New protecting groups for 1,2-diols (boc- and moc-ethylidene). Cleavage of acetals with bases

Article abstract of DOI:10.1021/ol0062289

1,2-Diols react at rt with alkyl propynoates, in the presence of 4-dimethylaminopyridine, to give cyclic acetals which are quite stable to acid-catalyzed hydrolysis or methanolysis. 1,3-Diols and 1,4-diols do not form acetals with alkyl propynoates under the same conditions. Deprotection is accomplished with bases (via elimination and addition/elimination steps).

Full text of DOI:10.1021/ol0062289

ORGANIC
LETTERS
2000
Vol. 2, No. 18
2809-2811
New Protecting Groups for 1,2-Diols
(Boc- and Moc-ethylidene). Cleavage of
Acetals with Bases
Xavier Ariza, Anna M. Costa, Montserrat Faja, Oriol Pineda, and Jaume Vilarrasa*
Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica, UniVersitat de Barcelona,
08028 Barcelona, Catalonia, Spain, EU
Vilarrasa@qo.ub.es
Received June 19, 2000
ABSTRACT
1,2-Diols react at rt with alkyl propynoates, in the presence of 4-dimethylaminopyridine, to give cyclic acetals which are quite stable to
acid-catalyzed hydrolysis or methanolysis. 1,3-Diols and 1,4-diols do not form acetals with alkyl propynoates under the same conditions.
Deprotection is accomplished with bases (via elimination and addition/elimination steps).
The addition of nucleophiles to triple bonds conjugated with
electron-withdrawing groups has many synthetic applica-
tions.1-3 Often, as illustrated in Scheme 1 (top) for certain
there are exceptions.1 In this context, we focused our attention
on compounds with two nucleophilic sites close together,
as shown in Scheme 1. Initially, one of the nucleophilic sites
would become protected by a 2-(methoxycarbonyl)ethenyl
group (Mocvinyl)4 or 2-(tert-butoxycarbonyl)ethenyl group
(henceforward Bocvinyl). These reaction intermediates could
react with the propynoate ester (remaining or in excess) either
to afford a diprotected derivative or to cyclize intramolecu-
larly (Scheme 1, bottom).5,6 In this second case, the two
nucleophilic sites of the molecule would become protected
Scheme 1
by
a 2-(methoxycarbonyl)ethylidene (Moc-ethylidene,
“Mocdene”) or 2-(tert-butoxycarbonyl)ethylidene group (Boc-
ethylidene, “Bocdene”). We report here on the formation,
stability, and cleavage of these acetals, which show a striking
(2) Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241 (addition
of primary alcohols to methyl propynoate, catalyzed by Bu3P).
(3) Kuroda, H.; Tomita, I.; Endo, T. Synth. Commun. 1996, 26, 1539
(formation of dithioacetals via conjugate addition).
(4) Faja, M.; Ariza, X.; Ga´lvez, C.; Vilarrasa, J. Tetrahedron Lett. 1995,
36, 3261. Costa, A. M.; Faja, M.; Farra`s, J.; Vilarrasa, J. Tetrahedron Lett.
1998, 39, 1835 (protection of N3 of pyrimidine nucleosides).
(5) For the formation of cyclic acetals via conjugate addition (of alkoxide
to O-CHdCH-COOMe), see: Evans, P. A.; Garber, L. T. Tetrahedron
Lett. 1996, 37, 2927.
nucleophile additions to esters of propynoic acid (propiolic
acid), only the adduct of configuration E is obtained, although
(1) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon: Oxford, 1992; p 345. MacPherson, D. T.; Rami, H. K. In
ComprehensiVe Organic Functional Group Transformations, Vol. 4;
Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Kirby, G. W., Eds.;
Elsevier: Oxford, 1995; p 195. Arjona, O.; Iradier, F.; Medel, R.; Plumet,
J. J. Org. Chem. 1999, 64, 6090, and references therein. For “anomalous”
reactions (γ- or R-addition instead of â-addition, in the presence of Ph3P
and AcOH), see: Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116,
10819. Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997, 119, 7595.
(6) For the formation of cyclic acetals from dialkoxides and 1,2-bis-
(phenylsulfonyl)ethene, see: Che´ry, F.; Rollin, P.; De Lucchi, O.; Cossu,
S. Tetrahedron Lett. 2000, 41, 2357, and references therein.
10.1021/ol0062289 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/05/2000

