Hydrogen Isotope Exchange with Iridium(I) Complexes Supported by Phosphine-Imidazolin-2-imine P,N Ligands

Article abstract of DOI:10.1002/adsc.201601291

Phenylene-bridged hybrid phosphine-imidazolin-2-imine^RP,N^R′ligands (R=Ph, Cy, i-Pr, t-Bu; R′=Me, i-Pr) were prepared from 1,2-dibromobenzene by palladium-catalyzed C–N coupling with 1,3,4,5-tetramethylimidazolin-2-imine or 1,3-diisopropyl-4,5-dimethylimidazolin-2-imine, followed by lithiation with tert-butyllithium and reaction with the chlorophosphines (R₂PCl). Their reaction with the dimeric iridium complex [Ir(cod)Cl]₂(cod=1,5-cyclooctadiene) and subsequent anion exchange with sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBArF₂₄) or potassium hexafluorophosphate (KPF₆) afforded iridium complexes of the type [(^RP,N^R′)Ir(cod)]BArF₂₄or [(^RP,N^R′)Ir(cod)]PF₆, respectively. The latter PF₆salts were structurally characterized, revealing short Ir—N bonds as an indication of electron-rich nitrogen donor atoms. The former complexes were tested for their applicability in catalytic H/D exchange. In particular, the complex with the ligand^t-BuP,N^Meshowed remarkable performance in H/D exchange with a broad range of aromatic substrates, including ketones, amides, esters, heterocycles and nitro compounds, and also promoted H/D exchange at aromatic Boc-protected amines, benzylamines and methoxy derivatives. (Figure presented.).

Full text of DOI:10.1002/adsc.201601291

FULL PAPERS
DOI: 10.1002/adsc.201601291
Hydrogen Isotope Exchange with Iridium(I) Complexes
Supported by Phosphine-Imidazolin-2-imine P,N Ligands
Kristof Jess,a Volker Derdau,b,* Remo Weck,b Jens Atzrodt,b Matthias Freytag,a
Peter G. Jones,a and Matthias Tamma,*
a
Institut fꢀr Anorganische und Analytische Chemie, Technische Universitꢁt Braunschweig, Hagenring 30, 38106
Braunschweig, Germany
Fax : (+49)-531-391-5387; e-mail: m.tamm@tu-bs.de
Sanofi, R&D, Integrated Drug Discovery, Med. Chem., Isotope Chemistry & Metabolite Synthesis, Industriepark Hçchst,
b
65926 Frankfurt am Main, Germany
E-mail: Volker.Derdau@sanofi.com
Received: November 21, 2016; Revised: December 22, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201601291.
Abstract: Phenylene-bridged hybrid phosphine-imi- acterized, revealing short Ir—N bonds as an indica-
R
dazolin-2-imine P, NR’ ligands (R=Ph, Cy, i-Pr, t-Bu; tion of electron-rich nitrogen donor atoms. The
R’=Me, i-Pr) were prepared from 1,2-dibromoben- former complexes were tested for their applicability
zene by palladium-catalyzed C–N coupling with in catalytic H/D exchange. In particular, the complex
1,3,4,5-tetramethylimidazolin-2-imine or 1,3-diiso- with the ligand t-BuP, NMe showed remarkable per-
propyl-4,5-dimethylimidazolin-2-imine, followed by formance in H/D exchange with a broad range of ar-
lithiation with tert-butyllithium and reaction with the omatic substrates, including ketones, amides, esters,
chlorophosphines (R2PCl). Their reaction with the heterocycles and nitro compounds, and also promot-
dimeric iridium complex [Ir(cod)Cl]2 (cod=1,5-cy- ed H/D exchange at aromatic Boc-protected amines,
clooctadiene) and subsequent anion exchange with benzylamines and methoxy derivatives.
sodium
tetrakis[3,5-bis(trifluoromethyl)phenyl]bo-
rate (NaBArF24) or potassium hexafluorophosphate
(KPF6) afforded iridium complexes of the type Keywords: deuterium labelling; homogeneous cataly-
[(RP, NR’)Ir(cod)]BArF24 or [(RP, NR’)Ir(cod)]PF6, re- sis; hydrogen isotope exchange; imidazolin-2-imines;
spectively. The latter PF6 salts were structurally char- iridium catalysis; isotopes; N,P ligands
Introduction
ADME profiling[39–42] of new drug candidates
(ADME=absorption, distribution, metabolism and
Hydrogen isotope exchange (HIE) allows the direct excretion). Homogeneous iridium catalysts have
substitution of hydrogen by its isotopes (deuterium proved to be highly efficient for selective label intro-
and tritium) at the target molecule itself and thus cir- duction at the ortho-position[22,23,43–45] next to a direct-
cumvents the need for additional chemical synthesis ing group, with commercial Crabtreeꢂs catalyst
[46,47]
steps (e.g., precursor synthesis or stepwise prepara- [(cod)Ir(PCy3)(py)]PF6
(A, Figure 1) and Kerrꢂs
[48–52]
tion from isotopically enriched starting materials).[1] catalysts [(cod)Ir(IMes)(PR3)]PF6
(B) being the
Thus, HIE is commonly employed to insert deuterium most prominent catalysts applied today. These cata-
(D) atoms into pharmaceutical drug candidates for lysts allow for HIE with molecular hydrogen isotopes
use as internal standards for mass spectrometry,[2–6] (D2/T2) according to Figure 1, which is beneficial es-
for kinetic isotope studies,[7–12] and for alteration of re- pecially for the incorporation of tritium, for which T2
action pathways in total syntheses.[13–15] Additionally, is a very convenient source.[18] In particular, Kerrꢂs
tritium (T)[16–18] atoms can be incorporated by HIE la- catalysts can be used under very mild reaction condi-
belling[19–22] to provide radioactive tritium tracers, tions at room temperature for selective labelling of
which are important drug discovery tools[23–25] for, a broad range of substrates with different directing
e.g., radio
ACHTUNGTRENNUNGliACHTUNGTRENNUNG
gand,[26–29] protein[30,31] and covalent[32] groups, including, for example, ketones, amides,
binding assays, for photoaffinity labelling[33–38] and for esters, heterocycles and primary sulfonamides.[53–55] To
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Scheme 1. Resonance structures 1A and 1B of RP, NR’ Ligands
with an imidazolin-2-imine unit (left) and iridium complexes
of type 2 (right).
imine moiety at the metal atom might lead to metal-
ligand cooperation in bond activation processes,[80] for
example, by heterolytic dihydrogen cleavage. Herein,
we present the synthesis of P,N-ligand-decorated iridi-
Figure 1. Top : General iridium-catalyzed HIE reaction.
