CCl3CN: A crucial promoter of M CPBA-mediated direct ether oxidation

Article abstract of DOI:10.1021/ol1018079

The direct oxidation of ether sp³ C-H bonds using the new reagent system mCPBA/CCl₃CN/MeCN has been developed. CCl ₃CN in MeCN drastically alters the reactivity of m-chloroperbenzoic acid (mCPBA), and chemoselective transformation of methyl ethers to ketones was realized under mild conditions. Radical-based mCPBA-mediated oxidation was suggested as the reaction mechanism. The present new reaction expands the utility of methyl ethers as stable synthetic precursors of carbonyl compounds and of mCPBA as a radical-based C-H oxidizing agent.

Full text of DOI:10.1021/ol1018079

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4195-4197
CCl3CN: A Crucial Promoter of
mCPBA-Mediated Direct Ether Oxidation
Shin Kamijo, Shoko Matsumura, and Masayuki Inoue*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
inoue@mol.f.u-tokyo.ac.jp
Received August 2, 2010
ABSTRACT
The direct oxidation of ether sp3 C-H bonds using the new reagent system mCPBA/CCl3CN/MeCN has been developed. CCl3CN in MeCN
drastically alters the reactivity of m-chloroperbenzoic acid (mCPBA), and chemoselective transformation of methyl ethers to ketones was
realized under mild conditions. Radical-based mCPBA-mediated oxidation was suggested as the reaction mechanism. The present new reaction
expands the utility of methyl ethers as stable synthetic precursors of carbonyl compounds and of mCPBA as a radical-based C-H oxidizing
agent.
Oxidation of organic compounds is of fundamental impor-
tance in chemistry.1 Among the numerous oxidants, m-
chloroperbenzoic acid (mCPBA) is one of the most frequently
used reagents in synthetic laboratories.2 Its unique reactivity
is characterized by a weak O-O bond and a nucleophilic
OH group. The O-O bond of mCPBA transfers an oxygen
atom to electron-rich substrates, such as alkenes, sulfides,
selenides, and amines, while the nucleophilic attack of
mCPBA on ketones and aldehydes results in insertion of an
oxygen atom to generate esters (Baeyer-Villiger oxidation).
Under these oxidation conditions, the sp3 C-H bonds of
substrates are completely inert.3,4 In this paper, we describe
mCPBA-mediated oxidation of sp3 C-H bonds of ethers by
applying newly developed conditions. CCl3CN in MeCN
drastically alters the reactivity of mCPBA without the aid
of a metal catalyst, and chemoselective transformation of
stable ethers to ketones is realized at room temperature
through a radical-based mechanism.5-7 The present findings
broaden the synthetic utility of mCPBA as a C-H oxidizing
agent.
The conditions for mCPBA-mediated sp3 C-H oxidation
of ethers were screened and optimized using cyclododecyl
methyl ether 1a (Table 1). Treatment of 1a with mCPBA (2
(4) The more reactive CF3CO3H has been applied to C-H bond
oxidation. (a) Deno, N. C.; Messer, L. A. J. Chem. Soc., Chem. Commun.
1976, 1051. (b) Moody, C. J.; O’Connell, J. L. Chem. Commun. 2000, 1311.
(c) Camaioni, D. M.; Bays, J. T.; Shaw, W. J.; Linehan, J. C.; Birnbaum,
(1) Ley, S. V. ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 7.
(2) Handbook of Reagents for Organic Synthesis: Oxidizing and
Reducing Agents; Burke, S. D., Danheiser, R. L., Eds.; Wiley: Chichester,
1999; pp 84-89.
J. C. J. Org. Chem. 2001, 66, 789
(5) For a review of metal-free C-H functionalizations, see: Fokin, A. A.;
Schreiner, P. R. AdV. Synth. Catal. 2003, 345, 1035
.
.
(3) Examples of mCPBA-mediated C-H bond oxidation are quite limited
and generally require high temperatures (>60 °C). (a) Takaishi, N.; Fujikura,
Y.; Inamoto, Y. Synthesis 1983, 293. (b) Schneider, H.-J.; Mu¨ller, W. J.
Org. Chem. 1985, 50, 4609. (c) Tori, M.; Sono, M.; Asakawa, Y. Bull.
Chem. Soc. Jpn. 1985, 58, 2669. (d) Shiao, M.-J.; Lin, J. L.; Kuo, Y.-H.;
Shih, K.-S. Tetrahedron Lett. 1986, 27, 4059. (e) Fossy, J.; Lefort, D.; Sorba,
J. Top. Curr. Chem. 1993, 164, 99. (f) Bravo, A.; Bjorsvik, H.-R.; Fontana,
F.; Minisci, F.; Serri, A. J. Org. Chem. 1996, 61, 9409. (g) Ma, D.; Xia,
(6) For direct ether oxidation using dioxirane and oxaziridine, see: (a)
Curci, R.; D’Accolti, L.; Fiorentino, M.; Fusco, C.; Adam, W.; Gonza´lez-
Nun˜ez, M. E.; Mello, R. Tetrahedron Lett. 1992, 33, 4225. (b) van Heerden,
F. R.; Dixon, J. T.; Holzapfel, C. W. Tetrahedron Lett. 1992, 33, 7399. (c)
Arnone, A.; Bernardi, R.; Cavicchioli, M.; Resnati, G. J. Org. Chem. 1995,
60, 2314
.
(7) For a recent Mn-catalyzed direct ether oxidation, see: (a) Kamijo,
S.; Amaoka, Y.; Inoue, M. Chem. Asian J. 2010, 5, 486. (b) Kamijo, S.;
Amaoka, Y.; Inoue, M. Synthesis 2010, 2475.
C.; Tian, H. Tetrahedron Lett. 1999, 40, 8915
.
10.1021/ol1018079  2010 American Chemical Society
Published on Web 08/24/2010

