A simple and cost-effective method for the regioselective deuteration of phenols

Article abstract of DOI:10.1002/ejoc.201500192

A highly effective and operationally simple method for the deuteration of phenols using NaOH as a catalyst and D₂O as the deuterium source is presented. A high regioselectivity for the ortho and/or para hydrogens relative to the oxygen atom was

Full text of DOI:10.1002/ejoc.201500192

FULL PAPER
DOI: 10.1002/ejoc.201500192
A Simple and Cost-Effective Method for the Regioselective Deuteration of
Phenols
Miao Zhan,[a][‡] Ruixue Xu,[a][‡] Ye Tian,[a] Hongxia Jiang,[a] Lifeng Zhao,[a]
Yongmei Xie,*[a] and Yuanwei Chen*[a,b]
Keywords: Isotopic labeling / Deuterium / Regioselectivity / Aromatic substitution / Phenols
A highly effective and operationally simple method for the
deuteration of phenols using NaOH as a catalyst and D2O as
the deuterium source is presented. A high regioselectivity for
the ortho and/or para hydrogens relative to the oxygen atom
was achieved, as well as a high degree of deuterium incorpo-
ration. The method also has a high functional-group toler-
ance, and allowed the deuteration of complex pharmaceuti-
cally interesting substrates.
ture of D3PO4, BF3 and D2O has been used for the deutera-
tion of polyphenolic substrates such as flavonoids, isofla-
vonoids, and lignans at activated positions after several re-
action cycles over a period of 1–4 d.[10] And recently,
Pohjoispää et al. reported a method with capricious selec-
tivity for the electrophilic deuteration of methylenedioxy-
substituted aromatic compounds.[11] These methods often
suffer from low efficiencies of deuterium exchange,[8] and
they require expensive or difficult-to-access catalysts and
deuterium sources.[7–9] Moreover, these published protocols
often gave perdeuterated phenols without any selectivity,
and they sometimes gave moderate to low degrees of deu-
teration. Therefore, a convenient, site-selective, and highly
efficient labelling method is needed.
We surmised that phenols could be regioselectively deu-
terated through electrophilic aromatic substitution. As pre-
viously described, anilines were efficiently deuterated at the
ortho and/or para positions relative to the nitrogen in the
presence of concentrated HCl (1 equiv.) in D2O.[5b] The aim
of this investigation was to find an efficient similar method
for the regioselective deuteration of phenols in basic D2O
(Scheme 1).
Introduction
Deuterium-labelled compounds are essential tools for the
study of reaction mechanisms and kinetics, analysis of drug
metabolism, structural elucidation of biological macromole-
cules, and quantitative analysis of environmental pollutants
and residual pesticides, and they may be used as functional
materials and as internal standards in analytical methods.[1]
Recently, deuterium-labelled drugs have attracted great
interest within the pharmaceutical community, as the intro-
duction of deuterium as a hydrogen bioisostere can signifi-
cantly improve the pharmacokinetic properties (ADMET)
of a great many drugs.[2] As such, deuterium incorporation
has experienced a renaissance, partly as a result of this
growing interest from the pharmaceutical industry.[2,3]
Thus, the development of site-selective and post-synthetic
deuterium-labelling methods is desired.
There are numerous methods for the preparation of
deuterium-labelled aromatic molecules,[4] and they include
pH-dependent[5a–5c] and transition-metal-mediated proto-
cols.[5d–5h] A number of H–D exchange methods have been
reported for the preparation of deuterium-labelled phenols.
For example, the H–D exchange reactions catalysed by
transition metals [Pt(C)/D2O/H2,[6a,6b] Pd(C)/Pt(C)/D2O/
H2,[6c] Pt(C)/iPrOH,[6d] Ir[7] and Rh[8]], and microwave-en-
hanced metal-catalysed exchange reactions.[9] Also, a mix-
[a] State Key Laboratory of Biotherapy and Cancer Center,
West China Hospital, Sichuan University, and Collaborative
Innovation Center for Biotherapy,
Scheme 1. Base-catalysed deuteration of substituted phenols.
