Triazabicyclodecene: An effective isotope exchange catalyst in CDCl 3

Article abstract of DOI:10.1021/jo070307h

(Chemical Equation Presented) We describe the first effective H/D exchange reaction with acidic substrates in CDCl₃ at room temperature. The particularly mild reaction conditions involved (solvent, base, and temperature) allow the chemoselective deuteration of ketones over esters. An NMR study was conducted with the aim of rationalizing the results obtained in the presence of TBD as catalyst.

Full text of DOI:10.1021/jo070307h

source would be favorable for the deuteration of sensitive
substrates. To the best of our knowledge, the only significant
example of deuterium labeling of acidic substrates in CDCl3
has been reported by Messinger.5 The author described the
deuteration of aryl alkyl ketones in refluxing CDCl3 in the
presence of basic aluminum oxide. This work prompted us to
investigate an alternative procedure at room temperature, more
suitable for the deuteration of a wide range of compounds.
Initially, we considered the use of a small and diverse collection
of usual bases, HONa, MeONa, pyridine, Et3N, DMAP, and
DBU (30 mol % each), for the deuteration of the 4′-methoxy-
acetophenone 1a in CDCl3 at room temperature. The total
deuterium incorporation was determined by 1H NMR spectros-
copy after 0.5, 12, and 64 h (Table 1). HONa, MeONa, pyridine,
Et3N, and DMAP allowed very poor deuterium incorporation
of 1a in CDCl3 (<22% after 64 h, entries 2-6). Only the
stronger base DBU (pKa ) 23.9)6 afforded a moderate deuterium
labeling of 1a after 64 h (62%, entry 7), while this base was
known to afford high isotope incorporation in D2O.7 On the
basis of these initial results, we turned our attention toward
guanidine-based compounds, known as highly basic organo-
catalysts. Surprisingly, treatment of 1a with the acyclic guani-
dine 1,1,3,3-tetramethylguanidine (TMG, pKa ) 23.7) or with
the monocyclic guanidine 2 did not allow any deuterium
incorporation. In contrast, a good level of deuterium incorpora-
tion was obtained with the bicyclic guanidine MTBD (pKa )
25.7) after 64 h at room temperature (85%, entry 10), and its
supported analogue, PSTBD, afforded a similar labeling of 1a
but at 50 °C (86%, entry 16). Finally, the use of 1,5,7-
triazabicyclo[4.4.0]dec-5-ene (TBD, pKa ) 26.2) led to the
highest deuterium incorporation, far from the second more active
base MTBD, since deuterium incorporation reached 92% within
only 0.5 h at room temperature (vs 9% for MTBD, entries 10
and 12). Moreover, the deuteration of 1a catalyzed by 1 mol %
of TBD afforded 76% of deuterium incorporation after 12 h,
while only traces of deuteration were observed with MTBD
under the same conditions (<2%, entry 11). Finally, an
optimization study revealed that 10 mol % of TBD was
sufficient to reach 92% of deuterium incorporation within 12 h
(entry 14). Finally, reaction carried out with basic aluminum
oxide, successfully used by Messinger in refluxing CDCl3, has
shown only 9% of isotope incorporation after 64 h at room
temperature (entry 17).5
Triazabicyclodecene: An Effective Isotope
Exchange Catalyst in CDCl3
Cyrille Sabot,† Kanduluru Ananda Kumar,†
Cyril Antheaume,‡ and Charles Mioskowski*,†
Laboratoire de Synthe`se Bio-Organique, UMR 7175/LC1-CNRS,
SerVice Commun de RMN, IFR85, UniVersite´ Louis Pasteur de
Strasbourg, 74 route du Rhin, B.P. 60024,
67401 Illkirch cedex, France
mioskow@aspirine.u-strasbg.fr
ReceiVed February 14, 2007
We describe the first effective H/D exchange reaction with
acidic substrates in CDCl3 at room temperature. The par-
ticularly mild reaction conditions involved (solvent, base,
and temperature) allow the chemoselective deuteration of
ketones over esters. An NMR study was conducted with the
aim of rationalizing the results obtained in the presence of
TBD as catalyst.
Deuterium-labeled compounds have become increasingly
important, particularly for structure elucidation of large mol-
ecules (proteins, oligonucleotides)1 and for mechanistic studies
of chemical2 and biological3 transformations in combination with
NMR spectroscopy. Deuterium labeling of organic compounds
can be achieved by means of syntheses starting from suitable
isotope marker precursors or via isotope exchange reactions.
The latter approach appears to be more valuable since the
deuterium can possibly be introduced post-synthetically. How-
ever, most of the H/D exchange reactions reported in the
literature for acidic compounds involve fairly strenuous protic
conditions4 that are not compatible with sensitive functional
groups. In this note, we report high level of deuterium
incorporation of sensitive substrates at room temperature in
CDCl3 as deuterium source as well as solvent.
To explain the disparity of the catalytic activity observed
between TBD and other bases of comparable nature and basicity,
the H/D exchange reaction of 4′-methoxyacetophenone 1a
1
catalyzed by TBD in CDCl3 was investigated by means of H
NMR spectroscopy.8 When TBD was dissolved in CDCl3, no
N-H signal was observed, demonstrating a total deuterium
exchange. In contrast, TBD underwent no detectable deuterium
incorporation in CD2Cl2. When 1 equiv of CDCl3 was added
to the latter solution, the N-H signal of intensity 1 was half
decreased and a singlet signal of intensity 0.5 at 7.27 ppm
appeared, corresponding to the chloroform peak. Thus, these
Deuterium incorporation is by far more difficult to achieve
in aprotic CDCl3 than in protic polar solvents such as MeOD
and D2O, partly due to limited strength of bases in this medium.
In return, the use of CDCl3, a weak nucleophile, as deuterium
* Corresponding author. Tel: +33 (0)3 90 24 42 97.
† Laboratoire de Synthe`se Bio-organique.
‡ Service Commun de RMN.
(1) Hodge, R. P.; Brush, C. K.; Harris, C. M.; Harris, T. M. J. Org.
Chem. 1991, 56, 1553.
(2) Hornback, J. M.; Vadlamani, B. J. Org. Chem. 1980, 45, 3524.
(3) Schwab, J. M.; Klassen, J. B. J. Am. Chem. Soc. 1984, 106, 7217.
(4) (a) Arrowsmith, C. H.; Kresge, A. J. J. Am. Chem. Soc. 1986, 108,
7918. (b) Fodor-Csorba, K.; Galli, G.; Holly, S.; Ga´cs-Baitz, E. Tetrahedron
Lett. 2002, 43, 3789.
(5) Kunick, C.; Messinger, P. Chem. Ber. 1986, 119, 1429.
(6) (a) The pKa of conjugate acid in all cases. (b) Kovacˇevic´, B.; Maksic´,
Z. B. Org. Lett. 2001, 3, 1523.
(7) Berthelette, C.; Scheigetz, J. J. Labelled Compd. Radiopharm. 2004,
47, 891.
(8) For related NMR spectra, see Supporting Information (S40).
10.1021/jo070307h CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/27/2007
J. Org. Chem. 2007, 72, 5001-5004
5001

