Carbene-Catalyzed α,?-Deuteration of Enals under Oxidative Conditions

Article abstract of DOI:10.1021/acscatal.0c00636

Organic compounds with deuterated allyl groups are very attractive for drug entities to enhance pharmacokinetic properties, since allylic C-H bonds are prone to metabolic oxidation and the deuterated versions can be less prone to such metabolism. However, direct deuteration at allylic C-H moieties is still a challenge. Few examples have been reported by transition-metal catalysis and no such reports have been documented in an organocatalytic fashion. Herein, a carbene-catalyzed C-H deuteration of enal at allylic C(sp3) and C(sp2) centers is disclosed. Addition of the carbene catalyst to the aldehyde moiety of enals to eventually activate the α- A nd ?-carbon atom under oxidative conditions is critical to achieve high deuterium incorporation. Key mechanistic steps of our reaction include carbene catalyst addition, azolium ester formation, remote ?-carbon activation, reversible α- A nd ?-carbon enolization, and iterative H/D exchanges. The reaction is performed under mild conditions using D2O as the deuterium source to efficiently afford α,?-deuterated 2-alkenoic acids and their derivatives in good to excellent yields and high deuterium incorporation. These labeled products containing carbonyl and allyl bifunctionalities are valuable building blocks for further transformations, eventually leading to otherwise challenging labeled targets including deuterated allylic derivatives, aliphatic derivatives and polydeuterated drugs (e.g., Ibuprofen). The convenient and scalable synthesis has application potential for materials and pharmaceuticals.