Chengdu 610041, P. R. China
E-mail: xieym@scu.edu.cn
ywchen@scu.edu.cn
Results and Discussion
http://sklb.scu.edu.cn/
[b] Hinova Pharmaceuticals Inc., Suite 801, Building C1,
#88 South KeYuan Road, Chengdu Tianfu Life Science Park,
Chengdu 610041, P. R. China
Initially, NaOH (1 equiv.) was used as base together with
D2O (75 equiv.) as deuterium source for the deuteration of
o-cresol. The reaction mixture was heated to 180 °C for
30 min under microwave irradiation, and the level of deuter-
[‡] These authors contributed equally to this work.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500192.
3370
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 3370–3373

Regioselective Deuteration of Phenols
ium incorporation reached 96% at the ortho and para posi- trast, this method allows the deuteration of phenol with
tions (Table 1, entry 1). When the reaction time was de- high regioselectivity at the ortho and para positions
creased to 15 min, this also led to a high deuterium content (Table 2, entry 3). Electron-rich and electron-deficient
(Table 1, entry 2). However, decreasing the temperature led phenols were efficiently deuterated, including 4Ј-hydroxy-
to a lower degree of deuteration (Table 1, entry 4). We were acetophenone (Table 2, entry 9), which was also deuterated
pleased to find that decreasing the amount of catalyst fur- at the α-position, and even sterically hindered substituents
ther to 50 mol-% resulted in a higher deuterium content were tolerated (Table 2, entry 5). Various halogen-substi-
(97%; Table 1, entry 5). Moreover, the use of 10 mol-% of tuted phenols were successfully labelled. Due to the double-
NaOH still gave a high degree of deuterium incorporation
(96.5%; Table 1, entry 6). As expected, increasing or lower-
ing the amount of D2O influenced the degree of deuteration
Table 2. Deuteration of phenols under microwave irradiation.[a]
(Table 1, entries 7 and 8). KOtBu, another strong base, gave
a deuterium incorporation of 96% (Table 1, entry 9). How-
ever, KOAc, a weak base, gave only a moderate level of
deuterium labelling of o-cresol (Table 1, entry 10). Stoichio-
metric amounts of concentrated HCl, which was used for
the deuteration of anilines under microwave irradiation at
180 °C,[5b] gave deuterium incorporation of 67–88% with-
out selectivity (Table 1, entry 11). Neutral D2O induces only
partial deuteration of phenols even under near-critical con-
ditions.[12] A comparable result was observed with conven-
tional heating in an oil bath in a sealed tube (Table 1, en-
try 12). We tested the pH of the above reaction systems,
and this indicated that basic conditions facilitate the H–D
exchange reaction. Under basic conditions, the phenoxide
ion might be generated, and this could result in a more
regioselective transformation compared to the phenol.[13]
We speculate that the phenols were deuterated in the phen-
oxide ion form. For reasons of convenience and cleanliness,
the optimized conditions were taken to be: NaOH (50 mol-
%) in D2O (75 equiv.), heating to 180 °C under microwave
irradiation for 15 min.
Table 1. Optimization of deuteration conditions on o-cresol.
Entry
Catalyst
(mol-%)
pH
Time
[min]
T
[°C]
D content
[%][a]
1
2
3
4
5
6
7
8
NaOH (100)
NaOH (100)
NaOH (100)
NaOH (100)
NaOH (50)
NaOH (10)
NaOH (50)
NaOH (50)
KOtBu (50)
KOAc (50)
HCl (100)
10.71
10.71
10.71
10.71
9.28
8.69
9.28
9.28
9.26
6.45
0.60
9.28
30
15
5
180
180
180
160
180
180
180
180
180
180
180
180
95
96
91
87
15
15
15
15
15
15
15
30
15
97
96.5
97.5[b]
94.5[c]
96
9
10
11
12
55[d]
67–88[e]
96[f]
NaOH (50)
[a] Unless otherwise stated, reactions were conducted with o-cresol
(2 mmol) in D2O (3 mL) heated under microwave irradiation. The
deuterium content was calculated on the basis of 1H NMR spec-
troscopy. [b] 150 equiv. of D2O. [c] 37.5 equiv. of D2O. [d] Average
deuterium content of the ortho and para positions. [e] O-cresol was
labelled without selectivity. [f] Oil bath.
