Deuterated Aryl Alkyl Ethers Synthesis via Nucleophilic Etherification of Aryl Alkyl Ethers and Thioethers with Deuterated Alcohols

Article abstract of DOI:10.1055/s-0037-1611898

A transition-metal-free etherification protocol that is capable of synthesizing deuterated ethers is described. A wide range of aryl alkyl ethers and thioethers were suitable for this transformation owing to the mild reaction conditions. Besides, a series of sterically bulky deuterated alcohols were successfully incorporated into cyano-substituted arenes. The results of mechanistic studies suggested this reaction might take place via nucleophilic aromatic substitution pathway.

Full text of DOI:10.1055/s-0037-1611898

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
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S. Li et al.
Letter
Synlett
Deuterated Aryl Alkyl Ethers Synthesis via Nucleophilic Etherification
of Aryl Alkyl Ethers and Thioethers with Deuterated Alcohols
Shuai Lia
Xia Wanga
Deuterated aryl ether synthesis enabled by alcohol interconversion
Xin-Ge Yang*b
Gui-Quan Yuc
Xue-Qiang Wang*a
CN
CN
D
O
D
KOt-Bu
XMe
HO
R2
+
R1
R2
R1
0
0
0
0-0
0
0
3-1
6
3
1-9
1
5
8
20 examples
up to 97% yield
R1, R2 = alkyl
broad substrate scope
a Molecular Science and Biomedicine Laboratory, State Key Laboratory of
Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical
Engineering, Hunan Provincial Key Laboratory of Biomacromolecular
Chemical Biology, Hunan University, Changsha, Hunan 410082,
P. R. of China
X = O or S
easy operation
transition-metal-free
wangxq@hnu.edu.cn
b College of Chemistry and Chemical Engineering, Linyi University, Linyi,
Shandong 276000, P. R. of China
yxgyg@163.com
c Lanling County Inspection and Testing Center, Linyi, Shandong 277700,
P. R. of China
Received: 12.06.2019
Accepted after revision: 09.07.2019
Published online: 15.08.2019
source.7 The Beller group also utilized a Ru complex to
achieve selective ,-deuteration of bioactive amines.8
Apart from the transition-metal-catalyzed deuteration pro-
tocols, the deuteration reaction could be achieved by transi-
tion-metal-free processes in a highly efficient manner. Re-
cently, Liu and co-workers described the development of
dehalogenative deuteration of (hetero)arylhalides reaction
enabled by KOMe–disilane system.9 Deuterium could also
be induced onto a wide range of azoarenes and pharmaceu-
ticals using heterocyclic phosphonium salts as C–H bond
activating agents.10
DOI: 10.1055/s-0037-1611898; Art ID: st-2019-k0309-l
Abstract A transition-metal-free etherification protocol that is capa-
ble of synthesizing deuterated ethers is described. A wide range of aryl
alkyl ethers and thioethers were suitable for this transformation owing
to the mild reaction conditions. Besides, a series of sterically bulky deu-
terated alcohols were successfully incorporated into cyano-substituted
arenes. The results of mechanistic studies suggested this reaction
might take place via nucleophilic aromatic substitution pathway.
Key words deuterium, ether, thioether, etherification, nucleophilic
In 2017, the FDA approved deuterium-containing com-
pound deutetrabenazine as a clinical drug for the treatment
of Huntington’s disease and for tardive dyskinesias (Scheme
1, part I).11 As shown in Scheme 1, its synthesis usually re-
lies on Williamson etherification with deuterated alkyl ha-
lides as deuterium source (Scheme 1, part II).12 Notably, this
reaction is only applicable to simple and less sterically hin-
dered alkyl halides. The preparation of deuterated aryl
ethers with bulky alkyl chain is rather unexplored. There-
fore, the development of simple yet practical technique to
generate deuterated ethers is under urgent need for drug
development community. As part our research interest in
C–O bond formation, we recently reported the ether syn-
thesis via C–O/C–S bond cleavage using aryl alkyl ethers
and aryl alkyl thioethers as readily available starting mate-
rials.13 These transformations were highlighted by the ex-
cellent substrate scope and functional group tolerance. The
mechanistic studies suggested that these etherification
processes proceeded via nucleophilic aromatic substitution
pathway. Inspired by our recently developed etherification
protocols, we envisioned these methods would be em-
ployed to prepare deuterated aryl alkyl ethers.