Bottom: Active iridium complexes for HIE.
the best of our knowledge, however, there is no gen- um complexes [(RP, NR’)Ir(cod)]X {X=PF6, BArF24,
eral HIE method known to label Boc-protected BArF24 =tetrakis[3,5-bis(trifluoromethyl)phenyl]bo-
(Boc=tert-butyloxycarbonyl) arylamines or aryl rate}; the latter complexes were employed as catalysts
ethers selectively at the ortho-positions.
for HIE reactions with several aryl substrates.
Recently, Pfaltz and Muri also investigated the HIE
capacity of cationic iridium complexes of type C, with
phosphine-oxazoline and -imidazoline P,N ligands Results and Discussion
(Figure 1).[56] Although originally developed for asym-
metric hydrogenation of olefins,[57,58] these catalysts Synthesis and Characterization of Ligands and
proved efficient in the HIE reaction of a wide range Complexes
of substrates. The authors found electron-rich phos-
R
phorus groups such as dicyclohexylphosphines or For the synthesis of the desired P, NR’ ligands, a route
phosphonites to be especially beneficial in promoting starting from the known imidazolin-2-imines 3a and
H/D exchange. Stimulated by these results, we aimed 3b[79] was chosen. The first step is a palladium-cata-
at combining the known imidazolin-2-imine motif[59] lyzed C–N coupling reaction according to Buchwald
with phosphines to form a new class of P,N ligands and Hartwig,[81,82] attaching 3a or 3b to o-dibromoben-
with electron-rich nitrogen atoms. Imidazolin-2- zene with bis[(2-diphenylphosphino)phenyl] ether
imines are a subclass of guanidines, which are of con- (DPEPhos) as ligand and KO-t-Bu as base
siderable interest as ligands in transition metal (Scheme 2).[83] Within 5 hours, the desired coupling
chemistry[59–63] or in the field of organic synthesis.[64–66] products 4a or 4b formed, which were isolated as off-
Ligands with this functional group generally act as ef- white powders after removal of toluene, aqueous
ficient electron-donor ligands towards transition work-up with diethyl ether and recrystallization from
metals because of an effective charge delocalization n-hexane/toluene mixtures.
R
within the guanidine CN3 unit, which leads to en-
For the synthesis of the P, NR’ ligands 1, the bromo
hanced basicity and nucleophilicity.[64] Bidentate eth- precursors 4a and 4b were lithiated with tert-butyl-
ylene-[67–71] or ferrocene-bridged[72,73] and tridentate lithium and subsequently converted to the desired li-
pyridine-bridged[74–76] bis(imidazolin-2-imine) ligands gands by addition of R2PCl (R=Ph, Cy, i-Pr, t-Bu,
have already been used in organometallic and coordi- Table 1). Work-up involved extraction (1a/e: water/
nation chemistry.
CH2Cl2; 1b–d/f–h: water/toluene) under inert gas. Re-
In Scheme 1, the general structure of hybrid phos-
R
phine-imine P, NR’ ligands of type 1 is presented (R=
Ph, Cy, i-Pr, t-Bu; R’=Me, i-Pr), in which a soft phos-
phine is combined with a hard and electron-rich N
donor site. Resonance structure 1B illustrates the pos-
sibility of extensive electron donation towards transi-
tion metals, a consequence of the ability of the imida-
zolium moiety to effectively stabilize a positive
charge.[77–79] The target iridium complexes of type 2
are also presented in Scheme 1. It should be noted
Scheme 2. Synthesis of bromide species 4a and 4b via C–N
coupling reaction. Reaction conditions: 1 mol% Pd(OAc)2,
1.5 mol% DPEPhos, 2.4 equiv. KO-t-Bu, toluene, 808C, 5
that the presence of a basic amido-type imidazolin-2- hours. Yields: 74% (4a), 80% (4b).
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R
Table 1. Synthesis of P, NR’ ligands 1a–h.
R’
Me
i-Pr
R
Ph
Cy
i-Pr
t-Bu
Ph
Cy
i-Pr
t-Bu
Complex
1a
75
ꢀ11.6
1b
79
ꢀ2.0
1c
1d
70
16.4
1e
71
ꢀ11.8
1f
71
ꢀ0.7
1g
1h
72
16.6
Yield [%]
93[b]
6.2
91[b]
7.8
31P [ppm][a]
[a]
NMR spectroscopic values obtained in C6D6 at room temperature.
An oil was obtained; no purification after work-up.
[b]
action and isolation of the ligands was easiest for 1a/ larization and charge delocalization within the CN3
b/e/f, with R=Ph or Cy, first because the reactions unit, as expressed by resonance structure 1B
were selective and secondly because the low solubility (Scheme 1).[84,85] Accordingly, the C1–N1 bond lengths
of the products allows facile removal of impurities by are significantly longer compared to related imine li-
washing with n-hexane to obtain white solids. In the gands,[69,74,76,79] which can be ascribed to the considera-
case of 1c and 1g (R=i-Pr), the reactions were also ble deviation of the imidazolin-2-imine moiety from
comparably selective, but their isolation was more dif- a coplanar arrangement, as indicated by Nendo–C1–
ficult, since the products were obtained as oils, which N1–C8 torsion angles of ca. 40–458.
eventually crystallized within a few days or weeks.
