One-pot and regioselective synthesis of functionalized γ-lactams via a metal-free sequential Ugi 4CR/Intramolecular 5-exo-dig cyclization reaction

Article abstract of DOI:10.1016/j.tet.2020.131389

A new one-pot and regioselective synthesis of functionalized γ-lactams by a metal-free Ugi 4CR/intramolecular 5-exo-dig cyclization sequence under mild conditions has been developed. The reaction of propenoic acids, aldehydes, amines, and isocyanides produced γ-lactams regioselectively in 72–89percent yields via sequential Ugi 4CR/intramolecular 5-exo-dig cyclization reaction in the presence of Cs₂CO₃.

Full text of DOI:10.1016/j.tet.2020.131389

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One-pot and regioselective synthesis of functionalized γ-lactams via a metal-free
sequential Ugi 4CR/Intramolecular 5-exo-dig cyclization reaction
Yan-Mei Yan, Meng-Liang Wang, Yu-Long Liu, Ying-Chun He
PII:
S0040-4020(20)30551-2
https://doi.org/10.1016/j.tet.2020.131389
TET 131389
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 May 2020
Revised Date: 3 July 2020
Accepted Date: 6 July 2020
Please cite this article as: Yan Y-M, Wang M-L, Liu Y-L, He Y-C, One-pot and regioselective synthesis
of functionalized γ-lactams via a metal-free sequential Ugi 4CR/Intramolecular 5-exo-dig cyclization
reaction, Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.131389.
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One-Pot and Regioselective Synthesis of
Functionalized γ-lactams via a Metal-Free
Sequential Ugi 4CR/Intramolecular 5-exo-
dig Cyclization Reaction
Leave this area blank for abstract info.
Yan-Mei Yana, Meng-Liang Wangb,*, Yu-Long Liuc and Ying-Chun Heb,*
a Department of Chemistry, Taiyuan Normal University, Jinzhong, 030619, P. R. of China
b Institute of Applied Chemistry, Shanxi University, Taiyuan 030006, P. R. of China
c Shanxi Bethune Hospital & Shanxi Academy of Medical Sciences, Taiyuan 030006, P. R. of China

1
Tetrahedron
journal homepage: www.elsevier.com
One-Pot and Regioselective Synthesis of Functionalized γ-lactams via a Metal-Free
Sequential Ugi 4CR/Intramolecular 5-exo-dig Cyclization Reaction
Yan-Mei Yana, Meng-Liang Wangb, , Yu-Long Liuc and Ying-Chun Heb,
a Department of Chemistry, Taiyuan Normal University, Jinzhong, 030619, P. R. of China
b Institute of Applied Chemistry, Shanxi University, Taiyuan 030006, P. R. of China
c Shanxi Bethune Hospital & Shanxi Academy of Medical Sciences, Taiyuan 030006, P. R. of China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new one-pot and regioselective synthesis of functionalized γ-lactams by a metal-free Ugi
4CR/intramolecular 5-exo-dig cyclization sequence under mild conditions has been developed.
The reaction of propenoic acid, aldehydes, amines, and isocyanides produced γ-lactams
regioselectively in 72-89% yields via sequential Ugi 4CR/intramolecular 5-exo-dig cyclization
reaction in the presence of Cs2CO3.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
γ-lactam
regioselective
metal-free
propenoic acid
Ugi reaction
1. Introduction
Owing to the advantages of rendering sufficient structural
diversity, molecule complexity, high atom economy, exceptional
efficiency, and convenient one-pot operation, multicomponent
reactions (MCRs) have gained extreme popularity in drug
discovery, natural products synthesis, biology and material
science[1]. Among the variants of MCRs, isocyanide-based
multicomponent reactions (IMCRs) have been a practical venue
to access diverse highly valuable molecules[2]. In particular, the
Ugi four-component reaction (Ugi 4CR) has been widely
investigated in organic chemistry for a long history since its first
discovery[3]. In addition, the combination of Ugi 4CR with
appropriate post-transformations has been a superior tool for the
synthesis of functionalized heterocyclic compounds[4]. In our
previous work, the sequential Ugi/aza-Wittig, Ugi/Wittig and
Ugi/intramolecular alkyne-azide cycloaddition (IAAC) reaction
have prepared multisubstituted [1,2,3]-triazolo[1,5-a]-quinoxalin-
4(5H)-ones, quinoxalin-2(1H)-ones, indoles and benzimida-
zoles[5].
Figure 1. Examples of some biologically important molecules
containing γ-lactam motifs.
