Tritiodefluorination of alkyl C–F groups

Article abstract of DOI:10.1002/jlcr.3782

A straightforward methodology of fluorine substitution by tritium/deuterium is reported. The described method is selective towards the F─C (sp³) group and leaves both the aromatic F─C (sp²) and F₂─C (sp³) moieti

Full text of DOI:10.1002/jlcr.3782

Marek Ales (Orcid ID: 0000-0001-9031-8263)
Tritiodefluorination of alkyl C–F groups
Břetislav Brož a Aleš Marek*
,
a
Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences,
Flemingovo n. 542/2, Prague 6, 16610, Czech Republic
A straightforward methodology of fluorine substitution by tritium/deuterium is
reported. The described method is selective towards the F–C(sp3) group and leaves both
the aromatic F–C(sp2) and F2–C(sp3) moieties unaffected. Alkylfluorides, readily
synthesized from appropriate alcohols by treatment with diethylaminosulfur trifluoride
(DAST) reagent in an overall yield up to 76 %, undergoes activation with the boron-
based Lewis acid B(C6F5)3, and stoichiometric in situ reduction with a tritide/deuteride
reagent – the [TMP2(3)H][2(3)HB(C6F5)3] system of frustrated Lewis pair. This
methodology provides an isolated yield of up to 93 % of regio-specifically labeled small
organic compounds with superior 2H-enrichment of over 95 %. The specific activity of
prepared 1-(2-[3H]-ethyl)naphthalene was determined at 29.0 Ci/mmol. The site
selectivity of the Lewis acid / [TMP2(3)H][2(3)HB(C6F5)3] approach is orthogonal to
currently used methods and allows for isotopic labeling of complementary positions in
molecules. Reported labeling methodology proceeds well at ultra-mild reaction
conditions (220 mbar of T2), allowing very low consumption of the radioactive source
(4.2 Ci/156 GBq), and producing limited amount of radioactive waste.
Keywords: tritiodefluorination, deuterodefluorination, C–F activation, frustrated Lewis pairs;
hydrogen activation; tritium labeled alkane; deuterium labeled alkane; non-metallic reagent,
ultra-mild reaction conditions, very low tritium pressure
* Corresponding author: tel. +420 220 183 395, e-mail: ales.marek@uochb.cas.cz
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/jlcr.3782
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1. Introduction
Tritium is the most versatile radioisotope used for identifying organic
compounds in biochemical research.(1-4) Most frequently, tritiations are carried out using
carrier-free tritium gas in the presence of a noble metal catalyst in order to reduce double
or triple bonds,(5-9) tritiodehalogenation of appropriate synthetic precursors or to carry
out 1H/3H exchanges on the desired molecule.(10-14) Catalytic dehalogenations of organic
halides, using tritium gas, provide a state-of-the-art approach of site-selective labeling,
while yielding high specific activity (S.A.) of the labeled material (Figure 1).(15) The
advantage of this method over other available methodology is the accessibility of
halogenated compounds. Aryl halides are the most common type of substrate,(10, 16-18)
although halogen–C(sp3) bonds required the activation by functionality such as
carbonyl, carbonate or aryl to accelerate otherwise slow reaction.(10, 18-22) Achieved
specific activities typically range between of 20–80 Ci/mmol for tritiodeiodinations, 14–
25 Ci/mmol for tritiodebrominations, and 8–16 Ci/mmol for tritiodechlorinations.(10)
Organic iodines and bromines undergo the reaction significantly more readily than
chlorines. Since the carbon-fluorine bond is considered the strongest carbon-halide bond
(bond energy of 490 kJ/mol), substrates containing C–F bonds are highly resistant to
tritiolysis, and deemed unsuitable substrates.(18, 23-25) Few examples were reported on
the reduction of alkylfluoride bonds, using harsh reaction conditions such as lithium
powder to form organolithium compound, followed by the subsequent quenching of the
reaction mixture by the addition of D2O to finally yield deuterated heptanes.(26)
Literature also reports the reduction of 4-fluoro-1,1’-biphenyl with LiAlD4 catalyzed by
NbCl5 under reflux conditions.(27) Caputo and Stephan spectroscopically studied the
fluorophilicity of the boron-based Lewis acid B(C6F5)3 in the activation of a series of
alkyl fluorides.(28, 29) Stoichiometric reaction of B(C6F5)3 / alkyl fluoride with the salt
[tBu3P1H][1HB(C6F5)3], yielded partial conversion of both studied substrates, 1-
fluoropentane and 1-fluoroadamantane, producing pentane and adamantane
respectively.
