Burgess iridium(I)-catalyst for selective hydrogen isotope exchange

Article abstract of DOI:10.1002/jlcr.3512

We have evaluated the commercially available Burgess catalyst in hydrogen isotope exchange reactions with several substrates bearing different directing group functionalities and have obtained moderate to high (50%-97%D) deuterium incorporations. The broa

Full text of DOI:10.1002/jlcr.3512

Burgess Iridium(I)-Catalyst for selective Hydrogen Isotope Exchange
Annina Burhop, Raphail Prohaska, Remo Weck, Jens Atzrodt* and Volker Derdau*
Sanofi-Aventis Deutschland GmbH, Integrated Drug Discovery, Med. Chem., Isotope Chemistry &
Metabolite Synthesis, Industriepark Höchst, G876, 65926 Frankfurt, Germany; Correspondence to
Jens.Atzrodt@sanofi.com or Volker.Derdau@sanofi.com
Abstract
We have evaluated the commercially available Burgess catalyst in Hydrogen Isotope Exchange
(HIE) reactions with several substrates bearing different directing group functionalities and have
obtained moderate to high (50-97%D) deuterium incorporations. The broad applicability in HIE
reactions makes the Burgess catalyst a possible alternative compared to other commercially
available iridium(I)catalysts.
Keywords: hydrogen isotope exchange, CH-activation, deuterium, Burgess catalyst
Introduction
Hydrogen isotope exchange (HIE)[1] is widely utilized for selective installation of C–D[2] or C–T[3] bonds
in organic molecules. The HIE approach enables a direct incorporation of deuterium or tritium into
the desired target molecule and thus circumvents the need for additional synthetic steps (e.g.
precursor synthesis or multi-step routes from isotopically labelled building blocks).[4]
Homogeneous iridium(I) catalysts[5] have proved to be highly efficient for selective label introduction
at the ortho-position next to
a directing group, with commercial Crabtree’s catalyst
[(COD)Ir(PPh3)(py)]PF6 1[6] and Kerr’s catalysts [(COD)Ir(IMes)(PR3)]PF6 2[7] being the most prominent
such catalysts applied today (scheme 1). Both catalysts utilize molecular hydrogen isotopes (D2/T2)
which is especially beneficial for selective tritium labelling[8] because T2 is a convenient tritium
source.[9] In particular, Kerr’s catalysts can be used under very mild reaction conditions at room
temperature for selective labeling of a broad range of substrates with different directing groups,
including e.g. ketones, amides, esters, aldehydes, primary sulfonamides, and several heterocycles.[10]
Despite recent progress, a number of interesting functionalities found ubiquitously throughout drug
motifs still present significant challenges for established HIE protocols.
Some of these limitations have been recently overcome by the introduction of a new generation of
Ir-catalysts with bidentate P,N or NHC,N ligand structure. An early example was reported by Pfaltz et
al. which utilized the non-commercial hydrogenation phosphine-oxazoline P,N catalyst 4 in the HIE
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reaction of different functionalities including more challenging sulfones and sec. sulfonamides.[11]
Another new class of bidentate iridium(I) catalysts with phenylene-bridged hybrid phosphine-
imidazolin-2-imine P,N ligands has been recently introduced by Tamm.[12] Tamm’s catalyst 5 showed
remarkable performance with a broad range of known directing groups, and even promoted
selective H/D exchange at aromatic Boc-protected amines, benzyl amines and methoxy derivatives,
which had not been recognized previously as directing groups for ortho selective HIE.[12]
H
D
DG
[Ir], D2
DG
time, solvent
H
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
1 (Crabtree)
3 (Kerr)
2 (Kerr)
bidentate Ir complexes (2nd. Generation)
R'
N
O
N
O
N
PR2
R2P
N
O
+
+
Ir
N
+
Ir
N
Ir
N
iPr
Ph
R'
-
iPr
BArF24
-
BArF24
BArF24
-
4 (Pfaltz)
5 (Tamm)
6 (Burgess)
Scheme 1: mono- and bidentate Ir complexes utilized for HIE.