γ-lactam and its derivatives have been found as a privileged
skeleton in a large number of natural products and important
pharmaceutical agents (Figure 1)[6]. They often possess a wide
array of pharmacological activities, like antiviral[7], cytotoxic[8],
-derable research efforts have been focused on the development
of the synthesis of γ-lactams. The traditional synthetic method for
the construction of γ-lactam is based on the cyclization of the
dialkyl and primary amines[11]. Moreover, other approaches also
anti-inflammatory[9] and antimicrobial[10]. Consequently, consi
———
Corresponding author. e-mail: heyingchun@sxu.edu.cn
Corresponding author. e-mail: mlwang1966@yeah.net

2
Tetrahedron
Scheme 2 Preparation of propenoic acid 3
ed by removing HBr with NEt3, gave (Z)-methyl-2-bromo-3-
arylacrylates 2. Subsequently, a Pd(0) and Cu(I)-catalyzed
coupling reaction of compounds (Z)-methyl-2-bromo-3-
arylacrylates 2 with 1-alkynes under the Sonogashira conditions
and successive hydrolysis reaction were performed. Then, the
addition of diluted H2SO4 to the reaction mixture to obtain the
propenoic acid 3[22].
Scheme 1 Approaches of MCRs to γ-lactam
have been reported, such as the expansion of β-lactams[12],
radical addition-cyclization reaction [13], cycloaddition
reaction[14], formation [3+2] annulations[15], metal carbenoid
C-H insertion reaction[16] and transition-metal-catalyzed
intramolecular allylic alkylation reaction[17]. Although these
approaches provide complementary strategies to γ-lactams, it
should be noted that they suffer from low efficiency, metal
contamination of the products and a lack of diversity.
In the outset of our study, (E)-2-benzylidene-4-phenylbut-3-
ynoic acid (3a), 4-chlorobenzaldehyde (4a), p-methylaniline (5a)
and tert-butylisocyanide (6a) were chosen as standard substrates
Recently, MCRs have enabled rapid metal-free access to
highly functionalized γ-lactams with amplified molecular
complexity starting from readily available compounds. Pdacios
and co-workers documented the first highly enantioselective
three-component reaction of pyruvate derivatives, amines and
aldehydes to efficiently afforded 3-amino-1,5-dihydro-2H-pyrrol-
2-ones (Scheme 1a)[18]. Ding’s group developed a facile
synthesis of 5-oxopyrrolidine-2-carboxamides via Ugi 4CR/SN
cyclization starting from Baylis-Hillman bromides (Scheme 1b)
[19]. Despite the remarkable advances, it is still highly desirable
to develop a novel, metal-free and robust methodology to
construct γ-lactams with amplified molecular complexity from
readily available starting materials based on MCRs.
In recent years, intramolecular cyclization reaction of alkynes
which involved the addition of a nucleophile to carbon-carbon
triple bonds to form C-C, C-O, C-N bond have been used for the
synthesis of a variety of biologically interesting heterocycles[20].
The combination of Ugi 4CR with a following intramolecular
cyclization of alkynes has attracted considerable attention for the
construction of diverse heterocyclic scaffolds[21]. Continuing
our interest in the development of new strategies for the synthesis
of biologically relevant compounds utilizing sequential Ugi 4CR
/intramolecular cyclization of alkynes, herein we wish to report a
one-pot two-step, metal-free, efficient and atom economical
protocol for the regioselective synthesis of functionalized γ-
lactams through intramolecular 5-exo-dig cyclization of the Ugi
adduct under basic conditions (Scheme 1c). To the best of our
knowledge, there is no report previously on the sequential Ugi
4CR/intramolecular cyclization to prepare γ-lactams regio-
selectively by using propenoic acid as acid component in the Ugi
reaction. It is interesting that in spite of Ugi 4CR product
comprises multiple nucleophilic centers and two electrophilic
sites, the reaction was completely regioselective and provided
only γ-lactams.
Scheme 3 Regioselective preparation of compound 8a
Table
1
Optimization of reaction conditions for the
regioselective synthesis of compound 8aa
Entry
Base
solvent
Yield (%)b
Temp (°C)
1
2
3
-
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
80
80
80
80
80
80
80
80
80
70
110
0
0
0
NEt3
NaHCO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
KtOBu
Cs2CO3
Cs2CO3
Cs2CO3
4
50
70
85
75
40
77
60
0
5c
6
7d
8
9
10
11
THF
toluene
a
Standard conditions: (E)-2-benzylidene-4-phenylbut-3-ynoic
acid 3a (1 mmol), 4-chlorobenzaldehyde 4a (1 mmol), p-methyl-
aniline 5a (1 mmol), tert-butylisocyanide 6a (1 mmol), base (1
mmol), solvent (5 mL), 4-5 h.
b Isolated yield based on (E)-2-benzylidene-4-phenylbut-3-ynoic
acid 3a.
