Unexpected Synthesis of 2,3,5,6-Tetrahydro-1H-pyrrolo[3,4-c]pyridine-1,3,6-triones by a Double Michael Addition/CS2 Extrusion/Double Cyclization Sequence

Article abstract of DOI:10.1002/ejoc.201701097

Bis adducts derived from a double Michael addition of rhodanine to an azo-ene system of two molecules of 1,2-diaza-1,3-dienes (DDs) have furnished the corresponding 2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-1,3,6-triones by means of a CS₂ extrusion/double cyclization sequence. The incorporation of two units (4 and 2 atoms) of DDs into the fused bicyclic heterocycles represents a new application of this versatile class of molecules in heterocyclic synthesis.

Full text of DOI:10.1002/ejoc.201701097

DOI: 10.1002/ejoc.201701097
Full Paper
Cascade Reactions
Unexpected Synthesis of 2,3,5,6-Tetrahydro-1H-pyrrolo[3,4-c]-
pyridine-1,3,6-triones by a Double Michael Addition/CS2
Extrusion/Double Cyclization Sequence
[
a]
[a]
[a]
[a]
Giacomo Mari, Lucia De Crescentini,* Gianfranco Favi, Stefania Santeusanio,
[
b]
[a]
Samuele Lillini, and Fabio Mantellini*
Abstract: Bis adducts derived from a double Michael addition means of a CS extrusion/double cyclization sequence. The in-
2
of rhodanine to an azo-ene system of two molecules of 1,2- corporation of two units (4 and 2 atoms) of DDs into the fused
diaza-1,3-dienes (DDs) have furnished the corresponding bicyclic heterocycles represents a new application of this versa-
2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-1,3,6-triones
by tile class of molecules in heterocyclic synthesis.
Introduction
the two molecules of DDs contribute to the final pyridine core
[
5,6]
with 3 and 2 atoms (Scheme 1; structure A).
Another exam-
One of the most intriguing targets of organic chemists is the
possibility to obtain complex transformations in a single-step
reaction by starting from a set of various reagents to give di-
rectly the final product.
ple is represented by pyridazines derived from the cyclodimeri-
zation of two molecules of DDs that results in a formal [4+2]
[7]
cycloaddition (Scheme 1; structure B).
This kind of transformations, in which several bonds are
formed in one sequence under the same reaction conditions
without isolating the intermediates and without adding addi-
tional reagents or catalysts, are commonly called domino or
[
1,2]
cascade reactions.
It appears clear that the advantages of this synthetic meth-
odology can be of economical, ecological, and of operative in-
terest, because it increases the synthetic efficiency and de-
creases the amount of solvents, reagents, and catalysts used
[
1,2]
and the number of laboratory operations required.
The utility and versatility of 1,2-diaza-1,3-dienes (DDs) in the
construction of a variety of heterocyclic rings are well known
and are demonstrated by significant activity in this field over
[
3]
recent years. In particular, they can react as Michael acceptors
in conjugated additions, and they can also be employed in
cycloaddition reactions with a wide range of partners.[3,4]
In most cases reported in the literature for the Michael addi-
tion, DD participates with one unit in the construction of the
final heterocycle, whereas there are only a few examples in
which it takes part with two units. In particular, in the spiro-
heterocycle-pyridines previously synthesized by our group
starting from DDs and some oxindole or barbiturate derivatives,
Scheme 1. Participation of two DD units in a heterocyclic assembly.
Recently, Shelke and Suryavanshi have reported the synthe-
sis of a tetrazocine derived by a [4+4] cycloaddition reaction
[
7a]
(Scheme 1; structure C).
In the present work, for the first time, two units of DDs par-
ticipate in the construction of a system that contains two fused
heterocycles of the formed pyrrolo-pyridines with 4 and 2
atoms (Scheme 1; structure D). In particular, one unit of the
DDs contributes in both the pyridine and pyrrole nuclei of the
final molecule.
[
a] Department of Biomolecular Sciences, Organic Chemistry Section and
Organic Natural Compounds, University of Urbino “Carlo Bo”,
Via I Maggetti 24, 61029 Urbino (PU), Italy
E-mail: fabio.mantellini@uniurb
https://www.uniurb.it/docenti/fabio-mantellini
b] Dompé Farmaceutici s.p.a.,
Our initial intent was to obtain 4-oxo-2-thioxo-1-thia-3,8-di-
azaspiro[4.5]deca-6,9-diene-6,10-dicarboxylates
A (Figure 1,
[
Route B), because rhodanines represent a privileged scaffold in
drug discovery, and they are known to exhibit a wide spectrum
Via P. Castellino, 80131 Naples, Italy
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201701097.
[
8]
of pharmacological properties.
Eur. J. Org. Chem. 2017, 6291–6298
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So, we began our studies by carrying out a preliminary reac-
tion between 2 equiv. of DD 1d and 3-phenylrhodanine 2b,
chosen as examples, under basic conditions, by using 2 equiv.
of K CO . As expected, bis(hydrazone)-functionalized rhodanine
2
3
4d was formed in 93 % yield, which resulted from a double
Michael-type addition of rhodanine 2b to 2 equiv. of DD 1d
(
Table 1).
At this point, we have dealt with the development of a pro-
cedure for the cyclization of 4d by testing several solvents, such
as CH Cl , tetrahydrofuran (THF), EtOH, and acetonitrile, at dif-
2
2
ferent temperatures (room temp., reflux). Furthermore, a series
of catalysts were used, such as K CO , NaH, NaH/Amberlyst 15H,
2
3
MeONa, trifluoroacetic acid (TFA), CuCl , and ZnCl , and differ-
2
2
ent molar ratios of 4d/catalyst were employed (Table 1). We
observed that with EtOH or CH CN and NaH in an equimolar
3
ratio (Table 1, Entries 8 and 9) the reactions gave complicated
mixtures. The same behavior was pointed out by the reaction
in CH Cl with TFA as catalyst (Table 1, Entry 1), whereas no
2
2
reactions were detected with the use of CuCl or ZnCl in cata-
2
2
lytic amounts (Table 1, Entries 13 and 14). In all the other cases
Table 1, Entries 2–7 and 10–12), instead of the expected 4-oxo-
-thioxo-1-thia-3,8-diazaspiro[4.5]deca-6,9-diene-6,10-dicarbox-
(
2
ylate, a different product was achieved, which was isolated and
characterized as 2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-
Figure 1. Intent to synthesize 4-oxo-2-thioxo-1-thia-3,8-diazaspiro[4.5]deca-
1
,3,6-trione 6e, the formation of which took place with the loss
6
,9-diene-6,10-dicarboxylates A by supposed Route B and obtained Route C.
of CS . By taking into consideration that its boiling point is
2
4
6.3 °C, we decided to perform other tests at 55 °C and keep
open the reaction flask to facilitate the removal of CS and use
the best conditions found at room temperature, such as THF
and base (Table 1, Entries 15–17). The best results in terms of
2
Previously, some of us investigated the reaction between
DDs 1 and N-unsubstituted rhodanines 2′ (Figure 1, Route A).
In this case, the sulfur atom of the rhodanines acted as a nu-
cleophile. To avoid this eventuality, we planned to explore the
reaction between 2 equiv. of DDs 1 and some N-substituted
rhodanine derivatives 2 in which the carbon atom at position
[
9]
highest yield of 6e (61 %) involve the use of 5 equiv. of K CO3
2
(
Table 1, Entry 17).
