A regio- and stereoselective entry to (Z)-β-halo alkenyl sulfides and their applications to access stereodefined trisubstituted alkenes

Article abstract of DOI:10.1039/c4ob00103f

A mild and efficient preparation of (Z)-β-halo alkenyl sulfides via the K₂CO₃-promoted hydrothiolation of haloalkynes has been realized, producing (Z)-β-bromo and (Z)-β-chloro vinylic sulfides in high yields with excellent regio- and

Full text of DOI:10.1039/c4ob00103f

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A regio- and stereoselective entry to (Z)-β-halo alkenyl sulfides and their
applications to the access of stereodefined trisubstituted alkenes
Ge Liu,† Lichun Kong,† Ji Shen, and Gangguo Zhu*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A mild and efficient preparation of (Z)-β-halo alkenyl sulfides via the K2CO3-promoted hydrothiolation of
haloalkynes has been realized, producing (Z)-β-bromo and (Z)-β-chloro vinylic sulfides in high yields
with excellent regio- and stereoselectivity. This approach covers a variety of substrates, including both
aryl and alkyl haloalkynes. Meaningfully, it allows a facile access to stereodefined (Z)- or (E)-
10 trisubstituted olefins featuring the iterative cross-coupling of carbon–halide and carbon–sulfur bonds of β-
halo alkenyl sulfides.
Introduction
Alkenyl sulfides are key components in the synthesis of
important building blocks, biologically active compounds, as
15 well as novel materials.1 Hydrothiolation of alkynes2 proves to be
access of (Z)-β-halo alkenyl sulfides remains to be explored.
On the other hand, trisubstituted alkenes are ubiquitous
structural motifs in organic chemistry, and consequently, it is
a straightforward and atom-economic method toward vinylic 50 highly desirable to develop new and expeditious approaches to
sulfides. Up to date, a number of methods have been developed,
including the base-mediated,3 radical4 and metal-catalyzed5
approaches. Most of these developments focus on the addition of
20 S–H bond to terminal alkynes, while less attention has been paid
these compounds.10 Along this line, transition-metal-catalyzed
iterative cross-coupling strategy11 has emerged as a powerful tool
for constructing polysubstituted alkenes. However, the stepwise
cross-coupling of 1,2-dihaloalkenes12 has only met limited
to the hydrothiolation of nonterminal acetylenes, presumably due 55 success, mainly because of the following facts: (1) only limited
to the challenge of controlling regio- and stereoselectivity in
these cases. As such, to expand the scope and synthetic utility of
this reaction, further exploration of hydrothiolation of internal
25 alkynes is worthwhile.
methods13,14 are available for assembling stereocontrolled 1,2-
dihaloalkenes A, especially thermodynamically unfavorable (Z)-
isomers or mixed 1,2-dihaloalkenes (X ≠ X’); (2) problems are
encountered in the selective mono-coupling of C–X bond. As a
A promising result came from Kataoka and co-workers,6 where 60 result, the desired product B is often messed with the double-
the
regio-
and
stereoselective
hydrothiolation
of
substituted sideproduct C, regioisomer D, or elimination12d,14e
byproduct E (Scheme 1). These undesired products can not only
dramatically lower the reaction yield but also hamper the
purification.
alkynylselenonium was achieved with catalytic amount of
triethylamine. In 2007, Yorimitsu and Oshima reported an
30 elegant Pd-catalyzed hydrothiolation of alkynylphosphines,
leading to (Z)-1-phosphino-2-thio-1-alkenes in good yields.7a
Later, the same group described the synthesis of (Z)-β-amino
vinylic sulfides via a regio- and stereoselective radical addition of
thiols to ynamides.7b Recently, Chen and Dou reported a very
35 effective entry to (Z)-β-bromo alkenyl sulfides via a TBAF-
mediated reaction between thiols and 1,1-dibromoalkenes,8 which
was proposed to proceed via the bromoalkyne intermediates
generated in situ. Indeed, it represents the first example on the
regio- and stereoselective hydrothiolation of haloalkynes. Despite
40 the obvious success, there are some limitations in this protocol:
(1) the reaction is not applicable for aryl 1,1-dibromoalkenes
because alkynyl sulfides rather than alkenyl sulfides were
obtained in this context,9 (2) (Z)-β-chloro vinylic sulfides can
neither be synthesized by this method; (3) the utilization of
45 excessive TBAF results in poor functional-group compatibility.
Therefore, the development of mild and general protocol for the
1) MLn, R2M'
X'
X
H
R3
R1
R2 R2
+
H
R2 R2
+
R3
2) MLn, R3M'
R1
H
+
traditional
R1
R1
H
R1
H
X, X' = halides
A
B
C
D
E
1) MLn, R2M'
2) MLn, R3M'
RS
R1
X
H
R3
R1
R2
H
RSH, K2CO3
EtOH, rt to 50 oC
R1
X
A'
B
a mild and general approach to A'
exclusive coupling of the C-X bond
this work:
inhibition of elimination side reaction
65
Scheme 1 The summary of this work.
To tackle these challenges, we reasoned that replacement of a
carbon–halide bond of A with carbon–sulfur bond, the less
reactive and more stable one towards transition-metal-catalyzed
70 reactions, might be able to realize the selective mono-coupling of
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Page 2 of 11
A’ as well as inhibition of the elimination side reaction. As such,
5, 11 and 12). As such, the optimized reaction conditions for
continuing on our interest in the functionalization of heteroatom- 25 hydrothiolation of haloalkynes consisted of 1.3 equiv of K2CO3,
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DOI: 10.1039/C4OB00103F
substituted alkynes,14,15 we describe here an operationally simple
and efficient method for the synthesis of (Z)-β-halo alkenyl
sulfides via the regio- and stereoselective hydrothiolation of
haloalkynes, ultimately resulting in a new entry to stereodefined
(Z)- or (E)-trisubstituted alkenes featuring the iterative cross-
coupling of C–X and C–S bonds of β-halo vinylic sulfides.
EtOH as the solvent, and room temperature for 10 h, which
provided 3aa in 82% isolated yield (Table 1, entry 5).
5
Table 1 Optimization of the reaction conditions for hydrothiolation of
haloalkynesa
PyS
Br
H
base
Br
+
solvent, rt
SH
TBSO
N
Results and discussion
TBSO
1a
2a
3aa
30
Entry
Base
Solvent
Yield (%)b
Z/Ec
10 To explore a mild and general access to (Z)-β-halo alkenyl
sulfides, we decided to employ the silyl-substituted bromoalkyne
1a as a model substrate for screening the reaction conditions. To
our delight, promoted by 1.3 equiv of K2CO3, the hydrothiolation
of 1a with 2a occurred smoothly in DMF to afford β-bromo
15 alkenyl sulfide 3aa in good yield with excellent regio- and
stereoselectivity, while no α-regioisomer was observed (Table 1,
entry 1). We believed that the induce effect of bromine atom may
be responsible for the regioselective β-addition of thiols. Of the
solvent, environmentally friendly EtOH worked the best and
20 nonpolar solvents such as toluene and Et2O only resulted in trace
of 3aa (Table 1, entries 1–10). Screening of the base revealed
that the readily available K2CO3 was the most effective, and
deprotection of the TBS group was not detected (Table 1, entries
1
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
/
DMF
DMSO
NMP
CH3CN
EtOH
MeOH
i-PrOH
THF
toluene
Et2O
73
95/5
96/4
97/3
98/2
>98/2
>98/2
>98/2
>98/2
/
2
83
3
4
5
6
7
8
9
10
11
12
13
68
75
82
80
61
52
trace
trace
68
/
EtOH
EtOH
EtOH
>98/2
>98/2
/
59
trace
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), base (0.65 mmol), rt,
10 h. b Combined isolated yield. c Determined by GC.
Table 2 Scope of hydrothiolation of alkynyl halidesa
R2S
R1
X
H
K2CO3
R1
X
+
R2SH
EtOH, rt
1
2
3
PyS
Br
H
PyS
Br
PyS
Br
PyS
PhO
Br
PyS
TBDPSO
Br
H
PyS
Br
H
H
BnO
H
H
n-C8H17
TBSO
BzO
3aa, 82%
PyS
Br
n-C4H9
3ga
3ea, 75%
3fa, 83%
3ba
3ca
3da
, 74%
, 81%
, 92%
Br
PyS
Br
PyS
HO
PyS
Br
H
PyS
Br
H
PyS
Br
H
H
H
H
Et
OH
Ph
Cl
b
3ka
3la
, 75%
, 73%
, 70%
3ha
3ia
, 61%
3ja
, 77%
, 88%
PyS
Br
PyS
O
Br
PyS
Cl
PyS
Cl
PyS
BnO
Cl
H
PyS
Br
H
Ph
3
Ph
H
n-C8H17
H
O
H
H
b
b
c
3ma, 70%
3na, 91%
3oa
3pa
3qa
, 81% (Z/E = 97:3)
, 79%
, 80%
b,c
PyS
Cl
N
N
N
3sb
R = 4-H,
, 83% (Z/E = 90:10)
S
Br
H
b,c
S
Br
3tb
R = 4-F,
, 82% (Z/E = 93:7)
H
N
b,c
3ub
, 81% (Z/E = 93:7)
R = 4-Me,
n-C8H17
H
b,c
3vb
R = 4-OMe,
, 80% (Z/E = 97:3)
R
b,c
c
b
3wb
R = 3,4-(OMe)2,
, 91% (Z/E = 97:3)
3ra
, 82% (Z/E = 95:5)
3fb
, 80%
Me
N
N
S
S
N
N
N
S
Br
H
S
Br
H
Br
H
Br
S
S
Br
H
HN
N
N
n-C8H17
n-C8H17
n-C8H17
H
n-C8H17
n-C8H17
3fg
, 70%
b
3fc
, 78%
3fd
3fe
, 80%
3ff
, 76%
, 85%
a
35 Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), K2CO3 (0.65 mmol), EtOH, rt, 10 h. Unless otherwise noted, 3 were obtained with >98% Z-
stereoselectivity. b Run at 50 °C. c Determined by GC.
Once the optimal reaction conditions were established, the
scope and limitations of this reaction were then investigated. As
2
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illustrated in Table 2, the hydrothiolation reaction was found to
might favor the addition rather than substitution of ethynyl
be quite effective over a wide range of alkynyl halides. Good
yields were obtained with substrates possessing a number of
conventional protecting groups, such as tert-butyldimethylsilyl
bromides. As such, 2-mercaptopyrimidine (2b) was employed as
a thiol reagent, and as expected, the hydrDotOhIi:o1l0a.t1i0o3n9/pCr4oOduBc0t0310s3bF
was isolated in 83% yield by treating phenylethynyl bromide (1s)
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5
(TBS), benzoyl (Bz), benzyl (Bn), and tert-butyldiphenylsilyl 35 with 2b, albeit in a somewhat lower stereoselectivity (Z/E =
(TBDPS). For example, bromoalkyne 1f led to the formation of
3fa in 83% yield with excellent regio- and stereoselectivity
(Table 2, 3fa). The sterically demanding substrate 3g also served
as a viable substrate, although a high temperature of 50 °C was
10 need for full conversion (Table 2, 3ga). Moreover, functional
groups such as halides, unprotected alcohols, alkenes, alkynes,
aryl and heteroaryl groups were well tolerated (Table 2, 3ia–ma).
For instance, 2a added to 1j and 1k in a highly regio- and
stereoselective manner and furnished 3ja and 3ka in satisfactory
15 yields (Table 2, 3ja and 3ka). Remarkably, the reaction of 1n
underwent smoothly to produce the double hydrothiolation
product 3na in an excellent yield (Table 2, 3na).