Full text of DOI:10.1021/acscatal.0c00636

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Article
Carbene-Catalyzed #,#-Deuteration of Enals under Oxidative Conditions
Xiaolei Zhang, Qiao Chen, Runjiang Song, jun xu, Weiyi
Tian, Shaoyuan Li, Zhichao Jin, and Yonggui Robin Chi
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c00636 • Publication Date (Web): 13 Apr 2020
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ACS Catalysis
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Carbene-Catalyzed α,γ-Deuteration of Enals under Oxidative Conditions
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Xiaolei Zhang,†§ Qiao Chen,†§ Runjiang Song,†§ Jun Xu,†‡ Weiyi Tian,*‡ Shaoyuan Li,†ǁ Zhichao Jin,ǁ
and Yonggui Robin Chi*†ǁ
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†Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological
University, Singapore 637371, Singapore
‡School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Huaxi District, Guiyang 550025, China
ǁLaboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and
Agricultural Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, China
ABSTRACT: Organic compounds with deuterated allyl groups are very attractive for drug entities to enhance pharmacokinetic properties
since allylic C−H bonds are prone to metabolic oxidation and the deuterated versions can be less prone to such metabolism. However, direct
deuteration at allylic C−H moieties is still a challenge. Few examples have been reported by transition-metal catalysis and no such reports
have been documented in an organocatalytic fashion. Herein, a carbene-catalyzed C−H deuteration of enal at allylic C(sp3) and C(sp2) centers
is disclosed. Addition of the carbene catalyst to the aldehyde moiety of enals to eventually activate the α- and γ-carbon atom under oxidative
conditions is critical to achieve high deuterium incorporation. Key mechanistic steps of our reaction include carbene catalyst addition,
azolium ester formation, remote γ-carbon activation, reversible α- and γ-carbon enolization, and iterative H/D exchanges. The reaction is
performed under mild conditions using D2O as the deuterium source to efficiently afford α,γ-deuterated 2-alkenoic acids and their derivatives
in good to excellent yields and high deuterium incorporation. These labelled products containing carbonyl and allyl bifunctionalities are
valuable building blocks for further transformations, eventually leading to otherwise challenging labelled targets including deuterated allylic
derivatives, aliphatic derivatives and polydeuterated drugs (e.g. Ibuprofen). The convenient and scalable synthesis has application potential
for materials and pharmaceuticals.
KEYWORDS: carbene catalysis, C−H deuteration, allyl group, enal, polydeuteration
INTRODUCTION
Deuterium-labeled compounds exhibit distinct properties and
offer significant value for both fundamental research and practical
applications.1−3 In chemistry, study of kinetic isotope effects (KIE)
using deuterium-labeled compounds provides mechanistic insights
on reaction pathways.4−5 In biology and medicinal sciences,
deuterium-labeled compounds are frequently used for metabolism
elucidation6−7 and drug discovery.8−10 Pharmaceutical molecules
with part of the protium atoms replaced by the deuterium isotopes
can show improved pharmacological effects.8−10 Not surprisingly,
the development of catalytic H/D exchange methods for direct
conversion of carbon-hydrogen (C−H) bonds to carbon-deuterium
(C−D) bonds has received considerable attention.11−25 Although
there are many reports of H/D exchange at aromatic,12−17
aliphatic18−21 and olefinic22−25 C−H bonds, there are surprisingly
few such reports for allylic C−H bonds.26−27 Considering the fact
that allylic C−H bonds are prone to metabolic oxidation,6 direct
H/D exchange reactions at allyl groups are highly desirable for drug
entities to improve pharmacokinetic properties.8−10 Particularly,
Grotjahn and coworkers have reported, in 2009, a ruthenium-
catalyzed method for selective deuteration and isomerization of
non-activated alkenes at allyl groups (Chart 1a).26 However, in
addition to limited functional group tolerance, the side reactions,
such as C=C bond migration mediated by η3-allyl-metal
intermediate, increases the challenges associated with metal-
catalyzed allylic C−H deuteration reactions.
atoms.28,29 The reactions are carried out under mild conditions with
D2O as the deuterium source. As an important note, previous efforts
in using NHC as a base or covalent catalyst to facilitate H/D
exchanges mainly dealt with the α-carbons of carbonyl
compounds30−31 or the formyl groups of aldehydes.32−33
Specifically, Rovis and coworker described an NHC-catalyzed α-
carbon deuteration of α, α-dichloro aldehyde at ambient
temperature.31 Very recently, Yan group32 and Wang group33
independently reported the H/D exchange of formyl groups using
NHC catalysis to provide C1 deuterated aldehydes. To the best of
our knowledge, NHC-catalyzed H/D exchange at allylic C−H
bonds has not been disclosed until to date.
Our method is scalable and affords deuterium-enriched
unsaturated carboxylic acids/esters (or termed as α,γ-deuterated 2-
alkenoic acids) containing labelled allyls. Although H/D exchange
at the α-position of carboxylic acids has been documented by Stuart
and coworkers, extension to γ-position remains challenging.34
Commonly practiced routes to these labelled compounds involve
multistep synthesis, the use of expensive deuterated starting
materials and suffer from functional group tolerance.35 These
products are stable for storage and, more importantly, valuable for
further transformations at either carbonyl or allyl functional groups,
eventually leading to labelled targets. For example, deuterated allyl
derivatives can be easily accessed by harnessing the
decarboxylative functionalization methodologies, which may have
potentials in mechanistic investigations or pharmacokinetic studies.
In addition, hydrogenation of the C=C bond can give rise to
polydeuterated aliphatic derivatives which are difficult to access by
direct H/D exchange on the inert aliphatic C−H bonds. At last,
polydeuterated drug molecules (such as Ibuprofen) can be accessed,
Here we disclose an organocatalytic method for highly efficient
conversion of multiple protons at the α- and γ-carbon atoms of
enals to deuterium isotopes (Chart 1b). Our reaction involves
addition of N-heterocyclic carbene (NHC) catalyst to the aldehyde
moiety of enals to eventually activate the α- and γ-carbon
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Chart 1. Direct Deuteration of Allylic C−H Bonds.
1
2
3
Previous work:
H bondsref. 26
a) Ru-catalyzed isomerization and deuteration of allylic C
4
5
6
7
8
9
via:
Cp
PF6
Ruthenium cat:
N
D
P
Ru
N
N
P
H3C
Ru
R
R'
D D
R
R'
+
D2O
N
R
R'
D
H H
H
3-metal intermediate
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This work:
b) NHC-catalyzed deuteration of allylic C H bonds
O
via:
NHC cat:
N
N
O
R'
O
R'
N
R'
O
Mes
R