2. Results and discussion
c K2CO3 (3 mmol)
The propenoic acid 3 were prepared as illustrated in Scheme
2. Bromination of the (E)-methyl cinnamates 1 with Br2, follow-
d Cs2CO3 (3 mmol)

3
Table 2 Regioselective synthesis of γ-Lactams 8 via a metal-free Sequential Ugi 4CR/intramolecular
5-exo-dig cyclization reactiona
Entry
Ar
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R1
Ph
Ph
Ph
R2
R3
R4
Yield (%)b
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
4-ClC6H4
4-ClC6H4
Ph
4-CH3C6H4
4-ClC6H4
4-BrC6H4
4-CH3C6H4
C6H5
4-CH3OC6H4
4-CH3C6H4
4-CH3C6H4
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
85
75
72
84
81
88
82
77
4-CH3C6H4
Ph
Ph
Ph
Ph
8g
8h
4-CH3C6H4
9
8i
8j
Ph
Ph
Ph
Ph
4-CH3C6H4
4-CH3C6H4
t-Bu
t-Bu
83
82
10
11
12
13
14
15
16
17
18
19
8k
8l
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-CH3C6H4
4-FC6H4
Ph
4-FC6H4
Ph
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
4-ClC6H4
2-ClC6H4
4-NO2C6H4
4-ClC6H4
HCHO
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
3-CH3C6H4
4-CH3C6H4
3-CH3C6H4
2-BrC6H4
t-Bu
t-Bu
c-C6H11
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
78
89
83
85
84
0
0
0
0
8m
8n
8o
8p
8q
8r
8s
Ph
Ph
Ph
Ph
4-CH3C6H4
20
8t
Ph
Ph
4-CH3C6H4
t-Bu
0
a Reaction condition: 1) MeOH, r.t., 12-24 h; 2) MeCN, CS2CO3, 80 °C, 4-5 h.
b Isolated yields based on propenoic acids 3
to optimize the reaction (Scheme 3). To our delight, they
processed smoothly in methanol at room temperature for 12
hours, then the solvent was changed to acetonitrile and the
reaction mixture was heated to reflux for 4-5 h. The reaction did
not afford any product in the absence of a base or the presence of
weaker bases such as NEt3, NaHCO3 (Table 1, entry 1-3).
Pleasingly, a positive result encouraged us, with 1 equiv. K2CO3
as a base, the desired product 8a was formed in 50% isolated
yield, which increased to 70 % when K2CO3 was used in 3-fold
excess (Table 1, entry 4 and 5). We assumed that a stronger base
was probably helpful for improving reaction efficiency. Among
the bases screened, it was revealed that 1 equiv. Cs2CO3 was the
most effective base to provide cyclization products 8a (Table 1,
entry 1-8). Next, the effect of solvents was also investigated with
1 equiv. Cs2CO3 as a base. The screening results showed that
acetonitrile was found to be the best choice. Switching to other
solvents such as DMF, THF, and toluene resulted in a decreased
yield (Table 1, entry 9-11).
Figure 2 ORTEP drawing of compound 8a with 50% probability
thermal ellipsoids
components with different substituents carried out smoothly to
give the corresponding γ-Lactams 8 in moderate to good yields
(Table 2, compounds 8a-8o, 72-89%). In good to high yields
afforded when aldehydes or acids carrying an electron-
withdrawing group and amines carrying an electron-donating
group were utilized (Table 2, compounds 8a, 8f, 8l, 8n, 8o, 84%-
89%). Two different heteroaryl aldehydes were also explored to
get the desired products in moderate yields (Table 2, compounds
8i, 8j, 82%-83%). However, no products were reached when
aliphatic aldehydes or amines, aromatic aldehyde with strongly
electron withdrawing group (-NO2) group, and ortho-substituted
aromtic aldehydes or amines were used (Table 2, compounds 8p-
8t). It is noteworthy that isocyanides have little effect.
The exact structure of compound 8a was confirmed by NMR,
HRMS, and X-ray. Furthermore, a single crystal was obtained
from the MeCN/DCM solution, and the X-ray structure analysis
verified the proposed structure. It is noteworthy that two double
bonds all have E configuration, and five-membered ring of γ-
lactam system adopts a planar conformation (Figure 2).
With the optimized reaction conditions in hand (Table 1,
entry 6), various propenoic acids 3, aldehydes 4, amines 5 and
isocyanides 6 were employed for the one-pot metal-free Ugi
4CR/intramolecular 5-exo-dig cyclization reaction. The four-
To gain an understanding of the reaction mechanism, we
conducted the control experiment. As shown in Scheme 4,
comparable results are observed with or without TEMPO as an

4
Tetrahedron
coupling constants (Hz) and integration. 13C NMR spectra were
recorded on a Varian Mercury 500/600 (125/150 MHz) with
complete proton decoupling spectrophotometers (CDCl3: 77.0
ppm).
