Full text of DOI:10.1016/j.tet.2018.04.072

Accepted Manuscript
Divergent synthesis of functionalized thioethers via multicomponent reaction of
benzynes
Hui Jian, Qiang Wang, Wei-Hua Wang, Zhi-Juan Li, Cheng-Zhi Gu, Bin Dai, Lin He
PII:
S0040-4020(18)30476-9
10.1016/j.tet.2018.04.072
TET 29487
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 February 2018
Revised Date: 18 April 2018
Accepted Date: 21 April 2018
Please cite this article as: Jian H, Wang Q, Wang W-H, Li Z-J, Gu C-Z, Dai B, He L, Divergent synthesis
of functionalized thioethers via multicomponent reaction of benzynes, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.04.072.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Benzyne-induced synthesis of diverse functionalized thioethers

ACCEPTED MANUSCRIPT
synthesis of functionalized
multicomponent reaction of benzynes
Divergent
thioethers
via
a
a
a
a
a
a
Hui Jian, Qiang Wang, Wei-Hua Wang, Zhi-Juan Li, Cheng-Zhi Gu, Bin Dai, Lin
a
He*
a
Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan,
School of Chemistry and Chemical Engineering, Shihezi University, Xinjiang Uygur
Autonomous Region 832000, People’s Republic of China
Abstract: Diverse functionalized thioethers were efficiently synthesized through the
multicomponent reaction of benzynes, cyclic thioethers and different nucleophiles.
Both inorganic salts (KF, KCl, KBr, and KSCN) and silylated reagents (TMSCN,
TMSN , TMSCl) can be utilized as efficient nucleophiles for the reaction.
3
Keywords: benzyne, thioether, multicomponent reaction
Introduction
Thioethers are privileged motifs found in many natural products, biologically
1
active compounds and pharmaceuticals. Over the past several decades,
considerable efforts have been exerted to develop new methodologies for the
2
synthesis of these significant frameworks. Several different strategies, such as
transition metal catalyzed cross-coupling reaction and hydrothiolation,
organocatalytic sulfa-Michael reaction and sulfenylation reaction, have been
well established for the construction of thioethers. Despite remarkable progress
made in this research field, the development of efficient protocols for the
synthesis of thioethers that bearing some specific functional groups, such as
3
4
fluorine atom and cyano group, is still lacking.
Benzynes are highly reactive intermediates that are utilized widely in organic
5
synthesis. The electrophilic benzyne can undergo N-, O-, C-insertion with
6
different nucleophiles and trigger a broad variety of transformations. However,
7
reactions initiated by S-insertion of benzyne are very limited. Recently, Studer
and co-workers reported that the linear vinyl thioethers can react with benzyne
1

ACCEPTED MANUSCRIPT
through [3+2] cycloaddition to form cyclic sulfonium ylide, and after proton
transfer and β-elimination reaction, afford trisubstituted alkenes. Subsequently,
8
through the S-insertion of linear thioethers and benzyne, Xu and co-workers
developed a novel method to generate sulfonium ylide, which can be
9
intercepted by isatin to form spiroepoxy oxindoles in high yield. Tan, Xu and
co-workers further extended the study to allyl and propargyl thioethers, which
can undergo [2,3] sigmatropic rearrangement with benzyne through sulfonium
10a
10b
intermediate. Very recently, Tan, Xu , Hoye and their co-workers reported
independently that benzynes can undergo multicomponent reaction with cyclic
thioethers and different acidic proton-containing nucleophiles, such as acetic
acid, phenol and amide, to give the ring-opening products. As part of our
11
ongoing project, we envisaged that the S-arylation of cyclic ethers can lead to
the formation of sulfonium intermediate, which can undergo ring-opening
reaction with different nucleophiles to produce various functionalized
thioethers. And herein, we wish to report this result.
Results and discussion
12
We initiated our studies with the commercially available Kobayashi’s reagent
and tetrahydrothiophene 2a. To our delight, with 3.0 equiv KF/18-crown-6
1
a
and 2.0 equiv H O as additives, benzyne reacted with tetrahydrothiophene and
2
fluoride anion smoothly at room temperature in THF to produce the fluorinated
thioether 3a in 59% yield (Table 1, entry 1). However, when H O was excluded
2
from the same reaction conditions, only a small amount of product was formed
(
Table 1, entry 2). Used 2.0 equiv ethanol as the additive, the product can be
obtained in 45% yield (Table 1, entry 3). A brief screening of the reaction
media revealed that DCM was the best choice with respect to the reaction yield
(
Table 1, entries 4-7). Other fluoride sources, such as CsF/18-crown-6, TBAF
and TBAT can also promote the reaction in good yield (Table 1, entries 8-10).
In the absence of the crown ether, KF or CsF can only promote the reaction in
very low efficiency (Table 1, entries 11 and 12). Increasing the amount of
2

ACCEPTED MANUSCRIPT
tetrahydrothiophene to 5.0 equiv cannot improve the reaction yield (Table 1,
entry 13). Neither reducing the amount of water to 1.0 equiv nor increasing to
3
.0 equiv can improve the the yield (Table 1, entries 14 and 15).
a
Table 1 Optimization of reaction conditions
b
Entry
Additives
solvent
THF
Time (h)
12
Yield (%)
1
2
3
4
5
6
7
8
9
KF (3 equiv), 18-C-6 (3 equiv), H O (2 equiv)
59
2
KF (3 equiv), 18-C-6 (3 equiv)
THF
12
<10
45
KF (3 equiv), 18-C-6 (3 equiv), EtOH (2 equiv)
THF
12
KF (3 equiv), 18-C-6 (3 equiv), H O (2 equiv)
CH CN
12
58
2
3
KF (3 equiv), 18-C-6 (3 equiv), H O (2 equiv)
DCM
DCE
12
76
2
KF (3 equiv), 18-C-6 (3 equiv), H O (2 equiv)
12
64
2
KF (3 equiv), 18-C-6 (3 equiv), H O (2 equiv)
toluene
DCM
DCM
DCM
THF
12
<10
72
2
CsF (3 equiv), 18-C-6 (3 equiv), H O (2 equiv)
12
2
TBAF (3 equiv), H O (2 equiv)
12
60
2
1
0
1
TBAT (3 equiv), H O (2 equiv)
12
72
2
1
CsF (3 equiv), H O (2 equiv)
24
<10
<10
70
2
c
12
KF (3 equiv), H O (2 equiv)
THF
24
2
1
1
1
3
KF (3 equiv), 18-C-6 (3 equiv), H O (2 equiv)
THF
12
2
4
5
KF (3 equiv), 18-C-6 (3 equiv) , H O (1 equiv)
DCM
DCM
12
51
2
KF (3 equiv), 18-C-6 (3 equiv) , H O (3 equiv)
12
70
2
a
b
Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), solvent 1 mL, room temperature ; Isolated
c
yield; 2a (0.5 mmol).
With the optimal reaction conditions in hand (Table 1, entry 4), the generality of the
reaction was subsequently studied and the results are summarized in Table 2.
Symmetrical benzynes with electron-donating or withdrawing groups efficiently
undergo the multicomponent reaction to produce the desired products in moderate to
good yields (Table 2, entries 1-4). On the other hand, unsymmetrical benzynes can
also react with 2a and KF smoothly, affording the corresponding products as an
3

ACCEPTED MANUSCRIPT
inseparable mixture of two regioisomers in good yield (Table 2, entries 5-8). Notably,
when unsymmetrical 3-methoxy substituted benzyne precursor 1i was employed for
the reaction, the fluorinated product 3i was obtained in 78% yield with complete
1
3
regioselectivity (Table 2, entry 9). Thietane 2b was proved to be a good candidate
for the reaction, providing 3j in 74% yield (Table 2, entry 10). However, when thiane
was used for the reaction, 3k was only obtained in 28% yield (Table 2, entry 11).
Different inorganic salts, such as KCl, KBr and KSCN were also proved to be
competent nucleophiles for the reaction, giving chloro-, bromo- and
thiocyanate-substituted thioethers in good to high yields (Table 2, entries 12-14).
a
Table 2 Evaluation of substrate scope
b
Entry
1
1
2
Time (h)
Product
3a
Yield (%)
76
1
2
1
a
2a
2a
c
2
24
24
24
63
56
57
1
b
3b
3
2a
2a
1
c
3c
d
4
1
d
3d
5
2a
24
77
e
e
m-3e : o-3e’ = 2:1
m-3f : p-3f’ = 1.1:1
1
e
6
7
2a
2a
24
24
69
60
1
f
4

