Deuterodechlorination of Aryl/Heteroaryl Chlorides Catalyzed by a Palladium/Unsymmetrical NHC System

Article abstract of DOI:10.1021/acs.joc.6b01609

The catalytic deuterodechlorination of aryl/heteroaryl chlorides was developed with a palladium/unsymmetrical NHC system, and the precisely controlled introduction of deuterium into a variety of aryl/heteroaryl compounds was achieved with a high level of efficiency, selectivity, and deuteration degree. This method was also successfully applied to the transformation of bioactive agents even in a gram-scale synthesis. The crystal structure analysis of Pd-NHC complexes led to the observation of Pd-arene interaction.

Full text of DOI:10.1021/acs.joc.6b01609

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Article
Deuterodechlorination of Aryl/Heteroaryl Chlorides
Catalyzed by a Palladium/Unsymmetrical NHC System
Masami Kuriyama, Norihisa Hamaguchi, Gemba Yano, Kotaro Tsukuda, Kanako Sato, and Osamu Onomura
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01609 • Publication Date (Web): 17 Sep 2016
Downloaded from http://pubs.acs.org on September 21, 2016
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Deuterodechlorination of Aryl/Heteroaryl Chlorides
Catalyzed by a Palladium/Unsymmetrical NHC System
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Masami Kuriyama,* Norihisa Hamaguchi, Gemba Yano, Kotaro Tsukuda, Kanako Sato,
and Osamu Onomura*
Graduate School of Biomedical Sciences, Nagasaki University,
1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
mkuriyam@nagasaki-u.ac.jp; onomura@nagasaki-u.ac.jp
Ph Ph
NEt2
3
NEt2
3
Cl
HN
N
HN
N
cat. PdNHC
N
N
Ph2CDOH (1.2 equiv)
Ph
Cs2CO3, toluene
Cl
D
Ph
40 examples
10 mmol (3.12 g)
99% (2.83 g), >99% D
Abstract: The catalytic deuterodechlorination of aryl/heteroaryl chlorides was developed with a
palladium/unsymmetrical NHC system, and the precisely-controlled introduction of deuterium into a
variety of aryl/heteroaryl compounds was achieved with the high level of efficiency, selectivity, and
deuteration degree. This method was also successfully applied to the transformation of bioactive agents
even in a gram-scale synthesis. The crystal structure analysis of Pd-NHC complexes led to the
observation of Pd-arene interaction.
Introduction
Deuterated compounds are highly important for the metabolic analysis of bioactive agents as well
as the mechanistic study of chemical and enzymatic reactions.1 2 Moreover, the incorporation of
,
deuterium into pharmaceutical molecules has recently attracted growing interest due to its beneficial
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effects to improve their therapeutic and metabolic profiles.3 Consequently, vigorous efforts have been
made to develop various catalytic deuteration reactions.4 Particularly, the catalytic deuterium intro-
duction into aryl/heteroaryl groups is quite significant owing to their ubiquity in pharmaceutical and
bioactive agents.5 As a typical deuteration method for this class of compounds, catalytic H/D exchange
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has been actively pursued.6 7 In this process, multiple reactive sites in a molecule are basically deu-
,
terated depending on the respective reactivities. Meanwhile, deuterodehalogenation is known as a
powerful transformation,8 where catalytic methods are expected to enable a precise, efficient, and
versatile deuterium introduction for fine chemical synthesis. However, catalytic Cl/D exchange has
remained rather limited despite the advantages of aryl/heteroaryl chlorides, such as lower cost, wider
diversity, and higher stability, because the low reactivity of chlorides demands much effort to achieve
high efficiency especially in the presence of heterocycles.9 The deuterogenative dechlorination required
a deuterated solvent and suffered from the difficulty in control of chemoselectivity.10 The Pd-catalyzed
method with a solid D source resulted in only a moderate D content under microwave irradiation,11
while a liquid D source was necessary as a solvent even with the dual enhancement by high Pd catalyst
loading and microwave assistance. 12 Therefore, the catalytic Cl/D exchange for aryl/heteroaryl
chlorides remains a quite challenging process in spite of its high significance in the light of drug
development. Herein, we report the catalytic deuterodechlorination of aryl/heteroaryl chlorides with a
palladium/unsymmetrical NHC system.
Results and Discussion
At the outset, the effects of ligands were examined in the catalytic deuterodechlorination of aryl
chloride 2a with D source 1a (1.2 equiv) in the presence of a Pd catalyst (1 mol %) formed in situ
(Table 1). The Pd-catalyzed Cl/D exchange with no ligand gave only traces of product (entry 1). In
unsymmetrical NHC precursors (Scheme 1), which were developed as stable solids with a simple two-
step procedure, methyl groups at the 4- and 5-position were found to be effective (entries 2-3). While
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2,6-diisopropylphenyl group gave a small improvement, a larger benzyl unit had no better influence
(entries 4-5). Imidazolium chloride L5 with the steric effect derived from benzhydryl groups led to 92%
yield and >99% D (entry 6), but a lower reaction temperature of 70 ºC decreased the yield to 16%.
Investigation of symmetrical NHC ligands13 (Figure 1) was conducted only to provide low yields
(entries 7-10), and the bulky aryl groups with benzhydryl units in IPr*·HCl14 as well as methyl groups
at the 4- and 5-position in MeIMes·HCl were ineffective, giving a mildly-reduced D content in the case
of IPr*·HCl (entries 9-10). Subsequently, phosphines were also evaluated (entries 11-16). The Pd-
catalyzed deuteration with Ph3P afforded only trace amount of desired product 3a (entry 11). On the
other hand, higher electron-donating ability and steric hindrance influenced D content in a positive way,
although chemical yields remained at the low level (entries 12-14). Therefore, bulky and electron-rich
phosphines15 were examined (entries 15-16). The use of t-Bu3P·HBF4 gave a low yield in spite of a
high deuteration degree. SPhos16 was also applied but only a slight improvement was observed. Then,
the investigation of -deuterioalcohols in this reaction system17 revealed that-alkylated D sources 1b-
d showed decrease in yield compared with a reagent 1a (entries 6 and 17-19). A D source 1a was
readily prepared as a stable solid from benzophenone with lithium aluminum deuteride, while deu-
terated reagents 1b-d were obtained as liquid-state compounds. Meanwhile, a deuterioformate salt such
as DCO2Na was not effective to afford no desired product. The screening of palladium sources, bases,
and solvents was also conducted, and allylpalladium(II) chloride dimer, cesium carbonate, and toluene
proved to be most suitable (Table S1 in the Supporting Information).
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Scheme 1. Synthesis of Unsymmetrical NHC Ligand Precursors
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R
R
3
4
5
6
7
8
O
O
R
R
R
R
CH3CO2H
(5 equiv)
Ar2CH2Cl
(1 equiv)
H2N Ar1
Cl
Ar1
NH4OAc
+
N
N
N
N
Ar1
(1.2 equiv) (1.2 equiv)
H
CHCl3
reflux
THF
reflux
Ar2
HO
O
Im1-3
4568%
L1: 59% L4: 51%
L2: 70% L5: 69%
L3: 48%
n
(1 equiv)
9
R
R
i-Pr
Ph Ph
Cl
Cl
Cl
R
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N
N
N
R
N
N
N
Ph
i-Pr
Ph
L5
R
L1 (R = H)
L3 (R = Me)
L4 (R = i-Pr)
L2 (R = Me)
Table 1. Effect of ligands a
Ligand (2 mol %)
[Pd(allyl)Cl]2 (0.5 mol %)
Cl
D
OH
+
R1
R2
Cs2CO3 (1 equiv)
toluene (2 mL)
90 °C, 3 h
D
MeO
OMe
MeO
OMe
2a
(1 mmol)
1
3a
(1.2 equiv)
yield
(%)
D content
(%)
entry
ligand
1
1
2
3
4
5
6
7
8
9
none
L1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
trace
33
45
50
43
92
31
23
30
29
trace
7
ND
>99
>99
>99
>99
>99
>99
99
L2
L3
L4
L5
IMes·HCl
SIMes·HCl
MeIMes·HCl
IPr*·HCl
Ph3P
99
10
11
12
13
14
15
16
17
18
19
93
ND
30
(4-FPh)3P
(4-MeOPh)3P
(2-MePh)3P
t-Bu3P·HBF4
SPhos
10
11
26
28
85
43
26
41
62
98
98
L5
99
L5
99
L5
>99
OH
OH
Me
OH
OH
n-Bu
n-Bu
D
D
D
D
1a
1b
1c
1d
a
Reaction conditions: 2a (1 mmol), 1 (1.2 mmol), ligand (2 mol %), Pd (1 mol %), Cs2CO3 (1 mmol), toluene (2 mL),
90 °C, 3 h. D content was determined by 1H-NMR.
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R
R
3
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N
N
N
N
Cl
Cl
MeIMes·HCl (R= H)
MeIMes·HCl (R= Me)
SIMes·HCl
Ph
Ph
Ph Ph
PCy2
OMe
N
N
Cl
MeO
Ph Ph
Ph
Ph
IPr*·HCl
SPhos
Figure 1. Symmetrical NHC precursors and SPhos
To acquire more information on the catalyst system, the 1:1 molar ratio complexes of Pd(II)/L5
were prepared (Scheme 2). After L5 was treated with lithium tert-butoxide, [Pd(allyl)Cl]2 was added to
the resulting reaction mixture to give neutral complex C1 in 89% yield. In addition, cationic complex
C2 was obtained in 80% yield by the conversion of complex C1 with AgSbF6. The chemical structures
of both C1 and C2 were determined by X-ray crystallography. In particular, the Pdarene interaction
was observed in complex C2 (Figure 2), which was known in phosphine-based metal catalysts as a
possible factor for the improvement of catalyst stability, activity, and lifetime,15a and the Pd center was
found in the concave space formed by the aryl rings. In the X-ray crystal structure, the Pd(II)C(10)
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distance was 2.376 Å. This value was marginally larger than that of a reported Pd(II)arene distance,15a
which could relate to the observation of slightly broad methyl signals in the 1H NMR spectrum of C2.
