Regio- And chemo-selective cyclization of allenic-Ugi products for the synthesis of 3-pyrroline skeletons

Article abstract of DOI:10.1039/c9ob01963d

A highly efficient and stable novel class of allenic-Ugi products through a Crabbé homologation reaction is successfully demonstrated. Then, a regio- and chemo-selective cyclization of allenic-Ugi derivatives in a 5-exo-dig fashion to access 3-pyrroline skeletons is developed. Also, computational studies were performed and explained to provide insights into the reaction mechanism. This approach displays high bond-forming efficiency and atom economy with high yields.

Full text of DOI:10.1039/c9ob01963d

Organic &
Biomolecular Chemistry
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Regio- and chemo-selective cyclization of allenic-
Ugi products for the synthesis of 3-pyrroline
skeletons†‡
Cite this: Org. Biomol. Chem., 2019,
17, 8858
a,b
Kamran Amiri, a Hormoz Khosravi, a Saeed Balalaie,
*
Farhad Golmohammadi,a Muhammad U. Anwar c and Ahmed Al-Harrasi*c
A highly efficient and stable novel class of allenic-Ugi products through a Crabbé homologation reaction
is successfully demonstrated. Then, a regio- and chemo-selective cyclization of allenic-Ugi derivatives in
a 5-exo-dig fashion to access 3-pyrroline skeletons is developed. Also, computational studies were per-
formed and explained to provide insights into the reaction mechanism. This approach displays high bond-
forming efficiency and atom economy with high yields.
Received 7th September 2019,
Accepted 18th September 2019
DOI: 10.1039/c9ob01963d
rsc.li/obc
In recent years, a wide range of synthetic approaches have
been developed for the synthesis of pyrroline backbones using
Introduction
Over the past few years, allenes have emerged as powerful and different catalytic systems.10,11 N-Carbamoyl allenes were used
versatile building blocks in organic synthesis. Allene moieties as starting materials and their cyclization was done using
have been identified in several natural products, molecular silver ions to get 3-pyrrolines.10a Tanaka et al. reported the
materials and bioactive compounds.1 Synthesis of compounds cyclization of unactivated allenes with potassium carbonate
containing allene moieties and their corresponding cyclization under reflux conditions to access 3-pyrrolines.10d Recently,
reactions are useful approaches for the synthesis of extended [3 + 2] annulation of allenoates with azomethine ylides
heterocyclic skeletons.2 Thus, numerous synthetic protocols (Scheme 1c) has been reported by Zhou et al. as an efficient
have been reported for the preparation of allenes from readily approach for the synthesis of 3-pyrrolines.11a
available organic compounds.3 One method is the allenylation
Due to the importance of allenes in cyclization reactions,
of terminal alkynes (ATA) via homologation which was orig- designing suitable reactions for the synthesis of functionalized
inally reported by Crabbé and coworkers.4 This framework was heterocyclic backbones is an interesting subject in organic syn-
applied for a broad spectrum of transformations, such as cycli- thesis. In this regard, using generation of allenes in multicom-
zation of nitrogen-containing heterocycles in particular pyrro- ponent reactions such as the Ugi reaction shows high potential
line structures. 3-Pyrrolines are a privileged class of nitrogen- for the synthesis of multifunctional compounds. Also, post-
ous cores, existing as a subunit in many natural products and transformation reactions represent the most powerful method-
bioactive molecules. Scaffolds containing 3-pyrroline moieties ology for the generation of complex molecules.12 Since the
exhibit various biological activities such as anti-bacterial,5 presence of an active functional compound plays an essential
antioxidant,6 anti-inflammatory,7 anti-tumor,8 and anti- role in cyclization reactions, formation of an allene moiety in
microbial9 effects (Fig. 1).
the structure of the molecule could enhance its activity for the
cyclization reaction. Recently as part of our ongoing interest in
designing post-transformation reactions,13 we decided to syn-
thesize a new class of stable allene moiety containing pseudo-
peptides through the homologation reaction of terminal
aPeptide Chemistry Research Center, K. N. Toosi University of Technology,
P. O. Box 15875-4416, Tehran, Iran. E-mail: balalaie@kntu.ac.ir;
Fax: +98-21-22889403; Tel: +98 21 23064226
bMedical Biology Research Center, Kermanshah University of Medical Sciences,
Kermanshah, Iran
cNatural and Medical Sciences Research Center, University of Nizwa, P.O. Box 33,
Postal Code 616, Birkat Al Mauz, Nizwa, Sultanate of Oman
†Dedicated to Prof. Barahman Movassagh on the occasion of his 60th birthday.
‡Electronic supplementary information (ESI) available. CCDC 1904044 and
1904045. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c9ob01963d
Fig. 1 Examples of bioactive 3-pyrroline structures.
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Table 1 Substrate scope for the synthesis of compounds 5a–m
Scheme 1 Representative reactions for the synthesis of a 3-pyrroline
structure and synthesis of allenic-Ugi products.
Table 2 Optimization of reaction conditions for the synthesis of 6a
Scheme 2 Synthesis of a 3-pyrroline skeleton.
Entry Catalyst (mol%) Solvent
Amine (mmol)
Yielda,b (%)
alkynes of Ugi-adducts. This novel class of allenic pseudopep-
tides are highly stable and desirable and have not been
reported so far. Subsequently, the cyclization reaction was
employed for the regio- and chemo-selective synthesis of 3-pyr-
roline skeletons as shown in Scheme 2.
1
2
3
4
5
6
7
8
9
10
CuBr (40)
CuBr (50)
CuBr (60)
CuBr (60)
CuI (60)
CuCl (60)
CuOAc (60)
CuBr (60)
CuBr (60)
CuBr (60)
Dioxane DIPEA (2.5)
Dioxane DIPEA (2.5)
Dioxane DIPEA (2.5)
Dioxane DIPEA (2)
Dioxane DIPEA (2.5)
Dioxane DIPEA (2.5)
Dioxane DIPEA (2.5)
Toluene DIPEA (2.5)
Dioxane Pyrrolidine (2.5)
37
61
84
77
42
16
19
68
53
Dioxane Morpholine (2.5) 24
Results and discussion
a Isolated yields. b Time of reaction was 12 h.
At the outset of our study, we selected the reaction of benz-
aldehyde 1a and propargylamine as a source of terminal
alkyne 2, benzoic acid 3a, and t-butyl isocyanide 4a in EtOH at
room temperature as a model reaction in order to access the amine in the presence of 60 mol% CuBr at 100 °C in dioxane
Ugi-adduct 5a. To extend the diversity of the reactions, (Table 2, entry 3). The compound 6a was separated and its
different carboxylic acids, isocyanides and benzaldehyde structure was determined by 1H and 13C NMR spectroscopic,
derivatives were used. The data are shown in Table 1. In the HRMS (ESI) and FT-IR analyses.
second step, we envisioned the preparation of an allenic-Ugi
To further extend the reaction scope, we examined some
product by the homologation reaction, according to previously other aldehydes, carboxylic acids, and isocyanides. The struc-
reported conditions.14 Reaction conditions were optimized by tures of the other allenic-Ugi products are shown in Table 3.
performing the homologation of terminal alkyne containing
Finally, we tried to explore the optimized reaction con-
pseudopeptides with different secondary amines and parafor- ditions for a 5-exo-dig intramolecular cyclization reaction of an
maldehyde in the presence of various copper catalysts result- allenic-Ugi adduct. In this regard, the model reaction was
ing in the construction of 6a. As shown in Table 2, the best examined with various bases in different solvents and the
result for the ATA reaction was obtained by using diisopropyl- results are summarized in Table 4. Initially to screen the
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Table 3 Substrate scope for the synthesis of allenic-Ugi products 6a–
Table 5 Structures of synthesized 3-pyrroline skeletons 7a–m
m
Table 4 Optimized reaction conditions for the synthesis of 7a
(Table 4, entries 5–10). We achieved the best result in DMF
(Table 4, entry 3). Although the reaction proceeded well in
DMSO, the best solvent was DMF and other solvents gave
inferior results. It is noteworthy that raising the reaction
temperature to 80 °C did not improve the yield (Table 4,
entries 11–13). Based on these results, we defined the
reaction of the allenic-Ugi adduct (1 mmol) and t-BuOK
(1.2 mmol) in DMF (2 mL) at room temperature as the best-
optimized reaction conditions.
The scope and generality of the 5-exo-dig cyclization reac-
tion were then investigated via the optimized reaction con-
ditions, and the results are summarized in Table 5.
The structures of compounds 7a and 7f were further con-
firmed by single-crystal diffraction analysis (Fig. 2).
The experimental results show that intra C-nucleophilic
addition to the allene moiety is highly regio- and chemo-
selective. To explain the selectivity, DFT calculations were
carried out at the B3LYP/6-31G(d) level in the gas phase (see
computation details). Under the basic reaction conditions, it is
possible to form two deprotonated isomers of the allenic-Ugi
product (anions A and B) (Fig. 3) in which the relative free
Entry
Base
Solvent
Temp (°C)
Yielda,b (%)
1
2
3
4
5
6
7
8
K2CO3
DMF
DMF
DMF
DMF
DMSO
Toluene
Dioxane
MeCN
DCE
MeOH
DMF
rt
rt
rt
rt
rt
rt
rt
rt
rt
11
63
94
81c
93
16
21
23
15
—
27
88
94
Cs2CO3
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
K2CO3
9
10
11
12
13
rt
80
80
80
Cs2CO3
t-BuOK
DMF
DMF
a Isolated yields. b In all cases the amount of the base was 1.2 mmol.
c Amount of the base was 1 mmol.
energy (Grel) and chemical hardness (η) of anion B (Grel
=
effect of the employed base, the reaction was performed by 0.0 kcal mol−1, η = 2.80 eV) are lower than those of anion A
using 1.2 equivalents of K2CO3 at room temperature in DMF. (Grel = 1.1 kcal mol−1, η = 3.52 eV); thus anion B is more reac-
However, the isolated yield was very low (Table 2, entry 1). tive than anion A and the possibility of formation of anion B is
We explored different bases such as K2CO3, Cs2CO3, and higher than that of anion A.
t-BuOK. Consequently, the best result was obtained with
Six probable intramolecular attacks and their related tran-
t-BuOK (Table 4, entry 3). Reducing the amount of the base sition states (TS) have been considered (Fig. 4). Among all,
from 1.2 equiv. to 1 equiv. had a negative impact on yields the addition of a deprotonated chiral center to β carbon (TS2)
(Table 4, entry 4). For improving the yield of the cyclization has the lowest activation energy (ΔE‡) which is 21.0 kcal
reaction, the effects of different solvents were studied mol−1 and can be performed at the reaction temperature
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Fig. 2 ORTEP structures of 7a and 7f.
Fig. 3 DFT details for anions A and B (calculated at the PCM (DMF)/
B3LYP/6-31G(d) level).