90:10) as compared to that of alkyl counterparts. Furthermore,
the reaction was applicable for other aryl bromoacetylenes,
providing (Z)-β-bromo vinylic sulfides in good yields and high
stereoselectivity (Table 2, 3sb–wb). In particular, 4-fluorophenyl
40 ethynylbromide (1t) coupled with 2b to give 81% of 3tb as a
93:7 mixture of Z/E isomers, while the reaction of 4-
methoxyphenyl and 3,4-dimethoxyphenyl substrates 1v and 1w
produced the desired (Z)-β-bromo vinylic sulfides 3vb and 3wb
in similar stereoselectivity (Z/E = 97:3), indicating that the
45 electronic effect of bromoalkynes has little influence on this
reaction. Unfortunately, the hydrothiolation of aryl chloroalkynes
only gave the corresponding products in synthetic useless
stereoselectivity even after a number of efforts.
Pleasingly, the reaction between alkynyl chloride 1o and 2a
occurred uneventfully forming (Z)-β-chloro olefinic sulfide 3oa
The scope of this reaction with respect to thiol nucleophiles
20 in 79% yield, albeit at elevated reaction temperature (50 °C) 50 proved to be satisfactory. Under the standard reaction conditions,
(Table 2, 3oa). Likewise, chloroalkynes 1p–r, possessing ether,
alkene, or alkyne substituents, all led to the desired products in
good yields and excellent stereoselectivity (Table 2, 3pa–ra). Of
note, this protocol represents a mild and effective protocol for the
not only 2b but also the bulky thiol 2c added to 1f regio- and
stereoselectively, providing 3fb and 3fc in good yields (Table 2,
3fb and 3fc). Other thiols bearing additional functionality
underwent the hydrothiolation reaction smoothly to generate the
25 regio- and stereoselective synthesis of (Z)-β-chloro vinyl 55 expected products in good yields with excellent stereoselectivity
sulfides.16
(Table 2, 3fd–fg). For example, the stereospecific addition of p-
toluenethiol (2e) to 3f furnished 3fe8 in 80% yield (Table 2, 3fe).
The regio- and stereochemistry of this reaction was determined
by the NOE measurements, and further confirmed by comparison
Then, we turned our attention to extend this reaction to aryl
bromoacetylenes, although it8,9 was reported that acetylenic
sulfides could be obtained by the treatment of aryl bromoalkynes
30 with thiols. We envisioned that using soft thiol nucleophiles 60 of the data of products 3fa and 3fe–g with the literature.8
Table 3 The selective mono-coupling of 3a
Entry
R1
R2
R3M/4
Yield (%)b
3
1
2
3
4
5
6
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
TBSO(CH2)2
PhOCH2
n-C8H17
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyrimidyl
2-pyrimidyl
2-pyrimidyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
PhB(OH)2/4a
PhB(OH)2/4a
PhB(OH)2/4a
PhB(OH)2/4a
PhB(OH)2/4a
PhB(OH)2/4a
PhB(OH)2/4a
PhB(OH)2/4a
90/5a
70/5b
83/5c
79/5d
76/5e
67/5f
72/5g
75/5h
76/5ic
70/5jd
75/5k
85/5l
3aa
3da
3fa
3ga
3ha
3ia
n-C4H9(CH)Et
Ph(CH2)2
Cl(CH2)3
2-cyclohexenyl
PhC≡CCH2OCH2
4-Me-C6H4
4-MeO-C6H4
3,4-(OMe)2-C6H3
TBSO(CH2)2
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
3la
3ma
3ub
3vb
3wb
3aa
3fa
3fa
3fa
3fa
3fa
3fa
3fa
3fa
3fa
3fa
3fa
3fa
PhB(OH)2/4a
PhB(OH)2/4a
PhB(OH)2/4a
4-Me-C6H4B(OH)2/4b
4-Me-C6H4B(OH)2/4b
3-Me-C6H4B(OH)2/4c
2-Me-C6H4B(OH)2/4d
4-MeO-C6H4B(OH)2/4e
4-F-C6H4B(OH)2/4f
4-CF3-C6H4B(OH)2/4g
2-naphthylB(OH)2/4h
2-thienylB(OH)2/4i
(E)-styrylB(OH)2/4j
MeB(OH)2/4k
80/5m
75/5n
84/5o
79/5p
82/5q
85/5r
68/5s
75/5t
76/5u
trace
n-C8H17
n-C8H17
n-C8H17
MeMgCl/4l
MeZnCl/4m
84/5ve
80/5ve
a Reaction conditions for the Suzuki coupling: 3 (0.5 mmol), 4 (0.65 mmol), Pd(dba)2 (0.025 mmol), XPhos (0.05 mmol), K2CO3 (0.75 mmol), toluene, 50
oC, 10 h. b Isolated yield. c Z/E = 93:7. d Z/E = 95:5. e The reaction was run with 5 mol% of Pd(PPh3)4 in THF at rt for 8 h.
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Next, the stepwise cross-coupling of (Z)-β-bromo alkenyl
sulfides was investigated. Treatment of 3aa with 5 mol%
Pd(dba)2, 10 mol% of PPh3, 1.5 equiv of K2CO3, and 1.3 equiv of
PhB(OH)2 in THF at 80 °C for 10 h furnished the Suzuki17
coupling product 5a in 62% yield, and the C–S bond was
completely intact under the reaction conditions. Utilizing toluene
instead of THF as the solvent resulted in a better yield (80%).
Finally, the evaluation of ligands revealed that Xphos18 was the
most effective ligand for this reaction, leading to 5a in 90% yield
10 (Table 3, entry 1). Therefore, running the reaction with 5 mol%
of Pd(dba)2, 10 mol% of Xphos, 1.5 equiv of K2CO3, and 1.3
equiv of PhB(OH)2 in toluene at 80 °C appeared to the optimized
reaction conditions for the Suzuki coupling of 3.
As demonstrated in Table 3, in general, the Suzuki coupling of
15 (Z)-β-bromo alkenyl sulfides 3 proceeded smoothly and provided
olefinic sulfides 5 in high yields. Various functional groups like
OTBS, OPh, F, Cl, Me, OMe, C–C double and triple bonds were
well tolerated under the reaction conditions. (Z)-β-Bromo vinylic
sulfide 3fa gave rise to 5c in 83% yield, while the reaction of 3ga
20 produced 5d in 79% yield (Table 3, entries 3 and 4), implying the
steric hindrance of 3 has no significant correlation with the yield.
On the other hand, the scope of this reaction with regard to
boronic acids was investigated. In this respect, 4-, 3-, and 2-
tolylboronic acids 4b–d reacted with 3fa to give the desired
25 products in respective yields of 80%, 75%, and 84%, which
indicated that the Suzuki coupling of 3 is not sensitive to steric
hindrance of boronic acids (Table 3, entries 14–16). Introducing
either electron-donating or electron-withdrawing groups into the
benzene ring of 4 did not significantly affect the reaction yield, as
30 demonstrated by the coupling of boronic acids 4e–g (Table 3,
entries 17–19). The reaction of heteroaryl boronic acid 4i took
place as well, forming the expected product 5t in 75% yield
(Table 3, entry 21). Additionally, the attempts to install a methyl
group into 5 with the use of MeB(OH)2 (4k) failed; fortunately,
35 the utilization of Kumada coupling19 with MeMgCl (4l) or
Negishi coupling20 with MeZnCl (4m) came to rescue, providing
the methylation product 5v in high yields (Table 3, entries 22–25).
The stereochemistry of alkenyl sulfides 5 was identified by NOE
measurements, and further confirmed by an X-ray diffraction
40 analysis of 5i (see ESI‡).
5
Table 4 Synthesis of trisubstituted alkenes via the Ni-catalyzed C–S bond couplinga
Entry
R1
R2
R3
R4M/4
Yield (%)b
5
1
2
3
4
5
6
7
8
TBSO(CH2)2
n-C8H17
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyrimidyl
2-pyrimidyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
2-pyridyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
MeMgCl/4l
MeMgCl/4l
MeMgCl/4l
MeMgCl/4l
MeMgCl/4l
MeMgCl/4l
MeMgCl/4l
MeMgCl/4l
MeMgCl/4l
MeMgCl/4l
MeMgCl/4l
MeMgCl/4l
MeMgCl/4l
MeMgCl/4l
MeMgCl/4l
MeMgCl/4l
80/6a
88/6b
trace
72/6c
79/6d
85/6ec
81/6f
78/6g
76/6h
72/6i
5a
5c
5d
5e
5g
5i
n-C4H9(CH)Et
Ph(CH2)2
2-cyclohexenyl
4-Me-C6H4
4-MeO-C6H4
TBSO(CH2)2
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
5j
5l
4-Me-C6H4
4-Me-C6H4
3-Me-C6H4
2-Me-C6H4
4-MeO-C6H4
4-F-C6H4
4-CF3-C6H4
2-naphthyl
2-thienyl
(E)-styryl
Ph
9
5m
5n
5o
5p
5q
5r
5s
5t
5u
5c
5c
5c
5c
5c
10
11
12
13
14
15
16
17
18
19
20
21
22
77/6j
77/6k
86/6lc
68/6m
81/6n
66/6od
80/6p
trace
MeMgCl/4l
EtMgCl/4n
PhMgCl/4o
4-Me-C6H4MgCl/4p
4-MeO-C6H4MgCl/4q
CH2=CHCH2MgBr/4r
Ph
Ph
Ph
Ph
69/6qe
75/6rf
67/6s
67/6t
n-C8H17
a Reaction conditions: 5 (0.25 mmol), 4 (0.50 mmol), Ni(PPh3)2Cl2 (0.025 mmol), THF, rt, 10 h. b Isolated yield. c E/Z = 93:7. d E/Z = 95:5. e Z/E = 97:3. f
Z/E = 91:9.
45
Finally, the elaboration of stereodefined trisubstituted alkenes 50 found that the steric hindrance of R1 group has a significant effect
was achieved by the Ni-catalyzed coupling of C–S bond21 with
Grignard reagents. In the presence of 10 mol% of Ni(PPh3)2Cl2,
5a underwent the coupling with 4l to generate the (E)-
trisubstituted alkene 6a in 80% yield (Table 4, entry 1). We
on the reaction. For example, the reaction of 5c resulted in 6b11e
in 88% yield, while the bulky substrate 5d was almost unreactive
(Table 4, entries 2 and 3). In contrast, 5m–o were converted into
the corresponding products in comparable yields, which
This journal is © The Royal Society of Chemistry [year]
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Organic & Biomolecular Chemistry
demonstrated the steric hindrance of R3 has little influence on the 55 MHz): δ –5.4, 18.2, 25.8, 40.7, 60.6, 113.4, 120.6, 123.5, 135.9,
coupling reaction (Table 4, entries 9–11). Gratifyingly, the
stereodefined 1,3-diene products could be assembled by this
protocol, as shown by the production of 6d and 6p (Table 4,
entries 5 and 17). It should be noted that 5b and 5h were not
136.9, 149.9, 156.9; MS (EI, m/z): 375 (2), 373 (M+, 3), 294
View Article Online
(M+–79Br, 38), 163 (13); HRMS (EI) calDcdOI:fo10r.1C01359H/C244BOrBN0O01S0S3iF
(M+) 373.0531, found 373.0535.
1
5
Compound 3ba. 134.3 mg, 74% yield, colorless oil; H NMR
amenable to this reaction, owing to the cleavage of allylic or 60 (CDCl3, 600 MHz): δ 2.94 (t, J = 6.2 Hz, 2H), 4.48 (t, J = 6.2 Hz,
propagylic C–O bond under the reaction conditions.
