Metal-Free Oxidative Esterification of Ketones and Potassium Xanthates: Selective Synthesis of α-Ketoesters and Esters

Article abstract of DOI:10.1021/acs.joc.9b03272

A novel and efficient oxidative esterification for the selective synthesis of α-ketoesters and esters has been developed under metal-free conditions. In the protocol, various α-ketoesters and esters are available in high yields from commercially available ketones and potassium xanthates. Mechanistic studies have proven that potassium xanthate not only promotes oxidative esterification but also provides an alkoxy moiety for the reaction, which involves the cleavage and reconstruction of C-O bonds.

Full text of DOI:10.1021/acs.joc.9b03272

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Article
Metal-free Oxidative Esterification of Ketones and Potassium
Xanthates: Selective Synthesis of #-Ketoesters and Esters
Xianglin Luo, Runfa He, Qiang Liu, Yanping Gao, Jingqing Li,
Xiuwen Chen, Zhongzhi Zhu, Yubing Huang, and Yibiao Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03272 • Publication Date (Web): 25 Mar 2020
Downloaded from pubs.acs.org on March 26, 2020
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Metal-free Oxidative Esterification of Ketones and
Potassium Xanthates: Selective Synthesis of α-Ketoesters
and Esters
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Xianglin Luo, a Runfa He, a Qiang Liu, a,b Yanping Gao, a Jingqing Li, a Xiuwen Chen, a Zhongzhi
Zhu, a Yubing Huang* a and Yibiao Li* a
aSchool of Biotechnology and Health Sciences, Wuyi University, Jiangmen, Guangdong Province
529090, China; bCenter of Basic Molecular Science, Department of Chemistry, Tsinghua
University, Beijing 100084, China
E-mail: wyuchemhyb@126.com; leeyib268@126.com
O
I2
OR2
R1
ROCS K
2


acts as a promoter
acts as a reactant
DMSO/H2O (1:2)
S
O
O
ROCS K
2
25 examples
+
R1
KS
(R1 = Ar or Het)
OR2
 Cleavage and reconstruction of C-O bonds
 Highly selective synthesis
O
NH4I
R1 OR2
DMSO/H2O (4:1)
12 examples
Abstract: A novel and efficient oxidative esterification for the selective synthesis of
α-ketoesters and esters has been developed under metal-free conditions. In the
protocol, various α-ketoesters and esters are available in high yields from
commercially available ketones and potassium xanthates. Mechanistic studies have
proven that potassium xanthate not only promotes oxidative esterification but also
provides an alkoxy moiety for the reaction, which involves the cleavage and
reconstruction of C-O bonds.
INTRODUCTION
α-Ketoesters and esters are key structural scaffolds in many biologically active
compounds, intermediates1 and pharmaceuticals.2 They are often used as synthetic
precursors for a variety of organic transformations,3 especially in the enantioselective
synthesis of chiral molecules.4 Traditional approaches for constructing α-ketoesters
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include esterification of α-ketoacyl halides5 or α-ketoacids,6 oxidation of α-hydroxy
esters7, etc.,8 but these approaches suffer from problems such as low conversion, large
amounts of byproducts and limited substrate scope. In recent years, effective
approaches to synthesize α-ketoesters have gradually emerged, such as oxidative
dehydrogenative coupling of α-carbonyl aldehydes and alcohols,9 decyanation
esterification of β-ketonitriles,10 copper-catalyzed aerobic oxidation of (hetero)aryl
acetimidates11 and oxidative esterification via C–C bond cleavage.12 Some of these
approaches require the use of transition metal catalysts, hypervalent iodine reagents or
difficult-to-prepare raw materials. The use of inexpensive and readily available
ketones as raw materials has also attracted many chemists, such as Jiao,13 Song,14
Guo15 and Wang,16 who have constructed a series of α-ketoesters through
Cu-catalyzed oxidative esterification, microfluidic synthesis or electrochemical
synthesis. Despite the diversity of synthetic strategies, continued exploration of
efficient strategies for constructing α-ketoesters using simple conditions and readily
available raw materials is still required.
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Scheme 1. Our Works to Construct Organic Molecules with Xanthates
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Our previous work:
Xanthate as a thiol surrogate for the construction of thienopyridines
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8
9
S
R2
ref.19a
O
Cu
R1
R1
a)
b)
N
+
N
KS
OEt
S
R2
S
OH
F
ref.19b
Pd/Cu
I
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R2
R1
R2
R1
+
+
KS
OEt
S
N
N
F
Xanthate as a promoter for the conversion of alkynes
R2
Semihydrogenation of alkynes
ref. 19c
ref. 19d
H2O
R1
R2
c)
R1
S
metal-free
KS
OEt
H2O
O
O
R1
R2
Oxidation of alkynes
d)
R1
R2
This work :
Xanthate as both reactant and promoter for the construction of a-ketoesters and esters
O
I2
OR
Ar
O
Het
DMSO/H2O (1:2)
O
S
Ar
Het
+
e)
KS
OR
O
NH4I
OR
Ar
Het
DMSO/H2O (4:1)
Xanthates are inexpensive and safe chemical materials that are readily prepared
on a large scale from inexpensive alcohols and carbon disulfide.17 Due to their high
reactivity and availability, xanthates have been used in organic conversion in
interesting ways.18 Recently, our group has committed to studying the application of
xanthates in organic synthesis for constructing diverse organic molecules.19 Xanthate
can act as a thiol surrogate to construct functionalized thienopyridines by
transition-metal-catalyzed thiolation cyclization processes19a-19b (Scheme 1, a and b).
Furthermore, xanthate can also act as a promoter for the semihydrogenation of
alkynes to synthesize (E)-alkenes19c (Scheme 1, c) or the oxidation of alkynes to
synthesize substituted benzils19d (Scheme 1, d). As part of our ongoing exploration of
the potential reactivity of xanthates, we would like to develop more conversion
reactions involving xanthates under simple reaction conditions. Herein, we propose a
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metal-free oxidative esterification for the selective synthesis of α-ketoesters and esters
from ketones and potassium xanthates. It is worth noting that potassium xanthate can
not only promote the oxidative esterification of ketones but also provide an alkoxy
moiety for the oxidative esterification reaction, wherein different C-O bonds can be
reconstructed through the divergent routes.
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RESULTS AND DISCUSSION
Acetophenone (1a) and potassium ethyl xanthate (2) were selected as model
substrates for condition optimization (Table 1). Initially, the reaction was conducted
with iodine (4 equiv) as an additive in DMSO at 80 °C for 12 h to give traces of 3a
and 4a (entry 1). We speculated that the addition of water was beneficial to this
oxidative esterification, so different proportions of a DMSO/H2O solvent mixture
were then examined (entries 2-6). When the DMSO/H2O (v/v = 1:2) solvent mixture
was used, the yield of product 3a was increased to 51% (entry 5). Increasing the
amount of potassium ethyl xanthate to 3 equivalents could increase the yield of 3a to
87% (entry 8), while reducing the amount of iodine to 2 equivalents rapidly decreased
the yield of 3a (entry 9). The effect of temperature on the reaction was also
investigated, and neither higher nor lower temperatures could further promote the
reaction (entries 10-11). No reaction occurred when iodine was removed from the
reaction (entry 12). Subsequently, the reaction was carried out with NH4I as an
additive in a DMSO/H2O solvent mixture at 150 °C to promote the formation of 4a
(entries 13-16). After screening different solvent mixture compositions, DMSO/H2O
(v/v = 4:1) was concluded to be most suitable for the formation of 4a, and the yield of
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4a was increased to 74% (entry 16). In addition, reducing the amount of potassium
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ethyl xanthate resulted in
a
lower yield of 4a (entry 17). When
8
9
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added as radical scavengers, the
oxidative esterification was not affected (Table 1, entry 18).
