Access to Polysubstituted (Furyl)methylthioethers via a Base-Promoted S-H Insertion Reaction of Conjugated Enynones

Article abstract of DOI:10.1021/acs.joc.9b02053

A convenient and applicable approach to the construction of diverse functionalized (2-furyl)methylthioether derivatives via base-promoted S-H insertion of conjugated enynones with thiophenols or thiols has been developed. This reaction features readily av

Full text of DOI:10.1021/acs.joc.9b02053

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Article
Access to Polysubstituted (Furyl)methylthioethers via Base-
Promoted S-H Insertion Reaction of Conjugated Enynones
Wanqing Wu, Yang Chen, Meng Li, Weigao Hu, and Xuemin Lin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02053 • Publication Date (Web): 08 Oct 2019
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Access to Polysubstituted (Furyl)methylthioethers via
Base-Promoted S-H Insertion Reaction of Conjugated
Enynones
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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a,b,
b
b
b
b
Wanqing Wu, * Yang Chen, Meng Li , Weigao Hu , Xuemin Lin
a
State Key Laboratory of Luminescent Materials and Devices, South China University of
Technology, Guangzhou 510640, China
b
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of
Chemistry and Chemical Engineering, South China University of Technology, Guangzhou
10640, China
5
Fax: +86-20-87112906; Tel: +86-20-87112906; E-mail: cewuwq@scut.edu.cn
O
O
R1
O
R2
EWG
OOC
R1
M
3
S
+
R S-H
EWG
3
H
R S
R2
COO
CNKSPR1 inhibitor
3
5 examples
up to 91% yield
S-H Insertion of conjugated enynones
Late-stage functionalization of Glutathione
Broad substrate scope and high atom economy
3
2
C(sp )-S and C(sp )-O bond formations in one pot
Abstract:
A convenient and applicable approach to the construction of diverse functionalized
2-furyl)methylthioether derivatives via base-promoted S-H insertion of conjugated
(
enynones with thiophenols or thiols has been developed. This reaction features readily
available starting materials, high atom economy, broad substrate scope and versatile
operation. Moreover, the synthetic utility of this method has been demonstrated by the
efficient synthesis of CNKSPR1 inhibitor precursor and late-stage functionalization of
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glutathione.
Introduction
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Sulfur-containing compounds are well known for their wide existence in a large
number of natural products, pharmaceutical compounds and bioactive molecules.1
Furthermore, all of the top 10 best-selling drugs in 2012 were sulfur-containing
2
compounds. Among which, (2-furyl)methylthioethers are quite extraordinary due to
their widespread occurrence in different kinds of anti-cancer drugs. For example,
compound A inhibits the process of UDP-glucose dehydrogenase in the treatment of
prostate cancer, and B is proved to act as an inhibitor of leukotriene biosynthesis,
while C is illustrated to have certain effects in stunting the growth of cancer cells
3
(
Figure 1). Thus, the synthesis of (furyl)methylthioether core structure has received
much interest over the past few years, and most of the approaches mainly proceed
4
through two pathways: (i) intramolecular cyclization of unsaturated thioethers and
5
(ii) sulfuration of furan rings. However, limitations still exist, such as narrow
substrate scope, harsh reaction conditions and prefunctionalization of the starting
materials. Therefore, the exploration of new and general methods to assemble the
2-furyl)methylthioether skeleton is of significant importance.6
(
2-quinolyl
O
2-quinolyl
O
N
H
S
O
NO2
O
O
R
S
(
O
S
COOH
O
A)
(B)
(C)
Anticarcinogen
UDP-Glucose Dehydrogenase Inhibitor Inhibitor of Leukotriene Biosynthesis
Figure 1. Biologically Active Molecules with (2-Furyl)methylthioether Skeleton
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On the other hand, as readily available and versatile synthons, conjugated enynones
exhibit abundant and tunable reactivities in the building of different functionalized
7
8
9
9,10
B,11 P,12 Si,13 etc.) insertion
furans. In particular, the X-H (X = C, O, N,
1
1
1
1
1
1
1
1
1
1
2
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0
reactions of conjugated enynones, which can construct various furan rings as well as
forming multiple new C-X bonds in one step, have been investigated broadly in recent
years. Generally, the main reaction modes of X-H insertion reactions include (Scheme
1
, Eqn. a): (i) the carbene insertion of X-H (X = C, O, N, B, P) in the transition metal
catalysis; (ii) the organocatalytic approach via a sulfur or phosphine-mediated ylide
intermediate especially for N/O-H insertion. Despite many elegant works that have
been achieved in this field, the S-H insertion reaction of conjugated enynones remains
unexplored, which might be ascribed to the distinct coordination nature of sulfur atom
and the instability of the newly generated C-S bond in the presence of transition
14
15
metals. As our continuous interest in the construction of multi-substituted furans,
herein, we present an S-H insertion reaction of conjugated enynones with thiophenols
3
2
or thiols under mild reaction conditions, in which the C(sp )-S and C(sp )-O bonds are
formed in one pot with high atom and step economy (Scheme 1, Eqn. b).
Scheme 1. General X-H Insertion Strategy of Conjugated Enynones
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Previous work of X-H insertion:
R1
[M]
O
Nu-H
R2
EWG
[
M] = Rh, Au,
Ru, Cu, Zn
Nu = B, C, N, O, P
O
(i)
Int-I
R1
[
M]
EWG
R1
O
R2
H
(
Eqn. a)
EWG
R1
R2
Nu
0
1
2
3
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9
0
1
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0
1
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9
0
(ii)
O
ylide
R2
precursor
EWG
Nu-H
THT, PPh3
Nu = C, N, O
[P]/[S]
Int-II
This work:
O
R1
R1
EWG
R1
3
O
R2
R S
H
O
1,2-H Migration
R2
(Eqn. b)
EWG
EWG
H
3
R S
R2
HSR3
Result and Discussion
We commenced our investigations by monitoring the reaction of
3-(3-phenylprop-2-yn-1-ylidene)pentane-2,4-dione (1a) and 4-methylbenzenethiol
(
2b) to establish the optimal reaction system (Table 1). To our delight, the desired
product 1-(2-methyl-5-(phenyl(phenylthio)methyl)furan-3-yl) ethan-1-one (3b) was
o
obtained in 72% yield when the reaction was conducted in MeCN at 50 C under the
treatment of 2.0 equiv of K CO (Table 1, entry 1). Encouraged by this result, other
2
3
bases such as DABCO, Et N, and DBU were then investigated for this 5-exo-dig
3
cyclization reaction, and DBU gave the best result (Table 1, entries 2-5). Control
experiment suggested that the base was essential to this reaction (Table 1, entry 6).
Further investigation of the base dosage revealed that 1.0 equiv of base was preferable
for this transformation (Table 1, entries 7 and 8). The examination of temperature
o
showed that 60 C was the optimal choice, giving 3a in 91% isolated yield (Table 1,
entries 9-11). In addition, the employment of other solvents including DMSO, DMF,
Et N and MeCN, did not show much positive effect (Table 1, entries 12-15). Thus, the
3
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optimal conditions for this reaction were defined as follows: DBU (1 equiv) as base in
o
MeCN at 60 C for 6 h (Table 1, entry 10).
Table 1. Optimization of the Reaction Conditionsa
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
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3
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5
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0
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0
O
O
O
O
SH
Base
+
S
Solvent, Temperature
3b
1a
2b
o
yield (%)b
72
entry
Base (equiv)
K CO (2)
temp ( C)
solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
DMF
1
2
3
4
5
6
7
8
9
50
50
50
50
50
50
50
50
40
60
70
60
60
60
60
2
3
KOH (2)
n.d.
33
DABCO (2)
Et N (2)
3
20
DBU (2)
-
89
n.d.
90
DBU (1)
DBU (0.5)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
66
59
1
0
96 (91)
43
1
1
12
13
10
85
1
1
4
5
Et N
3
75
MeCN
22
aReaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), base, and solvent (2.0 mL) for 6 h. n.d. =
b
1
not detected. Determined by H NMR using CH NO as internal standard. Data in parentheses is
3
2
isolated yield.
