An unprecedented method for the generation of tert -butylperoxy radical using DIB/TBHP protocol: Solvent effect and application on allylic oxidation

Article abstract of DOI:10.1021/ol100603q

Figure presented Tert-Butylperoxy radical was generated with PhI(OAc) ₂ and tBuOOH. Ester solvent was found to be critical and the protocol was applied in the allylic oxidation of various olefinic substrates, which gave the corresponding α,β-unsaturated enones in good yield and regioselectivity.

Full text of DOI:10.1021/ol100603q

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2128-2131
An Unprecedented Method for the
Generation of tert-Butylperoxy Radical
Using DIB/TBHP Protocol: Solvent Effect
and Application on Allylic Oxidation
Yi Zhao and Ying-Yeung Yeung*
Department of Chemistry, National UniVersity of Singapore, 3 Science DriVe 3,
Singapore 117543
chmyyy@nus.edu.sg
Received March 17, 2010
ABSTRACT
tert-Butylperoxy radical was generated with PhI(OAc)2 and tBuOOH. Ester solvent was found to be critical and the protocol was applied in the
allylic oxidation of various olefinic substrates, which gave the corresponding r,ꢀ-unsaturated enones in good yield and regioselectivity.
Allylic oxidation of olefins is an important and useful organic
transformation. The corresponding R,ꢀ-unsaturated enone
products are commonly known as pharmacophores and
building blocks in many organic syntheses.1 In particular,
allylic oxidation of ∆5-steroids to ∆5-en-7-ones is of interest
because ∆5-en-7-ones show excellent results in the prevention
and treatment of cancer and can inhibit the biosynthesis of
sterol.2 Several metallic based allylic oxidations were
documented, which generally encountered problems such as
long reaction time, limited scope, low functional group
tolerance, low regioselectivity, high cost, and/or difficult
catalyst preparation.3
reported the ligand exchange between diacetoxyiodobenzene
(DIB) (1) and tert-butyl hydroperoxide (TBHP) to give
bis(tert-butylperoxy)iodobenzene (2), which readily under-
went elimination to yield 4 and decomposed through a 4 f
5 f 6 sequence accompanied by the evolution of molecular
oxygen at -75 °C (Scheme 1, eq 1).4 An interesting strategy
using a fixed apical ligand to provide a stable tert-butylp-
(3) Examples for metal-based allylic oxidation: Cr-based: (a) Muzart,
J. Chem. ReV. 1992, 92, 113–140. (b) Fousteris, M. A.; Koutsourea, A. I.;
Nikolaropoulos, S. S.; Riahi, A.; Muzart, J. J. Mol. Catal., A: Chem. 2006,
250, 70. Cu-based: (c) Salvador, J. A. R.; Sa´ e Melo, M. L.; Campos Neves,
A. S. Tetrahedron Lett. 1997, 38, 119–122. (d) Arsenou, E. S.; Koutsourea,
A. I.; Fousteris, M. A.; Nikolaropoulos, S. S. Steroids 2003, 68, 407. Co-
based: (e) Salvador, J. A. R.; Clark, J. H. Chem. Commun. 2001, 6, 33–34.
(f) Jurado-Gonzalez, M.; Sullivan, A. C.; Wilson, J. R. H. Tetrahedron
Lett. 2003, 44, 4283–4286. Fe-based: (g) Barton, D. R. H.; Le Gloahec,
V. N. Tetrahedron 1998, 54, 15457–15468. Pd-based: (h) Yu, J. Q.; Corey,
E. J. J. Am. Chem. Soc. 2003, 125, 3232–3233. (i) Yu, J. Q.; Wu, H. C.;
Corey, E. J. Org. Lett. 2005, 7, 1415–1417. Rh-based: (j) Catino, A. J.;
Forslund, R. E.; Doyle, M. P. J. Am. Chem. Soc. 2004, 126, 13622–13623.
(k) Catino, A. J.; Nichols, J. M.; Choi, H.; Gottipamula, S.; Doyle, M. P.
Org. Lett. 2005, 7, 5167–5170. (l) Choi, H.; Doyle, M. P. Org. Lett. 2007,
9, 5349–5352. (m) McLaughlin, E. C.; Choi, H.; Wang, K.; Chiou, G.;
Doyle, M. P. J. Org. Chem. 2009, 74, 730–738. (n) McLaughlin, E. C.;
Doyle, M. P. J. Org. Chem. 2008, 73, 4317–4319. Mn-based: (o) Shing,
T. K. M.; Yeung, Y.-Y.; Su, P. L. Org. Lett. 2006, 8, 3149–3151. Sodium
chlorite: (p) Silvestre, S. M.; Salvador, J. A. R. Tetrahedron 2007, 63, 2439.
Bi-based: (q) Salvador, J. A. R.; Silvestre, S. M. Tetrahedron Lett. 2005,
46, 2581.
In contrast, sporadic studies were reported on the nonme-
tallic based generation of tert-butylperoxy radical 3 and
application on allylic oxidation.5 In 1968, Milas et al.
(1) Page, P. C. B.; McCarthy, T. ComprehensiVe Organic Synthesis;
Trost, B. M., Ed.; Pergamon: Oxford, UK, 1991; Vol. 7, pp 83-149.
(2) (a) Cheng, K. P.; Nagana, H.; Bang, L.; Ourisson, G. J. Chem. Res.
(S) 1977, 217. (b) Nagana, H.; Poyser, J. P.; Cheng, K. P.; Bang, L.;
Ourisson, G. J. Chem. Res. (S) 1977, 218. (c) For a review see: Parish,
E. J.; Kizito, S. A.; Qiu, Z. Lipids 2004, 801. (d) Arsenou, E. S.; Fousteris,
M. A.; Koutsourea, A. I.; Nikolaropoulos, S. S. Mini ReV. Med. Chem.
2003, 3, 557. (e) Smith, L. Lipids 1996, 31, 453. (f) Peng, S.-K.; Morin,
R. J. In The Biological Effects of Cholesterol Oxides; CRC Press, Boca
Raton, FL, 1992. (g) Salvador, J. A. R.; Silvestre, S. M.; Moreira, V. M.
Curr. Org. Chem. 2006, 10, 2227–2257.
10.1021/ol100603q  2010 American Chemical Society
Published on Web 04/13/2010