Furthermore, the Grignard reagents were varied with 5c acting
as the coupling partner. As a result, the utilization of EtMgCl (4n)
2H), 6.82 (s, 1H), 7.08–7.15 (m, 1H), 7.32 (d, J = 7.9 Hz, 1H),
7.46 (t, J = 7.7 Hz, 2H), 7.58 (qd, J = 7.7, 1.3 Hz, 2H), 8.02 (d, J
= 8.2 Hz, 2 H), 8.51 (d, J = 4.2 Hz, 1H); 13C NMR (CDCl3, 150
MHz): δ 36.7, 62.3, 113.6, 120.9, 123.7, 128.4, 129.5, 130.0,
10 instead of 4l only produced trace of the desired product because
of the occurrence of β-H elimination process (Table 4, entry 18). 65 133.0, 135.7, 136.8, 150.2, 156.3, 166.3; HRMS (ESI) calcd for
On the contrary, aryl Grignard reagents were found to be
effective coupling partners, for instance, the reaction of 5c with
PhMgCl (4o) provided (Z)-trisubstituted alkene 6q in good yield
15 with excellent stereoselectivity (Table 4, entry 19). In addition,
CH2=CHCH2MgBr (4r) also resulted in a reasonable yield of 6t
under the standard conditions (Table 4, entry 22).
C16H15BrNO2S (M+H)+ 364.0007, found 364.0006.
1
Compound 3ca. 135.7 mg, 81% yield, yellow oil; H NMR
(CDCl3, 400 MHz): δ 4.24 (s, 2H), 4.52 (s, 2H), 7.03–7.10 (m,
2H), 7.24–7.37 (m, 6H), 7.54 (td, J = 7.8, 1.7 Hz, 1H), 8.45 (d, J
70 = 4.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 72.0, 72.3, 114.7,
120.8, 123.3, 127.6, 127.7, 128.3, 135.7, 136.7, 137.5, 149.9,
156.3; HRMS (ESI) calcd for C15H15BrNOS (M+H)+ 336.0058,
found 336.0065.
Conclusions
1
Compound 3da. 147.7 mg, 92% yield, yellow oil; H NMR
In conclusion, we have developed an operationally simple and
20 efficient protocol for the synthesis of (Z)-β-halo alkenyl sulfides
via the K2CO3-promoted hydrothiolation of acetylenic halides
under the mild reaction conditions, providing (Z)-β-bromo and
(Z)-β-chloro alkenyl sulfides in high yields with good to excellent
stereoselectivity. Both aryl and alkyl haloalkynes are effective
25 substrates for this reaction. It constitutes a new advance in the
development of regiocontrolled hydrothiolation of nonterminal
alkynes. Notably, a new effective entry to stereodefined (Z)- or
(E)-trisubstituted olefins featuring the iterative cross-coupling the
C–X and C–S bonds of β-halo alkenyl sulfides has also been
30 realized in this report.
75 (CDCl3, 600 MHz): δ 4.80 (d, J = 1.5 Hz, 2H), 6.97 (d, J = 8.0
Hz, 2H), 7.00 (t, J = 7.4 Hz, 1H), 7.06–7.12 (m, 1H), 7.17 (t, J =
1.4 Hz, 1H), 7.30 (t, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 1H),
7.54–7.60 (m, 1H), 8.49 (d, J = 4.8 Hz, 1H); 13C NMR (CDCl3,
150 MHz): δ 70.1, 114.7, 115.5, 120.8, 121.3, 123.1, 129.4, 133.9,
80 136.8, 149.8, 155.9, 157.7; HRMS (ESI) calcd for C14H13BrNOS
(M+H)+ 321.9901, found 321.9907.
Compound 3ea. 181.1 mg, 75% yield, white solid, mp 89–91
°C; 1H NMR (CDCl3, 400 MHz): δ 1.08 (s, 9H), 4.37 (d, J = 1.6
Hz, 2H), 6.98–7.08 (m, 2H), 7.27 (t, J = 1.5 Hz, 1H), 7.34–7.50
85 (m, 7H), 7.65 (dd, J = 6.5, 1.3 Hz, 4H), 8.37 (d, J = 3.6 Hz, 1H);
13C NMR (CDCl3, 100 MHz): δ 19.2, 26.7, 66.8, 115.0, 120.4,
122.0, 127.7, 129.8, 132.7, 134.8, 135.4, 136.7, 149.8, 156.7;
HRMS (ESI) calcd for C24H27BrNOSSi (M+H)+ 484.0766, found
Experimental section
484.0767.
General
1
90
Compound 3fa.8 135.7 mg, 83% yield, yellow oil; H NMR
(400 MHz, CDCl3): δ 0.85 (t, J = 6.9 Hz, 3H), 1.16–1.28 (m,
10H), 1.43–1.53 (m, 2H), 2.41 (t, J = 7.4 Hz, 2H), 6.63 (s, 1H),
7.03–7.10 (m, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.55 (td, J = 7.9, 1.8
Hz, 1H), 8.47 (dd, J = 4.8, 0.9 Hz, 1H); 13C NMR (CDCl3, 100
Unless otherwise noted, materials obtained from commercial
suppliers were used without further purification. 1H and 13C
35 NMR spectra were measured on a 400 or 600 MHz NMR
spectrometers using CDCl3 as the solvent with tetramethylsilane
(TMS) as the internal standard. Chemical shifts were given in δ
relative to TMS, and the coupling constants were given in Hz.
Column chromatography was performed using silica gel (300–
40 400 mesh). High-resolution mass spectra (HRMS) analyses were
carried out using a TOF MS instrument with EI or ESI source.
95 MHz): δ 14.0, 22.6, 28.1, 28.7, 29.1, 29.1, 31.7, 37.4, 110.7,
120.7, 123.8, 136.7, 139.9, 150.0, 156.8.
1
Compound 3ga. 117.4 mg, 75% yield, yellow oil; H NMR
(CDCl3, 600 MHz): δ 0.81–0.94 (m, 6H), 1.18–1.29 (m, 4H),
1.42–1.58 (m, 4H), 2.31–2.38 (m, 1H), 6.80 (s, 1H), 7.00–7.06
100 (m, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.53 (td, J = 8.0, 1.6 Hz, 1H),
8.43 (d, J = 4.2 Hz, 1H); 13C NMR (CDCl3, 150 MHz): δ 11.6,
13.9, 22.5, 26.0, 29.3, 32.5, 50.7, 114.6, 120.0, 122.3, 136.4,
142.3, 149.5, 157.4; MS (EI, m/z): 315 (4), 313 (M+, 5), 234
(M+–79Br, 53), 177 (5); HRMS (EI) calcd for C14H20BrNS (M+)
105 313.0500, found 313.0502.
General procedure for K2CO3-promoted hydrothiolation of
haloalkynes
To a mixture of 2-mercaptopyridine (2a) (66.6 mg, 0.6 mmol)
45 and K2CO3 (89.7 mg, 0.65 mmol) in 2 mL of EtOH was added
bromoalkyne 1a (186.6 mg, 0.5 mmol). After stirring at room
temperature for 10 h, the reaction mixture was quenched with
water, extracted with EtOAc, dried over Na2SO4 and
concentrated. Column chromatography on silica gel (petroleum
50 ether/EtOAc = 20:1) gave 3aa as a yellow oil (152.9 mg, 82%
yield); 1H NMR (CDCl3, 400 MHz): δ 0.00 (s, 6H), 0.85 (s, 9H),
2.63 (t, J = 6.0 Hz, 2H), 3.72 (t, J = 6.1 Hz, 2H), 6.73 (s, 1H),
7.04–7.11 (m, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.56 (td, J = 7.8, 1.8
Hz, 1H), 8.47 (dd, J = 4.7, 0.8 Hz, 1H); 13C NMR (CDCl3, 100
1
Compound 3ha. 140.4 mg, 88% yield, yellow oil; H NMR
(CDCl3, 400 MHz): δ 2.71–2.79 (m, 2H), 2,80–2.87 (m, 2H),
6.58 (s, 1H), 7.07 (d, J = 8.0 Hz, 2H), 7.09–7.14 (m, 1H), 7.15–
7.21 (m, 1H), 7.21–7.28 (m, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.59
110 (td, J = 7.8, 1.6 Hz, 1H), 8.52 (d, J = 4.1 Hz, 1H); 13C NMR
(CDCl3, 100 MHz): δ 34.6, 39.2, 111.4, 120.9, 124.1, 126.1,
128.3, 136.8, 138.8, 140.5, 150.0, 156.4; MS (EI, m/z): 321 (6),
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

Organic & Biomolecular Chemistry
Page 6 of 11
1
319 (M+, 6), 241 (11), 240 (M+–79Br, 59), 162 (3); HRMS (EI)
calcd for C15H14BrNS (M+) 319.0030, found 319.0038.
Compound 3pa. 116.4 mg, 80% yield, yellow oil; H NMR
60 (CDCl3, 400 MHz): δ 4.26 (d, J = 1.3 Hz, 2H), 4.53 (s, 2H), 6.87
View Article Online
Compound 3ia. 88.8 mg, 61% yield, yellow oil; 1H NMR
(CDCl3, 600 MHz): δ 1.82–1.90 (m, 2H), 2.54 (t, J = 7.1 Hz,
2H ), 3.40 (t, J = 6.3 Hz, 2H), 6.63 (s, 1H), 6.98–7.04 (m, 1H),
7.19 (d, J = 7.4 Hz, 1H), 7.49 (td, J = 7.8, 1.8 Hz, 1H), 8.39 (d, J
(t, J = 1.3 Hz, 1H), 7.04–7.10 (m, 1H), 7.23–7.40 (m, 6H), 7.55
DOI: 10.1039/C4OB00103F
(td, J = 7.8, 1.9 Hz, 1H), 8.45 (d, J = 4.0 Hz, 1H); 13C NMR
(CDCl3, 100 MHz): δ 71.2, 72.3, 120.7, 123.2, 125.4, 127.7,
127.7, 128.4, 132.2, 136.7, 137.5, 149.9, 156.4; HRMS (ESI)
5
= 4.8 Hz, 1H); 13C NMR (CDCl3, 150 MHz): δ 30.4, 34.0, 43.6, 65 calcd for C15H15ClNOS (M+H)+ 292.0563, found 292.0560.
111.9, 120.9, 124.0, 136.9, 138.0, 150.0, 156.0; MS (EI, m/z):
Compound 3qa. 127.6 mg, 81% yield, yellow oil, Z/E = 97:3;
1H NMR (CDCl3, 600 MHz): δ 4.41 (s, 2H), 4.42 (s, 2H), 6.93 (s,
1H), 7.03–7.09 (m, 1H), 7.29–7.38 (m, 4H), 7.42 (dd, J = 7.8, 1.6
Hz, 2H), 7.55 (td, J = 7.8, 1.8 Hz, 1H), 8.47 (d, J = 4.5 Hz, 1H);
293 (6), 291 (M+, 7), 214 (37), 212 (M+–79Br, 100), 148 (20);
10 HRMS (EI) calcd for C10H11BrClNS (M+) 290.9484, found
290.9479.
Compound 3ja. 120.5 mg, 77% yield, white solid, mp 114– 70 13C NMR (CDCl3, 150 MHz): δ 58.1, 70.6, 84.3, 86.8, 120.7,
116 °C; 1H NMR (CDCl3, 400 MHz): δ 1.18–1.30 (m, 1H), 1.46–
1.61 (m, 3H), 1.62–1.78 (m, 4H), 1.79–1.88 (m, 2H), 5.29 (br,
15 1H), 6.97–7.05 (m, 1H), 7.26–7.33 (m, 2H), 7.52 (td, J = 7.8, 1.7
Hz, 1H), 8.31 (d, J = 4.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
122.3, 123.3, 125.9, 128.2, 128.5, 131.7, 131.8, 136.8, 150.0,
156.3; HRMS (ESI) calcd for C17H15ClNOS (M+H)+ 316.0563,
found 316.0564.
