Organocatalytic Deuteration Induced by the Dynamic Covalent Interaction of Imidazolium Cations with Ketones

Article abstract of DOI:10.1002/adsc.202001507

In this article, we suggest a new organocatalytic approach based on the dynamic covalent interaction of imidazolium cations with ketones. A reaction of N-alkyl imidazolium salts with acetone-d₆ in the presence of oxygenated bases generates a dynamic organocatalytic system with a mixture of protonated carbene/ketone adducts acting as H/D exchange catalysts. The developed methodology of the pH-dependent deuteration showed high selectivity of labeling and good chiral functional group tolerance. Here we report a unique methodology for efficient metal-free deuteration, which enables labeling of various types of α-acidic compounds without trace metal contamination. (Figure presented.).

Full text of DOI:10.1002/adsc.202001507

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DOI: 10.1002/adsc.202001507
Organocatalytic Deuteration Induced by the Dynamic Covalent
Interaction of Imidazolium Cations with Ketones
Konstantin I. Galkin,a Evgeniy G. Gordeev,a and Valentine P. Ananikova,*
a
Zelinsky Institute of Organic Chemistry Russian Academy of Sciences,
Leninsky Prospekt, 47, Moscow, 119991, Russia
Fax: +7 499 135–53-28
Phone: +7 499 137–29-44
E-mail: val@ioc.ac.ru
Manuscript received: December 3, 2020; Revised manuscript received: December 22, 2020;
Version of record online: January 7, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001507
Abstract: In this article, we suggest a new organocatalytic approach based on the dynamic covalent
interaction of imidazolium cations with ketones. A reaction of N-alkyl imidazolium salts with acetone-d6 in the
presence of oxygenated bases generates a dynamic organocatalytic system with a mixture of protonated
carbene/ketone adducts acting as H/D exchange catalysts. The developed methodology of the pH-dependent
deuteration showed high selectivity of labeling and good chiral functional group tolerance. Here we report a
unique methodology for efficient metal-free deuteration, which enables labeling of various types of α-acidic
compounds without trace metal contamination.
Keywords: organocatalysis; dynamic covalent chemistry; N-heterocyclic carbenes; pharmaceuticals; deuteration
Introduction
currently underway.[4b,6] Extremely important is to
develop metal-free catalytic systems, which would
Deuterium labeling is a promising synthetic approach allow deuteration of pharmaceutical substances without
that affords new pharmaceuticals with enhanced metal contamination. Several metal-based catalytic
pharmacokinetic properties and reduced toxicity, systems suffer from trace metal contamination of the
whereas the pharmacodynamic properties of deuterated products, where purification to required level (typically
drugs and their non-labeled analogs are generally <1 ppm of trace metal contamination) is costly and
identical.[1] This is possible because deuterated com- rather difficult to achieve.
pounds are metabolized more slowly owing to the
Deuteration of functional groups that are directly
increased strength of CÀ D bonds as compared with involved in drug metabolism is required to achieve
CÀ H bonds.[2] Moreover, deuteration at specific posi- desired metabolic effects, and selective post-modifica-
tions in a drug molecule may provide metabolic tion is one of the most efficient approach. In this
stabilization of the drug (by causing a reduction in the regard, deuteration at the α-position to pharmacophoric
rate of its degradation) or its safe disposal (by switch- functional groups in drugs and other bioactive com-
ing its degradation pathways away from toxic pounds without side processes such as racemization or
metabolites).[3] In 2016, the first deuterated pharma- decomposition is an important and challenging task. In
ceutical deutetrabenazine (a derivative of tetrabena- some cases, deuteration methods suitable for labeling
zine, deuterated at six hydrogen positions in the two of drugs should not produce significant effects on
methoxy groups) was approved by FDA.[4] Increasing sensitive asymmetric centers, since such effects are
the half-life of active metabolites allowed to signifi- usually difficult to control. The general approaches to
cantly reduce the dose and concomitantly the adverse the α-deuteration include transition metal-catalyzed
effects of the drug in Huntington’s chorea patients.[5] labeling or pH-dependent H/D exchange.[7] The dis-
Leading pharmaceutical companies are now keen on advantages of the first approach are the risks of metal
developing deuterated analogs for other drugs, and contamination and that the introduction of the directing
several clinical trials for deuterated drug candidates are group to the starting substrate is usually required to
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achieve the high selectivity of labeling (Scheme 1A). and ketones leading to the formation of a mixture of
The classical methods of pH-dependent deuteration the C2 and C4 adducts as kinetic and thermodynamic
involve acid- or base-catalyzed H/D exchange between products, respectively (Scheme 2A).[12] This phenom-
a deuterated solvent and a substrate through the enon, explained by in situ generation of the H-bonded
formation of an enolate intermediate in the case of abnormal NHCs (aNHCs) and the ditopic carbanionic
carbonyl compounds (Scheme 1B).[7b,8] For α-deutera- NHCs (dcNHCs) along with the classical C2 carbenes
tion of compounds with low-acidic protons, the from the cationic imidazolium precursors, reflects the
presence of strong bases or protic deuterated solvents dynamic nature of organocatalysis mediated by a
is generally required,[9] which may be undesirable for covalent interaction of NHCs with carbonyl substrates.
the labeling of drugs and other complex substrates due In the case of ketones, the formation of the C4 adducts
to the side processes such as hydrolysis, racemization, by aNHC- and dcNHC-based mechanisms was found
or re-esterification. N-heterocyclic carbenes (NHCs) possible, and the preference for the dcNHC pathway
have received significant attention as efficient organo- was theoretically explained. In particular, we studied
catalysts for medicinal chemistry.[10] Several recent the addition of imidazolium cations to acetone and
publications demonstrate the successful application of some other ketones in the presence of various bases by
NHCs for the catalysis of H/D exchange, including the high-resolution electrospray ionization mass spectrom-
labeling of some complex bioactive compounds.[1f,11] etry (HRMS-ESI, see Table S1 for details). The strong
However, the organocatalytic pH-dependent deutera- influence of steric properties of imidazolium salts on
tion of carbonyl compounds with NHC as a proton their reactivity with ketones was evident: the highest
shuttle showed high efficiency of labeling only for relative intensities of the peaks with (m/z) correspond-
highly acidic substrates (Scheme 1C).[11c]
ing to the imidazolium cation/ketone adducts were
In our previous work, we described the ambident detected for the salts containing α-unbranched N-alkyl
reactivity of imidazolium cations towards aldehydes substituents with chloride or acetate as a counterion.
