A simple method for α-position deuterated carbonyl compounds with pyrrolidine as catalyst

Article abstract of DOI:10.1002/jlcr.3210

A simple, cost-effective method for deuteration of carbonyl compounds employing pyrrolidine as catalyst and D₂O as deuterium source was described. High degree of deuterium incorporation (up to 99%) and extensive functional group tolerance were achieved. It is the first time that secondary amines are used as catalysts for H/D exchange of carbonyl compounds, which also allow the deuteration of complex pharmaceutically interesting substrates. A possible catalytic mechanism, based on the hydrolysis of 1-pyrrolidino-1- cyclohexene, for this pyrrolidine-catalyzed H/D exchange reaction has been proposed. Pyrrolidine has been shown to be an efficient catalyst for deuteration of carbonyl compounds. The method also allowed the deuteration of complex pharmaceutically interesting substrates. Preliminary experiment showed that the enamine and/or iminium activation modes may be involved. Copyright

Full text of DOI:10.1002/jlcr.3210

Research Article
Received 19 February 2014,
Revised 9 April 2014,
Accepted 6 May 2014
Published online 3 July 2014 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3210
A simple method for α-position deuterated
carbonyl compounds with pyrrolidine as catalyst†
a
a
b
a
*
Miao Zhan, Tao Zhang, Haoxi Huang, Yongmei Xie,
and Yuanwei Chena,c
*
A simple, cost-effective method for deuteration of carbonyl compounds employing pyrrolidine as catalyst and D2O as
deuterium source was described. High degree of deuterium incorporation (up to 99%) and extensive functional group
tolerance were achieved. It is the first time that secondary amines are used as catalysts for H/D exchange of carbonyl
compounds, which also allow the deuteration of complex pharmaceutically interesting substrates. A possible catalytic
mechanism, based on the hydrolysis of 1-pyrrolidino-1-cyclohexene, for this pyrrolidine-catalyzed H/D exchange reaction
has been proposed.
Keywords: isotope exchange; deuterium; chemoselectivity; ketones; deuterium oxide; pyrrolidine
isotope exchange reactions on a preparative scale. The aim of
Introduction
the investigation was to seek a facile and efficient method to
Isotope-labeled compounds have been widely used in many
label aryl methyl ketones with deuterium, employing the
areas. For example, they have been used as deuterated
secondary amine-pyrrolidine as catalyst. The first example that
the secondary amine as catalyst for deuteration of α-proton of
solvents,1g research tools in drug metabolism studies,1a
structural elucidation of biological macromolecules,1b,1h,1i
a carbonyl function was described here (Scheme 1), which may
internal standard for validation of quantitative bioanalytical
go through enamine and/or iminium modes.
assays,1l reaction mechanism1c,1k and kinetic1d studies,
quantitative analysis of environmental pollutants and residual
Results and discussion
pesticides,1j optical materials,1e and so forth. In addition, some
deuterium-enriched compounds have been studied as drug Initially, pyrrolidine (10 mol%) as catalyst, D2O (75 eq) as
candidates in recent years because of the kinetic isotopic deuterium source, and anhydrous THF as cosolvent were used
effects.2 The development of diverse and selective synthetic for the deuteration of acetophenone at room temperature. The
methods of deuterated materials is desired as the results of the deuterium incorporation reached to 97% within 6 h. The
new demands for suitably deuterated compounds.