TABLE 1. Bases Screening for Deuteration of
4′-Methoxyacetophenone 1a in CDCl3 at Room Temperature
SCHEME 1. Plausible Deuterium Transfer Involved in
Deuteration Reaction Catalyzed by TBD in CDCl3
1
exchange in CDCl3 by H NMR spectroscopy, which could
therefore explain their inefficiency for the deuteration of 1a.10
In addition, no example of H/D exchange between a guanidine
and CDCl3 is described in the literature. Only a H/D exchange
between the N-H proton of an amidine and CDCl3 has been
reported.11
Next, deuterium labeling of a number of ketones 1a-n was
explored using the optimized reaction conditions (e.g., 10 mol
% of TBD, rt, 12 h). Results obtained are summarized in
Table 2.
Total Incorporation Yield (%)a
entry
catalyst
0.5 h
12 h
64 h
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
-
0
0
2
0
13
3
0
22
6
It is noteworthy that all deuterated products were obtained
cleanly in high chemical yield (>95%) after workup, without
further purification. Repeating the labeling procedure once with
4′-methoxyacetophenone 1a afforded complete deuteration of
the methyl group of the ketone (>98% yield, entry 1). For other
acetophenone derivatives, it appeared that the nature of the
substituent on the aromatic ring or methyl group did not have
significant effect on the global deuterium incorporation. Indeed,
the 4′-nitroacetophenone 1c gave high level of deuterium
labeling (92% yield, entry 3) as well as the 2-methoxy-,
2-methyl-, 2-chloroacetophenones 1d-f with 93, 97, and 85%
of deuterium incorporation, respectively (entries 4-6). However,
an attempt to deuterate the isobutyrophenone 1g was less
satisfactory (21% yield, entry 7) probably due to steric
hindrance. To further demonstrate the scope of this method,
highly base-sensitive compounds, such as the 1-phenylpropane-
1,2-dione 1h,12 were deuterated in good yield (77% yield with
1% TBD, entry 8). In addition, the 2-acetoxyacetophenone 1i
was chemoselectively deuterated at the carbon atom R to the
phenyl carbonyl group (95% yield, entry 9) since no deuterium
incorporation was detected (1H/2H NMR) on the acetyl group.
To the best of our knowledge, this is the first example of a
selective deuteration of a methylene group of a ketone in the
presence of an acetate group. Indeed, an attempt to deuterate 1i
in usual protic media (D2O, MeOD) with MeONa, HONa, or
TBD ended up in partial or complete deprotection of the
substrate leading to 2-hydroxyacetophenone. This example
underlines the superiority of CDCl3 over protic media for the
labeling of compounds bearing sensitive functional groups. In
addition, deuterium incorporation at the carbon atom R to the
phenyl carbonyl group of 1i was only 21% with Messinger’s
methodology (e.g., refluxing CDCl3, 12 h). Moreover, the
reaction was successfully extended to heteroaromatic ketones
1k and 1l (89 and 90% yield, entries 11 and 12). Finally,
deuteration of two aliphatic ketones, benzylacetone 1m and
cyclodecanone 1n, was successfully achieved with 84 and 94%
of deuterium incorporation, respectively (entries 13 and 14).
HONa
MeONa
pyridine
Et3N
0
0
0
0
0
0
DMAP
DBU
TMG
0
0
0
<2
0
13
0
62
0
2
0
9
0
92
51
76
n.d
n.d
2
0
ndb
85
nd
92
nd
92
nd
86
9
MTBD
MTBDc
TBD
43
<2
92
76
92
22
67
3
TBDc
TBDd
PSTBD
PSTBDe
basic aluminum oxide
a Calculated on the basis of 1H NMR spectrum. b Not determined. c 1
mol %. d 10 mol %. e Reaction carried out at 50 °C.
results highlight the very efficient isotopic exchange between
TBD and CDCl3. To further rationalize the proton-deuterium
exchange reaction, 1 equiv of 4′-methoxyacetophenone 1a was
added to a solution of deuterated TBD (TDB-d1)9 in CD2Cl2.
Immediately the singlet signal of intensity 3 at 2.56 ppm
corresponding to the methyl ketone group of 1a was partially
replaced by a multiplet of intensity 2, and a peak of intensity 1
at 4.82 ppm corresponding to the NH proton of TBD appeared.
This observation suggests a fast and total D/H exchange between
TBD-d1 and the methyl ketone 1a. On the basis of these NMR
studies, we proposed a plausible catalytic cycle (Scheme 1) in
which TBD acts as a deuterium transfer catalyst between CDCl3
and the ketone 1a due to the presence of a labile proton in its
structure. Thus, TBD would behave as a neutral base in the
course of all the H/D exchange process. None of the other bases
tested exhibits both high basicity and a labile proton in their
structure. Indeed, replacement of the NH labile proton of TBD
with a methyl group (MTBD) did not change significantly its
basicity but led to an important loss of the labeling catalyst
activity. Moreover, despite the presence of a potential labile
N-H proton in TMG and 2, we did not observe any H/D
(10) For related NMR spectra, see Supporting Information (S9-S10).
(11) Lo¨få, S.; Ahlberg, P. J. Chem. Soc., Chem. Commun. 1981, 998.
(12) Turro, N. J.; Lee, T. J. Am. Chem. Soc. 1970, 92, 7467.
(9) For TBD-d1 preparation, see: Kaempfen, U.; Eschenmoser, A. HelV.
Chim. Acta 1989, 72, 185.
5002 J. Org. Chem., Vol. 72, No. 13, 2007

