Highly Substituted Medium-Sized Ring-Fused Azocinoquinoline

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Highly Substituted Medium-Sized Ring-Fused Azocinoquinoline Scaffolds by a Post-Ugi-4CR Reductive Carbopalladation Cyclization Helya Janatian Ghazvini, Thomas J. J. Mueller, Frank Rominger, and Saeed Balalaie J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01269 • Publication Date (Web): 30 Jul 2019 Downloaded from pubs.acs.org on August 2, 2019

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The Journal of Organic Chemistry

Highly Substituted Medium-Sized Ring-Fused Azocinoquinoline Scaffolds by a Post-Ugi-4CR Reductive Carbopalladation Cyclization Helya Janatian Ghazvini, † Thomas J. J. Müller, *‡ Frank Rominger, § and Saeed Balalaie *†,∥ †

Peptide Chemistry Research Center, K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran, [email protected], Tel:+98-21-23064226, Fax: +98-21-22889403

‡

Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf,

Universitätsstrasse 1, D-40225 Düsseldorf, Germany, [email protected], Tel: +49 211 8112298

§ Organisch-Chemisches

Institut der Universität Heidelberg, Im Neuenheimer Feld 270, D-69120

Heidelberg, Germany ∥ Medical

Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran

ABSTRACT A concise synthesis of quinoline-fused eight-membered ring from simple starting materials is described. Reductive cyclo-carbopalladation of suitable Ugi-4CR substrates as a key step leads to the regio- and diastereoselective formation of 1,2dihydroazocino[4,3-b]quinolin-3-ones under mild reaction conditions with good yields in short reaction time.

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Keywords: Post-Ugi transformation, Azocinoquinoline, Reductive Carbopalladation Cyclization

INTRODUCTION In comparison to five- and six-membered rings, compounds containing seven-, eightand nine-membered rings are more rarely found in nature and hardly isolated by synthetic approaches. However these scarce products have significant biological activities and pharmaceutical properties. Like LY-4115751 and LY-4501392, known ϒsecretase inhibitors that are under development for amyloid-based therapeutic intervention in Alzheimer’s disease. Furthermore, inspired by an interesting monocyclic medium-ring marine natural product, named, Octalactin A3, Buszek and co-workers4 prepared a speculative eight-membered lactam via ring-closing metathesis with antiproliferative activities similar to anticancer drugs (Figure 1).

Figure 1. Some medium-sized bioactive lactams and natural products.

Alternatively, in recent years elegant direct cyclization methods by applying transitionmetal catalysts leading to 7-, 8- and 9-membered rings using various gold,8 indium,9 and copper10 catalysts have been presented. Among all these transition metal-catalyzed reactions, Pd-catalyzed transformations are widely used in cyclic carbopalladation of alkynes for the rapid construction of four- to nine-membered rings.11 By these methods,


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various seven-membered benzazepines,12 benzodiazepines,13 and benzoxepines11d along

with

eight-membered

dibenzazocinones,14

dibenzoxocines,11e

and

azocinoindoles15 have been prepared by Van der Eycken, Majumdar and Ghosh. Encouraged by these strategies and based upon our previous works on metal-catalyzed cyclizations of functionalized quinoline-carbaldehydes for the generation of bioactive heterocycles,16 and experiences in diversity-oriented synthesis of 3-hydroxyisoquinoline blue emitters by sequential Ugi four-component reaction-reductive Heck cyclization,17 we herein report a concise approach to highly substituted medium-sized ring-fused azocinoquinoline scaffolds by Ugi-4CR followed by palladium-assisted intramolecular 8exo-dig reductive cyclization (Scheme 1).

Scheme 1. A two-step route to azocinoquinoline scaffolds

RESULTS AND DISCUSSION In the outset, 2-alkynylquinoline-3-carbaldehydes 1 were easily prepared by a two–step reported protocol.18 The Ugi-4CR carried out using 2-(phenylethynyl)quinoline-3carbaldehyde (1a), 2-iodobenzoic acid (2a), benzylamine (3a), and tert-butylisocyanide (4a) in methanol. The precipitated adduct 5a was then separated and directly submitted to the palladium-catalyzed reductive cyclization. This cyclization was achieved sing sodium formate in the presence of Pd(PPh3)4 as catalyst in a mixture of DMF/water (Scheme 2).



Scheme

2.

Synthesis

of

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benzylidene-N-(tert-butyl)

azocino[4,3-b]quinoline-7-carboxamide

(6a)

tetrahydrobenzo-[6,7]-

through

Ugi-4CR/cyclo-

carbopalladation/hydride capture sequence

The structure of the isolated product 6a was unambiguously assigned by 1H and

13C

NMR spectroscopy, HRMS data and corroborated by X-ray crystallography (Figure 2). The structural assignment additionally supports a syn-carbopalladation-hydride capture sequence that exclusively occurred in 8-exo-dig fashion. The eight-membered ring adopts a pseudo-boat conformation in the solid state. According to the

1H

NMR

spectrum of 6a, the amide proton at δ 4.45 is considerably shielded in comparison to the amide proton of the precursor 5a which appears at δ 8.87. This upfield shift rationalizes by the shielding anisotropy cone of the benzoyl moiety, as also can be seen in the X-ray structure analysis. The two diastereotopic benzylic protons can be found as two doublets at δ 4.02 and 5.44 with large geminal coupling constants (2J = 14.7 Hz). As for the amide proton the difference in their chemical shifts arises from a deshielding anisotropy cone, however, this time of the exocyclic double bond. In comparison, the diastereostopic benzyl protons of the precursor 5a only show minimal differences in the resonances that appear as two doublets at δ 4.45 and 4.63. The Z-configuration of the exocyclic double bond supports the cis-carbopalladation of the alkyne group, which, by appearance as single diastereomer in all cases and serendipitously no product arising from an intramolecular hydroamination of the alkyne was detected.


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Figure 2. ORTEP structure of compound (6a); displacement ellipsoids are drawn at the 50% probability level.

Interested by these finding we sought to explore the optimized reaction condition for the synthesis of 6a from Ugi-adduct 5a as a model substrate by employing two different reducing agents, catalysts and solvents (Table 1). It is noteworthy to mention that formic acid does not act as an effective reducing agent (Entry 1). While, the presence of water is necessary for the solubility of the reducing agent, the cyclization step does not proceed without using water as co-solvent (Entry 2). Among the examined Pd-catalysts, highest yield was obtained with Pd(PPh3)4 (Entry 3-5). And finally, DMA, toluene, THF and acetonitrile were tested as solvents at their boiling temperature (reflux condition under inert atmosphere) and they all were found to be less effective than DMF/H2O (Entry 6-9). The optimal condition was identified using 1.5 equivs of sodium formate with 4mol% Pd(PPh3)4 in the 3:1 mixture of DMF/water under an inert atmosphere at 80 °C for 1h (Entry 5).



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Table 1. Optimization of reaction condition for the synthesis of (6a)a

Yieldb (%)

Entry

Reducing agent

Catalyst(%)

Solvent

1

HCOOH

Pd(PPh3)4

DMF/H2O

-

2

HCOONa

Pd(PPh3)4

DMF

-

3

HCOONa

PdCl2+2PPh3

DMF/H2O

38

4

HCOONa

PdCl2(PPh3)2

DMF/H2O

64

5c

HCOONa

Pd(PPh3)4

DMF/H2O

84

6

HCOONa

Pd(PPh3)4

DMA/H2O

75

7

HCOONa

Pd(PPh3)4

Toluene/H2O

-

8

HCOONa

Pd(PPh3)4

THF/H2O

-

9

HCOONa

Pd(PPh3)4

CH3CN/H2O

-

aAll

reactions were performed using 5a (1.0 mmol, 0.677 g), reducing agent (1.5 mmol), palladium catalyst (4 mol%)

in the mixture of organic solvent/water (4/1.3 mL) at 80 °C to reflux temperature for 1-5h. bIsolated yields after flash chromatography on silica gel and recrystallization from n-Hexane/EtOAc. cOptimized condition.

With this optimized reaction condition in hand, we explored the substrate scope and generality of the process. A series of quinoline carbaldehydes bearing aliphatic and aromatic alkynyl chains 1a-f, ortho-halobenzoic acides 2a-c along with various amines 3a-c and two different isocyanides 4a, b were employed in the synthesis of the Ugi-4CR substrates (Table 2).


