Flexible Entry into 3-Arylpent-2-enedioic Acids via Heck-Matsuda Arylation of Dimethyl Glutaconate with Arenediazonium Tosylates

Article abstract of DOI:10.1055/s-0037-1611211

For the preparation of compound libraries of Michael acceptors with tunable reactivity toward nuclophilic selenocysteine residue of thioredoxin reductase, a range of 3-arylglutaconic acids were required. The existing methods at the time had limited scope or involved several steps. A hitherto undescribed protocol for direct palladium(II) acetate-catalyzed arylation of glutaconic acid dimethyl ester at position 3 has been developed with a diverse set of arenediazonium tosylates followed by hydrolysis. This generally good-yielding two-step sequence displayed a propensity to deliver E -configured coupling products while compounds mostly featured in the literature were predominantly Z -configured. The possibility for preparing a library of 4-arylpyridine-2,6(1 H,3 H)-diones has been exemplified.

Full text of DOI:10.1055/s-0037-1611211

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–G
paper
A
en
D. Dar’in et al.
Paper
Synthesis
Flexible Entry into 3-Arylpent-2-enedioic Acids via Heck–Matsuda
Arylation of Dimethyl Glutaconate with Arenediazonium Tosylates
Dmitry Dar’ina
Grigory Kantina
Olga Bakulinaa
Raivis Žalubovskisb
Mikhail Krasavin*a,1
CO2H
CO2Me
Ar-N2 TsO
NaOH
CO2H
Ar
CO2Me
H2O/THF
r. t.
Pd(OAc)2
MeOH, r. t.
15 h
Predominantly (E)
16 examples
32–90% (2 steps)
(E/Z)
a Saint Petersburg State University, Saint Petersburg 199034,
Russian Federation
m.krasavin@spbu.ru
b Latvian Institute of Organic Synthesis, Riga 1006, Latvia
Received: 27.12.2018
Accepted after revision: 29.01.2019
Published online: 25.02.2019
R
R
N
EtO2C
EtO2C
DOI: 10.1055/s-0037-1611211; Art ID: ss-2018-z0867-op
Ar
Abstract For the preparation of compound libraries of Michael accep-
tors with tunable reactivity toward nuclophilic selenocysteine residue of
thioredoxin reductase, a range of 3-arylglutaconic acids were required.
The existing methods at the time had limited scope or involved several
steps. A hitherto undescribed protocol for direct palladium(II) acetate-
catalyzed arylation of glutaconic acid dimethyl ester at position 3 has
been developed with a diverse set of arenediazonium tosylates followed
by hydrolysis. This generally good-yielding two-step sequence dis-
played a propensity to deliver E-configured coupling products while
compounds mostly featured in the literature were predominantly Z-
configured. The possibility for preparing a library of 4-arylpyridine-
2,6(1H,3H)-diones has been exemplified.
5
[4]
O
CO2H
CO2H
[3]
[1]
O
Ar
NH
Ar
O
Ar
S
(E)- or (Z)-1
4
2
[2]
O
Ar
NH
NH
Key words arylpent-2-enedioic acids, glutaconic acid, diazonium to-
sylate, Pd-catalyzed coupling, regiospecificity, ester hydrolysis, imide
synthesis
3
Scheme 1 Illustrative uses of 3-arylglutaconic acids as building blocks
in organic synthesis
The potential of 3-arylpent-2-enedioic acids 1 (hereaf-
ter referred to as 3-arylglutaconic acids) as building blocks
for synthetic chemistry is illustrated by the synthesis of
benzothiophene-fused pyranones 2,2 1,2-benzodiazepin-
ones 3,3 4-aryl-2-pyridones 4,4 and polysubstituted benz-
enes 55 (Scheme 1).
In our research program directed at developing selective
inhibitors of selenocycteine enzyme thioredoxin reductase
(TrxR),6 we envisioned 3-arylglutaconic imides 6 (possibly
derived from (E)-17) to act as potential Michael acceptors
for the reactive selenol of the Sec (selenocysteine) residue8
whose reactivity can be tuned so as not to affect the abun-
dant group of enzymes where cysteine (Cys, i.e., the less re-
active thiol) is crucial for catalytic activity. While examples
of -alkyl,-aryl-substituted Michael acceptors similar to 6
reacting with thiol nucleophiles are known,9 the electro-
philicity of 6 is likely to depend strongly on the nature of
the Ar and R substituents. Thus, if these substituents are
varied within a wide range, a situation where 6 does not re-
act with thiols but continues to form adducts with selenols,
can be identified (Scheme 2).
"reactivity
dials"
O
CO2H
RNH2
– 2 H2O
R
N
CO2H
Ar
Ar
O
(E)-1
6
X
HSe
SH
Sec
Cys
Scheme 2 3-Arylglutaconic imides 6 as Michael acceptors with tunable
reactivity
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

B
D. Dar’in et al.
Paper
Synthesis
However, while the range of available primary amines
(both aromatic and aliphatic) is distinctly wide, only seven-
teen 3-arylglutaconic acids 1 are registered in SciFinder as
commercially available10 and those exclusively contain elec-
tron-rich aryl groups. The known methods for the prepara-
tion of 1 are limited, on the one hand, to Fridel–Crafts-type
alkylation of electron-rich aromatics with keto acid 7 (gen-
erated, in turn, from oxidation–decarboxylation of citric
acid under the reaction conditions).11 While this method is
relatively straightforward (and is, therefore, reflected by the
products in the commercial domain), its scope is clearly
limited to the introduction of electron-rich aromatic
groups. An alternative method,12 potentially allowing for
greater diversity of aromatic groups in 1, involves conjugate
addition of dimethyl malonate anion to 3-arylpropiolic acid
esters 8 followed by global hydrolysis and decarboxylation.