Scheme 1
.
Comparison of Previous Studies and Present Work
Table 1. Allylic Oxidation of Cholesteryl Acetate (8) in
Different Solvents
eroxy iodane was reported.5a Alternatively,we describe herein
the first solvent-assisted nonmetallic based generation of
reactive and controllable tert-butylperoxy radical 4 using
DIB/TBHP protocol as well as the application on allylic
oxidation (Scheme 1, eq 2).
Initially, a DIB/TBHP (1:3) mixture was used in the allylic
oxidation of cholesteryl acetate (8) at 0 °C. Various solvents
were studied and it was found that the reaction performed
exceptionally smooth in ethyl acetate, resulting in the
formation of 3ꢀ-acetoxycholest-5-ene-7-one (8a) in 46%
yield (Table 1, entry 7). Further examination of bulkier ester
solvents showed that n-butyl butanoate was superior to the
others (Table 1, entry 11). A comparison of similarly bulky
solvents indicated the electron-rich ester unit is important
to the reaction (Table 1, entries 5 and 10).
The effect of additive was also investigated. The signifi-
cance of additive in various allylic oxidations was well
documented. In our studies, K2CO3 (0.5 equiv) was also
found to be effective. Moreover, acetate salts including
NaOAc, KOAc, and Mg(OAc)2·4H2O could promote the
allylic oxidation.6
a Reactions were carried out with substrate (0.5 mmol), DIB (0.5 mmol),
and TBHP (1.5 mmol) in solvent (0.13 M). b Isolated yield.
good yields, resulting in the formation of the corresponding
∆5-en-7-ones (Table 2). For example, allylic oxidation of
cholesteryl acetate (8) commonly required 24-48 h to
achieve acceptable yield,2,3 while the reaction was completed
in 5 h with 82% yield when using the DIB/TBHP protocol
(Table 2, entry 1).
Other than ∆5-steroids, a number of simple olefins and
benzylic substrates were also subjected to the studies. The
scope of the DIB/TBHP allylic oxidation process was
indicated by the 14 examples listed in Table 3. The reactions
proceeded smoothly even at -20 °C and similar regioselec-
tivities were observed in which oxidation occurred at the
less hindered allylic carbon. Electron-deficient olefins are
commonly known as being inactive toward allylic oxidation.
Surprisingly, the DIB/TBHP protocol could promote the
formation of enones 23a-26a from the corresponding
alkenes (Table 3, entries 8-11). In general it is noteworthy
that the reaction protocol is highly compatible with various
protecting groups (OAc, OBz, silyl, acetal), functional groups
(ketone, nitro, cyano), and rigid ring (four-membered ring).
Toward the understanding of the mechanism, we believed
bis(tert-butylperoxy)iodobenzene (2) was generated as re-
ported by the literature.4 It is important to notice that large
numbers of gas bubbles were evolved instantly and gave
iodobenzene when the allylic oxidations were performed in
nonester solvents, which indicated a significant number of
tert-butylperoxy radicals 4 were decomposed due to the
Having identified the appropriate solvent and potential
additives, the other parameters were varied systematically
to achieve the optimum conditions,6 which were then applied
on the allylic oxidation of various ∆5-steroids.7 The reactions
proceeded smoothly with excellent regioselectivities and
(4) Milas, N. A.; Plesnicar, B. J. Am. Chem. Soc. 1968, 90, 4450–4453.
(5) (a) Ochiai, M.; Ito, T.; Takahashi, H.; Nakanishi, A.; Toyonari, M.;
Sueda, T.; Goto, S.; Shiro, M. J. Am. Chem. Soc. 1996, 118, 7716–7730.
(b) Dohi, T.; Takenaga, N.; Goto, A.; Fujioka, H.; Kita, Y. J. Org. Chem.
2008, 73, 7365–7368.
(6) For details, please see the Supporting Information.
(7) Representative procedure: To a solution of cholesterol acetate (8)
(214 mg, 0.5 mmol) in n-butyl butanoate (1 mL) was added diacetoxy-
iodobenzene (1) (312 mg, 1.5 mmol) and Mg(OAc)2·4H2O (124 mg, 1.0
mmol) at 0 °C. The resulting suspension was vigorously stirred and a
solution of tert-butyl hydroperoxide (6.0 M in decane, 333 µL, 2.0 mmol)
was added dropwise over 30 min. The solution was further stirred for 4.5 h
at 0 °C and filtered. The filtrate was chromatographed on silica gel eluted
with n-hexanes/EtOAc (10:1) to yield 3ꢀ-acetoxycholest-5-ene-7-one (8a)
as a white solid (181 mg, 82%).
Org. Lett., Vol. 12, No. 9, 2010
2129