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Table 2. Synthesis of Ugi-adducts (5a-o)a

aAll

reactions were performed using 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol) and 4 (1.0 mmol) in Methanol (3 mL) at

room temperature for 24 h, the precipitate was filtered and used for the next step

However, the major limitation of this investigation is by using anilines in Ugi-4CR that led to the formation of trace amount of desired product (14%). Therefor we decided to use benzylamine (3a), furfurylamine (3b) and 2-phenylethylamine (3c) instead. Scope of the acid moiety was examined by using 2-iodobenzoic acid (3a), 2-Bromobenzoic acid (3b) as well as 2-iodo-5-hydroxybenzoic acid19 (3c) and consequently Ugi adducts 5a-o were synthesized in 69-95% yields, which provided the 8-membered azocinoquinolines in the post-Ugi reductive cyclization in good yields (Table 3). Based on the outcome of this observation, we found out that desired product 6a was synthesized from ortho-iodo Ugi-adduct 5a and ortho-bromo Ugi-adduct 5n in 84% and 67% respectively. Even hydroxyl functional group was well tolerated and the desired product 6n was obtained in acceptable yield (76%).



Table 3. Synthesis of azocinoquinoline carboxamides (6a-n)a

aAll

reactions were performed using Ugi adducts 5a –m (1.0 mmol), sodium formate ( 1.5 mmol, 0.102 g), Pd(PPh3)4

(4 mol%, 0.07 g) in the mixture of DMF/water ( 4/1.3 ml) at 80 °C for 1 h.

The possible reaction mechanism for the reductive Heck cyclization20 reaction is shown in scheme 3. After the initial oxidative addition of palladium complex into the C-I bond of 5 and coordination to give complex 7 cis-carbopalladation of triple bond furnishes Econfigured complex (8). Then, after the coordination of formate to give formate complex 9, decarboxylation produces the hydride complex (10). Finally that product (6) is released by reductive elimination.


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Scheme 3. Proposed reaction mechanism for the synthesis of 6a

For

investigating

the

effect

of

quinoline

core

in

the

cyclization

step

2-

(phenylethynyl)benzaldehyde was used in Ugi-4CR and consequently cyclized product 12 obtained in 23% yield (Scheme 4). Replacing the quinoline core as an electronwithdrawing substituent at the alkyne’s terminal carbon, causes variation of alkyne polarization by changing the electronic contribution on the alkyne moiety. This phenomenon leads to the lower cyclization barrier and consequently higher yields.21



Scheme 4. Ugi-4CR/cyclo-Carbopalladation/hydride capture reaction of 2(phenylacetynyl)benzaldehyde

CONCLUSION In summary we have disclosed a concise diastereo- and regioselective cyclization approach to highly functionalized azocinoquinolines based upon a cyclizing reductive carbopalladation of Ugi-4CR substrates containing alkynyl quinolone and ortho-iodo benzoyl moieties. Medium-sized rings with fused quinolines are potentially bioactive against depression and anxiety disorders.22 Investigations on the biological properties of these novel highly functionalized azocinoquinolines are currently underway. EXPERIMENTAL SECTION General considerations: Reagents and solvents were purchased reagent grade and used without further purification. All reactions involving palladium catalysts were conducted in dried and degassed Schlenk tubes under argon atmosphere. Flash column chromatography was performed using silica gel (63-200 mesh). 1H and

13C

NMR spectra were recorded at

300 and 75 MHz. Chemical shifts are given in δ using TMS as internal standard and coupling constants (J) are given in Hertz. High resolution mass spectra were recorded on Mass-ESI-POS (FT-ICR) spectrometer. Melting points were measured using Electrothermal 9100 apparatus and are uncorrected. General procedure for the synthesis of Ugi-adducts (5a-o): To a solution of aldehyde 1 (1 mmol) in MeOH (3 mL), was added amine 3 (1.0 mmol) and the reaction mixture was stirred for 1h at room temperature. Then 2-Iodobenzoic acid (2) (1.0 mmol) and isocyanide 4 (1.0 mmol) were added and the mixture was stirred for 24h at room temperature. The progress of the reaction was monitored by TLC


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(n-hexane/EtOAc 3/1). After completion of the reaction the colorless precipitate 5 was filtered, washed with MeOH, and dried in vacuo. General procedure for the synthesis of compounds (6a-n): To a flame dried and argon flushed screw-cap Schlenk tube was added Ugi-adduct 5 (1.0 mmol), sodium formate (1.5 mmol), and Pd(PPh3)4 (4mol%, 0.04 mmol) and the vial was flushed three times with argon. Then DMF (4 mL) and distilled water (1.3 mL) were added and allowed to stir at 80 °C in oil bath until complete conversion (monitored by TLC, n-hexane/EtOAc 3/1, app. 1 h). After completion of the reaction, the vial was cooled and the reaction mixture was diluted with EtOAc (20 mL). The organic phase was washed with water (3 x 20 mL), dried (anhydrous MgSO 4) and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography using n-hexane/EtOAc (3/1) as an eluent. N-Benzyl-N-(2-(tert-butylamino)-2-oxo-1-(2-(phenylethynyl)quinolin-3-yl)ethyl)-2iodobenzamide (5a): Colorless powder; 0.644 g (95%); Mp 245-247 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 1.42 (s, 9H, t-Bu), 4.45 (d, J = 16.4 Hz, 1H, CH2-Ph), 4.63 (d, J = 15.6 Hz, 1H, CH2-Ph), 6.37 (s, 1H, C(sp3)-H), 6.86 – 7.02 (m, 6H, H-Ar), 7.08 – 7.44 (m, 6H, H-Ar), 7.45 – 7.53 (m, 1H, H-Ar), 7.53 – 7.66 (m, 2H, H-Ar), 7.65 – 7.88 (m, 3H, H-Ar), 8.08 (d, J = 8.4 Hz, 1H, H-Ar), 8.87 (brs, 1H, NH);

13C{1H}

NMR (CDCl3, 75 MHz)

δ (ppm) 28.7, 51.9, 52.4, 60.0, 92.7, 94.4, 121.4, 126.7, 127.2, 127.5, 127.8, 128.0, 128.1, 128.4, 128.6, 129.4, 130.3, 130.7, 132.7, 135.9, 138.3, 139.2, 139.2, 141.8, 144.3, 147.6, 167.2, 172.0. Anal. Calcd for C37H32IN3O2: C, 65.59; H, 4.76; N, 6.20. Found: C, 65,71; H, 4.80; N, 6.28. N-Benzyl-N-(2-(cyclohexylamino)-2-oxo-1-(2-(phenylethynyl)quinolin-3-yl)ethyl)-2iodobenzamide (5b): Colorless powder; 0.648 g (92%); Mp 219-220 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 1.09 – 1.43 (m, 5H, H-cyclohexyl), 1.50 – 1.77 (m, 3H, Hcyclohexyl), 1.84 – 2.14 (m, 2H, H-cyclohexyl), 3.73 – 4.01 (m, 1H H-cyclohexyl), 4.47 (d, J = 16.9 Hz, 1H, CH2-Ph), 4.63 (d, J = 16.9 Hz, 1H, CH2-Ph), 6.40 (s, 1H, C(sp3)-H), 6.43 – 6.55 (m, 1H, H-Ar), 6.88 – 7.05 (m, 6H, H-Ar), 7.13 – 7.20 (m, 1H, H-Ar), 7.28 – 7.36 (m, 3H, H-Ar), 7.39 – 7.55 (m, 3H, H-Ar), 7.63 – 7.85 (m, 3H, H-Ar), 8.08 (d, J = 8.5 Hz, 1H, H-Ar), 8.89 (brs, 1H, NH);

13C{1H}

NMR (CDCl3, 75 MHz) δ (ppm) 24.8,

24.9, 25.5, 32.7, 33.0, 49.1, 52.3, 59.6, 86.8, 92.7, 94.3, 121.4, 126.7, 127.1, 127.4,



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127.4, 127.8, 128.1, 128.3, 128.6, 129.4, 130.3, 130.7, 132.6, 135.9, 138.6, 139.1, 141.7, 144.3, 147.6, 166.9, 172.0. Anal. Calcd for C39H34IN3O2: C, 66.57; H, 4.87; N, 5.97. Found: C, 66.72; H, 4.95; N, 6.09. N-(2-(tert-Butylamino)-2-oxo-1-(2-(phenylethynyl)quinolin-3-yl)ethyl)-2-iodo-Nphenethylbenzamide (5c): Colorless powder; 0.602 g (87%); Mp 244-246 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 1.52 (s, 9H, t-Bu), 1.92 – 2.08 (m, 1H, CH2-Ph), 2.44 – 2.63 (m, 1H, CH2-Ph), 3.04 – 3.27 (m, 1H, CH2-Bn), 3.43 – 3.65 (m, 1H, CH2-Bn), 6.24 (d, J = 7.3 Hz, 2H, H-Ar), 6.64 (s, 1H, C(sp3)-H), 6.83 – 7.00 (m, 4H, H-Ar), 7.01 – 7.16 (m, 2H, H-Ar), 7.29 – 7.45 (m, 4H, H-Ar), 7.50 – 7.59 (m, 1H, H-Ar), 7.65 – 7.75 (m, 2H, H-Ar), 7.75 – 7.88 (m, 3H H-Ar), 8.22 (d, J = 8.5 Hz, 1H, H-Ar), 9.04 (brs, 1H, NH); 13C{1H}