Scheme 2. Synthesis of PdNHC complexes
Ph
Ph
Ph Ph
Cl
1) LiOt-Bu
2) [Pd(allyl)Cl]2
N
N
N
N
Ph
Ph
THF, rt
Ph
Pd
89% yield
Ph
Cl
C1
L5
Ph
Ph
AgSbF6
CH2Cl2, rt
80% yield
N
N
Ph
Ph
Pd

SbF6
C2
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Pd
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N
C10

Figure 2. Crystal structure of C2. In the ellipsoid presentation (50% probability), H atoms and SbF6
were omitted for clarity. In the spacefilling presentation, an allyl anion was also omitted for clarity.
While the catalysts formed in situ from Pd(II) and L5 in 1:1 and 1:2 molar ratios, respectively, led
to 76% and 94% yields with >99% D (entries 1-2 in Table 2), the chemical yields obtained with
complexes C1 and C2 were well accorded with the result of entry 1 (entries 3 and 5) and the catalytic
Cl/D exchange with the catalysts formed in situ from C and L5 gave the same yields as entry 2 (entries
4 and 6). These results suggested that one NHC derived from L5 in a complex catalyst would be
required for the core formation to achieve high catalytic performance whereas the second L5 for a Pd
atom might be significant to improve the stability of precatalysts.
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Table 2. Catalytic deuterodechlorination with C1 and C2
4
5
6
7
8
Cl
D
OH
Catalyst (1 mol %)
+
Ph
Ph
Cs2CO3 (1 equiv)
toluene (2 mL)
90 °C, 16 h
D
MeO
OMe
MeO
OMe
2a
(1 mmol)
1a
3a
(1.2 equiv)
9
10
11
12
13
14
15
16
17
18
19
20
21
yield
D content
(%)
entry
catalyst
Pd/L5
(%)
76
94
75
94
76
94
1a,b
2a,c
3
Pd(II)+L5
Pd(II)+L5
C1
1/1
1/2
1/1
1/2
1/1
1/2
>99
>99
>99
>99
>99
>99
4a,d
C1+L5
C2
5
6a,d
C2+L5
a The catalyst was formed in situ. b [Pd(allyl)Cl]2 (0.5 mol %), L5 (1 mol %). c [Pd(allyl)Cl]2 (0.5 mol %), L5 (2 mol %). d
C (1 mol %), L5 (1 mol %).
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Investigation of aryl chlorides in the Pd-catalyzed deuterodechlorination was conducted on the
basis of optimized conditions (Scheme 3). The sterically hindered as well as electron-rich substrates
gave the desired products efficiently with no reductive deprotection of a benzyl group (3b-d). The
epoxy moiety was well tolerated with high yields in spite of the concern about nucleophilic or reductive
ring-opening, and no racemization in a chiral epoxide was observed (3e-g). The electron-poor aryl
chlorides with a reducible nitro or enone group also led to no side reaction (3h-i), and IMes·HCl and
IPr*·HCl did not show adequate effects (3i). Both ester and amide groups proved to be suitable without
problems such as transesterification (3j-k). This catalytic system sufficiently tolerated thioether as well
as amino moieties to give high yields (3l-m). In the presence of a free OH or NH group, the deuteration
reactions smoothly proceeded with no decrease in D content (3n-o). Additionally, the triple intro-
duction of deuterium was successfully achieved (3p). In these examinations, quantitative D-efficiencies
were observed in addition to high selectivity and functional group tolerance.
Scheme 3. Scope of aryl chlorides
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L5 (2 mol %)
[Pd(allyl)Cl]2 (0.5 mol %)
OH
Cl
D
+
3
4
5
R
R
Ph
Ph
Cs2CO3 (1.5 equiv)
toluene (2 mL)
90 °C, 16 h
D
2
1a
3
(1 mmol)
(1.2 equiv)
6
7
8
9
Me
D
D
D
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BnO
BnO
Me
BnO
3d
99%, >99% D
Me
3b
3c
99%, >99% D
99%, >99% D
D
O
O
O
O
D
O
O
D
3e
3fa
3g
93%, >99% D
94%, >99% D
93%, >99% D
D
O
O
NO2
On-Bu
D
D
3h
3ib
3j
98%, >99% D
98%, >99% D
94%, >99% D
O
Bn
N
D
S
NMe2
Bn
D
D
3k
3lc
3mc,d
99%, >99% D
96%, >99% D
82%, >99% D
O
O
D
D
D
Me
NO2
OH
N
H
D
D
3nc,d,e
3od
3pc,f
83%, >99% Dg
80%, >99% D
99%, >99% D
a 3f (91% ee) was obtained from 2f (91% ee). IMes·HCl, SIMes·HCl, and SPhos gave 0% yield, while IPr*·HCl led to
33% (91% D). c The catalyst (3 mol %). d 100 °C. e Cs2CO3 (3 equiv). f 1a (3.6 equiv), Cs2CO3 (4.5 equiv). g All the reactive
sites gave >99% D.
b
Influence of varying heteroaryl chlorides in the catalytic deuterodechlorination was investigated
(Scheme 4). In a series of chlorinated pyridine and quinoline substrates, chlorine atoms were efficiently
replaced by deuterium (5a-f). Electron-rich heteroaryl chlorides such as indole, benzofuran, and thio-
phene, as well as benzothiophene derivatives were also found to be good reaction partners (5g-k).
Moreover, hereroaryl chlorides bearing a few heteroatoms such as nitrogen, oxygen, and sulfur were
explored. Pyrimidine, cinnoline, and benzothiazole cores were deuterated with adequate efficiency (5l-
n). This deuteration method was successfully applied to the 6-chloro-7-azaindole derivative, as well as
6-chloroimidazopyridine (5o-p). The heteroaryl chloride containing oxazolopyridine moiety reacted
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sufficiently, leading to 74% yield (5q). The double deuterated quinoline was also effectively prepared
in one step (5r). All the various deuterated heteroaryls were obtained in quantitative D-incorporations.
6
7
8
9
Scheme 4. Scope of heteroaryl chlorides
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L5 (2 mol %)
Cl
OH
D
[Pd(allyl)Cl]2 (0.5 mol %)
+
Het
Het
Ph
Ph
Cs2CO3 (1.5 equiv)
toluene (2 mL)
90 °C, 16 h
D
4
1a
5
(1 mmol)
(1.2 equiv)
D
D
N
OBn
N
OBn
D
N
OBn
5a
99%, >99% D
5b
97%, >99% D
5c
99%, >99% D
D
D
N
NBn2
N
N
CF3
D
5d
92%, >99% D
5e
5f
97%, >99% D
97%, >99% D
n-Hex
n-Bu
D
D
S
D
N
O
Me
97%, >99% D
5h
5i
5g
94%, >99% D
96%, >99% D
D
D
N
N
D
S
S
MeO
OMe
5k
5la,b,c
5jb
93%, 99% D
72%, >99% D
90%, >99% D
D
D
D
N
N
Me
N
N
5ma,b
S
N
5na,b,c
91%, >99% D
5ob
86%, >99% D
99%, >99% D
D
Ph
N
Ph
N
O
D
N
D
N
D
N
n-Bu
5p
5qa,b,c,e
74%, >99% D
5rb,d
95%, >99% D
97%, >99% Df
a
b
c
d
e
f
The catalyst (3 mol %). 100 °C. Cs2CO3 (2 equiv). 1a (2.4 equiv), Cs2CO3 (3 equiv). 32 h. Both reactive sites
gave >99% D.
To evaluate the synthetic utility18 of this catalytic process, bioactive molecules bearing a variety of
functional groups were examined as substrates (Scheme 5). In the incorporation of deuterium into
oxygen-function compounds (7a-b), excellent chemical yields and quantitative D contents were ob-
served, while the highly functionalized spiro molecule gave 95% yield and 97% D (7c). Besides,
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bioactive agents with a nitrogen-containing heterocycle also led to high levels of chemical yield and
deuteration degree even in the presence of a piperidine, phenothiazine, or quinoline core with additional
groups such as hydroxy and amino moieties (7d-f).
8
9
Scheme 5. Catalytic deuterodechlorination of bioactive compounds and their derivatives a
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O
O
Me
H
D
Oi-Pr
D
O
H
H
O
BnO
7ac
7b
92%, >99% D
95%, >99% D
(from fenofibrate)
(from an estrone derivative)
D
HO
MeO
O
MeO
D
O
O
N
3
O
7cb,e
OMe
F
7d
94%, >99% D
(from haloperidol)
95%, 97% D
(from (+)-griseofulvin)
NMe2
NEt2
HN
3
D
N
S
D
N
7ed
90%, >99% D
(from chlorpromazine HCl salt)
7f
98%, >99% D
(from chloroquine)
a Reaction conditions: substrate 6 (1 mmol), 1a (1.2 mmol), L5 (2 mol %), [Pd(allyl)Cl]2 (0.5 mol %), Cs2CO3 (1.5 mmol),
toluene (2 mL), 90 °C, 16 h. b The catalyst (3 mol %). c 100 °C. d Cs2CO3 (2.5 equiv). e 1a (1.5 equiv).
Furthermore, the gram-scale catalytic deuterodechlorination of chloroquine (6f) was conducted,
and the desired product was obtained in 99% yield and >99% D (Scheme 6), in which the practical
isolation by only back extraction was applicable in addition to the regular method by column chromato-
graphy. The quantitatively recovered benzophenone was readily converted into -deuteriobenzhydrol
(1a), which was applied to another deuterodechlorination without problems.
Scheme 6. Gram-scale catalytic deuterodechlorination of chloroquine
NEt2
3
NEt2
3
HN
N
HN
L5 (2 mol %)
[Pd(allyl)Cl]2 (0.5 mol %)
Ph2CDOH (1a: 1.2 equiv)
Cs2CO3 (1.5 equiv)
toluene (20 mL)
Cl
D
N
6f
7f
(99%, >99% Da
90 °C, 16 h
(10 mmol)
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a The resulting benzophenone was recovered in 99% (9.9 mmol).