4.2 One-Pot and regioselective synthesis of functionalized γ-
lactams 8
A mixture of propenoic acids 3 (1 mmol), aldehydes 4 (1
mmol), amines 5 (1 mmol) and isocyanides 6 (1 mmol) were
stirred in methanol (5 mL) at room temperature for 12-24 h, then
the solvent was evaporated under reduced pressure. MeCN (5 mL)
and Cs2CO3 (0.326 g, 1 mmol) were added to the reaction system
and the reaction mixture were heated to 80 °C for 4-5 h to form γ-
lactams 8. The solvent was removed under reduced pressure and
the residue was purified by flash chromatography on silica ge
(petroleum ether/ethyl acetate = 100 : 1, V: V) to give 8.
Scheme 4 Mechanism exploration
additive which showing that the reaction did not undergo a
radical pathway. Based on the result presented above and
previous reports[23], we postulated a plausible mechanism for
the regioselective formation of these γ-Lactams (Scheme 5). Two
amide moieties, a triple and a C-H bond together exist in the
structure of Ugi adduct 7. Initially, under the action of Cs2CO3,
the C-H bond which has an acidic character could be
deprotonated to form the carbanion. Subsequently, the carbanion
regioselectively adds to the triple bond in Ugi adduct 7 by
intramolecular nucleophilic addition to form γ-Lactams 8.
4.2.1 3,4-di((E)-benzylidene)-N-(tert-butyl)-2-(4-chlorophenyl)-5
-oxo-1-(p-tolyl)pyrrolidine-2-carboxamide (8a)
1
yellow solid (yield 476 mg, 85%). mp: 213-214 °C. H NMR
(CDCl3, 600 MHz): δ 7.69 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.21
(d, J = 8.4 Hz, 4H), 7.07 (d, J = 8.4 Hz, 2H), 7.01-7.00 (t, J = 7.2
Hz, 1H), 6.93-6.77 (m, 9H), 6.67 (s, 1H), 6.10 (s, 1H), 2.29 (s,
3H), 1.25 (s, 9H); 13C NMR (CDCl3, 150 MHz): δ 169.7, 168.2,
136.8, 136.2, 136.1, 136.0, 134.9, 134.2, 133.9, 133.8, 130.9,
129.7, 129.5, 129.4, 129.1, 128.9, 128.5, 128.3, 128.1, 127.9,
127.1, 125.0, 124.3, 120.4, 77.4, 52.0, 28.4, 20.9; HRMS (ESI):
m/z [M + H]+ calcd for C36H34ClN2O2: 561.2303; found:
561.2306.
4.2.2 3,4-di((E)-benzylidene)-N-(tert-butyl)-1,2-bis(4-chloroph-
enyl)-5-oxopyrrolidine-2-carboxamide (8b)
1
yellow solid (yield 435 mg, 75%). mp: 166-167 °C. H NMR
(CDCl3, 600 MHz): δ 7.69 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.35
(d, J = 9 Hz, 2H), 7.25-7.24 (t, J = 7.8 Hz, 4H), 7.02-7.01 (t, J =
7.2 Hz, 1H), 6.94-6.78 (m, 9H), 6.65 (s, 1H), 6.01 (s, 1H), 1.26 (s,
9H); 13C NMR (CDCl3, 125 MHz): δ 169.6, 167.9, 136.2, 136.0,
135.9, 135.2, 134.8, 134.1, 131.5, 130.7, 129.7, 129.5, 129.3,
128.9, 128.3, 128.0, 127.2, 125.5, 124.5, 77.2, 52.2, 28.4; HRMS
(ESI): m/z [M + H]+ calcd for C35H31Cl2N2O2: 581.1757; found:
581.1754.
Scheme 5. Plausible mechanism for the regioselective formation
of γ-Lactams
3. Conclusion
In conclusion, we have introduced a new one-pot and
regioselective preparation of functionalized γ-lactams by a metal-
free Ugi 4CR/intramolecular 5-exo-dig cyclization reaction under
mild conditions. The used propenoic acids, aldehydes, amines
and isocyanides can be varied broadly and produced γ-lactams
with amplified molecular complexity. Moreover, mild reaction
conditions, metal-free, easy work, atomic economy and good to
excellent yields all make it useful in synthetic and medicinal
chemistry.
