Allyl, methallyl, prenyl, and methylprenyl ethers as protected alcohols: Their selective cleavage with diphenyldisulfone under neutral conditions

Article abstract of DOI:10.1021/ol049135q

Diphenyldisulfone is a mild and efficient reagent for selective cleavage of methylprenyl (2,3-dimethylbut-2-en-1-yl), prenyl (3-methylbut-2-en1-yl), and methallyl (2-methylallyl) ethers. These reaction conditions are compatible with the presence of other protecting groups such as acetals, acetates, and allyl, benzyl, and TBDMS ethers. Exposure of 2,3-dimethylbut-2-en-1-yl and 3-methylbut-2-en1-yl ethers to diphenyldisulfone led to the formation of 2,3-dimethylbuta-1,3-diene and isoprene, respectively. 2-Methylallyl ethers undergo isomerization to 2-methylpropenyl ethers, which are easily hydrolyzed into the corresponding free alcohols and isobutyraldehyde.

Full text of DOI:10.1021/ol049135q

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2693-2696
Allyl, Methallyl, Prenyl, and Methylprenyl
Ethers as Protected Alcohols: Their
Selective Cleavage with
Diphenyldisulfone under Neutral
Conditions
Dean Markovic´ and Pierre Vogel*
Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology,
EPFL-BCH, CH-1015 Lausanne, Switzerland
pierre.Vogel@epfl.ch
Received May 12, 2004
ABSTRACT
Diphenyldisulfone is a mild and efficient reagent for selective cleavage of methylprenyl (2,3-dimethylbut-2-en-1-yl), prenyl (3-methylbut-2-en1-
yl), and methallyl (2-methylallyl) ethers. These reaction conditions are compatible with the presence of other protecting groups such as
acetals, acetates, and allyl, benzyl, and TBDMS ethers. Exposure of 2,3-dimethylbut-2-en-1-yl and 3-methylbut-2-en1-yl ethers to diphenyldisulfone
led to the formation of 2,3-dimethylbuta-1,3-diene and isoprene, respectively. 2-Methylallyl ethers undergo isomerization to 2-methylpropenyl
ethers, which are easily hydrolyzed into the corresponding free alcohols and isobutyraldehyde.
The protection and deprotection of alcohols is a central theme
of organic chemistry. Sophisticated synthetic schemes may
fail because of protective groups that cannot be removed
under suitable conditions without product decomposition.
Some of the most valuable protective groups for alcohols1
include allyl ethers, which can be cleaved under a variety
of conditions.2,3 In most cases, metal-catalyzed isomerization
(Pd, Rh, Ir) of the allyl ether into the corresponding alkenyl
ether and subsequent acidic hydrolysis are used to liberate
the desired alcohol together with propanal.4 The latter method
can be applied to methallyl and more substituted allyl ethers.
The higher the degree of substitution of the allyl ether, the
slower is the transition-metal-catalyzed isomerization.5 We
report here that in the presence of a catalytic amount of
diphenyldisulfone, methallyl, prenyl, and methylprenyl ethers
are cleaved readily, the fastest reaction occurring with the
most substituted allyl systems. Significantly, allyl ethers are
not affected. These reactions are initiated by the benzene-
sulfonyl radical formed from thermal homolysis of (PhSO2)2.6
(3) (a) Ho, T. L.; Wong, C. M. Synth. Commun. 1974, 4, 109-111. (b)
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(1) For reviews, see: (a) Kocien´ski, P. J. In Protecting Groups; Enders,
D., Noyori, R., Trost, B. M., Eds.; Thieme Verlag: Stuttgart, 1994. (b)
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1616.
(2) Guibe´, F. Tetrahedron 1997, 40, 13509-13556.
10.1021/ol049135q CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/16/2004

