Regioselective Hydrogenolysis of Donor-Acceptor Cyclopropanes with Zn-AcOH Reductive System

Article abstract of DOI:10.1021/acs.joc.7b01549

A convenient low-cost method for regioselective ring-opening of donor-acceptor cyclopropanes with the Zn-AcOH reductive system was developed. The general character of the method was displayed via efficient reduction of a representative series of 2-(het)arylcyclopropane-1,1-diesters as well as donor-acceptor cyclopropanes with other types of electron-withdrawing activating groups. This method opens a rapid access to γ-substituted propyl-1,1-diesters, ketoesters, cyanoesters, cyanoamides, dinitriles, etc., many of which are not readily accessible with alternative methods. The utility of the synthesized compounds was demonstrated by transforming them into valuable acyclic and cyclic compounds (including pharmacologically relevant carbazoles, δ-lactams, and oxindole derivatives).

Full text of DOI:10.1021/acs.joc.7b01549

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Article
Regioselective Hydrogenolysis of Donor-Acceptor
Cyclopropanes with Zn-AcOH Reductive System
Konstantin L. Ivanov, Elena V. Villemson, Gennadij V. Latyshev, Stanislav I.
Bezzubov, Alexander G. Majouga, Mikhail Ya. Mel'nikov, and Ekaterina M. Budynina
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01549 • Publication Date (Web): 11 Aug 2017
Downloaded from http://pubs.acs.org on August 11, 2017
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Regioselective Hydrogenolysis of Donor-Acceptor Cyclopropanes with Zn-AcOH Reductive
System
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Konstantin L. Ivanov,† Elena V. Villemson,† Gennadij V. Latyshev,† Stanislav I. Bezzubov,‡
Alexander G. Majouga,†,§ Mikhail Ya. Melnikov,† Ekaterina M. Budynina*,†
†Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1ꢀ3, Moscow
119991 Russia
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‡Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences,
Leninskiy pr. 31, Moscow 119991 Russia
§National University of Science and Technology “MISiS”, Leninskiy pr. 4, Moscow 119991,
Russia
ekatbud@kinet.chem.msu.ru
ABSTRACT: A convenient lowꢀcost method for regioselective ringꢀopening of donorꢀacceptor
cyclopropanes with the ZnꢀAcOH reductive system was developed. The general character of the
method was displayed via efficient reduction of
(het)arylcyclopropaneꢀ1,1ꢀdiesters as well as donorꢀacceptor cyclopropanes with other types of
electronꢀwithdrawing activating groups. This method opens a rapid access to ꢀsubstituted
a
representative series of 2ꢀ
γ
propylꢀ1,1ꢀdiesters, ketoesters, cyanoesters, cyanoamides, dinitriles, etc., many of which are not
readily accessible with alternative methods. The utility of the synthesized compounds was
demonstrated by transforming them into valuable acyclic and cyclic compounds (including
pharmacologically relevant carbazoles, δꢀlactams and oxindole derivatives).
INTRODUCTION
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Donorꢀacceptor (DA) cyclopropanes are widely known as versatile easily modifiable
building blocks for the construction of variously functionalized acyclic and cyclic compounds,
mostly due to their tendency to undergo heterolytic cleavage of the selectively activated CꢀC
bond between donor and acceptor substituents (Scheme 1).1–13 This mode of reactivity defines
the principal trends in the research of these compounds and, thus, has been and is being
investigated systematically and thoroughly.
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Scheme 1. Two Types of Activated C-C Bond Cleavage in DA Cyclopropanes
Meanwhile, homolytic small ringꢀopening is a much rarer reactivity of DA cyclopropanes,
exemplified by ringꢀopening reduction14–29 as well as several other isolated examples.30–32 Two
reductive systems are mainly used in relation to DA cyclopropanes: SmI2ꢀAlkOH19–24 and H2ꢀ
Pd/C25,26 (Scheme 2, A). However they are relatively expensive and may cause overreduction
(SmI2) or hydrogenation of multiple bonds (Pd). At the same time, the application of much
cheaper and milder Znꢀbased reductive systems for DA cyclopropane reduction was limited to
several specific cases (Scheme 2, B).27–29
Scheme 2. Reactions of DA Cyclopropanes with Various Reductive Systems
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Twoꢀ and threeꢀcomponent ZnꢀEtOH or ZnꢀZnCl2ꢀEtOH systems were used for the
reduction of 2ꢀarylꢀsubstituted ketocyclopropanes while 2ꢀalkylꢀsubstituted analogs were found
to be stable under those conditions.27 Unusual ringꢀopening rearrangement was recently reported
for annulated nitrocyclopropanes upon treatment with a ZnꢀHClꢀMeOH reductive system,29
although the application of similar conditions for 2ꢀaryl and alkylꢀsubstituted cyclopropaneꢀ1,1ꢀ
nitroesters resulted in nitroꢀtoꢀamino group reduction without small ring cleavage.28 Therefore,
currently there is no general method for ringꢀopening reduction of DA cyclopropanes with Znꢀ
based reductive systems.
Here we report a practical and lowꢀcost method for efficient regioselective hydrogenolysis
of differently substituted DA cyclopropanes with the ZnꢀAcOH reductive system (Scheme 2).
The method allows for rapid reduction of 2ꢀ(het)arylꢀsubstituted cyclopropaneꢀ1,1ꢀdiesters,
ketoesters, cyanoesters, cyanoamides, dinitriles 1 into the corresponding functionalized propane
derivatives 2. Commonly, these compounds are perceived as products of alkylation of active
methylene compounds. Though this approach appears to be more convenient, many alkylating
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agents, especially those with electronꢀabundant (het)aryl substituents, are unstable or even
inaccessible. Moreover, in order to avoid double alkylation, a significant excess of the methylene
component has to be added. Therefore, our approach is a new advanced alternative affording 2,
including those variations of it with highly electronꢀabundant aryl and hetaryl substituents. The
proposed procedure provides desired compounds with sufficient purity to obviate
chromatography and can be easily scaled up with no loss in efficiency.
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RESULTS AND DISCUSSION
Reduction of 2-(het)arylcyclopropane-1,1-diesters into 2-(het)arylethylmalonates
At the beginning of this study, we carried out a brief series of experiments using
cyclopropane 1a as a model substrate which was treated with different Znꢀcontaining reductive
systems (Table 1). We revealed that the traditional ZnꢀNH4Cl reductive system provided
complete conversion of 1a within 45 min in MeOH under reflux leading to 2a in 62% NMR
yield along with styrene 3a (11%) and lactone 4a (5%) (entry 1). Introducing a strong Brønsted
acid, aq HCl, at ambient temperature resulted in 92% conversion of 1a in 15 min and increase in
the percentage of lactone 4a, while the yield of the desired product 2a decreased (entry 2). For an
identical reaction at 0 °C, only 20% conversion was achieved (entry 3). The best results were
obtained when ZnꢀAcOH reductive systems were examined (entries 4ꢀ7). We have found that
ZnꢀAcOH in a 20:10 ratio allowed for complete conversion of 1a in just 5 min in MeOH as well
as EtOH under reflux. In both cases, only trace amounts of 3a and 4a were detected while the
yields of 2a were comparable (entries 4, 5). Twofold decrease in the initial amount of ZnꢀAcOH
afforded the best result: 2a was isolated in a 77% yield (entry 6). Further decrease in ZnꢀAcOH
loading led to noticeable deceleration (entry 7). It is noteworthy that even substoichiometric
amounts of AcOH (0.5 equiv) were found to be sufficient, although complete 1aꢀintoꢀ2a
conversion was achieved in 200 min.
Table 1. Optimization of the reaction conditions
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Yield [%]a
2a
entry
1c
Zn/H+ (mol%)
T [°C]
reflux
t [min]
1a
3a
4a
Zn (20)/NH4Cl (20)
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ꢀ
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Zn (20)/HCl (15)
Zn (20)/HCl (15)
Zn (20)/AcOH (10)
Zn (20)/AcOH (10)
Zn (10)/AcOH (5)
Zn (5)/AcOH (3)
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80
ꢀ
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68
77d
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ꢀ
13
ꢀ
ꢀb
ꢀb
0
ꢀ
reflux
refluxc
reflux
reflux
ꢀb
ꢀb
5
ꢀ
b
b
5
-
-
-
15
2
ꢀb
ꢀb
aNMR yield. bOnly trace amounts were detected. cEthanol was used as a solvent. dIsolated yield.
Afterwards, we studied the scope of DA cyclopropanes available for this process. Initially, a
series of cyclopropaneꢀ1,1ꢀdiesters 1b-w, containing various aryl and hetaryl substituents, was
examined under optimized conditions (Table 2). In most cases, reductive ring opening proceeds
efficiently under standard conditions in MeOH under reflux in 5 min, leading to corresponding
ethylmalonates
2
in good yields. Slightly reduced reactivity was observed for
phenylcyclopropane 1b whose reaction was carried out in EtOH under reflux; furthermore,
reaction time was extended up to 70 min. A slight discrepancy was revealed between the
reactivities of 2ꢀthienylꢀcyclopropane 1s, which was converted into 2s in 15 min in MeOH under
reflux, and 3ꢀthienylꢀderivative 1t whose complete conversion into 2t was achieved in ca. 1 h.
However, this difference was completely negated in ethanol under reflux. The steric effect of
orthoꢀsubstituents in the aromatic ring also reduces the reactivity of the starting compounds. The
reduction of cyclopropanes 1g-j with orthoꢀsubstituted electronꢀabundant aryls as well as oꢀ
methoxycarbonyl 1m and naphthyl 1o derivatives, generally takes more time to complete.
Among them, 5ꢀchloroꢀ2ꢀmethoxymethoxyꢀcyclopropane 1i was found to be the least reactive
substrate, undergoing transformation into 2i in 1 h. It is noteworthy that deprotection of MOMꢀ
or EOMꢀderivatives was not observed under the studied conditions. The reduction of
cyclopropane 1n, containing electronꢀdeficient 3ꢀpyridine substituent, was the slowest, with the
conversion to 2n completed in 270 min. The decrease in the yield of furyl derivative 1r is caused
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by partial furan ring opening into 1,4ꢀdiketone under studied conditions. However, the obtained
products 2 were mostly pure.
Table 2. Variation of Electron-Donating Groupsa,b
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aReaction conditions: 0.1 M solution of 1 (0.5
b
mmol), Zn (5 mmol), AcOH (2.5 mmol). Isolated
c
d
yield. MeOH was used as a solvent. Yield in 2.5
(for 1a) and 5.2 (for 1d) gramꢀscale synthesis.
eEtOH was used as a solvent.