TABLE 2. Deuteration of Ketones 1a-n with 10 mol % of TBD in
TABLE 3. Deuteration of Acidic Compounds Catalyzed by TBD
a
a
CDCl3
in CDCl3
a All reactions were carried out with 10 mol % of TBD, 0.72 mmol of
the substrate in 3 mL of CDCl3, at room temperature for 12 h. b Calculated
on the basis of 1H NMR spectrum. c Unlabeled starting alkyne was
recovered. d Before workup. e 10 mol % of PSTBD at room temperature.
f Deuteration at the methylene position. g Deuteration at the vinyl position.
were carried out using the optimized conditions (e.g., 10 mol
% of TBD, rt, 12 h).
First, the deuteration of terminal alkynes was studied and
achieved successfully. Labeling of phenylacetylene 3a, usually
carried out by means of strong ionic bases,13 was obtained in
good yield (90%, entry 1). In the case of the 4-phenylbut-1-
yne 3b, deuteration took place exclusively at the terminal
position of the alkyne (1H/2H NMR). No deuterium incorpora-
tion was observed with the disubstituted alkyne 3c, and the
unlabeled starting alkyne was recovered. The 2-ethynyl-1-
methylimidazole 3d was labeled in 96% yield prior to workup.
However, after workup, the deuterium incorporation dropped
to 31% yield, presumably due to D/H exchanges with unlabeled
water. It is noteworthy that revert D/H exchange was only
observed with the compound 3d-d1. Interestingly, the same
reaction carried out with PSTBD at room temperature avoided
the aqueous treatment and afforded 84% yield of deuterium
incorporation of 3d. Moreover the methyl-1-phenylacetate 4, a
base-sensitive group, was efficiently deuterated with TBD (93%,
entry 5).14 This method should be widely applicable to a variety
of alkyl-1-phenylacetate derivatives. It is important to outline
that common procedures for the deuteration of alkyl esters in
protic solvents led to concomitant transesterification, therefore,
they are very substrates limited.15 Interestingly, indene 6
a All reactions were carried out with 10 mol % of TBD, 0.72 mmol of
the ketone in 3 mL of CDCl3, at room temperature for 12 h. b Calculated
on the basis of 1H NMR spectrum. c After repeating the labeling procedure
once with fresh TBD and CDCl3. d Not applicable. e Calculated on the basis
of mass spectroscopy. f 1 mol % of TBD. g Reaction carried out with
Messinger’s methodology: basic aluminum oxide in refluxing CDCl3 for
12 h.
(13) Zeller, K.-P.; Kowallik, M.; Haiss, P. Org. Biomol. Chem. 2005, 3,
2310.
(14) Filippo, J. S.; Romano, L. J. J. Org. Chem. 1975, 40, 782.
(15) Baldwin, J. E.; Ghatlia, N. D. J. Am. Chem. Soc. 1989, 111, 3319.
These results prompted us to investigate the scope of our
methodology to other acidic molecules (Table 3). All reactions
J. Org. Chem, Vol. 72, No. 13, 2007 5003

