Cyanoacetylenes as Triggers and Partners in KOH-Assisted

Jul 2, 2019 - Anastasiya G. Mal'kina ... 1H and 13C NMR spectra for all new compounds (PDF) ... K. V. Belyaeva, L. P. Nikitina, A. G. Mal'kina, A. V. ...
0 downloads 0 Views 763KB Size
Download PDF
Article Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX

pubs.acs.org/joc

Cyanoacetylenes as Triggers and Partners in KOH-Assisted Assemblies of Quinoline-Based Dihydropyrimido[1,2‑a]quinolin-3ones on Water Kseniya V. Belyaeva, Lina P. Nikitina, Anastasiya G. Mal’kina, Andrei V. Afonin, Alexander V. Vashchenko, and Boris A. Trofimov*

Downloaded via KEAN UNIV on July 17, 2019 at 04:38:15 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., Irkutsk 664033, Russian Federation S Supporting Information *

ABSTRACT: Arylcyanoacetylenes trigger the assembly of dihydropyrimido[1,2-a]quinolin-3-ones in good to excellent yields on the platform of quinolines in the presence of KOH in aqueous media at room temperature. This green on-water methodology provides a simple one-pot access to a novel family of the pharmaceutically prospective compounds.

■

INTRODUCTION The sustainable interest in conjugated bicyclic 6−6 systems, pyrimidoquinolines, is primarily inspired by their structural similarity with natural biologically active compounds, in particular with pyrimidine bases.1 Several reviews2,3 and experimental papers4 are devoted to the synthesis and study of the properties of pyrimido[1,2-a]quinolines. This motif is embedded in numerous biologically active compounds and natural products exhibiting antibacterial, antifungal,4a,5,6 and antiallergic7 activities. The pyrimido[1,2-a]quinoline scaffold is a key structural unit of chromophores and siderophores.2 When the carbonyl group stands in position 3, these compounds are actually δ-lactams, close derivatives of aminoquinoline cinnamic acid, which are flagship compounds in bio and medicinal chemistry.8 Pyrimidinone with the δ-lactam moiety is a key pharmacophore scaffold met in a number of commercially important popular drugs for treatment of HIV (Raltegravir),9 erectile dysfunction (Viagra and Sildenafil), 10 herpes diseases (Aciclovir),11 and so forth (Figure 1). Therefore, to develop a rational environmentally healthy strategy for fusion of the quinoline ring with pyrimidinone cycles for construction of the pyrimidoquinolinone scaffold now is one of the challenges in pharmaceutically oriented synthesis. One might expect that the fusion of the pyrimidinone structure with the quinoline cycle could further enhance and extend pharmaceutically valuable properties of such novel molecules. In this context, the representatives of pyrimidoquinolinones were reported to possess antiplatelet activity.12 At present, dihydropyrimido[1,2-a]quinolin-3-ones, still limited in number, are assembled from (i) quinoline, DMAD, and arylisocyanate (only one example, the reaction proceeds in CH2Cl2, which is toxic and cancerogenic and arylisocyanates are lacrimators);13 (ii) 3-(5,5-dimethyl-3oxocyclohex-1-enylamino)carboxylic acids and aldehydes with © XXXX American Chemical Society

Figure 1. Representatives of pyrimidinone drugs and pyrimidoquinoline bioactive compounds.

malononitrile (or unsaturated dinitriles);14−16 (iii) 5-oxo-2,5dihydroisoxazole-4-carboxylate and 2-chloroquinolines.17 One rapidly developing trend in modern organic chemistry is so-termed “on-water” synthesis.18 Such reactions feature numerous advantages with regard to environmental friendliness, cost efficiency, and feasibility of implementation.19 It is not surprising because water is an omnipresent natural substance, indispensable for all living organisms. No wonder the organic chemistry community is now searching for “onwater” syntheses.20

■

RESULTS AND DISCUSSION Here, we report an environmentally benign one-pot synthesis of dihydropyrimido[1,2-a]quinolin-3-ones based on activation of the quinoline ring by complexing it with readily available21 Received: June 5, 2019 Published: July 2, 2019 A

