Reductive Knoevenagel Condensation with the Zn-AcOH System

Article abstract of DOI:10.1055/s-0040-1705940

An efficient gram-scale one-pot approach to 2-substituted malonates and related structures is developed, starting from commercially available aldehydes and active methylene compounds. The technique combines Knoevenagel condensation with the reduction of the C=C bond in the resulting activated alkenes with the Zn-AcOH system. The relative ease with which the C=C bond reduction occurs can be traced to the accepting abilities of the substituents in the intermediate arylidene malonates.

Full text of DOI:10.1055/s-0040-1705940

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 52, A–G
paper
A
en
K. L. Ivanov et al.
Paper
Synthesis
Reductive Knoevenagel Condensation with the Zn–AcOH System
Konstantin L. Ivanov
Mikhail Ya. Melnikov
Ekaterina M. Budynina*
Department of Chemistry, Lomonosov Moscow
State University, Leninskie gory 1-3, Moscow
119991, Russian Federation
ekatbud@kinet.chem.msu.ru
EDeMkeapataieClrroteimnrkraeetnMsbptu.oodBnf@udCdkihnyiengnmeiAnti.uascthrheyom,rL.ommsuo.nruosov Moscow State University, Leninskie gory 1-3, Moscow 119991, Russian Federation
Received: 21.05.2020
Accepted after revision: 16.09.2020
Published online: 29.10.2020
O
PPAR agonists
JTT-501: R–R' = NH-O
(Reglitazar, Pfizer)
JTP20993: R, R' = OMe
O
O
R
DOI: 10.1055/s-0040-1705940; Art ID: ss-2020-t0283-op
N
O
O
R'
O
O
O
Abstract An efficient gram-scale one-pot approach to 2-substituted
malonates and related structures is developed, starting from commer-
cially available aldehydes and active methylene compounds. The tech-
nique combines Knoevenagel condensation with the reduction of the
C=C bond in the resulting activated alkenes with the Zn–AcOH system.
The relative ease with which the C=C bond reduction occurs can be
traced to the accepting abilities of the substituents in the intermediate
arylidene malonates.
anticancer agent
NH3
Pt
HO
(
)
6
N
N
H
O
O
NH3
H
A. Pharmacological utility
B. Synthetic utility
EWG
(Het)Ar
CH
EWGs
• aromatic substitution •
via • alkylation • acylation • halogenation •
• reduction • nucleophilic substitution •
• decarboxylation • complexation •
etc.
EWG'
1
Het
Ar
C. Practicable approach
EWG
EWG'
EWG
EWG'
Key words electron transfer, malonate, reduction, reductive alkyla-
tion, zinc
Reductive Knoevenagel condensation
O
1. Condensation
EWG
Het
Ar
Het
Ar
2. Reduction
Het
Ar
EWG'
Nu
• cyanoacetates • malononitrile •
• nitroacetates • ring 1,3-diketones • • HCO2H–Et3N • BH3–amine • NaBH4
2
1
(Het)arylmethylmalonates 1 as well as their analogues
with other electron-withdrawing groups (EWGs, i.e., COR,
CONR2, CN, etc.) attract significant interest in the context of
their pharmacological and synthetic utility. Among 1,3-di-
carbonyl derivatives 1, dual PPAR agonists with antihyper-
glycemic and antihyperlipidemic activities [e.g., JTT-501
(Reglitazar), JTP20993 and their structural analogues]1 as
well as anticancer agents2 have been reported (Scheme 1A).
The synthetic utility of compounds 1 is associated with pos-
sible modifications of the pronucleophilic CH acidic center,
the aromatic ring, and EWGs (Scheme 1B).
Among the primary synthetic approaches to com-
pounds 1, the sequence that involves Knoevenagel conden-
sation between aldehydes and active methylene com-
pounds followed by the reduction of the newly formed C=C
bond in alkenes 2 can be called essential (Scheme 1C). This
technique is a valuable alternative to direct alkylation of ac-
tive methylene compounds if one considers the possibility
of double alkylation as well as the frequently preferable
availability of aldehydes as compared to the corresponding
alkyl halides. Meanwhile, it is well known that the viability
[H]
• H2–[M] • CO–H2O–[Rh] • Fe(CO)5
•
•
• Meldrum's or barbituric acids •
• CaH2–[Pt] or [Pd] • Hantzsch ester •
This work
Nu
[H]
• malonates • etc.
• low-cost Zn–AcOH system •
Scheme 1 Concept of this work
of a multi-step synthesis can be significantly improved by
its reorganization into a step-, time- and waste-economy
one-pot protocol requiring no isolation of intermediates.3
The approach of simultaneous Knoevenagel condensa-
tion and reduction with an H2–Pd/C system has been re-
ported as early as 1944.4 As of now, several protocols for re-
ductive Knoevenagel condensation have been developed,
employing different reducing agents: H2 with noble metal-
based catalysts (Rh,5 Pd6); syngas–[Ru];7 CO with noble-
metal-based catalysts;8 Fe(CO)5;9 HCO2H–Et3N;10 BH3–
amine;11 NaBH3CN;12 NaBH4;13 NaTeH4;14 CaH2;15 organic
hydrides (Hantzsch ester, 2,3-dihydro-1H-benzimidazoles
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
K. L. Ivanov et al.
Paper
Synthesis
or 2-phenyl-2,3-dihydro-1,3-benzothiazole generated in
situ);16,17 and even HI formed in situ.18 In almost all of these
cases, very reactive substrates, such as cyanoacetates, malo-
nonitrile, nitroacetates, ring 1,3-diketones, Meldrum’s or
barbituric acid derivatives, were used as active methylene
compounds. These can rapidly and efficiently afford inter-
mediate products with high electron affinity. At the same
time, malonate derivatives usually exhibit poor results in
these tandem processes.6a,f,8c,15,16a Therefore, a bypass syn-
thetic approach to malonates via Meldrum’s acid deriva-
tives was developed.16b
completely converted into the corresponding alkanes 1
within 10 minutes in MeOH under reflux, regardless of the
donating ability of a (het)aryl substituent in 2.
Znp (10 equiv)
AcOH (5 equiv)
CO2Me
CO2Me
MeOH (0.3 M)
10 min, Δ
R
CO2Me
R
CO2Me
2
1
Me
Cl
MeO
1a: 79%
1b: 86%
1e: 83%
1h: 80%
MeO
The ability of the Zn–H+ systems to reduce electrophilic
alkenes, particularly donor-acceptor substrates such as
chalcone,19 has been known since the 19th century. Since
that time, Zn–H+ systems were successfully used for hy-
drogenolysis of ,-unsaturated compounds, including 1,3-
dicarbonyl derivatives generally synthesized via Knoevena-
gel condensation (Scheme 2).20 However, the use of this
low-cost and convenient reducing agent in a one-pot reduc-
tive Knoevenagel condensation is restricted to a single ex-
ample reported for highly reactive barbiturate deriva-
tives.20c Herein, we describe an efficient technique for one-
pot Knoevenagel condensation and C=C bond hydrogenoly-
sis with the Zn–AcOH system, allowing for the introduction
of poorly reactive malonates as well as other commonly
used active methylene compounds.
