Microwave-enhanced aromatic dehalogenation studies: A rapid deuterium-labelling procedure

Article abstract of DOI:10.1016/S0040-4039(00)01941-9

Rapid (<1 min) and specific deuterium labelling is achieved through the microwave-enhanced dehalogenation of a number of N-4-picolyl-4-halogenobenzamides using deuterated formate as solid deuterium donor and either homogeneous or heterogeneous catalysts; the percentage deuterium incorporation is a function of the kind of solvent used.

Full text of DOI:10.1016/S0040-4039(00)01941-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 331–332
Microwave-enhanced aromatic dehalogenation studies: a rapid
deuterium-labelling procedure
John R. Jones,a,* William J. S. Lockley,b Shui-Yu Lua and Stewart P. Thompsonb
aDepartment of Chemistry, University of Surrey, Guildford, Surrey GU2 7XH, UK
bMedicinal Chemistry Department, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough,
Leicestershire LE11 5RH, UK
Received 12 October 2000; accepted 2 November 2000
Abstract—Rapid (<1 min) and specific deuterium labelling is achieved through the microwave-enhanced dehalogenation of a
number of N-4-picolyl-4-halogenobenzamides using deuterated formate as solid deuterium donor and either homogeneous or
heterogeneous catalysts; the percentage deuterium incorporation is a function of the kind of solvent used. © 2000 Elsevier Science
Ltd. All rights reserved.
Of the various methods used to prepare deuterium and
tritium labelled compounds aromatic dehalogenation is
second only to hydrogenation in importance.1 Never-
theless, like hydrogenation, the reaction suffers from
several limitations. For example the low solubility of
both D2 and T2 gas in many organic solvents lead to
slow rates and inefficient isotope usage. Moreover in
the case of tritium the storage of the radioactive waste
is becoming an increasingly serious and expensive issue.
Hence there is a need for cleaner, faster and more
isotope-efficient procedures.
We have modified2 the classical hydrogenation proce-
dure by replacing D2/T2 gas with solid isotope donors,
such as formates and when these reactions are coupled
to microwave irradiation1,3–5 large accelerations in rates
are achieved. The donors can be used in stoichiometric
concentrations so that in the case of tritium little or no
radioactive waste is produced. It seemed logical there-
fore to investigate whether these improvements could
be extended to aromatic dehalogenation reactions and
here we report our initial deuteration findings. Some
examples of the use of formates in dehalogenation
studies have been reported,6–8 however none describe
the utility of these agents for labelling organic com-
pounds under microwave irradiation.
The N-4-picolyl-4-halogenobenzamide system (1–3)
was chosen as the basic substrate structure because (a)
the Cl, Br, and I derivatives were all easily synthesised,
* Corresponding author. Tel.: +00-44-1483-259313; fax: +00-44-
1483-876851; e-mail: j.r.jones@surrey.ac.uk
Scheme 1. Dehalogenation under microwave conditions.
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01941-9

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J. R. Jones et al. / Tetrahedron Letters 42 (2001) 331–332
Table 1. Typical percentage deuterium incorporation (D%)
5. Alcohols, such as C2H5OH, i-C3H7OH and n-
C4H9OH, are good solvents for the dehalogenation
of all three types of substrates, but the percentage
deuterium incorporation is always lower10 than
when the aprotic solvent DMSO is used (Table 1).
6. Both homogeneous [Pd(OAc)2 and Wilkinson’s cat-
alyst] and heterogeneous (Pd/C) catalysts are effec-
tive for all three substrates but the ease of
separation in the latter case is counterbalanced by a
tendency for biphenyl by-product formation7 via
palladium-mediated coupling. RhCl3 is only effec-
tive for debromination and deiodination in DMSO
and caused decomposition of 1 in alcohol.
under different conditions
Substrate
Catalyst
D-donor
Solvent
D%
1
Pd/C
Pd/C
Pd/C
Pd(OAc)2
Pd(OAc)2
DCOOK/H2O
HCOOK/D2O
HCOOK/H2O
DCOOK/H2O
HCOOK/D2O
C2H5OH 50–67
C2H5OH
C2D5OD 15
5
2, 3
DMSO
DMSO
\95
0
(b) satisfactory purification procedures were to hand,
(c) they yield strong pseudomolecular ions in both
positive and negative ion HPLC–MS and (d) have
simple NMR spectra.
Even with our simple experimental procedure it is still
possible to perform parallel reactions. For example,
three test tubes each containing substrate, DCOOK and
solvent, but different catalysts, can be irradiated in the
microwave oven. Coupled with the rapidity of the
reactions, this option provides a useful method for high
though-put screening of reduction reactions since large
numbers of substrates or catalysts can now be investi-
gated without the need to handle gaseous hydrogen
donors.11,12
In a typical labelling reaction aqueous DCOOK solu-
tion (5 mg/10 ml, 31 ml, 0.18 mmol), the substrate 2 (35
mg, 0.12 mmol) and palladium acetate catalyst (5.4 mg,
0.024 mmol) were mixed with DMSO (1.0 cm3) in a
borosilicate glass test tube. The latter was purged with
nitrogen gas, then placed in a beaker (250 cm3) in an
upright position and subjected to microwave heating
(20 s, 20% power setting, Matsui BT 169 microwave
oven) under atmospheric pressure (Scheme 1). On com-
pletion, the black suspension was filtered off, and the
filtrate diluted in dichloromethane (DCM, 10 cm3). The
DCM solution was then washed with water (3×5 cm3),
and dried over anhydrous Na2SO4. Removal of the
solvent afforded deuterated product 5 as yellow crystals
(24 mg, 94%). The product was dissolved in acetone-d6
In conclusion, rapid and specific deuterium labelling
can be achieved through microwave-enhanced catalytic
dehalogenation using deuterated formate. The dehalo-
genation procedure described will also have applica-
tions in other areas of organic synthesis, since the
reaction can be carried out in alternative microwave-
effective protic solvents such as water.
1
to record the H NMR spectrum, and in acetone to
2
record the H NMR spectrum. For HPLC–MS analy-
sis, reaction mixtures were used without further separa-
tion except where the heterogeneous catalyst was used
in which case the solids were filtered off before analysis.
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