DOI: 10.1021/acs.joc.9b01482 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

also as a reactant. Without KOH at room temperature (rt), the process almost does not take place: the yield of 3a is just 4% (entry 1). Upon increasing the KOH loading to 10−20 mol %, the yield of 3a grows (to 67−70%, entries 2, 3). At a higher KOH concentration (30 mol %), the yield does not noticeably change (66%, entry 4). At elevated temperature (55−60 °C), the reaction expectedly proceeds faster (6 instead of 24 h), though the yield of the target product considerably drops (29%, entry 6), meaning that side processes are accelerated faster than the desired one. Some interference of a side reaction is likely indicated by the higher conversion of quinoline 1a as compared to the yields. An attempt to improve the annulation efficiency by increasing the loading of cyanoacetylene 2a did not lead to positive results (entry 5). Analysis of the 1H NMR spectra of reaction mixtures revealed trace amounts of the product of 2,3-difuctionalization of the quinoline ring, 3-cyano-2-phenylquinoline 4 (Scheme 2), that is, the reaction such as that shown in Scheme 121a still occurs here as a minor process.

arylcyanoacetylenes in a two-phase micelle-like heterogeneous alkaline aqueous system. A forerunner of this synthesis was our recent double one-pot 2,3-functionalization of quinolines under the action arylacylacetylenes in a KOH/H2O/MeCN system (Scheme 1).22 Scheme 1. One-Pot Double 2,3-Functionalyzation of Quinolines by Arylacylacetylenes in the KOH/H2O/MeCN System

Surprisingly, this 2,3-difunctionalization with cyanophenylacetylene appeared to be inefficient.22a Further systematic study of this issue led us to discovery of new reaction, namely, the annulation of quinolines with arylcyanoacetylenes in water to assemble dihydropyrimido[1,2-a]quinolin-3-ones. First, for a better understanding of the influence of reaction conditions on the yield of the target compounds, we have chosen, as a reference, the reaction between quinoline 1a and cyanophenylacetylene 2a in water in the presence of KOH to afford dihydropyrimido[1,2-a]quinolin-3-one 3a. The reaction progress was followed by IR spectroscopy (disappearance of the CN absorption band at 2262 cm−1 in the starting acetylene 2a). Selective representative results of these experiments are given in Table 1. Generally, at 1:1 reactant molar ratio, the annulation proceeds at 20−60 °C to produce the target product in 4−70% yields depending on the KOH concentration, temperature, and water content. As follows from the structure of 3a, water is incorporated in the molecule serving in this reaction not only as solvent but

Scheme 2. Double 2,3-Functionalization of Quinoline 1a with Cyanophenylacetylene 2a

The key step of this double 2,3-functionalization of quinoline is the hydration of the 1,3-dipolar primary intermediate and its rearrangement to an intermediate aminal which further undergoes multiposition domino transformations.21a This implies that at a higher content of H2O, this reaction should be more expressed. The experiments confirm that this assumption is true. In fact, when the reaction mixture was 10 times diluted (the KOH loading remain the same) and the process was conducted at 55−60 °C, we managed to isolate product 4 in 9% yield (entry 9). An important feature of this reaction is that it proceeds as a two-phase process because the reactants, insoluble in water, upon mixing form the organic layer wherein the annulation occurs. When the reaction mixture was homogenized by addition of MeCN (entry 8), the yield of the target product sharply dropped (10%), thus indicating the key role of the heterogeneous character of the process. Eventually, the following conditions for the annulation studied may be considered as provisionally optimal ones: 1a/ 2a molar ratio is 1:1, 20 mol % of KOH, water, rt. Consequently, the substrate scope was investigated using the conditions thus found (Scheme 3). A strong substituent effect is observed for arylcyanoacetylenes 2a−f. Surprisingly, both electron-donating and electronwithdrawing substituents in their benzene ring decrease the yields of the target products which are 16−70% (cf. compounds 3a−f). The reason for such a contradiction is likely that donor substituents (Me, Et, and OEt) reduce the electrophilicity of the triple bond and thereby lower the concentration of the primary 1,3-dipole intermediate, while

Table 1. Synthesis of Dihydropyrimido[1,2-a]quinolin-3one 3a: Yield/Conditions Relationshipa

entry

KOH (mol %)

t (h)

conversion of 1a (%)

yield of 3a (%)