For the preparation of the iridium(I) complexes of
Washing with, or recrystallization from, n-hexane, type 2, the P,N ligands 1a–h were added to CH2Cl2
proved unsuccessful for the purification of 1c and 1g solutions of [Ir(cod)Cl]2. Subsequent treatment with
or to obtain solid products. Nevertheless, the purity of NaBArF24
yielded
the
desired
complexes
the oils was high enough for further reactions. In the [(RP, NR’)Ir(cod)]BArF24 (2a–h), which were purified
case of 1d and 1h (R=t-Bu) the reactions were not as by column chromatography (Table 2). The yields
selective, according to the 31P NMR spectra of the ranged from 71 to 79% (for 2a–d, R’=Me) and from
crude reaction mixtures after work-up. Moreover, pu- 81 to 94% (for 2e–h, R’=i-Pr). In the solid state, the
rification was only possible by crystallization from n- complexes were reasonably stable towards air and
hexane, which afforded only a small amount of pure moisture, except for complexes 2a and 2e (R=Ph),
material (ca. 50%). Crystallization from the mother which were found to be slightly air-sensitive. Upon
liquors led to slightly impure products. Nevertheless, coordination, the 31P NMR signals show the expected
these fractions could be used for further reactions, shift to lower field. For the N-isopropyl derivatives
with a 10–20% decrease in yield in the next step.
2e–h, P,N coordination to the iridium atom and hin-
The 31P NMR spectra of all phosphine-imines 1 ex- dered rotation around the N–Cimine bond affords two
hibit one signal in the expected range. In the doublets or two singlets for the diastereotopic i-Pr
1H NMR spectra of the N-methyl derivatives 1a–d, methyl groups in the H and 13C NMR spectra, re-
1
two sharp singlets are observed for the two different spectively. After recrystallization, complexes 2b and
types of methyl groups, indicating fast rotation 2c were isolated as crystals suitable for X-ray diffrac-
around the N–Cimine bond on the NMR time scale. Ac-
cordingly, only one broad doublet (for 1f and 1g) or
one broad signal (for 1e and 1h) are found for the i-
Pr methyl groups in the N-isopropyl derivatives. Crys-
tals suitable for X-ray diffraction analysis were ob-
tained for the compounds 1a, 1b and 1d; selected
structural data are assembled in the Supporting Infor-
mation, Table S1. As one representative, the molecu-
lar structure of t-BuP, NMe (1d) is shown in Figure 2. As
expected, the exocyclic C–N bonds (a: C1–N1) are
shorter than the endocyclic bonds (b: C1–N2, c: C1–
N3), however, the structural parameter 1=2a/(b+c)
of 0.96 for all three ligands (Supporting Information,
Figure 2. Molecular structure of 1d with thermal displace-
ment parameters drawn at 50% probability. Hydrogen
atoms omitted. Selected bond distances and angles are as-
Table S1) reveals a comparatively large degree of po- sembled in the Supporting Information, Table S1.
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Table 2. Synthesis of iridium complexes 2a–l.
ꢀ
ꢀ
A-
R’
R
BArF24
PF6
Me
Me
i-Pr
i-Pr
i-Pr
Ph
Cy
t-Bu
Ph
Cy
t-Bu
Ph
Cy
i-Pr
t-Bu
Complex
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
Yield [%]
76
29.7
79
34.6
71
72
54.9
86
30.1
86
34.7
81
42.3
94
60
29.4
77
34.2
77
41.7
81
54.6
31P [ppm][a]
43.4[b]
56.8[b]
[a]
[b]
NMR spectroscopic values obtained in CDCl3 at roomt temperature, except for those indicated with
In (CD3)2CO.
.
[b]
tion analysis. However, both compounds 2b and 2c almost perpendicular orientation of the imidazole
displayed serious disorder, not just of the BArF24 plane towards the metal coordination sphere. The iri-
counter-ion (see Figures S3 and S4 in the Supporting dium atoms reside in distorted square-planar environ-
Information).
ments, with N1–Ir–P1 angles of 81–828, which com-
Therefore, the corresponding PF6 salts 2i–l were pare well with some structurally characterized iridium
synthesized in order to obtain more reliable structural complexes with phosphine-oxazoline ligands, with
data, which are assembled in the Supporting Informa- values from 84.4[86] to 89.28.[87] The Ir–P bond lengths
tion, Table S1. As one representative, the molecular were found to increase with increasing steric bulk
structure of 2l is shown in Figure 3. It is noteworthy from 2.2688(11) to 2.3498(8) ꢄ (t-Bu>Cy>i-Pr>
that the complexes 2i–2l show significantly longer Ph). Compared to other Ir(cod) complexes with P,N
N1–C1 bond lengths of 1.365(5)–1.379(4) ꢄ in com- ligands,[86,88,89] the Ir–N1 bond lengths of 2.049(3)–
parison with the free ligands 1a–d, i.e., 1.3082(19)– 2.0606(18) ꢄ are short, revealing again the strong
1.3146(16) ꢄ, which is accompanied by a decrease of electron-donating ability of the imidazolin-2-imine
the endocyclic C1–N2 and C1–N3 bond lengths. The moiety.[59] A marked trans influence of the phospho-
resulting structural parameter 1 of 1.02–1.03 in the rus atom is reflected by noticeably longer Ir–Ccod
complexes 2i–l points to a higher degree of polariza- bond lengths, viz. 2.167(4)–2.227(4) ꢄ (trans) versus
tion of the C1–N1 bonds upon metal complexation. 2.107(4)–2.145(4) ꢄ (cis).
This is in accordance with torsion angles Nendo–C1–
N1–C8 between 76.7(6)8 and 86.4(5)8, indicating an
Catalytic Studies
All synthesized iridium complexes with the BArF24
counter anion were tested in the H/D exchange of
aryl substrates. The standard set-up for this reaction
included a carousel reactor, which was connected via
a three-way stopcock to a vacuum line and could be
switched to a balloon filled with deuterium. To start
the reaction, the atmosphere in the reaction vessels
was removed under vacuum and refilled with D2 gas.
