedure for the preparation of
tertꢁbutyl 2ꢁ(4ꢁoxoꢁ3ꢁ(phenylthio)butoxy) acetate (4a). To a solution of THF (10 mL), tertꢀbutyl
2ꢀ(butꢀ3ꢀynꢀ1ꢀyloxy)acetate (2a, 0.184 g, 1 mmol) and thiophenol (0.22 g, 2 mmol) was added
TBHP (1 ꢀL) and H2O (1 ꢀL), the mixture was stirred at 25oC for 48 h. After the completion of
the reaction, the solvent was evaporated under vacuum to yield the crude product, which was
purified by column chromatography (silica gel, petroleum ether/EtOAc = 40:1) to give tertꢀbutyl
2ꢀ(4ꢀoxoꢀ3ꢀ(phenylthio)butoxy)acetate (4a).
1
Tertꢁbutyl 2ꢁ(4ꢁoxoꢁ3ꢁ(phenylthio)butoxy)acetate (4a). Yellow oil, 72% yield (223 mg); H
NMR (400 MHz, CDCl3): δ 9.52 (d, J = 2.8 Hz, 1H), 7.42–7.40 (m, 2H), 7.34–7.23 (m, 3H), 3.93
(d, J = 3.3 Hz, 2H), 3.90–3.82 (m, 1H), 3.78–3.62 (m, 2H), 2.24–2.12 (m, 1H), 1.94–1.86 (m,
1H), 1.47 (s, 9H); 13C NMR (101 MHz, CDCl3): δ 189.9, 164.9, 129.0, 126.6, 124.6, 123.9, 77.2,
64.2, 63.5, 49.2, 23.7, 23.5; HRMS (ESI) m/z: (M+Na)+ Calcd for C16H22O4SNa 333.1137, found
333.1134.
2ꢁ(Phenylthio)hexanal (4b).6 Yellow oil, 78% yield (162 mg); 1H NMR (400 MHz, CDCl3): δ
9.34 (d, J = 4.3 Hz, 1H), 7.38–7.34 (m, 2H), 7.30–7.24 (m, 3H), 3.52–3.46 (m, 1H), 1.84–1.74
(m, 1H), 1.71–1.59 (m, 1H), 1.56–1.28 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz,
DMSOꢀd6): δ 190.8, 128.2, 127.3, 124.6, 123.6, 52.3, 24.5, 23.0, 17.8, 9.4, 9.2; MS (ESI) m/z:
(M+H)+ Calcd for C12H17OS 209.1, found 209.1.
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2ꢁ(Phenylthio)pentanal (4c).7 Yellow oil, 64% yield (124 mg); H NMR (400 MHz, CDCl3):
δ 9.37 (d, J = 4.3 Hz, 1H), 7.42–7.35 (m, 2H), 7.33–7.26 (m, 3H), 3.58–3.50 (m, 1H), 1.80–1.74
(m, 1H), 1.71–1.42 (m, 3H), 0.97 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 195.3,
132.8, 131.9, 129.2, 128.1, 56.6, 29.9, 20.2, 13.8; MS (ESI) m/z: (M+H)+ Calcd for C11H15OS
195.1, found 195.1.
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1
2ꢁ(Phenylthio)heptanal (4d).8 Yellow oil, 71% yield (157 mg); H NMR (400 MHz, CDCl3):
δ 9.36 (d, J = 2.1 Hz, 1H), 7.40–7.36 (s, 2H), 7.30–7.22 (m, 3H), 3.52–3.50 (m, 1H), 1.91–1.73
(m, 1H), 1.73–1.61 (m, 1H), 1.61–1.52 (m, 1H), 1.49–1.39 (m, 1H), 1.20–1.15 (m, 4H), 0.89 (s,
3H); 13C NMR (75 MHz, CDCl3): δ 195.3, 132.7, 131.9, 129.1, 128.1, 56.8, 31.4, 27.8, 26.6, 22.4,
