Selective deuteration of (hetero)aromatic compounds via deutero-decarboxylation of carboxylic acids

Article abstract of DOI:10.1039/c2ob25157d

A practical, mild and highly selective protocol for the monodeuteration of a variety of arenes and heteroarenes is presented. Catalytic amounts of Ag(i) salts in DMSO/D₂O are shown to facilitate the deutero-decarboxylation of ortho-substituted

Full text of DOI:10.1039/c2ob25157d

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Cite this: Org. Biomol. Chem., 2012, 10, 3172
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COMMUNICATION
Selective deuteration of (hetero)aromatic compounds via
deutero-decarboxylation of carboxylic acids†
Rachel Grainger, Arif Nikmal, Josep Cornella and Igor Larrosa*
Received 19th January 2012, Accepted 1st March 2012
DOI: 10.1039/c2ob25157d
commonly used for mechanistic investigations of catalytic cycles
A practical, mild and highly selective protocol for the mono-
deuteration of a variety of arenes and heteroarenes is pre-
sented. Catalytic amounts of Ag(I) salts in DMSO/D2O are
shown to facilitate the deutero-decarboxylation of ortho-sub-
stituted benzoic and heteroaromatic α-carboxylic acids in
high yields with excellent levels of deuterium incorporation.
and reaction pathways,2 in stable-isotope tracer studies, as
analytical standards,3 in neutron scattering,4 and for the synthesis
of drug compounds with enhanced metabolic stability.5 On the
other hand, tritium is arguably the most versatile radionuclide
available, with tritiated compounds regularly exploited as radio-
tracers in the pharmaceutical industry from drug discovery level
to clinical studies.1,6 Synthetic methods for the preparation of
deuterated compounds are regularly applied towards the syn-
thesis of their tritium-labelled isotopologues, and deuteration
methodologies are commonly used as synthesis optimisation
tools for subsequent tritium labelling.1 Despite the high demand,
methods for the selective incorporation of a single deuterium
into an aromatic ring are scarce.1,7,8 The most common protocol
involves halogen/D exchange; this is usually mediated by strong
bases, with the consequent limitation in functional group scope.
H/D exchange reactions can also be employed with the use of
strong acids,9 bases,10 or transition metal catalysts.11 However,
Synthetic procedures able to incorporate deuterium (D) and
tritium (T) into organic molecules are highly sought after for a
plethora of applications:1 deuterium-labelled compounds are
School of Biological and Chemical Sciences, Queen Mary University of
London, Joseph Priestley Building, Mile End Road, E1 4NS, London,
UK. E-mail: i.larrosa@qmul.ac.uk; Fax: +44 (0)20 7882 7427;
Tel: +44 (0)20 7882 8404
†Electronic supplementary information (ESI) available: Experimental
procedures and characterisation of new compounds. See DOI: 10.1039/
c2ob25157d
Table 1 Optimisation of the Ag(I)-catalysed deutero-decarboxylationa
Entry
Substrate
AgX
(Mol %)
D2O (equiv.)
Solvent
Yieldb (%)
D (%)c
1
2
3
4
5
6
7
8
9
Na-1a
Na-1a
Na-1a
K-1a
K-1a
K-1a
1a
1a
1a
1a
AgNO3
AgOTFA
AgOAc
AgNO3
AgOTFA
AgOAc
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
(20)
(20)
(20)
(20)
(20)
(20)
(10)
(10)
(10)
(10)
10
10
10
10
10
10
0
10
50
100
DMSO
DMSO
DMF
DMF
DMF
35
20
61
39
30
20
100
100
92
48
87
92
85
77
70
77
0
82
92
91
DMF
DMSO
DMSO
DMSO
DMSO
10
a Reaction conditions: the reactions were carried out using 1.0 equiv. of the substrate and the indicated amounts of Ag(I) catalyst and D2O in a 0.2 M
solution of the stated solvent. b The yield of 2a was determined by 1H NMR analysis using mesitylene as an internal standard. c The extent of
deuteration of 2a was determined by 1H NMR analysis using mesitylene as an internal standard.
3172 | Org. Biomol. Chem., 2012, 10, 3172–3174
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Table 2 Substrate scope for the deutero-decarboxylation of homo-
and hetero-aromatic carboxylic acidsa
Scheme 1 Ag(I)-catalysed proto- and deutero-decarboxylations of
benzoic acids (eqn (1) and (2), respectively).
these processes are generally non-selective, and only several
examples are known where good selectivity is achieved.12
Accordingly, there is a great need for the development of mild
and selective methodologies for the incorporation of deuterium
into aromatic rings.
