Synthesis of Spiro-β-lactam-pyrroloquinolines as Fused Heterocyclic Scaffolds through Post-transformation Reactions

Article abstract of DOI:10.1021/acs.joc.0c01817

A sequential post-transformation of Ugi four-component reaction/nucleophilic substitution was developed for the synthesis of spiro-β-lactam-pyrroloquinolines. This method involves the Ugi-4CR of 2-chloro-3-formyl quinolines 1a-h, amines 2a-d, 2-chloroacetic acid 3, and isocyanides 4a, 4b for the synthesis of versatile precursors 5a-v. The Ugi adducts were intramolecularly cyclized under basic conditions through the sequential nucleophilic aromatic substitution (SNAr)/second-order nucleophilic substitution (SN2) reaction to give spiro-β-lactam-pyrroloquinoline scaffolds 6a-t. This approach is an efficient method for the synthesis of fused bioactive heterocyclic backbones containing quinoline, pyrrolidone, and β-lactam with high bond-forming efficiency.

Full text of DOI:10.1021/acs.joc.0c01817

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Article
Synthesis of Spiro-#-lactam-pyrroloquinolines as Fused
Heterocyclic Scaffolds through Post-transformation Reactions
Farhad Golmohammadi, Saeed Balalaie, Vaezeh Fathi Vavsari, Muhammad U Anwar, and Ahmed Al-Harrasi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01817 • Publication Date (Web): 16 Sep 2020
Downloaded from pubs.acs.org on September 16, 2020
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Synthesis of Spiro-β-lactam-pyrroloquinolines as Fused Heterocyclic Scaffolds through
Post-transformation Reactions
a
a,b
a
c
Farhad Golmohammadi , Saeed Balalaie* , Vaezeh Fathi Vavsari , Muhammad U. Anwar ,
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Ahmed Al-Harrasi*
a
Peptide Chemistry Research Center, K. N. Toosi University of Technology, P. O. Box 15875-4416,
Tehran, Iran, balalaie@kntu.ac.ir, Tel:+98-21-23064226, Fax: +98-21-22889403
Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
b
c
Natural and Medical Sciences Research Center, University of Nizwa, P.O. Box 33, Postal Code 616,
Birkat Al Mauz, Nizwa, Sultanate of Oman
ABSTRACT
A sequential post-transformation of Ugi four-component reaction/nucleophilic substitution was
developed for the synthesis of spiro-β-lactam-pyrroloquinolines. This method involves the Ugi-
4CR of 2-chloro-3-formyl quinolines 1a-h, amines 2a-d, 2-chloroacetic acid 3, and isocyanides
4
a-b for the synthesis of versatile precursors 5a-v. The Ugi adducts were intramolecularly cyclized
under basic conditions through the sequential S Ar/S 2 reaction to give spiro-β-lactam-
N
N
pyrroloquinoline scaffolds 6a-t. This approach is an efficient method for the synthesis of fused
bioactive heterocyclic backbones containing quinoline, pyrrolidone and β-lactam with high bond
forming efficiency.
KEYWORDS
Post-transformation reaction, Ugi-4CR/Nucleophilic substitution, Fused heterocyclic scaffolds,
Spiro-β-lactam, Pyrroloquinoline.
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▪ INTRODUCTION
The developed organic chemistry is recently called as the art of synthesis that is due to the creation
of complex organic molecules containing multi-fused heterocyclic moieties. Fused heterocyclic
structures are found among different kinds of bioactive organic compounds, for example trapidil
(triazolopyrimidine) as an antiplatelet drug, natural camptothecin (pyrano[3',4':6,7] indolizino[1,2-
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b]quinoline) as an antitumor agent, and zolpidem (imidazopyridine) as a hypnotic agent. In this
respect, the production of fused heterocyclic structures is considered a privileged task for scientists
2
from the viewpoint of their synthesis and their medicinal activities. In terms of their synthesis,
designing a reaction to fuse heterocycles together is a burgeoning challenge in the world of organic
synthesis. In recent years, many contributions have led to the synthesis of the fused heterocycles
involving multistep sequences for assembling the starting materials, including microwave-assisted
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4
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techniques, intramolecular C–H activation, catalyzed by transition metals, or even metal-free
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methodologies. Another environmentally benign approach known as the post-transformation
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reactions is also developed to fuse heterocycles. The use of Ugi four-component reaction (4CR)
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post-transformations has received significant attention. The most important parameter of a post-
transformation synthesis is manipulated by targeted selection of the starting materials that could
undergo further reactions, such as Heck, Suzuki, and substitution nucleophilic reactions, to give a
complex cyclized structure.9
The chemistry of spiro-β-lactams has been explored for the preparation of a wide range of
biologically important fused heterocycles.10 Various reactive β-lactams (azetidin-2-one) are
reported as antibacterial agents.11 Spiro-β-lactam are also found in nature; (S)-chartelline A
isolated from the marine bryozoan Chartella papyracea (Figure 1).12 Besides, pyrrolo[2,3-
b]quinolines, as aza-analogue of furoquinoline alkaloids, have greatly drawn the attention of
synthetic chemists in recent years. Most of the known synthetic routes for the preparation of these
compounds involve very complicated multistep reactions or require the presence of a metal
complex catalyst.13
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Figure 1. The Structure of Natural Chartelline A from the Marine Bryozoan Chartella
Papyracea
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Prompted by the above mentioned topics and following of our interest in Ugi–post-
transformational reactions, herein, we wish to report a concise post-transformation approach for
the synthesis of spiro-β-lactam-pyrroloquinoline through a sequential Ugi-4CR/nucleophilic
substitution reaction, employing 2-chloro-3-formylquinoline derivatives (as the aldehyde moiety)
in the Ugi-4CR. It is noteworthy that the substitution reaction includes sequential S
N
Ar and S 2
N
mechanisms to cyclize the Ugi adducts. As shown in Scheme 1, by treating 2-chloro-3-formyl
quinolines 1a-h with amines 2a-d, chloroacetic acid 3, and isocyanides 4a-b through Ugi-4CR, a
series of Ugi adducts 5a-v were synthesized containing two nucleophile and two electrophile
centers which can directly undergo intramolecular cyclization reaction in the presence of
potassium t-butoxide as the base to give the desired spiro-β-lactam-pyrroloquinolines 6a-t.
Scheme 1. Two Step Preparation of Spiro-β-lactam-pyrroloquinoline Scaffolds 6a-t via Ugi/
S
N
Ar/S 2 Post-transformation Reactions
N
▪ RESULTS AND DISSCUSSIONS
The desired bifunctional precursors 2-chloro-3-formyl quinolines 1a-h were synthesized utilizing
.14
a previously reported Vilsmeier-Haack cyclization from acetanilides in the presence of POCl
3
Our primary investigations focused on the production of 5a via Ugi-4CR of 2-chloro-3-
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formylquinoline 1a, benzylamine 2a, 2-chloroacetic acid 3, and cyclohexyl isocyanide 4a in
methanol at ambient temperature for 24 h as the model reaction. For the synthesis of target product
6
a from Ugi adduct 5a, the reaction conditions were initially optimized as shown in Table 1. In
this regard, the selected adduct 5a was exposed to different inorganic and organic bases in various
solvents at high temperatures. Carbonate salts (Cs CO and K CO ) in polar, nonpolar, and even
protic solvents (CH CN, DMF, DMSO, toluene, MeOH, CHCl , dioxane) did not give the product
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higher than 30% yield. By the use of t-BuOK in different solvents (Table 1, entries 1-5), the highest
reaction yield was found in dioxane. Hence, the effect of some other bases, including NaOMe,
Et N, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO),
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was examined in this reaction in dioxane (entries 6-9); however, none of them were effective. So,
the effect of temperature over the reaction in t-BuOK/dioxane was investigated (entries 10 and
1
1). Entry 11 shows the optimum conditions for the model reaction.
Table 1. Optimization of the Reaction Conditions for the Synthesis of 6a as Model Reactiona
b
Entry
Base (2eq)
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
NaOMe
Solvent
DMF
DMSO
Toluene
Conditions
100 °C
100 °C
100 °C
reflux
100 °C
100 °C
100 °C
100 °C
100 °C
50 °C
Time (h)
Yield (%)
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33
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65
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75
88
CH CN
3
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Et
3
N
DBU
DABCO
t-BuOK
t-BuOK
1
0
6
3
c
1
1
80 °C
a
b
All reactions was performed using 5a (1.0 mmol, 0.484 g), the base (2 eq) and 5 mL of solvent. Isolated yields after
c
flash chromatography. Optimized reaction conditions.
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To study the generality of these conditions to produce the spiro-β-lactam-pyrroloquinoline
derivatives, a series of Ugi adducts (Table 2) were primarily synthesized by using 2-chloro-3-
formyl quinolines 1a-h, amines 2a-c, and isocyanides 4a-b. Subsequently, these pseudo-peptide
Ugi adducts 5a-v were treated with t-BuOK under optimum conditions to obtain spiro-β-lactam-
pyrroloquinolines 6a-t (Table 3). The highest product yields were observed for 6a-b. By
comparing the results, it is obvious that the presence of electron-donating groups on quinoline
moiety led to the decrease of product yields; the lowest yields were found for quinoline including
dimethyl groups 6i and 6m, while methoxy including quinolines 5q-r gave no cyclized products.
The presence of electron-withdrawing substituents on the quinoline moiety did not affect the
results significantly.
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Table 2. Substrate Scope for the Synthesis of Ugi-Adducts 5a-va
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aAll reactions were performed using 2-chloro-3-formyl quinoline 1 (1.0 mmol), primary amine 2 (1.0 mmol),
chloroacetic acid 3 (1.0 mmol), and isocyanide 4 (1.0 mmol) in 5 mL of methanol at room temperature for 24 h. The
precipitate was filtered and used for the next step.
Table 3. Generality and Scope of the Spiro-β-lactam-pyrroloquinoline Skeletons 6a-ta
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All reactions were performed using Ugi-adducts 5a-v (1.0 mmol), potassium tert-butoxide (2.0 eq) in dioxane (5
b
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mL) at 80 °C. Reaction was completed in 3 h. Reaction was completed in 6h.
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All Ugi adducts and spiro-β-lactam-pyrroloquinolines were characterized by FT-IR, H and C
NMR, DEPT, and HRMS-ESI spectral analysis. In addition, X-ray diffraction analysis of the
products 6b confirmed the formation of pyrrolidinone and β-lactam moieties (see SI, S93-S95).
In order to propose a reaction mechanism for the formation of spiro-β-lactam-pyrroloquinolines,
a sequential S
N
Ar/S 2 mechanism seems to proceeded this reaction (Scheme 2). According to the
N
previously reported mechanisms for the reaction of 2-chloro-3-formyl quinolines, a nucleophilic
substitution reaction primarily occurred over quinoline moiety followed by a nucleophilic aromatic
substitution which is due to high electrophilicity at C2-position of quinoline. Therefore, the
conjugate base of quinoline 5 is produced by treating it with t-BuOK. In the structure of 7, the
anion form of amide attacks to the C-Cl through a S
ring. The second equivalent of the base reacts with the hydrogen atom of pyrrolidinone moiety in
intermediate 8 to give carbanion 9. Intramolecular S 2 reaction of the latter leads to the target
product 6. Based on this proposed S Ar/S 2 mechanism, it can be concluded that t-BuOK plays
N
Ar mechanism to constitute a pyrrolidinone
N
N
N
as the proper base for the deprotection of amide and nucleophilic substitution on quinoline ring
because of the existence of chlorine at C2-position. Then, after proton abstraction from –CH, a
strong carbanion is formed and acts as a nucleophile, Cl atom of ClCH
2
CO is a suitable leaving
2 reaction.
group, and finally, heating provides the required activation energy for the S
N
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Scheme 2. The Proposed Mechanism for the Synthesis of Spiro-β-lactam-pyrroloquinolines
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Considering the success of this reaction, to confirm the effect of 2-chloro-3-formyl quinoline in
the construction of the products, it was replaced with another β-halogenated carbaldehyde. Thus,
2
-bromobenzaldehyde 7 was treated with benzyl amine 2a, 2-chloroacetic acid 3, and isocyanide
b (Scheme 3). The obtained Ugi adduct 11 was exposed to basic condition at 80 °C producing
4
piperazine-2,5-dione 12 in good yield. Therefore, such replacement gave piperazine-2,5-dione
instead of spiro-β-lactam-pyrroloquinolines that shows the tendency of 2-chloro-3-formyl
quinoline to proceed the nucleophilic substitution reaction. Consequently, the formation of spiro-
β-lactam-pyrroloquinolines owes to the high electrophilicity of 2-position at quinoline moiety
because of the presence of nitrogen atom in its structure increasing its electrophilic properties
compared to the simple phenyl ring in 2-bromobenzaldehyde 10.
Scheme 3. Control Experiment for the Synthesis of Piperazine-2,5-dione 12
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In conclusion, two-step sequential Ugi-4CR/S
N
Ar/S 2 was employed in the synthesis of spiro-β-
N
lactam-pyrroloquinoline scaffolds 6a-t. The method is simple, safe, metal free and gives high
yields of pure products. These products are valuable owing to the presence of β-lactam as
antibacterial agent. The fused pyrroloquinoline moiety is also found in the structure of many
natural products. This reaction plays a remarkably important role in providing innovative ways for
the preparation of new β-lactam antibiotics.
