B(C6F5)3-Catalyzed Regioselective Deuteration of Electron-Rich Aromatic and Heteroaromatic Compounds

Article abstract of DOI:10.1021/acs.orglett.7b02701

Deuterium labeled compounds find widespread application in life science. Herein, the deuteration of electron-rich (hetero)aromatic compounds employing B(C₆F₅)₃ as the catalyst and D₂O as the deuterium source is reported. This protocol is highly efficient, simply manipulated, and successfully applied in the deuteration of 23 substrates including natural neurotransmitter-like melatonin. It is assumed that the weakening of the O-D bond ultimately results in the formation of electrophilic D⁺.

Full text of DOI:10.1021/acs.orglett.7b02701

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
B(C6F5)3‑Catalyzed Regioselective Deuteration of Electron-Rich
Aromatic and Heteroaromatic Compounds
Wu Li, Ming-Ming Wang, Yuya Hu, and Thomas Werner*
Leibniz Institute for Catalysis at the University of Rostock, Albert-Einstein-Straße 29a, 18059 Rostock, Germany
S
* Supporting Information
ABSTRACT: Deuterium labeled compounds find widespread application in
life science. Herein, the deuteration of electron-rich (hetero)aromatic
compounds employing B(C6F5)3 as the catalyst and D2O as the deuterium
source is reported. This protocol is highly efficient, simply manipulated, and successfully applied in the deuteration of 23
substrates including natural neurotransmitter-like melatonin. It is assumed that the weakening of the O−D bond ultimately
results in the formation of electrophilic D+.
sotopically labeled molecules find widespread application in
1
Iboth academia and industry. Deuterium labeled compounds
are of particular interest. They are used in various areas of
science, e.g. in the elucidation of reaction mechanisms by
kinetic isotope effects,2 as internal standards in analytical
chemistry, to explore metabolic pathways of drug molecules,3 to
improve the pharmacokinetic properties of drugs,4 and to study
protein structures and dynamics.5 Thus, hydrogen−deuterium
exchange reactions (H/D exchange reactions) are of particular
interest and provide an essential tool for the preparation of
deuterium-labeled compounds.6 This methodology allows the
rapid and cost efficient synthesis of labeled molecules by the
displacement of a hydrogen atom which is bonded to a carbon
by a deuterium atom. As a result, several methods for the
Tris(pentafluorophenyl)-borane (B(C6F5)3) is a versatile
incorporation of deuterium into aromatic molecules have been
catalyst for different organic transformations including the
hydrogenation9 and hydrosilylation10 of CO and CC
developed including pH-dependent aromatic H/D exchange.
Commonly Brønsted acids or alternatively Lewis acids in
double bonds.11 We recently reported the B(C6F5)3 catalyzed
Michael reaction using aromatic C(sp2)−H nucleophiles.12
combination with a deuterium source such as D2O, C6D6, or
AcOD are employed to mediate the exchange (eq 1).7
Furthermore, it plays a significant role as a component of
frustrated Lewis pairs (FLP).13 Generally, the coordination of
Moreover, elaborated protocols based on transition metals
(e.g., Ir, Ru, Rh, Pd, Pt) catalyzed H/D exchange with high
tolerance toward a number of functional groups and efficient
deuterium incorporation have been reported (eq 2).8 The site
selectivity of transition metal catalyzed H/D exchange reactions
is often predictable and dependent on directing groups, which
enable the selective functionalization of the ortho-positions of
aromatic and heteroaromatic substrates. Even though great
advances have been made, the required ligands and/or
expensive transition metals may not be readily accessible or
economically viable. This leads to an increasing interest in the
development of H/D exchange reactions due to the growing
demand for labeled compounds. Notably, most of the above-
mentioned H/D exchange methods catalyzed by transition
metals are based on an initial cleavage of a C−H bond by the
catalysts and subsequent incorporation of the deuterium (eq 2).