In our own work, we have utilized a borane-based Lewis acid B(C6F5)3 to generate the
corresponding frustrated Lewis pair (FLP) with a sterically demanding amine (2,2,6,6-
tetramethylpiperidine, TMP), under atmosphere of deuterium/tritium gas, to form
[TMP2(3)H][2(3)HB(C6F5)3].(30) The salt FLP-2H2 was efficiently used for the direct
reduction of carbonyl compounds, yielding alcohols with both high 2H-enrichment
(>95 %) and high isolated yields (up to 97 %). We have also illustrated the ability of
FLP to carried out the splitting of tritium molecule (3H–3H bond dissociation energy
446.9 kJ/mol) under very mild reaction conditions – (505 mbar of 3H2, r.t., 1h).(30) The
reagent [TMP3H][3HB(C6F5)3] was further successfully employed for the reduction of
p-(N-Boc)-benzaldehyde to produce p-(N-Boc)-aminophenyl-[3H]-methanol isolated in
an excellent yield (367 mCi) and S.A. of 24.3 Ci/mmol. Recently, we have further
reduce consumption of tritium gas as the FLP-assisted reduction of carbonyl
compound was successfully carried out at 190 mbar of T2 (2.5 Ci, 93 GBq), providing
tritium labeled alcohol 3-methoxyphenyl-[3H]-methanol with S.A. of 27.1 Ci/mmol.(31)
It is noteworthy an outstanding selectivity of FLP-3H reagent at reduction of carbonyl
compounds providing 94 % radiochemical purity of desired crude product.
Our research, as well as other contributors in literature, have demonstrated the
unique reactivity of FLPs in the activation of molecule of deuterium for the heterolytic
2
cleavage of H–2H molecule (bond dissociation energy 443.4 kJ/mol).(32-34) We are
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continuously developing new FLP applications for hydrogen labeling transformations.
Herein, we investigate the fluorophilicity of Lewis acid B(C6F5)3 in the activation of C–
F bonds for the stoichiometric reaction with [TMP2(3)H][2(3)HB(C6F5)3].
2. Results and discussion
To reach maximal defluorination-labeling conversion power of the complex
system of B(C6F5)3 and FLP-2H2, as a source of deuteride, we decided to use a ratio of
Lewis acid : Lewis base : fluorinated derivatives of 3:2:1 in dry CH2Cl2 under an
2
atmosphere of H2. Although Caputo stated that a ratio of 2:1:1 leads to the full
conversion of their chosen fluoroalkanes in an NMR-tube-experiment study; it is
1
noteworthy that based on their depicted H spectra they have reach a conversion of
below 50 % for 1-fluoropentane (no data in terms of the conversion nor the reaction
time were further provided).(28) Achieving a full conversion of starting material remains
an imperative, since we are seeking a preparative scale of this reaction. Based on our
experience with the reactivity of FLP-2H2 reagents used for reduction of polarized
double bonds, there is a need for the use of 1.5–2.0 eq of this reagent to reach full
conversion of reduced material unless the substrate is activated by electron withdrawing
group.(30)
fluoroadamantane
Monofluorinated
([F]- ),
compounds
1-fluorotetradecane
([F]-
and
1
),
1-
1-(2-
2
3-fluoro-1-phenylpropane
([F]-
3
)
fluoroethyl)naphthalene ([F]-
4
), provided in all cases the desired 2H-labeled derivatives
[2H]-(1–4) with high isolated yield (75–93 %) and excellent H-enrichment (>95 %,
2
1
determined by H NMR) after a short period of time (Scheme 1). Reaction conditions
were optimized with use of 1-fluorotetradecane ([F]-
conversion of 90 % was achieved, and after 4 hours of reaction time a full conversion
of alkylfluoride [F]- was witnessed. No other byproduct was detected in the crude
1); after 2 hours of reaction time a
1
1
reaction mixture by H NMR. To ensure the full conversion of alkylfluorides, our
experiments were allowed to react overnight. The reaction course was followed by
measurement of NMR spectra, where the characteristic signals were found to be absent.
For instance, for 1-fluorotetradecane ([F]-1) the characteristic signal for the CH2F
moiety in 1H spectra at 4.43 ppm (2H, dt, 2JF,H = 47.3 Hz and 3JH,H = 6.2 Hz) as well as
the multiplet of FCH2CH2 at 1.77–1.60 ppm were found to be absent. In the 13C NMR
spectra the disappearance of the doublets at 84.4 ppm (1JF,C = 164 Hz, FCH2), 30.6 ppm
(2JF,C = 19.4 Hz, FCH2CH2), and 25.3 ppm (3JF,C = 5.5 Hz, FCH2CH2CH2) were witnessed
.
The deuterium incorporation in the product [2H]-1 was unambiguously confirmed showing the
characteristic 1:1:1 triplet at 14.0 ppm (JC,D = 19.2 Hz, DCH2). For the detailed procedure,
2
spectra and full characterization of the isolated H-labeled products, as well as the
corresponding synthetic precursor see the Supplementary Information section. In the
reaction between FLP-2H2 and 1-fluorotetradecane ([F]-
1), where a ratio of 2:1 were
used, and no additional B(C6F5)3 were added for the activation of the C–F bond, no
conversion of this fluoroalkane were witnessed after 20 hours of reaction time. To
emphasize the applicability of this complementary labeling concept, we decided to test
1-fluorotetradecane as a model substrate under the reaction conditions used as a golden
standard for hydrogendehalogenations – substrate / [Pd/C; 30 %] (1 eq, w/w) / Et3N (6
eq) / EtOAc / 2H2 (1.5 bar) – over prolonged period of time of 48 hours. As was expected,
no conversion of this alkyl fluoride was detected. It is noteworthy to underline the
selectivity and mildness of FLP-2H2 reagents since the reagent tolerates most of the
frequent functional groups such as nitro, methoxy, silylethers, N-Boc, N-Bn,
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trialkylamines, C(sp2)-halogens, (hetero)arenes, non-activated ketons, sulfonamides,
ester functionalities, ferrocenes, zirconocenes, etc.(30, 35-38)
The secondary carbon F–C(sp3) moiety employed for C–F analogous activation
showed elimination of the HF leading to olefin formation as a major product (see
Supplementary Information) of reaction (80 % yield). Full conversion of 3-fluoro-1,5-
2
diphenylpentane ([F]-
5
5
) was observed and the desired H-labeled 3-[2H]-1,5-
diphenylpentane ([2H]-
) was isolated in 20 % yield with 2H-enrichment over 95 %.
On the other hand, attempts to carry out C–F activation in both polyfluorinated
alkanes (such as the F2–C(sp3) moiety [F]-6) synthesized using the DAST reagent and
carbonyl compound; see Supplementary Information) and fluoroarenes (the F–C(sp2)
moiety [F]-
hours (Scheme 2). No C–F activation was achieved with commercially available
Betamethasone ([F]- ) bearing sterically very demanding fluorine group on the C-9
7) turned out to be fruitless even after prolonged reaction time up to 140
8
position. The methylation of OH groups, to support the solubility of such otherwise
polar substrate in reaction medium, had no increase in the reactivity and was thus not of
any help.
Except for 1-fluorotetradecane ([F]-1), 1-fluoroadamantane ([F]-2) and
Betamethasone ([F]-8) all other alkylfluorides [F]-(3–7), used in this work, were
prepared from the appropriate alkylalcohols or aldehydes and their treatment with
diethylaminosulfur trifluoride (DAST) reagent in CH2Cl2 at 0°C.(39, 40) Overall yield up to 76
% were obtained (see Supplementary Information).
The successful isolation of the series of deuterium-labeled alkanes [2H]-(1–5) was
encouraging for the application of this procedure analogically for the tritium experiment. The
ability of FLP to activate tritium molecules under subatmospherical pressure of carrier-free
3
tritium gas (505 mbar), producing [B(C6F5)3 H][3HTMP] was proved recently.(30) To optimize
the conditions for routine use in radiochemistry, we investigated the further suppression of
tritium consumption, and attempted the experiment under very low pressure of carrier-free
tritium gas (220 mbar, 4.2 Ci, 156 GBq). To ensure full conversion of fluorinated precursor
[F]-4 in short period of reaction time (2 h), we decided to increase the ratio of Lewis acid :
Lewis base : fluorinated substrate to 6:4:1 (Scheme 3). A solution of 1-(2-
fluoroethyl)naphthalene ([F]-
ability of borane/FLP-3H reagent to substitute fluorine atom in [F]-
two hours of reaction, a crude product was lyophilized and subjected to flash column
chromatography providing desired tritium labeled alkane [3H]-
[100.8 mCi
(3.72 GBq)]. Full conversion of [F]- as
was achieved according to 1H NMR of [3H]-
4
, 2.6 mg) in dry DCM was used as substrate to prove
4
by tritium. After
4
4
4
characteristic signals of substrate [F]-
4 completely disappeared (Figure 4.15.2 in
Supplementary Information, the bottom spectrum). The structure of desired product [3H]-
4 was unequivocally identified by 3H, 1H NMR, and HR-MS spectrometry. The chemical shift
3
1
of H signal at 1.38 ppm in the CH2CH2T moiety is identical to CH2CH2H of H-
standard, as well as to CH2CH2D of ([2H]- ). Characteristic tritium signal in the 3H-1H
coupled spectrum is split to a triplet of triplets (2JT,H = 13.8 Hz, 3JT,H = 8.0 Hz). Specific
activity (S.A.) of [3H]-
was calculated based on the HR-MS spectrum (Figure 4.15.3
in Supplementary Information, the bottom spectrum) at 29.0 Ci/mmol (1.07
TBq/mmol). The measured signal of desired product [3H]-
perfectly matches with its
4
4
4
simulation (calculated 158.1021 Da, found 158.1020 Da), and no un-labeled product
was detected (C12H12, M = 156.0939 Da).
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The outstanding S.A. (precisely one tritium per labeled position) was reached
due to a different mechanism employed in reported methodology compare to traditional
hydrogen dehalogenations catalyzed by [Pd0] initiation of oxidative addition among C-
halogen bond (Figure 1) under atmosphere of hydrogen gas, ending up with reductive
elimination. Increasing aryl C-halogen bond dissociation energies in the order I (223
kJ/mol) < Br (281 kJ/mol) < Cl (340 kJ/mol) < F (453 kJ/mol), combined with an
increasing halogens electronegativities I < Br < Cl < F, ends up with a trend of measured
dehalogenation rates of different halo group in the order I >> Br > Cl, fluorine leaving
as an unsuitable substrate.(10) Here the mechanism is based on the substitution of fluorine
by hydrogen. The particular C–F bond is significantly weakened by interaction with a
strong lewis acid such as B(C6F5)3, which makes possible substitution of fluorine by
deuteride/tritide delivered in this case by a FLP-2(3)H reagent.
3. Conclusion
As a proof-of-concept, we reported a detailed study of site-specific deuterium-labeled
alkanes by employing C–F activation of 1°, 2° and 3° alkyl fluorides as a complementary
tool to existing deuterium labeling methods. Our intention was to design a synthetic
protocol applicable for tritium labeling of special candidates where one or more C–F
moieties could be selectively and efficiently used for site specific late stage labeling.