R
OH
R
N
D2O
+
H

D
D
H
H
D
N
H
N
up to 98% yield
96% D-incorporation
oxidation
D2O as deterium source
vinyl dienolate intermediate
metal-free
mild condition, scalable
downstream derivatization
deuterated allylic derivatives
deuterated aliphatic derivatives
polydeuterated drug
O
CD3
CD
CD3
3 O
CD3
[94%]
CD3
Br
NO2
OH
H
D3C
D3C
OH
Ar
Ar
Ar
OR
Ar
Ar
OH
[85%]
CD3
D
D
D
D
O
CD3
CD3
CD3
D3C
CD3
[89%]
H D
NO2
SiPh3
BF3K
Ar
D
Ibuprofen
-labelled
8.8 D atoms per molecule
D
D
D
O
Potential applications:
mechanistic investigation
pharmacokinetic study
deuterated drug discovery
thus proving an additional synthetic tool in the growing field of
deuterated drug discovery.
(2.0 equiv.) resulted in 2a with nearly quantitative yield and 91%
Dα and 93% Dγ deuteration (entry 13).
Table 1. Reaction Optimization.a
RESULTS AND DISCUSSION
We started by using cinnamaldehyde with a β-methyl substituent
(1a) as a model enal substrate and D2O as the deuterium source.
Selected results from relatively intensive condition screenings are
summarized in Table 1. With DABCO as the base, nitrobenzene as
the oxidant, and CH3CN as the solvent, triazolium-based NHC pre-
catalysts with an N-phenyl (A)36 or pentafluorophenyl (B)37
substituent were ineffective in converting 1a to the corresponding
carboxylic acid (2a) (entries 1-2). When triazolium NHC pre-
catalyst with an N-mesityl substituent (C)38 was used, 2a was
obtained in 81% yield with a very encouraging degree of
deuteration on both α- and γ-carbon atoms (entry 3). Specifically,
74% and 80% of the proton atoms were replaced by deuterium
isotopes on the α- and γ-carbon atoms, respectively. Extensive
additional studies with achiral triazoliums (A to D39),
imidazolium40 (E), and thiazolium41 (F)-based NHC pre-catalysts
did not lead to satisfactory product yields or deuteration levels
(entries 1-6; also see SI). We then found that the use of
aminoindanol-derived pre-catalyst G42 could lead to much better
results, with 2a formed in 91% isolated yield, 77% α-deuteration
(Dα) and 90% γ-deuteration (Dγ) (entry 7). We next further
optimized the reaction conditions using G (racemic form) as the
NHC pre-catalyst (entries 8-13). Several oxidants (DQ, phenazine,
hexachloroethane) previously used in NHC oxidative catalysis43−47
were then evaluated, among which the use of phenazine offered the
best results based on the yield, deuterium incorporation (Dα, Dγ)
and the content of unlabeled CH3 residue (entry 9, 90% yield, 73%
Dα, 92% Dγ and 1.7% unlabeled CH3 moiety, see SI-Figure S1).

NHC precursor
(20 mol%)
CD
3 O
CH3
O
DABCO (1.0 equiv.)
+
D2O
Ph
Ph
OH

H
Oxidant
(2.0 equiv.)
CH3CN (0.1 M), N2, T oC, 24 h
D
H
1a
b
2a
, yield
D: -deuterationc
D: -deuterationc
NHC precursor:
O
BF4
BF4
Cl
Cl
BF4
N
O
N
N
N
N
N
N
N
N
N
N
S
Mes
Ar
A
N
Mes
Mes
Mes
Mes
Ar
= Ph
G
B
C
E
F
(racemic)
D
C6F5
Mes
Oxidant:
tBu
tBu
O
Cl
Cl
NO2
N
N
Cl
Cl
Cl
Cl
O
tBu
tBu
phenazine
C2Cl6
nitrobenzene
DQ
Yieldb
Dα/Dγ
[%]
c
Entry NHC
Oxidant
T/oC
[%]
1
2
3
4
5
6
7
A
B
C
D
E
F
nitrobenzene
nitrobenzene
nitrobenzene
nitrobenzene
nitrobenzene
nitrobenzene
nitrobenzene
25
25
25
25
25
25
25
trace
trace
81
/
/
74/80
68/85
/
70
n.d.
43
o
72/83
77/90d
Elevated temperature (80 C) further improved the degree of α-
deuteration to 88% (entry 12). Increasing the loading of DABCO
G
91
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ACS Catalysis
unsaturated carboxylic acid (6) as one of the products (Scheme 1b).
8
9
G
G
G
G
G
G
DQ
25
25
25
40
80
80
31
90
53/56
73/92e
/
1
2
3
4
5
6
7
8
Independent treatment of β,γ-unsaturated aldehyde (4) under an
otherwise identical condition also afforded products 5 and 6 in
nearly full conversion and high deuterium incorporations (Scheme
1b). In both cases (using 3 or 4 as the substrate), no cyclopropane
ring opening products were detected. The results support a
reversible enolization, deprotonation and deuterium-protonation
processes during our catalytic H/D exchange reaction. No H/D
exchanges were observed for the α,β-unsaturated carboxylic acid
under current deuteration conditions.
phenazine
C2Cl6
10
11
12
13f
n.d.
95
phenazine
phenazine
phenazine
83/92
88/91
91/93g
96
98
aConditions: 1a (0.1 mmol, E/Z = 3/1), D2O (40 equiv.), NHC
precursor (20 mol%), DABCO (1.0 equiv.), oxidant (2.0 equiv.),
CH3CN (1 mL), 25 C, N2 atmosphere and 24 h. Isolated yield
after workup. cDeuterium incorporations (Dα and Dγ) were
determined by 1H NMR analysis of the product. dWith 4.3%
unlabeled CH3. eWith 1.7% unlabeled CH3. f2.0 equiv. of DABCO.
gWith 0.3% unlabeled CH3. n.d. = not detected.
o
b
Scheme 2. A Proposed Mechanism for NHC-Catalyzed
Deuteration of α- and γ-Carbon Atoms of Enal.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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56
57
58
59
60
CH3
O
H
CH3
H
O
N
Ph
Ph
H
H
N
N
I
CH3 OH
Scheme 1. Control Experiments to Probe the Mechanism.
N
Ph
N
a) Utilization of NHC and oxidant is critical for effective H/D exchange
CD3
D
O
N
N
H
N
N
Results
II
N
N