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Table 1. Optimization of the Reaction Conditions a
O
O
O
S
additive
OEt
OEt
+
+
KS
OEt
solvent, T
O
1a
2a
3a
4a
entry
1
additive (equiv)
I2 (4)
solvent (v/v)
DMSO
yield of 3a (%) b
yield of 4a (%) b
trace
n.r.
trace
44
trace
n.r.
n.r.
25
2
I2 (4)
DMSO/H2O (4:1)
DMSO/H2O (2:1)
DMSO/H2O (1:1)
DMSO/H2O (1:2)
DMSO/H2O (1:3)
DMSO/H2O (1:2)
DMSO/H2O (1:2)
DMSO/H2O (1:2)
DMSO/H2O (1:2)
DMSO/H2O (1:2)
DMSO/H2O (1:2)
DMSO/H2O (1:2)
DMSO/H2O (1:1)
DMSO/H2O (2:1)
3
I2 (4)
4
I2 (4)
5
I2 (4)
51
5
6
I2 (4)
16
trace
6
7 c
8 d
I2 (4)
78
I2 (4)
87
trace
7
9 d
I2 (2)
trace
26
10 e
11 f
12 d
13 g
14 g
15 g
I2 (4)
35
I2 (4)
85
7
-
n.r.
39
n.r.
trace
59
NH4I (2)
NH4I (2)
NH4I (2)
26
34
40
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16 g
17 h
18 i
NH4I (2)
NH4I (2)
I2 (4)
DMSO/H2O (4:1)
DMSO/H2O (4:1)
DMSO/H2O (1:2)
13
74
57
trace
83
trace
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a Reaction conditions: acetophenone 1a (0.5 mmol), EtOCS2K 2 (0.5 mol) and iodine in solvent (2
b
c
d
e
mL) at 80 °C for 12 h. Isolated yield. EtOCS2K (1.0 mol). EtOCS2K (1.5 mmol). EtOCS2K
f
g
h
(1.5 mmol,) at 60 °C. EtOCS2K (1.5 mmol) at 100 °C. EtOCS2K (1.5 mmol) at 150 °C.
EtOCS2K (1.0 mmol) at 150 °C. i TEMPO (1.5 mmol). n.r. = no reaction.
With the optimal reaction conditions in hand, the scope of ketones for the
synthesis of α-ketoesters was then investigated, and the results are summarized in
Scheme 2. The reaction of acetophenone containing a methyl substituent at the
ortho-position of the phenyl ring proceeded well to give the desired product (3b) in
64% yield. Both electron-rich groups (Me, iBu, Me2N, and Ph) and electron-deficient
groups (CN, I, Br, F and CF3) at the para-position of acetophenone were tolerated in
the oxidative esterification, and the reactions delivered the target products (3c-3k) in
moderate to excellent yields. When a trifluoromethyl substituent was present at the
meta-position of acetophenone, the reaction delivered the target product (3l) in a
moderate yield of 63%. Chloro-substituted acetophenones were suitable substrates,
and the reactions delivered 3m and 3n in yields of 86% and 84%, respectively.
1-(Benzo[d][1,3]dioxol-5-yl)ethanone
seemed
to
react
better
than
1-(2,3-dihydro-1H-inden-5-yl)ethanone, and the corresponding product (3o) was
obtained at a higher yield of 81%. Notably, 2-acetonaphthone was a good substrate to
deliver the corresponding product (3q) in 73% yield. In addition, thiophene could also
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be used in the oxidative esterification to give the target product (3r) in a lower yield.
Scheme 2. Substrate Scope of Ketones for the Synthesis of α-Ketoesters a,b
8
9
O
O
S
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I2
OEt
R1
R1
+
KS
OEt
DMSO/H2O (1:2)
80 oC, 12 h
O
1
2a
3
O
O
O
OEt
OEt
OEt
O
O
O
Me
Me
3a,
3d,
3c,
3f,
87%
74%
3b,
64%
O
O
O
OEt
OEt
OEt
OEt
O
O
Me
O
O
iBu
NC
F
N
Ph
Br
3e,
62%
Me
73%
78%
O
O
O
OEt
OEt
O
O
I
3g,
3h,
3i,
O
82%
49%
78%
O
O
OEt
OEt
OEt
O
O
O
F3C
3j,
74%
CF3
3l,
3k,
83%
63%
O
O
O
OEt
OEt
OEt
O
O
O
O
O
Cl
Cl
Cl
3n,
3m,
3o,
O
86%
84%
81%
O
O
OEt
OEt
OEt
S
O
O
O
3p,
41%
3q,
3r,
33%
73%
a Reaction conditions: ketone 1 (0.5 mmol), EtOCS2K 2a (3 equiv, 1.5 mmol) and iodine (4 equiv,
2.0 mmol) in DMSO/H2O (3 mL, v/v = 1:2) at 80 °C for 12 h. b Isolated yield.
Next, we investigated the reaction scope with respect to xanthates (Scheme 3).
Potassium xanthates containing various groups, such as propyl, isopropyl, n-butyl,
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isobutyl, n-pentyl and benzyl, were found to be compatible under the current
oxidative conditions. The reactions of the alkyl-containing xanthates with
acetophenone gave the corresponding products (3s-3w) in moderate to good isolated
yields. The application of potassium xanthate containing benzyl substituents to the
reaction was unsatisfactory, and only a trace amount of the desired product (3x) was
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detected.
Moreover,
the
reactions
of
4-methoxyacetophenone
and
4-phenylacetophenone with potassium butylxanthate could also proceed smoothly,
giving the target product (3y-3z) in 49% and 78% yields, respectively.
Scheme 3. Substrate Scope of Xanthates for the Synthesis of α-Ketoesters a,b
O
O
S
OR2
I2
+
R1
R1
KS
OR2
DMSO/H2O (1:2)
80 °C, 12 h
O
1
2
3
O
O
O
OnPr
OiBu
OiPr
OnBu
O
O
O
3t,
O
3u,
65%
Onpentyl
81%
3s,
83%
O
O
OBn
O
O
O
c
3v,
3w,
3x,
82%
78%
<5%
O
O
OnBu
OnBu
O
O
MeO
Ph
3y,
49%
3z,
78%
a Reaction conditions: ketone 1 (0.5 mmol), potassium xanthate 2 (3 equiv, 1.5 mmol) and iodine
(4 equiv, 2.0 mmol) in DMSO/H2O (3 mL, v/v = 1:2) at 80 °C for 12 h. b Isolated yield. c GC
yield.