1 2 3 4 5b 6c 7d 8d,e 9c,d 10d 11

none 10 20 30 20 20 20 20 20 220 20g

24 24 24 24 24 6 72 72 6 24 24

12 77 79 83 79 83 94 91 89 83 83

4 67 70 66 64 29 66 10 51f 60 59

a Conditions: 1a (0.5 mmol), 2a (0.5 mmol), and H2O (0.045 mL), rt. b1a (0.5 mmol), 2a (0.6 mmol), and H2O (0.045 mL). c Temperature was 55−60 °C. d1a (0.5 mmol), 2a (0.5 mmol), and H2O (0.5 mL). eFor homogenizations of the reaction mixture, 0.25 mL MeCN was employed. f3-Cyano-2-phenylquinoline 4 also was isolated in 9% yield. gNaOH was used instead of KOH.

B

DOI: 10.1021/acs.joc.9b01482 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry Scheme 3. Scope of the Substratesa

The reaction proves to be well extendable to the isoquinoline series. Thus, the reaction between isoquinoline 5 and arylcyanoacetylenes 2a,c,f under the above optimal conditions gave pyrimidoisoquinolinones 6a−c in 50−92% yields (Scheme 4). Scheme 4. Synthesis of Dihydro-2H-pyrimido[2,1a]isoquinolin-2-ones 6a−c and X-ray Structure of 6aa

a

Conditions: 5 (0.5 mmol), 2 (0.5 mmol), H2O (0.045 mL), 20 mol % KOH, rt.

Structures of the synthesized pyrimidoquinolinones 3 and 6 were proven using 1H and 13C NMR spectroscopy data; in the case of the isoquinoline derivative 6a, X-ray diffraction analysis was executed (Scheme 4). An attempt to extend the reaction over the pyridine under similar conditions led to oligomeric products.24 The annulation mechanism is assumed to start with quinoline ring activation by reversible complexing of the pyridine moiety with cyanoacetylenes to generate 1,3(4)dipolar intermediate A (Scheme 5), in which the heterocyclic

a

Conditions: 1 (0.5 mmol), 2 (0.5 mmol), H2O (0.045 mL), 20 mol % KOH, rt. bBecause of the lethargic character of the reaction at rt, it was necessary to carry out the annulation at 55−60 °C.

electron-withdrawing substituents [CN and MeC(O)], on the contrary, enhance the electrophilicity of cyanoacetylenes thus making them more reactive in adverse side processes, for example, oligomerization and hydration. In this case, the reaction rate (the process duration) roughly follows the same trend. The nature of substituents in the quinoline core also considerably influences the yield of the target product and the reaction time (cf. compounds 3g,i−m). The best yield of 88% is reached for pyrimidoquinolinone 3g. This is explained by the higher basicity of 3-methylquinoline 1b compared to quinoline 1a (pKa for 1b = 5.17 and pKa for 1a = 4.95, respectively) and, hence, a larger concentration of the 1,3-dipolar adduct quinoline/cyanoacetylene. This basicity/ yield dependence is further evidenced by the lowest yield of pyrimidoquinolinone 3k (16%) obtained from 6-chloroquinoline 1e having the lowest basicity (pKa for 1e = 4.18) in the series of quinolines studied. The decreased yield (30%) of target product 3i in the case of 4-methylquinoline 1c is likely due to side nucleophilic addition of the C-acidic methyl group to cyanophenylacetylene, as was previously observed23 for 2methylquinoline. Because the reaction mixtures represent twophase systems, the yield and reaction time should also depend on the reactant composition in the organic phase, which is different for diversely hydrophilic/hydrophobic starting compounds. Therefore, the substituent effect in this case should be determined not only by electronic and steric characteristics of the reactants but also by the physical properties (the mutual solubility, hydrophilic/hydrophobic balance).

