Silver-catalyzed regioselective deuteration of (hetero)arenes and α-deuteration of 2-alkyl azaarenes

Article abstract of DOI:10.1039/d0ra02358b

A simple silver-catalyzed regioselective deuteration of (hetero)arenes and α-deuteration of 2-alkyl azaarenes has been described. This strategy provides an efficient and practical avenue to access various deuterated electron-rich arenes, azaarenes and α-d

Full text of DOI:10.1039/d0ra02358b

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Silver-catalyzed regioselective deuteration of
(hetero)arenes and a-deuteration of 2-alkyl
azaarenes†
Cite this: RSC Adv., 2020, 10, 25475
b
a
Baobiao Dong,ab Xuefeng Cong
*
*
and Na Hao
Received 13th March 2020
Accepted 28th June 2020
A simple silver-catalyzed regioselective deuteration of (hetero)arenes and a-deuteration of 2-alkyl
azaarenes has been described. This strategy provides an efficient and practical avenue to access various
deuterated electron-rich arenes, azaarenes and a-deuterated 2-alkyl azaarenes with good to excellent
deuterium incorporation utilizing D2O as the source of deuterium atoms.
DOI: 10.1039/d0ra02358b
rsc.li/rsc-advances
Deuterium-labelled organic compounds are of great interest the growing demand for deuterium-labelled compounds in
and importance, as they are widely used as internal standards in synthetic chemistry and pharmaceutical industry.
analytical chemistry,1 tools for elucidation of reaction mecha-
In past decades, silver has demonstrated their high efficiency
nisms,2 metabolic or pharmacokinetic probes,3 and as biologi- as special mild Lewis acids, becoming catalysts of rst choice
cally active compounds and pharmaceuticals.4 Indeed, the rst for many types of catalytic reactions generally performed under
deuterated drug, deutetrabenazine, which is recognized as mild reaction conditions and through experimentally simple
a different orphan drug for the treatment of chorea versus tet- procedures.8 However, despite considerable progress, silver-
rabenazine, was approved by the US Food and Drug Adminis- catalyzed selective H/D exchange reaction has remained much
tration in April 2017. As a result, the development of efficient less explored to date.9 Quite recently, Huang reported an effi-
and selective routes for the synthesis of deuterium labeled cient Ag2CO3-catalyzed H/D exchange of ve-membered heter-
organic compounds is a subject of increasing interest. Among oarenes using D2O as deuterium source at ambient
possible approaches to incorporate deuterium atoms into an temperature, but external base such as 1 equiv. of K2CO3 and
organic molecule,5 the H/D exchange reaction, which enables a phosphine ligand were still needed.9b We here developed
the direct deuterium labelling of the desired target molecule a practical and selective silver-catalyzed deuteration of (hetero)
without the need to prefunctionalize the starting materials, arenes and a-deuteration of 2-alkyl azaarenes utilizing D2O as
represents the most straightforward and atom-efficient method. the source of deuterium atom under mild neutral conditions
In recent years, extensive studies on H/D exchange reactions of that does not require any other additives (Scheme 1c). This
aromatic compounds have been reported, including acid/base protocol represents a practical and efficient method of silver-
promoted pH-dependent H/D exchange reactions of electroni- catalyzed regioselective H/D exchange reaction under mild
cally activated aromatic compounds6 (Scheme 1a) and transi-
tion metal catalyzed site-selective H/D exchange reactions7
(Scheme 1b). Among these, transition-metal-catalyzed reactions
have gained signicant momentum because these catalysts can
control the site selectivity of H/D exchange reactions. However,
the required ligands, the introduction of directing groups and/
or the complexity of catalyst synthesis may not be readily
accessible or economically viable. Therefore, there remains
room to develop a simple, cost efficient and universal deutera-
tion strategy with broad substrate scope, especially in view of
aDepartment of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical
University, Luzhou 646000, China. E-mail: haona@swmu.edu.cn
bJilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis,
Department of Chemistry, Northeast Normal University, Changchun 130024, China.
