Regioselective α-Deuteration of Michael Acceptors Mediated by Isopropylamine in D2O/AcOD

Article abstract of DOI:10.1021/acs.orglett.0c03839

Site-specific hydrogen/deuterium exchange is an important method to access deuterated compounds for chemical and biological studies. Herein is reported the first method for the regioselective α-deuteration of enals and enones. The transformation features D2O and AcOD as deuterium sources and amines as organocatalysts. The deuteration strategy is scalable and works on enals with a variety of substituted arene or heterocycle motifs as well as enones. The method has been applied to the synthesis of deuterated drug precursors.

Full text of DOI:10.1021/acs.orglett.0c03839

pubs.acs.org/OrgLett
Letter
Regioselective α‑Deuteration of Michael Acceptors Mediated by
Isopropylamine in D2O/AcOD
Vinod G. Landge,* Kendra K. Shrestha, Aaron J. Grant, and Michael C. Young*
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ABSTRACT: Site-specific hydrogen/deuterium exchange is an important method to access deuterated compounds for chemical
and biological studies. Herein is reported the first method for the regioselective α-deuteration of enals and enones. The
transformation features D2O and AcOD as deuterium sources and amines as organocatalysts. The deuteration strategy is scalable and
works on enals with a variety of substituted arene or heterocycle motifs as well as enones. The method has been applied to the
synthesis of deuterated drug precursors.
he sustainable synthesis of deuterated pharmaceutical
compounds is gaining momentum in chemical synthesis
Selective deuteration of enals and enones proves to be more
challenging than other Michael acceptorsthe presence of
multiple sites of reactivity can lead to poor selectivity, while the
electrophilicity of the carbonyl can lead to side reactions. In a
recent example, NHCs were shown to promote ipso-
deuteration of aldehydes (Scheme 1a),13 though yields were
improved when the α-position was blocked.
T
because replacing hydrogen with deuterium can alter the
absorption, distribution, metabolism, and excretion properties
of drug candidates while retaining their biological potencies.1
Deuterium-labeled compounds have found many applications:
they serve as useful probes for identifying drug metabolites in
vivo2 and are important for mechanistic studies in organic and
metal-catalyzed reactions.3 Notably, the US Food and Drug
Administration has recently cleared deutetrabenzine for use,
making it the first drug approved specifically as its deuterated
analogue.4 The synthesis of organic compounds that are
selectively labeled with deuterium at nonacidic positions,
however, remains a challenging synthetic problem.5 Recently,
nonregioselective synthesis of deuterated molecules has been
achieved by using transition-metal catalysts for the deuteration
of unactivated aromatic6 or aliphatic7 C−H bonds, while the
use of directing groups has allowed H/D exchange to occur
site-selectively at C−H bonds proximal to the directing group.8
Michael acceptors, such as enones and enals, are important
building blocks in the synthesis of drugs and natural products.
As a result, many methods have been studied for the
regioselective deuteration of these species. For example,
ruthenium catalysts have been used for the β-deuteration of
vinyl carboxylic acids and esters using D2O and CD3OD.
respectively.9 Subsequently, our group reported the β-H/D
exchange on cinnamic acid derivatives, using low catalyst
loadings of rhodium and D2O as a deuterium source.10
However, cheap and metal-free approaches toward deuterium
incorporation are still sought to reduce the cost of deuterated
drugs.11 Styrenes and cinnamate esters, which are not very
electrophilic, can undergo selective α-H/D exchange using
organocatalytic systems.12
This is because these substrates are known to undergo
organocatalyzed reactions such as benzoin condensation and γ-
butyrolactone formation unless the α-position is blocked.14
Notably, this limits the ability of organocatalytic protocols to
access H/D exchange at the α-position of these substrates.
More recently, a carbene-catalyzed C−H deuteration
reaction of enals was reported that gave high α,γ-selectivity
on allylic C(sp3) and C(sp2) centers (Scheme 1b).15 The
method, however, was not demonstrated to give the deuterated
aldehyde product but rather the carboxylic acid derivatives, and
did not work for heterocyclic compounds. As part of our
continuing interest in the synthesis of deuterated compounds,
we wondered if replacing the NHC catalyst with a weaker
nucleophile could facilitate selective α-deuteration while
preventing cyclizations that require blocking of the β-position.
