Synthesis of functionalized β-lactams and pyrrolidine-2,5-diones through a metal-free sequential ugi-4CR/cyclization reaction

Article abstract of DOI:10.1021/jo5010422

An efficient approach for the synthesis of functionalized β-lactams and pyrrolidine-2,5-diones was achieved through a sequential Ugi-4CR/cyclization reaction. Diversity-oriented synthesis, good to high yields, easy workup, and short reaction times are advantages of this procedure.

Full text of DOI:10.1021/jo5010422

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Article
Synthesis of functionalized #-lactams and pyrrolidine-2, 5-
diones through Metal-free sequential Ugi-4CR/ cyclization
Elmira Ghabraie, Saeed Balalaie, Saber Mehrparvar, and Frank Rominger
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5010422 • Publication Date (Web): 08 Aug 2014
Downloaded from http://pubs.acs.org on August 12, 2014
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Synthesis of functionalized β-lactams and pyrrolidine-2, 5-diones through Metal-free
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sequential Ugi-4CR/ cyclization
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Elmira Ghabraie†, Saeed Balalaie*†‡, Saber Mehrparvar†, Frank Rominger┴
†Peptide Chemistry Research Center, K. N. Toosi University of Technology, P. O. Box 15875-
4416 Tehran, Iran, balalaie@kntu.ac.ir
‡Medical Biology Research Center, Kermanshah University of Medical Sciences,
Kermanshah, Iran
┴Organisch-Chemisches Institut der Universitaet Heidelberg, Im Neuenheimer Feld 270,
69120 Heidelberg, Germany
Abstract:
An efficient approach for the synthesis of functionalized β-lactams and pyrrolidine-2,5-
diones was achieved through sequential Ugi-4CR/cyclization reaction. Diversity-oriented
synthesis, good to high yields, easy work-up and short reaction times are advantages of this
procedure.
Keywords: Sequential Ugi-4CR/ cyclization, Ugi post-transformation, β-lactams,
pyrrolidine-2, 5-diones, Metal-free reaction
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Introduction
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Synthesis of molecules with high diversity and complexity using readily available starting
materials is an interesting approach in combinatorial chemistry and drug discovery. In this
regard, combining the multicomponent reactions (MCRs) with post MCR transformation has
been used as an efficient method for the synthesis of highly functionalized compounds.1
Among these sequential reactions, Ugi-4CR/post transformation is the most powerful
approach for the synthesis of polyfunctional compounds.2
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N-substituted-2-alkynamides have proved to be valuable building blocks in organic
synthesis.3 In recent years, some functionalized N-substituted-2-alkynamides were
synthesized through Ugi-4CR in our research group. These compounds were used for further
post-transformation reactions such as nucleophilic addition or cyclization using suitable
starting materials and palladium catalysts.4 Recently, Van der Eycken used these starting
materials to construct heterocyclic skeletons in the presence of different gold catalysts.5
Meanwhile
,
palladium catalyst was used for the transition-metal catalyzed
cycloisomerization of alkynyl N-acyl enamines to access lactams.6 Zhang et al. reported a
highly enantioselective cycloisomerization approach to access functionalized lactams using
Rh based catalysts. 7 Due to the biological activities of lactams,8 finding the new method that
allows formation of C-N bond and stereoselective generation of functionalized lactams is an
interesting subject in organic synthesis. In all the reported cyclization reactions with these
starting materials, use of a metal catalyst is necessary. But, development of metal-free
approach is an interesting challenge in organic synthesis.9 Ugi/post-transformation has been
reported for the for the synthesis of β-lactams, but the using of functionalized starting
materials has an important role in cyclization reaction process.10
In continuation of our previous research works based on the cyclization reactions of
functionalized N-substituted-2-alkynamides,4 we were encouraged to investigate the
cyclization products through these compounds in metal-free reaction conditions. Herein, we
report a metal-free cyclization through sequential Ugi-4CR/cyclization reaction for the
synthesis of functionalized β-lactams and pyrrolidine-2,5-diones.
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Scheme 1. Synthesis of β-lactams and pyrrolidine-2, 5-diones through metal-free sequential
Ugi-4CR/ cyclization
Results and Discussion
In the first step, Ugi-4CR of benzaldehyde, aniline, tert-butyl isocyanide and phenyl propiolic
acid was chosen as the model reaction. The N-substituted 2-alkynamide 5a was precipitated
and separated, followed by the treatment with different bases and solvents. During the
optimization of the reaction conditions, it was revealed that potassium carbonate (K2CO3)
was the most effective base to provide cyclization products compared to other bases. (Table
1, entries 8-11) Carrying out the reaction in acetonitrile led to the synthesis of β-lactam 6a
and in methanol the sole product was pyrrolidine-2,5-dione 7a. (Table 1) With our optimized
reaction conditions in hand, carrying out the reaction in DMF led to a mixture of two
products 6a and 7a (75:25), respectively.
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Table 1. Optimization of reaction conditions for the synthesis of β-lactam 6a and pyrrolidine-
2,5-dione 7a.
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Entry base
solvent T (°C)
6a (%) 7a (%)
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K2CO3 CH2Cl2 Rt
K2CO3 MeCN 80
-
-
2
95
75
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K2CO3 DMF
K2CO3 THF
K2CO3 H2O
120
25
-
4
Reflux -
Reflux -
5
-
6
K2CO3 Toluene Reflux -
K2CO3 MeOH Reflux -
Cs2CO3 MeOH Reflux -
CsOAc MeOH Reflux -
-
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94
54
-
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10
11
Et3N
MeOH Reflux trace
MeOH Reflux 10
-
DIEA
-
The reaction was performed using 1a (1 mmol), 2a (1 mmol),
3a (1 mmol), 4a (1 mmol), the base (1 eq) and 5 ml of solvent.
On the basis of this information and in order to explore the above reaction scope, different
aldehydes, anilines and isocyanides were used as starting materials. In all cases, the β-lactam
skeleton with some functional groups was produced in good to high yields. The results are
summarized in table 2. The products with β-lactam skeleton (6a-n) were obtained in 63-95%
yields. The lowest yield (63%) was obtained for compound 6g which trifluoromethyl
benzaldehyde was used as aldehyde and cyclohexyl isocyanide as isocyanide. A significant
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point in formation of β-lactams is the E-geometry for double bond in all cases. It seems that
the secondary interaction (π- π stacking) could affect the geometry of formed β-lactams.
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Table 2. Synthesis of functionalized β-lactams 6(a-n) through sequential Ugi 4-CR/cyclization
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6c (89%)
6f (64%)
6a (94%)
6d (82%)
6b (74%)
6e (66%)
6h (90%)
6g (63%)
6i (95%)
6l (83%)
6k (94%)
6n (87%)
6j(80%)
6m (89%)
X-ray crystallographic data could confirm the structure. Double bond has E configuration and
orientation of two aryl group has a suitable condition for π-π stacking. (Figure 1)
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Figure 1. ORTEP structure of compound 6i
After finding the best reaction condition in hand, we screened a range of N-substituted-2-
alkynamides in one-pot sequential Ugi-4CR/intramolecular nucleophilic cyclization in
methanol. The results are summarized in table 3. The obtained products were pyrrolidine-2,5-
diones with regioselectivity 7a-o and the double bond in the structure of products had E
configuration. The progress of reactions were monitored by TLC, and comparison of data
showed that the pyrrolidine-2,5-dione 7a was produced through β-lactam intermediate in high
yield.