ACCEPTED MANUSCRIPT
e
1
g
m-3g : p-3g’ = 1:1.4
8
9
2a
2a
24
24
76
78
e
α-3h : β-3h’ = 1:1.25
1
h
3
i
1
i
1
0
1a
1a
1a
1a
1a
24
24
24
24
24
74
28
90
58
61
2
b
3j
f
11
2
c
3k
g
h
i
1
1
2
2a
2a
2a
3
l
S
Br
4
3
3
m
1
4
3
n
a
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), solvent 2.0 mL, room
b
c
d
temperature; Isolated yield; Using 3.0 equiv TBAF as fluoride source; Using 3.0
e
19
equiv TBAT as fluoride source; the regioselectivity was determined by F NMR
f
o
g
analysis of the crude products; Conducted the reaction at 40 C; Added 3.0 equiv
h
i
KCl; Added 3.0 equiv KBr; Added 3.0 equiv KSCN.
Surprisingly, under the same reaction conditions, thiirane reacted with benzyne to
provide vinyl thioether 4a in 75% yield, and no fluorinated product was obtained
(Scheme 1, eq 1). We postulated that the high ring strain of the three-membered cyclic
sulfonium leads to very fast intramolecular β-elimination and resulted in the
1
4
formation of the vinyl thioether products.
More interestingly, when α-methyl
substituted tetrahydrothiophene 2e was used for the reaction, a similar β-elimination
5

ACCEPTED MANUSCRIPT
reaction was observed and vinyl thioehters 4b and 4c were obtained as an inseparable
mixture of 5:1 regioisomers in 72% total yield (Scheme 1, eq 2).
Scheme 1 Reaction of benzyne with thiirane and α-methyl tetrahydrothiophene
Silylated reagents such as trimethylsilyl cyanide, Ruppert–Prakash reagent and
trimethylsilyl azide are important nucleophiles in organic synthesis. We subsequently
explored the multicomponent reaction of benzynes, cyclic thioethers and different
silylated nucleophiles. When trimethylsilyl cyanide (5a) was used as a nucleophile
and the reaction was conducted in THF, the desired thioether 6a was obtained in 89%
yield (Table 3, entry 1). Electron-donating groups substituted benzynes gave higher
yield than those bearing electron withdrawing substituents (Table 3, entries 2-5).
Unsymmetrical benzynes underwent the reaction efficiently to deliver the
corresponding cyanated products as an inseparable mixture of two regioisomers
(Table 3, entries 6-9). Once again, 1i provided the desired product with complete
regioselectivity (Table 3, entry 10). Both thietane and thiane reacted very well, giving
the corresponding products 6k and 6l in 90% and 88% yields, respectively (Table 3,
entries 11 and 12). α-Methyl tetrahydrothiophene underwent the reaction smoothly to
afford 6m in 72% yield and no β-elimination product was formed (Table 3, entry 13).
Trimethylsilyl azide and trimethylsilyl chloride were also proved to be suitable
reactants for the reaction, producing the corresponding functionalized thioethers in
high yields (Table 3, entries 14-17). However, other silylated reagents, such as the
Ruppert–Prakash reagent and (difluoromethyl)trimethylsilane didn’t afford the desired
product under the same reaction conditions (Table 3, entries 18 and 19). Interestingly,
thiirane underwent a β-elimination reaction to give vinyl thioether 4a in good 66%
6

ACCEPTED MANUSCRIPT
yield under the same reaction conditions (Table 3, entry 20).
a
Table 3 Reaction of benzynes, cyclic thioethers and silylated reagents
Time
Yield
Entry
1
1
2
5
Product
b
(h)
(%)
TMSCN
1a
2a
6
89
94
86
64
49
82
80
70
5
a
6
a
2
3
4
5
6
7
8
1b
1c
2a
2a
2a
2a
2a
2a
2a
5a
5a
5a
5a
5a
5a
5a
7
8
7
6
b
6c
1
j
6d
1d
1e
1f
24
8
6e
c
m-6f :o-6f’ = 1.7:1
7
c
m-6g:p-6g’ = 1:1
1g
6
c
p-6h:m-6h’ = 1.5:1
9
1h
1i
2a
2a
5a
5a
7
7
76
84
c
α-6i : β-6i’ = 1:1
MeO
S
CN
4
1
0
7

ACCEPTED MANUSCRIPT
6j
1
1
1a
1a
1a
1a
1a
1a
1a
2b
2c
2e
2a
2a
2c
2c
5a
5a
7
24
7
90
88
72
84
89
65
86
k
12
13
14
15
16
6l
5a
6
m
S
N3
4
TMSN3
7
5
b
6
n
TMS-Cl
24
24
12
5
c
6
o
p
q
5b
6
d
17
5c
6
TMS-CF3
1
8
9
1a
1a
2a
2a
24
24
/
/
/
5
d
TMS-CF H
2
1
/
5
e
2
0
1a
2d
5a
7
66
4
a
a
b
Reaction conditions: 1a ( 0.2 mmol), 2a (0.4 mmol), 5a ( 0.3 mmol), solvent 2 mL;
c
19
Isolated yield; the regioselectivity was determined by F NMR analysis of the crude
d
products; The reaction was conducted in refluxing THF.
1
0a
10b
Based on the pioneering work of Tan, Xu and Hoye, a plausible mechanism
was proposed and depicted in Scheme 1. Tetrahydrothiophene undergoes nucleophilic
addition with benzyne to form zwitterion species I, and after 1,4-proton shift, to form
8

ACCEPTED MANUSCRIPT
the unstable cyclic sulfonium ylide II. The intermediate II gets a proton from water to
give species III, and after the following nucleophilic attack of the fluorine anion, to
produce the final product.
Scheme 2 Proposed Mechanism
Conclusions
In summary, a multicomponent reaction of benzynes, cyclic thioethers and non-proton
containing nucleophiles has been described. The transition-metal free conditions,
simple procedure and divergent nucleophiles provide a new methodology for the
synthesis of functionalized thioethers.
Experimental Section
General experimental Methods
Unless otherwise indicated, all reactions were conducted under nitrogen
1
atmosphere in oven-dried glassware with magnetic stirring bar. H NMR (400
13
19
MHz, CDCl ), C NMR (100 MHz, CDCl ) and F NMR (376 MHz, CDCl3)
3
3
spectra were recorded on a Bruker-DMX 400 spectrometer in CDCl3, with
tetramethylsilane as an internal standard and reported in ppm (δ). Benzyne
precursors, cyclic thioethers and silylated reagents are obtained from
commercial supplies and used without purification. Anhydrous THF, toluene,
DCM, CH CN were distilled from sodium or calcium hydride. Petroleum ether
3
(
PE), where used, has a boiling point range of 60–90 °C.
General experimental Methods
General procedure for synthesis the functionalized thioethers (3a-3n)
To a suspention of KF (35 mg, 0.6 mmol), 18-crown-6 (158 mg, 0.6 mmol) in
9