Subsequently, to investigate the scope of this protocol for the synthesis of esters,
various aryl methyl ketones and potassium xanthates were examined using NH4I as an
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additive at 150 °C (Scheme 4). Gratifyingly, acetophenone bearing varied groups
(MeO, Ph and NO2) at the para-position reacted well with potassium ethyl xanthate,
and the reaction yielded the desired products (4a-4d) in moderate to good yields.
1-(Benzo[d][1,3]dioxol-5-yl)ethanone was also a good substrate to give the expected
product (4e) in 61% yield. Furthermore, potassium propylxanthate could also be
applied to the reaction (4f-4j), and the corresponding products were delivered in
moderate to good yields, wherein the products 4f and 4g were obtained in 76% and
73% yields, respectively. Pleasantly, phenylacetone was found to be applicable in this
oxidative esterification and converted to the desired product (4k) in 31% yield. In
addition, benzylideneacetone was proven to be an inappropriate substrate.
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Scheme 4. Substrate Scope for the Synthesis of Esters a,b
O
O
S
NH4I
OR2
R1
R1
+
KS
OR2
DMSO/H2O (4:1)
150 °C, 12 h
1
2
4
O
O
O
OEt
OEt
OEt
MeO
Ph
4a,
4d,
74%
4c,
78%
4b,
51%
O
O
O
O
O
OEt
OnPr
OEt
OnPr
OnPr
O2N
71%
4e,
4f,
76%
61%
O
O
O
OnPr
OnPr
MeO
Ph
F3C
4g,
73%
4h,
4k,
4i,
50%
49%
O
O
O
OEt
OEt
31%
c
4l,
<5%
4j,
41%
a Reaction conditions: ketone 1 (0.5 mmol), potassium xanthate 2 (3 equiv, 1.5 mmol) and NH4I (2
equiv, 2.0 mmol) in DMSO/H2O (2.5 mL, v/v = 4:1) at 150 °C for 12 h. b Isolated yield. c GC
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yield.
5
6
7
To further explore the applicable scope of the reaction, 4-methylpropiophenone
8
9
and butyrophenone were used instead of acetophenone under standard conditions
(Scheme 5). The reaction did not form α-ketoester derivatives as expected but
generated thioether products (6a and 6b) in excellent yields, which were probably
obtained by nucleophilic substitution of the -SMe produced by DMSO. We believe
that the presence of an α-alkyl substituent prevented the α-C atom of the ketone from
being further oxidized. Furthermore, we speculated that the oxidative esterification of
the ketones may occur via the formation of 2-iodomethyl ketone. Finally, we studied
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the preparation of thioether on
a
gram-scale, obtaining 0.49g of
2-(methylthio)-1-(p-tolyl)propan-1-one 6b in 75% yield, which confirmed the
practicability of this method in organic synthesis (See experiment section).
Scheme 5. Investigation of Other Ketones under Standard Conditions
O
O
S
I2 (508 mg, 2.0 mmol )
DMSO
Me
Me
+
(a)
KS
OEt
/H2O (1:2)
SMe
80 oC 12 h
5a
2a
6a,
82%
75 mg, 0.5 mmol
240 mg, 1.5 mmol
O
O
S
Me
Me
I2 (508 mg, 2.0 mmol )
+
KS
OEt
(b)
DMSO
/H2O (1:2)
SMe
81%
Me
Me
80 oC, 12 h
5b
2a
240 mg, 1.5 mmol
6b,
75 mg, 0.5 mmol
To explore the plausible mechanism of the oxidative esterification reaction, a series
of control experiments were performed (Scheme 6). First, since
2-iodo-1-phenylethanone (7) and phenylglyoxylic acid (8) could react with potassium
ethyl xanthate under the action of iodine and be converted to 3a in 76% and 63% GC
yields, respectively, they were considered to be possible reaction intermediates (Eqn.
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a). Subsequent experimental results indicated that 2-hydroxy-1-phenylethanone and
2-oxo-2-phenylacetaldehyde are not reaction intermediates (Eqn. b). To further
demonstrate the effect of xanthate, we conducted comparative experiments using
acetophenone and tert-butanol 11 as substrates (Eqn. c and Eqn. d). The formation of
different α-ketoesters could be detected only when potassium xanthate was added,
which demonstrated that xanthate not only acted as a reactant but also acted as a
promoter for the oxidative esterification (Eqn. d). Next, we tried to oxidize
compounds 12 and 14 directly to α-ketoesters in the presence of iodine and potassium
xanthate, but it did not work (Eqn. e and Eqn. f). When acetophenone and ethyl
xanthate were only reacted for 6 h, intermediate 15 ([M+H]+ = 255.0151) could be
detected in the reaction, which was confirmed by HRMS (Eqn. g). Compound 16
could be converted to 4a with 32% GC yield under the action of NH4I, which proved
that compound 16 may be an intermediate (Eqn. h). It is worth adding that the
reaction of acetophenone with compound 18 could also deliver the α-ketoester
product (3t) in good yield (Eqn. i). The isotopic labelling experiment using H2O18
were conducted to verify the oxygen atom of the oxidative esterification products may
not from water in this transformation (Eqn. j). It is possible to obtain oxygen atoms
from DMSO by Kornblum oxidation.
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Scheme 6. Mechanistic Studies
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O
O
O
7
O
I2 (508 mg, 2.0 mmol)
EtOCS2K (240 mg, 1.5 mmol)
OEt
OEt
3a
I
OH
76%, 63%
Eqn.a
or
DMSO (1 mL), H2O (2 mL)
O
O
O
80 oC, 12 h
8
123 mg, 0.5 mmol
75 mg, 0.5 mmol
O
O
I2 (508 mg, 2.0 mmol)
EtOCS2K (240 mg, 1.5 mmol)
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OH
3a,
n.r.
or
Eqn.b
Eqn.c
DMSO (1 mL), H2O (2 mL)
80 oC, 12 h
O
9
10
67 mg, 0.5 mmol
68 mg, 0.5 mmol
O
O
I2 (508 mg, 2.0 mmol)
K2CO3 (208 mg, 1.5 mmol)
DMSO (1 mL), H2O (2 mL)
80 oC, 12 h
OtBu
3aa,
n.r.
tBuOH
11
+
O
1a
60 mg, 0.5 mmol 110 mg, 1.5 mmol
O
O
O
I2 (508 mg, 2.0 mmol)
EtOCS2K (240 mg, 1.5 mmol)
OtBu
OEt
+
tBuOH
11
+
Eqn.d
Eqn.e
O
DMSO (1 mL), H2O (2 mL)
O
1a
80 oC, 12 h
3a,
O
36%
3aa,
52%
60 mg, 0.5 mmol
110 mg, 1.5 mmol
O
I2 (508 mg, 2.0 mmol)
EtOCS2K (240 mg, 1.5 mmol)
O
O
O
13,
n.r.
DMSO (1 mL), H2O (2 mL)
80 oC, 12 h
12
106 mg, 0.5 mmol
O
O
I2 (508 mg, 2.0 mmol)
EtOCS2K (240 mg, 1.5 mmol)
OEt
S
OEt
3a,
n.r.