Ph
OD
(eq. 1)
(eq. 1)
CD3
O
O
CH3
O
NHC
DABCO (2.0 equiv.)
CH3CN, N2, 25 oC, 15 h
yield: 95%, (E/Z) = 3.9/1
(E): D = 47%, D = 15%
(Z): D = 58%, D = 18%
N
+
D2O
Ar
H
oxidant
Ar
H
OD-
CD3

H
D
CH2 or CHD or CD2
CH or CD
(eq. 2)
1b, (E/Z) = 5/1
(eq. 2)
G (20 mol%)
DABCO (2.0 equiv.)
CH3CN, N2, 25 oC, 15 h
[D]
Ar
CH3
H
O
O
CD3
yield: 75%, (E/Z) = 3.2/1
(E): D = 44%, D = 49%
D' = 42%
(Z): D = 57%, D = 7%,
D' = 16%
[D']
D
N
Ar:
Ph
Ph
NHC
[D
O
]
N
N
D
O
D

(eq. 3)
G (20 mol%)
DABCO (2.0 equiv.)
Phenazine (2.0 equiv.)
CH3CN, N2, 25 oC, 15 h
V
III
base
CD3
(eq. 3)
D
O
O
yield: 90%, (E/Z) > 20/1
CH2
D
O
Ar
O
OH
D = 66%, D = 87%
CD3
O
NHC
Ph
D
Ph
NHC
IV
b) Observation of C=C bond migration supports reversible enolization and H/D exchanges
Ph
NHC
D
O
D
H
H
O
H
O
O
standard
Ph
via:
NHC
via:
deuteration conditions
Ph
NHC
iterative
H
H
D
H
H
H
CH2
O
,-unsaturated aldehyde
4, (E/Z)= 3.3/1
,-unsaturated aldehyde
3, (E/Z) = 2/1
DH2C
O
Ph
NHC
Results from 4
Results from 3
Ph
NHC

