COMMUNICATION
For the preparation of the requisite [18O]-2 precursor for
[18O]-1, we chose to explore Pd-catalysed allylic ester hy-
drolysis, using H218O as the nucleophile, with an expected
high propensity for linear substitution.[12] Allylic carbonate 3
underwent smooth and quantitative hydrolysis, with one
equivalent of H2O in pre-dried THF, employing 5 mol% Pd
catalyst. However, with H218O (70 atom% 18O), [18O]-2 was
obtained with low 18O incorporation (Scheme 3).
Sodium carboxylates were thus tested as suitably soft nu-
cleophiles in the Pd-catalysed reaction of chloride 5; a com-
pound readily synthesised from allyl dimethyl malonate and
trans-1,4-dichloro-2-butene. It soon became apparent that
acetate was significantly less reactive than benzoate, possi-
bly due to stronger ion-pairing[2] of the Na+ with the ace-
tate. However, the wider commercial availability of isotopi-
cally labelled acetate salts led us to focus on NaOAc as nu-
cleophile, to give 8, and an in situ salt metathesis with tetra-
butylammonium chloride was employed to rapidly drive the
reaction to completion. With Na18OAc (>95 atom%
18O2)[17] as the nucleophile, the reaction proceeded smoothly
to give [18O2]-8 in 94% isolated yield (98% 18O2; ESI-MS).
Methanolysis in the presence of a catalytic amount of
K2CO3 yielded the desired allylic alcohol [18O]-2 in 65%
[16]
yield (unoptimised) and with full retention of 18O (MS/
NMR). Ring-closing metathesis on neat [18O]-2 gave approx-
imately 250 mL (53%) of [18O]-allyl alcohol containing
<1.5% water and in high chemical and isotopic purity
(Scheme 5).
Scheme 3. Pd-catalysed allylic hydrolysis with allyl methyl carbonate 3,
proceeding via a hydrogencarbonate intermediate 4.
Rigorous drying of the solvent and the reaction atmos-
phere, as well as pre-rinsing of the glassware surface with
H218O, ruled out exogenous water as being the cause of the
low 18O incorporation. Control experiments also ruled out
18O/16O exchange in the carbonyl groups of substrate 3 or
product 2 during the reaction, as well as 18O/16O exchange in
the hydroxyl group in 2 during column chromatography on
silica gel.
In a detailed study[13] of Pd-catalysed asymmetric hydroly-
sis of cycloalkenyl carbonates in (unlabelled) water, using
the Trost standard ligand,[14] Lꢂssem and Gais[13] proposed
that hydrogen carbonate anion, not hydroxide, was the
active nucleophile. An analogous mechanism operating in
the generation of [18O]-2, would reduce the isotope incorpo-
ration in the primary reaction product ([18O]-4, 70% atom),
to just 23% 18O after spontaneous decarboxylation; an out-
come fully consistent with the 22% 18O detected in [18O]-2
by MS/13C NMR spectroscopy. Substrates bearing chloride
(5) and tosylate (6) leaving groups were subjected to similar
reaction conditions, but triene 7, slowly generated via
NaOH-mediated elimination,[15] was the sole detectable
product; reinforcing the requirement for a soft nucleophile
to induce attack of the p-allyl moiety, rather than a-depro-
tonation (Scheme 4).
Scheme 5. Synthesis of 18O-allyl alcohol, [18O]-1 >98% 18O, in a pure
state, by RCM. [Ru]=Hoveyda–Grubbs second generation catalyst.[11a]
In summary, we have demonstrated the utility of an RCM
approach for the preparation of volatile olefins, in the other-
wise non-trivial preparation of 18O-allyl alcohol.[7,8] Whilst
we have employed an allyl malonate building block, for
which there are numerous isotopically labelled examples,[18]
other linking units capable of undergoing kinetically-fav-
oured ring-closure should be equally amenable. The strategy
can be applied to any such appropriate terminal, or inter-
nal,[19] labelled volatile olefin whose synthesis demands sev-
eral synthetic manipulations and for which isolation is re-
quired, free of solvent, water and other contaminants, on a
relatively small scale using simple apparatus. Since there is a
union of the termini of two separate alkene moieties in the
final RCM step, the approach allows parallel assembly of
the components required for preparation of mixed-label al-
kenes, for example, CD2=13C(H)R; relay-type RCM may
also be of utility in this regard.[20] The intermolecular nature
of the propagation of RCM by catalytic metal–alkylidene in-
termediates also means that diene pairs could be co-reacted
to generate isotopomeric and isotopologous alkene mixtures
in defined ratios, which would be of use in cross-over experi-
Scheme 4. Effect of nucleofuge in 3, 5 and 6, on outcome of reaction with
hydroxide.
Chem. Eur. J. 2011, 17, 4724 – 4726
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4725