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A tentative reaction mechanism for this palladium-catalyzed deuterodechlorination of aryl/hetero-
aryl chlorides is presented in Scheme 7. After the formation of a NHC-ligated Pd complex in the
presence of a base, an aryl chloride is oxidatively added to a Pd(0) complex to give an aryl-palladium
intermediate. Subsequently, base-promoted displacement of a chloride anion generates a -deuterio-
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alkoxy-palladium species, which undergoes -deuterium elimination leading to an aryl-palladium-
deuteride complex. Finally, reductive elimination affords a deuterated product and regenerates a Pd(0)
catalyst. A similar mechanism was recently proposed in the report of a deuteration method for aryl
bromides.9c
Scheme 7. Plausible reaction mechanism
Ar Pd Cl
Ph2CDOH
Ar Cl
Pd(II)
NHC•HCl
+
base
base
Ph
D
Ph
Ar Pd
O
PdLn
(NHC)2Pd(II)
(precatalyst)
Ph2C
O
Ar
D
Ar Pd
D
Conclusion
In summary, the effective catalytic deuterodechlorination for aryl/heteroaryl chlorides was de-
veloped with the palladium/unsymmetrical NHC system, which required only a small excess of a
deuterated chemical as a D source. NHC precursor L5 and D source 1a were easily prepared as stable
solids. Investigation of the Pd-NHC complexes suggested that the Pd-arene interaction may play a key
role in the catalyst performance. This process allowed for the high level of efficiency, selectivity,
generality, and deuteration degree. The catalytic Cl/D exchange of bioactive molecules was also
successfully achieved even in a gram-scale synthesis. We believe that this method will serve as an
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useful transformation in research areas requiring precisely-controlled synthesis such as drug
development.
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Experimental Section
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1
General. All melting points are not corrected. IR spectra were expressed in cm–1. H and 13C NMR
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spectra were taken at 500 and 100 MHz respectively. Chemical shift values are expressed in ppm
relative to internal or external TMS. Abbreviations are as follows: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad. A double-focusing magnetic sector mass spectrometer was used for
low- and high-resolution EI-MS and FAB-MS. The products were isolated by silica gel column
chromatography. The degree of deuterium incorporation was determined by 1H-NMR (500 MHz). All
reactions were performed under argon atmosphere unless otherwise specified. Toluene was distilled
from sodium benzophenone ketyl under argon. Aryl chlorides 2b-g, 2j, 2l-m, 2o, 4c-d, 4h, 4k, and 6b
19
20
a
a
were synthesized as new compounds. 4a , 4b19b, 4g19c, 4j19c, 4m19d, 4o19e, 4p19f, 4q19g, MeIMes·HC ,
IPr*·HCl20b, and 2,6-bis(diphenylmethyl)-4-methylaniline20b for Im-3 were prepared as previously
reported. Chloroquine 6f was obtained from purchased chloroquine diphosphate salt by treatment with
aqueous 10% NaOH solution. All other chemicals were used as received.
General synthetic procedure of 1-arylimidazoles. This modified procedure for synthesis of 1-
arylimidazoles was optimized on the basis of Orru’s method.21 Exceptionally, 1-(2,4,6-trimethyl-
phenyl)-1H-imidazole was prepared according to Waymouth’s report.22 To a aniline derivative (12
mmol) in dry CHCl3 (20 mL), diacetyl (861 mg, 10 mmol), acetic acid (3.0 g, 50 mmol), NH4OAc (925
mg, 12 mmol), paraformaldehyde (480 mg, 10 mmol), and H2O (0.5 mL) were added and the mixture
was refluxed for 48 h. After removal of the solvent, the dark residue was dissolved in Et2O and basified
to pH 14 in an ice bath with aqueous 40% KOH solution. The resulting mixture was extracted with
Et2O and the combined organic layers were washed with H2O and dried over Na2SO4. Concentration
and purification through silica gel column chromatography gave a 1-arylimidazole.
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1-Mesityl-4,5-dimethyl-1H-imidazole (Im1). Silica gel chromatography (hexane/AcOEt = 3/1)
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gave 1.46 g of the product (6.8 mmol, 68% yield) as pale brown solids of mp 130-131 °C. H-NMR
(500 MHz, CDCl3): δ 1.84 (s, 3H), 1.93 (s, 6H), 2.24 (s, 3H), 2.34 (s, 3H), 6.97 (s, 2H), 7.25 (s, 1H).
13C-NMR (100 MHz, CDCl3): δ 8.0 (CH3), 12.8 (CH3), 17.2 (CH3), 20.9 (CH3), 122.5 (C), 128.9 (CH),
132.4 (C), 133.8 (C), 134.4 (CH), 136.0 (C), 138.6 (C). IR (ATR): 770, 1490 cm-1. HRMS (EI) m/z:
(M+) Calcd for C14H18N2: 214.1470; Found: 214.1461.
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1-(2,6-Diisopropylphenyl)-4,5-dimethyl-1H-imidazole (Im2). Silica gel chromatography (hex-
ane/AcOEt = 1/2) gave 1.59 g of the product (6.2 mmol, 62% yield) as brown oil. 1H-NMR (500 MHz,
CDCl3): δ 1.09 (d, J = 7.1 Hz, 6H), 1.14 (d, J = 7.1 Hz, 6H), 1.85 (s, 3H), 2.26 (s, 3H), 2.32-2.40 (m,
13
2H), 7.24 (s, 1H), 7.27 (d, J = 7.8 Hz, 2H), 7.42 (t, J = 7.8 Hz, 1H). C-NMR (100 MHz, CDCl3): δ
8.1 (CH3), 12.6 (CH3), 22.8 (CH3), 24.8 (CH3), 27.6 (CH), 123.3 (C), 123.5 (CH), 129.5 (CH), 131.5
(C), 133.4 (C), 135.3 (CH), 146.7 (C). IR (ATR): 770, 1490 cm-1. HRMS (EI) m/z: (M+) Calcd for
C17H24N2: 256.1939; Found: 256.1933.
1-(2,6-Dibenzhydryl-4-methylphenyl)-4,5-dimethyl-1H-imidazole (Im3). This 1-arylimidazole
was prepared with 2.5 mmol of diacetyl. Silica gel chromatography (hexane/AcOEt = 2/1) gave 585 mg
1
of the product (1.13 mmol, 45% yield) as pale yellow solids of mp 87-88 °C. H-NMR (500 MHz,
CDCl3): δ 1.30 (s, 3H), 2.15 (s, 3H), 2.26 (s, 3H), 4.99 (s, 2H), 6.61 (s, 1H), 6.86 (s, 2H), 6.89 (d, J =
13
7.2 Hz 4H), 6.95 (d, J = 7.2 Hz, 4H), 7.15-7.25 (m, 12H). C-NMR (100 MHz, CDCl3): δ 7.6 (CH3),
12.8 (CH3), 21.7 (CH3), 51.3 (CH), 123.3 (C), 126.5 (CH), 128.3 (CH), 128.4 (CH), 129.2 (CH), 129.5
(CH), 129.6 (CH), 132.3 (C), 133.8 (C), 135.6 (CH), 138.8 (C), 142.4 (C), 142.78 (C), 142.85 (C). IR
(ATR): 700, 1490 cm-1. HRMS (EI) m/z: (M+) Calcd for C38H34N2: 518.2722; Found: 518.2719.
General synthetic procedure of imidazolium chlorides. To a 1-arylimidazole (2.0 mmol) in dry
THF (2 mL) was added an arylmethyl chloride (2.0 mmol). The mixture was refluxed for 15 h and then
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evaporated until THF was moderately reduced without complete drying. The resulting solids were
filtered and washed with THF giving a desired imidazolium chloride.
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3-Mesityl-1-(2,4,6-trimethylbenzyl)imidazolium chloride (L1). The desired product was obtain-
ed in 59% yield (414 mg, 1.17 mmol) as white solids of mp 286-287 °C. 1H-NMR (500 MHz, CDCl3):
δ 2.08 (s, 6H), 2.30 (s, 3H), 2.349 (s, 3H), 2.354 (s, 6H), 6.05 (s, 2H), 6.94 (s, 2H), 7.01 (s, 2H), 7.03 (t,
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J = 1.8 Hz, 1H), 7.11 (t, J = 1.8 Hz, 1H), 11.01 (s, 1H). C-NMR (100 MHz, CDCl3): δ 17.2 (CH3),
19.5 (CH3), 20.70 (CH3), 20.72 (CH3), 48.0 (CH2), 121.3 (CH), 123.6 (CH), 125.7 (C), 129.6 (CH),
129.7 (CH), 130.6 (C), 133.9 (C), 137.9 (C), 138.1 (CH), 139.5 (C), 141.0 (C). IR (ATR): 760, 1190,
1540 cm-1. HRMS (FAB) m/z: [M–Cl]+ Calcd for C22H27N2: 319.2174; Found: 319.2157.
3-Mesityl-4,5-dimethyl-1-(2,4,6-trimethylbenzyl)imidazolium chloride (L2). The desired pro-
duct was obtained in 70% yield (535 mg, 1.40 mmol) as white solids of mp 285-286 °C. 1H-NMR (500
MHz, CDCl3): δ 1.91 (s, 3H), 2.01 (s, 6H), 2.13 (s, 3H), 2.28 (s, 3H), 2.34 (s, 6H), 2.35 (s, 3H), 5.99 (s,
2H), 6.89 (s, 2H), 7.02 (s, 2H), 9.92 (s, 1H). 13C-NMR (100 MHz, CDCl3): δ 7.8 (CH3), 8.8 (CH3), 17.1
(CH3), 19.6 (CH3), 20.5 (CH3), 20.6 (CH3), 47.1 (CH2), 125.4 (C), 127.5 (C), 128.1 (C), 128.6 (C),
129.6 (CH), 129.7 (CH), 134.3 (C), 135.1 (CH), 137.3 (C), 138.9 (C), 141.0 (C). IR (ATR): 850, 1550
cm-1. HRMS (FAB) m/z: [M–Cl]+ Calcd for C24H31N2: 347.2487; Found: 347.2488.
3-(2,6-Diisopropylphenyl)-4,5-dimethyl-1-(2,4,6-trimethylbenzyl)imidazolium chloride (L3).
The desired product was obtained in 48% yield (403 mg, 0.95 mmol) as white solids of mp 267-268 °C.