Recently, we developed an operationally simple, high yielding
proto-decarboxylation of ortho-substituted benzoic and hetero-
aromatic α-carboxylic acids catalysed by Ag2CO3.13,14 This
process is believed to proceed via an aryl–Ag(I) intermediate that
is subsequently protonated (Scheme 1, eqn (1)). We hypo-
thesised that if this reaction was carried out in the presence of a
D+ source, it could lead to selective incorporation of deuterium
(Scheme 1, eqn (2)).15
Initially, in order to completely avoid the presence of H+ in
the reaction, we tested the decarboxylation of K and Na salts of
benzoic acid 1a (Table 1, entries 1–6) with a variety of Ag(I)
catalysts, in combination with 10 equiv. of D2O.16 Gratifyingly,
good levels of deuterium incorporation were observed in the
resulting arene 2a, albeit in moderate to good yields. Pleasingly,
direct decarboxylation of the carboxylic acid 1a with Ag2CO3
afforded higher yields and a similarly good level of deuteration
when carried out in the presence of 50 equiv. of D2O (entries
7–10).
With this optimised protocol in hand, we examined the scope
of the reaction (Table 2). The standard reaction conditions con-
sistently afforded high yields (82–100%) and deuteration selec-
tivities (91–99%) with a variety of substituted benzoic acids.
This methodology allows the synthesis of arenes deuterated
ortho to a variety of electron-withdrawing substituents such as
Cl (2a), F (2b), Br (2c) and NO2 (2d–f) under very mild and
practical conditions: the benzoic acid is simply mixed with the
catalyst and 50 equiv. of D2O, and heated up in DMSO. After
the reaction, the residual amounts of starting material are easily
removed during aqueous workup, affording high purity product
after solvent evaporation, thus removing the need for column
chromatography or distillation. Alternative routes to these sub-
strates generally involve treatment of the corresponding ortho-
halo arene with a strong alkyl-lithium base, followed by quench
with D+, and sometimes challenging purifications.17
This protocol can also be successfully applied to heteroaro-
matic carboxylic acids (Table 2, 2g–m). Thus, furans and benzo-
furans, selectively deuterated at position 2, can be easily
prepared. Similarly, it is possible to selectively deuterate pyridine
at positions 2, 3 or 4 by judicious choice of the carboxylic acid
starting material (2i–k). Finally, quinolines are also amenable for
selective deuteration at the position α to the heteroatom (2l–m).
a Reaction conditions: all the reactions were carried out with 10 mol%
Ag2CO3, 1.0 equiv. of aromatic carboxylic acid (1) and 50 equiv. of
D2O in a 0.2 M DMSO solution at 120 °C for 16 h. b Yields of isolated
c
analytically pure material. Percentage of deuteration was determined
d
by 1H NMR analysis using mesitylene as an internal standard. The
yield was determined by 1H NMR analysis using mesitylene as an
internal standard. e The reaction was carried out at 140 °C.
Remarkably, this method is completely selective for the C
bearing the carboxylic acid and no deuteration is observed at any
other position, as determined by 2H NMR, even for arenes
bearing electron-donating MeO substituents (2f) and for the
nucleophilic furan 2h.
In conclusion, we have developed a mild and practical metho-
dology for the Ag(I)-catalysed deutero-decarboxylation of a
variety of aromatic acids, bearing the carboxyl motif ortho to a
functional group or α to a heteroatom. The protocol is
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cally useful functionalities such as halogens and nitro groups.
Moreover, it is high yielding and affords excellent levels of
selective deuterium incorporation. It is envisaged that this meth-
odology should be easily adapted towards the tritium-labelling
of pharmaceutically interesting molecules to aid drug develop-
ment and clinical studies.
During the preparation of this manuscript, a methodology
describing silver and copper mediated decarboxylative deutera-
tions was reported by Goossen.18
We gratefully acknowledge the European Research Council
for a Starting Research Grant (to I.L.), Pfizer Limited and the
Engineering and Physical Sciences Research Council for a
CASE studentship (R.G.), QMUL for a studentship (J.C.) and
Harold Toms for NMR analysis.
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