Scheme 5. Proposed Pathway for the Dihydropyrimidoquinolinone 3 Synthesis

system is positively charged at the nitrogen atom and at C2, the latter might also have a higher lowest unoccupied molecular orbital localization. The negative site of this dipolar intermediate, being mainly concentrated at the carbon atom adjacent to the CN moiety, is neutralized with a proton from water to give intermediate B of the ammonium hydroxide type. The strongly basic hydroxide anion (thus released) of this intermediate attacks the CN bond to produce intermediate C with a nitrogen anionic center, which attacks the C(2) atom to close the hydroxyl pyrimidine ring (intermediate D), which then prototropically rearranges to the final product. Probably, sequence A → D is realized in a shorter concerted mode (Scheme 6), avoiding the formation of nitrogen-centered anion C as kinetically independent particle, and the process represents a simultaneous transfer of the electron pairs. C

DOI: 10.1021/acs.joc.9b01482 J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

■

Scheme 6. Concerted Mode of the Proposed Pathway

Article

EXPERIMENTAL SECTION

NMR spectra were recorded on a Bruker DPX-400 spectrometer (400.13 MHz for 1H and 100.62 MHz for 13C) in DMSO-d6 and CDCl3. Internal standards were HMDS (for 1H nuclei δ 0.05 ppm) or residual solvent signals (for 13C nuclei δ 77.16 ppm). The resonance signals of carbon atoms were assigned based on 1H−13C HSQC and 1 H−13C HMBC experiments. Coupling constants (J) were measured from one-dimensional spectra, and multiplicities were abbreviated as follows: s (singlet), br s (broad singlet), d (doublet), dd (doublet of doublets), q (quartet), t (triplet), m (multiplet). IR spectra were recorded on a two-beam Bruker Vertex 70 spectrometer, in a microlayer from chloroform or in tablets with KBr. Elemental analysis was carried out on a FLASHEA 1112 Series analyzer. Mass spectra were recorded on an Agilent 6210 HRMS-TOF-ESI mass spectrometer. Electrostatic sputtering, registration of positive ions. Sample solventMeCN with the addition of 0.1% heptafluorobutanoic acid and with the addition of the calibration mixture for the mass spectrometer. Melting points were determined on a Kofler hot stage apparatus. Commercial samples of quinolines 1a−c, acetylene 2a, and isoquinoline 5 were used. Quinolines 1d,e were prepared by methylation of the corresponding hydroxyl and mercapto quinolines.26 Samples of arylcyanoacetylenes 2b−f were obtained according to reported methods.21a Products 3a−m and 6a−c were separated and purified by recrystallization from MeCN or EtOH or column chromatography. Column and thin-layer chromatography were carried out on silica gel (0.06−0.2 mm) with chloroform/toluene/ ethanol (20:4:1) mixtures as the eluant. General Procedures. Method A. A mixture of quinoline 1 (1 equiv), acetylene 2 (1 equiv), H2O (5 equiv), KOH (20 mol %) was stirred at 20−25 °C for appropriate time. Next, the reaction mixture was washed consequently with Et2O (5 × 1 mL) and MeCN (2 × 1 mL) to separate the main part of pyrimidoquinoline 3. Concentrated organic layers were passed through the chromatography column to deliver 2-aryl-3-cyanoquinoline 4, initial quinoline 1, and remains of target pyrimidoquinoline 3. Method B. A mixture of quinoline 1 (1 equiv), acetylene 2 (1 equiv), H2O (5 equiv), and KOH (20 mol %) in small amounts of MeCN (for homogenization of reaction mixture) was stirred at 55− 60 °C for the appropriate time. Next, the reaction mixture was cooled to rt, washed consequently with Et2O (5 × 1 mL) and MeCN (2 × 1 mL) to separate the main part of pyrimidoquinoline 3. Concentrated organic layers passed through the chromatography column to deliver 2-aryl-3-cyanoquinoline 4, initial quinoline 1, and remains of target pyrimidoquinoline 3. 1-Phenyl-4,4a-dihydro-3H-pyrimido[1,2-a]quinolin-3-one (3a). Method A. From a mixture of quinoline (1a) (65 mg, 0.5 mmol), acetylene 2a (64 mg, 0.5 mmol), H2O (45 mg, 2.5 mmol), and KOH (6 mg, 20 mol %) (24 h), product 3a (96 mg, 70%) was obtained as light-yellow powder, mp 267−268 °C (washed with Et2O and MeCN). Initial quinoline (1a) was recovered (13 mg, conversion was 79%). IR (KBr): 1631 (CC), 1653 (CO) cm−1. 1H NMR (400.13 MHz, DMSO-d6): δ 8.10 (s, 1H, NH), 7.63−7.61 (m, 2H, Ho from Ph), 7.46−7.44 (m, 3H, Hm,p from Ph), 7.17−7.15 (m, 1H, H7), 6.85−6.79 (m, 3H, H-6, H-8, H-9), 6.14 (s, 1H, H-2), 6.11−6.09 (m, 1H, H-10), 5.96 (dd, 3J5,6 = 10.0 Hz, 3J4a,5 = 5.4 Hz, 1H, H-5), 5.73 (d, 3J4a,5 = 5.4 Hz, 1H, H-4a) ppm. Because of poor solubility of 3a in any solvents, there is no chance to check the 13C NMR spectrum. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H15N2O+, 275.1179; found, 275.1179. Also, side 2-phenylquinoline-3-carbonitrile (4a) (6 mg, 5%) was isolated as white powder, mp 197−198 °C (EtOH).22a 1H NMR and IR spectra are similar to the literature data.27 1-(4-Methylphenyl)-4,4a-dihydro-3H-pyrimido[1,2-a]quinolin-3one (3b). Method A. From a mixture of quinoline (1a) (65 mg, 0.5 mmol), acetylene 2b (71 mg, 0.5 mmol), H2O (45 mg, 2.5 mmol), and KOH (6 mg, 20 mol %) (48 h), product 3b (82 mg, 57%) was obtained as light-yellow powder, mp 265−266 °C (EtOH). Initial quinoline (1a) (26 mg, conversion was 60%) and acetylene 2b (7 mg, conversion was 90%) were recovered. IR (microlayer): 1607, 1657

