Microwave mediated hydrogen deuterium exchange: A rapid synthesis of 2H-substituted benzimidazole

Article abstract of DOI:10.1016/j.tetlet.2005.05.110

Deuterium aromatic substituted compounds were prepared by microwave irradiation of the parent unlabeled compounds in the presence of deuterium oxide and deuterium chloride. The percentage of deuterium incorporation was investigated under various reaction

Full text of DOI:10.1016/j.tetlet.2005.05.110

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5195–5197
Microwave mediated hydrogen deuterium exchange:
a rapid synthesis of H-substituted benzimidazole
2
Srirajan Vaidyanathan and Bruce W. Surber*
Abbott Laboratories, Dept. R46V, AP9, 100 Abbott Park Road, IL 60064, USA
Received 20 April 2005; revised 24 May 2005; accepted 25 May 2005
Available online 15 June 2005
Abstract—Deuterium aromatic substituted compounds were prepared by microwave irradiation of the parent unlabeled compounds
in the presence of deuterium oxide and deuterium chloride. The percentage of deuterium incorporation was investigated under
2
various reaction conditions. A rapid synthesis of H-substituted benzimidazole under microwave irradiation is described.
Ó 2005 Elsevier Ltd. All rights reserved.
Deuterium labeled drug entities are widely used as inter-
nal standards in Mass Spectrometry in the pharmaceuti-
cal industry.1 Synthesis of these drug entities requires an
appropriate deuterium labeled starting material.
Though there are many commercially available deute-
rium labeled starting materials known, synthetic chem-
ists often face many constraints because of the
limitation of availability of the labeled reagents as well
as the number of mass units that must be added. So
there is a great need to devise new methodologies for
deuterium labeling. In the literature, there are very few
reports for deuterium labeling and very often the reac-
tion conditions are extreme, time consuming, and low
yielding.2
simple reaction conditions and its application to the
preparation of the ED analogue, H-ABT-724.
2
Readily available p-aminophenol was used as model
compound for our study. This was dissolved in 35% deu-
terium chloride in deuterium oxide6 and the reaction
mixture was irradiated in a CEM microwave oven at
9 W and 100 °C for 30 min (Scheme 1). This resulted
in deuterium incorporation of varying percentage be-
tween M+1 and M+4 with 25% unreacted starting mate-
rial. Encouraged by this result, we carried out systematic
correlation studies and optimal conditions were found
to be 175 °C at 140 W for 20 min. Under these reaction
conditions, we obtained 84% of M+4 and 16% of M+3
and there was no unreacted starting material7 (Table 1).
The deuterium incorporation on the aromatic ring was
In recent years, microwave technology received wide
attention in organic chemistry because of the versatility,
speed, and cleaner reaction products.3 Varma and
co-workers have reported the use of microwaves in
solvent-free reactions.4 The use of microwave for deute-
rium labeling in heterocyclic and carbohydrate chemis-
try was reported.5 In our ongoing research in CNS
(erectile dysfunction, ED), we faced the challenge of pre-
paring a higher mass ED isotopomer by deuterium
incorporation. This prompted an exploration of new
synthetic methodologies for deuterium incorporation
with an emphasis in microwave mediation. Herein,
we wish to report the synthesis of deuterium labeled
aromatic compounds using microwave irradiation and
1
proved by H NMR spectroscopy. MS analysis of the
crude sample 1 treated with water to remove labile deu-
terium showed a mass peak at m/e 114, which corre-
sponds to the M+4 product with four deuteriums on
the aromatic ring.
As a comparative case study between the conventional
heating and microwave irradiation, p-amino phenol
was dissolved in 35 wt % deuterium chloride in
NH2
NH2
D
D
D
D
D2O, DCl, MW*
OH
OH
1
Keywords: Microwave; Deuterium.
*
Corresponding author. Tel.: +1 8479373880; fax: +1 8479382336;
e-mail: bruce.surber@abbott.com
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.110