NMR (CDCl3, 75 MHz) δ (ppm) 28.9, 36.2, 49.4, 52.1, 58.5, 86.8, 92.8, 94.3,

121.3, 126.2, 126.8, 127.6, 127.8, 128.1, 128.3, 128.4, 128.8, 129.0, 129.5, 129.7, 130.4, 131.0, 132.0, 132.9, 137.6, 138.1, 139.3, 142.3, 144.6, 147.7, 167.7, 171.7. Anal. Calcd for C38H34IN3O2: C, 65.99; H, 4.96; N, 6.08. Found: C, 66.17; H, 4.98; N, 6.15. N-(2-(tert-Butylamino)-2-oxo-1-(2-(phenylethynyl)quinolin-3-yl)ethyl)-N-(furan-3ylmethyl)-2-iodobenzamide (5d): colorless powder; 0.548 g (82%); Mp 237-238 °C; 1H{13C}

NMR (CDCl3, 300 MHz) δ (ppm) 1.45 (s, 9H, t-Bu), 4.27 (d, J = 16.5 Hz, 1H,

CH2-furyl), 4.61 (d, J = 16.6 Hz, 1H, CH2-furyl), 5.42 (brs, 1H, H-furyl), 5.87 (brs, 1H, Hfuryl), 6.48 (s, 1H, C(sp3)-H), 6.64 (brs, 1H, H-furyl,), 6.86 – 7.08 (m, 2H, H-Ar), 7.07 – 7.37 (m, 5H, H-Ar), 7.43 – 7.54 (m, 1H, H-Ar), 7.56 – 7.67 (m, 2H, H-Ar), 7.69 – 7.87 (m, 3H, H-Ar), 8.12 (d, J = 8.5 Hz, 1H, H-Ar), 8.73 (brs, 1H, NH);

13C{1H}

NMR (CDCl3,

75 MHz) δ (ppm) 28.8, 44.8, 51.9, 59.5, 86.9, 92.7, 93.9, 108.4, 110.2, 121.5, 126.7, 127.4, 127.9, 128.0, 128.1, 128.4, 128.6, 129.4, 129.6, 130.3, 130.7, 132.7, 138.0, 139.1, 141.6, 142.0, 144.4, 147.5, 149.4, 167.3, 171.6. Anal. Calcd for C35H30IN3O3: C, 62.97; H, 4.53; N, 6.29. Found: C, 63.18; H, 4.65; N, 6.38. N-(2-(Cyclohexylamino)-2-oxo-1-(2-(phenylethynyl)quinolin-3-yl)ethyl)-2-iodo-Nphenethylbenzamide (5e): Colorless powder; 0.653 g (91%); Mp 180-182 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) 1.12 – 1.24 (m, 1H, H-cyclohexyl), 1.36 – 1.48 (m, 3H, Hcyclohexyl), 1.55 – 1.83 (m, 3H, H-cyclohexyl), 1.95 – 2.25 (m, 3H, H-cyclohexyl), 2.35 – 2.74 (m, 1H, CH2-Ph), 2.78 – 2.89 (m, 1H, CH2-Ph), 3.06 – 3.28 (m, 1H, CH2-Bn), 3.37 – 3.68 (m, 1H, CH2-Bn), 3.86 – 4.17 (m, 1H, H-cyclohexyl), 6.18 (d, J = 7.2 Hz, 1H,


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H-Ar), 6.30 (d, J = 7.3 Hz, 1H, H-Ar), 6.68 (s, 1H, C(sp3)-H), 6.75 – 6.97 (m, 3H, H-Ar), 6.96 – 7.11 (m, 2H, H-Ar), 7.20 – 7.32 (m, 4H, H-Ar), 7.32 – 7.74 (m, 6H, H-Ar), 7.75 – 8.03 (m, 1H, H-Ar), 8.15 (d, J = 8.7 Hz, 1H, H-Ar), 8.80 (brs, 1H, NH);

13C{1H}

NMR

(CDCl3, 75 MHz) δ (ppm) 15.1, 25.0, 25.6, 28.8, 32.9, 33.2, 36.2, 49.2, 58.4, 86.7, 92.9, 93.9, 121.4, 125.4, 126.1, 127.0, 127.6, 128.0, 128.1, 128.2, 128.3, 129.3, 129.7, 130.2, 132.4, 132.7, 137.7, 139.2, 142.4, 143.6, 144.1, 146.6, 167.4, 171.5; Anal. Calcd for C40H36IN3O2: C, 66.95; H, 5.06; N, 5.86. Found: C, 67.12; H, 5.14; N, 5.98. N-Benzyl-N-(2-(tert-butylamino)-1-(5,7-dimethyl-2-(phenylethynyl) quinolin-3-yl)-2oxoethyl)-2-iodobenzamide (5f): Colorless powder; 0.621 g (88%); Mp 245-247 °C; 1H{13C}

NMR (CDCl3, 300 MHz) δ (ppm) 1.42 (s, 9H, t-Bu), 2.37 (s, 3H, CH3), 2.46 (s,

3H, CH3), 4.45 (d, J = 16.9 Hz, 1H, CH2-Ph), 4.61 (d, J = 14.5 Hz, 1H, CH2-Ph), 6.33 (s, 1H, C(sp3)-H), 6.58 – 6.36 (m, 1H, H-Ar),6.74 – 7.03 (m, 6H, H-Ar), 7.21 – 7.37 (m, 4H, H-Ar), 7.43 – 7.67 (m, 4H, H-Ar), 7.70 – 7.97 (m, 2H, H-Ar), 8.73 (brs, 1H, NH);

13C{1H}

NMR (CDCl3, 75 MHz) δ (ppm) 20.1, 20.6, 28.7, 51.9, 52.4, 60.2, 87.1, 92.7, 93.8, 121.6, 125.5, 127.0, 127.2, 127.5, 127.9, 128.0, 128.2, 128.8, 129.2, 130.2, 132.6, 136.1, 137.1, 137.7, 139.2, 141.2, 142.0, 143.3, 146.8, 167.4, 172.0. Anal. Calcd for C39H36IN3O2: C, 66.38; H, 5.14; N, 5.96. Found: C, 66.61; H, 5.23; N, 6.11. N-benzyl-N-(2-(tert-butylamino)-1-(6,7-dimethyl-2-((4-pentylphenyl)ethynyl) quinolin-3-yl)-2-oxoethyl)-2-iodobenzamide (5g): Colorless powder; 0.566 g (73%); Mp 187-190 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 0.83 – 0.98 (m, 4H, H-npentyl), 1.29 – 1.34 (m, 3H, H-n-pentyl), 1.37 (s, 9H, t-Bu), 1.55 – 1.66 (m, 2H, H-npentyl), 2.42 (s, 3H, CH3), 2.46 (s, 3H, CH3), 2.60 (t, J = 7.8, 7.8 Hz, 2H, H-n-pentyl), 4.42 (d, J = 16.6 Hz, 1H, CH2-Ph), 4.59 (d, J = 14.1 Hz, 1H, CH2-Ph), 6.30 (s, 1H, C(sp3)-H), 6.85 – 7.06 (m, 6H, H-Ar), 7.08 – 7.23 (m, 4H, H-Ar), 7.30 – 7.66 (m, 3H, HAr), 7.74 – 7.87 (m, 2H, H-Ar), 8.75 (brs, 1H, NH);

13C{1H}

NMR (CDCl3, 75 MHz) δ

(ppm) 14.0, 20.1, 20.6, 22.5, 28.7, 30.8, 31.4, 36.0, 51.8, 52.5, 60.4, 92.7, 94.4, 118.8, 125.4, 127.2, 127.3, 127.5, 128.0, 128.1, 130.2, 132.5, 136.0, 137.1, 137.6, 139.1, 141.2, 143.4, 144.6, 146.9, 167.3, 172.0. Anal. Calcd for C44H46IN3O2: C, 68.12; H, 5.98; N, 5.42. Found: C, 68.34; H, 6.10; N, 5.51. N-(2-(cyclohexylamino)-2-oxo-1-(2-(phenylethynyl)quinolin-3-yl)ethyl)-N-(furan-2ylmethyl)-2-iodobenzamide (5h): Colorless powder; 0.527 g (76%); Mp 212-215 °C;