D
5, yield: 45%
5, yield: 49%
H/D exchange at -carbon

H/D exchange at -carbon
D
D
D = 92%, D = 92%
D = 92%, D = 92%
D O
D
O
6, yield: 52%
(E)/(Z) = 3/1
6, yield: 48%
(E)/(Z) = 1/0.9
(E): D = 92%, D = 84%
A plausible pathway of our NHC-catalyzed deuteration reaction
involving oxidation, reversible enolization, and iterative H/D
exchange is illustrated in Scheme 2. The nucleophilic addition of
the NHC to the aldehyde group of enal leads to intermediate I50,51
and the subsequently formation of a Breslow intermediate II49
which undergoes an oxidation to generate an α,β-unsaturated
triazolium ester intermediate III.44 γ-C−H deprotonation and
enolization of III under basic conditions affords a vinyl dienolate
intermediate IV28,29 that behaves as a key intermediate for iterative
H/D exchange at both α- and γ-carbon atoms. Finally, hydrolysis
of the deuterated α,β-unsaturated triazolium ester intermediate V
yields the corresponding unsaturated carboxylic acid with
regeneration of the carbene catalyst. This hydrolysis step appears
to be much slower than the enolization and H/D exchange steps,
which is in consistent with our previous study on NHC-catalyzed
dynamic kinetic resolution of carboxylic esters.52 Alkene positional
isomerization/migration was observed in transition metal-catalyzed
allylic deuteration reactions via η3-allylic-metal intermediates.26 In
our organic catalytic reaction, this type of C=C bond migration is
likely attributed to the competing hydrolysis pathway of the β,γ-
unsaturated triazolium ester intermediate in the presence of D2O. It
is worth mentioning that NHC-catalyzed reactions in water have
been reported by our group53 and we believe that the utilization of
non-expensive D2O as the deuterium source can add additional
values for the carbene-catalyzed incorporation of deuterium into
organic molecules.
+
OH
OH
(E): D = 93%, D = 86%
(Z): D = 93%, D = 85%
D
6 (E/Z)
D
(Z): D = 91%, D = 82%
5 (E)
In metal-catalyzed allylic C−H deuteration reactions, the allyl
can directly react with the metal center to activate the C−H bonds
for subsequent H/D exchange.26 Although it has been established
that nucleophilic addition of a carbene to an aldehyde moiety of
enal can activate the allylic γ-C−H bonds under oxidative
conditions,47 this activation have been used mainly for C−C bond
formation, and have not been developed for C−D bond formation.
Control experiments were conducted to gain mechanistic insights
into the reaction pathways (Scheme 1). In the absence of carbene
catalyst, H/D exchange of 1b at α- and γ-carbon is ineffective in
the presence of DABCO, especially at the γ-position (Dα = 47−58%,
Dγ = 15−18%, Scheme 1a, eq. 1). Interestingly, addition of a
catalytic amount (20 mol%) of carbene precursor (G) promoted the
γ-deuteration (Dγ = 49%) for the (E)-isomer but caused a low
degree of deuteration (Dγ = 7%) for the (Z)-isomer, which indicated
that the γ-deprotonation of the (E)-isomer might be more favored
over the (Z)-isomer. The distinct reactivity of (E)- and (Z)-enals in
NHC-catalyzed reactions has been previously documented by our
group.48 Deuteration at the aldehyde site (D' = 16−42%, Scheme
1a, eq. 2) could also be detected in the presence of the carbene
catalyst (likely via reversible Breslow intermediate formation).49
When the external oxidant (phenazine) was added, (E)-carboxylic
acid was isolated as the thermodynamically stable product with
significantly enhanced deuteration at γ-carbon position (Dγ = 87%,
Scheme 1a, eq. 3). These control experiments indicate that
formation of an azolium ester intermediate44 under the oxidative
conditions is responsible for the effective H/D exchange. When γ-
cyclopropyl-substituted enal (3) was used as a substrate, C=C bond
isomerization/migration was observed with the formation of β,γ-
With acceptable conditions in hand, the scope of this
transformation was investigated using electronically and
structurally diverse enals as substrates (Table 2). The reactions
afforded (E)-α,β-unsaturated carboxylic acids (or esters) with
simultaneous deuteration on both α- and γ-carbon atoms. We first
evaluated enals bearing β-aryl substituents (2a-r). In general,
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substituents on the β-aryl ring of enals with both electronic-
Table 3. Substrate Scope of Enals with β-Alkyl
Substituents.a
1
2
3
4
5
6
7
8
donating and electronic-withdrawing groups were well-tolerated,
as exemplified by methoxyl (2b-d), acetal (2e), methyl (2f) as
electronic-donating substituents and trifluoromethyl (2g), fluoro
(2k) as electronic-withdrawing groups. The reactions generally
afforded excellent yields and high degrees of deuteration at α- and
γ-positions (Table 2). An enal with a 2-naphthyl substituent could
also be effectively deuterated to afford 2h that is as a useful synthon
for naphthopyran-2-ones.54 Slightly decreased yields of 2i and 2j
(84 and 85% yields) were observed for enals bearing ortho-
substituents at the β-aryl ring likely due to steric effects. Notably,
our metal-free protocol is compatible with halogen substituents in
the substrates (2k-n). These halogen substituents can be directly
utilized for further derivatizations such as cross couplings.
Replacing the hydrogen atom on the γ-carbon with phenyl (Ph) or
CH3 led to an erosion on product yield for 2o and 2p (85 and 60%,
respectively) with negligible effects on deuterium incorporations.
Conformationally constrained enals (with the γ-and phenyl-
substituents connected to form a ring) were also well tolerated,
affording deuterated derivatives of cinnamic acids (2q and 2r)
exhibiting interesting bioactivities in regulating plant growth.55
D
H
R2
R1
R2
R1
D
R2
R1
G
(20 mol%)
O
O
D
D
O
H

DABCO (2.0 equiv.)
+
OR'
+
H
D2O
Phenazine (2.0 equiv.)
CH3CN, N2
80 oC, 24 h
then esterification
OR'

D
D
H
1a
2w'-2z'
2s-2z
yieldb
D: -deuterationc
D: -deuterationc
R':
NO2
Variation of -alkyl substituent
CD3
O
O
H
[90%]
D3C
CD3
O
CD3
O
9
OR'
OR'
, yield: 64%
OR'
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OR'
D
D
2v
D
D
[90%]
D
D [88%]
2t
2u
, yield: 47%
, yield: 62%
d
2s
, yield: 71%
D = 54%, D = 50%
D = 84%, D = 95% D = 81%, D = 95%
O
O
O
O
[91%]
[88%]
[91%]
[92%]
D
D
D
D
D
D
OR'
OR'
OR'
OR'
D
D
[89%]
D
D
D
D
[91%]
D
D
D
[89%]
D
[91%]
D
[89%]
D
[87%]
D
[91%]
D
[92%]
2w'e
2we
2x'e
2xe
yield: 55%, ratio = 1:1.3
yield: 61%, ratio = 1:2.9
O
O
O
O
[92%]
[89%]
[90%]
D
[92%]
D
D
D
D
D
OR'
OR'
D
OR'
OR'
[91%]
D
[89%]
D
D
D
[91%]
D
D
D
[90%]
D
[92%]
Table 2. Substrate Scope of Enals with β-Aryl and γ-
D
D
[91%]
D
[91%]
D
D
Substituents. a
[89%]
2y'e
2ye
yield: 66%, ratio = 2.5:1d
2z'e
2ze
yield: 57%, ratio = 1:7.4
D
H
R
G
(20 mol%)
R
D
D
H
O
O

workup
DABCO (2.0 equiv.)
aConditions: 1 (0.2 mmol), D2O (40 equiv.), G (20 mol%),
DABCO (2.0 equiv.), phenazine (2.0 equiv.), CH3CN (2 mL), 80
oC, N2 atmosphere and 24 h. bIsolated yields after workup.
+
D2O
Phenazine (2.0 equiv.)
CH3CN, N2, 80 oC, 24 h
Ar
OH/R'
Ar
H

H
b
1a
2a-2r
, yield
D: -deuterationc
D: -deuterationc
R':
NO2
1
cDeuterium incorporations (Dα and Dγ) were determined by H
d
o
e
Variation of aryl and substituent
NMR analysis of the product. Reacted at 40 C. Isolated and
characterized in pure form.
CD3
O
CD3
D
O
O
O
CD3
D
O
OH
We next studied enals bearing β-alkyl substituents (2s-z) (Table
3). Enals with the β-substituent as methyl, 1-adamantanyl or tert-
butyl unit could all be effectively D-labelled, albeit with a moderate
reduction in product yields (47-71%). A β-monosubstituted enal
afforded moderate level of deuteration at the α- and γ-carbons (2v),
probably owing to the less favored dienolization pathway for the β-
monosubstituted α,β-unsaturated acyl triazolium intermediate.47
Interestingly, the cyclo-alkylated substituted enals gave rise to two
types of products as α,β- and β,γ-unsaturated carboxylic esters (2w-
z, 2w’-z’) in moderate combined yields (55-66%) and high degrees
of deuterium incorporations (87-92%). This C=C bond migration
(2w’-z’) operates via a pathway similar to that of enal substrates 3
and 4 (Scheme 2b). As a technical note, here the reaction products
(2w-z, 2w’-z’) were isolated and characterized as the
corresponding carboxylic esters in pure form after esterification
with p-nitrophenol. This is because the carboxylic acid adducts are
volatile or only weekly visible under UV during thin-layer
chromatography. Noteworthy that α-methyl substituted enal, α,β-
unsaturated carboxylic acid and β-ester substituted enal are non-
effective substrates under current deuteration conditions (see SI-
general procedure).
OH
D
OH
O
O
2c
, yield: 90%
2a
2b, yield: 95%
, yield: 98%
D = 92%, D = 94%
D = 91%, D = 93%
D = 91%, D = 95%
CD3
D
O
CD3
D
O
CD3
D
O
O
O
O
OH
OH
OH
2f
, yield: 94%
2d
2e
, yield: 88%
, yield: 96%
D = 91%, D = 93%
D = 90%, D = 96%
D = 92%, D = 96%
CD3
D
O
CD3
D
O
O
CD3
D
O
OH
OH
OR'
F3C
d
2h
2i
2g
, yield: 96%
, yield: 84%
, yield: 94%
D = 89%, D = 94%
D = 90%, D = 94%
D = 90%, D = 94%
CD3
D
O
CD3
O
CD3
D
O
OH
OH
OR'
D
F
Cl
d
2l
, yield: 92%
2k
, yield: 95%
2j
, yield: 85%
D = 90%, D = 96%
D = 91%, D = 94%
D = 92%, D = 94%
D
Ph
CD3
D
O
CD3
O
O
D
OH
OH
OH
D
D
I
Br
2m
2n
2o
, yield: 85%
, yield: 90%
, yield: 90%
Scheme 3. Scale-up Reactions.
D = 92%, D = 95%
D = 92%, D = 95%
D = 94%, D = 94%
D
D
D
H3C
G (10 mol%)
a)
CH3
O
CD3
D
O
O
O
O
D
D
D
DABCO (2.0 equiv.)
+
D2O
40 equiv.
H
OH
OH
Phenazine (2.0 equiv.)
CH3CN (0.1 M), N2
OR'
OH
H
D
D
D
Br
Br
80 oC, 36 h
e
2m,
,
445 mg yield: 91%
3-(4-bromophenyl)but-2-enal
d,e
2r
, yield: 83%
2p
2q, yield: 95%
, yield: 60%
D = 91%, D = 94%
chromatography free
2.0 mmol
D = 92%, D = 94%
D = 90%, D = 91%
D = 93%, D = 93%
NH2
b)
aConditions: 1 (0.2 mmol), D2O (40 equiv.), G (20 mol%),
DABCO (2.0 equiv.), phenazine (2.0 equiv.), CH3CN (2 mL), 80
oC, N2 atmosphere and 24 h. The E-isomer of enal is used except
for 1a (E/Z = 3/1) and 1b (E/Z = 5/1). bIsolated yields after workup.
(10 mol%)
G
NH3
CH3
H
O
CD3
D
O
DABCO (2.0 equiv.)
Phenazine (2.0 equiv.)
1.0 equiv.
Et2O
+
H
D2O
40 equiv.
H3C
O
D3C
CH3CN (0.1 M), N2
40 oC, 36 h
7
, 2.0 g, yield: 65%
D = 89 %, D = 88%
recrystallization
3-methylbut-2-enal
1.0 g, 12 mmol
cDeuterium incorporations (Dα and Dγ) were determined by H
1
NMR analysis of the product. dIsolated as para-nitrophenyl esters.
eReacted at 40 oC.
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ACS Catalysis
Scheme 4. Synthetic Applications.
1
2
a) Synthesis of deuterated allylic derivativesa
CD3
O
3
OH
4
5
D
2a
D = 90%, D = 94%
6
7
8
9
iii)
i)
ii)
CD3
Br
CD3
CD3
NO2
SiPh3
D
D
D
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9
, yield: 91%
8
, yield: 76%
D = 90%, D = 94%
10
, yield: 70%
D = 90%, D = 94%
D = 90%, D = 94%
quick access to allylic derivatives with labelled allylic methyl and vinyl sites
b) Synthesis of deuterated isobutyl derivativesb
[87%]
1)
B2(pin)2
[87%]
CD3
O
O
CD3
Cu(acac)2 (30 mol%)
LiOH H2O, MgCl2
CD3
O
1) raney Ni. H2
2) esterification
BF3K
O
N
D3C
D3C
OH
D3C
2) KHF2
2 steps
H
D
[89%]
H
D [89%]
D
11
2 steps
80% yield
O
55% yield
12
13
D  89% D  88%
access to saturated carboxylic ester and trifluoroborate with a labelled isobutyl group
c) Synthesis of -CD -benzeneacetic acidb

3
[94%]
[94%]
CD3
CD3
CD3
CD3
O
NaNO2
AcOH
NO2
[89%]
NO2
OH
NaBH4
THF/MeOH
iii)
OH
H
D
D
O
DMSO
D
Br
Br
Br
Br
2m
D = 91%, D = 94%
access to -methyl-benzeneacetic acid with a benzylic -CD3 group
14
, yield: 65%
16
, yield: 90%
15
, yield: 92%
D = 91%, D = 94%
d) Synthesis of polydeuterated Ibuprofenb
[94%]
CD3
1)
K2CO3, toluene/H2O, 80 o
OH
Pd(OAc)2 (5 mol%)
RuPhos (10 mol%)
[87%]
CD3
[94%]
CD3
[85%]
CD3
C
O
BF3K
OCH3
D3C
D3C
+
2)
KOH, MeOH/H2O, rt
2 steps
[89%]
D
H
H
D [89%]
O
18, D-
Ibuprofen
labelled
8.8 D/molecule
Br
17
13
87% yield
access to Ibuprofen with multiple -CD3 groups
aConditions: (i) CuCl (10 mol%), Ph3SiH, t-BuOOH, t-BuOH, 110 oC; (ii) Dess-Martin periodinane, Et4NBr, CH2Cl2, 25 oC; (iii) CuCl (20
mol%), tert-butyl nitrite, CH3CN, 80 oC, air. bFor reaction details, see SI.
Our method is amenable for scale-up via simple operations
without the need of column chromatography (Scheme 3). For
example, deuteration of 3-(4-bromophenyl)but-2-enal on a 2.0
mmol scale under standard condition could provide 2m (445 mg)
in 91% yield, 91% Dα and 94% Dγ (Scheme 3a) after a simple acid-
base workup process. Deuteration of 3-methylbut-2-enal was
carried out on gram scale using 10 mol% of NHC catalyst at 40 oC.
Decarboxylative borylation60 of 12 followed by treatment with
KHF2 furnished the deuterated isobutyl trifluoroborate 13 in
appreciable yields (55% yields over two steps). Furthermore,
selectively labelled α-CD3-benzeneacetic acid 16 can be obtained
from 2m via a three-step process (with 54% overall yield)
involving decarboxylative nitration,58 reduction61 and oxidation62
(Scheme 4c). In all these transformations, the deuterium isotopes
were retained. Notably, isobutyl and α-methyl-acetic moieties are
widely presented in pharmaceuticals and nature products.63 These
deuterated molecule architectures might have applications in
organic synthesis, mechanistic studies and medicinal sciences.
To further demonstrate the utility of these products, we
developed a concise route for access to polydeuterated Ibuprofen
by using the deuterated synthons generated from our catalytic
reactions and downstream derivatizations (Scheme 4d). Briefly,
Suzuki coupling64 of 13 and 17 followed by hydrolysis afforded
deuterium-labeled Ibuprofen (18) in 87% yield over two steps. The
multi deuterium isotope-labelled Ibuprofen contains 8.8 deuterium
atoms per molecule at the aliphatic carbon atoms with <0.1%
unlabeled compound, as confirmed by 1H NMR and mass spectrum.
Our approach provides a unique route toward the selective
incorporation of one or multiple −CD3 groups into pharmaceuticals
and other functional molecules, which can benefit the discovery of
deuterated drugs.
A
chromatography-free
process
was
developed
via
recrystallization of the acid product with naphthalen-1-
ylmethanamine (1.0 equiv.) to afford the corresponding salt 7 (2.0
g) in 65% isolated yield, 89% Dα and 88% Dγ (Scheme 3b).
The deuterium-enriched products from our reactions can be
readily transformed to other functional molecules at either carbonyl
sites or allylic sites (Scheme 4). For example, deuterated carboxylic
acids could undergo decarboxylative silylation,56 bromination57
and nitration58 to afford vinylsilane (8), vinyl bromide (9) and
nitroolefin (10), respectively (Scheme 4a). These labelled allyl
derivatives may have potential in pharmacokinetic studies or
mechanism investigations. Moreover, hydrogenation of the C=C
bond of a labelled allyl group can give rise to deuterated aliphatic
moieties which are difficult to access by direct H/D exchange on
the inert aliphatic C−H bonds. As shown in Scheme 4b, the fully
deuterated 3-methyl-2-butenoic acid with two allylic −CD3
substituents at the β-carbon (11) could be converted to the saturated
carboxylic ester (12) and trifluoroborate (13), that contain a
deuterated isobutyl group. Specifically, hydrogeneration59 of 11
catalyzed with Raney nickel followed by esterification with N-
hydroxyphthalimide generated a redox-active ester 12 in 80% yield.
CONCLUSION
In summary, we have developed a metal-free method for
efficient H/D exchange of enals at allylic C(sp3) and C(sp2) sites.
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Page 6 of 8
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convenient to use, and inexpensive deuterium source. It offers a
unique solution towards α,γ-deuterated 2-alkenoic acids/esters with
allylic functionality that allows for wide synthetic transformations.
A vast class of labelled molecules including allylic derivatives,
aliphatic derivatives and polydeuterated drugs can be readily
accessed. These deuterated targets are other wisely difficult to
access. The synthetic method is convenient and amenable for scale-
up and may find applications in the field of materials and
pharmaceuticals.
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AUTHOR INFORMATION
Corresponding Author
*Email: tianweiyi@gyctcm.edu.cn, robinchi@ntu.edu.sg
Author Contributions
§X. Z., Q. C. and R. S. contributed equally.
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
The Supporting Information contains experimental details and
compound characterizations. This material is available free of
charge on the ACS Publications website: http://pubs.acs.org.
ACKNOWLEDGMENT
We acknowledge financial supports by National Research
Foundation (NRF) Singapore under its NRF Investigatorship
(NRF-NRFI2016-06), the Ministry of Education of Singapore
(MOE2016-T2-1-032; MOE2018-T3-1-003; RG108/16; RG1/18),
A*STAR Individual Research Grant (A1783c0008; A1783c0010),
GSK-EDB Trust Fund, Nanyang Research Award Grant, Nanyang
Technological University; the National Natural Science
Foundation of China (No. 21772029, 21472028), National Key
Technologies R&D Program (No. 2014BAD23B01), The 10 Talent
Plan (Shicengci) of Guizhou Province ([2016]5649), the Natural
Science Foundation of Guizhou Province ([2018]2802); the
Guizhou
Province
First-Class
Disciplines
Project
(GNYL(2017)008), Guizhou University of Traditional Chinese
Medicine (China) and Guizhou University (China).
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Table of Contents
CD3
OH
R'
O
R'
O
CD3

R
R
O
NHC
OH
H

D3C
D
D
H
H
D
H
D
D2O
oxidation
D-labelled Ibuprofen
D-labelled
Carboxylic acid
Enal
8.8 D atoms per molecule
mild reaction condition
metal-free deuteration
D2O as deterium source
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