1H-NMR (500 MHz, CDCl3): δ 1.17 (d, J = 6.9 Hz, 6H), 1.19 (d, J = 6.9 Hz, 6H), 1.92 (s, 3H), 2.21
(septet, J = 6.9 Hz, 2H), 2.23 (s, 3H), 2.27 (s, 3H), 2.34 (s, 6H), 6.04 (s, 2H), 6.89 (s, 2H), 7.31 (d, J =
13
8.0 Hz, 2H), 7.53 (t, J = 8.0 Hz, 1H), 9.71 (s, 1H). C-NMR (100 MHz, CDCl3): δ 8.2 (CH3), 9.2
(CH3), 19.6 (CH3), 20.7 (CH3), 22.7 (CH3), 24.8 (CH3), 28.4 (CH), 47.3 (CH2), 124.7 (CH), 125.3 (C),
128.0 (C), 128.5 (C), 128.6 (C), 129.9 (CH), 131.8 (CH), 134.8 (CH), 137.7 (C), 139.4 (C), 145.5 (C).
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IR (ATR): 810, 1460 cm-1. HRMS (FAB) m/z: [M–Cl]+ Calcd for C27H37N2: 389.2957; Found:
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389.2955.
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1-(2,4,6-Triisopropylbenzyl)-3-(2,6-diisopropylphenyl)-4,5-dimethylimidazolium
chloride
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(L4). The desired product was obtained in 51% yield (515 mg, 1.01 mmol) as white solids of mp 208-
209 °C. 1H-NMR (500 MHz, CDCl3): δ 1.07 (d, J = 6.8 Hz, 6H), 1.18 (d, J = 6.8 Hz, 6H), 1.22-1.25 (m,
18H), 2.02 (s, 3H), 2.24 (septet, J = 6.8 Hz, 2H), 2.69 (s, 3H), 2.88 (septet, J = 6.8 Hz, 1H), 3.16 (septet,
J = 6.8 Hz, 2H), 5.79 (s, 2H), 7.08 (s, 2H), 7.29 (d, J = 7.8 Hz, 2H), 7.51 (t, J = 7.8 Hz, 1H), 8.00 (s,
13
1H). C-NMR (100 MHz, CDCl3): δ 8.5 (CH3), 9.8 (CH3), 23.1 (CH3), 23.5 (CH3), 24.1 (CH3), 24.7
(CH3), 28.2 (CH), 29.6 (CH), 34.0 (CH), 45.0 (CH2), 121.5 (C), 122.1 (CH), 124.8 (CH), 127.9 (C),
129.4 (C), 129.7 (C), 131.9 (CH), 132.1 (CH), 145.6 (C), 148.7 (C), 151.4 (C). IR (ATR): 760, 1540
cm-1. HRMS (FAB) m/z: [M–Cl]+ Calcd for C33H49N2: 473.3896; Found: 473.3901.
3-(2,6-Dibenzhydryl-4-methylphenyl)-4,5-dimethyl-1-(2,4,6-trimethylbenzyl)imidazolium
chloride (L5). The desired product was obtained in 69% yield (941 mg, 1.37 mmol) as white solids of
1
mp 214-215 °C. H-NMR (500 MHz, CDCl3): δ 1.26 (s, 3H), 2.15 (s, 6H), 2.23 (s, 6H), 2.28 (s, 3H),
4.99 (s, 2H), 5.66 (s, 2H), 6.80 (s, 2H), 6.83 (s, 2H), 6.92-6.95 (m, 8H), 7.20-7.28 (m, 12H), 8.63 (s,
13
1H). C-NMR (100 MHz, CDCl3): δ 7.6 (CH3), 9.1 (CH3), 19.8 (CH3), 20.7 (CH3), 21.5 (CH3), 47.0
(CH2), 51.4 (CH), 125.2 (C), 127.0 (CH), 127.1 (CH), 128.2 (C), 128.5 (CH), 128.6 (CH), 128.7 (CH),
129.2 (CH), 129.7 (CH), 130.4 (CH), 134.7 (CH), 137.4 (C), 139.2 (C), 140.7 (C), 141.1 (C), 141.4 (C).
IR (ATR): 700, 1490 cm-1. HRMS (FAB) m/z: [M–Cl]+ Calcd for C48H47N2: 651.3739; Found:
651.3743. Anal. Calcd for C48H47N2Cl: C, 83.87; H, 6.89; N, 4.08. Found: C, 83.77; H, 7.04; N, 4.01.
Typical synthetic procedure of -deuterioalcohols. Benzophenone (546 mg, 3 mmol) in THF (5
mL) was added to the suspension of lithium aluminum deuteride (63 mg, 1.5 mmol) in THF (4.2 mL) at
0 °C. After the reaction mixture was stirred for 30 min at 0 °C, water was added. The resulting mixture
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was extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4. Concentration
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and purification through silica gel chromatography gave -deuteriobenzhydrol (1a).
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-Deuteriobenzhydrol (1a). Silica gel chromatography (hexane/AcOEt = 5/1) gave 531 mg of the
product (2.87 mmol, 96% yield) as white solids of mp 64-65 °C. >99% D (D content was judged with
the peak at 5.80 ppm (a deuterated site) compared to the peak at 7.32-7.40 ppm by 1H-NMR). 1H-NMR
(500 MHz, CDCl3): δ 2.20 (s, 1H), 7.25-7.28 (m, 2H), 7.32-7.35 (m, 4H), 7.37-7.40 (m, 4H). 13C-NMR
(100 MHz, CDCl3): δ 75.4 (t, JC-D = 22.4 Hz, C), 126.5 (CH), 127.3 (CH), 128.3 (CH), 143.7 (C). IR
(ATR): 730, 1040, 1190, 1490, 1600, 3260 cm-1. HRMS (EI) m/z: (M+) Calcd for C13H11DO: 185.0951;
Found: 185.0958.
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-Deuterio--phenylethanol (1b). This compound was prepared from acetophenone (4 mmol).
Silica gel chromatography (hexane/ AcOEt = 7/1) gave 468 mg of the product (3.80 mmol, 95% yield)
as colorless oil. >99% D (D content was judged with the peak at 4.90 ppm (a deuterated site) compared
1
to the peak at 7.34-7.39 ppm by 1H-NMR). H-NMR (500 MHz, CDCl3): δ 1.50 (s, 3H), 1.76 (s, 1H),
7.26-7.29 (m, 1H), 7.34-7.39 (m, 4H). 13C-NMR (100 MHz, CDCl3): δ 24.8 (CH3), 69.6 (t, JC-D = 21.5
Hz, C), 125.3 (CH), 127.3 (CH), 128.3 (CH), 145.8 (C). IR (ATR): 700, 750, 1130, 1450, 2970, 3330
cm-1. HRMS (EI) m/z: (M+) Calcd for C8H9DO: 123.0794; Found: 123.0796.
-Deuterio--cyclohexylbenzenemethanol (1c). This compound was prepared from cyclohexyl-
(phenyl)methanone (8 mmol). Silica gel chromatography (hexane/AcOEt = 8/1) gave 1.52 g of the
product (7.94 mmol, 99% yield) as colorless oil. >99% D (D content was judged with the peak at 4.37
1
1
ppm (a deuterated site) compared to the peak at 1.97-2.01 ppm by H-NMR). H-NMR (500 MHz,
CDCl3): δ 0.89-0.97 (m, 1H), 1.01-1.27 (m, 4H), 1.36-1.40 (m, 1H), 1.59-1.68 (m, 3H), 1.75-1.79 (m,
2H), 1.97-2.01 (m, 1H), 7.25-7.36 (m, 5H). 13C-NMR (100 MHz, CDCl3): δ 25.8 (CH2), 25.9 (CH2),
26.2 (CH2), 28.6 (CH2), 29.0 (CH2), 44.6. (CH), 78.6 (t, JC-D = 21.5 Hz, C), 126.6 (CH), 127.2 (CH),
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128.0 (CH), 143.6 (C). IR (ATR): 700, 760, 1450, 2850, 2920, 3370 cm-1. HRMS (EI) m/z: (M+) Calcd
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5
for C13H17DO: 191.1420; Found: .191.1420.
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5-Deuterio-5-nonanol (1d). This compound was prepared from nonan-5-one (8 mmol). Silica gel
chromatography (hexane/AcOEt = 10/1) gave 1.15 g of the product (7.92 mmol, 99% yield) as colorless
oil. >99% D (D content was judged with the peak at 3.59 ppm (a deuterated site) compared to the peak
at 0.91 ppm by 1H-NMR). 1H-NMR (500 MHz, CDCl3): δ 0.91 (t, J = 7.1 Hz, 6H), 1.25 (s, 1H), 1.27-
1.50 (m, 12H). 13C-NMR (100 MHz, CDCl3): δ 13.7 (CH3), 22.5 (CH2), 27.6 (CH2), 36.8 (CH2), 71.0 (t,
JC-D = 21.5 Hz, C). IR (ATR): 2860, 2870, 2930, 2960, 2970, 3340 cm-1. HRMS (EI) m/z: (M+) Calcd
for C9H19DO: 145.1577; Found: 145.1571.
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Allylchloro{4,5-dimethyl-3-[2,6-bis(diphenylmethyl)-4-methylphenyl]-1-(2,4,6-trimethyl-
benzyl)imidazol-2-ylidene}palladium(II) (C1). A reaction flask was charged with ligand precursor L5
(289 mg, 0.42 mmol) and LiOt-Bu (39 mg, 0.49 mmol). After dry THF (28 mL) was added, the reaction
mixture was stirred for 4 h at room temperature. Then, [Pd(allyl)Cl]2 (77 mg, 0.21 mmol) was added.
