Practical Method for Reductive Deuteration of Ketones with Magnesium and D2O

Article abstract of DOI:10.1021/acs.orglett.9b04536

α-Deuterated alcohols have important applications in pharmaceuticals and mechanism studies. Here, we report a new and practical strategy for the reductive deuteration of ketones using a Mg/BrCH₂CH₂Br/D₂O system, which affords α-deuterated alcohols in good yields and with almost quantitative incorporation of deuterium. The synthetic value of this method has been demonstrated by the easy access to deuterated drugs or drug derivatives. This method may inspire the discovery of other deuterium-containing drugs.

Full text of DOI:10.1021/acs.orglett.9b04536

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Letter
Practical Method for Reductive Deuteration of Ketones with
Magnesium and D2O
Nengbo Zhu, Min Su, Wen-Ming Wan, Yajun Li, and Hongli Bao*
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ABSTRACT: α-Deuterated alcohols have important applications
in pharmaceuticals and mechanism studies. Here, we report a new
and practical strategy for the reductive deuteration of ketones using
a Mg/BrCH2CH2Br/D2O system, which affords α-deuterated
alcohols in good yields and with almost quantitative incorporation
of deuterium. The synthetic value of this method has been
demonstrated by the easy access to deuterated drugs or drug
derivatives. This method may inspire the discovery of other deuterium-containing drugs.
ince deuterium was discovered in 1931 by Harold C.
Urey,1 who received the 1934 Nobel Prize for his
between carbonyl compounds and secondary alcohols
(Strategy B) and could be adopted to deuterated version if
α-deuterated secondary alcohols are applied.10 Single electron
reduction (SER) by a reducing reagent to form a carbon
radical which abstracts a deuterium from the surrounding
molecules is another potential pathway but would be less
useful as this method not only suffers from the tendency of the
carbon radical to dimerize, producing pinacol-type products,
but also needs expensive R-D reagents like d8-THF (Strategy
C). The umpolung strategies D11 undergo double SER to
directly afford carbanion species that can be deuterated to
produce α-deuterated alcohols. In terms of a practical and
general synthesis of α-deuterated alcohols in large quantities,
the umpolung strategies which use D2O as the deuterium
source have great advantages in price, supply, and safety.
Among all these deuterium sources utilized in strategies A−D,
D2O is the best reagent because it can be obtained in large
quantities at the lowest price.12 For general comparison, the
price of D2O is only 2% of that for NaBD4 and 0.2% of that for
LiAlD4. However, the umpolung strategies have rarely been
utilized in the reductive deuteration of ketones because these
methods would require a large excess amount of D2O or
CD3OD (typically more than 100 equiv).13
S
contributions, there has been significant interest in the use of
deuterium, and the number of deuterium-labeled compounds
reported has increased dramatically.2 Examples of the use of
deuterium to facilitate mechanistic, spectroscopic, and tracer
studies can be found within almost every subdiscipline in the
life and physical sciences.3 Among these applications,
preparation of deuterated pharmaceuticals and other bio-
logically active compounds attracted great attention because
the precision deuteration of drugs allows one to proceed
beyond establishment of the pharmacokinetic parameters of a
drug and might provide an opportunity to solve problems of
metabolism-mediated toxicity, drug interactions, and low
bioactivation.4 The use of deuterium also offers opportunities
to discover new drugs by merely substituting deuterium for
hydrogen in drugs that have already been approved.5 α-
Deuterated alcohols6 enjoy a range of uses. They work as key
intermediates in the processing of deuterium-containing
biologically active compounds, including deuterium-containing
drugs (Figure 1A).7 They serve as deuterium sources in the
synthesis of other deuterated compounds and have potential
applications in material science.8 Reductive deuteration of
carbonyl compounds is the most straightforward process to
deliver α-deuterated alcohols.6a−c In principle, there are several
different strategies based on different mechanistic pathways to
reduce carbonyl compounds to α-deuterated alcohols (Figure
1B). Nucleophilic addition of a deuteride anion (D−) to a
carbonyl group (Strategy A) is the traditional pathway. Alkali
metal deuteride salts like lithium aluminum deuteride (LiAlD4)
or sodium borodeuteride (NaBD4) serve as the common
sources of the deuteride anion.2j The deuteride species can also
be generated in situ from metal catalysts and D2 in the form of
deuterium gas or its precursors.9 Meerwein−Ponndorf−Verley
reduction, a frequently used method for the reductive
hydrogenation of carbonyl compounds, features rearrangement
Herein, we report a practical method for the reductive
deuteration of ketones with a Mg/BrCH2CH2Br/D2O system,
affording α-deuterated alcohols in yields as high as 88% and
deuterium incorporation in excess of 98%. Only 1.5 equiv of
D2O is required for the deuteration, while alternative methods
need a large excess amount of D2O or CD3OD.