Direct arylation of glutaconic acid, which would offer the
level of flexibility varying the pendant aryl groups in 1
(and, ultimately, in 6), is lacking in the literature (Scheme
3).
um tosylates.18 Not only are they more stable toward chem-
ical decomposition and explosion compared to convention-
ally used tetrafluoroborates, they are more cleanly prepared
by diazotization of respective anilines in the presence of
p-toluenesulfonic acid in a variety of polar organic solvents
and even water.19 Hence preparing various arenediazonium
tosylates 9 and testing them in the Heck–Matsuda arylation
of glutaconic acid dimethyl ester became our primary ob-
jective.
Initial experiments involving preparation of 9 demon-
strated that the arenediazonium salts were sufficiently
pure to be used in the Heck–Matsuda arylation step with-
out further purification. Thus, the syntheses of 1 were
planned accordingly. Treatment of aniline with tert-butyl
nitrite in a 1:3 mixture of THF and glacial acetic acid led to
the formation of the anticipated diazonium salt 9, which
was isolated by filtration. Mild, ambient-temperature cou-
pling of the latter with commercially available dimethyl
glutaconate (sold as a ~6.7:1 mixture of E- and Z-isomers
according to 1H NMR analysis of the reagent received from
the vendor) yielded, after brief fractionation on silica gel,
the crude Heck–Matsuda coupling product 10. The latter
In this work, we set off to investigate the Heck13 aryla-
tion of glutaconic acids with arenediazonium species,14
which has been amply exemplified for a number of -sub-
stituted acrylates.15 Herein, we present the results of our
study.
Arenediazonium salts were recognized by Matsuda and
co-workers as exceptionally reactive partners for the Heck
reaction.16 This finding not only linked the Matsuda–Heck
reaction to a vaster (compared to that of aryl halides and
triflates) reagent space of commercially available anilines
but also extended the reaction’s scope to include partners
previously considered poorly reactive or altogether unreac-
tive (such as -substituted acrylates, vide supra).17
1
was analyzed by H NMR spectroscopy to reveal its suffi-
ciently high purity (so as not to necessitate further purifica-
tion prior to subsequent hydrolysis), generally excellent
yield (in the range 81–98%, except for 10k whose yield was
estimated to be around 50%) and higher E/Z ratio (~10:1
throughout). Without further purification and characteri-
zation, esters 10 were subjected to alkaline hydrolysis to
give pure 3-arylglutaconic acids 1 in moderate to excellent
yields over two steps (from dimethyl glutaconate) predomi-
nantly in the E-configured form (as assigned by NOESY
spectroscopy, see the experimental section), except for
products 1d, 1i, and 1o containing an o-substituted aryl
group, in which the E/Z isomeric ratio was lower or even re-
In terms of selecting a suitable counterion for the arene-
diazonium cations, our efforts were guided by the recently
reported convenient preparation and use of arenediazoni-
OH
HO2C
CO2H
CO2H
H2SO4
O
1) CH2(CO2Me)2
base
HO2C
CO2H
CO2H
CO2H
7
Ar
CO2Me
ArH
Ar
2) KOH, EtOH
reflux
H2SO4
8
(electron-rich)
(Z)- or (E)-1
this work
CO2R
CO2R
(R = H or Me)
ArX
+
Scheme 3 Two approaches to 3-arylglutaconic acids 1 featured in the literature at the onset of this study, and the direct arylation approach investigat-
ed in this work
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

C
D. Dar’in et al.
Paper
Synthesis
CO2Me
Ar
Ar
t-BuONO
CO2Me
Pd(OAc)2
CO2Me
NaOH
CO2H
TsOH
Ar-NH2
Ar-N2 TsO
H2O/THF
THF/AcOH
CO2Me
CO2H
r. t.
9a–p
0 °C to r.t.
1 h
MeOH, r. t.
15 h
10a–p
1a–p
Scheme 4 Preparation of 3-arylglutaconic acids 1a–p
Table 1 3-Arylglutaconic Acids 1a–p Synthesized in this Work
versed (Scheme 4, Table 1). It should be noted that attempt-
ed direct arylation of glutaconic acid did not produce satis-
factory results.
Compound
Ar
Ph
Yield (%)a
E/Z ratio
1a
1b
1c
1d
1e
1f
58b
58b
85b
46b
66b
45b
55b
73b
63c
E only
E only
E only
3:1
As it is evident from examples presented in Table 1, the
arylation method reported herein displays a broad scope
with respect to both electron-donating and electron-with-
drawing groups in the aromatic portion and a good func-
tional group tolerance with substituents such as carboxam-
ide 1k, ketone 1n, and primary sulfonamide 1p remaining
intact and not requiring protection. The fact that the aryla-
tion products 1 are obtained as a sole E-isomer (or are sig-
nificantly enriched in it) is also notable as previously re-
ported approaches have been reported to give significantly
higher proportions of the Z-isomer.20,21
4-MeOC6H4
4-F3CC6H4
2-MeOC6H4
4-FC6H4
E only
E only
E only
12:1
4-O2NC6H4
3-O2NC6H4
4-F3COC6H4
2-ClC6H4
1g
1h
1i
1:1.3
O
O
Having gained access to a range of E-configured 3-aryl-
glutaconic acids 1 that had not been featured in the litera-
ture, we were keen to apply some of them in the synthesis
of 3-arylglutaconic imides 6. Examples of direct 1 → 6 con-
version involving direct thermal7 or mixed anhydride22 ac-
tivation have been sporadically reported in the literature.