1H{13C}

Page 14 of 27

NMR (CDCl3, 300 MHz) δ (ppm) 1.00 – 1.45 (m, 5H, H-cyclohexyl), 1.45 – 1.82

(m, 3H, H-cyclohexyl), 1.84 – 2.23 (m, 3H, H-cyclohexyl), 3.75 – 4.02 (m, 1H, Hcyclohexyl), 4.25 (d, J = 16.7 Hz, 1H, CH2- furyl), 4.64 (d, J = 16.7 Hz, 1H, CH2- furyl), 5.41 (brs, 1H, H-furyl), 5.86 (brs, 1H, H-furyl), 6.58 (s, 1H, C(sp3)-H), 6.84 (d, J = 8.0 Hz, 1H, H-Ar), 6.91 – 7.07 (m, 2H, H-Ar), 7.05 – 7.20 (m, 2H, H-Ar), 7.22 – 7.35 (m, 3H, H-Ar), 7.42 – 7.52 (m, 1H, H-Ar), 7.55 – 7.64 (m, 2H, H-Ar), 7.66 – 7.84 (m, 3H, H-Ar), 8.11 (d, J = 8.6 Hz, 1H, H-Ar), 8.70 (brs, 1H, NH);

13C{1H}


24.8, 24.9, 25.5, 32.8, 33.1, 44.7, 49.0, 59.1, 86.9, 92.7, 93.8, 108.3, 110.1, 121.5, 126.7, 127.4, 128.0, 128.3, 128.6, 129.3, 130.3, 130.7, 132.7, 138.2, 139.0, 141.5, 141.9, 144.3, 147.5, 149.3, 167.0, 171.5. Anal. Calcd for C37H32IN3O3: C, 64.07; H, 4.65; N, 6.06. Found: C, 64.19; H, 4.65; N, 6.10. N-Benzyl-N-(2-(tert-butylamino)-1-(6-methyl-2-(phenylethynyl)quinolin-3-yl)-2oxoethyl)-2-iodobenzamide (5i): Colorless powder; 0.581 mg (84%); Mp 238-240 °C; 1H{13C}

NMR (CDCl3, 300 MHz) δ 1.46 (s, 9H, t-Bu), 2.42 (s, 3H, CH3), 4.46 (d, J = 16.9

Hz, 1H, CH2-Ph), 4.65 (d, J = 17.7 Hz, 1H, CH2-Ph), 6.34 (s, 1H, C(sp3)-H), 6.68 – 7.14 (m, 8H, H-Ar), 7.17 – 7.38 (m, 4H, H-Ar), 7.37 – 7.61 (m, 4H, H-Ar), 7.77 (d, J = 7.8 Hz, 1H, H-Ar), 7.98 (d, J = 8.6 Hz, 1H, H-Ar), 8.68 (brs, 1H, NH);

13C{1H}

NMR (CDCl3, 75

MHz) δ (ppm) 21.7, 28.8, 51.9, 59.7, 86.8, 92.7, 94.0, 121.4, 126.9, 127.3, 127.9, 128.1, 128.2, 129.2, 129.7, 130.1, 132.5, 133.1, 136.2, 137.5, 139.2, 142.0, 143.5, 146.2, 167.5, 172.0. Anal. Calcd for C38H34IN3O2: C, 65.99; H, 4.96; N, 6.08. Found: C, 66.16; H, 5.04; N, 6.18. N-(2-(tert-Butylamino)-1-(2-(cyclopropylethynyl)quinolin-3-yl)-2-oxoethyl)-2-iodoN-phenethylbenzamide (5j): Colorless powder; 0.453 g (69%); Mp 215-216 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 0.86 – 0.97 (m, 2H, H-cyclopropyl), 1.05 (dt, J = 5.3, 2.7, 2.7 Hz, 2H, H-cyclopropyl), 1.46 (s, 9H, t-Bu), 1.54 – 1.64 (m, 1H, H-cyclopropyl), 1.96 – 2.17 (m, 1H, CH2-Ph), 2.49 – 2.78 (m, 1H, CH2-Ph), 2.96 – 3.26 (m, 1H, CH2Bn), 3.31 – 3.63 (m, 1H, CH2-Bn), 6.37 (s, 1H, C(sp3)-H), 6.53 (d, J = 2.9 Hz, 2H, H-Ar), 6.86 – 7.04 (m, 3H, H-Ar), 7.07 – 7.21 (m, 1H, H-Ar), 7.35 – 7.48 (m, 2H, H-Ar), 7.52 – 7.63 (m, 1H, H-Ar), 7.66 – 7.94 (m, 3H, H-Ar), 8.01 – 8.14 (m, 1H, H-Ar), 9.09 (brs, 1H, NH);

13C{1H}

NMR (CDCl3, 75 MHz) δ (ppm) 0.6, 9.1, 28.8, 36.1, 49.4, 51.9, 58.2, 92.9,

100.1, 126.3, 126.4, 127.3, 127.7, 128.1, 128.3, 128.7, 129.6, 130.5, 130.6, 137.6,


Page 15 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


137.9, 139.4, 142.1, 144.9, 147.5, 167.7, 171.7. Anal. Calcd for C35H34IN3O2: C, 64.12; H, 5.23; N, 6.41. Found: C, 64.24; H, 5.27; N, 6.53. N-Benzyl-N-(2-(cyclohexylamino)-1-(6-ethyl-2-(phenylethynyl)quinolin-3-yl)-2oxoethyl)-2-iodobenzamide (5k): Colorless powder; 0.651 g (89%); Mp 231-233 °C; 1H{13C}

NMR (CDCl3, 300 MHz) δ (ppm) 1.06 – 1.47 (m, 9H, H-cyclohexyl, CH3), 1.52 –

1.78 (m, 3H, H-cyclohexyl), 1.97 – 2.06 (m, 1H, H-cyclohexyl), 2.75 (q, J = 8.0, 7.8, 7.8 Hz, 2H, CH2), 3.82 – 4.02 (m, 1H, H-cyclohexyl), 4.47 (d, J = 17.4 Hz, 1H, CH2-Ph), 4.64 (d, J = 17.0 Hz, 1H, CH2-Ph), 6.40 (s, 1H, C(sp3)-H), 6.68 (s, 1H, H-Ar), 6.91 (s, 6H, H-Ar), 7.12 (s, 1H, H-Ar), 7.19 – 7.34 (m, 4H, H-Ar, H-Ar), 7.36 – 7.49 (m, 3H, HAr), 7.58 (d, J = 8.9 Hz, 1H, H-Ar), 7.77 (d, J = 8.1 Hz, 1H, H-Ar), 8.01 (d, J = 8.7 Hz, 1H, H-Ar), 8.78 (brs, 1H, NH).

13C{1H}

NMR (CDCl3, 75 MHz) δ (ppm) 15.0, 24.9, 25.6,

28.8, 32.7, 33.0, 49.1, 52.1, 59.6, 86.9, 92.7, 94.0, 121.5, 125.5, 127.0, 127.3, 128.0, 128.2, 129.2, 129.4, 130.2, 132.1, 132.5, 136.1, 138.1, 139.1, 141.9, 143.4, 143.7, 146.4, 167.1, 172.0. Anal; Calcd for C41H38IN3O2: C, 67.30; H, 5.24; N, 5.74. Found: C, 67.50; H, 5.32; N, 5.83. N-benzyl-2-bromo-N-(2-(tert-butylamino)-2-oxo-1-(2-(phenylethynyl)quinolin-3yl)ethyl)benzamide (5n): Colorless powder; 0.524 g (83%); Mp 250-251 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 1.41 (s, 9H, t-Bu), 4.45 (d, J = 16.8 Hz, 1H, CH2-Ph), 4.62 (d, J = 15.5 Hz, 1H, CH2-Ph), 6.44 (s, 1H, C(sp3)-H), 6.78 – 6.97 (m, 5H, H-Ar), 7.03 – 7.24 (m, 3H, H-Ar), 7.29 – 7.42 (m, 4H, H-Ar), 7.44 – 7.52 (m, 1H, H-Ar), 7.55 – 7.64 (m, 3H, H-Ar), 7.65 – 7.77 (m, 2H, H-Ar), 8.07 (d, J = 8.5 Hz, 1H, H-Ar), 8.78 (brs, 1H, NH);