total deuterium incorporation was confirmed by 1H NMR
For the preparation of deuterium-labeled carbonyl spectroscopy. As THF was partially immiscible in the reaction
compounds, strong base catalyzed H–D exchange reactions system, the other cosolvents, such as 1,4-dioxane, acetonitrile
provided a facile method for the exchange of acidic hydrogen and 1,2-dimethoxyethane were investigated at room
atoms for deuterium by means of keto-enol equilibrium.3 There temperature. As a result, all of them afforded 97% of deuterium
was also an acid-catalyzed H–D exchange of α-proton of a incorporation within only 3 h. Without cosolvent, the system
carbonyl.4 Mioskowski’s group reported that 1,5,7-triazabicyclo allowed 95.7% of deuterium incorporation after 12 h at room
[4.4.0]dec-5-ene (TBD) showed to be an isotope exchange temperature. A two-phase reaction (D2O/CHCl3) gave only 10%
catalyst in CDCl3 at room temperature toward ketones and other of deuterium incorporation overnight because these two
acidic substrates.3e Although other methods for deuteration of
ketones are available, such as using the Pd/C-H2-D2O system5,
aState Key Laboratory of Biotherapy, West China Hospital, West China Medical
School, Sichuan University, Chengdu 610041, China
other catalysts such as calcium vanadate apatite,6 antibody
38C2,7 cyclooctadieneiridium(I) acetylacetonate,8 Ir-NHC
complexes,9 and Pd/C utilizing NaBD4 for catalyst activation10
bChengdu ChemPartner Co. Ltd, Building no. 3, no. 88 South Keyuan Road,
were also used. Eames’s group indicated that the regioselective Chengdu Tianfu Life Science Park, Chengdu 610041, China
C-deuteration of a series of related acyclic and exocyclic enolates
cChengdu HC Pharmaceutical Co. Ltd, Suite 801, Building C1, no. 88 South
Keyuan Road, Chengdu Tianfu Life Science Park, Chengdu 610041, China
derived from substituted aryl ketones.11 It required two steps for
deuteration of ketones; the first step was formation of enolate
derivatives and then deuteration of them with [D4]acetic acid.
In decades, significant efforts have been made to develop
proline derived catalytic reactions, mainly based on enamine
and/or iminium activation modes.12 However, no attempts have
*Correspondence to: Yongmei Xie and Yuanwei Chen, State Key Laboratory of
Biotherapy, West China Hospital, West China Medical School, Sichuan University,
Chengdu 610041, China.
E-mail: xieym@scu.edu.cn; ywchen@scu.edu.cn
†
Additional supporting information may be found in the online version of this
been made for a secondary amine as catalyst for deuterium article at the publisher’s web-site.
J. Label Compd. Radiopharm 2014, 57 533–539
Copyright © 2014 John Wiley & Sons, Ltd.

M. Zhan et al.
Table 2. Deuteration of various substrates catalyzed by
pyrrolidine in D2O and cosolvent a
Entry
1
D content (%)
Yield (%)b
96
Scheme 1. Deuteration of various carbonyl compounds by pyrrolidine-D2O/
cosolvent system.
solvents were not miscible. Finally, 1,4-dioxane was chosen as
cosolvent. For these substrates with poor solubility, acetonitrile
was used as cosolvent.
2
3
95
90
With 1,4-dioxane as cosolvent and 75 eq (H : D = 1 : 50) of D2O
as deuterium source, pyrrolidine and other secondary amines
were studied for deuteration of acetophenone within 3 h at
room temperature (Table 1). Pyrrolidine (10 mol%) formed 97%
of isotope incorporation after 3 h (Table 1, entry 1). Comparable
deuterium incorporation was obtained with piperidine (93.3%,
Table 1, entry 2). Whereas other secondary amines were less
effective (entries 3–5), and isotope incorporation was unable to
be observed without a catalyst (entry 6). Less amount of
pyrrolidine resulted in a slow rate of incorporation (entries 7
and 8). Then, the optimized reaction conditions were obtained
(10 mol% of pyrrolidine, 75 eq of D2O, 1,4-dioxane as cosolvent,
room temperature, 12 h).
To investigate the scope of this H–D exchange method,
various ketones were used as substrates (Table 2).
Spectrographically pure labeled ketones were obtained through
extraction, and no further purification was required. For
acetophenone derivatives, it appeared that the nature of the
substituent on the aromatic ring did not have significant effect
on the deuterium incorporation after 12 h. Indeed, the 4’-
methoxy gave high level of deuterium labeling (97.3%, Table 2,
entry 2) as well as 3’-dimethylamino, 4’-nitro, 4’-bromo, 2,3’-
dichloroacetophenone with 97.7, 97, 97 and 92% of deuterium
incorporation after 12 h, respectively (Table 2, entries 3–6). An
attempt to deuterate the isobutyrophenone at room temperature
was unsuccessful probably because of steric hindrance. In contrast,
98% of deuterium incorporation was achieved at 100 °C (Table 2,
entry 7). Substrates, such as 4-acetylbenzoic acid, which has
carboxylic group, also could achieve 96% of deuterium
4
94
92
93
5
6c
7d
90
8e
91
89
94
9f
10g
Table 1. Effect of the catalysts for deuteration of
a
acetophenone
Entry
Catalyst (mol %)
Pyrrolidine (10)
Piperidine (10)
Diethylamine(10)
1,4-Oxazinan (10)
Thiomorpholine (10)
None
D content (%)
11g
12
90
92
1
2
3
4
5
6
7
8
97
93.3
85
12.7
9.3
0
Pyrrolidine (5)
Pyrrolidine (1)
88.7(96)b
44.7 (94.3)c
13
14
90
aThe reaction was conducted with 1 mmol of the substrate in
1.5 mL of D2O and 1.5mL 1,4-dioxane at room temperature
for 3 h. The D content was calculated on the basis of 1H NMR
spectrum.