A variety of substituted phenols were subjected to the
optimized conditions to evaluate the scope of the reaction
(Table 2). Spectroscopically pure labelled phenols could eas-
ily be isolated by acidification and simple extraction, and
no further purification was required. Traditional methods
[a] Unless otherwise stated, reactions were carried out with the sub-
strate (2 mmol) and NaOH (0.5 equiv.) in D2O (3 mL) at 180 °C for
15 min under microwave irradiation. The deuterium content was
calculated on the basis of 1H NMR spectroscopy. [b] Isolated yield.
gave perdeuterated phenol without selectivity.[6–9] In con- [c] 1 equiv. of NaOH, 30 min.
Eur. J. Org. Chem. 2015, 3370–3373
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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M. Zhan, R. Xu, Y. Tian, H. Jiang, L. Zhao, Y. Xie, Y. Chen
FULL PAPER
directing effects of 3-iodophenol, the 2-position was
labelled preferentially. It has previously been reported that
substituted anisoles were labelled under microwave-medi-
ated conditions.[5a,5e] In contrast, an attempt to deuterate
the anisole under the optimized conditions was unsuccess-
ful, which indicates that the OH group is essential for the
regioselectivity. As noted above, when methoxy-substituted
phenols were subjected to the reaction conditions, deuter-
ium was only observed ortho and/or para to the phenol oxy-
gen (Table 2, entries 10 and 11). Interestingly, not only the
5- and 7-positions, but also the 2-position of 8-hydroxy-
quinoline was labelled, which might be due to the acidity
of the 2-position (Table 2, entry 13). It has been reported
that perdeuterated 4-aminophenol was obtained in the pres-
ence of concentrated HCl (1 equiv.) in D2O under micro-
wave irradiation at 180 °C.[5a] Surprisingly, by our method,
this compound incorporated deuterium only at the posi-
tions ortho to the phenolic hydroxyl group (Table 2, en-
try 14). Moreover, the method also allowed the deuteration
of 4-methylcatechol, which indicates that this protocol
could be used for the deuteration of substrates containing
multiple phenolic hydroxyl groups (Table 2, entry 15). Sub-
strates with carboxy or nitro groups underwent little to no
deuteration. Base-sensitive compounds containing amide,
ester, or cyano groups decomposed under the reaction con-
ditions.
Experimental Section
Representative Procedure for Deuteration Reactions: In a microwave
reaction vial with a magnetic stirrer bar, o-cresol (1 equiv., 2 mmol)
was added, followed by NaOH (0.5 equiv., 40 mg) and D2O
(75 equiv., 3 mL). The vial was sealed and heated in the microwave
synthesis apparatus for 15 min at 180 °C. Then the mixture was
cooled to room temperature, HCl (0.1 m aq.; 10 mL) was added,
and the mixture was extracted with ethyl acetate (2ϫ 10 mL). The
organic layer was washed with brine (5 mL), dried with anhydrous
Na2SO4, and filtered. The filtrate was concentrated to give [D2]o-
1
cresol. The total incorporation yield was determined by H NMR
spectroscopy relative to the intensity of a nonexchangeable proton
in the molecule, and was confirmed by H NMR spectroscopy.
2
[2H]o-Cresol (Table 1, entry 1): Brown liquid (94%). 1H NMR
(400 MHz, CDCl3): δ = 7.12 (s, 1 H), 7.07 (s, 1 H), 6.84 (t, J =
7.4 Hz, 0.03 H), 6.76 (d, J = 8.0 Hz, 0.03 H), 4.79 (br. s, 1 H), 2.25
2
(s, 3 H) ppm. H NMR (61.4 MHz, CHCl3): δ = 6.91 (s), 6.83 (s)
ppm.