4.2.3 3,4-di((E)-benzylidene)-1-(4-bromophenyl)-N-(tert-butyl)-2
-(4-chlorophenyl)-5-oxopyrrolidine-2-carboxamide (8c)
1
yellow solid (yield 449 mg, 72%). mp: 196-197 °C. H NMR
(CDCl3, 500 MHz): δ 7.69 (s, 1H), 7.53 (d, J = 11 Hz, 2H), 7.40
(d, J = 11 Hz, 2H), 7.30-7.23 (m, 4H), 7.02-7.00 (t, J = 9 Hz, 1H),
6.95-6.77 (m, 9H), 6.65 (s, 1H), 6.00 (s, 1H), 1.25 (s, 9H); 13C
NMR (CDCl3, 125 MHz): δ 169.5, 167.9, 136.2, 136.0, 135.9,
135.7, 134.8, 134.1, 131.8, 130.6, 129.7, 129.5, 129.3, 128.3,
128.0, 127.2, 125.7, 124.5, 119.4, 77.2, 52.2, 28.4; HRMS (ESI):
m/z [M + K]+ calcd for C35H30BrClKN2O2: 663.0811; found:
663.0809.
4. Experimental Section
4.1 General
General information: Reactions were generally carried out in
an appropriate round bottom flask with magnetic stirring. Unless
otherwise noted, materials were purchased from commercial
suppliers and used without further purification. The X-ray
diffraction data were collected on a Bruker APEX-II CCD
equipped with 1K CCD instrument by using a graphite
monochromator utilizing Mo-Kα radiation (λ=0.71073Å). HRMS
(ESI) was performed on a Thermo Scientific LTQ Orbitrap XL.
1H NMR spectra were recorded in CDCl3 on a Varian Mercury
500 or 600 spectrometer and resonances were relative to TMS.
Data are reported as follows: chemical shift, multiplicity (s =
single, d = doublet, t = triplet, q = quartet, m = multiplet),
4.2.4 3-((E)-benzylidene)-N-(tert-butyl)-4-((E)-4-methylbenzylid-
ene)-5-oxo-2-phenyl-1-(p-tolyl)pyrrolidine-2-carboxamide (8d)
1
yellow solid (yield 453 mg, 84%). mp: 160-161 °C. H NMR
(CDCl3, 500 MHz): δ 7.66 (s, 1H), 7.55 (d, J = 9 Hz, 2H), 7.24-
7.18 (m, 5H), 7.05-6.91 (m, 5H), 6.84-6.78 (m, 4H), 6.68 (s, 1H),
6.60 (d, J = 10 Hz, 2H), 6.10 (s, 1H), 2.27 (s, 3H), 2.12 (s, 3H),
1.26 (s, 9H); 13C NMR (CDCl3, 125 MHz): δ 169.9, 168.6, 138.2,
138.1, 135.9, 135.6, 135.2, 134.2, 133.6, 133.4, 129.7, 129.5,
129.4, 129.2, 128.9, 128.2, 127.9, 127.8, 127.0, 125.6, 124.8,
78.2, 51.9, 28.4, 21.1, 20.9; HRMS (ESI): m/z [M + H]+ calcd for
C37H37N2O2: 541.2850; found: 541.2845.

5
4.2.5 3,4-di((E)-benzylidene)-N-(tert-butyl)-2-(4-chlorophenyl)-
5-oxo-1-phenylpyrrolidine-2-carboxamide (8e)
124.7, 123.7, 75.1, 52.0, 28.3, 20.9; HRMS (ESI): m/z [M +
H]+ calcd for C34H33N2O2S: 533.2257; found: 533.2257.
1
yellow solid (yield 442 mg, 81%). mp: 197-198 °C. H NMR
4.2.11 3-((E)-benzylidene)-N-(tert-butyl)-2-(4-chlorophenyl)-4-
((E)-4-methylbenzylidene)-5-oxo-1-(p-tolyl)pyrrolidine-2-carbox-
amide (8k)
(CDCl3, 500 MHz): δ 7.70 (s, 1H), 7.55 (d, J = 11 Hz, 2H), 7.38-
7.28 (m, 4H), 7.23-7.13 (m, 3H), 7.03-6.77 (m, 10H), 6.69 (s,
1H), 6.07 (s, 1H), 1.23 (s, 9H); 13C NMR (CDCl3, 125 MHz): δ
169.6, 168.1, 136.7, 136.6, 136.2, 136.1, 134.9, 134.5, 133.8,
130.7, 129.4, 129.2, 128.8, 128.3, 128.1, 127.9, 127.2, 126.1,
124.9, 124.1, 77.4, 52.0, 28.3; HRMS (ESI): m/z [M + H]+ calcd
for C35H32ClN2O2: 547.2147; found: 547.2143.