At this point, we tested the same reaction between 1d and
2
b with K CO (5 equiv.) at 55 °C to obtain 2,3,5,6-tetrahydro-
2 3
5
could act as nucleophile.
After the formation of bis adducts by means of a double
1
H-pyrrolo[3,4-c]pyridine-1,3,6-trione 6e directly in a one-pot
procedure. Indeed, product 6e was formed in 66 % yield
Michael addition of one molecule of rhodanine 2 to two mol-
ecules of DD 1, the intramolecular ring closure could have fur-
nished the desired spiro derivatives A in analogy to what was
(
Table 1, Entry 18).
So, with these optimal conditions in hand, we explored the
reactions of various DDs 1a–1h with rhodanines 2a–2d both
by step-by-step (Scheme 2, Path A) and one-pot methods
[
5,6]
previously observed
(Figure 1, Route B).
But the reactions surprisingly furnished the interesting
,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-1,3,6-triones 6 (Fig-
(Scheme 2, Path B).
2
In particular, by applying Path A, the reaction of DDs 1a, 1c–
ure 1, Route C). These bicyclic compounds represent a new fam-
ily of HIV-1 integrase inhibitors that showed low micromolar
inhibitory potency in vitro HIV-1 integrase assays, with good
selectivity for strand-transfer reactions relative to 3′-processing
1
e with rhodanines 2a–2d in THF with K CO (2 equiv.) at room
2 3
temperature, bis(hydrazone)-functionalized rhodanines 4a–4f
were obtained in good to excellent yields (79–93 %), and the
reactions were completed in 0.1–0.5 h (Scheme 2, Path A;
Table 2).
[
10]
inhibition.
They have reported in the literature to be pre-
pared by “Plummer cyclization-deprotonation-cycloaddition”
[
10]
cascade reactions of imidosulfoxides.
Basic treatment of 4a−4f with K CO (5 equiv.) in THF at
2
3
5
5 °C in an open flask furnished the corresponding 2,3,5,6-tetra-
hydro-1H-pyrrolo[3,4-c]pyridine-1,3,6-triones 6a, 6c–6e, 6j, and
l, in 2.0–5.0 h in acceptable yields (39–61 %; Scheme 2, Path A;
Table 2).
More conveniently, 2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]-
of rhodanines. To start our investigations, we have prepared pyridine-1,3,6-triones 6a–6l were obtained in good yields (43–
-ethyl-, 3-phenyl-, 3-(4-chlorophenyl)- and 3-(4-methoxy)-2-thi- 66 %) by means of a one-pot procedure by carrying out the
oxothiazolidin-4-ones 2a–2d in accordance with the procedure reaction between DDs 1a–1g and rhodanines 2a–2d in THF
6
Results and Discussion
Several methods are reported in the literature for the synthesis
[
11]
3
[
11a]
reported by Ravi et al.
with K CO (5 equiv.) at 55 °C in an open flask. Under these
2 3
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Table 1. Screening of different conditions in the cyclization reaction of bis(hydrazone)-functionalized rhodanine 4d for the synthesis of 2,3,5,6-tetrahydro-1H-
[
a]
pyrrolo[3,4-c]pyridine-1,3,6-trione 6e.
Entry
Solvent
Temperature
°C]
Catalyst (C)
Molar ratio of 4d/C
Yield of 6e[b]
[
[%]
1
2
3
4
5
6
7
8
9
CH
THF
THF
THF
THF
THF
THF
2
Cl
2
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
reflux
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
55 °C
TFA
NaH
NaH
NaH
1:0.1
1:0.1
1:1.5
1:2
complicated mixture
14
14
16
13
25
15
[
c]
NaH
1:3
NaH, then Amberlyst 15H
NaH, then Amberlyst 15H
1:2:2
1:0.75:0.75
1:1
EtOH
NaH
NaH
complicated mixture
complicated mixture
CH
3
CN
1:1
1
1
0
1
THF
THF
THF
NaOMe
NaOMe
NaOMe
CuCl
ZnCl
1:0.1
1:1.5
1:5
1:0.1
1:0.1
1:1
8
32
21
c]
1
2[
1
1
1
1
1
3
4
5
6
7
CH
CH
2
Cl
Cl
2
2
no reaction
no reaction
2
2
2
THF
THF
THF
THF
NaH
NaOMe
21
52
61
55 °C
55 °C
55 °C
1:1
K
K
2
CO
CO
3
1:5
[
d]
[e]
[f]
1
8
2
3
1:5
66
[
0
[
a] The reactions were performed on a 0.5 mmol scale of 4d in 3 mL of solvent. [b] Yields of isolated 6e based on 4d. [c] The reaction was performed on a
.5 mmol scale of 4d in 100 mL of solvent. [d] The reaction was performed in a one-pot procedure by starting from 1d (1.0 mmol) and 2b (0.5 mmol).
e] Molar ratio of rhodanine 2b/K CO . [f] Yield of isolated 6e based on 2b.
2
3
Scheme 2. Synthesis of dialkyl 2,2′-[(3-substituted 4-oxo-2-thioxothiazolidine-5,5-diyl)bis(4-alkoxy-4-oxobutan-3-yl-2-ylidene)]bis(hydrazinecarboxylates) 4a–4f
and of 2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-1,3,6-triones 6a–6l; proposed mechanism.
conditions the reactions were completed in 1.0–5.0
Scheme 2, Path B; Table 2).
h
ducts 4 were formed. If products 3 have been obtained, it
would have given us the opportunity to add them to DD mol-
(
Any attempt to isolate mono adduct 3, which derives from ecules different from the starting ones.
the Michael-type addition of rhodanine 2 to 1 equiv. of DD 1, The plausible mechanism of this cascade reaction involves
failed (Scheme 1); in fact, from tests carried out under different preliminary double attack (Michael-type) of the carbon atom in
conditions with a DD/rhodanine equimolar ratio, only bis ad- the 5 position of rhodanine 2 to the terminal carbon atom of
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Table 2. Yields and reaction times for the synthesis of dialkyl 2,2′-[(3-substituted-4-oxo-2-thioxothiazolidine-5,5-diyl)bis(4-alkoxy-4-oxobutan-3-yl-2-ylid-
ene)]bis(hydrazinecarboxylates) 4a–4f and of 2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-1,3,6-triones 6a–6l.
