Stereoretentive Deuteration of α-Chiral Amines with D2O

Article abstract of DOI:10.1021/jacs.6b07879

We present the direct and stereoretentive deuteration of primary amines using Ru-bMepi (bMepi = 1,3-(6′-methyl-2′-pyridylimino)isoindolate) complexes and D₂O. High deuterium incorporation occurs at the α-carbon (70-99%). For α-chiral amines, complete retention of stereochemistry is achieved when using an electron-deficient Ru catalyst. The retention of enantiomeric purity is attributed to a high binding affinity of an imine intermediate with ruthenium, as well as to a fast H/D exchange relative to ligand dissociation.

Full text of DOI:10.1021/jacs.6b07879

Communication
pubs.acs.org/JACS
Stereoretentive Deuteration of α‑Chiral Amines with D2O
Lillian V. A. Hale and Nathaniel K. Szymczak*
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
S
* Supporting Information
ABSTRACT: We present the direct and stereoretentive
deuteration of primary amines using Ru-bMepi (bMepi =
1,3-(6′-methyl-2′-pyridylimino)isoindolate) complexes
and D2O. High deuterium incorporation occurs at the α-
carbon (70−99%). For α-chiral amines, complete
retention of stereochemistry is achieved when using an
electron-deficient Ru catalyst. The retention of enantio-
meric purity is attributed to a high binding affinity of an
imine intermediate with ruthenium, as well as to a fast H/
D exchange relative to ligand dissociation.
euterium- and tritium-labeled compounds are widely
applied in the pharmaceutical industry to enhance the
D
pharmacokinetic properties of a drug, as metabolic tracers, and
as mass spectrometry standards.1 For drug development, D/T
labeling offers a powerful approach for further modifications
based on the known characteristics of the protio molecule. As a
result of the kinetic isotope effect, the C−D bond is more inert
toward metabolic oxidation compared with the C−H
isotopologue. Thus, improvements in pharmaceutical residence
times can be achieved at low cost and with predictable
outcomes.1a Since this concept was first applied to bioactive
molecules,2 a substantial effort has been devoted to prepare and
patent deuterium-labeled pharmaceuticals.1e,3 However, labeled
compounds are commonly prepared via multistep syntheses
and require expensive labeled starting materials. As an
alternative strategy, isotope exchange through C−H bond
activation allows direct labeling and ideally may be used as a
late-stage modification of a complex molecule.4
Figure 1. Select deuterated bioactive primary amines (top).
Conceptual development of stereoretentive H/D exchange using
hydrogen transfer (bottom).
presence of primary amines, leading to a mixture of
products.9a,11 Furthermore, many bioactive compounds contain
α-chiral amines, which can racemize through a prochiral imine
intermediate during reversible β-hydride elimination.12,13
Finally, D2 is commonly employed as the deuterium source,
which is more expensive than D2O and imposes additional
operational challenges.14 To overcome these limitations, we
present a stereoretentive protocol for labeling primary amines
that employs inexpensive D2O.
We recently reported a series of Ru-bMepi complexes
(bMepi = 1,3-(6′-methyl-2′-pyridylimino)isoindolate) that are
excellent alcohol and amine dehydrogenation catalysts.15 For
amine dehydrogenation, imine intermediates remain coordi-
nated to Ru following reversible β-hydride elimination from a
Ru−amido intermediate (Figure 1).16 This high binding affinity
avoids the more commonly observed transamination reaction.11
Due to the higher binding affinity of the imine vs the amine, we
hypothesized that a chiral amine would retain its stereo-
chemistry during a reversible β-hydride elimination process.
This affinity could be exploited for stereoretentive deuteration
if H/D exchange with the Ru−H occurs faster than reversible
amine dehydrogenation.
The primary amine unit is an important functional group
found in a variety of pharmaceutical drugs and is commonly
metabolized through oxidative deamination by amine oxidase
enzymes.5 For such compounds, the in vivo efficacy can be
significantly improved by deuterium incorporation at a C−H
bond that is adjacent to the primary amine nitrogen atom. For
example, the bioactive compounds tryptamine,2 amphetamine,6
and dopamine7 have been targeted for deuterium incorporation
at the α-C−H position to slow metabolic oxidation (Figure 1).