Reduction of DA cyclopropanes containing various electron-withdrawing activating groups
Next, DA cyclopropanes 1x-ae with various electronꢀwithdrawing substituents were studied
in their reactions with ZnꢀAcOH (Table 3). We have found that hemimalonates 1x,y (irrespective
of the donating abilities of the aryl substituents) and dinitrile 1ac exhibited high reactivity
towards the ZnꢀAcOH reductive system, affording products 2x,y,ac under standard conditions
(MeOH, reflux, 5 min). Ketoester 1z and cyanoester 1aa were found to be more reactive vs. their
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diester analog 1b. Reduction of 2ꢀpyridylꢀderivative 1ad under identical conditions led to the
desired product 2ad in a 55% yield only. Meanwhile, the fragmentation product, methyl 2ꢀ
(pyridinꢀ2ꢀyl)acetate, was additionally isolated in a 30% yield (see below, Scheme 5). Within the
studied series of DA cyclopropanes, amides 1ab,ae were the least reactive substrates: their
complete conversion into the corresponding products 2ab,ae could only be achieved in 270 min.
Table 3. Varying Electron-Withdrawing Groupsa,b
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aReaction conditions: 0.1 M solution of 1 (0.5
b
mmol), Zn (5 mmol), AcOH (2.5 mmol). Isolated
c
d
yield. MeOH was usd as a solvent. EtOH was
e
used as a solvent. Methyl 2ꢀ(pyridinꢀ2ꢀyl)acetate
was additionally isolated in a 30% yield.
Reaction mechanism
In most of the studied reactions, trace amounts of the corresponding styrenes 3 were
detected. Thus, relatively lowꢀintensive characteristic resonances of CH=CH2 triꢀspine systems
1
of 3 were observed in the H NMR spectra of most reaction mixtures. For the reduction of
cyclopropanes 1 with electronꢀabundant aryl substituents, molar percentages of styrenes 3 were
higher than for the reactions of cyclopropanes containing the phenyl group or electronꢀ
withdrawing aryls. In the reduction of 2ꢀpyridineꢀderivative 1ad, the desired product 2ad was
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obtained along with the corresponding methylene compound, methyl 2ꢀ(pyridinꢀ2ꢀyl)acetate, in a
65:35 ratio.
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The reduction of 2,2ꢀdiphenylcyclopropaneꢀ1,1ꢀdiester 1af with ZnꢀAcOH (20:10 equiv) for
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5 min in MeOH under reflux proceeded with 50% conversion according to the H NMR
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spectrum of the reaction mixture. However, the molar percentage of the immediate reduction
product 2af was only 7%, whereas the major components of the reaction mixture were 1,1ꢀ
diphenylethylene 3af (43%) and dimethylmalonate, apparently pointing to fragmentation of 2af
(Scheme 3).
Scheme 3. Reduction of 2,2-Diphenylcyclopropane-1,1-Diester 1af
To identify the source of hydrogen in 2, we carried out the reduction of 1a in CH3OD and
obtained 2a, monoꢀdeuterated at the benzylic carbon. Therefore, the formation of 2 via radical
hydrogen abstraction from the solvent is highly unlikely, whereas the protonation of the
intermediate benzyl anion seems more probable. The KIE value of 4.3, measured with the
mixture of CH3OHꢀCD3OD (1:4) acting as a medium, is consistent with proton transfer
occurring during the reaction. These results, along with DFT calculations (B3LYP/maꢀdefꢀ
SVP/PCM) and wellꢀknown data related to the reduction of cyclopropanes with metalꢀbased
systems, allowed us to propose a mechanism for the studied process, visualized in Scheme 4.
Single electron transfer (SET) from Zn to 1 could lead to anionꢀradical I-1, which is known
to rearrange to the acyclic anionꢀradical form I-2. The synergistic effect of an aryl group at C2
and strong anionꢀstabilizing groups at C1 ensures that this rearrangement is fast.33–35 The
calculation suggests that dissociative electron transfer (DET)36,37 occurs upon the addition of an
electron to the LUMO of 1, directly affording I-2.38 This key intermediate undergoes the second
SET (path a) with the formation of dianion I-3,21,22 yielding reduction product 2 via protonation.
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Alternatively, protonation of I-2 leads to radical I-4. Single electron reduction of I-4 with
subsequent protonation gives 2. However, the more stable tautomeric form I-4′ and especially
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the reduced form I-5 are prone to
βꢀscission. DFT calculations show that this process is
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characterized by a relatively high activation barrier (ꢁG≠ = 20.9 kcal/mol), being
thermodynamically unfavorable (ꢁG298 = 6.6 kcal/mol) toward I-4′. On the other hand, it is
extremely fast and exergonic (ꢁG≠ = 0.6 kcal/mol, ꢁG = ꢀ39.6 kcal/mol) for I-5.39 This is
especially significant for 1af since the benzhydryl radical is known to accept electrons at a much
lower rate than benzyl,40 allowing for the tautomerization of I-4 to I-4′ and subsequent
fragmentation to proceed more readily.
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Scheme 4. Proposed Mechanism of DA Cyclopropane Reduction with Zn-AcOH System
Transformations of the synthesized compounds
The presence of several functional groups in 2 furnishes various opportunities of their
transformation and, thus, makes them valuable precursors of various acyclic and cyclic
compounds.
A rapid access to tetralins and their heterocyclic analogs can be provided via SEAr in the
cases when 2 contains an electronꢀabundant (het)aryl substituent.41,42 Thus, carbazole derivative
543 was obtained directly from indolylmalonate 2u in a good yield (Scheme 5).
Scheme 5. Transformation of 2u into Carbazole 5
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The presence of malonyl or similar CHꢀactivated motifs in the molecules of compounds 2
opens up a plethora of opportunities for their transformations. The reactions of 2 with such Cꢀ
electrophiles as alkyl and acyl halides, electrophilic alkenes (Michael acceptors), etc. allow for
the prolongation and additional functionalization of the alkyl chain in 2. Such preinstallation
provides accesss to further easy assembly of the cyclic moiety in the target structures. In this
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context, we developed a divergent strategy for the synthesis of functionalized
δꢀlactones 7 and
lactams 8 which are structural fragments of bioactive compounds44,45 (Scheme 6).
Scheme 6. Divergent Strategy for the Synthesis of δ-Lactones 7 and δ-Lactams 8
In order to obtain alkylated products 6, arylmalonates 2 were treated with acrolein, methylꢀ
or phenylvinyl ketones in the presence of NaB(OMe)4 as a catalyst46 (Table 4). The efficiency of
this method was demonstrated with a short series of compounds 2, affording Michael adducts 6a-
d in good yields. While using acrolein or phenylvinyl ketone as Michael acceptors, yields of the
corresponding products 6a and 6d were reduced due to repeated Michael addition acting as a
side process and leading to tangible oligoꢀ and polymerization. In particular, the product of
double Michael addition 6d′ was isolated in a 5% yield from the reaction of 2d with phenylvinyl
ketone. Diethyl ester analog of 6c was used in the synthesis of natural 4ꢀ(pꢀmethoxyphenethyl)ꢀ
cyclohexꢀ2ꢀenꢀ1ꢀone.47
Table 4. Synthesis of Intermediate Products 6 via Alkylation of 2a,b
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aReaction conditions: 0.1 M solution of 2
(0.5 mmol) in MeCN, Michael acceptor (0.7ꢀ
1.0 mmol), NaB(OMe)4 (4 mg, 0.025 mmol).
bIsolated yield. cYield in 2.5 gramꢀscale
synthesis.
Reduction of 6a with NaBH4 in methanol results in a mixture of the target lactone 7 and
intermediate alcohol I-6 which undergoes complete cyclization into 7 after heating in benzene
under reflux (Scheme 7).
Scheme 7. Synthesis of δ-Lactone 7
Lactams 8 were synthesized from ketones 6 under Borch reductive amination48 conditions
(Table 5). In the case of AcONH4, reaction proceeded as a cascade of reductive amination and
spontaneous 1,6ꢀlactamization,49 directly yielding lactams 8a-c. This domino reaction proceeded
with high diastereoselectivity, predominantly yielding diastereomers 8a-c with a cisꢀrelationship
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between ArCH2CH2 and R′ substituents. The structure of the major isomer (3RS,6RS)ꢀ8b was
unambiguously proved by single crystal Xꢀray analysis.38,50
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8
9
Spontaneous lactamization did not proceed under the same conditions when benzylamine
was employed. Therefore, lactam 8d was obtained via initial synthesis of acyclic amine 9
followed by its lactamization under harsher conditions. In this case, significant decrease in
diastereoselectivity was observed.
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Table 5. Synthesis of δ
-Lactams 8a,b
aReaction conditions: 0.1 M solution of 6 (0.5 mmol) in
MeOH, NaBH3CN (0.7 mmol), AcONH4 (5 mmol) or
b
BnNH2 (1 mmol), heating under reflux for 3 h. Isolated
yield. cTwoꢀstep yield starting from 6b.
The same concept related to preliminary arylation of 2 was used in the synthesis of oxindole
derivative 11. Intermediate acyclic product 10 was obtained by nucleophilic aromatic
substitution in 1ꢀchloroꢀ2,4ꢀdinitrobenzene (Scheme 8). Further reduction of NO2 groups in the
aryl fragment, followed by γꢀlactamization, led to the assembly of the oxindole core in the final
product 11.
Scheme 8. Synthesis of Oxindole 11
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CO2Me
CO2Me
MeO2C CO2Me
4-Tol
1) NaH, DMF
rt, 20 min
Cl
2)
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9
O2N
NO2
68%
4-Tol
2a
O2N
10:
Zn-AcOH
EtOH,
NO2
4-Tol
73%
MeO2C
O
N
H2N
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11:
H
CONCLUSION
In conclusion, we have developed a practical method for regioselective hydrogenolysis of
DA cyclopropanes via reductive cleavage of the activated CꢀC bond between the donor and
acceptor substituents with a ZnꢀAcOH reductive system. This system proved to be efficient for
the conversion of 2ꢀ(het)arylꢀsubstituted cyclopropanes, activated with ester, keto, cyano, amide
groups etc. as acceptors, into the correspondingly functionalized propane derivatives.
The proposed mechanism for the studied process includes initial homolytic smallꢀring
opening via electron transfer, followed by the transformation of the generated radical anion into
the final propane derivative via proton and electron transfer. Fragmentation of acyclic
intermediates yielding the corresponding styrene and an active methylene compound was
revealed as the principal side process.
In order to show the potential utility of the synthesized products, selected representatives
were transformed into derivatives of carbazole,
EXPERIMENTAL SECTION
General Information
δꢀlactone and lactam as well as oxindole.