Entry
1
R1
R2
R3
2
R4
4
Time
h]
Yield
[%][
6
Time
[h]
Yield
[%]
Time
[h]
Yield
[%]
a]
[b]
[c]
[
1
3
4
5
6
7
8
9
1a
1b
1a
1c
1d
1e
1f
1g
1b
1c
1c
1d
Et
Me
Et
Me
Et
CO
CO
CO
CO
CO
CO
CO
CO
2
Me
tBu
Me
Me
Me
Me
Me
Me
Bu
Me
Me
Me
Me
Me
Me
2a
2a
2b
2b
2b
2b
2b
2c
2c
2c
2d
2d
Et
Et
4a
0.1
79
6a
6b
6c
6d
6e
6f
6g
6h
6i
4.5
42
4.0
5.0
4.5
4.0
4.0
5.0
4.5
4.0
4.0
4.5
1.5
1.0
44
58
60
55
66
63
43
46
51
58
59
64
2
2
Ph
Ph
Ph
Ph
Ph
4b
4c
4d
0.1
0.2
0.2
85
92
93
5.0
5.0
4.5
53
53
61
2
Et
2
tBu
2
Et
Me
Et
2
Bn
Me
tBu
Me
Me
Me
Me
Et
2
4-ClC
4-ClC
4-ClC
6
H
H
H
4
10
11
12
13
CO
CO
CO
2
6
6
4
2
2
Et
Et
tBu
4
4e
4f
0.2
0.5
88
93
6j
6k
6l
5.0
2.0
39
61
4-MeOC
4-MeOC
6
H
4
CO
2
6
H
4
[
[
a] Yields of pure isolated products referred to rhodanines 2a–2d. [b] Yields of pure isolated products referred to bis(hydrazones) 4a–4f (Scheme 2, Path A).
c] Yields of pure isolated products referred to rhodanines 2a–2d in the one-pot procedure (Scheme 2, Path B).
the azo-ene system of two molecules of DD 1, with the forma- carbonyl moiety occurred to give the corresponding 7-acetyl-5-
tion of bis(hydrazone) intermediate 4. The key step in the con- amino-4-methyl-2-phenyl-1H-pyrrolo[3,4-c]pyridine-1,3,6-
[
14]
struction of the tetrahydro-1H-pyrrolo[3,4-c]pyridine-1,3,6-tri- (2H,5H)-trione 7a in very good yield (83 %; Scheme 3).
one system is the opening of the 2-thioxothiazolidin-4-one ring,
which results in the loss of CS . This process is triggered by the
2
removal from the base of the acidic proton originally located in
the 4-position of the first azo-ene molecule, with subsequent
activation of the nitrogen atom from the rhodanine core. Its
nucleophilic attack on the ester function of the second DD mol-
ecule promotes the formation of the pyrrolidine-2,5-dione core
of non-isolated intermediate 5. Further cyclization to obtain the
pyridin-2(1H)-one nucleus occurs as a result of the basic re-
moval of the analogous proton that derives from the second
Scheme 3. Hydrolytic cleavage of 2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]-
pyridine-1,3,6-trione 6e to 7-acetyl-5-amino-4-methyl-2-phenyl-1H-
pyrrolo[3,4-c]pyridine-1,3,6(2H,5H)-trione 7a.
molecule of DD that promotes the nucleophilic attack of the
2
sp nitrogen atom at the ester carbonyl function originally lo-
cated in the first DD (Scheme 2).
It is noteworthy that a double interaction between the two
fragments derived from the two DDs occurs, and in the one-
pot procedure this cascade reaction furnishes two new single
Conclusions
carbon–nitrogen bonds and a single and a double carbon– By starting from 1,2-diaza-1,3-dienes and rhodanine derivatives,
carbon bond.
we have developed a synthetic strategy to have access to
The two activated protons play a crucial role by promoting 2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-1,3,6-triones by
the double nitrogen nucleophilic attack onto the ester function means of a double Michael addition/CS extrusion/double cycli-
2
of the other fragments.
zation sequence. To the best of our knowledge, this work repre-
To the best of our knowledge, just one example of ring- sents the first example of a ring-opening/ring-closing process
opening/ring-closing process of the rhodanine core is reported with concomitant extrusion of carbon disulfide from the
[
12]
in the literature.
Differently from this, our sequence occurs rhodanine core. The easy availability of the starting materials,
with the loss of a molecule of carbon disulfide, which activates the simplicity of the experimental method, and the potential
the substituted nitrogen atom of the rhodanine as nucleophile biological activities and utilities of products can increase the
in the first cyclization event.
synthetic usefulness of this new procedure. Furthermore, by
The structures of compounds 4 and 6 were confirmed by 1D employing a step-by-step approach highly functionalized
and 2D NMR spectroscopic measurements, and the data are rhodanines could be easily obtained in satisfactory yields.
directly comparable to those reported in the literature for simi-
[
10,13]
lar compounds.
Further evidence of the proposed structure for compounds Experimental Section
6
was furnished by the hydrolytic cleavage of the hydrazone
General Information: All chemicals and solvents were purchased
from commercial suppliers and used as received. Rhodanines 2a–
d were obtained in accordance with the procedure reported in
moiety in position 7 of the pyridine ring of compound 6e, cho-
sen as an example, that was obtained under heterogeneous
2
[
14]
[11a]
conditions with acetone/water (9:1) and Amberlyst 15H.
Under these acidic conditions also the loss of the tert-butoxy- and ethyl, phenyl, 4-chlorophenyl, or 4-methoxyphenyl isothio-
the literature:
A mixture of thioglycolic acid (0.92 g, 10 mmol)
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cyanates (12 mmol) in methanol (8 mL) and water (100 mL) was
heated in an oil bath at 100 °C for 4 h. 1,2-Diaza-1,3-dienes 1a–1g
were prepared as reported[ and used as (E,E)/(E,Z) isomers. Melt-
ing points were determined in open capillary tubes. FTIR spectra
were obtained as nujol mulls. All H and C NMR spectra were
recorded at 400 and 100 MHz, respectively. Proton and carbon spec-
1.85 (s, 3 H, CH ), 2.08 (s, 3 H, CH ), 3.74 (s, 3 H, OCH ), 3.74 (s, 3 H,
3
3
3
OCH ), 4.18 (s, 1 H, CH), 4.19–4.31 (m, 4 H, 2 OCH CH ), 4.69 (br. s,
3
2
3
15]
1 H, CH), 7.44–7.56 (m, 5 H, Ar), 7.80 (br. s, 1 H, NH), 7.95 (br. s, H,
NH) ppm. 13C NMR (100 MHz, CDCl , 25 °C): δ = 14.4 (q), 14.6 (q),
3
1
13
15.2 (q), 17.5 (q), 52.8 (q), 53.1 (q), 58.2 (s), 62.1 (t), 62.3 (d), 65.8 (d),
128.3 (d), 129.3 (d), 129.4 (d), 136.0 (s), 146.0 (s), 153.1 (s), 153.9 (s),
tra were referenced internally to solvent signals by using values of 168.4 (s), 169.4 (s), 171.2 (s), 204.0 (s) ppm. IR (nujol): ν˜
= 3234,
max
–
1
δ = 2.50 ppm for proton (middle peak) and δ = 39.50 ppm for
3159, 3127, 1741, 1701 cm . HRMS (ESI): calcd. for C H N O S
25 32 5 9 2
+
carbon (middle peak) in [D ]DMSO, and δ = 7.27 ppm for proton
[M + H] 610.1641; found 610.1641. MS (ESI): m/z = 610.55 [M +
6
+
and δ = 77.00 ppm for carbon (middle peak) in CDCl . All NH groups
H ]. C H N O S (609.6717): calcd. C 49.25, H 5.13, N 11.49; found
3
25 31 5 9 2
exchanged with D O. Pre-coated aluminum oxide plates (0.25 mm)
C 49.12, H 5.11, N 11.62.
2
were employed for analytical thin layer chromatography. All new
compounds showed satisfactory elemental analysis. Mass spectra
were recorded in the ESI mode. The nomenclature was generated
by using ACD/IUPAC Name (version 3.50, 5 Apr. 1998), Advanced
Chemistry Development Inc., Toronto, ON, Canada.
Di-tert-butyl 2,2′-[(4-Oxo-3-phenyl-2-thioxothiazolidine-5,5-
diyl)bis(4-ethoxy-4-oxobutan-3-yl-2-ylidene)]bis(hydrazine-
carboxylate) (4d): White solid (1.29 g, 93 % yield). M.p. 138–141 °C.
