Investigations into the mechanism of regioselective C-deuteriation of enolates under 'base-free' conditions

Article abstract of DOI:10.1016/S0040-4039(00)00897-2

Regioselective C-deuteriation of enolates was efficiently achieved by quenching the corresponding base-free enolate in the presence of a carbonyl chelating deuterium source. We comment on factors (such as the presence of base and the structural nature of the deuterium reagent) that are responsible for this observed regioselectivity and comment on the role of the deuterium source. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00897-2

Tetrahedron Letters 41 (2000) 5753±5756
Investigations into the mechanism of regioselective
C-deuteriation of enolates under `base-free' conditions
Gregory S. Coumbarides, Jason Eames* and Neluka Weerasooriya
Department of Chemistry, Queen Mary and West®eld College, Mile End Road, London E1 4NS, UK
Received 15 February 2000; accepted 2 June 2000
Abstract
Regioselective C-deuteriation of enolates was eciently achieved by quenching the corresponding base-
free enolate in the presence of a carbonyl chelating deuterium source. We comment on factors (such as the
presence of base and the structural nature of the deuterium reagent) that are responsible for this observed
regioselectivity and comment on the role of the deuterium source. # 2000 Elsevier Science Ltd. All rights
reserved.
The continuing development of novel synthetic methodology for direct incorporation of non-
radioactive isotopic labels within organic molecules for both chemical and biological mechanistic
studies is paramount.1 Some of this attention has been concerned with deuterium incorporation
involving simple carbon hydrogen bond exchange reactions,2 many of which have relied on a
deprotonation±deuteriation strategy involving relatively acidic centres,3 most notably adjacent to
a carbonyl group.4 For synthetic ease, most H D exchange reactions are usually performed
under thermodynamic control5 by using an excess of the deuterium source, which is generally
used as the solvent, to drive the reaction to completion.6 However, there are some problems
associated with this protocol, such as overall D-eciency, cost and the diculty associated with
product separation (due to incomplete substitution or over incorporation). We believe that deu-
teriation under kinetic control7 would solve many of these problems, such as single incorporation
of deuterium, but this type of methodology has been studied far less. Indeed in some cases direct
incorporation has been shown to be rather problematic due to a number of factors.8 Firstly, the
method of enolate generation is particularly important since many have additional competing
bases present, such as diisopropylamine (derived from the original lithium amide base, e.g. LDA),
which can cause contamination via internal proton return in the deuteriation step.9 This has
partially been solved by further deprotonation to form enolate-amide complexes,4,10,11 or by
ensuring the formation of a less basic amine.4 Of similar importance is the less obvious concept of
* Corresponding author. E-mail: j.eames@qmw.ac.uk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00897-2

5754
regioselective C-deuteriation which potentially leads directly to the a-deuteriated carbonyl func-
tionality rather than the corresponding reaction proceeding via the enol by O-deuteriation, tau-
tomerisation of which under aqueous work-up can result in the loss of the deuterium label.
Ideally, the method of choice would involve the use of enolates in the absence of additional
bases, coupled with the use of an ecient C-deuteriating reagent. It is rather surprising that such
methodology has not been studied to date. We have previously shown that carbonyl chelating
proton donors, such as acetoacetate and acetic acid are an ecient method for regioselective
C-protonation of enolates under the required `base-free' conditions.12 We now wish to report our
studies into regioselective C-deuteriation of such `base-free' enolates using an analogous carbonyl
chelating deuterium donor such as acetic acid-d4 under kinetic control. We comment on factors
(such as the presence of base and the structural nature of the deuteriating agent) on the observed
regioselectivity and discuss the role of such deuterium sources.
Scheme 1.
We ®rst established the need for such a process by attempting to synthesise the tetralone 1-d
under traditional base-enolate conditions. Formation of the tetralone enolate 2 by the addition of
LDA to 1 and attempted deuteriation with acetic acid-d4 gave only recovered tetralone 1 with no
deuterium incorporation (Scheme 1).13 This was unexpected since it is well documented11 that
deuteriation of the residual diisopropylamine in 2 and the formation of the mixed ammonium salt
3 is more than likely responsible for this internal proton return. By using less acidic D-sources,
such as D2O and MeOH-d4, where deuterium transfer to the amine is no longer kinetically
favourable, it is still rather surprising that complete incorporation does not occur. However, the
deuterium enriched tetralone 1 ([D]:[H]=52:48; 72% and [D]:[H]=55:45; 67%) was isolated
using D2O and MeOH-d4, respectively, but similar e€ects have been reported.14
Scheme 2.
Repeating this reaction under Koga's `base-free' lithium enolate15 procedureÐby the addition
of MeLi to the preformed silyl enol ether 4 (derived from 2-methyl tetralone 1)Ðgenerates the `base-
free' enolate 5 of the parent tetralone 1 (Scheme 2).15 Simple addition of acetic acid-d4 (1 equiv.)
to this stirred solution at ^78ꢀC gave the tetralone 1-d in acceptable yield (68%) with near com-
plete incorporation (determined by 1H NMR).13 This regiocontrol is even more remarkable, when
considering that addition of a non-chelating deuterium source such as DCl gave no incorpora-
tion, presumably due to O-deuteriation,11,16 to give the enol 6, tautomerisation of which, in the
presence of water (on aqueous work-up), leads to the non-deuterium incorporated tetralone 1. In