Table 1. Screening of Additives and Solvents for the Oxidation
of Methyl Ether 1aa
Scheme 1
.
Suggested Radical Mechanism for Direct Ether
Oxidation
additive
(X equiv)
yield,
%b (recovery)
entry
solvent
1c
2
3
4
5
6
7
-
-
CHCl3
MeCN
MeCN
MeCN
MeCN
9.8 (63)
<1.0 (99)
68d (15d)
trace (98)
7.9 (89)
CCl3CN (2)
Cl2CHCN (2)
(CCl3CO)2O (2)
-
CCl3CN/MeCN (1/1)
CCl3CN
88d (10d)
<1.0 (99)
-
4,4′-thiobis(6-t-
8
butyl-m-cresol) (0.1) CCl3CN/MeCN (1/1)
(C6H5COO)2 (0.1) MeCN
1.4 (98)
13 (84)
mCPBA and CCl3CN in polar solvent (MeCN) is in equi-
librium with minute amounts of the highly unstable peroxy-
imidate A.11 The O-O bond of A is more activated by the
attached imidate than that of mCPBA12 and consequently is
more prone to undergo homolytic cleavage. Thus, the low
concentration of radical initiator A would continuously
liberate oxyradical C at room temperature. Next, C abstracts
hydrogen from 1 to generate ArCOOH and radical D, which
in turn reacts with mCPBA to generate E.13 In this step,
oxyradical C is regenerated to propagate the chain reaction.
Lastly, ejection of MeOH from E furnishes the product 2.
NMR monitoring of the reaction revealed that production
of the end compounds in Scheme 1 (MeOH, ArCOOH, and
2) was in accordance with consumption of ether 1a and
therefore supported the suggested mechanism.14 Overall,
mCPBA has two roles in this radical chain reaction: it
functions as an oxyradical precursor through A and as an
oxygen atom donor upon formation of E.
To explore the substrate scope and chemoselectivity of
the present transformation, variously substituted ethers were
treated under the optimized conditions (Table 2). First,
oxidation of cyclododecyl ethers was investigated (entries
1-7). Similar to the case of methyl ether 1a (entry 1),
oxidations of the octyl 1b, isopropyl 1c, and benzyl ethers
1d all produced ketone 2a (entries 2-4). The sterically more
demanding t-butyl group of 1e, on the other hand, impeded
the oxidation (entry 5). 4-Pentenyl ether 1f and the cyclo-
hexanone analogue 1g were both converted into 2a (entries
9e
a Conditions: methyl ether 1a, mCPBA (2 equiv; 70 wt %), additive (X
equiv), solvent (entries 3-5, 0.1 M; entries 1, 2, 6-9, 0.2 M), 0 °C for
0.5 h then rt for 24 h. b NMR yield. c The reaction was performed at 60 °C
for 24 h. d Isolated yield. e The reaction was performed under a desk lamp.
equiv) in CHCl3 generated only a small amount of ketone
even at elevated temperature (entry 1), and negligible
formation of 2a occurred in MeCN (entry 2). In sharp
contrast to these results, addition of 2 equiv of CCl3CN in
MeCN significantly promoted the conversion of 1a into
ketone 2a at room temperature (68% yield, entry 3). Thus,
the reaction mode appeared to become different only by
addition of CCl3CN. Interestingly, Cl2CHCN and trichloro-
acetic anhydride, which are less electrophilic reagents than
CCl3CN, exhibited a much smaller effect as promoters
(entries 4 and 5). The yield of 2a was increased to 88% in
a solvent mixture of CCl3CN and MeCN (entry 6), whereas
use of CCl3CN as a sole solvent produced just a trace amount
of 2a (entry 7). These data demonstrated that mCPBA,
CCl3CN, and MeCN are essential for the ether oxidation.8,9
The radical scavenger 4,4′-thiobis(6-t-butyl-m-cresol) (0.1
equiv)10 inhibited the mCPBA oxidation of 1a in CCl3CN/
MeCN (entry 8), while the radical initiator benzoyl peroxide
(0.1 equiv) promoted formation of 2a even in the absence
of CCl3CN when irradiated by a fluorescent lamp (entry 9).
It is likely, therefore, that a radical-based mechanism is
operating in the direct ether oxidation.
(11) For peroxyimidate derived from H2O2 and CCl3CN known as an
epoxidation reagent, see: (a) Payne, G. B.; Deming, P. H.; Williams, P. H.
J. Org. Chem. 1961, 26, 659. (b) Arias, L. A.; Adkins, S.; Nagel, C. J.;
Bach, R. D. J. Org. Chem. 1983, 48, 888.
The observed data indicated that the radical chain reaction
is involved in the conversion of 1 to 2. Scheme 1 illustrates
the mechanistic hypothesis of the reaction. Due to the
strongly electrophilic nature of CCl3CN, a mixture of
(12) The dissociation energy of the O-O bond generally decreases upon
attachment of electron-withdrawing groups [e.g., AcO-OH (40.6 kcal/mol),
AcO-OAc (33.5 kcal/mol), and AcO-ONO2 (31.4 kcal/mol)]. See: Mo-
lecular Structure and Spectroscopy. In Handbook of Chemistry and Physics,
87th ed.; Lide, D. R., Ed.; CRC Press: Boca Raton, FL, 2006; p 64.
(13) For oxygen donation of mCPBA to a carbon radical, see ref 3e.
(14) B should abstract a hydrogen to give CCl3C(O)NH2. Detection of
A and CCl3C(O)NH2 by NMR analysis has not yet been successful. Since
only 0.1 equiv of the radical inhibitor completely inhibited the oxidation
(entry 8, Table 1), we assumed that the concentrations of A and the resulting
CCl3C(O)NH2 are extremely low in the reaction mixture.
(8) Light or O2 had a small effect for the reaction in entry 6 because
2a was consistently produced under the conditions strictly without light
or O2.
(9) Oxidations of butylbenzene and triphenylmethane were not successful
under the same conditions as shown in entry 6.
(10) Kishi, Y.; Aratani, M.; Tanino, H.; Fukuyama, T.; Goto, T. J. Chem.
Soc., Chem. Commun. 1972, 64.
4196
Org. Lett., Vol. 12, No. 18, 2010