94
bProlonged to 6 h.
cOvernight.
(Continues)
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M. Zhan et al.
deuterium incorporation was detected (1H/2H NMR) on the
cyclopropyl group (Table 2, entry 11). Delightfully, strong base
sensitive 4’-cyanoacetophenone afforded 96.3% of deuterium
incorporation (Table 2, entry 14). Moreover, the reaction was also
employed to heteroaromatic ketones, 3-acetylpyridine (97.3%,
Table 2, entry 15). Additionally, the 2-acetoxyacetophenone was
chemselectively deuterated at the α-carbon atom to the phenyl
carbonyl group (98%, Table 2, entry 16) because no deuterium-
incorporation was detected (1H/2H NMR) on the acetyl group.
Furthermore, the study from Sabot et al. implied deuterating
2-acetoxyacetophenone using usual base such as MeONa, NaOH,
or TBD ended up in partial or complete deprotection of the
substrate leading to 2-hydroxyacetophenone,3e which may
suggest that the superiority of pyrrolidine over other strong base
for the labeling of compounds bearing sensitive functional
groups. 4’-Piperazinoacetophenone with piperidyl on
acetophenone afforded 73% of deuteration incorporation
without catalyst at 60 °C after 12 h through intermolecular
catalytic reactions, and 94.3% of deuterium incorporation was
achieved when 10 mol% of pyrrolidine was used (Table 2, entry
17). Finally, deuteration of several aliphatic ketones were
successfully achieved (Table 2, entries 18–20).
These results prompted us to investigate the scope of our
methodology to other substrates. Interestingly, oxindole
underwent 92.5% of deuterium incorporation at the benzylic
position (Table 2, entry 21). Previous exchange methods for
oxindole analogs were D2SO4/D2O system.13 Moreover the
ethyl-1-phenylacetate, a base-sensitive group, was efficiently
deuterated with pyrrolidine (Table 2, entry 22), which may
suggest that this method should be applicable to a variety of
alkyl-1-phenylacetate derivatives. However, they are very
substrate-limited, as common procedures for the deuteration
of alkyl esters in protic solvents may lead to concomitant
transesterification.14
Table 2. (Continued)
Entry
15
D content (%)
Yield (%)b
88
16g
17g
93
88
18g
19g
20j
91
40i
Not isolated
21g
22g
90
96
To further evaluate the substrate scope of our novel catalytic
deuteration procedure, FDA-approved drug ondansetron
featuring a carbonyl moiety was chosen as a benchmark
compound. Ondansetron is used to prevent nausea and
vomiting caused by cancer chemotherapy, radiation therapy,
and surgery.15 Its deuterated fashion has been protected by
the patent, but no implementations were introduced.16 As
aUnless otherwise noted, the reaction was conducted with
1 mmol of the substrate and 10 mol% of pyrrolidine in
1.5 mL D2O/1,4-dioxane at room temperature for 12 h. The D
content was calculated on the basis of 1H NMR spectrum.
bIsolated yield.
c45 °C, 36 h.
d100 °C, 12 h.
e1.2 eq of pyrrolidine.
f50 mol% of pyrrolidine.
g60 °C, 12 h.
Scheme 2. Deuteration of ondansetron by pyrrolidine-D2O/1,4-dioxane system.
hAcetonitrile as cosolvent.
iThe low isolated yield of the deuteration is due to its low
boiling point and volatile nature.
jWithout cosolvent.
incorporation with 1.2eq of pyrrolidine (Table 2, entry 8). With
10 mol% of pyrrolidine, 4-aminoacetophenone was deuterated at
a slow rate probably because of the formation of imine
intermediate of 4-aminoacetophenone itself. When the catalyst
was up to 50 mol%, the 4-aminoacetophenone gave high level of
deuterium labeling (96%, Table 2, entry 9) at room temperature
after 12 h. The deuteration of cyclopropyl 2-fluorobenzyl ketone
proceeded at the benzylic position selectively because no Scheme 3. A possible mechanism for the H–D exchange reaction.