Eqn.f
O
DMSO (1 mL), H2O (2 mL)
80 oC, 12 h
S
14
120 mg, 0.5 mmol
O
O
I2 (508 mg, 2.0 mmol)
EtOCS2K (240 mg, 1.5 mmol)
S
OEt
15, D
etected by HRMS
Eqn.g
Eqn.h
([M + H]+ = 255.0151)
DMSO (1 mL), H2O (2 mL)
80 oC, 6 h
O
S
1a
60 mg, 0.5 mmol
O
O
O
S
NH4I (145 mg, 1.0 mmol)
OH
OEt
+
S
OEt
DMSO (2 mL), H2O (0.5 mL)
150 oC, 12 h
16
17,
62%
4a,
32%
113 mg, 0.5 mmol
O
O
S
OiPr
I2 (508 mg, 2.0 mmol)
iPrO
+
S
3t,
75%
OiPr
Eqn.i
Eqn.j
S
DMSO (1 mL), H2O (2 mL)
80 oC, 12 h
O
S
1a
18
60 mg, 0.5 mmol 405 mg, 1.5 mmol
O
O
O
I2 (508 mg, 2.0 mmol)
EtOCS2K (240 mg, 1.5 mmol)
DMSO (1 mL), H2O18 (2 mL)
80 oC, 6 h
18OEt
OEt
or
18O
3a'
Not detected by HRMS
O
1a
3a''
Not detected by HRMS
60 mg, 0.5 mmol
Although the mechanism is not completely clear yet, a possible reaction pathway
for the formation of α-ketoesters and esters was proposed (Scheme 7). Initially, the
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iodine radical (I•) and methanthiol (CH3SH) are produced through a series of
transformations with I2 and DMSO. Iodine radicals can react with methanthiol to
liberate CH3S• radicals (Scheme 7, equations 1-2). The methylthiyl radical (CH3S•)
selectively adds to the C=C double bond of A from enol isomerism of acetophenone
to form intermediate B, which undergoes further single-electron oxidation to afford a
MeS-substituted carbocation C and produces thioether products 6.22 On the other hand,
the oxidation of potassium xanthates by I2 gives xanthogen disulfides. Subsequently,
xanthate radical are produced with the aid of methylthiyl radical or a thermal
decomposition process (Scheme 7, equation 3). Under the action of iodine,
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acetophenone (1) was converted to 2-iodo-1-phenylethanone D in media containing
23, 24
iodine
and then further converted to 2,2,2-triiodo-1-phenylethan-1-one E. The
xanthate radical selectively adds to the C=C double bond of enol J to form
intermediate carbon radical K, which undergoes further single-electron oxidation to
afford a xanthate-substituted carbocation L, followed by Kornblum oxidation under
the action of DMSO to generate compound M,25a, 25b, which could convert in situ to
phenylglyoxylic acid N through the departure of ethanol and CS2.25c Target product
3a was eventually obtained by dehydration condensation between phenylglyoxylic
acid N and ethanol with the aid of HI. In the presence of NH4I, iodine could be slowly
generated from NH4I after undergoing a series of reactions at a high temperature. 20a, 22
Under high-temperature conditions, intermediate D could be further converted to
intermediate E, followed by xanthate radical selectively adds to the carbonyl of
2,2,2-triiodo-1-phenylethan-1-one E gave the intermediate G. Subsequently, the
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intermediate G liberate CI3• radicals and release intermediate H. Intermediate H was
then decomposed into benzoic acid, which was ultimately converted to the desired
product 4a through dehydration condensation with ethanol.
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Scheme 7. Plausible Mechanistic Pathway

(1)
(2)
(CH3)2SO
MeSH
I
+ MeSH
MeS
S
+
HI
S
S
I
or
MeS
I2
(3)
EtOCS2K
S
S
S

EtO
OEt
EtO
OH
O
O
OH
OH
R
R
R
R
R
SET
MeS
R = H
H+
SMe
SMe
SMe
A
I2
1
6
C
B
R = H
O
I
O
HI
I
I
O
EtO
S
I
I
I
2 I2
S
I
C 3
O
G
S
I
S
F
OEt
D
E
2 HI
l
C 3
S
OH
O
OH
O
S
I
S
S
OEt
H2O
EtO
SSCOEt
O
H
I
J
K
H
I
CS2 EtOH
+
H+
SET
O
O
H+
S
OEt
S
OEt
DMSO
EtOH
Kornblum
oxidation
O
S
I
S
M
O
L
H2O
CS2 EtOH
+
OEt
O
O
4a
O
H
OEt
EtOH
O
H+
O
3a
N
Based on the results obtained in the control experiments, we used potassium
xanthate as a promoter to achieve oxidative esterification between acetophenone and
alcohols in the presence of I2. As shown in Scheme 8, when reducing the loading of
potassium xanthate to 2 equivalents and raising the temperature to 90 °C, the reaction
of acetophenone with neomenthol delivered corresponding products 3ab in yield of
77%, respectively. It could be seen that potassium xanthate has attractive application
potential in the synthesis of a-ketoesters via oxidative esterification.
Scheme 8. Oxidative Esterification Between Acetophenone and Alcohols
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Promoted by EtOCS2K and I2
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7
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9
O
O
I2 (508 mg, 2.0 mmol)
EtOCS2K (160 mg, 1.0 mmol)
O
HO
+
DMSO (1 mL), H2O (2 mL)
90 °C, 12 h
O
1a
60 mg, 0.5 mmol
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3ab,
312 mg, 2 mmol
77%
CONCLUSION
In summary, we have discovered a simple and practical protocol for the synthesis
of a range of valuable α-ketoester derivatives and ester derivatives from commercially
available ketones and potassium xanthates. With dimethyl sulfoxide as both solvent
and cooxidant, diverse α-ketoesters are offered in good yields under metal-free
conditions. In this protocol, potassium xanthate not only provides an alkoxy moiety
for the reaction through the cleavage of the C-O bond but also promotes oxidative
esterification, by which different C-O bonds can be reconstructed through divergent
routes. Furthermore, simple operations, inexpensive and readily available substrates,
broad substrate scopes and high selectivity provide a great advantage for oxidative
esterification. Ongoing studies are focusing on further studying the mechanism of this
reaction and expanding the synthetic application of potassium xanthates.
EXPERIMENTAL SECTION
General Information: Unless otherwise noted, all commercial materials and solvents
were used without further purification and all the reactions were carried out in a
1
Schlenk tube equipped with magnetic stir bar. H NMR spectra were recorded in
CDCl3 at 400 MHz (or 600 MHz) and 13C {1H} NMR spectra were recorded in CDCl3
at 100 MHz (or 150 MHz) respectively, H and C {1H} NMR were referenced to
1
13
CDCl3 at δ 7.26 and 77.0 respectively. GC–MS was obtained using electron ionization
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(Agilent Technologies 7890A/5975C). HRMS spectra were acquired using an Agilent
6210 ESI/TOF mass spectrometer and MAT 95XP (Double-focusing Magnetic Sector
Analyzer), Thermo (EI, 70eV). TLC was performed using commercially prepared
100-400 mesh silica gel plates (GF254), and visualization was effected at 254 nm. All
the other chemicals were purchased from Aldrich Chemicals. Commercial reagents
were used without further purification.
