Frustrated Lewis pairs: A real alternative to deuteride/tritide reductions

Article abstract of DOI:10.1002/jlcr.3774

Deuterium- and tritium-labeled compounds play a principal role in tracing of biologically active molecules in complicated biochemical systems. The state-of-the-art techniques using noble metal catalysts or strong reducing agents often suffers from low fun

Full text of DOI:10.1002/jlcr.3774

Marek Ales (Orcid ID: 0000-0001-9031-8263)
Frustrated Lewis pairs: A real alternative to deuteride / tritide reductions
Sabina Doubková a, Aleš Marek*
a Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences,
Flemingovo n. 542/2, Prague 6, 16610, Czech Republic
Deuterium- and tritium-labeled compounds play a principal role in tracing of
biologically active molecules in complicated biochemical systems. The state-of-the-art
techniques using noble metal catalysts or strong reducing agents often suffers from low
functional group tolerances, poor selectivity, tricky or multistep synthesis of reagents, and low
specific activity of the labeled product. Herein, we demonstrate a mild and non-metallic
technique of deuteration and tritiation of polarized double bonds, such as carbonyl compounds,
yielding labeled alcohols of high specific activities. This, one pot synthesis uses carrier-free
hydrogen gas in situ activated by a freshly prepared frustrated Lewis pair, generating reducing
reagents. This labeling strategy shows better selectivity and functional group tolerances
compared to current reductive methods. Reported is an example of the selective reduction of
the aldehyde moiety of 3-acetylbenzaldehyde. What makes this technology groundbreaking is
its mildness, selectivity and generation of limited amount of radioactive waste as almost no
3
byproducts were generated after use of [B(C6F5)3 H][3HTMP] reducing reagent.
Radiochemical purity of desired 3H-labeled product in a crude reaction mixture was determined
of over 94 %. This work provides, to the community of radiochemists, a practical protocol for
FLP-assisted deuterium / tritium labeling technology.
Keywords: frustrated Lewis pairs; hydrogen activation; deuterium labeled alcohol; tritium
labeled alcohol; non-metallic reagent, labeled building block
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1. Introduction
The widespread use of isotopically labeled compounds have become well-established
and an essential tool for the identification of drug candidates, drugs and drug metabolites in
complex analytical and biochemical schemes of pharmaceutical, biological and agrochemical
research.(1-9) The visualization of synthetized or isolated natural compounds is a fundamental
aspect for studies of their action, affinity, and toxicity. Tritium, the most versatile radionuclide,
readily labels small organic molecules of interest and is traditionally used in ligand-biological
receptor-structure-activity studies or in administration, distribution, metabolism and excretion
(ADME) studies.(2, 3, 10-13)
The current status of tritium chemistry methodologies comprises out of a portfolio of
few fundamental synthetic approaches that radiochemist can chose from: metal-catalyzed
exchange (HIE),(14-21) tritiodehalogenation,(22-28) multiple bond reduction(27, 29-31) with T2 and
tritides reduction (Figure 1).(22, 23, 32-34) The quite inert molecule of hydrogen always needs to
be activated before any intended application.(35-38) The HIE approach has recently reached a
significant improvement in terms of achieved specific activity (S.A.),(21, 39, 40) however, still
suffers from low site-specificity label incorporation and the requirement of vast numbers of
trials to develop workable reaction conditions, using up time and often the precious compound.
Tritiodehalogenation represents a golden standard for hydrogen-labeling of iodinated -,
brominated -, chlorinated - as well as some fluorinated synthetic precursors, providing
regiospecifically labeled material possessing high S.A. The tritiation of unsaturated carbon-
carbon bonds is limited by availability of the starting material and by the drawback of double
bond migration throughout the carbon skeleton, due to noble metal catalyst assisted
hydrogenation allowing isotopic scrambling, providing unspecific multi-labeling of desired
compound. Commercially available tritides are unstable and possess low specific activity. A
wide range of tritides can be freshly synthetized in house from carrier-free tritium with
treatment of nBuLi-TMEDA system, producing LiT which can be used for generation of
variety of boro- and aluminium-tritides, silanes or stannanes.(13, 22, 23, 32-34, 41) The synthesis of
such tritides can be experimentally tricky and is always very sensitive to the quality of the
reagents and the operator’s skill. In house generated tritides possessing S.A. are generated in
low yield and are subsequently used without isolation and purification in the complex mixture.
Since these tritides are used without purification, their use in the synthesis of labeled
compounds always lead to the production of many unwanted byproducts. In general, the low
tolerance of harsh reagent, such as tritides and noble metal catalysts of platinum group, to other
sensitive functionalities adjacent to labeled molecule is an issue every synthetic chemist need
to be aware of. The need for sophisticated tritium labeling methodologies for compounds with
biological importance are steadily becoming more important.
Polarized double bonds such as imines, enamines, alkylenolethers, and carbonyl
compounds represent a convenient synthetic precursors for isotopic hydrogen labeling of
amines, ethers and alcohols (Scheme 1). It is known that reduction of imines, enamines and
silylethers can be catalyzed by FLPs,(42-44) however aldehydes reacts with FLPs
stoichiometrically providing stabile alkoxyborate intermediates.(45-50) The saturation of
polarized double bonds by FLPs can be described as the nucleophilic addition of hydrides to
the polar double bond prior to proton transfer. The H2-activated linked P/B system
MesPCH2CH2B(C6F5)2 can deliver hydride to benzaldehyde, forming the corresponding
phosphonium borate zwitterion.(49) Subsequently, Repo and Rieger published analogous
chemistry using bulky nitrogen bases.(46) The computational investigations by the Privalov
group suggest that ketone hydrogenation using B(C6F5)3 (1) as a catalyst is energetically
viable.(51) Stephan,(52, 53) Ashley,(54) and the Soós(55) groups independently reported FLP-based
carbonyl reduction using of weak coordinating solvent as the base. Nucleophilic ethers (Et2O,
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1,4-dioxane) were shown to be capable of reversibly splitting H2 in combination with boron
based Lewis acids, however, under conditions not applicable for tritium experiments (the need
of pressurized vessel – 5-60 bar, 70-100 °C, multiple days of reaction). Recently, we have
reported a study focusing on the use of the FLP-2H2 system for the reduction of carbonyl
compounds under mild conditions applicable to tritium experiments (sub-atmospheric
pressure).(47)
We have also confirmed the ability of the FLP system [B(C6F5)3][2,2,6,6-
tetramethylpiperidine (TMP)] to heterolytically split molecules of tritium to generate the
reducing reagent [TMP3H][3HB(C6F5)3].(47) Apart from reports from our group, there is no
other comprehensive study in the use of FLPs for deuterium/tritium isotopic labeling of organic
compounds (deuterodefluorination of alkyl C–F groups using the FLP system is communicated
in our work in this special issue). Recently, Soós et al. reported a study in the size-exclusion
design of Lewis acid for FLP-mediated deuterium reduction of both quinolone and 2-methyl-
8-chloroquinolone, however, the reactions were carried out under rather harsh conditions (8
atm, 105 °C, 17h).(56)
2. Results and discussion
In our previous work we studied the reactivity of various phosphine-, carbene-, and
nitrogen-based FLPs, generating appropriate FLPs, after a reaction with boron-based Lewis
acid B(C6F5)3. The most reliable reaction condition for the reduction of any carbonyl
compounds proved to be the coordinative action of N-based Lewis base 2,2,6,6-
tetramethylpiperidine (TMP) with B(C6F5)3 used in 1 molar excess to the reduced substrate.
