A highly selective H/D exchange reaction of 1,4-dihydropyridines

Article abstract of DOI:10.1039/C9OB00575G

Herein, we report a simple, economical, and effective acid-mediated method for the in situ deuteration of Hantzsch esters and their 4-substituted derivatives, including some drugs that constitute important calcium channel blockers which are effective for

Full text of DOI:10.1039/C9OB00575G

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Highly selective H/D exchange reaction of 1,4‐dihydropyridines
Kaiqian Wang,a Xiaoping Chen,b,c Peng Xiao,*c Ping Wang*b and Feng Liang*a
Received 00th January 20xx,
Accepted 00th January 20xx
Herein, we report a simple, economical, and effective acid‐mediated method for the in situ deuteration of
Hantzsch esters and their 4‐substituted derivatives, including some drugs that constitute important calcium
channel blockers effective for hypertension treatment. Hydrogen isotope exchange occurred selectively at
α‐alkyl C‐H bonds in the 2,6‐substituents.
DOI: 10.1039/x0xx00000x
method,14 we did a lot of optimization to reduce the amount of
reagents and improve efficiency. Moreover, we expanded the
range of substrates, and have explored the mechanism.
Introduction
Hydrogen isotope incorporation is widely used in numerous
fields, such as organic synthesis1 and tracer2 and mechanistic
studies.3 Application of hydrogen‐isotope‐labelled molecules
can facilitate absorption, distribution, metabolism, and
excretion (ADME) studies.4 Introducing hydrogen isotopes into
active drug molecules may alter their pharmacokinetic and
pharmacodynamic properties, and deuterated drugs may even
be directly applied in clinical pharmacology.5 This field has
attracted more attention since the first deuterated drug,
Austedo, was approved for use in the U.S.A., and thus hydrogen
isotope exchange (HIE) can be expected to show greater
potential in drug discovery and development.6
In the past 20 years, numerous methods have been
developed to obtain hydrogen‐isotope‐labelled compounds.
Metal catalysts, such as those based on Ir,7 Co,8 Fe,9 Pd,10 and
Ru,11 have been applied to accomplish HIE with high selectivity
and efficiency. Recently, metal‐free hydrogen‐isotope‐labelling
processes have also been extensively developed.12 Acid‐
mediated labelling processes are the traditional way for
achieving HIE, and they are still attractive for incorporating
hydrogen isotopes into electronically activated aromatic and
unsaturated molecules.13
Results and discussion
At the beginning of our research, we found that Hantzsch
esters were deuterated in an unexpected manner. LC‐MS
analysis showed products with a distribution of masses. 1H NMR
analysis showed that some of the reactant was oxidized and
that deuterium was incorporated into the methyl groups at the
2‐ and 6‐positions of the 1,4‐dihydropyridine. It should be noted
that mainly the substrate 1a and the corresponding oxidized
product 1a’ remained in this reaction system. The remaining
unoxidized 1a‐d6 had the same D incorporation as the oxidized
product 1a’‐d6, as confirmed by NMR spectroscopy. The
oxidation of 1a involved unknown hydrogen transfer under the
heating and acidic conditions. More details were discussed in
Table 1 Optimization of the conditions
Entry
1
2
3
4
5
6
7
8
Variations
nonea
no TFA‐d
TFA
3 eq. TFA‐d
RT
70 °C
air
DMF
DMA
MeOH
MeOD
D incorporation (%)b
85c
0
Herein, we describe a simple and cost‐effective acid‐
mediated method for introducing deuterium into 1,4‐
dihydropyridines and their derivatives in excellent yield and
with high incorporation. Compared with the reported
63
82
38
75
45
74
83
15
75
a The State Key Laboratory of Refractories and Metallurgy, Coal Conversion and New
Carbon Materials Hubei Key Laboratory, School of Chemistry
Engineering, Wuhan University of Science and Technology, Wuhan 430081, China.
E‐mail: feng_liang@wust.edu.cn
& Chemical
9
10
11
b Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of
Chemistry and Chemical Engineering Shanghai Jiao Tong University, 800
Dongchuan Road, Shanghai 200240, P. R. China. E‐mail: wangp1@sjtu.edu.cn
c Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education
and Guangdong Province, College of Physics and Optoelectronic Engineering,
Shenzhen University, Shenzhen 518060, P.R.China. E‐mail:
a Standard conditions: 1a (0.2 mmol, 50.7 mg), D2O (10 mmol,
181 μL), TFA‐d (0.3 mmol, 23 μL), N‐methylpyrrolidone (NMP,
b
2 mL), N2, 50 °C for 24 h. D incorporation determined by
1H NMR spectroscopy. c Average of two parallel reactions.
pengxiao_px@szu.edu.cn
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faster at an α‐position with respect to nitrogen than at an α‐position
with respect to carbonyl.
ESI. As shown in Table 1, we performed a series of experiments
aimed at optimizing the D incorporation. An oxidized product
was obtained with 85% D incorporation at the methyl groups in
the 2‐ and 6‐positions under the standard conditions (50 eq.
Following these experiments, we tried to expand the
substrate scope to 4‐substituted 1,4‐dihydropyridines.
Numerous 4‐substituted 1,4‐dihydropyridine pharmaceutical
molecules have proved effective as calcium channel blockers
and are used for hypertension treatment, such as Nifedipine,
Nisodipine, Nimodipine, Lacidipine, and Amlodipine.16 First, we
examined the reaction with Nifedipine under the standard
conditions in Scheme 1. To our delight, only little oxidation
D2O, 1.5 eq. TFA‐d, 0.1
M substrate in NMP, N2, 50 °C, 24 h).
