Evaluation of a P,N-ligated iridium(I) catalyst in hydrogen isotope exchange reactions of aryl and heteroaryl compounds

Article abstract of DOI:10.1002/jlcr.3595

We have developed a novel and efficient iridium-catalyzed hydrogen isotope exchange reaction method with secondary and tertiary sulfonamides at ambient temperatures. Furthermore N-oxides and phosphonamides have been successfully applied in hydrogen isotop

Full text of DOI:10.1002/jlcr.3595

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Evaluation of a P,N-Ligated Iridium(I) Catalyst in Hydrogen
Isotope Exchange Reactions of Aryl and Heteroaryl
Compounds
Mégane Valero[a], Annina Burhop[a], Kristof Jess[b], Remo Weck[a], Matthias Tamm[b],*, Jens
Atzrodt[a],* and Volker Derdau[a],*
[a]
[b]
M. Valero, A. Burhop, R. Weck, Dr. Jens Atzrodt, Dr. Volker Derdau,
R&D, Integrated Drug Discovery, Isotope Chemistry & Metabolite
Synthesis, Sanofi Germany
Industriepark Höchst, G876, 65926 Frankfurt/Main
E-mail: Jens.Atzrodt@sanofi.com; Volker.Derdau@sanofi.com
Dr. Kristof Jess, Prof. Dr. Matthias Tamm, Institut für Anorganische
und Analytische Chemie, Technische Universität Braunschweig,
Hagenring 30, 38106 Braunschweig, Germany
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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doi: 10.1002/jlcr.3595
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Abstract: We have developed a novel and efficient iridium-catalyzed hydrogen isotope exchange (HIE) reaction method with
secondary and tertiary sulfonamides at ambient temperatures. Furthermore N-oxides and phosphonamides have been
successfully applied in HIE reactions with moderate to excellent deuterium introduction.
Introduction
1
]
Commercial catalysts developed by Crabtree and Kerr (scheme 1), i.e. [(cod)Ir(PPh3)(py)]PF6 (1)[
and
[(COD)Ir(IMes)(PR3)]PF6 (2),[2] utilizing T2 gas as tritium source have leveraged the routine use of HIE[3] for highly
selective tritium labelling of organic molecules.[4] The very high selectivity of the H/T exchange for the ortho-position
next to a directing group enables a specific tritium introduction into biologically and chemically stable positions. In
consequence, those HIE methods facilitated a possibility to overcome metabolic stability issues associated with earlier
tritiation methods.[5] Thus today, tritium tracers are widely utilized for ADME-profiling[6,7] of new drug candidates
but also as a discovery tool for photoaffinity labelling[8] and for radioligand,[9] protein[10] and covalent binding[11]
assays. In particular, Kerr’s catalysts 2 and 3 are widely applied for mild and selective ortho-labelling employing a
broad range of directing groups such as ketones, amides, esters, primary sulfonamides and several heterocycles.[12]
Despite recent progress, a number of interesting functionalities, ubiquitous throughout drug motives, still present
significant challenges for established HIE protocols.
Some of those limitations could be recently overcome by introduction of a new generation of Ir-catalysts with bidentate
ligands. The highly air- and moisture-sensitive, non-commercial catalysts 4 with phosphine-oxazoline P,N ligands,
originally developed by Pfaltz for asymmetric hydrogenation of olefins, proved efficient also in the HIE reaction of weakly
coordinating substrates such as sulfones and secondary sulfonamides.[13] Based on a comprehensive screening of
readily available Ir-catalysts, we recently identified another hydrogenation catalyst to have also an appreciable HIE
capacity, viz. the commercial, air-stable Burgess catalyst 5.[14] With this catalyst, we have developed the first practical
HIE protocol for selective ortho-deuteration of various secondary and tertiary sulfonamides as well as sulfonyl ureas.[15]
A similar reactivity was also observed for monodentate Kerr catalysts of the type [(COD)Ir(NHC)Cl] (3),[16] which proved
even more efficient in the HIE reaction of secondary sulfonamides and ureas, while 5 resulted in greater deuterium
incorporation for tertiary sulfonamides.[Error! Bookmark not defined.a] This method was also applied to sulfo drugs and even
adopted to the special conditions required for selective tritium labelling (5–10 eq. of T2 gas, low pressure). However, the
elevated temperatures of 100–120°C required to obtain reasonable deuterium incorporation still remains an important
limitation of this method.[Error! Bookmark not defined.]