After the mixture was stirred for 3 h at room temperature, the resulting mixture was filtered through
celite. Concentration and purification through silica gel chromatography (hexane/AcOEt = 4/1) gave
311 mg of the product (0.37 mmol, 89% yield) as pale yellow solids of mp 205- 206 °C, which were
1
recrystallized from CH2Cl2/hexane. H-NMR (500 MHz, CDCl3): δ 0.07 (s, 3H), 1.56-1.57 (m, 1H),
1.61 (s, 3H), 2.28 (s, 3H), 2.29 (s, 3H), 2.44 (s, 6H), 2.66 (d, J = 6.7 Hz, 1H), 3.06 (d, J = 13.5 Hz, 1H),
4.18 (dd, J = 1.5, 7.5 Hz, 1H), 4.75-4.83 (m, 1H), 5.75 (d, J = 15.7 Hz, 1H), 5.77 (s, 2H), 5.86 (d, J =
15.7 Hz, 1H), 6.85 (s, 2H), 6.96-7.25 (m, 22H). 13C-NMR (100 MHz, CDCl3): δ 7.21, 8.93, 20.8, 21.1,
21.7, 49.6, 50.0, 50.7, 50.9, 71.9, 114.4, 125.8, 126.2, 126.3, 128.03, 128.05, 128.08, 129.4, 129.56,
129.63, 129.7, 129.8, 129.9, 130.0, 130.7, 135.2, 137.3, 137.5, 138.0, 142.1, 142.3, 142.4, 142.5, 143.1,
143.4, 181.3. IR (ATR): 700, 1450, 1490 cm-1. HRMS (FAB) m/z: [M–Cl]+ Calcd for C51H51N2106Pd:
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797.3082; Found: 797.3095. Anal. Calcd for C51H51ClN2Pd: C, 73.46; H, 6.16; N, 3.36. Found: C,
73.36; H, 5.83; N, 3.26.
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Allyl{4,5-dimethyl-3-[2,6-bis(diphenylmethyl)-4-methylphenyl]-1-(2,4,6-trimethylbenzyl)-
imidazol-2-ylidene}palladium(II) hexafluoroantimonate (C2). Complex C1 (50 mg, 0.06 mmol) in
dry CH2Cl2 (16 mL) was treated with AgSbF6 (21 mg, 0.06 mmol) for 1 h at room temperature. The
resulting mixture was filtered through celite. Concentration and purification through silica gel chro-
matography (hexane/AcOEt = 1/1.5) gave 50 mg of the product (0.048 mmol, 80% yield) as pale
yellow solids of mp 147-148 °C, which were recrystallized from CH2Cl2/pentane. 1H-NMR (500 MHz,
CDCl3): δ 1.02 (s, 3H), 1.20 (d, J = 11.7 Hz, 1H ), 1.77-1.78 (m, 1H), 2.32 (s, 3H), 2.34 (s, 3H), 2.32-
2.34 (m, 1H), 2.41 (s, 3H), 2.51 (s, 3H), 2.69 (s, 3H), 2.90 (d, J = 13.7, Hz, 1H), 4.67-4.77 (m, 1H),
4.93-5.04 (m, 4H), 6.90 (t, J = 7.3 Hz, 4H), 6.97 (d, J = 7.8 Hz, 2H), 7.04 (s, 1H), 7.09-7.12 (m, 3H),
7.20-7.28 (m, 13H), 7.39 (s, 1H). 13C-NMR (100 MHz, CDCl3): δ 8.19, 9.10, 20.77, 20.84, 21.8, 46.4,
51.6, 51.7, 52.1, 90.2, 112.8, 118.1, 126.1, 126.9, 127.0, 127.16, 127.19, 128.49, 128.55, 128.6, 128.82,
128.83, 129.0, 129.1, 129.5, 129.6, 129.7, 140.0, 141.50, 141.53, 141.58, 141.61, 141.65, 141.70, 142.1,
174.2. IR (ATR): 700, 1450, 1490 cm-1. HRMS (FAB) m/z: [M–SbF6]+ Calcd for C51H51N2106Pd:
797.3082; Found: 797.3090. Anal. Calcd for C51H51F6N2PdSb: C, 59.23; H, 4.97; N, 2.71. Found: C,
59.36; H, 4.82; N, 2.74.
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Typical procedure for the palladium-catalyzed deuterodechlorination of aryl/heteroaryl
chlorides. 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. Then, aryl chloride 2b (219 mg, 1.0 mmol) and -deuterio-
alcohol 1a (222 mg, 1.2 mmol) were added at room temperature. The reaction mixture was stirred for
16 h at 90 °C and cooled to room temperature. Water was added, and then the resulting mixture was
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extracted with CH2Cl2. The combined organic layers were dried over MgSO4. Concentration and purifi-
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cation through silica gel column chromatography gave desired product 3b.
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1-Deuterio-3,5-dimethoxybenzene (3a). Silica gel chromatography (hexane/Et2O = 100/1) gave
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131 mg of the product (0.94 mmol, 94% yield) as colorless oil. >99% D (D content was judged with the
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peak at 7.19 ppm (a deuterated site) compared to the peak at 6.47 ppm by H-NMR). H-NMR (500
MHz, CDCl3): δ 3.80 (s, 6H), 6.47 (t, J = 2.4 Hz, 1H), 6.51-6.52 (m, 2H). 13C-NMR (100 MHz,
CDCl3): δ 55.2 (CH3), 100.5 (CH), 106.1 (CH), 129.6 (t, JC-D = 24.0 Hz, C), 160.9 (C). IR (ATR): 1200,
1430, 1600 cm-1. HRMS (EI) m/z: (M+) Calcd for C8H9DO2: 139.0744; Found: 139.0756.
1-Benzyloxy-4-deuteriobenzene (3b). Silica gel chromatography (hexane/Et2O = 100/1) gave 184
mg of the product (0.99 mmol, 99% yield) as white solids of mp 38-39 °C. >99% D (D content was
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judged with the peak at 6.97-7.00 ppm (a deuterated site) compared to the peak at 5.07 ppm by H-
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NMR). H-NMR (500 MHz, CDCl3): δ 5.07 (s, 2H), 6.97-7.00 (m, 2H), 7.28-7.34 (m, 3H), 7.37-7.40
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(m, 2H), 7.44 (d, J = 7.6 Hz, 2H). C-NMR (100 MHz, CDCl3): δ 69.8 (CH2), 114.8 (CH), 120.7 (t,
JC-D = 24.0 Hz, C), 127.5 (CH), 127.9 (CH), 128.6 (CH), 129.4 (CH), 137.1 (C), 158.9 (C). IR (ATR):
1010, 1240, 1590 cm-1. HRMS (EI) m/z: (M+) Calcd for C13H11DO: 185.0951; Found: 185.0938.
1-Benzyloxy-4-deuterio-3-methylbenzene (3c). Silica gel chromatography (hexane/Et2O =
100/1) gave 198 mg of the product (0.99 mmol, 99% yield) as colorless oil. >99% D (D content was
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judged with the peak at 6.77-6.82 ppm (a deuterated site) compared to the peak at 2.33 ppm by H-
NMR). 1H-NMR (500 MHz, CDCl3): δ 2.33 (s, 3H), 5.05 (s, 2H), 6.78 (dd, J = 2.5, 8.2 Hz, 1H), 6.82
(d, J = 2.5 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.38 (t, J = 7.2 Hz, 2H), 7.43 (d,
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J = 7.2 Hz, 2H). C- NMR (100 MHz, CDCl3): δ 21.4 (CH3), 69.8 (CH2), 111.6 (CH), 115.7 (CH),
121.5 (t, JC-D = 24.0 Hz, C), 127.5 (CH), 127.9 (CH), 128.6 (CH), 129.1 (CH), 137.2 (C), 139.4 (C),
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158.9 (C). IR (ATR): 730, 1030, 1240, 1600 cm-1. HRMS (EI) m/z: (M+) Calcd for C14H13DO:
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199.1107; Found: 199.1112.
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1-Benzyloxy-4-deuterio-3,5-dimethylbenzene (3d). Silica gel chromatography (hexane/Et2O =
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100/1) gave 211 mg of the product (0.99 mmol, 99% yield) as colorless oil. >99% D (D content was
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judged with the peak at 6.62 ppm (a deuterated site) compared to the peak at 7.30-7.44 ppm by H-
NMR). 1H-NMR (500 MHz, CDCl3): δ 2.29 (s, 6H), 5.03 (s, 2H), 6.62 (s, 2H), 7.32 (t, J = 7.2 Hz, 1H),
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7.38 (t, J = 7.2 Hz, 2H), 7.43 (d, J = 7.2 Hz, 2H). C-NMR (100 MHz, CDCl3): δ 21.3 (CH3), 69.7
(CH2), 112.6 (CH), 122.4 (t, JC-D = 23.2 Hz, C), 127.5 (CH), 127.8 (CH), 128.5 (CH), 137.3 (C), 139.1
(C), 159.0 (C). IR (ATR): 850, 1060, 1590 cm-1. HRMS (EI) m/z: (M+) Calcd for C15H15DO: 213.1264;
Found: 213.1262.
2-[(4-Deuteriophenoxy)methyl]oxirane (3e). Silica gel chromatography (hexane/Et2O = 10/1)
gave 141 mg of the product (0.93 mmol, 93% yield) as colorless oil. >99% D (D content was judged
with the peak at 6.96 ppm (a deuterated site) compared to the peak at 2.84 ppm by 1H-NMR). 1H-NMR
(500 MHz, DMSO-d6): δ 2.71 (dd, J = 2.7, 5.1 Hz, 1H), 2.84 (dd, J = 4.3, 5.1 Hz, 1H), 3.31-3.34 (m,
1H), 3.82 (dd, J = 6.5, 11.3 Hz, 1H), 4.31 (dd, J = 2.7, 11.3 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 7.29 (d,
J = 8.7 Hz, 2H). 2H-NMR (61 MHz, CHCl3): δ 6.95 (brs). 13C-NMR (100 MHz, CDCl3): δ 44.6 (CH2),
50.1 (CH), 68.6 (CH2), 114.6 (CH), 120.9 (t, JC-D = 24.8 Hz, C), 129.4 (CH), 158.5 (C). IR (ATR): 840,
1040, 1240, 1590 cm-1. HRMS (EI) m/z: (M+) Calcd for C9H9DO2: 151.0744; Found: 151.0730.