Absolutely no deuteration occurred when TFA‐d was omitted,
showing acid to be critical for D incorporation. The D
incorporation decreased to 63% when TFA‐d was replaced by
non‐deuterated TFA, that is relying on the decreased ratio of
D:H in the reaction mixture. D incorporation did not increase
when the amount of TFA‐d increased to 3 equivalents. The
effect of temperature on the reaction was also investigated. At
room temperature, the D incorporation decreased to 38%, and
at 70 °C it was slightly lower at 75%. If the reaction system was
not degassed or exposed to air, the D incorporation decreased
to 45%. In examining various solvents, we found that non‐protic
1
occurred. However, H NMR analysis of the purified product
revealed only 24% D incorporation. We then performed a series
of experiments to optimize the D incorporation (Table 2). We
increased the amount of TFA‐d and allowed the reaction to
proceed for 48 h at 70 °C. The D incorporation reached a peak
value of 80% (an average of two parallel reactions) when 10 eq.
of TFA‐d was used. It was confirmed that no D incorporation
occurred in the absence of acid. We then varied the number of
equivalents of D2O. Without D2O, 15% D could still be
incorporated. Less D2O led to lower D content, but more D2O
did not result in a better D incorporation. Considering the
amount and the cost of TFA‐d used in the reaction system, we
examined some other cheaper acids. The strong Lewis acid
solvents worked much better than protic solvents.
D
incorporations of 74%, 83%, 15%, and 75% were achieved in
media of DMF, DMAc, CH3OH, and CH3OD, respectively. To
confirm the relationship between oxidation and deuteration,
we performed the experiment under standard conditions with
1a’ prepared previously,15 whereupon 85% D incorporation
showed the deuteration and oxidation processes to be
independent of one another. During these optimization
processes, we also found that the D incorporation did not
change when the deuterated product was immersed in
chloroform‐d for 3 days. (see the ESI for more details)
BF3ꞏOEt2 was found to behave well, affording 76%
D
incorporation. And 68% D was incorporated while TfOH was
used. Finally, we investigated the effect of time and extended
the deuteration process to about 150 h, but the D content of
the product did not rise beyond 80%. (more details are provided
in the ESI)
Having optimized the conditions, we applied derivatives of 1a in
the reaction system. As shown in Scheme 1, we first changed the
alkyl groups of the 3,5‐ester substituents from ethyl to isopropyl and
Having optimized the reaction conditions, we then applied them
tert‐butyl, whereupon 77% and 81% D incorporations in the 2,6‐ to different 4‐substituted 1,4‐dihydropyridines (Scheme 2). With a
methyl groups were obtained, respectively (Scheme 2, 1b’‐d6 and phenyl substituent at the 4‐position (2a‐d6), the D incorporation was
1c’‐d6). Considering the different reactivities of methyl, ethyl, and 77% under the standard conditions in Table 2. A product with 77% D
isopropyl groups, we obtained 71% D incorporation for a 2° carbon content (2b‐d6) was obtained with electron‐withdrawing group 2‐
centre, whereas for a 3° carbon atom only 18% D incorporation was bromophenyl substituent at the 4‐position. With electron‐donating
achieved (Scheme 2, 1d’‐d4 and 1e’‐d2). This could be attributed to groups such as furyl and thienyl at the 4‐position (2d‐d7 and 2e‐d6),
the greater steric hindrance of the 3° carbon centre, which might
Table 2 Optimization of the conditions for 4‐substituted DHP
derivatives
hamper the HIE reaction. And this result would contribute to the
discussion of mechanism. When the 3,5‐ester groups were
substituted with acetyl groups, all four methyl groups showed
deuterium incorporation (1f’‐d12). The D incorporations were 71% in
the 2,6‐methyl groups and 61% in the 3,5‐substituents. HIE was thus
Entry
1
2
3
4
Variations
1.5 eq. TFA‐d, 50 °C, 24 h
6 eq. TFA‐d
nonea
D incorporation (%)b
24
74
80c
0
no TFA‐d
5
6
7
8
9
10
no D2O
100 eq. D2O
TFA
TfOH
BF3ꞏOEt2
150 h
15
76
71
68
76
79
a Standard conditions: 2m (0.2 mmol, 69.3 mg), D2O (10 mmol,
181 μL ), TFA‐d (2 mmol, 154 μL ), NMP (2 mL), N2, 70 °C for
48 h. b D incorporation determined by 1H NMR spectroscopy.
c Average of two parallel reactions.
Scheme 1 Substrate scope of Hantzsch ester derivatives.
2 | J. Name., 2012, 00, 1‐3
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a
Scheme 3 Control experiments. Standard conditions as in
b
Table 2. Standard conditions as in Table 1 using CH2Cl2 as
solvent.
Scheme 2 Deuteration of 4‐substituted 1,4‐dihydropyridines. a
3 eq. TFA‐d was used. b 20 eq. BF3∙OEt2 was used.
position (2d‐d7). As yet, we are unable to explain this phenomenon.
All of the deuterated 4‐substituted 1,4‐dihydropyridines in Scheme 2
were isolated in excellent yields.
products with 81% and 82% D incorporation were isolated. With a
pyridyl group at the 4‐position, however, the D incorporation
decreased to 36%. Presumably, the basic pyridyl moiety consumed
some active protons or deuterons. Using 20 equivalents of BF3ꞏOEt2
in place of TFA‐d resulted in 70% D content in the isolated product
(2c‐ d6). With 4‐hydroxy3‐methoxyphenyl substituents at the 4‐
position, the isolated products had 80% D incorporation (2f‐d6). We
then investigated the effects of alkyl substituents. With a methyl
group, we obtained a product with 77% D content (2g‐d6).
We also performed some control experiments with a view to
explaining the HIE mechanism in this reaction system (Scheme 3).
Replacing the ester groups in the 3,5‐positions with cyano groups
(3a‐d0) or removing the methyl group at the 2,6‐positions (3b‐d0) led
to absolutely no D incorporation. We oxidized 2g and 2m to obtain
the corresponding pyridines 3c and 3d using Pd/C.15 Under the
conditions in Scheme 2, 3d was deuterated at the same position with
a similar D content (3d‐d6, 78%). For 3c, all three methyl groups
directly linked to the pyridyl cycle were deuterated simultaneously,
although the 78%D content of the methyl group in the 4‐position was
slightly higher than the 70% D content of the methyl groups in the
2,6‐positions (3c‐d9). The position between the two ester groups may
have been activated for faster HIE. We also tried to deuterate 2,6‐
and 2,4‐lutidines, but without success (3e‐d0 and 3f‐d0). No
significant deuteration occurred at any methyl group of ethyl (E)‐but‐
2‐enoate (3g‐d1, 17%). However, the situation was very different
when an amino group was present at the 3‐position (3h). Evidently,
3h underwent enamine exchange and existed in the imine form in
the presence of TFA. The α‐ methylene unit of the imine was 95%
deuterated, with 21% D incorporation at the α‐methyl group (3h’‐d5).
Finally, we carried out an experiment using 79% D content 2m‐d6
under the standard conditions in Scheme 2, with non‐deuterated
reagents (TFA and H2O). After 48 h, the D content at the 2,6‐methyl
groups decreased to 12%. A C‐D bond is more stable than a C‐H
bond,18 but the HIE reaction in this acidic system was evidently
reversible. Thus, it is not difficult to understand why deuteration
could not be forced to completion.
Cyclohexyl‐,
isopropyl‐,
and
3‐pentyl‐substituted
1,4‐
dihydropyridines all served as good radical precursors,17 and
products with 80%, 77%, and 77% D isotope purity were isolated,
respectively (2h‐d6, 2i‐d6, and 2j‐d6). Next, we performed
deuteration experiments on the important pharmaceutical
molecules Nisodipine, Nimodipine, Amlodipine, and Lacidipine. The
first three of these molecules had asymmetric substituent patterns
on the pyridine ring. Varying the alkyl groups in the 3,5‐positions did
not affect the D content, 80% deuterium‐labelled Nisodipine (2k‐d6)
was obtained. With 2‐methoxyethyl acetate at the 3‐position and a
meta‐nitrophenyl group at the 4‐position of Nimodipine (2l‐d6), the
D incorporation decreased slightly to 68%. For Amlodipine, 80% D
incorporation occurred at the methyl group in the 6‐position, while
77% D incorporation occurred in the methylene unit at the 2‐position
(2n‐d5). tert‐ Butyl could also be tolerated under these conditions,
with 80% D incorporation and very little deprotection after reaction
for 48 h (2o‐d6). Interestingly, the secondary amino group of most of
the 4‐substituted 1,4‐dihydropyridines was not deuterated after
purification, but it was 67% deuterated with a 2‐furyl group in the 4‐
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cycles. The resulting mixture was stirred at 50 °C (or 70 °C) for 24 h
(or 48 h), cooled to room temperature, diluted with EA and then
washed with saturated NaHCO3 and brine. The organic layer was
dried over anhydrous Na2SO4 and concentrated in vacuo. The crude
product was further purified by silica gel chromatography. Hydrogen
1
isotope distribution of the products was determined by LC‐MS. H
NMR was performed to determine deuterium incorporation.
Diethyl 2,6‐bis(methyl‐d3)pyridine‐3,5‐dicarboxylate (1a’‐d6). 1a
(50.7 mg, 0.2 mmol) and TFA‐d (23 μL, 0.3 mmol) were used
according to general procedure 1 to obtain 1a’‐d6 as a white solid
(36.5 mg, 0.142 mmol, 71%, 85% D). The same result was obtained
as 1a’ (50.3 mg, 0.2 mmol) and TFA‐d (23 μL, 0.3 mmol) were used
according to general procedure 1. 1H NMR (500 MHz, CDCl3) δ 8.64
(s, 1H), 4.37 (q, J = 7.2 Hz, 4H), 2.82 ‐ 2.76 (m, 0.9H), 1.39 (t, J = 7.1
Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 166.0, 162.3, 141.0, 123.2, 61.5,
24.9, 24.8, 24.7, 24.5, 24.4, 24.3, 24.2, 24.1, 14.4.
Diisopropyl 2,6‐bis(methyl‐d3)pyridine‐3,5‐dicarboxylate (1b’‐
d6). 1b (56.3 mg, 0.2 mmol) and TFA‐d (23 μL, 0.3 mmol) were used
according to general procedure 1 to obtain 1b’‐d6 as a white solid
(40.4 mg, 0.142mmol, 71%, 77% D). 1H NMR (500 MHz, CDCl3) δ 8.59
(s, 1H), 5.24 (hept, J = 6.3 Hz, 2H), 2.82 ‐ 2.76 (m, 1.4H), 1.37 (d, J =
6.3 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 165.8, 161.8, 140.9, 123.8,
69.2, 24.9, 24.8, 24.8, 24.7, 24.6, 24.5, 24.4, 24.2, 22.0.