Instead of reacting at the ipso position, a weaker nucleophile
would favor conjugate addition, which would allow H/D
exchange at the α-position. Herein, we report the first example
Received: November 19, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03839
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Scheme 1. Organocatalytic Approaches for H/D Exchange
Table 1. Optimization of Reaction Conditions
of α,β-Unsaturated Aldehydes
a
entry
reaction conditions
standard conditions
absence of AcOD
D (%)
yield (%)
1
2
3
4
5
6
7
8
96
0
0
97
97
98
96
93
82
65
96
96
97
97
95
93
97
93
35
no amine
AcOH instead of AcOD
triethylamine used as amine
piperidine used as amine
pyrrolidine used as amine
iPrNH2 (0.5 equiv) used as amine
iPrNH2 (1 equiv) used as amine
iPrNH2 (2 equiv) used as amine
iPrNH2 (3 equiv) used as amine
at 60 °C
80
62
93
85
77
90
95
96
0
90
90
70
10
9
10
11
12
13
14
15
16
at 80 °C
reaction time was 8 h
reaction time was 4 h
THF instead of AcOD
a
Reaction conditions: cinnamaldehyde (0.3 mmol), amine (0.9
mmol), and mixture of D2O/AcOD (1:1) 1 mL, heated at 100 °C
for 14 h.
levels of H/D exchange (entries 14 and 15). When AcOD was
replaced by THF, the reaction was significantly inhibited,
demonstrating the need for both an organic solvent as well as
an acidic additive (entry 16).
With the optimized conditions in hand (Scheme 2), we set
out to probe the versatility of our method in the deuteration of
various substituted cinnamaldehydes. Various electron-poor
and electron-rich para-substituted cinnamaldehydes underwent
deuteration at the α-position in good yield (2a−2g). In the
case of 2h, deuterium incorporation was observed at both the
α position and the positions ortho to the aniline group, likely
caused by acid-mediated SEAr with D+.17
of a metal-free regioselective α-deuteration of enals and enones
mediated by isopropyl amine using D2O and AcOD as
deuterium sources. The deuteration strategy is scalable and
works on enals with a variety of substituted arene or
heterocycle motifs, as well as acyclic enones (Scheme 1d).
We began our study on the regioselective α-deuteration of
enals and other Michael acceptors using 4-nitrocinnamalde-
hyde (1a) as a model substrate and D2O and AcOD as the
deuterium sources. AcOD was expected to serve multiple roles,
including as a deuterium source, as an acid catalyst, and finally
as an organic cosolvent to facilitate dissolution of the substrate
in the reaction medium. Initially, 1a and isopropylamine were
combined in a mixture of deuterium oxide and AcOD in a ratio
of 1:1, and the reaction mixture was heated at 100 °C (bath
temperature) for 14 h to yield the expected product 2a with
96% deuterium incorporation at the α position in 97% isolated
yield (Table 1, entry 1). Gratifyingly, in the present reaction
conditions no Baylis−Hillman, lactone dimerization, or
aromatic cyclization16 products were observed.
Notably, deuterium incorporation was not observed in the
absence of both acid and amine (entries 2 and 3). Performing
the reaction with AcOH instead of AcOD led to a predictable
decrease in the levels of deuteration (entry 4). Tertiary and
secondary amines were also effective for promoting this
deuteration reaction and gave 2a in moderate yields, albeit
with lower deuterium incorporation under the optimized
conditions (entries 5−7). The optimal stoichiometry of
isopropylamine was also investigated (entries 8−11), although
the use of 3 equiv of amine gave the highest level of
deuteration and best reproducibility. When the reaction was
carried out at 60 °C, we did not observe the expected product
because of the low solubility of the substrate (entry 12). The
reaction could occur at 80 °C but resulted in lower deuterium
incorporation (entry 13). Shortening the time also led to lower
Notably, the reaction could tolerate a SVI-containing
substrate and afforded the product 2i in good yield with
nearly full H/D exchange. The reaction scope was further
explored for other substituted and unsubstituted cinnamalde-
hydes, which were all tolerated (2j−2o). Less soluble π-
conjugated substrates were also effectively deuterated (2p and
2q) under the reaction conditions. It is noteworthy that
heterocyclic enals such as furfuryl (2r), pyrrolyl (2s),
thiophenyl (2t), benzothiophenyl (2u), and indolyl (2v) also
proceeded efficiently and yielded the corresponding deuterated
products in good yields. Notably, the lower rate of deuteration
(80%) for substrate 2r could be improved to 90% by allowing
the reaction to proceed for an additional 10 h. Perhaps
unsurprisingly, in addition to α-deuteration, the electron-rich
pyrrolyl group underwent deuteration at every position of the
heteroarene (2s). Even a ferrocenyl enal could participate in
the reaction with good deuterium incorporation, albeit with
relatively low recovery due to decomposition. Interestingly, in
the cases of 2i and 2v, we observed minor deuteration at the
2
ipso position, which was confirmed by H NMR and high-
resolution mass spectrometry. Despite the utility to deuterate
aromatic enal substrates, aliphatic enals gave only decom-
position products during the reaction.