Based on a comprehensive screening of readily available Ir-catalysts, we recently identified another
bidentate hydrogenation catalyst that displays a remarkable HIE capacity - the commercially
available, air stable Burgess catalyst 6.[13] Burgess catalyst 6 was initially developed for asymmetric
hydrogenation of olefins but hasn’t been applied for HIE before.[14] However, with this catalyst we
were able to develop the first practical HIE protocol for selective ortho-deuteration of various
secondary and tertiary sulfonamides, as well as for sulfonyl ureas.[15] A similar reactivity was found
for the mono-dentate Kerr catalyst of type [(COD)Ir(NHC)Cl] 3.[15,16] The method can be applied to
sulfa drugs and even adopted to the special conditions required for selective tritium labelling. Based
on these exciting results we became interested in investigating 6 further as a potential new catalyst
for ortho selective HIE. Thus, here we would like to report initial results evaluating the scope and
limitation of Burgess catalyst 6 in HIE reactions with different types of directing groups.
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Results and discussion
We started our studies with a solvent screen of three model compounds, 4-phenylacetophenone 7,
2-phenylimidazole 8 and 1-naphthylamine 9 in a HIE reaction with Burgess catalyst 6 at room
temperature (table 1). 4-phenylacetophenone 7 and 2-phenylimidazole 8 were selected as model
substrates due to their different polarity/basicity and because both are known to work well in the
HIE reaction with Kerr catalyst 2. In contrast 1-naphthylamine 9 was selected because aromatic
amines represent a much more challenging functionality for HIE reactions and have been
successfully labelled only utilizing iridium dionates.[17] In an initial solvent screen (table 1), catalyst 6
showed a very good performance in the HIE reaction with both model substrates 7 and 8 at room
temperature in a broad range of different solvents. Only 2-methyltetrahydrofuran (entry 5),[18]
alcohols (entry 3 and 9) or fluorobenzene (entry 6) resulted in considerable lower deuterium
incorporations in substrates 7 or 8. Good deuterium incorporations for 1-naphthylamine 9
(selectively in the peri-position)[19] were only observed in dichloromethane and MTBE. As the highest
deuterium introduction efficiency of the model substrates was found in dichloromethane[7b] we
decided to test all following reaction in this solvent.
Table 1:
Solvent screening of the HIE reaction of 4-phenylacetophenone 7, 2-phenylimidazole 8
and 1-naphthylamine 9 with Burgess catalyst 6 in different solvents.a,b
D
O
D
NH2
N
N
D
D
D
7
8
9
Entry
Solvent
7
%Db
8
%Db
9
%Db
1
2
3
4
5
6
7
8
9
dichloromethane
MTBE
ethanol
cyclohexane
2-MeTHF
fluorobenzene
isopropylacetate
methylcyclohexane
1-butanol
toluene
chlorobenzene
96
89
18
82
9
16
83
88
12
97
85
91
95
80
87
6
88
70
91
78
54
73
81
70
22
16
13
18
41
15
22
24
33
10
11
aConditions: substrate 7, 8 or 9 (25 µmol), Burgess catalyst 6 (10 mol%), solvent (2 mL), D2 (1 atm), rt 2h;
bpercentage of deuterium incorporation determined by LC-MS; position of deuterium determined by 1H-
NMR.
Next we optimized the catalyst loading required to obtain deuterium incorporations in the model
reactions with 6 (table 2). While for ketone 7 a catalyst loading of 3 mol% was already sufficient to
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obtain >90%D, for imidazole 8 and 1-naphylamine 9 at least 10 mol% of 6 were needed to obtain
similar incorporation levels (room temperature, 2h).
Table 2 Screening of catalyst amount in the HIE reaction of 4-phenylacetophenone 7, 2-
phenylimidazole 8 and 1-naphthylamine 9 with Burgess catalyst 6 in dichloromethane.a,b
Catalyst
(mol%)
6
Entry
7
%Db
51
93
95
96
96
8
%Db
9
%Db
1
2
3
4
5
1
3
5
7
10
5
11
49
80
91
10
12
19
22
78
aConditions: substrate 7, 8 and 9 (25 µmol), Burgess catalyst 6, dichloromethane (2 mL), D2 (1atm), rt, 2h.
bpercentage of deuterium incorporation determined by LC-MS.
