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Iron-Catalyzed Reductive Deuteration of Ketones and Imines

Di-Di Chen, Yu-Tong Gu, Xu-Ya Ma, Xia Tian, Jian-Rong Han, Ying-Zhuang Xu, Qiushi Cheng,*
Shouxin Liu,* and Wei Su*
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ABSTRACT: An iron-catalyzed reductive deuteration has been

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developed for the efficient synthesis of deuterated alcohols and amines.

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This method employs cost-effective DMSO-d6 as the deuterium source

and (Bpin)2 as the reductant, achieving high levels of D-incorporation
(up to 99%) across various substrates, including aryl alkyl ketones, diaryl
ketones, aryl aldimines, and aryl ketimines. Mechanistic studies indicate
that the ionic iron−boron intermediate generated under conditions of
excess base, high temperature, and polar solvents serves as a crucial intermediate for reducing C�O and C�N bonds to form
radical anions through single electron transfer (SET), which then undergo deuterium atom transfer (DAT) to afford the reductive
deuteration products.

D euterium-labeled compounds have become indispensable

tools across various disciplines, including chemistry,
materials science, and life sciences.1−3 Among these, α-
Scheme 1. Radical Reductive Deuteration

deuterated alcohols and amines are particularly significant,

not only because hydroxyl and amino groups are prevalent in
bioactive molecules4 but also because of their critical role as
intermediates in the synthesis of deuterated candidate drugs
and functional materials.5 The reductive deuteration of
carbonyl compounds and imines has emerged as one of the
most popular methods for synthesizing α-deuterated alcohols
and amines.6 However, earlier studies revealed that the use of
expensive deuterated reductants, such as LiAlD4, NaBD4 or D2
under metal catalysis, severely restricted the practicality of
reductive deuteration.7
Recently, radical reductive deuteration has garnered
considerable interest due to its mild reaction conditions,
cost-effective deuterium sources, and high levels of D-
incorporation.8 This burgeoning interest has spurred the
development of various methodologies for photochemical,9
electrochemical,10 and single-electron reductant-promoted11
radical deuteration. For example, in the context of synthesizing
α-deuterated alcohols (Scheme 1a), Bao reported a magne- reduction deuteration of imines (Scheme 1b), the Walsh
sium-mediated reductive deuteration for diaryl ketones that group, as well as the Chen and Fan groups, respectively,
utilizes only 1.5 equiv of D2O.12 Moreover, photoinduced utilized Ir(III) as photocatalyst to accomplish the deuteration
of diaryl ketimines and cyclic N-sulfonylimines.17,18 The Li and
reductive deuteration of ketones has been successfully
Huang group successfully employed DMSO-d6 as deuterium
accomplished using CdSe quantum dots13 and ultrathin
source for the electrochemical deuteration of N-aryl sub-
ZnIn2S4,14 along with conjugated aryl amines,15 which can
function either as catalysts or in the absence of a catalyst.16
However, these reactions primarily apply to diaryl ketone Received: April 22, 2025
substrates, with only a limited number of cases involving other Revised: May 22, 2025
types of ketones, such as cyclopentanone, cyclohexanone, and Accepted: June 5, 2025
phenylbenzyl ketone.14 Additionally, the reaction efficiency for
aryl alkyl ketones, such as butyrophenone12 and 3-pyridine
acetone,14 remains notably low. Regarding the radical

© XXXX American Chemical Society https://doi.org/10.1021/acs.orglett.5c01616

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Organic Letters pubs.acs.org/OrgLett Letter