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With the optimized reaction conditions in hand, we then investigated the generality
and limitations of thiophenols or thiols for this cyclization reaction, and the results are
summarized in Table 2. Gratifyingly, a wide range of substitution patterns of
thiophenols were compatible in this transformation and the desired products could be
obtained in moderate to excellent yields. For instance, different para-substituted
0
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9
0
thiophenols with either electron-donating groups (-Me, -tBu, -NH , -OMe, etc.) or
2
electron-withdrawing groups (-COOMe, -CF , etc.) were converted into the
3
corresponding cyclization products in 44-91% yields (3b-3g). Moreover, different
halo groups, including -F, -Cl, -Br, were well tolerated in this reaction, which allowed
the subsequent functionalization to assemble structurally diverse molecules. The steric
hindrance had little effect on this reaction due to the fact that ortho-tBu substituted
thiophenol proceeded well in this chemical process and transformed to the target
product 3n in 76% yield. Satisfactory yields were observed when disubstituted
thiophenols were used in this reaction (3o-3p). It should be noted that the thiophenols
containing heterocyclic or naphthyl rings were also well tolerated, and the desired
products 3q and 3r could be formed in moderate yields. Importantly, the thiols were
also applicable to this transition-metal-free system and the corresponding furan
products 3s and 3t were obtained in 91% and 93% yields, respectively. The structure
of 3s was further unambiguously elucidated by X-ray crystallography (see the
Supporting Information for details).16 Pleasingly, the reactions of
3-(3-(trimethylsilyl)prop-2-yn-1-ylidene)pentane-2,4-dione with different thiols also
proceeded smoothly to produce the corresponding (2-furyl)methylthioethers 3u-3w in
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excellent yields (88%, 92% and 89%, respectively).
Table 2. Substrate Scope of Thiophenols or Thiolsa
Yield
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Entry
2
Product
[%]
3a, 82%
2a, R = H
3
a, R = H
3b, 91%
2b, R = Me
O
O
3b, R = Me
SH
2c, R = t-Bu
d, R = OMe
2e, R = NH2
3c, 90%
3d, 44%
3e, 63%
3f, 90%
3
3
c, R = t-Bu
d, R = OMe
2
1
3e, R = NH2
f, R = COOMe
S
R
2f, R = COOMe
g, R = CF3
3
2
3g,
3h
3i, R = Br
R = CF3
R = Cl
3g,
86%
2h, R = Cl
R
,
3
3
h, 84%
i, 86%
2i, R = Br
O
O
Cl
SH
2
3
4
5
81
89
79
82
Cl
S
2
j
3j
O
O
F
SH
SH
SH
S
F
2
k
3k
O
O
Cl
S
Cl
2
l
3l,
O
O
Br
S
Br
2m
3m
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
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5
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5
5
5
5
6
O
O
SH
S
6
76
2
n
0
1
2
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5
6
7
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9
0
1
2
3
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0
1
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0
3n
O
O
Cl
Cl
SH
Cl
Cl
S
7
8
86
2o
3o
O
O
SH
S
75
2
p
3p
O
O
SH
S
S
S
9
55
2q
3q
O
O
SH
S
10
55
2r
3r
SH
O
O
1
1
S
91
2s
3s
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O
O
SH
S
1
1
1
1
2
3
4
5
93
88
92
89
2
t
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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9
0
1
2
3
4
5
6
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8
9
0
3t
O
O
SH
S
2u
1
3u, R = TMS
O
O
SH
S
2v
1
3v, R = TMS
O
O
SH
S
2w
1
3w, R = TMS
a
o
Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), DBU (0.2 mmol), MeCN (2.0 mL) at 60 C
b
1
for 6 h. Isolated yields were given. Unless otherwise stated, R = Ph.
Next, the scope of different conjugated enynones was evaluated (Table 3). It was
1
found that the reaction was tolerated to a broad range of R groups on the alkyne
terminus, including alkyl- and bromo-substituted arenes, giving the corresponding
products 3x and 3y in 80% and 82% yields, respectively. Interestingly, when
1
TMS-substituted enynone substrate (R = TMS, 1z) was employed as the substrate,
the desilylated furan product 3z was isolated in 82% yield while TIPS-substituted
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enynone (R = TIPS, 1aa) was converted to 3aa, in which the silicon substituent was
retained. Delta ketone substituted ene-yne-ketone 1ab also reacted with 2b smoothly
and the desired product 3ab could be provided in 71% yield. Additionally, when one
of the carbonyl groups was replaced by other electron-withdrawing substituents, such
as ester and tosyl group (1ac-1ae), the reactions still proceeded well and afforded the
expected furan derivatives 3ac-3ae in 56-86% yields. In addition, the strained-ring
0
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
substituent in R position (1af) was also a suitable substrate for this transformation,
and the desired product 3af was obtained in 86% yield. Moreover, the substrates with
2
R replaced by phenyl or substituted phenyl groups (1ag-1ai) were able to transfer to
the corresponding cyclization products in 63-72% yields (3ag-3ai).
Table 3. Substrate Scope of Conjugated Enynonesa
Entry
1
Product
Yield [%]
O
O
O
O
1
80
S
R
3x
1x
O
O
O
O
2
3
Br
82
Br
S
R
3y
1y
O
O
O
O
82
S
TMS
R
3z
1z
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O
O
O
O
TIPS
R
4
5
6
7
8
9
94
71
56
81
85
86
S
TIPS
1aa
3aa
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
O
S
O
R
3
ab
1ab
O
Ts
O
Ts
S
R
3
ac
1ac
O
O
nBuO
O
O
nBuO
S
R
3
ad
1ad
O
O
O
tBuO
O
tBuO
S
R
3
ae
1ae
O
O
O
O
O
O
S
R
1af
3af
O
O
O
O
O
O
1
0
63
S
R
1ag
3
ag
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
5
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6
F
O
O
F
O
O
O
1
1
72
O
S
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
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9
0
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9
0
1
2
3
4
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8
9
0
1ah
R
3ah
O
O
O
O
O
O
1
2
O
O
63
S
1ai
R
3ai
a
o
Reaction conditions: 1 (0.2 mmol), 2b (0.24 mmol), DBU (0.2 mmol), MeCN (2.0 mL) at 60 C
for 6 h. Isolated yields were given.
To further demonstrate the applicablity of this method, glutathione, a common
natural product with multiple nucleophilic groups, was employed as the substrate in
this reaction. Fortunately, the desired product 3aj was isolated in 76% yield under the
standard conditions with excellent chemoselectivity, which provided more
possibilities for furhter applications in biochemistry, proteomics, and drug delivery,17
such as late-stage functionalization of amino acids (Scheme 2).
Scheme 2. Late-Stage Functionalization of Glutathione
O
O
O
O
HOOC
DBU (1 equiv)
HOOC
NH
NH
NH2
O
NH2 O
HN
O
O
MeCN/H O
2
HN
SH
COOH
o
S
5
0 C, 3 h
TMS
COOH
3aj, 76%
1aj
2z
Notably, this method could also be applied to the synthesis of a precursor of
1
8
CNKSPR1 inhibitor, a potential drug in blocking the growth of mut-KRAS cancer
cells. The desired product 3ak was isolated in 85% yield under the optimal conditions
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(Scheme 3), indicating the potential value in medicinal chemistry.
Scheme 3. Synthesis of CNKSPR1 Inhibitor Precursor
O
O
O
O
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
OOC
nBuO
n
O Bu
DBU (1 equiv)
SH
S
+
S
MeCN, 60 °C, 6 h
O
TMS
COO
O
CNKSPR1 inhibitor
1ak
2ak
3ak, 85%
The utility of the newly formed (2-furyl)methylthioethers as useful building blocks
for further elaborations was demonstrated (Scheme 4). For instance, in the presence of
NaIO or m-CPBA as oxidants, 3z was converted to the sulfone or sulfoxide products
4
1
9
4 and 5 in 91% and 76% yields, respectively (Scheme 4a and 4b). Additionally, the
Suzuki coupling reaction of 3ai proceeded well and the desired conjugated product 6
2
0
was afforded in 82% yield (Scheme 4c), thus allowing for great structural diversity.
