Oxidative cleavage of p-methoxybenzyl ethers with methyl(trifluoromethyl) dioxirane

Article abstract of DOI:10.1021/ol051856h

(Chemical Equation Presented) The ability of methyl(trifluoromethyl) dioxirane to cleave p-methoxylbenzyl ethers oxidatively in the presence of various additional functional groups has been investigated. These reactions, performed in aqueous acetonitrile,

Full text of DOI:10.1021/ol051856h

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4665-4667
Oxidative Cleavage of p-Methoxybenzyl
Ethers with
Methyl(trifluoromethyl)dioxirane
Leo A. Paquette,*,† Matthew M. Kreilein,† Matthew W. Bedore,† and Dirk Friedrich‡
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette.1@osu.edu
Received August 2, 2005
ABSTRACT
The ability of methyl(trifluoromethyl)dioxirane to cleave p-methoxylbenzyl ethers oxidatively in the presence of various additional functional
groups has been investigated. These reactions, performed in aqueous acetonitrile, transform a reasonably robust aryl substituent into a dienyl
aldehydo ester. The originally generated E,Z-isomer undergoes slow conversion to the more stable E,E-form at 20 °C.
The virtue of p-methoxybenzyl (PMB) ethers as utilitarian
protecting groups has been extensively touted.1 Most often
Scheme 1
recognized is their ability to engage in deprotection, fre-
quently involving DDQ under very mild conditions. As part
of a program targeting the enhanced oxygenation of exten-
sively substituted taxanes, we have identified the feasibility
of effecting the oxidative cleavage of this otherwise quite
robust functional group with methyl(trifluoromethyl)diox-
irane. To our knowledge, reports of this type of oxidative
cleavage have not previously been disclosed.
The discovery of this chemistry began with the early
observation that 12,3 but not 33 undergoes epoxidation
smoothly when treated with dimethyldioxirane4 (Scheme 1).
Yields of 2 in the vicinity of 50% were routinely realized
under dilute reaction conditions. The acquisition of HMBS,
COSY, and HMQC data convincingly established the product
to be the C12-C13 oxirane having an exo-oriented hetero-
atom.
Comparable reactivity was not observed with the bromine-
containing derivative 3, which was recovered intact following
workup. This result can be attributed to steric constraints
provided by the bromine substituent, to electronic deactiva-
tion of the double bond, or to a combination of these factors.
In light of the established 1000-fold greater reactivity of
methyl(trifluoromethyl)dioxirane,5 its use in the context of
† The Ohio State University.
‡ Present address: Sanofi-Aventis Pharmaceuticals, Inc., 1041 U.S. Route
202/206, P.O. Box 6800, Bridgewater, NJ 08807-0800.
(1) Kocienski, P. J. Protecting Groups, 3rd ed.; Georg Thieme Verlag:
Stuttgart, 2004; pp 257-269.
(2) Paquette, L. A.; Hofferberth, J. E. J. Org. Chem. 2003, 68, 2266.
(3) Kreilein, M. M. Ph.D. Dissertation, The Ohio State University, 2005.
(4) (a) Adam, W.; Curci, R.; Edward, J. O. Acc. Chem. Res. 1989, 22,
205. (b) Murray, R. W. Chem. ReV. 1989, 89, 1187. (c) Curci, R. In
AdVances in Oxygenated Processes; Baumstark, A. L., Ed.; JAI Press:
Greenwich, CT, 1990; Vol. 2, p 1.
(5) Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887.
10.1021/ol051856h CCC: $30.25
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1 and 3 was next probed. Where 1 was concerned, faster
reaction was noted, and 2 was similarly produced in 50%
yield.
With the focus now turned to 3,3 the dominant pathway
for its consumption involved oxidative cleavage of the
p-methoxybenzyl group to deliver the E,Z-configured alde-
hydo ester 4 (Scheme 2). The isolated yield of 4 was 46%
trifluoroacetone.6 The adoption of this procedure, referred
to as method B in Table 1, was compared in selected
examples with modifications involving changes in the timing
of reagent addition. The efficacies associated with these
changes proved not to be dramatically different. Notwith-
standing, our preference is to use method C (see for example
the oxidation of 9). In contrast, the sensitivity of 14-21 to
chromatographic purification was clearly contributory in part
to the reduced yields observed for the oxidative ring cleavage.
The utilization of Florisil or deactivated silica gel (6% H2O
w/w) was often more tolerant of the sensitive functionality
contained in 14-21.