ACCEPTED MANUSCRIPT
anhydrous DCM (2.0 mL) was added H O (7.2 ꢀL, 0.4 mmol), cyclic thioether
2
2
(0.3 mmol) and benzyne precursor 1 (0.2 mmol). The mixture was stirred at
room temperature until full consumption of the aryne precursor as indicated by
TLC. The solvent was then removed under reduced pressure and the crude
material was purified by column chromatography (PE) to afford the desired
product.
1
(
4-fluorobutyl)(phenyl)sulfane(3a): Colorless oil; 28 mg, Yield: 76 %, H
NMR (400 MHz, CDCl ) δ 7.30 – 7.24 (m, 2H), 7.24 – 7.17 (m, 2H), 7.14 –
3
7
.05 (m, 1H), 4.44 (t,
J = 5.8 Hz, 1H), 4.32 (t, J = 5.7 Hz, 1H), 2.89 (t, J = 7.1
13
Hz, 2H), 1.91 – 1.56 (m, 4H). C NMR (100 MHz, CDCl ) δ 136.4, 129.4,
3
1
29.0, 126.1, 83.6 (d,
J
= 165.2 Hz), 33.4, 29.5 (d,
J = 19.9 Hz), 25.1 (d, J = 4.8
19
Hz). F NMR (376 MHz, CDCl ) δ -218.50; FTIR (film) 3431, 2971, 2925,
3
-1
1
633, 1480, 1438, 1384, 1088, 1047, 1025, 737 cm ; HRMS (ESI) m/z calcd
+
+
for C H FS [M+H] 185.0795, found 185.0799.
10
14
(3,4-dimethylphenyl)(4-fluorobutyl)sulfane(3b): Colorless oil; 26.7 mg,
1
Yield: 63 %, H NMR (400 MHz, CDCl ) δ 7.14 (s, 1H), 7.10 (d,
J
= 7.9 Hz,
3
1
2
H), 7.05 (d,
J
= 7.8 Hz, 1H), 4.50 (t,
J
= 5.9 Hz, 1H), 4.38 (t,
J
= 5.7 Hz, 1H),
13
.91 (t, = 7.0 Hz, 2H), 2.23 (s, 3H), 2.22 (s, 3H), 1.91 – 1.68 (m, 4H). C
J
NMR (100 MHz, CDCl ) δ 137.3, 135.0, 132.6, 131.4, 130.2, 127.6, 83.6 (d,
J
3
19
=
165.0 Hz), 34.1, 29.4 (d,
J = 19.6 Hz), 25.1 (d, J = 4.8 Hz), 19.7, 19.3. F
NMR (376 MHz, CDCl ) δ -218.55; FTIR (film) 3441, 3012, 2961, 2857, 2360,
3
-1
+
1
597, 1457, 1384, 1187, 1040, 810 cm ; HRMS (ESI) m/z calcd for C H FS
12 18
+
[
M+H] 213.1108, found 213.1107.
(3,4-dimethoxyphenyl)(4-fluorobutyl)sulfane(3c): Colorless oil; 27.3mg,
1
Yield: 56 %, H NMR (400 MHz, CDCl ) δ 6.98 (dd,
J
= 8.3, 2.1 Hz, 1H), 6.94
= 5.9 Hz, 1H), 4.39 (t,
= 7.0 Hz, 2H), 1.93 – 1.64
m, 4H). C NMR (100 MHz, CDCl ) δ 149.1, 148.5, 126.7, 124.2, 115.0,
3
(
d,
J
= 2.1 Hz, 1H), 6.81 (d,
J
= 8.3 Hz, 1H), 4.51 (t,
J
J
=
5.7 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 2.88 (t,
J
13
(
3
111.6, 83.6 (d, J = 165.1 Hz), 55.9, 35.4, 29.3 (d, J = 19.8 Hz), 25.2 (d, J = 4.7
1
0

ACCEPTED MANUSCRIPT
Hz). F NMR (376 MHz, CDCl ) δ -218.57; FTIR (film) 3442, 2959, 2838,
19
3
-1
2
360, 1639, 1584, 1505, 1252, 1137, 1026, 804 cm ; HRMS (ESI) m/z calcd
+
+
for C H FO S [M+H] 245.1006, found 245.1005.
12
18
2
(3,4-difluorophenyl)(4-fluorobutyl)sulfane(3d): Colorless oil; 25 mg, Yield:
1
5
4
1
1
3
3
7 %, H NMR (400 MHz, CDCl ) δ 7.21 – 7.11 (m, 1H), 7.12 – 7.02 (m, 2H),
3
.52 (t,
J
= 5.7 Hz, 1H), 4.40 (t,
J
= 5.5 Hz, 1H), 2.93 (t,
J
= 7.0 Hz, 2H), 1.94 –
= 118.7, 12.9 Hz),
= 5.9, 4.0 Hz), 125.9 (dd, = 6.1,
= 17.6 Hz), 83.5 (d, = 165.2 Hz),
J = 4.5 Hz). F NMR (376 MHz, CDCl ) δ
13
.66 (m, 4H). C NMR (100 MHz, CDCl ) δ 150.9 (dd,
J
3
48.5 (dd,
.6 Hz), 118.7 (d,
4.2, 29.3 (d, = 19.8 Hz), 24.9 (d,
136.59, -140.52, -218.80; FTIR (film) 3450, 2964, 2871, 1598, 1504, 1406,
J
= 116.0, 12.9 Hz), 132.7 (dd,
J
J
J
= 18.3 Hz), 117.7 (d,
J
J
19
J
3
-
-
1
+
+
1
2
273, 1200, 905, 811 cm ; HRMS (ESI) m/z calcd for C H F S [M+H]
10 12 3
21.0606, found 221.0612.
(4-fluorobutyl)(m-tolyl)sulfane(3e) and (4-fluorobutyl)(o-tolyl)sulfane(3e’) A
mixture of inseparable regioisomers in 2:1 ratio; Colorless oil; 30.5 mg, Yield: 77 %,
1
H NMR (400 MHz, CDCl ) of 3e: δ 7.25 (d, J = 8.0 Hz, 1H), 7.19 – 7.13 (m, 3H),
3
4
1
1
.52 (t, J = 6.0 Hz, 1H), 4.40 (t, J = 5.8 Hz, 1H), 2.94 (t, J = 5.6 Hz, 2H), 2.37 (s, 3H),
1
3
.82 – 1.71 (m, 4H). C NMR (100 MHz, CDCl ) δ 137.6, 135.7, 130.1, 127.9, 126.4,
3
25.6, 83.6 (d, J = 165.1 Hz), 32.5, 29.6 (d, J = 19.8 Hz), 24.9 (d, J = 4.8 Hz), 20.4.
1
9
1
F NMR (376 MHz, CDCl ) δ -218.61. H NMR (400 MHz, CDCl ) of 3e’: δ 7.13 –
3
3
7
.11 (m, 1H), 7.10 – 7.06 (m, 2H), 6.99 (d, J = 4.0 Hz, 1H), 4.51 (t, J = 6.0 Hz, 1H),
.39 (t, J = 7.0 Hz, 1H), 2.95 (t, J = 8.0 Hz, 2H), 2.32 (s, 3H), 1.92 – 1.82 (m, 4H).
4
1
3
C NMR (100 MHz, CDCl ) δ 138.7, 136.1, 129.9, 128.8, 126.9, 126.2, 83.6 (d, J =
3
1
9
1
65.3 Hz), 33.3, 29.4 (d, J = 13.8 Hz), 25.1 (d, J = 4.8 Hz), 21.4. F NMR (376 MHz,
CDCl ) δ -218.60; FTIR (film) 3439, 2965, 2923, 2358, 1635, 1471, 1384, 1066,
3
-1
+
+
1
047, 881, 744 cm ; HRMS (ESI) m/z calcd for C H FS [M+H] 199.0951,
11 16
found 199.0959.
(4-fluorobutyl)(3-methoxyphenyl)sulfane(3f)
and
(4-fluorobutyl)(4-methoxyphenyl)sulfane(3f’) A mixture of inseparable
1
1