Fig. 4 Relative activation energies, the geometry of transition state
structures and the intermediate (ΔE is related to the reaction of anion A
to form INT1, ΔE‡ is the activation energy and ΔΔE‡ is the relative acti-
vation energy; energies are given in kcal mol−1).
(Fig. 4). The attack of the amide moiety on γ carbon is barrier-
less (Scheme S1‡); thus, its intermediate (INT1) has been
compared with other transition states. The energy of INT1 is
higher than that of TS2 (41.4 kcal mol−1); so it can be said
that formation of INT1 is impossible under the reaction
conditions.
the central position of the allene in a 5-exo-dig fashion to
provide the preferentially 5-membered ring products C after
protonation of B.
The local Fukui function15 and LUMO contribution ana-
lysis (LUMO-CA)16 model (Scheme S2, ESI‡) cannot predict
the regioselectivity of the reaction, but β carbon has the
lowest orbital electronegativity (OE)17 and the highest
Mulliken charge (Fig. 3 and S2, ESI‡). Therefore, it is
reasonable that an intra-C-nucleophile attack on β carbon
has the lowest barrier energy which leads to the main
product.
On the basis of the above observations, a tentative mecha-
nism pathway is drawn in Scheme 3. Under basic reaction con-
Scheme 3
A
plausible mechanism for formation of 3-pyrroline
ditions, the intermediate A is formed, followed by an attack on derivatives.
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N-(2-(tert-Butylamino)-1-(3-nitrophenyl)-2-oxoethyl)-N-(prop-
Conclusion
2-yn-1-yl)benzamide (5b). Colorless solid mp. 132–133 °C,
1
In conclusion, we have successfully established an efficient yield 85%, Rf = 0.37 (n-hexane/EtOAc 4 : 1); H NMR (400 MHz,
and novel route for the regio- and chemo-selective synthesis of CDCl3) δ 8.36 (brs, 1H, H–Ar), 8.20 (t, J = 7.4 Hz, 1H, H–Ar),
3-pyrroline skeletons through a 5-exo-dig intramolecular cycli- 7.88–7.78 (m, 1H, H–Ar), 7.60 (t, J = 8.0 Hz, 2H, H–Ar), 7.56 (d,
zation reaction of a stable allenic-Ugi intermediate, generated J = 8.0 Hz, 1H, H–Ar), 7.47 (t, J = 7.4 Hz, 2H, H–Ar), 7.45 (d, J =
by the ATA reaction from Ugi-adducts. The regio- and chemos- 8.0 Hz, 1H, H–Ar), 6.45 (s, 1H, C(sp3)–H), 5.96 (brs, 1H, –NH),
electivities were explained by DFT calculations. This protocol 4.29 (dd, J = 18.4, 2.4 Hz, 1H, –CH
̲N), 4.09 (dd, J = 18.4, 2.4 Hz,
is highly diverse and productive. Further experiments on asym- 1H, –CHN), 2.09 (s, 1H, propargylic H), 1.39 (s, 9H, H-tBu);
̲
metric addition reactions are in progress in our lab.
172.5, 167.5, 148.3, 137.1, 135.5, 134.6, 130.8, 129.7, 128.7,
127.1, 124.6, 123.4, 87.6, 79.2, 72.9, 62.2, 52.0, 28.6; ESI (+)
(m/z): for C22H23N3NaO4 [M + Na]+ 415.3.
N-(2-(tert-Butylamino)-1-(2-chlorophenyl)-2-oxoethyl)-3-chloro-
Experimental section
N-(prop-2-yn-1-yl)benzamide
(5c).
Colorless
solid,
General information
mp. 204–205 °C, yield 88%, Rf = 0.33 (n-hexane/EtOAc 4 : 1); 1H
NMR (400 MHz, CDCl3) (mixture of two rotamers (67 : 33))
δ 7.74–7.52 (m, 3H, H–Ar, mixture of two rotamers), 7.46–7.40
(m, 2H, H–Ar, mixture of two rotamers), 7.38–7.31 (m, 3H,
H–Ar, mixture of two rotamers), 6.24 (s, 1H, N–H, major
rotamer), 5.70 (s, 1H, C(sp3)–H, mixture of two rotamers), 5.39
All reagents and solvents were purchased commercially and
used as received without further purification. All reactions
were monitored by thin layer chromatography (TLC) on Merck
silica gel 60 F254 plates. Column chromatography purification
was performed on silica gel (63–200 mesh ASTM). Melting
points (mp) were measured via an Electrothermal 9100 appar-
atus and were uncorrected. Fourier transform infrared (FT-IR)
spectra were recorded on an AABFT-IR (FTLA 2000) spectro-
photometer with KBr disks. NMR (1H and 13C) spectra were
recorded on a Bruker 300 MHz, 400 MHz or 600 MHz NMR
spectrometer in CDCl3 or DMSO-d6 at room temperature. The
(brs, 1H, N–H, minor rotamer), 4.26–4.14 (m, 1H, –CH
̲N,
mixture of two rotamers), 4.12–3.85 (m, 1H, –CHN, mixture of
̲
two rotamers), 2.04 (s, 1H, propargylic H, minor rotamer), 1.88
(s, 1H, propargylic H, major rotamer), 1.41 (s, 9H, H-tBu,
mixture of two rotamers); 13C NMR (100 MHz, CDCl3) (for the
major rotamer) δ 170.8, 168.2, 136.9, 134.4, 132.4, 132.3, 130.8,
130.5, 130.0, 129.9, 127.5, 127.3, 126.0, 125.5, 96.1, 79.2, 71.5,
60.4, 52.0, 28.6; ESI (+) (m/z): for C44H4435Cl4N4NaO4 [2M +
Na]+ 857.3, and; ESI (−) (m/z): for C22H2235Cl2N2O2 [M − H]−
415.2.
N-(2-(tert-Butylamino)-1-(2-chlorophenyl)-2-oxoethyl)-4-meth-
oxy-N-(prop-2-yn-1-yl)benzamide (5d). Colorless solid, mp.
164–165 °C, yield 82%, Rf = 0.39 (n-hexane/EtOAc 4 : 1); 1H
NMR (400 MHz, CDCl3) δ 7.70–7.49 (m, 3H, H–Ar), 7.43–7.37
(m, 1H, H–Ar), 7.35–7.28 (m, 2H, H–Ar), 6.91 (d, J = 8.6 Hz, 2H,
1
abbreviations of multiplicity for H NMR data are reported as
follows: s (singlet), d (doublet), t (triplet), q (quartet) and m
(multiplet). Coupling constants (J) and chemical shifts (δ) were
expressed in Hz and ppm, respectively. High-resolution mass
spectrometry (ESI-HRMS) measurements were performed
using an Agilent Q-TOF LC-MS spectrometer.
General procedure for the synthesis of Ugi-4CR 5a–m
To a solution of aromatic aldehydes 1a–g (1 mmol) in ethanol H–Ar), 6.10 (brs, 1H, –NH), 5.93 (s, H, C(sp3)–H), 4.26 (d, J =
(5 ml) was added the propargyl amine 2 (1 mmol, 55 mg), and 18.2 Hz, 1H, –CHN), 4.00 (dd, J = 18.2, 1.9 Hz, 1H, –CHN), 3.82
̲
̲
the mixture was stirred at room temperature for 1 h. Then, car- (s, 3H, O–CH3), 1.91 (s, 1H, propargylic H), 1.42 (s, 9H, H-tBu);
boxylic acids 3a–e (1 mmol) were added, and stirring was con- 13C NMR (100 MHz, CDCl3) δ 172.2, 168.6, 161.3, 136.7, 132.9,
tinued for 15 min, followed by the addition of isocyanides 4a 130.8, 130.2, 129.8, 129.4, 127.3, 127.2, 113.6, 96.1, 79.5, 71.2,
and 4b (1 mmol). The mixture was stirred for 24 h at room 60.9, 55.3, 52.0, 28.7; ESI (+) (m/z): for C23H2635ClN2O3
temperature. The progress of the reaction was monitored by [M + H]+ 413.2, and for C46H5035Cl2N4NaO6 [2M + Na]+ 847.3.
TLC (n-hexane/EtOAc 3 : 1). The precipitate formed was filtered
N-(1-(2-Chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-(prop-
and dried. In some cases (5d, 5g, 5k, 5l, and 5m), purification 2-yn-1-yl)benzamide (5e). Colorless solid, mp. 169–170 °C, yield
was done using preparative TLC (n-hexane/EtOAc 4 : 1). Yields 84%, Rf = 0.39 (n-hexane/EtOAc 4 : 1); 1H NMR (400 MHz,
(82–90%).
CDCl3) (mixture of two rotamers (65 : 35)) δ 7.72–7.53 (m, 3H,
N-(2-(tert-Butylamino)-2-oxo-1-phenylethyl)-N-(prop-2-yn-1- H–Ar, mixture of two rotamers), 7.47–7.39 (m, 4H, H–Ar,
yl)benzamide (5a).18 Colorless solid mp. 141–142 °C, yield mixture of two rotamers), 7.36–7.29 (m, 2H, H–Ar, mixture of
86%, Rf = 0.33 (n-hexane/EtOAc 4 : 1); 1H NMR (400 MHz, two rotamers), 6.33 (s, 1H, C(sp3)–H, major rotamer), 6.11 (brs,
CDCl3) δ 7.63–7.54 (m, 2H, H–Ar), 7.45–7.42 (m, 4H, H–Ar), 1H, C(sp3)–H, minor rotamer), 5.91 (s, 1H, NH, major
7.40–7.33 (m, 4H, H–Ar), 5.87 (s, 2H, C(sp3)–H, NH), 4.18 (dd, rotamer), δ 5.52 (brs, 1H, NH, minor rotamer), 4.25 (dd, J =
J = 18.3, 2.3 Hz, 1H, CH2–N), 4.01 (d, J = 18.3 Hz, 1H, CH2–N), 18.0, 2.3 Hz, 1H, –CH
̲N, mixture of two rotamers), 3.95 (d, J =
2.00 (s, 1H, propargylic H), 1.39 (s, 9H, H-tBu); 13C NMR 18 Hz, 1H, –CH
̲
(100 MHz, CDCl3) δ 172.4, 168.4, 135.4, 134.7, 130.3, 129.8, H–cyclohexyl, mixture of two rotamers), 2.04–1.88 (m, 3H, pro-
128.9, 128.7, 128.5, 127.1, 96.1, 76.7, 71.6, 62.8, 51.9, 28.7; ESI pargylic H, H–cyclohexyl, mixture of two rotamers), 1.76–1.60
(−) (m/z): for C22H23N2O2 [M − H]− 347.3.