Successful labeling of 1-(2-[3H]-ethyl)naphthalene using reported strategy under very
mild reaction conditions offers a synthetic protocol generally applicable for smooth
tritium labeling of organic compounds yielding radio tracers with maximal achievable
specific activity per labeled bond. Ultra mild reaction conditions, non-metallic character of
reagent, commercial availability of reagents, proven excellent selectivity, very high yield and
full conversion of proper substrates, synthetically readily available monofluorinated substrates,
and unambiguous selectivity towards various C–F moieties paved the way for use of this
concept as a complementary tool for tritium labeling experiments of applicable substrates.
4. Experimental section
General
The 1H/3H-, 13C- and 19F-NMR spectra were recorded at 300/320, 400 or 600 MHz; 75,
100 or 150 MHz and 377 or 470 MHz with a Bruker Avance II 300 MHz, Avance III™
HD 400 MHz or Avance III™ HD 600 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). Liquid
scintillation measurements were done on a PerkineElmer TriCarb 2900 liquid
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scintillation counter (LSC) in a Rotiszint Eco+ cocktail. B(C6F5)3, Betamethasone and
1-fluorotetradecane were purchased from TCI Europe N.V.. 2,2,6,6-
Tetramethylpiperidine and 1-fluoroadamantane were purchased from Fluorochem Ltd..
4.1 Generation of the Lewis acid / FLP-2H2 reagent
A well-dried 3-mL deuteration flask was filled with deuterium gas (1200 mbar) at room
temperature and then, the 0.1M solution of B(C6F5)3 in dry CH2Cl2 (200 μmol, 3 eq.),
and neat TMP (133 μmol, 2 eq.), were added consecutively. After stirring the reaction
mixture for 1 hour, the Lewis acid / FLP-2H2 reagent was prepared, and used in the next
step of reaction sequence. For details see SI (GP–2).
4.2 General procedure for the activation of fluoride substrates
The appropriate alkyl fluoride [F]-(1–5) (67 μmol, 1 eq.) in dry CH2Cl2 (350 μL), was
added to the freshly prepared Lewis acid / FLP-2H2 reagent. The reaction mixture was
vigorously stirred and allowed to react overnight at room temperature. The mixture was
then diluted by water (2 mL) and product extracted by addition of CH2Cl2 (3 × 2 mL).
The combined organic layers were dried by MgSO4 and solvent was evaporated. The
crude product was purified by short column (n-hexane or CH2Cl2, silica gel 60, column
7×Ø1.5 cm, 20 mL of mobile phase) to get rid of polar reagents. After evaporation of
solvent, the corresponding pure deutero-alkanes [2H]-(1–5) were isolated. See SI (GP–
3) for details.
4.2.1 The synthesis of 1-[2H]-tetradecane ([2H]-1).
Derivative [2H]-
1 was prepared from 1-fluorotetradecane ([F]-1) (14.5 mg, 67 μmol)
using the general procedure, and was isolated as colourless oil (12.4 mg, 93 % yield).
1H NMR (CDCl3, 400.1 MHz) δ (ppm) : 1.39–1.19 (24H, m, 12×CH2), 0.95–0.80 (5H,
13
m, CH3 + CH2D). C NMR (100.8 MHz, CDCl3) δ (ppm): 32.09, 32.07, 29.9, 29.8,
29.7, 29.5, 22.9, 22.8, 14.3, 14.0 (t1:1:1, JCD = 19.1 Hz). EI-HRMS: For C14H29D+ [M]+
calcd. 199.2410 Da, found 199.2414 Da.