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▪
EXPERIMENTAL SECTION
General Considerations. All reagents and solvents were commercially purchased 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 carried out
on silica gel (63-200 mesh ASTM). Melting points (mp) were recorded using an Electrothermal
9100 apparatus and were uncorrected. Fourier transform infrared (FT-IR) spectra were recorded
1
13
as KBr pellets using an AABFT-IR (FTLA 2000) spectrophotometer. The H-NMR and C-NMR
spectra were recorded on a Bruker NMR spectrometer at 600 and 150 MHz or 300 and 75 MHz
respectively. All chemical shifts were expressed in parts per million (δ) using TMS as internal
standard and CDCl or DMSO-d6 as solvent, and coupling constants (J) were expressed in Hertz.
3
High-resolution mass spectrometry (ESI-HRMS) measurements were obtained on an Agilent Q-
TOF LC-MS, a Thermo Scientific Advantage and a Thermo Scientific Executive spectrometer.
Crystal Growth for XRD porpose: CH
2
Cl was used as solvent at room temperature for crystal
2
preparation.
General procedure of the synthesis of Ugi adducts (5a-v). To the stirring solution of
aldehyde 1a-h (1 mmol) in MeOH (5 mL) the primary amine 2a-d (1 mmol) was added and, the
reaction mixture was stirred for 1h at room temperature. Then, chloroacetic acid 3 (1 mmol, 94.5
mg) was added, and stirring was continued for 15 min, followed by the addition of isocyanide 4a-
b (1 mmol). The mixture was stirred at room temperature for 24h. The progress of the reaction
was monitored by thin-layer chromatography (TLC) (n-hexane/ EtOAc 3:1). After the completion
of the reaction, the formed precipitate 5a-v was filtered, wash with MeOH, and dried in vacuo.
Yields (58-92%)
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1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
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3
4
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
General procedure of the synthesis of spiro-β-lactam-pyrroloquinolines (6a-t). Ugi-
adduct 5 (1 mmol) was added to a solution of t-BuOK (2 eq) in dioxane (5.0 mL) in a round-bottom
flask, and the reaction mixture was stirred at 80 °C in oil bath for 3-6 hr. The progress of the
reaction was checked by using TLC. After completion, the reaction mixture was cooled to room
temperature, water was addded and the mixture was extracted with EtOAc (3 × 10 mL). The
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
organic phase was combined, washed with saturated brine, dried over anhydrous MgSO , filtered,
4
and concentrated under vacuum. The obtained residue was purified by flash column
chromatography on silica gel using (n-hexane/EtOAc 7:1) as the eluent to afford the spiro-β-
lactam-pyrroloquinoline 6a-t. Yields (54-88%)
General procedure of the synthesis of Ugi adduct 11.
A solution of 2-bromobenzaldehyde 7 (1 mmol) in MeOH (5 mL), was added by benzylamine 2a
(1 mmol), and the reaction mixture was stirred for 1h at room temperature. Then, chloroacetic acid
3 (1mmol, 94.5 mg) and tert-butyl isocyanide 4b (1 mmol) were added and stirring was continued
at room temperature for 24 h. The progress of the reaction was monitored by using thin-layer
chromatography (TLC) (n-hexane/ EtOAc 3:1). After the completion of the reaction, the desired
product 11 was precipitated, the colorless precipitate was filtered, washed with MeOH, and dried
in vacuo. Yiled (59%)
General procedure of the synthesis of 2,5-diketopiperazine 12.
Ugi-adduct 8 (1 mmol) was added to a solution of t-BuOK (2 eq) in dioxane (5 mL), and the
reaction mixture was stirred at 80 °C in oil bath for 4 h. The progress of the reaction was monitored
by using TLC. After completion, the reaction mixture was cooled to room temperature, water was
added and the mixture was extracted with EtOAc (3 × 10 mL). The organic phase was combined,
washed with saturated brine, dried over anhydrous MgSO , filtered, and concentrated under
4
vacuum. After the evaporation of the solvent, the resulting residue was purified by flash column
chromatography on silica gel using (n-hexane/EtOAc 7:1) as the eluent to afford the desired
product 12 as a colorless powder, 68%.
N-Benzyl-2-chloro-N-(1-(2-chloroquinolin-3-yl)-2-(cyclohexylamino)-2-
ᵒ
1
oxoethyl)acetamide (5a): Yield 86% (415 mg); Colorless powder; mp: 181-183 C, H-NMR
600 MHz, CDCl ): δ (ppm) 8.54 (s, 1H, H-4-quinoline), 7.92 (d, J = 8.4 Hz, 1H, H-Ar), 7.77 (d,
(
3
J = 8.1 Hz, 1H, H-Ar), 7.72 (t, J = 7.4 Hz, 1H, H-Ar), 7.55 (t, J = 7.1 Hz, 1H, H-Ar), 7.08-7.05
3
(
m, 3H, H-Ar), 7.00-6.99 (m, 2H, H-Ar ), 6.32 (s, 1H, C(sp )−H), 6.10 (brs, 1H, -NH-amide), 4.79
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(
d, J = 17.4 Hz, 1H, -CH(A)-N ), 4.70 (d, J = 17.4 Hz, 1H, -CH(B)-N), 4.09 (d, J = 12.7 Hz, 1H,
-CH(A)-Cl ), 4.05 (d, J = 12.7 Hz, 1H, -CH(B)-Cl), 3.84-3.73 (m, 1H, -NCH-Cyclohexyl), 1.93-
1
1
.83 (m, 2H, H-Cyclohexyl), 1.71–1.61 (m, 2H, H-Cyclohexyl), 1.59-1.53 (m, 1H, H-Cyclohexyl),
1
3
1
.37-1.27 (m, 2H, H-Cyclohexyl), 1.20-1.03 (m, 3H, H-Cyclohexyl); C{ H} NMR (150 MHz,
): δ(ppm) 168.3, 166.9, 150.7, 146.8, 140.6, 135.8, 131.5, 128.7, 128.0, 127.7, 127.6, 126.7,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CDCl
3
126.5, 126.0, 59.5, 50.1, 49.0, 41.9, 32.7, 29.7, 25.4, 24.8, 24.7; HRMS (ESI) m/z: Calcd for
+
C
26
H28Cl
2
N
3
O
2
[M + H] 484.1223, Found 484.1212.
N-Benzyl-N-(2-(tert-butylamino)-1-(2-chloroquinolin-3-yl)-2-oxoethyl)-2-chloroacetamide
ᵒ
1
(5b): Yield 89% (407 mg); Colorless powder, mp: 224-226 C; H NMR (600 MHz, CDCl ):
3
δ(ppm) 8.51 (s, 1H, H-4-quinoline), 7.90 (d, J = 8.4 Hz, 1H, H-Ar), 7.77 (d, J = 8.4 Hz, 1H, H-
Ar), 7.71 (t, J = 7.3 Hz, 1H, H-Ar), 7.54 (t, J = 7.1 Hz, 1H, H-Ar), 7.10-7.03 (m, 3H, H-Ar), 6.97
3
(d, J = 6.0 Hz, 2H, H-Ar), 6.29 (s, 1H, C(sp )−H), 6.02 (s, 1H, -NH-amide), 4.80 (d, J = 17.5 Hz,
1H, -CH(A)-N), 4.71 (d, J = 17.5 Hz, 1H, -CH(B)-N), 4.10 (d, J = 12.8 Hz, 1H, -CH(A)-Cl), 4.05
1
3
1
(d, J = 12.8 Hz, 1H, -CH(B)-Cl), 1.33 (s, 9H, t-Bu); C{ H} NMR (150 MHz, CDCl
3
): δ(ppm)
1
5
68.3, 167.2, 150.8, 147.0, 140.3, 135.9, 131.4, 128.7, 128.0, 127.9, 127.6, 126.7, 126.6, 125.9,
+
9.6, 52.0, 49.9, 42.0, 28.5; HRMS (ESI) m/z: Calcd for C24
H26Cl
2
N
3
O [M + H] 458.1369,
2
Found 458.1360.
-Chloro-N-(1-(2-chloroquinolin-3-yl)-2-(cyclohexylamino)-2-oxoethyl)-N-(furan-2
2
ᵒ
1
ylmethyl) acetamide (5c): Yield 58% (274 mg); Colorless powder, mp: 164-166 C; H NMR
600 MHz, CDCl ): δ(ppm) 8.51 (s, 1H, H-4-quinoline), 7.96 (d, J = 8.4 Hz, 1H, H-Ar), ), 7.82 (d,
(
3
J = 8.1 Hz, 1H, H-Ar), 7.75 (t, J = 7.5 Hz, 1H, H-Ar), 7.58 (t, J = 7.5 Hz, 1H, H-Ar), 7.17 (s, 1H,
3
H-Ar-furfuryl), 6.23 (s, 1H, C(sp )−H), 6.01 (s, 1H, H-Ar-furfuryl), 5.95 (d, J = 7.3 Hz, 1H, -NH-
amide), 5.45 (s, 1H, H-Ar-furfuryl), 4.67 (AB quartet, J = 17.3 Hz, 2H, -CH -N), 4.45 (d, J = 12.8
2
Hz, 1H, -CH(A)-Cl), 4.34 (d, J = 12.8 Hz, 1H, -CH(B)-Cl), ), 3.84-3.76 (m, 1H, -NCH-
Cyclohexyl), 1.93-1.85 (m, 2H, H-Cyclohexyl), 1.72-1.64 (m, 2H, H-Cyclohexyl), 1.62-1.57 (m,
13
1
1
H, H-Cyclohexyl), 1.39-1.29 (m, 2H, H-Cyclohexyl), 1.18-1.05 (m, 3H, H-Cyclohexyl); C{ H}
NMR (150 MHz, CDCl ): δ(ppm) 167.7, 166.9, 151.0, 149.1, 147.1, 142.7, 140.1, 131.3, 128.2,
3
128.0, 127.5, 126.7, 126.5, 110.4, 108.2, 59.1, 48.8, 43.0, 41.7, 32.7, 25.4, 24.7; HRMS (ESI) m/z:
+
Calcd for C24
H26Cl
2
N
3
O
3
[M + H] 474.1341, Found 474.1334.
N-(tert-Butyl)-2-(2-chloro-N-(2-methoxyphenyl)acetamido)-2-(2-chloroquinolin-3-yl)
ᵒ
1
acetamide (5d): Yield 79% (374 mg); Colorless solid, mp: 227-229 C; H NMR (300 MHz,
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2
2
2
2
2
2
2
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3
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3
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5
5
5
5
5
5
5
5
6
CDCl
3
) (mixture of two rotamers (83:17)): δ(ppm) 8.33 (s, 1H, H-4-quinoline, minor rotamer),
8.05 (s, 1H, H-4-quinoline, major rotamer), 7.89 (d, J = 8.7 Hz, 1H, H-Ar, mixture of two
rotamers), 7.72-7.59 (m, 2H, H-Ar, mixture of two rotamers), 7.53-7.37 (m, 2H, H-Ar, mixture of
two rotamers), 7.15 (t, J = 7.9 Hz, 1H, H-Ar, mixture of two rotamers), 6.95 (t, J = 7.6 Hz, 1H, H-
Ar, major rotamer), 6.87 (t, J = 7.6 Hz, 1H, H-Ar, minor rotamer), 6.79 (s, 1H, -NH-amide, mixture
of two rotamers), 6.69 (t, J = 7.5 Hz, 1H, H-Ar, minor rotamer), 6.62 (s, 1H, C(sp3)−H, major
rotamer), 6.44 (d, J = 8.6 Hz, 1H, , H-Ar, major rotamer), 6.30 (s, 1H, C(sp3)−H, minor rotamer),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
.90-3.77 (m, 2H, -CH
rotamers), 1.41 (s, 9H, t-Bu, mixture of two rotamers); C{ H} NMR (75 MHz, CDCl
rotamer : δ(ppm) 167.8, 167.3, 155.2, 151.9, 146.7, 141.5, 131.9, 131.0, 130.9, 128.0, 127.7, 126.9,
2
-Cl, mixture of two rotamers), 3.34 (s, 3H, -O-CH
3
, mixture of two
1
3
1
3
) for major
1
26.3, 126.0, 125.5,121.1, 111.1, 60.4, 55.0, 51.7, 42.7, 28.7; HRMS (ESI) m/z: Calcd for
+
Na [M+Na]+
C
24
H26Cl
2
N
3
O
3
[M + H] 474.1346, Found 474.1349, Calcd for C24
H25Cl
2
N
3
O
3
496.1165, Found 496.1170.