1
H NMR (400 MHz, CDCl , 25 °C): δ = 1.23–1.27 (m, 6 H, 2 OCH CH ),
3
2
3
1
.51 [s, 9 H, C(CH ) ], 1.56 [s, 9 H, C(CH ) ], 1.84 (s, 3 H, CH ), 2.09
3 3 3 3 3
General Procedure for the Synthesis of Dialkyl 2,2′-[(3-Substi- (s, 3 H, CH ), 4.11 (s, 1 H, CH), 4.17–4.23 (m, 4 H, 2 OCH CH ), 4.67
3
2
3
tuted 4-oxo-2-thioxothiazolidine-5,5-diyl)bis(4-alkoxy-4-oxo-
butan-3-yl-2-ylidene)]bis(hydrazinecarboxylates) 4a–4f: To a
magnetically stirred solution of 1,2-diaza-1,3-dienes 1a, 1c, or 1d
(br. s, 1 H, CH), 7.45–7.56 (m, 5 H, Ar), 7.65 (br. s, 1 H, NH), 7.77 (br.
s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl , 25 °C): δ = 13.9 (q), 14.0
3
(q), 14.5 (q), 17.6 (q), 28.2 (q), 28.4 (q), 58.2 (s), 59.1 (d), 59.2 (d),
61.9 (t), 62.1 (t), 62.2 (t), 81.5 (s), 81.7 (s), 128.4 (d), 129.3 (d), 136.2
(s), 145.3 (s), 151.9 (s), 152.6 (s), 168.0 (s), 169.0 (s), 177.4 (s), 204.4
(
4.2 mmol) and 3-ethyl-, 3-phenyl-, 3-(4-chlorophenyl)-, or 3-(4-
methoxyphenyl)-2-thioxothiazolidin-4-ones 2a–2d (2.0 mmol) in
THF (10 mL) at room temperature, potassium carbonate (2.0 mmol)
was added. After the disappearance of the reagents (0.1–0.5 h; TLC
monitoring), the K CO was filtered off, the reaction solvent was
–
1
(s) ppm. IR (nujol): ν
= 3328, 3225, 1724, 1746, 1700 cm . MS
˜
max
+
(ESI): m/z = 694.00 [M + H ]. C31H43N O S (693.8312): calcd. C
5
9 2
53.66, H 6.25, N 10.09; found C 53.78, H 6.29, N 10.02.
2
3
evaporated under reduced pressure, and the crude mixture was
purified by column chromatography with silica gel (cyclohexane/
ethyl acetate mixtures) to afford the corresponding bis(hydrazone)-
functionalized rhodanines 4a–4f, which were crystallized from di-
ethyl ether/petroleum ether (b.p. 40–60 °C).
Diethyl 2,2′-{[3-(4-Chlorophenyl)-4-oxo-2-thioxothiazolidine-
5
,5-diyl]bis(4-methoxy-4-oxobutan-3-yl-2-ylidene)}-
bis(hydrazinecarboxylate) (4e): White solid (1.13 g, 88 % yield).
1
M.p. 182–184 °C. H NMR (400 MHz, CDCl , 25 °C): δ = 1.29–1.37
3
(
m, 6 H, 2 OCH CH ), 1.83 (s, 3 H, CH ), 2.09 (s, 3 H, CH ), 3.73 (s, 3
2 3 3 3
Dimethyl 2,2′-[(3-Ethyl-4-oxo-2-thioxothiazolidine-5,5-
diyl)bis(4-ethoxy-4-oxobutan-3-yl-2-ylidene)]bis(hydrazine-
H, OCH ), 3.74 (s, 3 H, OCH ), 4.17 (s, 1 H, CH), 4.20–4.33 (m, 4 H, 2
3 3
OCH CH ), 4.68 (s, 1 H, CH), 7.40 (d, J = 8.4 Hz, 2 H, Ar), 7.51 (d, J =
2 3
1
3
carboxylate) (4a): White solid (887.2 mg, 79 % yield). M.p. 141–
9.2 Hz, 2 H, Ar), 7.84 (br. s, 1 H, NH), 7.98 (br. s, 1 H, NH) ppm.
C
1
1
43 °C. H NMR (400 MHz, CDCl , 25 °C): δ = 1.13–1.23 (m, 9 H, 2
NMR (100 MHz, CDCl , 25 °C): δ = 14.4 (q), 14.4 (q), 14.5 (q), 15.2
3
3
OCH CH , NCH CH ), 1.87 (s, 3 H, CH ), 1.99 (s, 3 H, CH ), 3.76 (s, 3
(q), 17.6 (q), 52.9 (q), 53.2 (q), 58.2 (s), 59.0 (d), 62.1 (t), 65.8 (d),
2
3
2
3
3
3
H, OCH ), 3.79 (s, 3 H, OCH ), 4.02–4.12 (m, 7 H, CH, 2 OCH CH , 129.7 (d), 129.8 (d), 134.5 (s), 135.4 (s), 145.8 (s), 153.1 (s), 155.8 (s),
3
3
2
3
13
NCH CH ), 4.51 (br. s, 1 H, CH), 8.24 (br. s, 2 H, 2 NH) ppm. C NMR
168.5 (s), 169.5 (s), 177.1 (s), 203.7 (s) ppm. IR (nujol): ν
100 MHz, CDCl , 25 °C): δ = 11.0 (q), 13.8 (q), 13.9 (q), 14.8 (q), 17.2 3209, 1718, 1752, 1698 cm . MS (ESI): m/z = 643.31 [M – H ].
= 3332,
2
3
˜
max
–
1
+
(
(
(
(
3
q), 39.6 (t), 52.8 (q), 58.2 (s), 58.7 (d), 61.0 (d), 61.8 (t), 62.1 (t), 146.0 C H ClN O S (644.1168): calcd. C 46.62, H 4.69, N 10.87; found C
25
30
5 9 2
s), 146.3 (s), 154.1 (s), 154.7 (s), 167.5 (s), 168.5 (s), 177.0 (s), 203.4
46.75, H 4.71, N 10.73.
–
1
s) ppm. IR (nujol): ν˜
= 3239, 1737, 1715, 1666 cm . MS (ESI):
max
+
Di-tert-butyl 2,2′-{[3-(4-Methoxyphenyl)-4-oxo-2-thioxothiazol-
idine-5,5-diyl]bis(4-ethoxy-4-oxobutan-3-yl-2-ylidene)}-
bis(hydrazinecarboxylate) (4f): White solid (1.34 g, 93 % yield).
M.p. 169–171 °C (dec.) H NMR (400 MHz, CDCl , 25 °C): δ = 1.21–
m/z = 562.70 [M + H ]. C H N O S (561.6289): calcd. C 44.91, H
5
2
1 31 5 9 2
.56, N 12.47; found C 45.04, H 5.59, N 12.35.
1
Dimethyl 2,2′-[(4-Oxo-3-phenyl-2-thioxothiazolidine-5,5-
diyl)bis(4-ethoxy-4-oxobutan-3-yl-2-ylidene)]bis(hydrazine-
carboxylate) (4b): White solid (1.03 g, 85 % yield). M.p. 145–147 °C.
