Hydrogen-Isotope Exchange (HIE) Reactions of Secondary and Tertiary Sulfonamides and Sulfonylureas with Iridium(I) Catalysts

Article abstract of DOI:10.1002/ejoc.201601599

For the first time we report the optimized hydrogen-isotope exchange (HIE) conditions for the selective aromatic deuteriation of various sulfonylureas and tertiary sulfonamides, as well as for a broad range of secondary sulfonamides. Based on a comprehens

Full text of DOI:10.1002/ejoc.201601599

DOI: 10.1002/ejoc.201601599
Full Paper
Hydrogen-Isotope Exchange
Hydrogen-Isotope Exchange (HIE) Reactions of Secondary and
Tertiary Sulfonamides and Sulfonylureas with Iridium(I)
Catalysts
Annina Burhop,[a] Remo Weck,[a] Jens Atzrodt,*[a] and Volker Derdau*[a]
Abstract: For the first time we report the optimized hydrogen- However, for tertiary sulfonamides, the commercially available
isotope exchange (HIE) conditions for the selective aromatic
deuteriation of various sulfonylureas and tertiary sulfonamides,
as well as for a broad range of secondary sulfonamides. Based
on a comprehensive screening of readily available Ir catalysts,
the Kerr-type NHC catalyst 5 proved to be most efficient in
the HIE reaction of secondary sulfonamides and sulfonylureas.
Burgess catalyst 6, not yet utilized in HIE reactions, resulted in
a much higher incorporation of deuterium. Finally, we tested
the new HIE protocol for the labelling of a series of sulfa drugs
and adapted the conditions to allow for selective tritium label-
ling.
Introduction
contributed catalysts to this field, with Crabtree's
[(cod)Ir(PPh3)(py)]PF6
and Kerr's [(cod)Ir(IMes)(PR3)]PF6,[19]
[18]
Molecules labelled with isotopes are important in a wide range
of different scientific fields, for example, in optoelectronics,[1]
microbial ecology,[2] clinical pharmacology,[3] diagnostics,[4] pro-
teomics,[5] metabolomics[6] and drug discovery.[7] In pharma-
ceutical research, stable isotope-labelled compounds are util-
ized as internal standards for LC–MS/MS assay validation,[8] for
metabolic pathway elucidation[9] and more recently also as
“heavy drugs”.[10] Additionally, radioactive tritium tracers are
increasingly used as discovery tools, for example, in radio-
ligand,[11] protein[12] and covalent binding[13] assays, for photo-
affinity labelling,[14] tissue distribution[15] and for the ADME
(Absorption Distribution Metabolism Excretion) profiling[16] of
new drug candidates. The most elegant way to introduce a
hydrogen isotope (deuterium or tritium) into an organic com-
pound is through a hydrogen-isotope exchange (HIE) reac-
tion.[17] HIE allows for direct isotope incorporation into the tar-
get molecule itself and thus circumvents the need for additional
synthetic steps (e.g., precursor synthesis or a stepwise prepara-
tion from isotopically enriched starting materials). Nowadays,
the most efficient methods for selective ortho-directed HIE reac-
tions (selective introduction of a hydrogen isotope at the ortho
position next to a directing group) are based on homogeneous
iridium(I) complexes, which have demonstrated a high reactivity
and at the same time good functional group tolerance and
regioselectivity. In the last 30 years many groups have
both commercially available, the most popular. In particular, the
latter is widely employed for the selective labelling of sub-
strates at the ortho position to a broad range of directing
groups, for example, ketones, acids, amides, esters and several
heterocycles, including pyridines, pyrimidines, imidazoles and
oxazoles.[19,20]
However, despite recent progress in the field, there are still
a number of interesting functionalities that have not been fully
explored or not utilized at all as directing groups, for example,
sulfonamides. Secondary and tertiary sulfonamides and sulfon-
ylureas represent particularly important structural motifs in sev-
eral classes of drugs (sulfa drugs), including sulfonamide anti-
biotics (Figure 1), for example, sulfamethoxazole (1),[21] protease
inhibitors for the treatment of HIV, for example, darunavir (2),[22]
PDE5 inhibitors for the treatment of erectile dysfunction, for
example, sildenafil (Viagra, 3),[23] sulfonylureas for the treatment
of diabetes mellitus, for example, glibenclamide (4)[24] as well as
[a] Sanofi-Aventis Deutschland GmbH, Integrated Drug Discovery, MedChem,
Isotope Chemistry & Metabolite Synthesis,
Industriepark Höchst, Frankfurt, Germany
E-mail: Volker.Derdau@sanofi.com
Jens.Atzrodt@sanofi.com
www.sanofi.com
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201601599.