Here, we further investigate the FLP-2H2 (2) reducing system, using commercially available
material (such as ordinary carbonyl compounds) providing isotopically labeled alcohols. The
desired labeled product can be used as a suitable labeled building block for further synthetic
transformations.(57)
To optimize the reaction conditions for the reduction of aldehydes by the FLP-2H2
reagent (2), we investigated the conversion of 3-methoxybenzaldehyde (3) to the corresponding
alcohol. The methoxy group has different chemical shift in 1H NMR for substrate 3 and product
17, and was effectively used to determine the conversion of substrate 3. One equivalent of 2
afforded 74 % conversion of 3 and 56 % isolated yield of (3-methoxyphenyl)methan-[2H]-ol
(17) respectively. The full conversion of substrates was achievable in all cases when 1.5-2.0 eq
of 2 was used. To ensure full conversion of both the activated and deactivated aldehydes, and
straightforward isolation of the labeled products, we decided to use 2.0 eq of reagent 2 in further
experiments. It was determined that both dry toluene and dichloromethane (Table 1) could act
as suitable solvents for FLP-2H2 reduction. The reaction carried out in dry acetonitrile only
afforded poor conversion of 3 (Table 1, Entry 6). The use of dry THF indicated limited
applicability due to slow nucleophilic reaction of the solvent with 1, producing a jelly-like
adduct of (THF)->B(C6F5)3, after overnight storage in the refrigerator (Table 1, Entry 7).
Nitrogen-based Lewis bases proved to be unequivocally the best counterparts to B(C6F5)3,
affording high rate of substrate conversion and no byproduct formation at all. Both 2,2,6,6-
tetramethylpiperidine (TMP) and 1,2,2,6,6-pentamethylpiperidine (PMP) can be conveniently
used to afford similar outcomes in terms of achieved conversion, isolated yield, and isotope
enrichment (S.A.).(47) On the other hand, phosphin-based Lewis base such as (tBu)3P and
(Mes)3P provided low conversion or/and unidentified byproducts formation (Table 1, Entry 8,
9).A noteworthy and valuable aspect of this study is the fruitful use of very low pressure of
hydrogen (≈ 200 mbar) for FLP-assisted hydrogen labeling, providing generally the same
achievements as with the use of atmospheric pressure of hydrogen (1 bar) (Table 1). This
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approach represents a high-value benefit for its use in tritium chemistry in terms of limited
radioactive tritium gas consumption as well as suppression of radioactive waste generation.
The most useful aspect in the daily use of reagent 2 is the shelf-stability of a borane 1
stock solution, used for FLP in situ generation, when needed. Thus, long term storage was of
our interest. Borane 1 dissolved in dry toluene (0.1M, 10 mL) and was stored in the refrigerator
(4 °C). One portion (1 mL) was used every two weeks to carry out the reduction of aldehyde 3
under conditions displayed in Table 1, Entry 4. After two months of storage, no observable
1
decrease of both the conversion of 3 (>99 %; determined by H NMR and GC-MS
2
measurements) and the H-enrichment of product 17 (>95 %; determined by 1H NMR) were
witnessed. After another 6 months of storage, lower reconversion of 3 was witnessed, reaching
only 91 % of product formation but still with the retention of the level of deuterium labeling.
The Lewis acid 1 is very hydrophilic, forming in the presence of water a neutral adduct
of [H2O->B(C6F5)3].2H2O.(58) This aqua complex inhibits any further formation of the reactive
frustrated Lewis pair (2). To study the moisture tolerance of reagent 1, an addition of 0.5 eq of
H2O was added into a freshly prepared borane solution of 1, before the reagent was used for
FLP generation under conditions similar to Table 1, Entry 4. A diminished conversion of 3 to
92 % was witnessed. An addition of 2 eq of water completely inhibited the reaction course and
no conversion was observed.
To broaden the insights into the reactivity of 2 towards various carbonyl compounds,
heteroaromates (9-14) and isotopomers (4-6 and 11-13) were investigated (Table 1, Entry 12-
29). The full conversion of substrates was achieved in all cases providing the appropriate
labeled alcohol with 2H-enrichment of over 95 %. For the isolated yields of the products, see
Table 1. The same system used for aldehyde hydrogenations proved to be capable of
hydrogenating 9-anthracenecarboxylate 15 to the corresponding 9,10-dihydroanthracen-9-yl-
10-[2H])methan-[2H]-ol 29. This reactivity is in accordance with the data of FLP
hydrogenations of polycyclic aromatic hydrocarbons (PAHs) reported in literature.(59)
To investigate the affinity of 2 towards ketone functionalities, various substrates
bearing a ketone moiety (31-38) were used in the reduction with 2 under general conditions
(Table 2). The ketone moiety proved to be entirely unreactive under the general conditions,
unless the ketone moiety was strongly activated by an electron withdrawing group (Table 2,
Entry 1 and 2). The reduction of substrate 31, substituted with a nitro group, provided a
2
deuterium labeled secondary alcohol 39 in high yield with high H-enrichment (>95 %), and
showing full conversion of starting ketone 31 in a short reaction time of only 10 min.
2
The selectivity of [B(C6F5)3 H][2HTMP] (2) was unequivocally proven with reaction of
3-acetylbenzaldehyde (16), bearing both aldehyde and ketone group. Under general conditions
(Table 1, Entry 31) the aldehyde functionalization was completely reduced, providing high 2H-
enrychment (>95 %) of the corresponding labeled alcohol 30, leaving ketone moiety
unaffected.
The successful isolation of the series of [2H]-labeled alcohols was encouraging for the
application of this procedure analogically for the tritium experiment. Recently, we have
illustrated the ability of FLP to activate tritium molecules under subatmospherical pressure of
3
carrier-free tritium gas (505 mbar), producing [B(C6F5)3 H][3HTMP] used in an one pot
3
synthesis for reduction of p-(N-Boc)-benzaldehyde, affording the corresponding H-labeled
alcohol in high S.A. of 24.3 Ci/mmol. To optimize the conditions for routine use in
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radiochemistry, we investigated the further suppression of tritium consumption, and attempted
the experiment under very low pressure of carrier-free tritium gas (190 mbar, 2.5 Ci, 93 GBq).
The successful reduction of aldehyde 3 was the definitive proof of the generation of the
3
[B(C6F5)3 H][3HTMP] reducing reagent under the above mentioned conditions. To ensure the
full conversion of the precursor 3 in a short time (3 h), excess of FLP (2 eq) was employed.
The reduction of precursor 3 and the subsequent hydrolysis of the alkoxyborate intermediate
(not isolated) gave the desired [3H]-labeled benzyl alcohol 40 [full conversion of 3 according
to HPLC (215 nm), Figure 2, the middle chromatogram].