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Table 3. Synthesis of pyrrolidine-2,5-dione derivatives
4CR/Cyclization via β-lactam 6 intermediate
7(a-o) through sequential Ugi
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7a (94%)
7d (97%)
7b (91%)
7e (86%)
7c (84%)
7f (83%)
7i (88%)
7l (72%)
7o (74%)
7h (68%)
7k (82%)
7g (90%)
7j (76%)
7m (81%)
7n (83%)
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The structures of 6(a-n) and 7(a-o) were assigned by H-NMR and C-NMR spectroscopy
and also proved by ESI-HRMS. There are two prominent differences in the NMR spectra of
these two sets of compounds. The first one is the highly characteristic peak at 4-5 ppm for
NH in pyrrolidine-2,5-dione which was not observed in β-lactam derivatives. The second one
is the difference in the chemical shift of carbonyl amide in β-lactam (162-166 ppm) and
pyrrolidine-2,5-dione (170-176 ppm). For two compounds 7b and 7d the ORTEP structure
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could confirm the products. (Supporting information) The H-1H-COSY 2D NMR was used
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for determining of the structure of compounds. The 2D H NMR of the compounds 6n and
7m were provided as attachment in supporting information section.
In another try, the reaction was investigated using propiolic acid instead of phenyl propiolic
acid. In this case, the intermediate 8 could not convert to the desired pyrrolidine-2,5-dione
and MeOH was added to the triple bond.
Scheme 2. Nucleophilic addition of methanol to N-substituted-2-alkynamide 8 and formation of
unexpected product 9
The same reaction was also checked with 2-butyn-oic acid and trimethylsilyl propiolic acid in
methanol and the desired products were not formed. The structure of product was confirmed
based on the NMR spectra. According to the NMR data, when 2-butyn-oic acid was used the
reaction in methanol led to the methyl ether. The Ugi-4CR was carried out using
trimethylsily propiolic acid and its reaction was studied in methanol in the presence of
potassium carbonate which led to the acetal 9 with the elimination of trimethylsilyl group.
In the structure of functionalized N-substituted 2-alkynamides 5, there are two amide
moieties, triple bond and also a C-H bond. The C-H bond has an acidic character which could
be deprotonated using a suitable base and form the carbanion which in turn could be added to
the triple bond through intramolecular nucleophilic addition. A plausible mechanism for these
cyclization reactions is depicted in scheme 3. The reactions proceed via the formation of
intermediate 5 through Ugi-4CR. There are two feasible pathways from 5 in different
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solvents. Initially, the carbanion is formed by the addition of the base. (Scheme 3) It is
reasonable to assume that the intramolecular nucleophilic addition of carbanion to triple bond
in Ugi product 5, form the β- lactam skeleton in both solvents. But, it can act as an
intermediate in MeOH and the attack of methoxide to the carbonyl group in β- lactam
skeleton takes place immediately from the one direction to afford the pyrrolidine-2,5-dione
with regioselectivity.
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Scheme 3. Plausible mechanism for the formation of β- lactam 6(a-n) and pyrrolidine-2,5-
dione 7(a-o) in methanol.
Formation of different products in various solvents, could be attributed this observation to the
basicity of K2CO3 in MeCN and MeOH. Potassium carbonate in MeCN could deprotonate the
acidic C(sp3)-H in Ugi product, but in MeOH, methoxide anion is produced which is stronger
nucleophile than K2CO3 and in addition to the deprotonating of C-H, it can activate the NH
amide and so the second cyclization occurs.
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In conclusion, we have developed a novel and efficient method for the synthesis of two
distinct sets of functionalized β-lactams and pyrrolidine-2,5-dione from the same Ugi adducts
5 involving Ugi-4CR/cyclization sequence in metal-free reaction conditions. Good to
excellent yields, short reaction times, easy work-up, and high bond forming efficiency, atom
economy and application of this approach in combinatorial chemistry are the advantages of
this approach.
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Experimental Section
General information
High resolution mass spectra were recorded on Mass-ESI-POS and Mass-ESI-NEG (FT-ICR)
spectrometer.
General procedure for the synthesis of polysubstituted β-lactams (6a-n) through
sequential Ugi-4CR/ cyclization
To a solution of aldehyde 1(1 mmol) in MeOH (5 ml) was added aniline as a primary amine 2
(1 mmol), and the reaction mixture was stirred at room temperature (25°C) for 1 h. Then
phenyl acetylene carboxylic acid 3 (1 mmol) was added and stirring was continued for 15
min, followed by addition of isocyanid 4 (1 mmol). The mixture was stirred for 24 h. The
progress of the reaction was monitored using TLC (petroleum ether/ EtOAc 3:1). After
completion of reaction, the N-substituted-2-alkynamides 5 was precipitated, separated and
was transferred to a flask which contained 10 ml MeCN. Then K2CO3 (1 eq) was added to the
mixture and the mixture was heated under reflux condition for 1-2 h. The progress of reaction
was monitored using TLC (hexane/ EtOAc 4:1). After cooling to room temperature the
desired product was precipitated, the yellowish sediment was filtered.
(E)-3-benzylidene-N-(tert-butyl)-4-oxo-1,2-diphenylazetidine-2-carboxamide (6a):
1
White powder; 385 mg(94%), m.p.: 172-173 °C; IR (KBr, cm-1): υ =1670, 1749, 3343; H
NMR (CDCl3,300 MHz): δ(ppm) = 1.22 (s, 9H, t-Bu), 6.09 (s, 1H, NH), 7.03 (td, J = 7.4, 0.9
Hz, 1H, H-Ar), 7.20-7.39 (m, 11H, H-Ar, C=CH), 7.52 (d, J = 8.1 Hz, 2H, H-Ar), 7.65 (dd, J
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= 7.2, 1.1 Hz, 2H, H-Ar); C NMR (CDCl3, 75 MHz): δ(ppm) = 28.3, 52.0, 76.6, 118.3,
124.5, 126.5, 128.3, 128.7, 128.9, 128.9, 129.1, 130.2, 130.6, 131.9, 134.8, 136.7, 141.0,
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163.0, 166.2; Mass: HR-MS (ESI-POS) = Calc. for C27H27N2O2 [M+H]+ 411.20676, Found
411.20670. Calc. for C27H26N2NaO2 [M+Na]+ 433.18871, Found 433.18865.
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(E)-3-benzylidene-N-(tert-butyl)-2-(3-nitrophenyl)-4-oxo-1-phenylazetidine-2-
carboxamide(6b):
White powder; 337 mg(74%), m.p.: 182-184 °C; IR (KBr, cm-1): υ = 1673, 1740, 3383; H
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NMR (CDCl3, 300 MHz): δ(ppm) = 1.30 (s, 9H, t-Bu), 6.34 (s, 1H, NH), 7.08 (t, J = 7.3 Hz,
1H, H-Ar), 7.25-7.54 (m, 10H, H-Ar, C=CH), 7.97 (d , J = 7.8 Hz, 1H, H-Ar), 8.14 (d, J = 8.2
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Hz, 1H, H-Ar), 8.60 (s, 1H, H-Ar); C NMR (CDCl3, 75 MHz): δ(ppm) = 28.4, 52.5, 74.6,
118.0, 123.9, 125.1, 128.1, 128.9, 129.4, 129.7, 130.7, 130.8, 131.1, 134.4, 136.0, 136.6,
139.6, 148.3, 162.5, 165.5; Mass: HR-MS (ESI-POS) = Calc. for C27H26N3O4 [M+H]+
456.19182, Found 456.1917 Calc. C27H25N3NaO4 [M+Na]+ 478.17377, Found 478.17373
(E)-3-benzylidene-N-(tert-butyl)-4-oxo-1-phenyl-2-(pyridin-3-yl)azetidine-2-
carboxamide (6c):
White powder; 366 mg(89%), m.p.: 161-162 °C; IR (KBr, cm-1): υ = 1675, 1744, 3339; H
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NMR (CDCl3, 300 MHz): δ(ppm) = 1.27 (s, 9H, t-Bu), 6.25 (s, 1H, NH), 7.07 (t, J = 7.4 Hz,
1H, H-Ar), 7.21-7.37 (m, 7H, H-Ar, C=CH), 7.44 (d, J = 6.5 Hz, 2H, H-Ar), 7.47 (d, J = 8.2
Hz, 2H, H-Ar), 7.95 (d, J = 9.3 Hz, 1H, H-Ar), 8.53 (d, J = 4.7 Hz, 1H, H-Ar), 8.93 (s, 1H,
13
H-Ar); C NMR (CDCl3, 75 MHz): δ(ppm) = 28.3, 52.3, 74.3, 118.1, 123.3, 125.0, 127.8,
128.8, 129.2, 130.4, 130.6, 130.7,131.3, 136.1, 136.2, 139.6, 149.9, 150.0, 162.6, 165.6;
Mass: HR-MS (ESI-POS) = Calc. for C26H26N3O2 [M+H]+ 412.20195, Found 412.20195.