Di‐tert‐butyl 2,6‐bis(methyl‐d3)pyridine‐3,5‐dicarboxylate (1c’‐
d6). 1c (61.8 mg, 0.2 mmol) and TFA‐d (23 μL, 0.3 mmol) were used
according to general procedure 1 to obtain 1c’‐d6 as a white solid
(44.8 mg, 0.144 mmol, 72%, 81% D). 1H NMR (500 MHz, CDCl3) δ 8.51
(s, 1H), 2.79 ‐ 2.74 (m, 1.2H), 1.59 (d, J = 1.1 Hz, 18H). 13C NMR (126
MHz, CDCl3) δ 165.6, 161.2, 140.9, 124.8, 82.2, 28.3, 25.0, 24.9, 24.8,
24.7, 24.6, 24.5, 24.4, 24.2.
Diethyl 2,6‐bis(ethyl‐1,1‐d2)pyridine‐3,5‐dicarboxylate (1d’‐d4).
1d (28.1 mg, 0.1 mmol) and TFA‐d (12 μL, 0.150 mmol) were used
according to general procedure 1 to obtain 1d’‐d4 as a pale yellow
solid (23.2 mg, 0.082 mmol, 82%, 71% D). 1H NMR (500 MHz, CDCl3)
δ 8.60 (s, 1H), 4.39 (q, J = 7.1 Hz, 4H), 3.22‐3.13 (m, 1.2H), 1.41 (t, J =
7.1 Hz, 6H), 1.29 (d, J = 8.5 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 167.0,
166.2, 141.4, 122.8, 61.6, 30.5, 30.2, 14.4, 14.0, 14.0, 13.9.
Scheme 4 Proposed mechanism.
From the above experimental results, it was clear that carbonyl or
ester groups in the 3,5‐positions of 1,4‐ dihydropyridines directed
deuteration towards alkyl groups at the 2,6‐positions. Our protocol
is also suitable for the corresponding pyridines. Deuteration is not
possible without a Brønsted or Lewis acid. The electron‐donating or
‐withdrawing properties of substituents at the 4‐position had little
effect HIE carbon centres. On the basis of these observations, an
acid‐promoted enol interconversion and enamine exchange is
proposed in Scheme 4. The reaction proceeds to the right under
acidic and heating conditions. A study of the detailed reaction
mechanism, including how oxygen affected deuteration, is now in
progress in our laboratory.
Experimental
Materials and methods
All reagents were purchased from commercial sources and used
without further purification unless otherwise noted. Reactions were
monitored by thin‐layer chromatography (TLC). Visualization was
achieved under a UV lamp (254 nm and 365 nm). Column
1
chromatography was performed using 200‐300 mesh silica gels. H
and 13C NMR spectra were acquired on 400 and 500 MHz Bruker NMR
instruments. NMR chemical shifts were reported in ppm and were
referenced to TMS (δ = 0.00 ppm, 1H NMR) or the residual solvent
1
peak for CDCl3 (δ = 7.26 ppm, H NMR; δ = 77.16 ppm, 13C NMR).
Diethyl 2,6‐bis(propan‐2‐yl‐2‐d)pyridine‐3,5‐dicarboxylate (1e’‐
d2). 1e (61.9 mg, 0.2 mmol) and TFA‐d (23 μL, 0.3 mmol) were used
according to general procedure 1 to obtain 1e’‐d2 as a white solid
(46.1 mg, 0.150 mmol, 75%, 19% D). 1H NMR (400 MHz, CDCl3) δ 8.43
(s, 1H), 4.37 (q, J = 7.1 Hz, 4H), 3.86 (hept, J = 6.7 Hz, 1.6H), 1.39 (t, J
= 7.1 Hz, 6H), 1.28 (d, J = 6.7 Hz, 12H). 13C NMR (101 MHz, CDCl3) δ
169.4, 166.7, 140.3, 122.2, 61.5, 32.9, 22.3, 22.2, 14.4.
1,1'‐(2,6‐bis(methyl‐d3)pyridine‐3,5‐diyl)bis(ethan‐1‐one‐2,2,2‐
d3) (1f’‐d12). 1f (38.7 mg, 0.2 mmol) and TFA‐d (23 μL, 0.3 mmol)
were used according to general procedure 1 to obtain 1f’‐d12 as a
pale yellow solid (26.0 mg, 0.128 mmol, 64%, 71% D, 61% D). 1H NMR
(500 MHz, CDCl3) δ 8.23 (s, 1H), 2.77 – 2.71 (m, 1.7H), 2.62 – 2.57 (m,
2.4H). 13C NMR (126 MHz, CDCl3) δ 199.4, 160.4, 138.0, 130.3, 29.5,
29.4, 29.3, 29.3, 29.2, 29.1, 29.0, 28.8, 24.9, 24.8, 24.7, 24.6, 24.5,
24.4, 24.2.
Following abbreviations are used for multiplicities: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad. Coupling
constants (J) are reported in Hertz.
Analytical LC‐MS were performed to determine the distribution of
hydrogen isotopes of the products on a Shimadzu LC‐MS 2020
system equipped with Hedera C18 column (2.1 x 100 mm, 3 μm;
heater set on 40 °C) involved a mobile phase of 0.1% formic acid (FA)
in water (solvent A) and 0.1% formic acid (FA) in acetonitrile (solvent
B) at a flow rate of 0.3 mL/min. All of the samples were performed
over the same gredient: from 15 to 55% B in 3 min, then from 55 to
95% B in 7 min, and 95% B for 5 min, 0.1% FA, λ = 254 nm.