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H
D
DG
H
[Ir], D2
DG
time, solvent
D
DG = directing group
monodentate Ir complexes utilized for HIE
Mes
R
Mes
Ir
N
N
R
Cl
PCy3
N
PR3
N
N
+
Ir
+
Ir
Mes
Mes
-
PF6
-
PF6
3 (Kerr)
2 (Kerr)
1 (Crabtree)
bidentate Ir complexes
N
N
O
O
+
N
O
Ph
N
P
Ir
N
iPr
R2P
N
+
Ir
N
+
Ir
iPr
BArF24
-
-
-
BArF24
BArF24
4 (Pfaltz)
6 (Tamm)
5 (Burgess)
Scheme 1: Mono- and bidentate Ir complexes utilized for HIE
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Recently, we have developed another C-H activation catalysts, [(tBuP,NMe)Ir(cod)]BArF24 (6), with bidentate P,N
ligands bearing the imidazolin-2-imine group[17] as an electron-rich nitrogen donor group.[18] In addition to the high HIE
reactivity for known directing groups such as acetyl, heterocycles, sulfones, nitro groups and benzyl amines, 6 proved to
be also highly active for H/D exchange of Boc-protected anilines, which had not been recognized previously as a
directing group for HIE. After optimization, even substrates with the weakly coordinating methoxy group showed a good
degree of deuteration.[Error! Bookmark not defined.] In continuous efforts to broaden our synthetic repertoire for fast tritium
labelling, we have further investigated the substrate scope of 6 in more detail and wish to report on expanded
applications of the new catalyst system 6.
Results and Discussion
We started to evaluate Tamm’s catalyst 6 in the HIE reaction of tertiary sulfonamide 7 in different solvents at room
temperature.
To our delight, we found high deuterium incorporation in chlorobenzene (Table 1). The catalytic HIE reaction with our
model substrate 7 was strongly influenced by the solvent. In most solvents, none or only poor deuterium exchange was
observed; however, high deuterium incorporation was found in chlorobenzene (entry 9). The strong influence of
chlorobenzene in HIE reactions has been observed earlier,[Error! Bookmark not defined.,Error! Bookmark not defined.] however the effect
is still lacking a full theoretical understanding.
Table 1: Solvent screening of catalyst 6 in the HIE reaction with tertiary sulfonamide 7.a
H
O
S
D
O
S
catalyst 6
N
N
O
O
N
N
D2
H
D
7
7a
Entry Solvent
%D 7ab
Yield 7ac [%]
1
2
3
4
5
6
7
8
9
dichloromethane
chloroform
MTBE
ethanol
cyclohexane
MeTHF
isopropylacetate
1-butanol
chlorobenzene
fluorobenzene
toluene
22
12
11
0
15
0
0
0
82
16
0
72
72
79
80
67
81
79
83
78
65
70
10
11
a
Conditions (repeated three times): substrate 7 (10 µmol, 2.5 mg), catalyst 6 (10 mol%), solvent (2 mL), D2 (1 atm), rt, 2 h . b Positions and
percentage of deuterium incorporation determined by 1H NMR. c Isolated yield.
In the next step, we tried to find optimized conditions for a subsequent broader substrate screening (Table 2). We
modified catalyst content and reaction time and found that generally 10 mol-% catalyst 6 are needed to obtain high
deuterium introduction for substrate 7 within two hours (entry 9). Even though higher excess of deuterium was used in
the optimization reactions, the deuteration reached a plateau after 30 min (entry 7) not proceeding significantly by
longer reaction times up to 6h (entry 10).
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Table 2: Optimization of catalyst content and reaction time in the HIE reaction of tertiary sulfonamide 7.a
Entry
1
2
3
4
5
6
7
Catalyst 6 [mol%]
Time [min]
300
300
120
5
%D 7ab
0
3
5
0
7,5
10
10
10
10
10
10
10
32
15
44
69
80
82
85
89
10
15
30
60
120
300
8
9
10
a Conditions (repeated two times): substrate 7 (10 µmol, 2.5 mg), catalyst 6, chlorobenzene (2 mL), D2 (1 atm), rt. b Positions and percentage of
deuterium incorporation determined by 1H NMR. c Isolated yield.