Calc. C26H25N3NaO2 [M+Na]+ 434.18391, Found 434.18390.
(E)-3-benzylidene-N-(tert-butyl)-4-oxo-1-phenyl-2-(4-(trifluoromethyl)phenyl)azetidine-
2-carboxamide (6d):
White powder; 392 mg(82%), m.p.: 164-166 °C; IR (KBr, cm-1): υ = 1670, 1751, 3349; H
1
NMR (CDCl3, 300 MHz): δ(ppm) = 1.27 (s, 9H, t-Bu), 6.23 (s, 1H, NH), 7.08 (t, J = 7.1 Hz,
1H, H-Ar), 7.24-7.34 (m, 6H, H-Ar, C=CH), 7.41 (d , J = 6.7 Hz, 2H, H-Ar), 7.48 (d, J = 8.4
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Hz, 2H, H-Ar), 7.59 (d, J = 8.2 Hz, 2H, H-Ar), 7.80 (d, J = 8.2 Hz, 2H, H-Ar); C NMR
(CDCl3, 75 MHz): δ(ppm) = 28.3, 52.3, 75.4, 118.1, 124.9, 125.7, 127.5, 128.8, 128.9, 129.2,
130.6, 130.7, 131.2, 131.3, 136.2, 138.5, 140.0, 162.7, 165.7;Mass: HR-MS (ESI-POS) =
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Calc. for C28H26F3N2O2 [M+H]+ 479.19417, Found 479.19409. Calc. C28H25F3N2NaO2
[M+Na]+ 501.17613, Found 501.17603.
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(E)-3-benzylidene-N-(tert-butyl)-2-(4-cyanophenyl)-4-oxo-1-phenylazetidine-2-
carboxamide (6e):
White powder; 287 mg(66%), m.p.: 182-184 °C; IR (KBr, cm-1): υ = 1670, 1751, 3349; H
1
NMR (CDCl3,300 MHz): δ(ppm) = 1.27 (s, 9H, t-Bu), 6.25 (s, 1H, NH), 7.09 (t, J = 7.4 Hz,
1H, H-Ar), 7.24-7.35 (m, 6H, H-Ar, C=CH), 7.42 (t , J = 7.7 Hz, 4H, H-Ar), 7.61 (d, J = 7.4
Hz, 2H, H-Ar), 7.79 (d, J = 8.4 Hz, 2H, H-Ar); 13C NMR (CDCl3, 75 MHz): δ(ppm) = 28.3,
52.4, 75.0, 112.8, 118.0, 118.2, 125.1, 127.9, 128.8, 129.3, 130.7, 130.8, 131.1, 132.4, 136.0,
139.6, 139.7, 162.6, 165.4; Mass: HR-MS (ESI-POS) = Calc. for C28H26N3O2 [M+H]+
436.20202, Found 436.20195. Calc. C28H25N3NaO2 [M+Na]+ 458.18398, Found 458.18390.
(E)-3-benzylidene-N-(tert-butyl)-4-oxo-1-phenyl-2-(pyridin-2-yl)azetidine-2-
carboxamide (6f):
White powder; 263 mg(64%), m.p.: 159-161 °C; IR (KBr, cm-1): υ = 1673, 1755, 3214, 3429;
1H NMR (CDCl3, 300 MHz): δ(ppm) = 1.35 (s, 9H, t-Bu), 7.02 (t, J = 7.4 Hz, 1H, H-Ar),
7.13 (s, 1H, NH), 7.21-7.69 (m, 12H, H-Ar, H-pyrid, C=CH), 8.63 (d, J = 4.7 Hz, 1H, H-Ar),
13
9.67 (s, 1H, H-Ar); C NMR (CDCl3, 75 MHz): δ(ppm) = 28.5, 51.8, 73.2, 117.3, 123.4,
123.5, 124.1, 125.6, 128.4, 129.0, 129.8, 130.3, 132.1, 137.0, 138.2, 142.1, 147.7, 156.1,
162.7, 165.0; Mass: HR-MS (ESI-POS) = Calc. for C26H26N3O2 [M+H]+ 412.20195, Found
412.20195. Calc. for C26H25N3NaO2 [M+Na]+ 434.18393, Found 434.18390. Calc. for
C26H25KN3O2 [M+K]+ 450.15787, Found 450.15784.
(E)-3-benzylidene-N-cyclohexyl-4-oxo-1-phenyl-2-(4-(trifluoromethyl)phenyl)azetidine-
2-carboxamide (6g):
White powder; 317 mg(63%), m.p.: 166-168 °C; IR (KBr, cm-1): υ = 1668, 1750, 3342; H
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NMR (CDCl3, 300 MHz): δ(ppm) = 1.00-1.88 (m, 10H, H-cyclohexyl), 3.85-3.95 (m, 1H, N-
CH), 6.34 (d, J = 7.5, 1H, NH), 7.08 (t, J = 7.3 Hz, 1H, H-Ar), 7.24-7.46 (m, 10H, H-Ar,
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C=CH), 7.58 (d, J = 8.2 Hz, 2H, H-Ar), 7.83 (d , J = 8.1 Hz, 2H, H-Ar); C NMR (CDCl3,
75 MHz): δ(ppm) = 24.5, 25.2, 32.4, 32.6, 48.9, 74.9, 118.0, 124.9, 125.5, 125.7, 127.9,
128.7, 128.9, 129.3, 130.7, 130.9, 131.2, 136.1, 138.2, 139.6, 162.8, 165.5; Mass: HR -MS
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(ESI-POS) = Calc. for C30H28F3N2O2 [M+H]+ 505.20978, Found 505.20974. Calc. for
C30H27F3N2NaO2 [M+Na]+ 527.19168, Found 527.19168. Calc. for C30H27F3KN2O2 [M+K]+
543.16567, Found 543.16562.
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(E)-3-benzylidene-N-(tert-butyl)-4-oxo-1-phenyl-2-(thiophen-2-yl)azetidine-2-
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carboxamide (6h):
Yellow powder; 374 mg(90%), m.p.: 174-176 °C; IR (KBr, cm-1): υ = 1670, 1749, 3338; H
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NMR (CDCl3, 300 MHz): δ(ppm) = 1.24 (s, 9H, t-Bu), 6.23 (s, 1H, NH), 6.92 (t, J = 4.6 Hz,
1H, H-thienyl), 7.08 (t, J = 7.5 Hz, 1H, H-Ar), 7.18 (s, 1H, =CH), 7.26-7.53 (m, 11H, H-Ar,
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H-thienyl); C NMR (CDCl3, 75 MHz): δ(ppm) = 28.2, 52.2, 72.2, 117.9, 124.7, 126.6,
126.8, 128.2, 128.7, 128.8, 129.1, 130.4, 130.9, 131.5, 136.2, 136.3, 141.3, 162.6, 166.1;
Mass: HR-MS (ESI-POS) = Calc. for C25H25N2O2S [M+H]+ 417.16319, Found 417.16313.
Calc. C25H24N2NaO2S [M+Na]+ 439.14515, Found 439.14507.