Scheme 4. Synthetic Applications
O
O
O
O
S
NaIO (1.2 equiv)
4
(
a)
b)
1
2
3z, R = 4-Me, R = CH CO
3
O
4
, 91%
O
O
O
S
R2
R1
m-CPBA (1 equiv)
(
1
S
3z, R = 4-Me,
2
R = CH3CO
5, 76%
Pd(OAc) , (5 mol %)
O
O
2
PPh (5 mol %), PhB(OH)
S
3
2
(
c)
1
2
3
al, R = 4-Br, R = CH CO
3
Ph
6, 82%
To gain more insight into the reaction mechanism, several control experiments
were performed (Scheme 5). The deuterium-experiment indicated that the hydrogen
atom at methylene position of 3aa/d1-3aa was from thiophenols (Scheme 5a).
Moreover, when radical inhibitor (2,2,6,6-tetramethyl-1- piperidinyloxyl), BHT
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(2,6-di-tert-butyl-p-cresol) or 1,1-diphenylethylene was added respectively to the
system under the standard reaction conditions, the corresponding product 3b could be
obtained in moderate to good yields, suggesting that a radical process should not be
involved (Scheme 5b).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5. Mechanistic Studies
62% [D]
81% [D]
O
O
O
H/D
TIPS
SH/D
DBU (1 equiv)
+
O
(a)
CDCl3, 60 °C, 6 h
S
TIPS
1aa
2a/d1-2a
3aa/d1-3aa, 82%
O
O
O
SH
Ph
standard conditions
+
O
(b)
(
(
a) TEMPO (2 equiv): 23%
b) BHT (2 equiv): 80%
(c) 1,1-Diphenylethylene (2 equiv): 87%
S
Ph
1a
2b
3b
a
1
Determined by H NMR using CH NO as internal standard.
3
2
Based on the above experimental results and previous reports,21 a plausible
mechanism is proposed in Scheme 6. First, the reaction is initiated by the
regioselective attack of thiophenol or thiols to the alkyne moiety of conjugated
enynones, giving the allene intermediate A,7d which would undergo a 5-exo-dig
9
cyclization to provide the intermediate B. Finally, proton transfer of B affords the
furan product 3.
Scheme 6. Proposed Mechanism
R2
R2
O
O
O
R2
C
O
O
R2
R1
R1
R1
R1
DBU
O
O
O
R3
R3
R3
R3
4
4
HSR4
R SH
B
R S
4
R SH
1
A
3
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Conclusion
In summary, we have developed a metal-free synthesis of (2-furyl)methylthioether
derivatives via S-H insertion of conjugated enynones, in which constructed the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
C(sp )-S and C(sp )-O bonds in one pot. Moreover, this method can be highlighted by
its application in the synthesis of the precursor of CNKSPR1 inhibitor and late-stage
functionalization of glutathione. The high atom economy and good chemoselectivity,
broad functional group tolerance as well as the mild reaction conditions make the
present protocol attractive.
Experimental Section
General Information
1
Melting points were determined with a Buchi Melting Point B-545 instrument. H and
13C NMR spectra were recorded using a Bruker DRX-400 spectrometer using CDCl3
as solvent. The chemical shifts are referenced to signals at 7.26 and 77.0 ppm,
respectively, and chloroform is solvent with TMS as the internal standard. IR spectra
were obtained either as potassium bromide pellets or as liquid films between two
potassium bromide pellets with a Bruker TENSOR 27 spectrometer. Mass spectra
were recorded on a Thermo Scientific ISQ gas chromatograph-mass spectrometer.
The data of HRMS was carried out on a high-resolution mass spectrometer
(LCMS-IT-TOF). TLC was performed by using commercially prepared 100-400 mesh
silica gel plates and visualization was effected at 254 nm. All the reaction
temperatures reported are oil bath temperatures. Unless otherwise noted, all reagents
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
and solvents were obtained from commercial suppliers and used without further
purification.
Typical Procedure for the Synthesis of Conjugated Enynones9d
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
To a 25 mL round bottom flask, a mixture of 1,3-diketones (0.5 mmol, 50 mg), AcOH
(
0.1 mmol, 6 mg), pyrrolidine (0.05 mmol, 3.6 mg) and dry MgSO (0.5 mmol, 60
4
mg) was added to a solution of alkyne aldehyde (0.6 mmol, 78 mg) in toluene (10 mL,
o
0
.05 M). The reaction was carried out at 40 C stirring for 4 h and monitored by TLC.
After the completion of the reaction, the reaction mixture was filtered through celite
and removal of the solvent by rotary evaporation to give the crude product. The
conjugated enynones were purified by chromatography on silica gel with the
appropriate mixture of petroleum ether and ethyl acetate (5: 1 for 1ac and 20: 1 for
other conjugated enynones) in 63-96% yields.
1
a-1x, 1az, 1aa, 1ab, 1ad, 1af, 1ag, and 1ai are known compounds and the NMR data
are in good agreement with the literature.9a,9c,12 1y, 1ac, 1ad and 1ah are unknown
compounds and the corresponding analytical data are shown as bellow:
3-(3-(3-Bromophenyl)Prop-2-yn-1-ylidene)pentane-2,4-dione (1y): Yellow oil
1
(
96%, 139 mg); H NMR (400 MHz, CDCl ) δ 7.58 (s, 1H), 7.52 (d, J = 8.1 Hz, 1H),
3
7
.39 (d, J = 7.7 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 6.89 (s, 1H), 2.54 (s, 3H), 2.37 (s,
1
3
1
3H); C{ H} NMR (100 MHz, CDCl ) δ 200.3, 195.2, 149.8, 134.2, 132.8, 130.4,
3
-1
1
29.7, 123.2, 122.1, 121.1, 104.1, 85.8, 30.7, 27.0 ppm; νmax(KBr)/cm = 2926, 2193,
+
1680, 1578, 1367, 1237, 877, 780; HRMS-ESI (m/z) calcd for C H BrO [M + H] :
1
4
12
2
2
91.0021, found 291.0016.
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(E)-6-Phenyl-3-tosylhex-3-en-5-yn-2-one (1ac): Yellow oil (71%, 115 mg); H
NMR (400 MHz, CDCl ) δ 7.82 (d, J = 8.1 Hz, 2H), 7.61 (s, 1H), 7.49 (d, J = 7.4 Hz,
3
2
H), 7.44 (d, J = 7.1 Hz, 1H), 7.38 (t, J = 7.5 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 2.60
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
(s, 3H), 2.42 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 193.6, 148.8, 144.8, 136.7,
3
1
32.2, 130.7, 129.6, 128.7, 128.7, 126.2, 120.9, 110.3, 84.2, 34.2, 21.6 ppm;
-1
νmax(KBr)/cm = 3649, 3545, 2926, 2183, 1634, 1302,1140, 674; HRMS-ESI (m/z)
+
calcd for C H SO Na [M + Na] : 347.0718, found 347.0714.
1
9
16
3
Butyl (E)-2-Acetyl-5-phenylpent-2-en-4-ynoate (1ad): Yellow oil (90%, 122 mg);
1
H NMR (400 MHz, CDCl ) δ 7.48 (d, J = 6.8 Hz, 2H), 7.37 (d, J = 7.6 Hz, 3H), 7.02
3
(
s, 1H), 4.34 (t, J = 6.7 Hz, 2H), 2.40 (s, 3H), 1.78 - 1.66 (m, 2H), 1.44 (dd, J = 15.1,
1
3
1
7.5 Hz, 2H), 1.22 (t, J = 7.0 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H); C{ H} NMR (100
MHz, CDCl ) δ 193.9, 165.5, 141.4, 132.1, 129.9, 128.5, 124.5, 121.9, 106.3, 85.4,
3
-1
6
5.5, 30.7, 19.1, 14.0, 13.6 ppm; νmax(KBr)/cm = 3572, 3423, 2391, 2192, 1682,
+
1570, 1369, 778; HRMS-ESI (m/z) calcd for C H NaO [M + Na] : 293.1154, found
1
7
18
3
2
93.1147.