J. Label Compd. Radiopharm 2014, 57 533–539
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M. Zhan et al.
Figure 1. 1H NMR trace of the pyrrolidine catalyzed deuteration of cyclohexanone (Table 2, entry 20).
expected, 97% of deuterium incorporation was achieved by our
system (Scheme 2).
Conclusions
In summary, pyrrolidine has been shown to be an efficient isotope
exchange catalyst in D2O/1,4-dioxane at a mild condition toward a
wide range of substrates. This synthetic method is compatible with
sensitive functional groups. Finally, an easy workup provides
spectrographically pure labeled ketones. To some extent,
hydrolysis of 1-pyrrolidino-1-cyclohexene in D2O supported the
enamine and/or iminium mechanism. Further investigations to
apply chiral catalysts for the deuterium reaction is underway.
Outlined in Scheme 3 is a possible mechanism for the
deuteration of carbonyl compounds. Reaction of pyrrolidine with
carbonyl compounds results in the formation of the iminium I
and tautomerization of the iminium to enamine II. With D2O as
solvent, the reversible tautomerization of enamine II to iminium
III, and subsequent hydrolyzation could give the deuterium-
labeled compound IV. IV goes through further deuteration as
same as I to IV until the formation of a fully α-deuterated
carbonyl product. However, the keto-enol equilibrium mechanism
cannot be completely excluded.
To study the reaction process, cyclohexanone (38 mg),
pyrrolidine (10 mol%) and D2O (1 mL) was loaded into an NMR
tube, which was monitored every 20 min (Figure 1). After
123 min, cyclohexanone was successfully achieved with 98% of
deuterium incorporation.
Experimental section
General information
1H NMR and 2H NMR spectra were recorded on Bruker Avance III 400
(Bruker Corporation, Karlsruhe, Germany) (400 MHz for 1H NMR and
2
61.4 MHz for H NMR). Chemical shifts (δ) are expressed in ppm and are
To confirm the enamine and/or iminium mechanism, 20 mg of internally referenced (1H NMR: 0.00 ppm for TMS in CDCl3; 4.70 ppm for
DSS in D2O. 2H NMR: 7.26 ppm for CDCl3 in CHCl3; 8.32 ppm for CDCl3
1-pyrrolidino-1-cyclohexene was added to 1 mL of D2O. At the
in DMSO). Deuterium content was determined by comparison with the
beginning, 1-pyrrolidino-1-cyclohexene was not soluble in D2O;
integration of deuterated position and nondeuterated position.
after 2 h, the solution was clear because the hydrolyzates of
Deuterium incorporation was assigned by 2H NMR. The MS systems used
1-pyrrolidino-1-cyclohexene are water soluble. The 1H NMR
were the Quattro Premier XE mass spectrometer and the Q-TOF premier
indicated that 1-pyrrolidino-1-cyclohexene had been hydrolysed
mass spectrometer (Waters Micromass, Milford, Massachusetts, USA),
completely, which confirmed the mechanism above to a certain
extent (Figure 2).
which were used for LC/MS analysis and accurate mass detection,
respectively. Both were equipped with a standard ESI source.
General procedure for the evaluation of catalysts (Table 1)
To a solution of catalyst in 1.5 mL of D2O with 1.5 mL of cosolvent (if
necessary) was added acetophenone (120.1 mg, 1 mmol). The reaction
mixture was stirred for 3 h at room temperature, poured into 10 mL of
water, and extracted with diethyl ether (2 × 10 mL). The organic layer
was washed with water (5 mL) and brine (5 mL), dried over anhydrous
Na2SO4, and filtered. Filtrate was concentrated to afford acetophenone-
d3. The total incorporation yield was determined by 1H NMR
spectroscopy relative to the intensity of a nonexchangeable proton in
the molecule.
Typical procedure for deuteration of acetophenone.
To a solution of 10 mol% of pyrrolidine (7.1 mg, 0.1 mmol) in 1.5 mL of
D2O with 1.5 mL anhydrous dioxane as cosolvent was added
acetophenone (120.1 mg, 1 mmol). The reaction mixture was stirred at
room temperature for 12 h, followed by water (10 mL), then extracted
Figure 2. The hydrolysis of 1-pyrrolidino-1-cyclohexene in D2O.
with diethyl ether (2 × 10 mL).The organic layer was washed with water
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M. Zhan et al.
[2H]-Isobutyrophenone (Table 2, entry 7)
(5 mL) and brine (5 mL), dried over anhydrous Na2SO4, and filtered. The
filtrate was concentrated to afford acetophenone-d3.
The procedures for deuteration of the substrates in Table 2, entries 2,
3, 4, 5, 12, 13, 14, 15, and 20, were the same as acetophenone-d3.
For substrates in Table 2, entries 10, 11, 16, 18, 19, 21, and 22 were
similar to that for acetophenone-d3, except that the room temperature
was changed to 60 °C.
Isobutyrophenone-d3 was obtained similarly to that of acetophenone-
d3, except that the room temperature was changed to 100 °C.
Colorless oil, 90% yield. 1H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 7.2 Hz,
2H), 7.55 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.2 Hz, 2H), 3.56 (s, 0.02H), 1.21
(s, 6H) ppm. 2H NMR (61.4 MHz, CHCl3): δ = 3.56 (s) ppm.
[2H]-Acetophenone (Table 2, entry 1)
[2H]-4-Acetylbenzoic acid (Table 2, entry 8)
Colorless oil, 96% yield. 1H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 7.6 Hz,
2H), 7.53 (t, J = 7.2 Hz, 1H), 7.45(t, J = 8 Hz, 2H), 2.58 (s, 0.09H) ppm. 2H
NMR (61.4 MHz, CHCl3): δ = 2.59 (s) ppm.
To a solution of 1.2 eq of pyrrolidine (85.3 mg, 1.2 mmol) in 1.5 mL of
D2O was added 4-acetylbenzoic acid (120.1 mg, 1 mmol). The reaction
mixture was stirred at room temperature for 12 h, followed by 2 eq of
acetic acid glacial in water (10 mL), then extracted with dichloromethane
(2 × 10 mL).The organic layer was washed with water (5 mL) and brine
(5 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was
concentrated to afford 4-acetylbenzoic acid-d3.
[2H]-4’-Methoxyacetophenone (Table 2, entry 2)
White solid, 95% yield. 1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.8 Hz,
2H), 6.93 (d, J = 8.8 Hz, 2H), 3.87(s, 3H), 2.52 (s, 0.08H) ppm. 2H NMR
(61.4 MHz, CHCl3): δ = 2.53 (s) ppm.
White solid, 91% yield. 1H NMR (400 MHz, DMSO-d6): δ = 13.32 (bs, 1H),
8.06 (s, 4H), 2.60 (s, 0.11H) ppm. 2H NMR (61.4 MHz, DMSO-d6): δ = 2.64 (s)
ppm. HRMS m/z 190.0560 [M + Na]+.
[2H]-3’-Dimethylaminoacetophenone (Table 2, entry 3)
[2H]-4-Aminoacetophenone (Table 2, entry 9)
Light yellow solid, 90% yield. 1H NMR (400 MHz, CDCl3): δ = 7.29
The procedures for deuterated 4-aminoacetophenone was obtained
similarly to that of acetophenone-d3, except that the 10 mol% of
pyrrolidine was changed to 50 mol%.
2
(m, 3H), 6.92 (m, 1H), 2.99(s, 6H), 2.55 (s, 0.07H) ppm. H NMR (61.4 MHz,
CHCl3): δ = 2.58 (s) ppm. HRMS m/z 167.1263 [M + H]+.
[2H]-4’-Bromoacetophenone (Table 2, entry 4)
Light yellow solid, 89% yield. 1H NMR (400 MHz, CDCl3): δ = 7.80
(d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.4 Hz, 2H), 4.15 (bs, 2H), 2.47 (s, 0.12H) ppm.
2H NMR (61.4 MHz, CHCl3): δ = 2.48 (s) ppm. HRMS m/z 161.0771
[M + Na]+.