Table 2. Oxidation of Various Ethersa
Figure 1. mCPBA oxidations of olefin 1f and ketone 1g in the
absence of CCl3CN.
Next, the methyl ethers of substituted carboskeletons were
subjected to the reaction (Table 2, entries 8-14). The
oxidation of the seven-membered ring 1h gave ketone 2b in
high yield (entry 8). Importantly, only the methyl ethers of
the differentially protected diols 1i-1l (entries 9-12) were
oxidized to the carbonyl groups of 2c-2f. The electron-
withdrawing acetyl (1i) and mesyl (1j) groups and the
sterically bulky TBDPS (1k) and trityl groups (1l) effectively
protected the hydroxy functionalities, demonstrating the high
chemoselectivity of the reaction. When 4 equiv of mCPBA
was applied to cis- and trans-substituted cyclohexyl methyl
ethers 1m and 1n, the ether oxidation and the Baeyer-Villiger
oxidation occurred simultaneously to generate lactone 3
(entries 13 and 14).
In conclusion, we have developed a method for the direct
ether oxidation using the new reagent system mCPBA/
CCl3CN/MeCN. Robust methyl ethers were chemoselectively
reacted with mCPBA in the presence of other potentially
reactive oxygen functionalities under mild and operationally
simple conditions. The present oxidation expands the syn-
thetic potential of methyl ethers as stable precursors of
carbonyl compounds and of mCPBA as a radical-based C-H
oxidizing agent. Applications of the new reagent system as
well as further mechanistic investigations are ongoing in our
laboratory.
a Conditions: ether 1, mCPBA (2 equiv; 70 wt %), CCl3CN/MeCN (1/
1; 0.2 M), 0 °C for 0.5 h then rt for 24 h. b Isolated yield of ketone and
recovery of starting material. c Treated with 4 equiv of mCPBA in CCl3CN/
MeCN (1/1; 0.1 M). d Lactone 4b was isolated in 32% yield. e Treated with
1.2 equiv of mCPBA.
6 and 7).15 Since the mCPBA oxidation of olefin 1f and six-
membered ketone 1g in the absence of CCl3CN afforded the
corresponding epoxide 4a and seven-membered lactone 4b,
respectively (Figure 1), entries 6 and 7 clearly verified the
enhanced reactivity of the mCPBA/CCl3CN/MeCN reagent
system.
Acknowledgment. This research was financially supported
by Grant-in-Aids for Young Scientists (S) to MI and (B) to
SK.
Supporting Information Available: Experimental pro-
cedures and spectroscopic and analytical data for relevant
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Neither epoxide 4a nor the olefinic derivatives were isolated upon
treatment of 1f with the mCPBA/CCl3CN/MeCN reagent system. The olefin
and alcohol moieties of the cleaved 4-pentenol were likely to be oxidized
to give the mixture of products.
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