Figure 1. Secondary and tertiary sulfonamide (urea) drugs.
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non-steroidal anti-inflammatory COX-2 inhibitors of the oxicam with N-methyl-4-methylbenzenesulfonamide (7).[27] For the
class[25] and hepatitis C anti-viral RNA polymerase inhibitors.[26] same substrate, Pfaltz and co-workers[32] reported earlier deu-
terium incorporations of up to 95 % at elevated temperature
(90 °C) when testing iridium P,N complexes, well known as
asymmetric catalysts for double-bond reductions, for their HIE
reactivity. Unfortunately, neither the yields of labelled 7 nor the
application of these catalysts to the HIE of other secondary sulf-
onamides has been reported. Another limitation for further util-
ization might be the high air and moisture sensitivity of the
non-commercially available catalysts, which require glove-box
conditions for their preparation. To the best of our knowledge,
successful HIE in tertiary sulfonamides or sulfonylureas has not
yet been reported.
Recently, Kerr et al. reported a successful HIE protocol for
primary sulfonamides with deuterium incorporations of up to
95 % by using a catalyst of the type [(cod)Ir(NHC)Cl] (5) at room
temperature (Figure 2).[27] Earlier reports also described the use
of Crabtree's catalyst,[28,29] iridium 1,3-dionate[30] and an in situ
generated iridium–pyridine complex.[31] Although all of these
methods are quite successful for HIE reactions involving pri-
mary sulfonamides, most known protocols fail to give desirable
results for higher-substituted sulfonamides. For example, Kerr's
NHC catalysts [(cod)Ir(NHC)PR3] and [(cod)Ir(NHC)Cl] (5) yielded
poor deuterium incorporations of only 7 and 8 % D, respec-
tively, when employed at room temperature in a HIE reaction
Results and Discussion
In our continuing efforts to broaden our synthetic repertoire for
fast tritium labelling we became interested in a new, convenient
HIE protocol as known procedures have failed for secondary
and tertiary sulfonamides. Stimulated by the recent reports of
Kerr[27] and Pfaltz[32] and their co-workers, we started our own
studies with a careful evaluation of commercially available or
readily accessible catalysts, for example, through short catalyst
syntheses without the need for glove-box conditions. Even
though the difference in reactivity between primary, secondary
and tertiary sulfonamides might be considered moderate, our
initial catalyst screening at room temperature revealed only
very limited deuterium incorporation in secondary and tertiary
sulfonamides in contrast to the high deuterium efficiencies re-
ported for primary sulfonamides.[27] Clearly, substitution at the
sulfonamide has a strong effect on the HIE reaction. Thus we
repeated all the experiments at elevated temperatures in a
high-boiling solvent like chlorobenzene (see Table 1).
To our great delight, under these conditions the
[(cod)Ir(NHC)Cl] catalyst (5; Table 1, entry 7) as well as Burgess'
catalyst [(cod)Ir{(adamantyl-oxazolyl)-ethyl(iPr2Ph)-imidazolyl}]-
Figure 2. Previous and present work of HIE reactions with sulfonamides.