(E)-3-benzylidene-N-(tert-butyl)-2-(4-chlorophenyl)-4-oxo-1-phenylazetidine-2-
carboxamide (6i):
White powder; 422 mg(95%), m.p.: 184-185 °C; IR (KBr, cm-1): υ = 1671, 1747, 3341,3341;
1H NMR (CDCl3, 300 MHz): δ(ppm) = 1.24 (s, 9H, t-Bu), 6.17 (s, 1H, NH), 7.06 (t, J = 7.0
Hz, 1H, H-Ar), 7.21-7.35 (m, 8H, H-Ar, C=CH), 7.41 (d, J = 6.8 Hz, 2H, H-Ar), 7.48 (d, J =
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7.9 Hz, 2H, H-Ar), 7.61 (d, J = 8.4 Hz, 2H, H-Ar); C NMR (CDCl3, 75 MHz): δ(ppm) =
28.3, 52.2, 75.6, 118.2, 124.8, 127.1, 128.8, 129.0, 129.1, 129.8, 130.5, 130.7, 131.5, 133.1,
135.0, 136.3, 140.4, 162.8, 165.8; Mass: HR-MS (ESI-POS) = Calc. for C27H26ClN2O2
[M+H]+ 445.16781, Found 445.16773. Calc. C27H25ClN2NaO2 [M+Na]+ 467.14977, Found
467.14968. colourless crystal (polyhedron), dimensions 0.170 x 0.110 x 0.110 mm3, crystal
system monoclinic, space group C2/c, Z=8, a=25.069(3) Å, b=10.0489(12) Å, c=20.245(2)
Å, alpha=90 deg, beta=110.317(2) deg, gamma=90 deg, V=4782.8(10) Å3, rho=1.236 g/cm3,
T=200(2) K, Thetamax= 25.027 deg, radiation Mo Kalpha, lambda=0.71073 Å, 0.5 deg
omega-scans with CCD area detector, covering the asymmetric unit in reciprocal space with a
mean redundancy of 10.42and a completeness of 99.9% to a resolution of 0.84Å, 44807
reflections measured, 4210 unique (R(int)=0.0469), 3255 observed (I > 2σ (I)), intensities
were corrected for Lorentz and polarization effects, an empirical absorption correction was
applied using SADABS based on the Laue symmetry of the reciprocal space, mu=0.19mm-1,
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Tmin=0.90, Tmax=0.99, structure refined against F2 with a Full-matrix least-squares algorithm
using the SHELXL (Version 2014-1) software, 407 parameters refined, hydrogen atoms were
treated using appropriate riding models, goodness of fit 1.14 for observed reflections, final
residual values R1(F)=0.057, wR(F2)=0.133 for observed reflections, residual electron
density -0.23 to 0.24 eÅ-3. CCDC 991555 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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(E)-3-benzylidene-N-(tert-butyl)-4-oxo-1-phenyl-2-(3,4,5-trimethoxyphenyl)azetidine-2-
carboxamide (6j):
White powder; 400 mg(80%), m.p.: 136-138 °C; IR (KBr, cm-1): υ = 3368, 3327, 1740, 1673;
1H NMR (CDCl3, 300 MHz): δ(ppm) = 1.19 (s, 9H, t-Bu), 3.70 (s, 6H, OMe), 3.83 (s, 3H,
OMe), 6.04 (s, 1H, NH), 6.82 (s, 2H, H-Ar), 7.06 (t, J = 7.3 Hz, 1H, H-Ar), 7.23-7.38 (m, 8H,
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H-Ar, C=CH), 7.54 (d, J = 8.2 Hz, 2H, H-Ar); C NMR (CDCl3, 75 MHz): δ(ppm) = 28.2,
52.0, 56.1, 60.9, 105.4, 118.4, 124.7, 126.3, 128.8, 128.9, 130.2, 130.4, 132.1, 136.8, 138.4,
141.2, 153.3, 162.8, 166.4; Mass: HR-MS (ESI-POS) = Calc. for C30H33N2O5 [M+H]+
501.23807, Found 501.23807. Calc. C30H32N2NaO5 [M+Na]+ 523.22021., Found 523.22023.
Calc. C30H32KN2O5 [M+K]+ 539.19422, Found 539.19423.
(E)-3-benzylidene-1-(4-bromophenyl)-N-(tert-butyl)-4-oxo-2-phenylazetidine-2-
carboxamide (6k):
1
White powder; 464 mg(95%), m.p.: 212-214 °C; IR (KBr, cm-1): υ = 3337, 1750, 1674; H
NMR (CDCl3,300 MHz): δ(ppm) = 1.19 (s, 9H, t-Bu), 6.00 (s, 1H, NH), 7.26-7.30 (m, 6H,
H-Ar, -C=CH), 7.32-7.33 (m, 2H, H-Ar), 7.36-7.41 (m, 3H, H-Ar), 7.43-7.47 (m, 2H, H-Ar),
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7.59-7.63 (m, 2H, H-Ar); C NMR (CDCl3, 75 MHz): δ(ppm) = 28.3, 52.1, 76.8, 117.2,
119.9, 126.6, 128.0, 128.9, 129.2, 129.4, 130.3, 130.4, 131.8, 134.8, 135.9, 141.3, 162.6,
165.9; Mass: HR-MS (ESI-POS) = Calc. for C27H2679BrN2O2 [M+H]+ 489.11721, Found
489.11721.
(E)-3-benzylidene-N-cyclohexyl-4-oxo-1-phenyl-2-(p-tolyl)azetidine-2-carboxamide (6l):
1
White powder; 373 mg(83%), m.p.: 154-156 °C; IR (KBr, cm-1): υ = 3337, 1746, 1670; H
NMR (CDCl3,300 MHz): δ(ppm) = 0.95-1.07 (m, 3H, H-cyclohexyl), 1.25-1.32 (m, 2H, H-
cyclohexyl), 1.50-1.52 (m, 3H, H-Ar), 1.75-1.84 (m, 2H, H-Ar), 2.30 (s, 1H, -Me), 3.83-3.92
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(m, 1H, CH- cyclohexyl), 6.19 (d, J = 7.8, Hz, 1H, NH), 7.03 (t, J = 7.4 Hz, 1H, H-Ar), 7.14
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(d, J = 8.1 Hz, 2H, H-Ar), 7.21-7.31 (m, 6H, H-Ar, C=CH), 7.44-7.56 (m, 6H, H-Ar); C
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NMR (CDCl3, 75 MHz): δ(ppm) = 21.2, 24.4, 25.3, 32.3, 32.6, 48.6, 76.1, 118.2, 124.5,
126.9, 128.2, 128.6, 129.0, 129.6, 130.2, 130.9, 131.2, 131.7, 136.6, 139.0, 140.5, 163.2,
166.2; Mass: HR-MS (ESI-POS) = Calc. for C30H31N2O2 [M+H]+ 451.23834, Found
451.23828. Calc. C30H30N2NaO2 [M+Na]+ 473.22036, Found 473.22029. Calc. C30H30KN2O2
[M+K]+ 489.19436, Found 489.19428.
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(E)-3-benzylidene-N-cyclohexyl-4-oxo-1,2-diphenylazetidine-2-carboxamide (6m):
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Yellow powder; 388 mg(89%), m.p.: 150-152 °C; IR (KBr, cm-1): υ = 3358, 1737, 1669; H
NMR (CDCl3,300 MHz): δ(ppm) = 0.87-1.12 (m, 3H, H-cyclohexyl), 1.27-1.36 (m, 2H, H-
cyclohexyl), 1.51-1.53 (m, 3H, H-cyclohexyl), 1.78-1.86 (m, 2H, H-cyclohexyl), 3.83-3.95
(m, 1H, CH- cyclohexyl), 6.24 (d, J = 7.7, Hz, 1H, NH), 7.04 (t, J = 7.0 Hz, 1H, H-Ar), 7.18-
7.29 (m, 6H, H-Ar), 7.31-7.38 (m, 3H, H-Ar, C=CH), 7.40 (d, J = 7.7 Hz, 2H, H-Ar), 7.49 (d,
J = 8.4 Hz, 2H, H-Ar), 7.67 (d, J = 7.1 Hz, 2H, H-Ar); 13C NMR (CDCl3, 75 MHz): δ(ppm) =
24.4, 25.3, 32.3, 32.6, 48.7, 76.1, 115.4, 118.2, 124.6, 127.2, 128.3, 128.6, 128.9, 129.0,
129.1, 129.5, 130.3, 130.9, 131.6, 134.3, 136.5, 140.3, 163.1, 166.1; Mass: HR-MS (ESI-
POS) = Calc. for C29H29N2O2 [M+H]+ 437.22209, Found 437.22214. Calc. C29H28N2NaO2
[M+Na] + 459.20408, Found 459.20412. Calc. C29H28KN2O2 [M+K]+ 475.17806, Found
475.17809.