E-mail: congxf010@nenu.edu.cn
† Electronic supplementary information (ESI) available: Experimental details, and
Scheme 1 Selective H/D exchange reactions.
characterization data. See DOI: 10.1039/d0ra02358b
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neutral conditions, efficiently affording a wide range of rich arenes, and the results are listed in Table 2. We were
deuterated electron-rich arenes, azaarenes and a-deuterated 2- pleased to nd out that highly selective H/D exchanges with
alkyl azaarenes through experimentally simple procedures.
good to excellent degrees of deuteration were achieved. A variety
Initially, we began our studies by examining the model of substituted 1,2,3,4-tetrahydroquinolines were smoothly
deuteration of 1,2,3,4-tetrahydroquinoline (1a) with D2O using converted to the deuterated isotopologues with high levels of
various commercially available silver salts as the catalyst. To our deuterium incorporation (2a–2f). The bromide and dimethyl-
delight, 94% deuterium incorporation was achieved in the phenylsilyl substituents could be well tolerated in this catalytic
ortho- and para-positions by using 10 mol% AgOTf in CDCl3 at system. The deuteration of indoline derivatives as well as N-
90 ꢀC (Table 1, entry 1). Other silver salts such as Ag2CO3, methyl aniline derivatives could be achieved with good to
Ag3PO4, AgBF4, AgOAc and Ag2O were also tested as catalysts, excellent deuterium incorporation in the ortho- and para-posi-
but gave low deuterium incorporation (entries 2–6). AgOTf tions (2g–2l). The 9,10-dihydroacridine 1m was also deuterated
showed higher activity probably because of the slow release of to afford 2m in 88% yield with excellent deuterium incorpora-
TfOH in the reaction.9a Control experiment suggests that AgOTf tion. Moreover, other electron-rich aromatic compounds such
is necessary in this reaction (Table 1, entry 7). We then tested as 1,3,5-trimethoxybenzene (1n) and multi-substituted anisole
various solvents for this deuteration, and found that THF and (1o) were also suitable substrates for the selective deuteration
1,4-dioxane can also give good results, but DCE, CH3CN affor- affording 2n and 2o with good deuterium incorporation. The
ded a slightly low deuterium incorporation (entries 8–11). The conversion of N,N-disubstituted aniline derivatives such as N,N-
reduction of the D2O amount from 20 to 5 equiv. led to dimethylaniline under the standard conditions only led to quite
a decrease in deuterium incorporation from 94% to 62% (Table poor D-incorporation (<20% D incorporation).
1, entry 12). When the reaction temperature was decreased to
Subsequently, this catalytic system was applied to the
60 ꢀC, the efficiency of deuterium incorporation dramatically deuteration of indole and azole derivatives. The deuteration of
decreased, only giving 58% deuterium incorporation in the these compounds is of great interest and importance, as they
ortho- and para-positions (entry 13). In addition, under standard
reaction conditions, other Lewis acids such as Cu(OTf)2,
Zn(OTf)2, ZnCl2, FeCl3, and La(OTf)3 could also catalyze the H/D
exchange, but giving a low deuterium incorporation, especially
in the para-position.10,11
Table 2 Silver-catalyzed selective deuteration of various electron-
rich arenesa
With the optimized catalytic system in hand, we evaluated
the scope and limitations of this selective H/D exchange reac-
tion. We rstly examined the deuteration of various electronic-
Table 1 Optimization of conditions for the silver-catalyzed deutera-
tion of 1aa
Entry
[Ag]
Solvent
Deuterium incorporation (D1, D2)b
1
2
3
4
5
6
7
8
AgOTf
Ag2CO3
Ag3PO4
AgBF4
AgOAc
Ag2O
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
DCE
94%, 94%
11%, 8%
21%, 23%
91%, 58%
21%, 10%
13%, 10%
<5%, <5%
74%, 81%
94%, 93%
90%, 90%
77%, 91%
62%, 62%
58%, 58%
—
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
9
THF
10
11
12c
13d
1,2-Dioxane
CH3CN
CDCl3
CDCl3
a
Reaction conditions: 1a (0.5 mmol), [Ag] (0.025 mmol), D2O (10 mmol),
b
solvent (1.0 mL), 90 ꢀC for 18 h. Deuterium incorporation was
a
Reaction conditions: 1 (0.5 mmol), AgOTf (0.025 mmol), D2O (10
determined by 1H NMR. c D2O (2.5 mmol). d At 60 ꢀC.
b
mmol), CDCl3 (1.0 mL), 90 ꢀC for 18 h. Isolated yield are given. 1,4-
dioxane (1.0 mL) was used.