However, the labeling protocols for these compounds require
multistep syntheses, resolution techniques for α-chiral amines,
and/or use expensive labeled starting materials.6−8
A promising alternative strategy to incorporate deuterium
into the amine unit is to employ catalytic hydrogen transfer
using a ruthenium catalyst in D2O.9,10 This approach exploits
reversible dehydrogenation/hydrogenation coupled with H/D
exchange processes. However, the direct labeling of primary
amines in this manner faces major challenges. (De)-
hydrogenation catalysts often facilitate transamination in the
To evaluate whether chiral amines retain their stereo-
chemistry during the H/D exchange reaction, we selected
(S)-1-phenylethylamine (7, Figure 2) as our model substrate.
Notably, 7 is used as an advanced building block for syntheses
Received: July 29, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b07879
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Journal of the American Chemical Society
Communication
Figure 2. Stereoretentive deuterium incorporation of (S)-1-phenyl-
ethylamine with 1 and 2. a1 mol % 1 in methylcyclohexane. b2 mol % 2
in Me-THF.
of more complex molecules and is commercially available.17 In
a sealed vessel containing 1.24 mmol of (S)-1-phenylethyl-
amine, 1 mol% 1, and a 15:85 ratio of methylcyclohexane to
D2O, 71% deuterium incorporation was observed into the α-
C−H position.18 Significantly, H/D exchange proceeded with
90% ee.
Figure 3. Deuteration of primary amines with 2 and D2O. Deuterium
incorporation was determined by 2H NMR spectroscopy. Percent
recovery shown in parentheses. aFormed from the deprotection of 3,4-
dimethoxyphenylethylamine.
The preservation of the stereochemistry in 7 is atypical in the
absence of a chiral ligand.19 Thus, we propose that two key
factors influence stereoretention with 1: (1) H/D exchange on
ruthenium is fast in comparison to ligand (imine) exchange,
and (2) the binding affinity of the imine intermediate is directly
related to the retention of configuration for (S)-1-phenylethyl-
amine. The Ru−H/Ru−D exchange reaction was evaluated
using 1 by adding 3 equiv of D2O to a solution of 1 in THF-
d8.20 The appearance of HOD and H2O after 10 min confirmed
exchange of the Ru−H with D2O. In contrast to amine
dehydrogenation by 1, which requires at least 100 °C,16 the H/
D exchange of 1 with D2O occurred at 35 °C. The facile
exchange at low temperatures suggests that H/D scrambling of
the Ru−H bond is much faster than amine dehydrogenation.21
To further mitigate racemization of chiral amine substrates, a
more electrophilic Ru catalyst was selected to limit dissociation
of the prochiral imine intermediate. The cationic complex
Ru(bMepiMe)(PPh3)(OTf)2 (2, Figure 2)22 was hypothesized
to have a higher binding affinity for the imine ligand and, by
extension, higher stereoretention compared to 1. Optimal
conditions were obtained by using a 15:85 ratio of 2-
methyltetrahydrofuran (Me-THF) to D2O in a sealed 3 mL
tube,23 with 2 mol% 2 for 20 h, which resulted in 95%
deuterium incorporation with complete retention of stereo-
chemistry (Figure 2).
Based on the limited number of amine deuteration
procedures,9,10,14 we applied our optimized conditions to a
variety of chiral and achiral primary amines. For all substrates,
high deuterium incorporation was identified at the α-carbon
(Figure 3).18 Notably, the presence of electron-withdrawing or
-donating substituents on the substrate did not have a negative
impact on the deuterium incorporation or enantiomeric purity.
Substrates 8 and 9, which contain para-methoxy and para-
chloro substituents, proceeded with complete retention of
stereochemistry and 99 and 88% incorporation of deuterium,
respectively. Deuterated bioactive compounds, such as
dopamine (11),7 tryptamine (12),2 and D-amphetamine
(13),6 as well as precursors to bioactive compounds (10, 14,
15),24 were obtained using our methodology. Importantly, a
simple acidic workup removed the ruthenium catalyst, 2. For
example, <4 ppm Ru was detected by ICP-OES after the
isolation of the ammonium chloride salt of 4-methoxy-2-
phenethylamine (6). The convenient workup and low level of
Ru further highlights the potential to employ Ru-bMepi
complexes for pharmaceutical applications.25 The simple
protocol for deuteration, coupled with the high deuterium
incorporation, product recovery, and low residual metal
content, demonstrates the broad utility of this catalytic
deuteration method.
