Base-catalyzed deuterium and tritium labelling of 1-biphenyl-4-ylpropane-1, 2-dione and deuteration of aryl methyl ketones

Article abstract of DOI:10.1002/jlcr.879

A synthesis and a base-catalyzed exchange reaction was developed under mild conditions to deuterate and subsequently tritiate the methyl group of the base sensitive diketone 1-biphenyl-4-ylpropane-1,2-dione depicted in Figure 1. Using Et₃N as b

Full text of DOI:10.1002/jlcr.879

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2004; 47: 891–894.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.879
Note
Base-catalyzed deuterium and tritium labelling of
1-biphenyl-4-ylpropane-1,2-dione and deuteration of
aryl methyl ketones
Carl Berthelette* and John Scheigetz
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research,
!
P.O. Box 1005, Pointe-Claire/Dorval, Quebec, Canada H9R 4P8
Summary
A synthesis and a base-catalyzed exchange reaction was developed under mild
conditions to deuterate and subsequently tritiate the methyl group of the base sensitive
diketone 1-biphenyl-4-ylpropane-l,2-dione depicted in Figure 1. Using Et3N as base,
deuterium incorporation of the methyl group was 88.9% and the tritium incorpora-
tion gave a specific radioactivity of 119 mCi/mmol. The scope of the exchanges was
extended to methyl aryl ketones 224. Copyright # 2004 John Wiley & Sons, Ltd.
Key Words: base-catalyzed exchange; tritium; labelled compounds; aryl methyl
ketone; diketone
Figure 1. Structure of 1-Biphenyl-4-ylpropane-1,2-dione
Introduction
In the course of our medicinal chemistry efforts, we were seeking a fast and
efficient method of labelling a methyl aryl diketone and several aryl methyl
ketones with deuterium or tritium for use in enzyme and pharmacokinetic
studies. Recently, we have completed a base-catalyzed exchange reaction
*Correspondence to: C. Berthelette, Department of Medicinal Chemistry, Merck Frosst Centre for Thera-
!
peutic Research, P.O. Box 1005, Pointe-Claire/Dorval, Quebec, Canada H9R 4P8.
E-mail: carl berthelette@merck.com
Copyright # 2004 John Wiley & Sons, Ltd.
Received 14 June 2004
Revised 16 July 2004
Accepted 19 July 2004

892
C. BERTHELETTE AND J. SCHEIGETZ
Table 1. Comparative deuterium exchanges on diketone and aryl methyl ketones using
DBU and Et3N as bases
Compound
Substrate
Deuteration DBU
Decomposition
Deuteration Et3N
1.2% d0
3.9% d1
1
21.5% d2
73.3% d3
0.6% d0
0.0% d1
4.0% d2
95.4% d3
0.4% d0
2.4% d1
21.9% d2
75.3% d3
2
3
4
1.5% d0
6.1% d1
17.7% d2
74.7% d3
0.5% d0
10.1% d1
24.9% d2
64.5% d3
0.0% d0
0.4% d1
0.0% d2
99.6% d3
71.6% d0
20.8% d1
6.9% d2
0.7% d3
method that we used to deuterate and tritiate aryl methyl sulfones and we
decided here to extend the scope of this method to aryl methyl ketones. In this
respect, we successfully used 1,8-diazabicyclo [5,4,0] undecen-7-ene (DBU) and
triethylamine (Et3N) as bases for the exchanges and the results are listed in
Table 1. Although compounds 224 were not required tritiated for the studies,
this methodology is readily applicable for tritiation with tritiated water
(compounds 224 were obtained from our in-house sample collection). The
deuterium incorporation for the methyl groups was calculated using mass
spectrometry and the isotopic incorporation ranged from 88.5 to 99.7% with
DBU as base and from 12.2 to 90.7% with Et3N.
Results and discussion
a-Hydrogens of ketones are readily exchanged under basic conditions with the
rates of exchange depending upon the base and on the medium employed.1
DBU, which is a stronger base than triethylamine induced exchange more
rapidly and very high conversion was obtained after 18 h for ketones 224. The
base sensitive diketone 1 decomposed upon treatment with DBU but a
successful deuteration or tritiation using triethylamine as a milder base was
achieved. In contrast, the exchange using triethylamine on the vinylogous
ketone 4 provided only a low deuterium incorporation.
3
To study enzyme kinetics, 1 was required as either 14C or H labelled and
having a specific activity preferably greater than 90 mCi/mmol. Direct tritium
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 891–894

BASE-CATALYZED DEUTERIUM
893
Scheme 1. Synthesis of 1a
labelling was a much more attractive option than a radioactive total synthesis
with carbon-14. Tritiated 1c was obtained by direct exchange with a 50% yield
after a straightforward chromatography and the specific activity obtained was
119 mCi/mmol. The synthesis of non-labelled compound 1a is depicted in
Scheme 1. Both the syntheses of 1a and the intermediate l-biphenyl-4-
ylacetone 7 were already reported but each by totally different pathways.2
Scheme 1 had certain advantages useful for our own needs. A Grignard
reaction on the Weinreb3 amide 6 gave 7 in 98% yield. Compound 7 was
subsequently oxidized with pyridinium chlorochromate to the diketone 1a in
24% yield using a method developed by Bonadies and Bonini.4 Exchanges
were then carried out as described in the Experimental Section using the
typical procedure for deuterium or tritium exchanges.
Experimental
Deuterium incorporation was calculated based on the intensities of protonated
molecules and their isotopic peaks using a linear matrix program on a
Micromass Quattro LC (electrospray mode) coupled with a Waters 2790
HPLC. Radioactivity measurements were perfonned on a Beckmann Coulter
LS6000SC liquid scintillation counter using Ultima Gold XR (Packard
Bioscience #6013119).
Typical procedure for deuterium or tritium exchanges
To a solution of the substrate (20 mg) in THF (500 ml) containing DBU (5 ml)
or Et3N (10 ml) was added deuterium oxide (200 ml, 99.9 at% d) or tritiated
water (200 ml, 80 mCi/mmol). The mixture was stirred in a closed vial at room
temperature for 18 h. To the mixture was added ethyl acetate (2 ml) and 1 N
HC1 (1 ml) containing saturated brine (3 drops). The mixture was stirred for
30 s and most of the top layer removed and transferred to a new vial. The
bottom layer was re-extracted with ethyl acetate (1 ml) twice and the combined
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 891–894

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C. BERTHELETTE AND J. SCHEIGETZ
extracts washed twice with dilute brine (1 ml). The combined organics were
dried (Na2SO4) and the solutions pipetted off from the salts. The clear
solutions were concentrated and pumped on to obtain exact weights. Typical
yields of the deuterated products were between 16 and 19 mg and the detailed
exchange results are listed in Table 1.
Conclusion
In summary, we have developed an efficient synthesis of labelled l-biphenyl-4-
ylpropane-l,2-dione 1 by using deuterated or tritiated water and triethylamine
in a base-catalyzed exchange reaction. The method was extended to deuterate
aryl methyl ketones with DBU or Et3N as bases and is applicable to tritiation.
Depending upon requirements, advanced substrates such as compounds 224
can be labelled rapidly in good yield.
Acknowledgements
The authors gratefully acknowledge Dave Percival of the Biology Department
at Merck Frosst for discussions and experimental contributions not described
herein.
References
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1985; 26: 1375. (d) Coller BAW, Roy Jackson W, Stragalinou A, Strauss JUG.
Tetrahedron Lett 1979; 20: 2261. (e) Kabalka GW, Pagni RM, Bridwell P, Walsh E,
Hassaneen HM. J Org Chem 1981; 46: 1513.
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Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 891–894