3
1.77 (m, 6 H, 2 OCH CH ), 1.51 [s, 9 H, C(CH ) ], 1.55 [s, 9 H, C(CH ) ],
2
3
3 3
3 3
1.83 (s, 3 H, CH ), 2.08 (s, 3 H, CH ), 3.84 (s, 3 H, OCH ), 4.09 (s, 1 H,
3
3
3
1
H NMR (400 MHz, CDCl , 25 °C): δ = 1.23–1.36 (m, 6 H, 2 OCH CH ),
CH), 4.16–4.23 (m, 4 H, 2 OCH CH ), 4.66 (s, 1 H, CH), 7.03 (d, J =
3
2
3
2 3
1
.84 (s, 3 H, CH ), 2.08 (s, 3 H, CH ), 3.73 (br. s, 3 H, CH ), 3.73 (s, 3
9.2 Hz, 2 H, Ar), 7.37 (d, J = 8.4 Hz, 2 H, Ar), 7.64 (br. s, 1 H, NH),
3
3
3
H, OCH ), 4.18 (s, 1 H, CH), 4.19–4.30 (m, 4 H, 2 OCH CH ), 4.67 (br.
7.75 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl , 25 °C): δ = 14.0
3
2
3
3
s, 1 H, CH), 7.43–7.55 (m, 5 H, Ar), 7.98 (br. s, 1 H, NH), 8.17 (br. s, 1
(q), 14.0 (q), 14.5 (q), 17.6 (q), 28.2 (q), 28.4 (q), 55.4 (q), 58.2 (s),
59.2 (d), 61.9 (t), 61.9 (t), 62.2 (t), 65.8 (d), 81.5 (s), 81.7 (s), 114.6 (d),
128.7 (s), 129.4 (d), 145.4 (s), 151.8 (s), 160.0 (s), 168.0 (s), 169.0 (s),
H, NH) ppm. 13C NMR (100 MHz, CDCl , 25 °C): δ = 14.4 (q), 14.4
3
(q), 14.6 (q), 17.5 (q), 52.7 (q), 52.8 (q), 53.0 (q), 53.1 (q), 58.1 (s),
5
1
1
1
8.9 (d), 59.0 (d), 62.1 (t), 128.2 (d), 128.3 (d), 129.3 (d), 136.0 (d),
45.4 (s), 146.0 (s), 153.3 (s), 153.4 (s), 154.1 (s), 168.4 (s), 169.4 (s),
177.5 (s), 204.7 (s) ppm. IR (nujol): ν˜
= 3246, 3150, 3109, 1754,
max
–
1
+
1693 cm . MS (ESI): m/z = 724.67 [M + H ]. C32H45N O10S2
5
71.1 (s), 204.0 (s) ppm. IR (nujol): ν˜max = 3241, 3160, 1741, 1720, (723.8572): calcd. C 53.10, H 6.27, N 9.68; found C 53.01, H 6.26, N
690 cm–1. MS (ESI): m/z = 608.72 [M – H ]. C25H31N O S
+
9.78.
5
9 2
(
1
609.6717): calcd. C 49.25, H 5.13, N 11.49; found C 49.14, H 5.10, N
1.65.
General Procedure for the Synthesis of 2,3,5,6-Tetrahydro-1H-
pyrrolo[3,4-c]pyridine-1,3,6-triones 6a, 6c–6e, 6j, and 6l by
Starting from 4a–4f (Path A): To a magnetically stirred solution of
bis(hydrazone)-functionalized rhodanines 4a–4f (1.0 mmol) in THF
(6 mL) heated at 55 °C in an oil bath, potassium carbonate
Diethyl 2,2′-[(4-Oxo-3-phenyl-2-thioxothiazolidine-5,5-
diyl)bis(4-methoxy-4-oxobutan-3-yl-2-ylidene)]bis(hydrazine-
carboxylate) (4c): White solid (1.12 g, 92 % yield). M.p. 135–137 °C.
1
H NMR (400 MHz, CDCl , 25 °C): δ = 1.28–1.37 (m, 6 H, 2 OCH CH ),
(5.0 mmol) was added. The flask was kept open to remove CS by
3
2
3
2
Eur. J. Org. Chem. 2017, 6291–6298
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6295
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
+
evaporation (b.p. 49.3 °C). After the disappearance of products 4
2.0–5.0 h; TLC monitoring), the K CO was filtered off, the reaction
[M + H ]. C H N O (441.3942): calcd. C 54.42, H 4.34, N 15.87;
20 19 5 7
(
found C 54.57, H 4.38, N 15.76.
2
3
solvent was evaporated under reduced pressure, and the crude mix-
ture was purified by column chromatography with silica gel (cyclo-
hexane/ethyl acetate mixtures) to afford the corresponding 2,3,5,6-
tetrahydro-1H-pyrrolo[3,4-c]pyridine-1,3,6-triones 6a, 6c–6e, 6j, and
Ethyl 2-(1-{5-[(Ethoxycarbonyl)amino]-4-methyl-1,3,6-trioxo-2-
phenyl-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridin-7-
yl}ethylidene)hydrazinecarboxylate (6d): Pale yellow powder
(
1
165.2 mg, 35 % yield, Path A; 258.6 mg, 55 % yield, Path B). M.p.
6l, which were crystallized from diethyl ether/petroleum ether (b.p.
1
82–184 °C. H NMR (400 MHz, CDCl , 25 °C): δ = 1.28–1.34 (m, 6
3
4
0–60 °C).
H, 2 OCH CH ), 2.16 (s, 3 H, CH ), 2.84 (s, 3 H, CH ), 4.25–4.33 (m, 4
2
3
3
3
H, 2 OCH CH ), 7.34–7.37 (m, 2 H, Ph), 7.39–7.42 (m, 1 H, Ph), 7.47–
2
3
General Procedure for the Synthesis of 2,3,5,6-Tetrahydro-1H-
pyrrolo[3,4-c]pyridine-1,3,6-triones 6a–6l in a One-Pot Proce-
dure (Path B): To a magnetically stirred solution of 1,2-diaza-1,3-
dienes 1a–1g (2.1 mmol) and 3-ethyl-, 3-phenyl-, 3-(4-chloro-
phenyl)-, or 3-(4-methoxyphenyl)-2-thioxothiazolidin-4-ones 2a–2d
1
3
7.51 (m, 2 H, Ph), 7.58 (br. s, 1 H, NH), 8.04 (s, 1 H, NH) ppm.
C
NMR (100 MHz, CDCl , 25 °C): δ = 14.3 (q), 14.5 (q), 14.6 (q), 15.6
3
(q), 62.1 (t), 63.6 (t), 105.1 (s), 125.8 (s), 126.5 (d), 128.5 (d), 129.1
(d), 131.2 (s), 136.7 (s), 142.4 (s), 153.6 (s), 155.8 (s), 161.0 (s), 163.4
(
1
s), 164.7 (s) ppm. IR (nujol): ν˜
= 3343, 3239, 1722, 1675,
max
(1.0 mmol) in THF (5 mL) heated at 55 °C in an oil bath, potassium
–
1
+
631 cm . MS (ESI): m/z = 470.15 [M + H ]. C H N O (469.4473):
22 23 5 7
carbonate (5.0 mmol) was added. The flask was kept open to re-
calcd. C 56.29, H 4.94, N 14.92; found C 56.36, H 4.96, N 14.81.
move CS by evaporation. After the disappearance of the reagents
2
(
1.0–5.0 h; TLC monitoring), the K CO was filtered off, the reaction
tert-Butyl 2-(1-{5-[(tert-Butoxycarbonyl)amino]-4-methyl-1,3,6-
2
3
solvent was evaporated under reduced pressure, and the crude mix- trioxo-2-phenyl-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridin-7-
ture was purified by column chromatography with silica gel (cyclo-
yl}ethylidene)hydrazinecarboxylate (6e): Pale yellow powder
hexane/ethyl acetate mixtures) to afford the corresponding 2,3,5,6- (216.2 mg, 41 % yield, Path A; 346.1 mg, 66 % yield, Path B). M.p.