Scheme 1. General approaches to deuteration of α-acidic compounds: transition metal-catalyzed deuteration (A) or pH-dependent
H/D exchange (B–D).
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control of deuterium incorporation by the proposed
method was found for the low acidic substrates:
efficient labeling of acetate esters, lactones and
acetonitrile is opposed to retarded reactivity towards
secondary linear and tertiary esters.
Results and Discussion
We have explored the principal possibility for the
development of pH-dependent α-deuteration using a
dynamic organocatalytic system based on imidazolium
cation/ketone adducts (which are tertiary imidazolium
alcohols with labile hydroxyl group) as H/D transfer
mediators. Firstly, we applied a catalytic system based
on the commercially available imidazolium salts 1a
[Cl]–1c[Cl] and acetone-d6 (and, for comparison, some
other protic and aprotic deuterated solvents), which
served as both an aprotic deuterated solvent and a
source for formation of imidazolium alcohols, in the
presence of moderately basic oxygenates or amines.
Cyclohexanone 7 and 2-ethoxyethyl acetate 12 were
chosen as the model substrates (Table 1, Table S3, and
Table S4). Most combinations of imidazolium salts,
bases and deuterated solvents showed low efficiency
of deuteration (Table 1, entries 1–4). As was expected,
a combination of [1a]Cl with acetone-d6 in the
presence of oxygenated bases showed the highest
catalytic activity for deuteration (entries 6–9).
Scheme 2. The dynamic covalent bonding of imidazolium
carbenes to carbonyl compounds (possible substituents in the
structure I-d include deuterated normal (C2) and abnormal (C4
or C5) monoadducts of imidazolium cations with acetone-d6; in
the structure II-d include deuterated diadducts of imidazolium
cations with acetone-d6).
After optimization of the reaction conditions,
products 7–d4 and 12–d3 were obtained with 97% and
91% degree of substitution in the presence of sodium
acetate and potassium carbonate, respectively. For
comparison, when deuteration of 12 was performed in
For the reaction of some sterically unhindered imida- the protic deuterated solvents (D2O or methanol-d4,
zolium salts with acetone in the presence of potassium entries 4, 5), high efficiency of labeling was achieved
carbonate as a base, the peak with (m/z) corresponding in the case of deuterated methanol, but re-esterification
to diadduct was also detected. “Abnormal” adducts was also considerable.
[1aa]Cl and [1ab]Cl formed by the reaction of the
The influence of the nature of imidazolium salt on
ionic liquid 1-butyl-3-methyl-imidazolium chloride the efficiency of the H/D exchange was also studied.
([BMIm]Cl, [1a]Cl) with acetone or acetophenone, No deuteration was observed in the presence of salts
respectively, were isolated in pure form and charac- [1b]Cl and [1c]Cl, which are poorly soluble in acetone
terized.
(Table 1, entries 2 and 3). Strong influence of steric
In this work, we used these findings for the properties of the catalysts on the degree of deuteration
development of a new organocatalytic approach to the was noted: only the N-methyl substituted imidazolium
pH-dependent deuteration based on the dynamic cations [1a]+, [1c]+, and [1d]+, containing α-un-
covalent interaction of imidazolium carbenes with branched substituents at the second nitrogen atom,
deuterated acetone (Scheme 1D, Scheme 2B). The showed high catalytic activity (entries 8–12). The N-
catalytic system containing sterically unhindered N- ethyl substituted salts [1e]Cl and [1f]Cl showed lower
alkyl imidazolium salts (as NHC, dcNHC or aNHC catalytic activity, and no deuteration was observed
precursors) and acetone-d6 in the presence of oxy- with the N-isopropyl substituted salts [1g]Cl and [1h]
genated bases was efficiently utilized for α-deuteration Cl (entries 13–15). Similarly, no deuteration occurred
of model compounds and pharmaceuticals including in the presence of benzimidazolium salt [1i]Cl and
low acidic substrates (esters, lactones and acetonitrile). C(4,5)-substituted imidazolium salt [1j]Cl. In contrast,
The tertiary imidazolium alcohols formed by nucleo- the C2-substituted imidazolium salt [1k]Cl, capable of
philic addition of imidazolium cations to acetone-d6 at forming C4 adducts with ketones, showed moderate
the C2 and C4 carbene centers were identified as H/D catalytic activity (entries 16–18). The importance of
transfer mediators in the deuteration process. Steric the nature of counterion was also significant: the
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deuterated products were afforded in moderate to high
yields (Scheme 3 and Figure 1). Aryl and alkyl
Table 1. Optimization of reaction conditions for the deuteration
of esters.
N Imidazolium salt
T, Solvent
[D],
%
o
[a]
°
C
*
1
[BMIm]Cl, [1a]Cl or [IMes H] 80 CDCl3 or
0–3
Cl, [1b]Cl
CD3CN
2
3
4
5
6
7
8
9
[1b]Cl
[EMIm]Cl, [1c]Cl
–
–
[1a]Cl
[1a]Cl
[1a]Cl
[1a]Cl
80 acetone-d6
80 acetone-d6
80 D2O
0
4
0[b]
98[c]
13[d]
75
91
84
81
90
76
37
35
0
80 CD3OD
80 acetone-d6
60 acetone-d6
80 acetone-d6
100 acetone-d6
80 acetone-d6
80 acetone-d6
80 acetone-d6
80 acetone-d6
80 acetone-d6
10 [1a][OAc]
11 [1c][OAc]
12 [HMIm]Cl, [1d]Cl
13 [E2Im]Cl, [1e]
14 [BEIm]Cl, [1f]
15 [IMIm]Cl, [1g]Cl or [I2Im]Cl, 80 acetone-d6
[1h]Cl
16 [1i]Cl[e]
80 acetone-d6
80 acetone-d6
80 acetone-d6
80 acetone-d6
80 acetone-d6
80 acetone-d6
0
0
17 [BM(4,5-M2)Im]Cl, [1j]Cl
18 [BM(2-E)Im]Cl, [1k]Cl
19 [1a]Br (IÀ or [BF4]À )
20 [1a]Cl
33
0
0[f]
0
Scheme 3. Deuteration of representative carbonyl-containing
21 –
compounds and nitriles.