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General Procedure for the synthesis of α-ketoesters 3. A 25 mL Schlenk tube was
charged with aryl methyl ketone 1 (0.5 mmol), potassium xanthate 2 (240 mg, 3 equiv,
1.5 mmol), iodine (508 mg, 4 equiv, 2.0 mmol), DMSO (1 mL), H2O (2 mL) and a
o
magnetic stirring bar. The Schlenk tube was then immersed in an oil bath at 80 C
stirring for 12 h. After the reaction finished, the reaction mixture was diluted with
ethyl acetate and passed through Celite. After evaporation of the solvent the residue
was adsorbed on silica gel and the crude product was purified by column
o
chromatography (eluent: petroleum ether (60-90 C)/ethyl acetate = 20:1), affording
the α-ketoesters as a yellow liquid.
General Procedure for the synthesis of esters 4. A 25 mL Schlenk tube was
charged with aryl methyl ketone 1 (0.5 mmol), potassium xanthate 2 (240 mg, 3 equiv,
1.5 mmol), NH4I (2 equiv, 1.0 mmol), DMSO (2 mL), H2O (0.5 mL) and a magnetic
stirring bar. The Schlenk tube was then immersed in an oil bath at 150 oC stirring for
12 h. After the reaction finished, the reaction mixture was diluted with ethyl acetate
and passed through Celite. After evaporation of the solvent the residue was adsorbed
on silica gel and the crude product was purified by column chromatography (eluent:
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petroleum ether (60-90 C)/ethyl acetate = 20:1), affording the esters as a yellow
6
7
liquid.
8
9
Gram-scale synthesis of thioethers 6b: A 25 mL Schlenk tube was charged with
1-(p-tolyl)propan-1-one 5b (0.50g, 3.38 mmol), potassium ethyl xanthate (1.60g, 3
equiv, 10 mmol), iodine (3.4g, 4 equiv, 13.5 mmol), DMSO (1.5 mL), H2O (3 mL)
and a magnetic stirring bar. The Schlenk tube was then immersed in an oil bath at 80
oC stirring for 12 h. After the reaction finished, the reaction mixture was diluted with
ethyl acetate and passed through celite. After evaporation of the solvent the residue
was adsorbed on silica gel and the crude product was purified by column
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o
chromatography (eluent: petroleum ether (60-90 C)/ethyl acetate = 20:1), affording
the 2-(methylthio)-1-(p-tolyl)propan-1-one 6b (0.49g, 75 %) as a yellow liquid.
Ethyl-2-oxo-2-phenylacetate (3a)11: Brown liquid (77 mg, 87% yield); Rf = 0.48
(petroleum ether/ethyl acetate = 20:1); 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.6
Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.8 Hz, 2H), 4.45 (q, J = 7.2 Hz, 2H),
1.42 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.4, 163.8, 134.8,
132.5, 130.0, 128.8, 62.3, 14.1.
Ethyl-2-oxo-2-o-tolylacetate (3b)26: Yellow liquid (61 mg, 64% yield); Rf = 0.56
(petroleum ether/ethyl acetate = 20:1); 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.7
Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 8.0 Hz, 2H), 4.43 (q, J = 7.1 Hz, 2H),
2.61 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.8,
164.6, 141.3, 133.6, 132.3, 132.2, 131.3, 125.9, 62.2, 21.4, 14.1.
Ethyl-2-oxo-2-(p-tolyl)acetate (3c)9b: Yellow liquid (71 mg, 74% yield); Rf = 0.47
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(petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 8.2
Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 4.44 (q, J = 7.1 Hz, 2H), 2.43 (s, 3H), 1.41 (t, J =
7
8
9
13
7.2 Hz, 3H); C{1H} NMR (125 MHz, CDCl3) δ 186.1, 164.0, 146.2, 130.1, 130.0,
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129.6, 62.2, 21.9, 14.1.
Ethyl-2-(4-isobutylphenyl)-2-oxoacetate (3d): Yellow liquid (73 mg, 62% yield); Rf
= 0.48 (petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 7.93 (d,
J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 4.45 (q, J = 7.2 Hz, 2H), 2.56 (d, J = 7.2 Hz,
2H), 1.91 (dd, J = 13.5, 6.8 Hz, 1H), 1.43 (t, J = 7.2 Hz, 3H), 0.92 (s, 3H), 0.91 (s,
13
3H); C{1H} NMR (125 MHz, CDCl3) δ 186.1, 164.1, 149.9, 130.2, 130.0, 129.6,
62.2, 45.5, 30.1, 22.3, 14.1; ESI-HRMS (m/z): [M+H]+ calcd for C14H19O3, 235.1329,
found: 235.1326.
Ethyl-2-(4-(dimethylamino)phenyl)-2-oxoacetate (3e)27: Yellow liquid (81 mg,
1
73% yield); Rf = 0.52 (petroleum ether/ethyl acetate = 2:1); H NMR (500 MHz,
CDCl3) δ 7.90 (d, J = 9.1 Hz, 2H), 6.66 (d, J = 9.1 Hz, 2H), 4.41 (q, J = 7.2 Hz, 2H),
3.10 (s, 6H), 1.41 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 184.1,
165.0, 154.4, 132.5, 120.2, 110.8, 61.8, 40.0, 14.2.
Ethyl-2-([1,1'-biphenyl]-4-yl)-2-oxoacetate (3f)11: Yellow liquid (99 mg, 78% yield);
1
Rf = 0.62 (petroleum ether/ethyl acetate = 20:1); H NMR (400 MHz, CDCl3) δ 8.08
(t, J = 10.4 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 7.6 Hz, 2H), 7.47 (t, J = 7.4
Hz, 2H), 7.43 – 7.39 (m, 1H), 4.47 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 185.9, 163.8, 147.6, 139.4, 131.2, 130.6, 129.0,
128.6, 127.5, 127.3, 62.3, 14.1.
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ethyl 2-(4-cyanophenyl)-2-oxoacetate (3g)28: Yellow liquid (83 mg, 82% yield); Rf
= 0.49 (petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 8.12 (d,
J = 8.2 Hz, 2H), 7.79 (d, J = 8.3 Hz, 2H), 4.44 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (125 MHz, CDCl3) δ 184.4, 162.3, 135.5, 132.5 (2C), 130.3(2C),
117.8, 117.5, 62.8, 13.9. GC-MS (EI, 70 ev) m/z 203, 175, 130, 102.
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Ethyl-2-(4-iodophenyl)-2-oxoacetate (3h)8b: Yellow liquid (74 mg, 49% yield); Rf =
0.55 (petroleum ether/ethyl acetate = 20:1);1H NMR (400 MHz, CDCl3) δ 7.81 (d, J =
7.6 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 4.37 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz,
13
3H); C{1H} NMR (100 MHz, CDCl3) δ 185.4, 163.1, 138.2, 137.6, 131.1, 103.6,
62.5, 14.0.