behaVior, as they are quite stable to acidic media while they
can be cleaVed with strong bases.
When, in a series of parallel experiments, (S,S)-1,2-
diphenyl-1,2-ethanediol (1) was treated with 1.1 equiv of
tert-butyl propynoate in CH3CN at rt, in the presence of 0.5
equiv of 4-dimethylaminopyridine, triethylamine, or N-
ethyldiisopropylamine, O-substituted derivatives were formed
at rates decreasing in this order. Thus, the experiment with
DMAP gave 97% of acetal 1a within 30 min (Table 1, entry
Table 1. Reaction of Diols with tert-Butyl Propynoate (1.1
equiv) and DMAP (0.5 equiv) in CH3CN at Room
Temperature,a unless Otherwise Indicated
Figure 1. NOE noted in 2a. Byproducts 7 and 8 (of the reactions
of 1 and 2, respectively, with methyl propynoate and DMAP at rt).
THP derivatives, etc.,8 as a new stereocenter is created during
the protection step, but organic chemists are used to
managing these cases. Finally, the diisopropylidene acetal
of D-mannitol (6) afforded 6a in excellent yield (Table 1,
entry 6).
Methyl propynoate was also investigated as an alternative
to tert-butyl propynoate, the corresponding “Mocdene”
acetals forming equally well in most cases, with similar
stereoselectivities. However, some byproducts were isolated
in 15-25% yields, such as 7 (from 1) and (()-8 (from 2).
Nevertheless, it sufficed to carry out the reactions between
-20 and 0 °C, instead of at rt, to avoid the appearance of
these transesterification byproducts.
1,3-Diols 9 and 10 did not afford the corresponding six-
membered cyclic acetals but mixtures of mono-Bocvinyl and
bis-Bocvinyl derivatives, or of the mono-Mocvinyl and bis-
Mocvinyl derivatives (see Scheme 2), under our reaction
Scheme 2
a At 0.1 M substrate concentrations. b Similar results in THF and in
CH2Cl2. c 2.2 equiv of tert-butyl propynoate was used. d In DMF, with 2
equiv of tert-butyl propynoate; in CH3CN (where 6 is scarcely soluble),
with only 1.1 equiv of reagent, the yield was 99%, but 24 h was required
to complete the reaction.
1), Et3N required 1-2 h to complete the acetal formation,
while the catalytic activity of N-ethyldiisopropylamine was
very low. Without base, no reaction took place, even in
refluxing CH3CN. With Me3P or with Bu3P,2 the acetal yields
never exceeded 50%. The meso form of 1,2-diphenyl-1,2-
ethanediol (2) reacted similarly with tert-butyl propynoate
to afford 94% of the acetal 2a (Table 1, entry 2), with the
“Bocdene” group cis to the phenyl groups, as shown by a
NOESY experiment (in CDCl3 at 500 MHz, summarized in
Figure 1). 1-Phenyl-1,2-ethanediol (3), cis-1,2-cyclopen-
tanediol (4),7 and 5′-O-trityluridine (5) gave the two possible
stereoisomers. In general, the presence of epimers is a well-
known handicap of ethylidene acetals, benzylidene acetals,
conditions (in which no alkoxide ions are involved5). With
a large excess of alkyl propynoates, only the bis-derivatives
(7) As expected, no cyclized product was observed in the case of trans-
1,2-cyclopentanediol.
(8) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis; Wiley: New York, 1999.
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Org. Lett., Vol. 2, No. 18, 2000