Table 1. Screening of iridium catalysts in the HIE reaction of N-methyl-4-methylbenzenesulfonamide (7).[a,b]
Entry
Catalyst
Dinc 7a[a,b]
Yield[c] of 7a
[%]
[%]
1
2
3
4
5
6
7
8
9
[(cod)Ir(Py)PCy3] (Crabtree)
0
0
0
91
96
94
97
96
93
91
94
92
97
[(cod)Ir(acac)]
[(cod)Ir(acacF6)]
[(cod)Ir(MeCp)]
0
[(cod)Ir(NHC)PPh3] (Kerr)
[(cod)Ir(NHC)PBn3] (Kerr)
[(cod)Ir(NHC)Cl] (Kerr, 5)
25
30
79
81
0
[(cod)Ir{(adamantyloxazolyl)ethyl(iPr2Ph)imidazolyl}]BArF (Burgess, 6)
[(cod)Ir(Py)2]
10
[(cod)Ir(PPh3)Cl]
0
[a] Reagents and conditions: substrate 7 (10 μmol, 2 mg), catalyst (10 mol-%), chlorobenzene (2 mL), D2 (1 atm), 2 h, 100 °C. [b] Positions and percentage of
deuterium incorporation were determined by 1H NMR spectroscopy. [c] Isolated yield.
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BArF (6; entry 8) showed similar high HIE reactivity towards the
secondary sulfonamide 7 selected as our model substrate. It is
worth mentioning that, to the best of our knowledge, the Bur-
gess catalyst 6, developed as a catalyst for the asymmetric
hydrogenation of olefins,[33] has never been applied in HIE reac-
tions before. Even though both catalysts showed very similar
results in this model reaction, we decided to study both to gain
more insights into their differences.
Subsequent solvent screening (Table 2) with catalysts 5 and
6 revealed no or only very limited HIE reactivity in boiling
methyl tert-butyl ether (MTBE; Table 2, entry 1), ethanol (en-
try 2), 2-methylhydrofuran (2MeTHF, entry 3), isopropyl acetate
(entry 4), 1-butanol (entry 5) and dichloromethane (DCM, en-
try 8). Chlorobenzene, selected for the initial catalyst screening,
turned out to be the best solvent for both catalysts (entry 6).
In toluene, moderate deuteriation was observed (entry 7).
In the next optimization step we varied parameters such as
temperature, time and catalyst loading (Table 3). In the model
reaction of 7 with catalyst 5 (Table 3, entries 1–8), temperatures
above 100 °C (entries 3–8) and a catalyst loading of 10 mol-%
were needed to obtain good deuterium incorporation within
Table 3. Optimization of the HIE reaction of N-methyl-4-methylbenzene-
sulfonamide (7) in chlorobenzene.[a,b,c]
Entry
Cat
T
[°C]
t
[h]
Catalyst
[mol-%]
Dinc
7a
Yield[c,d] 7a
[b,c]
[%]
[%]
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
60
80
2
2
2
2
2
2
2
1
10
10
10
10
10
5
33
58
82
80
73
33
79
84
93
91
93
92
89
90
91
96
100
120
130
100
100
120
20
10
9
6
6
6
6
6
6
60
80
80
100
100
120
2
2
2
2
2
1
10
5
10
3
5
10
42
45
84
71
93
70
81
84
81
80
84
79
10
11
12
13
14
[a] Reagents and conditions: substrate 7 (10 μmol, 2 mg), catalyst, chloro-
benzene (2 mL), D2 (1 atm). [b] Positions and percentage of deuterium incor-
poration were determined by 1H NMR spectroscopy. [c] Repeated three times.
[d] Isolated yield.
2 h. At lower temperatures (entries 1 and 2) and with a catalyst hydrogen atoms of N-aryl substituents are not exchanged even
loading below 10 mol-% (entry 6) the D incorporation dropped in cases in which the N-aryl ortho position represents the only
significantly whereas a higher catalyst loading (20 mol-%) exchangeable hydrogen atoms, as in methanesulfonanilide 8.
seemed to have no additional benefit (entry 7). Finally, we fur- This finding is in good agreement with the detailed mechanistic
ther investigated the scope and limitations of the reaction by investigations reported previously for primary sulfonamides by
using a 10 mol-% catalyst loading of 5 at 120 °C for 1 h under Kerr and Tuttle,[27] which suggests a similar mechanism for sec-
a deuterium atmosphere (entry 8) However, similar results were ondary sulfonamides too.
observed to those achieved at lower temperatures (100 °C) for
a reaction time of 2 h (entry 3 vs. entry 8). For Burgess' catalyst
6 we found the highest deuterium incorporation at 100 °C for
a 2 h reaction time and a 5 mol-% catalyst loading (entry 13).