(S)-(+)-2-[(3-Deuteriophenoxy)methyl]oxirane (3f). Silica gel column chromatography (hex-
ane/benzene = 1/1) gave 142 mg (0.94 mmol, 94% yield) of the product as colorless oil. >99% D (D
content was judged with the peak at 7.28-7.31 ppm (a deuterated site) compared to the peak at 4.31
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ppm by H-NMR). [α]21 +11.8 (c 1.58, EtOH). 91% ee (HPLC: Daicel Chiralcel OD-H, hexane/i-
D
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PrOH = 9/1, 0.8 mL/min, 220 nm, (S)-isomer 14.3 min and (R)-isomer 9.0 min). H-NMR (500 MHz,
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DMSO-d6): δ 2.71 (dd, J = 2.7, 5.1 Hz, 1H), 2.84 (dd, J = 4.3, 5.1 Hz, 1H), 3.31-3.34 (m, 1H), 3.82 (dd,
J = 6.5, 11.4 Hz, 1H), 4.31 (dd, J = 2.7, 11.4 Hz, 1H), 6.94-6.97 (m, 3H), 7.28-7.31 (m, 1H). 13C-NMR
(100 MHz, CDCl3): δ 44.3 (CH2), 49.9 (CH), 68.5 (CH2), 114.4 (CH), 114.5 (CH), 121.0 (CH), 129.1 (t,
JC-D = 24.0 Hz, C), 129.4 (CH), 158.4 (C). IR (ATR): 790, 840, 1050, 1220, 1590 cm-1. HRMS (EI)
m/z: (M+) Calcd for C9H9DO2: 151.0744; Found: 151.0737.
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2-[(2-Deuteriophenoxy)methyl]oxirane (3g). Silica gel chromatography (hexane/benzene = 1/1)
gave 140 mg of the product (0.93 mmol, 93% yield) as colorless oil. >99% D (D content was judged
with the peak at 6.93-6.97 ppm (a deuterated site) compared to the peak at 4.31 ppm by 1H-NMR). 1H-
NMR (500 MHz, DMSO-d6): δ 2.71 (dd, J = 2.7, 5.1 Hz, 1H), 2.84 (t, J = 5.1 Hz, 1H), 3.31-3.37 (m,
1H), 3.82 (dd, J = 6.3, 11.2 Hz, 1H), 4.31 (dd, J = 2.7, 11.2 Hz, 1H), 6.93-6.97 (m, 2H), 7.28-7.31 (m,
2H). 13C-NMR (100 MHz, CDCl3): δ 44.4 (CH2), 49.9 (CH), 68.5 (CH2), 114.2 (t, JC-D = 24.2 Hz, C),
114.5 (CH), 121.1 (CH), 129.3 (CH), 129.4 (CH), 158.4 (C). IR (ATR): 760, 840, 1050, 1230, 1590
cm-1. HRMS (EI) m/z: (M+) Calcd for C9H9DO2: 151.0744; Found: 151.0746.
1-Deuterio-2-nitrobenzene (3h). Silica gel chromatography (hexane/benzene = 3/1) gave 121 mg
of the product (0.98 mmol, 98% yield) as pale yellow oil. >99% D (D content was judged with the peak
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at 8.23-8.25 ppm (a deuterated site) compared to the peak at 7.54-7.57 ppm by H-NMR). H-NMR
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(500 MHz, CDCl3): δ 7.54-7.57 (m, 2H), 7.71 (dt, J = 1.0, 7.5 Hz, 1H), 8.23-8.25 (m, 1H). C-NMR
(100 MHz, CDCl3): δ 123.2 (t, JC-D = 25.7 Hz, C), 123.5 (CH), 129.2 (CH), 129.3 (CH), 134.6 (CH),
148.2 (C). IR (ATR): 1340, 1520 cm-1. HRMS (EI) m/z: (M+) Calcd for C6H4DNO2: 124.0383; Found:
124.0362.
(E)-4-(4-Deuteriophenyl)but-3-en-2-one (3i). Silica gel chromatography (hexane/AcOEt = 10/1)
gave 144 mg of the product (0.98 mmol, 98% yield) as pale yellow solids of mp 39-40 °C. >99% D (D
content was judged with the peak at 7.40 ppm (a deuterated site) compared to the peak at 6.73 ppm by
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1H-NMR). 1H-NMR (500 MHz, CDCl3): δ 2.39 (s, 3H), 6.73 (d, J = 16.4 Hz, 1H), 7.40 (d, J = 8.1 Hz,
2H), 7.52 (d, J = 16.4 Hz, 1H), 7.55 (d, J = 8.1 Hz, 2H). 13C-NMR (100 MHz, CDCl3): δ 27.4 (CH3),
127.2 (CH), 128.3 (CH), 128.9 (CH), 130.2 (t, JC-D = 24.0 Hz, C), 134.5 (C), 143.5 (CH), 198.5 (C). IR
(ATR): 990, 1190, 1680 cm-1. HRMS (EI) m/z: (M+) Calcd for C10H9DO: 147.0794; Found: 147.0771.
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Butyl 4-deuteriobenzoate (3j). Silica gel chromatography (hexane/benzene = 5/1) gave 168 mg
of the product (0.94 mmol, 94% yield) as colorless oil. >99% D (D content was judged with the peak at
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7.55 ppm (a deuterated site) compared to the peak at 7.45 ppm by H-NMR). H-NMR (500 MHz,
CDCl3): δ 0.99 (t, J = 7.5 Hz, 3H), 1.45-1.52 (m, 2H), 1.73-1.79 (m, 2H), 4.33 (t, J = 6.5 Hz, 2H), 7.45
(d, J = 8.0 Hz, 2H), 8.05 (d, J = 8.0 Hz, 2H). 13C-NMR (100 MHz, CDCl3): δ 13.6 (CH3), 19.1 (CH2),
30.6 (CH2), 64.7 (CH2), 128.1 (CH), 129.5 (CH), 130.5 (C), 132.4 (t, JC-D = 24.8 Hz, C), 166.6 (C). IR
(ATR): 1100, 1270, 1720, 2960 cm-1. HRMS (EI) m/z: (M+) Calcd for C11H13DO2: 179.1057; Found:
179.1056.
4-Deuterio-N,N-dimethylbenzamide (3k). Silica gel chromatography (benzene/AcOEt = 2/1)
gave 149 mg of the product (0.99 mmol, 99% yield) as colorless oil. >99% D (D content was judged
with the peak at 7.04 ppm (a deuterated site) compared to the peak at 7.32 ppm by 1H-NMR). 1H-NMR
(500 MHz, benzene-d6): δ 2.29 (brs, 3H), 2.76 (brs, 3H), 7.04 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 7.8 Hz,
2H). 13C-NMR (100 MHz, CDCl3): δ 34.9 (CH3), 39.2 (CH3), 126.8 (CH), 128.0 (CH), 128.9 (t, JC-D
=
24.8 Hz, C), 136.2 (C), 171.4 (C). IR (ATR): 860, 1080, 1620 cm-1. HRMS (EI) m/z: (M+) Calcd for
C9H10DNO: 150.0903; Found: 150.0906.
4-Deuterio-N,N-dibenzylbenzeneamine (3l). Silica gel chromatography (hexane/benzene = 10/1)
gave 263 mg of the product (0.96 mmol, 96% yield) as colorless oil. >99% D (D content was judged
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with the peak at 6.73-6.75 ppm (a deuterated site) compared to the peak at 4.65 ppm by 1H-NMR). H-
NMR (500 MHz, CDCl3): δ 4.65 (s, 4H), 6.73-6.75 (m, 2H), 7.16 (d, J = 8.8 Hz, 2H), 7.23-7.26 (m,
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6H), 7.31-7.34 (m, 4H). 13C-NMR (100 MHz, CDCl3): δ 54.1 (CH2), 112.4 (CH), 116.5 (t, JC-D = 24.8
Hz, C), 126.6 (CH), 126.9 (CH), 128.6 (CH), 129.1 (CH), 138.6 (C), 149.2 (C). IR (ATR): 730, 1350,
1590 cm-1. HRMS (EI) m/z: (M+) Calcd for C20H18DN: 274.1580; Found: 274.1576.
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3-Deuteriophenyl isopropyl sulfide (3m). Silica gel chromatography (hexane/i-Pr2O = 200/1)
gave 126 mg of the product (0.82 mmol, 82% yield) as colorless oil. >99% D (D content was judged
with the peak at 7.30-7.33 ppm (a deuterated site) compared to the peak at 3.43 ppm by 1H-NMR). 1H-
NMR (500 MHz, CD3CN): δ 1.26 (d, J = 6.5 Hz, 6H), 3.43 (septet, J = 6.5 Hz, 1H), 7.24 (dt, J = 1.0,
7.5 Hz, 1H), 7.30-7.33 (m, 1H), 7.38-7.40 (m, 2H). 13C-NMR (100 MHz, CDCl3): δ 23.0 (CH3), 38.1
(CH), 126.6 (CH), 128.5 (t, JC-D = 24.0 Hz, C), 128.8 (CH), 131.8 (CH), 131.9 (CH), 135.5 (C). IR
(ATR): 660, 1580, 2960 cm-1. HRMS (EI) m/z: (M+) Calcd for C9H11DS: 153.0722; Found: 153.0726.
3-Deuteriobenzoic acid (3n). Deuterated product 3n was directly converted into allyl 3-deuterio-
benzoate (3n’) for purification. 3-Deuteriobenzoic acid (3n) was allylated according to the reported
procedure.23 To the reaction mixture was added water, and the mixture was acidified with 10% HCl.
The resulting mixture was extracted with CH2Cl2. The combined organic layers were dried over MgSO4
and concentrated to give the crude product. The solution of crude product in THF (1 mL) was added to
the mixture of n-Bu4NHSO4 (20 mg, 0.05 mnol) and KF (290 mg, 5.0 mmol) in THF (1 mL). Sub-
sequently, allyl bromide (133 mg, 1.1 mmol) was added, and then the reaction mixture was stirred for 3
h at room temperature. After water was added, the resulting mixture was extracted with i-Pr2O. The
combined organic layers were dried over Na2SO4. Concentration and purification through silica gel
column chromatography (hexane/benzene = 5/1) gave 131 mg of allyl 3-deuteriobenzoate (3n’) (0.80
mmol, 80% yield) as a colorless oil. >99% D (D content was judged with the peak at 7.43-7.46 ppm (a
1
deuterated site) compared to the peak at 4.83 ppm by 1H-NMR). H-NMR (500 MHz, CDCl3): δ 4.83
(dt, J = 1.0, 5.6 Hz, 2H), 5.29 (dd, J = 1.0, 10.5 Hz, 1H), 5.42 (dd, J = 1.5, 17.3 Hz, 1H), 6.01-6.09 (m,
1H), 7.43-7.46 (m, 1H), 7.56 (d, J = 7.5 Hz, 1H), 8.06-8.08 (m, 2H). 13C-NMR (100 MHz, CDCl3): δ
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65.4 (CH2), 118.2 (CH2), 128.1 (t, JC-D = 24.8 Hz, C), 128.4 (CH), 129.5 (CH), 129.6 (CH), 130.2 (C),
132.3 (CH), 132.9 (CH), 166.3 (C). IR (ATR): 640, 1090, 1110, 1250, 1430, 1720, 3080 cm-1. HRMS
(EI) m/z: (M+) Calcd for C10H9DO2: 163.0744; Found: 163.0747.
