Ruthenium-catalyzed selective α-deuteration of aliphatic nitriles using D2O

Article abstract of DOI:10.1039/c8cc03971b

Selective catalytic α-deuteration of aliphatic nitriles using deuterium oxide as a deuterium source is reported. A PNP-ruthenium pincer complex catalyzed the α-deuteration of aliphatic nitriles including acetonitrile. Efficient deuteration occurred with a low catalyst load (0.2 to 0.5 mol%) and under mild conditions. A [2+2] cycloadduct formation from nitrile functionality and a deprotonated catalytic intermediate, followed by an imine-enamine tautomerization and a H/D exchange between the enamine intermediate and deuterium oxide leading to the selective deuteration at the α-position of the nitrile, is proposed as a plausible reaction mechanism.

Full text of DOI:10.1039/c8cc03971b

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Ruthenium-catalyzed selective a-deuteration
of aliphatic nitriles using D2O†
Cite this:DOI: 10.1039/c8cc03971b
Varadhan Krishnakumar and Chidambaram Gunanathan
*
Received 18th June 2018,
Accepted 10th July 2018
DOI: 10.1039/c8cc03971b
rsc.li/chemcomm
Selective catalytic a-deuteration of aliphatic nitriles using deuterium commonly used NMR solvent and other deuterated nitrile
oxide as a deuterium source is reported. A PNP–ruthenium pincer compounds are used as chemical probes. Despite the wide-
complex catalyzed the a-deuteration of aliphatic nitriles including spread use of deuterated nitrile compounds, synthetic methods
acetonitrile. Efficient deuteration occurred with a low catalyst load for the preparation of aliphatic nitriles are scarce and they
(0.2 to 0.5 mol%) and under mild conditions. A [2+2] cycloadduct suffer from a low level of deuterium incorporation, the require-
formation from nitrile functionality and a deprotonated catalytic ment of polar substituents on the g-position, limited substrate
intermediate, followed by an imine–enamine tautomerization and a scope and the repetition of tedious processes to achieve higher
H/D exchange between the enamine intermediate and deuterium deuteration.9,10 Thus, the selective catalytic deuteration of nitriles
oxide leading to the selective deuteration at the a-position of the using deuterium oxide is desirable and atom economical.
nitrile, is proposed as a plausible reaction mechanism.
We have reported the selective a-deuteration of primary
alcohols and the a,b-deuteration of secondary alcohols using
Deuterium isotopes introduced into organic compounds exert ruthenium pincer complex [(PNPPh)RuHCl(CO)] 1 (PNP = bis(2-
their influence in enhancing the molecular properties of the (diphenylphosphino)ethyl)amine) and deuterium oxide, in
resultant labelled products. Such labelled molecules have which we have demonstrated the facile O–H/O–D bond activa-
found widespread application1 as NMR solvents, polymeric tion of alcohols and deuterium oxide by 1 in the presence of a
materials,2 chemical and biological probes and are commonly base.11 Complex 1 also catalyzed the selective deuteration of the
used as internal standards in quantitative mass spectral sp-C–H bond of terminal alkynes.12 Recently, we have also
studies3 and drug development.4 The notable importance of reported the selective a-deuteration of primary and secondary
such deuteration is that the introduction of deuterium labels amines, as well as amino acids using deuterium oxide.13
on the metabolically susceptible C–H bonds of a compound can A mono-hydrido-bridged dinuclear ruthenium complex14 catalyzed
increase its metabolic stability and thus enhance its therapeutic this chemo- and regioselective transformation and the reaction
efficacy. SD-809 (the deuterium-labelled version of the commer- proceeded via N–H activation.13 In a continuation of our efforts to
cial drug tetrabenazine) was tested on human beings with develop efficient and direct deuteration of organic compounds
Huntington’s disease and has already been approved by the using deuterium oxide, herein we report the selective a-deuteration
US FDA (as Austedos) after successful phase III clinical trials.5,6 of aliphatic nitriles using catalyst 1.
There are more such deuterium-containing drug candidates
under evolution.
Preliminary studies began on the deuteration of acetonitrile.
Upon the reaction of acetonitrile (0.5 mmol) with catalyst 1
Nitriles are an important class of organic compound, as (0.1 mol%) and KOtBu (0.5 mol%) in deuterium oxide at 60 1C
many of them are bioactive molecules and there are more than for 24 h, 49% deuteration was observed. A similar reaction at
30 nitrile-containing compounds currently being used as 70 1C provided 92.3% deuteration. When 0.2 mol% of catalyst 1
pharmaceuticals.7 In addition, there are several nitrile-embedded was used, an efficient deuteration of 95.7% (against a theore-
candidates under clinical development.8 Acetonitrile-d3 is a tical maximum of 96.4%) was obtained (entry 1 in Table 1).