Compound 3ra. 102.9 mg, 82% yield, yellow oil, Z/E = 95:5;
δ 22.0, 25.4, 36.9, 74.9, 120.3, 120.8, 122.4, 136.8, 144.9, 149.1, 75 1H NMR (CDCl3, 400 MHz): δ 1.45–1.54 (m, 2H), 1.55–1.65 (m,
158.2; HRMS (ESI) calcd for C13H17BrNOS (M+H)+ 314.0214,
found 314.0204.
2H), 2.00–2.09 (m, 2H), 2.15–2.24 (m, 2H), 6.36 (t, J = 4.1 Hz,
1H), 6.71 (s, 1H), 6.95–7.04 (m, 2H), 7.48 (td, J = 7.9, 1.9 Hz,
1H), 8.39 (dd, J = 4.8, 0.9 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
δ 21.7, 22.4, 25.8, 26.8, 119.9, 121.7, 123.0, 130.6, 133.7, 136.4,
20
Compound 3ka. 94.5 mg, 73% yield, yellow oil; 1H NMR
(CDCl3, 400 MHz): δ 2.63 (t, J = 4.9 Hz, 2H), 3.78–3.86 (m, 2H),
4.50 (br, 1H), 6.93 (s, 1H), 7.03–7.09 (m, 1H), 7.35 (d, J = 8.0 80 137.4, 149.4, 158.5; MS (EI, m/z): 255 (1), 253 (4), 251 (M+, 6),
Hz, 1H), 7.57 (td, J = 8.0, 1.8 Hz, 1H), 8.34 (d, J = 4.9 Hz, 1H);
13C NMR (CDCl3, 100 MHz): δ 42.9, 58.6, 117.8, 120.7, 124.0,
216 (M+–35Cl, 100), 173 (19); HRMS (EI) calcd for C13H14ClNS
(M+) 251.0535, found 251.0538.
25 135.6, 137.0, 149.6, 157.6; MS (EI, m/z): 261 (3), 259 (M+, 4),
180 (M+–79Br, 100), 163 (20); HRMS (EI) calcd for
C9H10BrNOS (M+) 258.9666, found 258.9670.
Compound 3sb. 121.2 mg, 83% yield, yellow oil, Z/E = 90:10;
1H NMR (CDCl3, 600 MHz): δ 6.93 (t, J = 4.8 Hz, 1H), 7.15 (s,
85 1H), 7.27–7.31 (m, 3H), 7.58–7.63 (m, 2H), 8.42 (d, J = 4.8 Hz,
2H); 13C NMR (CDCl3, 150 MHz): δ 115.6, 117.2, 127.3, 128.3,
128.4, 138.4, 138.9, 157.4, 170.0; MS (EI, m/z): 294 (11), 292
(M+, 13), 215 (16), 213 (100), 212 (2); HRMS (EI) calcd for
C12H9BrN2S (M+) 291.9670, found 291.9673.
1
Compound 3la. 103.3 mg, 70% yield, yellow oil; H NMR
(CDCl3, 600 MHz): δ 1.46–1.55 (m, 2H), 1.56–1.64 (m, 2H),
30 2.00–2.07 (m, 2H), 2.18–2.26 (m, 2H), 6.39 (t, J = 4.0 Hz, 1H),
6.93 (s, 1H), 6.99–7.08 (m, 2H), 7.51 (td, J = 7.9, 1.8 Hz, 1H),
8.43 (d, J = 4.0 Hz, 1H); 13C NMR (CDCl3, 150 MHz): δ 21.7,
22.5, 25.8, 27.0, 113.1, 120.0, 122.1, 130.9, 134.8, 136.5, 140.8,
149.4, 158.4; MS (EI, m/z): 297 (5), 295 (M+, 7), 217 (18), 216
35 (M+–79Br, 100), 214 (5); HRMS (EI) calcd for C13H14BrNS (M+)
295.0030, found 295.0031.
90
Compound 3tb. 127.1 mg, 82% yield, yellow oil, Z/E = 93:7,
mp 64–66 oC; 1H NMR (CDCl3, 400 MHz): δ 6.90–6.99 (m, 3H),
7.06 (s, 1H), 7.52–7.58 (m, 2H), 8.40 (d, J = 4.8 Hz, 2H); 13C
NMR (CDCl3, 100 MHz): δ 115.2 (d, J = 21.5 Hz), 117.2, 129.1
(d, J = 8.2 Hz), 135.1 (d, J = 3.1 Hz), 137.4, 144.6, 157.5, 162.6
1
Compound 3ma. 125.7 mg, 70% yield, yellow oil; H NMR
95 (d, J = 247 Hz), 169.8; MS (EI, m/z): 311 (8), 310 (M+, 9), 233
(15), 231 (100), 199 (2); HRMS (EI) calcd for C12H8BrFN2S (M+)
309.9576, found 309.9581.
(CDCl3, 600 MHz): δ 4.38 (s, 2H), 4.41 (s, 2H), 7.03–7.09 (m,
1H), 7.12 (s, 1H), 7.26–7.38 (m, 4H), 7.41 (d, J = 6.5 Hz, 2H),
40 7.54 (td, J = 7.8, 1.3 Hz, 1H), 8.46 (d, J = 4.2 Hz, 1H); 13C NMR
(CDCl3, 150 MHz): δ 58.1, 71.3, 84.3, 86.7, 115.3, 120.7, 122.2,
Compound 3ub. 123.9 mg, 81% yield, yellow oil, Z/E = 93:7,
o
1
mp 79–81 C; H NMR (CDCl3, 400 MHz): δ 2.30 (s, 3H), 6.91
123.4, 128.2, 128.5, 131.6, 135.2, 136.8, 149.9, 156.1; HRMS 100 (t, J = 4.9 Hz, 1H), 7.08 (s, 1H), 7.10 (s, 2H), 7.49 (d, J = 8.2 Hz,
(ESI) calcd for C17H15BrNOS (M+H)+ 360.0058, found 360.0058.
2H), 8.41 (d, J = 4.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ
21.1, 114.9, 117.1, 127.2, 129.0, 136.1, 138.2, 138.4, 157.4,
170.2; MS (EI, m/z): 308 (4), 306 (M+, 4), 227 (69), 226 (3), 147
(21); HRMS (EI) calcd for C13H11BrN2S (M+) 305.9826, found
Compound 3na. 220.2 mg, 91% yield, white solid, mp 124–
1
45 126 °C; H NMR (CDCl3, 600 MHz): δ 1.38–1.46 (m, 4H), 2.37
(t, J = 6.1 Hz, 4H), 6.58 (s, 2H), 7.03–7.12 (m, 2H), 7.23 (d, J =
8.0 Hz, 2H), 7.56 (td, J = 7.8, 1.8 Hz, 2H), 8.46 (d, J = 4.0 Hz, 105 305.9828.
2H); 13C NMR (CDCl3, 150 MHz): δ 27.1, 36.8, 110.9, 120.7,
123.8, 136.7, 139.3, 149.9, 156.4; HRMS (ESI) calcd for
50 C18H19Br2N2S2 (M+H)+ 484.9356, found 484.9354.
Compound 3vb. 128.8 mg, 80% yield, yellow oil, Z/E = 97:3,
mp 90–92 oC; 1H NMR (CDCl3, 400 MHz): δ 3.75 (s, 3H), 6.74–
6.81 (m, 2H), 6.90 (t, J = 4.8 Hz, 1H), 7.02 (s, 1H), 7.46–7.53 (m,
2H), 8.39 (d, J = 4.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ
1
Compound 3oa. 111.8 mg, 79% yield, yellow oil; H NMR
(CDCl3, 600 MHz): δ 0.86 (t, J = 7.0 Hz, 3H), 1.16–1.30 (m, 110 55.1, 113.6, 113.8, 117.1, 128.6, 131.3, 137.7, 157.4, 159.7,
10H), 1.43–1.57 (m, 2H), 2,40 (t, J = 5.8 Hz, 2H), 6.43–6.50 (m,
1H), 7.01–7.13 (m, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.51–7.60 (m,
55 1H), 8.47 (d, J = 4.6 Hz, 1H); 13C NMR (CDCl3, 150 MHz): δ
14.0, 22.5, 28.0, 28.7, 29.0, 29.1, 31.7, 36.1, 120.5, 121.5, 123.4,
170.1; MS (EI, m/z): 323 (11), 322 (M+, 10), 243 (100), 242 (8),
212 (9); HRMS (EI) calcd for C13H11BrN2OS (M+) 321.9775,
found 321.9769.
Compound 3wb. 160.2 mg, 91% yield, yellow oil, Z/E = 97:3,
o
1
136.3, 136.6, 149.9, 156.8; HRMS (ESI) calcd for C15H23ClNS 115 mp 104–106 C; H NMR (CDCl3, 400 MHz): δ 3.79 (d, J = 2.6
(M+H)+ 284.1240, found 284.1242.
Hz, 6H), 6.71 (d, J = 8.4 Hz, 1H), 6.88 (t, J = 4.8 Hz, 1H), 7.00
6
| Journal Name, [year], [vol], 00–00
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Organic & Biomolecular Chemistry
(s, 1H), 7.07 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 8.4, 2.1 Hz, 1H),
1H), 7.56 (d, J = 7.5 Hz, 2H), 8.45 (d, J = 4.3 Hz, 1H); 13C NMR
8.37 (d, J = 4.9 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 55.6, 60 (CDCl3, 100 MHz): δ –5.4, 18.2, 25.8, 42.7, 61.5, 120.0, 122.6,
55.7, 110.3, 110.5, 113.6, 117.1, 120.1, 131.6, 138.0, 148.4,
149.1, 157.3, 170.0; HRMS (ESI) calcd for C14H14BrN2O2S
(M+H)+ 352.9959, found 352.9955.
127.5, 127.9, 129.0, 129.1, 136.2, 136.5, 138.2, 149V.7ie,w1A5r8tic.8le;OMnliSne
DOI: 10.1039/C4OB00103F
(EI, m/z): 371 (M+, 6), 256 (3), 240 (2), 226 (60); HRMS (EI)
5
calcd for C21H29NOSSi (M+) 371.1739, found 371.1742.
Compound 3fb. 131.2 mg, 80% yield, yellow solid, mp 40–41
Compound 5b. 111.7 mg, 70% yield, yellow oil, mp 113–115
1
1
°C; H NMR (CDCl3, 400 MHz): δ 0.84 (t, J = 6.8 Hz, 3H), 65 oC; H NMR (CDCl3, 600 MHz): δ 4.87 (d, J = 1.5 Hz, 2H),
1.19–1.28 (m, 10H), 1.49–1.58 (m, 2H), 2.57 (t, J = 7.5 Hz, 2H),
6.73 (s, 1H), 6.99 (t, J = 4.8 Hz, 1H), 8.51 (d, J = 4.9 Hz, 2H);
6.98–7.03 (m, 1H), 7.04–7.09 (m, 3H), 7.28–7.37 (m, 6H), 7.47
(s, 1H), 7.55 (td, J = 7.8, 1.9 Hz, 1H), 7.65 (d, J = 7.4 Hz, 2H),
8.55 (ddd, J = 4.9, 1.8, 0.8 Hz, 1H); 13C NMR (CDCl3, 150
MHz): δ 71.4, 115.0, 120.3, 121.1, 122.3, 126.6, 128.0, 128.2,
10 13C NMR (CDCl3, 100 MHz): δ 14.0, 22.5, 28.0, 28.8, 29.0, 29.1,
31.7, 37.8, 113.5, 117.0, 138.5, 157.5, 170.7; MS (EI, m/z): 329
(3), 328 (M+, 3), 249 (M+–79Br, 100), 150 (33), 149 (6); HRMS 70 129.4, 129.4, 135.4, 136.8, 137.2, 149.9, 158.2, 158.3; HRMS
(EI) calcd for C14H21BrN2S (M+) 328.0609, found 328.0608.
