A simple, cost-effective method for the regioselective deuteration of anilines

Article abstract of DOI:10.1021/ol801763j

(Chemical Equation Presented) A highly effective and operationally simple method for the regioselective deuteration of anilines is presented. A variety of electron-rich and electron-deficient anilines are efficiently deuterated at the ortho and/or para po

Full text of DOI:10.1021/ol801763j

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4351-4353
A Simple, Cost-Effective Method for the
Regioselective Deuteration of Anilines
Andrew Martins and Mark Lautens*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
Received July 30, 2008
ABSTRACT
A highly effective and operationally simple method for the regioselective deuteration of anilines is presented. A variety of electron-rich and
electron-deficient anilines are efficiently deuterated at the ortho and/or para position with respect to the nitrogen in the presence of 1 equiv
of conc HCl in D2O. Under the present conditions, aromatic methoxy groups do not facilitate deuteration, enabling a chemo- and regioselective
deuteration of p-anisidine.
Isotopically labeled molecules are essential tools for the study
of reaction mechanisms and metabolic pathways and as
internal standards in analytical methods. The deuterium atom
is the most common isotopic label and is the primary source
for determining kinetic isotope effects in mechanistic studies.
A wide variety of deuterated compounds are commercially
available; however, they can be prohibitively expensive.
Thus, synthetic chemists, most often in academic laboratories,
must synthesize labeled compounds themselves.
There are numerous methods for the incorporation of
deuterium into aromatic molecules,1 and while many recent
approaches employ the use of transition metals,2 the com-
plexes, ligands, or reagents employed may not be readily
accessible or economically viable. Thus, a simple, cost-
effective method for the deuteration of aromatic molecules
is highly desirable. Herein we report a simple strategy for
the synthesis of regioselectively deuterated anilines under
microwave irradiation which uses HCl and D2O.
While exploring the reaction mechanisms of palladium-
catalyzed coupling reactions in our laboratories, we required
an aryl iodide with a deuterium at the position ortho to the
iodide. As anilines serve as convenient synthetic precursors
to aryl iodides, we sought a method to make deuterated
anilines. We came across a microwave-mediated method for
the deuteration of 2-methylaniline3 via formation of the
anilinium hydrochloride salt, H-D exchange of the salt, and
heating through several cycles in a domestic microwave.
While our adaptation of this method to a commercial
microwave worked exceedingly well for the substrate we
tested,4 we found that the procedure was tedious and time-
consuming. We surmized that a simple alternative would be
to simply heat an anilinium hydrochloride, formed in situ in
acidic D2O. As the deuteration is proposed to occur via
electrophilic aromatic substitution upon deuteronium ions,3
we postulated that the low concentration of hydronium ion
with respect to deuteronium ion could enable nearly complete
deuteration. Thus, we aimed to develop a general method
for the deuteration of anilines.
(1) For an excellent review of modern methods of deuterium incorpora-
tion, see: Atzrodt, J.; Derdau, V.; Fey, T.; Zimmerman, J. Angew. Chem.,
Int. Ed. 2007, 46, 7744–7765.
(2) Selected examples using (a) Ir: Golden, J. T.; Andersen, R. A.;
Bergman, R. G. J. Am. Chem. Soc. 2001, 123, 5837–5838. Garman, R. N.;
Hickey, M. J.; Kingston, L. P.; McAuley, B.; Jones, J. R.; Lockley, W. J. S.;
Mather, A. N.; Wilkinson, D. J. J. Label Compd. Radiopharm 2005, 48,
75–84. (b) Ru: Alexakis, E.; Hickey, M. J.; Jones, J. R.; Kingston, L. P.;
Lockley, W. J. S.; Mather, A. N.; Smith, T.; Wilkinson, D. J. Tetrahedron
Lett. 2005, 46, 4291–4293. (c) Pd: Derdau, V.; Atzrodt, J. Synlett 2006,
1918–1922. Matsubara, S.; Yokota, Y.; Oshima, K. Org. Lett. 2004, 6, 2071–
2073.
Using 2-methyl-3-nitroaniline (1a) as our model substrate,
we explored the use of both catalytic and stoichiometric
amounts of a variety of Brønsted and Lewis acids in D2O
under microwave irradiation. While some catalytic Lewis
(3) Barthez, J. M.; Filikov, A. V.; Frederiksen, L. B.; Huguet, M.-L.;
Jones, J. R.; Lu, S.-Y. Can. J. Chem. 1998, 76, 726–728.
(4) Martins, A.; Lautens M. Submitted for publication.
10.1021/ol801763j CCC: $40.75
Published on Web 08/30/2008
2008 American Chemical Society