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3-Deuterio-N-methylbenzamide (3o). Silica gel chromatography (benzene/AcOEt = 3/1) gave
135 mg of the product (0.99 mmol, 99% yield) as white solids of mp 74-75 °C. >99% D (D content was
judged with the peak at 7.42-7.50 ppm (a deuterated site) compared to the peak at 7.75-7.77 ppm by
1H-NMR). 1H-NMR (500 MHz, CDCl3): δ 3.03 (d, J = 4.8 Hz, 3H), 7.43 (dd, J = 7.5, 8.2 Hz, 1H), 7.49
(d, J = 7.5 Hz, 1H), 7.75-7.77 (m, 2H). 13C-NMR (100 MHz, CDCl3): δ 26.5 (CH3), 126.8 (CH), 126.9
(CH), 128.0 (t, JC-D = 24.8 Hz, C), 128.2 (CH), 131.0 (CH), 134.4 (C), 168.5 (C). IR (ATR): 690, 1550,
1630, 2930, 3320 cm-1. HRMS (EI) m/z: (M+) Calcd for C8H8DNO: 136.0747; Found: 136.0749.
2,4,6-Trideuterionitrobenzene (3p). Silica gel chromatography (hexane/benzene = 8/1) gave 105
mg of the product (0.83 mmol, 83% yield) as pale yellow oil. >99% D (D content was judged with the
peak at 7.71 and 8.25 ppm (deuterated sites) compared to the peak at 7.56 ppm by 1H-NMR). 1H-NMR
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(500 MHz, CDCl3): δ 7.56 (s, 2H). C-NMR (100 MHz, CDCl3): δ 123.1 (t, J = 25.7 Hz, C), 129.0
(CH), 134.3 (t, J = 25.7 Hz, C), 148.0 (C). IR (ATR): 690, 860, 1340, 1510 cm-1. HRMS (EI) m/z: (M+)
Calcd for C6H2D3NO2: 126.0509; Found: 126.0507.
2-Benzyloxy-4-deuteriopyridine (5a). Silica gel chromatography (hexane/benzene = 1/1.5) gave
185 mg of the product (0.99 mmol, 99% yield) as colorless oil. >99% D (D content was judged with the
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peak at 7.62 ppm (a deuterated site) compared to the peak at 8.18 ppm by H-NMR). H-NMR (500
MHz, CDCl3): δ 5.38 (s, 2H), 6.81 (s, 1H), 6.88 (d, J = 5.1 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.38 (t, J
= 7.3 Hz, 2H), 7.46-7.48 (m, 2H), 8.18 (d, J = 5.1 Hz, 1H). 13C-NMR (100 MHz, CDCl3): δ 67.3 (CH2),
111.0 (CH), 116.6 (CH), 127.7 (CH), 127.8 (CH), 128.3 (CH), 137.3 (C), 138.2 (t, JC-D = 24.8 Hz, C),
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146.8 (CH), 163.5 (C). IR (ATR): 700, 990, 1220, 1560 cm-1. HRMS (EI) m/z: (M+) Calcd for
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C12H10DNO: 186.0903; Found: 186.0902.
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2-Benzyloxy-5-deuteriopyridine (5b). Silica gel chromatography (hexane/benzene = 1/1) gave
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181 mg of the product (0.97 mmol, 97% yield) as colorless oil. >99% D (D content was judged with the
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peak at 6.88 ppm (a deuterated site) compared to the peak at 8.18 ppm by H-NMR). H-NMR (500
MHz, CDCl3): δ 5.38 (s, 2H), 6.81 (dd, J = 1.5, 8.4 Hz, 1H), 7.30-7.33 (m, 1H), 7.36-7.39 (m, 2H),
7.46-7.48 (m, 2H), 7.58 (dd, J = 1.5, 8.4 Hz, 1H), 8.18 (d, J = 1.5 Hz 1H). 2H-NMR (61 MHz, CHCl3):
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δ 6.86 (brs). C-NMR (100 MHz, CDCl3): δ 67.3 (CH2), 111.2 (CH), 116.5 (t, JC-D = 24.8 Hz, C),
127.7 (CH), 127.9 (CH), 128.3 (CH), 137.3 (C), 138.4 (CH), 146.7 (CH), 163.6 (C). IR (ATR): 740,
990, 1590 cm-1. HRMS (EI) m/z: (M+) Calcd for C12H10DNO: 186.0903; Found: 186.0899.
2-Benzyloxy-6-deuteriopyridine (5c). Silica gel chromatography (hexane/benzene = 1.5/1) gave
185 mg of the product (0.99 mmol, 99% yield) as colorless oil. >99% D (D content was judged with the
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peak at 8.18 ppm (a deuterated site) compared to the peak at 6.88 ppm by H-NMR). H-NMR (500
MHz, CDCl3): δ 5.38 (s, 2H), 6.81 (dd, J = 1.0, 8.3 Hz, 1H), 6.88 (d, J = 7.1 Hz, 1H), 7.30-7.33 (m,
1H), 7.36-7.39 (m, 2H), 7.46-7.48 (m, 2H), 7.58 (dd, J = 7.1, 8.3 Hz 1H). 13C-NMR (100 MHz,
CDCl3): δ 67.3 (CH2), 111.2 (CH), 116.7 (CH), 127.7 (CH), 127.9 (CH), 128.4 (CH), 137.4 (C), 138.5
(CH), 146.5 (t, JC-D = 27.3 Hz, C), 163.6 (C). IR (ATR): 1250, 1590 cm-1. HRMS (EI) m/z: (M+) Calcd
for C12H10DNO: 186.0903; Found: 186.0907.
2-(Dibenzylamino)-5-deuteriopyridine (5d). Silica gel chromatography (hexane/benzene =
1.5/1) gave 254 mg of the product (0.92 mmol, 92% yield) as colorless oil. >99% D (D content was
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judged with the peak at 6.58 ppm (a deuterated site) compared to the peak at 7.38 ppm by H-NMR).
1H-NMR (500 MHz, CDCl3): δ 4.80 (s, 4H), 6.46 (dd, J = 0.8, 8.5 Hz, 1H), 7.23-7.26 (m, 6H), 7.29-
7.32 (m, 4H), 7.38 (dd, J = 2.0, 8.5 Hz, 1H), 8.20-8.21 (m, 1H). 13C-NMR (100 MHz, CDCl3): δ 50.8
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(CH2), 105.7 (CH), 111.9 (t, JC-D = 25.7 Hz, C), 126.9 (CH), 127.0 (CH), 128.5 (CH), 137.3 (CH),
138.4 (C), 148.0 (CH), 158.6 (C). IR (ATR): 1240, 1490, 1580 cm-1. HRMS (EI) m/z: (M+) Calcd for
C19H17DN2: 275.1533; Found: 275.1530.
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8-Deuterioquinoline (5e). Silica gel chromatography (benzene/AcOEt = 10/1) gave 126 mg of the
product (0.97 mmol, 97% yield) as colorless oil. >99% D (D content was judged with the peak at 8.12
ppm (a deuterated site) compared to the peak at 7.73 ppm by 1H-NMR). 1H-NMR (500 MHz, CDCl3): δ
7.41 (dd, J = 4.2, 8.3 Hz, 1H), 7.56 (dd, J = 7.0, 8.1 Hz, 1H), 7.73 (d, J = 7.0 Hz, 1H), 7.83 (dd, J =
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1.7, 8.1 Hz, 1H), 8.17 (dd, J = 1.7, 8.3 Hz, 1H), 8.93 (dd, J = 1.7, 4.2 Hz, 1H). C-NMR (100 MHz,
CDCl3): δ 120.8 (CH), 126.2 (CH), 127.5 (CH), 128.0 (C), 128.9 (t, JC-D = 24.8 Hz, C), 129.0 (CH),
135.7 (CH), 148.0 (C), 150.1 (CH). IR (ATR): 790, 1490 cm-1. HRMS (EI) m/z: (M+) Calcd for
C9H6DN: 130.0641; Found: 130.0645.
4-Deuterio-2-(trifluoromethyl)quinoline (5f). Silica gel chromatography (hexane/benzene = 3/1)
gave 192 mg of the product (0.97 mmol, 97% yield) as colorless solids of mp 53-54 °C. >99% D (D
content was judged with the peak at 8.37 ppm (a deuterated site) compared to the peak at 7.92 ppm by
1H-NMR). 1H-NMR (500 MHz, CDCl3): δ 7.67-7.70 (m, 1H), 7.75 (s, 1H), 7.82-7.85 (m, 1H), 7.92 (dd,
J = 1.0, 8.5 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H). 13C-NMR (100 MHz, CDCl3): δ 116.5 (q, JC-F = 2.5 Hz,
CH), 121.6 (q, JC-F = 275.6 Hz, C), 127.6 (CH), 128.5 (CH), 128.7 (C), 130.0 (CH), 130.8 (CH), 137.7
(t, JC-D = 24.8 Hz, C), 147.1 (C), 147.9 (q, JC-F = 34.8 Hz, C). IR (ATR): 770, 1120, 1200 cm-1. HRMS
(EI) m/z: (M+) Calcd for C10H5DF3N: 198.0515; Found: 198.0505.
2-Deuterio-1-methyl-1H-indole (5g). Silica gel chromatography (hexane/benzene = 10/1) gave
128 mg of the product (0.97 mmol, 97% yield) as colorless oil. >99% D (D content was judged with the
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peak at 7.31 ppm (a deuterated site) compared to the peak at 7.53 ppm by H-NMR). H-NMR (500
MHz, DMSO-d6): δ 3.78 (s, 3H), 6.40 (d, J = 0.7 Hz, 1H), 7.00-7.03 (m, 1H), 7.12-7.15 (m, 1H). 7.42
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(dd, J = 0.7, 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H). 13C-NMR (100 MHz, CDCl3): δ 32.4 (CH3), 100.6
(CH), 109.1 (CH), 119.2 (CH), 120.8 (CH), 121.4 (CH), 128.4 (C), 128.5 (t, JC-D = 27.3 Hz, C), 136.6
(C). IR (ATR): 730, 1230, 1470 cm-1. HRMS (EI) m/z: (M+) Calcd for C9H8DN: 132.0798; Found:
132.0801.
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5-Butyl-2-deuteriobenzofuran (5h). Silica gel chromatography (hexane/i-Pr2O = 400/1) gave 164
mg of the product (0.94 mmol, 94% yield) as colorless oil. >99% D (D content was judged with the
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peak at 7.58 ppm (a deuterated site) compared to the peak at 7.39-7.41 ppm by H-NMR). H-NMR
(500 MHz, CDCl3): δ 0.93 (t, J = 7.5 Hz, 3H), 1.33-1.41 (m, 2H), 1.60-1.66 (m, 2H), 2.70 (t, J = 7.5
Hz, 2H), 6.70 (d, J = 0.8 Hz, 1H), 7.11 (dd, J = 1.5, 8.3 Hz, 1H), 7.39 (s, 1H), 7.40 (d, J = 8.3 Hz, 1H).
13C-NMR (100 MHz, CDCl3): δ 13.9 (CH3), 22.2 (CH2), 34.2 (CH2), 35.5 (CH2), 106.2 (CH), 110.9
(CH), 120.4 (CH), 125.0 (CH), 127.5 (C), 137.3 (C), 144.7 (t, JC-D = 30.6 Hz, C), 153.5 (C). IR (ATR):
810, 1030, 1450 cm-1. HRMS (EI) m/z: (M+) Calcd for C12H13DO: 175.1107; Found: 175.1107.
2-Deuterio-3-n-hexylthiophene (5i). Silica gel chromatography (hexane/i-Pr2O = 200/1) gave
163 mg of the product (0.96 mmol, 96% yield) as colorless oil. >99% D (D content was judged with the
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peak at 6.93 ppm (a deuterated site) compared to the peak at 0.88 ppm by H-NMR). H-NMR (500
MHz, CDCl3): δ 0.88 (t, J = 6.5 Hz, 3H), 1.30-1.35 (m, 6H), 1.62 (quintet, J = 7.5 Hz, 2H), 2.62 (t, J =
7.5 Hz, 2H), 6.93 (d, J = 4.8 Hz, 1H), 7.23 (d, J = 4.8 Hz, 1H). 13C-NMR (100 MHz, CDCl3): δ 14.0
(CH3), 22.5 (CH2), 29.0 (CH2), 30.2 (CH2), 30.5 (CH2), 31.6 (CH2), 119.6 (t, JC-D = 27.3 Hz, C), 124.9
(CH), 128.3 (CH), 143.1 (C). IR (ATR): 720, 830, 1460 cm-1. HRMS (EI) m/z: (M+) Calcd for
C10H15DS: 169.1035; Found: 169.1039.
2-Deuteriobenzothiophene (5j). Silica gel chromatography (hexane/benzene = 400/1) gave 122
mg of the product (0.90 mmol, 90% yield) as colorless oil. >99% D (D content was judged with the
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peak at 7.44 ppm (a deuterated site) compared to the peak at 7.82-7.90 ppm by H-NMR). H-NMR
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(500 MHz, CDCl3): 7.32-7.38 (m, 3H), 7.83 (dd, J = 1.8, 7.0 Hz, 1H), 7.88-7.90 (m, 1H). C-NMR
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(100 MHz, CDCl3): 122.5 (CH), 123.6 (CH), 123.7 (CH), 124.17 (CH), 124.21 (CH), 126.1 (t, JC-D
=
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28.1 Hz, C), 139.6 (C), 139.7 (C). IR (ATR): cm-1 730, 840, 1450, 2920. HRMS (EI) m/z: (M+) Calcd
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for C8H5DS: 135.0253; Found: 135.0254.
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3-Deuteriobenzothiophene (5k). Silica gel chromatography (hexane/benzene = 400/1) gave 125
mg of the product (0.93 mmol, 93% yield) as colorless oil. 99% D (D content was judged with the peak
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at 6.96 ppm (a deuterated site) compared to the peak at 7.55-7.59 ppm by H-NMR). H-NMR (500
MHz, benzene-d6): 6.91 (s, 1H), 7.04-7.07 (m, 1H), 7.12-7.15 (m, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.58
(d, J = 8.0 Hz, 1H). 13C-NMR (100 MHz, CDCl3): 122.5 (CH), 123.58 (CH), 123.62 (t, JC-D = 25.7 Hz,
C), 124.1 (CH), 124.2 (CH), 126.2 (CH), 139.5 (C), 139.7 (C). IR (ATR): 720, 860, 1460, 2920 cm-1.
HRMS (EI) m/z: (M+) Calcd for C8H5DS: 135.0253; Found: 135.0252.
2-Deuterio-4,6-dimethoxypyrimidine (5l). Silica gel chromatography (hexane/AcOEt = 15/1)
gave 101 mg of the product (0.72 mmol, 72% yield) as colorless oil. >99% D (D content was judged
with the peak at 8.46 ppm (a deuterated site) compared to the peak at 6.06 ppm by 1H-NMR). 1H-NMR
(500 MHz, CDCl3): δ 3.95 (s, 6H), 6.06 (s, 1H). 13C-NMR (100 MHz, CDCl3): δ 53.9 (CH3), 90.3 (CH),
157.2 (t, JC-D = 31.0 Hz, C), 171.3. (C). IR (ATR): 700, 1190, 1260, 1590 cm-1. HRMS (EI) m/z: (M+)
Calcd for C6H7DN2O2: 141.0649; Found: 141.0645.
4-Deuteriocinnoline (5m). Silica gel chromatography (benzene/AcOEt = 4/1) gave 113 mg of the
product (0.86 mmol, 86% yield) as pale yellpw oil. >99% D (D content was judged with the peak at
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8.24 ppm (a deuterated site) compared to the peak at 9.40 ppm by H-NMR). H-NMR (500 MHz,
DMSO-d6): δ 7.88-7.91 (m, 1H), 7.96-8.00 (m, 1H), 8.10 (dd, J = 0.7, 8.5 Hz, 1H), 8.48 (dd, J = 0.7,
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8.5 Hz, 1H), 9.40 (s, 1H). C-NMR (100 MHz, CDCl3): δ 122.0, (t, JC-D = 25.7 Hz, C), 125.6 (C),
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126.4 (CH), 129.5 (CH), 130.4 (CH), 130.9 (CH), 144.8 (CH), 150.6 (C). IR (ATR): 770, 1140, 1570
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cm-1. HRMS (EI) m/z: (M+) Calcd for C8H5DN2: 131.0594; Found: 131.0597.
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5-Deuterio-2-methylbenzo[d]thiazole (5n). Silica gel chromatography (benzene/i-Pr2O = 20/1)
gave 137 mg of the product (0.91 mmol, 91% yield) as colorless oil. >99% D (D content was judged
with the peak at 7.48 ppm (a deuterated site) compared to the peak at 7.39 ppm by 1H-NMR). 1H-NMR
(500 MHz, DMSO-d6): δ 2.80 (s, 3H), 7.39 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H), 8.03 (dd, J = 0.5, 8.0 Hz,
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1H). 13C-NMR (100 MHz, CDCl3): δ 19.8 (CH3), 121.2 (CH), 122.1 (CH), 124.4 (CH), 125.5 (t, JC-D
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24.8 Hz, C), 135.5 (C), 153.2 (C), 166.8 (C). IR (ATR): 1170, 1520 cm-1. HRMS (EI) m/z: (M+) Calcd
for C8H6DNS: 150.0362; Found: 150.0365.
6-Deuterioimidazo[1,2-a]pyridine (5o). Silica gel chromatography (AcOEt and AcOEt/MeOH =
10/1) gave 118 mg of the product (0.99 mmol, 99% yield) as pale yellow oil. >99% D (D content was
judged with the peak at 6.78 ppm (a deuterated site) compared to the peak at 8.14 ppm by 1H-NMR).
1H-NMR (500 MHz, CDCl3): 7.17 (d, J = 9.1 Hz, 1H), 7.58-7.60 (m, 1H), 7.62-7.64 (m, 2H), 8.14 (s,
1H). 13C-NMR (100 MHz, CDCl3): 111.6 (t, JC-D = 25.7 Hz, C), 112.0 (CH), 117.3 (CH), 123.9 (CH),
125.4 (CH), 133.0 (CH), 145.0 (C). IR (ATR): 710, 1130, 1500, 1630 cm-1. HRMS (EI) m/z: (M+)
Calcd for C7H5DN2: 119.0594; Found: 119.0594.
1-Butyl-6-deuterio-3-phenyl-1H-pyrrolo[2,3-b]pyridine (5p). Silica gel chromatography (hex-
ane/benzene = 1/1) gave 238 mg of the product (0.95 mmol, 95% yield) as pale yellow oil. >99% D (D
content was judged with the peak at 8.37 ppm (a deuterated site) compared to the peak at 8.22 ppm by
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1H-NMR). H-NMR (500 MHz, CDCl3): δ 0.96 (t, J = 7.4 Hz, 3H), 1.37-1.44 (m, 2H), 1.88-1.94 (m,
2H), 4.35 (t, J = 7.4 Hz, 2H), 7.12 (d, J = 7.9 Hz, 1H), 7.27-7.30 (m, 1H), 7.43-7.46 (m, 3H), 7.64 (dd,
J = 1.2, 8.3 Hz, 2H), 8.22 (d, J = 7.9 Hz, 1H). 13C-NMR (100 MHz, CDCl3): δ 13.6 (CH3), 20.0 (CH2),
32.3 (CH2), 44.2 (CH2), 114.8 (C), 115.8 (CH), 118.6 (C), 125.1 (CH), 126.0 (CH), 126.9 (CH), 128.0
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