B
https://dx.doi.org/10.1021/acs.orglett.0c03839
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a
Scheme 2. Substrate Scope for the Deuteration of Enals
Scheme 3. Substrate Scope for the Deuteration of Other
Michael Acceptors
a
a
Reaction conditions: enal (0.3 mmol), amine (0.9 mmol), and
mixture of D2O/CH3COOD (1:1) 1 mL, heated at 100 °C for 24 h.
Reactions performed in triplicate and the average yield/deuteration
b
c
reported. Pyridine instead of iPrNH2. Solvent ratio adjusted to
a
Reaction conditions: enal (0.3 mmol), amine (0.9 mmol), and
mixture of D2O/AcOD (1:1) 1 mL, heated at 100 °C for 14 h.
Reactions performed in triplicate, and the average yield/deuteration is
d
D2O/CH3COOD/THF (1:1:1) 1.5 mL. D2O replaced with EtOD.
b
reported. For 24 h.
substituted chalcones underwent deuteration at the α-position
in good yield (4b−4f). A furfuryl-containing chalcone gave
product in good yield with a good amount of deuteration.
Surprisingly, in the case of a methyl cedryl ketone derivative,
deuteration was observed at the γ′-position, without any
observed deuteration at the α-position (4h). The same was
observed on methyl cedryl ketone, with deuteration at the γ-
and α′-positions (4i). Notably, our protocol was compatible
with a vanillin-based dibenzylidene acetone (4j). A less soluble
dieneone showed only 6% deuteration and only a slightly
improved 15% when an additional 500 μL of tetrahydrofuran
was added to aid solubilization (4k).
We next set our sights on other α,β-unsaturated carbonyls
(Scheme 3). Commercially available 4-phenylbut-3-en-2-one
was deuterated at the α and α′-positions in 49% and 88%
conversion, respectively (4a), under the standard reaction
conditions. For some substrates, including 4a, we found
through reoptimization that addition of pyridine instead of the
isopropylamine gave increaseds deuteration at α- and α′-
positions in 95% and 96% conversion, respectively (for details,
see the SI). The deuteration at α′ is due to simple enolization
using AcOD. Furthermore, electron-rich and electron-poor
C
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The natural product curcumin could also be subjected to the
reaction conditions to give deuteration of the enones (4l). In
the case of an alkylated aromatic enone, we observed
deuteration at the α-position, but also significant isomerization
to the β,γ-unsaturated ketone (4m). Other α,β-unsaturated
Michael acceptors were also used in the reaction. Ethyl
cinnamate gave decomposition under the standard conditions,
but was returned in good yield with negligible deuteration
when D2O was replaced with EtOD (4n). Similarly, cinnamic
acid did not undergo deuteration under the reaction conditions
(4o). Unsurprisingly, a vinyl nitro compound fully decom-
posed to the aldehyde via a reverse Henry reaction (4p).
With a reasonable understanding of the reaction scope, we
hoped to demonstrate the applicability toward the synthesis of
selectively deuterated drug precursors. A number of statin
drugs can be synthesized from enals, including fluvastatin18
and pitavastatin.19 As such, we took the commercially available
precursor for each and subjected it to our modified conditions
with additional tetrahydrofuran added to aid solubility
(Scheme 4). The fluvastatin precursor 5 was achieved with
Scheme 5. Scale-Up and Synthetic Applications
Scheme 4. Approaches for Synthesis of Deuterated α,β-
Unsaturated Carbonyl Compounds
a
Enal (6 mmol), amine (18 mmol), and mixture of D2O/AcOD (1:1)
b
10 mL, heated at 100 °C for 24 h. 2a (1 equiv), NaBH4 (1.5 equiv),
MeOH, rt. 2a (1 equiv), I2 (1 equiv), aq NH4OH, rt. 2a (1 equiv),
ketone (1 equiv) NaOH (1.3 equiv) EtOH:H2O (1:1), rt. (i) 2a (1
c
d
e
equiv), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide
(1.5 equiv), 18-crown-6 (2 mol %), K2CO3 (1.5 equiv), toluene,
f
100 °C. (ii) 85% H3PO4, THF, 80 °C. (i) 2a (1 equiv), primaquine
(1 equiv), CHCl3, 70 °C. (ii) NaBH4 (1.5 equiv), MeOH, RT.
deuterium oxide and acetic acid as a deuterium source. The
present methodology has a broad substrate scope and can
easily be scaled up for synthetic applications. Significantly,
heterocyclic α,β-unsaturated aldehydes were well tolerated.