[2H]2,6-Dimethylphenol (Table 1, entry 2): Pale brown solid (91%).
1H NMR (400 MHz, CDCl3): δ = 6.97 (s, 2 H), 6.78–6.73 (m, 0.05
H), 4.61 (br. s, 1 H), 2.25 (s, 6 H) ppm. 2H NMR (61.4 MHz,
CHCl3): δ = 6.86 (s) ppm.
[2H]Phenol (Table 1, entry 3): Pale brown liquid (89%). 1H NMR
(400 MHz, CDCl3): δ = 7.23 (s, 2 H), 6.92 (t, J = 7.4 Hz, 0.04 H),
6.83 (d, J = 8.5 Hz, 0.08 H), 5.42 (br. s, 1 H) ppm. 2H NMR
(61.4 MHz, CHCl3): δ = 7.00 (s), 6.91 (s) ppm.
[2H]4-Cumylphenol (Table 1, entry 4): White solid (97%). 1H NMR
(400 MHz, CDCl3): δ = 7.30–7.19 (m, 4 H), 7.16 (t, J = 6.7 Hz, 1
H), 7.09 (s, 2 H), 6.72 (d, J = 9.2 Hz, 0.04 H), 1.65 (s, 6 H) ppm.
2H NMR (61.4 MHz, DMSO): δ = 6.74 (s) ppm.
To further evaluate the substrate scope of our new cata-
lytic deuteration procedure, the FDA-approved drug
desvenlafaxine, featuring a phenolic hydroxyl moiety, was
chosen as a benchmark compound. Desvenlafaxine is used
for the treatment of adult patients with major depressive
disorder.[14] As expected, a deuterium incorporation of 98%
was achieved with a yield of 93% using NaOH (0.5 equiv.)
in D2O (150 equiv.), and heating to 180 °C under microwave
irradiation for 30 min (Scheme 2).
[2H]2,6-Diisopropylphenol (Table 1, entry 5): Pale yellow liquid
1
(93%). H NMR (400 MHz, CDCl3): δ = 7.06 (s, 2 H), 6.90 (t, J
= 7.6 Hz, 0.09 H), 4.79 (s, 1 H), 3.16 (dt, J = 13.7, 6.9 Hz, 2 H),
1.27 (d, J = 6.9 Hz, 12 H) ppm. 2H NMR (61.4 MHz, CHCl3): δ
= 7.04 (s) ppm.
[2H]4-Bromophenol (Table 1, entry 6): Pale brown solid (93%). H
1
NMR (400 MHz, CDCl3): δ = 7.33 (s, 2 H), 6.72 (d, J = 9.2 Hz,
2
0.12 H) ppm. H NMR (61.4 MHz, CHCl3): δ = 6.79 (s) ppm.
[2H]4-Chloro-2-fluorophenol (Table 1, entry 7): Pale brown liquid
(89%). 1H NMR (400 MHz, CDCl3): δ = 7.09 (dd, J = 10.3, 2.4 Hz,
1 H), 7.00 (s, 1 H), 6.92 (t, J = 8.9 Hz, 0.05 H), 4.84 (br. s, 1 H)
2
ppm. H NMR (61.4 MHz, CHCl3): δ = 6.94 (s) ppm.
[2H]3-Iodophenol (Table 1, entry 8): Pale brown solid (91%). 1H
NMR (400 MHz, [D6]DMSO): δ = 9.76 (br. s, 1 H), 7.16–7.14 (m,
0.05 H), 7.12 (s, 0.02 H), 6.97 (s, 1 H), 6.80–6.75 (m, 0.04 H) ppm.
2H NMR (61.4 MHz, DMSO): δ = 7.11 (s), 6.73 (s) ppm.
Scheme 2. Deuteration of Desvenlafaxine using the NaOH/D2O
system under microwave irradiation.