NMe
MeN
MeO
OMe
1j: 83%
1m: 81%
1p: 66%
1r: 83%
Znp = zinc powder (315 μm)
Scheme 3 Hydrogenolysis of alkenes 2 with Zn–AcOH system
High concentration of reactants in the Knoevenagel step
together with acidic conditions (1:4 piperidine/AcOH was
used as a catalyst) provided an opportunity for combining
this step with C=C bond hydrogenolysis in a protic medium.
In our experience,21a even substoichiometric amounts of
AcOH (0.5 equiv) are sufficient to carry out hydrogenolysis
in AlkOH despite significant deceleration. Therefore, in the
one-pot synthesis of 1, we reduced the amounts of Zn and
AcOH to 3 and 2 equivalents, respectively, while replacing
MeOH with EtOH, with the aim of practicability (particular-
ly toward gram-scale synthesis). This optimization immedi-
ately differentiated alkenes 2 with respect to their accept-
ing abilities. We revealed that alkenes 2a–h with phenyl,
tolyl, mono-halogen-, and mono-alkoxyphenyl groups
readily underwent hydrogenolysis in the presence of Zn
powder in 10 minutes in EtOH under reflux (Scheme 4).
However, to achieve complete reduction of dimethoxy de-
rivative 2i, prolonged heating was required along with addi-
tional amounts of AcOH. These conditions triggered trans-
esterification. Therefore, for the highly donating 3,4,5-tri-
methoxy and 4-dimethylamino derivatives 2j,k, Zn dust
(<10 m) was used instead of Zn powder (315 m). Howev-
er, this made the isolation of 2 somewhat complicated. The
significant increase in the reaction time (2j: 1 h, 2k: 10 h)
and the use of MeOH as a solvent once again allowed to
synthesize 1j,k chemoselectively and in high yields. The use
of 4-nitrobenzaldehyde in the studied process is complicat-
ed by the involvement of the NO2 group. The treatment of
the corresponding alkene 2, dimethyl (4-nitro-
benzylidene)malonate, with Zn–AcOH resulted in rapid
NO2-into-NH2 reduction. However, further reduction pro-
ceeded ambiguously accompanied by side processes, in-
cluding retro-Knoevenagel condensation (that is typical for
compounds with electron-abundant groups)22 and irrevers-
ible conversion of the regenerated aldehyde into an alcohol.
R'
COR
CN
COAr
Ph
Ar'
COMe
ref. 20k
ref. 20i: R = OMe; R' = Me
Zn
AcOH
ref. 20j: R = OAlk, NH2; R' = H
O
O
CO2Et
Zn-Cu
X
EWG
NR
NR
Zn
O
O
MeOH
O
AcOH
Ar
X'
EWG'
ref. 20h
ref. 20a–d: R = H, Alk
Zn
AcOH
CO2R
CO2R
R'
ref. 20e:
R = H
R' =
ref. 20f:
R = Et
R' =
ref. 20g:
R = Et
R' =
Me
OMe
Me
Me
O
O
MeO
Scheme 2 Examples of 1,3-dicarbonyl derived-alkene hydrogenolysis
with Zn–H+ systems
Initially, we tested the isolated malonate derivatives 2
under conditions that were identical to those developed
earlier in our group for donor-acceptor cyclopropane
hydrogenolysis and reductive condensation of NO2-substi-
tuted Knoevenagel alkenes, leading to quinoline derivatives
(Scheme 3).21 In the presence of 10 equivalents of Zn pow-
der and 5 equivalents of AcOH, alkenes 2a,b,e,h,j,m,p,r are
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

C
K. L. Ivanov et al.
Paper
Synthesis
minutes with low chemoselectivity. The NMR yield of the
target alkane 1v only amounted to 60%, whereas the un-
identified side products were found to be inseparable by
means of column chromatography. Among the possible
competitive processes prohibiting chemoselectivity, the
Clemmensen-like reduction of a keto group as well as the
radical dimerization of conjugated ketones of the 2v type
can be singled out.19b
i. piperidine (5 mol%)
AcOH (20 mol%)
benzene or toluene
EWG
EWG
Δ, 1–5 h
R
R
O
ii. Zn (3 equiv)
AcOH (2 equiv)
AlkOH, Δ
EWG
CO2R'
CO2R'
50 mmol
50 mmol
1
R
CO2R'
2
The application of the developed one-pot process for al-
iphatic aldehydes is less viable since in this case direct al-
kylation of active methylene compounds is more relevant
due to frequent availability of the corresponding alkyl ha-
lides. However, in order to demonstrate the applicability of
our one-pot protocol for aliphatic aldehydes, we used isova-
leraldehyde in reactions with dimethyl malonate and meth-
yl cyanoacetate (Scheme 5). The Knoevenagel steps were
completed in 1.5 hours (2w) and 0.5 hour (2x). The rate of
hydrogenolysis of alkyl-substituted methylidenemalonate
2w with the Zn–AcOH system was comparable with that for
arylidenemalonates with donor (het)aryl substituents (e.g.,
2k,n,o). 85% conversion of 2w into 1w was achieved in 8
hours. As one should expect, cyanoester 2x exhibited high-
er reactivity versus malonate 2x.
EWG = CO2Me, R' = Me, R =
Me
1a: Znp, EtOH 1b: Znp, EtOH
t-Bu
1c: Znp, EtOH 1d: Znp, EtOH
40 min, 94% 10 min, 97%
F
10 min, 94%
10 min, 95%
Cl
Br
MeO
OMe
1e: Znp, MeOH 1f: Znp, MeOH 1g: Znp, EtOH 1h: Znp, EtOH
10 min, 93% 10 min, 81% 10 min, 97% 10 min, 95%
MeO
MeO
S
MeO
Me2N
OMe
1i: Znp, EtOH
80 min, 95%
OMe
1j: Znd, MeOH
1k: Znd, MeOH 1l: Znd, MeOH
60 min, 95%
600 min, 81%
MeN
10 min, 75%
N
i. piperidine (5 mol%)
AcOH (20 mol%)
NMe
O
HN
50 mmol
EWG
CO2Me
toluene, Δ
1m: Znd, MeOH 1n: Znd, MeOH 1o: Znd, MeOH 1q: Znp, MeOH
ii. Znd (3 equiv)
AcOH (2 equiv)
MeOH, Δ
EWG
10 min, 87%
660 min, 76%
600 min, 78% 60 min, rt, 80%
COMe COMe
CO2Et COMe
1w,x
CN
COMe
CO2Me
50 mmol
CO2Me
Ph
CO2Me
Ph
1w: EWG = CO2Me, 1.5 h (i), 8 h (ii), 70%
(85% conversion of alkene 2w)
Znd = zinc dust (<10 μm)
Ph
Ph
1x: EWG = CN, 0.5 h (i), 5 h (ii), 83%
1s: Znp, EtOH 1t: Znp, EtOH 1u: Znp, EtOH
1v: Znp, MeOH
30 min, 0 °C, 60%a
2 min, 91%
2 min, 77%
2 min, 82%
Scheme 5 One-pot protocol with isovaleraldehyde
Znp = zinc powder (315 μm); Znd = zinc dust (< 10 μm). a NMR yield.