1
yellow solid (yield 448 mg, 78%). mp: 190-191 °C. H
NMR (CDCl3, 500 MHz): δ 7.67 (s, 1H), 7.52 (d, J = 10.5 Hz,
2H), 7.20 (d, J = 11 Hz, 4H), 7.07 (d, J = 10.5 Hz, 2H), 7.00-6.97
(m, 1H), 6.91-6.76 (m, 6H), 6.65-6.59 (m, 3H), 6.09 (s, 1H), 2.28
(s, 3H), 2.13 (s, 3H), 1.25 (s, 9H); 13C NMR (CDCl3, 125 MHz):
δ 169.8, 168.4, 138.3, 136.9, 136.1, 135.2, 135.0, 134.0, 133.7,
133.4, 130.9, 129.8, 129.6, 129.4, 129.1, 129.0, 128.5, 128.3,
128.0, 127.8, 127.1, 125.2, 124.3, 120.3, 77.4, 52.0, 29.4, 28.4,
21.1, 20.9; HRMS (ESI): m/z [M + K]+ calcd for C37H35ClKN2O2:
613.2019; found: 613.2023.
4.2.6 3,4-di((E)-benzylidene)-N-(tert-butyl)-2-(4-chlorophenyl)-
1-(4-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (8f)
1
yellow solid (yield 507 mg, 88%). mp: 155-156 °C. H
NMR (CDCl3, 500 MHz): δ 7.69 (s, 1H), 7.49 (d, J = 11 Hz, 2H),
7.22-7.19 (m, 4H), 7.02-7.00 (t, J = 9.25 Hz, 1H), 6.93-6.78 (m,
11H), 6.68 (s, 1H), 6.13 (s, 1H), 3.77 (s, 3H), 1.28 (s, 9H); 13C
NMR (CDCl3, 125 MHz): δ 169.8, 168.4, 157.7, 136.8, 136.3,
135.9, 135.0, 134.1, 133.9, 131.0, 130.0, 129.4, 129.1, 128.4,
128.1, 127.9, 127.2, 126.3, 125.0, 114.0, 77.7, 55.4, 52.1, 28.5;
HRMS (ESI): m/z [M + H]+ calcd for C36H34ClN2O3: 577.2252;
found: 577.2245.
4.2.12 3-((E)-benzylidene)-N-(tert-butyl)-2-(4-chlorophenyl)-4-
((E)-4-fluorobenzylidene)-5-oxo-1-(p-tolyl)pyrrolidine-2-carbox-
amide (8l)
1
yellow solid (yield 515 mg, 89%). mp: 177-178 °C. H
NMR (CDCl3, 500 MHz): δ 7.69 (s, 1H), 7.52 (d, J = 11 Hz, 2H),
7.22-7.18 (m, 4H), 7.08-7.05 (m, 3H), 6.93-6.84 (m, 6H), 6.61 (s,
1H), 6.50-6.48 (t, J = 10.75 Hz, 2H), 6.13 (s, 1H), 2.29 (s, 3H),
1.26 (s, 9H); 13C NMR (CDCl3, 125 MHz): δ 169.5, 168.2, 163.7,
161.2, 136.8, 136.1, 135.9, 134.9, 134.1, 133.8, 132.3, 130.9,
130.1, 130.0, 129.5, 129.4, 128.7, 128.1, 127.3, 125.0, 124.3,
114.3, 114.0, 77.4, 52.1, 28.4, 20.9; 19F NMR (376 MHz, CDCl3)
4.2.7 3,4-di((E)-benzylidene)-N-(tert-butyl)-5-oxo-2-phenyl-1-(p-
tolyl)pyrrolidine-2-carboxamide (8g)
1
yellow solid (yield 432 mg, 82%). mp: 142-143 °C. H
NMR (CDCl3, 500 MHz): δ 7.67 (s, 1H), 7.57-7.55 (m, 2H),
7.24-7.18 (m, 5H), 7.06-6.89 (m, 8H), 6.83-6.77 (m, 4H), 6.70 (s,
1H), 6.12 (s, 1H), 2.27 (s, 3H), 1.27 (s, 9H); 13C NMR (CDCl3,
125 MHz): δ 169.8, 168.5, 138.1, 136.5, 136.4, 135.9, 135.1,
134.2, 133.8, 129.6, 129.5, 129.4, 129.2, 128.9, 128.3, 127.9,
127.7, 127.1, 125.4, 124.7, 78.2, 51.9, 28.4, 20.9; HRMS (ESI):
m/z [M + H]+ calcd for C36H35N2O2: 527.2693; found: 527.2684.
δ
-112.694; HRMS (ESI): m/z [M
+
K]+ calcd for
C36H32ClFKN2O2: 617.1768; found: 617.1758.