14.0. MS (ESI) m/z: (M+H)+ Calcd for C13H19OS 223.1, found 223.1.
1
2ꢁ(Phenylthio)octanal (4e). Yellow oil, 68% yield (160 mg). H NMR (400 MHz, CDCl3): δ
9.36 (d, J = 4.3 Hz, 1H), 7.38 (dd, J = 7.5, 2.0 Hz, 2H), 7.33–7.27 (m, 3H), 3.52 (td, J = 7.4, 4.3
Hz, 1H), 1.87–1.75 (m, 1H), 1.73–1.59 (m, 1H), 1.52–1.38 (m, 2H), 1.36–1.28 (m, 6H), 0.88 (t, J
= 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 195.3, 132.7, 131.9, 129.1, 128.1, 56.8, 31.5, 28.9,
27.8, 26.9, 22.5, 14.0; HRMS (ESI) m/z: (M+H)+ Calcd for C14H21OS 237.1313, found 237.1323.
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2ꢁ(Phenylthio)nonanal (4f). Yellow oil, 64% yield (160 mg). H NMR (400 MHz, CDCl3): δ
9.36 (d, J = 4.1 Hz, 1H), 7.40–7.36 (m, 2H), 7.32–7.28 (m, 3H), 3.54–3.48 (m, 1H), 1.82–1.76
(m, 1H), 1.72–1.60 (m, 1H), 1.60–1.38 (m, 2H), 1.32–1.28 (m, 8H), 0.87 (t, J = 6.6 Hz, 3H); 13C
NMR (75 MHz, CDCl3): δ 195.3, 132.7, 131.9, 129.1, 128.1, 56.8, 31.7, 29.2, 29.0, 27.8, 26.9,
22.6, 14.1; HRMS (ESI) m/z: (M+H)+ Calcd for C15H23OS 251.1470, found 251.1515.
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2ꢁ(Phenylthio)decanal (4g). Yellow oil, 60% yeild (158 mg). H NMR (400 MHz, CDCl3): δ
9.34 (d, J = 4.3 Hz, 1H), 7.41–7.32 (m, 2H), 7.28–1.24 (m, 3H), 3.49 (td, J = 7.3, 4.4 Hz, 1H),
1.84–1.74 (m, 1H), 1.68–1.60 (m, 1H), 1.56–1.36 (m, 2H), 1.26–1.20 (m, 10H), 0.86 (t, J = 6.7
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Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 195.3, 132.7, 131.9 (d, J = 7.1 Hz, 2H), 7.27 (dd, J =
15.4, 7.5 Hz, 3H), 3.24 (d, J = 6.4 Hz, 1H), 1.17 (s, 9H); 13C NM, 129.1, 128.1, 56.8, 31.8, 29.3,
29.2, 29.1, 27.8, 26.9, 22.6, 14.1; HRMS (ESI) m/z: (M+H)+ Calcd for C16H25OS 265.1626,
found 265.1622.
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3,3ꢁDimethylꢁ2ꢁ(phenylthio)butanal(4h). Yellow oil, 51% yield (106 mg); H NMR (400
MHz, CDCl3): δ 9.47 (d, J = 6.4 Hz, 1H), 7.37 R (101 MHz, CDCl3): δ 195.9, 132.8, 129.9,
128.4, 69.3, 34.3, 28.5; HRMS (ESI) m/z: (M+K)+ Calcd for C12H16OSK 247.0559, found
247.0542.
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2ꢁCyclopropylꢁ2ꢁ(phenylthio)acetaldehyde(4i). Yellow oil, 52% yield (100 mg). H NMR
(400 MHz, CDCl3): δ 9.42 (d, J = 4.5 Hz, 1H), 7.40–7.34 (m, 2H), 7.30–7.24 (m, 3H), 2.91–2.83
(m, 1H), 1.05–0.95 (m, 1H), 0.78–0.66 (m, 2H), 0.53–0.38 (m, 2H); 13C NMR (75 MHz, CDCl3):
δ 194.5, 133.1, 129.1, 129.0, 128.1, 127.5, 127.1, 62.1, 9.4, 5.7, 4.3; HRMS (ESI) m/z: (M+H)+
Calcd for C11H13OS 193.0687, found 193.0681.