NMR spectra were acquired at room temperature if not specified otherwise; the chemical
shifts δ were measured in ppm with respect to solvent (1H: CDCl3, δ = 7.27 ppm; 13C: CDCl3, δ =
77.0 ppm). The structures of compounds were elucidated with the aid of 1D NMR (1H, 13C) and
2D NMR (1H–1H COSY, H–13C HSQC, H–13C HMBC, H–1H NOESY) spectroscopy. Low
resolution mass spectra were recorded using MALDI technique with a TOF mass analyzer;
anthracene was used as a matrix. High resolution mass spectra (HRMS) were performed using
1
1
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ESI and Orbitrap mass analyzer. Elemental analyses were performed with elemental analyser
instrument. Crystallographic data were collected at 150 K using graphite monochromatized Mo–
Kα radiation (λ = 0.71073 A) using a ωꢀscan mode. Absorption corrections based on
measurements of equivalent reflections were applied. The structures were solved by direct
methods and refined by full matrix least squares on F2 with anisotropic thermal parameters for all
nonꢀhydrogen atoms. Melting points (mp) were determined using capillary melting point
apparatus. Microwave reactions were performed in a microwave synthesis reactor Monowave
300 (Anton Paar) in sealed reaction vessels; the temperature was monitored with external IR
detector. Analytical thin layer chromatography (TLC) was carried out with silica gel plates
(silica gel 60, F254, supported on aluminium) visualized with UV lamp (254 nm). Column
chromatography was performed on silica gel 60 (230ꢀ400 mesh).
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DFT calculations were carried out with ORCA 4.0.0 suite of programs,51 at the B3LYP52,53
/
maꢀdefꢀSVP54,55 level of theory using RIJCOSX56 approximation. Conductorꢀlike PCM
model57,58 (MeOH as a solvent) was employed to account for solvation effects.
General Procedure for the Synthesis of Alkenes
The parent alkenes were synthesized via Knoevenagel condensation under piperidinium acetate
catalysis. Solution of the corresponding benzaldehyde (1 equiv), methylene component (1
equiv), piperidine (0.05 equiv) and acetic acid (0.2 equiv) in benzene (3 M regarding
benzaldehyde) was heated under reflux with 15ꢀmL DeanꢀStark trap for 2–6 h. After cooling to
the ambient temperature, reaction mixture was diluted with ethyl acetate, washed twice with
brine, dried with Na2SO4 and concentrated under reduced pressure. Residue was either purified
by column chromatography on silica gel or used without purification.
Dimethyl 2-[2-(ethoxymethoxy)benzylidene]malonate (S1)
S1 was synthesized from 2ꢀ(ethoxymethoxy)benzaldehyde (14.38 g, 79 mmol) and dimethyl
malonate (9.15 mL, 79 mmol). Yield 22.06 g (95%); yellowish oil; 1Н NMR (CDCl3, 600 MHz)
δ
= 1.22 (t, 3J = 7.1 Hz, 3H, CH3), 3.74 (q, 3J = 7.1 Hz, 2H, CH2O), 3.79 (s, 3H, CH3O), 3.85 (s,
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3H, CH3O), 5.28 (s, 2H, OCH2O), 6.95–6.98 (m, 1H, Ar), 7.18–7.20 (m, 1H, Ar), 7.34–7.36 (m,
3
4
5
2H, Ar), 8.13 (s, 1H, CH=); 13С NMR (CDCl3, 150 MHz)
δ
= 14.8 (1JСН = 127 Hz, CH3), 52.1
(1JСН = 148 Hz, CH3O), 52.2 (1JСН = 148 Hz, CH3O), 64.4 (1JСН = 143 Hz, CH2O), 93.2 (1JСН
=
6
7
8
9
165 Hz, OCH2O), 114.5 (CH), 121.4 (CH), 122.7 (C), 125.3 (C), 128.5 (CH), 131.9 (СH), 138.6
(CH), 155.9 (C), 164.4 (CO2Me), 166.9 (CO2Me); MS (MALDI–TOF) m/z: [M + Na]+ Calcd for
С15Н18NaO6+ 317; Found 317; Anal. Calcd for С15Н18O6: C, 61.22; H, 6.16. Found: C, 61.17; Н,
6.21.
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Dimethyl 2-[5-chloro-2-(methoxymethoxy)benzylidene]malonate (S2)
S2 was synthesized from 5ꢀchloroꢀ2ꢀ(methoxymethoxy)benzaldehyde (6.13 g, 30.6 mmol) and
dimethyl malonate (3.50 mL, 30.6 mmol). Yield 9.54 g (99%); yellowish oil; Rf = 0.29
(petroleum ether : diethyl ether, 2:1). 1Н NMR (CDCl3, 600 MHz)
(s, 3H, CH3O), 3.83 (s, 3H, CH3O), 5.18 (s, 2H, OCH2O), 7.09 (d, 3J = 8.7 Hz, 1H, Ar), 7.26 (dd,
δ = 3.45 (s, 3H, CH3O), 3.80
4
4
3J = 8.7, J = 2.6 Hz, 1H, Ar), 7.28 (d, J = 2.6 Hz, 1H, Ar), 7.99 (s, 1H, CH=); 13С NMR
(CDCl3, 150 MHz)
δ
= 52.4 (1JСН = 147 Hz, CH3O), 52.6 (1JСН = 147 Hz, CH3O), 56.3 (1JСН
=
143 Hz, CH3O), 94.8 (1JСН = 167 Hz, OCH2O), 116.0 (CH, Ar), 124.3 (C), 126.78 (C), 126.80
(C), 128.4 (CH, Ar), 131.4 (CH, Ar), 137.2 (CH=), 154.4 (C, Ar), 164.2 (CO2Me), 166.4
(CO2Me); MS (MALDI–TOF) m/z: [M + Na]+ Calcd for С14Н15ClNaO6+ 337; Found 337; Anal.
Calcd for С14Н15ClO6: C, 53.43; H, 4.80. Found: C, 53.25; Н, 4.84.
Dimethyl 2-[3-methoxy-2-(methoxymethoxy)benzylidene]malonate (S3)
S3 was synthesized from 3ꢀmethoxyꢀ2ꢀ(methoxymethoxy)benzaldehyde (3.93 g, 20 mmol) and
dimethyl malonate (2.29 mL, 20 mmol). Yield 5.59 g (90%); yellowish oil; Rf = 0.31 (petroleum
1
ether : diethyl ether, 1:1). Н NMR (CDCl3, 400 MHz)
δ = 3.53 (s, 3H, CH3O), 3.73 (s, 3H,
3
4
CH3O), 3.78 (s, 3H, CH3O), 3.79 (s, 3H, CH3O), 5.08 (s, 2H, OCH2O), 6.91 (dd, J = 7.6, J =
1.5 Hz, 1H, Ar), 6.92 (dd, 3J = 8.3, 4J = 1.5 Hz, 1H, Ar), 6.99 (dd, 3J = 8.3, 3J = 7.6 Hz, 1H, Ar),
8.13 (s, 1H, CH=); 13С NMR (CDCl3, 100 MHz)
δ = 52.2 (CH3O), 52.3 (CH3O), 55.6 (CH3O),
57.5 (CH3O), 98.9 (OCH2O), 114.3 (CH, Ar), 119.9 (CH, Ar), 124.2 (CH, Ar), 126.1 (C), 127.9
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(C), 139.2 (CH=), 145.0 (С, Ar), 152.1 (C, Ar), 164.3 (CO2Me), 166.6 (CO2Me); MS (MALDI–
3
4
5
+
TOF) m/z: [M + Na]+ Calcd for С15Н18NaO7 333; Found 333; Anal. Calcd for С15Н18O7: C,
6
7
58.06; H, 5.85. Found: C, 57.66; Н, 5.98.
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Dimethyl 2-[2-(methoxycarbonyl)benzylidene]malonate (S4)
S4 was synthesized from methyl 2ꢀformylbenzoate (4.58 g, 28 mmol) and dimethyl malonate
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(3.20 mL, 28 mmol). Yield 3.89 g (50%); colorless oil; Rf = 0.40 (petroleum ether : diethyl ether,
1
1:1). Н NMR (CDCl3, 600 MHz)
δ = 3.60 (s, 3H, CH3O), 3.85 (s, 3H, CH3O), 3.90 (s, 3H,
CH3O), 7.33 (br.d, 3J = 7.7 Hz, 1H, Ar), 7.42–7.46 (m, 1H, Ar), 7.49–7.53 (m, 1H, Ar), 8.05 (dd,
3J = 7.8, 4J = 1.4 Hz, 1H, Ar), 8.42 (br.s, 1H, CH=); 13С NMR (CDCl3, 150 MHz) = 52.1 (1JСН
δ
= 147 Hz, CH3O), 52.3 (1JСН = 147 Hz, CH3O), 52.5 (1JСН = 147 Hz, CH3O), 126.8 (С), 128.7
(CH, Ar), 128.9 (C), 129.3 (СH, Ar), 130.8 (СH, Ar), 132.3 (CH, Ar), 135.9 (C), 145.2 (СH=),
164.2 (СO2Me), 166.1 (СO2Me), 166.4 (СO2Me); MS (MALDI–TOF) m/z: [M + Na]+ Calcd for
C14H14NaO6+ 301; Found 301; Anal. Calcd for C14H14O6: С, 60.43; H, 5.07. Found: C, 60.43; Н,
5.01.
General Procedure for the Synthesis of Cyclopropanes 1
Cyclopropanes 1a-y,aa,ad were synthesized under CoreyꢀChaykovsky reaction conditions. To
suspension of NaH (1.1 equiv, 60% suspension in mineral oil) in dry DMF (0.5 M) Me3SOI (1.1
equiv) was added in one portion under inert atmosphere. After stirring for 20 min at ambient
temperature, resulting mixture was cooled with iceꢀwater bath, and alkene (1 equiv) was added
portionwise under vigorous stirring. The mixture was stirred for additional 3–7 h, quenched with
ice water (15 mL) and extracted with EtOAc (3×25 mL). Combined organic fractions were
washed with water (5×15 mL), dried with Na2SO4 and concentrated under reduced pressure.
Residue was purified by column chromatography on silica gel.
Dimethyl 2-[2-(ethoxymethoxy)phenyl]cyclopropane-1,1-dicarboxylate (1h)
1h was synthesized from alkene S1 (5.88 g, 20 mmol). Yield 4.37 g (71%); yellowish oil; Rf =
0.37 (petroleum ether : diethyl ether, 2:1). 1Н NMR (CDCl3, 600 MHz)
δ
= 1.24 (t, 3J = 7.1 Hz,
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3H, CH3), 1.75 (dd, J = 5.1, J = 9.2 Hz, 1H, CH2), 2.22 (dd, J = 5.1, J = 8.3 Hz, 1H, CH2),
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3.32 (s, 3H, CH3O), 3.35 (dd, 3J = 9.2, 3J = 8.3 Hz, 1H, CH), 3.74 (dq, 2J = 9.7, 3J = 7.1 Hz, 1H,
2
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CH2O), 3.79 (dq, J = 9.7, J = 7.1 Hz, 1H, CH2O), 3.80 (s, 3H, CH3O), 5.24 (s, 2H, OCH2O),
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6.90–6.92 (m, 1H, Ar), 6.98–7.00 (m, 1H, Ar), 7.08–7.10 (m, 1H, Ar), 7.19–7.22 (m, 1H, Ar);
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13С NMR (CDCl3, 150 MHz)
δ
= 15.0 (1JСН = 127 Hz, CH3), 18.5 (1JСН = 165 Hz, CH2), 28.5
(1JСН = 167 Hz, CH), 36.3 (C), 51.9 (1JСН = 147 Hz, CH3O), 52.5 (1JСН = 147 Hz, CH3O), 64.1
(1JСН = 142 Hz, CH2O), 93.3 (1JСН = 165 Hz, OCH2O), 113.8 (CH, Ar), 120.9 (CH, Ar), 123.7
(C, Ar), 127.7 (CH, Ar), 128.6 (СH, Ar), 157.1 (C, Ar), 167.1 (CO2Me), 170.3 (CO2Me); MS
(MALDI–TOF) m/z: [M + Na]+ Calcd for С16Н20NaO6 331; Found 331; Anal. Calcd for
+
С16Н20O6: C, 62.33; H, 6.54. Found: C, 62.17; Н, 6.61.
Dimethyl 2-[5-chloro-2-(methoxymethoxy)phenyl]cyclopropane-1,1-dicarboxylate (1i)
1i was synthesized from alkene S2 (9.54 g, 30.3 mmol). Yield 6.26 g (63%); yellowish oil; Rf =
0.41 (petroleum ether : ethyl acetate, 3:1). 1Н NMR (CDCl3, 600 MHz)
δ
= 1.72 (dd, 2J = 5.2, 3J
= 9.2 Hz, 1H, CH2), 2.14 (dd, 2J = 5.2, 3J = 8.4 Hz, 1H, CH2), 3.26 (dd, 3J = 9.2, 3J = 8.4 Hz, 1H,
2
CH), 3.36 (s, 3H, CH3O), 3.46 (s, 3H, CH3O), 3.77 (s, 3H, CH3O), 5.13 (d, J = 6.8 Hz, 1H,
2
4
3
OCH2O), 5.15 (d, J = 6.8 Hz, 1H, OCH2O), 6.95 (br.d, J = 2.6 Hz, 1H, Ar), 6.98 (d, J = 8.8
Hz, 1H, Ar), 7.12 (dd, 3J = 8.8, 4J = 2.6 Hz, 1H, Ar); 13С NMR (CDCl3, 150 MHz) = 18.5 (1JСН
= 166 Hz, CH2), 28.0 (1JСН = 169 Hz, CH), 36.2 (C), 52.1 (1JСН = 147 Hz, CH3O), 52.7 (1JСН
δ
=
147 Hz, CH3O), 55.9 (1JСН = 143 Hz, CH3O), 94.6 (1JСН = 166 Hz, OCH2O), 114.9 (CH, Ar),
125.7 (C, Ar), 126.0 (C, Ar), 127.9 (CH, Ar), 128.3 (СH, Ar), 155.4 (C, Ar), 166.8 (CO2Me),
170.0 (CO2Me); MS (MALDI–TOF) m/z: [M + Na]+ Calcd for С15Н17ClNaO6+ 351; Found 351;
Anal. Calcd for С15Н17ClO6: C, 54.80; H, 5.21. Found: C, 54.49; Н, 5.36.
Dimethyl 2-[3-methoxy-2-(methoxymethoxy)phenyl]cyclopropane-1,1-dicarboxylate (1j′)
1j′ was synthesized from alkene S3 (5.50 g, 17.7 mmol). Yield 3.73 g (65%); yellowish oil; Rf =
0.25 (petroleum ether : diethyl ether, 2:1). 1Н NMR (CDCl3, 600 MHz)
δ
= 1.75 (dd, 2J = 5.2, 3J
= 9.3 Hz, 1H, CH2), 2.18 (dd, 2J = 5.2, 3J = 8.3 Hz, 1H, CH2), 3.37 (s, 3H, CH3O), 3.47 (dd, 3J =
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9.3, 3J = 8.3 Hz, 1H, CH), 3.57 (s, 3H, CH3O), 3.76 (s, 3H, CH3O), 3.81 (s, 3H, CH3O), 5.06 (d,
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2J = 5.7 Hz, 1H, OCH2O), 5.16 (d, J = 5.7 Hz, 1H, OCH2O), 6.53 (br.d, J = 7.8 Hz, 1H, Ar),
6.81 (br.d, 3J = 8.2 Hz, 1H, Ar), 6.94 (dd, J = 8.2, 3J = 7.8 Hz, 1H, Ar); 13С NMR (CDCl3, 150
3
7
8
9
MHz)
δ
= 18.8 (1JСН = 165 Hz, CH2), 28.0 (1JСН = 168 Hz, CH), 37.3 (C), 52.1 (1JСН = 147 Hz,
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CH3O), 52.6 (1JСН = 147 Hz, CH3O), 55.7 (1JСН = 144 Hz, CH3O), 57.3 (1JСН = 143 Hz, CH3O),
98.9 (1JСН = 167 Hz, OCH2O), 111.7 (CH, Ar), 118.8 (CH, Ar), 123.5 (CH, Ar), 128.8 (C, Ar),
146.3 (С, Ar), 152.2 (C, Ar), 167.0 (CO2Me), 170.1 (CO2Me); MS (MALDI–TOF) m/z: [M +
+
Na]+ Calcd for С16Н20NaO7 347; Found 347; Anal. Calcd for С16Н20O7: C, 59.25; H, 6.22.
Found: C, 59.07; Н, 6.37.
General Procedure for the Synthesis of Cyclopropanes 1g,j
Cyclopropanes 1g,j were synthesized via acidic deprotection of 1h,j’. To 0.25 M solution of the
corresponding protected cyclopropane in methanol aq HCl (2 M for EOM, 1 M for MOM; 1
mL/mmol) was added dropwise under cooling (iceꢀwater bath). Resulting mixture was stirred at
ambient temperature for 24 h, quenched with water and extracted with ethyl acetate. Combined
organic fractions were washed with brine, once with aq NaHCO3, then dried with Na2SO4 and
concentrated under reduced pressure. Residue was purified by column chromatography on silica
gel.
Dimethyl 2-(2-hydroxyphenyl)cyclopropane-1,1-dicarboxylate (1g)50
1g was synthesized via deprotection of 1h (3.11 g, 10.1 mmol). Yield 2.26 g (90%); white
1
crystals; mp 89–90 °С; Rf = 0.22 (petroleum ether : diethyl ether, 1:1). Н NMR (CDCl3, 600
2
3
2
3
MHz)
δ = 1.81 (dd, J = 5.1, J = 9.2 Hz, 1H, CH2), 2.21 (dd, J = 5.1, J = 8.2 Hz, 1H, CH2),
3.15 (dd, 3J = 9.2, 3J = 8.2 Hz, 1H, CH), 3.41 (s, 3H, CH3O), 3.83 (s, 3H, CH3O), 5.54 (br.s, 1H,
3
OH), 6.83–6.89 (m, 2H, Ar), 7.03 (br.d, J = 7.5 Hz, 1H, Ar), 7.14–7.18 (m, 1H, Ar); 13С NMR
(CDCl3, 150 MHz)
δ
= 18.4 (1JСН = 166 Hz, CH2), 28.2 (1JСН = 166 Hz, CH), 36.2 (C), 52.4
(1JСН = 147 Hz, CH3O), 52.9 (1JСН = 147 Hz, CH3O), 115.7 (CH, Ar), 120.2 (CH, Ar), 121.1 (C,
Ar), 128.6 (CH, Ar), 128.9 (СH, Ar), 155.8 (C, Ar), 167.5 (CO2Me), 170.3 (CO2Me); MS
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(MALDI–TOF) m/z: [M + Na]+ Calcd for С13Н14O5Na+ 273; Found 273; Anal. Calcd for
С13Н14O5: C, 62.39; H, 5.64. Found: C, 62.72; Н, 5.93.
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Dimethyl 2-(2-hydroxy-3-methoxyphenyl)cyclopropane-1,1-dicarboxylate (1j)
1j was synthesized via deprotection of 1j’ (5.09 g, 15.7 mmol). Yield 3.88 g (88%); white solid;
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Rf = 0.27 (petroleum ether : diethyl ether, 1:1). Н NMR (CDCl3, 600 MHz)
δ = 1.76 (dd, J =
5.0, 3J = 9.3 Hz, 1H, CH2), 2.21 (dd, 2J = 5.0, 3J = 8.3 Hz, 1H, CH2), 3.33 (dd, 3J = 9.3, 3J = 8.3
Hz, 1H, CH), 3.39 (s, 3H, CH3O), 3.79 (s, 3H, CH3O), 3.86 (s, 3H, CH3O), 5.82 (s, 1H, OH),
3
4
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3
3
6.59 (dd, J = 7.6, J = 1.6 Hz, 1H, Ar), 6.74 (dd, J = 8.1, J = 7.6 Hz, 1H, Ar), 6.77 (dd, J =
8.1, J = 1.6 Hz, 1H, Ar); 13С NMR (CDCl3, 150 MHz)
δ
= 18.8 (1JСН = 166 Hz, CH2), 27.9
4
(1JСН = 168 Hz, CH), 36.3 (C), 52.1 (1JСН = 148 Hz, CH3O), 52.6 (1JСН = 148 Hz, CH3O), 56.0
(1JСН = 145 Hz, CH3O), 109.9 (CH, Ar), 118.9 (CH, Ar), 120.1 (CH, Ar), 120.6 (C, Ar), 145.5
(С, Ar), 146.2 (C, Ar), 167.3 (CO2Me), 170.3 (CO2Me); MS (MALDI–TOF) m/z: [M + Na]+
Calcd for С14Н16NaO6+ 303; Found 303; Anal. Calcd for С14Н16O6: C, 59.99; H, 5.75. Found: C,
59.74; Н, 5.73.