(m, 3H, H–cyclohexyl, mixture of two rotamers), 1.44–1.34 (m,
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2H, H–cyclohexyl, mixture of two rotamers), 1.28–1.11 (m, 3H, 204–205 °C, yield 83%, Rf = 0.36 (n-hexane/EtOAc 4 : 1); 1H
H–cyclohexyl, mixture of two rotamers); 13C NMR (100 MHz, NMR (400 MHz, CDCl3) δ 7.71–7.43 (m, 4H, H–Ar), 7.35 (t, J =
CDCl3) (for the major rotamer) δ 172.3, 168.1, 135.2, 132.5, 7.2 Hz, 1H, H–Ar), 7.27–7.19 (m, 3H, H–Ar), 6.24 (brs, 1H,
132.4, 131.0, 130.4, 130.3, 129.9, 128.4, 127.2, 127.1, 96.1, 79.3, C(sp3)–H), 6.01(brs, 1H, NH), 4.26 (dd, J = 18.3, 2.3 Hz, 1H,
71.3, 59.0, 48.8, 33.0, 25.5, 24.9, 24.8; ESI (−) (m/z): for CH2–N), 3.93 (dd, J = 18.3, 2.3 Hz, 1H, CH2–N), 3.88–3.81 (m,
C24H2435ClN2O2 [M − H]− 407.2.
1H, N–CH–cyclohexyl), 2.37 (s, 3H, –CH3), 2.01–1.90 (m, 3H,
3-Chloro-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)- propargylic H, H–cyclohexyl), 1.76–1.58 (m, 3H, H–cyclohexyl),
N-(prop-2-yn-1-yl)benzamide (5f). Colorless solid, mp. 1.41–1.31 (m, 2H, H–cyclohexyl), 1.24–1.11 (m, 3H, H–cyclo-
173–174 °C, yield 86%, Rf = 0.38 (n-hexane/EtOAc 4 : 1); 1H hexyl); 13C NMR (100 MHz, CDCl3) δ 172.5, 168.3, 140.6, 134.3,
NMR (400 MHz, CDCl3) (mixture of two rotamers (64 : 36)) 133.2, 132.3, 131.2, 130.4, 129.0, 127.8, 127.4, 127.3, 96.1, 79.3,
δ 7.67–7.47 (m, 3H, H–Ar, mixture of two rotamers), 7.45–7.40 71.4, 61.5, 48.8, 32.8, 25.5, 24.9, 24.7, 21.5; ESI (+) (m/z): for
(m, 2H, H–Ar, mixture of two rotamers), 7.37–7.29 (m, 3H, H– C50H5479Br2N4NaO4 [2M + Na]+ 957.4.
Ar, mixture of two rotamers), 6.33 (s, 1H, C(sp3)–H, major
N-(1-(2-Bromophenyl)-2-(cyclohexylamino)-2-oxoethyl)-3-chloro-
rotamer), 6.02 (brs, 1H, C(sp3)–H, minor rotamer), 5.91 (s, 1H, N-(prop-2-yn-1-yl)benzamide (5j). Colorless solid, mp.
NH, major rotamer), 5.49 (brs, 1H, NH, minor rotamer), 4.23 188–190 °C, yield 82%, Rf = 0.39 (n-hexane/EtOAc 4 : 1); 1H
(d, J = 18 Hz, 1H, –CH
̲N, mixture of two rotamers), 3.93–3.84 NMR (400 MHz, CDCl3) (mixture of two rotamers (77 : 23))
(m, 2H, –CHN, N–CH–cyclohexyl, mixture of two rotamers), δ 7.70–7.49 (m, 4H, H–Ar, mixture of two rotamers), 7.44–7.42
̲
2.04–1.91 (m, 3H, propargylic H, H–cyclohexyl, mixture of two (m, 1H, H–Ar, mixture of two rotamers), 7.38 (t, J = 7.6 Hz, 1H,
rotamers), 1.75–1.61 (m, 3H, H–cyclohexyl, mixture of two rota- H–Ar, mixture of two rotamers), 7.36 (t, J = 7.6 Hz, 1H, H–Ar,
mers), 1.42–1.32 (m, 2H, H–cyclohexyl, mixture of two rota- mixture of two rotamers), 7.28 (t, J = 7.5 Hz, 1H, H–Ar, mixture
mers), 1.25–1.07 (m, 3H, H–cyclohexyl, mixture of two rota- of two rotamers), 6.26 (s, 1H, C(sp3)–H, major rotamer), 6.01
mers); 13C NMR (100 MHz, CDCl3) (for the major rotamer) (s, 1H, C(sp3)–H, minor rotamer), 5.87 (s, 1H, NH, major
δ 170.8, 167.9, 136.9, 134.4, 133.0, 132.3, 130.9, 130.5, 130.0, rotamer), 5.42 (s, 1H, N–H, minor rotamer), 4.24 (d, J = 17.6
129.8, 127.6, 127.5, 127.3, 125.3, 96.1, 78.8, 71.6, 58.8, 48.8, Hz, 1H, –CH
32.8, 25.4, 24.8, 24.8; ESI (+) (m/z): for C24H2535Cl2N2O2 –CH
N, N–CH–cyclohexyl, mixture of two rotamers), 2.05–1.90
[M + H]+ 443.2, and for C48H4835Cl4N4NaO4 [2M + Na]+ 909.4.
(m, 3H, propargylic H, H–cyclohexyl, mixture of two rotamers),
̲N, mixture of two rotamers), 3.99–3.82 (m, 2H,
̲
N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-N-(prop-2-yn-1- 1.82–1.62 (m, 3H, CH–cyclohexyl, mixture of two rotamers),
yl)benzamide (5g). Colorless solid, mp. 138–139 °C, yield 87%, 1.48–1.32 (m, 2H, CH–cyclohexyl, mixture of two rotamers),
Rf = 0.38 (n-hexane/EtOAc 4 : 1); 1H NMR (400 MHz, CDCl3) 1.27–1.08 (m, 3H, CH–cyclohexyl, mixture of two rotamers);
δ 7.64–7.57 (m, 2H, H–Ar), 7.48–7.41 (m, 4H, H–Ar), 7.40–7.37 13C NMR (100 MHz, CDCl3) (for the major rotamer) δ 170.8,
(m, 4H, H–Ar), 6.02 (brs, 2H, C(sp3)–H, NH), 4.19 (d, J = 18.4 168.0, 136.9, 134.4, 133.9, 133.3, 131.1, 130.6, 130.5, 129.8,
Hz, 1H, CH2–N), 3.99 (dd, J = 18.3, 2.5 Hz, 1H, CH2–N), 127.9, 127.6, 127.5, 125.4, 78.8, 77.3, 71.7, 61.3, 48.9, 32.8,
3.93–3.85 (m, 1H, N–CH–cyclohexyl), 2.04–1.93 (m, 3H, pro- 25.4, 24.9, 24.8; ESI (−) (m/z): for C24H2379Br35ClN2O2 [M − H]−
pargylic H, H–cyclohexyl), 1.73–1.60 (m, 3H, H–cyclohexyl), 483.3.
1.43–1.32 (m, 2H, H–cyclohexyl), 1.22–1.12 (m, 3H, H–cyclo-
N-(2-(Cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl)-4-
hexyl); 13C NMR (100 MHz, CDCl3) δ 172.4, 168.1, 135.3, 134.5, methyl-N-(prop-2-yn-1-yl)benzamide (5k). Colorless solid,
130.4, 129.7, 128.9, 128.7, 128.6, 127.1, 96.1, 79.7, 72.0, 62.5, mp. 132–133 °C, yield 85%, Rf = 0.35 (n-hexane/EtOAc 4 : 1); 1H
48.7, 32.9, 25.5, 24.9, 24.8; ESI (+) (m/z): for C24H27N2O2 NMR (400 MHz, CDCl3) δ 7.64–7.29 (m, 4H, H–Ar), 7.20 (d, J =
[M + H]+ 375.3, and for C48H52N4NaO4 [2M + Na]+ 771.3.
7.5 Hz, 2H, H–Ar), 6.87 (d, J = 7.9 Hz, 2H, H–Ar), 6.35 (d, J =
N-(2-(Cyclohexylamino)-1-(3-nitrophenyl)-2-oxoethyl)-N-(prop- 7.7 Hz, 1H, N–H), 5.95 (brs, 1H, C(sp3)–H), 4.18 (d, J = 18.3 Hz,
2-yn-1-yl)benzamide (5h). Colorless white solid, mp. 1H, –CH2–N), 3.98 (d, J = 18.3 Hz, 1H, –CH2–N), 3.90–3.81 (m,
174–175 °C, yield 90%, Rf = 0.40 (n-hexane/EtOAc 4 : 1); 1H 1H, N–CH–cyclohexyl), 3.78 (s, 3H, O–CH3), 2.36 (s, 3H, –CH3),
NMR (400 MHz, CDCl3) δ 8.37 (brs, 1H, H–Ar), 8.21 (d, J = 8.2 2.05 (s, 1H, propargylic H), 1.97–1.87 (m, 2H, CH–cyclohexyl),
Hz, 1H, H–Ar), 7.84 (brs, 1H, H–Ar), 7.62–7.52 (m, 3H, H–Ar), 1.72–1.54 (m, 3H, CH–cyclohexyl), 1.42–1.27 (m, 2H, CH–cyclo-
7.51–7.42 (m, 3H, H–Ar), 6.68 (brs, 1H, C(sp3)–H), 6.06 (brs, hexyl), 1.19–1.04 (m, 3H, CH–cyclohexyl); 13C NMR (100 MHz,
1H, NH), 4.32 (d, J = 18.4 Hz, 1H, CH2–N), 4.09 (dd, J = 18.4, CDCl3) δ 172.4, 168.7, 159.7, 140.4, 132.5, 131.0, 129.1, 127.1,
2.3 Hz, 1H, CH2–N), 3.90–3.82 (m, 1H, N–CH–cyclohexyl), 2.09 126.6, 114.1, 80.0, 77.4, 71.7, 62.3, 55.2, 48.6, 32.7, 25.4, 24.8,
(t, J = 2.3 Hz, 1H, propargylic H), 1.97–1.87 (m, 2H, H–cyclo- 24.7, 21.4; ESI (+) (m/z): for C26H31N2O3 [M + H]+ 419.3, and for
hexyl), 1.72–1.58 (m, 3H, H–cyclohexyl), 1.42–1.32 (m, 2H, H– C52H60N4NaO6 [2M + Na]+ 859.6.
cyclohexyl), 1.22–1.11 (m, 3H, H–cyclohexyl); 13C NMR
N-(2-(Cyclohexylamino)-2-oxo-1-(p-tolyl)ethyl)-N-(prop-2-yn-
(100 MHz, CDCl3) δ 172.6, 167.3, 148.3, 137.0, 135.4, 134.5, 1-yl)benzamide (5l). Colorless solid, mp. 151–152 °C, yield
130.8, 129.7, 128.7, 127.1, 124.5, 123.4, 96.1, 79.1, 72.9, 62.5, 84%, Rf = 0.40 (n-hexane/EtOAc 4 : 1); 1H NMR (400 MHz,
48.8, 32.7, 32.6, 25.4, 24.8, 24.7; ESI (+) (m/z): for C24H26N3O4 CDCl3) δ 7.62–7.48 (m, 2H, H–Ar), 7.47–7.29 (m, 3H, H–Ar),
[M + H]+ 420.3, and for C48H50N6NaO8 [2M + Na]+ 861.5.