1
tetrahydro-1H-pyrrolo[3,4-c]pyridine-1,3,6-triones 6a–6l, which
were crystallized from diethyl ether/petroleum ether (b.p. 40–60 °C).
220–222 °C (dec.). H NMR (400 MHz, [D
and 1.48 [2 s, 18 H, 2 C(CH ], 2.06 (s, 3 H, CH
.38–7.40 (m, 2 H, Ph), 7.44–7.46 (m, 1 H, Ph), 7.49–7.53 (m, 2 H,
6
]DMSO, 25 °C): δ = 1.45
)
3
), 2.66 (s, 3 H, CH ),
3
3
3
7
Methyl 2-(1-{2-Ethyl-5-[(methoxycarbonyl)amino]-4-methyl-
13
Ph), 9.93 (br. s, 1 H, NH), 10.23 (s, 1 H, NH) ppm. C NMR (100 MHz,
D ]DMSO, 25 °C): δ = 14.0 (q), 16.9 (q), 27.8 (q), 28.0 (q), 79.4 (s),
1.4 (s), 104.2 (s), 125.9 (s), 127.4 (d), 128.3 (d), 128.7 (d), 131.7 (s),
1
,3,6-trioxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridin-7-
yl}ethylidene)hydrazinecarboxylate (6a): Pale yellow powder
149.7 mg, 38 % yield, Path A; 239.8 mg, 61 % yield, Path B). M.p.
[
6
8
1
1
(
35.6 (s), 142.7 (s), 152.4 (s), 152.7 (s), 154.2 (s), 160.0 (s), 163.3 (s),
1
2
7
35–237 °C (dec.). H NMR (400 MHz, CDCl , 25 °C): δ = 1.22 (t, J =
.2 Hz, 3 H, NCH CH ), 2.16 (s, 3 H, CH ), 2.79 (s, 3 H, CH ), 3.68 (q,
–1
3
64.7 (s) ppm. IR (nujol): ν˜
= 3314, 3253, 1725, 1712, 1677 cm .
max
2
3
3
3
+
HRMS (ESI): calcd. for C26H32N O [M + H] 526.2302; found
5
7
J = 7.2 Hz, 2 H, NCH CH ), 3.83 (s, 6 H, 2 OCH ), 7.60 (br. s, 1 H, NH),
+
2
3
3
5
26.2302. MS (ESI): m/z = 524.38 [M – H ]. C H N O (525.5536):
calcd. C 59.42, H 5.95, N 13.33; found C 59.49, H 5.99, N 13.20.
26 31 5 7
1
3
8
.16 (br. s, 1 H, NH) ppm. C NMR (100 MHz, CDCl , 25 °C): δ = 13.4
3
(q), 14.4 (q), 15.6 (q), 33.4 (t), 53.2 (q), 54.2 (q), 105.7 (s), 125.4 (s),
Ethyl 2-(1-{4-Butyl-5-[(ethoxycarbonyl)amino]-1,3,6-trioxo-2-
phenyl-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridin-7-
yl}pentylidene)hydrazinecarboxylate (6f): Pale yellow powder
(350.8 mg, 63 % yield, Path B). M.p. 194–196 °C (dec.). H NMR
400 MHz, CDCl , 25 °C): δ = 0.85–0.98 (m, 8 H, alkyl), 1.24–1.39 (m,
1
37.2 (s), 142.5 (s), 152.2 (s), 156.2 (s), 161.0 (s), 164.0 (s), 165.5 (s)
–
1
ppm. IR (nujol): ν˜
= 3331, 3239, 1753, 1721, 1672 cm . HRMS
max
+
(
(
ESI): calcd. for C H N O [M + H] 394.1363; found 394.1363. MS
ESI): m/z = 394.11 [M + H ]. C H N O (393.1284): calcd. C 48.85,
16 20 5 7
1
+
1
6 19 5 7
(
3
H 4.87, N 17.80; found C 48.94, H 4.85, N 17.68.
8
H, alkyl), 1.56–1.74 (m, 4 H, alkyl), 2.48–2.63 (m, 2 H, alkyl), 2.71–
tert-Butyl 2-(1-{5-[(tert-Butoxycarbonyl)amino]-2-ethyl-4- 3.09 (m, 2 H, alkyl), 4.21–4.32 (m, 4 H, 2 OCH CH ), 7.08 (br. s, 1 H,
2
3
methyl-1,3,6-trioxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]-
pyridin-7-yl}ethylidene)hydrazinecarboxylate (6b): Pale yellow
powder (277.7 mg, 58 % yield, Path B). M.p. 218–220 °C (dec.). H
NH), 7.37–7.41 (m, 3 H, Ph), 7.47–7.50 (m, 2 H, Ph), 8.06 and 8.27 (2
br. s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl , 25 °C): δ = 13.6 (q),
3
1
13.7 (q), 14.3 (q), 14.5 (q), 22.7 (t), 23.0 (t), 27.0 (t), 27.9 (t), 29.7 (t),
30.7 (t), 63.6 (t), 104.7 (s), 126.4 (s), 126.5 (d), 128.5 (d), 129.1 (d),
131.2 (s), 137.5 (s), 139.3 (s), 156.0 (s), 157.6 (s), 161.5 (s), 163.4 (s),
NMR (400 MHz, CDCl , 25 °C): δ = 1.22 (t, J = 7.2 Hz, 3 H, NCH CH ),
3
2
3
1
.50 [s, 18 H, 2 C(CH ) ], 2.13 (s, 3 H, CH ), 2.76 (s, 3 H, CH ), 3.67
3 3 3 3
(
q, J = 7.2 Hz, 2 H, NCH CH ), 7.38 (br. s, 1 H, NH), 7.89 (s, 1 H, NH)
164.5 (s), 165.3 ppm. IR (nujol): ν
= 3348, 3192, 1729, 1721,
2
3
˜
max
13
–1
+
ppm. C NMR (100 MHz, CDCl , 25 °C): δ = 13.4 (q), 14.4 (q), 15.6 1680 cm . MS (ESI): m/z = 552.37 [M – H ]. C H N O (553.6068):
3
28 35 5 7
(q), 28.0 (q), 28.2 (q), 33.3 (t), 81.4 (s), 83.8 (s), 105.1 (s), 125.6 (s),
calcd. C 60.75, H 6.37, N 12.65; found C 60.62, H 6.33, N 12.79.
1
36.7 (s), 141.4 (s), 152.1 (s), 154.5 (s), 160.9 (s), 164.2 (s), 165.7 (s)
Benzyl 2-[1-(5-{[(Benzyloxy)carbonyl]amino}-4-methyl-1,3,6-tri-
oxo-2-phenyl-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridin-7-yl)-
–
1
ppm. IR (nujol): ν˜
= 3358, 3190, 1735, 1718, 1678 cm . MS (ESI):
max
+
m/z = 476.38 [M – H ]. C H N O (477.5108): calcd. C 55.34, H
2
2 31 5 7
ethylidene]hydrazinecarboxylate (6g): Pale yellow powder
6
.54, N 14.67; found C 55.22, H 6.50, N 14.78.