(ESI) calcd for C20H18NOS (M+H)+ 320.1109, found 320.1110.
Compound 5c. 134.9 mg, 83% yield, yellow oil; 1H NMR
(CDCl3, 400 MHz): δ 0.88 (t, J = 6.6 Hz, 3H), 1,15–1.27 (m,
10H), 1.56–1.70 (m, 2H), 2.49 (t, J = 7.5 Hz, 2H), 6.96–7.04 (m,
75 2H), 7.17–7.25 (m, 2H), 7.29 (dd, J = 13.9, 6.3 Hz, 2H), 7.50 (td,
J = 7.8, 1.7 Hz, 1H), 7.55 (d, J = 7.5 Hz, 2H), 8.46 (d, J = 4.7 Hz,
1H); 13C NMR (CDCl3, 100 MHz): δ 14.1, 22.6, 28.8, 28.9, 29.2,
29.3, 31.8, 39.5, 120.0, 122.7, 127.4, 127.9, 129.2, 133.3, 135.8,
136.4, 136.4, 149.9, 158.9; MS (EI, m/z): 325 (M+, 2), 248 (8),
80 226 (67), 212 (33), ; HRMS (EI) calcd for C21H27NS (M+)
325.1864, found 325.1854.
1
Compound 3fc. 138.8 mg, 78% yield, yellow oil; H NMR
15 (CDCl3, 400 MHz): δ 0.84 (t, J = 6.9 Hz, 3H), 1.19–1.29 (m,
10H), 1.47–1.56 (m, 2H), 2.37 (s, 6H), 2.61 (t, J = 7.5 Hz, 2H),
6.61 (s, 1H), 6.71 (s, 1H); 13C NMR (CDCl3, 100 MHz): δ 14.0,
22.5, 23.8, 28.1, 28.8, 29.1, 29.2, 31.7, 37.4, 111.6, 116.2, 139.1,
167.3, 169.3; HRMS (ESI) calcd for C16H26BrN2S (M+H)+
20 357.1000, found 357.1004.
1
Compound 3fd. 140.3 mg, 85% yield, yellow oil; H NMR
(CDCl3, 600 MHz): δ 0.83 (t, J = 7.2 Hz, 3H), 1.08–1.26 (m,
10H), 1.33–1.39 (m, 2H), 1.93 (t, J = 7.6 Hz, 2H), 3.66 (s, 3H),
6.19 (s, 1H), 7.05 (s, 1H), 7.10 (s, 1H); 13C NMR (CDCl3, 150
25 MHz): δ 14.0, 22.4, 27.6, 28.5, 28.9, 28.9, 31.6, 33.8, 36.0, 102.3,
123.7, 129.9, 136.1, 141.1; MS (EI, m/z): 331 (1), 330 (M+, 1),
1
Compound 5d. 122.8 mg, 79% yield, yellow oil; H NMR
(CDCl3, 600 MHz): δ 0.90 (t, J = 7.0 Hz, 3H), 0.95 (t, J = 7.4 Hz,
3H), 1.28–1.37 (m, 4H), 1.54–1.72 (m, 4H), 2.32–2.40 (m, 1H),
249 (2), 151 (3), 114 (100); HRMS (EI) calcd for C14H23BrN2S 85 6.92–6.97 (m, 1H), 6.99 (s, 1H), 7.14–7.20 (m, 2H), 7.24 (t, J =
(M+) 330.0765, found 330.0767.
7.5 Hz, 2H), 7.37–7.41 (m, 1H), 7.62 (d, J = 7.6 Hz, 2H), 8.40
(ddd, J = 4.9, 1.8, 0.8 Hz, 1H); 13C NMR (CDCl3, 150 MHz): δ
11.7, 14.0, 22.8, 26.4, 29.5, 32.9, 51.6, 119.6, 122.0, 127.4, 127.9,
129.1, 135.9, 136.0, 136.2, 136.3, 149.2, 159.2; MS (EI, m/z):
1
Compound 3fe.8 136.0 mg, 80% yield, yellow oil; H NMR
30 (CDCl3, 600 MHz): δ 0.91 (t, J = 7.2 Hz, 3H), 1.13–1.34 (m,
10H), 1.36–1.44 (m, 2H), 2.11 (t, J = 7.4 Hz, 2H), 2.36 (s, 3H),
6.24 (s, 1H), 7.17 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H); 90 311 (M+, 4), 282 (48), 234 (24), 112 (100); HRMS (EI) calcd for
13C NMR (CDCl3, 150 MHz): δ 14.1, 21.1, 22.6, 28.1, 28.6, 29.0,
C20H25NS (M+) 311.1708, found 311.1706.
29.1, 31.7, 35.8, 102.2, 128.0, 129.7, 133.7, 138.2, 142.9.
Compound 5e. 120.5 mg, 76% yield, yellow oil; 1H NMR
(CDCl3, 600 MHz): δ 2.85 (t, J = 8.0 Hz, 2H), 3.02 (t, J = 7.0 Hz,
2H), 6.95 (s, 1H), 7.04–7.10 (m, 1H), 7.17–7.25 (m, 3H), 7.26–
1
35
Compound 3ff.8 145.5 mg, 76% yield, yellow oil; H NMR
(CDCl3, 400 MHz): δ 0.86 (t, J = 6.9 Hz, 3H), 1.19–1.29 (m,
10H), 1.51–1.59 (m, 2H), 2.54 (t, J = 7.5 Hz, 2H), 6.74 (s, 1H), 95 7.36 (m, 6H), 7.50–7.60 (m, 3H), 8.53 (dd, J = 4.9, 0.8 Hz, 1H);
7.35 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.78 (d, J = 8.0
Hz,1H), 7.96 (d, J = 8.1 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
40 δ 14.0, 22.5, 28.1, 28.6, 29.0, 29.1, 31.7, 37.7, 112.9, 120.9,
13C NMR (CDCl3, 150 MHz): δ 35.1, 41.3, 120.1, 122.9, 125.9,
127.5, 127.9, 128.2, 128.5, 129.1, 131.9, 136.2, 136.6, 136.7,
141.2, 149.8, 158.6; MS (EI, m/z): 317 (M+, 3), 240 (3), 226
(100), 149 (5); HRMS (EI) calcd for C21H19NS (M+) 317.1238,
122.3, 124.9, 126.2, 136.1, 139.2, 153.5, 163.0.
1
Compound 3fg.8 111.0 mg, 70% yield, yellow oil; H NMR 100 found 317.1242.
(CDCl3, 600 MHz): δ 0.85 (t, J = 5.6 Hz, 3H), 1.14–1.28 (m,
10H), 1.42–1.52 (m, 2H), 2.23 (t, J = 6.5 Hz, 2H), 6.36 (s, 1H),
45 8.44 (s, 1H), 12.42 (br, 1H); 13C NMR (CDCl3, 150 MHz): δ 14.0,
22.5, 27.8, 28.6, 29.0, 29.1, 31.7, 36.6, 106.0, 139.3, 146.4, 153.5.
Compound 5f. 96.8 mg, 67% yield, yellow oil; 1H NMR
(CDCl3, 600 MHz): δ 2.08–2.17 (m, 2H), 2,71 (t, J = 7.2 Hz, 2H),
3.59 (t, J = 6.4 Hz, 2H), 7.04–7.09 (m, 1H), 7.10 (s, 1H), 7.23–
7.30 (m, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.52–7.60 (m, 3H), 8.49
105 (dd, J = 4.9, 1.0 Hz, 1H); 13C NMR (CDCl3, 150 MHz): δ 31.1,
36.2, 44.0, 120.3, 123.0, 127.7, 128.0, 129.2, 131.0, 135.9, 136.8,
137.2, 149.7, 158.1; MS (EI, m/z): 291 (1), 289 (M+, 2), 254 (1),
226 (23), 212 (12); HRMS (EI) calcd for C16H16ClNS (M+)
289.0692, found 289.0697.
General procedure for the Suzuki coupling of 3
To a mixture of PhB(OH)2 (97.3 mg 0.65 mmol), Pd(dba)2 (14.3
mg, 0.025 mmol), XPhos (23.8 mg, 0.05 mmol), and K2CO3
50 (103.5 mg, 0.75 mmol) in 2 mL of toluene was added 3aa (186.5
mg, 0.5 mmol) under nitrogen atmosphere. The resulting mixture
was stirred at 80 °C overnight (around 10 h), then quenched with
water, extracted with EtOAc, dried over Na2SO4 and
concentrated. Column chromatography on silica gel (petroleum
55 ether/EtOAc = 15:1) gave 5a as a colorless oil (167.0 mg, 90%
yield); 1H NMR (CDCl3, 400 MHz): δ 0.05 (s, 6H), 0.90 (s, 9H),
2.71 (t, J = 6.2 Hz, 2H), 3.88 (t, J = 6.3 Hz, 2H), 6.96–7.03 (m,
1H), 7.08 (s, 1H), 7.19–7.33 (m, 4H), 7.49 (td, J = 7.9, 1.8 Hz,
110
Compound 5g. 105.5 mg, 72% yield, yellow oil; 1H NMR
(CDCl3, 600 MHz): δ 1.55–1.63 (m, 2H), 1.68–1.76 (m, 2H),
2.11–2.17 (m, 2H), 2.40–2.47 (m, 2H), 6.56 (t, J = 3.8 Hz, 1H),
6.95–7.01 (m, 1H), 7.08 (d, J = 8.1 Hz, 1H), 7.18–7.26 (m, 2H),
7.30 (t, J = 7.6 Hz, 2H), 7.42–7.49 (m, 1H), 7.62 (d, J = 7.6 Hz,
115 2H), 8.42 (d, J = 4.0 Hz, 1H); 13C NMR (CDCl3, 150 MHz): δ
22.0, 22.9, 26.0, 27.3, 119.5, 121.4, 127.5, 127.9, 128.3, 128.9,
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 7

Organic & Biomolecular Chemistry
Page 8 of 11
129.6, 129.9, 133.8, 136.4, 136.6, 149.2, 160.6; MS (EI, m/z):
385.1892.
1
293 (M+, 8), 260 (25), 216 (82), 112 (100); HRMS (EI) calcd for
C19H19NS (M+) 293.1238, found 293.1236.
60
Compound 5m. 135.6 mg, 80% yield, yellow oil; H NMR
(CDCl3, 400 MHz): δ 0.89 (t, J = 6.9 Hz, 3H), 1.2V2i–ew1.A3rt4icle(mOn,line
DOI: 10.1039/C4OB00103F
1
Compound 5h. 133.9 mg, 75% yield, yellow oil; H NMR
10H), 1.59–1.69 (m, 2H), 2.32 (s, 3H), 2.50 (t, J = 7.3 Hz, 2H),
6.97–7.05 (m, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz,
1H), 7.44–7.54 (m, 3H), 8.47 (dd, J = 4.9, 1.0 Hz, 1H); 13C NMR
5
(CDCl3, 600 MHz): δ 4.48 (d, J = 1.3 Hz, 2H), 4.51 (s, 2H), 7.02
(ddd, J = 7.4, 4.9, 0.9 Hz, 1H), 7.28–7.37 (m, 7H), 7.41–7.46 (m,
3H), 7.50 (td, J = 7.8, 1.9 Hz, 1H), 7.66 (d, J = 7.3 Hz, 2H), 8.47 65 (CDCl3, 100 MHz): δ 14.0, 21.2, 22.6, 28.8, 28.9, 29.1, 29.3, 31.8,
(ddd, J = 4.8, 1.8, 0.8 Hz, 1H); 13C NMR (CDCl3, 150 MHz): δ
58.1, 73.1, 84.8, 86.5, 120.2, 122.5, 127.8, 128.0, 128.1, 128.2,
39.5, 119.8, 122.5, 128.6, 129.1, 132.1, 133.5, 136.0, 136.4,
137.3, 149.7, 159.1; MS (EI, m/z): 339 (M+, 3), 248 (10), 240
(85), 226 (30); HRMS (EI) calcd for C22H29NS (M+) 339.2021,
found 339.2028.