At lower temperatures (entries 9–11) a higher catalyst loading
was needed to obtain a similarly large incorporation of D,
whereas at higher temperatures (120 °C) the catalyst activity
dropped significantly, probably due to the decomposition of
the catalyst. As the best general conditions we identified
5–10 mol-% catalyst loading, a temperature of 100–120 °C and
a 2 h reaction time.
As previously observed for other [(cod)Ir(NHC)PR3]-type cata-
lysts,[34] the catalytic activity of 5 is not affected by the presence
of an aniline moiety and thus, like 10, 11 is deuteriated only at
the o-benzenesulfonamide positions. Interestingly, 6 seems to
have a higher affinity than 5 towards the amine as a competing
directing group, which is indicated by an additional exchange
at the o-aniline position in 10. Repositioning of the amino func-
tion to the other ring system in 11 resulted in exclusive o-anil-
ine labelling with 6. Similarly, the nitro function showed a bet-
ter coordinating efficiency than the benzenesulfonamide moi-
ety for both catalysts leading to 50 (with 5) and 40 % (with 6)
For a more detailed evaluation of the scope of the reaction deuterium exchange at the ortho position of the nitro group in
we first modified the alkyl and aryl substitution pattern (Fig- 12. When using acid- or ester-substituted benzenesulfonamides
ure 3). Comparing different benzene- and methanesulfonamide 13 and 14, ortho-deuterium exchange next to both directing
derivatives (7–11), we found that the HIE reactions with both groups (ester/acid and sulfonamide) was observed, however, in
catalysts 5 and 6 are selective for arylsulfonamides, whereas the this case 6 was outperformed by 5 in terms of HIE efficiency.
Table 2. Solvent screening of the HIE of N-methyl-4-methylbenzenesulfonamide (7) with catalyst 5 or 6.[a,b]
Entry
Solvent
T [°C]
Catalyst 5
Yield[c] of 7a [%]
Catalyst 6
Yield[c] of 7a [%]
[b]
[b]
Dinc 7a [%]
Dinc 7a [%]
1
2
3
4
5
6
7
8
MTBE
ethanol
2-MeTHF
45
68
70
0
0
0
15
0
85
49
0
91
93
90
91
95
97
94
90
18
0
0
50
0
82
32
0
87
86
82
79
88
90
78
75
isopropyl acetate
1-butanol
chlorobenzene
toluene
79
100
100
100
30
DCM
[a] Reagents and conditions: substrate 7 (10 μmol, 2 mg), 1 μmol catalyst, solvent (2 mL), D2 (1 atm). [b] Positions and percentage of deuterium incorporation
determined by 1H NMR spectroscopy. [c] Isolated yield.
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example, the reaction of N,N-diethyl-4-chlorobenzenesulfon-
amide (23) yielded 84 % D incorporation with 6 compared with
33 % with 5. The same tendency for better deuterium incorpo-
ration with 6 was observed with the tertiary sulfonamides 24–
31. Functional groups like tertiary amines, acids, esters and
halogens did not affect the ortho selectivity or reactivity of the
Burgess-catalysed aromatic HIE reaction. However, primary
amines and ketones proved to be better coordinating groups
than tertiary sulfonamides and this led to preferred or addi-
tional exchange at the corresponding ortho positions (sub-
strates 24 and 31). Interestingly, the presence of an alternative
aromatic ring system in the pyrrole and indole derivatives 29–
31 led to a preferred exchange in the heterocycle.
Figure 4. Products of the HIE reactions of tertiary sulfonamides with catalyst
5 and 6.[a,b] [a] Reagents and conditions: substrate (22 μmol), 10 mol-% cata-
lyst 5, PhCl (1 mL), D2 (1 atm), 120 °C, 1 h (black); substrate (22 μmol), 5 mol-
% catalyst 6, PhCl (1 mL), D2 (1 atm), 100 °C, 2 h (green). [b] Positions and
percentage of deuterium incorporation were determined by 1H NMR spectro-
scopy. The values of Dinc [%] are presented in brackets. Each reaction was
repeated at least twice.