Other aliphatic nitrile compounds were subjected to the catalytic
School of Chemical Sciences, National Institute of Science Education and Research
deuteration under the optimized experimental conditions.
Aliphatic linear nitriles underwent selective deuteration only
at the a-CH2 protons of the nitrile functionality and no detect-
(NISER), HBNI, Bhubaneswar, Khurda-752050, India.
E-mail: gunanathan@niser.ac.in
† Electronic supplementary information (ESI) available: Experimental procedures,
able deuteration was observed at the b- and other CH protons.
However, the % of deuteration showed the substrate dependence.
NMR spectra of deuterated aliphatic nitriles and their spectral data. See DOI:
10.1039/c8cc03971b
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Table 1 Selective a-deuteration of aliphatic nitrilesa
The reaction of butyronitrile with catalyst 1 (0.2 mol%) provided
only 23% deuteration. The use of 0.5 mol% of catalyst 1 resulted in
63% deuteration (entry 2 in Table 1). Under similar conditions,
octanenitrile, nonanenitrile, undecanenitrile and dodecanitrile
showed 62–81% a-deuteration. 4-Phenylbutanenitrile and 5-phenyl-
pentanenitrile displayed 72% and 50% deuterium incorporation,
respectively, at the a-CH2 positions (entries 7 and 8 in Table 1). The
ruthenium-catalyzed conversion of nitriles to amides is known for
both aromatic and aliphatic nitriles in the presence of water.15
However, this developed protocol selectively deuterates the
a-position of the nitriles and the CN group remains intact.
Aliphatic dinitriles were found to be more reactive than
linear aliphatic nitriles and facile selective deuteration occurred
at both a-positions with 0.2 mol% of catalyst 1. Succinonitrile
exhibited excellent deuteration at both a-CH2 positions with a
high D content (Dn: 3.73, entry 9 in Table 1). Similarly, glutaro-
nitrile, adiponitrile and 2-methylglutaronitrile showed facile pre-
dominant deuteration at both a-CH2 positions (entries 10–12 in
Table 1). However, these dinitriles also showed deuteration at the
b-position in the range 5.3–17.5%, which eventually resulted in
a higher deuterium incorporation (2.47 to 4.24 Dn), making
these molecules suitable for use as an internal MS standard in
the analysis of life science samples.16 Furthermore, ethyl cyano-
acetate displayed efficient deuteration (94%) at the a-position
(entry 13 in Table 1). 1-Cyclohexeneacetonitrile displayed a
deuteration of 94.5% against a theoretical deuteration of 96.4%
(entry 14 in Table 1). Control experiments performed under the
standard experimental conditions with or without base and in
the absence of the catalyst resulted in no detectable deuteration
of acetonitrile, which confirms that the deuteration is truly a
catalytic process (entries 15 and 16 in Table 1).
Next, the deuteration of heteroatom- and heterocycle-
tethered aliphatic nitriles was explored. Initially 0.2 mol% of
complex 1 was used for the reaction, which resulted in partial
deuteration. Upon using 0.5 mol% of 1 and 1 mol% of base,
selective a-deuteration occurred on oxygen-attached 3-(hexyloxy)-
propanenitrile, 4-(hexyloxy)hexanenitrile, 3-((2,3-dihydro-1H-
inden-2-yl)oxy)propanenitrile and 3,30-(pentane-1,5-diylbis(oxy))-
bis(propanenitrile) (entries 1–4 in Table 2). A minor amount
of b-CH2 deuteration was also observed (entries 1 & 4). Notably,
sulfur-containing 3-(benzylthio)propanenitrile displayed exclu-
sive deuteration on the a-position (entry 5 in Table 2). Likewise,
nitrogen-attached linear aliphatic nitriles showed a moderate
to high a-deuteration of 67 to 85% (entries 6–9 in Table 2).
Similarly, other amines with nitrile functionality such as
3-(dipropylamino)propanenitrile and 3-(piperidin-1-yl)propane-
nitrile resulted in a higher degree of a-deuteration (entries 10
and 11 in Table 2). Heterocyclic compounds are well tolerated
and deuteration occurred only at the a-CH2 to the nitrile group.