ACCEPTED MANUSCRIPT
regioisomers in 1.1:1 ratio: Colorless oil; 29 mg, Yield: 69 %. H NMR (400
MHz, CDCl ) of 3f: δ 7.19 (t, = 8.0 Hz, 1H), 6.92 – 6.89 (m, 1H), 6.88 – 6.87
m, 1H), 6.73 – 6.70 (m, 1H), 4.49 (t, = 6.0 Hz, 1H), 4.37 (t, = 5.8 Hz, 1H),
.79 (s, 3H), 2.85 (t, = 8.0 Hz, 2H), 1.79 – 1.66 (m, 4H). C NMR (100 MHz,
CDCl ) δ 158.9, 137.8, 129.7, 126.3, 121.2, 114.5, 83.6 (d, = 165.0 Hz), 55.3,
= 4.8 Hz). F NMR (376 MHz, CDCl ) δ
1
J
3
(
J
J
13
3
J
J
3
19
3
5.5, 29.3 (d, J = 19.8 Hz), 25.2 (d, J
3
1
-
(
218.52. H NMR (400 MHz, CDCl ) of 3f’: δ 7.36 – 7.32 (m, 2H), 6.86 – 6.82
3
m, 2H), 4.51 (t,
J
= 6.0 Hz, 1H), 4.40 (t, J = 5.8 Hz, 1H), 3.79 (s, 3H), 2.96 (t,
1
3
J
1
2
2
= 6.0 Hz, 2H), 1.91 – 1.79 (m, 4H). C NMR (100 MHz, CDCl ) δ 159.9,
3
33.3, 114.6, 111.6, 83.6 (d,
J
= 165.1 Hz), 55.3, 33.1, 29.5 (d,
J
= 19.8 Hz),
19
5.0 (d,
J = 4.7 Hz). F NMR (376 MHz, CDCl ) δ -218.63; FTIR (film) 3442,
3
-1
960, 2360, 1636, 1493, 1384, 1244, 1171, 913, 743 cm ; HRMS (ESI) m/z
+
+
calcd for C H FOS [M+H] 215.0900, found 215.0900.
11
16
(
3-chlorophenyl)(4-fluorobutyl)sulfane(3g)
4-chlorophenyl)(4-fluorobutyl)sulfane(3g’)
and
(
A
mixture of inseparable
1
regioisomers in 1:1.4 ratio: Colorless oil; 26 mg, Yield: 60 %. H NMR (400
MHz, CDCl ) of 3g: δ 7.30 – 7.27 (m, 1H), 7.22 – 7.16 (m, 2H), 7.15 – 7.11 (m,
3
1
1
1
H), 4.52 (t,
J = 6.0 Hz, 1H), 4.41 (t, J = 5.8 Hz, 1H), 2.97 (t, J = 7.0 Hz, 2H),
13
.91 – 1.80 (m, 4H). C NMR (100 MHz, CDCl ) δ 134.7, 132.0, 129.9, 128.3,
3
26.8, 125.9, 83.5 (d,
J
= 165.3 Hz), 32.9, 29.4 (d, J = 19.9 Hz), 24.9 (d, J = 4.6
19
1
Hz). F NMR (376 MHz, CDCl ) δ -218.76. H NMR (400 MHz, CDCl ) of
3
3
3
2
1
2
2
g’: δ 7.27 – 7.22 (m, 4H), 4.51 (t,
J
= 4.0 Hz, 1H), 4.39 (t,
J
= 5.8 Hz, 1H),
13
.94 (t,
J = 8.0 Hz, 2H), 1.80 – 1.72 (m, 4H). C NMR (100 MHz, CDCl ) δ
3
38.7, 134.9, 130.6, 129.0, 83.5 (d,
J
= 165.3 Hz), 33.6, 29.4 (d,
J = 19.9 Hz),
19
4.9 (d,
J = 4.7 Hz). F NMR (376 MHz, CDCl ) δ -218.73; FTIR (film) 3441,
3
-
1
961, 2853, 2359, 2341, 1636, 1476, 1384, 1095, 1010, 811 cm ; HRMS (ESI)
+
+
m/z calcd for C H ClFS [M+H] 219.0405, found 219.0407.
10
13
(
4-fluorobutyl)(naphthalen-1-yl)sulfane(3h)
4-fluorobutyl)(naphthalen-2-yl)sulfane(3h’)
and
(
A
mixture of inseparable
1
2

ACCEPTED MANUSCRIPT
1
regioisomers in 1:1.25 ratio: Colorless oil; 35.5 mg, Yield: 76 %. H NMR (400
MHz, CDCl ) of 3h: δ 7.57 – 7.54 (m, 2H), 7.53 – 7.51 (m, 1H), 7.44 – 7.37 (m,
3
4
1
1
=
H), 4.50 (t,
J = 6.0 Hz, 1H), 4.38 (t, J = 5.8 Hz, 1H), 3.05 (t, J = 8.0 Hz, 2H),
13
.92 – 1.82 (m, 4H). C NMR (100 MHz, CDCl ) δ 133.9, 133.8, 133.5, 133.1,
3
28.4, 127.4, 126.9, 126.6, 126.3, 125.7, 83.6 (d,
J
= 165.1 Hz), 33.2, 29.5 (d, J
19
1
19.8 Hz), 25.1 (d,
J
= 5.0 Hz). F NMR (376 MHz, CDCl ) δ -218.54. H
3
NMR (400 MHz, CDCl ) of 3h’: δ 8.40 (d,
J
= 8.0 Hz, 1H), 7.83 (d,
H),7.78 – 7.76 (m, 1H), 7.73 – 7.71 (m, 3H), 7.50 – 7.45 (m, 1H), 4.48 (t,
.0 Hz, 1H), 4.36 (t, = 5.8 Hz, 1H), 3.00 (t, = 8.0 Hz, 2H), 1.82 – 1.72 (m,
H). C NMR (100 MHz, CDCl ) δ 134.0, 131.8, 128.6, 128.2, 127.7, 127.3,
J = 8.0 Hz,
3
1
6
4
1
2
3
J =
J
J
1
3
3
27.1, 126.4, 125.6, 125.1, 83.6 (d,
J
= 165.1 Hz), 33.9, 29.5 (d,
J = 19.8 Hz),
19
5.1 (d,
J = 5.0 Hz). F NMR (376 MHz, CDCl ) δ -218.50; FTIR (film) 3441,
3
-1
054, 2961, 2867, 1926, 1589, 1501, 1384, 1268, 1038, 813, 790 cm ; HRMS
+
+
(
ESI) m/z calcd for C H FS [M+H] 235.0951, found 235.0953.
14 16
(4-fluorobutyl)(3-methoxyphenyl)sulfane(3i): Colorless oil; 33.4 mg, Yield:
1
7
1
8 %, H NMR (400 MHz, CDCl ) δ 7.20 (t,
J
= 8.0 Hz, 1H), 6.95 – 6.89 (m,
= 2.1 Hz, 1H), 6.76 – 6.69 (m, 1H), 4.52 (t, = 5.8 Hz, 1H), 4.40
= 5.6 Hz, 1H), 3.80 (s, 3H), 2.97 (t, = 7.0 Hz, 2H), 1.98 – 1.69 (m, 4H).
C NMR (100 MHz, CDCl ) δ 159.9, 137.7, 129.7, 121.2, 114.5, 111.6, 83.6 (d,
3
H), 6.87 (t,
J
J
(
t,
J
J
13
3
19
J
= 165.1 Hz), 55.3, 33.1, 29.4 (d,
J = 19.8 Hz), 25.0 (d, J = 4.8 Hz). F NMR
(
376 MHz, CDCl ) δ -218.66; FTIR (film) 3452, 2960, 1590, 1575, 1479, 1283,
3
-
1
+
+
1
2
248, 1041, 862, 771 cm ; HRMS (ESI) m/z calcd for C H FOS [M+H]
11 16
15.0900, found 215.0904.
1
(
3-fluoropropyl)(phenyl)sulfane(3j): Colorless oil; 25 mg, Yield: 74 %, H
NMR (400 MHz, CDCl ) δ 7.37 – 7.32 (m, 2H), 7.32 – 7.24 (m, 2H), 7.22 –
3
7
.14 (m, 1H), 4.61 (t,
J = 5.7 Hz, 1H), 4.49 (t, J = 5.7 Hz, 1H), 3.04 (t, J = 7.2
13
Hz, 2H), 2.09 – 1.91 (m, 2H). C NMR (100 MHz, CDCl ) δ 135.9, 129.4,
3
1
29.0, 126.2, 82.2 (d,
J
= 165.6 Hz), 30.1 (d,
J = 20.2 Hz), 29.4 (d, J = 4.7 Hz).
19
F NMR (376 MHz, CDCl ) δ -221.05; FTIR (film) 3432, 2969, 2923, 1630,
3
1
3