5755
contrast, using D2O gave the required tetralone 1-d with near perfect isotopic incorporation
([D]:[H]>98:2) in 61% yield, presumably due to O-deuteriation being no longer favoured.17
MeOH-d4 behaved similarly, giving identical incorporation, but in a slightly improved yield (66%).
This reaction was also shown to be sensitive to the presence of the lithium counter-ion; without it,
in the case of the naked enolate 7, no incorporation was observed using acetic acid-d4, whereas
using D2O gave the tetralone 1-d in 72% yield ([D]:[H]=89:11). The presence of the lithium
cation is clearly important in both cases, but more so for acetic acid-d4 which presumably
requires carbonyl chelation18 to aid regioselective C-deuteriation as illustrated in 8 (Scheme 3).12
Scheme 3.
We next investigated the versatility of this procedure by synthesising the more challenging
single deuteriated ketones 10-d and 12-d. The simple addition of MeLi to their corresponding silyl
enol ethers 9 and 11, followed by the external addition of acetic acid-d4 gave the required ketones
10-d and 12-d with no over d2 incorporation, in excellent yield (Scheme 4). To probe the e€ect of
stereochemistry, we also chose to quench the chiral `base-free' enolate of 4-tert butylcyclohexane
14 with acetic acid-d4 which gave the 4-tert butylcyclohexane anti-15-d directly as a single dia-
stereoisomer in a moderate 52% yield.19 This diastereoselectivity was particular good due to the
complementarity of both reagent12 and substrate control.
Scheme 4.
In conclusion, we have shown20 that ecient regioselective C-deuteriation of enolates can
occur under kinetic control by using either D2O, MeOH-d4 and acetic acid-d4 under `base-free'
conditions. Furthermore, we believe that there are three factors which are responsible for such
ecient C-deuteriation: (a) the absence of diisopropylamine to prevent internal proton return; (b)

5756
for non-chelating D-sources, O-deuteriation can be avoided by ensuring that the analogous non-
isotopic acid has a pKa>1017 (e.g. D2O and MeOH-d4); and (c) for chelating proton donors, the
presence of a Lewis acidic lithium cation is essential to regioselectively direct C-deuteriation.
Acknowledgements
We thank the Faculty of Natural Science at Queen Mary and West®eld College (University of
London), London University Central Research Fund and The Nueld Foundation (NUF-NAF
99) for grants.
References
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13. Determined by integration of the 1H NMR spectrum of the corresponding methyl doublet at 1.28 ppm in 1 versus
the methyl singlet at 1.28 ppm in 1-d.
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1
19. The stereochemistry was assigned by the disappearance of one of the higher ®eld axial protons in the H NMR
spectrum.
20. Typical experimental procedure: A solution of MeLi (0.6 ml, 1.6 M in ether, 0.61 mmol) was added dropwise to
the silyl enol ether 4 (0.14 g, 0.60 mmol) at room temperature. This resulting solution was stirred for 1 h at room
temperature and then cooled to ^78ꢀC. Acetic acid-d4 (43 mg, 0.68 mmol) in THF (1 ml) was added dropwise to
this solution and stirred for a further 30 min. The reaction was quenched by the addition of water (10 ml). The
solution was extracted with ether (3Â20 ml), dried (MgSO4) and evaporated under vacuum. The residue was
puri®ed by ¯ash chromatography on silica gel eluting with light petroleum (40±60ꢀC):ether (9:1) to give the 2-
methyl-1-tetralone-d 1 (67 mg, 68%) as an oil; Rf [ether] 0.56; vmax(®lm, CHCl3)/cm^1 2965 and 2853 (CH), 2106
(CD), 1683 (CO), 1600 (CˆC), ꢀH (250 MHz, CDCl3) 8.00 (1 H, d, J 7.7, CH; Ar), 7.47 (1 H, dd, J 7.7 and 7.6,
CH; Ar), 7.25 (1 H, t J 7.7, CH; Ar), 7.22 (1 H, d, J 7.6, CH; Ar), 3.00 (2 H, m) CH2CˆC, 2.20 (1 H, dt, J 13.2 and
4.4, CHAHB), 1.87 (1 H, m, CHAHB) and 1.28 (3 H, s, MeCD); ꢀC (62.5 MHz, CDCl3) 200.8, 144.2, 133.1, 132.4,
128.7, 127.4, 126.6, 42.5, 31.3, 28.8 and 15.3 (found MH+, 162.1034. C11H12DO requires MH, 162.1029); m/z 162
(100%, M).