Reaction conditions: 12 (1 mmol), base (0.2 eq.), azolium salt
(0.5 eq.), d-solvent (1.5 mL).
[a] Degree of deuteration.
[b] Hydrolysis was detected.
[c] Re-esterification was detected.
[d] Sodium acetate as a base.
[e] 1-Butyl-3-methyl-1H-benzimidazolium chloride.
[f] Without base. 1-R-3-R1-imidazolium salts are denoted as
[RR1Im][anion]; C-substituted 1-R-3-R1-imidazolium salts
are denoted as [RR1(R2)Im][anion]; M, methyl; E, ethyl; I,
isopropyl; B, n-butyl; H, n-hexyl; IMes, 1,3-bis(2,4,6-
trimethylphenyl)-imidazol-2-ylidene. See Supporting Infor-
mation for more details on the optimization of the reaction
conditions.
deuteration occurred only with the salts with ClÀ or
acetate anion, but not with the salts with BrÀ , IÀ , or
BF4À anions (entries 10, 11, and 19). Deuteration of 12
did not proceed without [1a]Cl or in the absence of a
base (entries 20, 21).
To study the versatility of the developed catalytic
system, we tested a series of model carbonyl com-
pounds and bioactive substances including pharma-
ceuticals. With slight modifications of the reaction
conditions, high degrees of labeling were achieved for
the majority of the tested substrates. The desired
Figure 1. Deuteration of drugs and other bioactive compounds.
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ketones, including donor and acceptor acetophenones organocatalytic system (formed in situ from [1a]Cl
2–6 and cyclic ketones 7–9, were labeled with>90% and sodium acetate) (entries 8, 9). In the case of
degree of substitution. Similarly, drug molecules deuterated water under the same reaction conditions,
containing enolizable keto-groups, including tolperi- the degree of labeling of 29 was significantly lower
sone 24, androsterone 25, were successfully deuterated (13% and 9% of deuterium incorporation in methyl
with>70% degree of substitution. Enone 10, verbe- and methylene groups, respectively; entry 10). Such a
none 26 and the fungistatic drug griseofulvin 28 were poor efficiency of the sodium acetate/deuterated water
efficiently and selectively deuterated at the enolizable system in the deuteration process in comparison to
positions only. Mesityl oxide 11 was fully deuterated other used systems may be explained by its lowest
with>90% degree of substitution.
basicity (Table S2).
For evaluation of the performance of our organo-
Griseofulvin 28 was unable to undergo deuteration
catalytic approach, we compared labeling of griseoful- in the presence of sodium acetate or in a deuterated
vin 28 and pentoxyphilline 29 (a precursor for the water medium (Table 2, entries 1–3). When potassium
experimental deuterated phosphodiesterase inhibitor carbonate was chosen, an 85% degree of labeling of
CTP-499) as representative examples by organocata- only enolizable CH2 group in 28 was achieved using
lytic and classical methods based on protic deuterated the organocatalytic method (entries 4, 5). In contrast,
solvents (Table 2). In the presence of potassium deuteration of 28 by potassium carbonate in methanol-
°
carbonate, all used methods showed more than 90% d4 at 80 C result in multiple labeling of both meth-
degree of labeling of pentoxyphilline 29 (entries 11– ylene and vinyl protons, re-etherification by deuterated
13). Then sodium acetate was used as a base, methanol and approximately 32% decomposition (en-
compound 29 was deuterated with >70% efficiency try 7).
using deuterated methanol or [1a][OAc]/acetone-d6
Table 2. Deuteration of pentoxyphilline (29) and griseofulvin (28) by various methods.
No
Substrate
T, C
Base
Deuteration system
Degree of deuteration [D], %[a]
°
CD2
CD
CD3
CD3’
CD3’’
1
2
3
4
28
28
28
28
28
28
28
29
29
29
29
29
29
80
80
80
60
80
60
80
80
80
80
80
80
80
NaOAc
NaOAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOAc
NaOAc
NaOAc
K2CO3
K2CO3
K2CO3
Methanol-d4 or D2O
[1a]Cl/acetone-d6
D2O
[1a]Cl/acetone-d6
[1a]Cl/acetone-d6
Methanol-d4
Methanol-d4
[1a]Cl/acetone-d6
Methanol-d4
D2O
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
N/A
–
–
–
–
–
–
40
85
78
93
81
89
13
95
94
98
5
0
0
0
6
51
94
–
–
–
–
–
–
21
77
73
88
9
95
92
97
48
N/A
–
–
–
–
–
–
7[b]
8
9
10
11
12
13
[1a]Cl/acetone-d6
Methanol-d4
D2O
Reaction conditions: substrate (0.2 mmol), base (0.2 eq.), [1a]Cl (0.5 eq.), 0.6 mL of solvent.
[a] Was detected by NMR.
[b] Approximately 32% decomposition was observed by NMR.
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°
Decreasing of the reaction temperature to 60 C led
to smaller decomposition of the starting substrate, but
the low selectivity of labeling and partial re-ether-
ification were still considerable (entry 6). Thus, the
organocatalytic method can show higher efficiency and
selectivity of labeling in the case of complex ketonic
substrates than the classical approaches based on protic
deuterated solvents.
In contrast to reported methods, the deuteration
efficiency by our organocatalytic system strongly
depended on the acidity and steric properties of the
ester substrates. Deuteration of aryl esters 16 and 17
containing a relatively acidic proton at the α-position
to the ester group proceeded with a high degree of
substitution, accompanied by racemization in the case
of optically active substrates. Steric effects were
especially pronounced in the deuteration of unactivated
esters and nitriles: modifications of acetyl ester 12,
acetonitrile and famciclovir 30 proceeded with 91%,
94% and 77% deuterium incorporation respectively. In
contrast to acetyl esters, the more sterically hindered
secondary and tertiary esters 18–21 and butyronitrile
23 were deuterated with only 9–16% efficiency. Chiral
amino acid esters 21 and 22 resisted deuteration (0%).