10 128.4, 129.4, 131.7, 135.5, 136.6, 137.3, 149.9, 158.2; HRMS
(ESI) calcd for C23H20NOS (M+H)+ 358.1266, found 358.1263.
Compound 5i. 115.5 mg, 76% yield, white solid, Z/E = 93:7,
1
70
Compound 5n. 127.1 mg, 75% yield, yellow oil; H NMR
o
1
mp 136–138 C; H NMR (CDCl3, 400 MHz): δ 2.35 (s, 3H),
6.87 (t, J = 4.8 Hz, 1H), 7.14 (d, J = 8.1 Hz, 2H), 7.23–7.29 (m,
15 1H), 7.30–7.40 (m, 3H), 7.64–7.72 (m, 4H), 8.40 (d, J = 4.8 Hz,
2H); 13C NMR (CDCl3, 100 MHz): δ 21.1, 116.9, 127.2, 127.9,
(CDCl3, 400 MHz): δ 0.90 (t, J = 6.6 Hz, 3H), 1.23–1.34 (m,
10H), 1.61–1.67 (m, 2H), 2.32 (s, 3H), 2.50 (t, J = 7.5 Hz, 2H),
6.94–7.10 (m, 3H), 7.15–7.25 (m, 2H), 7.35 (s, 1H), 7.40 (d, J =
7.7 Hz, 1H), 7.49 (td, J = 7.8, 1.7 Hz, 1H), 8.46 (d, J = 4.2 Hz,
128.0, 128.9, 129.5, 131.1, 136.6, 137.1, 137.7, 138.8, 157.4, 75 1H); 13C NMR (CDCl3, 100 MHz): δ 14.0, 21.3, 22.6, 28.8, 28.9,
171.6; MS (EI, m/z): 304 (M+, 8), 225 (3), 213 (14), 193 (18);
HRMS (EI) calcd for C19H16N2S (M+) 304.1034, found 304.1033.
Crystal data for 5i (C19H16N2S, 304.66): triclinic, space group
P1, a = 11.0704(14) Å, b = 22.732(3) Å, c = 17.8836(17) Å, U =
13.0490(17) Å3, Z = 1, T = 296(2) K, absorption coefficient 0.201
mm-1, reflections collected 27224, independent reflections 13018
[R(int) = 0.0826], refinement by full-matrix least-squares on F2,
29.1, 29.3, 31.8, 39.4, 119.9, 122.7, 126.1, 127.8, 128.2, 129.9,
133.0, 135.8, 136.2, 136.4, 137.3, 149.7, 158.9; MS (EI, m/z):
339 (M+, 3), 248 (22), 226 (43), 111 (100); HRMS (EI) calcd for
C22H29NS (M+) 339.2021, found 339.2019.
20
80
Compound 5o. 142.4 mg, 84% yield, yellow oil; 1H NMR
(CDCl3, 400 MHz): δ 0.89 (t, J = 6.6 Hz, 3H), 1.20–1.34 (m,
10H), 1.60–1.70 (m, 2H), 2.31 (s, 3H), 2.54 (t, J = 7.3 Hz, 2H),
6.98–7.04 (m, 2H), 7.08–7.18 (m, 3H), 7.20 (d, J = 8.0 Hz, 1H),
7.39 (d, J = 7.2 Hz, 1H), 7.50 (td, J = 7.8, 1.9 Hz, 1H), 8.47 (dd,
25 data/restraints/parameters 13018/1/793, goodness-of-fit on F2 =
0.913, final R indices [I>2σ(I)] R1 = 0.0785, wR2 = 0.1706, R
indices (all data) R1 = 0.2186, wR2 = 0.2387, largest diff peak and
hole 0.806 and –0.282 e.Å-3. Crystallographic data for the
structure 5i have been deposited with the Cambridge
30 Crystallographic Data Centre as supplementary publication no.
CCDC 981003.
85 J = 4.9, 1.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 14.1, 20.0,
22.6, 28.6, 28.9, 29.2, 29.3, 31.8, 38.3, 119.8, 123.0, 125.2, 127.5,
129.1, 129.5, 134.6, 134.9, 136.1, 136.1, 136.2, 149.8, 159.2; MS
(EI, m/z): 339 (M+, 4), 248 (23), 240 (100), 226 (38); HRMS (EI)
calcd for C22H29NS (M+) 339.2021, found 339.2023.
Compound 5j. 112.0 mg, 70% yield, yellow solid, Z/E = 95:5,
90
Compound 5p. 140.2 mg, 79% yield, yellow oil; 1H NMR
(CDCl3, 400 MHz): δ 0.88 (t, J = 6.8 Hz, 3H), 1.22–1.30 (m,
10H), 1.57–1.67 (m, 2H), 2.47 (t, J = 7.3 Hz, 2H), 3.78 (s, 3H),
6.78–6.88 (m, 2H), 6.95 (s, 1H), 7.00 (ddd, J = 7.4, 4.9, 0.9 Hz,
1H), 7.21 (d, J = 8.0 Hz, 1H), 7.49 (td, J = 7.8, 1.9 Hz, 1H), 7.55
o
1
mp 107–109 C; H NMR (CDCl3, 400 MHz): δ 3.80 (s, 3H),
6.82–6.90 (m, 3H), 7.22–7.28 (m, 1H), 7.29–7.36 (m, 3H), 7.66
35 (d, J = 7.6 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 8.40 (d, J = 4.9 Hz,
2H); 13C NMR (CDCl3, 100 MHz): δ 55.2, 113.5, 116.9, 127.7,
128.0, 128.6, 129.4, 130.7, 134.1, 136.2, 136.7, 157.4, 159.4, 95 (d, J = 8.7 Hz, 2H), 8.43–8.48 (m, 1H); 13C NMR (CDCl3, 100
171.6; MS (EI, m/z): 321 (3), 320 (M+, 2), 289 (8), 241 (18), 240
(100); HRMS (EI) calcd for C19H16N2OS (M+) 320.0983, found
40 320.0989.
MHz): δ 14.0, 22.6, 28.8, 28.9, 29.1, 29.3, 31.8, 39.7, 55.1, 113.3,
119.8, 122.3, 128.9, 130.5, 130.7, 135.8, 136.5, 149.7, 158.9,
159.2; MS (EI, m/z): 355 (M+, 2), 256 (30), 248 (2), 160 (100);
HRMS (EI) calcd for C22H29NOS (M+) 355.1970, found
Compound 5k. 131.3 mg, 75% yield, yellow solid, mp 141–
143 oC; 1H NMR (CDCl3, 400 MHz): δ 3.86 (d, J = 6.5 Hz, 6H), 100 355.1971.
1
6.81 (d, J = 8.4 Hz, 1H), 6.87 (t, J = 4.8 Hz, 1H), 7.20–7.27 (m,
1H), 7.28–7.35 (m, 4H), 7.37 (dd, J = 8.4, 2.1 Hz, 1H), 7.66 (d, J
45 = 7.5 Hz, 2H), 8.39 (d, J = 4.8 Hz, 2H); 13C NMR (CDCl3, 100
MHz): δ 55.7, 55.8, 110.4, 110.6, 116.9, 120.0, 127.7, 128.0,
Compound 5q. 140.6 mg, 82% yield, yellow oil; H NMR
(CDCl3, 600 MHz): δ 0.90 (t, J = 7.1 Hz, 3H), 1.22–1.36 (m,
10H), 1.60–1.67 (m, 2H), 2.50 (t, J = 7.4 Hz, 2H), 6.94–7.03 (m,
3H), 7.04 (ddd, J = 7.3, 4.9, 0.8 Hz, 1H), 7.23 (d, J = 8.0 Hz,
129.3, 131.0, 134.3, 136.1, 136.6, 148.4, 148.8, 157.3, 171.4; 105 1H), 7.52 (td, J = 7.8, 1.9 Hz, 1H), 7.52–7.58 (m, 2H), 8.45–8.50
HRMS (ESI) calcd for C20H19N2O2S (M+H)+ 351.1167, found
351.1170.
(m, 1H); 13C NMR (CDCl3, 150 MHz): δ 14.0, 22.6, 28.7, 28.9,
29.1, 29.3, 31.8, 39.5, 114.8 (d, J = 21.5 Hz), 120.0, 122.7, 130.8
(d, J = 8.2 Hz), 132.4 (d, J = 3.2 Hz), 133.2, 134.5, 136.4, 149.9,
158.6, 161.9 (d, J = 246.1 Hz); MS (EI, m/z): 343 (M+, 2), 244
50
Compound 5l. 163.6 mg, 85% yield, yellow oil; 1H NMR
(CDCl3, 400 MHz): δ 0.03 (s, 6H), 0.88 (s, 9H), 2.32 (s, 3H),
2.69 (t, J = 6.3 Hz, 2H), 3.86 (t, J = 6.3 Hz, 2H), 7.00–7.07 (m, 110 (13), 230 (5), 152 (4); HRMS (EI) calcd for C21H26 FNS (M+)
2H), 7.10 (d, J = 8.0 Hz, 2H), 7.23–7.29 (m, 1H), 7.45 (d, J = 8.0
Hz, 2H), 7.52 (td, J = 7.9, 1.7 Hz, 1H), 8.46 (d, J = 4.2 Hz, 1H);
343.1770, found 343.1769.
Compound 5r. 167.0 mg, 85% yield, yellow oil; 1H NMR
(CDCl3, 600 MHz): δ 0.90 (t, J = 7.0 Hz, 3H), 1.24–1.35 (m,
10H), 1.62–1.70 (m, 2H), 2.54 (t, J = 7.4 Hz, 2H), 7.00 (s, 1H),
55 13C NMR (CDCl3, 100 MHz): δ –5.3, 18.3, 21.2, 25.9, 42.9, 61.5,
120.0, 122.6, 127.7, 128.7, 129.1, 133.3, 136.9, 137.6, 138.7,
149.4, 159.0; MS (EI, m/z): 385 (M+, 1), 254 (7), 240 (89), 148 115 7.04–7.09 (m, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.51–7.58 (m, 3H),
(3); HRMS (EI) calcd for C22H31NOSSi (M+) 385.1896, found
7.65 (d, J = 8.2 Hz, 2H), 8.50 (dd, J = 4.8, 0.9 Hz, 1H); 13C
8
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 9 of 11
Organic & Biomolecular Chemistry
NMR (CDCl3, 150 MHz): δ 14.1, 22.6, 28.7, 28.9, 29.2, 29.3,
128.8, 136.0, 138.4; MS (EI, m/z): 276 (M+, 3), 219 (100), 161
31.8, 39.4, 120.4, 123.3, 124.2(q, J = 270.3 Hz), 124.9 (q, J = 60 (3), 145 (27); HRMS (EI) calcd for C17H28OSi (M+) 276.1909,
View Article Online
3.7 Hz), 129.1, 129.4, 133.7, 136.6, 140.1, 150.1, 158.1; MS (EI,
m/z): 393 (M+, 1), 294 (11), 280 (8), 248 (8); HRMS (EI) calcd
for C22H26F3NS (M+) 393.1738, found 393.1738.
found 276.1915.