Thus, simple cost efficient methods for the deuteration of
aromatic and heteroaromatic substrates are highly desirable.
water to a Lewis acidic metal complex leads to the weakening of
the O−H bond.14 In this respect, the interaction of B(C6F5)3
with water has been thoroughly investigated by different
groups.15 Our concept was to utilize B(C6F5)3 for the catalytic
activation of D2O and the subsequent H/D exchange reaction
with C(sp2)−H nucleophiles (eq 3). Herein we report the
transition-metal-free deuteration of aromatic and heteroaro-
matic compounds utilizing readily available B(C6F5)3 as the
catalyst under mild conditions.
We chose the deuteration of N,N-dibenzylaniline (1a) with
D2O as the model reaction. Under the standard conditions,
96% deuterium incorporation was achieved in the ortho- and
para- positions (Table 1, entry 1).16 Control experiments in the
absence of B(C6F5)3 or D2O gave no product (entries 2 and 3).
Subsequently, we studied the influence of various reaction
Received: August 30, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02701
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Effect of Reaction Parameters on the B(C6F5)3
Catalyzed H/D Exchange
Scheme 1. Substrate Scope for the Conversion of N,N-
a
Disubstituted Anilines 1 in the B(C6F5)3 Catalyzed H/D
a
Exchange
b
entry variation from “standard conditions” deuterium incorporation (%)
1
−
96
−
−
0
2
without B(C6F5)3
3
without D2O
4
CD3OD instead of CDCl3
C6D5CD3 instead of CDCl3
D2O (3 equiv)
5
92
64
−
−
−
−
−
6
7
Zn(OAc)2 instead of B(C6F5)3
ZnCl2 instead of B(C6F5)3
FeCl3 instead of B(C6F5)3
Ph3CBF4 instead of B(C6F5)3
benzoic acid instead of B(C6F5)3
8
9
10
11
a
Standard reaction conditions: 1a (0.5 mmol), B(C6F5)3 (0.025
mmol), D2O (15 mmol), CDCl3 (1.0 mL), 80 °C for 24 h.
b
1
Deuterium incorporation was determined by H NMR.
parameters. In protic solvents such as CD3OD no product was
observed (entry 4), while the transformation proceeded also
efficiently in C6D5CD3 (entry 5). The reduction of the D2O
amount from 30 to 3 equiv led to a decrease in deuterium
incorporation from 96% to 64% (entry 1 vs 6).16 Notably,
under standard reaction conditions other Lewis acids such as
Zn(OAc)2, ZnCl2, FeCl3, and Ph3CBF4 could not catalyze the
H/D exchange (entries 7−10). In addition, no product was
formed when benzoic acid was employed as the catalyst (entry
11).
Subsequently, we evaluated the scope and limitations of this
reaction for the conversion of N,N-disubstituted aniline
derivatives 1a−m (Scheme 1). We were pleased to find out
that highly selective H/D exchanges with good to excellent
degrees of deuteration, as well as excellent isolated yields, were
achieved (2a−2m). Notably, the deuteration takes place in the
ortho- and para-position to nitrogen while no exchange was
observed in the (cyclo)alkyl and benzyl substituents at the
nitrogen. Moreover, this protocol tolerates various substituents
such as a methyl group in 2g−2i, a methoxy substituent in 2j,
and halogens in 2k and 2l. Deuterated triphenylamine 2m and
naphthyl derivative 2n were also isolated in moderate to good
deuterium incorporations. We converted 2n again under our
standard reaction conditions to increase the degree of
deuterium incorporation. However, after this second con-
version, 2n was obtained in similar yield, but no change in the
deuteration degree was observed. Julolidine (1o), a compound
with potential application in photoconductive and nonlinear
optical materials, was also deuterated to afford 2o in 85% yield
with good deuterium incorporation to the para-position with
respect to the nitrogen.17 We were pleased to find out that the
deuteration of indole derivative 1p as well as 1,2,3,4-
tetrahydroquinoline (1q) could be achieved with good to
excellent deuterium incorporations and excellent isolated yields
of 97% and >99%, respectively. The deuteration of these
compounds is of particular interest since they are frequently
observed substructures in natural products and bioactive
molecules. Nitrogen- and sulfur-containing heterocycles such
as 3-hexadecylthiophene (1r) and 1-benzyl-pyrrole (1s) were
a
Standard reaction conditions: 1 (0.5 mmol), B(C6F5)3 (0.025 mmol),
D2O (15 mmol), CDCl3 (1.0 mL), 80 °C for 24 h. Isolated yields are
given.