Ethyl (E)-2-(3-Fluorobenzoyl)-5-phenylpent-2-en-4-ynoate (1ah): Yellow oil (93%,
1
1
1
50 mg); H NMR (400 MHz, CDCl ) δ 7.74 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 9.1 Hz,
3
H), 7.59 - 7.35 (m, 2H), 7.28 (d, J = 10.2 Hz, 2H), 7.22 (t, J = 7.5 Hz, 2H), 7.13 (d, J
1
3
1
= 7.8 Hz, 2H), 4.25 (q, J = 7.0 Hz, 2H), 1.21 (t, J = 7.0 Hz, 3H); C{ H} NMR (100
MHz, CDCl ) δ 191.4, 164.0, 163.6-161.6 (J = 200 Hz), 140.4, 138.1 (J = 60 Hz)
3
132.2, 130.4-130.3 (J = 7.0 Hz), 129.7, 128.3, 125.2-125.1 (J = 90 Hz), 124.1, 121.3,
1
9
1
20.8-120.6 (J = 29 Hz), 115.7-115.6 (J = 11 Hz), 105.1, 84.7, 61.7, 13.9 ppm; F
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1
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-
1
NMR (376 MHz, CDCl ) δ -111.6; ν (KBr)/cm = 3068, 2958, 873, 2191, 1240,
3
max
+
7
61; HRMS-ESI (m/z) calcd for C H FNaO [M + Na] : 345.0903, found 345.0901.
20 15 3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
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4
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General Procedure for the Synthesis of (2-Furyl)methylthioethers (3)
To a solution of conjugated enynone (1, 0.20 mmol, 1.0 equiv) and DBU (0.2 mmol,
1.0 equiv) in MeCN (1 mL, 0.1 M) was added thiophenol or thiol (2, 0.24 mmol, 1.2
o
equiv). The mixture was stirred at 60 C (oil bath) for 6 h. After the reaction was
completed (monitored by TLC), the reaction was quenched with H O, and the crude
2
product was extracted with ethyl acetate (6 mL × 3). The combined organic extracts
were dried over MgSO and concentrated in vacuum. The resulting residue was
4
purified by column chromatography on silica gel with light petroleum ether/ethyl
acetate (10: 1 to 30: 1) as eluent to afford the desired products 3 in 44-94% yields.
1
-(2-Methyl-5-(phenyl(phenylthio)methyl)furan-3-yl)ethan-1-one (3a): Yellow oil
1
(82%, 53 mg); H NMR (400 MHz, CDCl ) δ 7.40-7.22 (m, 10H), 6.39 (s, 1H), 5.34
3
1
3
1
(
s, 1H), 2.54 (s, 3H), 2.32 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 194.0, 167.0,
3
158.4, 151.4, 138.3, 134.5, 132.3, 128.8, 128.6, 128.3, 127.9, 127.6, 122.0, 108.9,
-1
7
7.3, 77.00, 76.7, 51.2, 29.1, 14.4 ppm; νmax(KBr)/cm = 2924, 1672, 1564, 140,
+
1
228, 1020, 813, 743; HRMS-ESI (m/z) calcd for C H SO Na [M + Na] : 345.0925,
2
1
20
2
found 345.0918.
1
-(2-Methyl-5-(phenyl(p-tolylthio)methyl)furan-3-yl)ethan-1-one (3b): Yellow oil
1
(91%, 61 mg); H NMR (400 MHz, DMSO-d ) δ 7.36-7.24 (m, 7H), 7.10-7.12 (d, J =
6
8
.0 Hz, 2H), 7.08 (m, 2H), 6.58 (s, 1H), 5.73 (s, 1H), 2.31 (s, 3H), 2.27 (s, 3H);
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1
3
1
C{ H} NMR (100 MHz, DMSO-d ) δ 193.9, 157.8, 151.7, 138.9, 137.6, 132.2,
6
1
3
30.8, 130.1, 129.0, 128.6, 128.2, 122.4, 109.1, 49.6, 40.6, 40.4, 40.2, 40.0, 39.8, 39.6,
-1
9.4, 29.6, 21.0, 14.5 ppm; νmax(KBr)/cm = 3347, 3065, 2924, 1672, 1570, 1227,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
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5
6
0
1
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
+
951, 753 cm ; HRMS-ESI (m/z) calcd for C H NaSO [M + Na] : 359.1082, found
2
1
21
2
3
59.1080.
1-(5-(((4-(tert-Butyl)phenyl)thio)(phenyl)methyl)-2-methylfuran-3-yl)ethan-1-one
1
(3c): Yellow oil (90%, 68 mg); H NMR (400 MHz, DMSO-d ) δ 7.52-7.42 (m, 7H),
6
7
.34-7.29 (m, 2H), 6.57 (s, 1H), 5.78 (s, 1H), 2.48 (s, 3H), 2.31 (s, 3H), 1.23 (s, 9H);
1
3
1
C{ H} NMR (100 MHz, DMSO-d ) δ 193.9, 157.8, 151.8, 150.6, 139.2, 131.5,
6
1
29.1, 128.6, 128.2, 126.3, 122.3, 109.1, 49.4, 34.7, 31.4, 29.6, 14.5 ppm;
-1
-1
νmax(KBr)/cm = 3059, 2924, 1672, 1569, 1428, 1231, 1021, 951 cm ; HRMS-ESI
+
(m/z) calcd for C H SO [M + H] : 379.1726, found 379.1728.
2
4
27
2
1
-(5-(((4-Methoxyphenyl)thio)(phenyl)methyl)-2-methylfuran-3-yl)ethan-1-one
1
(3d): Yellow oil (44%, 31 mg); H NMR (400 MHz, CDCl ) δ 7.34-7.21 (m, 7H),
3
6
.75-6.73 (d J = 8.0 Hz, 2H), 6.36 (s, 1H), 5.18 (s, 1H), 3.73 (s, 3H), 2.54 (s, 3H),
1
3
1
2.31 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 193.9, 159.9, 158.1, 151.4, 138.5,
3
1
2
35.8, 128.5, 128.2, 127.7, 124.4, 121.9, 114.3, 108.7, 77.3, 77.0, 76.7, 55.1, 52.4,
-1
9.0, 14.3, 14.1 ppm; νmax(KBr)/cm = 3446, 2923, 2846, 1664, 1561, 1237, 1033
-1
+
cm ; HRMS-ESI (m/z) calcd for C H SO Na [M + Na] : 375.1031, found
2
1
20
3
3
75.1029.
1-(5-(((4-Aminophenyl)thio)(phenyl)methyl)-2-methylfuran-3-yl)ethan-1-one (3e):
1
Brown oil (63%, 42 mg); H NMR (400 MHz, CDCl ) δ 7.34-7.28 (m, 5H), 7.09 (d, J
3
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= 8.0 Hz, 2H), 6.52-6.50 (d, J = 32.0 Hz, 2H), 5.12 (s, 1H), 6.36 (s, 1H), 3.53 (s, 1H),
1
3
1
2
1
.54 (s, 3H), 2.33 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 194.2, 158.3, 151.75,
3
46.9, 138.8, 136.3, 128.5, 128.4, 127.7, 122.0, 121.4, 115.3, 108.7, 77.4, 77.1, 76.8,
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0
1
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4
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8
9
0
1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
52.8, 29.2, 14.5 ppm; νmax(KBr)/cm = 2990, 1757, 1666, 1562, 1456, 1383, 1241,
-1
+
1
053 cm ; HRMS-ESI (m/z) calcd for C H SNO Na [M + Na] : 360.1034, found
20 19 2
360.1025.