Scheme 4 One-pot Knoevenagel condensation and C=C bond reduc-
tion starting from (het)aryl aldehydes
In conclusion, we have developed a convenient one-pot
synthesis of 2-substituted malonates and their cyano- and
keto-analogues via reductive Knoevenagel condensation
from the commonly available aldehydes and active methy-
lene compounds with Zn–AcOH as a low-cost reductive sys-
tem. The developed protocol allows for the involvement of
malonate derivatives that usually exhibit low reactivity in
similar processes with other reducing agents. However, the
highly reactive 1,3-diketones demonstrate low chemoselec-
tivity in this approach. The tendency of intermediate
arylidenemalonates to undergo hydrogenolysis correlates to
the electronic nature of (het)aryl substituents conjugated
with the C=C bond.
The impact of the electronic nature of substituent R in 2
on the rate of hydrogenolysis was observed more palpably
for heteroaryl-substituted alkenes 2l–o,q. Alkene 2l, con-
taining the phenyl-like 2-thienyl group, as well as 2-indo-
lyl-substituted alkene 2m, were easily converted into al-
kanes 1l,m within 10 minutes in MeOH under reflux. How-
ever, for 2n,o with the 3-indolyl substituents of a more
donating nature, complete conversion to 1n,o could only be
achieved in 10–11 hours. Oppositely, 2-pyridyl-substituted
alkene 2q underwent very easy reduction at room tempera-
ture with Zn powder.
Next, we studied cyanoacetate, acetoacetates, and
acetylacetone in this one-pot process (Scheme 4). The hy-
drogenolysis of cyano and keto esters 2s–u proceeded more
intensively versus malonates, leading to 1s–u in high yields
within 2 minutes. Diketo derivative 2v was found to possess
the highest reactivity within the studied series of com-
pounds. The hydrogenolysis of 2v proceeded at 0 °C in 30
Reagents were purchased from commercial sources and used without
further purification. NMR spectra were acquired either on Bruker
Avance 400 MHz or on Bruker Avance 600 MHz spectrometers at r.t.;
the chemical shifts  were measured in ppm with respect to solvent
(1Н: CDCl3,  = 7.27; 13C: CDCl3,  = 77.0). Standard abbreviations are
used to designate the splitting patterns. Coupling constants (J) are
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

D
K. L. Ivanov et al.
Paper
Synthesis
given in hertz (Hz). The structures of compounds were elucidated
with the aid of 1D NMR (1H, 13C{1H}, 13C off-resonace decoupling).
High-resolution and accurate mass measurements were carried out
using a Bruker microTOF-Q ESI-TOF (Electro Spray Ionization/Time of
Flight) and Thermo Scientific LTQ Orbitrap mass spectrometers. Melt-
ing points were determined using Electrothermal IA 9100 capillary
melting point apparatus. Analytical TLC was carried out with silica gel
plates (silica gel 60, F254, supported on aluminum foil) visualized with
UV lamp (254 nm). Column chromatography was performed on silica
gel 60 (230–400 mesh). Zn powder (315 m) and Zn dust (<10 m)
are commercial products. Spectral data for compounds 1a,b,d–j,m–
o,s–u,x are consistent with those reported previously.
Dimethyl 2-(4-Methylbenzyl)malonate (1b)23a
Yield: 11.25 g (95%, GP2), 4.45 g (86% for 22 mmol run, GP1); colorless
oil; Rf = 0.83 (PE/EtOAc 2:1).
1Н NMR (CDCl3, 600 MHz):  = 2.32 (s, 3 H, CH3), 3.20 (br d, 3J = 7.8 Hz,
2 H, CH2), 3.67 (t, 3J = 7.8 Hz, 1 H, CH), 3.71 (s, 6 H, 2 × CH3O), 7.09 (br
s, 4 H, Ar).
13С NMR (CDCl3, 150 MHz):  = 20.9 (1JСН = 126 Hz, CH3), 34.3 (1JСН
=
132 Hz, CH2), 52.4 (1JСН = 148 Hz, 2 × CH3O), 53.6 (1JСН = 134 Hz, CH),
128.5 (2 × CH, Ar), 129.1 (2 × CH, Ar), 134.5 (С, Ar), 136.2 (С, Ar), 169.1
(2 × CO2Me).
Dimethyl (4-tert-Butylbenzyl)malonate (1c)
Hydrogenolysis of Knoevenagel Alkenes 2 with the Zn–AcOH Sys-
tem;21a General Procedure 1 (GP1)
Yield: 13.07 g (94%, GP2); yellowish oil; Rf = 0.86 (PE/EtOAc 2:1).
1Н NMR (CDCl3, 600 MHz):  = 1.31 (s, 9 H, 3 × CH3), 3.21 (br d, 3J = 7.8
Hz, 2 H, CH2), 3.69 (t, 3J = 7.8 Hz, 1 H, CH), 3.72 (s, 6 H, 2 × CH3O), 7.12–
7.15 (m, 2 H, Ar), 7.30–7.33 (m, 2 H, Ar).
13С NMR (CDCl3, 150 MHz):  = 31.3 (3 × CH3), 34.2 (CH2), 34.3 (C),
52.5 (2 × CH3O), 53.5 (CH), 125.4 (2 × CH, Ar), 128.3 (2 × CH, Ar), 134.6
(С, Ar), 149.5 (С, Ar), 169.3 (2 × CO2Me).
To a solution of the corresponding alkene 2 (1 equiv) in MeOH (0.3 M)
were added Zn powder (10 equiv) and AcOH (5 equiv) sequentially.
The reaction mixture was stirred under reflux for 10 min. The result-
ing suspension was cooled and then the remaining metallic Zn was
filtered off using EtOAc for washing. The combined organic fractions
were concentrated under reduced pressure. The residue was mixed up
with brine and extracted with EtOAc. The combined organic fractions
were washed once with H2O, dried (Na2SO4), and concentrated under
reduced pressure. The residue was purified by column chromatogra-
phy on silica gel (PE/EtOAc; or PE/Et2O).
HRMS (ESI): m/z [M – H]– calcd for C16H21O4–: 277.1445; found:
277.1447.
Dimethyl 2-(4-Fluorobenzyl)malonate (1d)23b
Yield: 11.63 g (97%, GP2); yellowish oil; Rf = 0.78 (PE/EtOAc 2:1).
1Н NMR (CDCl3, 600 MHz):  = 3.18 (br d, 3J = 7.8 Hz, 2 H, CH2), 3.63 (t,
One-Pot (OP) Reductive Knoevenagel Condensation with the Zn–
AcOH System; General Procedure 2 (GP2)
3
3J = 7.8 Hz, 1 H, CH), 3.68 (s, 6 H, 2 × CH3O), 6.95 (dd, JHH = 8.8 Hz,
CAUTION! Although we did not experience any problems with the
studied reactions, Zn dust is potentially flammable material. Its reac-
tions with acids are highly exothermic with releasing flammable H2
gas. Safety precautions are required.
3JHF = 8.6 Hz, 2 H, Ar), 7.15 (dd, 3JHH = 8.8 Hz, 4JHF = 5.3 Hz, 2 H, Ar).
13С NMR (CDCl3, 150 MHz):  = 33.8 (CH2), 52.5 (2 × CH3O), 53.5 (CH),
115.3 (2JСF = 21 Hz, 2 × CH), 130.2 (3JСF = 8 Hz, 2 × CH), 133.3 (4JСF = 3
Hz, С), 161.7 (1JСF = 245 Hz, С), 169.0 (2 × CO2Me).