aromatic substitution
The incorporation of deuterium into organic molecules
has recently gained extensive attention due to their wide
applications in pharmaceutical discoveries and develop-
ments (Scheme 1, part I),1 mechanistic studies of organic
transformations and many other research fields.2 In the
past few decades, numerous protocols have been developed
to prepare versatile deuterated compounds.3 For instance,
the deuterated products could be obtained via transition-
metal-catalyzed dehalogenative reduction reaction, and or-
ganometallic-reagent-mediated dehalogenative deutera-
tion reactions.4 The C–H bond-activation–functionalization
strategy could also be used for the efficient construction of
deuterated aromatic compounds. The Chirik group reported
the use of iron catalyst for selective deuteration of a series
of pharmaceuticals via C–H bond deuteration.5 In addition,
the selective deuteration of aliphatic moieties has been ex-
tensively studied. MacMillan and his colleagues utilized
iridium photoredox catalysis as an efficient tool to access
deuterated pharmaceutical molecules.6 The Szymczak
group reported the direct and stereoretentive deuteration
of primary amines using Ru catalyst and D2O as deuterium
We herein report the practical etherification of me-
thoxy arenes and aryl alkyl thioethers with sterically hin-
dered deuterated alcohols enabled by easily available potas-
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. Li et al.
Letter
Synlett
plained by the steric effect. These two examples highlighted
the utility of our protocol. We then studied the representa-
tive scope of methoxy benzonitriles. Heterocycles such as
benzofuran and pyridine could be well tolerated, offering
the corresponding products 3g and 3h in good yields.
(I) Representative deuterium-containing drug-related molecules
O
Cl
Me
Me
H
N
H
N
H
N
D3CO
D3CO
O
N
O
O
N
Me
D3CO
D3CO
CN
CN
D
deutetrabenazine
d6-tivozanib
KOt-Bu (2.0 equiv)
OMe
O
D
HO
+
R2
R1
R2
R
1,4-dioxane, 80 °C, 16 h
R
R1
OCD3
OCD3
1
2
3
Me
N
N
N
Me
Me
N
CN
H
CN
Me
O
D
CN
H
H
Me
O
O
O
O
N
D
N
D
N
MeO
N
H
Ph
O
Me
d3-NVS-CRF38
d6-ligand for GABAA-α6
3a, 78%
3b, 76%
3c, 97%
(II) Representative synthetic process to excess deutetrabenazine
CN
D
H
H
CN
CN
O
D
O
O
HO
HO
NH2
D3CO
D3CO
N
Cy
+
CD3
I
+
O
D
O
O
Cy
H
n-Pr
O
3d, 62%
3e, 95%
3f, 82%
Me
Me
H
D3CO
D3CO
CN
N
CN
D
...
CN
D
O
O
D
O
O
deutetrabenazine
Ph
Ph
Ph
(III) This work: etherification of aryl ethers with bulky deuterated alcohols
OMe
OMe
NC
X
3h, X = N, 69%
3i, X = C, 80%
O
D
D
KOt-Bu
3g, 73%
3j, 60%
R2
+
HO
NC
or
R1
R2
R1
Scheme 2 Substrate scope of etherification via C–O bond cleavage. Re-
agents and conditions: aryl alkyl ether (0.2 mmol), deuterated alcohol
(0.4 mmol), KOt-Bu (0.4 mmol), 1,4-dioxane (0.2 mL, 1 M), 80 °C, 16 h.