(E)-3-benzylidene-N-(tert-butyl)-1-(4-isopropylphenyl)-4-oxo-2-phenylazetidine-2-
carboxamide (6n):
1
White powder; 393 mg(87%), m.p.: 162-164 °C; IR (KBr, cm-1): υ = 3351, 1740, 1670; H
NMR (CDCl3,300 MHz): 1.17 (d, J = 6.9 Hz, 6H, -CH3), 1.22 (s, 9H, t-Bu), 2.78-2.83 (m,
1H, -CH), 6.09 (s, 1H, NH), 7.08 (d, J = 8.5 Hz, 2H, H-Ar), 7.23-7.29 (m, 4H, H-Ar), 7.30-
7.39 (m, 5H, H-Ar, C=CH), 7.42 (d, J = 8.5 Hz, 2H, H-Ar), 7.65 (d, , J = 6.2 Hz, 2H, H-Ar);
13C NMR (CDCl3, 75 MHz): δ(ppm) = 23.8, 23.9 28.3, 33.6, 52.0, 118.4, 126.1, 126.9, 128.3,
128.7, 128.9, 129.0, 130.1, 130.5, 131.9, 134.4, 135.0, 141.1, 145.2, 162.8, 166.3; Mass: HR-
MS (ESI-POS) = Calc. for C30H33N2O2 [M+H]+ 453.25344, Found 453.25348. Calc.
C30H32N2NaO2 [M+Na]+ 475.23552, Found 475.23553. Calc. C30H32KN2O2 [M+K]+
491.20949, Found 491.20950.
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General procedure for the synthesis of poly substituted pyrrolidine-2,5-dione through
One-pot Ugi 4CR/cyclization (7a-o)
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To a solution of aldehyde 1(1 mmol) in MeOH (5 ml) was added aniline as a primary amine 2
(1 mmol), and the reaction mixture was stirred at room temperature (25 °C) for 1 h. Then
phenyl acetylene carboxylic acid 3 (1 mmol) was added and stirring was continued for 15
min, followed by addition of isocyanid 4 (1 mmol). The mixture was stirred for 24 h. The
progress of the reaction was monitored using TLC (petroleum ether/ EtOAc 3:1). After
completion of reaction, K2CO3 (1 eq) was added to the mixture and then the mixture was
heated under reflux for 1-2 h. Reaction progress was monitored using TLC (hexane/ EtOAc
4:1). After cooling to room temperature the desired product was precipitated, the yellowish
sediment was filtered.
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(R,E)-4-benzylidene-1-(tert-butyl)-3-phenyl-3-(phenylamino)pyrrolidine-2,5-dione (7a):
1
Yellow powder, 385 mg(94%), m.p.:171-173°C, IR(KBr, cm-1): υ= 3389, 1763, 1698. H-
NMR (300 MHz, CDCl3): δ 1.50 (s, 9H, t-Bu), 4.45 (s, 1H, -NH), 6.28 (d, 2H, J = 8.3 Hz, H-
Ar), 6.72 (t, 1H, J = 7.0 Hz, H-Ar), 7.17 (t, 2H, J = 7.4 Hz, H-Ar), 7.23-7.28 (m, 1H, H-Ar),
7.33 (d, 2H, J = 7.3 Hz, H-Ar), 7.40-7.47 (m, 3H, H-Ar), 7.73 (d, 2H, J = 8.1 Hz, H-Ar), 7,93
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(s, 1H, =CH). C-NMR (75 MHz, CDCl3): δ 28.3, 59.1, 67.2, 116.4, 120.0, 126.3, 128.1,
128.6, 128.7, 129.1, 129.4, 129.9, 131.0, 133.1, 138.2, 138.5, 144.1, 170.6, 176.5. Mass: HR-
MS (ESI-POS) = Calc. for C27H27N2O2 [M+H]+ 411.20700, Found 411.20694. Calc. for
C27H26N2NaO2 [M+Na]+ 433.18908, Found 433.18900. Calc. for C27H26KN2O2 [M+K]+
449.16301, Found 449.16293.
(R,E)-4-benzylidene-1-(tert-butyl)-3-(4-chlorophenyl)-3-(phenylamino)pyrrolidine-2,5-
dione (7b):
1
Yellow powder, 404 mg(91%), m.p.: 197-199 °C, IR(KBr, cm-1): υ= 1705, 1768, 3424. H-
NMR (300 MHz, CDCl3): δ 1.56 (s, 9H, t-Bu), 4.36 (s, 1H, -NH), 6.29 (d, 2H, J = 8.0 Hz, H-
Ar), 6.74 (t, 1H, J = 7.3 Hz, H-Ar), 6.98 (t, 2H, J = 7.8 Hz, H-Ar), 7.20 (t, 2H, J = 7.3 Hz, H-
Ar), 7.27 (d, 1H, J = 5.6 Hz, H-Ar), 7.33 (d, 2H, J = 7.3 Hz, H-Ar), 7.39 (d, 2H, J = 8.5 Hz,
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H-Ar), 7.64 (d, 2H, J = 8.5 Hz, H-Ar), 7.91 (s, 1H, =CH). C-NMR (75 MHz, CDCl3): δ
28.3, 59.2, 66.8, 116.9, 120.5, 127.8, 128.2, 128.8, 129.5, 130.1, 131.0, 132.9, 135.2, 137.0,
138.6, 143.8, 170.4, 176.2. Mass: HR-MS (ESI-NEG) = Calc. for C27H26ClN2O2 [M+H]+
445.16745, Found 445.16750. Calc. for C27H25ClKN2O2 [M+K]+ 483.12336, Found
483.12340. yellow crystal (polyhedron), dimensions .18 x .10 x .10 mm3, crystal system
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monoclinic, space group P21/n, Z=4, a=12.8190(6) Å, b=10.5217(5) Å, c=18.1283(8) Å,
alpha=90 deg, beta=106.9487(12) deg, gamma=90 deg, V=2338.90(19) Å3, rho=1.264 g/cm3,
T=200(2) K, Thetamax= 25.106 deg, radiation Mo Kalpha, lambda=0.71073 Å, 0.5 deg
omega-scans with CCD area detector, covering the asymmetric unit in reciprocal space with a
mean redundancy of 6.74and a completeness of 99.5% to a resolution of 0.84Å, 28777
reflections measured, 4154 unique (R(int)=0.0445), 3053 observed (I > 2σ (I)), intensities
were corrected for Lorentz and polarization effects, an empirical absorption correction was
applied using SADABS based on the Laue symmetry of the reciprocal space, mu=0.19mm-1,
Tmin=0.89, Tmax=0.96, structure refined against F2 with a Full-matrix least-squares algorithm
using the SHELXL (Version 2014-1) software, 292 parameters refined, hydrogen atoms were
treated using appropriate riding models, goodness of fit 1.06 for observed reflections, final
residual values R1(F)=0.064, wR(F2)=0.155 for observed reflections, residual electron
density -0.30 to 0.58 eÅ-3. CCDC 991554 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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R,E)-4-(4-benzylidene-1-(tert-butyl)-2,5-dioxo-3-(phenylamino)pyrrolidin-3-
yl)benzonitrile (7c):
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Yellow powder, 365 mg(84%), m.p.:235-237 °C, IR(KBr, cm-1): υ= 3385, 1766, 1704,. H-
NMR (300 MHz, CDCl3): δ 1.54 (s, 9H, t-Bu), 4.45 (s, 1H, -NH), 6.45 (d, 2H, J = 7.9 Hz, H-
Ar), 6.84 (t, 1H, J = 7.3 Hz, H-Ar), 7.04 (t, 2H, J = 7.8 Hz, H-Ar), 7.21 (t, 2H, J = 7.3 Hz, H-
Ar), 7.26-7.32 (m, 1H, H-Ar), 7.40 (d, 2H, J = 7.3 Hz, H-Ar), 7.67 (d, 2H, J = 8.4 Hz, H-Ar),
7.77 (d, 2H, J = 8.4 Hz, H-Ar), 7,94 (s, 1H, =CH). 13C-NMR (75 MHz, CDCl3): δ 28.2, 59.5,
67.4, 112.9, 118.1, 118.5, 121.7, 127.3, 128.0, 128.3, 128.9, 130.4, 131.1, 132.6, 132.8,
139.4, 143.3, 143.4, 170.2, 176.0. Mass: HR-MS (ESI-POS) = Calc. for C28H26N3O2 [M+H]+
436.20262, Found 436.20250. Calc. for C28H25N3NaO2 [M+Na]+ 458.18468, Found
458.18454.