were obtained. 1,2-Benzenedimethanol (a 1,4-diol) did not
give a seven-membered cyclic acetal, either. Therefore, 1,3-
and 1,4-diols did not show any trend to form “Bocdene” or
“Mocdene” acetals. It means that, in polyol systems, five-
membered rings (dioxolanes) can be selectively obtained with
respect to six- (dioxanes) and seven-membered (dioxepanes)
rings. To check this assumption, triol 119 was treated with
1.1 equiv of tert-butyl propynoate and 0.5 equiv of DMAP
in CH3CN at rt for 90 min: 11a was formed exclusively (as
indicated by TLC) and was isolated in 91% yield.
Deprotection of “Bocdene” and “Mocdene” Acetals
Can Be Accomplished with a Base. Our hypothesis was
that a base was needed to produce the elimination that would
yield the Bocvinyl intermediate (Scheme 3), which could
Scheme 3
Stability of “Bocdene” and “Mocdene” Acetals to Acids
Is Noteworthy. The usual mechanism of acetal hydrolysis
through protonation of one oxygen atom, cleavage of one
C-O bond to give an oxonium-like cation, and so on (i.e.,
the reversal of the acid-catalyzed acetal formation) does not
work in these acetals; it is likely that the alkoxycarbonyl
group (like other EWG)6 disfavors the first two steps. The
results of the hydrolysis experiments may be summarized
as follows: (i) at rt, “Bocdene” and “Mocdene” acetals are
stable against AcOH/H2O, 1 M HCl/THF, and TsOH/
MeOH;8 in practice we hydrolyzed quantitatively the iso-
propylidene acetals of 6a with 70:30 AcOH/H2O without
touching at all its “Bocdene” acetal; (ii) on heating at 65 °C
for 5 days in 80:20 AcOH/H2O, the tert-butyl ester group
of 1a is hydrolyzed to carboxylic acid (95% yield) but no
further hydrolysis is detected; (iii) with 5 equiv of TFA in
CH2Cl2 at rt, conversion of the tert-butyl ester of 1a into
the carboxyl group is completed in a few days, but the acetal
group remains; and (iv) on heating for 1 day in refluxing
MeOH, in the presence of 1 equiv of TsOH or camphorsul-
fonic acid, only the expected transesterification, of tert-butyl
to methyl ester, is observed for 1a-3a, while no change
occurs with the corresponding “Mocdene” acetals, even with
a larger excess of TsOH.
be cleaved4 in situ by a good nucleophile such as pyrrolidine
via an addition-elimination mechanism. In practice, treat-
ment of 1a with pyrrolidine (5.0 equiv) and butyllithium
(2.0-2.5 equiv) in THF for 16 h at rt afforded 1 in 85-
90% yields. Compound 2a was similarly converted into diol
2. Deprotection can also be achieved by an alternative
procedure: by heating in a water bath the 3a/3b mixture
with neat pyrrolidine, 93% of 3 was recovered. Similarly,
heating of 6a in neat pyrrolidine yielded 6 in 94% yield.
In conclusion, via conjugate (hetero-Michael) additions,
with nucleophilic and basic catalysis, 1,2-diols have been
converted into “Bocdene” and “Mocdene” acetals in excellent
yields. Though the scope of these protecting groups (and
related NuNu′CHCH2-EWG systems) deserves to be studied
further, we have shown that the use of appropriate bases is
the method of choice for leading the reverse reaction to
completion. The rule that acetals are formed and cleaved
under acid catalysis, while being stable to bases, does not
work here: it has been overturned by the electronic effect
of the substituent.
Acknowledgment. Financial support from the Ministerio
de Educacio´n y Cultura (PM96-0033) is gratefully acknowl-
edged. Thanks are due to the CIRIT, Generalitat de Cata-
lunya, for doctorate grants to A.M.C. (1994-97) and M.F.
(1993-96). We also thank C. Esteve for a sample of triol
11.
In short, the tert-butyl ester of “Bocdene”, although it is
less reactive than standard Boc groups, may be eventually
removed by forcing the reaction conditions, but the acetal
function stands. Only when the carboxylic acid arising from
1a was heated in refluxing 2 M HCl/THF for 3-4 days we
were able to recover 60% of diol 1, accompanied by
byproducts. To summarize, acidic hydrolysis of “Bocdene”
and “Mocdene” acetals, to recover the diol, is difficult and
not useful in practice.
Supporting Information Available: Typical procedures
for protection and deprotection and spectral data for com-
pounds 1a, 2a, 3a, 3b, 4a, 4b, 5a, 5b, 6a, and 11a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Esteve, C.; Ferrero´, M.; Romea, P.; Urp´ı, F.; Vilarrasa, J. Tetrahedron
Lett. 1999, 40, 5079. Esteve, C. Masters Thesis, Universitat de Barcelona,
1999.
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