I 2 /TBHP-Promoted Approach to α-Keto Esters from Trifluoromethyl β-Diketones and Alcohols via C-C Bond Cleavage

Article abstract of DOI:10.1055/s-0036-1588833

A metal-free oxidative coupling reaction of trifluoromethyl β-diketones with alcohols for the synthesis of α-keto esters in good to excellent yields has been developed. Preliminary mechanistic studies suggest that an I ₂ /TBHP promoted sequential iodination, C-C bond cleavage, C-O bond formation and oxidation pathway is involved in this reaction.

Full text of DOI:10.1055/s-0036-1588833

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
letter
A
en
T. Shao et al.
Letter
Synlett
I2/TBHP-Promoted Approach to α-Keto Esters from Trifluorometh-
yl β-Diketones and Alcohols via C–C Bond Cleavage
Tongle Shaoa
Xiang Fang*a
Jun Zhoua
Chen Jina
Xueyan Yang*a
Fanhong Wub
a Laboratory for Advanced Material and Institute of Fine Chemicals, School
of Chemistry and Molecular Engineering, East China University of Science
and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China
fangxiang@ecust.edu.cn
yxy@ecust.edu.cn
b School of Chemical and Environmental Engineering, Shanghai Institute of
Technology, 120 Caobao Road, Shanghai 200235, P. R. of China
Received: 01.03.2017
Accepted after revision: 24.04.2017
Published online: 16.05.2017
tocols for intra- and intermolecular C–O, C–C or C–X
(X = heteroatom) bond formation under transition-metal-
free conditions.9–11 Although I2/TBHP or I2/DMSO promoted
C–H (sp3) functionalization of arylmethylketones with sec-
ondary amines for the synthesis of α-ketoamides has been
well studied,12 the use of the I2/TBHP system to promote
formation of α-keto esters from easily available materials
and alcohols has not been reported.
Our group has reported the decarboxylation of trifluo-
romethyl α-fluorinated gem-diols by cleavage of C–C bonds
through a mild release of the trifluoroacetate group.13 Here-
in, we want to present our work on I2/TBHP promoted C–O
bond formation between trifluoromethyl β-diketones and
alcohols through iodination, C–C bond cleavage, C–O bond
formation and oxidation pathway to construct α-keto esters
in a one-pot synthetic strategy (Scheme 1).
DOI: 10.1055/s-0036-1588833; Art ID: st-2017-w0151-l
Abstract A metal-free oxidative coupling reaction of trifluoromethyl
β-diketones with alcohols for the synthesis of α-keto esters in good to
excellent yields has been developed. Preliminary mechanistic studies
suggest that an I2/TBHP promoted sequential iodination, C–C bond
cleavage, C–O bond formation and oxidation pathway is involved in this
reaction.
Key words trifluoromethyl β-diketones, α-keto esters, C–C bond
cleavage, C–O coupling, alcohols
α-Keto esters are widely represented among many bio-
logically active compounds1 and they are also useful syn-
thetic precursors in organic synthesis,2 as well as being
used in many enantioselective transformations.3 As a con-
sequence, the development of mild and efficient methods
to synthesize α-keto esters is of considerable significance.
Although a large number of methods to synthesize such
molecules have been established, such as esterification of
α-ketoacyl halides, α-carbonyl aldehydes, and α-ketoacids
(Scheme 1, a),4 direct oxidative esterification of aryl ketones
with alcohols in the presence of oxidizing agents (Scheme
1, b),5 oxidation of α-hydroxy esters (Scheme 1, c),6 palladi-
um-catalyzed double carbonylation of aryl halides (Scheme
1, d),7 and some other methods (Scheme 1, e),8 some of
these methods suffer from drawbacks such as harsh reac-
tion conditions, difficult preparation for raw materials, and
use of toxic transition metals. Therefore, new protocols that
can be used to construct α-keto esters from easily available
materials under metal-free conditions are still highly desir-
able.