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Table 3 Silver-catalyzed selective deuteration of various azaarenesa
Table 4 Silver-catalyzed a-deuteration of 2-alkyl azaarenesa
a
Reaction conditions: 5 (0.5 mmol), AgOTf (0.025 mmol), D2O (10
mmol), THF (1.0 mL), 90 ꢀC for 18 h. Isolated yield are given.
and benzothiazole under the standard conditions could not
lead to D-incorporation.
Furthermore, by using this silver catalytic system, we also
successfully achieved the regioselective deuteration at the a-
positions of 2-alkyl azaarenes. As shown in Table 4, the
deuteration of 1,2,3,4-tetrahydroacridine gave the deuterated
product 6a efficiently with 95% deuterium incorporation
under the current reaction conditions. When the 2-methyl-
quinoxaline was employed, both methyl group and C3 position
were readily deuterated with high deuterium incorporation. In
addition, the a-positions of alkyl-substituted quinolines 5c, 5d
and 2-benzylpyridine 5e could be deuterated, giving the cor-
responding products in good yields, albeit with 24–40%
deuterium incorporation. Also, a-deuteration of oxindole 5f
gave deuterated product 6f in 96% yield and 91% deuterium
incorporation.
a
Reaction conditions: 3 (0.5 mmol), AgOTf (0.025 mmol), D2O (10
mmol), CDCl3 (1.0 mL), 90 ꢀC for 18 h. Isolated yield are given.
Conclusions
are frequently observed in many pharmaceuticals and biologi-
cally active molecules.12 As shown in Table 3, a range of indoles
with either electron-rich or electron-poor substituents were
smoothly deuterated at C3 positions to afford deuterium-
labelled products in excellent yields with good to excellent
deuterium incorporation (4a–4m). Notably, functional groups
such as chloride, ester, and aldehyde were well tolerated with
this catalytic system. The 2,5-dimethyl pyrrole (3n) was also
suitable substrate to afford 4n with 93% deuterium incorpora-
tion in the C3 and C4 positions. Remarkably, electron-decient
aza-arenes such as imidazoles and benzimidazole were also
readily deuterated at C2 positions with high levels of deuterium
incorporation. 1-Methyl benzimidazole (3q) could be also
employed in this catalytic system, affording 4q with 97%
deuterium incorporation. Also, 1,2,4-triazole could be smoothly
deuterated at C3 and C5 positions with excellent deuterium
incorporation. Unfortunately, the conversion of benzooxazole
In summary, we have developed an efficient silver-catalyzed
regioselective deuteration of (hetero)arenes and a-deuteration
of 2-alkyl azaarenes using the simple D2O as the deuterating
reagent. The reaction proceeds under neutral mild conditions
in high yields with a good to excellent degree of deuterium
incorporation. Electron-rich arenes and heteroarenes, such as
1,2,3,4-tetrahydroquinolines, indoline derivatives, N-methyl
anilines, 1,3,5-trimethoxybenzene and indoles, were all
deuterated with high deuterium incorporation. The protocol
was also applied to the deuteration of electron-decient azoles.
Moreover, the a-position deuteration of 2-alkyl azaarenes was
also achieved under mild neutral conditions.
Conflicts of interest
There are no conicts to declare.
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Improved Pharmacokinetic Properties, ACS Med. Chem.
Lett., 2014, 5, 1162–1166; (c) Y. Zhu, J. Zhou and B. Jiao,
Deuterated Clopidogrel Analogues as a New Generation of
Antiplatelet Agents, ACS Med. Chem. Lett., 2013, 4, 349–352;
(d) A. Mullard, Deuterated drugs draw heavier backing,
Nat. Rev. Drug Discovery, 2016, 15, 219–221; (e) T. G. Gant,
Using Deuterium in Drug Discovery: Leaving the Label in
the Drug, J. Med. Chem., 2014, 57, 3595–3611.
Acknowledgements
We gratefully acknowledge National Natural Science Founda-
tion of China (NSFC) (21702028), Department of Science and
Technology of Jilin Province (20180520206JH), the Collaborative
Fund of Luzhou Government and Southwest Medical University
(2019LZXNYDJ16) and the Research Fund of Southwest Medical
University (2017-ZRQN-037) for nancial support.
5 (a) T. Junk and W. J. Catallo, Hydrogen isotope exchange
reactions involving C–H (D, T) bonds, Chem. Soc. Rev.,
1997, 26, 401–406; (b) Y. Sawama, Y. Monguchi and
H. Sajiki, Efficient H–D Exchange Reactions Using
Heterogeneous Platinum-Group Metal on Carbon–H2–D2O
System, Synlett, 2012, 23, 959–972; (c) J. Atzrodt, V. Derdau,
W. J. Kerr and M. Reid, CÀH Functionalisation for
Hydrogen Isotope Exchange, Angew. Chem., Int. Ed., 2018,
57, 3022–3047; (d) J. Atzrodt, V. Derdau, T. Fey and
J. Zimmermann, The Renaissance of H/D Exchange, Angew.
Chem., Int. Ed., 2007, 46, 7744–7765.
Notes and references
1 (a) J. Atzrodt and V. J. Derdau, Pd- and Pt-catalyzed H/D
exchange methods and their application for internal MS
standard preparation from a Sano-Aventis perspective, J.
Label. Compd. Radiopharm., 2010, 53, 674–685; (b)
A. Nakanishi, Y. Fukushima, N. Miyazawa, K. Yoshikawa,
T. Maeda and Y. J. Kurobayashi, Quantitation of
Rotundone in Grapefruit (Citrus paradisi) Peel and Juice by
Stable Isotope Dilution Assay, J. Agric. Food Chem., 2017,
65, 5026–5033; (c) E. Stokvis, H. Rosing and J. H. Beijnen,
Stable isotopically labeled internal standards in
quantitative bioanalysis using liquid chromatography/mass
spectrometry: necessity or not?, Rapid Commun. Mass
Spectrom., 2005, 19, 401–407; (d) C.-Y. Kao and R. W. Giese,
Measurement of N7-(2‘-Hydroxyethyl)guanine in Human
DNA by Gas Chromatography Electron Capture Mass
Spectrometry, Chem. Res. Toxicol., 2005, 18, 70–75.
6 (a) A. Martins and M. Lautens, A Simple, Cost-Effective
Method for the Regioselective Deuteration of Anilines, Org.
Lett., 2008, 10, 4351–4353; (b) S. Rasku, K. Whl,
J. Koskimies and T. Hase, Synthesis of isoavonoid
deuterium
labeled
polyphenolic
phytoestrogens,
Tetrahedron, 1999, 55, 3445–3454; (c) J. C. Seibles,
D. M. Bollinger and M. Orchin, Synthesis of
Perdeuteriobenzo[a]pyrene, Angew. Chem., Int. Ed. Engl.,
1977, 16, 656–657; (d) J. L. Garnett, M. A. Long,
R. F. W. Vining and T. Mole, New simple method for rapid,
selective aromatic deuteration using organoaluminum
dihalide catalysts, J. Am. Chem. Soc., 1972, 94, 5913–5914;
2 (a) E. M. Simmons and J. F. Hartwig, On the Interpretation of
Deuterium Kinetic Isotope Effects in CÀH Bond
Functionalizations by Transition-Metal Complexes, Angew.