This mechanism is in keeping with the substituent effects. Indeed, an electron-donating group in the quinoline ring enhances its basicity and hence the concentration of intermediate A facilitates the reaction like an electron acceptor in cyanoacetylene molecules which makes the triple bond more electrophilic. The catalytic role of KOH can also be understood in terms of Schemes 5 and 6, which suppose as an important step hydroxide anion attack at the CN bond. Given the two-phase character of the reaction mixture, a particular role of the micellar catalysis should not be neglected. In fact, the reaction occurs in the organic phase representing a continuum of droplets (kind of microreactors), wherein the concentration of the reactants and the catalysts (quinolines, cyanoacetylenes, H2O, and KOH) and their spatial orientation are different from those which are outside, that is, in the aqueous phase. The importance of this phenomena is experimentally supported (Table 1, entry 8), wherein a drastic drop of the target product yield is observed for the “homogeneous protocol”. The cyanoacetylene-triggered assembly of dihydropyrimido[1,2-a]quinolin-3-ones on the quinoline scaffold represents, in its key step, intramolecular nucleophilic hydrogen substitution at C2 of the azine ring and, consequently, the dihydro derivatives formed (3) are actually the intermediates of this incomplete SNHAr process. The latter can be completed by the treatment of dihydro intermediates with an external oxidant, for example, DDQ as it is here exemplified by oxidation of pyrimido[1,2-a]quinolin-3-one 3g into SNHAr product 7 (Scheme 7). Scheme 7. Dehydrogenation of 3g

■

CONCLUSIONS In conclusion, we have disclosed the arylcyanoacetylenetriggered, KOH-assisted construction of dihydropyrimido[1,2a]quinolin-3-ones on quinoline platforms in water at rt. The reaction is carried out in a two-phase aqueous organic system, wherein the hydroxide anion acts both as a catalyst and a reactant. This water-driven, environmentally friendly green synthesis features one-pot implementation, atom economy, and energy saving that meets the PASE paradigm.25 In essence, the reaction studied is, in its key step, an incomplete SNHAr process, which can be finalized by external oxidation. The reactions provide rare, though pharmaceutically valuable building blocks and potential drug precursors, which may attract the interest of wide circles of organic and medicinal chemists. D