(R,E)-4-benzylidene-1-(tert-butyl)-3-(phenylamino)-3-(4
trifluoromethyl)phenyl)pyrrolidine-2,5-dione (7d):
1
Yellow powder, 464 mg(97%), m.p.:175-177 °C, IR(KBr, cm-1): υ= 3438, 1772, 1705. H-
NMR (300 MHz, CDCl3): δ 1.56 (s, 9H, t-Bu), 4.44 (s, 1H, -NH), 6.38 (d, 2H, J = 7.9 Hz, H-
Ar), 6.79 (t, 1H, J = 7.3 Hz, H-Ar), 7.02 (t, 2H, J = 7.8 Hz, H-Ar), 7.20 (t, 2H, J = 7.34 Hz,
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H-Ar), 7.29 (t, 1H, J = 7.3 Hz, H-Ar), 7.37 (d, 2H, J = 7.2 Hz, H-Ar), 7.67 (d, 2H, J = 8.4 Hz,
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H-Ar), 7.82 (d, 2H, J = 8.3 Hz, H-Ar), 7.95 (s, 1H, =CH). C-NMR (75 MHz, CDCl3): δ
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28.2, 59.3, 67.2, 117.6, 121.1, 126.1 (CF3), 126.9, 128.1, 128.3, 128.8, 130.2, 130.9, 131.1,
131.3, 132.7, 139.0, 142.2, 143.6, 170.3, 176.1. Mass: HR-MS (ESI-NEG) = Calc. for
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C28H24F3N2O2 [M+H]- 477.17984, Found
dimensions 0.290 x 0.180 x 0.120 mm3, crystal system triclinic, space group P
a=10.7819(15) Å, b=11.2776(18) Å, c=12.123(3) Å, alpha=114.810(4) deg, beta=97.625(4)
deg, gamma=108.463(3) deg, V=1207.3(4) Å3, rho=1.316 g/cm3, T=200(2) K, Thetamax
477.17979. yellow crystal (polyhedron),
, Z=2,
1
=
24.854 deg, radiation Mo Kalpha, lambda=0.71073 Å, 0.5 deg omega-scans with CCD area
detector, covering the asymmetric unit in reciprocal space with a mean redundancy of
3.36and a completeness of 99.0% to a resolution of 0.85Å, 14048 reflections measured, 4147
unique (R(int)=0.0280), 3168 observed (I > 2σ (I)), intensities were corrected for Lorentz and
polarization effects, an empirical absorption correction was applied using SADABS based on
the Laue symmetry of the reciprocal space, mu=0.10mm-1, Tmin=0.91, Tmax=0.96, structure
refined against F2 with a Full-matrix least-squares algorithm using the SHELXL (Version
2013-4) software, 347 parameters refined, hydrogen atoms were treated using appropriate
riding models, goodness of fit 1.05 for observed reflections, final residual values
R1(F)=0.043, wR(F2)=0.096 for observed reflections, residual electron density -0.22 to 0.32
eÅ-3. CCDC 991553 contains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(R,E)-4-benzylidene-1-(tert-butyl)-3-(phenylamino)-3-(p-tolyl)pyrrolidine-2,5-dione
(7e):
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Yellow powder, 365 mg(86%), m.p.:153-155 °C, IR(KBr, cm-1): υ= 3054, 1768, 1704. H-
NMR (300 MHz, CDCl3): δ 1.58 (s, 9H, t-Bu), 2.38 (s, 3H, -CH3), 4.40 (s, 1H, -NH), 6.24 (d,
2H, J = 7.9 Hz, H-Ar), 6.69 (t, 1H, J = 7.3 Hz, H-Ar), 6.96 (t, 2H, J = 7.8 Hz, H-Ar), 7.17 (t,
2H, J = 7.3 Hz, H-Ar), 7.22-7.27 (m, 3H, H-Ar), 7.32 (d, 2H, J = 7.2 Hz, H-Ar), 7.60 (d, 2H,
J = 8.2 Hz, H-Ar), 7.91 (s, 1H, =CH). 13C-NMR (75 MHz, CDCl3): δ 21.1, 28.3, 59.0, 66.9,
116.1, 119.8, 126.2, 128.0, 128.7, 129.7, 130.0, 131.0, 133.1, 135.6, 137.9, 139.0, 144.1,
170.6, 176.5. Mass: HR-MS (ESI-POS) = Calc. for C28H29N2O2 [M+H]+ 425.22272, Found
425.22265. Calc. for C28H28N2NaO2 [M+Na]+ 447.20475, Found 447.20467. Calc. for
C28H28KN2O2 [M+K]+ 463.17870, Found 463.17862.
(R,E)-4-benzylidene-1-cyclohexyl-3-phenyl-3-(phenylamino)pyrrolidine-2,5-dione (7f):
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Yellow powder, 362 mg(83%), m.p.:197-199 °C, IR(KBr, cm-1): υ= 3290, 1757, 1696. H-
NMR (300 MHz, CDCl3): δ 1.19-1.33 (m, 3H, H-cyclohexyl), 1.52-1.67 (m, 3H, H-
cyclohexyl), 1.79-1.82 (m, 2H, H-cyclohexyl), 2.08-2.21 (m, 2H, H-cyclohexyl), 4.05-4.13
(m, 1H, N-CH), 4.45 (s, 1H, -NH), 6.29 (d, 2H, J = 7.9 Hz, H-Ar), 6.73 (t, 1H, J = 7.3 Hz, H-
Ar), 6.97 (t, 2H, J = 7.8 Hz, H-Ar), 7.19 (t, 2H, J = 7.3 Hz, H-Ar), 7.25-7.30 (m, 1H, H-Ar),
7.34 (d, 2H, J = 7.4 Hz, H-Ar), 7.40-7.43 (m, 3H, H-Ar), 7.72(d, 2H, J = 6.2 Hz, H-Ar), 7.94
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(s, 1H, =CH). C-NMR (75 MHz, CDCl3): δ 25.0, 25.7, 25.8, 28.6, 28.7, 52.2, 67.2, 116.6,
120.3, 126.3, 128.2, 128.7, 128.8, 129.1, 129.3, 130.0, 131.1, 131.4, 133.0, 138.4, 138.7,
144.1, 169.7, 175.8. Mass: HR-MS (ESI-POS) = Calc. for C29H29N2O2 [M+H]+ 437.22204,
Found 437.22210. Calc. for C29H28N2NaO2 [M+Na]+ 459.20406, Found 459.20410. Calc. for
C29H28KN2O2 [M+K]+ 475.17794, Found 475.17799.