4ꢁPhenylꢁ2ꢁ(phenylthio)butanal (4k). Yellow oil, 12% yield (30 mg); 1H NMR (400 MHz,
CDCl3): δ 9.52 (d, J = 3.4 Hz, 1H), 7.46 (ddd, J = 6.5, 3.8, 1.5 Hz, 2H), 7.41–7.35 (m, 5H),
7.32–7.25 (m, 3H), 3.56 (td, J = 13.7, 6.9 Hz, 1H), 3.00–2.82 (m, 2H), 2.30–2.15 (m, 1H),
2.12–1.96 (m, 1H); 13C NMR (101 MHz, CDCl3): δ 194.4, 139.9, 132.8, 130.8, 128.7, 128.16,
128.10, 127.9, 125.9, 55.5, 32.2, 28.7; HRMS (CIꢀTOF) m/z: M+ Calcd for C16H16OS 256.0922,
found 256.0914.
5ꢁPhenylꢁ2ꢁ(phenylthio)pentanal (4l). Yellow oil, 44% yield (120 mg); 1H NMR (400 MHz,
CDCl3): δ 9.37 (d, J = 4.0 Hz, 1H), 7.37–7.32 (m, 2H), 7.32–7.26 (m, 5H), 7.22–7.16 (m, 3H),
3.51 (td, J = 6.9, 4.0 Hz, 1H), 2.70–2.64 (m, 2H), 1.96–1.58 (m, 4H)；13C NMR (75 MHz,
CDCl3): δ 195.3, 141.6, 136.7, 133.3, 131.8, 130.1, 129.4, 129.3, 128.69, 128.66, 128.5, 127.8,
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127.4, 126.3, 57.1, 35.7, 28.8, 27.5; HRMS (ESI) m/z: (M+Na)+ Calcd for C17H18OSNa 293.0976,
found 293.0967.
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Ethyl (Z/E)ꢁ3ꢁ(phenylthio)acrylate (3m).9 77% yield (150 mg); 1H NMR (400 MHz, CDCl3):
δ Zꢀisomer 7.78 (d, J = 14.9 Hz, 1H), 7.53–7.45 (m, 2H), 7.42–7.36 (m, 3H), 5.91 (d, J = 10.2 Hz,
1H), 4.26 (q, 2H), 1.33 (t, J = 7.2 Hz, 3H); Eꢀisomer 7.78 (d, J = 14.9 Hz, 1H), 7.53–7.45 (m, 2H,
ArH), 7.42–7.36 (m, 3H), 5.65 (d, J = 14.9 Hz, 1H), 4.16 (q, 2H), 1.26 (t, J = 7.0 Hz, 3H); MS
(ESI) m/z: (M+H)+ Calcd for C11H13O2S 209.1, found 209.1.
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(Z/E)ꢁ3ꢁ(phenylthio)allyl acetate(3n). 10 70% yield (146 mg); H NMR (400 MHz, CDCl3): δ
Z isomer 7.47–7.30 (m, 5H), 6.52 (dt, J = 15.1, 1.2 Hz, 1H), 6.00–5.73 (m, 1H), 4.83 (dd, J = 6.5,
1.2 Hz, 2H), 2.15 (s, 3H); E isomer 7.47–7.30 (m, 5H), 6.58 (dt, J = 15.1, 1.2 Hz, 1H), 6.00–5.73
(m, 1H), 4.65 (dd, J = 6.6, 1.2 Hz, 2H), 2.12 (s, 3H); HRMS (CIꢀTOF) m/z: M+ Calcd for
C11H12O2S 208.0558, found 208.0558.