Dimethyl 2-[2-(methoxycarbonyl)phenyl]cyclopropane-1,1-dicarboxylate (1m)
1m was synthesized from alkene S4 (1.41 g, 5.1 mmol); reaction time 24h. Conversion 85%,
1
yield 0.69 g (47%); colorless oil; Rf = 0.36 (petroleum ether : diethyl ether, 1:1). Н NMR
(CDCl3, 600 MHz)
δ
= 1.80 (dd, 2J = 5.1, 3J = 9.0 Hz, 1H, CH2), 2.18 (dd, 2J = 5.1, 3J = 8.5 Hz,
1H, CH2), 3.28 (s, 3H, CH3O), 3.76 (dd, 3J = 9.0, 3J = 8.5 Hz, 1H, CH), 3.80 (s, 3H, CH3O), 3.85
3
(s, 3H, CH3O), 7.23 (br.d, J = 7.8 Hz, 1H, Ar), 7.29–7.33 (m, 1H, Ar), 7.40–7.44 (m, 1H, Ar),
7.93 (dd, J = 7.8, 4J = 1.4 Hz, 1H, Ar); 13С NMR (CDCl3, 150 MHz)
δ
= 19.8 (1JСН = 165 Hz,
3
CH2), 32.8 (1JСН = 170 Hz, CH), 35.9 (C), 51.9 (1JСН = 147 Hz, CH3O), 52.0 (1JСН = 147 Hz,
CH3O), 52.5 (1JСН = 147 Hz, CH3O), 127.5 (CH, Ar), 129.6 (СH, Ar), 130.7 (СH, Ar), 131.5 (C,
Ar), 131.8 (CH, Ar), 135.8 (C, Ar), 167.1 (СO2Me), 167.3 (СO2Me), 170.1 (СO2Me); MS
(MALDI–TOF) m/z: [M + Na]+ Calcd for C15H16NaO6 315; Found 315; Anal. Calcd for
+
C15H16O6: С, 61.64; H, 5.52. Found: C, 61.30; Н, 5.56.
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1-(Methoxycarbonyl)-2-(3,4,5-trimethoxyphenyl)cyclopropanecarboxylic acid (1y)
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Dimethyl 2ꢀ(3,4,5ꢀtrimethoxyphenyl)cyclopropaneꢀ1,1ꢀdicarboxylate (1l) (1.78 g, 5.5 mmol) was
dissolved in the mixture of MeOH (4 mL) and 1.7 M aq NaOH (1.25 equiv, 4 mL). The solution
was stirred for 1.5 h, then was diluted with EtOAc and water to separate layers. The aqueous
layer was acidified with 5% HCl (pH 1), then extracted three times with EtOAc. The combined
organic layers were washed with brine, dried with Na2SO4 and concentrated under reduced
pressure. Yield 1.4 g (82%); white crystals, mp 122–123 °C; Rf = 0.47 (petroleum ether : ethyl
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acetate, 1:1). 1Н NMR (CDCl3, 600 MHz) = 2.24 (dd, 2J = 4.8, 3J = 9.4 Hz, 1H, CH2), 2.35 (dd,
δ
3
3
3
2J = 4.8, J = 8.6 Hz, 1H, CH2), 3.35 (dd, J = 9.4, J = 8.5 Hz, 1H, CH), 3.37 (s, 3H, CH3O),
3.82 (s, 3H, CH3O), 3.84 (s, 6H, 2×CH3O), 6.45 (s, 2H, Ar); 13С NMR (CDCl3, 150 MHz)
δ =
21.4 (CH2), 34.0 (C), 40.2 (CH), 52.7 (CH3O), 56.2 (2×CH3O), 60.9 (CH3O), 106.1 (2×CH, Ar),
129.7 (C, Ar), 137.7 (C, Ar), 153.0 (2×C, Ar), 170.9 (CO), 172.8 (CO); MS (MALDI–TOF) m/z:
+
[M + Na]+ Calcd for C15H18NaO7 333; Found 333; Anal. Calcd for C15H18O7: C, 58.06; H, 5.85.
Found: C, 57.62; Н, 5.92.
Methyl (1RS,2SR)-2-phenyl-1-(pyridin-2-yl)cyclopropane-1-carboxylate (1ad)
1ad was synthesized from methyl 3ꢀphenylꢀ2ꢀ(pyridinꢀ2ꢀyl)acrylate (510 mg, 2.13 mmol). Yield
1
426 mg (79%); colorless oil; Rf = 0.51 (petroleum ether : ethyl acetate, 3:1). Н NMR (CDCl3,
2
3
2
3
600 МHz)
δ = 1.82 (dd, J = 4.9, J = 9.1 Hz, 1Н, СН2), 2.42 (dd, J = 4.9, J = 7.8 Hz, 1Н,
3
3
СН2), 3.35(s, 3H, CH3), 3.41 (dd, J = 9.1, J = 7.8 Hz, 1Н, СН), 7.17–7.19 (m, 1Н, Py), 7.22–
7.24 (m, 1H, Ph), 7.29–7.31 (m, 2H, Ph), 7.33–7.34 (m, 2H, Ph), 7.56–7.57 (m, 1H, Py), 7.65–
7.68 (m, 1Н, Py), 8.56ꢀ8.58 (m, 1H, Py); 13С NMR (CDCl3, 150 МHz)
δ = 20.0 (CH2), 33.7
(CH), 39.6 (C), 51.7 (CH3), 121.7 (CH, Ar), 123.6 (CH, Ar), 126.8 (CH, Ar), 128.0 (2×CH, Ar),
128.9 (2×CH, Ar), 136.1 (CH, Ar), 136.4 (C, Ar), 149.0 (CH, Ar), 158.1 (C, Ar), 170.4
(CO2Me); Anal. Calcd for С16
Н
15NO : C, 75.87; H, 5.97; N, 5.53. Found: C, 76.25; H, 5.75; N,
2
5.57.
General Procedure for the Reductive Ring Opening of Cyclopropanes 1
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To 0.1 M solution of cyclopropane 1 (0.5 mmol) in the corresponding alcohol zinc dust (325 mg,
5 mmol) and acetic acid (150 ꢂL, 2.5 mmol) were sequentially added. The mixture was heated
under reflux for specified time. After cooling to the ambient temperature, remaining zinc was
filtered off and washed with ethyl acetate (5 mL). Filtrate was diluted with water (10 mL) and
extracted with ethyl acetate (2×20 mL), combined organic fractions were dried with Na2SO4 and
concentrated under reduced pressure. Product 2 was purified by column chromatography on
silica gel.
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Dimethyl [2-(4-methylphenyl)ethyl]malonate (2a)
MeOH, 5 min. Yield 96 mg (77%) (1.83 g, 73% for 10 mmol run); colorless oil; Rf = 0.20
1
(petroleum ether : diethyl ether, 3:1). Н NMR (CDCl3, 600 MHz)
δ = 2.20–2.26 (m, 2H,
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C(2)H2), 2.33 (s, 3H, CH3), 2.61–2.65 (m, 2H, C(3)H2), 3.39 (t, J = 7.6 Hz, 1Н, CH), 3.75 (s,
3
3
6H, 2×CH3O), 7.08 (d, J = 7.9 Hz, 2H, Ar), 7.11 (d, J = 7.9 Hz, 2H, Ar); 13С NMR (CDCl3,
150 MHz)
δ
= 20.9 (1JСН = 126 Hz, CH3), 30.4 (1JСН = 132 Hz, C(2)H2), 32.8 (1JСН = 127 Hz,
C(3)H2), 50.8 (1JСН = 132 Hz, CH), 52.4 (1JСН = 148 Hz, 2×CH3O), 128.3 (2×CH, Ar), 129.1
(2×CH, Ar), 135.6 (С, Ar), 137.3 (С, Ar), 169.7 (2×CO2Me); MS (MALDI–TOF) m/z: [M + K]+
+
Calcd for C14H18KO4 289; Found 289. Anal. Calcd for С14Н18O4: C, 67.18; H, 7.25. Found: C,
67.26; Н, 7.22.
Dimethyl (2-phenylethyl)malonate (2b)26,59
EtOH, 70 min. Yield 94 mg (80%); colorless oil; Rf = 0.54 (petroleum ether : diethyl ether, 2:1).
1Н NMR (CDCl3, 600 MHz)
7.5 Hz, 1Н, CH), 3.74 (s, 6H, 2×CH3O), 7.18–7.23 (m, 3H, Ph), 7.28–7.32 (m, 2H, Ph); 13С
= 30.2 (1JСН = 132 Hz, CH2), 33.2 (1JСН = 127 Hz, CH2), 50.7 (1JСН
=
δ
= 2.23–2.28 (m, 2H, CH2), 2.65–2.69 (m, 2H, CH2), 3.40 (t, 3J =
NMR (CDCl3, 150 MHz)
δ
130 Hz, CH), 52.3 (1JСН = 148 Hz, 2×CH3O), 126.1 (CH, Ph), 128.34 (2×CH, Ph), 128.37
+
(2×CH, Ph), 140.4 (С, Ar), 169.6 (2×CO2Me); HRMS (ESI) m/z: [M + H]+ Calcd for C13H17O4
237.1121; Found 237.1120.
Dimethyl [2-(4-fluorophenyl)ethyl]malonate (2c)
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EtOH, 70 min. Yield 104 mg (82%); colorless oil; Rf = 0.33 (petroleum ether : diethyl ether,
2:1). 1Н NMR (CDCl3, 600 MHz)
3J = 7.4 Hz, 1Н, CH), 3.73 (s, 6H, 2×CH3O), 6.96 (dd, JHH = 8.7, JHF = 8.8 Hz, 2H, Ar), 7.12
δ
= 2.17–2.22 (m, 2H, CH2), 2.60–2.64 (m, 2H, CH2), 3.36 (t,
3
3
8
9
3
4
(dd, JHH = 8.7, JHF = 5.4 Hz, 2H, Ar); 13С NMR (CDCl3, 150 MHz)
δ
= 30.4 (1JСН = 133 Hz,
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CH2), 32.4 (1JСН = 128 Hz, CH2), 50.7 (1JСН = 132 Hz, CH), 52.4 (1JСН = 148 Hz, 2×CH3O),
115.1 (2JСF = 21 Hz, 2×CH, Ar), 129.8 (3JСF = 8 Hz, 2×CH, Ar), 136.0 (4JСF = 3 Hz, С, Ar),
161.4 (1JСF = 243 Hz, С, Ar), 169.5 (2×CO2Me); HRMS (ESI) m/z: [M + H]+ Calcd for
+
C13H16FO4 255.1027; Found 255.1032.