A mixture of the corresponding aldehyde (50 mmol), active methy-
lene compound (50 mmol), piperidine (0.25 mL, 2.5 mmol), and AcOH
(0.58 mL, 10 mmol) in benzene (or toluene, if noticed, 40 mL) was
heated under reflux with a 20 mL Dean–Stark trap for 1–5 h (until ca.
1 mL of H2O was collected). The reaction mixture was allowed to cool
down to r.t. Then it was diluted with the corresponding alcohol (50
mL) (Scheme 4), followed by the addition of Zn metal in either pow-
dered or dust form (9.8 g, 0.15 mol) and AcOH (5.8 mL, 0.10 mol). In
the case of cyano and keto derivatives, AcOH was added dropwise
within 5 min under vigorous stirring. The reaction mixture was
stirred under conditions specified (Schemes 4 and 5). The resulting
suspension was cooled, if needed, and then the remaining Zn metal
was filtered off using EtOAc for washing (Büchner funnel was used in
the case of Zn dust). The combined organic fractions were concentrat-
ed under reduced pressure. The residue was mixed up with brine (50
mL) and extracted with EtOAc (2 × 120 mL). The combined organic
fractions were washed once with H2O (50 mL), dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (PE/EtOAc, or CH2Cl2).
Dimethyl 2-(4-Chlorobenzyl)malonate (1e)23a
Yield: 11.94 g (93%, GP2), 2.15 g (83% for 10 mmol run, GP1); yellow-
ish oil; Rf = 0.50 (PE/Et2O 2:1).
1Н NMR (CDCl3, 600 MHz):  = 3.19 (br d, 3J = 7.8 Hz, 2 H, CH2), 3.64 (t,
3J = 7.8 Hz, 1 H, CH), 3.71 (s, 6 H, 2 × CH3O), 7.14 (d, J = 8.3 Hz, 2 H,
3
Ar), 7.25 (d, 3J = 8.3 Hz, 2 H, Ar).
13С NMR (CDCl3, 150 MHz):  = 34.0 (1JСН = 132 Hz, CH2), 52.6 (1JСН
=
148 Hz, 2 × CH3O), 53.4 (1JСН = 134 Hz, CH), 128.7 (2 × CH, Ar), 130.2 (2
× CH, Ar), 132.7 (С, Ar), 136.2 (С, Ar), 169.0 (2 × CO2Me).
Dimethyl 2-(4-Bromobenzyl)malonate (1f)23c
Yield: 12.16 g (81%, GP2); yellowish oil; Rf = 0.54 (PE/Et2O 2:1).
1Н NMR (CDCl3, 600 MHz):  = 3.15 (br d, 3J = 7.8 Hz, 2 H, CH2), 3.62 (t,
3J = 7.8 Hz, 1 H, CH), 3.67 (s, 6 H, 2 × CH3O), 7.06 (d, J = 8.5 Hz, 2 H,
3
Ar), 7.37 (d, 3J = 8.5 Hz, 2 H, Ar).
13С NMR (CDCl3, 150 MHz):  = 33.9 (1JСН = 132 Hz, CH2), 52.5 (1JСН
=
148 Hz, 2 × CH3O), 53.1 (1JСН = 134 Hz, CH), 120.6 (C, Ar), 130.4 (2 ×
CH, Ar), 131.5 (2 × CH, Ar), 136.6 (С, Ar), 168.8 (2 × CO2Me).
Dimethyl 2-Benzylmalonate (1a)15,16b,23a
Yield: 10.41 g (94%, GP2: benzene), 10.09 g (91%, GP2: toluene), 2.45 g
(79% for 14 mmol run, GP1); colorless oil; Rf = 0.48 (PE/Et2O 2:1).
Dimethyl 2-(3-Methoxybenzyl)malonate (1g)23a
Yield: 12.29 g (97%, GP2); colorless oil; Rf = 0.71 (PE/EtOAc 2:1).
1Н NMR (CDCl3, 600 MHz):  = 3.24 (br d, 3J = 7.7 Hz, 2 H, CH2), 3.70 (t,
3J = 7.7 Hz, 1 H, CH), 3.70 (s, 6 H, 2 × CH3O), 7.19–7.25 (m, 3 H, C6H5),
7.27–7.31 (m, 2 H, C6H5).
1Н NMR (CDCl3, 600 MHz):  = 3.21 (br d, 3J = 7.8 Hz, 2 H, CH2), 3.68 (t,
3J = 7.8 Hz, 1 H, CH), 3.71 (s, 6 H, 2 × CH3O), 3.79 (s, 3 H, CH3O), 6.74–
6.79 (m, 2 H, Ar), 7.18–7.21 (m, 1 H, Ar).
13С NMR (CDCl3, 150 MHz):  = 34.6 (1JСН = 132 Hz, CH2), 52.4 (1JСН
=
148 Hz, 2 × CH3O), 53.5 (1JСН = 134 Hz, CH), 126.7 (CH, C6H5), 128.4 (2
× CH, C6H5), 128.6 (2 × CH, C6H5), 137.6 (С, C6H5), 169.1 (2 × CO2Me).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

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K. L. Ivanov et al.
Paper
Synthesis
13С NMR (CDCl3, 150 MHz):  = 34.7 (1JСН = 131 Hz, CH2), 52.5 (1JСН
=
1Н NMR (CDCl3, 600 MHz):  = 3.44 (br d, 3J = 7.7 Hz, 2 H, CH2), 3.70 (t,
3J = 7.7 Hz, 1 H, CH), 3.72 (s, 6 H, 2 × CH3O), 6.82–6.84 (m, 1 H, Th),
6.89 (dd, 3J = 5.2 Hz, 3J = 3.4 Hz, 1 H, Th), 7.13 (dd, 3J = 5.2 Hz, 4J = 1.2
Hz, 1 H, Th).
148 Hz, 2 × CH3O), 53.5 (1JСН = 134 Hz, CH), 55.1 (1JСН = 144 Hz, CH3O),
112.2 (CH, Ar), 114.4 (CH, Ar), 121.0 (CH, Ar), 129.5 (СH, Ar), 139.3 (C,
Ar), 159.7 (С, Ar), 169.2 (2 × CO2Me).
13С NMR (CDCl3, 150 MHz):  = 28.8 (1JСН = 133 Hz, CH2), 52.5 (1JСН
=
Dimethyl 2-(4-Methoxybenzyl)malonate (1h)15,23a
148 Hz, 2 × CH3O), 53.8 (1JСН = 134 Hz, CH), 124.2 (CH, Th), 125.9 (CH,
Th), 126.8 (CH, Th), 139.7 (С, Th), 168.6 (2 × CO2Me).
Yield: 11.96 g (95%, GP2), 2.61 g (80% for 13 mmol); colorless oil; Rf =
HRMS (ESI): m/z [M – H]– calcd for C10H11O4S–: 227.0384; found:
0.39 (PE/Et2O 2:1).
1Н NMR (CDCl3, 600 MHz):  = 3.15 (br d, 3J = 7.8 Hz, 2 H, CH2), 3.62 (t,
3J = 7.8 Hz, 1 H, CH), 3.67 (s, 6 H, 2 × CH3O), 3.74 (s, 3 H, CH3O), 6.79 (d,
3J = 8.8 Hz, 2 H, Ar), 7.09 (d, 3J = 8.8 Hz, 2 H, Ar).
227.0381.