7.22 (d, J = 7.9 Hz, 2H, H–Ar), 7.21–7.10 (m, 2H, H–Ar),
N-(1-(2-Bromophenyl)-2-(cyclohexylamino)-2-oxoethyl)-4-methyl- 6.13–5.58 (m, 2H, C(sp3)–H, N–H), 4.17 (d, J = 18.0 Hz, 1H,
N-(prop-2-yn-1-yl)benzamide (5i). Colorless solid, mp. –CH2–N), 3.97 (d, J = 18.0 Hz, 1H, –CH2–N), 3.89–3.81 (m, 1H,
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N–CH–cyclohexyl), 2.36 (s, 3H, CH3), 2.07 (s, 1H, propargylic HRMS-ESI (m/z): calcd for C23H27N2O2 [M + H]+ 363.2091,
H), 2.01–1.91 (m, 2H, CH–cyclohexyl), 1.77–1.56 (m, 3H, CH– found 363.2099.
cyclohexyl), 1.44–1.31 (m, 2H, CH–cyclohexyl), 1.26–1.09 (m,
N-(Buta-2,3-dien-1-yl)-N-(2-(tert-butylamino)-1-(3-nitrophe-
3H, CH–cyclohexyl); 13C NMR (150 MHz, CDCl3) δ 172.5, 168.4, nyl)-2-oxoethyl)benzamide (6b). Pale yellow, mp. 138–139 °C,
1
140.6, 138.6, 135.4, 132.4, 131.5, 130.3, 129.6, 127.0, 96.1, 79.9, yield 83%, Rf = 0.32 (n-hexane/EtOAc 3 : 1); H NMR (600 MHz,
72.0, 61.6, 48.7, 32.9, 25.5, 24.8, 24.7, 21.8, 21.2; ESI (−) (m/z): CDCl3) δ 8.34 (brs, 1H, H–Ar), 8.19 (dd, J = 8.2, 2.1 Hz, 1H, H–
for C25H27N2O2 [M − H]− 387.1.
Ar), 7.84–7.81 (m, 1H, H–Ar), 7.57 (t, J = 7.9 Hz, 1H, H–Ar), 7.49
N-(1-(3-Bromophenyl)-2-(cyclohexylamino)-2-oxoethyl)-3-meth- (d, J = 7.3 Hz, 2H, H–Ar), 7.47–7.40 (m, 3H, H–Ar), 6.62 (brs,
oxy-N-(prop-2-yn-1-yl)benzamide (5m). Colorless solid, mp. 1H, NH), 5.88 (brs, 1H, C(sp3)–H), 4.90 (brs, 1H, allenic H),
153–154 °C, yield 85%, Rf = 0.38 (n-hexane/EtOAc 4 : 1); 1H 4.68–4.60 (m, 2H, allenic H), 4.00–4.08 (m, 2H, –CH2–N), 1.39
NMR (400 MHz, CDCl3) δ 7.71–7.48 (m, 1H, H–Ar), 7.49 (d, J = (s, 9H, H-tBu); 13C NMR (151 MHz, CDCl3) δ 208.7, 173.2,
7.6 Hz, 1H, H–Ar), 7.47–7.36 (m, 1H, H–Ar), 7.33 (t, J = 7.9 Hz, 167.8, 148.3, 137.7, 135.5, 135.1, 130.3, 129.6, 128.6, 126.8,
1H, H–Ar), 7.27–7.22 (m, 1H, H–Ar), 7.21–7.06 (m, 2H, H–Ar), 124.1, 123.2, 87.6, 77.5, 62.9, 51.9, 47.6, 28.6; IR (KBr): νmax
=
6.99 (dd, J = 8.3, 1.9 Hz, 1H, H–Ar), 6.28 (brs, 1H, C(sp3)–H), 1957 (CvCvC), 1651 (CvO) cm−1; HRMS-ESI (m/z): calcd for
5.97 (brs, 1H, N–H), 4.23 (d, J = 18.3 Hz, 1H, –CH2–N), 4.03 C23H26N3O4 [M + H]+ 408.1945, found 408.1954.
(dd, J = 18.3, 2.1 Hz, –CH2–N), 3.92–3.83 (m, 1H, N–CH–cyclo-
N-(Buta-2,3-dien-1-yl)-N-(2-(tert-butylamino)-1-(2-chlorophe-
hexyl), 3.81 (s, 3H, O–CH3), 2.08 (s, 1H, propargylic H), nyl)-2-oxoethyl)-3-chlorobenzamide (6c). Colorless solid,
1.99–1.87 (m, 2H, CH–cyclohexyl), 1.76–1.55 (m, 3H, CH–cyclo- mp. 146–148 °C, yield 86%, Rf = 0.30 (n-hexane/EtOAc 3 : 1); 1H
hexyl), 1.41–1.30 (m, 2H, CH–cyclohexyl), 1.21–1.04 (m, 3H, NMR (600 MHz, CDCl3) (mixture of two rotamers (66 : 34))
CH–cyclohexyl); 13C NMR (100 MHz, CDCl3) δ 172.2, 167.7, δ 7.69 (brs, 1H, H–Ar, mixture of two rotamers), 7.49 (s, 1H,
159.5, 136.9, 136.1, 132.8, 131.8, 130.3, 129.8, 128.1, 122.7, H–Ar, mixture of two rotamers), 7.42–7.34 (m, 6H, H–Ar,
119.2, 116.8, 112.1, 96.1, 79.6, 72.3, 61.6, 55.4, 48.7, 32.8, 25.4, mixture of two rotamers), 6.15 (brs, 1H, C(sp3)–H, major
24.8, 24.7; ESI (−) (m/z): for C25H2679BrN2O3 [M − H]− 481.2.
rotamer), 5.72 (brs, 1H, NH, major rotamer), 5.37–5.34 (m, 2H,
C(sp3)–H, NH, minor rotamer), 5.13 (brs, 1H, allenic H, minor
rotamer), 4.69 (brs, 1H, allenic H, major rotamer), 4.53–4.45
(m, 2H, – allenic H, major rotamer), 4.33 (m, 2H, allenic H,
General procedure for the synthesis of allenic-Ugi products
(6a–m) through sequential Ugi-4CR/ATA reactions
To a stirred solution of propargylamine as a primary amine minor rotamer), 3.95–3.86 (m, 2H, –CH2–N, mixture of two
(1 mmol) in EtOH (2 mL) was added an aldehyde (1 mmol) rotamers), 1.42 (s, 9H, H-tBu, mixture of two rotamers); 13C
and the resulting solution was stirred at ambient temperature NMR (75 MHz, DMSO-d6) (for the major rotamer) δ 207.3,
for 20 min. A carboxylic acid was added to the reaction 169.7, 168.4, 138.4, 135.4, 134.0, 132.9, 130.9, 130.3, 130.2,
mixture and stirring was continued for 5 min. Afterwards, an 129.7, 127.6, 126.2, 125.7, 125.5, 86.3, 75.6, 62.8, 50.6, 44.1,
isocyanide (1 mmol) was added and the mixture was stirred at 28.1; IR (KBr): νmax = 1956 (CvCvC), 1685 (CvO) cm−1
;
room temperature for 24 h. The reaction progress was moni- HRMS-ESI (m/z): calcd for C23H2535Cl2N2O2 [M + H]+ 431.1491,
tored by TLC. After consumption of all the starting materials, found 431.1500.
the solvent was removed on a rotary evaporator. Thereafter, dry
N-(Buta-2,3-dien-1-yl)-N-(2-(tert-butylamino)-1-(2-chlorophe-
dioxane (2 mL), paraformaldehyde (2.5 mmol), CuBr nyl)-2-oxoethyl)-4-methoxybenzamide (6d). Colorless solid,
(60 mol%), and diisopropyl amine (2.5 mmol) were added to mp. 151–154 °C, yield 80%, Rf = 0.34 (n-hexane/EtOAc 3 : 1); 1H
the desired Ugi-4CR product. The resulting mixture was stirred NMR (300 MHz, CDCl3) δ 7.58 (brs, 1H, H–Ar), 7.47 (d, J =
under an Ar atmosphere for 12 h at 100 °C. After completion 9.0 Hz, 2H, H–Ar), 7.44–7.38 (m, 1H, H–Ar), 7.33–7.28 (m, 2H,
of the reaction (based on TLC), the resulting mixture was H–Ar), 6.87 (d, J = 9.0 Hz, 2H, H–Ar), 5.84 (brs, 2H, C(sp3)–H,
cooled to room temperature, was diluted with ether (5 mL) and NH), 4.95 (brs, 1H, allenic H), 4.55–4.39 (m, 2H, allenic H),
water (5 mL) and then the aqueous layer was extracted with 4.15–3.95 (m, 2H, –CH2–N), 3.82 (s, 3H, O–CH3), 1.41 (s, 9H,
ether (3 × 5 mL). The organic layer was washed with brine, H-tBu); 13C NMR (75 MHz, CDCl3) δ 208.3, 172.7, 168.5, 160.8,
dried over anhydrous MgSO4 and the solvent was removed 135.8, 133.2, 130.9, 129.9, 129.9, 128.9, 128.4, 127.2, 113.6,
under reduced pressure. The resulting crude product was puri- 87.5, 76.0, 55.7, 55.3, 54.9, 51.8, 28.6; IR (KBr): νmax = 1958
fied by column chromatography (n-hexane/EtOAc 3 : 1) to (CvCvC), 1683 (CvO) cm−1; HRMS-ESI (m/z): calcd for
afford the allenic-Ugi product. Yields (82–87%).
C24H2835ClN2O3 [M + H]+ 427.1997, found 427.2007.
N-(Buta-2,3-dien-1-yl)-N-(2-(tert-butylamino)-2-oxo-1-pheny-
N-(Buta-2,3-dien-1-yl)-N-(1-(2-chlorophenyl)-2-(cyclohexyl-
lethyl)benzamide (6a). Colorless solid, mp. 130–133 °C, yield amino)-2-oxoethyl)benzamide (6e). Colorless solid, mp.