(Z/E) 5ꢁ(Phenylthio)pentꢁ4ꢁenꢁ1ꢁol (3o). 77% yield (149 mg); 1H NMR (400 MHz, CDCl3): δ
Z isomer 7.42–7.31 (m, 4H), 7.28–7.21 (m, 1H), 6.29 (dt, J = 9.2, 1.2 Hz, 1H), 5.88 (dt, J = 9.2,
7.4 Hz, 1H), 3.73 (td, J = 6.4, 4.1 Hz, 2H), 2.40 (qd, J = 7.4, 1.2 Hz, 2H), 1.86 (s, 1H), 1.81–1.70
(m, 2H); E isomer 7.42–7.31 (m, 4H), 7.28–7.21 (m, 1H), 6.24 (dt, J = 14.9, 1.3 Hz, 1H (E)),
6.12–5.98 (m, 1H (Z)), 3.73 (td, J = 6.4, 4.1 Hz, 2H), 2.35–2.27 (m, 2H), 1.86 (s, 1H), 1.81–1.70
(m, 2H); 13C NMR (101 MHz, CDCl3): Z+E δ 136.0, 132.3, 129.03, 128.98, 128.91, 128.6, 126.3,
126.2, 123.7, 121.7, 62.2, 62.1, 31.9, 31.8, 29.4, 25.4; HRMS (CIꢀTOF) m/z: M+ Calcd for
C11H14OS 194.0765, found 194.0763.
(Z/E) 4ꢁ(Phenylthio)butꢁ3ꢁenꢁ1ꢁol (3p).11 Yellow oil, 17% yield (30 mg); 1H NMR (400 MHz,
CDCl3): δ Z isomer 7.43–7.30 (m, 4H), 7.27–7.23 (m, 1H), 6.41 (d, J = 9.3 Hz, 1H), 6.03–5.84
(m, 1H), 3.75 (t, J = 6.3 Hz, 2H), 2.59 (td, J = 7.4, 1.0 Hz, 2H), 1.96 (s, 1H); E isomer 7.43–7.30
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(m, 4H), 7.27–7.23 (m, 1H), 6.33 (d, J = 15.0 Hz, 1H), 6.03–5.84 (m, 1H), 3.79 (t, J = 6.4 Hz,
2H), 2.53– 2.42(m, 2H), 1.96 (s, 1H); HRMS (CIꢀTOF) m/z: M+ Calcd for C10H12OS 180.0609,
found 180.0599.
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(215 mg); 1H NMR (300 MHz, CDCl3): δ 7.25 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.6 Hz, 2H), 6.24
(t, J = 11.4 Hz, 1H), 6.02–5.71 (m, 1H), 4.08–3.88 (m, 2H), 3.72–3.46 (m, 2H), 2.56 (dd, J =
13.4, 6.7 Hz, 1H), 2.46 (dd, J = 13.4, 6.6 Hz, 1H), 2.32 (s, 3H), 1.48 (s, 9H); 13C NMR (75 MHz,
CDCl3): Z+E δ 168.7, 168.6, 135.5, 135.4, 131.3, 131.0, 129.4, 128.7, 128.6, 128.5, 126.7, 125.0,
123.6, 80.6, 80.5, 69.6, 69.3, 67.8, 67.7, 32.3, 28.5, 27.1, 20.0; HRMS (CIꢀTOF) m/z: (M+H)+
Calcd for C17H25O3S 309.1524, found 309.1526.
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Tertꢁbutyl 2ꢁ(4ꢁoxoꢁ3ꢁ(pꢁtolylthio)butoxy)acetate (4ba). Yellow oil, 23% yield (75 mg); H
NMR (400 MHz, CDCl3): δ 9.51 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 7.8 Hz, 2H), 7.10 (d, J = 7.8 Hz,
2H), 3.98–3.88 (m, 2H), 3.78 (td, J = 7.3, 2.2 Hz, 1H), 3.74–3.62 (m, 2H), 2.32 (s, 3H),
2.18–2.10 (m, 1H), 1.92–1.82 (m, 1H), 1.48 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 193.4, 168.5,
137.9, 133.3, 128.9, 128.8, 127.5, 126.0, 107.7, 80.7, 67.8, 67.1, 53.0, 27.1, 20.1; HRMS
(CIꢀTOF) m/z: M+ Calcd for C17H24O4S 324.1395, found 324.1395.