1
(
253.8 mg, 43 % yield, Path B). M.p. 199–201 °C (dec.). H NMR
(
5
400 MHz, CDCl , 25 °C): δ = 2.12 (s, 3 H, CH ), 2.80 (s, 3 H, CH ),
3
3
3
Methyl 2-(1-{5-[(Methoxycarbonyl)amino]-4-methyl-1,3,6-tri-
oxo-2-phenyl-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridin-7-
yl}ethylidene)hydrazinecarboxylate (6c): Pale yellow powder
.22 and 5.25 (2 s, 4 H, 2 OCH Ph), 7.34–7.51 (m, 15 H, 3 Ph), 7.64
2
13
(s, 1 H, NH), 8.12 (s, 1 H, NH) ppm. C NMR (100 MHz, CDCl , 25 °C):
3
δ = 14.6 (q), 14.8 (q), 27.8 (q), 67.8 (T), 69.1 (s), 105.1 (s), 126.4 (s),
126.5 (d), 128.3 (d), 128.5 (d), 128.6 (d), 128.6 (d), 128.7 (d), 128.8
(
(
(
1
2
209.3 mg, 37 % yield, Path A; 340.2 mg, 60 % yield, Path B). M.p.
1
69–172 °C. H NMR (400 MHz, CDCl , 25 °C): δ = 2.16 (s, 3 H, CH ),
3
3
d), 129.1 (d), 129.2 (s), 131.2 (s), 134.7 (s), 136.8 (s), 142.5 (s), 153.5
s), 153.5 (s), 155.5 (s), 160.9 (s), 163.3 (s), 164.6 (s) ppm. IR (nujol):
.83 (s, 3 H, CH ), 3.82 and 3.85 (2 s, 6 H, 2 OCH ), 7.34–7.37 (m, 2
3
3
H, Ph), 7.39–7.43 (m, 1 H, Ph), 7.47–7.51 (m, 2 H, Ph), 7.80 (br. s, 1
–
1
1
3
ν˜max = 3331, 3240, 1738, 1725, 1670 cm . MS (ESI): m/z = 592.12
H, NH), 8.20 (s, 1 H, NH) ppm. C NMR (100 MHz, CDCl , 25 °C): δ =
3
+
[
M + H ]. C H N O (593.5861): calcd. C 64.75, H 4.58, N 11.80;
32 27 5 7
1
4.5 (q), 14.6 (q), 15.5 (q), 15.6 (q), 53.3 (q), 54.1 (q), 54.2 (q), 105.1
found C 64.66, H 4.54, N 11.88.
(
(
ν
˜
s), 125.8 (s), 126.5 (d), 126.6 (d), 129.1 (d), 131.2 (s), 136.7 (s), 142.5
s), 153.5 (s), 156.2 (s), 161.0 (s), 163.3 (s), 164.7 (s) ppm. IR (nujol):
Methyl 2-(1-{2-(4-Chlorophenyl)-5-[(methoxycarbonyl)amino]-
= 3352, 3195, 1738, 1722, 1681 cm . MS (ESI): m/z = 442.27 4-methyl-1,3,6-trioxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]-
–
1
max
Eur. J. Org. Chem. 2017, 6291–6298
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© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
pyridin-7-yl}ethylidene)hydrazinecarboxylate (6h): Pale yellow
powder (220.2 mg, 46 % yield, Path B). M.p. 221–222 °C (dec.). H
25 °C): δ = 1.47 [s, 18 H, 2 C(CH ) ], 2.12 (s, 3 H, CH ), 2.78 (s, 3 H,
3
3
3
1
CH ), 3.81 (s, 3 H, OCH ), 6.97 (d, J = 9.2 Hz, 2 H, Ph), 7.26 (d, J =
3 3
1
3
NMR (400 MHz, CDCl , 25 °C): δ = 2.13 (s, 3 H, CH ), 2.80 (s, 3 H,
9.2 Hz, 2 H, Ph), 7.73 (br. s, 1 H, NH), 7.96 (s, 1 H, NH) ppm. C NMR
3
3
CH ), 3.79 and 3.83 (2 s, 6 H, 2 OCH ), 7.32 (d, J = 8.8 Hz, 2 H, Ph),
(100 MHz, CDCl , 25 °C): δ = 14.4 (q), 15.7 (q), 27.9 (q), 28.2 (q), 55.4
3
3
3
7
.45 (d, J = 8.8 Hz, 2 H, Ph), 8.34 (s, 1 H, NH), 8.61 (br. s, 1 H, NH)
(q), 81.3 (s), 83.4 (s), 104.6 (s), 114.3 (d), 123.9 (s), 125.7 (s), 127.8
13
ppm. C NMR (100 MHz, CDCl , 25 °C): δ = 14.6 (q), 14.7 (q), 15.5 (d), 136.4 (s), 141.8 (s), 152.2 (s), 153.3 (s), 154.5 (s), 159.4 (s), 161.0
3
(
q), 15.6 (q), 53.1 (q), 53.3 (q), 54.1 (q), 54.3 (q), 104.9 (s), 126.0 (s), (s), 163.8 (s), 165.2 (s) ppm. IR (nujol): ν˜
= 3302, 3150, 2982,
max
–
1
+
1
1
3
27.6 (d), 129.3 (d), 129.6 (s), 134.4 (s), 136.5 (s), 142.2 (s), 153.8 (s),
56.2 (s), 160.9 (s), 163.0 (s), 164.4 (s) ppm. IR (nujol): ν = 3325,
1739, 1719, 1709 cm . HRMS (ESI): calcd. for C H N O [M + H]
27 33 5 8
+
556.2407; found 556.2407. MS (ESI): m/z = 554.44 [M – H ].
239, 1752, 1735, 1718, 1670 cm . HRMS (ESI): calcd. for C27H33N O (555.5796): calcd. C 58.37, H 5.99, N 12.61; found C
˜
max
–
1
5
8
+
C H ClN O [M + H] 476.0973; found 476.0973. MS (ESI): m/z =
4
1
58.50, H 6.01, N 12.52.
20
19
5 7
+
76.10 [M + H ]. C H ClN O (475.8392): calcd. C 50.48, H 3.81, N
20 18 5 7
General Procedure for the Synthesis of 7-Acetyl-5-amino-4-
methyl-2-phenyl-1H-pyrrolo[3,4-c]pyridine-1,3,6(2H,5H)-trione
(7a) by Starting from 6e: To a magnetically stirred solution of
6e (1.0 mmol) in acetone/water (4.5:0.5 mL) at room temperature,
Amberlyst 15H (500 mg) was added. After the disappearance of
4.72; found C 50.59, H 3.82, N 14.65.
tert-Butyl 2-(1-{5-[(tert-Butoxycarbonyl)amino]-2-(4-chloro-
phenyl)-4-methyl-1,3,6-trioxo-2,3,5,6-tetrahydro-1H-
pyrrolo[3,4-c]pyridin-7-yl}ethylidene)hydrazinecarboxylate (6i):
Pale yellow powder; (284.8 mg, 51 % yield, Path B). M.p. 171–173 °C product 6e (3.0 h; TLC monitoring), Amberlyst 15H was filtered off,
1
(
2
7
dec.). H NMR (400 MHz, CDCl , 25 °C): δ = 1.49 [s, 18 H, 2 C(CH ) ],
the reaction solvent was evaporated under reduced pressure, and
the crude mixture was purified by column chromatography on silica
gel (cyclohexane/ethyl acetate mixtures) to afford 7a, which was
crystallized from diethyl ether/petroleum ether (b.p. 40–60 °C).