84%, Rf = 0.31 (n-hexane/EtOAc 3 : 1); 1H NMR (600 MHz, 165–164 °C, yield 81%, Rf = 0.36 (n-hexane/EtOAc 3 : 1); 1H
CDCl3) δ 7.52–7.49 (m, 3H, H–Ar), 7.43–7.35 (m, 7H, H–Ar), NMR (600 MHz, CDCl3) (mixture of two rotamers (63 : 37))
5.91 (brs, 1H, C(sp3)–H), 4.73 (brs, 1H, allenic H), 4.52 (brs, δ 7.72 (brs, 1H, H–Ar, mixture of two rotamers), 7.49 (d, J =
2H, allenic H), 4.02–3.94 (m, 2H, –CH2–N), 1.40 (s, 9H, H-tBu); 7.1 Hz, 2H, H–Ar, mixture of two rotamers), 7.45–7.37 (m, 4H,
13C NMR (151 MHz, CDCl3) δ 208.5, 172.9, 168.8 136.2, 135.2, H–Ar, mixture of two rotamers), 7.32–7.31 (m, 2H, H–Ar,
129.8, 129.5, 128.8, 128.6, 128.4, 126.9, 87.9, 76.5, 63.1, 51.8, mixture of two rotamers), 6.19 (s, 1H, C(sp3)–H, major
47.3, 28.6; IR (KBr): νmax = 1959 (CvCvC), 1670 (CvO) cm−1
;
rotamer), 5.98 (brs, 1H, NH, major rotamer), δ 5.84 (brs, 1H,
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C(sp3)–H, minor rotamer), 5.50 (brs, 1H, NH, minor rotamer), 3.84–3.81 (m, 1H, H–cyclohexyl, mixture of two rotamers), 1.90
5.22 (brs, 1H, allenic H, minor rotamer), 4.80 (brs, 1H, allenic (dd, J = 12.6, 4.5 Hz, 2H, H–cyclohexyl, mixture of two rota-
H, major rotamer), 4.49–4.40 (m, 2H, allenic H, mixture of two mers), 1.67–1.63 (m, 2H, H–cyclohexyl, mixture of two rota-
rotamers), 4.14–3.90 (m, 3H, –CH2–N, CH–cyclohexyl, mixture mers), 1.56 (d, J = 13.4 Hz, 1H, H–cyclohexyl, mixture of two
of two rotamers), 2.01–1.94 (m, 2H, H–cyclohexyl, mixture of rotamers), 1.36–1.30 (m, 2H, H–cyclohexyl, mixture of two rota-
two rotamers), 1.75–1.69 (m, 2H, H–cyclohexyl, mixture of two mers), 1.14–1.04 (m, 3H, H–cyclohexyl, mixture of two rota-
rotamers), 1.64–1.61 (m, 1H, H–cyclohexyl, mixture of two rota- mers); 13C NMR (151 MHz, CDCl3) (for the major rotamer)
mers), 1.44–1.36 (m, 2H, H–cyclohexyl, mixture of two rota- δ 208.5, 172.9, 168.5, 136.2, 135.1, 129.8, 129.4, 128.8, 128.5,
mers), 1.22–1.10 (m, 3H, H–cyclohexyl, mixture of two rota- 128.4, 126.8, 87.8, 76.5, 62.7, 48.6, 47.4, 32.8, 25.5, 24.8, 24.7;
mers); 13C NMR (151 MHz, CDCl3) (for the major rotamer) δ IR (KBr): νmax = 1956 (CvCvC), 1681 (CvO) cm−1; HRMS-ESI
208.3, 172.8, 168.2, 136.2, 135.8, 132.9, 131.1, 130.1, 129.9, (m/z): calcd for C25H29N2O2 [M
+
H]+ 389.2252, found
129.8, 128.4, 127.2, 126.9, 87.4, 76.1, 60.1, 48.7, 32.8, 25.5, 389.2261.
24.8, 24.8; IR (KBr): νmax = 1960 (CvCvC), 1650 (CvO) cm−1
;
N-(Buta-2,3-dien-1-yl)-N-(2-(cyclohexylamino)-1-(3-nitrophenyl)-
HRMS-ESI (m/z): calcd for C25H2835ClN2O2 [M + H]+ 423.1995, 2-oxoethyl)benzamide (6h). Pale yellow solid, mp. 148–149 °C,
1
found 423.2005.
yield 87%, Rf = 0.37 (n-hexane/EtOAc 3 : 1); H NMR (600 MHz,
N-(Buta-2,3-dien-1-yl)-N-(1-(2-chlorophenyl)-2-(cyclohexyl- CDCl3) δ 8.36 (brs, 1H, H–Ar), 8.21 (d, J = 8.2 Hz, 1H, H–Ar),
amino)-2-oxoethyl)-3-methylbenzamide (6f). Colorless solid, 7.90–7.80 (m, 1H, H–Ar), 7.58 (t, J = 8.0 Hz, 1H, H–Ar),
mp. 152–154 °C, yield 85%, Rf = 0.34 (n-hexane/EtOAc 3 : 1); 1H 7.51–7.44 (m, 5H, H–Ar), 6.68 (brs, 1H, C(sp3)–H), 5.90 (brs,
NMR (600 MHz, CDCl3) (mixture of two rotamers (69 : 31)) 1H, NH), 4.93 (brs, 1H, allenic H), 4.71–4.62 (m, 2H, allenic
δ 7.69 (brs, 1H, H–Ar, mixture of two rotamers), 7.48 (m, 2H, H), 4.05 (brs, 2H, –CH2–N), 3.92–3.86 (m, 1H, H–cyclohexyl),
H–Ar, mixture of two rotamers), 7.40 (t, J = 7.2 Hz, 1H, H–Ar, 1.99–1.93 (m, 2H, H–cyclohexyl), 1.74–1.69 (m, 2H, H–cyclo-
mixture of two rotamers), 7.37 (s, 1H, H–Ar, mixture of two hexyl), 1.64–1.61 (m, 1H, H–cyclohexyl), 1.44–1.36 (m, 2H,
rotamers), 7.36–7.33 (m, 3H, H–Ar, mixture of two rotamers), H–cyclohexyl), 1.24–1.15 (m, 3H, H–cyclohexyl); 13C NMR
6.22 (brs, 1H, C(sp3)–H, major rotamer), 5.86 (brs, 1H, NH, (151 MHz, CDCl3) δ 208.7, 173.2, 167.5, 148.4, 137.5, 135.4,
major rotamer), 5.68 (s, 1H, C(sp3)–H, minor rotamer), 5.43 134.9, 130.4, 129.6, 128.7, 126.8, 124.0, 123.2, 87.4, 77.4, 62.8,
(brs, 1H, NH, minor rotamer), 5.16 (brs, 1H, allenic H, minor 48.7, 47.0, 32.8, 32.7, 25.5, 24.7. IR (KBr): νmax = 1965
rotamer), 4.71 (brs, 1H, allenic H, major rotamer), 4.55–4.37 (CvCvC), 1666 (CvO) cm−1; HRMS-ESI (m/z): calcd for
(m, 2H, allenic H, mixture of two rotamers), 4.20–3.81 (m, 3H, C25H28N3O4 [M + H]+ 434.2100, found 434.2110.
–CH2–N, CH–cyclohexyl, mixture of two rotamers), 2.00–1.94
N-(1-(2-Bromophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-(buta-
(m, 2H, H–cyclohexyl, mixture of two rotamers), 1.75–1.69 (m, 2,3-dien-1-yl)-4-methylbenzamide (6i). Colorless solid, mp.
2H, H–cyclohexyl, mixture of two rotamers), 1.63 (d, J = 143–145 °C, yield 82%, Rf = 0.34 (n-hexane/EtOAc 3 : 1); 1H
12.8 Hz, 1H, H–cyclohexyl, mixture of two rotamers), 1.42–1.35 NMR (600 MHz, CDCl3) δ 7.71–7.63 (m, 2H, H–Ar), 7.41 (d, J =
(m, 2H, H–cyclohexyl, mixture of two rotamers), 1.22–1.09 (m, 7.9 Hz, 2H, H–Ar), 7.36 (t, J = 7.5 Hz, 1H, H–Ar), 7.24 (t, J = 7.8
3H, H–cyclohexyl, mixture of two rotamers); 1H NMR Hz, 1H, H–Ar), 7.20 (d, J = 7.9 Hz, 2H, H–Ar), 6.07–5.92 (m, 2H,
(300 MHz, chloroform-d at 55 °C) δ 7.61 (brs, 1H, H–Ar), C(sp3)–H, NH), 4.84 (brs, 1H, allenic H), 4.53–4.4 (m, 2H,
7.45–7.24 (m, 7H, H–Ar), 5.96 (brs, 1H, C(sp3)–H), 5.67 (brs, allenic H), 3.97–3.89 (m, 3H, –CH2–N, H–cyclohexyl), 2.38 (s,
1H, NH), 4.85 (brs, 1H, allenic H), 4.55–4.38 (m, 2H, allenic 3H, –CH3), 2.01–1.95 (m, 2H, H–cyclohexyl), 1.72–1.61 (m, 3H,
H), 3.97–3.80 (m, 3H, –CH2–N, CH–cyclohexyl), 1.99–1.87 (m, H–cyclohexyl), 1.43–1.36 (m, 2H, H–cyclohexyl), 1.23–1.12 (m,
2H, H–cyclohexyl), 1.71–1.57 (m, 3H, H–cyclohexyl), 1.43–1.32 3H, H–cyclohexyl); 13C NMR (151 MHz, CDCl3) δ 208.3, 172.9,
(m, 2H, H–cyclohexyl), 1.23–1.09 (m, 3H, H–cyclohexyl); 13C 168.3, 139.9, 134.6, 133.4, 133.2, 131.4, 130.2, 128.9, 127.8,
NMR (151 MHz, CDCl3) (for the major rotamer) δ 208.4, 171.3, 127.1, 126.4, 87.5, 76.1, 62.7, 48.7, 32.8, 25.5, 24.8, 24.8, 21.4;
167.9, 137.9, 135.8, 134.3, 132.7, 131.1, 130.3, 130.1, 130.9, IR (KBr): νmax = 1957 (CvCvC), 1672 (CvO) cm−1; HRMS-ESI
129.8, 127.3, 127.1, 125.1, 87.3, 76.2, 59.8, 48.8, 47.3, 32.8, (m/z): calcd for C26H3079BrN2O2 [M + H]+ 481.1321, found
25.4, 24.8, 24.7; IR (KBr): νmax = 1957 (CvCvC), 1684 (CvO) 481.1309.
cm−1; HRMS-ESI (m/z): calcd for C25H2735Cl2N2O2 [M + H]+
457.1651, found 457.1662.
N-(1-(2-Bromophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-(buta-
2,3-dien-1-yl)-3-chlorobenzamide (6j). Colorless solid, mp.