DOI: 10.1039/C4OB00103F
1
Compound 6b.11e 50.6 mg, 88% yield, colorless oil; H NMR
(CDCl3, 400 MHz): δ 0.91 (t, J = 6.6 Hz, 3H), 1.25–1.35 (m,
10H), 1.49–1.58 (m, 2H), 1.87 (d, J = 1.0 Hz, 3H), 2.18 (t, J =
5
Compound 5s. 127.5 mg, 68% yield, yellow oil; 1H NMR
(CDCl3, 600 MHz): δ 0.78 (t, J = 7.1 Hz, 3H), 1.13–1.25 (m, 65 7.5 Hz, 2H), 6.29 (s, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.26 (d, J =
10H), 1.53–1.61 (m, 2H), 2.44 (t, J = 7.3 Hz, 2H), 6.88 (ddd, J =
7.4, 4.9, 1.0 Hz, 1H), 7.04 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H),
7.3 Hz, 2H ), 7.33 (t, J = 7.5 Hz, 2H); 13C NMR (CDCl3, 100
MHz): δ 14.1, 17.7, 22.7, 28.0, 29.3, 29.3, 29.5, 31.9, 40.8, 124.6,
125.7, 128.0, 128.8, 138.7, 139.4.
10 7.28–7.34 (m, 2H), 7.35–7.40 (m, 1H), 7.60–7.70 (m, 4H), 7.86
(s, 1H), 8.36 (ddd, J = 4.9, 1.8, 0.7 Hz, 1H); 13C NMR (CDCl3,
Compound 6c.22 40.0 mg, 72% yield, colorless oil; H NMR
1
150 MHz): δ 14.0, 22.6, 28.8, 28.9, 29.2, 29.3, 31.8, 39.6, 120.0, 70 (CDCl3, 600 MHz): δ 1.99 (d, J = 1.1 Hz, 3H), 2.56 (t, J = 9.0
122.9, 125.9, 126.0, 127.0, 127.3, 127.4, 128.1, 128.5, 132.6,
133.0, 133.7, 133.9, 135.7, 136.5, 149.7, 158.8; MS (EI, m/z):
15 375 (M+, 5), 276 (13), 262 (3), 181 (100); HRMS (EI) calcd for
C25H29NS (M+) 375.2021, found 375.2017.
Hz, 2H), 2.92 (t, J = 7.9 Hz, 2H), 6.35 (s, 1H), 7.23–7.33 (m, 6H),
7.34–7.42 (m, 4H); 13C NMR (CDCl3, 150 MHz): δ 17.9, 34.7,
42.6, 125.4, 125.8, 125.9, 128.0, 128.3, 128.4, 128.8, 138.2,
138.5, 142.0.
Compound 5t. 124.1 mg, 75% yield, yellow oil; 1H NMR
(CDCl3, 600 MHz): δ 0.90 (t, J = 7.0 Hz, 3H), 1.23–1.34 (m,
10H), 1.59–1.70 (m, 2H), 2.49 (t, J = 7.4 Hz, 2H), 6.96–7.00 (m,
20 1H), 7.00–7.05 (m, 1H), 7.16–7.27 (m, 4H), 7.51 (td, J = 7.8, 1.8
Hz, 1H), 8.48 (d, J = 4.7 Hz, 1H); 13C NMR (CDCl3, 150 MHz):
75
Compound 6d.23 39.1 mg, 79% yield, yellow solid, mp 44–
1
46°C; H NMR (CDCl3, 600 MHz): δ 1.64–1.71 (m, 2H), 1.75–
1.82 (m, 2H), 2.04 (s, 3H), 2.23–2.29 (m, 2H), 2.35–2.42 (m, 2H),
6.07 (t, J = 4.1 Hz, 1H), 6.62 (s, 1H), 7.24 (t, J = 7.3 Hz, 1H),
7.30 (d, J = 7.3 Hz, 2H), 7.37 (t, J = 7.7 Hz, 2H); 13C NMR
δ 14.0, 22.6, 28.8, 29.0, 29.2, 29.3, 31.8, 39.7, 120.0, 121.7, 80 (CDCl3, 150 MHz): δ 15.1, 22.3, 23.1, 26.0, 26.2, 123.8, 125.2,
125.9, 127.2, 129.7, 129.9, 130.9, 136.6, 139.5, 149.9, 158.8;
HRMS (ESI) calcd for C19H26NS2 (M+H)+ 332.1507, found
25 332.1512.
125.9, 127.9, 129.3, 137.9, 137.9, 139.0.
Compound 6e.11n 44.2 mg, 85% yield, white solid, E/Z = 93:7,
mp 76–78 °C; 1H NMR (CDCl3, 600 MHz): δ 2.32 (d, J = 1.2 Hz,
3H), 2.42 (s, 3H), 6.87 (s, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.26–
85 7.29 (m, 1H), 7.39–7.45 (m, 4H), 7.48 (d, J = 8.1 Hz, 2H); 13C
NMR (CDCl3, 150 MHz): δ 17.4, 21.1, 125.8, 126.3, 126.9,
128.1, 129.0, 129.1, 136.9, 137.2, 138.5, 141.0.
1
Compound 5u. 133.4 mg, 76% yield, yellow oil; H NMR
(CDCl3, 400 MHz): δ 0.89 (t, J = 6.8 Hz, 3H), 1.24–1.34 (m,
10H), 1.55–1.63 (m, 2H), 2.46 (t, J = 7.5 Hz, 2H), 6.69 (d, J =
15.7 Hz, 1H), 6.77 (d, J = 10.5 Hz, 1H), 6.98–7.05 (m, 1H),
30 7.16–7.45 (m, 7H), 7.51 (td, J = 7.9, 1.8 Hz, 1H), 8.47 (dd, J =
4.8, 0.9 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 14.0, 22.6, 28.7,
Compound 6f.11n 45.4 mg, 81% yield, white solid, E/Z = 98:2,
1
mp 103–105 °C; H NMR (CDCl3, 600 MHz): δ 2.26 (d, J = 1.1
29.0, 29.1, 29.3, 31.8, 38.8, 119.8, 121.9, 125.9, 126.6, 127.8, 90 Hz, 3H), 3.84 (s, 3H), 6.79 (s, 1H), 6.89–6.94 (m, 2H), 7.21–7.25
128.5, 134.1, 134.4, 136.5, 137.1, 137.2, 149.8, 159.5; HRMS
(ESI) calcd for C23H30NS (M+H)+ 352.2099, found 352.2091.
Compound 5v. It was prepared from 3fa and 1.3 equiv of
MeMgCl with 5 mol% of Pd(PPh3)4 in THF at rt for 8 h, 110.5
(m, 1H), 7.34–7.40 (m, 4H), 7.46–7.51 (m, 2H); 13C NMR
(CDCl3, 150 MHz): δ 17.4, 55.3, 113.7, 126.2, 126.2, 127.0,
128.1, 129.1, 136.4, 136.8, 138.5, 158.9.
35
Compound 6g. 56.6 mg, 78% yield, yellow oil; 1H NMR
mg, 84% yield, colorless oil; 1H NMR (CDCl3, 400 MHz): δ 0.86 95 (CDCl3, 400 MHz): δ 0.12 (s, 6H), 0.94 (s, 9H), 1.91 (d, J = 1.3
(t, J = 6.8 Hz, 3H), 1.18–1.29 (m, 10H), 1.44–1.57 (m, 2H), 1.86
(d, J = 6.7 Hz, 3H), 2.31 (t, J = 7.5 Hz, 2H), 6.14 (q, J = 6.6 Hz,
Hz, 3H), 2.37 (s, 3H), 2.41 (t, J = 6.9 Hz, 2H), 3.82 (t, J = 6.9 Hz,
2H), 6.30 (s, 1H), 7.16 (s, 4H); 13C NMR (CDCl3, 100 MHz): δ –
5.3, 1.0, 18.2, 21.1, 25.9, 44.0, 62.3, 126.5, 128.7, 135.3, 135.4,
135.6; MS (EI, m/z): 290 (M+, 8), 233 (100), 203 (18), 175 (3);
40 1H), 6.95–7.01 (m, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.49 (td, J =
7.7, 1.8 Hz, 1H ), 8.43 (d, J = 3.9 Hz, 1H); 13C NMR (CDCl3,
100 MHz): δ 14.1, 15.8, 22.6, 28.5, 28.9, 29.2, 29.3, 31.8, 38.7, 100 HRMS (EI) calcd for C18H30OSi (M+) 290.2066, found 290.2067.
119.4, 121.3, 132.4, 133.8, 136.3, 149.7, 159.7; MS (EI, m/z):
263 (M+, 1), 248 (68), 150 (62), 137 (2); HRMS (EI) calcd for
45 C16H25NS (M+) 263.1708, found 263.1703.
Compound 6h. 46.4 mg, 76% yield, yellow oil; 1H NMR
(CDCl3, 400 MHz): δ 0.93 (t, J = 6.8 Hz, 3H), 1.28–1.38 (m,
10H), 1.50–1.56 (m, 2H), 1.88 (d, J = 1.2 Hz, 3H), 2.19 (t, J =
7.0 Hz, 2H), 2.37 (s, 3H), 6.27 (s, 1H), 7.11–7.21 (m, 4H); 13C
105 NMR (CDCl3, 100 MHz): δ 14.1, 17.7, 21.1, 22.7, 28.0, 29.3,
29.4, 29.6, 31.9, 40.8, 124.5, 128.7, 128.7, 135.2, 135.8, 138.7;
MS (EI, m/z): 244 (M+, 16), 145 (100), 131 (20), 130 (14);
HRMS (EI) calcd for C18H28 (M+) 244.2191, found 244.2187.
Compound 6i. 43.9 mg, 72% yield, yellow oil; 1H NMR
110 (CDCl3, 400 MHz): δ 0.95 (t, J = 6.8 Hz, 3H), 1.30–1.42 (m,
10H), 1.50–1.59 (m, 2H), 1.90 (d, J = 1.2 Hz, 3H), 2.21 (t, J =
7.0 Hz, 2H), 2.39 (s, 3H), 6.29 (s, 1H), 7.04 (d, J = 7.4 Hz, 1H),
7.08–7.14 (m, 2H), 7.21–7.29 (m, 1H); 13C NMR (CDCl3, 100
MHz): δ 14.1, 17.7, 21.4, 22.7, 28.0, 29.3, 29.6, 31.9, 40.8, 124.7,
115 125.9, 126.5, 127.9, 129.6, 137.4, 138.7, 139.2; MS (EI, m/z):
244 (M+, 16), 145 (100), 131 (48), 130 (20); HRMS (EI) calcd
General procedure for the Ni-catalyzed coupling of 5
To a mixture of Ni(PPh3)2Cl2 (16.4 mg, 0.025 mmol) and 5a
(92.3 mg, 0.25 mmol) in 1 mL of THF was added 3.0 M
MeMgCl solution in THF (0.17 mL, 0.5 mmol) under nitrogen
50 atmosphere. After stirring at room temperature for 10 h, the
reaction mixture was quenched with water, extracted with EtOAc,
dried over Na2SO4 and concentrated. Column chromatography on
silica gel (petroleum ether) gave 6a as a colorless oil (55.2 mg,
80% yield); 1H NMR (CDCl3, 400 MHz): δ 0.13 (s, 6H), 0.96 (s,
55 9H), 1.93 (d, J = 1.2 Hz, 3H), 2.44 (t, J = 6.8 Hz, 2H), 3.84 (t, J
= 6.9 Hz, 2H), 6.36 (s, 1H), 7.22 (t, J = 7.2 Hz, 1H), 7.28 (t, J =
7.1 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H); 13C NMR (CDCl3, 100
MHz): δ –5.3, 1.0, 18.2, 25.9, 44.0, 62.2, 125.9, 126.7, 128.0,
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 9

Organic & Biomolecular Chemistry
Page 10 of 11
for C18H28(M+) 244.2191, found 244.2193.