(Z/E) Tertꢁbutyl 2ꢁ((4ꢁ(oꢁtolylthio)butꢁ3ꢁenꢁ1ꢁyl)oxy)acetate (3ca). Yellow oil, 32% yield (99
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mg); H NMR (400 MHz, CDCl3): δ 7.32–7.30 (m, 1H), 7.18–7.10 (m, 3H), 6.24–6.14 (m, 1H),
5.99–5.82 (m, 1H), 4.0–3.96 (m, 2H), 3.68–3.56 (m, 2H), 2.65–2.55 (m, 1H), 2.54–2.45 (m, 1H),
2.38 (s, 1.5H, (Z isomer)), 2.35 (s, 1.5 H, (E isomer)), 1.48 (s, 9H); 13C NMR (101 MHz, CDCl3):
δ Z+E 169.1, 137.09, 137.06, 134.7, 134.3, 130.9, 129.7, 128.83, 128.77, 128.6, 126.06, 126.05,
126.03, 125.9, 124.4, 122.9, 81.13, 81.09, 70.2, 69.9, 68.3, 68.2, 32.9, 29.0, 27.6, 20.0, 19.7.
HRMS (CIꢀTOF) m/z: M+ Calcd for C17H24O3S 308.1446, found 308.1431.
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Tertꢁbutyl 2ꢁ(4ꢁoxoꢁ3ꢁ(oꢁtolylthio)butoxy)acetate(4ca). Yellow oil, 59% yield (191 mg); H
NMR (400 MHz, CDCl3): δ 9.43 (d, J = 3.4 Hz, 1H), 7.43–7.36 (m, 1H), 7.24–7.09 (m, 3H),
3.99–3.87 (m, 2H), 3.88–3.80 (m, 1H), 3.70 (td, J = 5.2, 1.3 Hz, 2H), 2.45 (s, 3H), 2.33–2.14 (m,
1H), 2.07–1.83 (m, 1H), 1.47 (s, 9H); 13C NMR (101 MHz, CDCl3): δ 194.5, 169.4, 140.4, 133.4,
131.2, 130.7, 128.3, 126.7, 81.8, 68.8, 68.2, 53.5, 28.8, 28.1, 20.9; HRMS (CIꢀTOF) m/z:
(M+H)+ Calcd for C17H24O4S 324.1395, found 324.1377.
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Tertꢁbutyl (E/Z)ꢁ2ꢁ((4ꢁ((2,6ꢁdimethylphenyl)thio)butꢁ3ꢁenꢁ1ꢁyl)oxy)acetate(3da). Yellow oil,
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84% yield (270 mg); H NMR (400 MHz, CDCl3): δ Z isomer 7.13–6.97 (m, 3H), 5.71 (dt, J =
9.3, 1.3 Hz, 1H), 5.64–5.55 (m, 1H), 3.93 (s, 2H), 3.57 (t, J = 6.8 Hz, 2H), 2.52 (qd, J = 6.8, 1.3
Hz, 2H), 2.40 (s, 6H), 1.42 (s, 9H); E isomer 7.13–6.97 (m, 3H), 5.87 (dt, J = 14.9, 1.3 Hz, 1H),
5.16–5.06 (m, 1H), 3.84 (s, 2H), 3.40 (t, J = 7.0 Hz, 2H), 2.39 (s, 6H), 2.27 (qd, J = 7.0, 1.3 Hz,
2H), 1.40 (s, 9H); 13C NMR (101 MHz, CDCl3): δ Z+E 169.23, 169.17, 142.7, 142.1, 132.4,
130.2, 128.3, 128.0, 127.73, 127.69, 127.6, 127.3, 124.4, 124.3, 122.8, 81.1, 81.0, 70.5, 69.9,
68.3, 32.7, 28.8, 27.7, 27.6, 21.6, 21.2; HRMS (CIꢀTOF) m/z: M+ Calcd for C18H26O3S 322.1603,
found 322.1619.