Indole-containing aliphatic nitriles were examined, and they
showed (entries 12 and 13 in Table 2) 67 to 94% deuteration
(the maximum theoretical % of deuteration is 97.5%). Unlike in
the Ru- or Ir-catalyzed deuteration of indole derivatives, the
highly active C2 and C3 positions are not affected by the C–H/D
exchange.17 The a-methylene protons of 3-phenathiazine
propionitrile were exclusively deuterated by catalyst 1 and the
Entry
1e
Product
CD3CN
O.D.b (%)
95.7
T.D.c (%)
96.4
Dnd
3a
3b
2.87
2
63
97.6
1.26
3
3c
3d
3e
3f
81
97.6
1.62
4
5
6
7
8
81
64
62
72
50
97.6
97.6
97.6
97.6
97.6
1.62
1.28
1.24
1.44
1.00
3g
3h
9e
3i
3j
93.3
91.5
88.5
95.2
93
3.73
3.95
4.24
10e
11e
3k
90.9
12e
13e
3l
94
94
97.6
97.5
2.47
1.88
3m
14
3n
94.5
96.4
2.16
15f
NR
NR
16g
a
Aliphatic nitrile (0.5 mmol), catalyst 1 (0.001 mmol, 0.2 mol%), KOtBu
(0.002 mmol, 0.5 mol%) and D2O (0.4 mL, 20 mmol) were charged in a
scintillation vial and heated to 70 1C. Entries 2–8: catalyst load used
b
0.0025 mmol, 0.5 mol%; base 1 mol%. Observed % of deuteration
(O.D.) calculated from the integration of the residual signals in the
c
1H NMR spectra. Maximum theoretical % of deuteration (T.D.).
d
Average number of catalytically introduced deuterium atoms per
e
molecule. Dichloroethane (0.5 mmol, 39.5 mL) was used as the
internal standard. 1 mol% of KOtBu, no catalyst. Without catalyst
f
g
and base. NR – No reaction.
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Table
2
Selective a-deuteration of heteroatom-containing aliphatic
Table 2 (continued)
nitrilesa
Entry
Product
O.D.b (%)
94
T.D.c (%)
1.88
Entry
1
Product
O.D.b (%)
95
T.D.c (%)
2.36
16
4p
4a
a
Nitrile (0.5 mmol), catalyst 1 (0.0025 mmol, 0.5 mol%), base (1 mol%),
and D2O (0.4 mL, 20 mmol) were charged in a scintillation vial and
b
heated to 70 1C. Calculated from the integration of the residual
signals in the 1H NMR spectra. The maximum theoretical % of
2
3
4b
4c
89
95
1.78
1.90
c
deuteration was 97.5%. Average number of catalytically introduced
d
deuterium atoms per molecule. The maximum theoretical % of
deuteration was 90.9%.
aromatic protons were unaffected. When 3-((tetrahydrofuran-
2-yl)methoxy)propanenitrile was subjected to catalysis, 96.5%
deuteration was attained at the a-CH2 positions. Amide-
containing nitriles provided 94% deuteration at the a-position
(entry 16 in Table 2).
4d
4d
80
3.80
5
6
4e
4f
91.5
85
1.83
1.96
Furthermore, the 2H NMR spectra that were recorded for the
representative compounds clearly confirmed the a-selective
deuteration of aliphatic nitriles (see the ESI†).
To understand the reaction mechanism, the deuteration
reactions catalyzed by complex 1 were probed using the
ESI-MS analyses of the reaction mixtures. Upon reaction of 1
with a base, an unsaturated amide-ligated intermediate I was
7
8
9
4g
4h
4i
67
1.78
1.38
1.37
69
68.5
10
11
4j
89
94
1.96
1.88
4k
12
13
4l
94
67
1.88
1.34
4m
14
15
4n
4o
79
1.58
1.93
96.5
Scheme 1 Proposed mechanism for the selective deuteration of aliphatic
nitriles.
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formed,12 which underwent Ru–H/D exchange with deuterium
oxide. This afforded intermediate complex I-D, which was
observed in situ using ESI-MS analysis (m/z 573 (M + H)+).
Nitrile coordination to the intermediate I-D led to the for-
mation of a [2+2]-cycloadduct II-D, which was in equilibrium
with its enamine form III-D. H/D exchange between the enam-
ine of III-D and deuterium oxide generated III-D2. Further
tautomerization, perhaps assisted by the base and deuterium
oxide, led to intermediate II-D2.18,19 Nitrile dissociation from
II-D2 could provide mono-deuterated nitrile or tautomerization
could result in the formation of a III-D-type intermediate,
which would undergo further H/D exchange and tautomeriza-
tion to provide a II-D3 intermediate that could liberate nitrile
with complete deuteration at the a-position and regenerate
the intermediate I-D to close the catalytic cycle. Interestingly,
a II-D3-type intermediate (m/z 669 (M + H)+) was observed in the
ESI-MS analysis of the deuteration reaction of glutaronitrile
catalyzed by 1 (Scheme 1).
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selective a-deuteration of aliphatic nitriles catalyzed by a ruthe-
nium pincer complex 1. The ability of the unsaturated inter-
mediate (I-D) formed from 1 to provide a [2+2] cycloadduct with
nitriles and subsequent tautomerization to an enamine form
plays an important role in the catalytic deuteration reactions.
This unprecedented catalytic protocol operates under mild
conditions with low catalyst loading. Notably, this method
can be applied for the large-scale synthesis of acetonitrile-d3
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