also suitable substrates for the selective H/D exchange
affording 2r and 2s in excellent isolated yields. Moreover,
electron-rich aromatic substrates such as 1,3-dimethoxybenzene
(1t) and 1,3,5-trimethoxybenzene (1u) were also readily
deuterated. Less active 2,4,6-trimethoxybenzaldehyde (1v)
afforded 2v in 98% yield with 48% deuterium incorporation
at the meta-positions. The conversion of electron-rich sulfur
containing substrates such as methyl phenyl sulfide and
dibenzothiophene under the standard conditions did not lead
to D-incorporation.
B
DOI: 10.1021/acs.orglett.7b02701
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Melatonin (3), also known as N-acetyl-5-methoxy trypt-
amine, is an ubiquitous natural neurotransmitter-like com-
pound which is primarily produced by the pineal gland in
animals regulating the sleep−wake cycle.18 Furthermore,
melatonin is involved in numerous other aspects of the
biological and physiologic functions.19 Under our standard
reaction conditions 3 could be converted into the deuterated
derivative 4 with excellent deuteration incorporation and an
95% isolated yield (Scheme 2).
underwent H/D exchange to yield the respective dedeuterated
products 1.
Scheme 4. B(C6F5)3 Catalyzed Dedeuteration Reactions
Scheme 2. Selective H/D Exchange in Melatonin (3)
Catalyzed by B(C6F5)3
In summary, we have developed the first B(C6F5)3 catalyzed
deuteration protocol for electron-rich aromatics and hetero-
aromatics using deuterium oxide (D2O) as a deuterium source.
In this process, the coordination of D2O to B(C6F5)3 leads to
the weakening of the O−D bond, formally producing D+ as an
electrophile. The reaction proceeds under mild conditions with
high yields and a good to excellent degree of deuterium
incorporation. We successfully illustrated that this method can
be applied to complex molecules and substructures, which are
frequently observed in natural products and pharmaceuticals,
e.g. in the deuteration of melatonin. This transformation not
only broadens the application of B(C6F5)3 in organic synthesis
but also provides a complementary approach to hydrogen−
deuterium exchange reactions. Initial studies of the mechanism
reveal that the transformation is an equilibrium reaction and
can thus also be employed for the dedeuteration of aromatic
compounds. Studies on the mechanism of this reaction as well
as other B(C6F5)3 catalyzed transformations will be reported in
due course.
Scheme 3. Putative Mechanism for the B(C6F5)3.Catalyzed
H/D Exchange
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02701.
A putative mechanism for the B(C6F5)3 catalyzed H/D
exchange is depicted in Scheme 3. We assume the weakening of
the O−D bond in deuterium oxide by coordination of D2O to
B(C6F5)3.20 This ultimately leads to the formation of a Lewis
acid−base adduct and subsequent generation of an acidic D+
and the complementary anion as previously reported for the
reaction with H2O (A).15b,c
Subsequently, an electrophilic aromatic substitution takes
place. The electrophilic attack of D+ leads to a resonance
stabilized arenium ion (B) followed by the departure of H+
under formation of the deuterated product 2. The degree of H/
D exchange might depend on equilibrium factors of the
involved H and D species. This also explains the observation
that the deuteration incorporation is lower if the amount of
D2O is reduced (cf. Table 1, entries 1 and 6).
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: thomas.werner@catalysis.de.
ORCID
Thomas Werner: 0000-0001-9025-3244
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Based on these results, we envisioned that B(C6F5)3 should
also be a feasible catalyst for retro-H/D exchange reactions.
Thus, the deuteration products 2a, 2q and 2v were converted in
the presence of 5 mol % B(C6F5)3 in CHCl3 and an excess of
H2O (Scheme 4). As expected, these substrates smoothly
We wish to thank Prof. M. Beller from the Leibniz Institute for
Catalysis for the support and advice. We also gratefully
acknowledge German Academic Exchange Service (DAAD)
for offering the fellowship to M.-M. Wang who came from
Shanghai Institute of Organic Chemistry, China.
C
DOI: 10.1021/acs.orglett.7b02701
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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