This discovery permits the cleavage of alkyl-substituted allyl
ethers under neutral conditions, without heavy metals and
with a useful reactivity sequence, i.e., methylprenyl > prenyl
> methallyl . allyl. Furthermore, other protected alcohols
such as silyl ethers, esters, and benzyl ethers are not affected
under these conditions.
Scheme 2. Diphenyldisulfone-Catalyzed Cleavage of
Methallyl (1b)-, Prenyl (1c)-, and Methylprenyl (1d)-Protected
Menthol Derivatives
Scheme 1. Deprotection of Menthol Derivatives 1a-g by
Diphenydisulfone
Menthol derivatives 1a-g (Table 1) were prepared fol-
lowing standard procedures.7 All compounds 1a-g remained
unchanged in CH2Cl2 after 24 h at 80 °C. In the presence of
10 mol % (PhSO2)2, allyl ether 1a, benzyl ether 1e, silyl
ether 1f, and acetate 1g were not affected by heating to 80
°C. In contrast, the methyl-substituted allyl ethers 1b, 1c,
and 1d were cleaved, and menthol was isolated nearly
quantitatively after aqueous workup.8
isobutyraldehyde. In the cases of 1c and 1d, no isomerized
ethers could be detected during the reactions as 1c and 1d
underwent fast 1,4-eliminations with formation of isoprene
and 2,3-dimethylbutadiene, respectively, together with men-
thol. The reactivity sequence was methylprenyl > prenyl >
methallyl . allyl.
Deprotection of methylprenyl ether 1d was examined with
hydrogen abstraction agents such as hexa-n-butylditin and
benzoyl peroxide at 80 °C in CD2Cl2. Benzoyl peroxide
deprotects methylprenyl ether 1d approximately four times
more slowly (half-life 23 h) than diphenyldisulfone (half-
life 6 h). With (Bu3Sn)2 we observed only traces of
deprotected menthol 2 after prolonged heating.
Table 1. Approximate Half-Life of 1a-g in Wet CD2Cl2 at 80
°C in the Presence of 10 Mol % (PhSO2)2
a
As a test for the usefulness of these new reactions, we
prepared the D-glucofuranoside derivative 7 according to
David’s method using dibutyltin oxide (Scheme 3).13
a N.R. ) no reaction.
In the case of 1b, isomerization into alkenyl ether 3b
1
(Scheme 2) could be monitored by H NMR. On addition
Scheme 3. Synthesis of D-Glucofuranoside Derivative 7a
of 1 mol of water 3b was hydrolyzed at 80 °C into 2 and
(4) (a) Gent, P. A.; Gigg, R. J. Chem. Soc., Chem. Commun. 1974, 277-
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2001, 57, 3435-3438.
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Tetrahedron 1997, 53, 13509-13556.
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2587-2592. (d) Kim, S.; Kee, I. S. Tetrahedron Lett. 1990, 31, 2899-
2900.
(8) Only 1b is deprotected on treating mixtures 1a + 1b, 1e + 1b, 1f +
1b and 1g + 1b under similar conditions. Similarly, only 1c or 1d is
deprotected when mixed with 1a, 1e, 1f, or 1g. Same observations were
made when cyclohexane was used as solvent.
a (a) Allyl bromide, NaH, Bu4NI, THF;9 (b) H2SO4, 50 °C,
MeOH/CH2Cl2;10 (c) methallyl iodide,11 Bu2SnO, toluene, reflux
methylprenyl bromide, NaH, Bu4NI12 (82%).
Compound 7 stayed unchanged upon heating to 80 °C in
CH2Cl2 (sealed tube). In the presence of 10 mol % (PhSO2)2
in CH2Cl2 and at 80 °C, 1,4-elimination occurred giving 6
+ 2,3-dimethylbutadiene (Scheme 4). The reaction was
2694
Org. Lett., Vol. 6, No. 16, 2004