Previous work
R2
O
H
O
O
H
R2
X
a
O
R1
R2
O
O
O
R1
OH
X = Cl, OH, H
O
O
R1
R2
R1
O
H
R2
O
This work
O
I2, TBHP, Na2CO3
DCE, 60 °C, 7 h
O
OH
CF3
H
R2
O
+
R1
R2
O
R1
O
In recent years, molecular iodine or iodide salt (such as
Bu4NI and TBAI) in combination with tert-butyl hydroper-
oxide (TBHP) as co-oxidant have emerged as efficient pro-
Scheme 1 Strategies for the synthesis of α-keto esters
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
T. Shao et al.
Letter
Synlett
It is noted that trifluoromethyl β-diketones exist exclu-
sively in the enol form.14 Initially, the reaction conditions
were optimized by using 4,4,4-trifluoro-3-hydroxy-1-
phenylbut-2-en-1-one (1a) and methanol (2a) as model
compounds; the results are shown in Table 1. The reaction
failed to proceed without TBHP or I2 (entries 1 and 2). To
our delight, methyl 2-oxo-2-phenylacetate (3aa) was ob-
tained in 49% yield in the presence of 1.0 equivalent of I2
and 1.2 equivalents of TBHP (70% aqueous solution) at 60 °C
for 7 hours (entry 3). A higher yield of 3aa (64%) was
achieved with 1.0 equiv. of Na2CO3 (entry 4), which was at-
tributed to accelerated cleavage of the C–C bond through
mild release of the trifluoroacetate unit under basic condi-
tions.13,15 Variations in the loading of I2 and TBHP suggested
that 1.1 equivalents of I2 and 2.5 equiv. of TBHP were found
to be optimal amounts (entries 5–10). Attempts to improve
the yield through the use of other common oxidants, such
as DDQ, MnO2 and H2O2, were unsuccessful (entries 11–13).
A lower yield of 3aa (74%) was obtained when the amount
of Na2CO3 was elevated from 1.0 to 1.2 equivalents (entries
9 and 15). Other bases, such as NaHCO3, NaOH, and NaOAc
also were tested, but provided the product 3aa in low yields
(entries 16–18). Subsequently, screening of solvents re-
vealed that 1,2-dichloroethane furnished the highest yield
(93%) (entries 9 and 19–23). Although a catalytic amount of
iodine in the I2/TBHP system has been reported,9–11 the con-
version of the reaction was only 40% and a low yield of 3aa
(33%) was achieved with 0.3 equivalents of iodine
(entry 24). Elevated reaction temperature and longer reac-
tion time also did not afford any better results (entries 25
and 26).
With optimized conditions in hand, we next sought to
define the scope of the reaction with respect to trifluoro-
methyl β-diketones. As shown in Scheme 2, the reaction be-
tween trifluoromethyl β-diketone bearing a methyl on the
aryl and methanol showed good reaction efficiency in this
protocol (3ab, 3ac). However, notable differences in results
were observed depending on the electronic characteristics
of the functional groups on the benzene of the trifluoro-
methyl β-diketones. More specifically, besides the desired
α-keto ester products, which were obtained in moderate
yields, aryl formic methyl ester by-products (4ad, 4ah, 4ai)
were also afforded in slightly lower yields with substrates
bearing electron-donating groups, such as methoxy, phenyl
and trifluoroethoxy (3ad, 3ah, 3ai). However, trifluoro-
methyl β-diketones substituted with electron-withdrawing
groups, such as F, Cl, and Br, afforded the corresponding α-