SMe
NC
bulky alcohols
Scheme 1 Representative deuterium possessing drug-related com-
pounds and their synthesis
While the employment of 3-hydroxy-[1,1′-biphenyl]-4-
carbonitrile gave the aimed product 3i in 80% yield, the in-
troduction of methoxy on the bottom phenyl ring signifi-
cantly lower down the yield to 60% (3j), which might be ra-
tionalized by the electron-donating nature of this function-
al group.14 Encouraged by these results, we next turned our
attention to the etherification of aryl alkyl thioethers. We
found that the use of 2-(methylthio)benzonitrile led to the
generation of desired product 3a in similar efficiency as
methoxybenzonitrile (81% yield). The presence of the
trifluoromethyl group at the ortho position of nitrile did not
significantly affect its reactivity, the deuterated alcohol 6b
was offered in 70% yield. Likewise, the starting materials
that possess substitution at the para position of nitrile
could take part in the etherification. As shown, the corre-
sponding products 3i, 6c, 6d, 6e were prepared in good
yields. Notably, thiophene was well tolerated, giving the
aimed ether in 67% yield (6d). Besides, naphthyl methyl
ether was applicable to this transformation, 6f was generat-
ed in 78% yield. We also had a look at the representative ex-
sium tert-butoxide (KOt-Bu) under simple reaction condi-
tions (Scheme 1, part III). We started our investigation by
studying the reactivity of 2-methoxybenzonitrile (1a) with
4-phenylcyclohexan-1-d-1-ol (2a). We found the desired
product 3a could be generated in 78% isolated yield in the
presence of KOt-Bu in 1,4-dioxane at 80 °C for 16 hours.
With the reaction conditions in hand, we next moved to the
substrate scope of this transformation. As summarized in
Scheme 2, a wide range of sterically bulky alcohols were
suitable for our etherification protocol. The use of cyclooc-
tan-1-d-1-ol delivered the corresponding deuterated ether
3b in 76% yield. The incorporation of bulkier dicyclohexyl-
methan-d-ol into arene was achieved, giving the desired
product in slightly lowered yield. Interestingly, steroidal
compounds exhibited high reactivity in the etherification
reaction, 3c and 3f were produced in 97% and 82% yield, re-
spectively. The difference with respect to yield might be ex-
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

C
S. Li et al.
Letter
Synlett
amples of deuterated alcohols. As pictured in Scheme 3, cy-
clooctan-1-d-1-ol, cyclohexan- 1-d-1-ol, and bicyclic deu-
terated alcohol were successfully reacted, giving the
corresponding products in good yields.
by adding benzyl bromide, and benzyl methyl ether was ob-
served in 72% yield. We thus suggest this transformation
should take a nucleophilic aromatic substitution course
based on our studies.13 Potassium tert-butoxide firstly
deprotonate the deuterated alcohol to generate the corre-
sponding alkoxide in situ, followed by nucleophilic attack-
ing to the aryl alkyl ether to generate the Meisenheimer in-
termediate, and the targeted product is then generated via
the leaving of methanethiolate (Scheme 5).
After investigating the generality of our newly devel-
oped etherification, we next carried out mechanistic stud-
ies (Scheme 4). We found that the presence of radical trap-
pers such as TEMPO, BHT, and 1,1-diphenylethylene in the
reaction system did not hamper the reaction, generating
the aimed deuterated ether in excellent yields.15 The ob-
tained results suggested that this transformation might not
take place via a radical pathway. To test the possibility of
nucleophilic aromatic substitution, we envisioned that we
could trap the in situ generated nucleofuge by adding an ac-
tive electrophile. To our delight, we could arrest methoxide
n-Pr
D
OH
OMe
KOt-Bu (2.0 equiv)
1,4-dioxane (1 M)
CN
D
+
radical scavenger
80 °C, 16 h
O
n-Pr
CN
1a
2e
(1.0 equiv)
(2.0 equiv)
3e
CN
CN
radical scavengera
D
Me
KOt-Bu (2.0 equiv)
SMe
O
D
HO
+
R2
R
R1
R2
1,4-dioxane, 80 °C, 16 h
R
R1
Me
Me
Me
Me
N
O
t-Bu
t-Bu
4
5
6
OH
TEMPO (1.0 equiv)
BHT (1.0 equiv)
1,1-diphenylethylene
(1.0 equiv)
CN
CN
CN
D
D
O
D
90% yield of 3e
95% yield of 3e
94% yield of 3e
O
F3C
O
Trapping MeO– b
OMe
n-Pr
Cl
D
OH
1) KOt-Bu (2.0 equiv)
1,4-dioxane (1 M)
3a, 81%
6b, 70%
6c, 69%
D
CN
+
+
BnOMe
O
80 °C, 16 h
2) BnBr (1.0 equiv)
CN
CN
CN
n-Pr
CN
D
D
O
D
O
O
72%
2e
1a
(2.0 equiv)
(1.0 equiv)
95% yield of 3e
Scheme 4 Mechanistic studies of the etherification. a Reagents and
conditions: ether 1a (0.5 mmol), deuterated alcohol 2e (1.0 mmol),
KOt-Bu (1.0 mmol), radical scavenger (0.5 mmol), 1,4-dioxane (0.5 mL,
1 M), 80 °C, 16 h. b Reagents and conditions: ether 1a (0.5 mmol), deu-
terated alcohol 2e (1.0 mmol), KOt-Bu (1.0 mmol), 1,4-dioxane (0.5
mL, 1 M), 80 °C, 16 h, followed by adding benzyl bromide (0.5 mmol),
stirred for 1 h.