We successfully achieved the synthesis of imides 6a–c in
moderate yield from 3-arylglutaconic acids 1b, 1l, and 1o,
respectively, in refluxing toluene employing azeotropic re-
moval of water. Notably, attempts to use thermal activa-
tion7 of dicarboxylic acids 1b and 1o toward imide forma-
tion with respective amines at 180 °C under microwave ir-
radiation in toluene resulted in a poor yield of target imides
6a(c). The formation of the latter was accompanied by the
accumulation of unwanted mixtures of decarboxylation
products 7a(c) and 8a(c), as observed by 1H NMR spectros-
copy. From this mixture, pure amides 7a and 7c were isolat-
ed chromatographically and characterized (Scheme 5). At-
tempted preparation of compounds 6 from diacarboxylic
acids 1 using acetic anhydride22 was similarly ineffective.
In conclusion, we have described a novel, flexible ap-
proach to 3-arylglutaconic acids via direct Heck–Matsuda
arylation of dimethyl glutaconate with arenediazonium to-
sylate salts catalyzed by Pd(II) acetate. The method proved
convenient and practically simple while displaying a wider
scope with respect to the aromatic groups, compared to the
previously reported approaches, and a tendency to yield E-
configured products. The latter can be employed directly in
the preparation of 3-arylglutaconic imides with inde-
1j
55b
E only
1k
32b
10:1
N
O
1l
90c
63c
57c
20:1
20:1
>20:1
1m
1n
3,5-(F3C)2C6H3
MeOC
1o
1p
mesityl
89c
82c
1:1.3
5:1d
H2NO2S
a Isolated yields over 2 steps (from dimethyl glutaconate).
b Analytically pure product obtained as a precipitate on acidification of the
alkaline solution after hydrolysis of 10.
c Analytically pure product obtained as a precipitate on acidification of the
alkaline solution after hydrolysis of 10 followed by extraction.
d Pure E-isomer was obtained in 41% yield by crystallization from MeCN.
pendently variable elements of molecular periphery. These
are intended as Michael acceptors with tunable reactivity
as potential selective inhibitors of selenocysteine enzymes
(such TrxR) not affecting the cell’s cysteinome.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

D
D. Dar’in et al.
Paper
Synthesis
O
N
O
MeO
CO2H
CO2H
CO2H
HN
RNH2
a
Ar
Ar
R
O
–H2O
O
N
6a, 43%
a or b
O
N
O
O
1b, 1l or 1o
O
–CO2
b
6c, 49%
6b, 45%
OMe
Ar
HN
O
R
Ar
HN
O
R
+
7
8
Scheme 5 Attempted (a) and successful (b) preparation of 3-arylglutaconic imides 6a–c. Reagents and conditions: a) toluene, reflux, Dean–Stark trap,
16 h; b) MW, 180 °C, toluene 1 h.
The oil-like precipitates (1i, 1l–p) were extracted with EtOAc (2 × 30
mL), dried (Na2SO4), filtered, and evaporated to dryness to give analyt-
ically pure title compounds.
NMR spectroscopic data were recorded on a 400 MHz (400.13 MHz
for 1H and 100.61 MHz for 13C) spectrometer in CDCl3 and DMSO-d6
and were referenced to residual solvent signals (H = 7.26 and 2.50;
C = 77.2 and 39.5, respectively). Coupling constants, J are reported in
Hz. Mass spectra were recorded with a HRMS-ESI-qTOF spectrometer
(electrospray ionization mode). Column chromatography was per-
formed on silica gel 60 (230–400 mesh). Melting points were mea-
sured with SMP 50 and are not corrected. For TLC analysis UV254 sili-
ca gel coated plates were used (Merck). Dimethyl glutaconate (E/Z
mixture) was purchased from Fluka and used as received. Microwave-
assisted reactions were performed using Biotage Initiator+ reactor.
(E)-3-Phenylpent-2-enedioic Acid (1a)
Yield: 1.40 g (58%); white solid; mp 141.5–144.1 °C.
1H NMR (400 MHz, DMSO-d6):  = 12.35 (br s, 2 H), 7.59–7.50 (m, 2
H), 7.46–7.35 (m, 3 H), 6.23 (s, 1 H, HC=), 4.13 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6):  = 171.7, 167.7, 150.8, 140.7, 129.6,
129.1, 126.9, 120.3, 36.3.
HRMS: m/z [M – H]– calcd for C11H9O4–: 205.0506; found: 205.0502.
3-Arylglutaconic Acids 1a–p; General Procedure
(E)-3-(4-Methoxyphenyl)pent-2-enedioic Acid (1b)
To a stirred ice-cooled solution or suspension of the respective aniline
(15.0 mmol) in THF (5 mL) was added a solution of p-TsOH·H2O (3.04
g, 16.0 mmol) in glacial AcOH (15 mL). The resulting suspension was
stirred for 5 min whereupon t-BuONO (2.44 mL, 22.5 mmol) was add-
ed in one portion. The mixture was stirred at 0 °C for 20 min, the ice
bath was removed, and the stirring was continued for 50 min at r.t.
The resulting solution was poured into Et2O (150 mL) and the mixture
was stirred for 30 min. The precipitate of 9 (crystalline in all cases ex-
cept for 9d) was separated, washed with Et2O, and dried in vacuo.
Yield: 1.48 g (58%); beige solid; mp 161.7–163.0 °C.