(R,E)-4-benzylidene-1-cyclohexyl-3-(phenylamino)-3-(4
(trifluoromethyl)phenyl)pyrrolidine-2,5-dione (7g):
1
Yellow powder, 454 mg(90%), m.p.:200-203 °C, IR(KBr, cm-1): υ= 3410, 1769, 1708. H-
NMR (300 MHz, CDCl3): δ 1.23-1.33 (m, 3H, H-cyclohexyl), 1.52-1.67 (m, 3H, H-
cyclohexyl), 1.80-1.83 (m, 2H, H-cyclohexyl), 2.05-2.18 (m, 2H, H-cyclohexyl), 4.03-4.12
(m, 1H, N-CH), 4.45 (s, 1H, -NH), 6.38 (d, 2H, J = 8.1 Hz, H-Ar), 6.80 (t, 1H, J = 7.3 Hz, H-
Ar), 7.01 (t, 2H, J = 7.8 Hz, H-Ar), 7.23 (t, 1H, J = 7.2 Hz, H-Ar), 7.25 (t, 1H, J = 7.2 Hz, H-
Ar), 7.31 (t, 1H, J = 7.2 Hz, H-Ar), 7.39 (d, 2H, J = 7.1 Hz, H-Ar), 7.66 (d, 1H, J = 8.4 Hz,
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H-Ar), 7.83 (d, 2H, J = 8.4 Hz, H-Ar), 7.947 (s, 1H, =CH). C-NMR (75 MHz, CDCl3): δ
24.9, 25.6, 25.7, 28.6, 28.7, 52.4, 67.3, 117.8, 121.3, 121.9, 126.2 (CF3), 126.9, 128.1, 128.4,
128.9, 130.4, 131.1, 132.7, 139.6, 142.1, 143.6, 169.4, 175.4. Mass: HR-MS (ESI-POS) =
Calc. for C30H28F3N2O2 [M+H]+ 505.20942, Found 505.20947. Calc. for C30H27F3N2NaO2
[M+Na]+ 527.19170, Found 527.19170. Calc. for C30H27F3KN2O2 [M+K]+ 543.16568, Found
543.16567.
(R,E)-4-benzylidene-1-(tert-butyl)-3-(phenylamino)-3-(pyridin-3-yl)pyrrolidine-2,5-
dione (7h):
1
Yellow powder, 279 mg(68%), m.p.:128-130 °C, IR(KBr, cm-1): υ= 3390, 1761, 1702. H-
NMR (300 MHz, CDCl3): δ 1.51 (s, 9H, t-Bu), 5.0 (brs, 1H, -NH), 6.47 (d, 2H, J = 7.8 Hz,
H-Ar), 6.81 (t, 1H, J = 7.2 Hz, H-Ar), 7.02 (t, 2H, J = 7.7 Hz, H-Ar), 7.08-7.28 (m, 4H, H-
Ar), 7.36-7.47 (m, 3H, H-Ar), 7.84-7.99 (m, 3H, H-Ar, =CH). 13C-NMR (75 MHz, CDCl3): δ
28.5, 36.5, 59.4, 116.0, 118.5, 120.1, 121.6, 127.6, 128.1, 128.3, 128.9, 129.1, 130.4, 131.3,
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132.5, 135.0, 139.6, 143.5, 170.1, 176.3. Mass: HR-MS (ESI-POS) = Calc. for C26H26N3O2
[M+H]+ 412.20166, Found 412.20166. Calc. for C26H25N3NaO2 [M+Na]+ 434.18381, Found
434.18383. Calc. for C26H25KN3O2 [M+K]+ 450.15770, Found 450.15772.
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dione (7i):
Yellow powder, 414 mg(88%), m.p.:185-187 °C, IR(KBr, cm-1): υ= 3504, 1762, 1701. H-
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NMR (300 MHz, CDCl3): δ 1.22-1.26 (m, 3H, H-cyclohexyl), 1.53-1.79 (m, 5H, H-
cyclohexyl), 2.06-2.18 (m, 2H, H-cyclohexyl), 3.68-3.75 (m, 1H, N-CH), 4.38 (s, 1H, -NH),
6.30 (d, 2H, J = 7.5 Hz, H-Ar), 6.75 (t, 1H, J = 7.0 Hz, H-Ar), 6.98 (t, 2H, J = 7.3 Hz, H-Ar),
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7.21-7.45 (m, 7H, H-Ar), 7.64 (d, 2H, J = 8.2 Hz, H-Ar), 7.93 (s, 1H, =CH). C-NMR (75
MHz, CDCl3): δ 24.8, 25.7, 25.8, 28.6, 28.7, 52.3, 66.9, 117.1, 120.8, 127.9, 128.2, 128.3,
128.8, 129.5, 130.2, 131.1, 132.8, 135.2, 136.8, 139.2, 143.8, 169.5, 175.6. Mass: HR-MS
(ESI-POS) = Calc. for C29H28ClN2O2 [M+H]+ 471.18383, Found 471.18375. Calc. for
C29H27ClN2NaO2 [M+Na]+ 493.16562, Found 493.16557. Calc. for C29H27ClKN2O2 [M+K]+
509.13969, Found 509.13962.
(R,E)-4-benzylidene-1-(tert-butyl)-3-((3,4-dimethylphenyl)amino)-3-phenylpyrrolidine-
2,5-dione (7j):
Yellow powder, 333 mg(76%), m.p.:150-152 °C, IR(KBr, cm-1): υ= 3394, 1761 1698. H-
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NMR (300 MHz, CDCl3): δ 1.59 (s, 9H, t-Bu), 2.04 (s, 3H, -CH3), 2.08 (s, 3H, -CH3), 4.3
(brs, 1H, -NH), 6.10 (d, 1H, J = 8.0 Hz, H-Ar), 6.15 (s, 1H, H-Ar), 6.75 (d, 1H, J = 8.0 Hz,
H-Ar), 7.18-7.30 (m, 3H, H-Ar), 7.39-7.41 (m, 5H, H-Ar), 7.69 (d, 2H, J = 6.9 Hz, H-Ar),
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7.91 (s, 1H, =CH). C-NMR (75 MHz, CDCl3): δ 18.8, 19.9, 28.3, 59.0, 67.4, 114.6, 118.9,
126.3, 128.1, 128.6, 128.9, 129.2, 129.3, 129.8, 131.2, 131.4, 133.2, 136.8, 138.0, 138.6,
142.1, 170.9, 176.9. Mass: HR-MS (ESI-POS) = Calc. for C29H31N2O2 [M+H]+ 439.23843,
Found 439.23835. Calc. for C29H30N2NaO2 [M+Na]+ 461.22063, Found 461.22051. Calc. for
C29H30KN2O2 [M+K]+ 477.19453, Found 477.19442.
(R,E)-4-benzylidene-1-cyclohexyl-3-(4-methoxyphenyl)-3-(phenylamino)pyrrolidine-2,5-
dione (7k):
Yellow powder, 382 mg(82%), m.p.:156-158 °C, IR(KBr, cm-1): υ= 3386, 1766, 1703. H-
1
NMR (300 MHz, CDCl3): δ 1.19-1.27 (m, 3H, H-cyclohexyl), 1.53-1.80 (m, 5H, H-
cyclohexyl), 2.09-2.22 (m, 2H, H-cyclohexyl), 3.82 (s, 1H, -OMe), 4.09 (t, 1H, J = 11.5 Hz,
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N-CH), 4.40 (s, 1H, -NH), 6.23 (d, 2H, J = 7.6 Hz, H-Ar), 6.70 (t, 1H, J = 7.2 Hz, H-Ar),
6.93-6.98 (m, 4H, H-Ar), 7.20 (t, 2H, J = 7.0 Hz, H-Ar), 7.28 (t, 1H, J = 7.0 Hz, H-Ar), 7.34
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(d, 2H, J = 7.4 Hz, H-Ar), 7.66 (d, 1H, J = 7.3 Hz, H-Ar), 7.90 (s, 1H, =CH). C-NMR (75
MHz, CDCl3): δ 25.0, 25.7, 25.8, 28.6, 28.8, 52.1, 55.3, 66.6, 114.7, 116.1, 120.0, 127.8,
128.2, 128.7, 129.9, 130.3, 131.1, 133.0, 138.5, 144.2, 160.1, 169.7, 176.0. Mass: HR-MS
(ESI-POS) = Calc. for C30H31N2O3 [M+H]+ 467.23276, Found 467.23279. Calc. for
C30H30N2NaO3 [M+Na]+ 489.21470, Found 489.21473.