S
3i, 72%
6d, 67%
6e, 83%
CN
D
CN
O
O
D
O
KOt-Bu
D
D
OMe
KO
CN
R2
R1
R2
R1
R2
D
D
D
OMe
CN
HO
O
R1
R2
R1
MeS
O
6f, 78%
6g, 76%
6h, 83%
CN
– MeS–
CN
SMe
CN
CN
D
O
O
D
Scheme 5 Plausible mechanism of etherification
OMe
OMe
In summary, we reported a practical etherification pro-
tocol capable of efficiently incorporating deuterated alco-
hols into nitrile-substituted aryl alkyl ethers and aryl alk-
ylthio ethers.16 It is worth noting that the mild reaction
conditions could tolerate a series of aryl ethers and deuter-
ated alcohols to access the pharmaceutically important
6i, 56%
6j, 75%
Scheme 3 Substrate scope of etherification via C–S bond cleavage.
Reagents and conditions: aryl alkyl thioether (0.2 mmol), deuterated al-
cohol (0.4 mmol), KOt-Bu (0.4 mmol), 1,4-dioxane (0.2 ml, 1 M), 80 °C,
16 h.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

D
S. Li et al.
Letter
Synlett
deuterated ethers that are not easily to prepare by Williamson
etherification. The preliminary mechanistic studies sug-
gested this transformation might happen via a classical nu-
cleophilic aromatic substitution pathway. We anticipate
this technique would find wide applications in pharmaceu-
tical discovery and development research field.
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Funding Information
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lics 2002, 21, 1554. (b) Gómez-Gallego, M.; Sierra, M. A. Chem.
Rev. 2011, 111, 4857. (c) Alonso, F.; Beletskaya, I. P.; Yus, M.
Chem. Rev. 2002, 102, 4009. (d) Johansen, S. K.; Sørensen, L.;
Martiny, L. J. Labelled Compd. Radiopharm. 2005, 48, 569.
(e) Janni, M.; Peruncheralathan, S. Org. Biomol. Chem. 2016, 14,
3091. (f) Kuriyama, M.; Hamaguchi, N.; Yano, G.; Tsukuda, K.;
Sato, K.; Onomura, O. J. Org. Chem. 2016, 81, 8934. (g) Donald, C.
S.; Moss, T. A.; Noonan, G. M.; Roberts, B.; Durham, C. E. Tetrahe-
dron Lett. 2014, 55, 3305. (h) Atzrodt, J.; Derdau, V.; Kerr, W. J.;
Reid, M. Angew. Chem. Int. Ed. 2018, 57, 3022.
(5) (a) Yu, R. P.; Hesk, D.; Rivera, N.; Pelczer, I.; Chirik, P. J. Nature
2016, 529, 195. (b) C–H Bond Activation, Vol. 292; Yu, J.-Q.; Shi,
Z., Ed.; Springer: Berlin, 2010. (c) Mkhalid, I. A. I.; Barnard, J. H.;
Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110,
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110, 624.
We thank Hunan University for the funding support.
H
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n
a
n
U
n
i
v
ersity(■
■
Grant
N
o
.
?
■
■)
Acknowledgment
We thank Prof. Wanxiang Zhao for discussions during the studies of
this project.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611898.
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p
p
orti
n
gInformati
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vial was capped, and the resulting reaction mixture was heated
to 80 °C and stirred for 16 h. The reaction mixture was then
allowed to cool to room temperature, diluted with Et2O (3 ml),
and then filtered through a plug of silica gel, washing with THF.