Methyl 4-(((4-Acetyl-5-methylfuran-2-yl)(phenyl)methyl)thio)benzoate (3f):
1
Yellow oil (90%, 68 mg); H NMR (400 MHz, DMSO-d ) δ 7.83 (d, J = 8.3 Hz, 2H),
6
7.54 - 7.45 (m, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.29 (d, J = 7.4 Hz, 2H), 6.66 (s, 1H),
1
3
1
6
.11 (s, 1H), 3.82 (s, 3H), 2.50 (s, 3H), 2.32 (s, 3H); C{ H} NMR (100 MHz,
DMSO-d ) δ 193.8, 166.2, 156.0, 151.0, 142.0, 138.2, 130.0, 129.2, 128.9, 128.6,
6
-1
1
28.5, 127.7, 122.5, 109.5, 52.6, 47.4, 29.6, 14.6 ppm. νmax(KBr)/cm = 2926, 2869,
+
1
676, 1563, 1227, 951, 808, 631; HRMS-ESI (m/z) calcd for C H SO [M + H] :
2
2
21
4
381.1155, found 381.1157.
1
-(2-Methyl-5-(phenyl((4-(trifluoromethyl)phenyl)thio)methyl)furan-3-yl)ethan-1
1
-one (3g): Yellow oil (86%, 67 mg); H NMR (400 MHz, DMSO-d ) δ 7.63 (d, J =
6
8
6
.4 Hz, 2H), 7.54 (d, J = 18.5 Hz, 4H), 7.36 (dd, J = 17.9, 10.2 Hz, 3H), 6.65 (s, 1H),
13
1
.10 (s, 1H), 2.49 (s, 3H), 2.29 (s, 3H); C{ H} NMR (100 MHz, DMSO-d ) δ 194.0,
6
158.1, 151.0, 138.2, 138.1, 129.8, 129.2, 128.6, 128.5, 126.1, 125.9, 123.2, 122.5,
1
9
1
09.5, 47.6, 29.6, 14.4 ppm; F NMR (376 MHz, DMSO-d ) δ -60.9 (s);
6
-1
νmax(KBr)/cm = 2938, 2850, 1719, 1672, 1280, 1113, 952, 700; HRMS-ESI (m/z)
+
calcd for C H F NaSO [M + Na] : 413.0799, found 413.0796.
2
1
17
3
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1-(5-(((4-Chlorophenyl)thio)(phenyl)methyl)-2-methylfuran-3-yl)ethan-1-one (3h)
1
Yellow oil (84%, 60 mg); H NMR (400 MHz, DMSO-d ) δ 7.52 (m, 2H), 7.50-7.44
6
(m, 3H), 7.38-7.29 (m, 4H), 6.62 (s, 1H), 6.00 (s, 1H), 2.50 (s, 3H), 2.31 (s, 3H);
1
1
1
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1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
C{ H} NMR (100 MHz, DMSO-d ) δ 193.8, 157.9, 151.2, 138.3, 137.1, 133.8,
6
1
34.0, 130.2, 129.5, 129.2, 128.6, 128.4, 127.5, 122.4, 109.4, 48.4, 40.6, 40.4, 40.2,
-1
40.0, 39.8, 39.6, 39.4, 29.6 ppm; νmax(KBr)/cm = 2931, 2850, 1675, 1582, 1266,
-1
+
1
116, 700 cm ; HRMS-ESI (m/z) calcd for C H ClSO Na [M + Na] : 379.0535,
20 17 2
found 379.0529.
1-(5-(((4-Bromophenyl)thio)(phenyl)methyl)-2-methylfuran-3-yl)ethan-1-one (3i):
1
Brown oil (86%, 69 mg); H NMR (400 MHz, DMSO-d ) δ 7.53-7.46 (m, 4H), 7.36
6
(s, 2H), 7.34-7.22 (m, 3H), 6.65 (s, 1H), 5.98 (s, 1H), 2.49 (s, 3H), 2.33 (s, 3H);
1
3
1
C{ H} NMR (100 MHz, DMSO-d ) δ 193.8, 158.0, 151.2, 138.5, 134.2, 133.3,
6
32.3, 129.1, 128.7, 128.3, 122.4, 121.0, 109.4, 47.6, 29.5, 14.5 ppm; νmax(KBr)/cm-1
1
-1
= 3063, 2923, 1671, 1563, 1225, 949, 820, 744 cm ; HRMS-ESI (m/z) calcd for
+
C H BrSO [M + Na] : 423.0030, found 423.0023.
2
0
17
2
1-(5-(((3-Chlorophenyl)thio)(phenyl)methyl)-2-methylfuran-3-yl)ethan-1-one (3j):
1
1
Yellow oil (81%, 58 mg); IR: H NMR (400 MHz, DMSO-d ) H NMR (400 MHz,
6
DMSO-d ) δ 7.50-7.52 (d, J = 7.3 Hz, 2H), 7.38-7.44 (m, 3H), 7.29 (s, 4H), 6.62 (s,
6
1
3
1
1H), 6.00 (s, 1H), 2.50 (s, 3H), 2.31 (s, 3H); C{ H} NMR (100 MHz, DMSO-d ) δ
6
1
93.9, 158.1, 150.9, 138.1, 133.9, 131.5, 130.1, 129.2, 128.6, 128.5, 128.1, 124.5,
122.5, 109.5, 47.6, 40.6, 40.4, 40.2, 40.0, 39.8, 39.6, 39.4, 29.6, 14.5 ppm;
-1
-1
νmax(KBr)/cm = 3067, 2924, 1673, 1225, 951, 755, 700, 629 cm ; HRMS-ESI (m/z)
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+
calcd for C H ClSO Na [M + Na] : 379.0535, found 379.0529.
2
0
17
2
1
-(5-(((2-Fluorophenyl)thio)(phenyl)methyl)-2-methylfuran-3-yl)ethan-1-one (3k):
1
Yellow oil (89%, 61 mg); H NMR (400 MHz, DMSO-d ) δ 7.48 (d, J = 25.4 Hz, 3H),
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7.33 (d, J = 32.8 Hz, 4H), 7.16 (d, J = 34.7 Hz, 2H), 6.61 (s, 1H), 5.82 (s, 1H), 2.48 (s,
1
3
1
3
H), 2.31 (s, 3H); C{ H} NMR (100 MHz, DMSO-d ) δ 193.8, 162.8, 160.4, 151.1,
6
138.2, 134.8, 130.7-130.6 (d, JC-F = 8.2 Hz), 129.0, 128.6, 125.3 (d, JC-F = 3.6 Hz),
22.4, 121.0 (d, JC-F = 15.3 Hz), 116.1 (d, JC-F = 17.0 Hz), 109.4, 48.6, 29.5, 14.4 ppm;
1
19
-1
F NMR (376 MHz, DMSO-d ) δ -108.8 ppm; ν (KBr)/cm = 2933, 2581, 1718,
6
max
+
1675, 1284, 1117, 830, 700; HRMS-ESI (m/z) calcd for C H FSO Na [M + Na] :
2
0
17
2
3
63.0831, found 363.0833.
1-(5-(((2-Chlorophenyl)thio)(phenyl)methyl)-2-methylfuran-3-yl)ethan-1-one (3l):
1
Yellow oil (79%, 56 mg); H NMR (400 MHz, DMSO-d ) δ 7.52 (m, 2H), 7.46 (m,
6
2
H), 7.39 (m, 2H), 7.35 (m, 2H), 7.30-7.15 (m, 3H), 6.64 (s, 1H), 6.00 (s, 1H), 2.49 (s,
1
3
1
3H), 2.32 (s, 3H); C{ H} NMR (100 MHz, DMSO-d ) δ 193.9, 158.1, 150.9, 138.1,
6
1
33.9, 131.5, 130.1, 129.2, 128.6, 128.5, 128.1, 124.5, 122.5, 109.5, 47.6, 40.6, 40.4,
-1
40.2, 40.0, 39.8, 39.6, 39.4, 29.6, 14.5 ppm; νmax(KBr)/cm = 2991, 1757, 1667, 1459,
-
1
+
1
3
240, 1530, 780, cm ; HRMS-ESI (m/z) calcd for C H ClSO Na [M + Na] :
20 17 2
79.0535, found 379.0529.