stituted aryl aldimines.19 Currently, the Ou and Su group has diminished D-incorporation (entries 1, 5, and 6). These results
significantly expanded the scope of imine substrates through are analogous to the phenomena observed in iron-catalyzed
electrochemical deuteration reactions utilizing D2O as alkene hydroboration, where the proportion of Markovnikov
deuterium source, compatible with structurally diverse products increases with the escalating amount of LiOtBu and
imines.20 Although a series of radical reductive deuteration higher reaction temperatures.21 Consequently, we postulate
reactions involving C�O and C�N bonds have been that reductive deuteration, akin to the Markovnikov hydro-
developed, the limitations in substrate scope, coupled with boration of alkenes, occurs via an ionic iron−boron
the necessity for photochemical or electrochemical reaction intermediate, Li+[FeBpin(OtBu)2]−, which is facilitated by
apparatus, render the advancement of new methods highly the formation in the presence of an excess of LiOtBu and
anticipated. elevated temperatures.
In our previous work on iron-catalyzed alkene hydro- With the optimized reaction conditions established, the
boration,21 we discovered that the ionic iron−boron scope of carbonyl compounds was investigated (Scheme 2).
intermediate [Fe(II)Bpin(OtBu)2]− possesses the capability Di(hetero)aryl ketones (2b-2f), which demonstrate compati-
of single-electron reduction. Building upon this, we hypothe- bility in previous radical deuteration, can also be efficiently
size that this intermediate could reduce carbonyl compounds converted into α-deuterated alcohols with high levels of
or imines to carbon radicals and subsequently abstract a deuteration in this iron-catalyzed reaction. Aryl aldehydes
deuterium from deuterated reagents to achieve reductive exhibit low reactivity, and α-monodeuterated primary alcohol
deuteration. Herein, we report an iron-catalyzed reductive 2g was obtained in 38% yield with 85% D-incorporation.
deuteration of carbonyl compounds and imines with DMSO-d6 Subsequently, aryl alkyl ketones, which have posed significant
as the deuterium source and (Bpin)2 as the reducing agent challenges in previous studies, was examined in detail. Primary
(Scheme 1c). This reaction exhibits broad substrate scope, (2h-2ab), secondary (2a, 2ac-2ag) and tertiary (2ah-2aj)
allowing for high yields and notable deuterium incorporation alkyl-substituted aryl ketones with diverse structures all
in the conversion of aryl alkyl ketones, diaryl ketones, aryl demonstrated smooth deuteration processes, resulting in α-
aldimines, and aryl ketimines. Furthermore, it is capable of or α, β- deuterated alcohols with good yields and high D-
yielding α,β-deuterated alcohols and amines from substrates incorporation. When scaled up to 8 mmol, 2af was obtained in
containing α-H. 68% yield and maintained D-incorporation. Substrates
The iron-catalyzed reductive deuteration was initiated using featuring electron-withdrawing groups (2j, 2m, and 2n),
isobutyrophenone 1a as the model substrate (Table 1). When electron-donating groups (2h, 2i, 2k, and 2l), and ortho
sterically hindered group (2o) on the aryl delivered the desired
Table 1. Effect of the Amount of LiOtBu and Temperaturea products in comparable yields. Furthermore, a diverse array of
functional groups, including ether (2e, 2g, 2q, 2v), thioether
(2i), fluorine (2j, 2m), chlorine (2n, 2u), acetal (2p), amine
(2aa), amide (2aj), ferrocene (2d), thiophene (2e, 2f, 2z, 2ai),
and furan (2s), have been demonstrated to exhibit excellent
tolerance. However, ester, aryl bromide, and aryl iodide were
found to be incompatible under the reaction conditions,
Entry LiOtBu (mmol) temp. (°C) α-D (%)b β-D (%)b yield (%)c
resulting in the generation of complex mixtures (see
1 0.4 80 97 98 93 Supporting Information, page S20). Notably, three drug
2 0.3 80 81 63 87
molecules featuring aryl ketone structures, namely, Donepezi,
3 0.2 80 79 61 92
Ebastine, and Haloperidol, successfully yielded α,β-deuterated
4 0.1 80 58 20 80
alcohols with high levels of D-incorporation (5-7). In the case
5 0.4 70 86 83 88
of Haloperidol, densely packed functional groups, including
6 0.4 60 83 70 83
a
aryl fluorides, aryl chlorides, aliphatic amines, and even free
Ketone 1a (0.1 mmol), FeCl2 (10 mol %), (Bpin)2 (0.2 mmol), hydroxyl, were all preserved during this reaction, demonstrat-
LiOtBu, MgSO4 (0.2 mmol), DMSO-d6 (0.5 mL), 12 h. bDetermined ing favorable compatibility. The incorporation of deuterium at
by 1H NMR. cIsolated yield.
the β-position of the hydroxyl group in the product has been
demonstrated to occur through H/D exchange between the
FeCl2 (10 mol %) was employed as the catalyst, along with carbonyl α-hydrogen in the substrate and DMSO-d6 under
(Bpin)2 as the reducing agent, LiOtBu as the base, and MgSO4 basic conditions; likewise, the introduction of deuterium at
as additive in DMSO-d6 at 80 °C for 12 h, an α,β-dideuterated both α-positions of thiophene (2e, 2f, 2z, 2ai) and benzylic
alcohol 2a was obtained with a yield of 93%, exhibiting D- sites (2c, 2l, 2s, 2u, 2v, 2x, 2z, 2ag, 2aj) can be ascribed to this
incorporation of 97% and 98% at the α- and β-positions, same reason (see Supporting Information page S16−19). The
respectively (entry 1). The incorporation of the β-D atom is decreased D-incorporation at the thiophene α-position of 2z,
presumed to occur through hydrogen isotope exchange in comparison to those of 2e and 2f, was attributed to the
involving the acidic carbonyl α-H in the substrate under competitive H/D exchange occurring at the benzyl and
basic conditions. Notably, both the amount of LiOtBu and the carbonyl α-positions.
reaction temperature significantly influence the D-incorpo- Motivated by the extensive compatibility of the ketone
ration of the products. Upon progressively decreasing the substrate, we subsequently extended this iron-catalyzed
amount of LiOtBu, it was observed that the D-incorporation reductive deuteration of imines (Scheme 3). By employing
gradually declined (entry 1−4), ultimately reaching α-D: 58% Fe(OTf)2 as the catalyst instead of FeCl2, α-substituted amine
and β-D: 20% with 0.1 mmol LiOtBu (entry 4). Furthermore, 4a was obtained in 92% isolated yield with 98% D-
sequentially lowering the reaction temperature from 80 to 70 incorporation. After the n-butyl group on the imine nitrogen
°C and subsequently to 60 °C correspondingly resulted in atom was substituted with more sterically hindered isobutyl
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Scheme 2. Scope of Carbonyl Compoundsa