Ethyl-2-(4-bromophenyl)-2-oxoacetate (3i)8b: Brown yellow liquid (100 mg, 78%
1
yield); Rf = 0.49 (petroleum ether/ethyl acetate = 20:1); H NMR (400 MHz, CDCl3)
δ 7.90 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 4.45 (q, J = 7.1 Hz, 2H), 1.42 (t, J
= 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.0, 163.1, 132.2, 131.4, 131.3,
130.4, 62.5, 14.0.
Ethyl-2-(4-fluorophenyl)-2-oxoacetate (3j)26: Yellow liquid (73 mg, 74% yield); Rf
1
= 0.48 (petroleum ether/ethyl acetate = 20:1); H NMR (500 MHz, CDCl3) δ 8.10 –
8.05 (m, 2H), 7.19 (dd, J = 11.9, 5.2 Hz, 2H), 4.44 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.2
13
Hz, 3H); C{1H} NMR (125 MHz, CDCl3) δ 184.5, 166.8 (d, JC-F =256.9 Hz, 1C),
163.4, 132.9 (d, JC-F =9.9 Hz, 1C), 128.9 (d, JC-F =2.9 Hz, 1C), 116.2 (d, JC-F =22.3 Hz,
1C), 62.5, 14.1.
Ethyl-2-(4-(trifluoromethyl)phenyl)-2-oxoacetate (3k): Brown liquid (102 mg,
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83% yield); Rf = 0.49 (petroleum ether/ethyl acetate = 20:1); H NMR (400 MHz,
CDCl3) δ 8.16 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 8.2 Hz, 2H), 4.48 (q, J = 7.1 Hz, 2H),
1.44 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 184.9, 162.8, 135.9,
135.6, 135.3, 130.4, 125.8 (q, JC-F =4.8 Hz, 1C), 62.7, 14.0; ESI-HRMS (m/z):
[M+Na]+ calcd for C11H9O3F3Na, 269.0396 , found: 269.0381.
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Ethyl 2-oxo-2-(3-(trifluoromethyl)phenyl)acetate (3l)29: Yellow liquid (77 mg,
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63% yield); Rf = 0.51 (petroleum ether/ethyl acetate = 20:1); H NMR (400 MHz,
CDCl3) δ 8.32 (s, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.67 (t, J =
7.8 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H); C{1H} NMR (100
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MHz, CDCl3) δ 184.6, 162.7, 133.2, 131.2, 131.1, 131.1, 131.1, 129.6, 126.8 (q, JC-F
=7.5 Hz, 1C), 62.8, 14.0.
Ethyl-2-(3-chlorophenyl)-2-oxoacetate (3m)26: Yellow liquid (91 mg, 86% yield);
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Rf = 0.62 (petroleum ether/ethyl acetate = 20:1); H NMR (400 MHz, CDCl3) δ 8.01
(s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H),
4.46 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
184.8, 162.9, 135.2, 134.7, 134.0, 130.1, 129.8, 128.2, 62.6, 14.0.
Ethyl 2-(3,4-dichlorophenyl)-2-oxoacetate (3n)30: Yellow liquid (103 mg, 86%
yield), Rf = 0.61 (petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3)
δ 8.14 (d, J = 2.0 Hz, 1H), 7.88 (dd, J = 8.4, 2.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H),
4.45 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
183.6, 162.8, 139.7, 133.7, 132.1, 131.8, 131.0, 129.0, 62.7, 14.0. GC-MS (EI, 70 ev)
m/z 246, 232, 218, 173, 145, 109.
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ethyl 2-(benzo[d][1,3]dioxol-5-yl)-2-oxoacetate (3o)31: Yellow liquid (90 mg, 81%
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yield); Rf = 0.62 (petroleum ether/ethyl acetate = 15:1); H NMR (500 MHz, CDCl3)
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δ 7.58 (dd, J = 8.2, 1.7 Hz, 1H), 7.44 (d, J = 1.7 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H),
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6.06 (s, 2H), 4.41 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H); C{1H} NMR (125
MHz, CDCl3) δ 184.4, 163.9, 153.4, 148.4, 127.7, 127.1, 108.5, 108.1, 102.2, 62.1,
14.0. GC-MS (EI, 70 ev) m/z 222, 149, 121, 65.
Ethyl-2-(2,3-dihydro-1H-inden-5-yl)-2-oxoacetate (3p): Yellow liquid (45 mg, 41%
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yield); Rf = 0.45 (petroleum ether/ethyl acetate = 20:1); H NMR (500 MHz, CDCl3)
δ 7.84 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 4.45 (q, J = 7.1 Hz,
2H), 2.97 (dd, J = 13.2, 7.2 Hz, 4H), 2.16 – 2.11 (m, 2H), 1.42 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 186.6, 164.3, 152.8, 145.2, 130.8, 128.8, 125.8,
124.7, 62.2, 33.2, 32.4, 25.3, 14.1; ESI-HRMS (m/z): [M+Na]+ calcd for C13H15O3,
219.1016, found: 219.1013.
Ethyl-2-(naphthalen-2-yl)-2-oxoacetate (3q)11: Yellow liquid (83 mg, 73% yield);
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Rf = 0.50 (petroleum ether/ethyl acetate = 20:1); H NMR (500 MHz, CDCl3) δ 8.56
(s, 1H), 8.05 (dd, J = 8.6, 1.6 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.7 Hz,
1H), 7.89 (d, J = 8.1 Hz, 1H), 7.68 – 7.63 (m, 1H), 7.59 (dd, J = 11.1, 4.0 Hz, 1H),
4.51 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
186.3, 163.9, 136.3, 133.5, 132.2, 130.0, 129.7, 129.6, 128.9, 127.9, 127.1, 123.9,
62.4, 14.1.
Ethyl-2-oxo-2-(thiophen-3-yl)acetate (3r)11: Yellow liquid (30 mg, 33% yield); Rf =
0.49 (petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 8.55 (dd, J
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= 2.8, 1.0 Hz, 1H), 7.69 (dd, J = 5.1, 0.9 Hz, 1H), 7.36 (dd, J = 5.1, 2.9 Hz, 1H), 4.42
(q, J = 7.1 Hz, 2H), 1.42 (dd, J = 8.9, 5.4 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3)
δ 178.1, 162.4, 137.8, 137.6, 127.8, 126.6, 62.5, 14.0.
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Propyl-2-oxo-2-phenylacetate (3s)11: Yellow liquid (80 mg, 83% yield); Rf = 0.49
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(petroleum ether/ethyl acetate = 20:1); H NMR (500 MHz, CDCl3) δ 8.00 (dd, J =
8.3, 1.2 Hz, 2H), 7.68 – 7.64 (m, 1H), 7.52 (t, J = 7.8 Hz, 2H), 4.35 (t, J = 6.7 Hz, 2H),
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1.80 (dt, J = 14.2, 7.1 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H); C{1H} NMR (125 MHz,
CDCl3) δ 186.5, 164.0, 134.9, 132.4, 130.0, 128.9, 67.7, 21.8, 10.3.