Because of the strong influence of the catalyst loading observed in the HIE reaction of 8, we
conducted a kinetic study in order to investigate the influence of the reaction time (scheme 2). In a
series of HIE reactions, 8 was treated either with 5 or 10 mol% of 6. The reactions were stopped
after certain time points and the deuterium incorporation was measured by LC-MS. The resulting
time/conversion curves depicted in scheme 2 revealed a much faster reaction with 10 mol% of 6,
with the final deuteration grade achieved after 30 min. In contrast, with a 5 mol% catalyst loading
the reaction proceeded much slower and took 5h to yield 90%D. From this experiment we
concluded that a catalyst loading of 10 mol% of 6 and a reaction time of 2h might be a good
compromise for a standard screening protocol when testing new substrates.
Scheme 2: Time /conversion curve for HIE reaction of 8 with catalyst 6 at room temperature.20
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Table 3
Tolerability testing in the HIE reaction of 4-phenylacetophenone 7 and 2-
phenylimidazole 8 with Burgess catalyst 6 with several additives.a,b
%D
(1 eq Add.)
7
%D
(10 eq Add.)
7
%D
(1 eq Add.)
8
%D 8
(10 eq Add.)
Entry
Additive
1
2
3
4
5
6
7
8
-
96
93
95
92
95
43
11
95
96
94
95
14
95
44
12
93
91
95
95
93
90
92
90
95
91
95
92
10
92
16
48
45
water
ethanol
HCl (1N)
NaOH (1N)
NEt3
acetonitrile
TSA
aConditions: 4-phenylacetophenone 7 or 2-phenylimidazole 8 (12,5 µmol), Burgess catalyst 6 (0,125 µmol),
b
dichloromethane (1 mL), D2 (1atm), rt, 2h. percentage of deuterium incorporation determined by LC-MS;
TSA = toluene sulphonic acid
Furthermore we examined the tolerability of Burgess catalyzed HIE reactions with 7 and 8 towards
several additives. Interestingly, the reaction was not influenced by addition of 1 or 10 eq. of water or
ethanol (table 3, entry 2 and 3). While 1 eq. or 10 eq of HCl (entry 4) had significant effects in the HIE
reaction of both compounds, even 10 eq. of 1N sodium hydroxide (entry 5) had no influence on the
deuteration result. The addition of 1 or 10 eq. of an organic base like triethylamine (entry 6) changed
the outcome dramatically, however not in the same way for both compounds. Surprisingly the effect
of acetonitrile differed between compound 7 and 8 (entry 7). While only 1 eq. of acetonitrile
inactivated the catalyst in the reaction with ketone 7, with imidazole 8 the HIE reaction worked well.
However, the deuteration of 8 was also decreased in the presence of 10 eq. of acetonitrile to 48%D.
With toluene sulphonic acid (TSA) there was no effect in the HIE reaction with compound 7, however
a significant decrease of deuteration was observed with 10 eq. of TSA for compound 8 (entry 8).
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O
N
N
[95]
N
O
[90]
H
N
N
O
[90]
[90]
[91]
H
10
11
12
13
14
O
OH
[72]
O
N
NO2
[86]
O
N
S
[85]
[50]
N
O
O
15
16
17
18
O
O
S
O
[52]
O
S
[60]
[57]
[55]
S
S
NH2
NH2
O
O
19
21
22
20
a
Scheme 3: Substrate evaluation of HIE reaction with Burgess catalyst 6, Conditions: substrate
(12,5 µmol), Burgess catalyst 6 (0,125 µmol), dichloromethane (1 mL), D2 (1atm), rt, 2h.
bpercentage of deuterium incorporation determined by 1H-NMR.