a
Ketone (0.1 mmol), FeCl2 (10 mol %), (Bpin)2 (0.2 mmol), LiOtBu (0.4 mmol), MgSO4 (0.2 mmol), DMSO-d6 (0.5 mL), 80 °C, 12 h. bLiOtBu
(0.2 mmol), 50 °C.

(4b), cyclohexyl (4c), and tert-butyl (4d), the corresponding process that included condensation and iron-catalyzed
products were still obtained with high D-incorporation, reductive deuteration, achieving an overall yield of 62% with
although the yields displayed a decline. In addition to N- 96% α-D and 82% β-D incorporation.
alkyl substituted aryl aldimines (4a-4i), N-aryl substituted aryl In order to gain insight into the underlying mechanism,
aldimines (4j-4l), N-alkyl substituted aryl ketimines (4m-4o), several experiments were conducted (Scheme 5). First, when
and N-aryl substituted aryl ketimines (4p-4r) could all the hydrogenation product 2a-H was subjected to iron-
smoothly yield the corresponding α- or α,β- deuterated amines catalyzed reductive deuteration conditions, neither the α-
as products with high D-incorporation. Furthermore, imines position nor the β-position of 2a-H exhibited deuterium
synthesized from benzophenone with NH3 (4s) or n- incorporation (Scheme 5a). This finding rules out the
butylamine (4t) are also suitable reaction substrates. It should possibility that the reaction proceeds prior to hydrogenation
be noted that the hydrogen atoms in the aldimine substrates followed by H/D exchange. Next, when MeOtBu was utilized
can mostly be retained to produce α-monodeuterated amines as solvent instead of DMSO-d6, the reaction yielded hydro-
(4a-4f, 4j-4l); however, in certain substrates, α,α-dideuterated boration product 2a-Bpin in a 60% yield, while only trace
amine products were obtained (4g-4i). amounts of the hydrogenation product were detected (Scheme
To investigate the application potential of this reaction, the 5b). Integrating the results of our previous iron-catalyzed
synthesis of deuterated analogues of drugs was conducted regiodivergent alkene hydroboration,21 we hypothesize that
(Scheme 4). Deuterated Butenafine 9, which had an distinct types of iron−boron intermediates tend to form in
incorporation of 3.4 D per molecule, was obtained through a different solvents, thereby facilitating the selective generation
three-step process involving the condensation of aldehyde and of various products. In ether solvents, the neutral iron−boron
amine followed by iron-catalyzed reductive deuteration and N- intermediate [FeBpin(OtBu)] was formed and subsequently
methylation, yielding an overall yield of 53%. Subsequently, underwent addition to carbonyl to yield α-Bpin substituted
deuterated Fendiline 11 was synthesized through a two-step alcohol 2a-Bpin. Furthermore, under treatment with LiOtBu in
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Scheme 3. Scope of Imines Scheme 5. Mechanistic Studies