room temperature for 12 h and quenched with 1 N HCl (1 mL).
The organic layer was washed with water (2 × 2 mL) and brine
(1 mL), dried over anhydrous Na2SO4, and filtered. Filtrate was
concentrated to afford 1b-d3. The total incorporation yield was
determined by 1H NMR spectroscopy relative to the intensity of a
nonexchangeable proton in the molecule, or by GC-MS. For
example, the global deuterium incorporation of compound 1b-d3
determined by GC-MS was calculated as follows: 1/3 × 5.3% +
2/3 × 28.5% + 3/3 × 65.6% ) 86.4% of total incorporation.
Moreover, the site of deuterium incorporation in the substrate was
determined by 2H NMR spectroscopy relative to CHCl3 (7.27 ppm).
underwent 94% of deuteration at the methylene position and
89% at the vinyl position next to the benzene ring. This result
suggests that the proton-deuterium exchange proceeds via an
allylic reorganization.16
In summary, TBD has shown to be an efficient isotope
exchange catalyst in CDCl3 at room temperature toward a wide
range of substrates. Our optimized conditions are compatible
with sensitive functional groups and allow chemoselective
deuteration of ketones over esters. In contrast, bases commonly
used in polar protic media did not lead to significant deuterium
incorporation in CDCl3. The superior ability of TBD for
deuteration could be ascribed to both its high pKa value and
the presence of a labile proton in its structure.
Acknowledgment. We thank Rhodia Recherches and the
CNRS for financial support to C.S., B. Kieffer (from E.S.B.S)
for allowing access to the 600 MHz spectrometer, and P.
Wehrung for mass analyses.
Experimental Section
Supporting Information Available: 1H/2H NMR data for all
labeled compounds and preparative procedures and characterization
data for 2 and 1i. This material is available free of charge via
Internet at http://pubs.acs.org.
Representative Procedure for Deuteration Reaction (Com-
pounds in Tables 2 and 3). For compound 1b: To a solution of
10 mol % of TBD (10 mg, 0.072 mmol) in 3 mL of CDCl3 was
added 1b (84 µL, 0.72 mmol). The reaction mixture was stirred at
(16) Bergson, G. Acta Chem. Scand. 1964, 8, 2003.
JO070307H
5004 J. Org. Chem., Vol. 72, No. 13, 2007