The chosen solvent for the first screening of sub-
strates and catalysts in the H/D exchange was di-
chloromethane. The reaction was conducted for 1 h at
room temperature with 5 mol% of catalyst. In a first
screening, the iridium complexes 2a–h and Crabtreeꢂs
Figure 3. Molecular structure of 2l with thermal displace-
catalyst A and Kerrꢂs catalyst B (with PR3 =PMe2Ph)
ment parameters drawn at 50% probability. Disordered t-Bu
were tested with substrates 5–9 (Table 3). As analyzed
by LC-MS, high degrees of deuteration with all tested
catalysts were found for 4-acetylbiphenyl (5), while
group, solvent molecule, counter-anion and hydrogen atoms
omitted. Selected bond distances and angles are assembled
in the Supporting Information, Table S1.
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Table 3. Screening of the H/D exchange of aryl substrates 5–
9 with catalysts 2a–h, A and B.[a]
showed a moderate degree of deuteration (31%). All
other substrates 11–14 in the first row of Figure 4
bearing amido, sulfone, ester or nitro directing groups
showed high degrees of deuteration under the chosen
conditions.
Aromatic Boc-protected substrates 15–18 (Boc=
tert-butyloxycarbonyl) underwent very good deuteri-
um incorporation (>95%). Even though we are
aware of a single report on the labelling of a Boc-pro-
tected indole in the peri-position,[90] the selective
deuteration in the ortho-position of Boc-protected
substrates has not been reported before to the best of
our knowledge and represents a useful extension of
the possible substrate scope for HIE. Moreover, the
1,1’-disubstituted ferrocene derivatives 18 and 19
showed excellent deuterium incorporation in the a-
positions, but also a low degree of deuteration in the
b-positions, which can be explained by a directing
effect across the two cyclopentadienyl rings. Another
outstanding feature of the catalyst system 2d is the
tolerance of primary amines in substrates 7 and 20,
since primary amines often coordinate strongly to-
wards the active iridium center and thus lead to deac-
tivation, as observed for Crabtreeꢂs[91] and Kerrꢂs cata-
lysts.[92] Moreover, if no competing directing group is
found in the substrate, benzylamines can also act as
directing groups, and substrate 21 is efficiently deuter-
ated.
Catalyst
Substrate
5
6
7
8
9
[c]
[c]
2a
2b
2c
2d
2e
2f
>95
<5
8
6
52
<5
19
18
50
33
34
<5
90
91
92
<5
54
48
56
<5
<5
–
–
>95
>95
>95
>95
>95
>95
>95
69
84
[c]
[c]
–
–
95
85
[c]
[c]
–
–
6
–
5
–
–
21
[c]
[c]
2g
2h
A
–
20
[c]
[c]
[c]
[c]
–
95
–
–
B[b]
[c]
[a]
Reaction conditions: 5 mol% [Ir] in CH2Cl2, ambient
temperature and 1 atm D2 pressure, 1 h. Values in %
denote the degree of deuteration, as determined by LC-
MS, for the expected indicated positions. Bold, under-
lined values highlight the best degrees of deuteration in
the column.
Remarkably, for 14 and 17 deuterium incorporation
was additionally observed at the positions ortho to
the methoxy groups. In hemilabile ligands, ether func-
tional groups are often used as very weakly coordinat-
ing oxygen donors, and thus this reactivity was not ex-
[b]
[c]
B with PR3 =PMe2Ph.
Not tested.
sufficient deuteration (ca. 50%) of the heterocyclic pected.[93–95] Since the degrees of deuteration, as de-
substrate 2-phenylpyridine (6) was only achieved with termined by 1H NMR, were quite low, a 2H NMR
the P(t-Bu)2 derivatives 2d and 2h. For the Boc-pro- spectrum was recorded for 14, which confirmed the
tected substrates 7–9, a high degree of deuterium in- deuterium incorporation ortho to the methoxy group.
corporation was generally found for the N-methyl de- Another tested compound, 4-methoxyphenol (22),
rivatives 2b–d, with 2d (R=t-Bu, R’=Me) showing which lacks other competing directing groups, showed
the overall best performance. Therefore, we chose 2d a reasonable degree of deuteration of 36% over all
for a broader substrate screening.
four positions with 2d; it should be noted that these
1
The results from the substrate screening with cata- positions could not be distinguished by H NMR spec-
lyst 2d are assembled in Figure 4. The same condi- troscopy. These results demonstrate the generally
tions as described for the catalyst screening were used very good performance of catalyst 2d. A similar sub-
(CH2Cl2 solution, 5 mol% of catalyst, 1 h, ambient strate screening was also conducted with complex 2b,
temperature and 1 atm D2 pressure) and every experi- but this catalyst was found to be equal or inferior to
ment was carried out twice. Additionally, H/D ex- 2d for all examples (see Supporting Information, Fig-
change reactions with substrates 5–9 were repeated ure S9).
1
with 2d and analyzed by H NMR spectroscopy to
The mass spectrum recorded for the deuteration
prove regioselectivity. The results obtained from the product 6 showed a predominant shift of the molecu-
1H NMR analysis were in good agreement with those lar ion mass by two units (+2), rather than the ex-
obtained from the LC-MS analysis. In the first row of pected +1 (major) and +2 (minor) pattern, which in-
Figure 4, substrates are assembled which have similar dicates strong binding of the substrate to the iridium
or the same directing groups as substrates that have center, resulting in an exchange of both hydrogen
been tested in HIE before and have shown good de- atoms before substrate dissociation from the catalyst.
grees of deuteration also with B and C.[51,54,56] Similar The explanation of strong coordination of 6 correlates
to 2-phenylpyridine (6), 2-phenylpyrimidine (10) only with the higher degrees of deuteration that were ob-
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Figure 4. Screening of the H/D exchange of substrates 10–23 with catalyst 2d. Reaction conditions: 5 mol% 2d in CH2Cl2, am-
bient temperature and D2 pressure, 1 hour. Values in brackets denote degree of deuteration [%] in the indicated position as
1
determined by H NMR spectroscopy. % Values denote isolated yields. All values are the average of two reactions. The left
box shows the examples from Table 3.