Isopropyl-2-oxo-2-phenylacetate (3t)11: Yellow liquid (62 mg, 65% yield); Rf =
0.55 (petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 7.99 (dd, J
= 8.3, 1.1 Hz, 2H), 7.67 – 7.64 (m, 1H), 7.51 (t, J = 7.8 Hz, 2H), 5.33 (td, J = 12.5,
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6.2 Hz, 1H), 1.42 (s, 3H), 1.41 (s, 3H); C{1H} NMR (125 MHz, CDCl3) δ 186.7,
163.6, 134.8, 132.4, 129.9, 128.9, 70.7, 21.7.
Butyl-2-oxo-2-phenylacetate (3u)11: Yellow liquid (83 mg, 81% yield); Rf = 0.58
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(petroleum ether/ethyl acetate = 20:1); H NMR (500 MHz, CDCl3) δ 7.99 (dd, J =
8.3, 1.1 Hz, 2H), 7.66 – 7.62 (m, 1H), 7.50 (t, J = 7.8 Hz, 2H), 4.38 (t, J = 6.7 Hz, 2H),
1.75 (dt, J = 14.6, 6.8 Hz, 2H), 1.42 (dt, J = 14.8, 7.5 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 186.4, 163.9, 134.8, 132.3, 129.9, 128.8, 66.0,
30.3, 18.9, 13.5.
Isobutyl 2-oxo-2-phenylacetate (3v)32: Yellow liquid (88.6 mg, 82% yield); Rf =
0.60 (petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 8.03 – 7.96
(m, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.8 Hz, 2H), 4.18 (d, J = 6.7 Hz, 2H),
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2.08 (dt, J = 13.4, 6.7 Hz, 1H), 1.00 (d, J = 6.8 Hz, 6H); C{1H} NMR (125 MHz,
CDCl3) δ 186.6, 164.1, 134.9, 132.5, 130.0 (2C), 128.9 (2C), 72.1, 27.7, 19.0 (2C).
GC-MS (EI, 70 ev) m/z 206, 123, 105, 77.
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Pentyl 2-oxo-2-phenylacetate (3w) 32: Yellow liquid (86 mg, 78% yield); Rf = 0.59
(petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 8.08 – 7.96 (m,
2H), 7.64 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H), 4.37 (t, J = 6.8 Hz, 2H), 1.84 –
1.70 (m, 2H), 1.42 – 1.32 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 186.4, 163.9, 134.8, 132.4, 129.9, 128.8, 66.3, 28.1, 27.8, 22.2, 13.8.
GC-MS (EI, 70 ev) m/z 220, 192, 178, 105, 77.
Butyl-2-(4-methoxyphenyl)-2-oxoacetate (3y)13: Brown liquid (58 mg, 49% yield);
Rf = 0.51 (petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 8.00 –
7.97 (m, 2H), 6.98 – 6.96 (m, 2H), 4.37 (t, J = 6.7 Hz, 2H), 3.89 (s, 3H), 1.75 (dd, J =
9.8, 5.3 Hz, 2H), 1.44 (dd, J = 15.1, 7.5 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H); 13C{1H}
NMR (125 MHz, CDCl3) δ 184.9, 164.9, 164.3, 132.5, 125.4, 114.2, 65.9, 55.6, 30.4,
19.0, 13.6.
Butyl-[1,1'-biphenyl]-4-carboxylate (3z)33: Yellow liquid (99 mg, 78% yield); Rf =
0.42 (petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 8.14 – 8.06
(m, 2H), 7.76 – 7.72 (m, 2H), 7.64 (dd, J = 5.2, 3.3 Hz, 2H), 7.49 (dd, J = 10.1, 4.7
Hz, 2H), 7.43 (ddd, J = 7.4, 3.7, 1.1 Hz, 1H), 4.42 (t, J = 6.7 Hz, 2H), 1.79 (dt, J =
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14.6, 6.8 Hz, 2H), 1.48 (dt, J = 15.0, 7.5 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H); C{1H}
NMR (125 MHz, CDCl3) δ 186.0, 164.0, 147.5, 139.4, 131.1, 130.6, 129.0, 128.6,
127.5, 127.3, 66.1, 30.4, 19.0, 13.6.
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Ethyl benzoate (4a)34: Yellow liquid (56 mg, 74% yield); Rf = 0.47 (petroleum
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ether/ethyl acetate = 20:1); H NMR (500 MHz, CDCl3) δ 8.05 (dd, J = 8.2, 1.2 Hz,
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2H), 7.74 – 7.49 (m, 1H), 7.43 (dd, J = 10.8, 4.7 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H),
1.40 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 166.6, 132.8, 130.4,
129.5, 128.3, 60.9, 14.3.
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Ethyl-4-methoxybenzoate (4b)35: Yellow liquid (46 mg, 51% yield); Rf = 0.63
(petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 8.01 – 7.98 (m,
2H), 6.91 (dd, J = 9.3, 2.3 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 1.38 (t, J =
13
7.1 Hz, 3H); C{1H} NMR (125 MHz, CDCl3) δ 166.4, 163.2, 131.5, 122.9, 113.5,
60.6, 55.4, 14.4; ESI-HRMS (m/z): [M+Na]+ calcd for C10H13O3, 181.0859, found:
181.0849.
Ethyl-[1,1'-biphenyl]-4-carboxylate (4c): Yellow liquid (88 mg, 78% yield); Rf =
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0.61 (petroleum ether/ethyl acetate = 20:1); H NMR (500 MHz, CDCl3) δ 8.12 (d, J
= 8.3 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 7.3 Hz, 2H), 7.47 (t, J = 7.6 Hz,
2H), 7.40 (t, J = 7.3 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 166.5, 145.5, 140.0, 130.0, 129.2, 128.9, 128.1,
127.2, 127.0, 61.0, 14.3; ESI-HRMS (m/z): [M+Na]+ calcd for C15H15O2, 227.1066,
found: 227.1055.
Ethyl-4-nitrobenzoate (4d)36: Yellow liquid (69 mg, 71% yield); Rf = 0.56
(petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 8.31 – 8.27 (m,
2H), 8.23 – 8.20 (m, 2H), 4.43 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (125 MHz, CDCl3) δ 164.7, 150.4, 135.8, 130.6, 123.5, 62.0, 14.2.
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Ethyl benzo[d][1,3]dioxole-5-carboxylate (4e): Yellow liquid (59 mg, 61% yield);
Rf = 0.59 (petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 7.67 –
7.64 (m, 1H), 7.47 (t, J = 2.7 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.03 (s, 2H), 4.33 (q,
J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 166.0,
151.4, 147.6, 125.2, 124.5, 109.4, 107.9, 101.7, 60.9, 14.3; ESI-HRMS (m/z):
[M+Na]+ calcd for C10H13O2, 165.0910, found: 165.0904.
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Propyl-benzoate (4f): Yellow liquid (69 mg, 84% yield); Rf = 0.59 (petroleum
ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 8.08 – 8.04 (m, 2H), 7.58 –
7.53 (m, 1H), 7.46 – 7.42 (m, 2H), 4.28 (t, J = 6.7 Hz, 2H), 1.80 (dd, J = 14.1, 6.8 Hz,
2H), 1.03 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 166.7, 132.8, 130.4,
129.5, 128.3, 66.5, 22.1, 10.5; ESI-HRMS (m/z): [M+Na]+ calcd for C10H13O2,
165.0910, found: 165.0904.