13C{1H}

NMR (CDCl3, 75 MHz) δ (ppm) 27.8, 28.7, 51.9, 59.7, 86.9, 94.4,

119.4, 121.4, 126.7, 127.1, 127.3, 127.4, 128.0, 128.4, 128.6, 129.4, 130.4, 130.7, 132.7, 136.0, 137.8, 138.2, 144.3, 147.5, 167.3, 170.7. ESI-MS (m/z): [M+H]+ Calcd for C37H33BrN3O2 632.2; Found 632.3. Anal. Calcd for C37H32BrN3O2: C, 70.48; H, 5.12; N, 6.66. Found: C, 70.34; H, 5.04; N, 6.95. N-benzyl-N-(2-(tert-butylamino)-1-(5,7-dimethyl-2-(phenylethynyl)quinolin-3-yl)-2oxoethyl)-5-hydroxy-2-iodobenzamide (5o): Colorless powder; 0.563 g (78%); Mp 174-176 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 1.46 (s, 9H, t-Bu), 2.24 (s, 3H, CH3), 2.45 (s, 3H, CH3), 4.48 (d, J = 16.6 Hz, 1H, CH2-Bn), 4.70 (d, J = 17.2 Hz, 1H, CH2-Bn), 6.37 (s, 1H, C(sp3)-H), 6.70 – 6.84 (m, 4H, H-Ar), 7.19 – 7.34 (m, 8H, H-Ar),



7.34 – 7.47 (m, 4H, H-Ar), 7.80 (brs, 1H, OH), 8.28 (brs, 1H, NH);

Page 16 of 27

13C{1H}

NMR (CDCl3,

75 MHz) δ (ppm) 0.6, 9.1, 28.8, 36.1, 49.4, 51.9, 58.2, 92.9, 100.1, 126.3, 126.4, 127.3, 127.7, 128.1, 128.3, 128.7, 129.6, 130.5, 130.6, 137.6, 137.9, 139.4, 142.1, 144.9, 147.5, 167.7, 171.7. ESI-MS (m/z): [M+H]+ Calcd for C39H37IN3O3 722.2; Found 722.3. Anal. Calcd for C39H36IN3O3: C, 64.91; H, 5.03; N, 5.82. Found: C, 64.60; H, 4.95; N, 6.10. (Z)-6-Benzyl-14-benzylidene-N-(tert-butyl)-5-oxo-5,6,7,14-tetrahydrobenzo[6,7] azocino[4,3-b]quinoline-7-carboxamide (6a): Colorless powder; 0.464 g (84%); Mp 225-227 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 0.85 (s, 9H, t-Bu), 4.02 (d, J = 14.7 Hz, 1H, CH2-Ph), 4.45 (brs, 1H, NH), 5.12 (s, 1H, C(sp3)-H), 5.44 (d, J = 14.7 Hz, 1H, CH2-Ph), 6.71 (s, 1H, =CH), 6.95 - 7.03 (m, 2H, H-Ar), 7.05 - 7.13 (m, 3H, H-Ar), 7.31 - 7.43 (m, 6H, H-Ar), 7.52 - 7.61 (m, 3H, H-Ar), 7.66 - 7.85 (m, 4H, H-Ar), 8.00 (d, J = 8.6 Hz, 1H, H-Ar);

13C{1H}

NMR (CDCl3, 75 MHz) δ (ppm) 28.4, 51.6, 51.9, 66.8,

126.6, 127.1, 127.2, 127.4, 127.5, 127.8, 127.9, 128.0, 128.6, 128.9, 129.0, 129.1, 129.3, 129.4, 129.6, 130.5, 130.5, 134.9, 135.4, 136.4, 136.8, 138.5, 138.5, 138.6, 139.5, 147.7, 154.7, 165.7, 172.2. HR-MS (ESI-POS) m/z: [M+Na]+ Calcd for C37H33N3O2Na 574.2470; Found 574.2473. IR  (cm-1) 3394, 2951, 1699, 1642. Recrystallization of compound (6a) was done in CHCl3/MeOH: white crystal (brick), dimensions 0.199 x 0.198 x 0.146 mm 3, crystal system monoclinic, space group P21/n, Z=4,

a=9.6064(10)

Å,

b=14.2833(14)

Å,

c=28.396(3)

Å,

alpha=90

deg,

beta=95.5588(19) deg, gamma=90 deg, V=3878.0(7) Å 3, rho=1.354 g/cm3, T=200(2) K, Thetamax= 25.027 deg, radiation MoKα, lambda=0.71073 Å, 0.5 deg omega-scans with CCD area detector, covering the asymmetric unit in reciprocal space with a mean redundancy of 3.38 and a completeness of 100.0% to a resolution of 0.84 Å, 23721 reflections measured, 6865 unique (R(int)=0.0674), 4011 observed (I > 2σ(I)), intensities were corrected for Lorentz and polarization effects, an empirical scaling and absorption correction was applied using SADABS23 based on the Laue symmetry of the reciprocal space, mu=0.48mm-1, Tmin=0.88, Tmax=0.94, structure solved with SHELXT2014 (Sheldrick 2014) and refined against F2 with a Full-matrix least-squares algorithm using the SHELXL-2018/3 (Sheldrick, 2018) software,23 458 parameters refined, hydrogen atoms were treated using appropriate riding models, goodness of fit 1.01 for


Page 17 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


observed reflections, final residual values R1(F)=0.051, wR(F2)=0.099 for observed reflections, residual electron density -0.37 to 0.33 eÅ-3. CCDC 1909179 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge

from

The

Cambridge

Crystallographic

Data

Centre

via

https://www.ccdc.cam.ac.uk/structures. (Z)-6-Benzyl-14-benzylidene-N-cyclohexyl-5-oxo-5,6,7,14tetrahydrobenzo[6,7]azocino[4,3-b]quinoline-7-carboxamide

(6b):

Pale

yellow

powder; 0.457 g (79%); Mp 255-256 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 0.19 – 0.44 (m, 1H, H-cyclohexyl), 0.56 – 0.78 (m, 1H, H-cyclohexyl), 0.78 – 0.99 (m, 1H, Hcyclohexyl), 0.99 – 1.22 (m, 3H, H-cyclohexyl), 1.20 – 1.51 (m, 3H, H-cyclohexyl), 1.51 – 1.71 (m, 1H, H-cyclohexyl), 2.95 – 3.17 (m, 1H, H-cyclohexyl), 4.04 (d, J = 14.9 Hz, 1H, CH2-Ph), 4.33 (d, J = 7.4 Hz, 1H, NH), 5.13 (s, 1H, C(sp3)-H), 5.42 (d, J = 14.9 Hz, 1H, CH2-Ph), 6.72 (s, 1H, =CH), 6.94 – 7.01 (m, 2H, H-Ar), 7.02 – 7.14 (m, 3H, H-Ar), 7.22 – 7.42 (m, 6H, H-Ar), 7.48 – 7.61 (m, 3H, H-Ar), 7.61 – 7.84 (m, 4H, H-Ar), 7.99 (d, J = 8.4 Hz, 1H, H-Ar);

13C{1H}

NMR (75 MHz, CDCl3) δ 24.3, 24.4, 25.1, 32.3, 32.4,

48.8, 51.5, 66.2, 126.6, 127.0, 127.2, 127.5, 127.6, 127.9, 127.9, 128.3, 128.8, 129.0, 129.3, 129.4, 129.6, 130.5, 130.6, 134.9, 135.3, 136.4, 136.6, 138.3, 138.7, 139.5, 147.8, 154.9, 166.1, 172.2. HR-MS (ESI-POS) m/z: [M+Na]+ Calcd for C39H35N3O2Na 600.2626; Found 600.2628. IR  (cm-1) 3427, 2923, 1678, 1648. (Z)-14-Benzylidene-N-(tert-butyl)-5-oxo-6-phenethyl-5,6,7,14tetrahydrobenzo[6,7]azocino[4,3-b]quinoline-7-carboxamide (6c): White powder; 0.492 g (87%); Mp 247-250 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 0.89 (s, 9H, tBu), 2.89 – 3.07 (m, 1H, CH2-Ph), 3.10 – 3.30 (m, 1H, CH2-Ph), 3.35 – 3.57 (m, 1H, CH2-Bn), 3.98 – 4.23 (m, 1H, CH2-Bn), 4.42 (brs, 1H, NH), 5.19 (s, 1H, C(sp3)-H), 6.67 (s, 1H, =CH), 6.91 (d, J = 6.4 Hz, 2H, H-Ar), 6.99 – 7.06 (m, 3H, H-Ar), 7.18 – 7.26 (m, 5H, H-Ar), 7.33 – 7.45 (m, 3H, H-Ar), 7.57 - 7.74 (m, 3H, H-Ar), 7.84 (dd, J = 8.2, 1.4 Hz, 1H, H-Ar), 7.94 (s, 1H, H-Ar), 8.00 (d, J = 8.4 Hz, 1H, H-Ar);

13C{1H}

NMR (CDCl3,

75 MHz) δ (ppm) 28.6, 34.0, 51.5, 51.6, 69.4, 126.3, 126.5, 127.2, 127.4, 127.5, 127.6, 127.9, 128.4, 128.8, 128.9, 129.5, 130.2, 130.7, 134.8, 135.3, 137.1, 138.3, 139.0, 139.3, 147.8, 155.0, 166.0, 171.8. HR-MS (ESI-POS) m/z: [M+Na]+ Calcd for C38H35N3O2Na 588.2626; Found 588.2637. IR  (cm-1) 3419, 2970, 1677, 1635.