N-(Buta-2,3-dien-1-yl)-N-(2-(cyclohexylamino)-2-oxo-1-pheny- 158–160 °C, yield 79%, Rf = 0.38 (n-hexane/EtOAc 3 : 1); 1H
lethyl)benzamide (6g). Colorless solid, mp. 140–142 °C, yield NMR (600 MHz, CDCl3) (mixture of two rotamers (70 : 30))
85%, Rf = 0.38 (n-hexane/EtOAc 3 : 1); 1H NMR (600 MHz, δ 7.66 (brs, 2H, H–Ar, mixture of two rotamers), 7.49 (s, 1H,
CDCl3) (mixture of two rotamers (80 : 20)) δ 7.51–7.43 (m, 4H, H–Ar, mixture of two rotamers), 7.42–7.32 (m, 5H, H–Ar,
H–Ar, mixture of two rotamers), 7.38–7.30 (m, 6H, H–Ar, mixture of two rotamers), 6.16 (brs, 1H, C(sp3)–H, major
mixture of two rotamers), 6.09–5.76 (m, 2H, C(sp3)–H, NH, rotamer), 5.85 (brs, 1H, NH, major rotamer), 5.66 (s, 1H,
major rotamer), 5.44 (brs, 1H, C(sp3)–H, minor rotamer), 5.13 C(sp3)–H, minor rotamer), 5.35 (brs, 1H, N–H, minor rotamer),
(s, 1H, NH, minor rotamer), 4.70 (brs, 1H, allenic H, mixture 5.16 (brs, 1H, allenic H, minor rotamer), 4.71 (brs, 1H, allenic
of two rotamers), 4.47 (brs, 2H, allenic H, mixture of two rota- H, major rotamer), 4.53–4.42 (m, 2H, allenic H, mixture of two
mers), 3.98–3.90 (m, 2H, –CH2–N, mixture of two rotamers), rotamers), 3.95–3.79 (m, 3H, –CH2–N, N–CH–cyclohexyl,
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mixture of two rotamers), 1.99–1.93 (m, 2H, CH–cyclohexyl, CH–cyclohexyl), 1.40–1.31 (m, 2H, CH–cyclohexyl), 1.26 (t, J =
mixture of two rotamers), 1.74–1.60 (m, 3H, CH–cyclohexyl, 6.6 Hz, 1H, CH–cyclohexyl), 1.16–1.07 (m, 3H, CH–cyclohexyl);
mixture of two rotamers), 1.43–1.34 (m, 2H, CH–cyclohexyl, 13C NMR (101 MHz, CDCl3) δ 208.5, 172.7, 168.0, 159.5, 137.1,
mixture of two rotamers), 1.20–1.07 (m, 3H, CH–cyclohexyl, 134.3, 131.9, 131.1, 129.7, 128.8, 122.7, 119.0, 118.9, 115.9,
mixture of two rotamers); 1H NMR (300 MHz, chloroform-d at 112.1, 87.9, 76.8, 62.2, 55.4, 48.6, 47.4, 32.8, 25.4, 24.8, 24.7; IR
55 °C) δ 7.72–7.58 (m, 2H, H–Ar), 7.51–7.44 (m, 1H, H–Ar), (KBr): νmax = 1956 (CvCvC), 1683 (CvO) cm−1; HRMS-ESI
7.39–7.18 (m, 5H, H–Ar), 5.92 (brs, 1H, C(sp3)–H), 5.65 (brs, (m/z): calcd for C26H3079BrN2O3 [M + H]+ 497.1471, found
1H, NH), 4.85 (brs, 1H, allenic H), 4.61–4.36 (m, 2H, allenic 497.1482.
H), 3.98–3.79 (m, 3H, –CH2–N, N–CH–cyclohexyl), 2.05–1.90
(m, 2H, CH–cyclohexyl), 1.73–1.56 (m, 3H, CH–cyclohexyl),
1.44–1.30 (m, 2H, CH–cyclohexyl), 1.26–1.10 (m, 3H, CH–cyclo-
General procedure for the synthesis of 3-pyrroline (7a–m)
through 5-exo-dig cyclization
hexyl), 13C NMR (151 MHz, CDCl3) (for the major rotamer) δ In a round-bottom flask, to a solution of the allenic-Ugi
208.3, 171.2, 167.9, 137.8, 134.3, 133.4, 131.3, 130.5, 129.8, adduct (1.0 mmol) in DMF (2.0 mL) was added t-BuOK
129.7, 127.9, 127.2, 126.5, 125.2, 125.1, 87.3, 76.2, 62.2, 48.8, (1.2 mmol) and stirred for 6 h at room temperature. The pro-
47.3, 32.8, 25.4, 24.8, 24.8; IR (KBr): νmax = 1954 (CvCvC), gress of the reaction was monitored using TLC. After com-
1688
(CvO)
cm−1
;
HRMS-ESI
(m/z):
calcd
for pletion of the reaction, the reaction mixture was washed with
water and extracted with EtOAc (3 × 5 mL). The organic phase
C25H2779Br35ClN2O2 [M + H]+ 501.0857, found 501.0844.
N-(Buta-2,3-dien-1-yl)-N-(2-(cyclohexylamino)-1-(4-methoxy- was washed with saturated brine and dried over anhydrous
phenyl)-2-oxoethyl)-4-methylbenzamide (6k). Colorless solid, MgSO4 and the solvent was removed under vacuum.
mp. 149–150 °C, yield 82%, Rf = 0.32 (n-hexane/EtOAc 3 : 1); 1H Purification of the residue was accomplished by column
NMR (600 MHz, CDCl3) δ 7.40 (d, J = 7.8 Hz, 4H, H–Ar), 7.17 chromatography (n-hexane/OAcEt 4 : 1) to afford the 3-pyrro-
(d, J = 7.8 Hz, 2H, H–Ar), 6.86 (d, J = 8.2 Hz, 2H, H–Ar), line. Yields (86–96%).
5.95–5.67 (m, 2H, C(sp3)–H, N–H), 4.72 (brs, 1H, allenic H),
1-Benzoyl-N-(tert-butyl)-3-methyl-2-phenyl-2,5-dihydro-1H-
4.59–4.44 (m, 2H, allenic H), 3.97–3.87 (m, 2H, –CH2–N), pyrrole-2-carboxamide (7a). Colorless solid, mp. 141–142 °C,
3.82–3.80 (m, 1H, N–CH–cyclohexyl), 3.78, (s, 3H, O–CH3), 2.34 yield 94%, Rf = 0.32 (n-hexane/EtOAc 4 : 1); 1H NMR (300 MHz,
(s, 3H, CH3), 1.92–1.89 (m, 2H, CH–cyclohexyl), 1.66–1.64 (m, CDCl3) δ 8.03 (s, 1H, NH), 7.44–7.27 (m, 10H, H–Ar), 5.49 (q,
2H, CH–cyclohexyl), 1.58–1.55 (m, 1H, CH–cyclohexyl), J = 1.9 Hz, 1H, vCH), 4.49 (dt, J = 14.4, 2.1 Hz, 1H, CH2–N),
1.37–1.30 (m, 2H, CH–cyclohexyl), 1.16–1.05 (m, 3H, CH–cyclo- 4.20 (dt, J = 14.5, 2.1 Hz, 1H, CH2–N), 1.63 (d, J = 1.9 Hz, 3H,
hexyl); 13C NMR (151 MHz, CDCl3) δ 208.5, 173.0, 168.8, 159.6, CH3), 1.42 (s, 9H, H-tBu); 13C NMR (75 MHz, CDCl3) δ 170.2,
139.8, 133.4, 130.9, 129.0, 127.1, 126.9, 114.1, 88.1, 76.5, 62.2, 169.6, 142.2, 138.5, 137.3, 129.7, 128.6, 128.2, 127.5, 126.2,
55.3, 48.5, 47.2, 32.9, 25.5, 24.8, 24.8, 21.4; IR (KBr): νmax
=
125.8, 118.4, 82.6, 57.0, 51.2, 28.7, 14.3.; IR (KBr): νmax = 1694
1955 (CvCvC), 1643 (CvO) cm−1; HRMS-ESI (m/z): calcd for (CvO) cm−1; HRMS-ESI (m/z): calcd for C23H27N2O2 [M + H]+
C27H33N2O3 [M + H]+ 433.2219, found 433.2207.
363.2152, found 363.2160.
N-(Buta-2,3-dien-1-yl)-N-(2-(cyclohexylamino)-2-oxo-1-(p-tolyl)
1-Benzoyl-N-(tert-butyl)-3-methyl-2-(3-nitrophenyl)-2,5-dihydro-
ethyl)benzamide (6l). Colorless solid, mp. 145–147 °C, yield 1H-pyrrole-2-carboxamide (7b). Pale yellow solid, mp.
80%, Rf = 0.36 (n-hexane/EtOAc 3 : 1); 1H NMR (600 MHz, 125–126 °C, yield 92%, Rf = 0.32 (n-hexane/EtOAc 4 : 1); 1H
CDCl3) δ 7.49–3.24157.44 (m, 2H, H–Ar), 7.44–7.35 (m, 5H, NMR (600 MHz, CDCl3) δ 8.20 (s, 1H, NH), 8.19 (d, J = 2.5 Hz,
H–Ar), 7.20–7.19 (m, 2H, H–Ar), 5.91 (brs, 2H, C(sp3)–H, N–H), 1H, H–Ar), 7.77 (d, J = 7.9 Hz, 1H, H–Ar), 7.70 (s, 1H, H–Ar),
4.74 (brs, 1H, allenic H), 4.51 (brs, 2H, allenic H), 3.97–3.87 7.59 (t, J = 7.9 Hz, 1H, H–Ar), 7.48–7.45 (m, 3H, H–Ar),
(m, 3H, –CH2–N, CH–cyclohexyl), 2.37 (s, 3H, CH3), 1.98–1.94 7.42–7.41 (m, 2H, H–Ar), 5.63 (s, 1H, vCH), 4.42 (d, J =
(m, 2H, CH–cyclohexyl), 1.72–1.68 (m, 3H, CH–cyclohexyl), 14.2 Hz, 1H, CH2–N), 4.31 (d, J = 14.2 Hz, 1H, CH2–N), 1.66 (s,
1.42–1.35 (m, 2H, CH–cyclohexyl), 1.22–1.09 (m, 3H, CH–cyclo- 3H, CH3), 1.43 (s, 9H, H-tBu); 13C NMR (151 MHz, CDCl3)
hexyl); 13C NMR (151 MHz, CDCl3) δ 208.5, 172.3, 168.7, 138.4, δ 170.2, 168.4, 148.3, 141.1, 140.7, 136.4, 133.0, 130.2, 129.1,
136.3, 132.0, 130.2, 129.7, 129.5, 128.4, 126.8, 87.9, 76.4, 62.5, 128.8, 125.8, 122.6, 121.6, 120.1, 81.6, 56.8, 51.6, 28.6, 14.1; IR
48.6, 47.3, 32.9, 25.5, 24.8, 24.8, 21.2; IR (KBr): νmax = 1961 (KBr): νmax = 1682 (CvO) cm−1; HRMS-ESI (m/z): calcd for
(CvCvC), 1683 (CvO) cm−1; HRMS-ESI (m/z): calcd for C23H26N3O4 [M + H]+ 408.2008, found 408.2017.