a
Imine (0.1 mmol), Fe(OTf)2 (10 mol %), (Bpin)2 (0.2 mmol),
LiOtBu (0.4 mmol), MgSO4 (0.2 mmol), DMSO-d6 (0.5 mL), 80 °C,
12 h. bLiOtBu (0.45 mmol). cSixteen h.

Scheme 4. Reaction Applications

radical adduct DMPO-C• (see Supporting Information, page

S19). It is noteworthy that substrates 12 and 14, which feature
α-oxygen atom substitution and α-nitrogen atom substitution,
respectively, undergo α-C−heteroatom bond cleavage in this
DMSO, compounds 2a-Bpin could be rapidly converted into reaction to yield α,β-dideuterated alcohols (Scheme 5d). Based
protodeboronation product 2a-H; and α-D incorporation was on previous work regarding the cleavage of α-C-heteroatom
limited to only 16% or 18% with DMSO-d6 as solvent or under bonds in carbonyl compounds,22 we postulate that the
standard conditions (Scheme 5b). These results eliminate the carbonyl first undergoes single-electron reduction (SER) to
possibility that the reaction occurs via carbonyl hydroboration, yield a radical anion intermediate, which is subsequently
followed by protodeboronation. When TEMPO was intro- followed by intramolecular electron transfer (intra-ET) to
duced as radical trapping agent, significant inhibition of the facilitate the cleavage of the α-C-heteroatom bond. Sub-
reductive deuteration was observed along with retention of sequently, three sets of control experiments were conducted
starting materials, indicating that the reaction may proceed (Supporting Information page S15−16). The experimental
through a radical mechanism (Scheme 5c). results indicated that when the para position of the aryl group
Furthermore, radical trapping experiments employing conjugated with C�O or C�N was substituted with an
DMPO (5,5-dimethyl-1-pyrroline N-oxide) as a spin-trapping electron-withdrawing group (-F), the reaction rate was
agent were conducted, with ESR spectroscopic analysis significantly higher compared with when it was substituted
revealing the characteristic signal of the carbon-centered with an electron-donating group (-OMe). This finding further
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corroborates that the reaction proceeds via a single-electron Provincial Key Laboratory of Photoelectric Control on
reduction mechanism. Surface and Interface, Hebei University of Science and
In summary, we have developed an iron-catalyzed reductive Technology, Shijiazhuang 050022, China
deuteration using DMSO-d6 as the deuterium source and Complete contact information is available at:
(Bpin)2 as the reducing agent. This method is compatible with https://pubs.acs.org/10.1021/acs.orglett.5c01616
a variety of structural aryl ketones and imines, particularly aryl
alkyl ketones, which were difficult to apply in previous works, Notes
providing a general approach for the synthesis of deuterated
benzyl alcohols and deuterated benzyl amines. The ionic iron− The authors declare no competing financial interest.
boron intermediate generated under conditions of excess base,
high temperature, and polar solvents was proposed to reduce
C�O and C�N to form radical anion intermediates through
■ ACKNOWLEDGMENTS
We acknowledge the National Natural Science Foundation of
a single electron transfer process, which can then achieve China (NSFC 21901059 to W.S.); the Central Guidance on
reductive deuteration via deuterium atom transfer. Local Science and Technology Development Fund of Hebei

■ ASSOCIATED CONTENT
Data Availability Statement
Province (No. 236Z2601G to W.S.); the Youth Top-notch
Talent Supporting Plan of Science and Technology Project of
Hebei Education Department (No. BJK2022051 to W.S.); the
The data underlying this study are available in the published Start-up Grant from Hebei University of Science and
article and its Supporting Information. Technology to W.S. and Q.C.
*
sı Supporting Information

The Supporting Information is available free of charge at

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