We then studied the HIE reaction of sulfobenzenes under the optimized reaction conditions (Scheme 2). Even though
for the the level of labelling achieved after 30 min was not significantly lower than after 120 min, we choosed a reaction
time of 2h for all further substrate screening to avoid any potential kinetic differences. The catalyst revealed high
reactivity and deuterium incorporation in the HIE reactions of primary, secondary and even tertiary sulfonamides. In the
case of the primary sulfonamide 8, catalyst 6 showed similar degree of deuteratium incorporation as compared to the
results reported by Kerr with catalyst 3 at room temperature, however with a higher amount of catalyst (10 mol%).[Error!
Bookmark not defined.]
Interestingly, with 6 secondary (9–11) and tertiary (12–15) sulfonamides underwent successful HIE
reactions at room temperature as well, which was achieved previously with catalysts 3 and 5 only at elevated
temperatures (> 80–120°C).[Error! Bookmark not defined.]
O
S
O
S
O
S
[88]
[92]
[69]
O
O
N
NH2
N
N
O
H
H
8, 83%
9, 80%
10, 75%
[92]
O
O
O
O
[82]
[85]
O
S
N
O
S
S
N
N
N
H
N
[86]
13, 76%
11, 88%
12, 87%
O
O
[86]
O
S
[43]
[89]
O
S
N
N
Cl
14, 73%
15, 82%
Scheme 2: HIE reactions of sulfobenzenes catalyzed by 6.a,b a) Conditions: substrate (22 µmol), catalyst 6 (10mol%),
chlorobenzene (2 mL), D2 (1atm), rt, 2 h. b) Positions and percentage of deuterium incorporation determined by 1H NMR and confirmed by LC-
MS isolated yields, all reactions have been repeated at least twice.
Next, we examined N-oxides as substrates for the directed HIE reaction with catalyst 6 (scheme 3). N-Oxides have
rarely been described as directing groups in HIE reactions,[19] which would in principle enable the labeling of pyridines or
quinolines after reductive cleavage of the N-O bond. This HIE approach can be convenient if direct labeling in the ortho-
positions of the heterocyclic nitrogen atom (Rh black, D2O[20] or THF-D2[21]) cannot be accomplished or if higher specific
activities in the case of tritium introduction are required.
In particular, the deuteration of the quinolone moiety in substrates 16–18 proceeded considerably well and selectively,
irrespective of other aromatic substituents. The 2- and 8-positions of 3-methylquinoline N-oxide 16 were deuterated in
73% and 100%, respectively. Similar results were obtained for 3-bromoquinoline N-oxide 17 and 6-methoxyquinoline N-
oxide 18 with deuterium incorporation in these positions higher than 80%. Interestingly, the level of deuterium
introduction dropped to approx. 50% at the 3-position in isoquinoline N-oxide 19 and in simple pyridine N-oxides 20 and
21. Since the 1-position of isoquinoline N-oxide 19 was still exchanged by deuterium in 93%, a significant electronic
effect can be considered as the steric differences between the 1- and 3-position are comparatively small.
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Br
O
N+
O
N+
O
N+
O
[73]
[96]
[94]
[100]
[83]
[96]
16, 72%
17, 77%
18, 81%
[54]
N+
N+
[46]
O
N+
O
[45]
O
[93]
19, 75%
20, 71%
21, 89%
Scheme 3: HIE reactions of N-oxides catalyzed by 6.a,b a) Conditions: substrate (5 µmol), catalyst 6 (10mol%), chlorobenzene (2
mL), D2 (1atm), rt, 2 h. b) Positions and percentage of deuterium incorporation determined by 1H NMR and confirmed by LC-MS, isolated yields,
all reactions have been repeated at least twice.
Furthermore, we have examined phosphonamides as they have never been applied in ortho-directed HIE reactions
before (Schema 4). To our great delight, we found good to excellent H/D exchange in the reaction of primary 22 (82%),
secondary 23 (70%), and tertiary phosphonamides 24–27 (60–99%).
O
P
O
O
P
[99]
[70]
[82]
P
N
N
NH2
HN
H
N
22, 89%
23, 99%
24, 67%
O
O
O
[99]
[99]
[60]
O
N
N
P
P
P
O
N
N
N
N
O
O
25, 99%
26, 70%
27, 71%
Scheme 4: HIE reactions of phosphonamides catalyzed by 6.a,b
a) Conditions: substrate (10 µmol), catalyst 6 (10mol%), chlorobenzene (1 mL), D2 (1atm), rt, 2 h. b) Positions and percentage of deuterium
incorporation determined by 1H NMR and confirmed by LC-MS, isolated yields, all reactions have been repeated at least twice.
Conclusion
We have extended the use of the newly discovered catalyst 6 by evaluation of the HIE reaction with sulfonamides, N-
oxides and phosphonamides under mild reaction conditions. The results emphasize the usefulness of this air-stable
catalyst and, in the case of sulfonamides, it seems to be more active than other commercially available iridium catalysts.
Experimental Section
General: All substrates and solvents were obtained from commercial suppliers and used without further purification, except for
the phosphonamides 23-27 (the preparation is described in the supporting information). Catalyst 6 was synthesized according
to procedures reported earlier.[Error! Bookmark not defined.] All labelling reactions were carried out on Radleys Synthesis station for
parallel solution phase chemistry. Flash column chromatography was carried out using Merck kieselgel 60 silica gel (particle
size: 63-200). The level and regioselectivity of deuterium incorporation in the substrate was determined by 1H-NMR. 1H (300, 500
MHz) and 13C (75, 125 MHz) NMR spectra were obtained on Bruker spectrometers in the solvents indicated. Chemical shifts
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are reported in ppm. Coupling constants are reported in Hz and refer to 3J H-H couplings, unless otherwise stated. The
distribution of hydrogen isotopes in the products was determined by a liquid chromatography-mass spectrometry (LC-MS)
system with a Symmetry Shield RP18 column, 3.9 x 150 mm, with a gradient program. LC column conditions were as follows:
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 rate: 0.6 mL/min; Detection: UV 254 nm and UV 210 nm.
General deuteration procedure: To a carousel tube was added the substrate of choice (10 µmol, unless otherwise stated) in solution
(500 µL) and iridium(I) catalyst (1.5 mg, 1.0 µmol, 10mol%, unless otherwise stated) in solution (500 µL) under air. The desired solvent
(1 mL) was added unless otherwise stated, rinsing the inner walls of the tube. The tube was sealed. The flask was evacuated and
flushed with deuterium via a balloon three times. After sealing the flask, the reaction was started and a red to clear/yellow colour change
was observed. The reaction mixture was stirred for 2 h at room temperature. To the solution was added 1 mL dichloromethane and the
mixture was transferred into a flask. The solvent was evaporated in vacuo. The residue was purified by chromatography with
MTBE/ethylacetate (4/1) or DCM/MeOH (95/5), depending on the substrate polarity. The product was analyzed by LC-MS and 1H-NMR.
The level and regioselectivity of deuterium incorporation in the substrate was determined by 1H-NMR. The integrals were calibrated
against a peak corresponding to a position not expected to be labelled.
Acknowledgements
Mégane Valero is participant in the EU Isotopics consortium. The ISOTOPICS project has received funding from the
European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant
agreement N°675071. Furthermore we would like to thank Dr. Martin Sandvoss for analytical support.
Keywords: hydrogen isotope exchange; iridium, deuterium, catalysis
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Entry for the Table of Contents
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We have developed an efficient
iridium-catalyzed hydrogen isotope
exchange (HIE) reaction method with
secondary and tertiary sulfonamides
at ambient temperatures applying a
recently discovered P,N-ligated
iridium catalyst. Furthermore N-
oxides and phosphonamides have
been successfully applied in HIE
reactions with moderate to excellent
deuterium introduction.
Mégane Valero, Annina Burhop, Kristof
Jess, Remo Weck, Matthias Tamm*,
Jens Atzrodt* and Volker Derdau*
H
D
DG
H
[Ir], D2
DG
time, solvent
D
DG = directing group
Page No. – Page No.
sulphonamides: 8 examples
phosphonamides: 6 examples
N-Oxides: 5 examples
N
N
N
P
[Ir] =
Evaluation of a P,N-Ligated
+
Ir
Iridium(I) Catalyst in Hydrogen
Isotope Exchange Reactions of Aryl
and Heteroaryl Compounds
up to 99% deuterium incorporation
high regioselectivity
-
BArF24
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