C. Joo et al. / Tetrahedron Letters 51 (2010) 6006–6007
6007
Table 1
In conclusion, we conducted a facile and simple method for the
oxidation of benzoins to benzils using sodium hydride in good to
excellent yields. Further studies of other related applications of this
protocol are currently ongoing in our laboratories.
Oxidation of benzoins 1 to benzils 2 using NaH
Entry
Substratea
Productb
Temp (°C)
Time (min)
Yieldc (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1e
1f
1f
1g
1h
2a
2b
2c
2d
2e
2e
2f
2f
2g
2h
25
25
25
25
25
0
25
0
25
25
90
15
30
9
15
6
10
6
15
6
91
80
88
70
Acknowledgments
d
5
This work supported by the NRF grant (No. 2009-0075000) to
H.H. and the NRF WCU program (R31-2008-000-10029-0) to J.W.Y.
52
d
5
45
90
86
References and notes
1
0
a
b
c
17
1. (a) Li, J. J.; Norton, M. B.; Reinhard, E. J.; Anderson, G. D.; Gregory, S. A.; Isakson,
P. C.; Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Seibert, K.; Zhang, Y.;
Zweifel, B. S.; Reitz, D. B. J. Med. Chem. 1996, 39, 1846–1856; (b) Campillo, N.;
García, C.; Goya, P.; Páez, J. A.; Carrasco, E.; Grau, M. J. Med. Chem. 1999, 42,
Substrates 1b, 1d–1f were prepared and characterized as described.
Products 2 were obtained and characterized as described.
Isolated yield.
TLC yield.
18
d
1
698–1704; (c) Muccioli, G. G.; Martin, D.; Scriba, G. K. E.; Poppitz, W.;
Poupaert, J. H.; Wouters, J.; Lambert, D. M. J. Med. Chem. 2005, 48, 2509–2517;
d) Singh, D. P.; Kumar, R.; Singh, J. Eur. J. Med. Chem. 2009, 44, 1731–1736.
(
2
.
.
(a) Yu, D. H.-S.; Torkelson, J. M. Macromolecules 1988, 21, 852–853; (b) Catalina,
F.; Peinado, C.; Blanco, M.; Alonso, A.; Allen, N. S. J. Photochem. Photobiol. A:
Chem. 2000, 131, 141–146; (c) Roy, P. K.; Surekha, P.; Rajagopal, C.; Chatterjee,
S. N.; Choudhary, V. Polym. Degrad. Stab. 2005, 90, 577–585; (d) Szablan, Z.;
Lovestead, T. M.; Davis, T. P.; Stenzel, M. H.; Barner-Kowollik, C. Macromolecules
2007, 40, 26–39.
(a) Friedman, M. J. Org. Chem. 1965, 30, 859–863; (b) Kadish, K. M.; Van
Caemelbecke, E.; D’Souza, F.; Lin, M.; Nurco, D. J.; Medforth, C. J.; Forsyth, T. P.;
Krattinger, B.; Smith, K. M.; Fukuzumi, S.; Nakanishi, I.; Shelnutt, J. A. Inorg.
Chem. 1999, 38, 2188–2198; (c) Du, G.; Mirafzal, G. A.; Woo, L. K.
Organometallics 2004, 23, 4230–4235.
OH
O
Ar'
Ar'
Ar
Ar
O
O
1
2
2 Na CO + 2 H O
2
3
2
3
2
NaHCO3
NaH
NaH
Na O
(
1 equiv)
O2
(1 equiv)
Ar'
HO2
2 NaOH
Ar
H
4.
5.
6.
Zinin, N. Ann. Chem. Pharm. 1840, 34, 186–192.
Weiss, M.; Appel, M. J. Am. Chem. Soc. 1948, 70, 3666–3667.
McKillop, A.; Swann, B. P.; Ford, M. E.; Taylor, E. C. J. Am. Chem. Soc. 1973, 95,
O
4
3
3
641–3645.
Figure 1. Proposed mechanism for the oxidation of benzoins 1 to benzils 2 using
NaH.
7.
Ranganathan, S.; Ranganathan, D.; Ramachandran, P. V. Tetrahedron 1984, 40,
3145–3151.
8
9
.
.
Hirano, M.; Oose, M.; Morimoto, T. Bull. Chem. Soc. Jpn. 1991, 64, 1046–1047.
Tymonko, S. A.; Nattier, B. A.; Mohan, R. S. Tetrahedron Lett. 1999, 40, 7657–
7
659.
entries 5–8). Treating the heteroatom-containing benzoin deriva-
tive 1g and the unsymmetric benzoin derivative 1h with sodium
hydride in THF gave the corresponding products 2g and 2h in
1
0. Namboodiri, V. V.; Polshettiwar, V.; Varma, R. S. Tetrahedron Lett. 2007, 48,
8839–8842.