-Chloro-N-(1-(2-chloroquinolin-3-yl)-2-(cyclohexylamino)-2-oxoethyl)-N-(2-methoxy
2
ᵒ
1
phenyl) acetamide (5e): Yield 76% (380 mg); Colorless solid, mp: 245-247 C; H NMR (300
MHz, CDCl ) (mixture of two rotamers (83:17)): δ(ppm) 8.30 (s, 1H, H-4-quinoline, minor
3
rotamer), 8.03 (s, 1H, H-4-quinoline, major rotamer), 7.97-7.84 (m, 1H, H-Ar, mixture of two
rotamers), 7.74-7.61 (m, 2H, H-Ar, mixture of two rotamers), 7.55-7.33 (m, 2H, H-Ar, mixture of
two rotamers), 7.22-7.10 (m, 1H, H-Ar, mixture of two rotamers), 7.04-6.91 (m, 1H, H-Ar, mixture
3
of two rotamers), 6.88-6.64 (m, 2H, H-Ar, C(sp )−H, mixture of two rotamers), 6.43 (d, J = 8.5
Hz, 1H, -NH-amide, mixture of two rotamers), 3.93-3.78 (m, 3H, -CH
mixture of two rotamers), 3.33 (s, 3H, -O-CH , mixture of two rotamers), 2.12-1.99 (m, 1H, -CH-
cyclohexyl, mixture of two rotamers), 1.89-1.55 (m, 4H, -CH-cyclohexyl, mixture of two
2
-Cl, -NCH-Cyclohexyl,
3
1
3
1
rotamers), 1.44-1.09 (m, 5H, -CH-cyclohexyl, mixture of two rotamers); C{ H} NMR (75 MHz,
CDCl ) for major rotamer : δ(ppm) 167.8, 167.4, 155.2, 151.9, 146.7, 141.6, 132.0, 131.0, 130.9,
27.9, 127.7, 127.0, 126.2, 125.9, 125.4, 121.0, 111.1, 60.0, 55.0, 49.0, 42.7, 32.9, 32.8, 25.5, 24.8;
3
1
+
MS (ESI) m/z: Found for C26
Anal. Calcd for C26
N-Benzyl-N-(2-(tert-butylamino)-1-(2,6-dichloroquinolin-3-yl)-2-oxoethyl)-2-chloro-
H28Cl
2
N
3
O
3
[M+H] 601.4 and C52
H54Cl
4
N
6
NaO [2M + Na] 1023.5;
6
H27Cl
2
N
3
O
3
: C, 62.40; H, 5.44; N, 8.40. Found: C, 62.52; H, 5.49; N, 8.51.
ᵒ
1
acetamide (5f): Yield 87% (427 mg); Colorless powder, mp: 206-209 C; H NMR (600 MHz,
CDCl
3
): δ(ppm) 8.44 (s, 1H, H-4-quinoline), 7.81 (d, J = 8.9 Hz, 1H, H-Ar), 7.74 (s, 1H, H-Ar),
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.63 (d, J = 8.5 Hz, 1H, H-Ar), 7.11-7.04 (m, 3H, H-Ar), ), 6.97 (d, J = 5.9 Hz, 2H, H-Ar), 6.27
3
(s, 1H, C(sp )−H), 5.99 (s, 1H, -NH-amide), 4.81 (d, J = 17.4 Hz, 1H, -CH(A)-N), 4.73 (d, J =
13
1
1
7.4 Hz, 1H, -CH(B)-N), 4.09 (AB quartet, J = 12.6 Hz, 2H, -CH
NMR (150 MHz, CDCl ): δ(ppm) 168.3, 166.9, 151.1, 145.4, 139.1, 135.7, 133.4, 132.2, 129.6,
28.7, 127.8, 127.6, 127.2, 126.6, 125.9, 59.4, 52.2, 49.9, 41.9, 28.5; HRMS (ESI) m/z: Calcd for
2
-Cl), 1.32 (s, 9H, t-Bu); C{ H}
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
+
C
24
H25Cl
3
N
3
O [M + H] 492.0786, Found 492.0777.
2
N-Benzyl-N-(2-(tert-butylamino)-1-(2-chloro-6-fluoroquinolin-3-yl)-2-oxoethyl)-2-
ᵒ
1
chloroacetamide (5g): Yield 83% (394 mg); Colorless powder, mp: 215-217 C; H NMR (600
MHz, CDCl ): δ(ppm) 8.48 (s, 1H, H-4-quinoline), 7.91-7.86 (m, 1H, H-Ar), 7.49-7.43 (m, 1H,
3
H-Ar), 7.38 (d, J = 7.6 Hz, 1H,H-Ar), 7.12-7.04 (m, 3H, H-Ar), 7.00-6.94 (m, 2H, H-Ar), 6.27 (s,
3
1
1
H, C(sp )−H), 5.99 (s, 1H, -NH-amide), 4.81 (d, 1H, J = 17.3 Hz, -CH(A)-N), 4.73 (d, 1H, J =
13
1
7.3 Hz, -CH(B)-N), 4.09 (AB quartet, 2H, J = 12.3 Hz, -CH
2
-Cl), 1.32 (s, 9H, t-Bu); C{ H}
NMR (150 MHz, CDCl
3
): δ(ppm) 168.3, 166.9, 161.6 (C-F, 1JC-F = 249.0 Hz), 160.0 (C-F, 1JC-F
=
2
1
2
49.0 Hz), 150.2, 144.1, 139.4, 135.8, 130.6 (C-F, 3JC-F = 9.0 Hz), 130.5 (C-F, 3JC-F = 9.0 Hz),
28.7, 127.6, 127.4, 127.3, 125.9, 121.6, 121.4, 111.2 (C-F, 2JC-F = 22.5 Hz), 111.1 (C-F, 2JC-F
=
2.5 Hz), 59.4, 52.2, 49.9, 41.9, 28.5; HRMS (ESI) m/z: Calcd for C24 FN
H
25Cl
2
3
O
2
[M + H]+
476.1318, Found 476.1327.
N-Benzyl-N-(2-(tert-butylamino)-1-(2-chloro-6-methylquinolin-3-yl)-2-oxoethyl)-2-chloro-
ᵒ
1
acetamide (5h): Yield 92% (433 mg); Colorless powder, mp: 210-212 C; H NMR (600 MHz,
CDCl
3
): δ(ppm) 8.38 (s, 1H, H-4-quinoline), 7.78 (d, J = 8.4 Hz, 1H, H-Ar), 7.56-7.49 (m, 2H, H-
3
Ar), 7.10-7.01 (m, 3H, H-Ar), 6.99-6.93 (m, 2H, H-Ar), 6.26 (s, 1H, C(sp )−H), 6.10 (s, 1H, -NH-
amide), 4.78 (d, J = 17.4 Hz, 1H, -CH(A)-N), 4.69 (d, J = 17.4 Hz, 1H, -CH(B)-N), 4.09 (d, J =
1
2.6 Hz, 1H, -CH(A)-Cl), 4.02 (d, J = 12.6 Hz, 1H, -CH(B)-Cl), 2.49 (s, 3H, -CH
3
), 1.33 (s, 9H,
): δ(ppm) 168.2, 167.3, 149.9, 145.7, 139.6, 137.7, 136.0,
33.7, 128.7, 127.5, 126.7, 126.5, 125.9, 59.7, 52.1, 49.8, 42.1, 28.5, 21.6; HRMS (ESI) m/z: Calcd
1
3
1
t-Bu); C{ H} NMR (150 MHz, CDCl
3
1
+
for C25
H28Cl
2
N
3
O [M + H] 472.1303, Found 472.1312.
2
N-Benzyl-N-(2-(tert-butylamino)-1-(2-chloro-6,7-dimethylquinolin-3-yl)-2-oxoethyl)-2-
ᵒ
1
chloroacetamide (5i): Yield 90% (436 mg); Colorless powder, 224-226 C; H NMR (600 MHz,
CDCl
3
): δ(ppm) 8.36 (s, 1H, H-4-quinoline), 7.65 (s, 1H, H-Ar), 7.49 (s, 1H, H-Ar), 7.12-7.03 (m,
3
3
H, H-Ar), 7.00-6.95 (m, 2H, H-Ar), 6.25 (s, 1H, C(sp )−H), 5.97 (s, 1H, -NH-amide), 4.76 (d, J
=
17.5 Hz, 1H, -CH(A)-N), 4.68 (d, J = 17.5 Hz, 1H, -CH(B)-N), 4.09 (d, J = 12.8 Hz, 1H, -
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CH(A)-Cl), 4.01 (d, J = 12.8 Hz, 1H, -CH(B)-Cl), 2.41 (s, 3H, -CH
3
), 2.39 (s, 3H, -CH ), 1.33 (s,
3
1
3
1
9H, t-Bu); C{ H} NMR (150 MHz, CDCl
3
): δ (ppm) 168.2, 167.4, 149.8, 146.2, 142.2, 139.2,
1
2
37.8, 136.0, 128.7, 127.5, 127.2, 127.1, 125.9, 125.4, 125.3, 59.8, 52.1, 49.8, 42.1, 28.5, 20.6,
+
0.1; HRMS (ESI) m/z: Calcd for C26
H30Cl
2
N
3
O [M + H] 486.1763, Found 486.1755.
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N-Benzyl-2-chloro-N-(2-(cyclohexylamino)-1-(2,6-dichloroquinolin-3-yl)-2-oxoethyl)
ᵒ
1
acetamide (5j): Yield 85% (440 mg); Colorless powder, mp: 218-220 C; H NMR (600 MHz,
CDCl ): δ(ppm) 8.44 (s, 1H, H-4-quinoline), 7.80 (d, J = 8.9 Hz, 1H, H-Ar), 7.74 (s, 1H, H-Ar),
.62 (d, J = 8.6 Hz, 1H, H-Ar), 7.12-7.03 (m, 3H, H-Ar), 7.01-6.95 (m, 2H, H-Ar), 6.31 (s, 1H,
3
7
3
C(sp )−H), 6.12 (d, J = 4.6 Hz, 1H, -NH-amide), 4.79 (d, J = 17.5 Hz, 1H, -CH(A)-N), 4.71 (d, J
= 17.5 Hz, 1H, -CH(B)-N), 4.08 (AB quartet, J = 12.6 Hz, 2H, -CH -Cl), 3.82-3.70 (m, 1H, -NCH-
Cyclohexyl), 1.91-1.82 (m, 2H, H-Cyclohexyl), 1.72-1.62 (m, 2H, H-Cyclohexyl), 1.60-1.53 (m,
2
13
1
1
H, H-Cyclohexyl), 1.37-1.26 (m, 2H, H-Cyclohexyl), 1.18-1.04 (m, 3H, H-Cyclohexyl); C{ H}
NMR (150 MHz, CDCl ): δ(ppm) 168.3, 166.7, 151.0, 145.4, 139.2, 135.7, 133.4, 132.2, 129.6,
28.7, 127.6, 127.2, 126.6, 126.0, 59.2, 50.1, 49.0, 41.8, 32.7, 32.6, 25.4, 24.7, 24.6; HRMS (ESI)
3
1
+
m/z: Calcd for C26
H27Cl
N
3 3
O [M + H] 518.1169, Found 518.1177.
2
N-Benzyl-2-chloro-N-(1-(2-chloro-6-fluoroquinolin-3-yl)-2-(cyclohexylamino)-2-oxoethyl)
ᵒ
1
acetamide (5k): Yield 80% (400 mg); Colorless powder, mp: 203-205 C; H-NMR (600 MHz,
CDCl ): δ(ppm) 8.49 (s, 1H, H-4-quinoline), 7.93-7.86 (m, 1H, H-Ar), 7.47 (t, J = 8.4 Hz, 1H, H-
3
Ar), 7.38 (d, J = 8.1 Hz, 1H, H-Ar), 7.14-7.05 (m, 3H, H-Ar), ), 7.02-6.95 (m, 2H, H-Ar), 6.31 (s,
3
1
H, C(sp )−H), 6.02 (brs, 1H, -NH-amide), 4.79 (d, J = 16.8 Hz, 1H, -CH(A)-N), 4.72 (d, J = 16.8
Hz, 1H, -CH(B)-N), 4.09 (AB quartet, J = 14.3 Hz, 2H, -CH
2
-Cl), 3.84-3.73 (m, 1H, -NCH-
Cyclohexyl), 1.94-1.82 (m, 2H, H-Cyclohexyl), 1.78-1.62 (m, 3H, H-Cyclohexyl), 1.60-1.53 (m
13
1
1
H, H-Cyclohexyl), 1.40-1.27 (m, 2H, H-Cyclohexyl), 1.20-1.05 (m, 2H, H-Cyclohexyl); C{ H}
NMR (150 MHz, CDCl
3
): δ(ppm) 168.3, 166.7, 161.7 (C-F, 1JC-F = 249.0 Hz), 160.0 (C-F, 1JC-F
=
2
1
2
49.0 Hz), 150.2, 144.1, 139.6, 135.7, 130.6 (C-F, 3JC-F = 9.0 Hz), 130.5 (C-F, 3JC-F = 9.0 Hz),
28.7, 127.6, 127.4, 127.3, 126.0, 121.6, 121.4, 111.3 (C-F, 2JC-F = 22.5 Hz), 111.1 (C-F, 2JC-F
=
2.5 Hz), 59.3, 50.2, 48.9, 41.9, 32.7, 29.7, 25.4, 24.7, 24.6; HRMS (ESI) m/z: Calcd for
+
C
26
H27Cl
2
FN
3
O
2
[M + H] 502.1448, Found 502.1441.
N-Benzyl-2-chloro-N-(1-(2-chloro-6-methylquinolin-3-yl)-2-(cyclohexylamino)-2-oxoethyl)
ᵒ
1
acetamide (5l): Yield 82% (407 mg); Colorless powder, mp: 189-191 C; H NMR (600 MHz,
CDCl
3
): δ(ppm) 8.38 (s, 1H, H-4-quinoline), 7.77 (d, J = 8.5 Hz, 1H, H-Ar), 7.55-7.49 (m, 2H, H-
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Ar), 7.11-7.03 (m, 3H, H-Ar), 7.01-6.96 (m, 2H, H-Ar), 6.30 (s, 1H, C(sp )−H), 6.22 (d, J = 7.7
Hz, 1H, -NH-amide), 4.77 (d, J = 17.6 Hz, 1H, -CH(A)-N), 4.68 (d, J = 17.6 Hz, 1H, -CH(B)-N),
4
.08 (d, J = 12.8 Hz, 1H, -CH(A)-Cl), 4.02 (d, J = 12.8 Hz, 1H, -CH(B)-Cl), 3.82-3.74 (m, 1H, -
NCH-Cyclohexyl), 2.49 (s, 3H, -CH ), 1.93-1.84 (m, 2H, H-Cyclohexyl), 1.72-1.60 (m, 2H, H-
Cyclohexyl), 1.59-1.52 (m, 1H, H-Cyclohexyl), 1.36-1.26 (m, 2H, H-Cyclohexyl), 1.18-1.03 (m,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
3H, H-Cyclohexyl); C{ H} NMR (150 MHz, CDCl
3
): δ(ppm) 168.3, 167.1, 149.8, 145.7, 139.7,
1
2
37.7, 135.9, 133.7, 128.7, 127.5, 126.8, 126.4, 126.0, 59.7, 50.1, 48.9, 41.9, 32.6, 25.4, 24.8, 24.7,
+
1.6; HRMS (ESI) m/z: Calcd for C27
H30Cl
2
N
3
O [M + H] 498.1535, Found 498.1527.
2
N-Benzyl-2-chloro-N-(1-(2-chloro-6,7-dimethylquinolin-3-yl)-2-(cyclohexylamino)-2-
ᵒ
1
oxoethyl) acetamide (5m): Yield 78% (398 mg); Colorless powder, mp: 209-211 C; H NMR
(600 MHz, CDCl
3
): δ (ppm) 8.35 (s, 1H, H-4-quinoline), 7.64 (s, 1H, H-Ar), 7.48 (s, 1H, H-Ar),
3
7
.13-7.05 (m, 3H, H-Ar), 7.03-6.97 (m, 2H, H-Ar), 6.27 (s, 1H, C(sp )−H), 6.01 (d, J= 6.3 Hz, 1H,
-NH-amide), 4.75 (d, J = 17.3 Hz, 1H, -CH(A)-N), 4.67 (d, 1H, J = 17.3 Hz, -CH(B)-N), 4.07 (d,
J = 12.8 Hz, 1H, -CH(A)-Cl), 4.01 (d, J = 12.8 Hz, 1H, -CH(B)-Cl), 3.83-3.74 (m, 1H, -NCH-
Cyclohexyl), 2.41 (s, 3H, -CH
3
), 2.39 (s, 3H, -CH ), 1.94-1.83 (m, 2H, H-Cyclohexyl), 1.72-1.61
3
(
m, 2H, H-Cyclohexyl), 1.59-1.52 (m, 1H, H- Cyclohexyl), 1.37-1.26 (m, 2H, H-Cyclohexyl),
13
1
1.18-1.01 (m, 3H, H-Cyclohexyl); C{ H} NMR (150 MHz, CDCl
3
): δ(ppm) 168.3, 167.2, 149.8,
1
4
5
46.4, 142.1, 139.2, 137.7, 136.0, 128.7, 127.5, 127.4, 127.1, 126.0, 125.3, 125.2, 59.8, 50.0, 48.9,
[M + H]+
2.0, 32.7, 25.4, 24.8, 24.7, 20.6, 20.0; HRMS (ESI) m/z: Calcd for C28
H
32Cl
2
N
3
O
2
+
12.1870, Found 512.1873, Calcd for C28
H31Cl
2
KN
3
O
2
[M + K] 550.1430, Found 550.1439.
N-(tert-Butyl)-2-(2-chloro-N-(furan-2-ylmethyl)acetamido)-2-(2,6-dichloroquinolin-3-yl)
ᵒ
1
acetamide (5n): Yield 83% (400 mg); Colorless powder, mp: 217-219 C; H NMR (600 MHz,
CDCl
3
): δ(ppm) 8.43 (s, 1H, H-4-quinoline), 7.88 (d, J = 8.9 Hz, 1H, H-Ar), 7.81 (d, J = 1.4 Hz,
3
1H, H-Ar), 7.67 (d, J = 8.7 Hz, 1H, H-Ar), 7.17 (s, 1H, H-Ar- furfuryl), 6.14 (s, 1H, C(sp )−H),
6
.01 (s, 1H, -NH-amide), 5.92 (s, 1H, H-Ar- furfuryl), 5.46 (s, 1H, H-Ar- furfuryl), 4.67 (s, 2H,
CH -N), 4.44 (d, J = 12.9 Hz, 1H, -CH(A)-Cl), 4.33 (d, J = 12.9 Hz, 1H, -CH(B)-Cl), 1.35 (s, 9H,
t-Bu); C{ H} NMR (150 MHz, CDCl
2
1
3
1
3
): δ(ppm) 167.6, 166.9, 151.4, 149.0, 145.4, 142.7, 139.0,
133.3, 132.2, 129.7, 127.9, 127.3, 126.7, 110.5, 108.2, 59.2, 52.1, 43.1, 41.7, 28.5; HRMS (ESI)
+
m/z: Calcd for C22
H
2335Cl
2
37ClN
3
O
3
[M + H] 484.0746, Found 484.0737.
N-(tert-Butyl)-2-(2-chloro-6-methylquinolin-3-yl)-2-(2-chloro-N-(furan-2-ylmethyl)
ᵒ
1
acetamido) acetamide (5o): Yield 81% (371 mg); Colorless powder, mp: 223-225 C; H NMR
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5
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5
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6
(
600 MHz, CDCl
3
): δ(ppm) 8.37 (s, 1H, H-4-quinoline), 7.83 (d, J = 8.2 Hz, 1H, H-Ar), 7.57 (d, J
= 8.4 Hz, 2H, H-Ar), 7.14 (s, 1H, H-Ar-furfuryl), 6.17 (s, 1H, H-Ar-furfuryl), 6.00 (s, 1H,
3
C(sp )−H), 5.97 (s, 1H, -NH-amide), 5.34 (s, 1H, H-Ar-furfuryl), 4.64 (s, 2H, CH
2
-N), 4.45 (d, J
), 1.35 (s, 9H,
): δ(ppm) 167.6, 167.4, 150.3, 149.3, 145.7, 142.5,
=
13.1 Hz, 1H, -CH(A)-Cl), 4.33 (d, J = 13.1 Hz, 1H, -CH(B)-Cl), 2.52 (s, 3H, -CH
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13 13
1
t-Bu); C C{ H} NMR (150 MHz, CDCl
3
139.4, 137.7, 133.6, 127.7, 126.8, 126.7, 126.6, 110.4, 107.9, 59.3, 52.0, 42.8, 41.8, 28.6, 21.6;
+
HRMS (ESI) m/z: Calcd for C23
H26Cl
2
N
3
O
3
[M + H] 462.1173, Found 462.1165.
N-(tert-Butyl)-2-(2-chloro-6-methylquinolin-3-yl)-2-(2-chloro-N-(2-methoxyphenyl)
ᵒ
1
acetamido) acetamide (5p): Yield 80% (389 mg); Colorless solid, mp: 223-225 C; H-NMR
(300 MHz, CDCl ) (mixture of two rotamers (84:16)): δ(ppm) 8.20 (s, 1H, H-4-quinoline, minor
3
rotamer), 7.91 (s, 1H, H-4-quinoline, major rotamer), 7.83-7.72 (m, 1H, H-Ar, mixture of two
rotamers), 7.68 (d, J = 7.3 Hz, 1H, H-Ar, mixture of two rotamers), 7.51-7.41 (m, 1H, H-Ar,
mixture of two rotamers), 7.24 (s, 1H, H-Ar, mixture of two rotamers), 7.14 (t, J = 8.2 Hz, 1H, H-
Ar, mixture of two rotamers), 6.97-6.85 (m, 1H, H-Ar, mixture of two rotamers), 6.82 (s, 1H,
C(sp3)−H, minor rotamer), 6.78 (s, 1H, C(sp3)−H, major rotamer), 6.68 (t, J = 7.7 Hz, 1H, H-Ar,
minor rotamer), 6.58 (s, 1H, -NH-amide, major rotamer), 6.43 (d, J = 8.2 Hz, 1H, H-Ar, major
rotamer), 6.25 (s, 1H, -NH-amide, minor rotamer), 3.90-3.79 (m, 2H, CH -Cl, mixture of two
2
rotamers), 3.33 (s, 3H, -O-CH
s, 3H, -CH
CDCl
30.8, 127.3, 126.7, 126.3, 126.0, 125.4, 121.0,111.1, 60.5, 54.9, 51.7, 42.8, 28.6, 21.5; MS (ESI)
3
, mixture of two rotamers), 2.46 (s, 3H, -CH
3
, minor rotamer), 2.41
13
1
(
3
, major rotamer), 1.39 (s, 9H, t-Bu, mixture of two rotamers); C{ H} NMR (75 MHz,
3
) for major rotamer : δ(ppm) 167.9, 167.3, 155.2, 151.0, 145.3, 140.8, 136.9, 133.3, 132.0,
1
2835Cl
N
3
O
3
[M + H] 488.3 and 999.5 for C50
+
H
5435Cl
N
4 6
O [M + Na] ; Anal.
+
m/z: Found for C25
Calcd for C25
N-Benzyl-N-(2-(tert-butylamino)-1-(2-chloro-5-methoxyquinolin-3-yl)-2-oxoethyl)-2-
H
2
6
H27Cl
2
N
3
3
O : C, 61.48; H, 5.57; N, 8.60. Found: C, 61.59; H, 5.61; N, 8.69.
ᵒ
1
chloroacetamide (5q): Yield 89% (433 mg); Colorless powder, mp: 199-201 C; H NMR (400
MHz, CDCl ): δ(ppm) 8.33 (s, 1H, H-4-quinoline), 7.58 (d, J = 8.8 Hz, 1H, H-Ar), 7.15-7.14 (m,
H, H-Ar), 7.13-7.09 (m, 1H, H-Ar), 7.06-6.98 (m, 3H, H-Ar), 6.94-6.89 (m, 2H, H-Ar), 6.23 (s,
3
1
3
1H, C(sp )−H), 6.14 (brs, 1H, -NH-amide), 4.72 (d, J = 17.8 Hz, 1H, -CH(A)-N), 4.63 (d, J = 17.8
Hz, 1H, -CH(B)-N), 4.05 (d, J = 13.0 Hz, 1H, -CH(A)-Cl), 3.97 (d, J = 13.0 Hz, 1H, -CH(B)-Cl),
13
1
3
1
.84 (s, 3H, -O-CH
3
), 1.28 (s, 9H, t-Bu); C{ H} NMR (100 MHz, CDCl ): δ(ppm) 168.2, 167.6,
3
62.2, 151.3, 149.1, 139.7, 136.1, 128.9, 128.7, 127.5, 125.9, 123.8, 121.9, 120.7, 106.1, 59.6,
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5.7, 52.1, 49.8, 42.1, 28.5; MS (ESI) m/z: Found for C25
Anal. Calcd for C25 : C, 61.48; H, 5.57; N, 8.60. Found: C, 61.54; H, 5.61; N, 8.70.
N-Benzyl-2-chloro-N-(1-(2-chloro-5-methoxyquinolin-3-yl)-2-(cyclohexylamino)-2-
H
27Cl
2
N
3
NaO [M + Na] 509.9862;
3
H27Cl
2
N
3
O
3
ᵒ
1
oxoethyl)acetamide (5r): Yield 86% (441 mg); Colorless powder, mp: 190-192 C; H NMR
400 MHz, CDCl ): δ(ppm) 8.34 (s, 1H, H-4-quinoline), 7.57 (d, J = 8.9 Hz, 1H, H-Ar), 7.17-7.14
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
2
2
2
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3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
3
(m, 1H, H-Ar), 7.13-7.09 (m, 1H, H-Ar), 7.07-7.00 (m, 3H, H-Ar), 6.98-6.92 (m, 2H, H-Ar), 6.24
3
(
s, 1H, C(sp )−H), 6.15 (brs, 1H, -NH-amide), 4.71 (d, J = 17.6 Hz, 1H, -CH(A)-N), 4.62 (d, J =
1
7.6 Hz, 1H, -CH(B)-N), 4.04 (d, J = 12.8 Hz, 1H, -CH(A)-Cl), 3.97 (d, J = 12.8 Hz, 1H, -CH(B)-
Cl), 3.84 (s, 3H, -O-CH ), 3.78-3.69 (m, 1H, -NCH-Cyclohexyl), 1.89-1.78 (m, 2H, H-
Cyclohexyl), 1.63-1.56 (m, 2H, H-Cyclohexyl), 1.54-1.48 (m, 1H, H-Cyclohexyl), 1.32-1.20 (m,
3
13
1
2
1
H, H-Cyclohexyl), 1.13-1.00 (m, 3H, H-Cyclohexyl); C{ H} NMR (100 MHz, CDCl
3
): δ(ppm)
68.3, 167.3, 162.3, 151.3, 149.2, 139.9, 136.0, 129.0, 128.7, 127.5, 126.0, 123.6, 121.9, 120.8,
106.2, 59.6, 55.7, 50.0, 48.9, 42.0, 32.7, 25.4, 24.8, 24.7; MS (ESI) m/z: Found for C27
H
29Cl
2
N
3
O
3
+
[M+H] 513.9998. Anal. Calcd for C27
H29Cl
2
N O: C, 63.04; H, 5.68; N, 8.17. Found: C, 63.10; H,
3
5
.71; N, 8.19.
N-Benzyl-2-chloro-N-(1-(2-chloro-5,7-dimethylquinolin-3-yl)-2-(cyclohexylamino)-2-
ᵒ
1
oxoethyl)acetamide (5s): Yield 80% (409 mg); Colorless powder, mp: 208-210 C; H NMR
(400 MHz, CDCl
3
): δ(ppm) 8.47 (s, 1H, H-4-quinoline), 7.46 (s, 1H, H-Ar), 7.14 (s, 1H, H-Ar),
3
7
1
.10-7.03 (m, 3H, H-Ar), 7.02-6.96 (m, 2H, H-Ar), 6.21 (s, 1H, C(sp )−H), 6.09 (d, J = 8.0 Hz,
H, -NH-amide), 4.71 (d, J = 17.7 Hz, 1H, -CH(A)-N), 4.63(d, J = 17.7 Hz, 1H, -CH(B)-N), 4.03
(d, J = 12.7 Hz, 1H, -CH(A)-Cl), 3.96 (d, J = 12.7 Hz, 1H, -CH(B)-Cl), 3.79-3.69 (m, 1H, -NCH-
Cyclohexyl), 2.50 (s, 3H, -CH ), 2.41 (s, 3H, -CH ), 1.89-1.79 (m, 2H, H-Cyclohexyl), 1.65-1.57
m, 2H, H-Cyclohexyl), 1.54-1.47 (m, 1H, H-Cyclohexyl), 1.33-1.28 (m, 1H, H-Cyclohexyl),
3
3
(
1
3
1
1.27-1.22 (m, 1H, H-Cyclohexyl), 1.12-0.99 (m, 3H, H-Cyclohexyl); C{ H} NMR (100 MHz,
CDCl ): δ(ppm) 168.3, 167.2, 150.4, 148.0, 141.9, 136.6, 136.0, 134.8, 130.4, 128.7, 127.6, 126.1,
25.2, 124.8, 124.3, 60.2, 50.3, 48.9, 42.0, 32.6, 32.5, 25.4, 24.8, 24.7, 22.0, 18.6; MS (ESI) m/z:
3
1
+
Found for C28
N, 8.20. Found: C, 65.66; H, 6.12; N, 8.23.
N-(tert-butyl)-2-(2-chloro-N-(4-methoxyphenyl)acetamido)-2-(2-chloroquinolin-3-
H32Cl
2
N
3
O
2
[M + H] 512.0133; Anal. Calcd for C28
H31Cl
2
N
3
O : C, 65.62; H, 6.10;
2
ᵒ
1
yl)acetamide (5t): Yield 82% (388 mg); Colorless powder, mp: 248-251 C; H NMR (400 MHz,
CDCl
3
): δ(ppm) 8.03 (s, 1H, H-4-quinoline), 7.87 (d, J = 8.5 Hz, 1H, H-Ar), 7.72-7.57 (m, 2H, H-
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6
Ar), 7.54 (d, J = 7.9 Hz, 1H, H-Ar), 7.43 (t, J = 7.5 Hz, 1H, H-Ar), 6.81-6.58 (m, 2H, H-Ar), 6.51-
3
6.35 (m, 1H, H-Ar), 6.34 (s, 1H, C(sp )−H), 6.11 (brs, 1H, -NH-amide), 3.81 (AB quartet, J = 13.8
1
3
1
Hz, 2H, -CH
2
-Cl), 3.56 (s, 3H, -O-CH
3
), 1.34 (s, 9H, t-Bu); C{ H} NMR (100 MHz, CDCl ):
3
δ(ppm) 167.8, 167.4, 159.6, 150.9, 147.1, 141.1, 131.3, 130.2, 128.1, 128.0, 127.4, 126.6, 126.2,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
6
1.4, 55.3, 52.1, 42.6, 28.6; MS (ESI) m/z: Found for C24
Calcd for C24
N-benzyl-2-chloro-N-(1-(2-chloro-6-methoxyquinolin-3-yl)-2-(cyclohexylamino)-2-
H
26Cl
2
N
3
O
3
[M + H] 474.2142; Anal.
H25Cl
2
N
3
O : C, 60.77; H, 5.31; N, 8.86. Found: C, 60.80; H, 5.34; N, 8.87.
3
ᵒ
1
oxoethyl)acetamide (5u): Yield 81% (416 mg); Colorless solid, mp: 198-201 C; H NMR (600
MHz, CDCl
3
): δ(ppm) 8.43 (s, 1H, H-4-quinoline), 7.81 (d, J = 9.1 Hz, 1H, H-Ar), 7.35 (d, J = 9.2
3
Hz, 1H, H-Ar), 7.13-7.06 (m, 3H, H-Ar), 7.03-6.98 (m, 3H, H-Ar), 6.25 (s, 1H, C(sp )−H), 6.08
(
d, J= 8.0 Hz, 1H, -NH-amide), 4.77 (d, J = 17.6 Hz, 1H, -CH(A)-N), 4.69 (d, J = 17.6 Hz, 1H, -
CH(B)-N), 4.09 (d, J = 13.2 Hz, 1H, -CH(A)-Cl), 4.04 (d, J = 13.2 Hz, 1H, -CH(B)-Cl), 3.89 (s,
3H, -O-CH ), 3.82-3.75 (m, 1H, -NCH-Cyclohexyl), 1.93-1.83 (m, 2H, H-Cyclohexyl), 1.72-1.62
m, 2H, H-Cyclohexyl), 1.60-1.54 (m, 1H, H- Cyclohexyl), 1.37-1.27 (m, 2H, H-Cyclohexyl),
3
(
1
3
1
1
1
.18-1.04 (m, 3H, H-Cyclohexyl); C{ H} NMR (150 MHz, CDCl
48.0, 143.0, 139.2, 135.8, 129.2, 128.7, 127.9, 127.6, 126.6, 126.1, 124.2, 105.4, 59.7, 55.7, 50.2,
[M + H]+
3
): δ(ppm) 168.2, 166.9, 158.5,
48.9, 41.9, 32.7, 29.7, 25.4, 24.8, 24.7; HRMS (ESI) m/z: Calcd for C27
14.1492, Found 514.1483.
N-benzyl-N-(2-(tert-butylamino)-1-(2-chloro-6-methoxyquinolin-3-yl)-2-oxoethyl)-2-
H30Cl
2
N
3
O
3
5
ᵒ
1
chloroacetamide (5v): Yield 84% (409 mg); Colorless solid, mp: 217-219 C; H NMR (600
MHz, CDCl
3
): δ(ppm) 8.43 (s, 1H, H-4-quinoline), 7.80 (d, J = 9.2 Hz, 1H, H-Ar), 7.34 (d, J = 9.2
3
Hz, 1H, H-Ar), 7.11-7.05 (m, 3H, H-Ar), 7.01-6.97 (m, 3H, H-Ar), 6.23 (s, 1H, C(sp )−H), 6.04
(
s, 1H, -NH-amide), 4.78 (d, J = 17.7 Hz, 1H, -CH(A)-N), 4.70 (d, J = 17.7 Hz, 1H, -CH(B)-N),
4.10 (d, J = 13.0 Hz, 1H, -CH(A)-Cl), 4.04 (d, J = 13.0 Hz, 1H, -CH(B)-Cl), 3.89 (s, 3H, -O-CH ),
): δ(ppm) 168.2, 167.2, 158.5, 148.0, 142.9,
3
1
3
1
1
1
2
.33 (s, 9H, t-Bu); C{ H} NMR (150 MHz, CDCl
3
39.1, 135.9, 129.2, 128.7, 127.9, 127.6, 126.7, 126.0, 124.2, 105.3, 59.7, 55.7, 52.1, 49.9, 42.0,
+
9.7, 28.5; HRMS (ESI) m/z: Calcd for C25
H28Cl
N
2 3
O
3
[M + H] 488.1344, Found 488.1352.
1-Benzyl-1'-cyclohexylspiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-2',4(1'H)-dione (6a):
ᵒ
-1
Yield 88% (362 mg); Colorless powder, mp: 179-181 C; IR (KBr, cm ) νmax = 1769 (C=O), 1720
-1
1
(
C=O), 1640 (C=N) cm ; H NMR (600 MHz, CDCl
3
): δ(ppm) 7.91 (s, 1H, H-4-quinoline), 7.68-
7
.62 (m, 2H, H-Ar), 7.59 (d, J = 7.0 Hz, 1H, H-Ar), 7.42-7.36 (m, 1H, H-Ar), 7.00 (t, J = 7.1 Hz,
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H, H-Ar), 6.97-6.92 (m, 3H, H-Ar), 4.38 (d, J = 11.4 Hz, 1H, -CO-CH(A)), 4.33 (d, J = 14.6 Hz,
1H, -CH(A)-N), 4.25 (d, J = 14.6 Hz, 1H, -CH(B)-N), 3.47 (d, J = 11.4 Hz, 1H, -CO-CH(B)),
.20-3.13 (m, 1H, -NCH-Cyclohexyl), 2.42-2.34 (m, 1H, H-Cyclohexyl), 2.32-2.24 (m, 1H, H-
Cyclohexyl), 1.88-1.80 (m, 2H, H-Cyclohexyl), 1.73-1.67 (m, 1H, H-Cyclohexyl), 1.65-1.53 (m,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
2
H, H-Cyclohexyl), 1.45-1.35 (m, 2H, H-Cyclohexyl), 1.33-1.23 (m, 1H, H-Cyclohexyl); C{ H}
NMR (150 MHz, CDCl ): δ(ppm) 173.2, 165.5, 155.2, 147.1, 133.4, 131.5, 130.5, 129.0, 128.5,
28.1, 128.0, 127.8, 125.1, 120.0, 58.6, 52.7, 49.8, 45.6, 29.7, 28.7, 25.8, 25.1; HRMS (ESI) m/z:
3
1
+
[2M+H]+
Calcd for C26
H
26
N
3
O
2
[M + H] 412.1977, Found 412.1986, Calcd for C52
H
51
N
6
O
4
8
23.3789, Found 823.3797.
1-Benzyl-1'-(tert-butyl)spiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-2',4(1'H)-dione (6b):
ᵒ
-1
Yield 85% (327 mg); Colourless crystal, mp: 195-197 C; IR (KBr, cm ) νmax = 1776 (C=O), 1720
-1
1
(
C=O), 1633 (C=N) cm ; H NMR (600 MHz, CDCl
7.66 (s, 1H, H-4-quinoline), 7.62 (t, J = 7.0 Hz, 1H, H-Ar), 7.60 (d, J = 7.5 Hz, 1H, H-Ar), 7.39
t, J = 7.5 Hz, 1H, H-Ar), 7.04 (t, J = 7.2 Hz, 1H, H-Ar), 7.03 (d, J = 7.3 Hz, 1H, H-Ar), 7.01 (d,
J = 6.9 Hz, 1H, H-Ar), 6.98 (d, J = 7.2 Hz, 2H, H-Ar), 4.37 (d, J = 14.7 Hz, 1H, -CH(A)-N), 4.20
d, J = 14.7 Hz, 1H, -CH(B)-N), 3.44 (d, J = 14.3 Hz, 1H, -CO-CH(A)), 3.13 (d, J = 14.3 Hz, 1H,
3
): δ(ppm) 7.85 (d, J = 8.3 Hz, 1H, H-Ar),
(
(
13
1
-CO-CH(B)), 1.70 (s, 9H, t-Bu); C{ H} NMR (150 MHz, CDCl
3
): δ(ppm) 174.0, 165.7, 156.9,
1
4
47.3, 133.5, 130.5, 130.1, 129.1, 128.5, 128.4, 128.0, 127.8, 125.1, 124.8, 120.0, 59.6, 58.9, 49.8,
+
5.4, 28.5; HRMS (ESI) m/z: Calcd for C24
H
24
N
3
O [M + H] 386.1869, Found 386.1864, Calcd
2
+
for C48
H
47
N
6
O
4
[2M + H] 771.3650, Found 771.3641.
For X-ray measurements, single crystals of 6b was mounted on a MiTeGen loop with grease and
examined using a Bruker D8 Venture APEX diffractometer equipped with a Photon 100 CCD area
detector at 296 (2) K using graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å). Data were
1
5
16
collected using APEX-II software, integrated using SAINT and corrected for absorption using
1
7
a multi-scan approach (SADABS). Final cell constants were determined from full leastsquares
refinement of all observed reflections. The structure was solved using intrinsic phasing
1
8
(SHELXT). All non-hydrogen atoms were located in subsequent difference maps and refined
anisotropically with SHELXL- 2016/6. Hydrogen atoms were added at calculated positions and
refined with a riding model. The structure has been deposited with the CCDC (CSD deposition
numbers 1989593).
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1
'-Cyclohexyl-1-(furan-2-ylmethyl)spiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-2',4(1'H)-
ᵒ
-1
dione (6c): Yield 70% (280 mg); Colorless powder, mp: 128-130 C; IR (KBr, cm ) νmax = 1789
-1 1
(C=O), 1727 (C=O), 1642 (C=N) cm ; H NMR (600 MHz, CDCl
3
): δ(ppm) 7.87 (d, J = 8.3 Hz,
1
H, H-Ar), 7.73 (s, 1H, H-4-quinoline), 7.64 (t, J = 8.3 Hz, 1H, H-Ar), 7.62 (d, J = 7.8 Hz, 1H, H-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ar), 7.39 (t, J = 7.4 Hz, 1H, H-Ar), 6.84 (s, 1H, H-Ar-furfuryl), 5.93 (d, J = 2.9 Hz, 1H, H-Ar-
furfuryl), 5.84 (s, 1H, H-Ar-furfuryl), 4.47 (d, J = 15.4 Hz, 1H, -CH(A)-N), 4.44-4.39 (m, 1H, -
NCH-Cyclohexyl), 4.19 (d, 15.4 Hz, 1H, -CH(B)-N), 3.45 (d, J = 14.3 Hz, 1H, -CO-CH(A)), 3.14
(d, 1H, J = 14.3 Hz, -CO-CH(B)), 2.50-2.40 (m, 2H, H-Cyclohexyl), 1.92-1.86 (m, 2H, H-
Cyclohexyl), 1.75-1.68 (m, 3H, H-Cyclohexyl), 1.47-1.39 (m, 2H, H-Cyclohexyl), 1.37-1.29 (m,
1
3
1
1H, H-Cyclohexyl); C{ H} NMR (150 MHz, CDCl
3
): δ(ppm) 173.3, 165.2, 155.4, 147.5, 146.8,
1
2
42.6, 130.6, 130.2, 128.1, 128.0, 125.5, 125.0, 120.1, 110.2, 109.9, 58.5, 52.5, 49.5, 37.4, 28.9,
+
8.7, 25.9, 25.2; HRMS (ESI) m/z: Calcd for C24
H
24
N
3
O [M + H] 402.2220, Found 402.2209
3
+
and Calcd for C24
H
23
N
3
NaO
3
[M + Na] 424.1985, Found 424.1977.
1
'-(tert-Butyl)-1-(2-methoxyphenyl)spiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-2',4(1'H)-
ᵒ
-1
dione (6d): Yield 68%; Colorless powder; mp: 155-157 C; IR (KBr, cm ) νmax = 1773 (C=O),
-1 1
1
732 (C=O), 1651 (C=N) cm ; H-NMR (600 MHz, CDCl
Ar), 7.90 (d, J = 8.3 Hz, 1H, H-Ar), 7.84 (s, 1H, H-4-quinoline), 7.65 (d, J = 8.0 Hz, 1H, H-Ar),
.61 (t, J = 7.7 Hz, 1H, H-Ar), 7.38 (t, J = 7.4 Hz, 1H, H-Ar), 7.00 (t, J = 7.8 Hz, 1H, H-Ar), 6.91
t, J = 7.7 Hz, 1H, H-Ar), 6.66 (d, J = 8.2 Hz, 1H, H-Ar), 3.59 (d, J = 14.6 Hz, 1H, -CO-CH(A)),
3
): δ(ppm) 8.15 (d, J = 8.0 Hz, 1H, H-
7
(
13
1
3
.27 (d, J = 14.6 Hz, 1H, -CO-CH(B)), 3.24 (s, 3H, -O-CH
3
), 1.89 (s, 9H, t-Bu); C{ H} NMR
(150 MHz, CDCl
3
): δ(ppm) 175.2, 164.3, 157.0, 149.0, 147.0, 129.7, 128.6, 128.4, 127.9, 125.9,
1
25.5, 125.0, 124.9, 123.3, 122.3, 121.30, 112.1, 62.0, 59.5, 55.3, 51.2, 28.9; HRMS (ESI) m/z:
+
[2M+Na]+
Calcd for C24
H
24
N
3
O
3
[M + H] 402.1748, Found 402.1757; Calcd for C48
H
46
N
6
NaO
6
825.3275, Found 825.3266.
'-Cyclohexyl-1-(2-methoxyphenyl)spiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-2',4(1'H)-
1
ᵒ
-1
dione (6e): Yield 69% (294 mg); Colorless powder, mp: 163-166 C; IR (KBr, cm ) νmax = 1774
-1 1
(C=O), 1732 (C=O), 1646 (C=N) cm ; H NMR (600 MHz, CDCl ): δ(ppm) 8.12 (d, J = 7.9 Hz,
3
1H, H-Ar), 7.99 (d, J = 8.3 Hz, 1H, H-Ar), 7.89 (s, 1H, H-4-quinoline), 7.67 (d, J = 7.9 Hz, 1H,
H-Ar), 7.64 (t, J = 7.7 Hz, 1H, H-Ar), 7.40 (t, J = 7.5 Hz, 1H, H-Ar), 7.00 (t, J = 7.7 Hz, 1H, H-
Ar), 6.91 (t, J = 7.7 Hz, 1H, H-Ar), 6.66 (d, J = 8.1 Hz, 1H, H-Ar), 4.61-4.54 (m, 1H, -NCH-
Cyclohexyl), 3.62 (d, J = 14.7 Hz, 1H, -CO-CH(A)), 3.30 (d, J = 14.7 Hz, 1H, -CO-CH(B)), 3.25
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(
s, 3H, -O-CH
3
), 2.58-2.48 (m, 2H, H-Cyclohexyl), 1.94-1.87 (m, 2H, H-Cyclohexyl), 1.84-1.77
(m, 2H, H-Cyclohexyl), 1.75-1.70 (m, 1H, H-Cyclohexyl), 1.52-1.43 (m, 2H, H-Cyclohexyl),
13
1
1
1
6
.40-1.30 (m, 1H, H-Cyclohexyl); C{ H} NMR (150 MHz, CDCl
49.1, 146.7, 130.2, 129.7, 128.1, 127.7, 126.1, 125.4, 125.2, 125.1, 123.1, 122.5, 121.3, 112.0,
1.6, 55.3, 52.7, 51.0, 29.7, 29.0, 26.0, 25.9, 25.2; HRMS (ESI) m/z: Calcd for C26 [M +
[M + Na] 450.1621, Found 450.1612.
-Benzyl-1'-(tert-butyl)-6'-chlorospiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-2',4(1'H)-
3
): δ(ppm) 174.1, 164.1, 155.4,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
26
N
3
O
3
+
+
H] 428.1920, Found 428.1909; Calcd for C26
H N
25 3
NaO
3
1
ᵒ
-1
dione (6f): Yield 68% (285 mg); Colorless powder, mp: 162-165 C; IR (KBr, cm ) νmax = 1777
-1 1
(C=O), 1728 (C=O), 1639 (C=N) cm ; H-NMR (600 MHz, CDCl
3
): δ(ppm) 7.77 (d, J = 8.6 Hz,
1H, H-Ar), 7.56-7.53 (m, 3H, H-Ar, H-4-quinoline), 7.05-6.98 (m, 3H, H-Ar), 6.97 (d, J = 7.3 Hz,
2
3
H, H-Ar), 4.29 (AB quartet, J = 14.6 Hz, 2H, -CH
2
-N), 3.43 (d, J = 14.3 Hz, 1H, -CO-CH(A)),
13
1
.12 (d, J = 14.3 Hz, 1H, -CO-CH(B)), 1.69 (s, 9H, t-Bu); C{ H} NMR (150 MHz, CDCl
3
):
δ(ppm) 173.8, 165.4, 157.1, 145.6, 133.3, 130.7, 130.5, 129.9, 129.5, 129.1, 128.5, 128.1, 126.5,
1
4
25.4, 121.3, 59.8, 58.7, 49.9, 45.5, 28.5; HRMS (ESI) m/z: Calcd for C24
H23ClN
3
O
[M + H]+
2
+
20.1326, Found 420.1335; Calcd for C48
H45Cl
N
2 6
O
4
[2M + H] 839.2595, Found 839.2603.
1
-Benzyl-1'-(tert-butyl)-6'-fluorospiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-2',4(1'H)-
ᵒ
-1
dione (6g): Yield 66% (265 mg); Colorless powder, mp: 224-227 C; IR (KBr, cm ) νmax = 1776
-1 1
(
C=O), 1726 (C=O), 1637 (C=N) cm ; H NMR (600 MHz, CDCl
Hz, 1H, H-Ar), 7.56 (s, 1H, H-4-quinoline), 7.38 (dt, J = 8.7, 2.8 Hz, 1H, H-Ar), 7.22 (dd, J = 8.6,
.7 Hz, 1H, H-Ar ), 7.03 (t, J = 7.1 Hz, 1H, H-Ar), 7.02 (d, J = 7.3 Hz, 1H, H-Ar), 7.00 (d, J = 6.8
Hz, 1H, H-Ar), 6.97 (d, J = 7.5 Hz, 2H, H-Ar), 4.29 (AB quartet, J = 14.7 Hz, 2H, -CH -N), 3.44
d, J = 14.3 Hz, 1H, -CO-CH(A)), 3.12 (d, J = 14.3 Hz, 1H, -CO-CH(B)), 1.70 (s, 9H, t-Bu);
3
): δ(ppm) 7.82 (dd, J = 9.0, 5.4
2
2
(
13
1
): δ(ppm) 173.8, 165.5, 160.3 (C-F, 1JC-F = 244.5 Hz), 158.6 (C-
C{ H} NMR (150 MHz, CDCl
3
F, 1JC-F = 244.5 Hz), 156.5, 144.1, 133.4, 130.5 (C-F, 3JC-F = 9.0 Hz), 130.4 (C-F, 3JC-F = 9.0 Hz),
1
1
29.9, 129.8, 129.1, 128.5, 128.0, 125.3, 125.2, 121.2, 119.6, 119.4, 111.4 (C-F, 2JC-F = 22.5 Hz),
11.2 (C-F, 2JC-F = 22.5 Hz), 59.7, 58.8, 49.9, 45.5, 28.5; HRMS (ESI) m/z: Calcd for C24
H23FN
3
O
2
+
+
[
M + H] 404.1640, Found 404.1647; Calcd for C48
807.3229.
-Benzyl-1'-(tert-butyl)-6'-methylspiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-2',4(1'H)-
H
45
F
2
N
6
O [2M + H] 807.3220, Found
4
1
ᵒ
-1
dione (6h): Yield 58% (231 mg); Colorless powder, mp: 179-182 C; IR (KBr, cm ) νmax = 1772
-1 1
(C=O), 1728 (C=O), 1638 (C=N) cm ; H NMR (600 MHz, CDCl ): δ(ppm) 7.75 (d, J = 8.5 Hz,
3
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6
1
H, H-Ar), 7.60 (s, 1H, H-4-quinoline), 7.45 (d, J = 8.5 Hz, 1H, H-Ar), 7.38 (s, 1H, H-Ar), 7.07-
7.01 (m, 3H, H-Ar), 6.96 (d, J = 6.9 Hz, 2H, H-Ar), 4.40 (d, J = 14.7 Hz, 1H, -CH(A)-N), 4.15 (d,
J = 14.7 Hz, 1H, -CH(B)-N), 3.43 (d, J = 14.3 Hz, 1H, -CO-CH(A)), 3.11 (d, J = 14.3 Hz, 1H, -
1
3
1
CO-CH(B)), 2.48 (s, 3H, -CH
3
), 1.67 (s, 9H, t-Bu); C{ H} NMR (150 MHz, CDCl ): δ(ppm)
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
73.9, 165.8, 156.3, 145.7, 134.9, 133.5, 132.1, 130.0, 129.1, 128.5, 128.1, 127.9, 126.9, 124.8,
119.8, 59.5, 58.9, 49.7, 45.3, 28.5, 21.3; HRMS (ESI) m/z: Calcd for C25
H
26
N
3
O
[M + H]+
2
+
4
00.2035, Found 400.2044; Calcd for C50
H
51
N
6
O
4
[2M + H] 799.4024, Found 799.4034.
1
2
-Benzyl-1'-(tert-butyl)-6',7'-dimethylspiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-
ᵒ
-1
',4(1'H)-dione (6i): Yield 54% (223 mg); Colorless powder, mp: 196-198 C; IR (KBr, cm ) νmax
-1 1
= 1774 (C=O), 1732 (C=O), 1634 (C=N) cm ; H NMR (600 MHz, CDCl ): δ(ppm) 7.65 (s, 1H,
3
H-4-quinoline), 7.59 (s, 1H, H-Ar), 7.35 (s, 1H, H-Ar), 7.08-7.03 (m, 3H, H-Ar), 6.97 (d, J = 7.1
Hz, 2H, H-Ar), 4.41 (d, J = 14.7 Hz, 1H, -CH(A)-N), 4.12 (d, J = 14.7 Hz, 1H, -CH(B)-N), 3.42
(d, J = 14.3 Hz, 1H, -CO-CH(A)), 3.11 (d, J = 14.3 Hz, 1H, -CO-CH(B)), 2.42 (s, 3H, -CH
3
), 2.39
): δ(ppm) 174.0, 165.9, 156.4,
46.1, 140.4, 134.7, 133.5, 129.7, 129.1, 128.5, 128.1, 127.9, 127.3, 123.2, 118.8, 59.4, 59.0, 49.7,
13
1
(s, 3H, -CH
3
), 1.66 (s, 9H, t-Bu); C{ H} NMR (150 MHz, CDCl
3
1
4
+
5.3, 28.5, 20.3, 19.8; HRMS (ESI) m/z: Calcd for C26
H
28
N
3
O [M + H] 414.2205, Found
2
+
414.2214; Calcd for C52
H
55
N
6
O
4
[2M + H] 827.4236, Found 827.4245.
1
-Benzyl-6'-chloro-1'-cyclohexylspiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-2',4(1'H)-
ᵒ
-1
dione (6j): Yield 69% (307 mg); Colorless powder, mp: 213-216 C; IR (KBr, cm ) νmax = 1779
-1 1
(C=O), 1735 (C=O), 1642 (C=N) cm ; H NMR (600 MHz, CDCl
3
): δ(ppm) 7.77 (d, J = 8.6 Hz,
1H, H-Ar), 7.55 (d, J = 7.5 Hz, 1H, H-Ar), 7.54 (brs, 1H, H-Ar), 7.50 (s, 1H, H-4-quinoline), 7.01-
6
1
.97 (m, 2H, H-Ar), 6.96-6.93 (m, 3H, H-Ar), 4.38 (d, J = 14.6 Hz, 1H, -CH(A)-N), 4.34-4.27 (m,
H, -NCH-Cyclohexyl), 4.21 (d, J = 14.6 Hz, 1H, -CH(B)-N), 3.46 (d, J = 14.4 Hz, 1H, -CO-
CH(A)), 3.15 (d, J = 14.4 Hz, 1H, -CO-CH(B)), 2.39-2.25 (m, 2H, H-Cyclohexyl), 1.89-1.82 (m,
2
1
H, H-Cyclohexyl), 1.73-1.66 (m, 1H, H-Cyclohexyl), 1.62-1.54 (m, 2H, H-Cyclohexyl), 1.42-
.33 (m, 2H, H-Cyclohexyl), 1.31-1.22 (m, 1H, H-Cyclohexyl); 13C{ H} NMR (150 MHz,
1
CDCl ): δ(ppm) 173.1, 165.2, 155.5, 145.8, 133.3, 130.8, 130.4, 130.1, 129.5, 129.0, 128.5, 128.1,
3
126.7, 125.8, 121.2, 58.5, 52.6, 49.7, 45.7, 28.7, 28.6, 25.8, 25.1; HRMS (ESI) m/z: Calcd for
+
NaO
[2M + Na]+
C
26
H25ClN
3
O
2
[M + H] 446.1521, Found 446.1530; Calcd for C52
H48Cl
2
N
6
4
9
13.2740, Found 913.2749.
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2
3
4
5
6
7
8
9
1
-Benzyl-1'-cyclohexyl-6'-fluorospiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-2',4(1'H)-
ᵒ
-1
dione (6k): Yield 67% (287 mg); Colorless powder; mp: 194-196 C; IR (KBr, cm ) νmax = 1765
-1 1
(
C=O), 1724 (C=O), 1643 (C=N) cm ; H NMR (600 MHz, CDCl
Hz, 1H, H-Ar), 7.53 (s, 1H, H-4-quinoline), 7.37 (dt, J = 8.6, 2.7 Hz, 1H, H-Ar), 7.20 (dd, J = 8.6,
.7 Hz, 1H, H-Ar), 6.99 (t, J = 7.4 Hz, 1H, H-Ar), 6.98 (d, J = 7.2 Hz, 1H, H-Ar),6.97-6.93 (m,
3
): δ(ppm) 7.83 (dd, J = 9.1, 5.2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3H, H-Ar), 4.39 (d, J = 14.6 Hz, 1H, -CH(A)-N), 4.34-4.28 (m, 1H, -NCH-Cyclohexyl), 4.19 (d,
J = 14.6 Hz, 1H, -CH(B)-N), 3.47 (d, J = 14.3 Hz, 1H, -CO-CH(A)), 3.15 (d, J = 14.3 Hz, 1H, -
CO-CH(B)), 2.40-2.27 (m, 2H, H-Cyclohexyl), 1.89-1.82 (m, 2H, H-Cyclohexyl), 1.72-1.68 (m,
1
H, H-Cyclohexyl), 1.63-1.55 (m, 2H, H-Cyclohexyl), 1.43-1.33 (m, 2H, H-Cyclohexyl), 1.32-
13
1
1.24 (m, 1H, H-Cyclohexyl); C{ H} NMR (150 MHz, CDCl ): δ(ppm) 173.0, 165.3, 160.2 (C-
3
F, 1JC-F = 244.5 Hz), 158.5 (C-F, 1JC-F = 244.5 Hz), 154.8, 144.2, 133.4, 130.4 (C-F, 3JC-F = 4.5
Hz), 130.3 (C-F, 3JC-F = 4.5 Hz), 130.1, 130.0, 129.0, 128.5, 128.0, 125.7, 125.6, 121.1, 119.7,
119.5, 111.7 (C-F, 2JC-F = 22.5 Hz), 111.5 (C-F, 2JC-F = 22.5 Hz), 58.6, 52.5, 49.6, 45.7, 28.7, 28.6,
+
2
5.9, 25.1; HRMS (ESI) m/z: Calcd for C26
H25FN
3
O
2
[M+H] 430.1941, Found 430.1951; Calcd
+
O
[M + 2H]2+
for C52
H
48
F
2
N
6
NaO
15.0613, Found 215.0621.
1-Benzyl-1'-cyclohexyl-6'-methylspiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-2',4(1'H)-
4
[2M + Na] 881.3635, Found 881.3644; Calcd for C26
H26FN
3
2
2
ᵒ
-1
dione (6l): Yield 60% (255 mg); Colorless powder; mp: 215-217 C; IR (KBr, cm ) νmax = 1778
-1
1
(C=O), 1733 (C=O), 1638 (C=N) cm ; H NMR (600 MHz, CDCl ): δ(ppm) 7.91-7.87 (m, 1H,
3
H-Ar), 7.60 (s, 1H, H-4-quinoline), 7.48 (d, J = 8.4 Hz, 1H, H-Ar), 7.37 (s, 1H, H-Ar), 7.02 (t, J
= 7.2 Hz, 2H, H-Ar), 6.99-6.94 (m, 3H, H-Ar), 4.46-4.37 (m, 1H, -NCH-Cyclohexyl), 4.29 (s, 2H,
-
CH
H, -CH
H-Cyclohexyl), 1.71-1.65 (m, 1H, H-Ar), 1.63-1.52 (m, 2H, H-Cyclohexyl), 1.45-1.36 (m, 2H, H-
2
-N), 3.46 (d, J = 14.3 Hz, 1H, -CO-CH(A)), 3.16 (d, J = 14.3 Hz, 1H, -CO-CH(B)), 2.48 (s,
3
3
), 2.38-2.30 (m, 1H, H-Cyclohexyl), 2.28-2.20 (m, 1H, H-Cyclohexyl), 1.87-1.80 (m, 2H,
1
3
1
Cyclohexyl), 1.32-1.24 (m, 1H, H-Cyclohexyl); C{ H} NMR (150 MHz, CDCl
3
): δ(ppm) 173.1,
65.5, 154.5, 135.2, 133.3, 133.2, 132.7, 132.6, 131.3, 131.1, 129.0, 128.5, 128.0, 127.2, 127.1,
25.1, 119.9, 58.6, 52.9, 49.6, 45.6, 29.7, 28.7, 28.6, 25.8, 25.1, 21.3; HRMS (ESI) m/z: Calcd for
1
1
+
+
C
27
H
28
N
3
O
2
[M + H] 426.2130, Found 426.2138; Calcd for C54
H
54
N
6
NaO [2M + Na] 873.3833,
4
Found 873.3842.
1
2
-Benzyl-1'-cyclohexyl-6',7'-dimethylspiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-
ᵒ
-1
',4(1'H)-dione (6m): Yield 58% (255 mg); Colorless powder; mp: 203-205 C; IR (KBr, cm )
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-1
1
ν
max = 1772 (C=O), 1717 (C=O), 1639 (C=N) cm ; H NMR (600 MHz, CDCl
3
): δ(ppm) 7.68 (s,
1H, H-4-quinoline), 7.60 (s, 1H, H-Ar), 7.37 (s, 1H, H-Ar), 7.08-7.01 (m, 3H, H-Ar), 6.99 (d, J =
7
4
.1 Hz, 2H, H-Ar), 4.34 (d, J = 14.7 Hz, 1H, -CH(A)-N), 4.33-4.30 (m, 1H, -NCH-Cyclohexyl),
.28 (d, J = 14.7 Hz, 1H, -CH(B)-N), 3.49 (d, J = 14.3 Hz, 1H, -CO-CH(A)), 3.18 (d, 1H, J = 14.3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hz, -CO-CH(B)), 2.46 (s, 3H, -CH
2.25 (m, 1H, H-Cyclohexyl), 1.90-1.83 (m, 2H, H-Cyclohexyl), 1.74-1.68 (m, 1H, H-Cyclohexyl),
.63-1.53 (m, 2H, H-Cyclohexyl), 1.45-1.36 (m, 2H, H-Cyclohexyl), 1.34-1.27 (m, 1H, H-
3
), 2.42 (s, 3H, -CH
3
), 2.39-2.34 (m, 1H, H-Cyclohexyl), 2.33-
1
13
1
Cyclohexyl); C{ H} NMR (150 MHz, CDCl
3
): δ(ppm) 173.3, 165.7, 154.8, 146.3, 140.5, 134.5,
1
33.4, 130.3, 129.0, 128.4, 127.9, 127.8, 127.6, 123.6, 118.7, 58.7, 52.3, 49.5, 45.5, 28.7, 28.6,
+
25.9, 25.2, 20.3, 19.8; HRMS (ESI) m/z: Calcd for C28
H
30
N
3
O [M + H] 440.2438, Found
2
+
4
40.2430; Calcd for C56
H
58
N
6
NaO
4
[2M + Na] 901.4415, Found 901.4406.
1
'-(tert-Butyl)-6'-chloro-1-(furan-2-ylmethyl)spiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-
ᵒ
-1
2',4(1'H)-dione (6n): Yield 79% (323 mg); Colorless powder; mp: 195-198 C; IR (KBr, cm )
-
1 1
ν
max = 1776 (C=O), 1734 (C=O), 1644 (C=N) cm ; H NMR (600 MHz, CDCl ): δ(ppm) 7.79 (d,
3
J = 8.8 Hz, 1H, H-Ar), 7.61 (s, 2H, H-Ar), 7.55 (dd, J = 8.8, 1.9 Hz, 1H, H-Ar), 6.86 (s, 1H, H-
Ar-furfuryl), 5.95 (d, J = 3.1 Hz, 1H, H-Ar-furfuryl), 5.87 (s, 1H, H-Ar-furfuryl), 4.45 (d, J = 15.4
Hz, 1H, -CH(A)-N), 4.21 (d, J = 15.4 Hz, 1H, -CH(B)-N), 3.41 (d, J = 14.3 Hz, 1H, -CO-CH(A)),
13
1
3
.10 (d, 1H, J = 14.3 Hz, -CO-CH(B)), 1.81 (s, 9H, t-Bu); C{ H} NMR (150 MHz, CDCl
3
):
δ(ppm) 173.9, 165.1, 157.2, 146.8, 145.6, 142.6, 130.6, 130.5, 129.8, 129.0, 126.5, 125.6, 121.5,
1
4
10.3, 109.9, 59.9, 58.7, 49.9, 37.3, 28.6; HRMS (ESI) m/z: Calcd for C22
10.1440, Found 410.1432.
H21ClN
3
O
3
[M + H]+
1
2
'-(tert-Butyl)-1-(furan-2-ylmethyl)-6'-methylspiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-
ᵒ
-1
',4(1'H)-dione (6o): Yield 61% (237 mg); Colorless powder; mp: 159-161 C; IR (KBr, cm )
-
1 1
ν
max = 1775 (C=O), 1731 (C=O), 1643 (C=N) cm ; H NMR (600 MHz, CDCl ): δ(ppm) 7.79 (d,
3
J = 8.4 Hz, 1H, H-Ar), 7.65 (s, 1H, H-4-quinoline), 7.45 (d, J = 8.5 Hz, 1H, H-Ar), 7.41 (s, 1H,
H-Ar), 6.90 (s, 1H, H-Ar-furfuryl), 5.94 (d, J = 3.1 Hz, 1H, H-Ar-furfuryl), 5.89 (s, 1H, H-Ar-
furfuryl), 4.38 (d, J = 15.4 Hz, 1H, -CH(A)-N), 4.26 (d, J = 15.4 Hz, 1H, -CH(B)-N), 3.41 (d, J =
14.2 Hz, 1H, -CO-CH(A)), 3.09 (d, J = 14.2 Hz, 1H, -CO-CH(B)), 2.48 (s, 3H, -CH
3
), 1.81 (s, 9H,
): δ(ppm) 174.0, 165.4, 156.4, 146.9, 145.4, 142.6, 134.9,
32.1, 129.6, 128.0, 126.9, 124.9, 120.0, 110.3, 109.8, 59.7, 58.8, 49.8, 37.2, 28.7, 21.3; HRMS
1
3
1
t-Bu); C{ H} NMR (150 MHz, CDCl
3
1
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4
5
6
7
8
9
+
(
ESI) m/z: Calcd for C23
H
24
N
3
O
3
[M + H] 390.1823, Found 390.1832; Calcd for C23
H
23
N
3
NaO
3
+
[M + Na] 412.1617, Found 412.1625.
1
2
'-(tert-Butyl)-1-(2-methoxyphenyl)-6'-methylspiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-
ᵒ
-1
',4(1'H)-dione (6p): Yield 65% (278 mg); Colorless powder; mp: 188-191 C; IR (KBr, cm )
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1 1
ν
max = 1765 (C=O), 1733 (C=O), 1655 (C=N) cm ; H NMR (600 MHz, CDCl
J = 8.0 Hz, 1H, H-Ar), 7.79 (d, J = 8.5 Hz, 1H, H-Ar), 7.75 (s, 1H, H-4-quinoline), 7.44 (d, J =
.6 Hz, 1H, H-Ar), 7.41 (s, 1H, H-Ar), 6.99 (t, J = 7.7 Hz, 1H, H-Ar), ), 6.90 (t, J = 7.7 Hz, 1H,
H-Ar), 6.65 (d, 1H, J = 8.2 Hz, H-Ar), 3.58 (d, J = 14.6 Hz, 1H, -CO-CH(A)), 3.25 (d, J = 14.4
3
): δ(ppm) 8.14 (d,
8
13
1
Hz, 1H, -CO-CH(B)), 3.24 (s, 3H, -O-CH
(150 MHz, CDCl ): δ(ppm) 175.2, 164.4, 156.4, 149.0, 145.3, 134.8, 131.7, 128.2, 128.1, 127.0,
25.9, 125.5, 124.9, 123.2, 122.3, 121.3, 112.1, 62.1, 59.3, 55.3, 51.2, 28.9, 21.3; HRMS (ESI)
3
), 2.45 (s, 3H, -CH ), 1.88 (s, 9H, t-Bu); C{ H} NMR
3
3
1
+
m/z: Calcd for C25
H
26
N
3
O
3
[M + H] 416.1874, Found 416.1867; Calcd for C25
H
25
N
3
NaO [M +
3
+
Na] 438.1590, Found 438.1580.
1
-Benzyl-1'-(tert-butyl)-5'-methoxyspiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-2',4(1'H)-
ᵒ
-1
dione (6q): Yield 57% (236 mg); Colorless powder; mp: 181-183 C; IR (KBr, cm ) νmax = 1770
-1 1
(
C=O), 1727 (C=O), 1622 (C=N) cm ; H NMR (400 MHz, CDCl ): δ(ppm) 7.62 (s, 1H, H-4-
3
quinoline), 7.52 (d, J = 8.9 Hz, 1H, H-Ar), 7.25 (d, J = 2.5 Hz, 1H, H-Ar), 7.13-7.06 (m, 4H, H-
Ar),7.02 (dd, J = 7.4, 2.1 Hz, 2H, H-Ar), 4.42 (d, J = 14.6 Hz, 1H, -CH(A)-N), 4.21 (d, J = 14.6
Hz, 1H, -CH(B)-N), 3.98 (s, 3H, -O-CH
3
), 3.46 (d, J = 14.2 Hz, 1H, -CO-CH(A)), 3.15 (d, J =
1
3
1
1
4.2 Hz, 1H, -CO-CH(B)), 1.73 (s, 9H, t-Bu); C{ H} NMR (100 MHz, CDCl ): δ(ppm) 174.2,
3
165.9, 161.4, 157.5, 149.2, 133.6, 130.2, 129.1, 128.8, 128.5, 127.9, 119.6, 117.2, 117.1, 107.7,
+
5
9.5, 59.0, 55.5, 49.6, 45.3, 28.6; MS (ESI) m/z: Found for C25
Calcd for C25
1-Benzyl-1'-cyclohexyl-5'-methoxyspiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-2',4(1'H)-
H
26
N
3
O
3
[M + H] 416.2991; Anal.
H
25
N
3
O : C, 72.27; H, 6.07; N, 10.11. Found: C, 72.31; H, 6.10; N, 10.14.
3
ᵒ
-1
dione (6r): Yield 62% (273 mg); Colorless powder, mp: 165-167 C; IR (KBr, cm ) νmax = 1770
-1
1
(
C=O), 1727 (C=O), 1625 (C=N) cm ; H NMR (400 MHz, CDCl ): δ(ppm) 7.59 (s, 1H, H-4-
3
quinoline), 7.50 (d, J = 8.9 Hz, 1H, H-Ar), 7.27 (d, J = 2.4 Hz, 1H, H-Ar), 7.08-7.02 (m, 4H, H-
Ar), 7.01-6.98 (m, 2H, H-Ar), 4.39-4.33 (m, 1H, -NCH-Cyclohexyl), 4.32 (AB quartet, J = 14.6
Hz, 2H, CH
2
-N), 3.98 (s, 3H, -O-CH
3
), 3.49 (d, J = 14.3 Hz, 1H, -CO-CH(A)), 3.19 (d, J = 14.3
Hz, 1H, -CO-CH(B)), 2.45-2.25 (m, 2H, H-Cyclohexyl), 1.92-1.85 (m, 2H, H-Cyclohexyl), 1.76-
1
.69 (m, 1H, H-Cyclohexyl), 1.66-1.55 (m, 2H, H-Cyclohexyl), 1.48-1.35 (m, 2H, H-Cyclohexyl),
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
1
1
.34-1.26 (m, 1H, H-Cyclohexyl); C{ H} NMR (100 MHz, CDCl ): δ(ppm) 173.5, 165.6, 161.5,
3
155.8, 149.4, 133.5, 130.9, 129.1, 129.0, 128.4, 127.9, 119.9, 117.1, 117.0, 107.5 58.8, 55.6, 52.3,
+
4
9.4, 45.5, 28.7, 28.6, 25.9, 25.2; MS (ESI) m/z: Found for C27
Anal. Calcd for C27
-Benzyl-1'-cyclohexyl-5',7'-dimethylspiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-
H
27
N
3
NaO
3
[M + Na] 464.0472;
H
27
N
3
O : C, 73.45; H, 6.16; N, 9.52. Found: C, 73.49; H, 6.20; N, 9.55.
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
ᵒ
-1
2',4(1'H)-dione (6s): Yield 70% (307 mg); Colorless powder, mp: 179-182 C; IR (KBr, cm )
-
1 1
ν
max = 1764 (C=O), 1714 (C=O), 1634 (C=N) cm ; H NMR (400 MHz, CDCl
H, H-4-quinoline), 7.56 (s, 1H, H-Ar), 7.09 (s, 1H, H-Ar), 7.07-7.03 (m, 1H, H-Ar), 7.02-7.01
m, 1H, H-Ar), 7.00-6.97 (m, 3H, H-Ar), 4.43 (d, J = 14.6 Hz, 1H, -CH(A)-N), 4.40-4.33 (m, 1H,
-NCH-Cyclohexyl), 4.20 (d, J = 14.6 Hz, 1H, -CH(B)-N), 3.52 (d, J = 14.3 Hz, 1H, -CO-CH(A)),
.21(d, J = 14.3 Hz, 1H, -CO-CH(B)), 2.50 (s, 3H, -CH ), 2.49 (s, 3H, -CH ), 2.45-2.31 (m, 2H,
H-Cyclohexyl), 1.92-1.86 (m, 2H, H-Cyclohexyl), 1.76-1.69 (m, 1H, H-Cyclohexyl), 1.68-1.59
3
): δ(ppm) 7.71 (s,
1
(
3
3
3
1
3
1
(m, 2H, H-Cyclohexyl), 1.48-1.26 (m, 3H, H-Cyclohexyl); C{ H} NMR (100 MHz, CDCl
3
):
δ(ppm) 173.5, 165.6, 155.1, 148.0, 140.5, 134.5, 133.8, 128.9, 128.4, 128.0, 127.9, 127.6, 125.7,
1
22.4, 118.1, 59.0, 53.5, 52.4, 49.7, 45.6, 28.8, 28.7, 25.9, 25.2, 21.7, 18.8; MS (ESI) m/z: Found
+
for C56
H
58
N
6
NaO
4
[2M + Na] 901.1141; Anal. Calcd for C28
H
29
N
3
2
O : C, 76.51; H, 6.65; N, 9.56.
Found: C, 76.54; H, 6.68; N, 9.59.
'-(tert-butyl)-1-(4-methoxyphenyl)spiro[azetidine-2,3'-pyrrolo[2,3-b]quinoline]-2',4(1'H)-
1
ᵒ
-1
dione (6t): Yield 72% (289 mg); Colorless powder; mp: 202-204 C; IR (KBr, cm ) νmax = 1767
-
1 1
(
C=O), 1721 (C=O), 1647 (C=N) cm ; H NMR (400 MHz, CDCl
quinoline), 8.00 (d, J = 8.3 Hz, 1H, H-Ar), 7.75-7.69 (m, 2H, H-Ar), 7.46 (t, J = 7.1 Hz, 1H, H-
Ar), 7.01 (d, J = 9.0 Hz, 2H, H-Ar), 6.73 (d, J = 9.0 Hz, 2H, H-Ar), 3.70 (s, 3H, -O-CH ), 3.63 (d,
J = 14.6 Hz, 1H, -CO-CH(A)), 3.34 (d, J = 14.6 Hz, 1H, -CO-CH(B)), 1.95 (s, 9H, t-Bu); C{ H}
NMR (100 MHz, CDCl ): δ(ppm) 174.0, 162.5, 156.9, 156.5, 147.7, 130.9, 130.5, 130.1, 128.6,
28.1, 125.4, 125.0, 120.2, 118.1, 114.5, 60.2, 59.1, 55.4, 49.7, 28.8; MS (ESI) m/z: Found for
3
): δ(ppm) 8.03 (s, 1H, H-4-
3
13
1
3
1
+
C
24
H
24
N
3
O
3
[M + H] 402.2573; Anal. Calcd for C24
H
23
N
3
3
O : C, 71.80; H, 5.77; N, 10.47. Found:
C, 71.83; H, 5.80; N, 10.50.
N-benzyl-N-(1-(2-bromophenyl)-2-(tert-butylamino)-2-oxoethyl)-2-chloroacetamide (11):
ᵒ
1
Yield 59% (266 mg); Colorless powder, mp: 163-164 C; H NMR (600 MHz, DMSO-d ) (mixture
6
of two rotamers (59:41)): δ(ppm) 8.07 (d, 1H, H-Ar, mixture of two rotamers), 7.46-7.35 (m, 2H,
H-Ar, mixture of two rotamers), 7.32-7.27 (m, 1H, H-Ar, mixture of two rotamers), 7.20-7.07 (m,
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H, H-Ar, mixture of two rotamers), 7.05-7.00 (m, 2H, H-Ar, mixture of two rotamers, and -NH-
3
amide, minor rotamer), 6.83 (brs, -NH-amide, major rotamer), 6.22 (s, 1H, C(sp )−H, major
3
rotamer), 5.67 (s, 1H, C(sp )−H, minor rotamer), 4.88 (d, J = 15.8 Hz, 1H, -CH(A)-N, minor
rotamer), 4.77 (d, J = 18.3 Hz, 1H, -CH(A)-N, major rotamer), 4.66 (d, J = 18.3 Hz, 1H, -CH(B)-
N, major rotamer), 4.57 (d, J = 13.6 Hz, 1H, -CH(B)-N, minor rotamer), 4.38 (d, J = 14.5 Hz, 1H,
-CH(A)-Cl, mixture of two rotamers), 4.33 (d, J = 14.2 Hz, 1H, -CH(B)-Cl, minor rotamer), 4.23
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(d, J = 14.2 Hz, 1H, -CH(B)-Cl, major rotamer), 1.17 (s, 9H, t-Bu, minor rotamer), 1.13 (s, 9H, t-
Bu, major rotamer); 13C{ H} NMR (150 MHz, DMSO-d
1
) for major rotamer : δ(ppm) 167.6,
6
1
67.0, 137.4, 136.0, 132.7, 130.0, 129.8, 128.1, 127.3, 127.0, 125.9, 125.6, 62.2, 50.6, 48.6, 42.8,
2581BrClN
O
2
[M + H] 453.0762, Found 453.0761, Calcd
+
28.1; HRMS (ESI) m/z: Calcd for C21
H
2
+
81 37
for C21
H
25BrClN
2
O
2
[M + H] 451.0782, Found 451.0783, Calcd for C21
H
25 Br ClN
2
2
O [M +
+
+
H] 455.0732, Found 455.0732, Calcd for C21
H24NaBrClN
2
O
2
[M + H] 473.0602, Found
3
7
+
473.0598, Calcd for C21
H
24NaBr ClN
2
O
2
[M + H] 475.0572, Found 473.0576, Calcd for
8
1
37
+
C
21
H
24Na Br ClN
2
O
2
[M + H] 477.0552, Found 477.0548.
(S)-4-benzyl-3-(2-bromophenyl)-1-(tert-butyl)piperazine-2,5-dione (12): Yield 68% (282
ᵒ
1
mg); Colorless powder, mp: 119-121 C; H-NMR (600 MHz, CDCl ): δ(ppm) 7.58 (d, J = 8.0 Hz,
3
1H, H-Ar), 7.30-7.25 (m, 4H, H-Ar), 7.20-7.15 (m, 3H, H-Ar), 7.10 (d, J = 7.6 Hz, 1H, H-Ar),
3
5
.25 (s, 1H, C(sp )-H), 5.24 (d, J = 14.1 Hz, 1H, -CO-CH(A)-N), 4.27 (s, 2H, -CH
2
-N), 3.41 (d, J
): δ(ppm)
13
1
=
14.7 Hz, 1H, -CO-CH(B)-N), 1.41 (s, 9H, t-Bu); C{ H} NMR (150 MHz, CDCl
3
1
2
63.9, 163.8, 136.4, 135.0, 134.1, 130.4, 130.3, 128.8, 128.7, 128.0, 123.6, 63.7, 58.4, 47.4, 46.8,
+
7.6; HRMS (ESI) m/z: Calcd for C21
H24BrN
2
O
2
[M + H] 415.1016, Found 415.1018, Calcd for
2481BrN
O
2
[M + H] 417.0995, Found 417.0998.
+
C
21
H
2
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
1
13
All H, C NMR spectra and HRMS for compounds 5a-r, 6a-p, 11 and 12 and IR spectra of
compounds 6a-p as well as X-ray crystallography data for compounds 6b are given in the
supporting information.
The codes CCDC 1989593 contain the supplementary crystallographic data for this paper. This
data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing at
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data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
▪
AUTHOR INFORMATION
Corresponding Authors
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*
E-mail: balalaie@kntu.ac.ir
aharrasi@unizwa.edu.om
ORCID
Saeed Balalaie: 0000-0002-5764-0442
Ahmed Al-Harrasi: 0000-0002-0815-5942
▪
ACKNOWLEDGMENT
S.B. thanks Alexander von Humboldt Foundation for the Linkage research Group program.
We acknowledge the deputy of Research University of Nizwa for the collaboration.
▪
REFERENCES
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