served in the presence of sterically more demanding ment in the degree of deuteration. Prompted by this
substituents (Table 3), which would also facilitate the result, the methoxy derivatives 14, 17 and 22 were
release of the substrate. For the latter, we assumed also tested with TBME. However, an increase of
that a stronger coordinating solvent might also be deuteration for the ortho-methoxy positions was not
beneficial, and accordingly, the deuteration of 2-phe- observed for 17, whereas a decrease of deuteration
nylpyridine (6) was tested in TBME (tert-butyl methyl was observed for 14 (73/3%) and 22 (6%). We explain
ether), 2-methyltetrahydrofuran and methanol. In this observation by the coordinating ability of TBME
TBME a high degree of deuteration of 97% was ach- which, on the one hand, facilitates the release of the
ieved (entry 1, Table 4, cf. 57% with CH2Cl2 as sol- strongly coordinated 2-phenylpyridine (6) from the
vent), whereas the other solvents showed no improve- complex but, on the other hand, hinders coordination
and subsequent deuteration of ether-functionalized
Table 4. Optimization of the reaction conditions.[a]
substrates.
For H/D exchange at 2-methoxynaphthalene (23)
as the model substrate, more weakly coordinating sol-
vents were chosen, and the reaction time and temper-
ature were additionally varied (Table 4). Reaction in
CH2Cl2 gave only low deuterium incorporation of 18/
6% in the two different positions (entry 2), whereas
the reaction in CCl4 afforded almost no incorporation
(entry 3). The highest degrees of deuterium incorpo-
ration with 98/10% were obtained with chloroform at
508C and a reaction time of 5 h (entry 6).
H/D exchange for substrates 22 and 24–27 was car-
ried out under the conditions used in entry 6. It was
observed that deuterium incorporation for 22 was
raised from 36 to 43% (Figure 5). Furthermore, sub-
strates 24, 25 and 26 were deuterated successfully
Entry Substrate Solvent t [h] T [8C] % Deuteration
1
2
3
4
5
6
6
TBME
CH2Cl2
CCl4
CHCl3
CHCl3
CHCl3
1
3
3
3
3
5
r.t.
r.t.
r.t.
r.t.
40
97
18/6
4/4
12/0
6/22
98/10
23
23
23
23
23
50
[a]
5 mol% 2d were used at 1 atm D2 pressure.
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more, the structurally complex molecule cabazitaxel
was successfully deuterated. Future work will aim at
exploring an even broader substrate scope and at un-
raveling potential catalytic mechanisms with the new
catalyst system. Additionally, complex 2d will be
tested for selective tritium labelling of several drugs
or drug-like molecules.
Experimental Section
Below, some general synthetic and catalytic procedures are
presented. For full experimental details see the Supporting
Information.
General Procedure for the Synthesis of Ligands 1a–h
Ligand precursor 4a or 4b (5.00 mmol, 1 equiv.) was dis-
solved in THF (50 mL). The solution was cooled to ꢀ808C,
and a solution of tert-butyllithium in n-pentane (1.7M,
5.9 mL, 10.00 mmol, 2 equiv.) was added dropwise. After
complete addition, the mixture was stirred for 1 h between
ꢀ80 and ꢀ708C, and then the relevant, freshly distilled
chlorophosphine R2PCl (R=Ph, Cy, i-Pr, t-Bu; 5.00 mmol,
1 equiv.), weighed in a syringe, was added dropwise. Subse-
quently, the solution was stirred for 1 h between ꢀ80 and
ꢀ708C and then allowed to reach room temperature, fol-
lowed by concentration under vacuum and treatment with
degassed water (10 mL). The product was taken up in
10 mL of CH2Cl2 (1a, 1e) or toluene (1b–d, 1f–h), and the
organic layer was transferred into a flask under N2. The
aqueous layer was extracted three more times with CH2Cl2
or toluene, respectively (5 mL each). The solution was dried
with MgSO4 (under N2) and filtered, and the volatiles were
removed under vacuum. Because of differing solubilities,
the work-up procedures differed for all compounds, as given
in detail in the Supporting Information.
Figure 5. Deuteration of various substrates with optimized
reaction conditions: 5 mol% (22–26) or 25 mol% (27) of 2d
in CHCl3, 508C, ambient D2 pressure, 5 h.
next to the methoxy group with degrees of deutera-
tion ranging from 25 to 69%. Deuterium incorpora-
tion of 13% was even found ortho to the sterically
more demanding dimethylamino group in 24. More-
over, the cytostatic drug cabazitaxel (27) was success-
fully deuterated to the extent of 91% at the ortho-po-
sitions of the benzoyl moiety.
General Procedure for the Synthesis of Complexes
2a–h
Conclusions
A new class of bidentate RP, NR’ ligands, bearing the
electron-rich imidazolin-2-imine group as N donor, is
introduced. These ligands were used for the synthesis
of iridium(I) complexes, which were tested in H/D ex-
change reactions with various aromatic substrates.
The complex [(t-BuP, N Me)Ir(cod)]BArF24 (2d) was
found to be particularly active in the deuteration of
a total of 23 substrates. 15 of these have functional
groups and structural motifs for which, to the best of
A solution of [Ir(cod)Cl]2 (0.5 equiv.) in CH2Cl2 (ca. 15 mL
per mmol of [Ir(cod)Cl]2) was treated with a solution of the
appropriate ligand (1a–h, 1.0 equiv.) in CH2Cl2 (ca.5 mL per
mmol of RP, NR’). After stirring overnight at room tempera-
ture, solid NaBArF24 (1.3 equiv.) was added, and the disper-
sion was stirred for an additional hour. Water (ca. 10 mL)
was then added, and the suspension was stirred for 10 min.