Tertꢁbutyl 2ꢁ(4ꢁoxoꢁ3ꢁ((2ꢁfluorophenyl)thio)butoxy)acetate(4ga). Yellow oil, 59% yield (193
1
mg). H NMR (400 MHz, CDCl3): δ 9.45 (s, 1H), 7.37 (t, J = 7.0 Hz, 1H), 7.30–7.22 (m, 1H),
7.02 (t, J = 7.7 Hz, 2H), 3.88 (t, J = 10.4 Hz, 2H), 3.78 (t, J = 6.7 Hz, 1H), 3.71–3.59 (m, 2H),
2.12 (dd, J = 13.7, 6.1 Hz, 1H), 1.84 (dd, J = 14.0, 5.6 Hz, 1H), 1.41 (s, 9H); 13C NMR (101
MHz, CDCl3): δ 194.2, 169.5, 162.9 (d, J = 247.3 Hz), 136.7 , 131.2 (d, J = 8.1 Hz), 124.7 (d, J =
7.7 Hz), 116.2 (d, J = 23.2 Hz), 81.7 , 68.5 (d, J = 74.1 Hz), 53.5, 28.4, 28.1; HRMS (CIꢀTOF)
m/z: (M+H)+ Calcd for C16H22O4FS 329.1223, found 329.1217.
Tertꢁbutyl 2ꢁ(4ꢁoxoꢁ3ꢁ((4ꢁfluorophenyl)thio)butoxy)acetate(4ha). Yellow oil, 91% yield (298
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mg); 1H NMR (400 MHz, CDCl3): δ 9.50 (d, J = 2.8 Hz, 1H), 7.47–7.37 (m, 2H), 7.03–6.96 (m,
2H), 3.93 (d, J = 2.2 Hz, 2H), 3.81–3.76 (m, 1H), 3.75–3.62 (m, 2H), 2.20–2.10 (m, 1H),
1.92–1.82 (m, 1H), 1.47 (s, 9H); 13C NMR (101 MHz, CDCl3): δ 194.1, 169.5, 163.2 (d, J =
249.5 Hz), 138.8 (d, J = 8.7 Hz), 136.5 (d, J = 8.4 Hz, 1H), 131.3 (d, J = 8.3 Hz), 116.4 (d, J =
22.0 Hz), 81.8, 68.8, 68.1, 54.3, 28.2, 28.1; HRMS (CIꢀTOF) m/z: M+ Calcd for C16H21O4FS
328.1145, found 328.1154.
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Tertꢁbutyl 2ꢁ(4ꢁoxoꢁ3ꢁ((2ꢁchlorophenyl)thio)butoxy)acetate(4ia). Yellow oil, 61% yield (210
mg); 1H NMR (400 MHz, CDCl3): δ 9.51 (dd, J = 2.8, 1.3 Hz, 1H), 7.44 (td, J = 7.7, 1.7 Hz, 1H),
7.36–7.29 (m, 1H), 7.13–7.05 (m, 2H), 3.93 (d, J = 4.6 Hz, 2H), 3.85 (td, J = 7.2, 2.8 Hz, 1H),
3.77–3.65 (m, 2H), 2.24–2.14 (m, 1H), 1.97–1.81 (m, 1H), 1.47 (s, 9H); 13C NMR (101 MHz,
CDCl3): δ 194.2, 169.4, 136.6, 131.2, 131.1, 124.7, 116.3, 116.0, 81.7, 68.8, 68.1, 53.4, 28.4,
28.1; HRMS (CIꢀTOF) m/z: M+ Calcd for C16H22O4ClS 345.0927, found 345.0939.