4.2.13 3,4-di((E)-benzylidene)-2-(4-chlorophenyl)-N-cyclohexyl-
5-oxo-1-(p-tolyl)pyrrolidine-2-carboxamide (8m)
1
yellow solid (yield 487 mg, 83%). mp: 233-234 °C. H
4.2.8 3,4-di((E)-benzylidene)-N-(tert-butyl)-5-oxo-1,2-di-p-tolyl
pyrrolidine-2-carboxamide (8h)
NMR (CDCl3, 500 MHz): δ 7.70 (s, 1H), 7.53 (d, J = 11 Hz, 2H),
7.19-7.16 (m, 4H), 7.05-6.75 (m, 12H, Ar-H), 6.68 (s, 1H), 6.27
(d, J = 10.5 Hz, 1H), 3.94-3.84 (m, 1H), 2.27 (s, 3H), 1.85-0.91
(m, 10H); 13C NMR (CDCl3, 125 MHz): δ 169.8, 168.3, 137.0,
136.3, 136.2, 135.7, 135.0, 134.2, 133.8, 131.1, 130.6, 129.4,
129.1, 128.4, 128.1, 127.8, 127.1, 124.9, 124.6, 77.2, 49.0, 32.7,
32.6, 25.2, 24.7, 24.6, 20.9; HRMS (ESI): m/z [M + H]+ calcd for
C38H36ClN2O2: 587.2460; found: 587.2452.
1
yellow solid (yield 416 mg, 77%). mp: 170-171 °C. H
NMR (CDCl3, 500 MHz): δ 7.66 (s, 1H), 7.44 (d, J = 10 Hz, 2H),
7.21 (d, J = 11 Hz, 2H), 7.06-6.88 (m, 10 H), 6.83-6.76 (m, 4H),
6.68 (s, 1H), 6.08 (s, 1H), 2.27 (d, J = 6.5 Hz, 6H), 1.25 (s, 9H);
13C NMR (CDCl3, 125 MHz): δ 169.8, 168.6, 137.6, 136.6, 135.8,
135.2, 135.0, 134.3, 133.7, 129.4, 129.2, 128.9, 128.6, 128.3,
127.6, 127.1, 125.6, 124.8, 78.2, 51.9, 28.4, 21.0; HRMS (ESI):
m/z [M + H]+ calcd for C37H37N2O2: 541.2850; found: 541.2842.
4.2.14 3-((E)-benzylidene)-N-(tert-butyl)-4-((E)-4-fluorobenzyl-
idene)-5-oxo-2-phenyl-1-(p-tolyl)pyrrolidine-2-carboxamide (8n)
1
4.2.9 3,4-di((E)-benzylidene)-N-(tert-butyl)-2-(furan-2-yl)-5-oxo
yellow solid (Yield 463 mg, 85%). mp: 175-176 °C. H
-1-(p-tolyl)pyrrolidine-2-carboxa-mide (8i)
NMR (CDCl3, 500 MHz): δ 7.68 (s, 1H), 7.56-7.54 (m, 2H),
7.25-7.16 (m, 5H), 7.04 (d, J = 10 Hz, 3H), 6.95-6.85 (m, 6 H),
6.65 (s, 1H), 6.50-6.47 (t, J = 10.75 Hz, 2H), 6.14 (s, 1H), 2.27 (s,
3H), 1.27 (s, 9H); 13C NMR (CDCl3, 125 MHz): δ 169.7, 168.5,
163.5, 161.1, 138.1, 136.2, 136.0, 135.0, 134.1, 133.7, 132.5,
130.0, 129.9, 129.5, 129.4, 129.3, 128.5, 127.9, 127.2, 125.4,
124.7, 78.2, 52.0, 28.4, 20.9; 19F NMR (376 MHz, CDCl3) δ -
113.079; HRMS (ESI): m/z [M + H]+ calcd for C36H34FN2O2:
545.2599; found: 545.2601.
1
yellow solid (yield 428 mg, 83%). mp: 203-204 °C. H
NMR (CDCl3, 500 MHz): δ 7.70 (s, 1H), 7.19 (d, J = 10.5 Hz,
2H), 7.11 (d, J = 10.5 Hz, 2H), 7.03-6.76 (m, 12H), 6.70 (s, 1H),
6.29-6.28 (m, 1H), 6.10 (s, 1H), 2.31 (s, 3H), 1.29 (s, 9H); 13C
NMR (CDCl3, 125 MHz): δ 169.7, 167.2, 149.9, 142.7, 136.4,
136.3, 135.3, 133.9, 133.8, 132.4, 129.4, 129.3, 129.2, 128.9,
128.4, 127.7, 127.1, 125.0, 124.6, 113.3, 110.3, 74.1, 51.9, 28.4,
21.0; HRMS (ESI): m/z [M + H]+ calcd for C34H33N2O3:
517.2486; found: 517.2489.