keto ester products in excellent yields (3ae, 3af, 3ag). A
higher yield (99%) was obtained with 3,4-difluoro-substi-
tuted substrate (3ak). Notably, halogens, such as Br and Cl,
usually provide a platform for further transformation. A
good yield was achieved when sterically crowed substrate
4,4,4-trifluoro-3-hydroxy-1-(naphthalen-1-yl)but-2-en-1-
Table 1 Optimization of Reaction Conditionsa
O
O
OH
CF3
O
I2, oxidant, base
+
MeOH
solvent, 60 °C, 7 h
O
1a
2a
3aa
Entry I2 (equiv) Oxidant (equiv) Base (equiv)
Solvent
3aa (%)b
1
2
1.0
–
–
–
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DCE
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.5)
TBHP (2.0)
TBHP (2.5)
TBHP (3.0)
DDQ (2.5)
MnO2 (2.5)
H2O2 (2.5)
–
–
3
1.0
1.0
1.1
1.2
1.1
1.1
1.1
1.1
1.1
1.1
1.1
–
49
64
76
74
77
82
89
79
trace
45
trace
80
74
47
35
41
93
44
35
48
85
33c
92
93
4
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.2)
NaHCO3 (1.0)
NaOH (1.0)
NaOAc (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25d
26e
NIS (1.1) TBHP (2.5)
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
0.3
1.1
1.1
TBHP (2.5)
TBHP (2.5)
TBHP (2.5)
TBHP (2.5)
TBHP (2.5)
TBHP (2.5)
TBHP (2.5)
TBHP (2.5)
TBHP (2.5)
TBHP (2.5)
TBHP (2.5)
TBHP (2.5)
dioxane
CH2Cl2
toluene
DMSO
DCE
DCE
DCE
a Reaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), I2, TBHP, base and sol-
vent (1.5 mL), 60 °C, 7 h, sealed tube.
b Isolated yield.
c The conversion of the reaction was 40%.
d The reaction mixture was heated at 80 °C for 7 h.
e The reaction was carried out at 60 °C for 10 h.
one was tested (3aj). Unfortunately, the desired product
was not detected with heterocycle substituted β-diketones
as substrates, such as 4,4,4-trifluoro-1-(furan-2-yl)-3-hy-
droxybut-2-en-1-one (3al).
Various alcohols were then examined for this transfor-
mation; the results are presented in Scheme 3. We were
pleased to find that the reaction between 1a and various al-
cohols 2 led to the formation of α-keto ester derivatives in
good to excellent yields, and no by-products were detected.
Primary alcohols with different length of linear aliphatic
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
T. Shao et al.
Letter
Synlett
I2 (1.1 equiv)
TBHP (2.5 equiv)
Na2CO3 (1.0 equiv)
I
2 (1.1 equiv)
O
O
OH
CF3
TBHP (2.5 equiv)
Na2CO3 (1.0 equiv)
O
O
OH
CF3
O
O
R2
O
R2OH
+
R1
+
MeOH
R1
R1
O
+
DCE, 60 °C, 7 h
DCE, 60 °C, 7 h
O
O
1a
2
3
1
2a
3
4
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
3aa: 87% (gram scale)a
3ba: 95%
3ca: 90%
3aa: 93%
3ab: 83%
3ac: 76%
O
O
O
O
O
O
O
O
O
O
O
O
4
7
O
O
O
O
O
O
O
F
Cl
3da: 91%
3ea: 94%
3fa: 89%
3ad/4ad: 58%/32%
3ae: 89%
3af: 83%
O
O
O
O
O
O
O
O
Ph
O
O
O
O
Br
Ph
CF3
O
O
O
O
O
O
Br
Ph
O
3ga: 68%
3ha: 80%
3ia: 78%
3ag: 90%
3ah/4ah: 45%/ 34%
3ai/ 4ai: 48%/35%
O
O
O
O
O
O
O
O
O
O
O
F
F
O
O
O
O
O
O
O
O
O
3ja: 62%
3ka: 94%
3la: 0%
3aj: 74%
3ak: 99%
3al: 0%
Scheme 3 Scope of the reaction with respect to alcohols for the syn-
thesis of α-keto esters. Reagents and conditions: 1 (0.5 mmol), alcohol
(1.5 mmol), I2 (0.55 mmol), TBHP (1.25 mmol), Na2CO3 (0.5 mmol),
1,2-dichloroethane (1.5 mL), 60 °C, 7 h, sealed tube. Isolated yields are
given. a Starting with 0.5 g 1a.
Scheme 2 Scope of the reaction with respect to trifluoromethyl β-dike-
tones for the synthesis of aryl α-keto esters. Reagents and conditions: 1
(0.5 mmol), methanol (1.5 mmol), I2 (0.55 mmol), TBHP (1.25 mmol),
Na2CO3 (0.5 mmol), 1,2-dichloroethane (1.5 mL), 60 °C, 7 h, sealed
tube. Isolated yields are given.
chain, such as methyl, ethyl, propyl, butyl, pentyl and octyl,
all afforded the corresponding products with excellent
yields (3aa–fa). Moderate to good yields of α-keto esters
(3ga–ia) were obtained when 2-bromoethanol and aromat-
ic alcohols, such as phenylmethanol (2h) and 2-phenyletha-
nol (2i) were tested. A moderate yield (60%) was generated
when a more complex alcohol (tetrahydrofuran-2-yl)meth-
anol (2j) was tested. Subsequently, a secondary alcohol,
propan-2-ol (2k) also was tested, and excellent yields com-
parable to primary alcohols were generated. Unfortunately,
the protocol was not applicable to tertiary alcohols, such as
tert-butanol (2l). A gram-scale experiment of 3aa was also
conducted with 87% yield, thus demonstrating the scalabil-
ity of our developed protocol.
To gain insight into the reaction mechanism, a number
of control experiments were conducted (Scheme 4). The re-
action between acetophenone and methanol did not result
in the formation of methyl 2-oxo-2-phenylacetate (3aa) un-
der optimized reaction conditions, which suggests that the
trifluoroacetate group plays a vital role in the formation of
2-iodo-1-arylethanones (Scheme 4, a). A control experi-
ment revealed that after removing the oxidant TBHP, the re-
action between trifluoromethyl α-iodinated gem-diol A
and methanol gave neither α-keto ester product 3aa nor α-
methoxy ketone C (Scheme 4, b). Furthermore, with 2.5
equiv. of TBHP added into the mixture, the reaction be-
tween iodinated gem-diol A and methanol gave the desired
product 3aa in 87% yield (Scheme 4, c). The TBHP played an
important role in the subsequent conversion of A into 3aa.
When 1.1 equiv. of TBHP was used in the reaction of 1a
with methanol under the optimized conditions, the conver-
sion of the reaction was 80% and α-keto ester 3aa was iso-
lated in 32% yield after 2 hours. The key intermediate, α-
methoxy ketone C was also obtained in 41% yield (Scheme
4, d). Next, α-methoxy ketone C can be easily converted into
the desired product 3aa in high yield with 2.5 equiv. of
TBHP (Scheme 4, e).
Based on the above results, a plausible mechanism for
this reaction is proposed in Scheme 5. Initially, trifluoro-
methyl β-diketones 1 are converted into iodinated products
A with addition of I2/TBHP, followed by release of the trifluo-
roacetate unit under basic conditions to generate the key
intermediate 2-iodo-1-arylethanones B.14,15b Next, B under-
goes oxidation by TBHP, and is then attacked by MeOH to
afford intermediate α-alkoxy ketones C.16 The generated 2-
methoxy-1-arylethanones C then proceed to a free radical
substitution of its methylene with a t-BuOO˙ generated
from homolytic cleavage of t-BuOOH to generate D, which
undergoes further oxidation by t-BuOOH to afford the de-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
T. Shao et al.
Letter
Synlett
I
2 (1.1 equiv)
O
O
TBHP (2.5 equiv)
O
Na2CO3 (1.0 equiv)
DCE, 60 °C, 7 h
MeOH
(a)
(b)
+
O
3aa: 0%
without I2
without TBHP
Na2CO3 (1.0 equiv)
O
O
O
HO OH
CF3
O
O
O
+
MeOH
+
O
3aa: 0%
DCE, 60 °C, 7 h
I
A
C: 0%
without I2
TBHP (2.5 equiv)
Na2CO3 (1.0 equiv)
O
HO OH
O
CF3
+
MeOH
(c)
DCE, 60 °C, 7 h
I
O
A
3aa: 87%
I2 (1.1 equiv)
TBHP (1.1 equiv)
Na2CO3 (1.0 equiv)
O
O
O
OH
CF3
O
O
+
MeOH
(d)
(e)
+
O
DCE, 60 °C, 2 h
1a
C: 41%
3aa: 32%
Conversion: 80%
O
O
I2 (1.1 equiv)
TBHP (2.5 equiv)
O
O
O
DCE, 60 °C, 3 h
C
3aa: 92%
Scheme 4 Related experiments
sired α-keto ester products 3.12a,c For substrates bearing
electron-donating functional groups, products 3 could be
further activated by molecular iodine and attacked by alco-
hol to afford intermediates E. After loss of molecular HI and
release methyl formate, the aryl formic ester by-products 4
are isolated.
In conclusion, we have developed a simple, transition-
metal-free, and convenient method for the synthesis of α-
keto esters from easy available trifluoromethyl β-diketones
and alcohols promoted by I2/TBHP.17
O
HO OH
CF3
O
O
OH
CF3
I2, TBHP
base
I
Ar
Ar
Ar
– CF3COO–
I
B
A
1
Funding Information
TBHP
MeOH
t-BuOOH
t-BuO + HO
t-BuOO + t-BuOH
The authors thank the National Natural Science Foundation of China
t-BuO + t-BuOOH
O
(No. 21672151) for financial support.
N
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a
l
N
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utra
l
Secince
F
o
u
n
d
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of
C
h
n
i
a
2(
1
6
7
2
1
5
1)
O
O
O
Ar
Ar
O
Ot-Bu
Supporting Information
D
C
t-BuOOH
Supporting information for this article is available online at
O
https://doi.org/10.1055/s-0036-1588833.
S
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p
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Products: 3
References
I
I2
O
O
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MeOH
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O
– HI
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O
– HI
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3
E
By-products: 4
Scheme 5 Proposed mechanism
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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Letter
Synlett
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(17) Typical Procedure for the Synthesis of 3 from 1
To a mixture of 1k (126 mg, 0.5 mmol), methanol 2a (48 mg, 1.5
mmol), I2 (140 mg, 0.55 mmol), tert-butyl hydroperoxide (112.7
mg, 1.25 mmol) and Na2CO3 (53 mg, 0.5 mmol) was added 1,2-
dichloroethane (1.5 mL) at room temperature. The reaction
mixture was then stirred at 60 °C for 7 h. When the reaction
was complete (monitored by TLC), the reaction was quenched
with 2 mL of saturated NH4Cl and 4 mL of saturated Na2S2O3
aqueous solution. After extraction with EtOAc and drying with
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
T. Shao et al.
Letter
Synlett
Na2SO4, the organic layer was concentrated under reduced pres-
sure and the residue was purified by column chromatography
on silica gel using hexanes/EtOAc (100:1 to 50:1) as eluent to
afford the desired products 3ak (99 mg, 99% yield).
J1 = 261.6 Hz, J2 = 13.1 Hz), 150.5 (dd, J1 = 253.5 Hz, J2 = 13.1 Hz),
129.5 (t, J = 4.0 Hz), 127.7 (dd, J1 = 8.1 Hz, J2 = 4.0 Hz), 119.3 (dd,
J1 = 18.2 Hz, J2 = 2.0 Hz), 117.9 (d, J = 18.2 Hz). 19F NMR (CDCl3,
376 MHz): δ = –125.53 to –125.65 (m, 1 F), –134.76 to –134.87
(m, 1 F). EI-MS: m/z (%) = 63, 93, 113, 141 (100), 142, 153, 172,
184, 200. HRMS: m/z calcd for [C9H6F2O3]+: 200.0285; found:
200.028.
Methyl 2-(3,4-Difluorophenyl)-2-oxoacetate (3ak)
White solid; m.p. 38.7–40.2 °C. 1H NMR (400 MHz, CDCl3): δ =
7.96–7.91 (m, 1 H), 7.90–7.86 (m, 1 H), 7.34–7.28 (m, 1 H), 3.99
(s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 182.9, 162.9, 154.8 (dd,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F