4.2.2 The synthesis of 1-[2H]-adamantane ([2H]-2).
The desired deuterated [2H]-
2 was prepared from 1-fluoroadamantane ([F]-2) (10.3 mg,
67 μmol) using the general procedure after 4 hours of reaction, and was isolated as a
colourless oil (7.2 mg, 78 % yield). 1H NMR (CDCl3, 400.1 MHz) δ (ppm) : 1.94–1.86
(3H, m, 3×CH), 1.82–1.72 (12H, m, 6×CH2). 13C NMR (100.8 MHz, CDCl3) δ (ppm):
37.8, 37.6, 28.3, 27.8 (t1:1:1, JCD = 20.1 Hz). EI-HRMS: For C10H15D+ [M]+ calcd.
137.1317 Da, found 137.1315 Da.
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4.2.3 The synthesis of 1-[2H]-3-phenylpropane ([2H]-3).
Derivative [2H]-
procedure. Due to volatility of
3
was prepared from 1-fluoro-3-phenylpropane ([F]-
3) using general
3
, product was isolated and characterized in a CH2Cl2
solution and the isolated yield could not be determined. A spectral characterization is in
accordance with those described in literature.(41) The deuterium incorporation was
unambiguously confirmed by signals showing characteristic H–D splitting constants for
1
13
CH2CH2D and CH2CH2D in H NMR and C–D splitting constants for CH2D in C
1
NMR. H NMR (CDCl3, 400.1 MHz) δ (ppm) : δ 7.31–7.25 (2H, m, ArH), 7.20–7.16
3
(3H, m, ArH), 2.62–2.56 (2H, m, ArCH2), 1.64 (2H, pt1:1:1, JH,H = 7.5 Hz,
3JH,D = 1.1 Hz, CH2CH2D), 0.93 (2H, tt1:1:1, 3JH,H = 7.4 Hz, 2JH,D = 2.0 Hz, CH2CH2D).
13C NMR (CDCl3, 100.8 MHz) δ (ppm) : 142.8, 128.6, 128.3, 125.7, 38.2, 24.6, 13.6
(t1:1:1, JC,D = 19.1 Hz). EI-HRMS: For C12H11D+ [M]+ calcd. 121.1002 Da, found
121.1006 Da.
4.2.4 The synthesis of 1-(2-[2H]-ethyl)naphthalene ([2H]-4).
Derivative [2H]-
4 was prepared from 1-(2-fluoroethyl)naphthalene ([F]-4) (11.7 mg,
67 μmol) using the general procedure, and was isolated as colourless oil (9.5 mg, 90 %
1
yield). H NMR (CDCl3, 400.1 MHz) δ (ppm) : 8.10–8.05 (1H, m, ArH), 7.89–7.84
(1H, m, ArH), 7.72 (1H, d, 3JH,H = 8.1 Hz, ArH), 7.55–7.45 (2H, m, 2× ArH), 7.45–7.39
(1H, m, ArH), 7.37–7.33 (1H, m, ArH), 3.13 (2H, t, J = 7.4 Hz, CH2CH2D), 1.38 (tt1:1:1
,
2
3JH,H = 7.5 Hz, JH,D = 2.0 Hz, 2H, CH2CH2D). 13C NMR (CDCl3, 100.8 MHz)
δ (ppm) : 140.4, 134.0, 131.9, 128.9, 126.5, 125.8, 125.5, 125.0, 123.9, 26.0, 14.9 (t1:1:1
,
JC,D = 19.5 Hz). EI-HRMS: For C12H11D+ [M]+ calcd. 157.1002 Da, found 157.1003 Da.
4.2.5 The synthesis of 1,5-diphenyl-3-[2H]-pentane ([2H]-5).
The desired deuterated [2H]-
5 was prepared from 1,5-diphenyl-3-fluoro-pentane ([F]-5)
(13.8 mg, 67 μmol) using the general procedure, and was isolated as a minor product
(2.9 mg, 20 %). Oily product was identified by HRMS: EI-HRMS: For C17H19D+ [M]+
calcd. 225.1628 Da, found 225.1629 Da.