4.2.15 3,4-di((E)-benzylidene)-N-(tert-butyl)-1-(4-chlorophenyl)-
5-oxo-2-(m-tolyl)pyrrolidine-2-carboxamide (8o)
4.2.10 3,4-di((E)-benzylidene)-N-(tert-butyl)-5-oxo-2-(thiophen-
1
2-yl)-1-(p-tolyl)pyrrolidine-2-carboxamide (8j)
yellow solid (yield 471 mg, 84%). mp: 169-170 °C. H
NMR (CDCl3, 600 MHz): δ 7.69 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H),
7.22-7.21 (m, 3H), 7.15-7.14 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 7.8
Hz, 1H), 7.02-6.89 (m, 7H), 6.83-6.78 (m, 4H), 6.69 (s, 1H), 6.08
(s, 1H), 2.28 (s, 3H), 1.24 (s, 9H); 13C NMR (CDCl3, 150 MHz):
δ 169.7, 168.1, 138.7, 136.8, 136.5, 136.2, 136.1, 134.9, 134.3,
133.8, 130.8, 129.5, 129.4, 129.1, 128.6, 128.3, 128.0, 127.9,
1
yellow solid (yield 436 mg, 82%). mp: 172-173 °C. H
NMR (CDCl3, 500 MHz): δ 7.74 (s, 1H), 7.33 (d, J = 10.5 Hz,
3H), 7.10 (d, J = 10.5 Hz, 2H), 7.03-6.75 (m, 13H), 5.98 (s, 1H),
2.30 (s, 3H), 1.24 (s, 9H); 13C NMR (CDCl3, 125 MHz): δ 169.4,
168.4, 140.9, 136.2, 135.9, 135.5, 135.1, 134.5, 134.1, 129.4,
129.3, 129.0, 128.6, 128.4, 127.8, 127.7, 127.4, 127.1, 126.0,

6
Tetrahedron
127.2, 127.0, 125.0, 121.2, 77.4, 52.0, 28.3, 21.5; HRMS (ESI):
[7] (a) K. Takahashi, M. Kawabata, D. Uemura, S. Iwadare, R.
Mitomo, F. Nakano, A. Matsuzaki, Tetrahedron Lett. 26 (1985),
1077-1078. (b) K. Kawazu, H. Kanzaki, G. Kawabata, S. Kawai,
A. Kobayashi, Biosci. Biotechnol. Biochem. 56 (1992), 1382-
1385.
m/z [M + H]+ calcd for C36H34ClN2O2: 561.2303; found:
561.2307.
Acknowledgements
We gratefully acknowledge financial support of this work by
[8] (a) J. M. Andrés, N. de Elena, R. Pedrosa, A. Pérez-Encabo,
Tetrahedron Asymmetry 12 (2001), 1503-1509. (b) M. J. K.
Rieser, F. John, K. V. Wood, J. L. McLaughlin, Tetrahedron Lett.
32 (1991), 1137-1140. (c) I. Baussanne, O. Schwardt, J. Royer,
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2259-2262. (d) A. Cavé, C. Chaboche, B. Figadère, J. C.
Harmange, A. Laurens, J. F. Peyrat, M. Pichon, M. Szlosek, J.
Cotte-Lafitte, A. M. Quéro, Eur. J. Med. Chem. 32 (1997), 617-
623.
Shanxi
(201901D211152,
Province
Science
201901D211422),
Foundation
for
Youths
and
Scientific
Technological Innovation programs of higher Education
Institutions in Shanxi (2019L0047, 2019L0775, 2019L0444) and
the College Students’ Innovation Program of Taiyuan Normal
University (CXCY1934).
Appendix A. Supplementary data
Supplementary data to this article can be found online at.
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Highlights
‹ We provided a new one-pot and regioselective synthesis of functionalized
γ-lactams by a metal-free Ugi 4CR/intramolecular 5-exo-dig cyclization
sequence.
‹ There is no report previously on the sequential Ugi 4CR/intramolecular
cyclization to prepare γ-lactams regioselectively by using propenoic acid as acid
component in the Ugi reaction.
‹ Owing to the high atom efficiency, the good yields, the mild reaction conditions,
metal-free and the easily available starting materials, the efficient synthesis will
make it useful in synthetic and medicinal chemistry.

Deciaration of Interest State
We wish to draw the attention of the Editor to the following facts which may be
considered as potential conflicts of interest.
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and that there are no other persons who satisfied the criteria for authorship but are not
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approved by all of us.
We confirm that we have given due consideration to the protection of intellectual
property associated with this work and there are no impediments to publication,
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Signed by all authors as followed:
Yan-Mei Yan: yanyanmei1019@yeah.net
Meng-Liang Wang: mlwang1966@yeah.net
Yu-Long Liu: yulongliu01@foxmail.com
Ying-Chun He: heyingchun@sxu.edu.cn