Many pharmaceutically relevant chiral amines contain
heterocycles, amide, and ester functional groups. Such func-
tional groups may erode the enantiomeric purity by competitive
coordination during reversible hydrogen transfer. To evaluate
this possibility, we examined the functional group tolerance and
stereoretention of 7 in the presence of several common
functional groups (Table 1).26 In the presence of other L-type
donor ligands, such as 2-butylthiophene (entry 1) and 3,5-
lutidine (entry 2), the deuterium incorporation decreased to
Table 1. Deuteration of (S)-1-Phenylethylamine in the
a
Presence of Common Functional Group Additives
entry
additive
% D
% ee
1
2
3
4
5
2-butylthiophene
3,5-lutidine
55
24
85
95
0
99
99
methyl benzoate
99
N-methyl-N-phenylacetamide
2-vinylnaphthalene
99
N/A
a
2
Deuterium incorporation was determined by H NMR spectroscopy
using acetonitrile-d3 as an internal standard
B
DOI: 10.1021/jacs.6b07879
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Journal of the American Chemical Society
Communication
55% and 24%; however, the enantiomeric purity was retained.
Notably, additives such as esters and amides did not decrease
deuterium incorporation or enantiomeric purity (entries 3 and
4). One limitation, however, is the incompatibility with
hydrogen acceptors such as 2-vinylnaphthalene (entry 5).
The proposed mechanism for deuterium incorporation relies
on a reversible hydrogen transfer process (Figure 1); hence, an
additive that irreversibly removes hydrogen, such as an alkene,
prevents deuterium incorporation. Overall, these results
highlight the potential and limitations of Ru-bMepi complexes
as late-stage stereoretentive deuteration catalysts with D2O.
The high binding affinity of the imine intermediate is
proposed to be crucial to the stereoretention. This hypothesis
was evaluated by comparing the dissociation energies of
prochiral imine with analogous ketone intermediates (derived
from alcohol precursors). Although the dissociation energy of
benzaldimine is endergonic by 8.2 kcal/mol, acetophenone
dissociation is exergonic by −3.9 kcal/mol (Figure 4).16,27
propose additional features of the Ru-bMepi catalyst system
that enable this transformation: (1) a reversible β-hydride
elimination step, (2) a faster H/D exchange process on
ruthenium than ligand exchange of the imine (vide supra), and
(3) limited rotation of the α-chiral amine, which may be
facilitated by ortho-CH3 groups in complexes 1 and 2. To assess
the first point, we examined the iridium pincer complex [C6H3-
2,6-(OPtBu2)2]IrH2. This complex is one of the few reported
catalysts in addition to 1 that facilitates the double dehydrogen-
ation of primary amines.15c,28 However, the mechanism is
distinct from 1. Amine dehydrogenation by 1 occurs via a rate-
determining hydride protonation step followed by fast and
reversible β-hydride elimination of a Ru−amido species.16 In
contrast, [C6H3-2,6-(OPtBu2)2]IrH2 facilitates a reversible N−
H bond oxidative addition followed by irreversible β-hydride
elimination.28a When [C6H3-2,6-(OPtBu2)2]IrHCl was sub-
jected to H/D exchange conditions,29 deuterium incorporation
of (S)-1-phenylethylamine provided only 7% deuterium
incorporation (Table 2, entry 3).
The ortho-CH3 groups may also contribute to high stereo
retention by limiting rotation around the Ru−imine bond.
Thus, we examined known inner-sphere (de)hydrogenation
catalysts that have reported imine-bound ruthenium inter-
mediates yet lack significant steric bulk around the ruthenium
center (Table 2). The ruthenium catalyst Ru(PCy3)2(H)2-
30
(H2)2 facilitates amine double dehydrogenation of 1-octyl-
amine to 1-octanenitrile,31 suggesting that this catalytic system
may also promote H/D exchange with high enantiomeric
purity. However, under our optimized conditions, we observed
61% deuterium incorporation into (S)-1-phenylethylamine,
with only 65% ee (entry 4). Similarly, the inner-sphere catalyst
RuCl2(PPh3)3 resulted in 94% deuterium incorporation but
only 68% ee (entry 5). These studies suggest that catalysts 1
and 2 have an additional feature that enables the retention of
enantiomeric purity. We propose that the ortho-CH3
substituents contribute to the high enantiomeric excess by
preventing rotation of the α-chiral amine when coordinated to
complexes 1 and 2.32 Our analysis of known (de)hydrogenation
catalysts highlights the unique role of the bMepi ligand. In the
absence of chiral ligands, stereoretentive hydrogen transfers are
not common.14 We have identified the key features of Ru-
bMepi complexes that enable stereoretention.