1-(5-(((2-Bromophenyl)thio)(phenyl)methyl)-2-methylfuran-3-yl)ethan-1-one
1
(
3m): Brown oil (82%, 66 mg); H NMR (400 MHz, DMSO-d ) δ 7.60-7.50 (m, 1H),
6
7.49-7.43 (m, 2H), 7.36-7.09 (m, 6H), 6.65 (s, 1H), 5.98 (s, 1H), 2.49 (s, 3H), 2.32 (s,
1
3
1
3
H); C{ H} NMR (100 MHz, DMSO-d ) δ 193.8, 158.1 150.9, 138.0, 136.1 133.3,
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131.0, 129.2, 128.6, 128.5, 123.9, 122.5, 109.5, 47.9, 40.6, 40.4, 40.2, 40.00, 39.8,
-1
3
9.6, 39.4, 29.6, 14.6 ppm; νmax(KBr)/cm = 3061, 2923, 2852, 1674, 1563, 1226, 747,
-1
+
6
30 cm ; HRMS-ESI (m/z) calcd for C H BrSO [M + Na] : 423.0030, found
20 17 2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
423.0023.
1
-(5-(((2-(tert-Butyl)phenyl)thio)(phenyl)methyl)-2-methylfuran-3-yl)ethan-1-one
1
(3n): Yellow oil (76%, 57 mg); H NMR (400 MHz, DMSO-d ) δ 7.49 (d, J = 7.3 Hz,
6
2
9
H), 7.40 - 7.23 (m, 7H), 6.58 (s, 1H), 5.75 (s, 1H), 2.48 (s, 3H), 2.31 (s, 3H), 1.23 (s,
13
1
H); C{ H} NMR (100 MHz, DMSO-d ) δ 193.8, 157.7, 151.9, 150.5, 139.0, 131.5,
6
131.22 129.1, 128.6, 128.1, 126.3, 122.3, 109.0, 49.4, 34.5, 31.4, 29.5, 14.5 ppm;
νmax(KBr)/cm-1 = 3067, 2961, 2867, 1675, 1563, 1227, 950, 825, 630 cm-1;
+
HRMS-ESI (m/z) calcd for C H SO Na [M + Na] : 401.1551, found 401.1555.
2
4
26
2
1
-(5-(((3,4-Dichlorophenyl)thio)(phenyl)methyl)-2-methylfuran-3-yl)ethan-1-one
1
(
3o): Yellow oil (86%, 67 mg); H NMR (400 MHz, DMSO-d ) δ 7.62 (s, 1H), 7.50
6
(d, J = 6.0 Hz, 3H), 7.40-7.26 (m, 4H), 6.63 (s, 1H), 6.03 (s, 1H, 3.36 (s, 2H), 2.48 (s,
1
3
1
3
H), 2.32 (s, 3H); C{ H} NMR (100 MHz, DMSO) δ 193.8, 158.1, 151.0, 138.1,
135.7, 132.4, 131.9, 131.2, 131.1, 130.3, 129.2, 128.7, 128.5, 122.4, 109.6, 48.5, 29.6,
-1
1
4.6 ppm; νmax(KBr)/cm = 3062, 2926, 1669, 1570, 1435, 1229, 1029, 817, 712;
+
HRMS-ESI (m/z) calcd for C H Cl SO Na [M + Na] : 413.0146, found 413.013.
2
0
16
2
2
1-(5-(((3,5-Dimethylphenyl)thio)(phenyl)methyl)-2-methylfuran-3-yl)ethan-1-one
1
(
3p): Yellow oil (75%, 53 mg); H NMR (400 MHz, DMSO-d ) δ 7.49 (d, J = 7.4 Hz,
6
2H), 7.36 (t, J = 7.3 Hz, 2H), 7.29 (d, J = 7.2 Hz, 1H), 6.98 (s, 2H), 6.85 (s, 1H), 6.60
1
3
1
(
s, 1H), 5.79 (s, 1H), 2.49 (s, 3H), 2.32 (s, 3H), 2.18 (s, 6H); C{ H} NMR (100
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5
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6
MHz, DMSO) δ 193.8, 157.8, 151.7, 139.0, 138.5, 134.2, 129.3, 129.0, 129.0, 128.7,
-1
1
28.2, 122.4, 109.2, 48.9, 29.6, 21.1, 14.5 ppm; νmax(KBr)/cm = 2926, 2836, 1659,
+
1
468, 1137, 1023, 751; HRMS-ESI (m/z) calcd for C H NaO S [M + Na] :
2
2
22
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
373.1238, found 373.1235.
1
-(2-Methyl-5-(phenyl(thiophen-2-ylthio)methyl)furan-3-yl)ethan-1-one
(3q):
1
Yellow oil (55%, 36 mg); H NMR (400 MHz, CDCl ) δ 7.39-7.31 (m, 6H), 6.95-6.91
3
1
3
1
(
m, 2H), 6.39 (s, 1H), 5.21 (s, 1H), 2.57 (s, 3H), 2.34 (s, 3H); C{ H} NMR (100
MHz, CDCl ) δ 194.0, 158.6, 150.7, 137.8, 135.9, 132.0, 131.0, 128.7, 128.4, 128.1,
3
-1
127.4, 122.1, 109.3, 77.6, 77.0, 76.7, 54.3, 29.1, 14.5 ppm; νmax(KBr)/cm = 2924,
-1
1
712, 1468, 1227, 794, 696, 479 cm ; HRMS-ESI (m/z)calcd for C H NaO S [M +
18 16 2 2
+
Na] : 351.0489, found 351.0483.
1
-(2-Methyl-5-((naphthalen-1-ylthio)(phenyl)methyl)furan-3-yl)ethan-1-one (3r):
o
1
Yellow solid (55%, 42 mg); m.p. 99.0-99.6 C; H NMR (400 MHz, CDCl ) δ
3
7.75-7.70 (m, 2H), 7.68-7.66 (m, 2H), 7.44-7.42 (m, 4H), 7.32-7.22 (m, 4H), 6.40 (s,
1
3
1
1
H), 5.45 (s, 1H), 2.53 (s, 3H), 2.28 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ
3
194.0, 158.4, 151.5, 138.4, 134.5, 132.4, 128.9, 128.7, 128.3, 127.9, 127.7, 122.1,
-1
1
08.9, 77.4, 76.7, 51.2, 29.1, 14.5 ppm; νmax(KBr)/cm = 3036, 2922, 1671, 1571,
-1
+
1
412, 1229, 952, 705 cm ; HRMS-ESI (m/z)calcd for C H NaO S [M + Na] :
24 20 2
395.1082, found 395.1081.
1
-(5-((Adamantan-1-yl)thio)(phenyl)methyl)-2-methylfuran-3-yl)ethan-1-one (3s):
o
1
White solid (91%, 69 mg); m.p. 105-107 C; H NMR (400 MHz, CDCl ) δ 7.37 (s,
3
2
H), 7.32 (t, J = 7.5 Hz, 2H), 7.25 (d, J = 8.0 Hz, 1 H), 6.43 (s, 1 H), 5.14 (s, 1 H),
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2.54 (s, 3 H), 2.36 (s, 3 H), 2.01 (s, 3 H), 1.85 (s, 6 H), 1.67 (s, 6 H); C{ H} NMR
(
100 MHz, CDCl ) δ 194.7, 158.5, 154.4, 141.6, 129.2, 128.6, 127.9, 122.7, 108.8,
3
-1
4
7.8, 44.2, 42.6, 36.7, 30.3, 29.7, 15.1 ppm; νmax(KBr)/cm = 3057, 2910, 2851, 1674,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
+
1563, 1406, 1227, 739, 702, cm ; HRMS-ESI (m/z)calcd for C H NaO S [M + Na] :
2
4
28
2
4
03.1707, found 403.1698.