Dimethyl [(1-Methyl-1H-indol-2-yl)methyl]malonate (1m)23f,g
13С NMR (CDCl3, 150 MHz):  = 33.8 (1JСН = 132 Hz, CH2), 52.3 (1JСН
=
Yield: 11.98 g (87%, GP2), 0.82 g (81% for 3.7 mmol run, GP1); yellow
solid; mp 83–84 °C (Lit.8 mp 87–89 °C); Rf = 0.32 (PE/Et2O 2:1). For
column chromatography, CH2Cl2 was used as an eluent.
1Н NMR (CDCl3, 400 MHz):  = 3.42 (d, 3J = 7.7 Hz, 2 H, CH2), 3.72 (s, 3
H, CH3N), 3.77 (s, 6 H, 2 × CH3O), 3.90 (t, 3J = 7.7 Hz, 1 H, CH), 6.26 (br
s, 1 H, Ind), 7.07–7.12 (m, 1 H, Ind), 7.18–7.23 (m, 1 H, Ind), 7.30 (br d,
3J = 8.2 Hz, 1 H, Ind), 7.55 (br d, 3J = 7.9 Hz, 1 H, Ind).
148 Hz, 2 × CH3O), 53.6 (1JСН = 134 Hz, CH), 54.9 (1JСН = 144 Hz, CH3O),
113.7 (2 × CH, Ar), 129.5 (С, Ar), 129.6 (2 × CH, Ar), 158.3 (С, Ar), 169.0
(2 × CO2Me).
Dimethyl 2-(3,4-Dimethoxybenzyl)malonate (1i)23d
Yield: 13.40 g (95%, GP2); yellowish oil; Rf = 0.52 (PE/EtOAc 2:1).
13С NMR (CDCl3, 100 MHz):  = 25.9 (CH2), 29.5 (CH3N), 51.0 (CH),
52.8 (2 × CH3O), 99.5 (CH, Ind), 108.9 (CH, Ind), 119.4 (CH, Ind), 120.1
(CH, Ind), 121.1 (CH, Ind), 127.6 (С, Ind), 136.5 (С, Ind), 137.4 (С, Ind),
169.0 (2 × CO2Me).
1Н NMR (CDCl3, 600 MHz):  = 3.15 (br d, 3J = 7.8 Hz, 2 H, CH2), 3.64 (t,
3J = 7.8 Hz, 1 H, CH), 3.69 (s, 6 H, 2 × CH3O), 3.83 (s, 3 H, CH3O), 3.84 (s,
3 H, CH3O), 6.71 (br d, 4J = 2.0 Hz, 1 H, Ar), 6.72 (dd, 3J = 8.0 Hz, 4J = 2.0
Hz, 1 H, Ar), 6.76 (br d, 3J = 8.0 Hz, 1 H, Ar).
HRMS (ESI): m/z [M + H]+ calcd for C15H18NO4+: 276.1230; found:
276.1231.
13С NMR (CDCl3, 150 MHz):  = 34.3 (CH2), 52.4 (2 × CH3O), 53.7 (CH),
55.69 (CH3O), 55.71 (CH3O), 111.1 (CH, Ar), 111.9 (CH, Ar), 120.7 (СH,
Ar), 130.1 (C, Ar), 147.7 (С, Ar), 148.7 (С, Ar), 169.1 (2 × CO2Me).
Dimethyl (1H-Indol-3-ylmethyl)malonate (1n)23g,h
HRMS (ESI): m/z [M – H]– calcd for C14H17O6–: 281.1031; found:
281.1031.
Yield: 9.91 g (76%, GP2); brown oil; Rf = 0.50 (PE/EtOAc 2:1).
1Н NMR (CDCl3, 600 MHz):  = 3.48 (br d, 3J = 7.7 Hz, 2 H, CH2), 3.74 (s,
6 H, 2 × CH3O), 3.90 (t, J = 7.7 Hz, 1 H, CH), 7.02–7.03 (m, 1 H, Ind),
Dimethyl 2-(3,4,5-Trimethoxybenzyl)malonate (1j)23e
3
7.17–7.20 (m, 1 H, Ind), 7.22–7.26 (m, 1 H, Ind), 7.34–7.36 (m, 1 H,
Ind), 7.65–7.67 (m, 1 H, Ind), 8.32 (br s, 1 H, NH).
Yield: 14.78 g (95%, GP2), 2.82 g (83% for 11 mmol run, GP1); colorless
solid; mp 75–76 °C; Rf = 0.29 (PE/Et2O 1:1).
13С NMR (CDCl3, 150 MHz):  = 24.6 (1JСН = 131 Hz, CH2), 52.4 (1JСН
=
1Н NMR (CDCl3, 600 MHz):  = 3.13 (br d, 3J = 7.8 Hz, 2 H, CH2), 3.63 (t,
3J = 7.8 Hz, 1 H, CH), 3.68 (s, 6 H, 2 × CH3O), 3.77 (s, 3 H, CH3O), 3.79 (s,
6 H, 2 × CH3O), 6.38 (s, 2 H, Ar).
148 Hz, 2 × CH3O), 52.7 (1JСН = 134 Hz, CH), 111.2 (CH, Ind), 111.6 (C,
Ind), 118.3 (CH, Ind), 119.3 (CH, Ind), 121.9 (CH, Ind), 122.6 (СH, Ind),
126.8 (С, Ind), 136.1 (С, Ind), 169.7 (2 × CO2Me).
13С NMR (CDCl3, 150 MHz):  = 34.9 (1JСН = 132 Hz, CH2), 52.4 (1JСН
=
148 Hz, 2 × CH3O), 53.5 (1JСН = 134 Hz, CH), 55.9 (1JСН = 144 Hz, 2 ×
CH3O), 60.6 (1JСН = 144 Hz, CH3O), 105.6 (2 × CH, Ar), 133.3 (C, Ar),
136.7 (С, Ar), 153.0 (2 С, Ar), 169.0 (2 × CO2Me).
Dimethyl [(1-Methyl-1H-indol-3-yl)methyl]malonate (1o)23i
Yield: 10.68 g (78%, GP2); brown solid; mp 78–79 °C; Rf = 0.59
(PE/EtOAc 2:1). For column chromatography, CH2Cl2 was used as an
eluent.
HRMS (ESI): m/z [M + Na]+ calcd for C15H20O7Na+: 335.1101; found:
335.1098.
1Н NMR (CDCl3, 600 MHz):  = 3.39–3.41 (m, 2 H, CH2), 3.72 (s, 6 H, 2
× CH3O), 3.74 (s, 3 H, CH3N), 3.80 (t, 3J = 7.6 Hz, 1 H, CH), 6.91 (br s, 1
H, Ind), 7.12–7.15 (m, 1 H, Ind), 7.22–7.25 (m, 1 H, Ind), 7.28–7.30 (m,
1 H, Ind), 7.59–7.61 (m, 1 H, Ind).
Dimethyl [4-(Dimethylamino)benzyl]malonate (1k)
Yield: 10.76 g (81%, GP2); yellow oil; Rf = 0.72 (PE/EtOAc 1:1).
1Н NMR (CDCl3, 600 MHz):  = 2.92 [s, 6 H, (CH3)2N], 3.15 (br d, 3J = 7.8
Hz, 2 H, CH2), 3.64 (t, 3J = 7.8 Hz, 1 H, CH), 3.71 (s, 6 H, 2 × CH3O), 6.85–
6.88 (m, 2 H, Ar), 7.06–7.09 (m, 2 H, Ar).