Limited examples of primary amine deuteration through C−
H bond activation have been reported,10 and even fewer exist
for α-chiral amines.14 Our study provides a new strategy to use
an achiral hydrogen transfer catalyst for the stereoretentive H/
D exchange of α-chiral aminesthe first homogeneous catalyst
to promote this transformation. We found that the highest
stereoretention is achieved with a catalyst that tightly
coordinates a prochiral imine intermediate, facilitates reversible
β-hydride elimination, and fast Ru−H/Ru−D exchange.
Overall, these studies provide a new method for stereoretentive
C−H activation and will likely find application for late-stage
deuteration as well as synthetic methodology.
Figure 4. Comparison of the binding affinity of alcohols and amines
and the effect on stereoretention.27
Consistent with these data, when (S)-1-phenylethanol was
subjected to conditions for H/D exchange, complete
racemization was observed. The requirement for a coordinated
imine intermediate is further supported by comparison with the
known outer-sphere catalyst, Shvo’s complex ([(η5-
Ph4C4CO)2H]Ru2(CO)4(μ-H)).13a,d We hypothesized that
the % ee may erode with catalysts that operate through an
outer-sphere mechanism due to face-to-face exchange of the
imine π-bond. Accordingly, a reduction in % ee was observed
with Shvo’s catalyst, providing deuterium incorporation of 78%
with 50% ee (Table 2, entry 2).
Although an imine-bound intermediate appears to be a
requirement for stereoretentive deuteration with 1 and 2, we
Table 2. Deuteration of (S)-1-Phenylethylamine with Known
Hydrogen Transfer Catalysts
entry
catalyst
% D
% ee
1
2
2
95
78
7
99
50
ASSOCIATED CONTENT
[(η5-Ph4C4CO)2H]Ru2(CO)4(μ-H))
[C6H3-2,6-(OPtBu2)2]IrHCl
Ru(PCy3)2(H)2(H2)2
■
a
S
3
N/A
65
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b07879.
4
5
61
94
RuCl2(PPh3)3
68
a
10 mol% NaOtBu added.
Experimental details and characterization data (PDF)
C
DOI: 10.1021/jacs.6b07879
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
K.-N. T.; Lin, S.; Kampf, J. W.; Szymczak, N. K. Chem. Commun.
(Cambridge, U. K.) 2016, 52, 2901.
(16) Hale, L. V. A.; Malakar, T.; Tseng, K.-N. T.; Zimmerman, P. M.;
Paul, A.; Szymczak, N. K. ACS Catal. 2016, 6, 4799.
(17) Nogradi, M. Stereoselective Synthesis: A Practical Approach, 2nd
ed.; VCH: Weinheim, 1995.
AUTHOR INFORMATION
■
Corresponding Author
*nszym@umich.edu
Notes
The authors declare no competing financial interest.
(18) Deuterium incorporation was also observed at other C−H
positions. See SI and Figure 3 for full details.
ACKNOWLEDGMENTS
(19) For a representative example, see: Bizet, V.; Pannecoucke, X.;
Renaud, J.-L.; Cahard, D. Angew. Chem., Int. Ed. 2012, 51, 6467.
(20) Note that a ruthenium−imine species could not be isolated;
thus, PPh3 was employed as an alternative L-type ligand.
(21) For a similar H/D exchange reaction with a ruthenium hydride,
see: Frost, B. J.; Mebi, C. A. Organometallics 2004, 23, 5317.
(22) Tseng, K.-N. T.; Kampf, J. W.; Szymczak, N. K. ACS Catal.
2015, 5, 411.
■
We thank Shantel Leithead for initial screening with 1-
octylamine, the Nagorny lab for use of their HPLC, and Prof.
Matzger and Dr. Antek Wong-Foy for providing select
substrates. This work was supported by the NIH (GM
111486). N.K.S. is an Alfred P. Sloan Research Fellow and a
Camille Dreyfus Scholar.
(23) The incorporation of deuterium is affected by the volume of the
reaction vessel. See SI for details.
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DOI: 10.1021/jacs.6b07879
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