In contrast to the linear secondary and tertiary esters,
deuterations of α-unsubstituted lactones 13–15 and
hypolipidemic drug simvastatin 31 proceeded with
high levels of deuterium incorporation. Based on these
results, we performed chemoselective deuteration of
lovastatin 32 containing both a non-epimerizable
lactone and an epimerizable alkyl ester. Labeling of
lovastatin at the lactone functional group proceeded
with a 90% degree of deuteration. Retention of the
configuration and the absence of any modification at
α-position in the chiral ester functional group in 32–d2
was confirmed by NMR, HPLC and X-ray analysis
(see Supporting Information).[13]
Scheme 4. The proposed general mechanism of deuteration.
imidazolium salts in the deuteration process: only
The α-substituted diastereomeric lactones pilocar- imidazolium salts [1a]Cl and [1k]Cl containing α-
pine and podophyllotoxin were insusceptible to deuter- unbranched N-alkyl substituents (which showed the
ation under the standard conditions but successfully highest amounts of the imidazolium cation/acetone
labeled in the presence of 1 eq. of potassium carbonate. adducts in the ESI-MS and NMR spectra) has the best
The labeling accompanied by stereoinversion at the C3 catalytic activity in the deuteration process (compare
position[14] yielded the corresponding more thermody- Table 1 and Table S1). Depending on the base used,
namically stable labeled epimers isopilocarpine 33–d1 activation of C2 or C4 positions in the initial
and picropodophyllotoxin 34–d1 with 96% and 99% imidazolium cation facilitates the formation of H-
degrees of deuteration, respectively. Thus, the pro- bonded NHC, aNHC or dcNHC species. The H-bonded
posed catalytic system showed high levels of chemo- carbene intermediate undergoes nucleophilic addition
selectivity and chiral functional group tolerance.
to deuterated acetone, predominantly by NHC (under
According to the mechanistic investigations carried kinetic control of the reaction - in the presence of
out in the present work and previous study of dynamic sodium acetate as a base) or dcNHC mechanisms
reactivity of imidazolium cations towards ketones,[12]
a
(under thermodynamic control of the reaction - in the
general pathway may be proposed for the deuteration presence of potassium carbonate as a base and at high
reaction as shown on Scheme 4 (see also Figure S3 for temperature) (Scheme 4A). In the second case, this
a more details). Relative intensities of the peaks in process led to the generation of the dynamic organo-
ESI-MS spectra corresponding to the imidazolium catalytic system by reversible formation of the proto-
cation/acetone adducts in the reaction mixtures were in nated carbene/ketone C4 monoadduct IA as the
accordance with the catalytic activity of corresponding thermodynamic product, as well as few amounts of
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diadduct II (predominantly via the addition of the selectivity of labeling by modifying the steric proper-
second molecule of acetone-d6 to the C4 adduct IA) ties of the substrates. The first selective deuteration of
and, probably, the C2 monoadduct IN (as the kinetic lovastatin achieved in this study holds promise for the
product) (Scheme 4B). According to DFT calculations development of deuterated drugs containing base-
of pKa of hydroxyl protons performed for the diadduct sensitive chiral centers. Facile access to diverse α-
II, hydroxyl at the “normal” position has 5 orders deuterated products enhances the availability of other
higher acidity than of the “abnormal” position (see deuterated drugs and drug candidates.
Supporting Information for more details). Thus, despite
under the thermodynamic control of the reaction, the
adducts containing alcoholic substituents at the C2
Experimental Section
General Details. Commercially available starting compounds,
reagents, and solvents were of analytical grade upon purchase
or purified prior to use by standard methods. Azolium salts
were obtained by using published synthetic protocols or
purchased commercially. NMR spectra were recorded using a
Bruker Fourier 300 HD, Bruker Avance III 400 and Bruker
DRX-500 spectrometers at the following frequencies: 300.1/
400.1/500.1 MHz (1H), 75.5/100.6/125.8 MHz (13C). 13C{2H}
NMR spectrum was recorded using zgig2h pulse program.
NMR chemical shifts were measured relative to residual solvent
peaks. The processing was carried out using the MestReNova
software. The following abbreviations were used to describe the
multiplicities: s=singlet, d=doublet, t=triplet, q=quartet,
position are formed in low amounts, their influence on
the efficiency of the deuteration process may be
significant.
We suggest that the catalytic activity of imidazo-
lium alcohols in the deuteration process could be
related to the acceleration of the deuterium ion transfer
from acetone-d6 to the substrate by fast H/D exchange
from the enolic form of deuterated acetone III to
adducts I or II, and then from adducts to the substrate
IV. Low activity of the developed catalytic system
towards linear secondary and tertiary esters may be
associated with steric factors and explained by the
concerted mechanism of H/D exchange between quint=quintet, sext=sextet, sept=septet, o=octet, n=nonet,
m=multiplet, br=broad. HRMS spectra were recorded on a
Bruker maXis instrument equipped with electrospray ionization
(ESI) or atmospheric pressure chemical ionization (APCI) ion
sources. Gas chromatography-mass spectrometry (GC-MS)
analysis was performed on an Agilent 5977 A quadrupole
instrument using electron ionization (EI) source with sample
injection via Agilent 7890 gas chromatograph. HPLC analyses
were accomplished using an Agilent 1200 series LC system
equipped with a reversed-phase Zorbax SBÀ C18 Rapid Reso-
deuterated adducts and the enolic form of ester
substrate (Scheme 4C). Difficulties in labeling at the α-
CH position in tertiary substituted ketones were
recently described for the deuteration with bulky
bases.[9b,11b] Chemoselective deuteration at the primary
α-CH positions over the secondary and tertiary
positions in ester substrates is described for the first
time here.
The high catalytic activity of the adducts as H/D
exchange mediators and chemoselectivity of the deut-
eration process are ensured by chemical properties of
the adducts, which combine the low nucleophilicity
°
lution column (2.1*50 mm, 1.8 μm) thermostated at 25 C. The
mobile phase consisted of 90% MeCN aqueous solution. Merck
silica gel plates with a QF-254 indicator were used for
analytical TLC. Visualization was accomplished with UV light
and high mobility of proton of hydroxyl group defined or by using a solution of (NH4)6Mo7O24 and H2SO4 in ethanol;
the plate was heated until the development of color.
by tertiary structure and the electron-accepting ca-
pacity of the cationic imidazolium core. The best
efficiency of [1a]Cl as compared to other imidazolium
salts for the deuteration process may be explained by
the higher reactivity of [1a]+ towards acetone (see
Table S1) and, as a consequence, by the higher
General procedure for deuteration of ketones. Unless
indicated otherwise, a mixture of ketone (1 mmol), sodium
acetate (16 mg, 0.2 mmol) and [1a]Cl (87 mg, 0.5 mmol) in
acetone-d6 (1.5 mL) was stirred in a sealed tube at 80 C for
12 h. Then the mixture was filtered through a thin pad of silica
°
concentration of the imidazolium cation/ketone adducts gel using CHCl3 as an eluent. The solvents were evaporated at a
°
reduced pressure (300 mbar, bath temperature 50 C) to give
desired deuterated products.
in the reaction mixture.