13С NMR (CDCl3, 150 MHz):  = 24.5 (1JСН = 132 Hz, CH2), 32.5 (1JСН
=
138 Hz, CH3N), 52.4 (1JСН = 148 Hz, 2 × CH3O), 52.8 (1JСН = 134 Hz, CH),
109.2 (CH, Ind), 110.3 (C, Ind), 118.5 (CH, Ind), 118.8 (CH, Ind), 121.5
(CH, Ind), 127.2 (СH, Ind), 127.4 (С, Ind), 136.8 (С, Ind), 169.5 (2 ×
CO2Me).
13С NMR (CDCl3, 150 MHz):  = 33.8 (1JСН = 132 Hz, CH2), 40.5 [1JСН
=
135 Hz, (CH3)2N], 52.3 (1JСН = 148 Hz, 2 × CH3O), 53.9 (1JСН = 134 Hz,
CH), 112.7 (2 × CH, Ar), 125.4 (C, Ar), 129.3 (2 × CH, Ar), 149.4 (С, Ar),
169.3 (2 × CO2Me).
Dimethyl [(1-Methyl-1H-indol-4-yl)methyl]malonate (1p)
HRMS (ESI): m/z [M + H]+ calcd for C14H20NO4+: 266.1387; found:
266.1389.
Yield: 1.03 g (66% for 5.7 mmol run, GP1); brown solid; mp 55–56 °C;
Rf = 0.26 (PE/Et2O 2:1).
1Н NMR (CDCl3, 600 MHz):  = 3.55 (br d, 3J = 7.7 Hz, 2 H, CH2), 3.71 (s,
Dimethyl (Thiophen-2-ylmethyl)malonate (1l)
3
6 H, 2 × CH3O), 3.79 (s, 3 H, CH3N), 3.92 (t, J = 7.7 Hz, 1 H, CH), 6.55
Yield: 8.53 g (75%, GP2); yellowish oil; Rf = 0.70 (PE/EtOAc 2:1).
(br d, 3J = 3.0 Hz, 1 H, Ind), 6.96 (d, 3J = 7.1 Hz, 1 H, Ind), 7.08 (d, 3J = 3.0
Hz, 1 H, Ind), 7.16 (dd, 3J = 8.1 Hz, 3J = 7.1 Hz, 1 H, Ind), 7.23 (d, 3J = 8.1
Hz, 1 H, Ind).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

F
K. L. Ivanov et al.
Paper
Synthesis
13С NMR (CDCl3, 150 MHz):  = 32.4 (1JСН = 133 Hz, CH2), 32.9 (1JСН
=
13С NMR (CDCl3, 150 MHz):  =13.9 (1JСН = 127 Hz, CH3), 29.4 (1JСН
=
138 Hz, CH3N), 52.4 (1JСН = 148 Hz, 2 × CH3O), 52.6 (1JСН = 134 Hz, CH),
98.8 (CH, Ind), 108.0 (CH, Ind), 119.3 (CH, Ind), 121.5 (CH, Ind), 127.6
(С, Ind), 128.6 (CH, Ind), 129.7 (С, Ind), 136.6 (С, Ind), 169.5 (2 ×
CO2Me).
128 Hz, COCH3), 33.9 (1JСН = 131 Hz, CH2), 61.2 (1JСН = 132 Hz, CH),
61.3 (1JСН = 148 Hz, CH2O), 126.6 (СH, C6H5), 128.5 (2 × CH, C6H5),
128.7 (2 × CH, C6H5), 138.1 (С, C6H5), 169.0 (CO2Et), 202.3 (COMe).
HRMS (ESI): m/z [M + H]+ calcd for C15H18NO4+: 276.1230; found:
Dimethyl 2-Isopentylmalonate (1w)
276.1239.
Yield: 5.98 g (70%, 85% conversion, GP2: toluene); colorless oil; Rf =
0.57 (PE/EtOAc 4:1).
1Н NMR (CDCl3, 600 MHz):  = 0.86 (d, 3J = 6.6 Hz, 6 H, 2 × CH3), 1.14–
1.18 (m, 2 H, CH2), 1.49–1.58 (m, 1 H, CH), 1.85–1.90 (m, 2 H, CH2),
3.29 (t, 3J = 7.6 Hz, 1 H, CH), 3.71 (s, 6 H, 2 × CH3O).
13С NMR (CDCl3, 150 MHz):  = 22.3 (1JСН = 124 Hz, 2 × CH3), 26.8 (1JСН
= 130 Hz, CH2), 27.8 (1JСН = 132 Hz, CH), 36.3 (1JСН = 126 Hz, CH2), 51.9
(1JСН = 132 Hz, CH), 52.3 (1JСН = 148 Hz, 2 × CH3O), 169.9 (2 × CO2Me).
Dimethyl (Pyridin-2-ylmethyl)malonate (1q)
Yield: 8.98 g (80%, GP2); green oil; Rf = 0.58 (PE/EtOAc 1:1).
1Н NMR (CDCl3, 600 MHz):  = 3.35 (br d, 3J = 7.6 Hz, 2 H, CH2), 3.67 (s,
6 H, 2 × CH3O), 4.10 (t, 3J = 7.6 Hz, 1 H, CH), 7.04–7.08 (m, 1 H, Py),
7.13–7.15 (m, 1 H, Py), 7.51–7.55 (m, 1 H, Py), 8.43–8.45 (m, 1 H, Py).
13С NMR (CDCl3, 150 MHz):  = 36.3 (1JСН = 131 Hz, CH2), 50.6 (1JСН
=
135 Hz, CH), 52.4 (1JСН = 148 Hz, 2 × CH3O), 121.5 (CH, Py), 123.3 (CH,
Py), 136.2 (CH, Py), 149.1 (CH, Py), 157.5 (C, Py), 169.4 (2 × CO2Me).
Methyl 2-Cyano-5-methylhexanoate (1x)8a
HRMS (ESI): m/z [M + H]+ calcd for C11H14NO4+: 224.0917; found:
224.0918.
Yield: 7.04 g (83%, GP2: toluene); yellowish oil; Rf = 0.52 (PE/EtOAc
4:1).
3
1Н NMR (CDCl3, 600 MHz):  = 0.92 (d, J = 6.7 Hz, 3 H, CH3), 0.93 (d,
3J = 6.7 Hz, 3 H, CH3), 1.34–1.44 (m, 2 H, CH2), 1.58–1.65 (m, 1 H, CH),
1.91–2.01 (m, 2 H, CH2), 3.49 (dd, 3J = 8.0 Hz, 3J = 6.0 Hz, 1 H, CH), 3.83
(s, 3 H, CH3O).
Tetramethyl 2,2′-(Benzene-1,4-diyldimethanediyl)malonate (1r)
Yield: 0.84 g (83% for 2.8 mmol run, GP1); colorless solid; mp 96–97
°C; Rf = 0.49 PE/EtOAc 2:1).
1Н NMR (CDCl3, 600 MHz):  = 3.19 (d, 3J = 7.8 Hz, 4 H, 2 × CH2), 3.65
(t, 3J = 7.8 Hz, 2 H, 2 × CH), 3.70 (s, 12 H, 4 × CH3O), 7.11 (s, 4 H, Ar).
13С NMR (CDCl3, 150 MHz):  = 34.3 (2 × CH2), 52.5 (4 × CH3O), 53.5
(2 × CH), 129.0 (4 × CH, Ar), 136.2 (2 С, Ar), 169.2 (4 × CO2Me).
13С NMR (CDCl3, 150 MHz):  = 21.9 (1JСН = 125 Hz, CH3), 22.1 (1JСН
=
125 Hz, CH3), 27.4 (1JСН = 132 Hz, CH), 27.7 (1JСН = 128 Hz, CH2), 35.5
(1JСН = 128 Hz, CH2), 37.4 (1JСН = 136 Hz, CH), 53.2 (1JСН = 148 Hz,
CH3O), 116.3 (CN), 166.6 (CO2Me).
HRMS (ESI): m/z [M + H]+ calcd for C18H23O8+: 367.1387; found:
367.1377.
Funding Information
Methyl 2-Cyano-3-phenylpropanoate (1s)15,23a
Research was supported by the Russian Foundation for Basic Re-
search, grant number 18-03-00549.
R
usianFo
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d
ationfor
B
asic
R
esearch(18-03-0
0
5
4
9
)
Yield: 8.64 g (91%, GP2); yellowish oil; Rf = 0.72 (PE/EtOAc 2:1).
1Н NMR (CDCl3, 600 MHz):  = 3.20 (dd, J = 13.9 Hz, J = 8.5 Hz, 1 H,
CH2), 3.29 (dd, 2J = 13.9 Hz, 3J = 5.8 Hz, 1 H, CH2), 3.76 (dd, 3J = 8.5 Hz,
3J = 5.8 Hz, 1 H, CH), 3.79 (s, 3 H, CH3O), 7.27–7.33 (m, 3 H, C6H5),
7.34–7.38 (m, 2 H, C6H5).
2
3
Acknowledgment
The NMR measurements were carried out at the Center for Magnetic
Tomography and Spectroscopy, Faculty of Fundamental Medicine of
Lomonosov Moscow State University.
13С NMR (CDCl3, 150 MHz):  = 35.6 (1JСН = 134 Hz, CH2), 39.4 (1JСН
=
138 Hz, CH), 53.4 (1JСН = 148 Hz, CH3O), 115.9 (CN), 127.7 (СH, C6H5),
128.8 (2 × CH, C6H5), 128.9 (2 × CH, C6H5), 135.1 (С, C6H5), 165.9
(CO2Me).
Supporting Information
Methyl 2-Benzyl-3-oxobutanoate (1t)23a
Supporting information for this article is available online at
Yield: 7.93 g (77%, GP2); yellow oil; Rf = 0.79 (PE/EtOAc 2:1).
1Н NMR (CDCl3, 600 MHz):  = 2.17 (s, 3 H, CH3), 3.17 (br d, 3J = 7.7 Hz,
https://doi.org/10.1055/s-0040-1705940. Su
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2 H, CH2), 3.67 (s, 3 H, CH3O), 3.81 (t, J = 7.7 Hz, 1 H, CH), 7.16–7.22
References
(m, 3 H, C6H5), 7.26–7.28 (m, 2 H, C6H5).
13С NMR (CDCl3, 150 MHz):  = 29.5 (CH3), 33.9 (CH2), 52.3 (CH3O),
60.9 (CH), 126.6 (СH, C6H5), 128.5 (2 × CH, C6H5), 128.6 (2 × CH, C6H5),
137.9 (С, C6H5), 169.4 (CO2Me), 202.2 (COMe).
(1) Shinkai, H.; Onogi, S.; Tanaka, M.; Shibata, T.; Iwao, M.;
Wakitani, K.; Uchida, I. J. Med. Chem. 1998, 41, 1927.
(2) Griffith, D.; Morgan, M. P.; Marmion, C. J. Chem. Commun. 2009,
6735.
Ethyl 2-Benzyl-3-oxobutanoate (1u)23j
(3) Hayashi, Y. Chem. Sci. 2016, 7, 866.
Yield: 9.02 g (82%, GP2); yellow oil; Rf = 0.85 (PE/EtOAc 2:1).
(4) Alexander, E. R.; Cope, A. C. J. Am. Chem. Soc. 1944, 66, 886.
(5) (a) Goettmann, F.; Grosso, D.; Mercier, F.; Mathey, F.; Sanchez,
C. Chem. Commun. 2004, 1240. (b) Verde-Sesto, E.; Merino, E.;
Rangel-Rangel, E.; Corma, A.; Iglesias, M.; Sánchez, F. ACS Sus-
tain. Chem. Eng. 2016, 4, 1078.
1Н NMR (CDCl3, 600 MHz):  = 1.19–1.22 (m, 3 H, CH3), 2.19 (br s, 3 H,
COCH3), 3.16 (dd, 2J = 14.2 Hz, 3J = 7.9 Hz, 1 H, CH2), 3.19 (dd, 2J = 14.2
Hz, 3J = 7.4 Hz, 1 H, CH2), 3.79 (dd, 3J = 7.9 Hz, 3J = 7.4 Hz, 1 H, CH),
4.13–4.20 (m, 2 H, CH2O), 7.16–7.22 (m, 3 H, C6H5), 7.26–7.29 (m, 2 H,
C6H5).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

G
K. L. Ivanov et al.
Paper
Synthesis
(6) (a) Baidossi, M.; Joshi, A. V.; Mukhopadhyay, S.; Sasson, Y. Tetra-
hedron Lett. 2005, 46, 1885. (b) Motokura, K.; Fujita, N.; Mori, K.;
Mizugaki, T.; Ebitani, K.; Kaneda, K. Tetrahedron Lett. 2005, 46,
5507. (c) Li, P.; Liu, H.; Yu, Y.; Cao, C.-Y.; Song, W.-G. Chem. Asian
J. 2013, 8, 2459. (d) Li, P.; Yu, Y.; Liu, H.; Cao, C.-Y.; Song, W.-G.
Nanoscale 2014, 6, 442. (e) Patankar, S. C.; Dodiya, S. K.; Yadav,
G. D. J. Mol. Catal. A: Chem. 2015, 409, 171. (f) Wang, H.; Wang,
Y.; Jia, A.; Wang, C.; Wu, L.; Yang, Y.; Wang, Y. Catal. Sci. Technol.
2017, 7, 5572.
(7) Abe, F.; Hayashi, T.; Tanaka, M. Chem. Lett. 1990, 19, 765.
(8) (a) Kolesnikov, P. N.; Usanov, D. L.; Barablina, E. A.; Maleev, V. I.;
Chusov, D. Org. Lett. 2014, 16, 5068. (b) Yagafarov, N. Z.; Usanov,
D. L.; Moskovets, A. P.; Kagramanov, N. D.; Maleev, V. I.; Chusov,
D. ChemCatChem 2015, 7, 2590. (c) Denmark, S. E.; Ibrahim, M.
Y. S.; Ambrosi, A. ACS Catal. 2017, 7, 613. (d) Muratov, K.;
Kuchuk, E.; Vellalath, S.; Afanasyev, O. I.; Moskovets, A. P.;
Denisov, G.; Chusov, D. Org. Biomol. Chem. 2018, 16, 7693.