Chem., Int. Ed., 2012, 51, 3066–3072; (b) T. Giagou and
M. P. Meyer, Kinetic Isotope Effects in Asymmetric
Reactions, Chem.–Eur. J., 2010, 16, 10616–10628.
¨¨
(e) M. Pohjoispaa, R. Mera-Adasme, D. Sundholm,
¨ ¨ ¨
S. Heikkinen, T. Hase and K. J. Wahala, Capricious
3 (a) E. M. Isin, C. S. Elmore, G. N. Nilsson, R. A. Thompson
and L. Weidolf, Use of Radiolabeled Compounds in Drug
Metabolism and Pharmacokinetic Studies, Chem. Res.
Toxicol., 2012, 25, 532–542; (b) P. Uhl, G. Fricker,
U. Haberkorn and W. Mier, Radionuclides in drug
development, Drug Discovery Today, 2015, 20, 198–208; (c)
A. E. Mutlib, Application of Stable Isotope-Labeled
Compounds in Metabolism and in Metabolism-Mediated
Toxicity Studies, Chem. Res. Toxicol., 2008, 21, 1672–1689;
(d) S. Nag, L. Lehmann, G. Kettschau, M. Toth,
T. Heinrich, A. Thiele, A. Varrone and C. Halldin,
Development of a novel uorine-18 labeled deuterated
uororasagiline ([18F]uororasagiline-D2) radioligand for
PET studies of monoamino oxidase B (MAO-B), Bioorg.
Med. Chem., 2013, 21, 6634–6641; (e) K. Y. Wong, Y. Xu and
L. Xu, Review of computer simulations of isotope effects on
biochemical reactions: from the Bigeleisen equation to
Feynman's path integral, Biochim. Biophys. Acta, Proteins
Proteomics, 2015, 1854, 1782–1794.
Selectivity in Electrophilic Deuteration of Methylenedioxy
Substituted Aromatic Compounds, Org. Chem., 2014, 79,
10636–10640.
7 (a) W. J. Kerr, D. M. Lindsay, M. Reid, J. Atzrodt, V. Derdau,
P. Rojahn and R. Weck, Iridium-catalysed ortho-H/D and -H/
T exchange under basic conditions: C–H activation of
unprotected tetrazoles, Chem. Commun., 2016, 52, 6669–
6672; (b) W. J. Kerr, M. Reid and T. Tuttle, Iridium-
Catalyzed C–H Activation and Deuteration of Primary
Sulfonamides: An Experimental and Computational Study,
ACS Catal., 2015, 5, 402–410; (c) B. McAuley, M. J. Hickey,
L. P. Kingston, J. R. Jones, W. J. S. Lockley, A. N. Mather,
E. Spink, S. P. Thompson and D. J. J. Wilkinson,
Convenient and efficient deuteration of functionalized
aromatics with deuterium oxide: catalysis by cycloocta-1,5-
dienyliridium(I) 1,3-dionates, J. Label. Compd. Radiopharm.,
2003, 46, 1191–1204; (d) D. Hesk, P. R. Das and B. J. Evans,
Deuteration of acetanilides and other substituted
aromatics using [Ir(COD)(Cy3P)(Py)]PF6 as catalyst, J. Label.
Compd. Radiopharm., 1995, 36, 497–502; (e) J. R. Heys,
A. Y. L. Shu, S. G. Senderoff and N. M. J. Phillips,
Deuterium exchange labelling of substituted aromatics
4 (a) A. Katsnelson, Heavy drugs draw heavy interest from
pharma backers, Nat. Med., 2013, 19, 656; (b) Y. Zhang,
M. D. Tortorella, Y. Wang, J. Liu, Z. Tu, X. Liu, Y. Bai,
D. Wen, X. Lu, Y. Lu and J. Talley, Synthesis of Deuterated
Benzopyran Derivatives as Selective COX-2 Inhibitors with
using
[IrH2(Me2CO)2(PPh3)2]BF4,
J.
Label.
Compd.