[2H]-4’-Phenylacetophenone (Table 2, entry 10)
White solid, 94% yield. 1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 8.4 Hz,
2H), 7.61 (d, J = 8.4 Hz, 2H), 2.56 (s, 0.09H) ppm. 2H NMR (61.4 MHz, CHCl3):
δ = 2.56 (s) ppm. HRMS m/z 201.9951 [M + H]+.
White solid, 94% yield. 1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 8.4 Hz,
2H), 7.69 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 7.2 Hz, 2H), 7.47 (t, J = 7.6 Hz,
J = 7.2 Hz, 2H), 7.40 (t, 1H), 2.62 (s, 0.24H) ppm. 2H NMR (61.4 MHz, CHCl3):
δ = 2.62 (s) ppm. HRMS m/z 222.0975 [M + Na]+.
[2H]-4-Nitroacetophenone (Table 2, entry 5)
[2H]-Cyclopropyl 2-fluorobenzyl ketone (Table 2, entry 11)
Light yellow solid, 92% yield. 1H NMR (400 MHz, CDCl3): δ = 8.33
(d, J = 8.8 Hz, 2H), 8.12 (d, J = 9.2 Hz, 2H), 2.66 (s, 0.09H) ppm. 2H NMR
(61.4 MHz, CHCl3): δ = 2.67 (s) ppm.
[2H]-2,3’-Dichloroacetophenone (Table 2, entry 6)
Colorless oil, 90% yield. 1H NMR (400 MHz, CDCl3): δ = 7.25 (m, 2H), 7.08
(m, 2H), 3.85 (s, 0.06H), 1.99 (m, 1H), 1.06 (m, 2H), 0.87 (m, 2H) ppm. 2H
NMR (61.4 MHz, CHCl3): δ = 3.87 (s) ppm. HRMS m/z 181.1490 [M + H]+.
[2H]-1-Tetralone (Table 2, entry 12)
Deuterated 2,3’-dichloroacetophenone was obtained at 45 °C for 36 h
similarly to the procedure for acetophenone-d3.
Light yellow solid, 93% yield. 1H NMR (400 MHz, CDCl3): δ = 7.93 (s, 1H),
7.83 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8 Hz, 1H), 7.43 (t, J = 8 Hz, 1H), 4.66
(s, 0.15H) ppm. 2H NMR (61.4 MHz, CHCl3): δ = 4.65 (s) ppm. HRMS m/z
190.9997 [M + H]+.
Light yellow liquid, 92% yield. 1H NMR (400 MHz, CDCl3): δ = 8.03
(d, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.25
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M. Zhan et al.
[2H]-4-Heptanone (Table 2, entry 19)
(d,J = 8.8 Hz, 1H), 2.97 (t, J = 6 Hz, 2H), 2.63 (s, 0.11H), 2.13 (t, J = 6 Hz, 2H)
ppm. 2H NMR (61.4 MHz, CHCl3): δ = 2.64 (s) ppm. HRMS m/z 171.0755
[M + Na]+.
[2H]-2-Acetonaphthone (Table 2, entry 13)
Colorless liquid, 40% yield. 1H NMR (400 MHz, CDCl3): δ = 2.35 (s,
0.28H), 1.59 (q, J = 7.2 , 4H), 0.9 (t, J = 7.2 Hz, 6H) ppm. 2H NMR
(61.4 MHz, CHCl3): δ = 2.35 (s) ppm.
White solid, 94% yield. 1H NMR (400 MHz, CDCl3): δ = 8.47 (s, 1H), 8.05
(d, J = 8.4 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.89 (m, 2H), 7.58 (dt, J = 19.6,
7.2 Hz, 2H), 2.70 (s, 0.09H) ppm. 2H NMR (61.4 MHz, CHCl3): δ = 2.70 (s)
ppm. HRMS m/z 196.0819 [M + Na]+.
[2H]-Cyclohexanone (Table 2, entry 20)
[2H]-4’-Cyanoacetophenone (Table 2, entry 14)
Cyclohexanone (38 mg), pyrrolidine (10 mol %, 2.8 mg) and D2O (1 ml)
was loaded into an NMR tube at room temperature. After 2 h, 97% of
deuterium incorporation was achieved.
1H NMR (400 MHz, D2O): δ = 2.20 (s, 0.04H), 1.70 (m, 4H), 1.57 (m, 2H)
ppm. 2H NMR (61.4 MHz, CDCl3): δ = 2.30 (s) ppm.