acids5 gave considerable amounts of deuteration, we found
that the best and most cost-effective results were obtained
from using 1 equiv of HCl in D2O, and heating to 180 °C
under microwave irradiation for 30 min. We also found that
microwave irradiation has a beneficial effect on the degree
of deuteration, as conventional heating did not afford
comparable results (Scheme 1).6,7
Table 1. Deuteration of Anilines under Microwave Irradiation
Scheme 1. Conventional Heating versus Microwave Irradiation
Under the optimized reaction conditions, a variety of
anilines were cleanly converted to the deuterated isotopo-
logues with high levels of deuterium incorporation (Table
1). Electron-rich and electron-deficient anilines were ef-
ficiently deuterated, including 2d, which was also deuterated
at the R-position.8 However, when the electron-withdrawing
substitutent is ortho to the aniline nitrogen, the degree of
deuterium incorporation is diminished para to the nitrogen
(as in 2g). The presence of several functional groups severely
inhibit deuterium incorporation; for instance, phenols, even
when containing an aniline nitrogen, undergo little to no
deuteration,9 while the presence of a pyridyl nitrogen led to
little to no deuterium incorporation on the parent ring.10
An interesting result emerged when p-anisidine (1o) was
subjected to the reaction conditions: while we expected that
the additional electron donation of the methoxy group would
enable complete deuteration of the aromatic ring, deuterium
was only observed ortho to the aniline nitrogen (Scheme 2).
Thus, under our reaction conditions, deuteration is regio- and
chemoselective for the aromatic positions activated by aniline
nitrogens.11
As previously mentioned, anilines serve as precursors to
aryl iodides. To show the synthetic utility of deuterated
anilines and to synthesize the required deuterated aryl iodide
a Run on 4 mmol scale.
(5) While Cu(OTf)2, Zn(OTf)2, and La(OTf)3 fared quite poorly (∼15%
D incorporation), 10 mol % of Sc(OTf)3 under microwave irradiation (180
°C, 30 min) gave considerable amounts of deuterated product (40% D ortho,
58% D para).
for our mechanistic studies, we were able to convert aniline
2a to the corresponding aryl iodide 3 (Scheme 3). No erosion
of deuterium content was observed under the reaction
conditions.
(6) Oil bath temperature was 180 °C, internal temperature not monitored.
Microwave temperature was internally monitored by the apparatus
.
(7) Surber also reported the benefits of microwave irrradiation using
concentrated DCl for the deuteration of 4-aminophenol. See: Vaidyanathan,
S.; Surber, B. W. Tetrahedron Lett. 2005, 46, 5195–5197
.
(8) Aside from R-deuteration, the levels of aromatic deuterium incor-
poration are much higher than the levels obtained by metal-catalyzed
methods.
Scheme 2. Chemoselective Deuteration of p-Anisidine
(9) 3-(N,N-Dimethyamino)phenol afforded <15% deuterium incorpora-
tion at the ortho and para positions.
(10) Following this trend, amidino or guanidino functional groups (such
as 2-aminopyridines or 2-aminopyrimidines) showed little to no deuterium
incorporation under the optimized conditions.
(11) To further test this hypothesis, basic aromatic compounds containing
multiple methoxy groups such as veratrylamine, brucine, and quinine were
tested and showed little to no deuterium incorporation.
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Org. Lett., Vol. 10, No. 19, 2008

Acknowledgment. We thank the National Science and
Engineering Research Council of Canada and Merck Frosst
Canada & Co. for financial support in the form of an
Industrial Research Chair and the University of Toronto for
additional support.
Scheme 3
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds are
available free of charge via the Internet at http://pubs.acs.org.
In summary, we have developed an efficient method for
the synthesis of regioselectively deuterated anilines under
microwave irradiation. The simple reaction conditions, high
levels of deuterium incorporation, and low cost of the
reagents make this a highly useful method for isotopic
labeling which in the future could be extended to the
incorporation of radioactive isotopes.12
OL801763J
(12) For reviews of microwave-assisted radiochemistry, see: (a) Elander,
N.; Jones, J. R.; Lu, S.-Y.; Stone-Elander, S. Chem. Soc. ReV. 2000, 239–
250. (b) Stone-Elander, S.; Elander, N. J. Labelled Compd. Radiopharm.
2002, 45, 715–746.
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