Radiopharm., 1993, 33, 431–438; (f) M. J. Hickey, J. R. Jones,
25478 | RSC Adv., 2020, 10, 25475–25479
This journal is © The Royal Society of Chemistry 2020

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Paper
L. P. Kingston, W. J. S. Lockley, A. N. Mather, B. M. McAuley
RSC Advances
8 (a) M. Naodovic and H. Yamamoto, Asymmetric Silver-
Catalyzed Reactions, Chem. Rev., 2008, 108, 3132–3148; (b)
Y. Yamamoto, Silver-Catalyzed CspÀH and CspÀSi Bond
Transformations and Related Processes, Chem. Rev., 2008,
108, 3199–3222; (c) Q.-Z. Zheng and N. Jiao, Ag-catalyzed
C–H/C–C bond functionalization, Chem. Soc. Rev., 2016, 45,
4590–4627; (d) G. Fang and X. Bi, Silver-catalysed reactions
of alkynes: recent advances, Chem. Soc. Rev., 2015, 44,
8124–8173; (e) K. Sekine and T. Yamada, Silver-catalyzed
carboxylation, Chem. Soc. Rev., 2016, 45, 4524–4532; (f)
and D. J. Wilkinson, Iridium-catalysed labelling of anilines,
benzylamines and nitrogen heterocycles using deuterium
gas
and
cycloocta-1,5-dienyliridium(I)
1,1,1,5,5,5-
hexauoropentane-2,4-dionate, Tetrahedron Lett., 2003, 44,
¨
3959–3961; (g) D. Giunta, M. Holscher, C. W. Lehmann,
R. Mynott, C. Wirtz and W. Leitner, Room Temperature
Activation of Aromatic C-H Bonds by Non-Classical
Ruthenium Hydride Complexes Containing Carbene
Ligands, Adv. Synth. Catal., 2003, 345, 1139–1145; (h)
B. Groll, M. Schnurch and M. D. Mihovilovic, Selective
Ru(0)-Catalyzed Deuteration of Electron-Rich and Electron-
Poor Nitrogen-Containing Heterocycles, J. Org. Chem.,
2012, 77, 4432–4437; (i) C. P. Lenges, P. S. White and
M. Brookhart, Hydrogen/Deuterium Exchange Reactions
˜
M. P. Munoz, Silver and platinum-catalysed addition of
O–H and N–H bonds to allenes, Chem. Soc. Rev., 2014, 43,
3164–3183.
9 (a) An example on the catalytic H/D exchange of arenes in
acidic solvents, in which silver salt was examined, see:
D. Munz, M. Webster-Gardiner, R. Fu, T. Strassner,
W. A. Goddard III and T. B. Gunnoe, Proton or Metal? The
H/D Exchange of Arenes in Acidic Solvents, ACS Catal.,
2015, 5, 769–775; (b) An example on the catalytic H/D
exchange of hydrogen isotope exchange of ve-membered
heteroarenes by Ag2CO3/JohnPhos, see: E.-C. Li, G.-Q. Hu,
Y.-X. Zhu, H.-H. Zhang, K. Shen, X.-C. Hang, C. Zhang and
W. Huang, Ag2CO3-Catalyzed H/D Exchange of Five-
Membered Heteroarenes at Ambient Temperature, Org.
Lett., 2019, 21, 6745–6749.
and
Transfer
Hydrogenations
Catalyzed
by
[C5Me5Rh(olen)2] Complexes: Conversion of Alkoxysilanes
to Silyl Enolates, J. Am. Chem. Soc., 1999, 121, 4385–4396;
(j) M. Zhan, H. Jiang, X. Pang, T. Zhang, R. Xu, L. Zhao,
Y. Liu, Y. Gong and Y. Chen, A convenient method for the
Ru(0)-catalyzed regioselective deuteration of N-alkyl-
substituted anilines, Tetrahedron Lett., 2014, 55, 5070–5073;
(k) S. Ma, G. Villa, P. S. Thuy-Boun, A. Homs and J. Q. Yu,
Palladium-Catalyzed ortho-Selective CÀH Deuteration of
Arenes: Evidence for Superior Reactivity of Weakly
Coordinated Palladacycles, Angew. Chem., Int. Ed., 2014, 53, 10 Other Lewis acids were also tested under the standard
734–737; (l) A. M. Krause-Heuer, N. R. Yepuri,
T. A. Darwish and P. J. Holden, Mild Conditions for
Deuteration of Primary and Secondary Arylamines for the
Synthesis of Deuterated Optoelectronic Organic Molecules,
Molecules, 2014, 19, 18604–18617; (m) H. Sajiki, N. Ito,
condition, however, gave a lower deuterium incorporation,
especially in the para-position, Cu(OTf)2 (75% D ortho,
75% D para), Zn(OTf)2 (60% D ortho, 20% D para), ZnCl2
(24% D ortho, 14% D para), FeCl3 (75% D ortho, 40% D
para), and La(OTf)3 (<10% D ortho, <10% D para).