DOI: 10.1021/acs.joc.9b01482 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry (CC, CO) cm−1. 1H NMR (400.13 MHz, CDCl3): δ 7.50−7.48 (m, 2H, H2′,6′ from Ar), 7.19−7.17 (m, 2H, H3′,5′ from Ar), 7.04 (d, 3 J7,8 = 9.2 Hz, 1H, H-7), 6.84−6.75 (m, 3H, H-6, H-8, H-9), 6.70 (br s, 1H, NH), 6.21 (d, 3J9,10 = 7.9 Hz, 1H, H-10), 6.13 (s, 1H, H-2), 5.89 (dd, 3J5,6 = 9.6 Hz, 3J4a,5 = 4.8 Hz, 1H, H-5), 5.75−5.73 (m, 1H, H-4a), 1.23 (s, 3H, Me) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 165.0 (C-3), 153.8 (C-1), 141.2 (C4′ from Ar), 137.6 (C-10a), 131.7 (C1′ from Ar), 130.1 (C-6; C3′,5′ from Ar), 129.1 (C-9), 127.9 (C-7), 127.4 (C2′,6′ from Ar), 121.9 (C-6a), 121.1 (C-8), 118.1 (C-5), 117.7 (C-10), 111.2 (C-2), 65.0 (C-4a), 21.6 (Me) ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H17N2O+, 289.1335; found, 289.1349. 1-(4-Ethylphenyl)-4,4a-dihydro-3H-pyrimido[1,2-a]quinolin-3one (3c). Method B. From a mixture of quinoline (1a) (65 mg, 0.5 mmol), acetylene 2c (78 mg, 0.5 mmol), H2O (45 mg, 2.5 mmol), and KOH (6 mg, 20 mol %) in 0.2 mL of MeCN (8 h), product 3c (81 mg, 54%) was obtained as light-yellow powder, mp 270−272 °C (EtOH). Initial quinoline (1a) (14 mg, conversion was 79%) and acetylene 2c (14 mg, conversion was 82%) were recovered. IR (microlayer): 1600, 1652 (CC, CO) cm−1. 1H NMR (400.13 MHz, CDCl3): δ 7.53−7.51 (m, 2H, H2′,6′ from Ar), 7.22−7.20 (m, 2H, H3′,5′ from Ar), 7.05 (d, 3J7,8 = 9.0 Hz, 1H, H-7), 6.84−6.76 (m, 3H, H-6, H-8, H-9), 6.22 (d, 3J9,10 = 8.0 Hz, 1H, H-10), 6.15 (s, 1H, H-2), 6.04 (br s, 1H, NH), 5.86 (dd, 3J5,6 = 9.8 Hz, 3J4a,5 = 4.6 Hz, 1H, H-5), 5.76−5.74 (m, 1H, H-4a), 2.66 (q, 3JH,H = 7.6 Hz, 2H, CH2 from Et), 1.23 (t, 3H, Me from Et) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 164.8 (C-3), 153.9 (C-1), 147.6 (C4′ from Ar), 137.7 (C-10a), 131.9 (C1′ from Ar), 130.2 (C-6), 129.3 (C-9), 128.9 (C3′,5′ from Ar), 127.9 (C-7), 127.5 (C2′,6′ from Ar), 121.8 (C-6a), 121.1 (C-8), 118.2 (C-5), 117.6 (C-10), 111.3 (C-2), 65.0 (C-4a), 28.9 (CH2 from Et), 15.4 (Me from Et) ppm. HRMS (ESI-TOF) m/ z: [M + H]+ calcd for C20H19N2O+, 303.1492; found, 303.1493. 1-(4-Ethoxyphenyl)-4,4a-dihydro-3H-pyrimido[1,2-a]quinolin-3one (3d). Method B. From a mixture of quinoline (1a) (45 mg, 0.35 mmol), acetylene 2d (60 mg, 0.35 mmol), H2O (32 mg, 1.75 mmol), and KOH (4 mg, 20 mol %) in 0.2 mL of MeCN (4 h), product 3d (37 mg, 33%) was obtained as grey-brown powder, mp 224−227 °C (EtOH). IR (microlayer): 1604, 1657 (CC, CO) cm−1. 