Page 18 of 27

(Z)-14-Benzylidene-N-(tert-butyl)-6-(furan-3-ylmethyl)-5-oxo-5,6,7,14tetrahydrobenzo[6,7]azocino[4,3-b]quinoline-7-carboxamide

(6d):

Colorless

powder; 0.396 g (73%); Mp 178-180 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 0.93 (s, 9H, t-Bu), 4.41 (d, J = 15.3 Hz, 1H, CH2-furyl), 4.78 (brs, 1H, NH), 5.11 (d, J = 14.9 Hz, 1H, CH2-furyl), 5.33 (s, 1H, C(sp3)-H), 6.31 (dd, J = 3.3, 1.9 Hz, 1H, H-furyl), 6.44 (d, J = 3.2 Hz, 1H, H-furyl), 6.65 (s, 1H, =CH), 6.83 – 6.94 (m, 2H, H-Ar), 7.00 – 7.09 (m, 3H, H-Ar), 7.26 (s, 1H, H-Ar), 7.33 – 7.40 (m, 3H, H-Ar), 7.55 (ddd, J = 8.0, 6.7, 1.2 Hz, 1H, H-Ar), 7.60 – 7.70 (m, 2H, H-Ar), 7.74 – 7.82 (m, 1H, H-Ar), 7.87 (s, 1H, H-Ar), 7.96 (d, J = 8.5 Hz, 1H, H-Ar);

13C{1H}

NMR (CDCl3, 75 MHz) δ (ppm) 15.2, 28.5, 45.0,

51.6, 67.3, 84.8, 110.3, 111.0, 126.5, 126.9, 127.2, 127.3, 127.4, 127.8, 128.6, 129.2, 129.3, 129.5, 130.4, 130.7, 134.7, 135.3, 135.8, 138.3, 138.6, 139.6, 142.5, 147.6, 150.3, 154.5, 165.9, 171.9. HR-MS (ESI-POS) m/z: [M+Na]+ Calcd for C35H31N3O3Na 564.2262; Found 564.2262. IR  (cm-1) 3423, 2927, 1678, 1637. (Z)-14-Benzylidene-N-cyclohexyl-6-(furan-3-ylmethyl)-5-oxo-5,6,7,14tetrahydrobenzo[6,7]azocino[4,3-b]quinoline-7-carboxamide

(6e):

Colorless

powder; 0.391 g (69%); Mp 233-236 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 0.40 – 0.60 (m, 1H, H-cyclohexyl), 0.73 – 0.87 (m, 1H, H-cyclohexyl), 0.90 – 1.03 (m, 1H, Hcyclohexyl), 1.08 – 1.29 (m, 3H, H-cyclohexyl), 1.39 – 1.57 (m, 3H, H-cyclohexyl), 1.64 – 1.76 (m, 1H, H-cyclohexyl), 3.02 – 3.20 (m, 1H, H-cyclohexyl), 4.49 (d, J = 15.4 Hz, 1H, CH2-furyl), 4.66 (d, J = 7.4 Hz, 1H, NH), 5.10 (d, J = 15.4 Hz, 1H, CH2-furyl), 5.36 (s, 1H, C(sp3)-H), 6.31 (dd, J = 3.2, 1.9 Hz, 1H, H-furyl), 6.46 (d, J = 3.2 Hz, 1H, Hfuryl), 6.70 (s, 1H, =CH), 6.90 – 6.96 (m, 2H, H-Ar), 7.01 – 7.11 (m, 3H, H-Ar), 7.25 (d, J = 1.8 Hz, 1H, H-Ar), 7.32 – 7.42 (m, 3H, H-Ar), 7.54 – 7.63 (m, 2H, H-Ar), 7.68 – 7.76 (m, 1H, H-Ar), 7.76 – 7.82 (m, 1H, H-Ar), 7.87 (s, 1H, H-Ar), 7.98 (d, J = 8.4 Hz, 1H, HAr);

13C{1H}

NMR (CDCl3, 75 MHz) δ (ppm) 24.4, 24.5, 25.2, 32.5, 32.5, 44.8, 48.9,

66.7, 110.2, 110.9, 126.6, 127.0, 127.2, 127.4, 127.5, 127.7, 127.8, 128.3, 129.1, 129.4, 129.6, 130.5, 130.7, 134.8, 135.3, 136.1, 138.2, 138.7, 139.4, 142.5, 147.7, 150.1, 154.9, 166.3, 171.9. HR-MS (ESI-POS) m/z: [M+Na]+ Calcd for C37H33N3O3Na 590.2419; Found 590.2424. IR  (cm-1) 3427, 2929, 1670, 1637. (Z)-14-Benzylidene-N-cyclohexyl-5-oxo-6-phenethyl-5,6,7,14tetrahydrobenzo[6,7]azocino[4,3-b]quinoline-7-carboxamide (6f): Colorless powder;


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0.527 g (89%); Mp 224-225 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 0.11 – 0.55 (m, 1H, H-cyclohexyl), 0.59 – 0.84 (m, 1H, H-cyclohexyl), 0.84 – 1.00 (m, 1H, H-cyclohexyl), 1.00 – 1.25 (m, 3H, H-cyclohexyl), 1.30 – 1.60 (m, 3H, H-cyclohexyl), 1.66 – 1.76 (m, 1H, H-cyclohexyl), 2.80 – 3.05 (m, 1H, H-cyclohexyl), 3.06 – 3.31 (m, 2H, CH2-Ph), 3.30 – 3.61 (m, 1H, CH2-Bn), 3.92 – 4.27 (m, 1H, CH2-Bn), 4.35 (d, J = 7.4 Hz, 1H, NH), 5.23 (s, 1H, C(sp3)-H), 6.71 (s, 1H, =CH), 6.92 (d, J = 8.1 Hz, 2H, H-Ar), 6.98 – 7.08 (m, 3H, H-Ar), 7.15 – 7.28 (m, 5H, H-Ar), 7.29 – 7.48 (m, 3H, H-Ar), 7.57 – 7.67 (m, 2H, H-Ar), 7.68 – 7.78 (m, 1H, H-Ar), 7.84 (d, J = 8.3 Hz, 1H, H-Ar), 7.86 – 8.07 (m, 2H, H-Ar); 13C{1H}

NMR (CDCl3, 75 MHz) δ (ppm) 24.5, 24.5, 25.2, 32.4, 32.5, 33.9, 49.0, 51.3,

68.8, 126.3, 126.5, 127.2, 127.3, 127.4, 127.5, 127.7, 127.9, 128.2, 128.3, 128.4, 128.5, 128.8, 129.3, 129.5, 130.4, 130.8, 134.7, 135.2, 137.0, 138.2, 138.5, 138.9, 139.4, 147.8, 155.3, 166.5, 171.8. HR-MS (ESI-POS) m/z: [M+Na]+ Calcd for C40H37N3O2Na 614.2783; Found 614.2786. IR  (cm-1) 3417, 2929, 1674, 1637. (Z)-6-Benzyl-14-benzylidene-N-cyclohexyl-10-ethyl-5-oxo-5,6,7,14tetrahydrobenzo[6,7]azocino[4,3-b]quinoline-7-carboxamide

(6g):

Colorless

powder; 0.533 g (88%); Mp 106-108 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 0.23 – 0.41 (m, 1H, H-cyclohexyl), 0.57 – 0.76 (m, 1H, H-cyclohexyl), 0.89 – 1.26 (m, 4H, Hcyclohexyl), 1.33 (t, J = 7.6 Hz, 3H, CH2CH3), 1.35 – 1.55 (m, 2H, H-cyclohexyl), 1.55 – 1.64 (m, 1H, H-cyclohexyl), 2.83 (q, J = 7.6 Hz, 2H, CH2CH3), 2.97 – 3.14 (m, 1H, Hcyclohexyl), 4.05 (d, J = 9.6 Hz, 1H, CH2-Ph), 4.35 (d, J = 7.5 Hz, 1H, NH), 5.25 (s, 1H, C(sp3)-H), 5.40 (d, J = 14.9 Hz, 1H, CH2-Ph), 6.70 (s, 1H, =CH), 6.90 – 7.01 (m, 2H, HAr), 7.02 – 7.15 (m, 3H, H-Ar), 7.21 – 7.42 (m, 6H, H-Ar), 7.50 – 7.68 (m, 5H, H-Ar), 7.76 (s, 1H, H-Ar), 7.92 (d, J = 8.6 Hz, 1H, H-Ar);

13C{1H}


(ppm) 15.2, 21.0, 24.4, 24.5, 25.1, 28.9, 32.4, 32.4, 48.8, 51.5, 53.5, 60.3, 66.3, 124.7, 126.7, 126.9, 127.5, 127.6, 127.8, 127.9, 128.3, 128.8, 128.9, 129.2, 129.3, 129.6, 130.4, 132.0, 134.7, 135.4, 136.4, 136.7, 138.4, 138.8, 139.0, 143.9, 146.6, 154.0, 166.2, 172.2. HR-MS (ESI-POS) m/z: [M+Na]+ Calcd for C41H39N3O2Na 628.2939; Found 628.2952. IR  (cm-1) 3424, 2927, 1661, 1674. (Z)-14-Benzylidene-N-cyclohexyl-10-ethyl-5-oxo-6-phenethyl-5,6,7,14tetrahydrobenzo[6,7]azocino[4,3-b]quinoline-7-carboxamide

(6h):

Colorless

powder; 0.471 g (76%); Mp 96-98 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 0.24 –



Page 20 of 27

0.45 (m, 1H, H-cyclohexyl), 0.63 – 0.82 (m, 1H, H-cyclohexyl), 0.81 – 0.96 (m, 1H, Hcyclohexyl), 0.97 – 1.29 (m, 3H, H-cyclohexyl), 1.35 (t, J = 7.6 Hz, 3H, CH2CH3), 1.38 – 1.63 (m, 3H, H-cyclohexyl), 1.64 – 1.79 (m, 1H, H-cyclohexyl), 2.86 – 2.87 (m, 2H, CH2CH3), 2.91 – 3.05 (m, 1H, H-cyclohexyl), 3.06 – 3.29 (m, 2H, CH2-Ph), 3.32 – 3.52 (m, 1H, CH2-Bn), 3.96 – 4.16 (m, 1H, CH2-Bn), 4.38 (d, J = 7.4 Hz, 1H, NH), 5.22 (s, 1H, C(sp3)-H), 6.67 (s, 1H, =CH), 6.87 – 6.94 (m, 2H, H-Ar), 6.97 – 7.05 (m, 3H, H-Ar), 7.13 – 7.26 (m, 5H, H-Ar), 7.27 – 7.41 (m, 3H, H-Ar), 7.55 – 7.65 (m, 3H, H-Ar), 7.89 (s, 1H, H-Ar), 7.97 (s, 1H, H-Ar);

13C{1H}

NMR (CDCl3, 75 MHz) δ (ppm) 15.3, 24.5, 25.2,

28.9, 31.4, 32.4, 32.5, 33.9, 36.5, 49.0, 51.3, 68.8, 124.7, 126.3, 126.6, 127.3, 127.4, 127.9, 128.3, 128.5, 128.7, 129.2, 129.3, 129.5, 130.3, 132.2, 134.5, 135.3, 137.0, 138.3, 138.6, 138.9, 139.0, 144.0, 146.7, 154.3, 162.5, 166.6, 171.8. HR-MS (ESI-POS) m/z: [M+Na]+ Calcd for C42H41N3O2Na 642.3096; Found 642.3097. IR  (cm-1) 3282, 2928, 1672. (Z)-6-Benzyl-14-benzylidene-N-(tert-butyl)-10-ethyl-5-oxo-5,6,7,14tetrahydrobenzo[6,7]azocino[4,3-b]quinoline-7-carboxamide

(6i):

Pale

yellow

powder; 0.429 g (74%); Mp 127-130 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 0.84 (s, 9H, t-Bu), 1.34 (t, J = 7.6 Hz, 3H, CH2CH3), 2.84 (q, J = 7.5, 6.6 Hz, 2H, CH2CH3), 4.02 (d, J = 14.9 Hz, 1H, CH2-Ph), 4.45 (brs, 1H, NH), 5.10 (s, 1H, C(sp3)-H), 5.43 (d, J = 14.7 Hz, 1H, CH2-Ph), 6.69 (s, 1H, =CH), 6.93 – 7.00 (m, 2H, H-Ar), 7.06 – 7.12 (m, 3H, H-Ar), 7.30 – 7.41 (m, 6H, H-Ar), 7.53 – 7.61 (m, 4H, H-Ar), 7.64 – 7.71 (m, 1H, HAr), 7.79 (s, 1H, H-Ar), 7.92 (d, J = 8.6 Hz, 1H, H-Ar);

13C{1H}


(ppm) 15.2, 28.5, 28.9, 51.5, 51.8, 66.9, 124.6, 126.7, 126.9, 127.5, 127.7, 127.9, 128.2, 128.5, 128.6, 129.0, 129.0, 129.1, 129.4, 129.4, 129.6, 130.5, 131.9, 134.7, 135.4, 136.5, 136.7, 138.5, 138.7, 139.1, 143.7, 146.6, 153.7, 165.8, 172.3. HR-MS (ESI-POS) m/z: [M+Na]+ Calcd for C39H37N3O2Na 602.2783; Found 602.2781. IR  (cm1)

3427, 2966, 1690, 1647.

Tert-butyl(Z)-6-Benzyl-14-benzylidene-9,11-dimethyl-5-oxo-5,6,7,14tetrahydrobenzo[6,7]azocino[4,3-b]quinoline-7-carboxylate (6j): Colorless powder; 0.441 g (76%); Mp 150-152 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 0.80 (s, 9H, tBu), 2.44 (s, 6H, 2CH3), 4.11 (d, J = 14.4 Hz, 1H, CH2-Ph), 4.40 (brs, 1H, NH), 5.08 (s, 1H, C(sp3)-H), 5.33 (d, J = 14.9 Hz, 1H, CH2-Ph), 6.66 (s, 1H, =CH), 6.92 – 6.97 (m, 2H,


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H-Ar), 7.09 (d, J = 7.0 Hz, 3H, H-Ar), 7.26 – 7.36 (m, 4H, H-Ar), 7.36 – 7.41 (m, 3H, HAr), 7.51 – 7.53 (m, 2H, H-Ar), 7.62 – 7.68 (m, 1H, H-Ar), 7.72 (s, 1H, H-Ar), 7.78 (s, 1H, H-Ar);

13C{1H}

NMR (CDCl3, 75 MHz) δ (ppm) 28.4, 29.7, 51.5, 51.8, 66.8, 126.6,

127.1, 127.2, 127.4, 127.5, 127.8, 127.9, 128.0, 128.6, 129.0, 129.3, 129.6, 130.5, 130.5, 134.9, 135.3, 136.4, 136.7, 138.4, 139.5, 147.7, 154.6, 165.6, 172.2. HR-MS (ESI-POS) m/z: [M+Na]+ Calcd for C39H37N3O2Na 602.2783; Found 602.2786. IR  (cm1)

2967, 1692, 1650.

(Z)-6-Benzyl-14-benzylidene-N-(tert-butyl)-10-methyl-5-oxo-5,6,7,14tetrahydrobenzo[6,7]azocino[4,3-b]quinoline-7-carboxamide

(6k):

Pale

yellow

powder; 0.458 g (81%); Mp 200-201 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 0.84 (s, 9H, t-Bu), 2.55 (s, 3H, CH3), 4.07 (d, J = 14.8 Hz, 1H, CH2-Ph), 4.42 (brs, 1H, NH), 5.10 (s, 1H, C(sp3)-H), 5.39 (d, J = 14.8 Hz, 1H, CH2-Ph), 6.69 (s, 1H, =CH), 6.89 – 7.02 (m, 2H, H-Ar), 7.04 – 7.15 (m, 3H, H-Ar), 7.23 – 7.36 (m, 3H, H-Ar), 7.36 – 7.42 (m, 3H, H-Ar), 7.47 – 7.61 (m, 4H, H-Ar), 7.65 – 7.71 (m, 1H, H-Ar), 7.74 (s, 1H, H-Ar), 7.89 (d, J = 8.5 Hz, 1H, H-Ar);

13C{1H}

NMR (CDCl3, 75 MHz) δ (ppm) 21.7, 28.5, 51.5, 51.9,

66.9, 125.9, 126.6, 127.0, 127.4, 127.7, 127.9, 128.6, 128.9, 129.0, 129.4, 129.6, 130.5, 132.9, 134.8, 135.4, 136.5, 136.7, 137.5, 138.5, 138.7, 138.8, 146.4, 153.7, 165.8, 172.2. HR-MS (ESI-POS) m/z: [M+Na]+ Calcd for C38H35N3O2Na 588.2626; Found 588.2639. IR  (cm-1) 3426, 2965, 1691, 1640. (Z)-N-(tert-Butyl)-14-(cyclopropylmethylene)-5-oxo-6-phenethyl-5,6,7,14tetrahydrobenzo[6,7]azocino[4,3-b]quinoline-7-carboxamide

(6l):

Pale

yellow

powder; 0.366 g (69%); Mp 215-217 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 0.37 – 0.47 (m, 1H, H-cyclopropyl), 0.55 – 0.68 (m, 1H, H-cyclopropyl), 0.86 (s, 9H, t-Bu), 1.90 – 2.11 (m, 2H, H-cyclopropyl), 2.80 – 3.14 (m, 2H, CH2-Ph), 3.66 – 4.00 (m, 2H, CH2Bn), 4.45 (brs, 1H, NH), 5.08 (s, 1H, C(sp3)-H), 7.12 – 7.22 (m, 5H, H-Ar), 7.27 – 7.37 (m, 2H, H-Ar), 7.41 – 7.48 (m, 1H, H-Ar), 7.53 – 7.64 (m, 3H, H-Ar), 7.77 – 7.85 (m, 3H, H-Ar), 8.26 (d, J = 8.7 Hz, 1H, H-Ar);

13C{1H}

NMR (CDCl3, 75 MHz) δ (ppm) 7.9, 8.0,

11.2, 28.6, 34.5, 51.6, 52.0, 61.7, 70.4, 126.3, 127.2, 127.3, 128.2, 128.3, 128.4, 128.6, 128.7, 129.2, 129.4, 129.9, 130.7, 139.4, 142.5, 145.6, 147.5, 155.5, 166.1, 171. HRMS (ESI-POS) m/z: [M+Na]+ Calcd for C35H35N3O2Na 552.2626; Found 552.2626. IR  (cm-1) 3285, 2964, 1683, 1625.



Page 22 of 27

(Z)-6-Benzyl-N-(tert-butyl)-10,11-dimethyl-5-oxo-14-(4-pentylbenz ylidene)-5,6,7,14-tetrahydrobenzo[6,7]azocino[4,3-b]quinoline-7-carboxamide (6m): Pale yellow powder; 0.383 g (59%); Mp 116-119 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 0.81 (s, 9H, t-Bu), 0.85 – 0.87 (m, 2H, H-n-pentyl), 1.21 – 1.29 (m, 4H, Hn-pentyl), 1.49 – 1.57 (m, 2H, H-n-pentyl), 1.70 – 1.96 (m, 1H, H-n-pentyl), 2.46 (s, 6H, 2CH3), 2.49 – 2.54 (m, 2H, H-n-pentyl), 4.15 (d, J = 14.9 Hz, 1H, CH2-Ph), 4.37 (brs, 1H, NH), 5.06 (s, 1H, C(sp3)-H), 5.30 (d, J = 14.9 Hz, 1H, CH2-Ph), 6.63 (s, 1H, =CH), 6.86 – 6.92 (m, 4H, H-Ar), 7.26 – 7.32 (m, 3H, H-Ar), 7.35 – 7.40 (m, 3H, H-Ar), 7.47 – 7.53 (m, 3H, H-Ar), 7.63 – 7.70 (m, 2H, H-Ar), 7.80 (s, 1H, H-Ar);

13C{1H}

NMR (CDCl3,

75 MHz) δ (ppm) 14.0, 20.1, 20.6, 22.5, 26.9, 28.5, 30.8, 31.3, 35.5, 51.4, 52.0, 67.0, 125.2, 126.2, 126.3, 127.7, 128.0, 128.6, 128.7, 128.8, 129.0, 129.4, 129.6, 130.3, 132.7, 134.6, 136.7, 137.5, 137.6, 138.3, 139.0, 141.0, 142.4, 147.0, 153.9, 166.0, 172.3. HR-MS (ESI-POS) m/z: [M+Na]+ Calcd for C44H47N3O2Na 672.3565; Found 672.3565. IR  (cm-1) 3424, 2924, 1689, 1646. (Z)-6-benzyl-14-benzylidene-N-(tert-butyl)-3-hydroxy-9,11-dimethyl-5-oxo-5,6,7,14tetrahydrobenzo[6,7]azocino[4,3-b]quinoline-7-carboxamide (6n): Orange powder; 0.453 g (76%); Mp 158-159 °C; 1H{13C} NMR (CDCl3, 300 MHz) δ (ppm) 0.80 (s, 9H, tBu), 2.44 (s, 6H, 2CH3), 4.10 (d, J = 14.9 Hz, 1H, CH2-Ph), 4.38 (brs, 1H, NH), 5.07 (s, 1H, C(sp3)-H), 5.33 (d, J = 15.0 Hz, 1H, CH2-Ph), 6.65 (s, 1H, =CH), 6.92 – 6.97 (m, 2H, H-Ar), 7.06 – 7.12 (m, 3H, H-Ar), 7.28 – 7.33 (m, 3H, H-Ar), 7.36 – 7.39 (m, 3H, H-Ar), 7.50 (s, 3H, H-Ar), 7.64 – 7.71 (m, 2H, H-Ar), 7.76 (brs, 1H, OH);

13C{1H}

NMR (CDCl3,

75 MHz) δ (ppm) 14.2, 20.1, 20.6, 28.5, 51.5, 52.9, 125.3, 126.1, 126.3, 127.5, 127.7, 127.9, 128.0, 128.4, 128.6, 128.9, 129.0, 129.4, 129.6, 130.4, 135.4, 136.6, 136.6, 137.9, 165.9, 171.2, 172.3. ESI-MS (m/z): [M+H]+ Calcd for C39H38N3O3 595.3; Found 595.4. Anal. Calcd for C39H37N3O3: C, 78.63; H, 6.26; N, 7.05. Found: C, 78.33; H, 6.14; N, 6.92. IR  (cm-1) 3424, 2924, 1689, 1646. (E)-6-Benzyl-12-benzylidene-N-(tert-butyl)-7-oxo-5,6,7,12-tetrahydro dibenzo[c,f]azocine-5-carboxamide (12): Light brown powder; 0.115 mg (23%); Mp 104-106 °C; 1H{13C} NMR (300 MHz, CDCl3) δ 0.85 (s, 9H, t-Bu), 4.01 (d, J = 14.8 Hz, 1H, CH2-Ph), 4.45 (brs, 1H, NH), 5.12 (s, 1H, C(sp3)-H), 5.44 (d, J = 14.7 Hz, 1H, CH2Ph), 6.71 (s, 1H, =CH), 6.91 – 7.02 (m, 2H, H-Ar), 7.04 – 7.16 (m, 3H, H-Ar), 7.30 –


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7.42 (m, 5H, H-Ar), 7.48 – 7.62 (m, 3H, H-Ar), 7.65 – 7.86 (m, 3H, H-Ar), 8.00 (d, J = 8.4 Hz, 1H, H-Ar).;

13C{1H}

NMR (CDCl3, 75 MHz) δ 28.5, 29.7, 51.6, 122.7, 125.0, 126.7,

126.8, 127.1, 128.1, 128.3, 128.4, 128.4, 128.6, 128.6, 129.4, 129.5, 136.4, 173.2. HRMS (ESI-POS) m/z: [M+H]+ Calcd for C34H33N2O2 501.2497; Found 501.1841. IR  (cm1)

3418, 2966, 1685, 1647.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: CIF files giving 1H and

13C

NMR spectra of compounds (5a-o) and all 1H,

13C

NMR, IR

spectra and HRMS for compounds (6a-n) as well as Xray crystallography data for compound (6a) AUTHOR INFORMATION Corresponding Authors * Email: [email protected], [email protected] ORCID Saeed Balalaie: 0000-0002-5764-0442 Thomas J. J. Müller: 0000-0001-9809-724X Helya Janatian Ghazvini: 0000-0003-0565-4284 Author Contributions Authors contributed equally. ACKNOWLEDGMENT Saeed Balalaie thanks Alexander von Humboldt for the research fellowship. We gratefully acknowledge German Academic Exchange Service (DAAD) for scholarship in the German-Iranian Scholarship program (GISP), and Iran National Science Foundation (INSF, Grant No 97020936) for financial support.



Page 24 of 27

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