Preparation of 4-[11C]Methylmetaraminol, a Potential PET Tracer for Assessment of Myocardial Sympathetic Innervation

Full text of DOI:10.1002/jlcr.475

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Labelled Cpd Radiopharm 2001; 44: 413–416.
DOI: 10.1002/jlcr.475
13
The Willgerodt-Kindler reaction: direct C
NMR evidence in support of carbon skeleton
integrity
Thomas J. Brewitt, Crist N. Filer, James M. Lacy and C.T. Peng*
PerkinElmer Life Sciences, Inc., 549 Albany St., Boston, MA 02118, USA
KeyWords: Willgerodt–Kindler reaction; 14C labelling; 13C NMR
Discussion
During the course of a lengthy multi-step synthesis of a 14C labelled
target compound we were required to prepare [methylene-14C]4-
methylsulfonylphenylacetic acid 1 as an intermediate. The most
expedient preparation of 1 appeared to be the Willgerodt-Kindler
reaction1 on acetophenone 2 for if 2 were labelled in the carbonyl
position with 14C, earlier studies2 had indicated that there should be no
carbon skeleton rearrangement. However, because of the importance of
the target compound’s final application we were still compelled to
unequivocally document the position of 14C labelling. We reasoned that
a comparison of the 13C NMR of 1 with that of unlabelled standard
would be convenient and conclusive.
Therefore, acetophenone 2 was prepared in good overall yield by a
two-step process. First, thioanisole was acylated with [carbonyl-14C]
*Correspondence to: C. T. Peng, PerkinElmer Life Sciences, Inc. 549 Albany St. Boston, Massa-
chusetts 02118 USA.
Copyright # 2001 John Wiley & Sons, Ltd.
Received 17 January 2001
Revised 5 February 2001
Accepted 26 February 2001
Published online \ \ \ \

414
T. J. BREWITT ET AL.
Figure 1. Partial 13C NMR of 1
acetyl chloride (55 mCi/mmol) using a literature procedure3 to afford
[carbonyl-14C] 4-thiomethylacetophenone which was them oxidized
with MCPBA4 to obtain 2. Intermediate 2 co-chromatographed on TLC
and provided a proton NMR (CDCl3) identical with authentic
unlabelled standard.y Its 13C NMR (CDCl3) corroborated the carbo-
nyl-14C labelling position: both methyl resonances were clearly observed
at 27 and 44 ppm, but there was no downfield carbonyl resonance.z
Acetophenone 2 was then subjected to classic Willgerodt-Kindler
reaction conditions using a literature procedure5 for the exact unlabelled
compound to afford key intermediate 1. Intermediate 1 co-chromato-
graphed on TLC, provided a convincing mass spectrum and proton
NMR (CDCl3) identical with authentic unlabelled standard,} but a
different and informative 13C NMR (CDCl3) (Figure 1) when compared
to that of authenticunlabelled standard (Figure 2). As seen above, the
13C NMR of 1 was in large part clearly missing the benzylic methylene
resonance at 40.6 ppm due to the major presence of 14C at this position.
y Available from Acros Organics, Cat. #42491-0025.
z All 13C NMR spectra were recorded on a Bruker 300 mHz instrument using J modulated spin echo
with reference on a ghost TMS peak.
} Available from Acros Organics, Cat. #42494–0025.
Copyright # 2001; John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 413–416

THE WILLGERODT–KINDLER REACTION
415
Figure 2. Partial 13C NMR of unlabelled 1
Our observation directly documents retention of the 14C label at the
benzylicposition of 1, thereby supporting the conclusion of earlier
investigators2 on a key mechanistic aspect of the Willgerodt-Kindler
reaction.} It also showcases the use of 13C NMR to conveniently
elucidate 14C labelling positions, a powerful technique that has only too
infrequently been cited in the literature.7
References
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} We are aware of at least one unsubstantiated report in the literature where the author claims the
migration of a methylene-14C label to the carboxyl group in a Willgerodt–Kindler reaction.6
Copyright # 2001; John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 413–416

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Copyright # 2001; John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 413–416