6.05 (d, J = 10.9 Hz, 1H), 6.49 (d, J = 15.6 Hz, 1H), 7.00–7.11
Compound 6j. 47.0 mg, 77% yield, yellow oil; 1H NMR
(CDCl3, 600 MHz): δ 0.90 (t, J = 7.0 Hz, 3H), 1.25–1.35 (m,
10H), 1.49–1.56 (m, 2H), 1.68 (d, J = 1.2 Hz, 3H), 2.19 (t, J =
7.5 Hz, 2H), 2.24 (s, 3H), 6.22 (s, 1H), 7.10–7.20 (m, 4H); 13C
NMR (CDCl3, 150 MHz): δ 14.1, 17.4, 19.9, 22.7, 28.0, 29.3,
29.4, 29.5, 31.9, 39.9, 123.7, 125.2, 126.1, 129.4, 129.6, 136.3,
138.0, 138.9; MS (EI, m/z): 244 (M+, 6), 145 (100), 131 (59), 130
(42); HRMS (EI) calcd for C18H28 (M+) 244.2191, found
60 (m, 1H), 7.22 (t, J = 7.3 Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.44
(d, J = 7.6 Hz, 2H); 13C NMR (CDCl3, 100DMOIH: 1z0).:10δ3V91ie/4wC.14AO,rti1Bcl60e.0O81n,0li3nFe
22.7, 27.9, 29.3, 29.4, 29.5, 31.9, 40.1, 124.9, 125.7, 126.0, 126.8,
128.5, 129.7, 138.1, 140.6; MS (EI, m/z): 257 (10), 256 (M+, 25),
157 (62), 143 (74), 129 (100); HRMS (EI) calcd for C19H28 (M+)
65 256.2191, found 256.2197.
Compound 6q. 50.4 mg, 69% yield, colorless oil, Z/E = 97:3;
1H NMR (CDCl3, 600 MHz): δ 0.91 (t, J = 7.0 Hz, 3H), 1.27–
1.39 (m, 10H), 1.41–1.46 (m, 2H), 2.52 (t, J = 7.3 Hz, 2H), 6.47
(s, 1H), 6.95 (d, J = 7.1 Hz, 2H), 7.04–7.14 (m, 3H), 7.16–7.21
70 (m, 2H), 7.26–7.31 (m, 1H), 7.33 (t, J = 7.2 Hz, 2H); 13C NMR
(CDCl3, 150 MHz): δ 14.1, 22.7, 27.9, 29.2, 29.3, 29.4, 31.9, 40.7,
126.0, 126.0, 126.8, 127.8, 128.4, 128.5, 128.9, 137.5, 141.4,
143.6; MS (EI, m/z): 292 (M+, 8), 193 (87), 179 (88), 115 (100);
HRMS (EI) calcd for C22H28 (M+) 292.2191, found 292.2188.
5
10 244.2188.
Compound 6k. 50.1 mg, 77% yield, yellow oil; 1H NMR
(CDCl3, 400 MHz): δ 0.90 (t, J = 6.9 Hz, 3H), 1.25–1.35 (m,
10H), 1.44–1.52 (m, 2H), 1.85 (d, J = 1.2 Hz, 3H), 2.15 (t, J =
7.2 Hz, 2H), 3.82 (s, 3H), 6.21 (s, 1H), 6.87 (d, J = 8.8 Hz, 2H),
15 7.18 (d, J = 8.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 14.1,
17.7, 22.7, 28.1, 29.3, 29.3, 29.5, 31.9, 40.8, 55.2, 113.4, 124.0,
129.9, 131.4, 137.9, 157.6; MS (EI, m/z): 260 (M+, 12), 161 (100),
147 (8), 146 (8); HRMS (EI) calcd for C18H28O (M+) 260.2140,
found 260.2138.
75
Compound 6r. 57.4 mg, 75% yield, colorless oil, Z/E = 91:9;
1H NMR (CDCl3, 600 MHz): δ 0.87 (t, J = 6.8 Hz, 3H), 1.24–
1.31 (m, 10H), 1.35–1.40 (m, 2H), 2.34 (s, 3H), 2.46 (t, J = 7.1
Hz, 2H), 6.40 (s, 1H), 6.93 (d, J = 7.3 Hz, 2H), 7.04 (t, J = 5.9
Hz, 3H), 7.09 (t, J = 8.0 Hz, 4H); 13C NMR (CDCl3, 150 MHz):
20
Compound 6l. 53.3 mg, 86% yield, yellow oil, E/Z = 93:7; 1H
NMR (CDCl3, 400 MHz): δ 0.93 (t, J = 6.8 Hz, 3H), 1.28–1.38
(m, 10H), 1.50–1.58 (m, 2H), 1.85 (d, J = 1.0 Hz, 3H), 2.19 (t, J 80 δ 14.1, 21.2, 22.6, 28.0, 29.2, 29.3, 29.4, 31.9, 40.8, 125.8, 125.9,
= 7.2 Hz, 2H), 6.25 (s, 1H), 6.98–7.07 (m, 2H), 7.17–7.25 (m,
2H); 13C NMR (CDCl3, 100 MHz): δ 14.1, 17.6, 22.7, 28.0, 29.3,
127.8, 128.4, 128.9, 129.1, 136.3, 137.8, 138.3, 143.6; HRMS
(ESI) calcd for C23H31 (M+H)+ 307.2426, found 307.2425.
Compound 6s. 53.9 mg, 67% yield, colorless oil; H NMR
1
25 29.4, 29.6, 31.9, 40.6, 114.8 (d, J = 21.0 Hz), 123.5, 130.2 (d, J
= 7.6 Hz), 134.7 (d, J = 3.2 Hz), 139.3, 161.0 (d, J = 243.3 Hz);
(CDCl3, 400 MHz): δ 0.91 (t, J = 6.7 Hz, 3H), 1.27–1.39 (m,
MS (EI, m/z): 248 (M+, 16), 149 (100), 135 (33); HRMS (EI) 85 10H), 1.40–1.49 (m, 2H), 2.49 (t, J = 7.3 Hz, 2H), 3.82 (s, 3H),
calcd for C17H25F (M+) 248.1940, found 248.1941.
6.43 (s, 1H), 6.84 (d, J = 8.6 Hz, 2H), 6.97 (d, J = 6.9 Hz, 2H),
7.03–7.14 (m, 5H); 13C NMR (CDCl3, 100 MHz): δ 14.0, 22.6,
28.1, 29.2, 29.3, 29.4, 31.9, 40.7, 55.2, 114.0, 125.9, 126.0, 127.8,
129.0, 129.7, 133.7, 138.0, 143.2, 158.7; MS (EI, m/z): 322 (M+,
Compound 6m. 50.7 mg, 68% yield, yellow oil; 1H NMR
30 (CDCl3, 600 MHz): δ 0.90 (t, J = 7.0 Hz, 3H), 1.24–1.36 (m,
10H), 1.49–1.58 (m, 2H), 1.86 (d, J = 1.2 Hz, 3H), 2.19 (t, J =
7.4 Hz, 2H), 6.28 (s, 1H), 7.33 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 90 2), 209 (12), 178 (43), 133 (100). HRMS (EI) calcd for C23H30O
8.2 Hz, 2H); 13C NMR (CDCl3, 150 MHz): δ 14.1, 17.8, 22.7,
27.9, 29.3, 29.3, 29.5, 31.9, 40.8, 123.6, 124.4 (q, J = 269.7 Hz),
35 124.9 (q, J = 3.8 Hz), 127.4 (q, J = 32.0 Hz), 129.0, 142.0, 142.3;
MS (EI, m/z): 298 (M+, 13), 199 (97), 186 (100), 153 (3); HRMS
(EI) calcd for C18H25F3 (M+) 298.1908, found 298.1917.
(M+) 322.2297, found 322.2295.
1
Compound 6t. 42.9 mg, 67% yield, colorless oil; H NMR
(CDCl3, 600 MHz): δ 0.92 (t, J = 6.9 Hz, 3H), 1.26–1.36 (m,
10H), 1.50–1.56 (m, 2H), 2.19 (t, J = 7.5 Hz, 2H), 3.01 (d, J =
95 6.1 Hz, 2H), 5.10–5.16 (m, 2H), 5.86–5.95 (m, 1H), 6.41 (s, 1H),
7.23 (t, J = 7.3 Hz, 1H), 7.27 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 7.6
Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 14.1, 22.7, 28.0, 29.3,
29.4, 29.5, 31.9, 35.4, 37.2, 115.9, 126.0, 126.0, 128.0, 128.5,
136.3, 138.2, 140.7; MS (EI, m/z): 257 (1), 256 (M+, 3), 199 (42),
Compound 6n. 56.7 mg, 81% yield, yellow oil; 1H NMR
(CDCl3, 400 MHz): δ 0.99 (t, J = 6.7 Hz, 3H), 1.34–1.45 (m,
40 10H), 1.58–1.65 (m, 2H), 2.01 (d, J = 1.1 Hz, 3H), 2.29 (t, J =
7.5 Hz, 2H), 6.50 (s, 1H), 7.42–7.54 (m, 3H), 7.75 (s, 1H), 7.81–
7.89 (m, 3H); 13C NMR (CDCl3, 100 MHz): δ 14.1, 17.9, 22.7, 100 179 (13), 158 (2). HRMS (EI) calcd for C19H28 (M+) 256.2191,
28.1, 29.3, 29.4, 29.6, 31.9, 40.8, 124.7, 125.3, 125.8, 127.1,
127.4, 127.5, 127.6, 127.7, 131.8, 133.4, 136.3, 140.0; MS (EI,
45 m/z): 280 (M+, 26), 181 (100), 167 (26); HRMS (EI) calcd for
C21H28 (M+) 280.2191, found 280.2188.
found 256.2195.
Acknowledgements
We are grateful for the financial support from Natural Science
Foundation of Zhejiang Province (LR12B02001), National
105 Science Foundation of China (21172199), and Open Research
Fund of Key Laboratory of the Ministry of Education for
Advanced Catalysis Materials (ZJHX201310).
Compound 6o. 38.9 mg, 66% yield, yellow oil, E/Z = 95:5; 1H
NMR (CDCl3, 600 MHz): δ 0.92 (t, J = 6.8 Hz, 3H), 1.26–1.36
(m, 10H), 1.48–1.55 (m, 2H), 2.00 (s, 3H), 2.20 (t, J = 7.6 Hz,
50 2H), 6.43 (s, 1H), 6.94 (d, J = 3.2 Hz, 1H), 7.03 (t, J = 3.7 Hz,
1H), 7.22 (d, J = 5.0 Hz, 1H); 13C NMR (CDCl3, 150 MHz): δ
14.1, 18.5, 22.7, 28.1, 29.3, 29.5, 29.7, 31.9, 41.0, 118.0, 123.7,
125.7, 126.7, 138.6, 141.8; MS (EI, m/z): 236 (M+, 5), 138 (14),
137 (100), 123 (8); HRMS (EI) calcd for C15H24S (M+) 236.1599,
55 found 236.1606.
Notes and references
a Department of Chemistry, Zhejiang Normal University, 688 Yingbin
110 Road, Jinhua 321004, China. E-mail: gangguo@zjnu.cn.
† These two authors contributed equally to this paper. ‡ Electronic
Supplementary Information (ESI) available: [Experimental details,
characterization of compounds 3, 5, 6, and X-ray data of 5i]. See
DOI: 10.1039/b000000x/
Compound 6p. 51.2 mg, 80% yield, yellow oil; 1H NMR
(CDCl3, 400 MHz): δ 0.93 (t, J = 7.0 Hz, 3H), 1.21–1.39 (m,
10H), 1.46–1.56 (m, 2H), 1.88 (s, 3H), 2.15 (t, J = 7.4 Hz, 2H),
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Page 11 of 11
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