ACCEPTED MANUSCRIPT
-1
1
584, 1480, 1438, 1384, 1050, 1021, 738 cm ; HRMS (ESI) m/z calcd for
+
+
C H FS [M+H] 171.0638, found 171.0630.
9
12
1
(
5-fluoropentyl)(phenyl)sulfane (3k): Colorless oil; 11 mg, Yield: 28 %, H
NMR (400 MHz, CDCl ) δ 7.37 – 7.30 (m, 2H), 7.31 – 7.25 (m, 2H), 7.21 –
3
7
.13 (m, 1H), 4.49 (t,
J = 6.0 Hz, 1H), 4.37 (t, J = 6.0 Hz, 1H), 2.93(t, J = 8.0
13
Hz, 2H), 1.79 – 1.63 (m, 4H), 1.60 – 1.50 (m, 2H). C NMR (100 MHz, CDCl )
3
δ 136.7, 129.1, 128.9, 125.8, 83.9 (d,
J
= 164.7 Hz), 33.5, 29.9 (d,
J = 19.7 Hz),
1
9
2
3
8.8, 24.5 (d,
J = 5.3 Hz). F NMR (376 MHz, CDCl ) δ -218.41; FTIR (film)
3
-1
431, 2969, 2926, 2359, 2342, 1633, 1480, 1384, 1045, 879, 740 cm ; HRMS
+
+
(
ESI) m/z calcd for C H FS [M+H] 199.0951, found 199.0950.
11 16
15
1
(
4-chlorobutyl)(phenyl)sulfane(3l) : Colorless oil; 36 mg, Yield: 90 %, H
NMR (400 MHz, CDCl ) δ 7.37 – 7.29 (m, 2H), 7.33 – 7.22 (m, 2H), 7.22 –
3
7
2
1
.11 (m, 1H), 3.53 (t, J = 6.5 Hz, 2H), 2.94 (t, J = 7.1 Hz, 2H), 1.98 – 1.85 (m,
13
H), 1.86 – 1.71 (m, 2H). C NMR (100 MHz, CDCl ) δ 136.3, 129.3, 128.9,
3
26.1, 44.5, 33.0, 31.4, 26.4.
16
1
(
4-bromobutyl)(phenyl)sulfane(3m) : Colorless oil; 28 mg, Yield: 58 %, H
NMR (400 MHz, CDCl ) δ 7.37 – 7.31 (m, 2H), 7.31 – 7.24 (m, 2H), 7.22 –
3
7
2
1
.13 (m, 1H), 3.40 (t, J = 6.6 Hz, 2H), 2.94 (t, J = 7.1 Hz, 2H), 2.07 – 1.94 (m,
13
H), 1.89 – 1.73 (m, 2H). C NMR (100 MHz, CDCl ) δ 136.3, 129.3, 128.9,
3
26.1, 33.1, 32.9, 31.6, 27.6.
phenyl(4-thiocyanatobutyl)sulfane(3n): Colorless oil; 20.4 mg, Yield: 61 %,
1
H NMR (400 MHz, CDCl ) δ 7.37 – 7.32 (m, 2H), 7.32 – 7.25 (m, 2H), 7.23 –
3
7
.15 (m, 1H), 2.99 – 2.90 (m, 4H), 2.05 – 1.90 (m, 2H), 1.85 – 1.73 (m, 2H).
13
C NMR (100 MHz, CDCl ) δ 135.8, 129.6, 129.0, 126.3, 112.1, 33.6, 33.1,
3
2
8.8, 27.3; FTIR (film) 3436, 2930, 2858, 2359, 2341, 2151, 1630, 1437, 1280,
-1
+
+
1
024, 907 cm ; HRMS (ESI) m/z calcd for C H NS [M+H] 224.0562,
11 14 2
found 224.0564.
17
1
phenyl(vinyl)sulfane(4a) : Colorless oil; 20.4 mg, Yield: 75 %, H NMR (400
MHz, CDCl ) δ 7.42 – 7.34 (m, 2H), 7.37 – 7.27 (m, 2H), 7.30 – 7.20 (m, 1H),
3
1
4

ACCEPTED MANUSCRIPT
= 16.6, 9.6 Hz, 1H), 5.36 (d, = 1.7 Hz, 1H), 5.33 (d,
H). C NMR (100 MHz, CDCl ) δ 134.3, 131.9, 130.5, 129.1, 127.1, 115.5.
6
1
.54 (dd,
J
J
J = 8.7 Hz,
13
3
(E)-pent-3-en-1-yl(phenyl)sulfane(4b)
and
18
pent-4-en-1-yl(phenyl)sulfane(4c) A mixture of inseparable regioisomers in 5:1
1
ratio: Colorless oil; 25.6 mg, Yield: 72 %. H NMR (400 MHz, CDCl ) of 4b: δ
3
7
.35 – 7.23 (m, 5H), 5.55 – 5.42 (m, 2H), 2.93 (t, J = 5.8 Hz, 2H), 2.34 – 2.29
13
(
m, 2H), 1.65 (d,
J
= 4.0 Hz, 3H). C NMR (100 MHz, CDCl ) δ 136.7, 129.1,
3
1
1
28.9, 128.8, 126.9, 125.8, 33.6, 32.3, 17.9. H NMR (400 MHz, CDCl ) of 4c:
3
δ 7.18 – 7.14 (m, 5H), 5.83 – 5.73 (m, 1H), 5.06 – 4.97 (m, 2H), 2.92 – 2.90 (m,
1
3
2
1
H), 2.22 – 2.16 (m, 2H), 1.78 – 1.70 (m, 2H), C NMR (100 MHz, CDCl ) δ
3
37.6, 131.1, 129.2, 129.1, 127.0, 115.4, 32.9, 32.7, 28.3.
General procedure for synthesis the functionalized thioethers (6a-6q)
To a solution of KF (35 mg, 0.6 mmol), 18-crown-6 (158 mg, 0.6 mmol) in
anhydrous THF (2.0 mL) was added H O (7.2 ꢀL, 0.4 mmol), benzyne
2
precursor
1 (0.2 mmol), cyclic thioether 2 (4 mmol) and silylated reagent 5 (0.3
mmol). The mixture was stirred at room temperature until full consumption of
the benzyne precursor as indicated by TLC. The solvent was then removed
under reduced pressure and the crude material was purified by column
chromatography (Al O ) to afford the desired product.
2
3
19
1
5
-(phenylthio)pentanenitrile(6a) : Colorless oil; 33.9 mg, Yield: 89 %, H
NMR (400 MHz, CDCl ) δ 7.38 – 7.31 (m, 2H), 7.31 – 7.24 (m, 2H), 7.23 –
3
7
4
2
5
9
1
2
1
.16 (m, 1H), 2.94 (t, J = 6.7 Hz, 2H), 2.34 (t, J = 6.9 Hz, 2H), 1.91 – 1.70 (m,
13
H). C NMR (100 MHz, CDCl ) δ 135.9, 129.6, 129.0, 126.3, 119.4, 32.9,
3
7.9, 24.3, 16.8.
-((3,4-dimethylphenyl)thio)pentanenitrile(6b): Colorless oil; 41.6 mg, Yield:
1
4 %, H NMR (400 MHz, CDCl ) δ 7.14 (s, 1H), 7.09 (dd,
J
J
= 7.8, 2.0 Hz,
= 6.8 Hz, 2H),
3
H), 7.05 (d,
J = 7.8 Hz, 1H), 2.89 (t, J = 6.7 Hz, 2H), 2.33 (t,
13
.23 (s, 3H), 2.22 (s, 3H), 1.88 – 1.65 (m, 4H). C NMR (100 MHz, CDCl ) δ
3
37.5, 135.3, 132.1, 131.7, 130.3, 127.9, 119.4, 33.6, 28.1, 24.3, 19.8, 19.4,
1
5

ACCEPTED MANUSCRIPT
1
8
2
5
8
2
6.8; FTIR (film) 3425, 2972, 2925, 2359, 2246, 1635, 1456, 1384, 1264, 1049,
-1
+
+
82 cm ; HRMS (ESI) m/z calcd for C H NS [M+H] 220.1155, found
13
18
20.1154.
-((3,4-dimethoxyphenyl)thio)pentanenitrile(6c): Colorless oil; 43 mg, Yield:
1
6 %, H NMR (400 MHz, CDCl ) δ 6.98 (dd,
J
= 8.2, 2.1 Hz, 1H), 6.94 (d,
= 8.3 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 2.86 (t, = 6.6
= 6.7 Hz, 2H), 1.88 – 1.64 (m, 4H). C NMR (100 MHz,
CDCl ) δ 149.1, 148.7, 126.2, 124.5, 119.4, 115.2, 111.7, 56.0, 55.9, 34.9, 28.1,
J =
3
.1 Hz, 1H), 6.81 (d,
J
J
13
Hz, 2H), 2.35 (t,
J
3
2
4.2, 16.8; FTIR (film) 3440, 2936, 2837, 2245, 1583, 1504, 1463, 1395, 1252,
-1
+
+
1
178, 853 cm ; HRMS (ESI) m/z calcd for C H NO S [M+H] 251.0975,
13
17
2
found 251.0975.
2
0
5
6
3
-(naphthalen-2-ylthio)pentanenitrile(6d) : Colorless oil; 31 mg, Yield:
1
4 %, H NMR (400 MHz, CDCl ) δ 7.82 – 7.70 (m, 4H), 7.54 – 7.34 (m, 3H),
3
13
.03 (t, J = 6.7 Hz, 2H), 2.33 (t, J = 6.8 Hz, 2H), 1.89 – 1.74 (m, 4H). C NMR
(
100 MHz, CDCl ) δ 133.8, 133.3, 131.9, 128.6, 127.8, 127.5, 127.4, 127.1,
3
1
5
4
2
26.7, 125.8, 119.4, 32.8, 27.9, 24.3, 16.8.
-((3,4-difluorophenyl)thio)pentanenitrile(6e): Colorless oil; 22 mg, Yield:
1
9 %, H NMR (400 MHz, CDCl ) δ 7.21 – 7.13 (m, 1H), 7.13 – 7.04 (m, 2H),
3
13
.92 (t,
J
= 6.6 Hz, 2H), 2.37 (t,
J
= 6.7 Hz, 2H), 1.87 – 1.73 (m, 4H). C NMR
= 100.6, 12.9 Hz), 148.6 (dd, = 98.2, 13.0
= 6.1, 3.7 Hz), 119.2 (d, = 6.3 Hz), 118.9,
J = 17.6 Hz), 33.8, 27.9, 24.2, 16.8; FTIR (film) 3431, 2974, 2927,
(
100 MHz, CDCl ) δ 151.1 (dd,
J
J
3
Hz), 132.3 – 131.9 (m), 126.3 (dd,
17.8 (d,
359, 2245, 1635, 1500, 1384, 1269, 1049, 771 cm ; HRMS (ESI) m/z calcd
J
J
1
-1
2
+
+
for C H F NS [M+H] 228.0653, found 228.0657.
11
12 2
5
-(m-tolylthio)pentanenitrile(6f) and 5-(o-tolylthio)pentanenitrile(6f’) A
mixture of inseparable regioisomers in 1.7:1 ratio: Colorless oil; 33.6 mg, Yield:
1
8
2 %. H NMR (400 MHz, CDCl ) of 6f: δ 7.20 – 7.13 (m, 4H), 2.91 (t,
J
= 5.8
3
13
Hz, 2H), 2.37 (s, 3H), 2.36 – 2.33 (m, 2H), 1.85 – 1.80 (m, 4H), C NMR (100
MHz, CDCl ) δ 137.8, 135.2, 130.3, 128.2, 126.5, 125.9, 119.4, 32.1, 28.0, 24.5,
3
1
6