1
1
1. Shei, C.-T.; Chien, H.-L.; Sung, K. Synlett 2008, 1021–1026.
2. Kirihara, M.; Ochiai, Y.; Takizawa, S.; Takahata, H.; Nemoto, H. Chem. Commun.
9
0% and 86% yields within 15 and 6 min, respectively (Table 1, en-
1
999, 1387–1388.
tries 9 and 10).
13. Choudary, B. M.; Kantam, M. L.; Rahman, A.; Reddy, Ch. V.; Rao, K. K. Angew.
Chem., Int. Ed. 2001, 40, 763–766.
To elucidate the role of oxygen in this process, we conducted
the reaction of benzoin 1a with sodium hydride in oxygen-free
THF, which was introduced by vacuum transfer at À78 °C. As a re-
sult, the moderate conversion (58%) was gained under this condi-
tion. It may seem obvious that oxygen plays an important role in
the oxidation of benzoins.
The most important parameter influencing chemical yield in the
reaction course is the controlled reaction time. It is noteworthy
that the color change of the reaction mixture from navy solutions
to yellow solutions represented the starting point of by-product
formation. Another point is that the basic work-up (aqueous NaH-
CO ) was required to obtain high yield of the benzils after comple-
3
tion of the reaction.
The proposed mechanism for the sodium hydride-mediated oxi-
dation of benzoins 1 to benzils 2 is illustrated in Figure 1. In the
first step, 1 equiv of NaH leads to complete deprotonation of the
hydroxyl group in the benzoins 1. In the second step,
of the resulting intermediate 3 is presumably transferred to molec-
ular oxygen, leading to transient formation of hydroperoxide 4 and
thus, simultaneously providing the desired benzil products 2.
Although the resulting hydroperoxide is not extremely reactive to-
ward benzions, however, it may potentially react with an addi-
tional equiv of NaH. Subsequently, 2 equiv of NaOH is released
into the solution and then, it can be almost neutralized by 2 equiv
1
1
4. Alamsetti, S. K.; Muthupandi, P.; Sekar, G. Chem. Eur. J. 2009, 15, 5424–5427.
5. (a) Qin, C.; Chen, J.; Wu, H.; Cheng, J.; Zhang, Q.; Zuo, B.; Su, W.; Ding, J.
Tetrahedron Lett. 2008, 49, 1884–1888; (b) Zhang, W.; Liu, M.; Wu, H.; Ding, J.;
Cheng, J. Tetrahedron Lett. 2008, 49, 5336–5338; (c) Zhang, Q.; Xu, C.-M.; Chen,
J.-X.; Xu, X.-L.; Ding, J.-C.; Wu, H.-Y. Appl. Organometal. Chem. 2009, 23, 524–
526.
16. Balalaie, S.; Golizeh, M.; Hashtroudi, M. S. Green Chem. 2000, 2, 277–278.
17. General procedure for the synthesis of benzoins 1b, 1d–1f.19 To a solution of
benzladehyde (15 mmol) in EtOH (8 mL) was added
6.3 mmol) in H O (1.5 mL). After stirring at reflux (80 °C) for 2 h, the reaction
mixture was cooled to room temperature, concentrated in vacuo, and extracted
with CH Cl and saturated aqueous NaHCO . The combined organic layers were
dried over Na SO and concentrated in vacuo. The residue was purified by flash
column chromatography to give 1b, 1d–1f. They were characterized by
NMR spectra, which are found to be identical to those reported previously:
a solution of NaCN
(
2
2
2
3
2
4
1
H
14
14
20b
14
1b, 1d, 1e,
and 1f
.
Benzoins 1a, 1c, and 1g were purchased from TCI
and 1h was purchased from Aldrich.
1
8. General procedure for the oxidation of benzoins 1 to benzils 2. To a solution of
benzoins 1 (0.5 mmol) in distilled THF (5 mL) was added NaH (60% dispersion
in mineral oil, 1.0 mmol) at 0 °C. While stirring, the dark-blue solution was
allowed to warm to room temperature. After stirring, until TLC analysis
indicated complete consumption of the starting material, the reaction
a-hydride
3
mixture was quenched with 0.1 M NaHCO (10 mL), extracted with EtOAc,
and washed with brine. The combined organic layers were dried over MgSO4
1
5b
and concentrated in vacuo. The residue was purified by flash column
1
chromatography to give 2. All the benzil products were characterized by
H
13
and C NMR spectra, which are found to be identical to those reported
previously.1
4,20
19. Singh, P.; Mittal, A.; Kumar, S. Bioorg. Med. Chem. 2007, 15, 3990–3996.
2
0. (a) Hoyos, P.; Sansottera, G.; Fernández, M.; Molinari, F.; Sinisterra, J. V.;
Alcántara, A. R. Tetrahedron 2008, 64, 7929–7936; (b) Shimakawa, Y.;
Morikawa, T.; Sakaguchi, S. Tetrahedron Lett. 2010, 51, 1786–1789.
of aqueous NaHCO
3
added for work-up, thereby producing the de-
sired product without any by-products.