3
3 3
.13 (s, 3 H, CH ), 2.82 (s, 3 H, CH ), 7.33 (d, J = 8.8 Hz, 2 H, Ph),
3 3
.45 (d, J = 8.8 Hz, 2 H, Ph), 7.48 (br. s, 1 H, NH), 7.86 (s, 1 H, NH)
13
ppm. C NMR (100 MHz, CDCl , 25 °C): δ = 14.5 (q), 14.7 (q), 15.5
3
(
q), 15.7 (q), 27.9 (q), 28.0 (q), 28.2 (q), 28.3 (q), 81.5 (s), 83.9 (s),
7
1
-Acetyl-5-amino-4-methyl-2-phenyl-1H-pyrrolo[3,4-c]pyridine-
1
1
1
1
04.4 (s), 126.1 (s), 127.8 (d), 127.8 (d), 129.2 (d), 129.3 (d), 129.8 (d),
34.2 (s), 136.1 (s), 141.7 (s), 152.1 (s), 153.7 (s), 154.4 (s), 160.9 (s),
63.2 (s), 164.6 (s) ppm. IR (nujol): ν˜max = 3328, 3205, 1732, 1718,
,3,6-(2H,5H)-trione (7a): White powder (257.8 mg, 83 % yield).
1
M.p. 171–173 °C. H NMR (400 MHz, CDCl , 25 °C): δ = 2.62 (s, 3 H,
CH ), 2.96 (s, 3 H, CH ), 5.05 (br. s, 2 H, NH ), 7.36–7.51 (m, 5 H, Ph)
ppm. C NMR (100 MHz, CDCl , 25 °C): δ = 15. 1 (q), 31.0 (q), 104.2
3
3
3
2
685 cm–1. MS (ESI): m/z = 558.30 [M – H ]. C26H30ClN O7
+
5
13
3
(559.9987): calcd. C 55.76, H 5.40, N 12.51; found C 55.84, H 5.44, N
(
(
s), 126.4 (d), 128.6 (d), 129.1 (d), 131.7 (s), 131.1 (s), 134.0 (s), 151.4
s), 159.2 (s), 163.5 (s), 164.9 (s), 197.5 (s) ppm. IR (nujol): ν˜
1
2.53.
=
max
–
1
+
Ethyl 2-(1-{2-(4-Chlorophenyl)-5-[(ethoxycarbonyl)amino]-4- 3300, 3201, 1720, 1685, 1615 cm . MS (ESI): m/z = 312.14 [M + H ].
methyl-1,3,6-trioxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]-
pyridin-7-yl}ethylidene)hydrazinecarboxylate (6j): Pale yellow
C H N O (311.2921): calcd. C 61.73, H 4.21, N 13.50; found C
61.85, H 4.25, N 13.39.
16 13 3 4
powder (194.8 mg, 39 % yield, Path A; 293.7 mg, 58 % yield, Path B).
1
M.p. 177–180 °C (dec.). H NMR (400 MHz, CDCl , 25 °C): δ = 1.23–
3
Acknowledgments
1
4
8
.29 (m, 6 H, 2 OCH CH ), 2.13 (s, 3 H, CH ), 2.80 (s, 3 H, CH ), 4.12–
2 3 3 3
.33 (m, 4 H, 2 OCH CH ), 7.32 (d, J = 8.0 Hz, 2 H, Ph), 7.44 (d, J = The authors gratefully acknowledge the financial support from
2
3
.0 Hz, 2 H, Ph), 7.93, 8.03, 8.16 and 8.33 (4 br. s, 2 H, 2 NH) ppm.
the University of Urbino “Carlo Bo”, and the PhD Programmes
of the Ministry of Education of Italy. They also thank Dr. Anna
Maria Gioacchini for her precious help in the execution and
interpretation of HR mass spectra.
1
3
C NMR (100 MHz, CDCl , 25 °C): δ = 14. 1 (q), 14.3 (q), 14.5 (q),
3
1
1
1
1
4.7 (q), 60.4 (t), 63.5 (t), 104.8 (s), 126.0 (s), 127.8 (d), 129.3 (d),
29.8 (s), 134.3 (s), 136.4 (s), 142.6 (s), 153.9 (s), 155.8 (s), 158.8 (s),
61.0 (s), 163.2 (s), 164.5 (s) ppm. IR (nujol): ν
= 3325, 3200, 1731,
˜
max
–1
+
714, 1680 cm . MS (ESI): m/z = 502.76 [M – H ]. C H ClN O
2
2
22
5 7
(
503.8924): calcd. C 52.44, H 4.40, N 13.90; found C 52.51, H 4.38, N Keywords: Heterocycles · Hydrazones · Michael addition ·
1
4.01.
Domino reactions · Ring opening · Ring closing
Ethyl 2-(1-{5-[(Ethoxycarbonyl)amino]-2-(4-methoxyphenyl)-4-
methyl-1,3,6-trioxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyr-
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idin-7-yl}ethylidene)hydrazinecarboxylate (6k): Pale yellow oil;
1
(
295.4 mg, 59 % yield, Path B). H NMR (400 MHz, CDCl , 25 °C): δ =
3
1
.26 (q, J = 7.2 Hz, 6 H, 2 OCH CH ), 2.12 (s, 3 H, CH ), 2.78 (s, 3 H,
[2] a) L. J. Sebren, J. J. Deverey III, C. R. J. Stephenson, ACS Catal. 2014, 4,
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3
CH ), 3.81 (s, 3 H, OCH ), 4.22–4.28 (m, 4 H, 2 OCH CH ), 6.97 (d, J =
8
8
3
3
2
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1
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.30 (s, 1 H, NH) ppm. C NMR (100 MHz, CDCl , 25 °C): δ = 14. 2
3
(
(
(
q), 14.4 (q), 14.4 (q), 15.6 (q), 60.4 (t), 55.4 (q), 60.3 (t), 63.3 (t), 105.0
s), 114.4 (d), 123.8 (s), 125.8 (s), 127.8 (d), 136.6 (s), 142.7 (s), 153.4
s), 155.7 (s), 159.4 (s), 161.0 (s), 163.6 (s), 165.0 (s) ppm. IR (nujol):
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1
ν˜
= 3305, 3148, 1737, 1720, 1701 cm . MS (ESI): m/z = 498.44
max
+
[
M – H ]. C H N O (499.4733): calcd. C 55.31, H 5.05, N 14.02;
23 25 5 8
found C 55.22, H 5.03, N 14.11.
tert-Butyl 2-(1-{5-[(tert-Butoxycarbonyl)amino]-2-(4-methoxy-
phenyl)-4-methyl-1,3,6-trioxo-2,3,5,6-tetrahydro-1H-
pyrrolo[3,4-c]pyridin-7-yl}ethylidene)hydrazinecarboxylate (6l):
Pale yellow solid; (338.9 mg, 61 % yield, Path A; 355.1 mg, 64 %
1
yield, Path B). M.p. 171–173 °C (dec.). H NMR (400 MHz, CDCl3,
Eur. J. Org. Chem. 2017, 6291–6298
www.eurjoc.org
6297
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Received: August 4, 2017
Eur. J. Org. Chem. 2017, 6291–6298
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6298
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim