Palladium-Catalyzed Synthesis of Deuterated Alkenes through Deuterodechlorination of Alkenyl Chlorides

Article abstract of DOI:10.1021/acs.oprd.9b00193

The palladium-catalyzed deuterodechlorination of alkenyl chlorides has been developed, and a variety of deuterated alkenes were synthesized with precise control of the deuterium incorporation. This catalytic process tolerates heterocyclic moieties and frameworks derived from bioactive agents. In addition to the double incorporation of deuterium, the gram-scale synthesis of a deuterated iminostilbene unit including a core substructure of carbamazepine was achieved in a high yield with an excellent degree of deuteration.

Full text of DOI:10.1021/acs.oprd.9b00193

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Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Synthesis of Deuterated Alkenes through
Deuterodechlorination of Alkenyl Chlorides
Masami Kuriyama,* Gemba Yano, Hirotoshi Kiba, Tetsuro Morimoto, Kosuke Yamamoto,
Yosuke Demizu, and Osamu Onomura*
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
S
* Supporting Information
ABSTRACT: The palladium-catalyzed deuterodechlorination of alkenyl chlorides has been developed, and a variety of
deuterated alkenes were synthesized with precise control of the deuterium incorporation. This catalytic process tolerates
heterocyclic moieties and frameworks derived from bioactive agents. In addition to the double incorporation of deuterium, the
gram-scale synthesis of a deuterated iminostilbene unit including a core substructure of carbamazepine was achieved in a high
yield with an excellent degree of deuteration.
KEYWORDS: deuteration, alkene, palladium, N-heterocyclic carbene
tion of alkenyl chlorides using an unsymmetrical N-
heterocyclic carbene (NHC) ligand.
INTRODUCTION
■
Deuterated molecules have been known to be highly useful
because of their wide application, such as metabolic analyses
of bioactive agents as well as mechanistic investigations of a
variety of reactions.1 In addition, site-specific incorporation of
deuterium into pharmaceutical compounds has been of
growing significance in drug development because of its
beneficial effects to improve their therapeutic profiles through
isotope-effect-based optimization of the metabolic stability and
toxicity of drugs.2 For example, deutetrabenazine was approved
by the U.S. Food and Drug Administration in 2017 as a
treatment agent for chorea associated with Huntington’s
disease.3 Since alkenes are among the most fundamental and
ubiquitous substructures in pharmaceutical and bioactive
molecules,4 catalytic synthetic processes for deuterated alkenes
as building blocks are quite important. The Pd-catalyzed
semideuterogenation of alkynes and metal-catalyzed H/D
exchange for alkenes have been investigated as representative
catalytic methods for the synthesis of deuterated alkenes, in
which multiple introduction of deuterium basically proceeds
depending on the respective reactivities of reactive sites in the
presence of excess amounts of deuterium sources, such as
deuterium gas, deuterated organic solvents, and deuterium
oxide.5,6 Although these processes make it possible to obtain
multideuterated alkenes with high efficiency, achievement of
precise site selectivity and high deuterium incorporation
remains challenging despite its necessity and importance in
production processes for pharmaceutical compounds. On the
other hand, deuterodehalogenation is also a powerful trans-
formation,7 but this type of method for the catalytic
preparation of deuterated alkenes is quite rare. While a few
examples of Br/D exchange for alkenyl bromides were reported
as catalytic processes with a radical initiator or transition
metal,8 no catalytic Cl/D exchange for alkenyl chlorides has
been found in spite of the advantageous features of
organochlorides, such as lower cost and higher stability.9
Herein we report the palladium-catalyzed deuterodechlorina-
RESULTS AND DISCUSSION
■
At the beginning, unsymmetrical NHC ligands were examined
in the palladium-catalyzed deuterodechlorination of alkenyl
chloride 1a with α-deuteriobenzhydrol as a stable, easy to
handle solid deuterium source (Table 1). We recently found
that this type of unsymmetrical NHC ligand precursor (Figure
1) was effective in transition-metal-catalyzed deuterodefunc-
tionalization processes.10 NHC ligand precursor L2 was more
suitable than imidazolium chloride L1, and methyl groups at
the 4- and 5-positions proved to be important for catalytic
efficiency (entries 1 and 2).11 The bulkier aryl group in NHC
precursor L3 delivered a better yield with a high degree of
deuteration (entry 3). On the other hand, the 2,4,6-
triisopropylbenzyl unit in imidazolium chloride L4 did not
lead to further improvement (entry 4). A ligand precursor
bearing benzhydryl moieties gave superior results, especially at
100 °C (92% yield and >99% D; entry 5). In the examination
of metal complexes, neither a zero-valent palladium complex
nor nickel complexes showed sufficient catalytic activity
(entries 5−8). Subsequently, a series of bases were screened,
and another option was found (entries 5 and 9−13). While
tribasic potassium phosphate and cesium fluoride as well as
inorganic carbonates except for cesium carbonate were less
effective (entries 5, 9, 10, 12, and 13), the catalytic
deuterodechlorination of 1a proceeded efficiently with an
excellent degree of deuteration in the presence of potassium
tert-butoxide (entry 11). The influence of the solvent was also
investigated (entries 5 and 14−17). The use of less polar
Special Issue: Honoring 25 Years of the Buchwald-Hartwig
Amination
Received: May 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.9b00193
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
a
Table 1. Optimization of the Reaction Conditions
entry
ligand
metal
base
solvent
yield (%)
D content (% D)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
L1
L2
L3
L4
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
Pd2(dba)3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
KOt-Bu
K3PO4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
DMA
12
60
81
80
89 (92 )
3
trace
trace
22
>99
93
>99
>99
>99 (>99 )
>99
ND
ND
>99
ND
>99 (>99 )
>99
>99
>99
>99
>99
ND
b
b
Ni(1-naph)Cl(PPh3)2
Ni(COD)2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
0
b
b
87 (96 )
28
45
77
64
20
0
CsF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMSO
a
b
Reaction conditions: 1a (1 mmol), Ph2CDOH (1.2 mmol), ligand (2 mol %), metal (1 mol %), base (1.5 mmol), solvent (2 mL), 90 °C, 16 h.
100 °C.
incorporation of deuterium with a chromane-derived substrate
proceeded smoothly with sufficient efficiency (2k). Addition-
ally, an iminostilbene-based compound and an estrone
derivative were examined, leading to high yields of the desired
deuterated products (2l and 2m). In most cases, excellent
degrees of deuteration were observed with high selectivity.
Moreover, this palladium-catalyzed deuterodechlorination was
applied to cycloalkenyl chloride 1l on a gram scale, and a
deuterated iminostilbene unit constituting the core framework
of carbamazepine was obtained in 82% yield with >99% D
(Scheme 2).
To examine the possibility of single electron transfer
processes, the palladium-catalyzed incorporation of deuterium
was conducted with radical scavengers such as 2,6-di-tert-butyl-
4-methylphenol (BHT) and 9,10-dihydroanthracene (DHA)
(Scheme 3). This catalytic deuteration reaction proceeded
smoothly even in the presence of these radical trapping
reagents, suggesting that single electron transfer processes
might not be included.
On the basis of all of these results, a tentative reaction
mechanism for the palladium-catalyzed deuterodechlorination
of alkenyl chlorides is shown in Scheme 4. After oxidative
addition of the alkenyl chloride to the Pd(0) complex, the
alkenylpalladium chloride intermediate is converted to an α-
deuterioalkoxypalladium species by displacement of the
chloride anion. Then β-deuterium elimination proceeds with
the formation of benzophenone to give the alkenylpalladium
deuteride complex. Finally, the deuterated alkene is formed as
the desired product through reductive elimination, leading to
regeneration of the Pd(0) catalyst.
Figure 1. Unsymmetrical NHC ligand precursors
solvents had a tendency to lead to higher yields, and toluene
proved to be suitable in this catalytic deuteration.
An investigation of a variety of alkenyl chlorides in the
palladium-catalyzed deuterodechlorination process was con-
ducted (Scheme 1). As well as a cycloalkenyl chloride with a
simple aryl moiety (1b),12 substrates bearing pyridyl and
thienyl groups with high coordinating ability to metal centers
were tolerated, giving the desired products in high yields with
excellent degrees of deuteration (2c and 2d). In the presence
of a cyclic amine unit as an important substructure in bioactive
compounds, deuterium incorporation was also achieved with
high efficiency (2e). In addition to a simple acyclic alkenyl
chloride bearing a naphthyl group (1f), a substrate with steric
hindrance close to a reactive site proved to be a suitable
reaction partner (2g). Neither an electron-donating group nor
an electron-withdrawing group led to a significant decrease in
yield and degree of deuteration (2h and 2i). The catalytic
preparation of a terminally deuterated alkene was also
accomplished with this deuteration method (2j). The double
CONCLUSION
■
Precisely deuterated alkenes were successfully synthesized
through the palladium-catalyzed deuterodechlorination reac-
B
DOI: 10.1021/acs.oprd.9b00193
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
a
Scheme 1. Substrate Scope
Scheme 4. Plausible Reaction Mechanism
high yields. In this process, a variety of substrates such as
heterocycles were tolerated, as well as iminostilbene and
estrone derivatives. In addition, the gram-scale synthesis of a
deuterated iminostilbene unit constituting the core framework
of carbamazepine was achieved with sufficient efficiency. We
believe that this palladium-catalyzed deuterium incorporation
method will contribute to the progress of catalytic production
processes for pharmaceutical compounds.
EXPERIMENTAL SECTION
■
General. All melting points are uncorrected. IR spectra are
expressed in cm−1. 1H and 13C NMR spectra were taken at 500
and 100 MHz, respectively. Chemical shift values are expressed
in parts per million relative to internal or external
tetramethylsilane. Abbreviations for multiplicities are as
follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
br, broad. Mass spectrometry (MS) and high-resolution mass
spectrometry (HRMS) were performed using electron
ionization (EI). The products were isolated by silica gel
column chromatography. Degrees of deuteration were
a
Conditions A: L5 (2 mol %), Pd (1 mol %), KOt-Bu (1.5 equiv).
b
Conditions B: L5 (6 mol %), Pd (3 mol %), Cs2CO3 (2 equiv). 0.5
c
d
e
f
g
1
mmol scale. 100 °C. 80 °C. 70 °C. KOt-Bu (2 equiv). Cs2CO3
determined by H NMR (500 MHz) analyses. All of the
h
i
(2.5 equiv). Ph2CDOH (2.4 equiv), KOt-Bu (2.25 equiv). GC yield.
reactions were performed under an argon atmosphere unless
otherwise specified. Toluene was distilled from sodium
benzophenone ketyl under an argon atmosphere. Alkenyl
chlorides 1a, 1c−i, and 1k−m were synthesized as new
chemical compounds. On the other hand, 1b,13 1j,14 α-
deuteriobenzhydrol,10a and the unsymmetrical NHC precur-
sors10a were prepared as previously reported.
j
0.33 M.
Scheme 2. Gram-Scale Deuterodechlorination of 1l
Typical Procedure for the Palladium-Catalyzed
Deuterodechlorination of Alkenyl Chlorides. Under an
argon atmosphere, a reaction tube was charged with ligand
precursor L5 (13.7 mg, 0.02 mmol), [Pd(allyl)Cl]2 (1.83 mg,
0.005 mmol), and Cs2CO3 (489 mg, 1.5 mmol). After toluene
(2.0 mL) was added, the mixture was stirred for 15 min at 80
°C and cooled to room temperature. Then alkenyl chloride 1a
(223 mg, 1.0 mmol) and α-deuteriobenzhydrol (222 mg, 1.2
mmol) were added. The reaction mixture was stirred for 16 h
at 100 °C and cooled to room temperature. Water was added,
and then the resulting mixture was extracted with AcOEt. The
combined organic layers were dried over Na2SO4. Concen-
tration and purification through silica gel column chromatog-
raphy gave the desired product 2a.
Scheme 3. Catalytic Deuterodechlorination in the Presence
of Additives
1-(4-Deuteriocyclohex-3-enyl)-4-methoxybenzene
(2a). Silica gel column chromatography (hexane/EtOAc =
100/1) gave 174 mg of the product (0.92 mmol, 92% yield) as
a colorless oil with >99% D (the D content was judged by
comparison of the peak at 5.76−5.77 ppm (a deuterated site)
tion of alkenyl chlorides. The adequate catalytic activity of the
palladium/unsymmetrical NHC system led to the production
of deuterated alkenes with excellent degrees of deuteration in
C
DOI: 10.1021/acs.oprd.9b00193
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
with the peak at 6.84−6.87 ppm by 1H NMR). 1H NMR (500
MHz, CDCl3): δ 1.67−1.76 (m, 1H), 1.88−1.93 (m, 1H),
2.08−2.29 (m, 4H), 2.73−2.79 (m, 1H), 3.79 (s, 3H), 5.76−
3.58−3.60 (m, 2H), 5.65−5.68 (m, 1H), 7.23−7.27 (m, 1H),
2
7.30−7.36 (m, 4H). H NMR (60 MHz, CHCl3): δ 5.78 (br
s). 13C NMR (100 MHz, CDCl3): δ 25.9 (CH2), 49.5 (CH2),
52.7 (CH2), 62.9 (CH2), 125.0 (t, JC−D = 24.0 Hz, C), 125.3
(CH), 127.1 (CH), 128.2 (CH), 129.3 (CH), 138.4 (C). IR
(ATR): 700, 1160, 3030 cm−1. HRMS (EI) m/z: calcd for
C12H14DN (M+) 174.1267, found 174.1269.
2
5.77 (m, 1H), 6.84−6.87 (m, 2H), 7.14−7.17 (m, 2H). H
NMR (60 MHz, CHCl3): δ 5.77 (br s). 13C NMR (100 MHz,
CDCl3): δ 25.7 (CH2), 29.9 (CH2), 33.5 (CH2), 39.2 (CH),
55.2 (CH3), 113.7 (CH), 126.66 (t, JC−D = 23.2 Hz, C),
126.72 (CH), 127.7 (CH), 139.6 (C), 157.9 (C). IR (ATR):
1180, 1240, 2910, 3030 cm−1. HRMS (EI) m/z: calcd for
C13H15DO (M+) 189.1264, found 189.1268.
2-(1-Deuteriovinyl)naphthalene (2f). Silica gel column
chromatography (hexane) gave 137 mg of the product (0.88
mmol, 88% yield) as a white solid with mp 66 °C and >99% D
(the D content was judged by comparison of the peak at 6.93
ppm (a deuterated site) with the peak at 5.33−5.34 ppm by 1H
(4-Deuteriocyclohex-3-enyl)benzene (2b). This reac-
tion was conducted on a 0.5 mmol scale. Silica gel column
chromatography (hexane) gave 70 mg of the product (0.44
mmol, 88% yield) as a colorless oil with >99% D (the D
content was judged by comparison of the peak at 5.75−5.76
ppm (a deuterated site) with the peak at 7.24−7.31 ppm by 1H
1
NMR). H NMR (500 MHz, CDCl3): δ 5.33−5.34 (m, 1H),
5.86−5.87 (m, 1H), 7.42−7.48 (m, 2H), 7.64 (dd, J = 1.7, 8.5
2
Hz, 1H), 7.75 (s, 1H), 7.79−7.82 (m, 3H). H NMR (60
MHz, CHCl3): δ 6.92 (br s). 13C NMR (100 MHz, CDCl3): δ
114.0 (CH2), 123.2 (CH), 125.9 (CH), 126.3 (CH), 126.4
(CH), 127.7 (CH), 128.1 (CH), 128.2 (CH), 133.2 (C),
133.6 (C), 135.0 (C), 136.7 (t, J = 23.2 Hz, C). IR (ATR):
890, 1510, 1680, 3080 cm−1. HRMS (EI) m/z: calcd for
C12H9D (M+) 155.0845, found 155.0844.
1
NMR). H NMR (500 MHz, DMSO-d6): δ 1.67−1.73 (m,
1H), 1.80−1.84 (m, 1H), 2.07−2.24 (m, 4H), 2.72−2.78 (m,
1H), 5.75−5.76 (m, 1H), 7.17−7.20 (m, 1H), 7.24−7.31 (m,
2
4H). H NMR (60 MHz, CHCl3): δ 5.80 (br s). 13C NMR
(100 MHz, DMSO-d6): δ 25.3 (CH2), 29.3 (CH2), 32.9
(CH2), 39.5 (CH), 126.0 (CH), 126.5 (t, JC−D = 24.8 Hz, C),
126.6 (CH), 126.9 (CH), 128.4 (CH), 147.1 (C). IR (ATR):
700, 1500, 3030 cm−1. HRMS (EI) m/z: calcd for C12H13D
(M+) 159.1158, found 159.1156.
(1-Deuterio-2-methylprop-1-enyl)benzene (2g). The
GC yield was 90%. Silica gel column chromatography
(hexane/benzene = 10/1) gave 74.2 mg of the product (0.56
mmol, 56% yield) as a colorless oil with >99% D (the D
content was judged by comparison of the peak at 6.24 ppm (a
deuterated site) with the peak at 7.29−7.32 ppm by 1H NMR).
1H NMR (500 MHz, CDCl3): δ 1.87 (s, 3H), 1.90 (s, 3H),
7.16−7.19 (m, 1H), 7.22−7.23 (m, 2H), 7.29−7.32 (m, 2H).
2H NMR (60 MHz, CHCl3): δ 6.31 (br s). 13C NMR (100
MHz, CDCl3): δ 19.2 (CH3), 26.7 (CH3), 124.8 (t, J = 23.2
Hz, C), 125.8 (CH), 128.1 (CH), 128.7 (CH), 135.4 (C),
138.7 (C). IR (ATR): 700, 1600, 1650 cm−1. HRMS (EI) m/
z: calcd for C10H11D (M+) 133.1002, found 133.1003.
3-(4-Deuteriocyclohex-3-enyl)pyridine (2c). Silica gel
column chromatography (hexane/AcOEt = 2/1) gave 148 mg
of the product (0.92 mmol, 92% yield) as brown oil with >99%
D (the D content was judged by comparison of the peak at
5.777−5.782 ppm (a deuterated site) with the peak at 8.45
ppm by 1H NMR). 1H NMR (500 MHz, CDCl3): δ 1.73−1.81
(m, 1H), 1.92−1.97 (m, 1H), 2.12−2.26 (m, 3H), 2.28−2.33
(m, 1H), 2.82−2.88 (m, 1H), 5.777−5.782 (m, 1H), 7.23 (dd,
J = 4.8, 7.8 Hz, 1H), 7.53 (dt, J = 2.2, 7.8 Hz, 1H), 8.45 (dd, J
2
= 1.5, 4.8 Hz, 1H), 8.51 (d, J = 2.2 Hz, 1H). H NMR (60
1-(1-Deuteriovinyl)-4-methoxybenzene (2h). The GC
yield was 86%. Silica gel column chromatography (hexane/
AcOEt = 50/1) gave 97.6 mg of the product (0.72 mmol, 72%
yield) as a colorless oil with 98% D (the D content was judged
by comparison of the peak at 6.66 ppm (a deuterated site) with
MHz, CHCl3): δ 5.78 (br s). 13C NMR (100 MHz, CDCl3): δ
25.2 (CH2), 29.2 (CH2), 32.7 (CH2), 37.5 (CH), 123.4 (CH),
126.1 (CH), 126.7 (t, JC−D = 24.0 Hz, C), 134.2 (CH), 142.2
(C), 147.5 (CH), 149.0 (CH). IR (ATR): 710, 810, 1020,
3030 cm−1. HRMS (EI) m/z: calcd for C11H12DN (M+)
160.1111, found 160.1117.
1
1
the peak at 5.10−5.11 ppm by H NMR). H NMR (500
MHz, DMSO-d6): δ 3.75 (s, 3H), 5.10−5.11 (m, 1H), 5.65−
2
2-(4-Deuteriocyclohex-3-enyl)thiophene (2d). Silica
gel column chromatography (hexane) gave 142 mg of the
product (0.86 mmol, 86% yield) as a yellow oil with 98% D
(the D content was judged by comparison of the peak at
5.740−5.744 ppm (a deuterated site) with the peak at 7.13
ppm by 1H NMR). 1H NMR (500 MHz, CDCl3): δ 1.70−1.78
(m, 1H), 2.08−2.25 (m, 4H), 2.41−2.47 (m, 1H), 3.09−3.15
(m, 1H), 5.740−5.744 (m, 1H), 6.84 (dt, J = 1.0, 3.4 Hz, 1H),
5.66 (m, 1H), 6.89−6.92 (m, 2H), 7.39−7.42 (m, 2H). H
NMR (60 MHz, CHCl3): δ 6.69 (br s). 13C NMR (100 MHz,
CDCl3): δ 55.2 (CH3), 111.4 (CH2), 113.9 (CH), 127.4
(CH), 130.4 (C) 135.9 (t, JC−D = 23.2 Hz, C), 159.4 (C). IR
(ATR): 830, 1030, 1240, 3070 cm−1. HRMS (EI) m/z: calcd
for C9H9DO (M+) 135.0794, found 135.0807.
4-(1-Deuteriovinyl)benzonitrile (2i). Silica gel column
chromatography (benzene/AcOEt = 10/1) gave 104 mg of the
product (0.80 mmol, 80% yield) as a colorless oil with >99% D
(the D content was judged by comparison of the peak at 6.73
2
6.93−6.95 (m, 1H), 7.13 (dd, J = 1.1, 5.1 Hz, 1H). H NMR
(60 MHz, CHCl3): δ 5.77 (br s). 13C NMR (100 MHz,
CDCl3): δ 25.2 (CH2), 30.9 (CH2), 33.8 (CH2), 35.2 (CH),
122.2 (CH), 122.5 (CH), 125.9 (CH), 126.5 (CH), 126.6 (t,
JC−D = 24.0 Hz, C), 151.4 (C). IR (ATR): 690, 810, 2910,
3030 cm−1. HRMS (EI) m/z: calcd for C10H11DS (M+)
165.0722, found 165.0725.
1
ppm (a deuterated site) with the peak at 5.45 ppm by H
1
NMR). H NMR (500 MHz, CDCl3): δ 5.45 (t, J = 1.5 Hz,
1H), 5.87 (t, J = 2.6 Hz, 1H), 7.48−7.50 (m, 2H), 7.60−7.63
(m, 2H). 2H NMR (60 MHz, CHCl3): δ 6.74 (br s). 13C NMR
(100 MHz, CDCl3): δ 111.1 (C), 117.6 (CH2), 118.9 (C),
126.7 (CH), 132.4 (CH), 135.0 (t, JC−D = 24.0 Hz, C), 141.8
(C). IR (ATR): 840, 1500, 2230, 3090 cm−1. HRMS (EI) m/
z: calcd for C9H6DN (M+) 130.0641, found 130.0638.
1,1′-(2-Deuterioethenylidene)bis(benzene) (2j). This
reaction was conducted on a 0.5 mmol scale. Silica gel column
chromatography (hexane) gave 76 mg of the product (0.46
mmol, 84% yield) as a colorless oil with >99% D (the D
1-Benzyl-4-deuterio-1,2,3,6-tetrahydropyridine (2e).
Silica gel column chromatography (hexane/benzene = 1/4)
gave 149 mg of the product (0.86 mmol, 86% yield) as a brown
oil with >99% D (the D content was judged by comparison of
the peak at 5.74−5.78 ppm (a deuterated site) with the peak at
5.65−5.68 ppm by 1H NMR). 1H NMR (500 MHz, CDCl3): δ
2.14−2.17 (m, 2H), 2.55−2.58 (m, 2H), 2.96−2.98 (m, 2H),
D
DOI: 10.1021/acs.oprd.9b00193
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Organic Process Research & Development
Article
content was judged by comparison of the peak at 5.45 ppm (a
deuterated site) with the peak at 7.29−7.35 ppm by 1H NMR).
1H NMR (500 MHz, CDCl3): δ 5.45 (s, 1H), 7.29−7.35 (m,
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.9b00193.
2
10H). H NMR (60 MHz, CHCl3): δ 5.50 (br s). 13C NMR
(100 MHz, CDCl3): δ 114.0 (t, JC−D = 24.0 Hz, CH), 127.7
(CH), 128.2 (CH), 128.3 (CH) 141.5 (C), 150.1 (C). IR
(ATR): 690, 1080, 1490 cm−1. HRMS (EI) m/z: calcd for
C14H11D (M+) 181.1002, found 181.1002.
Synthetic details of alkenyl chlorides and H, 13C, and
1
2H NMR spectra of products (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: mkuriyam@nagasaki-u.ac.jp.
*E-mail: onomura@nagasaki-u.ac.jp.
■
3,4-Dideuterio-7-methoxy-2,2-dimethyl-2H-chro-
mene (2k). This reaction was conducted on a 0.5 mmol scale.
Silica gel column chromatography (hexane/AcOEt = 20/1)
gave 93 mg of the product (0.48 mmol, 97% yield) as a
colorless oil with D1 > 99% D (the D1 content was judged by
comparison of the peak at 6.27 ppm (a deuterated site) with
the peaks at 6.37 and 6.40 ppm by 1H NMR) and D2 = 98% D
(the D2 content was judged by comparison of the peak at 5.47
ppm (a deuterated site) with the peaks at 6.37 and 6.40 ppm
ORCID
Masami Kuriyama: 0000-0002-4871-6273
Kosuke Yamamoto: 0000-0002-8189-7141
Yosuke Demizu: 0000-0001-7521-4861
Notes
1
1
by H NMR). H NMR (500 MHz, CDCl3): δ 1.42 (s, 6H),
3.77 (s, 3H), 6.37 (d, J = 2.5 Hz, 1H), 6.40 (dd, J = 2.5, 8.2
The authors declare no competing financial interest.
2
Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H). H NMR (60 MHz,
ACKNOWLEDGMENTS
■
CHCl3): δ 5.49 (br s), 6.29 (br s). 13C NMR (100 MHz,
CDCl3): δ 27.9 (CH3), 55.2 (CH3), 76.2 (C), 102.0 (CH),
106.6 (CH), 114.5 (C), 121.5 (t, J = 24.8 Hz, C), 126.9 (CH),
127.4 (t, J = 24.8 Hz, C), 154.2 (C), 160.7 (C). IR (ATR):
810, 1030, 1190, 1270, 1500 cm−1. HRMS (EI) m/z: calcd for
C12H12D2O2 (M+) 192.1119, found 192.1118.
This research was supported by JSPS KAKENHI (18K06582,
17H06961, and 16K08167) and a Research Grant for
Pharmaceutical Sciences from Takeda Science Foundation.
REFERENCES
■
(1) (a) Furuta, T.; Takahashi, H.; Kasuya, Y. Evidence for a
carbanion intermediate in the elimination of ammonia from L-
histidine catalyzed by histidine ammonia-lyase. J. Am. Chem. Soc.
1990, 112, 3633−3636. (b) Hall, L. R.; Hanzlik, R. P. Kinetic
deuterium isotope effects on the N-demethylation of tertiary amides
by cytochrome P-450. J. Biol. Chem. 1990, 265, 12349−12355.
(c) Davidova, I. A.; Gieg, L. M.; Nanny, M.; Kropp, K. G.; Suflita, J.
M. Stable Isotopic Studies of n-Alkane Metabolism by a Sulfate-
Reducing Bacterial Enrichment Culture. Appl. Environ. Microbiol.
2005, 71, 8174−8182. (d) Zimmer-De Iuliis, M.; Morris, R. H.
Kinetic Hydrogen/Deuterium Effects in the Direct Hydrogenation of
Ketones Catalyzed by a Well-Defined Ruthenium Diphosphine
Diamine Complex. J. Am. Chem. Soc. 2009, 131, 11263−11269.
(2) Reviews: (a) Sanderson, K. Big interest in heavy drugs. Nature
2009, 458, 269. (b) Harbeson, S. L.; Tung, R. D. Deuterium in Drug
Discovery and Development. Annu. Rep. Med. Chem. 2011, 46, 403−
417. (c) Meanwell, N. A. Synopsis of Some Recent Tactical
Application of Bioisosteres in Drug Design. J. Med. Chem. 2011, 54,
2529−2591. (d) Gant, T. G. Using Deuterium in Drug Discovery:
Leaving the Label in the Drug. J. Med. Chem. 2014, 57, 3595−3611.
(3) Dean, M.; Sung, V. W. Review of deutetrabenazine: a novel
treatment for chorea associated with Huntington’s disease. Drug Des.
Drug Des., Dev. Ther. 2018, 12, 313−319.
5-Allyl-10-deuterio-5H-dibenzo[b,f ]azepine (2l). This
reaction was conducted on a 0.5 mmol scale. Silica gel column
chromatography (hexane/AcOEt = 20/1) gave 98 mg of the
product (0.42 mmol, 84% yield) as a yellow oil with >99% D
(the D content was judged by comparison of the peak at 6.74
ppm (a deuterated site) with the peak at 5.74−5.82 ppm by 1H
1
NMR). H NMR (500 MHz, CDCl3): δ 4.39−4.40 (m, 2H),
5.08−5.11 (m, 1H), 5.27−5.31 (m, 1H), 5.74−5.82 (m, 1H),
6.74 (s, 1H), 6.96−6.99 (m, 4H), 7.05−7.07 (m, 2H), 7.22−
7.25 (m, 2H). 2H NMR (60 MHz, CHCl3): δ 6.77 (br s). 13
C
NMR (100 MHz, CDCl3): δ 53.5 (CH2), 117.6 (CH2), 120.6
(CH), 123.4 (CH), 128.7 (CH), 129.09 (CH), 129.13 (CH),
131.9 (t, JC−D = 24.0 Hz, C), 132.1 (CH), 133.7 (C), 133.8
(C), 135.2 (CH), 150.7 (C). IR (ATR): 880, 1110, 1230, 1480
cm−1. HRMS (EI) m/z: calcd for C17H14DN (M+) 234.1267,
found 234.1267.
(8S,9S,13R,14S)-17-Deuterio-3-methoxy-13-methyl-
7,8,9,11,12,13,14,15-octahydro-6H-cyclopenta[a]-
phenanthrene (2m). Silica gel column chromatography
(hexane/AcOEt = 50/1) gave 254 mg of the product (0.94
mmol, 94% yield) as white solid with >99% D (the D content
was judged by comparison of the peak at 5.90−5.93 ppm (a
deuterated site) with the peak at 5.74−5.75 ppm by 1H NMR).
1H NMR (500 MHz, CDCl3): δ 0.79 (s, 3H), 1.41−1.65 (m,
5H), 1.87−1.96 (m, 2H), 2.01 (ddd, J = 1.4, 11.2, 15.0 Hz,
1H), 2.21 (ddd, J = 3.0, 6.1, 15.0 Hz, 1H), 2.26−2.36 (m, 2H),
2.84−2.96 (m, 2H), 3.78 (s, 3H), 5.74−5.75 (m, 1H), 6.64 (d,
J = 3.0 Hz, 1H), 6.71 (dd, J = 2.8, 8.6 Hz, 1H), 7.20 (d, J = 8.6
Hz, 1H). 2H NMR (60 MHz, CHCl3): δ 5.96 (br s). 13C NMR
(100 MHz, CDCl3): δ 17.0 (CH3), 26.5 (CH2), 27.9 (CH2),
29.7 (CH2), 31.7 (CH2), 35.8 (CH2), 37.3 (CH), 44.5 (CH),
45.6 (C), 55.1 (CH3), 55.4 (CH), 111.4 (CH), 113.9 (CH),
126.1 (CH), 129.2 (CH), 133.2 (C), 138.0 (C), 143.7 (t, JC−D
= 24.0 Hz, C), 157.5 (C). IR (ATR): 670, 820, 1230, 1610,
3020 cm−1. HRMS (EI) m/z: calcd for C19H23DO (M+)
269.1890, found 269.1881.
(4) Reviews: (a) Jagtap, S. Heck ReactionState of the Art.
́
Catalysts 2017, 7, 267−319. (b) Cheng-Sanchez, I.; Sarabia, F. Recent
Advances in Total Synthesis via Metathesis Reactions. Synthesis 2018,
50, 3749−3786.
(5) (a) Yang, J.; Hong, K.; Bonnesen, P. V. A method for preparing
sodium acrylate-d3, a useful and stable precursor for deuterated acrylic
monomers. J. Labelled Compd. Radiopharm. 2011, 54, 743−748.
(b) Yabe, Y.; Sawama, Y.; Monguchi, Y.; Sajiki, H. Site-Selective
Deuterated-Alkene Synthesis with Palladium on Boron Nitride. Chem.
- Eur. J. 2013, 19, 484−488.
(6) (a) Corberan, R.; Sanau, M.; Peris, E. Highly Stable Cp*-Ir(III)
Complexes with N-Heterocyclic Carbene Ligands as C-H Activation
Catalysts for the Deuteration of Organic Molecules. J. Am. Chem. Soc.
2006, 128, 3974−3979. (b) Zhou, J.; Hartwig, J. F. Iridium-Catalyzed
H/D Exchange at Vinyl Groups without Olefin Isomerization. Angew.
Chem., Int. Ed. 2008, 47, 5783−5787. (c) Tse, S. K. S.; Xue, P.; Lin,
Z.; Jia, G. Hydrogen/Deuterium Exchange Reactions of Olefins with
Deuterium Oxide Mediated by the Carbonylchlorohydridotris-
E
DOI: 10.1021/acs.oprd.9b00193
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
(triphenylphosphine)ruthenium(II) Complex. Adv. Synth. Catal.
2010, 352, 1512−1522. (d) Hatano, M.; Nishimura, T.; Yorimitsu,
H. Selective H/D Exchange at Vinyl and Methylidene Groups with
D2O Catalyzed by an Iridium Complex. Org. Lett. 2016, 18, 3674−
3677. (e) Park, K.; Matsuda, T.; Yamada, T.; Monguchi, Y.; Sawama,
Y.; Doi, N.; Sasai, Y.; Kondo, S.-i; Sawama, Y.; Sajiki, H. Direct
Deuteration of Acrylic and Methacrylic Acid Derivatives Catalyzed by
Platinum on Carbon in Deuterium Oxide. Adv. Synth. Catal. 2018,
360, 2303−2307.
(7) Alonso, F.; Beletskaya, I. P.; Yus, M. Metal-Mediated Reductive
Hydrodehalogenation of Organic Halides. Chem. Rev. 2002, 102,
4009−4091.
(8) (a) Munusamy, R.; Dhathathreyan, K. S.; Balasubramanian, K.
K.; Venkatachalam, C. S. Cathodic reduction of N-(2-iodophenyl)-N-
alkylcinnamides: a novel sequential electrochemical radical cyclisation
and hydroxylation. J. Chem. Soc., Perkin Trans. 2 2001, 1154−1166.
(b) Postolache, C.; Matei, L. Synthesis of [α-T]polyacrylic acid. J.
Labelled Compd. Radiopharm. 2007, 50, 444−445. (c) Wood, M. E.;
Bissiriou, S.; Lowe, C.; Windeatt, K. M. Synthetic use of the primary
kinetic isotope effect in hydrogen atom transfer 2: generation of
captodatively stabilised radicals. Org. Biomol. Chem. 2013, 11, 2712−
2723.
(9) Littke, A. F.; Fu, G. C. Palladium-Catalyzed Coupling Reactions
of Aryl Chlorides. Angew. Chem., Int. Ed. 2002, 41, 4176−4211.
(10) (a) Kuriyama, M.; Hamaguchi, N.; Yano, G.; Tsukuda, K.; Sato,
K.; Onomura, O. Deuterodechlorination of Aryl/Heteroaryl Chlor-
ides Catalyzed by a Palladium/Unsymmetrical NHC System. J. Org.
Chem. 2016, 81, 8934−8946. (b) Kuriyama, M.; Kujirada, S.;
Tsukuda, K.; Onomura, O. Nickel-Catalyzed Deoxygenative Deutera-
tion of Aryl Sulfamates. Adv. Synth. Catal. 2017, 359, 1043−1048.
(11) The steric repulsion between the 2,4,6-trimethylbenzyl moiety
and the methyl groups at the 4- and 5-positions could be effective to
produce the Pd−arene interaction observed in ref 10a.
(12) The catalytic deuterodechlorination of 1b with the imidazolium
tetrafluoroborate salt gave the desired product 2b in 78% yield with
>99% D.
(13) Fujihara, T.; Nogi, K.; Xu, T.; Terao, J.; Tsuji, Y. Nickel-
Catalyzed Carboxylation of Aryl and Vinyl Chlorides Employing
Carbon Dioxide. J. Am. Chem. Soc. 2012, 134, 9106−9109.
(14) Ajvazi, N.; Stavber, S. Transformation of Tertiary Benzyl
Alcohols into the Vicinal Halo-Substituted Derivatives Using N-
Halosuccinimides. Molecules 2016, 21, 1325−1334.
F
DOI: 10.1021/acs.oprd.9b00193
Org. Process Res. Dev. XXXX, XXX, XXX−XXX