After separation of the organic layer, the aqueous phase
was extracted with small portions of CH2Cl2 until the ex-
tracts were colorless. The combined organic extracts were
our knowledge, efficient deuteration has not been re- dried over MgSO4 and concentrated. The crude solids were
purified by column chromatography (silica, Et2O/CH2Cl2
4:1!0:1), providing orange solids.
ported to date. The substrate scope includes examples
with known directing groups such as acetyl, heterocy-
cles, sulfones, nitro groups and benzylamines, but also
the Boc protecting group in anilines and other aro-
matic amines, which had not been recognized previ-
ously as a directing group for selective H/D exchange
in the ortho-position. After optimization, even sub-
strates with the weakly coordinating methoxy group
General Procedure for the Substrate Screening with
Catalyst 2d
A stock solution of catalyst 2d (0.0025 mmol catalyst/0.5 mL
CH2Cl2) was prepared. The reaction tubes of the carousel
reactor were loaded with solutions of the appropriate sub-
showed a sufficient degree of deuteration. Further- strate 5–22 (0.05 mmol) in CH2Cl2 (0.5 mL) and catalyst
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stock solutions (0.5 mL, 0.0025 mmol). The tubes were
sealed leaving the connection to the gas inlet open, evacuat-
ed until boiling was observed, and then refilled with deuteri-
um gas from a balloon four times. Stirring (1000 rpm) was
then started. After 1 h of reaction at room temperature (21–
248C), the reaction was stopped by two evacuation/refill
cycles with Ar or N2, and then the CH2Cl2 solution was com-
pletely evaporated. For substrates not containing primary
amines, the residue was dissolved in a small portion of dieth-
yl ether and passed through a filter pipette with silica
(length approx. 5 cm, conditioned with diethyl ether before-
hand) and completely eluted with 3 mL of diethyl ether.
The primary amines 7 und 20 were extracted with two por-
tions of boiling heptanes each (2ꢅ0.7 mL), filtered hot and
cooled to room temperature; on some occasions, the prod-
uct crystallized overnight at 48C. Product 21 was extracted
with two portions of boiling n-hexane (2ꢅ1 mL), filtered
hot, cooled to room temperature and filtered again. After
these work-up steps, the volatiles were completely removed
under vacuum to yield the products. To determine the
degree of deuteration, 1H NMR spectra of the products
were recorded in (CD3)2CO. The degree of deuteration was
determined by correlation of the respective integrals ob-
tained from the 1H NMR spectra of the (undeuterated)
starting material and the (deuterated) product. Integrals of
both spectra were calibrated against a constant integral.
Yields and degrees of deuteration were determined by the
average of two reactions.
[7] D. Wade, Chem. Bio. Interact. 1999, 117, 191–217.
[8] G. C. Lloyd-Jones, M. P. MuÇoz, J. Labelled Compd.
Radiopharm. 2007, 50, 1072–1087.
[9] A. E. Mutlib, Chem. Res. Toxicol. 2008, 21, 1672–1689.
[10] T. Giagou, M. P. Meyer, Chem. Eur. J. 2010, 16, 10616–
10628.
[11] M. Gomez-Gallego, M. A. Sierra, Chem. Rev. 2011,
111, 4857–4963.
[12] E. M. Simmons, J. F. Hartwig, Angew. Chem. 2012, 124,
3120–3126; Angew. Chem. Int. Ed. 2012, 51, 3066–3072.
[13] G. B. Dudley, S. J. Danishefsky, G. Sukenick, Tetrahe-
dron Lett. 2002, 43, 5605–5606.
[14] M. Miyashita, M. Sasaki, I. Hattori, M. Sakai, K.
Tanino, Science 2004, 305, 495–499.
[15] K. W. Quasdorf, A. D. Huters, M. W. Lodewyk, D. J.
Tantillo, N. K. Garg, J. Am. Chem. Soc. 2012, 134,
1396–1399.
[16] M. Saljoughian, Synthesis 2002, 1781–1801.
[17] D. Hesk, P. McNamara, J. Labelled Compd. Radio-
pharm. 2007, 50, 875–887.
[18] J. R. Heys, R. Voges, T. Moenius, Preparation of Com-
pounds Labeled with Tritium and Carbon-14, Wiley,
Chichester, 2009.
[19] C. N. Filer, J. Labelled Compd. Radiopharm. 2010, 53,
739–744.
[20] M. R. Chappelle, C. R. Hawes, J. Labelled Compd. Ra-
diopharm. 2010, 53, 745–751.
[21] W. J. S. Lockley, J. R. Heys, J. Labelled Compd. Radio-
pharm. 2010, 53, 635–644.
Crystal Structures
[22] P. H. Allen, M. J. Hickey, L. P. Kingston, D. J. Wilkin-
son, J. Labelled Compd. Radiopharm. 2010, 53, 731–
738.
[23] W. J. S. Lockley, A. McEwen, R. Cooke, J. Labelled
Compd. Radiopharm. 2012, 55, 235–257.
[24] J. A. Krauser, J. Labelled Compd. Radiopharm. 2013,
56, 441–446.
CCDC 1512931, CCDC 1512932, CCDC 1512933, CCDC
1512934, CCDC 1512935, CCDC 1512936, CCDC 1512937,
CCDC 1512938 and CCDC 1512939 contain the supplemen-
tary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
[25] C. S. Elmore, R. A. Bragg, Bioorg. Med. Chem. Lett.
2015, 25, 167–171.
[26] E. C. Hulme, M. A. Trevethick, Br. J. Pharmacol. 2010,
161, 1219–1237.
[27] J. Berry, M. Price-Jones, B. Killian, Methods Mol. Biol.
Acknowledgements
2012, 897, 79–94.
[28] D. Harder, D. Fotiadis, Nat. Protoc. 2012, 7, 1569–1578.
[29] J. J. Maguire, R. E. Kuc, A. P. Davenport, Methods
Mol. Biol. 2012, 897, 31–77.
We acknowledge Daniel Becker and Rolf Bꢀssing for prepa-
rative assistance.
[30] F. M. Musteata, Bioanalysis 2011, 3, 1753–1768.
[31] B. Buscher, S. Laakso, H. Mascher, K. Pusecker, M.
Doig, L. Dillen, W. Wagner-Redeker, T. Pfeifer, P.
Delrat, P. Timmerman, Bioanalysis 2014, 6, 673–682.
[32] T. Usui, M. Mise, T. Hashizume, M. Yabuki, S.
Komuro, Drug. Metab. Dispos. 2009, 37, 2383–2392.