C26H31N2O2 [M + H]+ 403.2406, found 403.2415.
N-(tert-Butyl)-1-(3-chlorobenzoyl)-2-(2-chlorophenyl)-3-methyl-
N-(1-(3-Bromophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-(buta- 2,5-dihydro-1H-pyrrole-2-carboxamide (7c). Colorless solid,
2,3-dien-1-yl)-3-methoxybenzamide (6m). Colorless solid, mp. 127–128 °C, yield 95%, Rf = 0.35 (n-hexane/EtOAc 4 : 1); 1H
mp. 154–155 °C, yield 83%, Rf = 0.39 (n-hexane/EtOAc 3 : 1); 1H NMR (600 MHz, CDCl3) δ 8.17 (s, 1H, NH), 7.48 (d, J = 7.8 Hz,
NMR (400 MHz, CDCl3) δ 7.51–7.47 (m, 2H, H–Ar), 7.37–7.28 1H, H–Ar), 7.44–7.42 (m, 2H, H–Ar), 7.41–7.40 (m, 1H, H–Ar),
(m, 3H, H–Ar), 7.01 (dt, J = 7.5, 1.2 Hz, 1H, H–Ar), 6.98–6.94 7.38–7.37 (m, 1H, H–Ar), 7.36–7.33 (m, 2H, H–Ar), 7.32–7.30
(m, 2H, H–Ar), 6.20 (s, 1H, C(sp3)–H), 5.83 (s, 1H, N–H), 4.78 (m, 1H, H–Ar), 5.59 (d, J = 2.1, 1H, vCH), 4.39 (dt, J = 14.3,
(brs, 1H, allenic H), 4.57–4.55 (m 2H, allenic H), 3.98–3.97 (m, 2.3 Hz, 1H, CH2–N), 4.10 (dt, J = 14.2, 2.3 Hz, 1H, CH2–N), 1.60
2H, –CH2–N), 3.85–3.82 (m, N–CH–cyclohexyl), 3.81 (s, 3H, (d, J = 2.1, 3H, CH3), 1.43 (s, 9H, H-tBu); 13C NMR (151 MHz,
O–CH3), 1.93–1.88 (m, 2H, CH–cyclohexyl), 1.67–1.58 (m, 2H, CDCl3) δ 170.2, 169.3, 145.5, 138.4, 134.6, 133.6, 131.8, 131.7,
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130.0, 129.9, 129.0, 126.8, 126.4, 124.4, 124.3, 120.3, 82.3, 56.7, 7.43–7.41 (m, 2H, H–Ar), 7.40–7.38 (m, 2H, H–Ar), 7.34–7.32
51.3, 29.7, 28.7; IR (KBr): νmax = 1687 (CvO) cm−1; HRMS-ESI (m, 3H, H–Ar), 5.51 (brs, 1H, vCH), 4.38 (d, J = 14.6, 1H, CH2–
(m/z): calcd for C23H2535Cl2N2O2 [M + H]+ 431.1329, found N), 4.23 (d, J = 14.7, 1H, CH2–N), 3.96–3.88 (m, 1H, H–cyclo-
431.1339.
hexyl), 2.03–2.00 (m, 1H, H–cyclohexyl), 1.92–1.8 (m, 1H,
N-(tert-Butyl)-2-(2-chlorophenyl)-1-(4-methoxybenzoyl)-3-methyl- H–cyclohexyl), 1.72–1.67 (m, 1H, H–cyclohexyl), 1.65 (brs, 3H,
2,5-dihydro-1H-pyrrole-2-carboxamide (7d). Colorless solid, CH3), 1.59–155 (m, 1H, H–cyclohexyl), 1.43–1.37 (m, 2H, H–
mp. 135–137 °C, yield 95%, Rf = 0.37 (n-hexane/EtOAc 4 : 1); 1H cyclohexyl), 1.34–1.30 (m, 1H, H–cyclohexyl), 1.27–1.17 (m, 3H,
NMR (600 MHz, CDCl3) δ 8.30 (s, 1H, NH), 7.47 (dd, J = 7.9, 1.5 H–cyclohexyl); 13C NMR (75 MHz, CDCl3) δ 170.2, 169.6, 142.1,
Hz, 1H, H–Ar), 7.44 (d, J = 8.4 Hz, 2H, H–Ar), 7.37 (dd, J = 7.8, 138.4, 137.3, 129.7, 128.6, 128.2, 127.5, 126.2, 125.8, 118.4,
1.3 Hz, 1H, H–Ar), 7.33 (t, J = 7.5 Hz, 1H, H–Ar), 7.28–7.25 (m, 82.1, 56.9, 48.3, 32.6, 32.5, 29.7, 25.6, 24.5; IR (KBr): νmax
=
1H, H–Ar), 6.93 (d, J = 8.4 Hz, 2H, H–Ar), 5.58 (brs, 1H, vCH), 1691 (CvO) cm−1; HRMS-ESI (m/z): calcd for C25H29N2O2
4.44 (d, J = 14.5 Hz, 1H, CH2–N), 4.14 (d, J = 14.4 Hz, 1H, CH2– [M + H]+ 389.2288, found 389.2297.
N), 3.85 (s, 3H, O–CH3), 1.59 (brs, 3H, CH3), 1.41 (s, 9H,
1-Benzoyl-N-cyclohexyl-3-methyl-2-(3-nitrophenyl)-2,5-dihydro-
H-tBu); 13C NMR (151 MHz, CDCl3) δ 170.8, 170.6, 160.7, 1H-pyrrole-2-carboxamide (7h). Pale yellow solid, mp.
137.2, 134.1, 131.8, 131.6, 129.8, 129.1, 128.8, 128.2, 126.7, 132–135 °C, yield 92%, Rf = 0.38 (n-hexane/EtOAc 4 : 1); 1H
120.6, 113.7, 82.3, 56.8, 55.4, 51.2, 28.7 (t-Bu and CH3 over- NMR (400 MHz, CDCl3) δ 8.19 (s, 1H, H–Ar), 8.18 (d, J = 6.1 Hz,
lapped); IR (KBr): νmax = 1678 (CvO) cm−1; HRMS-ESI (m/z): 1H, NH), 7.74 (d, J = 7.6 Hz, 2H, H–Ar), 7.57 (t, J = 7.6 Hz, 1H,
calcd for C24H2835ClN2O3 [M + H]+ 427.2013, found 427.2023.
H–Ar), 7.47–7.45 (m, 3H, H–Ar), 7.41–7.39 (m, 2H, H–Ar), 5.62
1-Benzoyl-2-(2-chlorophenyl)-N-cyclohexyl-3-methyl-2,5-dihydro- (q, J = 2.2 Hz, 1H, vCH), 4.41 (dt, J = 14.7, 2.2 Hz, 1H), 4.31
1H-pyrrole-2-carboxamide (7e). Colorless solid, mp. 137–140 °C, (dt, J = 14.7, 2.2 Hz, 1H), 3.96–3.87 (m, 1H, H–cyclohexyl),
yield 91%, Rf = 0.37 (n-hexane/EtOAc 4 : 1); 1H NMR (600 MHz, 2.04–1.99 (m, 1H, H–cyclohexyl), 1.91–1.85 (m, 1H, H–cyclo-
CDCl3) δ 8.36 (d, J = 8.0 Hz, 1H, NH), 7.46–7.45 (m, 2H, H–Ar), hexyl), 1.72–1.69 (m, 1H, H–cyclohexyl), 1.65 (d, j = 2.2 Hz, 3H,
7.44–7.42 (m, 3H, H–Ar), 7.39 (d, J = 7.8 Hz, 1H, H–Ar), 7.32 (t, CH3), 1.59–1.54 (m, 1H, H–cyclohexyl), 1.47–1.37 (m, 2H, H–
J = 7.5 Hz, 1H, H–Ar), 7.28 (d, J = 7.6 Hz, 1H, H–Ar), 5.58 (brs, cyclohexyl), 1.35–1.27 (m, 2H, H–cyclohexyl), 1.26–1.15 (m, 2H,
1H, vCH), 4.37 (d, J = 14.4 Hz, 1H, CH2–N), 4.10 (d, J = H–cyclohexyl); 13C NMR (101 MHz, CDCl3) δ 170.3, 168.4,
14.4 Hz, 1H, CH2–N), 3.95–3.89 (m, 1H, H–cyclohexyl), 148.3, 140.9, 140.6, 136.3, 132.9, 130.2, 129.1, 128.8, 125.8,
2.03–1.97 (m, 1H, H–cyclohexyl), 1.92–1.87 (m, 1H, H–cyclo- 122.6, 121.5, 120.1, 81.1, 56.8, 48.4, 32.5, 30.1, 25.5, 24.5, 14.1;
hexyl), 1.72–1.64 (m, 2H, H–cyclohexyl), 1.61 (brs, 3H, CH3), IR (KBr): νmax = 1683 (CvO) cm−1; HRMS-ESI (m/z): calcd for
1.57–1.54 (m, 1H, H–cyclohexyl), 1.45–1.35 (m, 3H, H–cyclo- C25H28N3O4 [M + H]+ 434.2080, found 434.2085.
