Metal-Free tert -Butyl Hydrogenperoxide (TBHP) Mediated Radical Alkylation of Enol Acetates with Alcohols: A New Route to β-Hydroxy Ketones

Article abstract of DOI:10.1055/s-0035-1561986

A metal-free TBHP-mediated radical alkylation of enol acetates with alcohols is described. This method provides a new route to a variety of β-hydroxy-ketones in moderate to good yields.

Full text of DOI:10.1055/s-0035-1561986

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
Y. Tang et al.
Letter
Synlett
Metal-Free tert-Butyl Hydrogenperoxide (TBHP) Mediated Radical
Alkylation of Enol Acetates with Alcohols: A New Route to β-Hy-
droxy Ketones
Yucai Tang
O
OH
OAc
metal-free
TBHP (4.0 equiv)
R3
R2
OH
Yuanyuan Fan
Ye Zhang
R3
R2
R1
+
R1
H
100 °C
Xiaoqing Li*
Xiangsheng Xu*
R1 = Me, OMe,
halide, CF3
primary and
secondary
alcohols
20 examples
22–78% yield
College of Chemical Engineering, Zhejiang University of
Technology, Hangzhou 310014, P. R. of China
xqli@zjut.edu.cn
future@zjut.edu.cn
Received: 30.01.2016
Accepted after revision: 14.03.2016
Published online: 21.04.2016
Table 1 Optimization of Reaction Conditionsa
OAc
O
OH
DOI: 10.1055/s-0035-1561986; Art ID: st-2016-w0068-l
OH
Conditions
+
H
Abstract A metal-free TBHP-mediated radical alkylation of enol ace-
tates with alcohols is described. This method provides a new route to a
variety of β-hydroxy-ketones in moderate to good yields.
1a
2a
3a
Key words metal-free, radical alkylation, enol acetates, alcohols,
β-hydroxyketones
Entry
Catalyst
Oxidant
Temp (°C)
Yield (%)b
1
2
TBAI
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBPBg
DTBPh
BPOi
100
100
100
100
100
100
100
100
100
90
0
Cu
15
Enol acetates, which can easily prepared from readily
available ketones, are powerful building blocks in organic
synthesis.1,2 Of these, the radical functionalization of enol
acetates toward α-functionalized ketones has gained much
attention in recent years. α-Trifluoromethyl ketones can be
synthesized by trifluoromethylation of enol acetates with
CF3SO2Na3a,b or CF3SO2Cl3c (Scheme 1, a). König and co-
workers developed a visible-light-mediated α-arylation of
enol acetates with aryl diazonium salts 3d (Scheme 1, b). In
2015, Vargas and co-workers3e have developed a practical
radical-ionic sequence for the preparation of 1,4-dicarbonyl
compounds via alkylation of enol acetates with iodoesters,
iodonitriles, or iodoacetamides (Scheme 1, c). Recently,
we,3f Yu,3c and Yadav’s group3g have independently devel-
oped an oxidative sulfonylation of enol acetates to access β-
keto sulfones using RSO2NHNH2 or RSO2Cl (Scheme 1, d).
Despite of the progress achieved in this field, the direct
functionalization of enol acetates with C(sp3)–H bond
gained less attention.
3
Cu(OAc)2
CuI
12
4
trace
n.d.c
32
5
FeCl3·6H2O
6
Co(OAc)2·4H2O
7
–
–
–
–
–
–
–
–
–
63
8d
9e
10
11
12f
13
14
15
15
32
58
120
100
100
100
100
27
26
n.r.
n.r.
n.d.
a Reaction conditions: 1a (0.3 mmol), 2a (2 mL), Catalyst (20 mol%) and
TBHP (4.0 equiv, 70% aq solution) at 100 °C, 10 h.
b Isolated yield.
c n.d. = not detected.
d TBHP (5.5 M in decane).