General procedure 1 for HIE reactions. To a 10 mL Schlenk tube
with a magnetic bar was added 1,4‐dihydropyridines (0.2 mmol), D2O
(10 mmol, 181 μL), TFA‐d (23 μL, 0.3 mmol (or 154 μL, 2 mmol)) and
NMP (2 mL). The solution was freezed in liquid nitrogen, then the
vessel was evacuated and backfilled with nitrogen following by being
warmed to room temperature. The operation was repeated for 3
Diethyl 2,6‐bis(methyl‐d3) ‐4‐phenyl‐1,4‐dihydropyridine ‐3,5‐
dicarboxylate (2a‐d6). 2a (65.9 mg, 0.2 mmol) and TFA‐d (46 μL, 0.6
4 | J. Name., 2012, 00, 1‐3
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mmol) were used according to general procedure 1 to obtain 2a‐d6 4.05 (m, 4H), 3.81 (s, 3H), 2.31 – 2.24 (m, 1.2H), 1.23 (t, J = 7.1 Hz,
as a white solid (65.1 mg, 0.194 mmol, 97%, 77% D). 1H NMR (500 6H). 13C NMR (126 MHz, CDCl3) δ 167.9, 145.9, 144.0, 143.9, 143.8,
MHz, CDCl3) δ 7.30 – 7.26 (m, 2H), 7.20 (t, J = 7.7 Hz, 2H), 7.11 (td, J 140.2, 120.5, 114.0, 111.0, 104.3, 104.3, 59.8, 55.8, 39.2, 19.5, 19.4,
= 7.0, 1.4 Hz, 1H), 5.88 (s, 1H), 4.98 (s, 1H), 4.12 – 4.04 (m, 4H), 2.32 19.4, 19.3, 19.2, 19.1, 19.0, 19.0, 18.9, 18.8, 18.7, 14.4.
– 2.25 (m, 1.4H), 1.21 (t, J = 7.1 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ
167.8, 147.9, 144.1, 128.1, 127.9, 126.2, 104.2, 59.8, 39.7, 19.5, 19.4, dicarboxylate (2g‐d6). 2g (53.5 mg, 0.2 mmol) and TFA‐d (154 μL, 2
Diethyl 4‐methyl‐2,6‐bis(methyl‐d3) ‐1,4‐dihydropyridine‐ 3,5‐
19.4, 19.3, 19.2, 19.1, 19.0, 18.9, 18.7, 14.4.
Diethyl 4‐(2‐bromophenyl) ‐2,6‐bis(methyl‐d3)
mmol) were used according to general procedure 1 to obtain 2g‐d6
‐1,4‐ as a pale yellow solid (50.8 mg, 0.186 mmol, 93%, 77% D). H NMR
1
dihydropyridine‐3,5‐dicarboxylate (2b‐d6). 2b (81.7 mg, 0.2 mmol) (500 MHz, CDCl3) δ 5.74 (s, 1H), 4.27 – 4.13 (m, 4H), 3.84 (q, J = 6.5
and TFA‐d (154 μL, 2 mmol) were used according to general Hz, 1H), 2.28 – 2.21 (m, 1.4H), 1.30 (t, J = 7.1 Hz, 6H), 0.98 (d, J = 6.5
procedure 1 to obtain 2b‐d6 as a pale yellow solid (81.2 mg, 0.196 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 168.0, 144.4, 104.8, 104.8, 59.7,
mmol, 98%, 77% D). 1H NMR (500 MHz, CDCl3) δ 7.41 (dd, J = 8.0, 1.3 28.6, 22.4, 19.5, 19.4, 19.3, 19.2, 19.2, 19.1, 19.0, 18.9, 18.8, 18.8,
Hz, 1H), 7.37 (dd, J = 7.8, 1.8 Hz, 1H), 7.15 (td, J = 7.5, 1.3 Hz, 1H), 14.6.
6.93 (ddd, J = 7.9, 7.2, 1.7 Hz, 1H), 6.07 (s, 1H), 5.35 (s, 1H), 4.09 (qd,
J = 7.1, 4.7 Hz, 4H), 2.25 – 2.19 (m, 1.4H), 1.19 (t, J = 7.1 Hz, 6H). 13
Diethyl 4‐cyclohexyl‐2,6‐bis(methyl‐d3) ‐1,4‐dihydropyridine ‐
3,5‐dicarboxylate (2h‐d6). 2h (67.1 mg, 0.2 mmol) and TFA‐d (154 μL,
C
NMR (126 MHz, CDCl3) δ 167.9, 147.6, 143.9, 143.9, 132.8, 131.7, 2 mmol) were used according to general procedure 1 to obtain 2h‐d6
1
127.7, 127.5, 122.7, 104.2, 104.1, 59.8, 39.8, 19.5, 19.4, 19.3, 19.2, as a pale yellow solid (58.7 mg, 0.172 mmol, 86%, 80% D). H NMR
19.2, 19.1, 19.0, 18.9, 18.8, 18.8, 18.7, 18.6, 14.5.
(400 MHz, CDCl3) δ 6.04 (s, 1H), 4.24 – 4.05 (m, 4H), 3.89 (d, J = 5.7
Diethyl 2,6‐bis(methyl‐d3) ‐1,4‐dihydro‐[4,4'‐bipyridine] ‐3,5‐ Hz, 1H), 2.28 – 2.20 (m, 1.2H), 1.65 – 1.58 (m, 2H), 1.57 – 1.46 (m,
dicarboxylate (2c‐d6). 2c (66.1 mg, 0.2 mmol) and BF3ꞏOEt2 (494 μL, 3H), 1.26 (t, J = 7.1 Hz, 6H), 1.17 (dq, J = 6.0, 3.0 Hz, 1H), 1.09 – 0.98
4 mmol) were used according to general procedure 1 to obtain 2c‐d6 (m, 3H), 0.88 (qd, J = 13.6, 12.6, 5.1 Hz, 2H). 13C NMR (101 MHz,
as a pale yellow solid (63.9 mg, 0.190 mmol, 95%, 70% D). 1H NMR CDCl3) δ 168.9, 144.7, 101.9, 59.6, 45.9, 38.4, 28.9, 26.8, 26.7, 19.4,
(500 MHz, CDCl3) δ 8.42 (d, J = 5.1 Hz, 2H), 7.24 – 7.21 (m, 2H), 6.50 19.2, 19.0, 18.8, 18.6, 14.5.