Propyl-4-methoxybenzoate (4g)35: Yellow liquid (71 mg, 73% yield); Rf = 0.46
(petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 8.02 – 7.98 (m,
2H), 6.93 – 6.90 (m, 2H), 4.24 (t, J = 6.7 Hz, 2H), 3.85 (s, 3H), 1.77 (dd, J = 14.2, 6.9
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Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H); C{1H} NMR (125 MHz, CDCl3) δ 166.4, 163.2,
131.5, 122.9, 113.5, 66.2, 55.4, 22.1, 10.5.
Propyl [1,1'-biphenyl]-4-carboxylate (4h)37: Yellow liquid (59 mg, 49% yield); Rf =
0.61 (petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 8.26 – 8.06
(m, 2H), 7.72 – 7.68 (m, 2H), 7.66 (dd, J = 5.2, 3.3 Hz, 2H), 7.50 (dd, J = 10.3, 4.8
Hz, 2H), 7.46 – 7.38 (m, 1H), 4.34 (t, J = 6.7 Hz, 2H), 1.98 – 1.70 (m, 2H), 1.08 (t, J
= 7.4 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 166.6, 145.5, 140.1, 130.1, 129.3,
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128.9, 128.1, 127.3, 127.0, 66.6, 22.2, 10.6.
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0.51 (petroleum ether/ethyl acetate = 20:1); H NMR (500 MHz, CDCl3) δ 8.18 (d, J
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= 8.1 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 4.34 (t, J = 6.7 Hz, 2H), 2.12 – 1.69 (m, 2H),
1.06 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 165.5, 134.3 (q, J = 32.4
Hz), 133.7, 129.9, 125.4 (q, J = 3.8 Hz), 123.7 (q, J = 273.4 Hz), 67.1, 22.0, 10.5;
ESI-HRMS (m/z): [M+H]+ calcd for C11H12F3O2, 233.0784, found: 233.0784.
Propyl 2-naphthoate (4j): Yellow liquid (44 mg, 41% yield); Rf = 0.52 (petroleum
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ether/ethyl acetate = 20:1); H NMR (500 MHz, CDCl3) δ 8.64 (s, 1H), 8.10 (dd, J =
8.6, 1.7 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.59 (dtd, J = 8.0,
6.9, 3.4 Hz, 2H), 4.38 (t, J = 6.7 Hz, 2H), 1.88 (dd, J = 14.2, 6.9 Hz, 2H), 1.10 (t, J =
7.4 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 166.9, 135.5, 132.5, 131.0, 129.4,
128.2, 128.1, 127.8, 126.6, 125.3, 66.7, 22.2, 10.6; ESI-HRMS (m/z): [M+H]+ calcd
for C14H15O2, 215.1066, found: 215.1074.
Ethyl 2-phenylacetate (4k)39: Yellow liquid (25.4 mg, 31% yield); Rf = 0.63
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(petroleum ether/ethyl acetate = 20:1); H NMR (500 MHz, CDCl3) δ 7.34 (ddd, J =
24.5, 12.2, 8.0 Hz, 5H), 4.19 (q, J = 7.1 Hz, 2H), 3.65 (s, 2H), 1.28 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 171.6, 134.1, 129.2 (2C), 128.5 (2C), 127.0, 60.8,
41.4, 14.1.
2-(Methylthio)-1-phenylbutan-1-one (6a): Yellow liquid (80 mg, 82% yield); Rf =
0.48 (petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 7.99 (dd, J
= 8.3, 1.1 Hz, 2H), 7.57 – 7.51 (m, 1H), 7.49 – 7.42 (m, 2H), 4.04 (t, J = 7.3 Hz, 1H),
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2.05 (dt, J = 14.5, 7.3 Hz, 1H), 1.91 (s, 3H), 1.82 (dt, J = 14.5, 7.4 Hz, 1H), 1.02 (t, J
= 7.4 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 194.4, 135.9, 132.8, 128.5, 128.3,
47.6, 21.7, 11.7, 10.8; ESI-HRMS (m/z): [M+H]+ calcd for C11H15OS, 195.0838,
found: 195.0828.
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2-(Methylthio)-1-(p-tolyl)propan-1-one (6b): Yellow liquid (79 mg, 81% yield); Rf
= 0.52 (petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 7.91 (d,
J = 8.2 Hz, 2H), 7.27 (dd, J = 9.5, 6.9 Hz, 2H), 4.32 (q, J = 6.8 Hz, 1H), 2.41 (s, 3H),
13
1.95 (s, 3H), 1.53 (d, J = 6.8 Hz, 3H); C{1H} NMR (125 MHz, CDCl3) δ 194.7,
143.8, 132.8, 129.2, 128.6, 40.6, 21.6, 15.1, 10.8; ESI-HRMS (m/z): [M+H]+ calcd
for C11H15OS, 195.0838, found: 195.0829.
1
O-ethyl S-(2-oxo-2-phenylethyl) carbonodithioate (11)40: H NMR (500 MHz,
CDCl3) δ 8.07 – 8.00 (m, 2H), 7.66 – 7.57 (m, 1H), 7.54 – 7.45 (m, 2H), 4.67 (s, 2H),
4.63 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
213.2, 192.3, 135.8, 133.7, 128.8 (2C), 128.4 (2C), 70.7, 43.5, 13.9. GC-MS (EI, 70
ev) m/z 240, 180, 151, 105 (100%), 77.
2-isopropyl-5-methylcyclohexyl 2-oxo-2-phenylacetate (3ab)11: White solid (111
mg, 77% yield); Rf = 0.62 (petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz,
CDCl3) δ 7.98 (d, J = 7.4 Hz, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H),
5.01 (td, J = 11.0, 4.4 Hz, 1H), 2.22 – 2.16 (m, 1H), 1.95 (dtd, J = 13.9, 7.0, 2.6 Hz,
1H), 1.74 (dd, J = 9.1, 6.9 Hz, 2H), 1.60 – 1.50 (m, 2H), 1.29 – 1.07 (m, 3H), 0.96 (d,
13
J = 6.6 Hz, 3H), 0.90 (d, J = 7.0 Hz, 3H), 0.84 (d, J = 7.0 Hz, 3H); C{1H} NMR
(125 MHz, CDCl3) δ 186.8, 163.9, 134.8, 132.5, 129.9 (2C), 128.9 (2C), 77.0, 46.8,
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Supporting Information
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Copies of NMR spectra for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
wyuchemhyb@126.com; Leeyib268@126.com;
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the Foundation of the Department of Education of Guangdong
Province (2017KZDXM085, 2018KQNCX272 and 2018KZDXM070), Science
Foundation for Young Teachers of Wuyi University (2019td06 and pdjh2019b0498)
and Chemical Industry Collaborative Innovation Center of Yueshan Town 2017 (368)
for financial support.
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