[2H]4Ј-Hydroxyacetophenone (Table 1, entry 9): Pale brown solid
1
(89%). H NMR (400 MHz, CDCl3): δ = 8.22 (br. s, 1 H), 7.91 (s,
2
2 H), 6.96 (d, J = 9.2 Hz, 0.07 H), 2.56 (s, 0.08 H) ppm. H NMR
(61.4 MHz, CHCl3): δ = 7.02 (s), 2.58 (s) ppm.
Conclusions
[2H]4-Methoxyphenol (Table 1, entry 10): Off-white solid (90%). 1H
NMR (400 MHz, CDCl3): δ = 6.79 (s, 2 H), 4.98 (br. s, 1 H), 3.76
An efficient method for the synthesis of regioselectively
deuterated phenols under microwave irradiation has been
developed. The ease of operation of the reaction, the high
levels of deuterium incorporation, and the low cost of the
reagents make this a very valuable method for isotopic
labelling. We envisage that this method could also be ex-
tended to the tritium labelling of pharmaceutically interest-
ing compounds for medicinal applications.
2
(s, 3 H) ppm. H NMR (61.4 MHz, CHCl3): δ = 6.84 (s) ppm.
[2H]3-Methoxyphenol (Table 1, entry 11): Pale brown liquid (90%).
1H NMR (400 MHz, CDCl3): δ = 7.13 (s, 1 H), 6.50 (d, J = 8.3 Hz,
0.03 H), 6.44–6.42 (m, 0.06 H), 5.19 (br. s, 1 H), 3.78 (s, 3 H) ppm.
2H NMR (61.4 MHz, CHCl3): δ = 6.50–6.57 (m) ppm.
[2H]4-Phenylphenol (Table 1, entry 12): White solid (94%). 1H
NMR (400 MHz, [D6]DMSO): δ = 9.55 (br. s, 1 H), 7.57 (d, J =
3372
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Regioselective Deuteration of Phenols
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[2H]8-Hydroxyquinoline (Table 1, entry 13): Pale brown solid
1
(87%). H NMR (400 MHz, CDCl3): δ = 8.78 (d, J = 3.2 Hz, 0.04
H), 8.16 (d, J = 8.3 Hz, 1 H), 7.49–7.38 (m, 2 H), 7.33 (d, J =
8.3 Hz, 0.04 H), 7.18 (d, J = 7.7 Hz, 0.04 H) ppm. 2H NMR
(61.4 MHz, DMSO): δ = 8.85 (s), 7.41 (s), 7.12 (s) ppm.
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1
(88%). H NMR (400 MHz, CDCl3): δ = 6.75 (s, 0.05 H), 6.69 (s,
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NMR (61.4 MHz, CHCl3): δ = 6.80–6.65 (m) ppm.
[2H]1-Naphthol (Table 1, entry 16): Pale brown solid (91%). 1H
NMR (400 MHz, CDCl3): δ = 8.22–8.13 (m, 1 H), 7.85–7.77 (m, 1
H), 7.53–7.45 (m, 2 H), 7.44 (d, J = 8.5 Hz, 0.06 H), 7.31 (s, 1 H),
6.82 (d, J = 7.4 Hz, 0.06 H), 5.37 (s, 1 H) ppm. 2H NMR
(61.4 MHz, CHCl3): δ = 7.52 (s), 6.89 (s) ppm.
[2H]Desvenlafaxine (Scheme 2): Off-white solid (91%). 1H NMR
(400 MHz, [D6]DMSO): δ = 6.96 (s, 2 H), 6.63 (d, J = 8.9 Hz, 0.04
H), 2.99 (dd, J = 12.2, 8.9 Hz, 1 H), 2.73–2.69 (m, 1 H), 2.33 (dd,
J = 12.4, 6.2 Hz, 1 H), 2.13 (s, 6 H), 1.56–0.99 (m, 10 H) ppm.
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This work was supported by National Natural Science Foundation
of China (NSFC) (grant number 81472418).
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Received: February 9, 2015
Published Online: April 17, 2015
Eur. J. Org. Chem. 2015, 3370–3373
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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