(9) Afanasyev, O. I.; Zarochintsev, A.; Petrushina, T.; Cherkasova, A.;
Denisov, G.; Cherkashchenko, I.; Chusova, O.; Jinho, O.; Man-
Seog, C.; Usanov, D. L.; Semenov, S. E.; Chusov, D. Eur. J. Org.
Chem. 2019, 32.
S.; Wang, Z. Synlett 2016, 27, 1864. (d) Jiang, G.; Liu, M.; Fang,
D.; Tan, P.; Huang, M.; Zhou, T.; Jiang, Z.; Xu, Z.; Wang, Z. RSC
Adv. 2018, 8, 8961. (e) Kalita, S.; Deka, D. Synlett 2018, 29, 477.
(18) Sakai, T.; Miyata, K.; Tsuboi, S.; Utaka, M. Bull. Chem. Soc. Jpn.
1989, 62, 4072.
(19) (a) Schneidewind, W. Ber. Dtsch. Chem. Ges. 1888, 21, 1323.
(b) Harries, C.; Hübner, F. Justus Liebigs Ann. Chem. 1897, 296,
295.
(20) (a) Conrad, M.; Reinbach, H. Ber. Dtsch. Chem. Ges. 1901, 34,
1339. (b) Chukhina, E. I. Zh. Obshch. Khim. 1958, 28, 2582.
(c) Jursic, B. S.; Stevens, E. D. Tetrahedron Lett. 2003, 44, 2203.
(d) Milite, C.; Feoli, A.; Sasaki, K.; La Pietra, V.; Balzano, A. L.;
Marinelli, L.; Mai, A.; Novellino, E.; Castellano, S.; Tosco, A.;
Sbardella, G. J. Med. Chem. 2015, 58, 2779. (e) Smith, L. I.;
Dobrovolny, F. J. J. Am. Chem. Soc. 1926, 48, 1693. (f) Yamamura,
K.; Miyake, H.; Murata, I. J. Org. Chem. 1986, 51, 251. (g) Saha, S.;
Ghosh, T.; Bandyopadhyay, C. Synth. Commun. 2008, 38, 2429.
(h) Sondengam, B. L.; Fomum, Z. T.; Charles, G.; Akam, T. M.
J. Chem. Soc., Perkin Trans. 1 1983, 1219. (i) Morel, G.; Foucaud,
A. Bull. Soc. Chim. Fr. 1970, 2354. (j) Mallia, C. J.; Englert, L.;
Walter, G. C.; Baxendale, I. R. Beilstein J. Org. Chem. 2015, 11,
875. (k) Andrés, M.; Bravo, M.; Buil, M. A.; Calbet, M.; Castillo,
M.; Castro, J.; Eichhorn, P.; Ferrer, M.; Lehner, M. D.; Moreno, I.;
Roberts, R. S.; Sevilla, S. Eur. J. Med. Chem. 2014, 71, 168.
(21) (a) Ivanov, K. L.; Villemson, E. V.; Latyshev, G. V.; Bezzubov, S. I.;
Majouga, A. G.; Melnikov, M. Ya.; Budynina, E. M. J. Org. Chem.
2017, 82, 9537. (b) Zaytsev, S. V.; Villemson, E. V.; Ivanov, K. L.;
Budynina, E. M.; Melnikov, M. Ya. Eur. J. Org. Chem. 2017, 2814.
(22) Ivanov, K. L.; Vatsouro, I. M.; Bezzubov, S. I.; Melnikov, M. Ya.;
Budynina, E. M. Org. Chem. Front. 2018, 5, 1655.
(10) (a) Tóth, G.; Kövér, K. E. Synth. Commun. 1995, 25, 3067.
(b) Mudhar, H.; Witty, A. Tetrahedron Lett. 2010, 51, 4972.
(c) Sun, H.; Ye, D.; Jiang, H.; Chen, K.; Liu, H. Synthesis 2010,
2577. (d) Wu, J.; Jiang, H. Synth. Commun. 2011, 41, 1218.
(11) (a) Hrubowchak, D. M.; Smith, F. X. Tetrahedron Lett. 1983, 24,
4951. (b) Linton, M.; Gonzalez, J.; Li, H.; Tatlock, J.; Jewell, T.;
Johnson, S.; Drowns, M.; Patel, L.; Blazel, J.; Ornelas, M. Synthesis
2010, 4015.
(12) Fillion, E.; Fishlock, D. Org. Lett. 2003, 5, 4653.
(13) (a) Dunham, J. C.; Richardson, A. D.; Sammelson, R. E. Synthesis
2006, 680. (b) Tayyari, F.; Wood, D.; Fanwick, P.; Sammelson, R.
Synthesis 2008, 279.
(14) Huang, X.; Xie, L. Synth. Commun. 1986, 16, 1701.
(15) Guyon, C.; Duclos, M.-C.; Sutter, M.; Métay, E.; Lemaire, M. Org.
Biomol. Chem. 2015, 13, 7067.
(16) (a) Ramachary, D. B.; Kishor, M.; Ramakumar, K. Tetrahedron
Lett. 2006, 47, 651. (b) Ramachary, D. B.; Venkaiah, C.; Reddy, Y.
V.; Kishor, M. Org. Biomol. Chem. 2009, 7, 2053. (c) Ramachary,
D. B.; Jain, S. Org. Biomol. Chem. 2011, 9, 1277. (d) Ramachary, D.
B.; Venkaiah, C.; Reddy, Y. V. Org. Biomol. Chem. 2014, 12, 5400.
(e) Peraka, S.; Hussain, A.; Ramachary, D. B. J. Org. Chem. 2018,
83, 9795.
(17) (a) Li, J.; Liu, Q.; Xing, R. G.; Shen, X. X.; Liu, Z. G.; Zhou, B. Chin.
Chem. Lett. 2009, 20, 25. (b) Yang, Y.-Q.; Lu, Z. Chin. J. Chem.
2014, 32, 650. (c) He, T.; Shi, R.; Gong, Y.; Jiang, G.; Liu, M.; Qian,
(23) (a) Takuwa, T.; Minowa, T.; Fujisawa, H.; Mukaiyama, T. Chem.
Pharm. Bull. 2005, 53, 476. (b) Boiadjiev, S. E.; Lightner, D. A.
J. Phys. Org. Chem. 1999, 12, 751. (c) Leypold, M.; Wallace, P. W.;
Kljajic, M.; Schittmayer, M.; Pletz, J.; Illaszewicz-Trattner, C.;
Guebitz, G. M.; Birner-Gruenberger, R.; Breinbauer, R. Tetrahe-
dron Lett. 2015, 56, 5619. (d) Buckley, T. F.; Rapoport, H. J. Am.
Chem. Soc. 1980, 102, 3056. (e) McBride, B. J.; Garst, M. E. Tetra-
hedron 1993, 49, 2839. (f) Liu, C.; Han, X.; Wang, X.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 3700.
(g) Bandini, M.; Eichholzer, A. Angew. Chem. Int. Ed. 2009, 48,
9533. (h) Somei, M.; Karasawa, Y.; Chikara Kaneko, A. Heterocy-
cles 1981, 16, 941. (i) Mu, X.; Chen, S.; Zhen, X.; Liu, G. Chem.
Eur. J. 2011, 17, 6039. (j) Liu, Y.; Mao, Y.; Hu, Y.; Gui, J.; Wang, L.;
Wang, W.; Zhang, S. Adv. Synth. Catal. 2019, 361, 1554.
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