The Burgess catalyzed HIE reaction worked well to give deuterium levels above 90% with aromatic
substrates containing ketone (7), imidazole (8), aldehyde (10), N-acyl (11), pyridine (12), pyrazine
(13) or oxazole (14) moieties as directing groups (scheme 3). Reasonable to moderate
hydrogen/deuterium exchange (50-86 %D) was found in reactions with amine (9), nitro (15), amide
(16, 17) and carboxylic acid (18) functions. For sulfobenzenes, e.g. sulfoxide (19), sulfone (20),
primary sulfonamide (21) and sulfonbenzamide (22) a moderate deuterium incorporation level was
also observed, with deuterium levels between 50-60%D. These results demonstrate the broad
applicability of the Burgess catalyst 6 in HIE reactions.[15, 21]
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+
-
BARF
Ar = iPr2Ph
N
O
N
N
Ir
Ar
1-Ad
6
3 D2, DCM
COD-d4
D
X
H
X
R
R
N
D
O
N
N
Ir
2 DCM
1-Ad
DCM
DCM
Ar
2 DCM
D
N
N
A
H
O
D
N
Ir
N
O
N
Ir
N
1-Ad
R
Ar
1-Ad
R
D
X
Ar
D
X
D
H
E
B
In equilibrium with
D2 (gaseous)
H
D
D
D
N
H
D
O
N
N
D
D
N
Ir
O
N
1-Ad
N
Ir
Ar
D
X
1-Ad
Ar
H
X
R
D
R
C
Scheme 4: Plausible mechanism of HIE catalyzed by 6.
According to the mechanism recently discussed by Kerr[16] the directed HIE reaction is started by
hydrogenation of the COD moiety (scheme 4). The free positions in the active iridium complex A are
proposed to be solvent and deuterium. The substrate displaces the solvent and coordination of the
iridium takes place at the heteroatoms of the directing group (B). Next, the metal inserts into the
CH-bond by a sigma-complex assisted metathesis process and the hydrogen atom is bound in the
coordination sphere of the iridium(III) metal (C). Between complexes C and D there are several
equilibria steps wherein H-D and D-D bonds are exchanged and exchange with the gaseous
deuterium depot is possible. In the reductive elimination step a deuterium atom is transferred to the
sp2-carbon (E). Finally the substrate is eliminated from the iridium complex and substituted by two
solvent molecules (A).
Conclusion
In summary, we have evaluated the commercial Burgess catalyst 6 in HIE reactions and obtained
moderate to high (50-97%D) deuterium incorporations using several directing group functionalities.
Its broad applicability in HIE reactions makes the Burgess catalyst 6 a possible alternative to
commonly used Crabtree’s 1 or Kerr’s 2 and thus it may complement the synthetic repertoire for fast
tritium labelling in the future.
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Acknowledgement
We would like to thank Gerald Scholz for analytical support and Dr. Seth Jones for proof reading the
manuscript.
Experimental Section
General
1H spectra were obtained on Bruker Avance 300 spectrometers in d6-DMSO. The chemical shifts (δ)
are expressed in ppm and are given relative to the residual proton signal of dmso-d6 (δ 2.50 ppm).
1
NMR assignments were made using additional 2D NMR experiments. The H NMR spectra listed
below show sequential the substrate before reaction, 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 an LC-MS system with a Symmetry Shield RP18 column,
3.9x150 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 nm and UV 210 nm.
General method: All screening methods were performed in a Heidolph synthesis 1 station. A vial (25
mL) was equipped with a stirring bar and the substrate stock solution (500 μL, 20 mM, 1 eq.). The
catalyst (10 mol-%) and the solvent (1.5 mL) were added and the vial was sealed. Then the vial was
evacuated until slight bubbling of the solution and refilled with deuterium gas from a balloon. This
procedure was repeated three times. The reaction was shaken under D2 atmosphere (1 atm) at room
temperature for 2 h. The crude reaction mixture was purified by silica gel chromatography
(MTBE/ethylacetate, 4/1) and analyzed by LCMS and 1H-NMR.
(for further details and NMR results see supporting information)
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18 We propose that 2-MeTHF coordinates to the iridium catalyst in competition to the substrate. In
comparison to MTBE the coordination seems to be much stronger as demonstrated by deuterium
introduction of <20% with model compounds 7,8 and 9.
19 The transition state seems to work only in a five membered ring iridium-arene complex (for the peri
position) and not via a four-membered ring necessary to exchange the hydrogen in the 2-position of 1-
naphthylamine 9.
20 A faster and more efficient deuterium exchange was observed in the kinetic study as compared to the
screening results in table 2 under similar conditions (entry 3 after 2 h). The reason for this small
discrepancy may be a different experimental set-up with Heidolph parallel Synthesizer (with shacking)
utilized for all screening reactions in contrast to the kinetic studies performed in a 50 mL flask with stirring.
21 We did not observe deuterium pressure dependency in any of our performed iridium-catalyzed HIE
reactions.
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