Table 2. Allylic Oxidation of ∆5-Steroids 8-15
Table 3. Allylic Oxidation of Substrates 16-29
a Reactions were carried out with substrate (0.5 mmol), DIB (1.5 mmol),
TBHP (2.0 mmol), and K2CO3 or Mg(OAc)2·4H2O in nPrCO2nBu (0.4 M).
b Mg(OAc)2·4H2O (1.0 mmol) was used as the additive in entries 1-3, while
K2CO3(0.25mmol)wasusedinentries4-8.c Isolatedyield.d nPrCO2nBu/n-hexanes
(1:1) was used due to the solubility issue.
dimerization to di-tert-butyltetraoxide (5) (Scheme 1).4 On
the other hand, no gas bubble was observed during the
reaction in n-butyl butanoate, leading us to hypothesize the
extra stabilization effect of ester solvent to the hypervalent
iodine(III) species. A set of simple experiments was carried
out by stirring a suspension of DIB/TBHP in n-hexane,
toluene, acetonitrile, or n-butyl butanoate in the absence of
olefinic substrate at 0 °C. The time period of oxygen gas
bubbles evolution was summerized in Table 4. Fast and
vigorous evolution of oxygen in nonpolar solvents could be
attributed to the rapid decomposition of 2 and hence coupling
of tBuOO· 4. On the other hand, σ-donor solvent, especially
for n-butyl butanoate, gave a much better control in the
generation of tBuOO· 4 which is reflected in the gentle and
sustainable evolution of O2. On the basis of this observation,
we speculated a further displacement of a tBuOO· 4 by the
ester solvent molecules, resulting in the formation of complex
a Reactions were carried out with substrate (0.5 mmol), DIB (1.5 mmol),
TBHP (2.0 mmol), and K2CO3 (0.25 mmol) in nPrCO2nBu (0.5 M).
b Isolated yield. c Low yield due to the high volatility.
7 (Scheme 1). This hypothesis was supported by a number
of studies, which clearly demonstrated that electron-deficient
hypervalent iodine(III) center could be stabilized by ligand
coordination.8,9 In our case, the bulky ester solvent coordina-
tion might serve as a protecting pocket that prevented rapid
2130
Org. Lett., Vol. 12, No. 9, 2010