Scheme 2
As in the 4 f 5 example, storage of 14-21 at room
temperature in a solvent-free state for the duration of 7-10
days resulted in quantitative E,Z f E,E isomerization (1H
NMR analysis). The apparent generality of this previously
unencountered reaction should prove of interest to those
planning to involve methyl(trifluoromethyl)dioxirane as a
reagent in complex molecule total synthesis settings. Im-
portant new applications of this chemistry may also evolve
in the future. To a limited extent, the oxidative cleavage of
p-methoxybenzyl ethers holds similarity to the ozonolytic
ring fission of the veratryl group (30) (Scheme 3). As utilized
Scheme 3
at 50% conversion. During the course of standing at room
temperature for one week, 4 underwent almost complete
conversion to its thermodynamically more stable E,E isomer
5. Under electrospray high-resolution mass spectral condi-
tions, both 4 and 5 (calcd for C41H55BrO12SiNa+ m/z
869.2538 and 871.2518) exhibit closely corresponding ions,
e.g., m/z ) 869.2511 and 871.2571. The 500 MHz 1H NMR
spectra of the product pair recorded on C6D6 solutions reveal
several distinctive features of interest. For example, the
signals for the olefinic protons of the side chain of compound
4 (δ 6.36 and 5.89, 12 Hz) differ significantly from those of
5 (δ 8.08 and 6.56, 16 Hz). The combination of DQF-COSY,
NOESY, HMQC, and Grad-HMBC studies involving 5
provided information fully diagnostic of its global structural
taxane-based features.
Products 4 and 5 are recognized to be more highly
functionalized than their precursor 3. In light of the apparent
tolerance of the reaction conditions to a variety of functional
groups, a general procedure was devised to gain some
appreciation of the scope of this transformation (Table 1).
The structural features of PMB ethers 6-13 were considered
to be sufficiently diverse for our purposes. As matters worked
out, the free hydroxyl in 6, the ester and amide groups
resident in 7 and 13, and the ketone and ether functionalities
found in 9, 10, and 12 tolerate the oxidative ring-cleavage
conditions well. The bromine substituent in 8 similarly plays
no adverse role.
by Woodward in his strychnine synthesis,7 this otherwise
stable aryl group can be oxidatively cleaved to 31 in a
completely selective manner for the purpose of unmasking
functionality amenable to further chemical change. The four-
electron ring opening of catechol (32) to cis,cis-muconic acid
monomethyl ester (33) under anaerobic conditions has also
been recognized for some time.8,9 As in the latter case,
aldehydo esters 14-29 hold the distinction of possessing
distinguishable functional groups. A limitation of the oxida-
(6) Takahata, H.; Banba, Y.; Sasatani, H.; Nemoto, H.; Kato, A.; Adachi,
I. Tetrahedron 2004, 60, 8199.
(7) (a) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.;
Daeniker, H. U.; Schenker, K. J. Am. Chem. Soc. 1954, 76, 4749. (b)
Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.;
Schenker, K. Tetrahedron 1963, 19, 247.
(8) (a) Rogic, M. M.; Demmin, M. M.; Hammond, W. B. J. Am. Chem.
Soc. 1976, 98, 7441. (b) Demmin, M. M.; Rogic, M. M. J. Org. Chem.
1980, 45, 4210.
(9) The oxidation of catechol to the muconic acids is also known:
McKague, A. B. Synth. Commun. 1999, 29, 1463.
Most protocols involving epoxidation with the fluorinated
dioxirane rely on the addition of a mixture of Oxone and
sodium bicarbonate to a solution containing the reactant and
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Org. Lett., Vol. 7, No. 21, 2005

Table 1. Results of Oxidative Cleavage and Thermal Equilibration
a Method A: Trifluoroacetone added to Oxone and NaHCO3. Method B: A mixture of Oxone and NaHCO3 added to trifluoroacetone. Method C: Oxone
added to a mixture of NaHCO3 and trifluoroacetone. b The yields are based on percent conversion. c The deactivated silica gel was prepared by addition of
6% H2O on a w/w basis and agitating the silica gel for several hours to guarantee homogeneity.
1
tions reported here is the low efficiency with which the
oxidized counterpart is produced at the present time.
including their recorded H NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
Supporting Information Available: General experimen-
tal details and characterization data for all compounds
OL051856H
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