(s, 1H), 5.00 (s, 1H), 4.13 – 4.05 (m, 4H), 2.34 – 2.27 (m, 1.8H), 1.21
Diethyl 4‐isopropyl ‐2,6‐bis(methyl‐d3) ‐1,4‐dihydropyridine ‐
(t, J = 7.1 Hz,61H). 13C NMR (126 MHz, CDCl3) δ 167.3, 156.7, 149.1, 3,5‐dicarboxylate (2i‐d6). 2i (59.1 mg, 0.2 mmol) and TFA‐d (154 μL,
145.3, 145.3, 123.6, 102.7, 102.7, 60.1, 39.6, 19.5, 19.4, 19.3, 19.2, 2 mmol) were used according to general procedure 1 to obtain 2i‐d6
1
19.1, 19.1, 18.9, 14.4.
as a white solid (53.0 mg, 0.176 mmol, 88%, 77% D). H NMR (500
Diethyl 4‐(furan‐2‐yl) ‐2,6‐bis(methyl‐d3)‐1,4‐dihydropyridine ‐ MHz, CDCl3) δ 5.92 (s, 1H), 4.15 (ddq, J = 39.2, 10.8, 7.1 Hz, 4H), 3.89
3,5‐dicarboxylate‐1‐d (2d‐d7). 2d (63.9 mg, 0.2 mmol) and TFA‐d (d, J = 5.5 Hz, 1H), 2.28‐2.22 (m, 1.4H), 1.56 (pd, J = 6.9, 5.4 Hz, 1H),
(154 μL, 2 mmol) were used according to general procedure 1 to 1.27 (t, J = 7.1 Hz, 6H), 0.72 (d, J = 6.9 Hz, 6H). 13C NMR (126 MHz,
obtain 2d‐d7 as a white solid (63.5 mg, 0.196 mmol, 98%, 81% D, ‐ND, CDCl3) δ 168.9, 144.8, 101.8, 59.7, 38.9, 35.6, 19.3, 19.2, 19.2, 19.1,
67% D). 1H NMR (500 MHz, CDCl3) δ 7.19 (dd, J = 1.8, 0.9 Hz, 0.3H), 19.0, 18.9, 18.8, 18.6, 14.5.
6.23 – 6.16 (m, 1H), 6.03 (s, 1H), 5.92 (d, J = 3.2 Hz, 1H), 5.19 (s, 1H),
4.21 – 4.09 (m, 4H), 2.31 – 2.25 (m, 1.1H), 1.25 (t, J = 7.1 Hz, 6H). 13
Diethyl 2,6‐bis(methyl‐d3) ‐4‐(pentan‐3‐yl)‐1,4‐ dihydropyridine‐
3,5‐dicarboxylate (2j‐d6). 2j (64.7 mg, 0.2 mmol) and TFA‐d (154 μL,
C
NMR (126 MHz, CDCl3) δ 167.7, 158.8, 158.7, 145.3, 140.9, 110.1, 2 mmol) were used according to general procedure 1 to obtain 2j‐d6
1
109.9, 104.5, 100.8, 59.9, 33.5, 19.5, 19.4, 19.3, 19.2, 19.2, 19.1, 19.0, as a white solid (55.4 mg, 0.168 mmol, 84%, 77% D). H NMR (500
18.9, 18.8, 18.8, 18.7, 18.5, 14.4.
Diethyl 2,6‐bis(methyl‐d3)
MHz, CDCl3) δ 5.70 (s, 1H), 4.21 – 4.09 (m, 5H), 2.27 – 2.21 (m, 1.4H),
‐4‐(thiophen‐3‐yl)‐1,4‐ 1.29 (t, J = 7.1 Hz, 6H), 1.14 (ddq, J = 20.9, 13.8, 7.1 Hz, 4H), 1.03 (qd,
dihydropyridine ‐3,5‐dicarboxylate (2e‐d6). 2e (67.1 mg, 0.2 mmol) J = 6.5, 4.5 Hz, 1H), 0.85 (t, J = 7.3 Hz, 6H). 13C NMR (126 MHz, CDCl3)
and TFA‐d (154 μL, 2 mmol) were used according to general δ 168.9, 144.7, 102.3, 59.7, 50.0, 34.6, 21.3, 19.4, 19.3, 19.2, 19.2,
procedure 1 to obtain 2e‐d6 as a pale yellow solid (67.3mg, 0.197 19.1, 19.0, 18.8, 18.7, 18.6, 14.4, 11.9.
mmol, 99%, 82% D). 1H NMR (500 MHz, CDCl3) δ 7.11 (dd, J = 5.0, 3.1
3‐isobutyl 5‐methyl 2,6‐bis(methyl‐d3)‐4‐(2‐nitrophenyl)‐1,4‐
Hz, 1H), 6.98 (dd, J = 5.0, 1.3 Hz, 1H), 6.91 (dd, J = 3.3, 1.3 Hz, 1H), dihydropyridine‐3,5‐dicarboxylate (2k‐d6). 2k (77.7 mg, 0.2 mmol)
5.96 (s, 1H), 5.13 (s, 1H), 4.19 – 4.07 (m, 4H), 2.30 – 2.24 (m, 1.1H), and TFA‐d (154 μL, 2 mmol) were used according to general
1.24 (t, J = 7.1 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 167.8, 148.0, procedure 1 to obtain 2k‐d6 as a yellow solid (74.9 mg, 0.190mmol,
1
144.6, 144.6, 127.7, 124.7, 120.4, 103.5, 103.5, 77.4, 77.2, 76.9, 59.9, 95%, 79% D). H NMR (500 MHz, CDCl3) δ 7.67 (dd, J = 8.1, 1.3 Hz,
34.7, 19.4, 19.3, 19.2, 19.2, 19.1, 19.0, 18.9, 18.8, 18.8, 18.7, 18.6, 1H), 7.51 (dd, J = 7.9, 1.5 Hz, 1H), 7.44 (td, J = 7.6, 1.3 Hz, 1H), 7.22
14.4.