Scheme 4. Deprotection of D-Glucofuranoside Derivative 7
Scheme 6. Deprotection of D-Glucofuranoside Derivative 11
presence of 10 mol % of diphenyldisufone. However, allylic
ether 22 gave exclusively cyclohexa-1,3-diene resulting from
a 1,4-elimination (Table 2).
complete in 26 h, and 6 could be isolated in 86% yield.
Further heating to 80 °C liberated diol 5 (isolated in 62%
yield) together with isobutyraldehyde (aqueous workup).
After further heating to 80 °C in the presence of 10 mol
% (PhSO2)2, the allyl ether of 5 remained intact (24 h; 95%
recovery of 5).
The same selectivity order of deprotection was observed
with D-glucofuranoside 11 prepared as outlined in Scheme
5.
Table 2. RO-Allyl Ethers 9 and 14-21 Are Cleaved into
Corresponding Alcohols ROH in the Presence of 10 Mol %
Diphenyldisulfone in CH2Cl2 at 80 °C
Scheme 5. Synthesis of D-Glucofuranoside Derivative 11a
a (a) Methallyl chloride, NaH, Bu4NI, THF,14 92%; (b) H2SO4 1
M, 50 °C, MeOH, CH2Cl2,10 71%; (c) prenyl bromide, Bu2SnO,
toluene, reflux;13 (d) allyl bromide, NaH, Bu4NI, THF,9 92%.
Upon heating of 11 to 80 °C in the presence of 10 mol %
(PhSO2)2, 1,4-elimination of the prenyl group occurred,
giving 12 and isoprene (Scheme 6). The reaction was finished
after 28 h and 12 could be isolated in 82% yield. Further
heating of 12 to 80 °C liberated diol 13 in 68% yield.
To test further the practicability of our new deprotection
method, we synthesized allylic ethers 9 and 14-22. Ethers
9 and 14-21 were easily cleaved on heating at 80 °C in the
(9) Li, J.; Wang, J.; Hui, Y.; Chang, C.-W. T. Org. Lett. 2003, 5, 431-
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Chem. 2001, 66, 2822-2827.
The mechanism of the isomerization of the methallyl ethers
23 might involve the formation of oxyallyl radical 24
(Scheme 7), as this isomerization was inhibited by radical
scavenging agents such as TEMPO. Both 1,4-elimination 1c
f 2 + isoprene and 1d f 2 + 2,3-dimethylbutadiene might
(12) Cennan, E. L.; Chen, X. J. Am. Chem. Soc. 1989, 111, 5787-5792.
(13) (a) Bravo, F.; Castillo´n, S. Eur. J. Org. Chem. 2001, 3, 507-516.
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Org. Lett., Vol. 6, No. 16, 2004
2695

rich the alkene,17 the better it stabilizes charge-transfer
•
configurations of the transition states, the PhSO2 radical
Scheme 7. Possible Mechanisms of Deprotection of
Methallyl, Prenyl, and Methylprenyl Ethers in the Presence of
Diphenyldisulfone
being an electrophilic species.18,19
It should be noticed that bond dissociation enthalpies for
the allyl C-H bond are not significantly different between
propene and 2-methylpropene.21 No doubt more work is
required to limit the number of possible mechanisms of the
reaction disclosed in this report.
Methylprenyl, prenyl, and methylallyl ethers become
valuable protected forms of alcohols, as they can be cleaved
under mild conditions that do not require acid, base, or heavy
metal reagents or catalysts.
Acknowledgment. We thank the Swiss National Science
Foundation (Grant 2000-20100002/1) and the Office Federal
de l’Education et de la Sciences (Grant COI. 0071, COST
D13/010/01) for financial support. We thank also Mr. Martial
Rey, Franscico Sepu´lveda, and Srinivas Reddy Dubbaka for
technical help.
imply the intermediacy of alkyl-substituted allyl radical
intermediates, as both reactions were also inhibited by
TEMPO. These radical intermediates might undergo fast
heterolysis15 that competes with other intermolecular hydro-
gen transfers required for the allyl f alkenyl isomerization.
Allyl silyl ethers have been isomerized into corresponding
enol silyl ethers in the presence of radical-chain initiators
and arenethiols as polarity reversal catalysts.16 In our case
(23 f 25) PhSO2H could play the role of polarity reversal
catalyst (mechanism B in Scheme 7).
Supporting Information Available: General procedures
and spectral and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL049135Q
The reactivity sequence methylprenyl > prenyl > meth-
allyl . allyl can be explained invoking a direct hydrogen
abstraction mechanism, the energy barrier of which depends
on the ionization energy of the alkene (the more electron-
(17) Walling, C. Free Radicals in Solution; John Wiley & Sons: New
York, 1957. Roberts, B. P. Chem. Soc. ReV. 1999, 28, 25-35.
(18) Takahara, Y.; Iino, M.; Matsuda, M. Bull. Chem. Soc. Jpn. 1976,
49, 2268-2271.
•
(19) A referee suggested that PhSO2 might react as DDQ and take an
electron from the oxygen atom,20 followed by R-deprotonation giving an
oxyallyl cation intermediate that is hydrolyzed into the corresponding alcohol
and aldehyde. Although the proposal cannot be rejected at this stage, it
seems to us that it does not explain the chemoselectivity observed, especially
the nonreaction of allyl ethers.
(20) (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885-888. (b) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.;
Yonemitsu, O. Tetrahedron 1986, 42, 3021-3028.
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R. D.; Mallard, W. G. J. Phys. Chem., Ref. Data Suppl. 1988, 17, 1 (http://
webbook.nist.gov).
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Damm, W.; Mohr, M.; Zinse, H.; Giese, B. Tetrahedron 2000, 56, 4117-
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