Received: December 18, 2019
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together with the accompanied pinacol (1b) were formed,
but control of the selectivity was challenging. With LiCl or
MgI2 as the additive, the reaction failed to deliver either the
targeted deuterated alcohol (1a) or the pinacol 1b (Figure 2).
When dibromomethane was employed as the additive, the
reaction afforded the α-deuterated alcohol (1a) in 7% yield
although with only 40% deuterium incorporation. 1,2-
Dibromoethane promoted the reaction, giving the α-
deuterated alcohol (1a) in 83% yield with more than 98%
deuterium incorporation and only 12% of pinacol (1b) as the
byproduct. Other alkyl bromides were investigated but failed to
further improve either the yield or the deuterium incorpo-
ration. 1,2-Dibromoethane appears to assume a unique role in
this reaction. Control experiments without the addition of
magnesium or BrCH2CH2Br were also carried out, and only a
trace amount of the desired products was detected in both
cases. The use of only 1.5 equiv of D2O demonstrates that this
method is highly efficient, economical, simple, and useful for
the synthesis of deuterated alcohols from carbonyl compounds.
With the optimal reaction conditions in hand, the scope of
substituted benzophenones was investigated, and the results
are summarized in Figure 3. In general, the variously
substituted benzophenones can be transformed into the
desired products in good yields and with >96% deuterium
incorporation. Substrates with a moderate electron-with-
drawing group, such as fluorine or chlorine, afforded the
corresponding products (2a−10a) in moderate to good yields.
Strong electron-withdrawing groups, such as the cyano (11)
and ester groups (12), which are sensitive under conditions of
the Grignard reaction, are also tolerated. Moreover, a terminal
olefin (13) that tends to be reduced with magnesium/
methanol remained unaffected under the reaction conditions.14
The reactions occurred smoothly with substrates containing an
t
electron-donating group, such as Me, Bu, OMe, Ph, and
NMe2, and delivered the corresponding product in 48−86%
yields (14a−31a).
Figure 1. (a) Representative examples of drugs prepared from
alcohols. (b) Potential strategies for synthesis of α-deuterated alcohols
by the reduction of ketones. (c) This work.
We explored the scope of other type of ketones. Substrates
with a five-, six-, or seven-membered ring underwent the
reaction smoothly to produce the corresponding products
(32a−35a) in 57−88% yields and with up to 97% deuteration
incorporation. The reactions also proceeded well with
pyridines, affording the target products in 61−82% yields
(38a−41a). A pyridine-fused tricyclic compound participated
in the reaction and afforded the desired product (42a) in 88%
yield. The two symmetric diketones that were tested offered an
opportunity for the selective reduction of one of the carbonyl
groups and afforded the monodeuterated products (43a and
44a) in moderate yields with the second carbonyl group
untouched. As examples, monoaryl ketone (36) and dialkyl
ketone (37) did not work well under the optimal reaction
conditions.
As shown in Figure 2, we began our study by screening the
additives required for the reaction of benzophenone (1) in
THF with a stoichiometric amount of D2O as the deuterium
source. The desired reductive deuteration product (1a)
To explore the synthetic potential of this method, direct
reductive deuteration of the drug molecules and synthesis of
various deuterated drug molecules was carried out as shown in
Figure 4. Fenofibrate,15 a drug for the treatment of
hyperlipidemia, mixed dyslipidemia, and hypertriglyceridemia,
can be selectively reduced to the corresponding deuterated
alcohols (45a). Esters, chlorides, and ethers are tolerated well
under the reductive conditions. Furthermore, several other
types of deuterated drugs or drug precursors were synthesized
through the current reductive deuteration method. First, we
examined the deuteration of diphenhydramine,16 a histamine
antagonist with antiallergic activity. Under basic reaction
Figure 2. Reductive deuteration of ketones with different additives.
B
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Figure 3. Substrate scope. Reaction conditions: ketone (1.0 mmol), BrCH2CH2Br (2.0 equiv), Mg (freshly peeled, 5.0 equiv), and D2O (1.5 equiv)
in THF (2 mL) at 70 °C for 2 h unless otherwise noted in the Supporting Information; isolated yield.
conditions, nucleophilic attack on chloroamine (52) by α-
deuterated alcohol (1a) led to the formation of deuterated
diphenhydramine (46a) in an excellent yield and with almost
quantitative deuterium incorporation. Buclizine7a,17 is an
antagonist with primarily antiemetic and antivertigo activities.
One-pot treatment of α-deuterated alcohol (7a) with
substituted piperazine (53) gave deuterated buclizine (48a)
in a moderate yield and without any deuterium loss. The
deuterated chloride intermediate (47a) that is important in the
synthesis of buclizine might also be used for other valuable
structural modifications. In addition, modafinil and adrafinil,18
central nervous system stimulants, have a sensitive sulfinyl
group and an amide. Nucleophilic attack of 2-mercaptoacetic
acid with an α-deuterated alcohol (1a) would afford
deuterated (benzhydrylsulfanyl)acetic acid (49a), which can
be used as the precursor for the synthesis of deuterated
modafinil (50a) and deuterated adrafinil (51a) according
published methods.18b In general, we developed an efficient
C
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Figure 4. Synthetic applications to deuterium-containing drugs and precursors.