Deuterated acetophenone (2–d3). The product 2–d3 was
isolated with a yield of 113mg (92%) and 96% deuterium
incorporation. 1H NMR (500 MHz, CDCl3) δ 7.98–7.91 (m,
2H), 7.54 (t, J=7.4 Hz, 1H), 7.44 (t, J=7.7 Hz, 2H), 2.56 (m,
labeled, 0.12H). 13C{1H} NMR (101 MHz, CDCl3) δ 198.3,
137.2, 133.2, 128.6, 128.3, 26.0 (labeled). Data in agreement
with the literature.[11b]
Conclusion
Ambident reactivity of imidazolium cations represents
a previously unexplored type of organocatalysis that
proceeds via dynamic covalent interaction of imidazo-
lium carbenes with ketones. A new efficient approach
to organocatalytic pH-dependent deuteration with the
involvement of carbene/acetone-d6 adducts as H/D
exchange mediators is proposed. Applicability of this
dynamic organocatalytic system for the deuteration of
weakly acidic model compounds and drugs is demon-
strated, along with the opportunity to control the
Deuterated 4-methylacetophenone (3–d3). The product 3–d3
was isolated in a yield of 129mg (94%) with 95% deuterium
incorporation. 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J=
8.1 Hz, 2H), 7.21 (d, J=8.1 Hz, 2H), 2.50 (m, labeled, 0.14H),
2.36 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 197.9, 143.8,
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134.7, 129.2, 128.4, 25.8 (labeled), 21.6. Data in agreement
with the literature.[11b]
Deuterated mesityl oxide (11–d10). The product 11–d10 was
isolated in a yield of 84mg (78%) with 92%/93%/97%
deuterium incorporation. The degree of deuteration was
Deuterated 4-methoxyacetophenone (4–d3). The product 4–d3
was isolated in a yield of 145mg (96%) with 95% deuterium
incorporation. 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J=
8.9 Hz, 2H), 6.88 (d, J=8.9 Hz, 2H), 3.81 (s, 3H), 2.48 (m,
labeled, 0.14H). 13C{1H} NMR (126 MHz, CDCl3) δ 196.8,
163.5, 130.6, 130.3, 113.7, 55.4, 25.7 (labeled). Data in
agreement with the literature.[11b]
1
determined by NMR using PhSiMe3 as an internal standard. H
NMR (300 MHz, CDCl3) δ 6.08 (s, labeled, 0.03H), 2.11 (m,
labeled, 0.49H), 1.85 (m, labeled, 0.20H). 13C{1H} NMR
(126 MHz, CDCl3) δ 198.8, 154.9, 124.1 (labeled), 31.0
(labeled), 27.0 (labeled), 21.92–18.20 (labeled).
General procedure for deuteration of esters. Unless indicated
otherwise, a mixture of ester (3 mmol), potassium carbonate
(84 mg, 0.6 mmol) and [1a]Cl (261 mg, 1.5 mmol) in 5 mL of
Deuterated 2-chloroacetophenone (5–d3). The product 5–d3
was isolated as a colorless liquid in a yield of 150mg (95%)
with 98% deuterium incorporation. 1H NMR (500 MHz, CDCl3)
δ 7.52 (dd, J=7.8, 1.0 Hz, 1H), 7.40–7.32 (m, 2H), 7.29 (td,
J=7.8, 1.6 Hz, 1H), 2.58 (m, labeled, 0.05H). 13C{1H} NMR
(126 MHz, CDCl3) δ 200.5, 139.1, 132.1, 131.3, 130.7, 129.5,
127.0, 30.0 (labeled).
°
acetone-d6 was stirred at 80 C for 12 h. Then the mixture was
filtered through a thin pad of silica gel and evaporated at a
reduced pressure (300 mbar). The obtained samples of pure
products were analyzed by NMR to determine the degree of
deuteration.
Deuterated 2-ethoxyethyl acetate (12–d3). A mixture of
compound 12 (1.4 mL, 10 mmol), potassium carbonate
(276 mg, 2 mmol) and [1a]Cl (873 mg, 5 mmol) in 15 mL of
acetone-d6 was used. After filtration, the product 12–d3 was
isolated by distillation in vacuo as a colorless liquid in a yield
Deuterated propiophenone (6–d2). The product 6–d2 was
isolated in a yield of 130mg (96%) with 99% deuterium
incorporation. 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J=
7.3 Hz, 2H), 7.51 (t, J=7.3 Hz, 1H), 7.42 (t, J=7.7 Hz, 2H),
2.94 (m, labeled, 0.01H), 1.18 (s, 3H). 13C{1H} NMR
(126 MHz, CDCl3) δ 200.9, 136.9, 132.9, 128.6, 128.0, 31.1
(labeled), 8.1. Data in agreement with the literature.[11b]
1
of 0.97g (72%) with 91% deuterium incorporation. H NMR
(500 MHz, CDCl3) δ 4.15 (t, J=4.8, 2H), 3.57 (t, J=4.8 Hz,
2H), 3.47 (q, J=7.0 Hz, 1H), 2.09–1.98 (m, labeled, 0.28H),
1.15 (t, J=7.0 Hz, 3H). 13C{H} NMR (101 MHz, CDCl3) δ
171.1, 68.3, 66.6, 63.7, 20.3 (labeled), 15.1.
Deuterated cyclohexanone (7–d4). A mixture of compound 7
(1.08 mL, 10 mmol), sodium acetate (164 mg, 2 mmol) and
[1a]Cl (873 mg, 5 mmol) in 15 mL of acetone-d6 was used.
After filtration, product 7–d4 was isolated by distillation in
vacuo in a yield of 842mg (86%) with 97% deuterium
Deuterated γ-butyrolactone (13–d2). Product 13–d2 was
isolated in a yield of 207mg (78%) with 98% deuterium
incorporation. 1H NMR (400 MHz, CDCl3) δ 4.23 (t, J=
7.1 Hz, 2H), 2.35 (m, labeled, 0.02H), 2.15 (quint, J=7.1, 2.4,
1.2 Hz, 2H). 13C{H} NMR (75 MHz, CDCl3) δ 177.9, 68.6,
27.2 (labeled), 22.0. Data in agreement with the literature.[9e]
1
incorporation. H NMR (500 MHz, CDCl3) δ 2.24 (m, labeled,
0.10H), 1.79 (m, 4H), 1.66 (m, 2H). 13C{1H} NMR (126 MHz,
CDCl3) δ 212.5, 41.3 (labeled), 26.9, 24.9. Data in agreement
with the literature.[9a]
Deuterated (S)-4-hydroxydihydrofuran-2(3H)-one (14–d2).
The product obtained under standard conditions was treated
with water. Compound 14–d2 was isolated as a colorless liquid
in a yield of 280mg (90%) with 91% deuterium incorporation.
1H NMR (300 MHz, CDCl3) δ 4.63 (br.d, J=3.8 Hz, 1H), 4.39
(dd, J=10.3, 4.3 Hz, 1H), 4.27 (dd, J=10.3, 1.0 Hz, 1H), 3.55
(s, 1H), 2.70 (m, labeled, 0.09H), 2.45 (br.s, labeled, 0.09H).
13C{H} NMR (75 MHz, CDCl3) δ 177.3, 76.5, 67.3, 37.3
(labeled).
Deuterated 3,3,5-trimethylcyclohexanone (8–d4). Potassium
carbonate (28 mg, 0.2 mmol) was used as a base. The product
8–d4 was obtained as a colorless liquid in a yield of 124mg
1
(88%) with 96% deuterium incorporation. H NMR (500 MHz,
CDCl3) δ 2.23 (m, labeled, 0.03H), 2.08 (br.s, labeled, 0.05H),
2.00–1.90 (m, 1H+m, labeled, 0.04H, overlapped), 1.82 (m,
labeled, 0.04H), 1.53 (dd, J=13.4, 3.7 Hz, 1H), 1.25 (t, J=
12.9 Hz, 1H), 1.00 (s, 1H), 0.97 (d, J=6.5 Hz, 3H), 0.83 (s,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ 212.2, 53.7 (labeled),
48.6 (labeled), 47.3, 35.3, 32.1, 29.7, 25.8, 22.5.
Deuterated δ-valerolactone (15–d2). Product 15–d2 was iso-
lated in a yield of 234mg (76%) with 97% deuterium
Deuterated cycloheptanone (9–d4). The product 9–d4 was
1
incorporation. H NMR (300 MHz, acetone-d6) δ 4.28 (m, 2H),
obtained in a yield of 99mg (85%) with 92% deuterium
2.45 (m, labeled, 0.05H), 1.82 (m, 4H). 13C{H} NMR (75 MHz,
CD2Cl2) δ 171.5, 69.8, 29.5 (labeled), 22.7, 19.3. Data in
agreement with the literature.[16]
1
incorporation. H NMR (500 MHz, CDCl3) δ 2.37 (m, labeled,
0.31H), 1.67–1.52 (m, 8H). 13C{1H} NMR (126 MHz, CDCl3) δ
215.4, 43.2 (labeled), 30.3, 24.2 (signal corresponds to non-
deuterated substrate), 24.1. Data in agreement with the
literature.[15]
Deuterated racemic methyl 2-phenylpropanoate (16–d1).
(R)-Methyl 2-phenylpropanoate or racemic methyl 2-phenyl-
propanoate were used. Product 16–d1 was isolated in a yield of
371mg (75%) with 97% deuterium incorporation. 1H NMR
(500 MHz, CDCl3) δ 7.40–7.18 (m, 5H), 3.73 (q, labeled,
0.03H), 3.66 (s, 3H), 1.50 (s, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 175.1, 140.6, 128.8, 127.6, 127.3, 52.1, 45.2 (labeled),
18.6. Data in agreement with the literature.[17]
Deuterated benzylideneacetone (10–d3). The product 10–d3
was isolated as a yellowish oil in a yield of 124mg (83%) with
1
95% deuterium incorporation. H NMR (500 MHz, CDCl3) δ
7.58–7.52 (m, 2H), 7.51 (d, J=16.3 Hz, 1H), 7.42–7.38 (m,
3H), 6.72 (d, J=16.3 Hz, 1H), 2.36 (m, labeled, 0.15H). 13C
{1H} NMR (101 MHz, CDCl3) δ 198.6, 143.6, 134.5, 130.6,
129.1, 128.4, 127.3, 27.0 (labeled).
Deuterated racemic methyl 2-acetamido-2-phenylacetate
(17–d1). R-enantiomer or racemic mixture of compound 17
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were used. The product 17–d1 was isolated as a white solid in a
yield of 555mg (89%) with 99% deuterium incorporation. H
NMR (500 MHz, CDCl3) δ 7.33 (m, 5H), 6.71 (br.s, 1H), 5.58
(d, J=7.3 Hz, labeled, 0.02H), 3.71 (s, 3H), 2.01 (s, 3H). 13C
{1H} NMR (126 MHz, CDCl3) δ 171.5, 169.8, 136.4, 129.1,
128.7, 127.4, 56.2 (labeled), 52.9, 23.0.
2.46 (d, J=7.2 Hz, 2H), 1.86 (n, J=6.8 Hz, 1H), 1.49 (s, 3H),
0.91 (d, J=6.8 Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ
175.3, 140.7, 137.8, 129.5, 127.2, 52.1, 45.2, 44.8 (labeled),
30.3, 22.5, 18.6. Data in agreement with the literature.[17]
1
Synthesis of deuterated grizeofulvin. Method A: a mixture of
grizeofulvin 28 (70 mg, 0.2 mmol), potassium carbonate
(5.5 mg, 0.04 mmol) and [1a]Cl (18 mg, 0.1 mmol) in 0.5 mL
Synthesis of deuterated tolperisone (24–d1). A mixture of
tolperisone 24 (49 mg, 0.2 mmol), sodium acetate (3.3 mg,
0.04 mmol) and [1a]Cl (18 mg, 0.1 mmol) in 0.5 mL of
°
of acetone-d6 was stirred at 80 C for 12 h. The reaction mixture
was then diluted with chloroform and washed by water.
Removal of the solvents afforded 65 mg of compound 28–d2 as
a yellowish powder (93% yield, 85% deuterium incorporation).
Method B: a mixture of grizeofulvin 28 (70 mg, 0.2 mmol),
potassium carbonate (5.5 mg, 0.04 mmol) in 0.5 mL of meth-
°
acetone-d6 was stirred at 80 C for 12 h. The reaction mixture
was then diluted with chloroform and filtered through a short
pad of silica gel using CHCl3:MeOH, 10:1 as an eluent. The
solvents were evaporated under reduced pressure to give 48 mg
of product 24–d1 as a colorless oil (98% yield, 96% deuterium
incorporation). 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J=
8.2 Hz, 2H), 7.25 (d, J=8.1 Hz, 2H), 3.74 (m, labeled, 0.04H),
2.84 (d, J=12.5 Hz, 1H), 2.39 (m, 8H), 1.50 (m, 4H), 1.36 (m,
2H), 1.16 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 203.6,
143.7, 134.4, 129.4, 128.6, 62.2, 55.0, 38.4 (labeled), 25.9,
24.3, 21.7, 16.9.
°
°
anol-d4 was stirred at 60 C or 80 C for 12 h. The degree of
deuteration was determined by NMR. 1H NMR (300 MHz,
CD2Cl2) δ 5.99 (s, 1H), 5.51 (s, 1H), 4.02 (s, 3H), 3.96 (s, 3H),
3.62 (s, 3H), 2.89 (m, 0.20H, labeled), 2.79 (q, J=6.2 Hz, 1H),
2.37 (m, labeled, 0.10H), 0.91 (d, J=6.7 Hz, 3H). 13C{H}
NMR (75 MHz, CD2Cl2) δ 196.7, 192.3, 171.1, 169.8, 165.0,
158.2, 105.4, 105.1, 97.2, 91.0, 90.1, 57.5, 57.2, 56.8, 40.0
(labeled), 36.77 (signal correspond to non-deuterated substrate),
36.70, 14.3.
Synthesis of deuterated androsterone (25–d2). A mixture of
androsterone 25 (106 mg, 0.4 mmol), potassium carbonate
(11 mg, 0.08 mmol) and [1a]Cl (36 mg, 0.2 mmol) in 1 mL of
Synthesis of deuterated pentoxifylline (29–d5). Method A: a
mixture of pentoxifylline 29 (56 mg, 0.2 mmol), base
(0.04 mmol) and [1a]Cl (18 mg, 0.1 mmol) in 0.5 mL of
°
acetone-d6 was stirred at 80 C for 12 h. The reaction mixture
was then diluted with chloroform and filtered through a short
pad of silica gel using CHCl3:MeOH, 20:1 as an eluent. The
solvents were evaporated under reduced pressure to give 78 mg
of product 25–d2 as a white powder (74% yield, 96% deuterium
°
acetone-d6 was stirred at 80 C for 12 h. The reaction mixture
was then diluted with chloroform and filtered through a short
pad of silica gel using CHCl3:MeOH, 20:1 as an eluent.
Removal of the solvents followed by washing with Et2O
afforded 55 mg of compound 29–d5 as a white powder (98%
yield, 73% (CD3) and 81% (CD2) deuterium incorporation using
sodium acetate as a base; 93% yield, 95% (CD3) and 95%
(CD2) deuterium incorporation using potassium carbonate as a
base). Method B: a mixture of pentoxifylline 29 (56 mg,
0.2 mmol) and base (0.04 mmol) in 0.5 mL of deuterated
1
incorporation). H NMR (500 MHz, CDCl3) δ 4.02 (m, 1H),
2.37 (m, labeled, 0.04H), 2.13 (d, J=12.0 Hz, labelled, 0.04H),
1.90 (m, 2H), 1.76 (m, 2H), 1.67–1.14 (m, 15H), 1.00 (m, 1H),
0.82 (s, 3H), 0.80 (m, 1H), 0.77 (s, 3H). 13C{1H} NMR
(126 MHz, CDCl3) δ 221.7, 66.4, 54.5, 51.6, 47.9, 39.2, 36.3,
35.9 (labeled) 35.8, 35.1, 32.2, 31.6, 30.9, 29.0, 28.3, 21.6,
20.1, 13.9, 11.3. Data in agreement with the literature.[18]
°
solvent was stirred at 80 C for 12 h. The degree of deuteration
was determined by NMR. H NMR (400 MHz, CDCl3) δ 7.49
Synthesis of deuterated verbenone 26–d4. A mixture of (S)-
(-)-verbenone 26 (30 mg, 0.2 mmol), sodium acetate (3.3 mg,
0.04 mmol) and [1a]Cl (18 mg, 0.1 mmol) in 0.5 mL of
1
(s, 1H), 3.92 (m, 5H), 3.49 (s, 3H), 2.40 (m, labeled, 0.10H),
2.04 (m, labeled, 0.14H), 1.56 (m, 4H). 13C{1H} NMR
(101 MHz, CDCl3) δ 209.0, 155.2, 151.4, 148.6, 141.5, 107.6,
42.4 (labeled), 40.8, 33.6, 29.7, 29.2 (labeled), 27.4, 20.8. Data
in agreement with the literature.[19]
°
acetone-d6 was stirred at 80 C for 12 h. The reaction mixture
was then diluted with chloroform and filtered through a short
pad of silica gel using CHCl3:MeOH, 20:1 as an eluent. The
solvents were evaporated under reduced pressure to give 26 mg
of compound 26–d4 as a colorless liquid (87% yield, 95%
Synthesis of deuterated famciclovir (30–d6). A mixture of
famciclovir 30 (96 mg, 0.3 mmol), potassium carbonate
(16.5 mg, 0.12 mmol) and [1a]Cl (27 mg, 0.15 mmol) in 1 mL
1
deuterium incorporation). H NMR (400 MHz, CDCl3) δ 5.71
(s, labeled, 0.05H), 2.79 (dt, J=9.2, 5.5 Hz, 1H), 2.63 (t, J=
5.5 Hz, 1H), 2.40 (t, J=5.9 Hz, 1H), 2.06 (d, J=9.2 Hz, 1H),
1.96 (m, labeled, 0.14H), 1.48 (s, 3H), 0.99 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 204.2, 170.2, 121.0 (labeled), 57.7,
54.2, 49.7, 41.0, 26.7, 22.8 (labeled), 22.2.
°
of acetone-d6 was stirred at 60 C for 12 h. The reaction mixture
was then diluted with chloroform and filtered through a short
pad of silica gel using CHCl3:MeOH, 20:1 as an eluent.
Removal of the solvents followed by washing with Et2O
afforded 78 mg of compound 30–d6 as a light-yellow powder
(81% yield, 77% deuterium incorporation). 1H NMR (300 MHz,
CDCl3) δ 8.64 (s, 1H), 7.76 (s, 1H), 5.22 (br.s, 2H), 4.17 (t, J=
7.0 Hz, 2H), 4.10 (d, J=5.2 Hz, 4H), 1.98 (m, labeled, 1.37H),
2.03–1.85 (m, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 171.0,
159.7, 153.5, 149.3, 142.5, 128.2, 63.7, 40.9, 35.0, 28.9, 20.4
(labeled).
Synthesis of deuterated ibuprofen (27–d1). A mixture of
ibuprofen 27 (44 mg, 0.2 mmol), sodium acetate (3.3 mg,
0.04 mmol) and [1a]Cl (18 mg, 0.1 mmol) in 0.5 mL of
°
acetone-d6 was stirred at 80 C for 12 h. The reaction mixture
was then diluted with chloroform and filtered through a short
pad of silica gel using CHCl3 as an eluent. The solvents were
evaporated under reduced pressure to give 34 mg of compound
27–d1 as a colorless oil (77% yield, 85% deuterium incorpo-
Synthesis of deuterated simvastatin (31–d2). A mixture of
simvastatin 31 (84 mg, 0.2 mmol), potassium carbonate
(5.5 mg, 0.04 mmol) and [1a]Cl (18 mg, 0.1 mmol) in 1 mL of
1
ration). H NMR (500 MHz, CDCl3) δ 7.21 (d, J=8.1 Hz, 2H),
7.10 (d, J=8.1 Hz, 2H), 3.71 (m, labeled, 0.15H), 3.66 (s, 3H),
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°
acetone-d6 was stirred at 80 C for 12 h. The solvents were
evaporated and the reaction mixture was purified by column
chromatography on silica gel using CHCl3:MeOH, 30:1.
Removal of the solvents followed by washing with Et2O
afforded 78 mg of compound 31–d2 as a white powder (93%
yield, 90% deuterium incorporation). 1H NMR (300 MHz,
CD2Cl2) δ 5.99 (d, J=9.7 Hz, 1H), 5.79 (dd, J=9.5, 6.1 Hz,
1H), 5.51 (m, 1H), 5.34 (q, J=3.1 Hz, 1H), 4.58 (m, 1H), 4.33
(t, J=3.5 Hz, 1H), 2.65 (m, labeled, 0.10H), 2.53 (m, labeled,
0.10H), 2.39 (m, 2H), 2.28 (m, 1H), 1.94 (m, 3H), 1.82 (m,
1H), 1.67 (m, 2H), 1.61–1.43 (m, 3H), 1.43–1.22 (m, 3H),
1.112 (s, 3H), 1.107 (s, 3H), 1.08 (d, J=7.4 Hz, 3H), 0.89 (d,
J=7.0 Hz, 3H), 0.82 (t, J=7.5 Hz, 3H). 13C{1H} NMR
(75 MHz, CDCl3) δ 178.2, 170.7, 133.0, 131.6, 129.8, 128.5,
76.6, 68.2, 62.6, 43.2, 38.4 (labeled), 37.6, 36.7, 36.2, 33.11,
33.06, 33.0, 30.8, 27.4, 24.9, 24.4, 23.2, 14.0, 9.5.
acetone-Et2O, the product was treated with H2O to give 22 mg
of compound 34–d1 as a colorless powder (55% yield and 99%
deuterium incorporation). 1H NMR (300 MHz, acetone-d6) δ
7.15 (s, 1H), 6.65 (s, 2H), 6.18 (s, 1H), 5.93 (s, 1H), 5.91 (s,
1H), 5.07 (d, J=6.3 Hz, 0.51H, OH), 4.58 (dd, J=9.3, 1.3 Hz,
1H), 4.51 (dd, J=9.8, 6.1 Hz, 1H), 4.44 (dd, J=9.3, 6.1 Hz,
1H), 3.96 (s, 1H), 3.80 (s, 6H), 3.74 (s, 3H), 3.40 (m, 0.01H,
labeled, overlapped with Et2O), 2.67 (dd, J=9.8, 6.3 Hz, 1H).
13C{1H} NMR (75 MHz, acetone-d6) δ 178.4, 154.6, 147.4,
147.3, 140.2, 135.4, 132.4, 108.8, 107.5, 105.6, 101.8, 70.1,
68.9, 68.8, 60.5, 56.5, 45.6 (labeled), 44.9, 44.0.
Acknowledgements
This work was supported by RSF grant No. 17-13-01176-p. We
thank Dr. Victor N. Khrustalev for carrying out X-ray analysis.
Synthesis of deuterated lovastatin 32–d2. A mixture of
lovastatin 32 (81 mg, 0.2 mmol), potassium carbonate (11 mg,
0.08 mmol) and [1a]Cl (18 mg, 0.1 mmol) in 1 mL of acetone-
References
°
d6 was stirred at 80 C for 12 h. The reaction mixture was then
diluted with chloroform and filtered through a short pad of
silica gel using CHCl3:acetone, 10:1 as an eluent. Removal of
the solvents followed by washing with Et2O afforded 69 mg of
compound 32–d2 as a white powder (85% yield, 90% deuterium
incorporation). 1H NMR (300 MHz, CD2Cl2) δ 5.98 (d, J=
9.7 Hz, 1H), 5.79 (dd, J=9.6, 6.1 Hz, 1H), 5.52 (br.s, 1H), 5.35
(m, 1H), 4.58 (m, 1H), 4.33 (s, 1H), 2.65 (m, labeled, 0.15H),
2.53 (m, labeled, 0.05H), 2.47–2.25 (m, 5H), 2.05–1.76 (m,
4H), 1.75–1.55 (m, 3H, overlapped with residual water), 1.53–
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37.0, 3.5, 33.3, 33.0, 31.1, 28.0, 27.3, 24.5, 23.0, 16.4, 14.0,
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mixture of podophyllotoxin 34 (41 mg, 0.1 mmol), potassium
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°
0.5 mL of acetone-d6 was stirred at 80 C for 12 h. The reaction
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celite. The solvents were evaporated and the reaction mixture
was purified by column chromatography on silica gel using
CHCl3:acetone, 3:1 as an eluent. After recrystallization from
Adv. Synth. Catal. 2021, 363, 1368–1378
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