5196
S. Vaidyanathan, B. W. Surber / Tetrahedron Letters 46 (2005) 5195–5197
Table 1. Optimization of the conditions for deuteration of p-aminophenol
Experiment
Temp (°C)
MW (W)
Time (min)
Mass spectroscopy results
1
2
3
4
5
6
100
150
150
175
175
175
9
50
30
5
M+1 (46%), M+2 (29%), M+3 and M+4 traces and starting material (25%)
M+1 (7%), M+2 (34%), M+3 (41%) and M+4 (18%)
M+1 (12%), M+2 (10%), M+3 (35%) and M+4 (42%)
M+1 (6%), M+2 (13%), M+3 (27%) and M+4 (53%)
M+3 (16%) and M+4 (84%)
50
15
15
20
60
140
140
140
M+3 (24%), M+4 (76%) and considerable decomposition
deuterium oxide and heated in an oil bath at 175 °C for
24 h. MS analysis showed 6% of M+4 and 28% of M+3
with major M+2 as 59%. MS analysis of the sample after
72 h at 175 °C showed 51% of M+4 and 35% of M+3.
Thus, microwave irradiation provides a higher order
of deuterium incorporation in higher percentage in
shorter time.
reaction mixture, the product precipitated out and was
filtered. When N-methyl aniline was used as substrate,
the reaction was carried out for 2 h to give 100% incor-
poration of M+3. The deuterium incorporation was as-
1
signed at ortho and para positions based on H NMR
and GC–MS. This methodology was successfully ex-
tended to the synthesis of deuterium labeled 2-[4-(2,6-
dimethylphenyl)piperazin-1-yl-methyl]1H-benzimidazole
2, a potent dopamine agonist for erectile dysfunction.
The compound 2 was purified by flash chromatography
using ethyl acetate/hexane as 1:1 eluant and character-
ized by NMR and MS spectroscopy.9,10 Deuterated o-
phenylenediamine was irradiated with bromoacetic acid
in the presence of DCl for 60 min. MS analysis showed a
mixture of M+3 (9%), M+4 (18%), M+5 (40%), M+6
(17%), and M+7 (16%). The crude reaction mixture
was neutralized with potassium carbonate and extracted
with ethyl acetate. The crude product, on microwave
irradiation in the presence of triethylamine and 2,6-di-
methylphenyl piperazine in DMF for 35 min, provided
2 (Scheme 2) as a mixture of M+3 (2%), M+4 (16%),
M+5 (36%), M+6 (38%), and M+7 (8%) in 30% yield
with no M+0.8
The methodology was tested with different aromatic
compounds (Table 2). When p-bromoaniline was irradi-
ated at medium power for 40 min, we observed M+2 in-
crease in mass and the deuterium incorporation was
assigned based on GC/MS, presumably on both posi-
tions8 ortho to the amino group. MS analysis also
showed traces of the singly deuterated isotopomer. Irra-
diating the reaction mixture for longer period of time
did not improve the incorporation of deuterium in the
molecule. Interestingly, we found the same phenomenon
for p-bromoanisole, in which the hydrogens were
exchanged with deuterium ortho to methoxy and this
was confirmed by GC/MS and NMR analysis.8
In the case of aniline, we observed M+3 as the major
product and the deuterium incorporation was found to
be at both ortho and para positions. On cooling the
When attempts were made to extend this methodology
to other aromatic compounds such as phenol and resor-
cinol, there was no deuterium incorporation observed,
apparently because of the low miscibility of the sub-
strate with aqueous medium. Addition of few drops of
DMSO-d6 to these reactions did not provide any appre-
ciable improvement.
Table 2. Scope of acid-catalyzed, mircowave-mediated aromatic
hydrogen/deuterium exchange
Substrate
Minutes
Number and percentage
of deuterium
4-Bromoaniline
Aniline
80
80
M+2 (100%)
M+3 (80%) and M+2 (20%)
M+2 (100%)
In summary, we have discovered an efficient labeling
methodology for deuteration of water-miscible elec-
tron-rich aromatic compounds by the use of microwave
irradiation. This methodology was extended to the
4-Bromoanisole
N-Methyl aniline
o-Phenylenediamine
80
160
20
M+2 (29%) and M+3 (71%)
M+4 (78%) and M+2 (22%)
D
D
DCl
BrCH2CO2H
MWI*
D
D
NH2
NH2
NH2
NH2
D2O
DCl,
MWI*
HN
Br
N
D
D
D
D
D
N
D
D
N
N
N
Et3N, DMF
MWI*
N
H
N
H
D D
D D
D
2
Scheme 2.

S. Vaidyanathan, B. W. Surber / Tetrahedron Letters 46 (2005) 5195–5197
5197
4. (a) Varma, R. S. Pure Appl. Chem. 2001, 73, 193; (b)
Varma, R. S. Tetrahedron 2002, 58, 1235.
stable label synthesis of ABT-724, a potent dopamine
agonist for erectile dysfunction.
5. (a) Anto, S.; Getvoldsen, G. S.; Harding, J. R.; Jones,
J. R.; Lu, S.-Y.; Russell, J. C. J. Chem. Soc., Perkin Trans.
2 2000, 2208; (b) Cioffi, E. A.; Bell, R. H.; Le, B.
Tetrahedron: Asymmetry 2005, 16, 471; (c) Koves, G. J. J.
Labelled Compd. Radiopharm. 1994, 34, 255.
Acknowledgments
We thank Jeff Wang for mass and David Whittern
for NMR spectral data. We also thank Dr. Stanley A.
Roberts for his encouragement.
6. Commercially available from Aldrich.
7. Preparation of [2H4]-p-aminophenol: p-aminophenol
(1 mmol) was dissolved in 35% DCl in D2O (1 mL) and
irradiated in a CEM robot microwave oven at 175 °C for
20 min at medium power (140 W). The precipitate
obtained by cooling the reaction mixture was filtered
and dried to afford 1 in quantitative yield.
References and notes
1. Walsky, R. L.; Opbach, R. S. Drug Metab. Dispos. 2004,
32, 647.
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3. (a) Kim, Y. J.; Varma, R. S. Tetrahedron Lett. 2005, 46,
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Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim, 2002, p
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8. The regioselective deuterium incorporation was assigned
1
based on H NMR and GC/MS.
9. Mp 204–205 °C, lit.10 203–205 °C. 1H NMR (CDCl3,
300 MHz): 2.38 (s, 6H); 2.74 (m, 4H); 3.21 (m, 4H); 7 (m,
3H); 9.9 (br s, 1H). MS (ESI): 327 (MH)+.
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Rohde, J.; Nelson, S. L.; Patel, M.; Kolasa, T.; Nakane,
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