Remarkably, our approach was successfully used for selective
α-deuteration of medicinally relevant precursors. A proposed
mechanism and supporting experiments can be found in the
Supporting Information.
84% deuterium incorporation at the α-position but also with
7% incorporation at the ipso-position. The pitavastatin
precursor 6 was isolated with 91% deuteration at the α-
position, but also a small amount of deuteration at both the
ipso-position and on the cyclopropyl side chain.
ASSOCIATED CONTENT
We also wanted to demonstrate that many traditional
reactions of enals could occur with retention of the deuterium
labeling. First, we attempted to scale up the reaction of the
model substrate 1a (Scheme 5). We were delighted to find that
even at 6 mmol scale (20 times the initial scale), the reaction
still worked well, despite reducing the ratio of substrate to
solvent, giving 2a in 91% yield with 95% incorporation of
deuterium. The reduction of 2a was achieved in good yield to
give 7, with only minor loss in deuterium labeling. The
aldehyde was converted to the nitrile via oxidative amination
using iodine and ammonium hydroxide to afford product 8 in
77% yield with 92% deuterium incorporation after the reaction.
Furthermore, 2a was used for condensation reactions to
prepare a dieneone (9) and dieneal (10), though notably with
some loss in deuterium labeling. Deuterated primaquine
derivative 11 can be easily prepared via the reductive
amination of primaquine and 2n.
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03839.
General information, detailed experimental procedures,
1
and H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Vinod G. Landge − Department of Chemistry & Biochemistry,
School of Green Chemistry & Engineering, The University of
Toledo, Toledo, Ohio 43606, United States; orcid.org/
0000-0003-1241-4561; Email: vinod.landge@utoledo.edu
Michael C. Young − Department of Chemistry &
Biochemistry, School of Green Chemistry & Engineering, The
University of Toledo, Toledo, Ohio 43606, United States;
orcid.org/0000-0002-3256-5562;
In conclusion, we have disclosed a versatile and efficient
amine-mediated method for the α-deuteration of α,β-
unsaturated aldehydes and ketones using a mixture of
Email: michael.young8@utoledo.edu
D
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Organic Letters
Authors
pubs.acs.org/OrgLett
Letter
(7) (a) Smith, J. D.; Durrant, G.; Ess, D. H.; Gelfand, B. S.; Piers, W.
E. H/D exchange under mild conditions in arenes and unactivated
alkanes with C6D6 and D2O using rigid, electron-rich iridium PCP
pincer complexes. Chem. Sci. 2020, 11, 10705. (b) Sattler, A.
Hydrogen/Deuterium (H/D) Exchange Catalysis in Alkanes. ACS
Catal. 2018, 8, 2296−2312. (c) Maegawa, T.; Fujiwara, Y.; Inagaki,
Y.; Esaki, H.; Monguchi, Y.; Sajiki, H. Mild and efficient H/D
exchange of alkanes based on C-H activation catalyzed by rhodium on
charcoal. Angew. Chem., Int. Ed. 2008, 47, 5394−5397.
Kendra K. Shrestha − Department of Chemistry &
Biochemistry, School of Green Chemistry & Engineering, The
University of Toledo, Toledo, Ohio 43606, United States
Aaron J. Grant − Department of Chemistry & Biochemistry,
School of Green Chemistry & Engineering, The University of
Toledo, Toledo, Ohio 43606, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03839
(8) (a) Liu, W.; Cao, L.; Zhang, Z.; Zhang, G.; Huang, S.; Huang, L.;
Zhao, P.; Yan, X. Mesoionic Carbene−Iridium Complex Catalyzed
Ortho-Selective Hydrogen Isotope Exchange of Anilines with High
Functional Group Tolerance. Org. Lett. 2020, 22, 2210−2214.
Funding
(b) Muller, V.; Weck, R.; Derdau, V.; Ackermann, L. Ruthenium-
̈
This work was supported in part through start-up funds from
The University of Toledo, the ACS Herman Frasch
Foundation (830-HF17), and the National Institutes of Health
(1R15GM131362−01).
(II)-Catalyzed Hydrogen Isotope Exchange of Pharmaceutical Drugs
by C−H Deuteration and C−H Tritiation. ChemCatChem 2020, 12,
100−104. (c) Eisele, P.; Ullwer, F.; Scholz, S.; Plietker, B. Mild,
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Kerr, W. J.; Lindsay, D. M.; McCabe, T. J. D.; Reid, M.; Tuttle, T.
Iridium-Catalysed ortho-Directed Deuterium Labelling of Aromatic
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Dr. Kristin Blake and Dr. Ian Riddington of The University of
Texas at Austin’s Mass Spectrometry Facility are acknowledged
for collection of high-resolution mass spectrometry data.
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