Figure 3. Products of the HIE reactions of different secondary sulfonamides
with catalyst 5 and 6.[a,b] [a] Reagents and conditions: substrate (22 μmol),
10 mol-% catalyst 5, PhCl (1 mL), D2 (1 atm), 120 °C, 1 h (black); substrate
(22 μmol), 5 mol-% catalyst 6, PhCl (1 mL), D2 (1 atm), 100 °C, 2 h (green).
[b] Positions and percentage of deuterium incorporation were determined by
1H NMR spectroscopy. The values of Dinc [%] are presented in brackets. Each
reaction was repeated at least twice.
Catalyst 5 performed much better in HIE reactions with sulf-
onylureas 32–34 with excellent deuterium-incorporation effi-
ciency of up to 97 D incorporation in the case of 1-(p-chloro-
Furthermore, we found no steric influence on yield and deu- benzenesulfonyl)-3-propylurea (32; Figure 5). Similarly to 14,
terium incorporation by the ortho-, meta- and para-substituted the presence of an ester function in 33 resulted in ortho-deuter-
methyl groups in substrates 15–17. Also, the presence of an ium exchange next to both directing groups. For the sulfonyl
electron-withdrawing chloro substituent in benzenesulfon- amide derivative 35, the two catalysts showed similar deuter-
amides 18–20 gave good results for deuterium incorporation, ium incorporation with 76 and 88 % D incorporation, respec-
ranging from 85 to 95 % for both catalysts. The slightly better tively.
HIE efficiency observed with 6 for the boronic acid derivative
21 was more striking with the boronic ester 22 (77 % D incor-
poration with 6 compared with 11 % with 5).
Finally, we tested our HIE protocol on a variety of drugs and
drug-like sulfonamides and sulfonylureas (Figure 6). As ex-
pected in the HIE reaction of sulfamethoxazole (1) with 5, a
Although both catalysts showed good results for the HIE re- highly selective deuteriation of the o-benzenesulfonamide posi-
actions with secondary sulfonamides 9–22, with 5 tending to tion (65 % D incorporation) was observed. In contrast, the treat-
be superior, particularly in the presence of ester or acid func- ment of 1 with 6 resulted in 0 % deuterium uptake, not even at
tionalities, much higher deuterium incorporations were the o-aniline position; we consider that an alternative stronger
achieved for tertiary sulfonamides 23–31 with 6 (Figure 4). For coordination of the catalyst at another heteroatom takes place.
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corporation in secondary sulfonamides with catalyst 5 than
with 6. The labelling of the dansyl moiety makes it in principle
possible to prepare bimodal imaging probes carrying a radio-
active (tritium) and fluorophore marker.
Interestingly, catalyst 6 proved to be superior for tertiary sulf-
onamides, as demonstrated for the drugs darunavir (2) and sil-
denafil (3), which were selectively ortho-deuteriated with 61
and 81 % D incorporation, respectively. The amino group in
darunavir (2) did not change the HIE ortho selectivity of the
catalyst, in contrast to model compound 11. In the case of our
sulfonylurea test substrates, catalyst 5 performed better than 6,
which was also found when applying the two catalysts to the
exchange reactions with glibenclamide (4) and urea 37. Al-
though for substrate 37 only a moderate 35 % D incorporation
was found, glibenclamide (4) proved to be an excellent sub-
strate for HIE with a remarkable 92 % deuteriation of the o-
benzenesulfonamide plus an additional 46 % at the ortho-
amide position.
Finally, we also tested whether our HIE protocol could be
applied under the special conditions required for tritium label-
ling. In this case typically only a 5–10-fold excess of tritium gas
is utilized and therefore the reaction conditions were optimized
by using a deuterium manifold system and glibenclamide (4)
as test substrate (see the Supporting Information for details).
With 10 mol-% catalyst 5 we evaluated the HIE reaction of 4
under two reduced pressures (89 and 240 mbar) with 10 equiv.
D2 at 100 °C over 2 and 5 h. Subsequently, the tritium reaction
was carried out with 2.3 Ci tritium gas at 100 °C to provide
Figure 5. Products of the HIE reactions of sulfonylureas 32–34 and sulfonyl
amide 35 with catalyst 5 and 6.[a,b] [a] Reagents and conditions: substrate
(22 μmol), 10 mol-% catalyst 5, PhCl (1 mL), D2 (1 atm), 120 °C, 1 h (black);
substrate (22 μmol), 5 mol-% catalyst 6, PhCl (1 mL), D2 (1 atm), 100 °C,
2 h (green). [b] Positions and percentage of deuterium incorporation were
determined by 1H NMR spectroscopy. The values of Dinc [%] are presented in
brackets. Each reaction was repeated at least twice.
The steroidal secondary sulfonamide 36 carrying the dansyl dye
was deuteriated selectively at the aromatic 2- and 8-positions
of the dansyl moiety next to the naphthalenesulfonamide func-
tion with 55 and 50 % D incorporation, respectively, using cata-
lyst 5. For the same substrate the use of catalyst 6 resulted
in much lower D incorporation at the same positions, thereby
confirming a general tendency to obtain better deuterium in-
tritium-labelled glibenclamide with
a specific activity of
9 Ci/mmol. The 3H NMR spectrum (Figure 7) of the product
reveals the highly selective incorporation of tritium into the o-
benzenesulfonamide and o-amide positions.[35]
Figure 7. 3H NMR spectrum of [3H]glibenclamide ([3H]4).
Conclusions
We have developed the first practical HIE protocol for the deu-
teriation of various secondary and tertiary sulfonamides as well
as sulfonylureas based on readily available iridium NHC catalyst
5 and the commercially available Burgess catalyst 6. The latter
catalyst has not been utilized for HIE reactions before but
proved to be most efficient particularly in the HIE reactions of
tertiary sulfonamides, whereas for secondary sulfonamides and
ureas a better deuterium incorporation was typically observed
Figure 6. Products of the HIE reactions of drug-like molecules with catalyst 5
or 6.[a,b] [a] Reagents and conditions: substrate (22 μmol), 10 mol-% catalyst
5, PhCl (1 mL), D2 (1 atm), 120 °C, 1 h (black); substrate (22 μmol), 10 mol-%
catalyst 6, PhCl (1 mL), D2 (1 atm), 100 °C, 2 h (green). [b] Positions and
percentage of deuterium incorporation were determined by 1H NMR spectro-
scopy. The values of Dinc [%] are presented in brackets.
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under the optimized conditions following the general method for
Kerr's catalyst 5 [substrate (10 μmol), catalyst 5 (10 mol-%), PhCl
(2 mL), 120 °C, 1 h] and Burgess' catalyst 6 [substrate (10 μmol),
catalyst 6 (5 mol-%), PhCl (2 mL), 100 °C, 2 h].
with catalyst 5. The method has a broad substrate scope, can
be applied to sulfa drugs and in principle even be adapted to
the special conditions required for selective tritium labelling.
Even though some of the hydrogen-isotope incorporations
achieved by this method might only be moderate, this degree Deuteriation of Compounds 1–4, 36 and 37: (Figure 6). Deuter-
ium incorporation into compounds 1–4, 36 and 37 (Figure 6) was
investigated under the following conditions for Kerr's catalyst 5
[substrate (10 μmol), catalyst 5 (10 mol-%), PhCl (2 mL), 120 °C, 1 h]
and Burgess' catalyst 6 [substrate (10 μmol), catalyst 6 (10 mol-%),
PhCl (2 mL), 100 °C, 2 h].
of labelling is typically sufficient for tritium labelling and most
related applications.
Experimental Section
Deuterium Manifold Reaction: The optimization of the deuteria-
tion of glibenclamide (4) was performed in the deuterium manifold
(RC TRITEC AG). Thus, the vial (1 mL) was loaded with the substrate
General: 1H and 13C NMR spectra were recorded with Bruker
Avance 300 and 500 spectrometers in [D6]DMSO. The chemical
shifts (δ) are expressed in ppm and are given relative to the residual
proton signal of [D6]DMSO (δ = 2.50 ppm). NMR assignments were
based on the results of additional 2D NMR experiments. The 1H
NMR spectra show the substrate before reaction, the substrate after
the reaction with catalyst 5 and the substrate after the reaction
with catalyst 6. Silica gel column chromatography was carried out
with SiO2 (Merck, 0.063–0.200 mesh). The purity of the products
was determined by using an LC–MS system with a Symmetry Shield
RP18 column (3.9 × 150 mm) with a gradient program under the
following conditions: mobile phase A: water (900 mL), acetonitrile
(100 mL), TFA (1 mL); mobile phase B: water (100 mL), acetonitrile
(900 mL), TFA (0.75 mL); flow 1.5 mL/min; detection UV 254 and
210 nm.