Dimethyl [2-(4-chlorophenyl)ethyl]malonate (2d)
EtOH, 10 min. Yield 3.74 g (72% for 19 mmol run); colorless oil; Rf = 0.53 (petroleum ether :
1
diethyl ether, 2:1). Н NMR (CDCl3, 600 MHz)
δ = 2.18–2.23 (m, 2H, CH2), 2.61–2.65 (m, 2H,
CH2), 3.36 (t, 3J = 7.4 Hz, 1Н, CH), 3.74 (s, 6H, 2×CH3O), 7.11 (d, 3J = 8.3 Hz, 2H, Ar), 7.26 (d,
3J = 8.3 Hz, 2H, Ar); 13С NMR (CDCl3, 150 MHz) = 30.2 (1JСН = 132 Hz, CH2), 32.6 (1JСН
δ
=
127 Hz, CH2), 50.7 (1JСН = 132 Hz, CH), 52.5 (1JСН = 147 Hz, 2×CH3O), 128.6 (2×CH, Ar),
129.8 (2×CH, Ar), 132.0 (С, Ar), 138.9 (С, Ar), 169.5 (2×CO2Me); HRMS (ESI) m/z: [M + H]+
+
Calcd for C13H16ClO4 271.0732; Found 271.0737.
Dimethyl [2-(4-bromophenyl)ethyl]malonate (2e)
MeOH, 5 min. Yield 117 mg (74%); colorless oil; Rf = 0.24 (petroleum ether : diethyl ether,
3:1). 1Н NMR (CDCl3, 600 MHz)
3J = 7.4 Hz, 1Н, CH), 3.73 (s, 6H, 2×CH3O), 7.05 (d, 3J = 8.4 Hz, 2H, Ar), 7.40 (d, 3J = 8.4 Hz,
2H, Ar); 13С NMR (CDCl3, 150 MHz) = 30.1 (1JСН = 132 Hz, CH2), 32.6 (1JСН = 128 Hz,
δ = 2.17–2.23 (m, 2H, CH2), 2.58–2.63 (m, 2H, CH2), 3.35 (t,
δ
CH2), 50.7 (1JСН = 132 Hz, CH), 52.5 (1JСН = 147 Hz, 2×CH3O), 120.0 (С, Ar), 130.2 (2×CH,
Ar), 131.5 (2×CH, Ar), 139.4 (С, Ar), 169.5 (2×CO2Me); Anal. Calcd for С13Н15BrO4: C, 49.54;
H, 4.80. Found: C, 49.56; Н, 4.91.
Dimethyl [2-(4-methoxyphenyl)ethyl]malonate (2f)
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MeOH, 5 min. Yield 98 mg (74%); colorless oil; Rf = 0.28 (petroleum ether : diethyl ether, 3:1).
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1Н NMR (CDCl3, 600 MHz)
7.5 Hz, 1Н, CH), 3.74 (s, 6H, 2×CH3O), 3.79 (s, 3H, CH3O), 6.83 (d, 3J = 8.7 Hz, 2H, Ar), 7.10
(d, 3J = 8.7 Hz, 2H, Ar); 13С NMR (CDCl3, 150 MHz) = 30.6 (1JСН = 132 Hz, CH2), 32.3 (1JСН
δ
= 2.18–2.23 (m, 2H, CH2), 2.58–2.62 (m, 2H, CH2), 3.38 (t, 3J =
δ
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= 128 Hz, CH2), 50.8 (1JСН = 132 Hz, CH), 52.4 (1JСН = 148 Hz, 2×CH3O), 55.2 (1JСН = 144 Hz,
CH3O), 113.8 (2×CH, Ar), 129.4 (2×CH, Ar), 132.4 (С, Ar), 158.0 (С, Ar), 169.7 (2×CO2Me);
Anal. Calcd for С14Н18O5: C, 63.15; H, 6.81. Found: C, 63.17; Н, 6.90.
Dimethyl [2-(2-hydroxyphenyl)ethyl]malonate (2g)
EtOH, 10 min. Yield 87 mg (69%); colorless oil; Rf = 0.47 (petroleum ether : ethyl acetate, 2:1).
1Н NMR (CDCl3, 600 MHz)
δ
= 2.17–2.21 (m, 2H, CH2), 2.66–2.68 (m, 2H, CH2), 3.40 (t, 3J =
3
7.1 Hz, 1Н, CH), 3.77 (s, 6H, 2×CH3O), 6.19 (s, 1H, OH), 6.84 (d, J = 7.8 Hz, 1H, Ar), 6.84–
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6.86 (m, 1H, Ar), 7.08 (dd, J = 7.9, J = 1.7 Hz, 1H, Ar), 7.12 (ddd, J = 7.8, J = 7.6, J = 1.7
Hz, 1H, Ar); 13С NMR (CDCl3, 150 MHz) = 27.8 (1JСН = 128 Hz, CH2), 28.8 (1JСН = 132 Hz,
δ
CH2), 50.5 (1JСН = 132 Hz, CH), 52.8 (1JСН = 148 Hz, 2×CH3O), 115.9 (CH, Ar), 120.4 (CH,
Ar), 126.1 (С, Ar), 127.9 (СH, Ar), 130.2 (СH, Ar), 154.2 (С, Ar), 170.2 (2×CO2Me); HRMS
+
(ESI) m/z: [M + Na]+ Calcd for C13H16NaO5 275.0890; Found 275.0891.
Dimethyl {2-[2-(ethoxymethoxy)phenyl]ethyl}malonate (2h)
EtOH, 70 min. Yield 101 mg (65%); colorless oil; Rf = 0.45 (petroleum ether : ethyl acetate,
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3:1). Н NMR (CDCl3, 600 MHz)
δ
= 1.24 (t, J = 7.1 Hz, 3H, CH3), 2.20–2.25 (m, 2H, CH2),
3
3
2.66–2.70 (m, 2H, CH2), 3.40 (t, J = 7.4 Hz, 1Н, CH), 3.73 (s, 6H, 2×CH3O), 3.74 (q, J = 7.1
3
3
4
Hz, 2H, CH2O), 5.24 (s, 2H, OCH2O), 6.93 (ddd, J = 7.5, J = 7.4, J = 1.0 Hz, 1H, Ar), 7.10
(dd, 3J = 8.2, 4J = 1.0 Hz, 1H, Ar), 7.12 (dd, 3J = 7.5, 4J = 1.7 Hz, 1H, Ar), 7.17 (ddd, 3J = 8.2, 3J
4
= 7.4, J = 1.7 Hz, 1H, Ar); 13С NMR (CDCl3, 150 MHz)
δ
= 15.0 (1JСН = 126 Hz, CH3), 28.0
(1JСН = 130 Hz, CH2), 28.9 (1JСН = 132 Hz, CH2), 51.1 (1JСН = 132 Hz, CH), 52.3 (1JСН = 147
Hz, 2×CH3O), 64.2 (1JСН = 142 Hz, CH2O), 93.0 (1JСН = 165 Hz, OCH2O), 113.8 (CH, Ar),
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121.4 (CH, Ar), 127.5 (СH, Ar), 129.3 (С, Ar), 130.1 (СH, Ar), 155.3 (С, Ar), 169.8
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+
(2×CO2Me); HRMS (ESI) m/z: [M + Na]+ Calcd for C16H22NaO6 333.1309; Found 333.1325.
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Dimethyl {2-[5-chloro-2-(methoxymethoxy)phenyl]ethyl}malonate (2i)
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EtOH, 70 min. Yield 109 mg (66%); colorless oil; Rf = 0.56 (petroleum ether : ethyl acetate,
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3:1). 1Н NMR (CDCl3, 600 MHz)
δ = 2.18–2.23 (m, 2H, CH2), 2.62–2.66 (m, 2H, CH2), 3.38 (t,
3J = 7.4 Hz, 1Н, CH), 3.46 (s, 3H, CH3O), 3.73 (s, 6H, 2×CH3O), 5.16 (s, 2H, OCH2O), 7.00
(br.d, 3J = 8.2 Hz, 1H, Ar), 7.10 (d, 4J = 2.6 Hz, 1H, Ar), 7.11 (dd, 3J = 8.2, 4J = 2.6 Hz, 1H, Ar);
13С NMR (CDCl3, 150 MHz)
δ
= 27.9 (1JСН = 129 Hz, CH2), 28.6 (1JСН = 132 Hz, CH2), 51.0
(1JСН = 132 Hz, CH), 52.4 (1JСН = 147 Hz, 2×CH3O), 56.0 (1JСН = 142 Hz, CH3O), 94.4 (1JСН
=
165 Hz, OCH2O), 115.0 (CH, Ar), 126.4 (C, Ar), 127.2 (СH, Ar), 129.9 (СH, Ar), 131.3 (С, Ar),
153.7 (С, Ar), 169.6 (2×CO2Me); HRMS (ESI) m/z: [M + H]+ Calcd for C15H20ClO6+ 331.0943;
Found 331.0949.
Dimethyl [2-(2-hydroxy-3-methoxyphenyl)ethyl]malonate (2j)
EtOH, 10 min. Yield 102 mg (72%); colorless oil; Rf = 0.49 (petroleum ether : ethyl acetate,
2:1). 1Н NMR (CDCl3, 600 MHz)
3J = 7.5 Hz, 1Н, CH), 3.74 (s, 6H, 2×CH3O), 3.87 (s, 3H, CH3O), 5.76 (s, 1H, OH), 6.71–6.80
(m, 3H, Ar); 13С NMR (CDCl3, 150 MHz) = 27.3 (1JСН = 128 Hz, CH2), 28.6 (1JСН = 133 Hz,
δ = 2.22–2.28 (m, 2H, CH2), 2.68–2.72 (m, 2H, CH2), 3.42 (t,
δ
CH2), 51.0 (1JСН = 132 Hz, CH), 52.4 (1JСН = 147 Hz, 2×CH3O), 55.9 (1JСН = 144 Hz, CH3O),
108.8 (CH, Ar), 119.3 (CH, Ar), 122.4 (СH, Ar), 126.2 (С, Ar), 143.6 (С, Ar), 146.3 (С, Ar),
169.8 (2×CO2Me); HRMS (ESI) m/z: [M + H]+ calcd for C14H19O6 283.1176; Found 283.1185.
+
Dimethyl [2-(1,3-benzodioxol-5-yl)ethyl]malonate (2k)
MeOH, 5 min. Yield 98 mg (70%); colorless oil; Rf = 0.22 (petroleum ether : diethyl ether, 2:1).
1Н NMR (CDCl3, 400 MHz)
7.5 Hz, 1Н, CH), 3.73 (s, 6H, 2×CH3O), 5.91 (s, 2H, CH2O), 6.61 (dd, 3J = 7.9, 4J = 1.6 Hz, 1H,
Ar), 6.66 (d, 4J = 1.6 Hz, 1H, Ar), 6.71 (d, 3J = 7.9 Hz, 1H, Ar); 13С NMR (CDCl3, 100 MHz)
δ
= 2.14–2.20 (m, 2H, CH2), 2.54–2.58 (m, 2H, CH2), 3.36 (t, 3J =
δ
= 30.5 (CH2), 32.9 (CH2), 50.6 (CH), 52.4 (2×CH3O), 100.7 (CH2O), 108.1 (CH, Ar), 108.8
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(CH, Ar), 121.2 (CH, Ar), 134.1 (С, Ar), 145.8 (С, Ar), 147.6 (С, Ar), 169.6 (2×CO2Me); MS
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4
5
+
(MALDI–TOF) m/z: [M + K]+ Calcd for C14H16KO6 319; Found 319; Anal. Calcd for
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С14Н16O6: C, 59.99; H, 5.75. Found: C, 60.04; Н, 5.77.
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Dimethyl [2-(3,4,5-trimethoxyphenyl)ethyl]malonate (2l)
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MeOH, 5 min. Yield 116 mg (71%); colorless oil; Rf = 0.40 (petroleum ether : ethyl acetate,
2:1). 1Н NMR (CDCl3, 600 MHz)
3J = 7.4 Hz, 1Н, CH), 3.74 (s, 6H, 2×CH3O), 3.81 (s, 3H, CH3O), 3.84 (s, 6H, 2×CH3O), 6.39 (s,
2H, Ar); 13С NMR (CDCl3, 150 MHz) = 30.4 (1JСН = 133 Hz, CH2), 33.7 (1JСН = 128 Hz,
δ = 2.19–2.24 (m, 2H, CH2), 2.57–2.61 (m, 2H, CH2), 3.39 (t,
δ
CH2), 50.8 (1JСН = 132 Hz, CH), 52.4 (1JСН = 148 Hz, 2×CH3O), 56.0 (1JСН = 144 Hz, 2×CH3O),
60.7 (1JСН = 144 Hz, CH3O), 105.5 (2×CH, Ar), 136.1 (C, Ar), 136.5 (С, Ar), 153.2 (2×С, Ar),
169.6 (2×CO2Me);
MS (MALDI–TOF) m/z: [M + K]+ Calcd for C16H22KO7 365; Found 365; Anal. Calcd for
C16H22O7: C, 58.89; H, 6.80. Found: C, 58.90; Н, 6.79.
Dimethyl {2-[2-(methoxycarbonyl)phenyl]ethyl}malonate (2m)
EtOH, 70 min. Yield 75 mg (51%); colorless oil; Rf = 0.40 (petroleum ether : ethyl acetate, 2:1).
1Н NMR (CDCl3, 400 MHz)
δ
= 2.17–2.25 (m, 2H, CH2), 2.96–3.02 (m, 2H, CH2), 3.43 (t, 3J =
7.4 Hz, 1Н, CH), 3.72 (s, 6H, 2×CH3O), 3.87 (s, 3H, CH3O), 7.22–7.28 (m, 2H, Ar), 7.38–7.44
(m, 1H, Ar), 7.88 (br.d, 3J = 7.7 Hz, 1Н, Ar); 13С NMR (CDCl3, 100 MHz) = 30.4 (1JСН = 133
δ
Hz, CH2), 31.8 (1JСН = 128 Hz, CH2), 51.3 (1JСН = 132 Hz, CH), 51.9 (1JСН = 148 Hz, CH3O),
52.4 (1JСН = 144 Hz, 2×CH3O), 126.3 (CH, Ar), 129.3 (C, Ar), 130.8 (СH, Ar), 131.1 (СH, Ar),
132.0 (СH, Ar), 142.5 (С, Ar), 167.6 (CO2Me), 169.6 (2×CO2Me); HRMS (ESI) m/z: [M + H]+
+
Calcd for C15H19O6 295.1176; Found 295.1182.
Dimethyl [2-(pyridin-3-yl)ethyl]malonate (2n)
EtOH, 270 min. Yield 77 mg (65%); colorless oil; Rf = 0.24 (petroleum ether : ethyl acetate,
1:1). 1Н NMR (CDCl3, 600 MHz)
δ = 2.18–2.24 (m, 2H, CH2), 2.62–2.66 (m, 2H, CH2), 3.36 (t,
3J = 7.4 Hz, 1Н, CH), 3.71 (s, 6H, 2×CH3O), 7.20 (dd, 3J = 7.8, 3J = 4.8 Hz, 1H, Py), 7.50 (ddd,
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3J = 7.8, 4J = 2.2, 4J = 1.7 Hz, 1H, Py), 8.43 (d, 4J = 2.2 Hz, 1H, Py), 8.44 (dd, 3J = 4.8, 4J = 1.7
3
4
5
13
Hz, 1H, Py); С NMR (CDCl3, 150 MHz)
δ
= 29.9 (1JСН = 133 Hz, CH2), 30.3 (1JСН = 128 Hz,
CH2), 50.7 (1JСН = 132 Hz, CH), 52.5 (1JСН = 147 Hz, 2×CH3O), 123.4 (CH, Py), 135.8 (С, Py),
135.9 (CH, Py), 147.7 (СH, Py), 149.8 (СH, Py), 169.3 (2×CO2Me); Anal. Calcd for С12Н15NO4:
C, 60.75; H, 6.37; N, 5.90. Found: C, 60.65; Н, 6.33; N, 5.60.
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Dimethyl [2-(naphthalen-1-yl)ethyl]malonate (2o)
EtOH, 70 min. Yield 96 mg (67%); colorless oil; Rf = 0.20 (petroleum ether : diethyl ether, 2:1).
1Н NMR (CDCl3, 600 MHz)
δ
= 2.38–2.44 (m, 2H, CH2), 3.14–3.19 (m, 2H, CH2), 3.54 (t, 3J =
3
4
3
7.4 Hz, 1Н, CH), 3.79 (s, 6H, 2×CH3O), 7.36 (dd, J = 7.0, J = 1.0 Hz, 1H, Ar), 7.43 (dd, J =
8.2, 3J = 7.0 Hz, 1H, Ar), 7.49–7.54 (m, 1H, Ar), 7.55–7.59 (m, 1H, Ar), 7.77 (br.d, 3J = 8.2 Hz,
1H, Ar), 7.89 (br.d, 3J = 8.0 Hz, 1H, Ar), 8.11 (br.d, 3J = 8.5 Hz, 1H, Ar); 13С NMR (CDCl3, 150
MHz)
δ
= 29.7 (1JСН = 132 Hz, CH2), 30.6 (1JСН = 128 Hz, CH2), 51.2 (1JСН = 132 Hz, CH), 52.4
(1JСН = 148 Hz, 2×CH3O), 123.6 (CH, Ar), 125.4 (CH, Ar), 125.5 (CH, Ar), 126.0 (CH, Ar),
126.3 (CH, Ar), 127.0 (CH, Ar), 128.7 (CH, Ar), 131.7 (С, Ar), 133.8 (С, Ar), 136.6 (С, Ar),
169.6 (2×CO2Me); HRMS (ESI) m/z: [M + H]+ Calcd for C17H19O4 287.1278; Found 287.1283.
+
Dimethyl [2-(1-methyl-1H-pyrrol-2-yl)ethyl]malonate (2p)
MeOH, 5 min. Yield 81 mg (67%); colorless oil; Rf = 0.54 (petroleum ether : ethyl acetate, 2:1).
1Н NMR (CDCl3, 600 MHz)
δ
= 2.22–2.27 (m, 2H, CH2), 2.62–2.66 (m, 2H, CH2), 3.50 (t, 3J =
3
7.3 Hz, 1Н, CH), 3.56 (s, 3H, CH3N), 3.76 (s, 6H, 2×CH3O), 5.92 (br.d, J = 3.4 Hz, 1H, Ar),
6.06 (br.d, 3J = 3.4 Hz, 1H, Ar), 6.57 (br. s, 1H, Ar); 13С NMR (CDCl3, 150 MHz)
δ
= 23.8 (1JСН
= 127 Hz, CH2), 27.9 (1JСН = 133 Hz, CH2), 33.3 (1JСН = 138 Hz, CH3N), 50.7 (1JСН = 132 Hz,
CH), 52.4 (1JСН = 148 Hz, 2×CH3O), 106.1 (CH, Ar), 106.5 (CH, Ar), 121.4 (CH, Ar), 130.9 (C,
Ar), 169.5 (2×CO2Me); MS (MALDI–TOF) m/z: [M + H]+ Calcd for C12H18NO4 240; Found
240; Anal. Calcd for C12H17NO4: C, 60.24; H, 7.16; N, 5.85. Found: C, 60.02; Н, 7.10; N, 5.89.
Dimethyl [2-(1-methyl-1H-pyrazol-4-yl)ethyl]malonate (2q)
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EtOH, 10 min. Yield 77 mg (64%); colorless oil; Rf = 0.10 (petroleum ether : ethyl acetate, 2:1).
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1Н NMR (CDCl3, 600 MHz)
δ
= 2.07–2.12 (m, 2H, CH2), 2.43–2.47 (m, 2H, CH2), 3.35 (t, 3J =
6
7
8
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7.5 Hz, 1Н, CH), 3.68 (s, 6H, 2×CH3O), 3.80 (s, 3H, CH3N), 7.13 (s, 1H, Ar), 7.25 (s, 1H, Ar);
13С NMR (CDCl3, 150 MHz) = 21.6 (1JСН = 128 Hz, CH2), 29.9 (1JСН = 132 Hz, CH2), 38.6
δ
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(1JСН = 141 Hz, CH3N), 50.6 (1JСН = 132 Hz, CH), 52.3 (1JСН = 148 Hz, 2×CH3O), 119.6 (C,
Ar), 128.4 (CH, Ar), 138.5 (CH, Ar), 169.5 (2×CO2Me); HRMS (ESI) m/z: [M + H]+ Calcd for
+
C11H17N2O4 241.1183; Found 241.1183.
Dimethyl [2-(5-methylfuran-2-yl)ethyl]malonate (2r)
MeOH, 5 min. Yield 44 mg (37%); colorless oil; Rf = 0.67 (petroleum ether : ethyl acetate, 2:1).
1Н NMR (CDCl3, 600 MHz)
δ
= 2.20–2.25 (m, 2H, CH2), 2.24 (br. s, 3H, CH3), 2.61–2.66 (m,
3
4
2H, CH2), 3.42 (t, J = 7.4 Hz, 1Н, CH), 3.73 (s, 6H, 2×CH3O), 5.83 (dq, 3J = 2.9, J = 1.0 Hz,
1Н, Fu), 5.88 (d, 3J = 2.9 Hz, 1Н, Fu); 13С NMR (CDCl3, 150 MHz)
δ
= 13.4 (1JСН = 128 Hz,
CH3), 25.6 (1JСН = 128 Hz, CH2), 27.3 (1JСН = 133 Hz, CH2), 50.7 (1JСН = 132 Hz, CH), 52.4
(1JСН = 147 Hz, 2×CH3O), 105.8 (CH, Fu), 106.3 (CH, Fu), 150.7 (C, Fu), 152.1 (C, Fu), 169.5
(2×CO2Me).
+
HRMS (ESI) m/z: [M + H]+ Calcd for C12H17O5 241.1071; Found 241.1067.
Dimethyl [2-(thien-2-yl)ethyl]malonate (2s)
EtOH, 10 min. Yield 83 mg (68%); colorless oil; Rf = 0.77 (Al2O3, petroleum ether : ethyl
acetate, 2:1). 1Н NMR (CDCl3, 600 MHz)
δ
= 2.25–2.30 (m, 2H, CH2), 2.86–2.91 (m, 2H, CH2),
3
3.43 (t, 3J = 7.5 Hz, 1Н, CH), 3.73 (s, 6H, 2×CH3O), 6.79–6.81 (m, 1H, Th), 6.91 (dd, J = 5.1,
3
13
3J = 3.4 Hz, 1Н, Th), 7.14 (dd, J = 5.1, 4J = 1.2 Hz, 1Н, Th); С NMR (CDCl3, 150 MHz)
δ
=
=
=
27.3 (1JСН = 130 Hz, CH2), 30.5 (1JСН = 133 Hz, CH2), 50.5 (1JСН = 132 Hz, CH), 52.5 (1JСН
148 Hz, 2×CH3O), 123.5 (1JСН = 186 Hz, CH, Th), 124.8 (1JСН = 166 Hz, CH, Th), 126.8 (1JСН
167 Hz, CH, Th), 142.9 (C, Th), 169.4 (2×CO2Me); MS (MALDI–TOF) m/z: [M + H]+ Calcd
for C11H15O4S 243; Found 243; Anal. Calcd for C11H14O4S: C, 54.53; H, 5.82. Found: C, 54.47;
Н, 5.50.
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Dimethyl [2-(thien-3-yl)ethyl]malonate (2t)
EtOH, 10 min. Yield 65 mg (54%); colorless oil; Rf = 0.59 (petroleum ether : ethyl acetate, 4:1).
1Н NMR (CDCl3, 600 MHz)
δ
= 2.22–2.27 (m, 2H, CH2), 2.67–2.72 (m, 2H, CH2), 3.39 (t, 3J =
8
9
4
7.4 Hz, 1H, CH), 3.74 (s, 6H, 2×CH3O), 6.94 (dd, 3J = 5.0, J = 1.3 Hz, 1Н, Th), 6.96–6.98 (m,
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1H, Th), 7.26 (dd, 3J = 5.0 Hz, 3J = 3.0 Hz, 1Н, Th); 13С NMR (CDCl3, 150 MHz)
δ
= 27.7 (1JСН
= 128 Hz, CH2), 29.5 (1JСН = 132 Hz, CH2), 50.9 (1JСН = 133 Hz, CH), 52.4 (1JСН = 147 Hz,
2×CH3O), 120.8 (CH, Th), 125.6 (CH, Th), 128.0 (CH, Th), 140.7 (C, Th), 169.6 (2×CO2Me);
HRMS (ESI) m/z: [M + H]+ Calcd for C11H15O4S+ 243.0686; Found 243.0687.
Dimethyl [2-(1-methyl-1H-indol-2-yl)ethyl]malonate (2u)
MeOH, 5 min. Yield 106 mg (73%), yellow crystals; mp 72–73 °C; Rf = 0.31 (petroleum ether :
diethyl ether, 2:1). 1Н NMR (CDCl3, 600 MHz)
δ
= 2.33–2.38 (m, 2H, CH2), 2.84 (t, 3J = 7.9 Hz,
3
2Н, CH), 3.56 (t, J = 7.3 Hz, 1H, CH2), 3.69 (s, 3H, CH3N), 3.77 (s, 6H, 2×CH3O), 6.31 (br.s,
3
3
3
3
1H, Ind), 7.11 (dd, J = 7.9 Hz, J = 7.8 Hz, 1Н, Ind), 7.20 (dd, J = 8.1 Hz, J = 7.9 Hz, 1Н,
Ind), 7.30 (d, 3J = 8.1 Hz, 1Н, Ind), 7.57 (d, 3J = 7.8 Hz, 1Н, Ind); 13С NMR (CDCl3, 150 MHz)
δ
= 24.3 (CH2), 27.7 (CH2), 29.3 (CH), 50.6 (CH3), 52.5 (2×CH3O), 99.5 (CH, Ind), 108.8 (CH,
Ind), 119.3 (CH, Ind), 119.8 (CH, Ind), 120.8 (CH, Ind), 127.6 (C, Ind), 137.4 (C, Ind), 138.8 (C,
Ind), 169.5 (2×CO2Me); MS (MALDI–TOF) m/z: [M]+ Calcd for C16H19NO4 289; Found 289;
Anal. Calcd for C16H19NO4: C, 66.42; H, 6.62; N, 4.84. Found: C, 66.52; Н, 6.47; N, 4.85.
Dimethyl [2-(1-methyl-1H-indol-3-yl)ethyl]malonate (2v)
MeOH, 5 min. Yield 97 mg (67%); colorless oil; Rf = 0.66 (petroleum ether : ethyl acetate, 2:1).
1Н NMR (CDCl3, 600 MHz)
δ
= 2.32–2.37 (m, 2H, CH2), 2.81–2.86 (m, 2H, CH2), 3.50 (t, 3J =
7.5 Hz, 1H, CH2), 3.758 (s, 6H, 2×CH3O), 3.763 (s, 3H, CH3N), 6.88 (s, 1H, Ind), 7.12–7.16 (m,
3
3
1H, Ind), 7.23–7.27 (m, 1H, Ind), 7.31 (br.d, J = 8.1 Hz, 1Н, Ind), 7.62 (br.d, J = 7.9 Hz, 1Н,
Ind); 13С NMR (CDCl3, 150 MHz)
δ
= 22.6 (CH2), 29.4 (CH2), 32.5 (CH), 51.0 (CH3), 52.4
(2×CH3O), 109.1 (CH, Ind), 113.0 (C, Ind), 118.7 (CH, Ind), 118.9 (CH, Ind), 121.5 (CH, Ind),
126.5 (CH, Ind), 127.6 (C, Ind), 137.0 (C, Ind), 169.9 (2×CO2Me); MS (MALDI–TOF) m/z:
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[M]+ Calcd for C16H19NO4 289; Found 289; Anal. Calcd for C16H19NO4: C, 66.42; H, 6.62; N,
4.84. Found: C, 66.59; Н, 6.40; N, 4.85.
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Dimethyl [2-(1-methyl-1H-indol-4-yl)ethyl]malonate (2w)
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MeOH, 5 min. Yield 109 mg (75%); colorless oil; Rf = 0.49 (petroleum ether : ethyl acetate,
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2:1). 1Н NMR (CDCl3, 600 MHz)
3J = 7.4 Hz, 1H, CH2), 3.77 (s, 6H, 2×CH3O), 3.80 (s, 3H, CH3N), 6.57 (dd, 3J = 3.1, 4J = 0.9 Hz,
δ = 2.38–2.43 (m, 2H, CH2), 2.97–3.01 (m, 2H, CH2), 3.49 (t,
3
3
1Н, Ind), 6.94–6.97 (m, 1H, Ind), 7.07 (d, J = 3.1 Hz, 1Н, Ind), 7.19 (dd, J = 8.2, 3J = 6.9 Hz,
3
1Н, Ind), 7.23 (br.d, J = 8.2 Hz, 1Н, Ind); 13С NMR (CDCl3, 150 MHz)
δ
= 29.5 (1JСН = 132
Hz, CH2), 30.9 (1JСН = 127 Hz, CH2), 32.8 (1JСН = 138 Hz, CH3), 51.1 (1JСН = 132 Hz, CH), 52.3
(1JСН = 147 Hz, 2×CH3O), 99.1 (CH, Ind), 107.5 (CH, Ind), 118.9 (CH, Ind), 121.6 (CH, Ind),
127.7 (C, Ind), 128.4 (CH, Ind), 132.7 (C, Ind), 136.7 (C, Ind), 169.8 (2×CO2Me); MS
(MALDI–TOF) m/z: [M + Na]+ Calcd for C16H19NNaO4 312; Found 312; Anal. Calcd for
C16H19NO4: C, 66.42; H, 6.62; N, 4.84. Found: C, 66.51; Н, 6.63; N, 4.87.
2-(Methoxycarbonyl)-4-phenylbutanoic acid (2x)
MeOH, 5 min. Yield 93 mg (84%); colorless oil; Rf = 0.34 (petroleum ether : ethyl acetate, 2:1).
1Н NMR (CDCl3, 600 MHz)
δ
= 2.25–2.35 (m, 2H, CH2), 2.71–2.75 (m, 2H, CH2), 3.48 (t, 3J =
7.4 Hz, 1Н, CH), 3.78 (s, 3H, CH3O), 7.21–7.26 (m, 3H, Ph), 7.31–7.35 (m, 2H, Ph), 11.48 (br.s,
13
1H, CO2H); С NMR (CDCl3, 150 MHz)
δ
= 30.2 (1JСН = 132 Hz, CH2), 33.1 (1JСН = 127 Hz,
CH2), 50.8 (1JСН = 132 Hz, CH), 52.5 (1JСН = 147 Hz, CH3O), 126.2 (CH, Ph), 128.4 (4×CH,
Ph), 140.2 (С, Ph), 169.5 (CO2Me), 175.1 (CO2H); HRMS (ESI) m/z: [M + H]+ Calcd for
+
C12H15O4 223.0965; Found 223.0964.
2-(Methoxycarbonyl)-4-(3,4,5-trimethoxyphenyl)butanoic acid (2y)
MeOH, 5 min. Yield 121 mg (77%); colorless oil; Rf = 0.11 (petroleum ether : ethyl acetate,
2:1). 1Н NMR (CDCl3, 600 MHz)
δ = 2.19–2.29 (m, 2H, CH2), 2.61–2.66 (m, 2H, CH2), 3.44 (t,
3J = 7.4 Hz, 1Н, CH), 3.77 (s, 3H, CH3O), 3.82 (s, 3H, CH3O), 3.84 (s, 6H, 2×CH3O), 6.40 (s,
13
2H, Ar); С NMR (CDCl3, 150 MHz)
δ = 30.4 (CH2), 33.6 (CH2), 50.7 (CH), 52.6 (CH3), 56.0
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