Table 4. Comparsion of O2 Evolution by DIB/TBHP in
Different Solvents
Scheme 2. Proposed Mechanism of the Allylic Oxidation
entrya
solvent
O2 evolution time period (min)
1
2
3
4
n-hexanes
toluene
MeCN
25
35
50
n-butyl butanoate
110
a Reactions were carried out with DIB (0.1 mmol) and TBHP (0.13
mmol) in the solvent (0.1 M) at 0 °C.
reductive elimination/coupling of tert-butylperoxy radical (2
f 4 f 5). The reactive but controllable tBuOO· 4 would
react with olefin to generate the allylic radical. Further
coupling of tBuOO· 4 with the allylic radical yielded the
peroxy ether (e.g., 30), which was evidenced by the suc-
cessful isolation of peroxy ether 30 when the reaction of
1-phenylcyclohexene (18) with DIB/TBHP was quenched
at 0 °C.6 Subjecting the intermediate 30 under standard allylic
oxidation conditions gave the desired enone 18a. Finally,
the reaction was terminated immediately upon the addition
of butylated hydroxytoluene (BHT), which further indicated
the radical nature of the reaction. Overall, a proposed reaction
mechanism is illustrated in Scheme 2.
to be important additives and ester solvent played a critical
role in the reaction. In general good yields and excellent
regioselectivies were observed for both simple and ∆5-steroid
olefinic substrates. Further investigations to clarify the
mechanism and on other applications are underway.
Acknowledgment. We thank the National University of
Singapore (Grant No. 143-000-384-133) for financial support.
Supporting Information Available: Experimental pro-
cedures and additional information. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL100603Q
In summary, a mild and efficient allylic oxidation with
inexpensive and commercially available DIB/TBHP protocol
has been developed. K2CO3 and Mg(OAc)2·4H2O were found
(9) (a) Hirt, U. H.; Spingler, B.; Wirth, T. J. Org. Chem. 1998, 63, 7674.
(b) Hirt, U. H.; Schuster, M. F. H.; French, A. N.; Wiest, O. G.; Wirth, T.
Eur. J. Org. Chem. 2001, 1569. (c) Ochiai, M.; Masaki, Y.; Shiro, M. J.
Org. Chem. 1991, 56, 5511. (d) Zhdankin, V. V.; Koposov, A. E.; Smart,
J. T.; Tykwinski, R. R.; McDonald, R.; Morales-Izquierdo, A. J. Am. Chem.
Soc. 2001, 123, 4095. (e) Ladziata, U.; Carlson, J.; Zhdankin, V. V.
Tetrahedron Lett. 2006, 47, 6301. (f) Zhdankin, V. V.; Koposov, A. Y.;
Yashin, N. V. Tetrahedron Lett. 2002, 43, 5735–5737.
(8) For reviews, see: (a) HyperValent iodine chemistry: modern deVelop-
ments in organic synthesis; Wirth, T., Ed.; Springer: Berlin, Germany, 2003;
Vol. 224. (b) Ochiai, M. Coord. Chem. ReV. 2006, 250, 2771–2781.
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