stock solution (100/200 μL, 40 mM, 1 equiv.) and the catalyst stock
solution (50/100 μL, 8 m , 0.1 equiv.). Then the reaction mixture
M
was frozen with liquid nitrogen, the vial was evacuated, charged
with D2 (10 equiv.) and the connection to the gas was closed. The
mixture was slowly warmed to room temperature and afterwards
heated to 100 °C. After the temperature was reached, the stirring
(500 rpm) and the time was started. The crude reaction mixture
was analysed by NMR spectroscopy.
Tritium Manifold Reaction: Based on the results in the deuterium
manifold (RC TRITEC AG), the 3H reaction was performed under the
following conditions: glibenclamide (4; 2.00 mg, 4 μmol) was dis-
solved in chlorobenzene (0.15 mL) and then catalyst 5 (10 mol-%,
0.4 μmol) was added. The 1 mL reaction flask was adapted to a
tritium manifold and the solution was frozen in liquid nitrogen. The
flask was evacuated and charged with tritium (2.30 Ci, 39.3 μmol).
The reaction mixture was then warmed to room temperature and
whilst stirring heated at 100 °C for 2 h. After cooling to room tem-
perature, the solvent was removed in vacuo. The labile tritium was
exchanged and removed by the addition of methanol and a freeze-
drying process (three times repeated). The solid residue was dis-
solved in dry methanol (1 mL) and purified by HPLC (Phenomenex
Gemini NX C18 10 × 150 mm, 5 μm, 9 mL/min flow, ACN/water
gradient program) and finally transferred through a SPE-C18 device
to ethanol to give 4 [877 MBq (23.7 mCi), 1 % RCY, 3.33 GBq/mmol
(9 Ci/mmol), >97 % radiochemical purity by HPLC].
General Method: All screening methods were performed in a Rad-
leys synthesis station for parallel solution-phase chemistry unless
mentioned otherwise. Thus, a vial (25 mL) was charged with a stir-
ring bar and the substrate stock solution (500 μL, 20 mM, 1 equiv.).
The catalyst and solvent (1.5 mL) were added to the vial. Then the
vial was sealed with an open connection to the gas inlet, evacuated
until slight bubbling of the solution and refilled with deuterium gas
from a balloon three times. The vial was closed and placed in the
preheated synthesis station. The reaction was stirred (500 rpm)
under a D2 atmosphere (1 atm) for the appropriate time and tem-
perature. The crude reaction mixture was purified by silica gel chro-
matography (MTBE/ethyl acetate, 4:1) and analysed by NMR spec-
troscopy.
Solvent Screening of the HIE Reaction of N-Methyl-4-methyl-
benzenesulfonamide (7) with Catalyst 5 or 6: The solvent screen-
ing was carried out with N-methyl-4-methylbenzenesulfonamide (7)
Acknowledgments
The authors would like to thank Dr. Martin Sandvoss and Gerald
Scholz for analytical support and Dr. Seth Jones for proof read-
ing of the manuscript.
in the listed solvents (500 μL, 20 mM, 1 equiv.) in the presence of
catalyst 5 or 6 (1 μmol, 10 mol-%, 0.1 equiv.) at the appropriate
temperature and for the stated time. The total volume of the reac-
tion mixture was 2 mL. All reactions were performed according to
the general method at the temperature and time stated in Table 2.
Keywords: Hydrogen-isotope exchange · C–H activation ·
Iridium · Homogeneous catalysis · Deuterium
Optimization of the HIE Reaction of N-Methyl-4-methyl-
benzenesulfonamide (7) in Chlorobenzene: The stock solution
of N-methyl-4-methylbenzenesulfonamide (7) in chlorobenzene
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Full Paper
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Received: December 15, 2016
Eur. J. Org. Chem. 2017, 1418–1424
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© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim