Catalytic formal [4 + 1] isocyanide-based cycloaddition: An efficient strategy for the synthesis of 1: H -cyclopenta [b] quinolin-1-one derivatives

Article abstract of DOI:10.1039/c8ob02857e

An unprecedented catalytic isocyanide-based cycloaddition of alkyl and aryl isocyanides with (Z)-2-(2-hydroxy-2-alkylvinyl)quinoline-3-carbaldehydes was developed for the direct and efficient synthesis of 1H-cyclopenta[b]quinolin-1-one derivatives. On the

Full text of DOI:10.1039/c8ob02857e

Organic &
Biomolecular Chemistry
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Catalytic formal [4 + 1] isocyanide-based
cycloaddition: an efficient strategy for the
synthesis of 1H-cyclopenta[b]quinolin-1-one
derivatives†
Cite this: DOI: 10.1039/c8ob02857e
Milad Motaghi, a Hormoz Khosravi, a Saeed Balalaie
*
a,b and Frank Romingerc
An unprecedented catalytic isocyanide-based cycloaddition of alkyl and aryl isocyanides with (Z)-2-(2-
hydroxy-2-alkylvinyl)quinoline-3-carbaldehydes was developed for the direct and efficient synthesis of
1H-cyclopenta[b]quinolin-1-one derivatives. On the basis of DFT calculations, a mechanism is proposed
involving formal [4 + 1] cycloaddition of isocyanides, followed by imine–enamine tautomerization and air
oxidation.
Received 15th November 2018,
Accepted 5th December 2018
DOI: 10.1039/c8ob02857e
rsc.li/obc
like system, Sun and co-workers represent triisopropylsilyl
(TIPS) vinyl ketenes as a C4 system in [4 + 1] cycloaddition
Introduction
Owing to their intrinsic properties as nucleophiles and electro- reaction sequences with a polar terminal carbonyl group
philes, isocyanides have emerged as one of the most beneficial (Scheme 1, eqn (2)).12 Therefore, further exploration of new C4
starting materials and have been widely applied in organic syn- partners in formal [4 + 1] isocyanide-based cycloaddition reac-
thesis.1,2 In the case of their formal cycloadditions, a literature tions remains highly desirable. In continuation of our studies
survey revealed a participation of isocyanides in [4 + 1],3 devoted to exploiting the potential of isocyanide-based reac-
[4 + 2],4 [6 + 3],5 [3 + 2],6 [3 + 3],7 [2 + 2 + 1],8 and [5 + 1] annu- tions and developing new synthesis methods,13 we offer an un-
lations.2b,9 Among these reaction types, the formal [4 + 1] iso- precedented formal [4 + 1] isocyanide-based cycloaddition of
cyanide-based cycloaddition has transpired as an efficient and aryl and alkyl isocyanides with (Z)-2-(2-hydroxy-2-alkylvinyl)
direct protocol for the synthesis of various five-membered quinoline-3-carbaldehydes to access 1H-cyclopenta[b]quinolin-
compounds.3 In 2003, Chatani et al. reported the first example 1-ones (Scheme 1, eqn (3)). The work was initiated by finding a
of catalytic formal [4 + 1] isocyanide-based cycloaddition using sufficient C4 center in quinoline core substrates. To pursue
α,β-unsaturated ketones with aryl isocyanides to access unsatu- our goal, we selected (Z)-2-(2-hydroxy-2-alkylvinyl)quinoline-3-
rated lactone derivatives (Scheme 1, eqn (1)).10 Afterward, carbaldehydes which were synthesized by silver catalyzed enoli-
many research groups started to use various kinds of dienes zation of 2-(alkylethynyl)quinoline-3-carbaldehydes.14 This
such as oxadienes, azadienes, acyl/thioacyl imines, nitro-ole-
fines, etc.3,11 However, the utilization of butadiene as a C4
source in reacting toward isocyanides remains a significant
challenge for organic chemists due to the lack of appropriate
polarization.3 In this regard, to find out a polarized butadiene-
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
cOrganisch-Chemisches Institut der Universität Heidelberg,
Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data, computational data, crystal structure analysis;
1H, 13C NMR and HRMS spectra for compounds. CCDC 1861937. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8ob02857e
Scheme 1 Representative reactivity profiles of isocyanides in formal
[4 + 1] cycloadditions.
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2a for 12 h, the desired product 3a was not detected with all
three silver salts (entries 1–3).
In the next screening, the reaction was monitored with a
catalytic amount of FeCl3, Sc(OTf)3, AlCl3, TiCl4, and InCl3. To
our surprise, the reaction gave the desired product 3a in
32–63% yields (entries 4–8). It is important to note that the
best yield was obtained in the case of InCl3 (entry 8, 63%).
These results encouraged us to screen various conditions by
using InCl3 as a catalyst. It is noteworthy that increasing the
reaction time to 24 h and temperature to 80 °C leads to the
best yield of desired product 3a (entry 9, 84%). When the
amount of tert-butyl isocyanide was lowered to 2.0 equivalents,
the yield of 3a was decreased to 73% (entry 10). Solvent screen-
ing revealed that the reaction worked equally well in THF and
EtOAc (entries 11 and 12). The non-coordinating solvents like
DCM were not suitable for this cycloaddition (entry 13).
Furthermore, desired product 3a was identified in 34% yield
when p-TsOH was used instead, which indicated that the
Brønsted acids could proceed the reaction (entry 14). When
the reaction was checked under the argon condition, the yield
of the desired product significantly decreased to 23%; there-
fore, the presence of air is vital in the reaction mechanism
(entry 15). The control reactions showed that the presence of
catalysts was essential for the reactions (entry 16). Further
optimizations are given in the ESI (Table S1†). With the
optimal reaction conditions in hand (Table 1, entry 9), we next
examined the generality of this reaction. Initially, we extended
the scope with cyclohexyl and phenyl isocyanides (Table 2).
Pleasingly, in addition to tert-butyl isocyanide, both these alkyl
and aryl isocyanides worked well, and the corresponding
cyclized products 3a–3c were obtained in 78–84% yields.
No significant variation in the yields was found with
various quinoline precursors. All the reactions were carried out
smoothly and afforded the corresponding desired products
3d–3i in 67–82% yields (Table 2). Moreover, the structure of
compound 3h was unambiguously confirmed by single-crystal
X-ray analysis (Fig. 2).
Fig. 1 Selected examples of cyclopenta[b]-fused quinoline motifs in
bioactive compounds.
quinoline-based scaffold provided suitable polarity for our
assumed C4 centers by both enol and aldehyde terminals
through the catalytic activation. Cyclopenta[b]quinolines are
valuable quinoline-containing carbocycles with a wide spec-
trum of contributions in natural products and drug-like com-
pounds (Fig. 1).15 In addition to their remarkable activities,
development of new and efficient methodologies for their syn-
thesis attracts continuous attention.16
Results and discussion
We commenced our investigations using (Z)-2-(2-hydroxyphe-
nylvinyl)quinoline-3-carbaldehyde 1a and tert-butyl isocyanide
2a as a model to optimize the reaction conditions (Table 1). At
first, three different silver salts were chosen as a catalyst.17 As
indicated in Table 1, when the reactions were conducted in
toluene at 60 °C using 3.0 equivalents of tert-butyl isocyanide
Table 1 Optimization of reaction conditionsa
Entry
Catalystb
Solvent
Temp. (°C)
Time (h)
Yieldc (%)
The generality of the reaction was further examined when
the R2-substituent was altered from phenyl to p-pentylphenyl
and cyclopropyl groups (Table 2, 3j–3n). However, when we
used 6-nitro and 6-chloro derivatives as electron withdrawing
groups on the quinoline core the desired product was not
detected. In order to understand the mechanistic aspect of
this unprecedented transformation, some mechanistic experi-
ments were performed (Scheme 2). The reaction of 2-(2-oxo-2-
phenylethyl)benzaldehyde 1q and cyclohexyl isocyanide 2b was
conducted under optimized conditions, and the reaction did
not proceed (Scheme 2, eqn (1)). Based on the outcome of this
observation, we believe that the pyridine moiety in the quino-
line core might be pivotal to perform the reaction. To confirm
our hypothesis (Z)-2-(2-hydroxy-2-phenylvinyl)nicotinaldehyde
1p was treated with cyclohexyl isocyanide 2b under optimized
conditions (Scheme 2, eqn (2)), and the desired product 3p
was isolated in 35% yield.
1
2
3
4
5
6
7
8
AgNO3
AgSbf6
AgOTf
FeCl3
Sc(OTf)3
AlCl3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
EtOAc
DCM
Toluene
Toluene
Toluene
60
60
60
60
60
60
60
60
80
80
Reflux
Reflux
Reflux
80
12
12
12
12
12
12
12
12
24
24
24
24
24
24
24
24
NRd
NRd
NRd
32
47
40
55
63
84
73
TiCl4
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
p-TsOH
InCl3
—
9
10e
11
12
13
14
15f
16
60
56
17
34
80
80
23
NRd
a Until otherwise noted, all reactions were carried out with (Z)-2-(2-
hydroxyphenylvinyl)quinoline-3carbaldehyde 1a (0.3 mmol), tert-butyl
isocyanide 2a (3.0 equiv.), solvent (3 ml), and air atmosphere.
b Catalyst (20 mol%). c Isolated yields. d NR = no reaction. e The amount
of tert-butyl isocyanide was 2.0 equiv. f The reaction was under argon
These results justify our hypothesis and to gain further
insight into the mechanism involved, DFT calculations were
conditions.
trifluoromethanesulfonate.
p-TsOH
=
p-toluenesulfonic
acid.
OTf
=
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Table 2 Scope of reaction substratesa,b
Scheme 2 Mechanistic experiments.
a Reaction conditions: 1a–f (0.3 mmol), 2a–c (3.0 equiv.), InCl3
(20 mol%), toluene (3 ml), air atmosphere, 80 °C, 24 h. b Isolated
yields.
Fig. 3 Relative Gibbs free energies (in kcal mol−1) of [4 + 1] cyclo-
addition transition structures between methyl isocyanide and 1a in the
presence of InCl3 (TS1 and TS2) and its absence (TS-Con.), calculated
with B3LYP/GENECP, SDD with a set of polarization functions for In and
6-31G(d) for H, C, N and O (activation free energies are given in
brackets).
Fig. 2 ORTEP structure of 3h.
carried out at the hybrid B3LYP functional (see the ESI† for to advance. In addition, this reaction is exothermic by
computational details). First, we have calculated the [4 + 1] −5.6 kcal mol−1 and leads to the generation of INT4 (Fig. S1†).
cycloaddition reaction between the methyl isocyanide, as a For catalysis with InCl3, we observed two discrete transition
model to investigate the isocyanide reactivity, and 1a without a states (Fig. 3, TS1 and TS2); in TS1, isocyanide attacks the alde-
catalyst. DFT calculations show that this reaction is performed hyde moiety which is activated with the InCl3 (TS1, ΔG‡
=
in a concerted manner (Fig. 3, TS-Con) with high activation 16.5 kcal mol−1) for the formation of INT2. Subsequently, the
free energy (ΔG‡ = 51.2 kcal mol−1); this result confirms that enol-function, which is activated by the quinoline core, attacks
the reaction cannot progress in mild temperatures without a the isonitrilium segment (TS2, ΔG‡ = 11.5 kcal mol−1).
catalyst (Table 1, entry 16) and requires very high temperature Moreover, the quinoline segment acts as a base in TS2 and
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deprotonation of the hydroxyl group in the presence of this mechanism, indium chloride could increase the electophilicity
moiety is barrier less. The overall barrier energy of cyclo- and reactivity of the compounds 1a–f, and it reacts as a LUMO-
addition in the presence of InCl3 is calculated to be ΔG‡
=
lowering catalyst.23
26.5 kcal mol−1 for TS2 (Fig. S1†); therefore, DFT calculations
On the basis of our results, a possible mechanism for the
confirm that the reaction can proceed under the optimized [4 + 1] cycloaddition reaction is depicted in Scheme 3.
conditions (Table 1, entry 9). The results of DFT calculations Compounds 1a–f react with isocyanides 2a–c in the presence
show that the pyridine moiety in the quinoline core plays an of InCl3 to give intermediate INT2. The intramolecular attack
important role in the progression of the reaction and acts as of the enolate segment to isonitrilium leads to INT3-Cat which
an internal base.
was transformed into INT5, followed by proton transfer and
In addition to DFT, NMR spectra of 1a–f indicated imine–enamine tautomerization. This tautomerization can be
the internal hydrogen bonding and relative stability of assisted by one or two water molecules under the reaction con-
the enol form of (Z)-2-(2-hydroxy-2-alkylvinyl)quinoline-3- ditions (Fig. S2†). Finally, INT5 was oxidized by air to form
carbaldehydes.
desired products.
Many studies have shown that the Frontier Molecular
Orbital (FMO) theory21 is a powerful tool to understand the be-
havior of the Lewis acid-catalyzed cycloaddition and organo-
catalytic cyclization reactions.22 In this work, FMO Energies
and reactivity indices such as chemical potential (μ), chemical
hardness (η) and global electrophilicity (ω) have been calcu-
lated for further investigation of Lewis acid impacts on this
cycloaddition reaction (Table 3).
Conclusions
In conclusion, we have developed an unprecedented and inter-
esting catalytic reaction between isocyanides and (Z)-2-(2-
hydroxy-2-alkylylvinyl)quinoline-3-carbaldehydes. The present
protocol was proposed involving two carbon–carbon bond for-
mation through a formal [4 + 1] cycloaddition, thus providing
a new reactivity pattern of isocyanide chemistry and new
access to the cyclopentenone-fused quinoline skeleton. Other
features included excellent atom economy, the simplicity of
operation and high atom-efficiency. DFT calculations were also
carried out to study the mechanistic aspects in this cyclo-
addition. Further expansion of new catalytic reactions based
on (Z)-2-(2-hydroxy-2-alkylylvinyl)quinoline-3-carbaldehydes as
C4 systems is underway in our laboratory.
Frontier Molecular Orbital Energies show that HOMOMe–NC
–
LUMO1a interaction controls this [4 + 1] cycloaddition reaction
and LUMO orbital energy of 1a decreases (chemical potential
(μ) decrease too) in the presence of InCl3 (Fig. S3†).
Meanwhile, the electrophilicity (ω) of 1a-InCl3 (4.58 eV) is
higher than that of 1a (2.28 eV). The chemical hardness (η) of
1a-InCl3 (2.67) is lower than that of 1a, suggesting that reactiv-
ity of 1a has been increased by indium chloride. In summary,
DFT calculations shows that in addition to changing the
Experimental section
Table 3 Calculated global properties of reactants at the B3LYP/
Typical procedure for the synthesis of quinoline-based starting
GENECP level (in eV)
materials
Global properties
2-Chloroquinoline-3-carbaldehydes. They were prepared by
the reported procedure.18
HOMO
LUMO
μ
η
ω
2-(Alkylethynyl)quinoline-3-carbaldehydes and 2-(alkylethy-
nyl)nicotinaldehyde. They were prepared by the Sonogashira
coupling reaction of 2-chloroquinoline-3-carbaldehydes and
2-Chloro-3-pyridinecarboxaldehyde with terminal alkynes.19 All
commercially available compounds were used as received.
Me–NC
1a
1a-InCl3
−8.04
−5.66
−6.29
0.91
−2.24
−3.61
−3.56
−3.96
−4.95
8.95
3.42
2.67
0.71
2.28
4.58
Typical procedure for the preparation of 1 using 1a as the
example
They were prepared by slight modification of a literature pro-
cedure.14 Unless otherwise specified, (Z)-2-(2-hydroxy-2-phenyl-
vinyl)quinoline-3-carbaldehyde 1a (as an example) derivatives
were synthesized via the following step: to a stirred solution of
2-(phenylethynyl)quinoline-3-carbaldehyde (640 mg, 2.50
mmol) and AgNO3 (5 mol%) in dioxane (8 mL) was added H2O
(2.0 equiv.). The solution was stirred for 1 h at rt. Upon com-
pletion of the reaction indicated by TLC, the reaction mixture
was washed with H2O and extracted with CH2Cl2 (20 mL) three
times. The combined organic phases were washed with brine,
Scheme 3 The proposed mechanism of formal [4 + 1] isocyanide-
based cycloaddition.
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dried over anhydrous Na2SO4, filtered and concentrated under cm−1; HRMS-ESI (m/z): calc. for C20H18NO2 [M + H]+ 304.1332,
reduced pressure. The residue was purified by column chrom- found 304.1336.
atography (n-hexane/EtOAc = 4 : 1 to 1 : 2) as the eluent to
afford the tautomeric mixture of 1a and 1a′ (610 mg, 95%).
(Z)-2-(2-Hydroxy-2-(4-pentylphenyl)vinyl)-6,7-dimethylquinoline-
3-carbaldehyde (1d). This compound was detected as a tauto-
meric mixture of enol (86%) and keto forms (14%) in chloro-
form solution. The characterization data are listed only for the
enol form. Red solid; m.p. 175–177 °C, yield 86%; 1H NMR
General procedure for the synthesis of 3 using 3a as the
examples
(Z)-2-(2-Hydroxy-2-phenylvinyl)quinoline-3-carbaldehyde (1a, (300 MHz, CDCl3): δ (ppm) = 16.34 (s, 1H, OH), 9.96 (s, 1H,
82.5 mg, 0.3 mmol) and InCl3 (13.3 mg, 20 mol%) were added CHO), 8.02 (s, 1H, H–Ar), 7.93 (d, J = 8.2 Hz, 2H, H–Ar), 7.34 (s,
to a tube equipped with a magnetic stirrer bar in 3 mL 1H, H–Ar), 7.33–7.24 (m, 3H, H–Ar), 7.21 (s, 1H, H–Ar),
toluene, and then tert-butyl isocyanide (2a, 3.0 equiv.) was 2.73–2.63 (m, 2H, H-n-pentyl), 2.36 (s, 3H, CH3), 2.29 (s, 3H,
added finally. The reaction mixture was stirred at 80 °C for CH3), 1.42–1.29 (m, 5H, H-n-pentyl), 0.95–0.88 (m, 4H, H-n-
24 h. After the reaction was completed (monitored by TLC), pentyl); 13C NMR (100 MHz, CDCl3): δ (ppm) = 189.6, 169.8,
the solvent was evaporated under vacuum and the product was 154.3, 150.5, 147.4, 146.1, 145.9, 138.6, 136.9, 133.7, 129.1,
purified by flash chromatography (n-hexane/EtOAc = 15 : 1) as 127.0, 124.8, 119.9, 118.5, 87.7, 35.9, 31.5, 31.0, 22.6, 20.9, 19.4,
the eluent to afford the desired product 3a, 84%.
14.1; IR (KBr): νmax = 3392 (OH); 1690 (CvO) cm−1; HRMS-ESI
(m/z): calc. for C25H28NO2 [M + H]+ 374.2115, found 374.2119.
3-Benzoyl-2-(tert-butylamino)-1H-cyclopenta[b]quinolin-1-one
Characterization data
(Z)-2-(2-Hydroxy-2-phenylvinyl)quinoline-3-carbaldehyde (1a). (3a). Navy blue solid, m.p. 163–165° C, Rf = 0.3 (n-hexane/
This compound was detected as a tautomeric mixture of enol EtOAc = 15 : 1), yield 84%; 1H NMR (300 MHz, CDCl3):
(90%) and keto forms (10%) in chloroform solution. The δ (ppm) = 11.03 (s, 1H, NH), 7.92 (s, 1H, H–Ar), 7.89–7.80 (m,
characterization data are listed only for the enol form. Red 2H, H–Ar), 7.60 (d, J = 7.9 Hz, 1H, H–Ar), 7.57–7.38 (m, 5H,
crystalline solid, m.p. 155–157 °C, yield 95%; 1H NMR H–Ar), 7.26 (ddd, J = 8.1, 6.9, 1.4 Hz, 1H), 1.61 (s, 9H, t-Bu); 13
C
(300 MHz, CDCl3): δ (ppm) = 16.28 (s, 1H, OH), 10.03 (s, 1H, NMR (75 MHz, CDCl3): δ (ppm) = 193.1, 188.4, 163.3, 157.5,
CHO), 8.15 (s, 1H, H–Ar), 8.05–7.97 (m, 2H, H–Ar), 7.67–7.57 150.4, 139.8, 132.1, 132.0, 131.3, 130.3, 129.1, 127.2, 125.6,
(m, 2H, H–Ar), 7.53–7.39 (m, 5H, H–Ar), 7.33–7.20 (m, 1H, 125.4, 122.2, 112.7, 54.7, 29.8; IR (KBr): νmax = 3419 (NH), 1721
H–Ar); 13C NMR (75 MHz, CDCl3): δ (ppm) = 189.5, 150.7, (CvO), 1635 (CvO) cm−1
;
HRMS-ESI (m/z): calcd for
147.9, 140.1, 139.2, 134.7, 130.9, 129.5, 128.4, 128.2, 127.0, C23H21N2O2 [M + H]+ 357.1598, found 357.1598.
126.0, 124.1, 121.4, 118.4, 88.5; IR (KBr): νmax = 3476 (OH);
3-Benzoyl-2-(cyclohexylamino)-1H-cyclopenta[b]quinolin-1-one
1698 (CvO) cm−1; HRMS-ESI (m/z): calc. for C18H14NO2 [M + (3b). Navy blue solid, m.p. 165–167 °C, Rf = 0.3 (n-hexane/
H]+ 276.1019, found 276.1020.
EtOAc = 15 : 1), yield 78%; 1H NMR (300 MHz, CDCl3):
(Z)-2-(2-Hydroxy-2-phenylvinyl)-6-methylquinoline-3-carbal- (mixture of two rotamers) δ (ppm) = 10.99 (s, 0H, NH (minor
dehyde (1b). This compound was detected as a tautomeric rotamer)), 10.41 (s, 1H, NH, (major rotamer)), 7.96 (s, 1H,
mixture of enol (90%) and keto forms (10%) in chloroform H–Ar), 7.88 (d, J = 7.4 Hz, 2H, H–Ar), 7.62 (d, J = 7.7 Hz, 1H,
solution. The characterization data are listed only for the enol H– Ar), 7.58–7.39 (m, 5H, H–Ar), 7.33–7.21 (m, 1H, H–Ar), 4.68
form. Red solid, m.p. 163–165 °C, yield 90%; 1H NMR (s, 1H, CH-cyclohexyl (major rotamer)), 4.40 (s, 0H, CH-cyclo-
(300 MHz, CDCl3): δ (ppm) = 16.35 (s, 1H, OH), 9.97 (s, 1H, hexyl (minor rotamer)), 2.17–1.94 (m, 2H, H-cyclohexyl),
CHO), 8.03 (s, 1H, H–Ar), 8.02–7.95 (m, 2H, H–Ar), 7.49–7.41 1.92–1.59 (m, 3H, H-cyclohexyl), 1.58–1.17 (m, 5H,
(m, 4H, H–Ar), 7.32 (d, J = 8.6 Hz, 3H, H–Ar), 2.38 (s, 3H, CH3); H-cyclohexyl); 13C NMR (75 MHz, CDCl3): (major rotamer)
13C NMR (75 MHz, CDCl3): δ (ppm) = 189.6, 150.9, 147.5, δ (ppm) = 192.8, 189.4, 163.2, 155.5, 150.5, 139.7, 132.1, 132.0,
139.0, 138.5, 136.4, 134.2, 130.7, 128.7, 128.6, 128.3, 128.2, 131.4, 130.3, 129.1, 129.1, 127.2, 125.5, 125.4, 122.3, 111.2,
126.9, 125.7, 121.7, 118.6, 88.2, 21.0; IR (KBr): νmax = 3419 51.8, 34.0, 33.4, 25.3, 24.3; IR (KBr) νmax = 3432 (NH), 1725
(OH); 1691 (CvO) cm−1; HRMS-ESI (m/z): calc. for C19H16NO2 (CvO), 1632 (CvO) cm−1
; HRMS-ESI (m/z): calc. for
[M + H]+ 290.1176, found 290.1177.
C25H23N2O2 [M + H]+ 383.1754, found 383.1755.
(Z)-2-(2-Hydroxy-2-phenylvinyl)-6,7-dimethylquinoline-3-car-
3-Benzoyl-2-(phenylamino)-1H-cyclopenta[b]quinolin-1-one
baldehyde (1c). This compound was detected as a tautomeric (3c). Navy blue solid, m.p. 174–176 °C, Rf = 0.3 (n-hexane/
mixture of enol (92%) and keto forms (8%) in chloroform solu- EtOAc = 15 : 1), yield 82%; 1H NMR (300 MHz, CDCl3): δ (ppm) =
tion. The characterization data are listed only for the enol 10.02 (s, 1H, NH), 8.01 (s, 1H, H–Ar), 7.96–7.87 (m, 2H, H–Ar),
form. Red solid, m.p. 172–174 °C, yield 87%; 1H NMR 7.68 (d, J = 8.0 Hz, 1H, H–Ar), 7.62–7.51 (m, 3H, H–Ar),
(300 MHz, CDCl3): δ (ppm) = 16.34 (s, 1H, OH), 9.93 (s, 1H, 7.48–7.40 (m, 2H, H–Ar), 7.39–7.26 (m, 3H, H–Ar), 7.25–7.15
CHO), 8.00 (d, J = 4.4 Hz, 3H, H–Ar), 7.46 (d, J = 4.0 Hz, 3H, (m, 3H, H–Ar); 13C NMR (75 MHz, CDCl3): δ (ppm) = 193.1,
H–Ar), 7.34 (s, 1H, H–Ar), 7.28 (s, 1H, H–Ar), 7.18 (s, 1H, 188.2, 163.6, 150.3, 149.8, 138.6, 137.2, 132.4, 132.2, 132.0,
H–Ar), 2.34 (s, 3H, CH3), 2.27 (s, 3H, CH3); 13C NMR (75 MHz, 130.4, 129.4, 128.9, 127.6, 126.3, 126.0, 125.8, 123.8, 122.1,
CDCl3): δ (ppm) = 189.5, 150.8, 147.3, 145.9, 139.3, 138.7, 116.1; IR (KBr) νmax = 3440 (NH), 1731 (CvO), 1637 (CvO)
133.9, 130.6, 129.0, 128.6, 128.3, 128.2, 126.9, 124.8, 120.0, cm−1
; HRMS-ESI (m/z): calc. for C25H17N2O2 [M +
H]+
118.7, 87.9, 20.8, 19.4; IR (KBr): νmax = 3392 (OH); 1690 (CvO) 377.1285, found 377.1285.
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3-Benzoyl-2-(tert-butylamino)-7-methyl-1H-cyclopenta[b]qui- 1.55–1.16 (m, 5H, H-cyclohexyl); 13C NMR (75 MHz, CDCl3):
nolin-1-one (3d). Navy blue solid, m.p. 158–160 °C, Rf = 0.3 (major rotamer) δ (ppm) = 192.6, 189.5, 162.8, 155.5, 149.3,
(n-hexane/EtOAc = 15 : 1), yield 80%; 1H NMR (300 MHz, 142.8, 139.8, 134.9, 131.3, 130.0, 129.9, 129.2, 129.1, 127.2,
CDCl3): (mixture of two rotamers) δ (ppm) = 10.99 (s, 1H, NH), 123.8, 121.4, 111.0, 51.7, 34.0, 33.4, 25.3, 24.4, 20.4, 19.5; IR
7.99–7.92 (m, 0H, H–Ar (minor rotamer)), 7.87 (s, 1H, H–Ar (KBr) νmax = 3423 (NH), 1718 (CvO), 1630 (CvO) cm−1
;
(major rotamer)), 7.85–7.81 (m, 2H, H–Ar), 7.57–7.48 (m, 1H, HRMS-ESI (m/z): calc. for C27H27N2O2 [M + H]+ 411.2067,
H–Ar), 7.45–7.35 (m, 3H, H–Ar), 7.33 (s, 2H, H–Ar), 2.40 (s, 3H, found 411.2068.
–CH3), 1.64 (s, 0H, t-Bu), 1.60 (s, 9H, t-Bu); 13C NMR (75 MHz,
3-Benzoyl-2-(tert-butylamino)-7-methoxy-1H-cyclopenta[b]
CDCl3): (major rotamer) δ (ppm) = 192.7, 189.5, 148.9, 139.7, quinolin-1-one (3h). Navy blue solid, m.p. 148–150 °C, Rf = 0.3
135.1, 134.0, 133.9, 131.5, 131.3, 129.6, 129.2, 128.8, 127.2, (n-hexane/EtOAc = 15 : 1), yield 67%; 1H NMR (300 MHz,
125.4, 125.0, 122.2, 119.3, 111.2, 51.8, 34.0, 33.4, 25.3, 24.4, CDCl3): δ (ppm) = 10.98 (s, 1H, NH), 7.87 (s, 1H, H–Ar),
21.1; IR (KBr) νmax = 3420 (NH), 1720 (CvO), 1637 (CvO) 7.86–7.80 (m, 2H, H–Ar), 7.57–7.48 (m, 1H, H–Ar), 7.46–7.32
cm−1; HRMS-ESI (m/z): calcd for C24H23N2O2 [M + H]+ (m, 3H, H–Ar), 7.15 (dd, J = 9.1, 2.9 Hz, 1H, H–Ar), 6.96 (d, J =
371.1754, found 371.1754.
2.8 Hz, 1H, H–Ar), 3.87 (s, 3H, CH3–OMe), 1.61 (s, 9H, t-Bu);
3-Benzoyl-2-(cyclohexylamino)-7-methyl-1H-cyclopenta[b] 13C NMR (75 MHz, CDCl3): δ (ppm) = 192.9, 188.8, 161.5,
quinolin-1-one (3e). Navy blue solid, m.p. 181–183 °C, Rf = 157.0, 156.9, 146.0, 139.9, 131.2, 131.1, 130.3, 129.0, 127.1,
0.3 (n-hexane/EtOAc = 15 : 1), yield 75%; 1H NMR (300 MHz, 126.3, 123.0, 122.4, 112.8, 109.2, 55.5, 54.5, 29.8; IR (KBr):
CDCl3): (mixture of two rotamers) δ (ppm) = 10.98 (s, 0H, NH νmax = 3392 (NH), 1725 (CvO), 1628 (CvO) cm−1; HRMS-ESI
(minor rotamer)), 10.39 (s, 1H, NH (major rotamer)), 7.88 (s, (m/z): calc. for C24H23N2O3 [M + H]+ 387.1703, found 387.1704.
1H, H–Ar), 7.85 (s, 2H, H–Ar), 7.56–7.48 (m, 1H, H–Ar), Red crystal (blank), dimensions 0.318 × 0.148 × 0.042 mm3,
7.46–7.27 (m, 5H, H–Ar), 4.64 (s, 1H, CH-cyclohexyl (major crystal system monoclinic, space group P21, Z = 2, a = 11.6212
rotamer)), 4.36 (s, 0H, CH-cyclohexyl (minor rotamer)), 2.41 (s, (12) Å, b = 6.9157(8) Å, c = 12.8041(14) Å, alpha = 90°g, beta =
0H, –CH3 (minor rotamer)), 2.40 (s, 3H, –CH3 (major 109.534(3)°, gamma = 90°, V = 969.82(18) Å3, rho = 1.323
rotamer)), 2.14–1.94 (m, 2H, H-cyclohexyl), 1.89–1.59 (m, 3H, g cm−3, T = 200(2) K, thetamax = 25.086°, radiation MoKα,
H-cyclohexyl), 1.53–1.24 (m, 5H, H-cyclohexyl); 13C NMR lambda = 0.71073 Å, 0.5° omega-scans with a CCD area detec-
(75 MHz, CDCl3): (major rotamer) δ (ppm) = 192.7, 189.5, tor, covering the asymmetric unit in reciprocal space with a
162.6, 155.4, 148.9, 139.8, 135.1, 134.0, 131.5, 129.6, 129.2, mean redundancy of 5.46 and a completeness of 99.9% to a
128.8, 127.2, 125.4, 125.0, 122.2, 111.2, 51.8, 34.0, 33.4, 25.3, resolution of 0.84 Å, 6224 reflections were measured, 3417
24.4, 21.1; IR (KBr): νmax = 3425 (NH), 1727 (CvO), 1609 unique (R(int) = 0.0437), 2017 observed (I > 2δ(I)), intensities
(CvO) cm−1; HRMS-ESI (m/z): calc. for C26H24N2O2 [M + H]+ were corrected for Lorentz and polarization effects, an empiri-
397.1911, found 397.1911.
cal scaling and absorption correction was applied using
3-Benzoyl-2-(tert-butylamino)-6,7-dimethyl-1H-cyclopenta[b] SADABS based on the Laue symmetry of the reciprocal space,
quinolin-1-one (3f). Navy blue solid, m.p. 163–165 °C, Rf = 0.3 mu = 0.09 mm−1, Tmin = 0.86, Tmax = 0.96; the structure was
(n-hexane/EtOAc = 15 : 1), yield 82%; 1H NMR (300 MHz, solved with SHELXT-2014 (Sheldrick 2014) and refined against
CDCl3): (mixture of two rotamers) δ (ppm) = 11.02 (s, 1H, NH), F2 with
a Full-matrix least-squares algorithm using the
7.97–7.91 (m, 0H, H–Ar (minor rotamer)), 7.87 (s, 1H, H–Ar SHELXL-2018/3 (Sheldrick, 2018) software,20 314 parameters
(major rotamer)), 7.85–7.78 (m, 2H, H–Ar (major rotamer)), were refined, hydrogen atoms were treated using appropriate
7.58–7.49 (m, 1H, H–Ar), 7.47–7.38 (m, 2H, H–Ar), 7.35 (s, 1H, riding models, Flack absolute structure parameter −2(5), good-
H–Ar), 7.21 (s, 1H, H–Ar), 2.31 (s, 6H, −2CH3), 1.62 (s, 0H, t-Bu ness of fit 1.01 for observed reflections, final residual values
(minor rotamer)), 1.60 (s, 9H, t-Bu (major rotamer)); 13C NMR R1(F) = 0.055, wR(F2) = 0.107 for observed reflections, residual
(75 MHz, CDCl3): (major rotamer) δ (ppm) = 192.9, 188.6, electron density −0.22 to 0.19 e Å−3. CCDC 1861937† contains
162.9, 157.5, 149.3, 142.8, 139.9, 134.9, 131.5, 131.2, 129.9, the supplementary crystallographic data for this paper.
129.1, 127.2, 123.9, 121.4, 112.5, 54.6, 29.8, 20.4, 19.5; IR
(KBr): νmax = 3405 (NH), 1715 (CvO), 1621 (CvO) cm−1
3-Benzoyl-2-(cyclohexylamino)-7-methoxy-1H-cyclopenta[b]
quinolin-1-one (3i). Navy blue solid, m.p. 146–148 °C, Rf = 0.3
;
HRMS-ESI (m/z): calc. for C25H25N2O2 [M + H]+ 358.1911, (n-hexane/EtOAc = 15 : 1), yield 73%; 1H NMR (300 MHz,
found 385.1913.
CDCl3): (mixture of two rotamers) δ (ppm) = 10.99 (s, 0H, NH
3-Bnzoyl-2-(cyclohexylamino)-6,7-dimethyl-1H-cyclopenta[b] (minor rotamer)), 10.38 (s, 1H, NH (major rotamer)), 7.91–7.84
quinolin-1-one (3g). Navy blue solid, m.p. 181–183 °C, Rf = 0.3 (m, 2H, H–Ar), 7.82 (s, 1H, H–Ar), 7.57–7.49 (m, 1H, H–Ar),
(n-hexane/EtOAc = 15 : 1), yield 76%; 1H NMR (300 MHz, 7.46–7.31 (m, 3H, H–Ar), 7.13 (ddd, J = 9.2, 6.4, 2.8 Hz, 1H,
CDCl3): (mixture of two rotamers) δ (ppm) = 11.01 (s, 0H, NH H–Ar), 6.92 (t, J = 2.6 Hz, 1H, H–Ar), 4.62 (s, 1H, CH-cyclohexyl
(minor rotamer)), 10.43 (s, 1H, NH (major rotamer)), 7.88 (d, (major rotamer)), 4.37 (s, 0H, CH-cyclohexyl (minor rotamer)),
J = 7.1 Hz, 2H, H–Ar), 7.84 (s, 1H, H–Ar), 7.55 (t, J = 7.3 Hz, 1H, 3.86 (s, 0H, CH3–OMe (minor rotamer)), 3.84 (s, 3H, CH3–OMe
H–Ar), 7.49–7.39 (m, 2H, H–Ar), 7.33 (s, 1H, H–Ar), 7.24 (s, 1H, (major rotamer)), 2.12–1.90 (m, 2H, H-cyclohexyl), 1.90–1.60
H–Ar), 4.67 (s, 1H, CH-cyclohexyl (major rotamer)), 4.36 (s, 0H, (m, 3H, H-cyclohexyl), 1.53–1.22 (m, 5H, H-cyclohexyl); 13C
CH-cyclohexyl (minor rotamer)), 2.32 (s, 6H, −2CH3), 2.05 (d, NMR (100 MHz, CDCl3) δ 192.6, 189.8, 161.5, 157.0, 156.3,
J = 9.4 Hz, 2H, H-cyclohexyl), 1.90–1.59 (m, 3H, H-cyclohexyl), 146.1, 139.8, 131.1, 130.3, 129.2, 127.2, 126.2, 123.1, 122.4,
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119.5, 111.2, 109.2, 55.6, 51.8, 34.0, 33.4, 25.3, 24.4; IR (KBr) 1632 (CvO) cm−1; HRMS-ESI (m/z): calc. for C30H35N2O2
νmax = 3416 (NH), 1726 (CvO), 1616 (CvO) cm−1; HRMS-ESI [M + H]+ 455.2693, found 455.2695.
(m/z): calc. for C26H25N2O3 [M + H]+ 413.1860, found 413.1862.
2-(Cclohexylamino)-6,7-dimethyl-3-(4-pentylbenzoyl)-1H-cyclo-
2-(tert-Butylamino)-3-(cyclopropanecarbonyl)-1H-cyclopenta penta[b]quinolin-1-one (3n). Navy blue solid, m.p. 163–165 °C,
[b]quinolin-1-one (3j). Navy blue solid, m.p. 232–234 °C, Rf = Rf = 0.3 (n-hexane/EtOAc = 15 : 1), yield 82%; 1H NMR
0.3 (n-hexane/EtOAc = 15 : 1), yield 79%; 1H NMR (300 MHz, (300 MHz, CDCl3): (mixture of two rotamers) δ (ppm) = 10.34
CDCl3): δ (ppm) = 11.15 (s, 1H, NH), 7.94 (d, J = 2.8 Hz, 1H, (s, 1H, NH), 7.86 (s, 2H, H–Ar), 7.82 (s, 1H, H–Ar), 4.63 (s, 1H,
H–Ar), 7.81 (d, J = 8.3 Hz, 1H, H–Ar), 7.70–7.55 (m, 2H, H–Ar), CH-cyclohexyl (major rotamer)), 4.36 (s, 0H, CH-cyclohexyl
7.36–7.26 (m, 1H, H–Ar), 4.23–4.10 (m, 1H, CH-cyclopropyl), (minor rotamer)), 2.73 (t, J = 7.5 Hz, 2H, H-n-pentyl), 2.33 (s,
1.55 (s, 9H, t-Bu), 1.28–1.18 (m, 2H, H-cyclopropyl), 1.13–1.02 6H, −2CH3), 2.09–1.95 (m, 2H, H-cyclohexyl), 1.88–1.59 (m,
(m, 2H, H-cyclopropyl); 13C NMR (100 MHz, CDCl3): δ = 199.7, 6H, H-cyclohexyl), 1.57–1.34 (m, 9H, H-n-pentyl), 1.33–1.24 (m,
188.9, 164.3, 155.7, 150.6, 132.1, 131.8, 130.4, 128.9, 125.5, 2H, H-cyclohexyl); 13C NMR (100 MHz, CDCl3): δ = 192.5,
125.3, 123.0, 113.0, 54.4, 29.8, 18.7, 12.0; IR (KBr): νmax = 3416 189.7, 163.0, 155.4, 149.4, 146.8, 142.7, 137.2, 134.9, 131.3,
(NH), 1729 (CvO), 1632 (CvO) cm−1; HRMS-ESI (m/z): calcd 130.0, 129.4, 129.1, 127.3, 123.8, 121.6, 111.3, 51.7, 36.1, 34.0,
for C20H21N2O2 [M + H]+ 321.1598, found 321.1598.
33.4, 31.4, 30.9, 25.3, 24.4, 22.6, 20.4, 19.6, 14.1; IR (KBr):
2-(Cyclohexylamino)-3-(cyclopropanecarbonyl)-1H-cyclopenta νmax = 3415 (NH), 1713 (CvO), 1607 (CvO) cm−1; HRMS-ESI
[b]quinolin-1-one (3k). Navy blue solid, m.p. 227–229 °C, Rf = (m/z): calc. for C32H37N2O2 [M + H]+ 481.2850, found 481.2852.
0.3 (n-hexane/EtOAc = 15 : 1), yield 65%; 1H NMR (300 MHz,
7-Benzoyl-6-(cyclohexylamino)-5H-cyclopenta[b]pyridin-5-one
CDCl3): δ (ppm) = 10.28 (d, J = 8.6 Hz, 1H, NH), 7.90 (s, 1H, (3p). Navy blue solid, m.p. 53–56 °C, Rf = 0.3 (n-hexane/EtOAc =
1
H–Ar), 7.78 (d, J = 8.2 Hz, 1H, H–Ar), 7.66–7.53 (m, 2H, H–Ar), 10 : 1), yield 35%; H NMR (400 MHz, CDCl3): δ 10.61 (s, 1H,
7.35–7.23 (m, 1H, H–Ar), 4.63–4.48 (m, 1H, CH-cyclohexyl), NH), 8.04 (dd, J = 5.2, 1.8 Hz, 1H, H–Ar), 7.67 (d, J = 7.4 Hz,
4.07 (tt, J = 7.9, 4.7 Hz, 1H, CH-cyclopropyl), 2.05–1.92 (m, 2H, 2H, H–Ar), 7.45 (dd, J = 7.3, 1.8 Hz, 1H, H–Ar), 7.41 (t, J =
H-cyclohexyl), 1.88–1.73 (m, 2H, H-cyclohexyl), 1.71–1.57 (m, 7.4 Hz, 1H, H–Ar), 7.33 (t, J = 7.4 Hz, 2H, H–Ar), 6.65 (dd, J =
1H, H-cyclohexyl), 1.55–1.24 (m, 5H, H-cyclohexyl), 1.25–1.18 7.3, 5.2 Hz, 1H, H–Ar), 4.52 (m, 1H, CH-cyclohexyl), 1.98–1.87
(m, 1H, H-cyclopropyl), 1.08 (dt, J = 8.3, 3.3 Hz, 1H, (m, 3H), 1.79–1.66 (m, 2H), 1.6 (dq, J = 13.2, 4.5 Hz, 1H),
H-cyclopropyl); 13C NMR (75 MHz, CDCl3):
δ
(ppm)
=
1.46–1.26 (m, 4H), 1.26–1.14 (m, 1H); 13C NMR (100 MHz,
199.5, 189.9, 164.3, 153.2, 150.6, 132.1, 131.8, 130.4, 128.9, CDCl3): δ 191.4, 190.4, 168.8, 154.4, 154.2, 139.9, 131.2, 130.9,
125.4, 125.3, 123.0, 111.6, 51.6, 34.1, 25.2, 24.4, 18.7, 11.8; IR 128.6, 127.5, 120.4, 118.3, 108.5, 52.0, 33.8, 29.7, 25.2, 24.3; IR
(KBr): νmax = 3405 (NH), 1718 (CvO), 1609 (CvO) cm−1
;
(KBr): νmax = 3432 (NH), 1725 (CvO), 1606 (CvO) cm−1
;
HRMS-ESI (m/z): calc. for C22H23N2O2 [M + H]+ 347.1754, LC-MS (ESI) (m/z): calc. for C21H20N2O2 [M + H]+ 233.2, found
found 347.1757. 233.2. Anal. Calcd for C21H20N2O2: C, 79.29; H, 4.32; N, 8.85;
3-(Cyclopropanecarbonyl)-2-(phenylamino)-1H-cyclopenta[b] O, 9.81. Found: C, 79.08; H, 4.21; N, 8.67; O, 9.76.
quinolin-1-one (3l). Navy blue solid, m.p. 234–236 °C, Rf = 0.3
(n-hexane/EtOAc = 15 : 1), yield 72%; 1H NMR (300 MHz,
CDCl3): δ (ppm) = 11.64 (s, 1H, NH), 7.95 (s, 1H, H–Ar),
Conflicts of interest
7.91–7.85 (m, 1H, H–Ar), 7.71–7.61 (m, 2H, H–Ar), 7.44–7.33
(m, 3H, H–Ar), 7.33–7.23 (m, 3H, H–Ar), 4.18 (tt, J = 7.9, 4.7 Hz,
There are no conflicts to declare.
1H, CH-cyclopropyl), 1.34–1.26 (m, 2H, H-cyclopropyl),
1.22–1.13 (m, 2H, H-cyclopropyl); 13C NMR (100 MHz, CDCl3): Acknowledgements
δ = 200.7, 187.8, 163.4, 151.1, 150.3, 137.0, 132.2, 132.0, 130.5,
Saeed Balalaie thanks Alexander von Humboldt foundation for
129.3, 129.2, 128.9, 126.6, 125.9, 125.8, 124.2, 123.1, 119.8,
the research fellowship and National Institute for Medical
Research Development (NIMAD, Grant No. 943185) for the
financial support.
115.5, 19.41, 12.8; IR (KBr): νmax = 3414 (NH), 1717 (CvO),
1621 (CvO) cm−1; HRMS-ESI (m/z): calc. for C22H17N2O2
[M + H]+ 341.1285, found 341.1285.
2-(tert-Butylamino)-6,7-dimethyl-3-(4-pentylbenzoyl)-1H-cyclo-
penta[b]quinolin-1-one (3m). Navy blue solid, m.p. 156–158 °C,
Notes and references
Rf = 0.3 (n-hexane/EtOAc = 15 : 1), yield 80%; 1H NMR
(400 MHz, CDCl3): δ = 10.88 (s, 1H, NH), 7.85 (s, 1H, H–Ar),
7.77 (d, J = 8.1 Hz, 2H, H–Ar), 7.34 (s, 1H, H–Ar), 7.22 (d, J =
7.5 Hz, 3H, H–Ar), 2.70 (t, J = 7.6 Hz, 2H, H-n-pentyl), 2.31 (s,
6H, −2CH3), 1.76–1.63 (m, 2H, H-n-pentyl), 1.58 (s, 9H, t-Bu),
1.44–1.29 (m, 4H, H-n-pentyl), 0.92 (t, J = 6.8 Hz, 3H, H-n-
pentyl); 13C NMR (100 MHz, CDCl3): δ = 192.8, 188.7, 163.1,
157.1, 149.3, 146.8, 142.6, 137.2, 134.9, 131.3, 129.9, 129.3,
129.1, 127.3, 123.9, 121.5, 112.9, 54.4, 36.0, 31.3, 30.9, 29.8,
22.6, 20.4, 19.6, 14.1; IR (KBr): νmax = 3416 (NH), 1729 (CvO),
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