[33] C. N. Filer, J. Radioanal. Nucl. Chem. 2009, 281, 521–
530.
References
[1] J. Atzrodt, V. Derdau, T. Fey, J. Zimmermann, Angew.
Chem. 2007, 119, 7890–7911; Angew. Chem. Int. Ed.
2007, 46, 7744–7765.
[2] R. H. Liu, D.-L. Lin, W.-T. Chang, C. Liu, W.-I. Tsay,
J.-H. Li, T.-L. Kuo, Anal. Chem. 2002, 74, 618–626.
[3] E. Stokvis, H. Rosing, J. H. Beijnen, Rapid Commun.
Mass Spectrom. 2005, 19, 401–407.
[34] L. Dubinsky, B. P. Krom, M. M. Meijler, Bioorg. Med.
Chem. 2012, 20, 554–570.
[35] J. Liu, C. Liu, W. He, Curr. Org. Chem. 2013, 17, 564–
579.
[4] M. Jemal, Y.-Q. Xia, Curr. Drug Metab. 2006, 7, 491–
[36] M. S. Panov, V. D. Voskresenska, M. N. Ryazantsev,
A. N. Tarnovsky, R. M. Wilson, J. Am. Chem. Soc.
2013, 135, 19167–19179.
502.
[5] J. Atzrodt, V. Derdau, J. Labelled Compd. Radiopharm.
2010, 53, 674–685.
[6] A. K. Hewavitharana, J. Chromatogr. A 2011, 1218,
359–361.
[37] V. T. G. Chuang, M. Otagiri, Molecules 2013, 18, 13831–
13859.
Adv. Synth. Catal. 0000, 000, 0 – 0
8
ꢃ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
[38] E. Smith, I. Collins, Future Med. Chem. 2015, 7, 159–
183.
ganocatalysts, John Wiley & Sons, Chichester, UK,
2009.
[39] P. Marathe, W. Shyu, W. Humphreys, Curr. Pharm. Des.
2004, 10, 2991–3008.
[65] X. Fu, C.-H. Tan, Chem. Commun. 2011, 47, 8210–
8222.
[40] D. Zhang, G. Luo, X. Ding, C. Lu, Acta Pharm. Sin. B
[66] J. E. Taylor, S. D. Bull, J. M. J. Williams, Chem. Soc.
2012, 2, 549–561.
Rev. 2012, 41, 2109–2121.
[41] E. M. Isin, C. S. Elmore, G. N. Nilsson, R. A. Thomp-
son, L. Weidolf, Chem. Res. Toxicol. 2012, 25, 532–542.
[42] N. Penner, L. Xu, C. Prakash, Chem. Res. Toxicol.
2012, 25, 513–531.
[67] J. Volbeda, P. G. Jones, M. Tamm, Inorg. Chim. Acta
2014, 422, 158–166.
[68] J. Bogojeski, J. Volbeda, M. Freytag, M. Tamm, Z. D.
ˇ ´
Bugarcic, Dalton Trans. 2015, 44, 17346–17359.
[43] J. R. Heys, J. Labelled Compd. Radiopharm. 2007, 50,
770–778.
[44] R. Salter, J. Labelled Compd. Radiopharm. 2010, 53,
645–657.
[45] G. N. Nilsson, W. J. Kerr, J. Labelled Compd. Radio-
pharm. 2010, 53, 662–667.
[46] R. Crabtree, Acc. Chem. Res. 1979, 12, 331–337.
[47] D. Hesk, P. R. Das, B. Evans, J. Labelled Compd. Radi-
opharm. 1995, 36, 497–502.
[48] J. A. Brown, S. Irvine, A. R. Kennedy, W. J. Kerr, S.
Andersson, G. N. Nilsson, Chem. Commun. 2008, 1115–
1117.
[49] A. R. Cochrane, C. Idziak, W. J. Kerr, B. Mondal, L. C.
Paterson, T. Tuttle, S. Andersson, G. N. Nilsson, Org.
Biomol. Chem. 2014, 12, 3598–3603.
[69] T. Glçge, F. Aal, S.-A. Filimon, P. G. Jones, J. Michaelis
de Vasconcellos, S. Herres-Pawlis, M. Tamm, Z. Anorg.
Allg. Chem. 2015, 641, 2204–2214.
[70] T. Glçge, K. Jess, T. Bannenberg, P. G. Jones, N. Lan-
genscheidt-Dabringhausen, A. Salzer, M. Tamm,
Dalton Trans. 2015, 44, 11717–11724.
ˇ
ˇ ´
[71] J. Bogojeski, J. Volbeda, Z. D. Bugarcic, M. Freytag, M.
Tamm, New J. Chem. 2016, 40, 4818–4825.
[72] K. Jess, D. Baabe, T. Bannenberg, K. Brandhorst, M.
Freytag, P. G. Jones, M. Tamm, Inorg. Chem. 2015, 54,
12032–12045.
[73] K. Jess, D. Baabe, M. Freytag, P. G. Jones, M. Tamm,
Eur. J. Inorg. Chem. DOI: 10.1002/ejic.201600841.
[74] D. Petrovic, T. Bannenberg, S. Randoll, P. G. Jones, M.
Tamm, Dalton Trans. 2007, 2812–2822.
[50] W. J. Kerr, M. Reid, T. Tuttle, ACS Catal. 2015, 5, 402–
410.
[75] T. K. Panda, D. Petrovic, T. Bannenberg, C. G. Hrib,
P. G. Jones, M. Tamm, Inorg. Chim. Acta 2008, 361,
2236–2242.
[76] S.-A. Filimon, D. Petrovic, J. Volbeda, T. Bannenberg,
P. G. Jones, C.-G. Freiherr von Richthofen, T. Glaser,
M. Tamm, Eur. J. Inorg. Chem. 2014, 5997–6012.
[77] N. Kuhn, M. Grathwohl, M. Steimann, G. Henkel, Z.
Naturforsch. B 1998, 53, 997–1003.