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(R,E)-4-(4-benzylidene-1-cyclohexyl-2,5-dioxo-3-(phenylamino)pyrrolidin-3-
yl)benzonitrile (7l):
1
Yellow powder, 332 mg(72%), m.p.:225-22 7°C, IR(KBr, cm-1): υ= 3393, 1771, 1705. H-
NMR (300 MHz, CDCl3): δ 1.17-1.32 (m, 3H, H-cyclohexyl), 1.49-1.82 (m, 5H, H-
cyclohexyl), 2.02-2.15 (m, 2H, H-cyclohexyl), 4.05 (tt, 1H, J = 12.3, 3.6 Hz, N-CH), 4.45 (s,
1H, -NH), 6.44 (d, 2H, J = 7.8 Hz, H-Ar), 6.84 (t, 1H, J = 7.3 Hz, H-Ar), 7.04 (t, 2H, J = 7.7
Hz, H-Ar), 7.24 (t, 2H, J = 7.4 Hz, H-Ar), 7.33 (t, 1H, J = 7.2 Hz, H-Ar), 7.42 (d, 2H, J = 7.3
Hz, H-Ar), 7.67 (d, 2H, J = 8.4 Hz, H-Ar), 7.79 (d, 2H, J = 8.4 Hz, H-Ar), 7.96 (s, 1H, =CH).
13C-NMR (75 MHz, CDCl3): δ 24.9, 25.6, 25.7, 28.6, 28.7, 52.4, 67.5, 113.0, 118.1, 118.6,
122.0, 127.3, 127.9, 128.4, 129.0, 129.2, 130.6, 131.2, 132.5, 132.8, 139.9, 143.1, 143.4,
169.2, 175.2. Mass: HR-MS (ESI-POS) = Calc. for C30H28N3O2 [M+H]+ 462.21785, Found
462.21781.
(R,E)-4-benzylidene-3-(4-bromophenyl)-1-cyclohexyl-3-(phenylamino)pyrrolidine-2,5-
dione (7m):
Yellow powder, 412 mg(81%), m.p.: 217-219°C, IR(KBr, cm-1): υ= 3330, 3056, 1764, 1701.
1H-NMR (300 MHz, CDCl3): δ 1.17-1.24 (m, 3H, H-cyclohexyl), 1.52-1.81 (m, 5H, H-
cyclohexyl), 2.01-2.22 (m, 2H, H-cyclohexyl), 4.02-4.1 (m, 1H, N-CH), 4.39 (s, 1H, -NH),
6.29 (d, 2H, J = 7.7 Hz, H-Ar), 6.84 (t, 1H, J = 7.3 Hz, H-Ar), 7.04 (t, 2H, J = 7.7 Hz, H-Ar),
7.24 (t, 2H, J = 7.4 Hz, H-Ar), 6.75 (t, 1H, J = 7.1 Hz, H-Ar), 6.97 (d, 2H, J = 7.4 Hz, H-Ar),
7.20-7.30 (m, 3H, H-Ar), 7.35 (d, 2H, J = 7.3 Hz, H-Ar), 7.53 (d, 2H, J = 8.3 Hz, H-Ar), 7.58
(d, 2H, J = 8.3 Hz, H-Ar), 7.93 (s, 1H, =CH). 13C-NMR (75 MHz, CDCl3): δ 25.0, 25.6, 25.7,
28.6, 28.7, 52.3, 66.9, 117.1, 120.8, 123.5, 128.1, 128.2, 128.3, 128.8, 130.3, 131.1, 132.4,
132.8, 137.3, 139.3, 143.8, 169.5, 175.5. Mass: HR-MS (ESI-POS) = Calc. for C29H28BrN2O2
[M+H]+ 515.13343, Found 515.13334. Calc. for C29H27BrKN2O2 [M+K]+ 553.08932, Found
553.08923.
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(R,E)-4-benzylidene-3-((4-bromophenyl)amino)-1-cyclohexyl-3-(p-tolyl)pyrrolidine-2,5-
dione (7n):
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Yellow powder, 439 mg(83%), m.p.:152-154°C, IR(KBr, cm-1): υ= 3310, 3401, 1764, 1702.
1H-NMR (300 MHz, CDCl3): δ 1.17-1.27 (m, 3H, H-cyclohexyl), 1.51-1.79 (m, 5H, H-
cyclohexyl), 2.02-2.23 (m, 2H, H-cyclohexyl), 2.36 (s, 3H, -CH3), 4.09 (m, 1H, N-CH), 4.43
(s, 1H, -NH), 6.06 (d, 2H, J = 8.4 Hz, H-Ar), 7.02 (d, 2H, J = 8.4 Hz, H-Ar), 7.16-7.28 (m,
7H, H-Ar), 7.58 (d, 2H, J = 7.9 Hz, H-Ar), 7.91 (s, 1H, =CH). 13C-NMR (75 MHz, CDCl3): δ
21.1, 25.0, 25.6, 25.7, 28.6, 28.8, 52.2, 66.8, 111.9, 117.3, 126.2, 128.1, 128.2, 130.1, 130.2,
130.9, 131.5, 132.8, 135.2, 138.7, 139.4, 143.2, 169.5, 175.6. Mass: HR-MS (ESI-POS) =
Calc. for C30H3079BrN2O2 [M+H]+ 529.14932, Found 529.14919.
(R,E)-4-benzylidene-3-((4-bromophenyl)amino)-1-(tert-butyl)-3-phenylpyrrolidine-2,5-
dione (7o):
Yellow powder, 361 mg(74%), m.p.:152-154°C, IR(KBr, cm-1): υ= 3310, 3060, 1762, 1698.
1H-NMR (300 MHz, CDCl3): δ 1.57 (s, 9H, t-Bu), 4.42 (s, 1H, -NH), 6.08 (d, 2H, J = 8.2
Hz, H-Ar), 7.05 (d, 2H, J = 8.2 Hz, H-Ar), 7.17 (t, 1H, J = 7.5 Hz, H-Ar), 7.18 (d, 1H, J = 6.8
Hz, H-Ar), 7.19-7.30 (m, 3H, H-Ar), 7.43-7.45 (m, 3H, H-Ar), 7.70 (d, 2H, J = 5.5 Hz, H-
Ar), 7.92 (s, 1H, =CH). 13C-NMR (75 MHz, CDCl3): δ 28.3, 59.2, 67.1, 111.8, 117.3, 126.3,
127.9, 128.2, 129.4, 129.5, 130.0, 130.8, 131.5, 132.9, 138.3, 143.1, 170.3, 176.0. Mass: HR-
MS (ESI-POS) = Calc. for C27H2679BrN2O2 [M+H]+ 489.11897, Found 489.11867. Calc. for
C27H2579BrN2NaO2 [M+Na]+ 511.10132, Found 511.10097. Calc. for C27H2579BrKN2O2
[M+K]+ 527.07544, Found 527.07507.
Acknowledgment:
Saeed Balalaie gratefully acknowledges Alexander von Humboldt foundation for research
fellowship.
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ASSOCIATED CONTENT
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Supporting Information
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Copies of H NMR, C NMR, H-1H-COSY 2D NMR, IR, HRMS spectra for compounds
6a-6n and 7a-7o; X-ray crystal data for compound 6i, 7b and 7d. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Corresponding Author
†Peptide Chemistry Research Center, K. N. Toosi University of Technology, P.O. Box 15875-
4416 Tehran, Iran, balalaie@kntu.ac.ir
‡Medical Biology Research Center, Kermanshah University of Medical Sciences,
Kermanshah, Iran
Author Contributions
†Peptide Chemistry Research Center, K. N. Toosi University of Technology, P.O. Box 15875-
4416 Tehran, Iran
‡ Medical Biology Research Center, Kermanshah University of Medical Sciences,
Kermanshah, Iran
┴Organisch-Chemisches Institut der Universitaet Heidelberg, Im Neuenheimer Feld 270,
69120 Heidelberg, Germany
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