Alcohols are inexpensive and readily available chemical
feedstocks and organic reactants.4 Carbon radicals generat-
ed by direct hydrogen abstraction of α-C(sp3)–H of alcohols
have been widely applied in the construction of various hy-
droxyl-containing compounds.5 As part of our continuing
efforts toward the development of efficient radical reac-
e Under N2.
f TBHP (2.0 equiv).
g TBPB = tert-Butyl peroxybenzoate.
h DTBP = di-tert-butylperoxide.
i BPO = benzoyl peroxide.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
Y. Tang et al.
Letter
Synlett
R2
R
(b)
R1
O
[Ru(bpy)3]Cl2
N2BF4
König's work
R1
O
I
R3O
Yu's work
O
O
R2
OAc
R3SO2Cl, Ir(ppy)3, hν
SO2R3
lauroyl peroxide
R3
R1
R2
R1O
R1
Cordero-Vargas's work
TBAI, TBHP
R3SO2NHNH2,
R2
(d)
O
or
(c)
FeCl3, O2
Langlois's and Duan's work
CF3SO2Na, Cu, TBHP
Yu's work
we and Yadav's work
CF3SO2Cl, Ir(ppy)3, hν
O
(a)
CF3
R1
R2
This work:
OAc
O
OH
R3
OH
R3
TBHP
R2
+
R1
(e)
R1
H
100 °C
R2
Scheme 1 Radical functionalization of enol acetates
tions,6 herein we disclose a direct approach for the metal-
free TBHP-mediated radical alkylation of enol acetates with
alcohols, allowing for convenient synthesis of synthetically
valuable β-hydroxy ketones through a radical process
(Scheme 1, e).7 Notably, in the present work some of the
synthesized compounds are not easily available by simple
aldol reactions, which are well-known methods for prepar-
ing β-hydroxy ketones.8
We commenced our studies by investigating the cou-
pling reaction of 1-phenylvinyl acetate (1a) and isopropa-
nol (2a). In the initial attempt, no product 3a was obtained
in the presence of TBAI as catalyst and TBHP as oxidant (Ta-
ble 1, entry 1). To our delight, the replacement of TBAI with
Cu and Cu(OAc)2 improved the desired product 3a to 15%
and 12% yield, respectively (Table 1, entries 2 and 3). In-
spired by the initial result, we first tested different metal
catalysts. We found that the radical alkylation occurs with a
higher yield of 3a when the reaction was performed with-
out catalyst (Table 1, entry 7), while the use of other cata-
lysts, including CuI, FeCl3·6H2O, and Co(OAc)2·4H2O, was less
efficient (Table 1, entries 4–6). Attempts to improve the
yield by changing various conditions, such as using anhy-
drous TBHP, an inert atmosphere, or increasing the reaction
temperature and the loading of oxidant, were fruitless (Ta-
ble 1, entries 8–12). The use of other oxidants, such as TBPB,
DTBP, and BPO, was ineffective (Table 1, entries 13–15).
With the optimized reaction conditions in hand, we
next investigated the scope of aryl enol acetates in this re-
action system (Scheme 2).9 In general, the reaction tolerat-
ed a wide variety of substrates, not only for the aryl enol ac-
etates bearing an electron-donating group (products 3b,g,j),
but also for a strong electron-withdrawing CF3 substituent
(products3f,i). It is worth noting that halogen atoms (F, Cl,
Br) on the substrate were also tolerated in this reaction
(products3c–e,h,k), thus these halogen atoms enable fur-
ther elaboration of the products into more complex mole-
cules. The application of polysubstituted aryl enol acetate
provided the desired product 3l as well. Moreover, the cou-
pling with enol acetates containing heteroatoms (O, S) de-
livered the desired products 3mand3n in 39% and 47%
yields, respectively. When the benzene ring of the substrate
was changed to an intraannular derivatized enol acetate,
the reaction provided the desired product 3o in moderate
yield. Further, the scope of alcohols was also examined. Lin-
ear primary aliphatic alcohols, such as ethanol, n-propanol,
and n-butanol, were well tolerated and provided the corre-
sponding products in good yields (products 3q,r,s), while
methanol gave no desired product (3p). The phenylmetha-
nol proved to be unsuitable in this reaction (product 3t).
Secondary alcohols, such as 2-butyl alcohol and cyclohexa-
nol, were also employed as radical precursors and showed
good tolerance under the optimized reaction conditions,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
Y. Tang et al.
Letter
Synlett
providing the corresponding β-hydroxy ketones (product
3u,v) in moderate yields. In all cases, the starting materials
were totally consumed and the corresponding ketones were
observed as side products.
OAc
H
OAc OH
R
R
OH
(I)
OH
TBHP
heat
R
R
H
R
(II)
[O]
OAc
O
OH
OH
R3
R2
R3
R2
TBHP (4.0 equiv)
100 °C
+
R1
R1
H
OAc OH
OAc OH
3
HO
R
1
2
O
OH
R
+
H2O
– H+
R
R
R
O
OH
O
OH
O
OH
R
– HOAc
(IV)
(III)
R
R
Scheme 3 Proposed preliminary mechanisms
R = H, 3a, 63%
R = Me, 3b, 53%
R = F, 3c, 62%
R = Cl, 3d, 78%
R = Br, 3e, 73%
R = CF3, 3f, 58%
R
R = Me, 3j, 36%
R = Cl, 3k, 22%
R = MeO, 3g, 58%
R = Br, 3h, 45%
R = CF3, 3i, 33%
Acknowledgment
O
O
OH
O
OH
OH
Financial support from the National Natural Science Foundation of
China (21102130) and the Natural Science Foundation of Zhejiang
Province (LY14B020005) is greatly appreciated.
X
X = O, 3m, 39%
X = S, 3n, 47%
3o, 28%
3l: 35%
Supporting Information
O
OH
O
OH
O
OH
Supporting information for this article is available online at
R
http://dx.doi.org/10.1055/s-0035-1561986.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
3t, n.d.
3u, 45%
R = H, 3p, 0%
R = Me, 3q, 60%
R = Et, 3r, 49%
R = n-Pr, 3s, 44%
References and Notes
O
OH
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Scheme 2 Substrate scope for the synthesis of β-hydroxy ketones. Re-
agents and conditions: 1a (0.3 mmol), 2a (2 mL), and TBHP (4.0 equiv,
70% aq solution) at 100 °C, 10 h. Isolated yields are given.
Based on the experimental results and previous re-
ports,5,6 a probable mechanistic explanation for this trans-
formation is shown in Scheme 3. Initially, the decomposi-
tion of TBHP at high temperature gives tert-butoxy and tert-
butylperoxy radicals, which subsequently abstract the α-H
of the alcohols to generate α-hydroxy carbon radicals I.
Then, radical intermediate II formed via addition of radicals
I to C–C double bonds of aryl enol acetates undergoes fur-
ther oxidation to afford carbocation intermediate III. Subse-
quently, nucleophilic addition of intermediate III with H2O
occurred to give hemiacetal intermediate IV. Finally, the de-
composition of hemiacetal intermediate IV afford products
3 with the loss of AcOH.
In summary, we have demonstrated an efficient metal-
free radical alkylation of enol acetates by direct sp3 C–H
functionalization of alcohols. This methodology provides a
simple way to construct β-hydroxy ketones which are im-
portant synthetic intermediates in biologically active com-
pounds and medicinal chemistry.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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Letter
Synlett
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(9) General Procedure for the Synthesis of Substituted β-
Hydroxy Ketones
A
Schlenk-type tube (with a Teflon high pressure valve)
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equipped with a magnetic stir bar was charged with enol ace-
tates 1 (0.3 mmol), alcohols 2 (2 mL), and TBHP (1.2 mmol, 70%
aq solution). The reaction tube was then sealed and placed in an
oil bath at 100 °C. After the reaction mixture was stirred for 10
h, it was allowed to cool to ambient temperature. The solvent
was then removed under reduced pressure, and the residue was
purified by column chromatography (EtOAc–PE) to afford the
desired products.
1-(4-Fluorophenyl)-3-hydroxy-3-methylbutan-1-one (3c)
Pale yellow oil; yield 62%. 1H NMR (500 MHz, CDCl3): δ = 8.02–
7.97 (m, 2 H), 7.19–7.12 (m, 2 H), 4.06 (s, 1 H), 3.13 (s, 2 H), 1.36
(s, 6 H). 13C NMR (125 MHz, CDCl3): δ = 199.9, 166.1 (d, J = 253.7
Hz), 133.7 (d, J = 3.0 Hz), 130.81 (d, J = 9.4 Hz), 115.8 (d, J = 21.3
Hz), 69.9, 48.5, 29.5. ESI-HRMS: m/z calcd for C11H14FO2 [M +
H]+: 197.0978; found: 197.0975.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D