ACCEPTED MANUSCRIPT
0.4, 16.9. H NMR (400 MHz, CDCl ) of 6f’: δ 7.28 – 7.25 (m, 1H), 7.12 –
1
2
6
1
1
2
3
.97 (m, 3H), 2.93 (t,
J = 5.8 Hz, 2H), 2.36 – 2.33 (m, 2H), 2.32 (s, 3H), 1.80 –
13
.74 (m, 4H), C NMR (100 MHz, CDCl ) δ 138.8, 135.6, 130.2, 128.9, 127.2,
3
26.5, 119.4, 32.9, 28.0, 24.3, 21.4, 16.8; FTIR (film) 3431, 2973, 2926, 2359,
-1
341, 1634, 1456, 1384, 1049, 880, 742 cm ; HRMS (ESI) m/z calcd for
+
+
C H NS [M+H] 206.0998, found 206.0996.
12
16
5
5
-((3-methoxyphenyl)thio)pentanenitrile(6g)
and
-((4-methoxyphenyl)thio)pentanenitrile (6g’) A mixture of inseparable
1
regioisomers in 1:1 ratio: Colorless oil; 35 mg, Yield: 80 %. H NMR (400 MHz,
CDCl ) of 6g: δ 7.20 (t,
J
= 8.0 Hz, 1H), 6.91 – 6.89 (m, 1H), 6.87 – 6.86 (m,
3
1
H), 6.75 – 6.72 (m, 1H), 3.79 (s, 3H), 2.95 (t, = 6.0 Hz, 2H), 2.35 (t, = 8.0
J
J
13
Hz, 2H), 1.84 – 1.78 (m, 4H). C NMR (100 MHz, CDCl ) δ 159.9, 137.2,
3
1
1
29.8, 125.8, 121.4, 119.3, 114.8, 55.3, 35.1, 27.9, 24.3, 16.8. H NMR (400
MHz, CDCl ) of 6g’: δ 7.36 – 7.32 (m, 2H), 6.86 – 6.83 (m, 2H), 3.79 (s, 3H),
3
13
2
.83 (t,
J = 8.0 Hz, 2H), 2.33 (t, J = 8.0 Hz, 2H), 1.78 – 1.67 (m, 4H). C NMR
(
100 MHz, CDCl ) δ 159.1, 133.6, 119.4, 114.7, 111.8, 55.4, 32.7, 28.1, 24.1,
3
1
8
2
5
5
6.8; FTIR (film) 3431, 2973, 2925, 2359, 2341, 1635, 1456, 1384, 1239, 1049,
-1
+
+
80 cm ; HRMS (ESI) m/z calcd for C H NOS [M+H] 222.0947, found
12
16
22.0944.
-((4-chlorophenyl)thio)pentanenitrile(6h)
and
-((3-chlorophenyl)thio)pentanenitrile (6h’) A mixture of inseparable
1
regioisomers in 1.5:1 ratio: Colorless oil; 31.6 mg, Yield: 70 %. H NMR (400
MHz, CDCl ) of 6h: δ 7.26 – 7.23 (m, 4H), 2.92 (t, J = 6.0 Hz, 2H), 2.36 (t, J =
3
1
3
6
1
.0 Hz, 2H), 1.81 – 1.79 (m, 4H). C NMR (100 MHz, CDCl ) δ 134.4, 130.9,
3
1
30.0, 129.2, 126.3, 33.2, 27.9, 24.2, 16.8. H NMR (400 MHz, CDCl ) of 6h’:
3
δ 7.29 (s, 1H),7.22 – 7.14 (m, 3H), 2.96 (t,
J = 6.0 Hz, 2H), 2.37 (t, J = 6.0 Hz,
1
3
2
1
H), 1.79 – 1.73 (m, 4H). C NMR (100 MHz, CDCl ) δ 138.2, 134.8, 132.3,
3
29.2, 128.6, 127.1, 119.3, 32.6, 27.8, 24.3, 16.8; FTIR (film) 3432, 2973,
1
7

ACCEPTED MANUSCRIPT
926, 2360, 2342, 1635, 1384, 1071, 1051, 903, 720 cm ; HRMS (ESI) m/z
-1
2
+
+
calcd for C H ClNS [M+H] 226.0452, found 226.0450.
11
13
20
5
-(naphthalen-1-ylthio)pentanenitrile(6i)
and
5
-(naphthalen-2-ylthio)pentanenitrile(6i’)
A
mixture
of
inseparable
1
regioisomers in 1:1 ratio: Colorless oil; 36.2 mg, Yield: 76 %. H NMR (400
MHz, CDCl ) of 6i: δ 7.78 (d,
J
= 8.0 Hz, 1H), 7.75 – 7.73 (m, 4H), 7.58 – 7.56
3
(
m, 2H), 3.02 (t,
J
= 6.0 Hz, 2H), 2.32 (t, = 5.8 Hz, 2H), 1.85 – 1.80 (m, 4H).
J
13
C NMR (100 MHz, CDCl ) δ 134.0, 133.4, 132.9, 128.6, 127.7, 127.4, 126.7,
3
1
1
26.3, 125.6, 125.0, 119.4, 33.5, 28.1, 24.4, 16.8. H NMR (400 MHz, CDCl )
3
of 6i’: δ 8.39 (d,
.97 (t, = 6.0 Hz, 2H), 2.30 (t,
100 MHz, CDCl ) δ 133.8, 133.1, 131.9, 128.8, 128.7, 127.8, 127.5, 127.1,
J
= 8.0 Hz, 1H), 7.84 (d,
J = 8.0 Hz, 1H), 7.54 – 7.38 (m, 5H),
13
2
J
J
= 5.8 Hz, 2H), 1.80 – 1.71 (m, 4H). C NMR
(
3
1
5
8
26.6, 125.8, 119.4, 32.8, 27.9, 24.3, 16.8.
-((3-methoxyphenyl)thio)pentanenitrile(6j): Colorless oil; 37 mg, Yield:
1
4 %, H NMR (400 MHz, CDCl ) δ 7.20 (t,
J
= 8.0 Hz, 1H), 6.90 (d,
J = 7.7
3
Hz, 1H), 6.87 (t,
.95 (t, = 6.0 Hz, 2H), 2.35 (t,
100 MHz, CDCl ) δ 159.9, 137.2, 129.8, 121.4, 119.4, 114.8, 111.8, 55.3, 32.7,
J
= 2.1 Hz, 1H), 6.73 (dd,
J = 8.6, 2.7 Hz, 1H), 3.79 (s, 3H),
13
2
J
J
= 8.0 Hz, 2H), 1.87 – 1.73 (m, 4H). C NMR
(
3
2
7.9, 24.3, 16.8; FTIR (film) 3425, 2972, 2926, 2359, 2339, 1657, 1630, 1384,
+
+
1
245, 1047, 880; HRMS (ESI) m/z calcd for C H NOS [M+H] 222.0947,
12 16
found 222.0948.
20
1
4
-(phenylthio)butanenitrile(6k) : Colorless oil; 32.1 mg, Yield: 90 %, H
NMR (400 MHz, CDCl ) δ 7.39 – 7.33 (m, 2H), 7.33 – 7.27 (m, 2H), 7.25 –
3
7
2
2
6
.18 (m, 1H), 3.02 (t, J = 6.9 Hz, 2H), 2.50 (t, J = 7.1 Hz, 2H), 1.98 – 1.91 (m,
13
H). C NMR (100 MHz, CDCl ) δ 134.8, 130.1, 129.2, 126.8, 119.1, 32.6,
3
4.9, 15.9.
21
1
-(phenylthio)hexanenitrile(6l): Colorless oil; 36.3 mg, Yield: 88 %, H
NMR (400 MHz, CDCl ) δ 7.37 – 7.24 (m, 4H), 7.22 – 7.14 (m, 1H), 2.92 (t,
J
3
13
=
7.0 Hz, 2H), 2.32 (t, J = 6.9 Hz, 2H), 1.75 – 1.52 (m, 6H). C NMR (100
1
8