Tertꢁbutyl (Z/E)ꢁ2ꢁ((4ꢁ((3ꢁchlorophenyl)thio)butꢁ3ꢁenꢁ1ꢁyl)oxy)acetate(3ja). Yellow oil,
24% yield (79 mg); δ 7.32 (dd, J = 6.4, 4.6 Hz, 1H), 7.27–7.16 (m, 3H), 6.30 (dd, J = 11.9, 10.5
Hz, 1H), 6.15–6.00 (m, 1H), 4.02 (s, 2H), 3.66 (t, J = 6.5 Hz, 2H), 2.62 (ddd, J = 13.6, 6.8, 1.2
Hz, 1H), 2.58–2.52 (m, 1H), 1.52 (s, 9H); 13C NMR (101 MHz, CDCl3): δ Z+E 169.1, 169.0,
138.1, 137.8, 134.3, 134.2, 134.1, 130.6, 129.5, 129.4, 127.6, 127.3, 126.1, 125.8, 125.7, 125.6,
122.9, 121.6, 81.16, 81.10, 69.8, 69.7, 68.3, 68.2, 32.9, 29.1, 27.6; HRMS (CIꢀTOF) m/z: M+
Calcd for C16H21O3SCl 328.0900, found 328.0905.
Tertꢁbutyl 2ꢁ(4ꢁoxoꢁ3ꢁ((3ꢁchlorophenyl)thio)butoxy)acetate(4ja). Yellow oil, 68% yield (234
mg); 1H NMR (400 MHz, CDCl3): δ 9.46 (d, J = 3.4 Hz, 1H), 7.55–7.34 (m, 2H), 7.28–7.14 (m,
2H), 3.93 (d, J = 3.8 Hz, 2H), 3.71 (t, J = 5.7 Hz, 2H), 2.30–2.20 (m, 1H), 2.11–1.93 (m, 1H),
1.47 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 193.4, 168.4, 135.5, 132.6, 129.1, 128.1, 126.4, 80.8,
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67.8, 67.1, 52.0, 27.6, 27.1; HRMS (CIꢀTOF) m/z: (MꢀC4H8)+ Calcd for C12H13O4SCl 288.0223,
found 288.0219.
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Hexꢁ1ꢁyneꢁ1ꢁd (2b’). 1H NMR (400 MHz, CDCl3): δ 2.19 (t, J = 6.9 Hz, 2H), 1.93 (s, 0.13H),
1.59–1.36 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H).
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2ꢁ(Phenylthio)hexanalꢁ1ꢁd (4b’). 1H NMR (400 MHz, CDCl3): δ 9.36 (d, J = 4.3 Hz, 0.13H),
7.42–7.34 (m, 2H), 7.33–7.27 (m, 3H), 3.51 (t, J = 7.2 Hz, 1H), 1.84–1.76 (m, 1H), 1.68–1.62 (m,
1H), 1.45–1.28 (m, 4H), 0.92 (t, J = 7.1 Hz, 3H). HRMS (CIꢀTOF) m/z: M+ Calcd for
C12H15OSD 209.0985, found 209.0992.
2,2,6,6ꢁTetramethylꢁ1ꢁ((phenylthio)oxy)piperidine (6).12 1H NMR (400 MHz, CDCl3): δ
7.75–7.63 (m, 2H), 7.50–7.34 (m, 3H), 1.84 (s, 1H), 1.67 (s, 4H), 1.57 (s, 4H), 1.51 (s, 3H), 1.48
(s, 3H), 1.38 (s, 1H), 0.91 (s, 2H); MS (ESIꢀTOF) m/z: (M+H)+ Calcd for C15H24NOS 266.2,
found 266.2.
ASSOCIATED CONTENT
Supporting Information
13
1H, C NMR spectra for compounds 3 and 4. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: jpzou@suda.edu.cn.
*E-mail: panxq@suda.edu.cn.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGEMENTS
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J.ꢀP.Z. thanks the grant support by National Natural Science Foundation of China (Nos.
20772088, 21172163, 21472133) and the Priority Academic Program Development of Jiangsu
Higher Education Institutions for financial support.
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