1-(5-((Benzylthio)(phenyl)methyl)-2-methylfuran-3-yl)ethan-1-one (3t): Yellow
1
oil (93%, 62 mg); H NMR (400 MHz, CDCl ) δ 7.35-7.25 (m, 10H), 6.41 (s, 1H),
3
13
1
4
.86 (s, 1H), 3.70- 3.59 (dd, 2H), 2.52 (s, 3H), 2.34 (s, 3H); C{ H} NMR (100 MHz,
CDCl ) δ 194.0, 158.3, 151.8, 138.5, 137.5, 129.0, 128.8, 128.6, 128.4, 127.9, 127.2,
3
-1
1
22.1, 108.5, 77.5, 77.2, 76.8, 46.2, 36.6, 29.2, 14.6 ppm; νmax(KBr)/cm = 2935,
-1
2836, 2046, 1866, 1670, 1578, 1477, 1029 cm ; HRMS-ESI (m/z) calcd for
+
C H SO Na [M + Na] : 359.1082, found 359.1076.
2
1
20
2
1
-(2-Methyl-5-((phenethylthio)methyl)furan-3-yl)ethan-1-one (3u): Yellow oil
1
(88%, 48 mg); H NMR (400 MHz, DMSO-d ) δ 7.27 (t, J = 7.3 Hz, 2H), 7.22-7.13
6
(
m, 3H), 6.61 (s, 1H), 3.75 (s, 2H), 2.80 (t, J = 7.2 Hz, 2H), 2.71 (t, J = 7.3 Hz, 2H),
1
3
1
2.50 (s, 3H), 2.34 (s, 3H); C{ H} NMR (100 MHz, DMSO-d ) δ 194.0, 157.5, 150.2,
6
1
40.9, 129.0, 128.8, 126.6, 122.4, 108.7, 35.6, 32.9, 29.6, 27.4, 14.6 ppm;
-1
νmax(KBr)/cm = 3034, 2925, 1672, 1571, 1021, 726; HRMS-ESI (m/z) calcd for
+
C H SO Na [M + Na] : 297.0925, found 297.0919.
1
6
18
2
1
-(5-((Butylthio)methyl)-2-methylfuran-3-yl)ethan-1-one (3v): Yellow oil (92%,
1
21 mg); H NMR (400 MHz, DMSO-d ) δ 6.61 (s, 1H), 3.73 (s, 2H), 2.52 (s, 3H),
6
2
.49 (d, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.55-1.44 (m, 2H), 1.36 (dt, J = 14.6, 7.3 Hz,
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5
5
5
5
5
5
6
1
3
1
2H), 0.88 (t, J = 7.3 Hz, 3H); C{ H} NMR (100 MHz, DMSO-d ) δ 194.0, 157.3,
6
-1
1
2
50.4, 122.5, 108.4, 31.2, 31.1, 29.6, 27.4, 21.8, 14.5, 14.0 ppm; νmax(KBr)/cm =
930, 2127, 1662, 1021, 826, 764; HRMS-ESI (m/z) calcd for C H NaO S [M +
1
2
18
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
Na] : 249.0925, found 249.0922.
1
-(5-((Cyclohexylthio)methyl)-2-methylfuran-3-yl)ethan-1-one (3w): Yellow oil
1
(89%, 45 mg); H NMR (400 MHz, DMSO-d ) δ 6.59 (s, 1H), 3.76 (s, 2H), 2.67 (s,
6
1
H), 2.51 (s, 3H), 2.36 (s, 3H), 1.91 (s, 2H), 1.68 (s, 2H), 1.56 (s, 1H), 1.26 (s, 5H);
13
1
C{ H} NMR (100 MHz, DMSO-d ) δ 194.0, 157.2, 150.8, 122.5, 108.2, 43.2, 33.4,
6
-1
29.6, 26.0, 25.8, 14.5 ppm; νmax(KBr)/cm = 2927, 1673, 1569, 1416, 854, 616;
+
HRMS-ESI (m/z) calcd for C H SO Na [M + Na] : 275.1082, found 275.1081.
1
4
20
2
1-(5-((4-Ethylphenyl)(p-tolylthio)methyl)-2-methylfuran-3-yl)ethan-1-one (3x):
1
Yellow oil (80%, 58 mg); H NMR (400 MHz, DMSO-d ) δ 7.38 (d, J = 8.0 Hz, 2H),
6
7
.26 (d, J = 8.1 Hz, 2H), 7.18 (s, 2H), 7.08 (d, J = 8.1 Hz, 2H), 6.57 (s, 1H), 5.69 (s,
1H), 2.56 (d, J = 22.7 Hz, 2H), 2.47 (s, 3H), 2.30 (s, 3H), 2.23 (s, 3H), 1.13 (s, 3H);
1
3
1
C{ H} NMR (100 MHz, DMSO-d ) δ 193.8, 157.6, 151.9, 143.7, 137.4, 136.1,
6
132.0, 131.1, 130.0, 128.5, 128.4, 122.4, 109.0, 49.4, 29.5, 28.2, 21.0, 15.8 14.5 ppm;
νmax(KBr)/cm-1 = 2966, 2926, 1676, 1563, 1404, 1227, 951, 808, 631 cm-1;
+
HRMS-ESI (m/z) calcd for C H NaO S [M + Na] : 421.1238, found 421.1238.
2
6
22
2
1-(5-((3-Bromophenyl)(p-tolylthio)methyl)-2-methylfuran-3-yl)ethan-1-one (3y):
1
Yellow oil (82%, 68 mg); H NMR (400 MHz, DMSO-d ) δ 7.63 (s, 1H), 7.48 (d, J =
6
7.8 Hz, 2H), 7.31 (s, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.10 (s, 2H), 6.62 (s, 1H), 5.80 (s,
1
3
1
1
H), 2.49 (s, 3H), 2.33 (s, 3H), 2.25 (s, 3H); C{ H} NMR (100 MHz, DMSO-d ) δ
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193.9, 158.0, 151.0, 141.6, 137.9, 132.4, 131.3, 131.2, 131.1, 130.2, 130.2, 130.1,
-1
1
27.7, 122.4, 122.1, 109.4, 48.7, 29.6, 21.1, 14.5 ppm; νmax(KBr)/cm = 2925, 2857,
-1
1
672, 1571, 1411, 1234, 804, 699 cm ; HRMS-ESI (m/z)calcd for C H BrO SNa
2
1
20
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
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2
2
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3
3
3
3
3
3
3
4
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4
4
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5
5
5
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5
6
0
1
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9
0
1
2
3
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7
8
9
0
1
2
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
[M + Na] : 437.0187, found 437.0182.
1
-(2-Methyl-5-((p-tolylthio)methyl)furan-3-yl)ethan-1-one (3z): Yellow oil (82%,
1
43 mg); H NMR (400 MHz, DMSO-d ) δ 7.50 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1
6
1
3
1
Hz, 2H), 6.74 (s, 1H), 4.38 (s, 2H), 2.71 (s, 3H), 2.53 (s, 3H), 2.48 (s, 3H); C{ H}
NMR (100 MHz, DMSO-d ) δ 193.7, 157.4, 149.5, 136.5, 131.8, 130.2, 130.1, 122.4,
6
-1
108.9, 30.4, 29.4, 20.9, 14.4 ppm; νmax(KBr)/cm = 3016, 2921, 1675, 1565, 1232,
-1
+
9
53, 805, 632 cm ; HRMS-ESI (m/z)calcd for C H NaO S [M + Na] : 283.0769,
15 16 2
found 283.0760.