Brown solid, 94% yield. 1H NMR (400MHz, CDCl3): δ =8.05 (d, J=8Hz, 2H),
7.79 (d, J = 8 Hz, 2H), 2.62 (s, 0.11H) ppm. 2H NMR (61.4 MHz, CHCl3):
δ = 2.64 (s) ppm.
[2H]-Oxindole (Table 2, entry 21)
[2H]-3-Acetylpyridine (Table 2, entry 15)
Light yellow liquid, 88% yield. 1H NMR (400 , CDCl3): δ = 9.18 (s, 1H),
8.80 (d, J = 4 Hz, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.44 (dd, J1 = 7.6 Hz,
J2 = 4.8 Hz, 1H), 2.62 (s, 0.08H) ppm. 2H NMR (61.4 MHz, CHCl3): δ = 2.62
(d) ppm.
Light yellow solid, 90% yield. 1H NMR (400vMHz, CDCl3): δ = 8.98 (bs,
1H), 7.21 (t, J = 7.6 Hz, 2H), 7.02 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H),
3.52 (s, 0.15H) ppm. 2H NMR (61.4 MHz, CDCl3): δ = 3.54 (s) ppm. HRMS
m/z 158.0551 [M + Na]+.
[2H]-Phenacyl acetate (Table 2, entry 16)
[2H]-Phenylacetic acid ethyl ester (Table 2, entry 22)
Light yellow liquid, 93% yield. 1H NMR (400 MHz, CDCl3): δ = 7.91 (d,
J = 8 Hz, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 5.32 (s, 0.06H),
2.23 (s, 3H) ppm. 2H NMR (61.4 MHz, CHCl3): δ = 5.33 (s) ppm. HRMS m/z
203.0655 [M + Na]+.
Colorless liquid, 96% yield. 1H NMR (400 MHz, CDCl3): δ = 7.29 (m, 5H),
4.14 (q, J =7.2Hz, 2H), 3.59 (s, 0.04H), 1.25 (t, J = 7.6 Hz, 3H) ppm. 2H NMR
(61.4 MHz, CDCl3): δ = 3.60 (s) ppm.
[2H]-4’-Piperazinoacetophenone (Table 2, entry 17)
Procedure for regioselective deuteration of ondansetron
Deuterated 4’-piperazinoacetophenone was obtained using
acetonitrile as cosolvent at 60 °C similarly to the procedure for
acetophenone-d3.
Light yellow solid, 88% yield. 1H NMR (400 MHz, CDCl3): δ = 7.88
(d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 3.31 (m, 4H), 3.03 (m, 4H), 2.49
To a solution of 20 mol% pyrrolidine (4.3 mg) in 1.5 mL of D2O with 1,4-
dioxane as cosolvent was added ondansetron (100 mg). The reaction
mixture was stirred at 80 °C for 12 h and then cooled to room
temperature. Deuterated ondansetron was obtained through filtration.
White solid, 98% yield.
2
(s, 0.17H), 1.92 (bs, 1H) ppm. H NMR (61.4 MHz, CHCl3): δ = 2.50 (s) ppm.
HRMS m/z 208.1547 [M + H]+
[2H]-Benzylacetone (Table 2, entry 18)
1H NMR (400 MHz, CDCl3): δ = 8.24 (m, 1H), 7.31 (m, 3H), 6.91 (d,
J= 15.2 Hz, 2H), 4.63–4.67 (d, J= 14.4 Hz, 2H), 4.04–4.08 (d, J= 14.8 Hz, 2H),
3.68 (s, 3H), 2.96–3.00 (m, 1H), 2.82–2.88 (m, 1 + 0.03H), 2.15–2.18 (m, 1H),
1.87–1.90 (m, 1H) ppm. HRMS m/z 295.1664 [M+ H]+.
Colorless oil, 91% yield. 1H NMR (400 MHz, CDCl3): δ = 7.28 (t, J = 7.6 Hz,
2H), 7.19 (t, J = 8 Hz, 3H), 2.88 (s, 2H), 2.73 (s, 0.12H), 2.10 (s, 0.08H) ppm.
2H NMR (61.4 MHz, CHCl3): δ = 2.75 (s), 2.13 (d) ppm.
Conflict of Interest
The authors did not report any conflict of interest.
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J. Label Compd. Radiopharm 2014, 57 533–539

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