4.3 The synthesis of 1-(2-[3H]-ethyl)naphthalene ([3H]-4).
Two-neck 1.4-mL hydrogenation flask equipped with a magnetic stir bar and septum
was mounted onto a tritiation manifold system. The flask was well dried by vacuum-
inert sequence, and a carrier-free tritium gas (220 mbar, 4.2 Ci/156 GBq) was released
into the flask. Subsequently, 0.1M B(C6F5)3 solution in dry DCM (0.9 mL, 90 μmol, 6
eq.) and 2,2,6,6-tetramethylpiperidin (10 μL, 8.4 mg, 60 μmol, 4 eq.) were added
consecutively via syringe and the reaction mixture was vigorously stirred for 1 hour. A
solution of 1-(2-fluoroethyl)naphthalene ([F]-4, 2.6 mg, 15 μmol, 1 eq.) in dry DCM
(250 μL) was injected, and the mixture was stirred for additional 2 hours. The reaction
mixture was then frozen by liquid nitrogen and an excessive tritium was back-trapped
on a uranium bed. The reaction mixture was filtered through a 0.22 μm PTFE syringe
filter, and the reaction flask was rinsed with methanol/water 2:1 mixture (5 × 0.8 mL)
and with 1M aqueous HCl (0.5 mL). To remove a labile activity, the crude product was
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repeatedly lyophilized by methanol/water 4:1 mixture (5 mL). The crude product was
dissolved in DCM (1.5 mL), and purified by flash column chromatography (DCM, silica
gel, column 10 cm × Ø1.2 cm, 20 mL of mobile phase). It was isolated 100.8 mCi
3
1
(3.72 GBq) of pure [3H]- . The desired product [3H]-
4 4 was identified by H and H
NMR spectrometry as well as by MS (Supplementary Information, 4.15). Specific
activity(MS) was determined of 29.0 Ci/mmol (1.07 TBq/mmol).
3H NMR (CDCl3, 320.1 MHz) δ (ppm) : 1.38 (1[3H], tt, 2JT,H = 13.8 Hz, 3JT,H = 8.0 Hz,
3
CH2CH2 H). 1H NMR (CDCl3, 300.1 MHz) δ (ppm) : 8.06 (1H, d, 3JH,H = 8.0 Hz,
ArH), 7.90 – 7.82 (1H, m, ArH), 7.71 (1H, d, 3JH,H = 8.2 Hz, 1H), 7.57 – 7.31 (4H, m,
3
3
4×ArH), 3.11 (2H, q, 3JH,H/T = 7.7 Hz, CH2CH2 H). 1H signal of CH2CH2 H detected at
1.38 ppm gets partially overlapped by grease used at lyophilization and was not
integrated. EI-HRMS: For C12H11T+ [M]+ calcd. 158.1021 Da, found 158.1020 Da.
Acknowledgments
The authors thank the Czech Academy of Sciences for the financial support of this
project within the program RVO: 61388963. We thank dr. Martin Svoboda from the
Mass spectrometry department of IOCB for willingness to measure samples containing
tritium labeled compounds.
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Figure 1: State-of-the-art approach used for hydrogendehalogenation labeling technique
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Scheme 1: Proper substrates for successful C–F activation allowing 2H-labeling by deuteride
nucleophile attack; i) 2H2 (1200 mbar); ii) 0.1M B(C6F5)3, CH2Cl2; iii) TMP (neat), 1h, r.t.; iv)
fluoroalkane, CH2Cl2; 16 h
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Scheme 2: Inert derivatives for C–F moiety activation; similar reaction conditions used as in
Scheme 1
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Scheme 3: Borane & FLP-assisted tritium labeling under very low pressure of tritium gas
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Graphical Table of Contents
Reliable protocol for tritiodefluorination of alkylfluorides is reported. The described method is
selective towards the F–C(sp3) group and leaves both the aromatic F–C(sp2) and F2–C(sp3)
moieties unaffected. The site selectivity of the Lewis acid / [TMP2(3)H][2(3)HB(C6F5)3]
approach is orthogonal to currently used methods and allows for isotopic labeling of
complementary positions in molecules.
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