ACCEPTED MANUSCRIPT
MHz, CDCl ) δ 136.3, 129.2, 128.9, 126.0, 119.6, 33.3, 28.3, 27.7, 25.0, 17.1.
3
1
5
-(phenylthio)hexanenitrile(6m): Colorless oil; 29.6 mg, Yield: 72 %, H
NMR (400 MHz, CDCl ) δ 7.44 – 7.36 (m, 2H), 7.36 – 7.25 (m, 2H), 7.30 –
3
7
–
1
2
.20 (m, 1H), 3.20 (m, 1H), 2.35 (t,
1.64 (m, 2H), 1.30 (d, = 6.7 Hz, 3H). C NMR (100 MHz, CDCl ) δ 134.4,
32.5, 128.9, 127.2, 119.4, 42.8, 35.5, 22.9, 21.3, 17.1; FTIR (film) 3441, 2960,
J = 7.0 Hz, 2H), 1.93 – 1.79 (m, 2H), 1.75
13
J
3
-1
924, 2359, 2244, 1635, 1437, 1383, 1246, 1052, 743 cm ; HRMS (ESI) m/z
+
+
calcd for C H NS [M+H] 206.0998, found 206.0996.
12
16
22
1
(
4-azidobutyl)(phenyl)sulfane(6n) : Colorless oil; 34.8 mg, Yield: 84 %, H
NMR (400 MHz, CDCl ) δ 7.37 – 7.31 (m, 2H), 7.31 – 7.23 (m, 2H), 7.22 –
3
7
4
2
.12 (m, 1H), 3.27 (t, J = 6.3 Hz, 2H), 2.93 (t, J = 6.8 Hz, 2H), 1.82 – 1.64 (m,
13
H). C NMR (100 MHz, CDCl ) δ 136.3, 129.3, 128.9, 126.1, 50.9, 33.3, 27.9,
3
6.3.
15
1
(
4-chlorobutyl)(phenyl)sulfane(6o) : Colorless oil; 36 mg, Yield: 89 %, H
NMR (400 MHz, CDCl ) δ 7.37 – 7.31 (m, 2H), 7.31 – 7.23 (m, 2H), 7.22 –
3
7
2
1
.13 (m, 1H), 3.54 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 7.1 Hz, 2H), 2.01 – 1.87 (m,
13
H), 1.86 – 1.74 (m, 2H). C NMR (100 MHz, CDCl ) δ 136.3, 129.3, 128.9,
3
26.1, 44.4, 33.0, 31.4, 26.4.
1
(
5-azidopentyl)(phenyl)sulfane(6p): Colorless oil; 28.2 mg, Yield: 65 %, H
NMR (400 MHz, CDCl ) δ 7.38 – 7.22 (m, 4H), 7.22 – 7.11 (m, 1H), 3.25 (t,
J
3
=
6.7 Hz, 2H), 2.92 (t, J = 7.2 Hz, 2H), 1.73 – 1.56 (m, 4H), 1.56 – 1.46 (m,
1
3
2
2
1
2
H). C NMR (100 MHz, CDCl ) δ 136.6, 129.1, 128.9, 125.9, 51.3, 33.5, 28.7,
3
8.5, 25.9; FTIR (film) 3430, 2972, 2931, 2095, 1630, 1480, 1438, 1384, 1288,
-1
+
+
050, 913 cm ; GC-MS (EI) m/z calcd for C H N S [M] 221.09, found
11
15
3
21.1
15
(
5-chloropentyl)(phenyl)sulfane(6q) : Colorless oil; 37.4 mg, Yield: 86 %,
1
H NMR (400 MHz, CDCl ) δ 7.37 – 7.28 (m, 2H), 7.32 – 7.22 (m, 2H), 7.22 –
3
7
2
.10 (m, 1H), 3.51 (t,
J
= 6.6 Hz, 2H), 2.92 (t,
J
= 7.1 Hz, 2H), 1.81 – 1.74 (m,
1
3
H), 1.75 – 1.60 (m, 2H), 1.64 – 1.51 (m, 2H). C NMR (100 MHz, CDCl ) δ
3
1
9

ACCEPTED MANUSCRIPT
1
36.6, 129.1, 128.9, 125.9, 44.8, 33.5, 32.1, 28.5, 26.1.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the National Natural Science Foundation of China
(
No. 21462034), the Young Scientists Foundation of Shihezi University (Nos.
RCZX201546, 2015ZRKXJQ05) and the Excellent Young Teachers Plan of
Bingtuan (CZ027203). We thank Mr. P. Grant of University of Auckland for
proofreading of this paper.
Notes and references
1
2
Fraústo DaSilva, J. R.; Williams, R. J. P. The Biological Chemistry of the
Elements. Oxford University Press: New York, 2001
For reviews, see: (a) Kondo, T.; Mitsudo, T. A. Chem. Rev. 2000
205-3220. (b) Sibiand, M.; Manyem, S. Tetrahedron. 2000 56, 8033-8061.
114, 8807-8864;
, 959-980; for
132
568-4569. (f) Takanori, O.; Naoya, K.; Masakatsu, S. Angew. Chem. Int. Ed.
.
,
100,
3
,
(
(
c) Chauhan, P.; Mahajan, S.; Enders, D. Chem. Rev. 2014
,
d) Enders, D.; Lüttgen, K.; Narine, A. A. Synthesis. 2007, 7
selected examples see: (e) Sun, J. W.; Fu, G. C. J. Am. Chem. Soc. 2010
,
,
4
2
2
012
012
,
,
51, 8551-8554. (g) Roggen,M.; Carreira, E. M. Angew. Chem. Int. Ed.
51, 8652-8655. (h) Xia, Y.; Lin, L.; Chang, F.; Fu, X.; Liu, X.; Feng, X.
Angew. Chem. Int. Ed. 2015
J. Am. Chem. Soc. 2014 136, 3655-3663. (j) Denmark, S. E.; Hartmann, E.;
Kornfilt, D. J. P.; Wang, H. Nat. Chem. 2014 , 1056-1064.
For selected examples, see: (a) Wang, Q.; Li, T. R.; Lu, L. Q.; Zhang, K.;
Xiao, W. J. and Li, M. M. J. Am. Chem. Soc. 2016 138, 8360-8363. (b) Orsi,
D. L.; Easley, B. J.; Lick, A. M.; Altman, R. A. Org. Lett. 2017 19
570-1573. (c) Sun, K.; Lv, Y. H.; Shi, Z. D.; Mu, S. Q.; Li, C. H.; Wang, X.
, 54, 13748-13752. (i) Denmark, S. E.; Chi, H. M.
,
,
6
3
,
,
,
1
Org. Biomol. Chem. 2017
,
15, 5258-5262. (d) Vasu, D.; Yorimitsu, H.; Osuka,
54, 7162-7166. (e) Civit, M. G.; Royes, J.;
A. Angew. Chem. Int. Ed. 2015
,
2
0