What makes this technology groundbreaking is besides its mildness and selectivity, also
generation of limited amount of radioactive waste as almost no byproducts were generated after
3
reduction made by [B(C6F5)3 H][3HTMP]; radiochemical purity of desired 3H-labeled product
in a crude reaction mixture was determined over 94 % [Figure 2, the bottom chromatogram,
and SI of ref(47)]. We determined the activity of the prepared 40 at 509 mCi with a specific
1
activity of 27.1 Ci/mmol (determined by H NMR) and radiochemical purity after HPLC
purification (>99 %). To our surprise, according to the 3H{1H} NMR spectrum of product 40,
two singlet peaks were observed. The expected singlet was observed at 4.65 ppm, however,
one other additional minor singlet peak was also observed in an up field shifted position at 4.62
3
ppm (see Supplementary Information). Similarly, according to the H-1H coupled NMR
spectrum, the product could be confirmed but with an additional doublet peak at 4.40 ppm and
a minor singlet peak at 4.37 ppm which belongs to tritium double-labeled methylene (see
Supplementary Information). The ratio between the integrated signal belonging to the mono-
labeled alcohol and the signal belonging to the double-labeled alcohol was found to be 5:1,
which accounts for the abundance of mono- and di-tritiated compound in sample of 10:1. It is
noteworthy that we had not seen the introduction of two tritium atoms on reduced p-(N-Boc)-
benzaldehyde when using the same reagent recently.(47) Moreover, we have not observed, in
any case, the incorporation of two deuterium atoms on the methylene group of labeled
1
benzaldehydes based on H NMR spectroscopy. Mass spectrometry provided inconclusive
data, possibly because of the very low amount of double labeled product (below 10 %), which
overlaps with the combined 13C+15N isotopic peak of the utterly dominated monolabeled
product. Additionally, because of the chemical nature and small mass of labeled alcohols, the
electron-ionization technique (EI) had to be used for their ionization. Due to nature of EI,
isotopic scrambling on the analyzed molecule could partly occur, providing misleading data in
terms of isotopic enrichment. For this reason, mass EI technique is not ideal (accurate enough)
for the determination of isotopic enrichment. One exception was the ionization of pyridin-3-
yl-methan-[2H]-ol (26) with the mild ESI technique, providing convincing data of no double
labeling. Formation of double-labeled alcohol is most likely an issue of the particular substrate
3, substituted with an electron withdrawing group in a meta-position. The mechanistic
implications of the additional-tritium introduction have not been investigated. However, we
hypothesize the mechanism might be based on the H/T exchange on methylene group of 3H-
labeled alcohol, when polarized as alkoxyborate intermediate.
To investigate the course of the reaction, a reaction was set up without the introduction
of any Lewis base, as suggested Nyhlén and Privalov, for the reduction of carbonyl moieties in
their computational study. In contradiction with this theory we have not achieved any
conversion of benzaldehyde under the conditions we have used, even after 14 days of reaction
under subatmospherical pressure of hydrogen (Scheme 3). The coordinative role of both Lewis
acid and Lewis base was demonstrated to be essential to activate hydrogen molecule under
such a low pressure of hydrogen. Repo and coworkers reported 29 % conversion of similar
reaction when harsh conditions were employed (1H2, 2 atm, 110 °C, 48h, toluene-d8).(54, 60)
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3. Conclusion
The need of rapid radiotracer synthesis in early stage of drug discovery has driven the research
for better, selective, regio-selective, reproducible, robust, and predictable tritium incorporation
techniques using ultra-mild reaction conditions providing high specific activity. A
stoichiometric carbonyl reductions using the pre-hydrogenated intramolecular FLP system
provided isotopically labeled alcohols in a high isolated yield using commercially available,
and non-toxic reagents. This system shows high selectivity of the aldehyde functionality over
ketone moiety, providing labeled alcohols as a final product or labeled building block.
4. Experimental section
4.1. General
The tritiation and deuterium reaction was performed on a custom-designed deuterium, and
tritium, respectively, manifold system manufactured by RC Tritec AG, Switzerland. Activities
were measured on a Perkin-Elmer TriCarb 2900TR liquid scintillation counter (LSC) in a
Zinsser Quicksafe A cocktail. The HPLC was performed on a system consisting of a WATERS
Delta 600 pump and controller, a WATERS 2487 UV detector and a RAMONA radio
chromatographic detector from Raytest (Germany) with interchangeable fluid cells. For the
preparative runs, the cell with a single small crystal of a solid scintillator was used; for
analytical runs, the column effluent was mixed with a Zinsser Quickszint Flow 302 cocktail in
13
the ratio of 1:3. The 1H-, C-NMR spectra were recorded at 300 and 400 MHz; 75 and 100
MHz with a Bruker Avance II 300 MHz, Avance III™ HD 400 MHz instrument, respectively,
at 25 °C (the solvents are indicated in parentheses). Chemical shifts are reported in ppm relative
to TMS. The mass spectra were obtained by the Bruker Daltonics Esquire 4000 system with
direct input (ESI, acetonitrile-H2O stream, a mass range of 50–1200 Da, Esquire Control
Software). The HR-mass spectra were obtained in the ESI mode either on a Waters-Micromass
Q-TOF Micro Mass Spectrometer or on a Thermo Fisher Scientific LTQ Orbitrap XLc. The
mass spectra of the labeled compounds were measured on a Thermo Finnigan LCQ Classic
spectrometer using electrospray ionization (ESI). Column chromatography was carried out
with SiO2 60 (a particle size of 0.040–0.063 mm, 230–400 mesh; Merck) and commercially
available solvents. Thin-layer chromatography (TLC) was conducted on aluminum sheets
coated with SiO2 60 F254 obtained from Merck, with visualization by a UV lamp (254 or 360
nm). Borane B(C6F5)3 was purchased from TCI Europe N.V.. 2,2,6,6-Tetramethylpiperidine
was purchased from Fluorochem Ltd.. To enhanced long-term reactivity of borane, the stock
solution of B(C6F5)3 (0.1 M), was prepared under an inert atmosphere of nitrogen, using dry
and distilled solvents (toluene or CH2Cl2), and allowed to be store in fridge (4 °C) to sustain
its quality for months.