1H NMR (400 MHz, DMSO-d6):  = 12.27 (br s, 2 H), 7.51 (d, J = 8.8 Hz,
2 H), 6.97 (d, J = 8.8 Hz, 2 H), 6.19 (s, 1 H, HC=), 4.12 (s, 2 H, CH2), 3.79
(s, 3 H, OCH3).
13C NMR (100 MHz, DMSO-d6):  = 171.9, 167.9, 160.6, 150.4, 132.7,
128.3, 118.1, 114.5, 55.7, 36.0.
HRMS: m/z [M – H]– calcd for C12H11O5–: 235.0612; found: 235.0609.
The crude aryl diazonium tosylate 9 thus obtained was dissolved or
suspended in MeOH (30 mL). Dimethyl glutaconate (1.45 mL, 10.0
mmol) and Pd(OAc)2 (112 mg, 0.5 mmol) were successively added
while stirring. After stirring at r.t. for 15 h, the mixture was concen-
trated under reduced pressure and partitioned between CH2Cl2 (40
mL) and H2O (25 mL). The organic layer was washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was briefly fraction-
ated on SiO2 using CH2Cl2 or CH2Cl2–acetone (5:1) as eluent. Fractions
containing arylation product were pooled and concentrated to give
compound 10 of at least 90% purity (according to 1H NMR analysis). It
was used in the next step without further purification.
(E)-3-[4-(Trifluoromethyl)phenyl]pent-2-enedioic Acid (1c)
Yield: 2.33 g (85%); pale yellow solid; mp 174.5–176.1 °C.
1H NMR (400 MHz, DMSO-d6):  = 12.51 (br s, 2 H), 7.83–7.69 (m, 4
H), 6.31 (s, 1 H, HC=), 4.15 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6):  = 171.6, 167.4, 149.3, 144.9, 129.6
(q, J = 32.0 Hz), 127.8, 125.9 (q, J = 3.8 Hz), 124.6 (q, J = 271.4 Hz),
122.4, 36.3.
HRMS: m/z [M – H]– calcd for C12H8F3O4–: 273.0369; found: 273.0367.
(E/Z)-3-(2-Methoxyphenyl)pent-2-enedioic Acid (1d)
Yield: 1.48 g (46%); E/Z = 3:1; beige solid.
To a stirred solution of the above compound 10 in THF (10 mL) was
added a solution of NaOH (1.0 g, 25.0 mmol) (or an equiv amount of
LiOH in case of 10k) in H2O (15 mL) and the mixture was stirred at r.t.
for 16 h (or 5 h in case of 10k). The resulting mixture was washed
with Et2O (30 mL) and the organic layer was extracted with H2O (5
mL). The combined aqueous phases were acidified with concd HCl to
pH ~2 and stirred in an ice bath for 1 h. The solid precipitates formed
were collected by filtration, washed with ice-cold H2O, and air-dried.
1H NMR (400 MHz, DMSO-d6):  (major, E) = 12.19 (br s, 2 H), 7.35
(ddd, J = 8.3, 7.4, 1.8 Hz, 1 H), 7.19 (dd, J = 7.5, 1.7 Hz, 1 H), 7.04 (dd, J =
8.4, 0.9 Hz, 1 H), 6.96 (td, J = 7.5, 1.0 Hz, 1 H), 5.92 (s, 1 H, HC=), 3.95
(s, 2 H, CH2), 3.78 (s, 3 H, OCH3);  (minor, Z) = 7.25 (ddd, J = 8.3, 7.4,
1.8 Hz, 1 H), 7.02 (dd, J = 7.6, 1.7 Hz, 1 H), 6.98 (dd, J = 8.3, 0.9 Hz, 1 H),
6.87 (td, J = 7.4, 1.0 Hz, 1 H), 6.00 (t, J = 1.0 Hz, 1 H, HC=), 3.73 (s, 3 H,
OCH3), 3.36 (d, J = 1.0 Hz, 2 H, CH2).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

E
D. Dar’in et al.
Paper
Synthesis
13C NMR (100 MHz, DMSO-d6):  (major, E) = 171.3, 167.5, 156.6,
151.1, 130.8, 130.5, 130.0, 122.6, 121.0, 112.0, 55.9, 37.7;  (minor, Z)
= 171.5, 166.7, 156.0, 147.7, 129.8, 129.4, 128.4, 123.2, 120.2, 111.5,
55.8, 44.1.
(E)-3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pent-2-enedioic Acid
(1j)
Yield: 1.45 g (55%); pale beige solid; mp 206.8–208.4 °C (dec.).
1H NMR (400 MHz, DMSO-d6):  = 12.27 (br s, 2 H), 7.10–6.98 (m, 2
H), 6.94–6.81 (m, 1 H), 6.16 (s, 1 H, HC=), 4.34–4.20 (m, 4 H), 4.09 (s, 2
H, CH2).
HRMS m/z [M – H]– calcd for C12H11O5–: 235.0601; found: 235.0598.
(E)-3-(4-Fluorophenyl)pent-2-enedioic Acid (1e)
13C NMR (100 MHz, DMSO-d6):  = 171.8, 167.8, 150.1, 144.9, 143.7,
Yield: 1.48 g (66%); pale yellow solid; mp 150.9–151.7 °C.
133.7, 120.1, 118.6, 117.6, 115.6, 64.7, 64.5, 36.0.
1H NMR (400 MHz, DMSO-d6):  = 12.37 (br s, 2 H), 7.64–7.54 (m, 2
H), 7.24 (t, J = 8.8 Hz, 2 H), 6.22 (s, 1 H, HC=), 4.12 (s, 2 H, CH2).
HRMS: m/z [M – H]– calcd for C13H11O6–: 263.0550; found: 263.0559.
13C NMR (100 MHz, DMSO-d6):  = 171.7, 167.6, 163.1 (d, J = 246.8
Hz), 149.8, 137.1 (d, J = 3.2 Hz), 129.2 (d, J = 8.4 Hz), 120.3, 116.0,
115.8, 36.3.
(E/Z)-3-[4-(Piperidine-1-carbonyl)phenyl]pent-2-enedioic Acid
(1k)
Yield: 1.02 g (32%); E/Z = 10:1; colorless solid; mp 158.6–159.6 °C
(dec.).
HRMS: m/z [M – H]– calcd for C11H8FO4–: 223.0401; found: 223.0401.
1H NMR (400 MHz, DMSO-d6):  = 12.41 (br s, 2 H), 7.59 (d, J = 8.3 Hz,
2 H), 7.40 (d, J = 8.3 Hz, 2 H), 6.28 (s, 1 H, HC=), 4.13 (s, 2 H, CH2), 3.58
(br s, 2 H), 3.29 (br s, 2 H), 1.75–1.35 (m, 6 H).
(E)-3-(4-Nitrophenyl)pent-2-enedioic Acid (1f)
Yield: 1.13 g (45%); yellow solid; mp 167.3–169.9 °C.
13C NMR (100 MHz, DMSO-d6):  = 171.7, 168.8, 167.6, 150.0, 141.4,
137.5, 127.4, 126.9, 121.0, 48.4 (br s), 42.8 (br s), 36.2, 26.4 (br s), 25.7
(br s), 24.5.
1H NMR (400 MHz, DMSO-d6):  = 12.57 (br s, 2 H), 8.24 (d, J = 8.8 Hz,
2 H), 7.81 (d, J = 8.9 Hz, 2 H), 6.36 (s, 1 H, HC=), 4.16 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6):  = 171.5, 167.3, 148.7, 147.9, 147.3,
HRMS: m/z [M – H]– calcd for C17H18NO5–: 316.1179; found: 316.1176.
128.4, 124.1, 123.4, 36.2.
HRMS: m/z [M – H]– calcd for C11H8NO6–: 250.0346; found: 250.0347.
(E)-3-{4-[(3r,5r,7r)-Adamantan-1-yl]phenyl}pent-2-enedioic Acid
(1l)
(E)-3-(3-Nitrophenyl)pent-2-enedioic Acid (1g)
Yield: 3.06 g (90%); pale beige solid; mp 204.0–206.8 °C (dec.).
Yield: 1.38 g (55%); yellow solid; mp 149.3–151.6 °C.
1H NMR (400 MHz, DMSO-d6):  = 12.32 (br s, 2 H), 7.48 (d, J = 8.6 Hz,
2 H), 7.39 (d, J = 8.7 Hz, 2 H), 6.23 (s, 1 H, HC=), 4.12 (s, 2 H, CH2),
2.08–2.04 (m, 3 H), 1.88–1.85 (m, 6 H), 1.77–1.72 (m, 6 H).
13C NMR (100 MHz, DMSO-d6):  = 171.8, 167.8, 152.5, 150.6, 137.7,
126.7, 125.5, 119.3, 42.9, 36.6, 36.2, 36.1, 28.7.
1H NMR (400 MHz, DMSO-d6):  = 12.56 (br s, 2 H), 8.30 (t, J = 1.9 Hz,
1 H), 8.24 (ddd, J = 8.2, 2.2, 0.8 Hz, 1 H), 8.00 (ddd, J = 7.8, 1.8, 1.0 Hz, 1
H), 7.71 (t, J = 8.0 Hz, 1 H), 6.36 (s, 1 H, HC=), 4.18 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6):  = 171.6, 167.3, 148.6, 148.5, 142.5,
133.5, 130.7, 124.1, 122.7, 121.6, 36.3.
HRMS: m/z [M – H]– calcd for C21H23O4–: 339.1602; found: 339.1600.
HRMS: m/z [M – H]– calcd for C11H8NO6–: 250.0346; found; 250.0345.
(E/Z)-3-[3,5-Bis(trifluoromethyl)phenyl]pent-2-enedioic Acid
(1m)
(E/Z)-3-[4-(Trifluoromethoxy)phenyl]pent-2-enedioic Acid (1h)
Yield: 2.12 g (73%); E/Z = 12:1; colorless solid; mp 152.7–154.2 °C.
1H NMR (400 MHz, DMSO-d6):  = 12.44 (br s, 2 H), 7.67 (d, J = 8.9 Hz,
2 H), 7.40 (d, J = 8.2 Hz, 2 H), 6.26 (s, 1 H, HC=), 4.13 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6):  = 171.6, 167.5, 149.3, 149.2 (q, J = 1.8
Hz), 139.9, 129.0, 121.4, 121.3, 120.5 (q, J = 256.8 Hz), 36.3.
HRMS: m/z [M – H]– calcd for C12H8F3O5–: 289.0318; found: 289.0314.
Yield: 2.15 g (63%); E/Z = 20:1; colorless solid; mp 164.1–165.7 °C.
1H NMR (400 MHz, DMSO-d6):  = 12.59 (br s, 2 H), 8.18 (s, 2 H), 8.12
(s, 1 H), 6.44 (s, 1 H, HC=), 4.24 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6):  = 171.7, 167.2, 147.7, 143.7, 131.0
(q, J = 33.0 Hz), 128.1–127.6 (m), 124.0, 123.7 (q, J = 273.0 Hz), 123.3–
122.6 (m), 36.2.
HRMS: m/z [M – H]– calcd for C13H7F6O4–: 341.0243; found: 341.0234.
(E/Z)-3-(2-Chlorophenyl)pent-2-enedioic Acid (1i)
Yield: 1.52 g (63%); E/Z 1:1.3; beige viscous oil, slowly solidified on
standing.
(E)-3-(3-Acetylphenyl)pent-2-enedioic Acid (1n)
Yield: 1.41 g (57%); pale beige solid; mp 160.0–162.0 °C (dec.).
1H NMR (400 MHz, DMSO-d6):  (E) = 9.32 (br s, 2 H, 2 × CO2H), 7.43–
7.38 (m, 1 H), 7.35–7.31 (m, 1 H), 7.30–7.25 (m, 2 H), 6.08 (s, 1 H,
HC=), 4.07 (s, 2 H, CH2);  (Z) = 7.43–7.38 (m, 1 H), 7.32–7.29 (m, 1 H),
7.28–7.22 (m, 1 H), 7.21–7.17 (m, 1 H), 6.20 (t, J = 1.0 Hz, 1 H, HC=),
3.52 (d, J = 1.0 Hz, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6):  (E) = 175.8, 171.1, 152.5, 140.3,
131.4, 130.2, 130.0, 129.9, 127.0, 123.6, 38.5;  (Z) 175.2, 169.7, 150.2,
137.2, 130.8, 129.4, 129.35, 129.32, 126.6, 123.0, 43.7.
1H NMR (400 MHz, DMSO-d6):  = 12.43 (br s, 2 H), 8.05 (t, J = 1.8 Hz,
1 H), 8.01–7.94 (m, 1 H), 7.80 (ddd, J = 7.9, 1.8, 1.0 Hz, 1 H), 7.57 (t, J =
7.8 Hz, 1 H), 6.32 (s, 1 H, HC=), 4.17 (s, 2 H, CH2), 2.62 (s, 3 H, COCH3).
13C NMR (100 MHz, DMSO-d6):  = 198.2, 171.7, 167.5, 150.1, 141.2,
137.6, 131.5, 129.6, 129.2, 126.4, 121.4, 36.3, 27.3.
HRMS: m/z [M – H]– calcd for C13H11O5–: 247.0601; found: 247.0601.
(E/Z)-3-Mesitylpent-2-enedioic Acid (1o)
Yield: 2.21 g (89%); E/Z = 1:1.3; colorless solid.
HRMS: m/z [M – H]– calcd for C11H8ClO4–: 239.0106; found: 239.0103.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

F
D. Dar’in et al.
Paper
Synthesis
1H NMR (400 MHz, DMSO-d6):  (E) = 12.27 (br s, 2 H, 2 × CO2H), 6.85
(s, 2 H), 5.72 (s, 1 H, HC=), 3.73 (s, 2 H, CH2), 2.21 (s, 3 H), 2.18 (s, 6 H);
 (Z) = 12.27 (br s, 2 H, 2 × CO2H), 6.80 (s, 2 H), 6.14 (t, J = 1.3 Hz, 1 H,
HC=), 3.18 (d, J = 1.3 Hz, 2 H, CH2), 2.21 (s, 3 H), 2.09 (s, 6 H).
13C NMR (101 MHz, CDCl3):  = 170.0, 165.2, 152.9, 138.2, 133.9,
133.8, 128.6, 122.0, 38.5, 38.1, 36.7, 26.4, 22.5, 21.0, 19.6.
HRMS: m/z [M + H]+ calcd for C19H26NO2: 300.1958; found: 300.1968.
13C NMR (100 MHz, DMSO-d6):  (E) = 171.0, 167.3, 151.3, 139.1,
136.9, 136.7, 128.7, 123.8, 39.8, 20.9, 20.1;  (Z) = 171.2, 166.3, 150.0,
135.9, 134.5, 133.6, 128.2, 122.4, 44.3, 21.0, 19.6.
Microwave-Assisted Reaction of Dicarboxylic Acids 1b and 1o with
Amines
A mixture dicaboxylic acid 1b or 1o (1 mmol) and amine (see below)
(1 mmol) in toluene (3 mL) was heated at 180 °C for 1 h in a micro-
wave reactor. Upon cooling to r.t., the reaction mixture was concen-
trated and subjected to column chromatography on silica eluting with
CHCl3.
HRMS: m/z [M – H]– calcd for C14H15O4–: 247.0965; found: 247.0968.
(E)-3-(4-Sulfamoylphenyl)pent-2-enedioic Acid (1p)
Yield: 2.34 g (82%); E/Z = 5:1; colorless solid; pure E-diastereomer was
isolated after recrystallization of diastereomeric mixture from MeCN;
yield: 1.17 g (41%), colorless solid; mp 275.2–280.0 °C (dec.).
1H NMR (400 MHz, DMSO-d6):  = 12.47 (br s, 2 H), 7.84 (d, J = 8.6 Hz,
2 H), 7.72 (d, J = 8.6 Hz, 2 H), 7.41 (s, 2 H, SO2NH2), 6.30 (s, 1 H, HC=),
4.15 (s, 2 H, CH2).
Reaction of 1b with 2-furylmethaneamine afforded 37 mg (12%) of 6a
and 77 mg (28%) of compounds 7a and 8a as 6.4:1 mixture (by 1H
NMR analysis). The latter was further purified by column chromatog-
raphy using CHCl3 as eluent to give 44 mg (16%) of pure 7a.
(E)-N-(Furan-2-ylmethyl)-3-(4-methoxyphenyl)but-2-enamide
(7a)
13C NMR (100 MHz, DMSO-d6):  = 171.6, 167.4, 149.5, 144.7, 144.0,
127.6, 126.4, 122.1, 36.2.
HRMS: m/z [M – H]– calcd for C11H10NO6S–: 284.0223; found:
284.0221.
Yield: 44 mg (16%); light yellow foam.
1H NMR (400 MHz, CDCl3):  = 7.47–7.34 (m, 3 H), 7.02–6.61 (m, 2 H),
6.34 (dd, J = 3.3, 1.9 Hz, 1 H), 6.27 (dd, J = 3.2, 0.8 Hz, 1 H), 6.00 (q, J =
1.3 Hz, 1 H), 5.97 (br s, 1 H), 4.53 (d, J = 5.6 Hz, 2 H), 3.83 (s, 3 H), 2.57
(d, J = 1.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 166.7, 160.01, 151.6, 151.0, 142.1,
134.8, 127.4, 117.7, 113.8, 110.5, 107.4, 55.3, 36.3, 17.5.
3-Arylglutaconic Imides 6a–c; General Procedure
To a solution of amine (1.1 mmol) in toluene (30 mL) was added diac-
id 1b, 1l, or 1o (1 mmol) and the mixture was heated at reflux with a
Dean–Stark trap for 16 h. Upon cooling to r.t., the mixture was con-
centrated and the respective title compound was isolated using flash
column chromatography on silica gel eluting with CHCl3.
For NOESY spectrum, see Supporting Information.
HRMS: m/z [M + Na]+ calcd for C16H17NO3Na: 294.1101; found:
294.1127.
1-(Furan-2-ylmethyl)-4-(4-methoxyphenyl)pyridine-2,6(1H,3H)-
dione (6a)
Reaction of 1o with isopentylamine afforded 45 mg (15%) of 6c and
108 mg (40%) of compounds 7c and 8c as 5.7:1 mixture (by H NMR
analysis). The latter was further purified by column chromatography
1
Yield: 127 mg (43%); orange foam.
1H NMR (400 MHz, CDCl3):  = 7.62–7.42 (m, 2 H), 7.34 (dd, J = 2.0, 0.9
Hz, 1 H), 7.10–6.77 (m, 2 H), 6.58 (t, J = 1.5 Hz, 1 H), 6.37 (dd, J = 3.2,
0.8 Hz, 1 H), 6.32 (dd, J = 3.3, 1.8 Hz, 1 H), 5.11 (s, 2 H), 3.87 (s, 3 H),
3.82 (d, J = 1.4 Hz, 2 H).
13C NMR (101 MHz, CDCl3):  = 169.5, 165.2, 161.9, 150.2, 148.5,
142.0, 127.4, 127.2, 114.7, 114.6, 110.4, 109.0, 55.5, 36.0, 35.3.
using CHCl3 as eluent to give 62 mg (23%) of pure 7c.
(E)-N-Isopentyl-3-mesitylbut-2-enamide (7c)
Yield: 62 mg (23%); light brown oil.
1H NMR (400 MHz, CDCl3):  = 6.87 (s, 2 H), 5.54 (q, J = 1.5 Hz, 1 H),
5.41 (s, 1 H), 3.53–3.22 (m, 2 H), 2.39 (d, J = 1.5 Hz, 3 H), 2.29 (s, 3 H),
2.20 (s, 6 H), 1.74–1.57 (m, 1 H), 1.52–1.36 (m, 2 H), 0.96 (d, J = 6.6 Hz,
6 H).
HRMS: m/z [M + H]+ calcd for C17H16NO4: 298.1074; found: 298.1064.
13C NMR (101 MHz, CDCl3):  = 166.5, 153.1, 140.9, 136.3, 133.9,
4-[4-(Adamantan-1-yl)phenyl]-1-(4-methoxybenzyl)pyridine-
2,6(1H,3H)-dione (6b)
128.2, 121.8, 38.6, 37.7, 26.0, 22.5, 20.9, 19.6, 19.5.
Yield: 197 mg (45%); light yellow foam.
For NOESY spectrum, see Supporting Information.
1H NMR (400 MHz, CDCl3):  = 7.70–7.38 (m, 6 H), 6.86 (d, J = 8.7 Hz, 2
H), 6.62 (d, J = 1.5 Hz, 1 H), 5.04 (s, 2 H), 3.82 (d, J = 1.6 Hz, 2 H), 3.80
(s, 3 H), 2.14 (pent, J = 3.1 Hz, 3 H), 1.94 (d, J = 2.9 Hz, 6 H), 1.87–1.74
(m, 6 H).
13C NMR (101 MHz, CDCl3)  = 169.9, 165.7, 159.0, 154.7, 148.9, 132.1,
130.7, 129.3, 125.7, 125.6, 116.2, 113.7, 55.2, 42.9, 41.9, 36.7, 36.5,
36.1, 28.8.
HRMS: m/z [M + H]+ calcd for C18H28NO: 274.2165; found: 274.2180.
Funding Information
This work was supported by the Russian Foundation for Basic Re-
search (project grant 18-515-76001) under «ERA.Net RUS plus» joint
program grant RUS_ST2017-309 and State Education Development
HRMS: m/z [M + H]+ calcd for C29H32NO3: 442.2377; found: 442.2373.
Agency of Republic of Latvia (‘THIOREDIN’).
R
u
si
a
n
F
o
u
n
d
ati
o
n
for
B
asi
c
R
esearc
h
(18-5
1
5-7
6
0
0
1)
1-Isopentyl-4-mesitylpyridine-2,6(1H,3H)-dione (6c)
Yield: 146 mg (49%); beige foam.
Acknowledgment
1H NMR (400 MHz, CDCl3):  = 6.93 (s, 2 H), 6.10 (t, J = 1.7 Hz, 1 H),
4.00–3.76 (m, 2 H), 3.48 (d, J = 1.7 Hz, 2 H), 2.32 (s, 3 H), 2.20 (s, 6 H),
1.76–1.58 (m, 1 H), 1.58–1.43 (m, 2 H), 1.00 (d, J = 6.6 Hz, 6 H).
Research Centre for Magnetic Resonance and the Center for Chemical
Analysis and Materials Research of Saint Petersburg State University
Research Park for obtaining the analytical data.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

G
D. Dar’in et al.
Paper
Synthesis
Supporting Information
(12) Balazs, L.; Kadas, I.; Tõke, L. Tetrahedron Lett. 2000, 41, 7583.
(13) Jagtap, S. Catalysts 2017, 7, 267.
(14) Roglans, A.; Pla-Quintana, A.; Moreno-Manas, M. Chem. Rev.
2006, 106, 4622.
(15) Selected examples: (a) Kamble, R. B.; Devalankar, D.;
Suryavanshi, G. New J. Chem. 2018, 42, 10414. (b) Pastre, J. C.;
Correia, C. R. D. Adv. Synth. Catal. 2009, 351, 1217.
(c) Kalkhambkar, R. G.; Laali, K. K. Tetrahedron Lett. 2011, 52,
1733. (d) Prediger, P.; da Silva, A. R.; Correia, C. R. D. Tetrahedron
2014, 70, 3333. (e) Pastre, J. C.; Correia, C. R. D. Org. Lett. 2006, 8,
1657.
(16) Kikukawa, K.; Nagira, K.; Wada, F.; Matsuda, T. Tetrahedron
1981, 37, 34.
(17) Bräse, S.; de Meijere, A. Cross-Coupling of Organyl Halides with
Alkenes – The Heck Reaction, In Metal-Catalyzed Cross-Coupling
Reactions and More; de Meijere, A.; Bräse, S.; Oestreich, M., Ed.;
Wiley-VCH: Weinheim, 2014, 533–664.
(18) Filimonov, V. D.; Trusova, M.; Postnikov, P.; Krasnokutskaya, E.
A.; Lee, Y. M.; Hawng, H. Y.; Kim, H.; Chi, K.-W. Org. Lett. 2008,
10, 3961.
(19) Kutonova, K. V.; Trusova, M. E.; Stankevich, A. V.; Postnikov, P.
S.; Filimonov, V. D. Beilstein J. Org. Chem. 2015, 11. 358.
(20) Khatri, A. I.; Samant, S. D. RSC Adv. 2015, 5. 2009.
(21) Butera, J.; Bagli, J.; Doubleday, W.; Humber, L.; Treasurywala, A.;
Loughney, D.; Sestanj, K.; Millen, J.; Sredy, J. J. Med. Chem. 1989,
32, 757.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611211. Copies of 1H and 13C NMR
spectra are provided.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
References
(1) Address correspondence to this author at the Laboratory of
Chemical Pharmacology, Institute of Chemistry, Saint Peters-
burg State University, 26 Universitetskyi prospekt, Peterhof
198504, Russian Federation.
(2) Buggle, K.; Ghogain, U. N.; Nangle, M.; MacManus, P. J. Chem.
Soc., Perkin Trans. 1 1983, 1427.
(3) Pednekar, S. R.; Samant, S. D.; Deodhar, K. D. Heterocycles 1984,
22, 1979.
(4) Pednekar, S.; Jain, A. K.; Menon, K. K. Indian J. Heterocycl. Chem.
2004, 14, 1.
(5) Khatri, A. I.; Samant, S. D. Synthesis 2015, 47, 343.
(6) Zhang, B.; Zhang, J.; Peng, S.; Liu, R.; Li, X.; Hou, Y.; Han, X.; Fang,
J. Exp. Opin. Ther. Pat. 2017, 27, 547.
(7) Patel, N. B.; Sharma, R. D. Synth. Commun. 2013, 43, 1250.
(8) Reich, H. J.; Hondal, R. J. ACS Chem. Biol. 2016, 11, 821.
(9) (a) Sanin, A. V.; Nenajdenko, V. G.; Kuzʼmin, V. S.; Balenkova, E.
S. J. Org. Chem. 1996, 61, 1986. (b) Chen, J.; Meng, S.; Wang, L.;
Tang, H.; Huang, Y. Chem. Sci. 2015, 6, 4184. (c) Chen, W.; Jing,
Z.; Chin, K. F.; Qiao, B.; Zhao, Y.; Yan, L.; Tan, C.-H.; Jiang, Z. Adv.
Synth. Catal. 2014, 356, 1292. (d) Wang, Y.-F.; Wu, S.; Karmaker,
P. G.; Sohail, M.; Wang, Q.; Chen, F.-X. Synthesis 2015, 47, 1147.
(10) SciFinder search performed on December 23, 2018.
(11) Peet, N. P.; Sunder, S. Heterocycles 1986, 24, 393.
(22) (a) Joshi, G. W.; Samant, S. D.; Deodhar, K. D.; Kulkarni, R. A.
Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1981, 20,
1050. (b) Hattori, K.; Kurihara, N.; Iwaki, T.; Inoue, T.; Akiyama,
T.; Hasegawa, Y. PCT Int. Appl. WO2013002357, 2013; Chem.
Abstr. 2013, 158, 158456.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G