ACCEPTED MANUSCRIPT
Vogels, C. M.; Westcott, S. A.; Cuenca, A. B.; Fernández, E. Org. Lett. 2016
,
18
, 3830-3833. (f) Kojima, N.; Suga, Y.; Hayashi, H.; Yamori, T.; Tanaka, T.
Bio. Med. Chem. Lett. 2011 21, 5745-5749. (g) Yan, X. L.; Wang, Z. L.;
Sudom, A.; Cardozo, M.; Di, Y. M. Bio. Med. Chem. Lett. 2010 20
071-7075.
For selected examples, see: (a) Park, N.; Park, K.; Jang, M.; Lee. S. J. Org.
Chem. 2011 76, 4371-4378. (b) Shang, L.; Chang, Y. H.; Luo, F.; He, J. N.;
Huang, X.; Zhang, L.; Kong, L. C.; Li, K. X.; Peng, B. J. Am. Chem. Soc.
,
,
,
7
4
,
2
2
017
017
,
,
139, 4211-4217. (c) Lo, J. C.; Kim, D.; Pan, C. M. J. Am. Chem. Soc.
139, 2484-2503. (d) Li, Y. J.; Miyazawa, K.; Koike, T.; Akita, M. Org
Chem. Frontier. 2015
M.; Baran, P. S. Nature. 2014
Sugae, T. J. Am. Chem. Soc. 2001
For reviews on benzynes, see: (a) Bhojgude, S. S.; Bhunia, A.; Biju, A. T. Acc.
Chem. Res. 2016 49, 1658-1670. (b) Bhunia, A.; Yetra, S. R.; Biju, A. T.
Chem. Soc. Rev. 2012 41, 3140-3152. (c) Bhojgude, S. S.; Biju, A. T. Angew.
Chem. Int. Ed. 2012 51, 1520-1522. (d) Tadross, P. M.; Stoltz, B. M. Chem.
Rev. 2012 112, 3550-3577. (e) Dubrovskiy, A. V.; Markina, N. A.; Larock, R.
C. Org. Biomol. Chem. 2013 11, 191-218. (f) Wu, C.; Shi, F. Asian J. Org.
Chem. 2013 , 116-125.
(a) Li, X. J.; Sun, Y.; Huang, X.; Zhang, L.; Kong, L. C. and Peng, B. Org.
Lett. 2017 19, 838-841. (b) Xu, D. Y.; Zhao, Y. L.; Song, D. P.; Zhong, Z. L.;
Feng, S. B.; Xie, X. G.; Wang, X. L. and She, X. G. Org. Lett. 2017 19
19
134-2137. (e) Dhiman, A. K.; Kumar, R.; Kumar, R. and Sharma, U. J. Org.
82, 12307-12317. (f) Xu, J. K.; Li, S. J.; Wang, H. Y. Chem.
Commun. 2017 53, 1708-1711. (g) Roy, T.; Thangaraj, M.; Gonnade, R. G.
Chem. Commun. 2016 52, 9044-9047. (h) Li, Y. Y.; Qiu, D. C.; Gu, R. R.;
Wang, J. L.; Shi, J. R.; Li, Y. J. Am. Chem. Soc. 2016 138, 10814-10817. (i)
,
2
, 319-323. (e) Lo, J. C.; Gui, J. H.; Yabe, Y.; Pan, C.
516, 343-348. (f) Sugoh, K.; Kuniyasu, H.;
123, 5108-5109.
,
,
5
,
,
,
,
,
,
2
6
,
,
,
3
600-3603. (c) Ahire, M. M.; Khan, R. and Mhaske, S. B. Org. Lett. 2017
,
,
2
Chem. 2017
,
,
,
,
2
1

ACCEPTED MANUSCRIPT
Shi, J.; Qiu, D.; Wang, J.; Xu, H.; Li, Y. J. Am. Chem. Soc. 2015
,
137
,
,
5670-5673. (j) Rao, B.; Tang, J.; Wei, Y.; Zeng, X. Chem-Asian J. 2016,
11
9
91-995. (k) Sundalam, S. K.; Nilova, A.; Seidl, T. L.; Stuart, D. R. Angew.
55, 8431-8434. (l) Tao, Y.; Zhang, F.; Tang, C. Y.; Wu,
X. Y.; Sha, F. Asian J. Org. Chem. 2014 , 1292-1301. (m) Thangaraj, M.;
Bhojgude, S. S.; Jain, S. J. Org. Chem. 2016 81, 8604-8611. (n) Fang, Y. S.;
Larock, R. C.; Shi, F. Asian. J. Org. Chem. 2014 , 55-57. (o) Zeng, Y. W.;
Li, G. Y.; Hu, J. B. Angew. Chem., Int. Ed. 2015 54, 10773-10777.
Li, Y. M.; Mueck-Lichtenfeld, C.; Studer, A. Angew. Chem. Int. Ed. 2016
4435-14438.
Xu, H. D.; Cai, M. Q.; He, W. J. RSC Adv. 2014
Tan, J. J.; Zheng, T. Y.; Xu, K. Org. Biomol. Chem. 2017
0(a) Zheng, T.; Tan, J. J.; Fan, R.; Su, S.; Liu, B.; Tan, C.; Xu, K. Chem.
Commun. 2018 54, 1303-1306; (b) Chen, J. H.; Palani, V.; Hoye, T. R. J. Am.
Chem. Soc. 2016 138, 4318-4321.
1(a) He, L.; Pian, J. X.; Shi, J. F.; Du, G. F.; Dai, B. Tetrahedron. 2014
Chem., Int. Ed. 2016
,
,
3
,
,
3
,
7
, 55,
1
8
9
1
,
4, 7623-7626.
,
15, 4946-4950.
,
,
1
,
70
400-2405. (b) Pian, J. X.; He, L.; Du, G. F.; Guo, H.; Dai, B. J. Org. Chem.
014 79, 5820-5826. (c) Liu, K.; Liu, L. L.; Gu, C. Z.; Dai, B.; He, L. RSC
, 33606-33610. (d) Jian, H.; Liu, K.; Wang, W. H.; Li, Z. J.; Dai,
B.; He, L. Tetrahedron Lett. 2017 58, 1137-1141. (e) Zhang, J.; Liu, K.; Jian,
H.; Li, Z. J.; He, L. Tetrahedron Lett 2017 58, 2964-2968; (f) Cong, Z. S.; Li,
Y. G.; Du, G. F.; Gu, C. Z.; Dai, B.; He. L. Chem. Commun. 2017 53
3129-13132. (g) He, L.; Guo, H.; Li, Y. Z.; Du, G. F.; Dai, B. Chem.
,
2
2
,
Adv. 2016, 6
,
.
,
,
,
1
Commun. 2014
,
50, 3719-3721; (h) Cong, Z. S.; Li, Y. G.; Chen, L.; Xing, F.;
15, 3863-3868.
2Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983 12, 1211-1214.
3The m-insertion selectivity is in accordance with literature: Liu, Z.; Larock, R.
C. Org. Lett. 2003 , 4673-4675.
Du, G. F.; Gu, C. Z.; He, L. Org. Biomol. Chem. 2017
,
1
1
,
,
5
2
2

ACCEPTED MANUSCRIPT
14Nakayama, J.; Takeue, S.; Hoshino, M. Tetrahedron Lett. 1984, 25,
2
679-2682.
5 Leicht, H.; Goettker-Schnetmann, I.; Mecking, S. J. Am. Chem. Soc. 2017, 139,
823-6826.
6Su, T.; Xie, S. S.; Wei, H. Bio. Med. Chem. 2013
7Suzuki, K.; Jeong, J.; Yamaguchi, K. New J. Chem. 2016
8Kennedy, N.; Lu, G.; Liu, P.; Cohen, T. J. Org. Chem. 2015
Lee, T. V.; Naina, V. Tetrahedron Lett. 1984, 25, 5559-5560.
Osman, N. A.; Mahmoud, A. H.; Klein, C. D. Med. Chem. Commun. 2014, 5,
571-1576.
1Tamai, T.; Fujiwara, K.; Higashimae, S.; Nomoto, A.; Ogawa, A. Org. Lett.
016 18, 2114-2117.
2Kim, S.; Yeon, K. M.; Yoon, K. S. Tetrahedron Lett. 1997
1
6
1
1
1
1
2
,
21, 5830-5840.
40, 1014-1021.
80, 8571-8582.
,
,
,
9
0
1
2
2
2
,
,
38, 3919-3922.
2
3