The crude mixture was concentrated in vacuo and purified by
flash column chromatography on silica gel to provide the corre-
sponding product 3a (43.1 mg, 78% yield) as a white solid (elu-
ent: hexanes/EtOAc = 30:1); mp 138.6 ℃ .
1H NMR (400 MHz, CDCl3):  = 7.60 (d, J = 7.7 Hz, 1 H), 7.55 (t, J =
8.0 Hz, 1 H), 7.36 (t, J = 7.4 Hz, 2 H), 7.27 (t, J = 8.1 Hz, 3 H), 7.07
(d, J = 8.5 Hz, 1 H), 7.02 (t, J = 7.6 Hz, 1 H), 2.66 (t, J = 11.8 Hz, 1
H), 2.33 (d, J = 12.1 Hz, 2 H), 2.08 (d, J = 12.1 Hz, 2 H), 1.78 (t, J =
13.0 Hz, 2 H), 1.67 (t, J = 12.9 Hz, 2 H) ppm. 13C NMR (101 MHz,
CDCl3):  = 159.98, 146.09, 134.19, 134.03, 128.55, 126.84,
126.35, 120.83, 116.80, 114.23, 103.35, 77.43 (t, J = 21.5 Hz),
43.33, 32.22, 32.03 ppm. HRMS (ESI): m/z calcd for
C
19H18DNONa [M + Na]: 301.1422; found: 301.1414. IR (neat):
3057, 2944, 2890, 2225, 1597, 1488, 1454, 1292, 746 cm–1
.
General Procedure 2
An oven-dried vial (4 ml) equipped with a magnetic stir bar was
charged with 2′-methoxy-3-(methylthio)-(1,1′-biphenyl)-4-
carbonitrile (4h, 0.2 mmol, 51 mg). The vial was then moved
into a N2-filled glovebox. KOt-Bu (0.4 mmol, 44.8 mg), cyclooc-
tan-1-d-1-ol (5h, 0.4 mmol, 51.4 mg), and 1,4-dioxane (0.2 mL)
were added to the vial. The vial was capped, and the resulting
reaction mixture was heated to 80 °C and stirred for 16 h. The
reaction mixture was then allowed to cool to room tempera-
ture, diluted with Et2O (3 mL), and then filtered through a plug
of silica gel, washing with THF. The crude mixture was concen-
trated in vacuo and purified by flash column chromatography
on silica gel to provide the corresponding product 6h (55.7 mg,
83% yield) as a rose-red solid (eluent: hexanes/Et2O = 10:1); mp
85.8 °C. 1H NMR (400 MHz, CDCl3):  = 7.55 (d, J = 7.9 Hz, 1 H),
7.39 (t, J = 7.8 Hz, 1 H), 7.31 (d, J = 7.5 Hz, 1 H), 7.26 (s, 1 H), 7.10
(d, J = 10.6 Hz, 2 H), 7.02 (d, J = 8.3 Hz, 1 H), 3.84 (s, 3 H), 2.01–
1.93 (m, 4 H), 1.89–1.78 (m, 2 H), 1.67 (dd, J = 13.2, 6.4 Hz, 1 H),
1.58 (dt, J = 12.8, 7.6 Hz, 6 H), 1.28 (d, J = 11.5 Hz, 1 H) ppm. 13
C
(16) Experimental Procedures
NMR (101 MHz, CDCl3):  = 159.49, 156.42, 144.82, 133.33,
130.63, 129.93, 129.20, 121.75, 121.17, 117.16, 115.47, 111.56,
101.37, 79.18 (t, J = 21.6 Hz), 55.69, 31.47, 27.15, 25.72, 23.03
ppm. HRMS (ESI): m/z calcd for C22H24DNO2Na [M + Na]:
359.1840; found: 359.1838. IR (neat): 3025, 2925, 2853, 2223,
General Procedure 1
An oven-dried vial (4 ml) equipped with a magnetic stir bar was
charged with 2-(methoxy)benzonitrile (1a, 0.2 mmol, 26.6 mg).
The vial was then moved into a N2-filled glovebox. KOt-Bu (0.4
mmol, 44.8 mg), 4-phenylcyclohexan-1-d-1-ol (2a, 0.4 mmol,
46.8 mg), and 1,4-dioxane (0.2 mL) were added to the vial. The
1605, 1556, 1465, 1405, 1244, 754 cm–1
.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E