1
-(2-Methyl-5-((p-tolylthio)(triisopropylsilyl)methyl)furan-3-yl)ethan-1-one (3aa):
1
Yellow oil (94%, 74 mg); H NMR (400 MHz, DMSO-d ) δ 7.18 (d, J = 7.8 Hz, 2H),
6
7.10 (d, J = 6.8 Hz, 2H), 6.38 (s, 1H), 3.97 (s, 1H), 2.48 (s, 3H), 2.28 (s, 3H), 2.24 (s,
1
3
1
3
H), 1.25 (dd, J = 14.5, 7.1 Hz, 3H), 1.09 (dd, J = 20.2, 7.2 Hz, 18H); C{ H} NMR
(100 MHz, DMSO-d ) δ 193.9, 156.5, 152.5, 136.4, 133.1, 130.2, 129.8, 122.7, 107.4,
6
-1
3
0.0, 29.5, 21.0, 19.0, 14.6, 11.6; νmax(KBr)/cm = 2924, 1672, 1564, 140, 1228,
+
1
020, 813, 743; HRMS-ESI (m/z) calcd for C H SiSO [M + H] : 417.2277, found
2
4
37
2
417.2275.
6
,6-Dimethyl-2-(phenyl(p-tolylthio)methyl)-6,7-dihydrobenzofuran-4(5H)-one
1
(3ab): Yellow oil (71%, 53 mg); H NMR (400 MHz, DMSO-d ) δ 7.47 (d, J = 7.3
6
Hz, 2H), 7.37 - 7.23 (m, 5H), 7.08 (s, 2H), 6.40 (s, 1H), 5.79 (s, 1H), 2.71 (s, 2H),
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3
1
2.51 (s, 2H), 2.24 (s, 3H), 1.03 (s, 6H); C{ H} NMR (100 MHz, DMSO-d ) δ 193.3,
6
1
5
66.8, 154.7, 138.7, 137.7, 132.4, 130.6, 130.1, 129.1, 128.6, 128.3, 120.2, 104.6,
-1
1.7, 49.6, 35.4, 28.5, 28.1, 21.1 ppm; νmax(KBr)/cm = 2985, 1727, 1689, 1382, 1240,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
+
1052, 693 cm ; HRMS-ESI (m/z)calcd for C H NaO S [M + Na] : 399.1389, found
2
4
24
2
3
99.1385.
2-Methyl-5-(phenyl(p-tolylthio)methyl)-3-tosylfuran (3ac): Yellow oil (56%, 50
1
mg); H NMR (400 MHz, DMSO-d ) δ 7.75 (d, J = 7.9 Hz, 2H), 7.45 - 7.22 (m, 7H),
6
7
.18 (d, J = 7.8 Hz, 2H), 7.00 (d, J = 7.7 Hz, 2H), 6.44 (d, s, 1H), 5.69 (s, 1H), 2.47 (s,
1
3
1
3H), 2.39 (s, 3H), 2.21 (d, J = 8.7 Hz, 3H); C{ H} NMR (100 MHz, DMSO-d ) δ
6
1
56.2, 153.0, 144.6, 139.5, 138.2, 137.9, 132.8, 130.5, 130.2, 130.0 129.1, 128.6,
-1
128.3, 127.0, 123.4, 108.2, 49.5, 21.5, 21.0, 13.0 ppm; νmax(KBr)/cm = 3040, 2926,
-1
2
853, 1671, 1571, 1405, 1231, 952, 761, 698, 629 cm ; HRMS-ESI (m/z)calcd for
+
C H O S [M + H] : 449.1240, found 449.1241.
2
6
25
3 2
Butyl 2-Methyl-5-(phenyl(p-tolylthio)methyl)furan-3-carboxylate (3ad): Yellow
1
oil (81%, 64 mg); H NMR (400 MHz, DMSO-d ) δ 7.34-7.05 (m, 9H), 6.40 (s, 1H),
6
5.76 (s, 1H), 4.12 (m, 2H), 3.34 (s, 3H), 2.24 (s, 3H), 1.58 (m, 2H), 1.36(m, 2H), 0.89
1
3
1
(
m, 3H); C{ H} NMR (100 MHz, DMSO-d ) δ 163.4, 158.9, 152.1, 138.8, 137.6,
6
1
32.1, 130.9, 130.1, 129.1, 128.6, 128.2, 114.0, 109.0, 64.0, 49.4, 40.6, 40.4, 40.2,
-1
40.0, 39.8, 39.6, 39.4, 30.7, 21.1, 19.2, 14.0 ppm; νmax(KBr)/cm = 2951, 1712, 1649,
-1
1
427, 1234, 1073, 1009, 806 cm ; HRMS-ESI (m/z)calcd for C H NaO S [M + Na]
24 26 3
+: 417.1500, found 417.1500.
tert-Butyl 2-Methyl-5-(phenyl(p-tolylthio)methyl)furan-3-carboxylate (3ae):
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Yellow oil (85%, 67 mg); H NMR (400 MHz, DMSO-d ) δ 7.46-7.44 (m, 2H),
6
7
3
.38-7.33 (m, 5H), 7.26-7.07 (m, 2H), 6.35 (s, 1H), 5.75 (s, 1H), 3.36 (s, 2H), 2.45 (s,
13
1
H), 2.27 (s, 3H), 1.46 (s, 9H); C{ H} NMR (100 MHz, DMSO-d ) δ 162.7, 158.3,
6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
151.8, 138.9, 137.5, 131.9, 134.0, 130.1, 129.6, 129.0, 128.6, 128.2, 115.4, 109.2,
6.4, 80.7, 49.4, 40.7, 40.4, 40.2, 40.0, 39.8, 39.6, 39.4, 28.3, 21.1, 14.0 ppm;
9
-1
-1
νmax(KBr)/cm = 2973, 1707, 1591, 1402, 1243, 1164, 1080, 804 cm ; HRMS-ESI
+
(
m/z)calcd for C H NaO S [M + Na] : 417.1500, found 417.1500.
2
4
26
3
Ethyl 2-Cyclopropyl-5-(phenyl(p-tolylthio)methyl)furan-3-carboxylate (3af):
1
Yellow oil (86%, 67 mg); H NMR (400 MHz, DMSO-d ) δ 7.43 (s, 2H), 7.29 (d, J =
6
4
7.6 Hz, 5H), 7.09 (d, J = 7.6 Hz, 2H), 6.31 (s, 1H), 5.71 (s, 1H), 4.19 (s, 2H), 2.66 (s,
1
3
1
1H), 2.24 (s, 3H), 1.25 (s, 3H), 1.02 (s, 2H), 0.79 (s, 2H); C{ H} NMR (100 MHz,
DMSO-d ) δ 163.5, 162.6, 151.0, 138.7, 137.6, 132.3, 130.8, 130.0, 129.0, 128.5,
6
-1
1
28.2, 113.4, 109.1, 60.3, 49.4, 21.1, 14.6, 9.4, 9.1, 8.9 ppm; νmax(KBr)/cm = 2926,
-1
1707, 1590, 1308, 1229, 1060, 804, 709 cm ; HRMS-ESI (m/z)calcd for
+
C H NaO S [M + Na] : 415.1344, found 415.1341.
2
4
24
3
Ethyl 2-Phenyl-5-(phenyl(p-tolylthio)methyl)furan-3-carboxylate (3ag): Yellow
1
oil (63%, 54 mg); H NMR (400 MHz, DMSO-d ) δ 7.81 (s, 2H), 7.54 (d, J = 7.3 Hz,
6
2
H), 7.49 - 7.24 (m, 8H), 7.13 (s, 2H), 6.60 (s, 1H), 5.90 (s, 1H), 4.21 (s, 2H), 2.26 (s,
1
3
1
3H), 1.22 (s, 3 H); C{ H} NMR (100 MHz, DMSO-d ) δ 162.9, 156.3, 153.4, 138.5,
6
1
37.7, 136.5, 132.3, 130.1, 130.0, 129.7, 129.2, 128.7, 128.6, 128.4, 128.3, 114.5,
-1
111.2, 60.8, 49.4, 21.0, 14.4 ppm; νmax(KBr)/cm = 2963, 1710, 1549, 1476, 1386,
-1
1
249, 1064, 1028, 801, 688, 495 cm ; HRMS-ESI (m/z)calcd for C H NaO S [M +
27 24 3
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