Figure 5. Proposed mechanism for the reductive deuteration of ketones.
and practical method for the synthesis of deuterium-containing
or deuterium-modified drugs.
the radical anion in the presence of a large excess of the proton
source. In our method, only 1.5 equiv of the deuterium source
(D2O) is required for the efficient formation of the desired α-
deuterated alcohols, and the use of alkyl bromides other than
1,2-dibromoethane all failed to provide the product with high
deuterium incorporation. These facts imply that a new reaction
mode utilizing BrCH2CH2Br might be involved. Inspired by
the comprehensive theoretical study of the Grignard reagent
formation,20 we conceived that the reaction may proceed
The mechanism of the reductive deuteration of carbonyl
compounds with magnesium as a reducing agent was reported
previously to proceed by a SER to give a radical anion. A
pinacol adduct was obtained by rapid dimerization of the
radical anion in the absence of interaction with an added
proton source.19 The desired alcohol was formed by
protonation of the carbanion obtained by a further SER of
D
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through a six-membered metallacyclic intermediate IV or
noncyclic metal intermediate V. A plausible mechanism was
proposed and depicted in Figure 5. First, SER of the carbonyl
compound and BrCH2CH2Br proceeded on the magnesium
surface to afford a radical anion I and an anchored Grignard
reagent, respectively. Followed by dissociation of II from the
metal surface, a second SER can afford the anchored metalated
intermediate III, which will lead to the diffusion of
intermediate IV or V. The desired α-deuterated alcohol is
produced upon deuteration by D2O. If the diffusion of the
radicals I and II from the metal surface occurs prior to the SER
process, a pinacol would be formed. We hypothesize that
intermediate IV or V might be responsible for the reductive
deuteration.
Academy of Sciences, Fuzhou 350002, P. R. China;
orcid.org/0000-0001-6690-2662
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04536
Author Contributions
H.B. directed the investigations and prepared the manuscript.
N.Z. and M.S. performed the synthetic experiments and
analyzed the experimental data. N.Z., Y.L., and W.W.
contributed to the discussion and preparation of the
manuscript.
Notes
The authors declare no competing financial interest.
In conclusion, a practical method for the reductive
deuteration of carbonyl compounds to α-deuterated alcohols
with excellent deuterium incorporation is reported. Only 1.5
equiv of D2O was required for the highly efficient trans-
formation. This method features mild reaction conditions,
good substrate scope, and excellent functional group tolerance.
The importance of this methodology has been demonstrated
by feasible reductive deuteration of fenofibrate and deuteration
of drugs or drug precursors such as diphenhydramine,
buclizine, modafinil, and adrafinil.
ACKNOWLEDGMENTS
■
We thank the National Key R&D Program of China (Grant
2017YFA0700103), the NSFC (Grants 21672213, 21871258,
and 21922112), the Strategic Priority Research Program of the
Chinese Academy of Sciences (Grant XDB20000000), and the
Haixi Institute of CAS (Grant CXZX-2017-P01) for financial
support.
REFERENCES
■
ASSOCIATED CONTENT
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■
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Experimental details, data, and spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Hongli Bao − State Key Laboratory of Structural Chemistry, Key
Laboratory of Coal to Ethylene Glycol and Its Related
Technology, Center for Excellence in Molecular Synthesis, Fujian
Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou 350002, P. R. China;
orcid.org/0000-0003-1030-5089; Email: hlbao@
fjirsm.ac.cn
Authors
Nengbo Zhu − State Key Laboratory of Structural Chemistry,
Key Laboratory of Coal to Ethylene Glycol and Its Related
Technology, Center for Excellence in Molecular Synthesis,
Fujian Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou 350002, P. R. China
Min Su − State Key Laboratory of Structural Chemistry, Key
Laboratory of Coal to Ethylene Glycol and Its Related
Technology, Center for Excellence in Molecular Synthesis,
Fujian Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou 350002, P. R. China
Wen-Ming Wan − State Key Laboratory of Structural
Chemistry, Key Laboratory of Coal to Ethylene Glycol and Its
Related Technology, Center for Excellence in Molecular
Synthesis, Fujian Institute of Research on the Structure of
Matter, Chinese Academy of Sciences, Fuzhou 350002, P. R.
China; orcid.org/0000-0002-3692-4454
Yajun Li − State Key Laboratory of Structural Chemistry, Key
Laboratory of Coal to Ethylene Glycol and Its Related
Technology, Center for Excellence in Molecular Synthesis,
Fujian Institute of Research on the Structure of Matter, Chinese
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