[51] J. Atzrodt, V. Derdau, W. J. Kerr, M. Reid, P. Rojahn,
R. Weck, Tetrahedron 2015, 71, 1924–1929.
[52] W. J. Kerr, D. M. Lindsay, M. Reid, J. Atzrodt, V.
Derdau, P. Rojahn, R. Weck, Chem. Commun. 2016,
52, 6669–6672.
[53] A. R. Cochrane, S. Irvine, W. J. Kerr, M. Reid, S. An-
dersson, G. N. Nilsson, J. Labelled Compd. Radio-
pharm. 2013, 56, 451–454.
[78] G. Frison, A. Sevin, J. Chem. Soc. Perkin Trans. 2 2002,
1692–1697.
[54] J. A. Brown, A. R. Cochrane, S. Irvine, W. J. Kerr, B.
Mondal, J. A. Parkinson, L. C. Paterson, M. Reid, T.
Tuttle, S. Andersson, G. N. Nilsson, Adv. Synth. Catal.
2014, 356, 3551–3562.
[55] P. W. C. Cross, J. M. Herbert, W. J. Kerr, A. H. McNeill,
L. C. Paterson, Synlett 2016, 27, 111–115.
[56] M. Parmentier, T. Hartung, A. Pfaltz, D. Muri, Chem.
Eur. J. 2014, 20, 11496–11504.
[79] M. Tamm, D. Petrovic, S. Randoll, S. Beer, T. Bannen-
berg, P. G. Jones, J. Grunenberg, Org. Biomol. Chem.
2007, 5, 523–530.
[80] J. R. Khusnutdinova, D. Milstein, Angew. Chem. 2015,
127, 12406–12445; Angew. Chem. Int. Ed. 2015, 54,
12236–12273.
[81] J. F. Hartwig, Angew. Chem. 1998, 110, 2154–2177;
Angew. Chem. Int. Ed. 1998, 37, 2046–2067.
[82] J. P. Wolfe, S. Wagaw, J.-F. Marcoux, S. L. Buchwald,
Acc. Chem. Res. 1998, 31, 805–818.
[57] S. J. Roseblade, A. Pfaltz, Acc. Chem. Res. 2007, 40,
1402–1411.
[58] D. H. Woodmansee, A. Pfaltz, in: Topics in Organome-
tallic Chemistry, Vol. 34, (Ed.: P. G. Andersson),
Springer, Berlin, New York, 2011.
[59] X. Wu, M. Tamm, Coord. Chem. Rev. 2014, 260, 116–
138.
[60] J. Sundermeyer, V. Raab, E. Gaoutchenova, U. Gar-
relts, N. Abacilar, K. Harms, in: Activating Unreactive
Substrates. The Role of Secondary Interactions (Eds.: C.
Bolm, E. F. Hahn), Wiley-VCH, Weinheim, 2009.
[61] O. Bienemann, A. Hoffmann, S. Herres-Pawlis, Rev.
Inorg. Chem. 2011, 31, 83–108.
[83] J. P. Sadighi, M. C. Harris, S. L. Buchwald, Tetrahedron
Lett. 1998, 39, 5327–5330.
[84] A. Neuba, R. Haase, M. Bernard, U. Flçrke, S. Herres-
Pawlis, Z. Anorg. Allg. Chem. 2008, 634, 2511–2517.
[85] J. Bçrner, U. Flçrke, K. Huber, A. Dçring, D. Kuckling,
S. Herres-Pawlis, Chem. Eur. J. 2009, 15, 2362–2376.
[86] S. P. Smidt, F. Menges, A. Pfaltz, Org. Lett. 2004, 6,
2023–2026.
[87] J. Blankenstein, A. Pfaltz, Angew. Chem. 2001, 113,
4577–4579; Angew. Chem. Int. Ed. 2001, 40, 4445.
[88] D. H. Woodmansee, M.-A. Mꢀller, M. Neuburger, A.
Pfaltz, Chem. Sci. 2010, 1, 72.
[62] H.-J. Himmel, Z. Anorg. Allg. Chem. 2013, 639, 1940–
1952.
[63] I. dos Santos Vieira, S. Herres-Pawlis, Eur. J. Inorg.
[89] A. Franzke, A. Pfaltz, Chem. Eur. J. 2011, 17, 4131–
4144.
Chem. 2012, 765–774.
[64] T. Ishikawa (Ed.) Superbases for organic synthesis.
Guanidines, amidines and phosphazenes and related or-
[90] R. Salter, M. Chappelle, A. Morgan, T. Moenius, P. Ac-
kermann, M. Studer, F. Spindler, in: Synthesis and Ap-
plications of Isotopically Labelled Compounds, (Eds.:
Adv. Synth. Catal. 0000, 000, 0 – 0
9
ꢃ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
U. Pleiss, R. Voges), John Wiley & Sons, Chichester,
2001.
[91] G. J. Ellames, J. S. Gibson, J. M. Herbert, A. H. Mc-
Neill, Tetrahedron 2001, 57, 9487–9497.
[92] Own unpublished results. No examples of primary and
secondary amines in the literature.
[93] J. C. Jeffrey, T. B. Rauchfuss, Inorg. Chem. 1979, 18,
2658–2666.
[94] C. S. Slone, D. A. Weinberger, C. A. Mirkin, in: Prog-
ress in Inorganic Chemistry, (Ed.: K. D. Karlin), John
Wiley & Sons, Inc, Hoboken, NJ, USA, 1997.
[95] P. Braunstein, F. Naud, Angew. Chem. 2001, 113, 702–
722; Angew. Chem. Int. Ed. 2001, 40, 680–699.
Adv. Synth. Catal. 0000, 000, 0 – 0
10
ꢃ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
Hydrogen Isotope Exchange with Iridium(I) Complexes
Supported by Phosphine-Imidazolin-2-imine P,N Ligands
11
Adv. Synth. Catal. 2017, 359, 1 – 11
Kristof Jess, Volker Derdau,* Remo Weck, Jens Atzrodt,
Matthias Freytag, Peter G. Jones, Matthias Tamm*
Adv. Synth. Catal. 0000, 000, 0 – 0
11
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ÞÞ
These are not the final page numbers!