4.2. General procedure for sub-atmospherical FLP-assisted deuteration
A round-bottomed reaction flask (3 mL) with a side arm, equipped with a magnetic stir bar,
was mounted onto this system and was dried by application of vacuum-inert sequence and filled
2
with H2 gas (200-1000 mbar). A 0.1M solution (dry toluene or CH2Cl2) of B(C6F5)3 (2 mL,
0.2 mmol) was added to the reaction flask via the septum in the sidearm. To this solution,
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2,2,6,6-tetramethylpiperidine (0.2 mmol) was added dropwise and the reaction mixture was
vigorously stirred for 1 h at room temperature. To a slightly yellowish solution of
[TMP2H][2HB(C6F5)3] a 1 M solution of appropriate carbonyl compound (0.1-0.2 mmol) was
added via the sidearm. The reaction was monitored by TLC (SiO2; Hexane/EtOAc/MeOH
7:3:0-1). The reaction was left to proceed until full conversion of starting material was achieved
(Table 1). The alkoxyborate intermediate was hydrolyzed by addition of 1 mL of 1N HCl for
20 min, or alternatively (applicable for basic-nature substrates), by 1 mL of distilled water for
1 hour. The reaction mixture was neutralized by the addition of 1M Na2CO3. Separated organic
phase was dried by Mg2SO4, and solvents were evaporated. The crude product was purified by
column chromatography (SiO2; Hexane/EtOAc/MeOH 7:3:0-1). For isolated yields see Table
1. Isotopic enrichment on the methylene position was determined by 1H NMR over 95 % in all
cases, as a decrease of corresponding signal in 1H spectrum (see Supplementary Information).
4.2.1. 3-Methoxyphenyl-[2H]-methanol (17). The title compound was prepared from 3
following general procedure. A colorless oil. (10.5 mg, 77 %). The product was purified by
column chromatography (SiO2, hexane/EtOAc, 7:3) Rf = 0.31. 1H NMR (400 MHz, CDCl3) δ:
1.65 (1H, bs, OH), 3.82 (3H, s, CH3), 4.66 (1H, s, CHD), 6.81–6.86 (1H, m, Ar), 6.91–6.97
(2H, m, Ar), 7.27–7.31 (1H, m, Ar). 13C NMR (100 MHz, CDCl3) δ: 55.4, 65.1 (t1:1:1, CD, JCD
= 22.0 Hz), 112.4, 113.4, 119.2, 129.7, 142.6, 160.0. HRMS (TOF MS EI+): Calculated for
C8H9DO2 139.0744. Found 139.0743.
4.2.2. 2-Fluorophenyl-[2H]-methanol (18). The title compound was prepared from 4 following
general procedure. A colorless oil. (11.8 mg, 93 %). The product was purified by column
1
chromatography (SiO2, hexane/EtOAc, 7:3) Rf = 0.37. H NMR (400 MHz, CDCl3) δ: 1.78
(1H, bs, OH), 4.75 (1H, s, CHD), 7.01–7.09 (1H, m, Ar), 7.15 (1H, J = 7.5, 1.2 Hz, Ar), 7.25–
7.32 (1H, m, Ar), 7.42 (1H, tdd, JHH = 7.5 and 0.6 Hz, 4JHF = 1.9 Hz, Ar). 13C NMR (100 MHz,
4
CDCl3) δ: 59.3 (td, CD, JCD = 21.9 Hz, JCF = 4.6 Hz), 115.4 (d, 2JCF = 21.19 Hz), 124.4 (d,
2
4JCF = 3.63 Hz), 127.8 (d, JCF = 15.25 Hz), 129.4 (d, 4JCF = 4.50 Hz), 129.5 (d, 3JCF = 7.62
Hz), 160.8 (d, 1JCF = 247.38 Hz). HRMS (TOF MS EI+): Calculated for C7H6DFO 127.0544.
Found 127.0546.
4.2.3. 3-Fluorophenyl-[2H]-methanol (19). The title compound was prepared from 5 following
general procedure. A colorless oil. (8.5 mg, 67 %). The product was purified by column
1
chromatography (SiO2, hexane/EtOAc, 7:3) Rf = 0.24. H NMR (400 MHz, CDCl3) δ: 1.71
(1H, bs, OH), 4.69 (1H, s, CHD), 6.98 (1H, tdd, 3JHF = 8.3 Hz, JHH = 2.7 and 0.9 Hz, Ar), 7.06–
7.15 (2H, m, Ar), 7.32 (1H, td, JHH = 7.8 Hz, 4JHF = 5.8 Hz, Ar). 13C NMR (100 MHz, CDCl3)
5
2
2
δ: 64.4 (td, CD, JCD = 22.1 Hz, JCF = 1.8 Hz), 113.8 (d, JCF = 21.22 Hz), 114.5 (d, JCF
=
21.22 Hz), 122.3 (d, 4JCF = 2.92 Hz), 130.2 (d, 3JCF = 8.47 Hz), 143.5 (d, 3JCF = 7.31 Hz), 163.1
(d, JCF = 246.89 Hz). HRMS (TOF MS EI+) Calculated for C7H6DFO 127.0544. Found
1
127.0546.
4.2.4. 4-Fluorophenyl-[2H]-methanol (20). The title compound was prepared from 6 following
general procedure. A colorless oil. (10.0 mg, 79 %). The product was purified by column
1
chromatography (SiO2, hexane/EtOAc, 7:3) Rf = 0.25. H NMR (400 MHz, CDCl3) δ: 1.67
(1H, bs, OH), 4.64 (1H, s, CHD), 7.01–7.09 (2H, m, ArH), 7.29–7.38 (2H, m, Ar). 13C NMR
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(100 MHz, CDCl3) δ: 64.5 (t, CD, JCD = 21.98 Hz), 115.5 (d, 2JCF = 21.36 Hz), 128.9 (d, 3JCF
4
1
= 7.80 Hz), 136.6 (d, JCF = 3.02 Hz), 162.5 (d, JCF = 240.31 Hz). HRMS (TOF MS EI+):
Calculated for C7H6DFO 127.0544. Found 127.0547.
4.2.5. 4-Chlorophenyl-[2H]-methanol (21). The title compound was prepared from 7 following
general procedure. A yellowish oil. (11.8 mg, 83 %). The product was purified by column
1
chromatography (SiO2, hexane/EtOAc, 7:3) Rf = 0.38. H NMR (400 MHz, CDCl3) δ: 2.00
13
(1H, bs, OH), 4.59 (1H, s, CHD), 7.20–7.24 (2×1H, m, Ar), 7.31–7.35 (2×1H, m, Ar). C
NMR (100 MHz, CDCl3) δ: 64.8 (t1:1:1, CD), 128.6, 129.0, 134.2, 137.7. HRMS (TOF MS
EI+): Calculated for C7H6DClO 143.0248. Found 143.0247.
4.2.6. Phenyl-[2H]-methanol (22). The title compound was prepared from 8 following general
procedure. A yellowish oil. (10.1 mg, 93 %). The product was purified by column
chromatography (SiO2, hexane/EtOAc, 7:3) Rf = 0.31. 1H NMR (400 MHz, CDCl3) δ: 1.65
(1H, bs, OH), 4.68 (1H, s, CHD), 7.27–7.39 (5×1H, m, ArH). 13C NMR (100 MHz, CDCl3) δ:
65.2 (t1:1:1, CD), 127.1, 127.8, 128.7, 140.9. HRMS (TOF MS EI+): Calculated for C7H7DO
109.0638. Found 109.0636.
4.2.7. 2-Thiophene-[2H]-methanol (23). The title compound was prepared from 9 following
the general procedure. A yellowish oil. (7.9 mg, 69 %). Purified by column chromatography
(SiO2, hexane/EtOAc, 7:3) Rf = 0.33. 1H NMR (400 MHz, CDCl3) δ: 1.74 (1H, bs, OH), 4.83
(1H, s, CHD), 6.99 (1H, dd, J = 5.0 and 3.5 Hz, Ar), 7.03 (1H, ddd, J = 3.5 and 1.3 and 0.8 Hz,
Ar), 7.29 (1H, dd, J = 5.0 and 1.3 Hz, Ar). 13C NMR (100 MHz, CDCl3) δ: 59.9 (t1:1:1, CD),
125.6, 125.8, 127.0, 144.0. HRMS (TOF MS EI+): Calculated for C5H5DOS 115.0202. Found
115.0200.
4.2.8. (1-Methyl-1H-imidazol-5-yl)-[2H]-methanol (24). The title compound was prepared
from 10 following general procedure. An amorphous solid. (7.7 mg, 69 %). The product was
purified by column chromatography (SiO2, hexane/EtOAc/MeOH, 7:3:0.5) Rf = 0.28. 1H NMR
(400 MHz, CDCl3) δ: 1.82 (1H, bs, OH), 3.88 (3H, s, CH3), 4.66 (1H, s, CHD), 6.97 (1H, s,
13
Ar), 7.79 (1H, s, Ar). C NMR (100 MHz, CDCl3) δ: 33.8, 53.7 (t1:1:1, CD, JCD = 22.0 Hz),
125.1, 132.0, 138.2. HRMS (TOF MS EI+): Calculated for C5H7DN2O 113.0699. Found
113.0703.
4.2.9. 2-Pyridine-[2H]-methanol (25). The title compound was prepared from 11 following
general procedure. A yellow oil. (6.7 mg, 63 %). The product was purified by column
chromatography (SiO2, hexane/EtOAc 7:3) Rf = 0.22. 1H NMR (400 MHz, CDCl3) δ: 4.68 (1H,
s, CHD), 4.84 (1H, bs, OH), 7.78 (1H, d, JHH = 8.2 Hz, Ar), 7.91 (1H, t, JHH = 6.8 Hz, Ar), 8.45
(1H, t, JHH = 8.0 Hz, Ar), 8.68 (1H, d, JHH = 6.0 Hz, Ar). 13C NMR (100 MHz, CDCl3) δ: 61.0
(t, CD, JCD = 22.71 Hz), 125.3, 139.5, 140.6, 144.8, 145.7. HRMS (TOF MS EI+): Calculated
for C6H6DNO 110.0590. Found 110.0682.
4.2.10. 3-Pyridine-[2H]-methanol (26). The title compound was prepared from 12 following
general procedure. A colorless oil. (9.6 mg, 87 %). The product was purified by column
1
chromatography (SiO2, hexane/EtOAc/MeOH 7:3:1) Rf = 0.46. H NMR (400 MHz, CDCl3)
δ: 2.23 (1H, bs, OH), 4.85 (1H, s, CHD), 7.67 (1H, dd, JHH = 8.14 and 6.04 Hz), 8.17 (1H, d,
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13
JHH = 6.13 Hz, Ar), 8.52 (1H, m, Ar), 8.59 (1H, s, Ar). C NMR (100 MHz, CDCl3) δ: 61.0
(t1:1:1, CD, JCD = 22.71 Hz), 125.3, 139.5, 140.6, 144.8, 145.7. HRMS (ESI+): Calculated for
C6H7DNO [M+H]+ 111.0669. Found 111.0663.
4.2.11. 4-Pyridine-[2H]-methanol (27). The title compound was prepared from 13 following
general procedure. An morphous solid. (8.9 mg, 81 %). The product was purified by column
chromatography (SiO2, hexane/EtOAc 7:3) Rf = 0.27. 1H NMR (400 MHz, CDCl3) δ: 2.17 (1H,
bs, OH), 4.94 (1H, s, CHD), 7.67 (2H, d, JHH = 6.54, Ar), 8.53 (2H, d, JHH = 6.13, Ar).
13C NMR (100 MHz, CDCl3) δ: 62.3 (t1:1:1, CD, JCD = 21.9 Hz), 122.4, 146.5, 158.1. HRMS
(TOF MS EI+) Calculated for C6H6DNO 110.0590. Found 110.0592.
4.2.12. Isoquinoline-[2H]-methanol (28). The title compound was prepared from 14 following
general procedure. An amorphous solid. (13.1 mg, 82 %). The product was purified by column
1
chromatography (SiO2, hexane/EtOAc/MeOH 7:3:1) Rf = 0.32. H NMR (400 MHz, CDCl3)
δ: 4.85 (1H, bs, OH), 4.91 (1H, m, CHD), 7.29 (1H, d, JHH = 8.5 Hz, Ar), 7.55 (1H, ddd, JHH
=
8.1 and 6.9 and 1.2 Hz, Ar), 7.68–7.77 (1H, m, Ar), 7.83 (1H, dd, JHH = 8.1 and 1.5 Hz, Ar),
13
8.05–8.10 (1H, m, Ar), 8.15 (1H, d, JHH = 8.5 Hz, Ar). C NMR (100 MHz, CDCl3) δ: 63.9
(t1:1:1, CD, JCD = 21.96), 118.5, 126.5, 127.8, 128.8, 129.2, 130.0, 137.0, 146.8, 159.0. HRMS
(TOF MS EI+): Calculated for C10H8DNO: Calculated 160.0747. Found 160.0754.
4.2.13. (10-[2H]-9,10-Dihydroanthracen-9-yl-10-d)-[2H]-methanol (29). The title compound
was prepared from 15 following general procedure. An orange oil. (16.7 mg, 78 %). The
1
product was purified by column chromatography (SiO2, hexane/EtOAc 7:3) Rf = 0.40. H
NMR (300 MHz, CDCl3) δ: 3.64 (1H, dt, JHH = 7.5 and 1.4 Hz, CHD-OH), 3.89 (1H, bs, Ar-
H-9), 4.10 (1H, d, JHH = 6.8 Hz, Ar-H-10), 7.21–7.28 (4H, m, Ar), 7.28–7.38 (4H, m, Ar). 13C
NMR (75 MHz, CDCl3) δ: 34.9 (td, CDH-10, JCD = 19.85 and 2.12 Hz), 50.1 (C-9), 66.2 (td,
CDH-OH, JCD = 22.20 and 4.60 Hz), 126.5, 127.0, 128.2, 128.6, 136.2, 136.6. HRMS (TOF
MS EI+): Calculated for C15H12D2ONa 235.1068 Found 235.1060.
4.2.14. [(3-hydroxy-[2H]methyl)phenyl]ethanone (30). The title compound was prepared from
16 following general procedure. A yellowih oil. (9.9 mg, 66 %). The product was purified by
column chromatography (SiO2, hexane/EtOAc/MeOH 7:3:1) Rf = 0.37. 1H NMR (300 MHz,
CDCl3) δ: 2.54–2.68 (3H, m, CH3), 4.75 (1H, m, CHD), 7.47 (1H, t, JHH = 7.6 Hz, Ar), 7.55–
13
7.62 (1H, m, Ar), 7.88 (1H, dt, JHH = 7.7 and 1.5 Hz, Ar), 7.93–7.98 (1H, m, Ar). C NMR
(75 MHz, CDCl3) δ: 26.8, 64.6 (t1:1:1, CD, JCD = 21.59 Hz), 126.8, 127.7, 123.0, 131.7, 137.5,
141.4, 198.2. HRMS (TOF MS EI+): Calculated for C9H9DO2 151.0744. Found 151.0745.
4.3. General procedure for very low pressure FLP-assisted tritiation
A 1 mL round bottomed side-arm flask equipped with a magnetic stir bar was mounted onto
the manifold system, evacuated to below 5×10-3 mbar and dried by vacuum-inert sequence.
Carrier-free tritium gas (190 mbar, 2.5 Ci, 93 GBq) stored on the uranium bed was released by
heating to 500 °C into reaction flask. A 0.1M solution of B(C6F5)3 (1 mL, 100 µmol) in toluene,
and 2,2,6,6-tetramethylpiperidine (18 µL, 100 µmol) was drop wise added and vigorously
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stirred for 1 h at room temperature. A solution of 3-methoxybenzaldehyde (3) (50 µL, 1M) in
toluene was added and the reaction was left react to for 2 h. The reaction solution was frozen
by liquid nitrogen, residual T2 was back-trapped on the uranium bed and the labeled
alkoxyborate was hydrolyzed by addition of 1N HCl (500 µL) for 1 hour. The crude product
was transported to a 50 mL flask and neutralized by addition 1 mL solution of 1M Na2CO3. To
get rid of the labile activity, reaction mixture was lyophilized three times by H2O-AcCN 50:50
(4 mL). The stock solution of the crude product was made by solution in 10 mL of H2O-MeOH
40:60. The HPLC analysis showed full conversion of 3 (215 nm) and the crude radioactive
yield was established at 549 mCi. Then 1/10 of the crude mixture was used for qualitative
analysis. The specific activity of pure 3-methoxyphenyl-[3H]-methanol (40) was established at
27.1 Ci/mmol following 1H NMR (see Supplementary Information).
4.3.1. 3-Methoxyphenyl-[3H]-methanol (40). The title compound was prepared from 3
following the general procedure. A colorless oil was obtained. Radioactive yield of pure 40
was determined at 509 mCi. Purified by HPLC, settings: Identification was done by UV
detection at 245 nm and LS-radiodetector (Figure 2, middle and bottom). Column: Luna
Phenylhexyl 5µ (250 mm × 10 mm). Flow: 4.7 ml/min. Eluents: (A) 99.9 % purified water, 0.1
% TFA; (B) 99.9 % acetonitrile, 0.1 % TFA. Gradient: 0–30 min, 5–40 % B, 30–35 min 40 %
B, 35–45 min 60 % B. The peak of 40 was detected at 15.4 min, starting material 3 (peak at
33.2 min, Figure 2, top) was not detected in a crude mixture at all (Figure 2, middle). The
labeled product 40 matches with a 1H standard on an analytical HPLC (using similar gradient
as for preparative HPLC). 1H NMR (300 MHz, CDCl3) δ: 3.82 (3H, s, CH3), 4.65 (1H, d, JHT
= 14.9 Hz, CHT), 4.77 (1H, bs, OH), 6.83–6.86 (1H, m, Ar), 6.92–6.95 (2H, m, Ar), 7.25–7.31
3
3
(1H, m, Ar). H{1H} NMR (320 MHz, CDCl3): δ 4.65 (s, 1T, CTH). H NMR (320 MHz,
DMSO-d6): δ 4.39 (d, 1T, J = 15.9 Hz, CTH). 3H{1H} NMR (320 MHz, CDCl3): δ 4.65 (s, 1T,
CTH).
Acknowledgments
The authors thank the Czech Academy of Sciences for the financial support of this project
within the program RVO: 61388963. The authors declare they have no conflict of interest.
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References
1.
Atzrodt J, Derdau V, Kerr WJ, Reid M. Deuterium- and Tritium-Labelled Compounds:
Applications in the Life Sciences. Angew Chem-Int Edit. 2018;57(7):1758-84.
2.
Graham Lappin ST. Radiotracers in Drug Development. Boca Raton CRC Press 2006.
320 p.
3.
Lockley WJS, McEwen A, Cooke R. Tritium: a coming of age for drug discovery and
development ADME studies. J Label Compd Radiopharm. 2012;55(7):235-57.
4. Atzrodt J, Derdau V. Pd- and Pt-catalyzed H/D exchange methods and their application
for internal MS standard preparation from a Sanofi-Aventis perspective. J Label Compd
Radiopharm. 2010;53(11-12):674-85.
5.
Fan TWM, Lorkiewicz PK, Sellers K, Moseley HNB, Higashi RM, Lane AN. Stable
isotope-resolved metabolomics and applications for drug development. Pharmacol Ther.
2012;133(3):366-91.
6.
of Medicinal Chemistry. 2014;57(9):3595-611.
7. Mullard A. Deuterated drugs draw heavier backing. Nat Rev Drug Discov.
2016;15(4):219-+.
Gant TG. Using Deuterium in Drug Discovery: Leaving the Label in the Drug. Journal
8.
Mutlib AE. Application of stable isotope-labeled compounds in metabolism and in
metabolism-mediated toxicity studies. Chem Res Toxicol. 2008;21(9):1672-89.
9.
biological activities. Phytochemistry Reviews. 2015;14(6):1053-72.
10. Loh YY, Nagao K, Hoover AJ, Hesk D, Rivera NR, Colletti SL, et al. Photoredox-
Oklestkova J, Rarova L, Kvasnica M, Strnad M. Brassinosteroids: synthesis and
catalyzed deuteration and tritiation of pharmaceutical compounds. Science.
2017;358(6367):1182-+.
11.
Marathe PH, Shyu WC, Humphreys WG. The use of radiolabeled compounds for
ADME studies in discovery and exploratory development. Current Pharmaceutical Design.
2004;10(24):2991-3008.
12.
Penner N, Klunk LJ, Prakash C. Human Radiolabeled Mass Balance Studies:
Objectives, Utilities and Limitations. Biopharmaceutics & Drug Disposition. 2009;30(4):185-
203.
13.
Klein AB, Bay T, Villumsen IS, Falk-Petersen CB, Marek A, Frolund B, et al.
Autoradiographic imaging and quantification of the high-affinity GHB binding sites in rodent
brain using H-3-HOCPCA. Neurochemistry International. 2016;100:138-45.
14.
Chem Soc Rev. 1997;26(5):401-6.
15. Atzrodt J, Derdau V, Fey T, Zimmermann J. The renaissance of H/D exchange. Angew
Chem-Int Edit. 2007;46(41):7744-65.
16. Derdau V, Atzrodt J, Holla W. H/D-exchange reactions with hydride-activated
catalysts. J Label Compd Radiopharm. 2007;50(5-6):295-9.
17. Lockley WJS. 30 Years with ortho-directed hydrogen isotope exchange labelling. J
Label Compd Radiopharm. 2007;50(9-10):779-88.
18. Lockley WJS, Heys JR. Metal-catalysed hydrogen isotope exchange labelling: a brief
overview. J Label Compd Radiopharm. 2010;53(11-12):635-44.
19. Salter R. The development and use of iridium(I) phosphine systems for ortho-directed
hydrogen-isotope exchange. J Label Compd Radiopharm. 2010;53(11-12):645-57.
20. Ma S, Villa G, Thuy-Boun PS, Homs A, Yu JQ. Palladium-Catalyzed ortho-Selective
Junk T, Catallo WJ. Hydrogen isotope exchange reactions involving C-H (D,T) bonds.
C-H Deuteration of Arenes: Evidence for Superior Reactivity of Weakly Coordinated
Palladacycles. Angew Chem-Int Edit. 2014;53(3):734-7.
This article is protected by copyright. All rights reserved.

21.
pharmaceuticals. Nature. 2016;529(7585):195-9.
22. Saljoughian M, Williams PG. Recent Developments in Tritium Incorporation for
Radiotracer Studies. Current Pharmaceutical Design. 2000;6(10):1029−56.
23. Saljoughian M. Synthetic tritium labeling: Reagents and methodologies. Synthesis-
Stuttgart. 2002(13):1781-801.
24. Elbert T, Patil MR, Marek A. Enantiospecific tritium labeling of 28-homocastasterone.
J Label Compd Radiopharm. 2017;60(3):176-82.
25. Marek A, Patil MR, Klepetarova B, Kohout L, Elbert T. A stereospecific pathway for
Yu RP, Hesk D, Rivera N, Pelczer I, Chirik PJ. Iron-catalysed tritiation of
the introduction of deuterium on the brassinosteroid skeleton by reductive dechlorination of
chlorocarbonates. Tetrahedron Letters. 2012;53(16):2048-50.
26.
isotopes of hydrogen. Tetrahedron. 2015;71(29):4874-82.
27. Alcaide A, Marconi L, Marek A, Haym I, Nielsen B, Mollerud S, et al. Synthesis and
Marek A, Klepetarova B, Elbert T. A facile method for steroid labeling by heavy
pharmacological characterization of the selective GluK1 radioligand (S)-2-amino-3-(6 3H -
2,4-dioxo-3,4-dihydrothieno.3,2-d pyrimidin1.2H)- yl) propanoic acid ( H-3 -NF608).
Medchemcomm. 2016;7(11):2136-44.
28.
Kuhne S, Nohr AC, Marek A, Elbert T, Klein AB, Brauner-Osborne H, et al.
Radiosynthesis and characterisation of a potent and selective GPR139 agonist radioligand.
RSC Adv. 2016;6(2):947-52.
29.
Marek A, Patil MR, Elbert T. The labeling of brassinosteroids by tritium. RSC Adv.
2015;5(80):65214-20.
30.
Tran PT, Larsen CO, Rondbjerg T, De Foresta M, Kunze MBA, Marek A, et al.
Diversity-Oriented Peptide Stapling: A Third Generation Copper-Catalysed Azide-Alkyne
Cycloaddition Stapling and Functionalisation Strategy. Chem-Eur J. 2017;23(14):3490-5.
31.
Di Giglio MG, Muttenthaler M, Harpsoe K, Liutkeviciute Z, Keov P, Eder T, et al.
Development of a human vasopressin V-1a-receptor antagonist from an evolutionary-related
insect neuropeptide. Scientific Reports. 2017;7:15.
32.
carbon-14: John Wiley & Sons; 2009.
33. Ulrich Pleiss RV. Synthesis and Applications of Isotopically Labelled Compounds:
Wiley; 2001. 728 p.
Voges R, Heys JR, Moenius T. Preparation of compounds labeled with tritium and
34.
Marek A, Pedersen MHF, Vogensen SB, Clausen RP, Frolund B, Elbert T. The labeling
of unsaturated gamma-hydroxybutyric acid by heavy isotopes of hydrogen: iridium complex-
mediated H/D exchange by C-H bond activation vs reduction by boro-deuterides/tritides. J
Label Compd Radiopharm. 2016;59(12):476-83.
35.
Kubas GJ. Chemistry - Breaking the H-2 marriage and reuniting the couple. Science.
2006;314(5802):1096-7.
36.
Revunova K, Nikonov GI. Main group catalysed reduction of unsaturated bonds. Dalton
Trans. 2015;44(3):840-66.
37.
38.
Power PP. Main-group elements as transition metals. Nature. 2010;463(7278):171-7.
Paradies J. Metal-Free Hydrogenation of Unsaturated Hydrocarbons Employing
Molecular Hydrogen. Angew Chem-Int Edit. 2014;53(14):3552-7.
39. Atzrodt J, Derdau V, Kerr WJ, Reid M. C-H Functionalisation for Hydrogen Isotope
Exchange. Angew Chem-Int Edit. 2018;57(12):3022-47.
40. Kerr WJ, Mudd RJ, Reid M, Atzrodt J, Derdau V. Iridium-Catalyzed Csp(3)-H
Activation for Mild and Selective Hydrogen Isotope Exchange. ACS Catal. 2018;8(11):10895-
900.
This article is protected by copyright. All rights reserved.

41.
Vogensen SB, Marek A, Bay T, Wellendorph P, Kehler J, Bundgaard C, et al. New
Synthesis and Tritium Labeling of a Selective Ligand for Studying High-Affinity gamma-
Hydroxybutyrate (GHB) Binding Sites. Journal of Medicinal Chemistry. 2013;56(20):8201-5.
42.
Stephan DW, Erker G. Frustrated Lewis Pairs: Metal-free Hydrogen Activation and
More. Angew Chem-Int Edit. 2010;49(1):46-76.
43.
44.
Stephan DW. Frustrated Lewis Pairs. J Am Chem Soc. 2015;137(32):10018-32.
Stephan DW. The broadening reach of frustrated Lewis pair chemistry. Science.
2016;354(6317):8.
45.
Chase PA, Welch GC, Jurca T, Stephan DW. Metal-free catalytic hydrogenation.
Angew Chem Int Ed Engl. 2007;46(42):8050-3.
46.
activation by amines and B(C6F5)3. Angew Chem Int Ed Engl. 2008;47(32):6001-3.
47. Marek A, Pedersen MHF. Frustrated Lewis pairs-assisted reduction of carbonyl
compounds. Tetrahedron. 2015;71(6):917-21.
48. Ekkert O, Kehr G, Daniliuc CG, Fröhlich R, Wibbeling B, Petersen JL, et al. Reaction
Sumerin V, Schulz F, Nieger M, Leskela M, Repo T, Rieger B. Facile heterolytic H2
of Unsaturated Vicinal Phosphane/Borane Frustrated Lewis Pairs with Benzaldehyde.
Zeitschrift für anorganische und allgemeine Chemie. 2013;639(14):2455-62.
49.
Spies P, Erker G, Kehr G, Bergander K, Frohlich R, Grimme S, et al. Rapid
intramolecular heterolytic dihydrogen activation by a four-membered heterocyclic phosphane-
borane adduct. Chem Commun (Camb). 2007(47):5072-4.
50.
Frustrated Lewis Pairs with Ketones and Esters. Chem-Asian J. 2012;7(6):1347-56.
51. Nyhlen J, Privalov T. On the possibility of catalytic reduction of carbonyl moieties with
Xu BH, Yanez RAA, Nakatsuka H, Kitamura M, Frohlich R, Kehr G, et al. Reaction of
tris(pentafluorophenyl)borane and H-2: a computational study. Dalton Trans. 2009(29):5780-
6.
52.
ketones and aldehydes to borinic esters. Dalton Trans. 2014;43(42):15723-6.
53. Mahdi T, Stephan DW. Enabling Catalytic Ketone Hydrogenation by Frustrated Lewis
Pairs. J Am Chem Soc. 2014;136(45):15809-12.
54. Scott DJ, Fuchter MJ, Ashley AE. Nonmetal Catalyzed Hydrogenation of Carbonyl
Compounds. J Am Chem Soc. 2014;136(45):15813-6.
55. Gyomore A, Bakos M, Foldes T, Papai I, Domjan A, Soos T. Moisture-Tolerant
Longobardi LE, Tang C, Stephan DW. Stoichiometric reductions of alkyl-substituted
Frustrated Lewis Pair Catalyst for Hydrogenation of Aldehydes and Ketones. ACS Catal.
2015;5(9):5366-72.
56.
Eros G, Nagy K, Mehdi H, Papai I, Nagy P, Kiraly P, et al. Catalytic Hydrogenation
with Frustrated Lewis Pairs: Selectivity Achieved by Size-Exclusion Design of Lewis Acids.
Chem-Eur J. 2012;18(2):574-85.
57.
Substitution of Alcohols. Synthesis-Stuttgart. 2016;48(7):935-59.
58. Danopoulos AA, Galsworthy JR, Green MLH, Cafferkey S, Doerrer LH, Hursthouse
Dryzhakov M, Richmond E, Moran J. Recent Advances in Direct Catalytic Dehydrative
MB. Equilibria in the B(C6F5)(3)-H2O system: synthesis and crystal structures of H2O center
dot B(C6F5)(3) and the anions HOB(C6F5)(3) (-) and F5C6)(3)B(mu-OH)B(C6F5)(3) (-).
Chem Commun. 1998(22):2529-30.
59.
hydrocarbons. Chem Commun. 2012;48(98):11963-5.
60. Lindqvist M, Sarnela N, Sumerin V, Chernichenko K, Leskela M, Repo T. Heterolytic
Segawa Y, Stephan DW. Metal-free hydrogenation catalysis of polycyclic aromatic
dihydrogen activation by B(C6F5)(3) and carbonyl compounds. Dalton Trans.
2012;41(15):4310-2.
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Figure 1: Common approaches for tritium labeling chemistry using carrier-free hydrogen
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3
Figure 2: Analytical chromatograms after the reduction of 3 with [B(C6F5)3 H][3HTMP]; top
– the starting material 3 (UV 215 nm); middle –crude reaction mixture (UV 215 nm); bottom
– LS-chromatogram of CRUDE reaction mixture.
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Scheme 1: General mechanism for FLP-activation of hydrogen molecule and FLP-H2
reduction of polarized double bonds
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Scheme 2: FLP-assisted tritium labeling using very low pressure of hydrogen
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Scheme 3: Prove of vital role of Lewis base while low pressure of hydrogen is used
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2
Table 1: Aldehyde reduction with [B(C6F5)3 H][2HTMP] (2)
Isolat
ed
Pressur
Conver
sion
Enrich
ment
(%)b
En
try
FLP-D2 /
Substrate
Lewis
base
Time
(h)
Substrate
Product
e 2H2
Solvent
yield
(%)
56
67
65
77
75
-
-
-
10
57
53
93
(mbar)
(%)a
1
2
3
4
5
6
7
8
9
1
1.2
1.5
2
2
2
2
2
2
2
1000
1000
1000
1000
1000
1000
1000
1000
1000
200
TMP
TMP
TMP
TMP
TMP
TMP
TMP
(tBu)3P
(Mes)3P
TMP
toluene
toluene
toluene
toluene
CH2Cl2
MeCN
THF
toluene
toluene
toluene
toluene
toluene
2
2
2
2
2
2
2
2
2
2
2
2
74
85
99
99
99
<5
<5
<5
99
99
99
99
>95
>95
>95
>95
>95
-
-
-
-
10
11
12
>95
>95
>95
1.5
2
200
1000
TMP
TMP
13
2
200
TMP
TMP
toluene
2
99
78
>95
14
2
1000
toluene
2
99
67
>95
15
16
2
2
2
1000
1000
TMP
TMP
TMP
toluene
toluene
toluene
2
2
2
99
99
79
83
>95
>95
17
18
1000
200
99
99
93
89
>95
>95
19
20
21
2
2
2
1000
1000
200
TMP
TMP
TMP
toluene
CH2Cl2
toluene
2
2
2
99
99
99
60
69
58
>95
>95
>95
22
2
1000
TMP
toluene
2
99
68
>95
23
2
1000
TMP
toluene
2
99
63
>95
>95
24
25
26
27
28
29
2
2
2
2
2
2
1000
200
TMP
TMP
TMP
TMP
TMP
TMP
toluene
toluene
toluene
toluene
toluene
toluene
0.25
2
99
99
99
99
99
99
87
79
81
75
82
73
1000
200
0.25
2
>95
>95
1000
200
2
2
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30
31
2
2
1000
1000
TMP
TMP
toluene
toluene
2
2
99
99
78
>95
>95
66
b
aAll conversions were determined by 1H NMR integration of the crude products. Deuterium
enrichment was determined by integration of labeled methylene group in H NMR (see
1
Supplementary Information).
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2
Table 2: Ketone functionality treated by the reductive reagent [B(C6F5)3 H][2HTMP] (2)
Isolated
FLP-D2 /
Substrate
Temperature Time Conversion
Enrichment
(%)b
Entry
1c
Substrate
Product
yield
(%)
42
(°C)
(h)
(%)a
2
3
r.t.
4
53
>95
>95
2c
r.t.
0.1
2
99
93
3
-
-
4
4
5
r.t.
r.t.
2
4
6
80
2
7
-
-
r.t.
2
0
-
-
8
9
r.t.
r.t.
80
2
4
4
2
-
10
-
11
12
-
-
80
r.t. d
4
17
b
aAll conversions were determined by 1H NMR integration of the crude products. Deuterium
1
enrichment was determined by integration of labeled methylene group in H NMR (see
Supplementary Information). cOur data(47) dReaction carried out in CH2Cl2.
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Graphical Table of Contents
Reliable protocol of the routine use of frustrated Lewis pairs for reducing of polarized double
bonds is reported. The described method is selective towards reduction of aldehydes and leaves
unaffected non-activated ketone moieties as well as other functionalities sensitive to standard
hydrogenation methods. Revolutionary is use of ultra-mild reaction conditions (200 mbar of
3H2), non-metallic character of very selective reagent providing 94 % radiochemical purity of
desired 3H-labeled product in a crude reaction mixture.
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