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
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
(1) (a) Hart, H.; Rappoport, Z.; Biali, S. E. In The Chemistry of Enols;
Rappoport, Z., Ed.; Wiley: Chichester, 1990. (b) Khusnutdinov,
R. I.; Shchadneva, N. A.; Mukhametshina, L. F. Russ. J. Org. Chem.
2010, 46, 820. (c) Trost, B. M.; Corte, J. R.; Gudiksen, M. S. Angew.
Chem. Int. Ed. 1999, 38, 3662. (d) Crimmins, M. T.; Mans, M. C.;
Rodriguez, A. D. Org. Lett. 2010, 12, 5028.
(2) Liston, A. J.; Howarth, M. J. Org. Chem. 1967, 32, 1034.
(3) (a) Langlois, B. R.; Laurent, E.; Roidot, N. Tetrahedron Lett. 1992,
33, 1291. (b) Lu, Y.; Li, Y.; Zhang, R.; Jin, K.; Duan, C. J. Fluorine
Chem. 2014, 161, 128. (c) Jiang, H.; Cheng, Y.; Zhang, Y.; Yu, S.
Eur. J. Org. Chem. 2013, 5485. (d) Hering, T.; Hari, D.-P.; König, B.
J. Org. Chem. 2012, 77, 10347. (e) Peralta-Hernandez, E.; Ble-
Gonzalez, E. A.; Gracia-Medrano-Bravo, V. A.; Cordero-Vargas, A.
Tetrahedron 2015, 71, 2234. (f) Tang, Y.; Fan, Y.; Gao, H.; Li, X.;
Xu, X. Tetrahedron Lett. 2015, 56, 5616. (g) Yadav, V. K.;
Srivastava, V.-P.; Yadav, L. D. S. Synlett 2016, 27, 427.
3v, 50%
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.
(4) Zhang, S.-Y.; Zhang, F.-M.; Tu, Y.-Q. Chem. Soc. Rev. 2011, 40,
1937.
(5) (a) Cheng, J. K.; Loh, T. P. J. Am. Chem. Soc. 2015, 137, 42.
(b) Zhou, W.; Qian, P.; Zhao, J.; Fang, H.; Han, J.; Pan, Y. Org. Lett.
2015, 17, 1160. (c) Zhou, W.; Ni, S.; Mei, H.; Han, J.; Pan, Y. Org.
Lett. 2015, 17, 2724. (d) Liu, Z.-Q.; Sun, L.; Wang, J.-G.; Han, J.;
Zhao, Y.-K.; Zhou, B. Org. Lett. 2009, 11, 1437. (e) Cui, Z.; Shang,
X.; Shao, X.-F.; Liu, Z.-Q. Chem. Sci. 2012, 3, 2853. (f) Li, Z.; Fan,
F.; Yang, J.; Liu, Z.-Q. Org. Lett. 2014, 16, 3396. (g) Correia, C. A.;
Yang, L.; Li, C.-J. Org. Lett. 2011, 13, 4581. (h) He, T.; Yu, L.;
Zhang, L.; Wang, L.; Wang, M. Org. Lett. 2011, 13, 5016. (i) Meng,
Y.; Guo, L.-N.; Wang, H.; Duan, X.-H. Chem. Commun. 2013, 49,
7540. (j) Zhou, Z.-Z.; Hua, H.-L.; Luo, J.-Y.; Chen, Z.-S.; Zhou, P.-
X.; Liu, X.-Y.; Liang, Y.-M. Tetrahedron 2013, 69, 10030.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D