H. Esaki, T. Maesawa, T. Maegawa and K. Hirota, Aromatic 11 Recently, Werner and coworkers reported B(C6F5)3-catalyzed
ring favorable and efficient H–D exchange reaction
catalyzed by Pt/C, Tetrahedron Lett., 2005, 46, 6995–6998;
(n) V. Derdau, J. Atzrodt, J. Zimmermann, C. Kroll and
regioselective deuteration of electron-rich aromatic and
heteroaromatic compounds, see: W. Li, M.-M. Wang, Y. Hu
and T.
Werner, B(C6F5)3-Catalyzed Regioselective
¨
F. Bruckner, Hydrogen-Deuterium Exchange Reactions of
Deuteration of Electron-Rich Aromatic and Heteroaromatic
Aromatic Compounds and Heterocycles by NaBD4-Activated
Compounds, Org. Lett., 2017, 19, 5768–5771.
Rhodium, Platinum and Palladium Catalysts, Chem.–Eur. 12 (a) T. Eicher and S. Hauptmann, The Chemistry of
J., 2009, 15, 10397–10404; (o) D. Zhao, H. Luo, B. Chen,
W. Chen, G. Zhang and Y. Yu, Palladium-Catalyzed H/D
Exchange Reaction with 8-Aminoquinoline as the Directing
Group: Access to ortho-Selective Deuterated Aromatic Acids
and b-Selective Deuterated Aliphatic Acids, J. Org. Chem.,
2018, 83, 7860–7866; (p) Y. Sawama, K. Park, T. Yamada
and H. Sajiki, New Gateways to the Platinum Group Metal-
Catalyzed Direct Deuterium-Labeling Method Utilizing
Hydrogen as a Catalyst Activator, Chem. Pharm. Bull., 2018,
Heterocycles, Wiley-VCH, Weinheim, 2003; (b) M. Ishikura,
T. Abe, T. Choshi and S. Hibino, Simple indole alkaloids
and those with a non-rearranged monoterpenoid unit, Nat.
Prod. Rep., 2013, 30, 694–752; (c) V. Sharma, P. Kumar and
D. Pathak, Biological Importance of the Indole Nucleus in
Recent Years: A Comprehensive Review, J. Heterocycl.
Chem., 2010, 47, 491–502; (d) A. J. Kochanowska-Karamyan
and M. T. Hamann, Marine Indole Alkaloids: Potential
New Drug Leads for the Control of Depression and Anxiety,
Chem. Rev., 2010, 110, 4489–4497; (e) J. S. Carey, D. Laffan,
C. Thomson and M. T. Williams, Analysis of the reactions
used for the preparation of drug candidate molecules, Org.
Biomol. Chem., 2006, 4, 2337–2347.
¨
66, 21–28; (q) J. Kruger, B. Manmontri and G. Fels, Iridium-
Catalyzed H/D Exchange, Eur. J. Org. Chem., 2005, 1402–
1408; (r) T. Yamada, K. Park, N. Yasukawa, K. Morita,
Y. Monguchi, Y. Sawama and H. Sajiki, Mild and Direct
Multiple Deuterium-Labeling of Saturated Fatty Acids, Adv.
Synth. Catal., 2016, 358, 3277–3282.
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