Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 473–474.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1201
Short Research Article
2
y
A novel synthesis of [ H ]2-methyl-3-butyn-2-ol
6
ALAN H. WADSWORTH and KENNETH W. M. LAWRIE*
GlaxoSmithKline, Isotope Chemistry, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 17 August 2006; Revised 2 November 2006; Accepted 22 November 2006
Keywords: deuterium; lithium acetylide; Grignard; acetone free acetylene
Introduction
pyrrolidine, CuI) prior to LC-MS analysis, which
confirmed 0.5% M0. Acetone is used in the commercial
2
1
3
[
H
6
]2-methyl-3-butyn-2-ol 3, synthesized from hex-
packing of acetylene into gas cylinders, so is likely to
adeuteroacetone 1 and acetylenic Grignard reagent 2,
was required as an intermediate in the synthesis of a
mass labelled internal standard. In general an increase
of at least 3 a.m.u. over the test substance and a very
high degree of isotopic incorporation (typically 50.1%
unlabelled) is required for such a standard. MS
analysis, however, of an advanced intermediate,
showed ꢀ0.5% of the corresponding unlabelled mole-
cular ion clearly deriving from the butynol. It seemed
likely that this arose from contamination of the
acetylenic Grignard reaction with unlabelled acetone.
be a contaminant in commercial acetylenic Grignard
reagents. An alternative source of an acetylenic orga-
nometallic reagent, guaranteed acetone-free, was
required. Generation of acetylene by dehydro-
4
bromination of readily available vinyl bromide, under
conditions that would lead to the eventual formation of
monolithium acetylide, was chosen. The generation of
vinyllithium from vinyl bromide and t-butyllithium is
carried out at ꢁ1208C. Above ꢁ1108C, however,
competitive formation of acetylene by dehydrobromina-
4
a
tion occurs. An attempt to prepare vinyllithium from
vinyl bromide and n-butyllithium in diethyl ether at 08C
resulted, after quenching with carbon dioxide, in a 34%
yield of acetylenedicarboxylic acid, presumably via the
2H
O
2H
2H
2H
2H
MgBr
4b
2H
formation of dilithium acetylide. The stoichiometric
2H
2H
2H
OH
reaction of acetylene with n-butyllithium at ꢁ788C is
4
c
2H
2H
known
to favour the formation of monolithium
°
THF, 20 C
2H
acetylide over that of dilithium acetylide. Treatment of
1
vinyl bromide with one equivalent of n-butyllithium at
3
5
ꢁ788C generated lithium monoacetylide , which was
Scheme 1
treated with hexadeuteroacetone at ꢁ788, allowed to
warm to room temperature, and the desired product 3
isolated in 43% yield. Mannich derivatization of a
sample followed by LC-MS analysis confirmed that
the desired product 3 had formed and contained no
detectable M0 (Scheme 2).
Results and discussion
A second batch of 3 was prepared as above (Scheme 1),
taking extra precautions to avoid contamination by
2
adventitious acetone. The [ H ] acetone 1 showed
6
(
NMR) no trace of unlabelled acetone. The product 3
2H
2
Br
2H
2H
was derivatized by
a
Mannich reaction (HCHO,
O
2H
2H
OH
2H
2H
2H
n-BuLi, THF, -78˚C
add (1), -78˚ to 20˚C
2H
2H
*
Correspondence to: K. W. M. Lawrie, GlaxoSmithKline, Isotope
2H 2
Chemistry, Medicines Research Centre, Gunnels Wood Road, Steven-
age SG1 2NY, UK. E-mail: ken.w.lawrie@gsk.com
H
y
Proceedings of the Ninth International Symposium on the Synthesis
1
43%
3
and Applications of Isotopically Labelled Compounds, Edinburgh,
1
6–20 July 2006.
Scheme 2
Copyright # 2007 John Wiley & Sons, Ltd.
Wadsworth, Alan H.