hexyl), 1.31–1.18 (m, 2H, H–cyclohexyl); 13C NMR (151 MHz,
2-(2-Bromophenyl)-N-cyclohexyl-3-methyl-1-(4-methylbenzoyl)-
CDCl3) δ 170.9, 170.7, 137.3, 136.9, 133.8, 131.8, 131.6, 129.9, 2,5-dihydro-1H-pyrrole-2-carboxamide (7i). Colorless solid,
129.7, 128.9, 128.5, 126.7, 126.2, 120.4, 81.6, 56.8, 48.2, 32.6, mp. 142–144 °C, yield 93%, Rf = 0.37 (n-hexane/EtOAc 4 : 1); 1H
32.2, 25.6, 24.4, 14.5; IR (KBr): νmax = 1668 (CvO) cm−1
;
NMR (600 MHz, CDCl3) δ 8.31 (d, J = 8.0 Hz, 1H, NH), 7.62 (d,
HRMS-ESI (m/z): calcd for C25H2835ClN2O2 [M + H]+ 423.2067, J = 7.9 Hz, 1H, H–Ar), 7.45 (d, J = 7.8 Hz, 1H, H–Ar), 7.40 (d, J =
found 423.2077. 7.8 Hz, 2H, H–Ar), 7.36 (t, J = 7.6 Hz, 1H, H–Ar), 7.23 (d, J = 7.8
1-(3-Chlorobenzoyl)-2-(2-chlorophenyl)-N-cyclohexyl-3-methyl- Hz, 2H, H–Ar), 7.19 (t, J = 7.6 Hz, 1H, H–Ar), 5.59 (brs, 1H,
2,5-dihydro-1H-pyrrole-2-carboxamide (7f). Colorless solid, vCH), 4.44 (d, J = 14.4 Hz, 1H, CH2–N), 4.16 (d, J = 14.4 Hz,
mp. 145–147 °C, yield 93%, Rf = 0.36 (n-hexane/EtOAc 4 : 1); 1H 1H, CH2–N), 3.94–3.88 (m, 1H, H–cyclohexyl), 2.40 (s, 3H,
NMR (600 MHz, CDCl3) δ 8.22 (d, J = 8.0 Hz, 1H, NH), 7.44 (s, –CH3), 2.01–1.98 (m, 1H, H–cyclohexyl), 1.88–1.85 (m, 1H,
1H, H–Ar), 7.42 (d, J = 8.8 Hz, 2H, H–Ar), 7.41–7.38 (m, 1H, H– H–cyclohexyl), 1.70–1.63 (m, 3H, H–cyclohexyl), 1.58 (brs, 3H,
Ar), 7.36–7.32 (m, 3H, H–Ar), 7.31.7.21 (m, 1H, H–Ar), 5.58 CH3–vinyl), 1.43–1.32 (m, 3H, H–cyclohexyl), 1.26–1.18 (m, 2H,
(brs, 1H, vCH), 4.37 (d, J = 14.3, 1H, CH2–N), 4.11 (d, J = 14.3, H–cyclohexyl); 13C NMR (151 MHz, CDCl3) δ 171.0 (two carbo-
1H, CH2–N), 3.94–3.88 (m, 1H, H–cyclohexyl), 2.02–1.99 (m, nyl peaks), 139.9, 135.3, 134.9, 134.8, 133.8, 130.2, 129.1,
1H, H–cyclohexyl), 1.90–1.86 (m, 1H, H–cyclohexyl), 1.72–1.64 129.0, 127.3, 126.5, 126.4, 120.9, 82.4, 56.9, 48.2, 32.6, 32.2,
(m, 2H, H–cyclohexyl), 1.61 (brs, 3H, CH3), 1.58–1.54 (m, 1H, 25.6, 24.5, 24.4, 21.4; IR (KBr): νmax = 1673 (CvO) cm−1
;
H–cyclohexyl), 1.45–1.38 (m, 2H, H–cyclohexyl), 1.37–1.31 (m, HRMS-ESI (m/z): calcd for C26H3079BrN2O2 [M + H]+ 481.1203
1H, H–cyclohexyl), 1.27–1.20 (m, 2H, H–cyclohexyl); 13C NMR found 481.1194.
(151 MHz, CDCl3) δ 170.4, 169.4, 138.3, 137.3, 134.6, 133.4,
2-(2-Bromophenyl)-1-(3-chlorobenzoyl)-N-cyclohexyl-3-methyl-
131.7, 131.7, 130.1, 130.0, 129.9, 129.1, 126.8, 126.4, 124.3, 2,5-dihydro-1H-pyrrole-2-carboxamide (7j). Colorless solid,
120.3, 81.7, 56.8, 48.2, 32.6, 32.2, 25.5, 24.4, 14.5; IR (KBr): mp. 130–132 °C, yield 96%, Rf = 0.39 (n-hexane/EtOAc 4 : 1); 1H
νmax
=
1669 (CvO) cm−1
;
HRMS-ESI (m/z): calcd for NMR (600 MHz, CDCl3) δ 8.16 (d, J = 8.0 Hz, 1H, NH), 7.63 (d,
J = 7.9 Hz, 1H, H–Ar), 7.48–7.47 (m, 1H, H–Ar), 7.45 (d, J =
C25H2735Cl2N2O2 [M + H]+ 457.1481, found 457.1492.
1-Benzoyl-N-cyclohexyl-3-methyl-2-phenyl-2,5-dihydro-1H- 8.0 Hz, 1H, H–Ar), 7.44–7.42 (m, 1H, H–Ar), 7.39–7.36 (m, 3H,
pyrrole-2-carboxamide (7g). Colorless solid, mp. 140–141 °C, H–Ar), 7.21 (t, J = 7.6 Hz, 1H, H–Ar), 5.60 (brs, 1H, vCH), 4.40
yield 90%, Rf = 0.34 (n-hexane/EtOAc 4 : 1); 1H NMR (600 MHz, (d, J = 14.3 Hz, 1H, CH2–N), 4.15 (d, J = 14.2 Hz, 1H, CH2–N),
CDCl3) δ 8.09 (d, J = 8.1 Hz, 1H, NH), 7.45–7.43 (m, 3H, H–Ar), 3.94–3.89 (m, 1H, H–cyclohexyl), 2.03–1.99 (m, 1H, H–cyclo-
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hexyl), 1.90–1.86 (m, 1H, H–cyclohexyl), 1.72–1.65 (m, 3H, 32.5, 25.6, 2.5, 14.3; IR (KBr): νmax = 1682 (CvO) cm−1
;
H–cyclohexyl), 1.59 (brs, 3H, CH3), 1.45–1.29 (m, 3H, H–cyclo- HRMS-ESI (m/z): calcd for C26H3059BrN2O3 [M + H]+ 497.1022,
hexyl), 1.27–1.18 (m, 2H, H–cyclohexyl); 13C NMR (151 MHz, found 497.1014.
CDCl3) δ 170.6, 169.3, 138.3, 137.2, 135.4, 134.5, 134.4, 130.3,
130.0, 129.9, 129.3, 127.4, 126.6, 124.4, 120.7, 120.4, 82.5, 56.9,
Computational details
48.2, 32.7, 32.2, 25.5, 24.5, 14.5; IR (KBr): νmax = 1670 (CvO)
cm−1; HRMS-ESI (m/z): calcd for C25H2779Br35ClN2O2 [M + H]+
501.0689, found 501.0677.
The structures of transition states have been fully optimized at
the B3LYP/6-31G(d)19 level in the gas phase (at 298.15 K). For
accurate comparison of anion (A and B) stability, optimized
anion structures were calculated at the PCM (DMF)/B3LYP/6-
31G(d) level. The compound 6g was selected as a model to
investigate the mechanism. Transition states (TS) were verified
with an intrinsic reaction coordinate (IRC) and single imagin-
ary frequency. The LUMO-CA was done through the Hirshfeld
method with Multiwfn20 (version 3.3.8). The other calculations
were performed via the Gaussian 09 program.21 The optimized
structures were outlined with the CYLView software.22 The
orbital electronegativity was calculated based on related refer-
ences using MarvinSketch 17.12.23 Chemical hardness η and
Local Fukui functions (electrophilicity index)15c,24 were calcu-
lated based on the subsequent formulas:
N-Cyclohexyl-2-(4-methoxyphenyl)-3-methyl-1-(4-methylben-
zoyl)-2,5-dihydro-1H-pyrrole-2-carboxamide (7k). Colorless
solid, mp. 142–144 °C, yield 90%, Rf = 0.34 (n-hexane/EtOAc
4 : 1); 1H NMR (600 MHz, CDCl3) δ 8.00 (d, J = 8.1 Hz, 1H, NH),
7.31 (d, J = 7.8 Hz, 2H, H–Ar), 7.26 (d, J = 8.6 Hz, 2H, H–Ar),
7.22 (d, J = 7.9 Hz, 2H, H–Ar), 6.91 (d, J = 8.6 Hz, 2H, H–Ar),
5.50 (brs, 1H, vCH), 4.35 (d, J = 14.5 Hz, 1H, CH2–N), 4.23 (d,
J = 14.4 Hz, 1H, CH2–N), 3.93–3.90 (m, 1H, H–cyclohexyl), 3.83
(s, 3H, O–CH3), 2.39 (s, 3H, CH3), 2.01–1.98 (m, 1H, H–cyclo-
hexyl), 1.91–1.88 (m, 1H, H–cyclohexyl), 1.72–1.68 (m, 2H,
H–cyclohexyl), 1.65 (brs, 3H, CH3), 1.58–1.55 (m, 1H, H–cyclo-
hexyl), 1.42–1.35 (m, 2H, H–cyclohexyl), 1.29–1.17 (m, 3H,
H–cyclohexyl); 13C NMR (151 MHz, CDCl3) δ 170.3, 169.8,
158.8, 142.0, 139.8, 134.5, 130.5, 129.1, 127.7, 126.0, 118.5,
113.6, 81.6, 56.8, 55.2, 48.3, 32.6, 29.7, 25.6, 24.6, 21.4, 14.3; IR
(KBr): νmax = 1673 (CvO) cm−1; HRMS-ESI (m/z): calcd for
C27H33N2O3 [M + H]+ 433.2235, found 433.2223.
η ¼ εLUMO ꢀ εHOMO
ð1Þ
ð2Þ
þ
fk ¼ qNK ꢀ qNKþ1
1-Benzoyl-N-cyclohexyl-3-methyl-2-(p-tolyl)-2,5-dihydro-1H-
pyrrole-2-carboxamide (7l). Colorless solid, mp. 141–142 °C,
yield 91%, Rf = 0.34 (n-hexane/EtOAc 4 : 1); 1H NMR (600 MHz,
CDCl3) δ 8.07 (d, J = 8.1 Hz, 1H, NH), 7.44–7.40 (m, 5H, H–Ar),
7.20 (d, J = 8.3 Hz, 2H, H–Ar), 7.22 (d, J = 8.3 Hz, 2H, H–Ar),
5.49 (brs, 1H, vCH), 4.36 (d, J = 14.6 Hz, 1H, CH2–N), 4.21 (d,
J = 14.5 Hz, 1H, CH2–N), 3.95–3.89 (m, 1H, H–cyclohexyl), 2.37
(s, 3H, CH3), 2.03–1.98 (m, 1H, H–cyclohexyl), 1.94–1.88 (m,
1H, H–cyclohexyl), 1.75–1.67 (m, 2H, H–cyclohexyl), 1.65 (brs,
3H, CH3), 1.60–1.54 (m, 1H, H–cyclohexyl), 1.45–1.35 (m, 2H,
H–cyclohexyl), 1.33–1.17 (m, 3H, H–cyclohexyl); 13C NMR
(151 MHz, CDCl3) δ 170.2, 169.8, 142.1, 137.3, 137.2, 135.4,
129.7, 129.0, 128.6, 126.2, 125.9, 118.4, 81.9, 57.0, 48.3, 32.6,
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Saeed Balalaie thanks Alexander von Humboldt for the
research fellowship. We thank the Iran National Science
Foundation (INSF, Grant No 97020936) for financial support.
References
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HRMS-ESI (m/z): calcd for C26H31N2O2 [M + H]+ 403.2174,
found 403.2165.
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