(ddd, J = 8.5, 7.2, 1.5 Hz, 1H), 6.14 (s, 1H), 5.76 (s, 1H), 3.83 – 3.75 (m,
Diethyl 4‐(4‐hydroxy‐3‐methoxyphenyl) ‐2,6‐bis(methyl‐d3) ‐1,4‐ 2H), 3.56 (s, 3H), 2.34 – 2.27 (m, 0.6H), 2.27 – 2.20 (m, 0.6H), 1.87
dihydropyridine‐3,5‐dicarboxylate (2f‐d6). 2f (75.1 mg, 0.2 mmol) (dt, J = 13.5, 6.7 Hz, 1H), 0.76 (d, J = 6.7 Hz, 3H), 0.71 (d, J = 6.7 Hz,
and TFA‐d (154 μL, 2 mmol) were used according to general 3H). 13C NMR (126 MHz, CDCl3) δ 167.8, 167.5, 147.9, 145.1, 145.0,
procedure 1 to obtain 2f‐d6 as a white solid (75.4 mg, 0.198 mmol, 142.5, 132.9, 131.2, 127.1, 124.1, 103.9, 103.5, 70.5, 51.1, 34.7, 27.6,
99%, 80% D). 1H NMR (500 MHz, CDCl3) δ 6.84 (d, J = 1.6 Hz, 1H), 6.75 19.1.
– 6.70 (m, 2H), 5.88 (s, 1H), 5.63 – 5.52 (m, 1H), 4.91 (s, 1H), 4.13 –
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 5
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DOI: 10.1039/C9OB00575G
ARTICLE
3‐isopropyl
Journal Name
5‐(2‐methoxyethyl)
2,6‐bis(methyl‐d3)‐4‐(3‐ 142.2, 127.7, 61.7, 23.0, 22.9, 22.8, 22.7, 22.6, 22.6, 22.5, 22.4, 22.3,
nitrophenyl)‐1,4‐dihydropyridine‐3,5‐dicarboxylate (2l‐d6). 2l (83.7 22.2, 22.2, 17.0, 16.9, 16.8, 16.7, 16.7, 16.6, 16.4, 16.3, 16.3, 16.2,
mg, 0.2 mmol) and TFA‐d (154 μL, 2 mmol) were used according to 14.3.
general procedure 1 to obtain 2l‐d6 as a pale yellow solid (79.8 mg,
Dimethyl 2,6‐bis(methyl‐d3) ‐4‐(2‐nitrophenyl)pyridine ‐3,5‐
0.188 mmol, 94%, 68% D). 1H NMR (400 MHz, CDCl3) δ 8.12 (t, J = 2.0 dicarboxylate (3d‐d6). 3d (68.9 mg, 0.2 mmol) and TFA‐d (154 μL, 2
Hz, 1H), 7.98 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 7.65 (dt, J = 7.7, 1.4 Hz, mmol) were used according to general procedure 1 to obtain 3d‐d6
1H), 7.36 (t, J = 7.9 Hz, 1H), 6.04 (s, 1H), 5.08 (s, 1H), 4.93 (p, J = 6.2 as a white solid (68.0 mg, 0.194 mmol, 97%, 78% D). 1H NMR (500
Hz, 1H), 4.22 – 4.10 (m, 2H), 3.59 – 3.47 (m, 2H), 3.33 (s, 3H), 2.35 – MHz, CDCl3) δ 8.18 (dd, J = 8.1, 1.3 Hz, 1H), 7.62 (td, J = 7.5, 1.4 Hz,
2.28 (m, 2H), 1.24 (d, J = 6.2 Hz, 3H), 1.07 (d, J = 6.2 Hz, 3H). 13C NMR 1H), 7.55 (ddd, J = 8.9, 7.6, 1.5 Hz, 1H), 7.18 (dd, J = 7.5, 1.5 Hz, 1H),
(126 MHz, CDCl3) δ 167.2, 166.7, 150.1, 148.2, 145.3, 144.5, 134.8, 3.48 (s, 6H), 2.64 – 2.59 (m, 1.3H). 13C NMR (126 MHz, CDCl3) δ 167.3,
128.7, 123.4, 121.4, 104.0, 103.1, 70.6, 67.4, 63.1, 59.0, 40.1, 22.2, 157.1, 147.7, 145.3, 133.0, 132.1, 130.7, 129.7, 124.9, 124.4, 52.3,
21.9, 19.6, 19.5, 19.4, 19.4, 19.3, 19.2, 19.1, 19.0.
Dimethyl 2,6‐bis(methyl‐d3) ‐4‐(2‐nitrophenyl)
23.6, 23.5, 23.5, 23.4, 23.3, 23.2, 23.1, 23.1, 23.0, 22.9, 22.8.
‐1,4‐
dihydropyridine‐ 3,5‐dicarboxylate (2m‐d6). 2m (69.3 mg, 0.2 mmol)
and TFA‐d (154 μL, 2 mmol) were used according to general
procedure 1 to obtain 2m‐d6 as a yellow solid (67.7 mg, 0.192 mmol,
Conclusions
In summary, we have found a simple, effective, economical, and
functional group compatible method for deuteration of 1,4‐
dihydropyridines and the corresponding pyridines, which
occurred selectively at the alkyl groups in the 2,6‐positions. 4‐
Substituted 1,4‐dihydropyridines were deuterated more slowly
than their unsubstituted counterparts. This protocol
complemented existing acid‐mediated labelling processes.
1
96%, 79% D). H NMR (500 MHz, CDCl3) δ 7.65 (dd, J = 8.1, 1.3 Hz,
1H), 7.50 (dd, J = 7.9, 1.5 Hz, 1H), 7.44 (td, J = 7.6, 1.4 Hz, 1H), 7.23
(ddd, J = 8.4, 7.2, 1.5 Hz, 1H), 6.15 (s, 1H), 5.70 (s, 1H), 3.57 (s, 6H),
2.32 – 2.23 (m, 1.3H). 13C NMR (126 MHz, CDCl3) δ 167.7, 147.9,
145.2, 145.2, 142.3, 132.9, 131.1, 127.1, 124.0, 103.6, 103.6, 51.1,
34.6, 19.4, 19.3, 19.2, 19.2, 19.1, 19.0, 18.9, 18.8, 18.8, 18.7, 18.6.
3‐ethyl
chlorophenyl)
5‐methyl
2‐((2‐aminoethoxy)methyl
‐d2)‐4‐(2‐
‐3,5‐
‐6‐(methyl‐d3)
‐1,4‐dihydropyridine
Conflicts of interest
dicarboxylate (2n‐d5). Amlodipine besylate (113.4 mg, 0.2 mmol)
and TFA‐d (154 μL, 2 mmol) were used according to general
procedure 1 to obtain 2n‐d5 as a wite solid (79.9 mg, 0.194 mmol,
97%, 80% D, 77% D). 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 1H), 7.37
(dd, J = 7.8, 1.7 Hz, 1H), 7.20 (dd, J = 8.0, 1.4 Hz, 1H), 7.11 (td, J = 7.5,
1.4 Hz, 1H), 7.01 (td, J = 7.5, 1.7 Hz, 1H), 5.38 (s, 1H), 5.07 (s, 2H), 4.81
– 4.67 (m, 0.5H), 4.07 – 3.96 (m, 2H), 3.68 (hept, J = 5.2 Hz, 2H), 3.58
(s, 3H), 3.09 (t, J = 4.7 Hz, 2H), 2.33 (d, J = 11.0 Hz, 0.6H), 1.16 (t, J =
7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 168.3, 167.4, 145.9, 145.2,
145.1, 145.1, 144.8, 132.4, 131.6, 129.3, 127.5, 127.0, 103.8, 102.2,
102.2, 102.1, 70.0, 68.2, 60.0, 50.9, 40.5, 37.3, 18.7, 14.3.
There are no conflicts to declare.
Acknowledgements
This work was supported by National Natural Science
Foundation of China (31771584), Shenzhen Basic Research
Project (JCYJ20170818100153423), Science Foundation of SZU
(Grant 000193) and Middle–aged Researchers in the Higher
Education Institutions of Hubei Province (T201702).
Diethyl (E)‐4‐(2‐(3‐(tert‐butoxy)‐3‐oxoprop‐1‐en‐1‐yl)phenyl)‐
2,6‐bis(methyl‐d3)‐1,4‐dihydropyridine‐3,5‐dicarboxylate (2o‐d6).
2o (91.1 mg, 0.2 mmol) and TFA‐d (154 μL, 2 mmol) were used
according to general procedure 1 to obtain 2o‐d6 as a white solid
(89.5 mg, 0.194 mmol, 97%, 80% D). 1H NMR (500 MHz, CDCl3) δ 8.44
(d, J = 15.8 Hz, 1H), 7.46 (dd, J = 7.9, 1.4 Hz, 1H), 7.40 (dd, J = 7.9, 1.3
Hz, 1H), 7.23 (td, J = 7.6, 1.4 Hz, 1H), 7.10 (td, J = 7.6, 1.4 Hz, 1H), 6.25
(d, J = 15.9 Hz, 1H), 5.99 (s, 1H), 5.32 (s, 1H), 4.05 (dq, J = 10.8, 7.2
Hz, 2H), 3.93 (dq, J = 10.8, 7.1 Hz, 2H), 2.31 – 2.24 (m, 1.2H), 1.53 (s,
9H), 1.13 (t, J = 7.1 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 167.6, 166.8,
148.5, 144.3, 144.3, 143.9, 132.0, 130.6, 130.1, 126.5, 125.5, 120.2,
104.7, 104.6, 80.2, 59.8, 35.8, 28.4, 19.2, 19.1, 19.0, 18.9, 18.8, 18.6,
14.4.
Diethyl 2,4,6‐tris(methyl‐d3)pyridine‐3,5‐dicarboxylate (3c‐d9).
3c (53.1 mg, 0.2 mmol) and TFA‐d (154 μL, 2 mmol) were used
according to general procedure 1 to obtain 3c‐d9 as a colorless oil
(53.8 mg, 0.196 mmol, 98%, 70% D, 78% D). 1H NMR (500 MHz, CDCl3)
δ 4.38 (q, J = 7.1 Hz, 4H), 2.50 – 2.44 (m, 1.8H), 2.24 – 2.20 (m, 0.7H),
1.36 (t, J = 7.1 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 168.4, 155.0,
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