1H NMR (400.13 MHz, CDCl3): δ 7.54−7.52 (m, 2H, H2′,6′ from Ar), 7.04 (d, 3J7,8 = 9.0 Hz, 1H, H-7), 6.89−6.86 (m, 2H, H3′,5′ from Ar), 6.83−6.75 (m, 3H, H-6, H-8, H-9), 6.44 (br s, 1H, NH), 6.23 (d, 3 J9,10 = 8.0 Hz, 1H, H-10), 6.09 (s, 1H, H-2), 5.88 (dd, 3J5,6 = 9.8 Hz, 3 J4a,5 = 4.6 Hz, 1H, H-5), 5.74−5.72 (m, 1H, H-4a), 4.04 (q, 3JH,H = 7.2 Hz, 2H, CH2 from OEt), 1.41 (t, 3H, Me from OEt) ppm. 13 C{1H} NMR (100.62 MHz, CDCl3): δ 165.1 (C-3), 161.3 (C4′ from Ar), 153.6 (C-1), 137.8 (C-10a), 130.1 (C-6), 129.2 (C-9), 129.0 (C3′,5′ from Ar), 127.9 (C-7), 126.6 (C1′ from Ar), 121.9 (C6a), 121.1 (C-8), 118.2 (C-5), 117.7 (C-10), 115.3 (C2′,6′ from Ar), 110.2 (C-2), 64.9 (C-4a), 63.8 (CH2 from OEt), 14.9 (Me from OEt) ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H19N2O2+, 319.1441; found, 319.1439. 4-(3-Oxo-4,4a-dihydro-3H-pyrimido[1,2-a]quinolin-1-yl)benzonitrile (3e). Method A. From a mixture of quinoline (1a) (65 mg, 0.5 mmol), acetylene 2e (76 mg, 0.5 mmol), H2O (45 mg, 2.5 mmol), and KOH (6 mg, 20 mol %) (24 h), product 3e (24 mg, 16%) was obtained as an yellow powder, mp 272−274 °C (MeCN). Initial quinoline (1a) was recovered (29 mg, conversion was 55%). IR (microlayer): 1600, 1651 (CC, CO), 2225 (CN) cm−1. 1H NMR (400.13 MHz, CDCl3): δ 7.73−7.67 (m, 4H, H2′,3′,5′,6′ from Ar), 7.09 (d, 3J7,8 = 9.0 Hz, 1H, H-7), 6.88−6.80 (m, 3H, H-6, H-8, H-9), 6.54 (br s, 1H, NH), 6.24 (s, 1H, H-2), 6.06 (d, 3J9,10 = 8.0 Hz, 1H, H-10), 5.91 (dd, 3J5,6 = 9.8 Hz, 3J4a,5 = 4.6 Hz, 1H, H-5), 5.78− 5.76 (m, 1H, H-4a) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 163.9 (C-3), 151.5 (C-1), 138.6 (C1′ from Ar), 136.8 (C-10a), 133.2 (C3′,5′ from Ar), 130.2 (C-6), 129.4 (C-9), 128.3 (C-7), 128.0 (C2′,6′ from Ar), 122.0 (C-6a), 121.9 (C-8), 118.3 (C4′ from Ar), 117.7 (C5), 117.5 (C-10), 114.3 (CN), 114.2 (C-2), 65.1 (C-4a) ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H14N3O+, 300.1131; found, 300.1129.

1-(4-Acetylphenyl)-4,4a-dihydro-3H-pyrimido[1,2-a]quinolin-3one (3f). Method A. From a mixture of quinoline (1a) (65 mg, 0.5 mmol), acetylene 2f (85 mg, 0.5 mmol), H2O (45 mg, 2.5 mmol), and KOH (6 mg, 20 mol %) (24 h), product 3f (88 mg, 56%) was obtained as yellow powder, mp 239−241 °C (EtOH). Initial quinoline (1a) was recovered (23 mg, conversion was 65%). IR (microlayer): 1603, 1661 (CC, CO) cm−1. 1H NMR (400.13 MHz, CDCl3): δ 7.98−7.96 (m, 2H, H3′,5′ from Ar), 7.72−7.70 (m, 2H, H2′,6′ from Ar), 7.08−7.06 (m, 1H, H-7), 6.84−6.80 (m, 3H, H-6, H-8, H-9), 6.57 (br s, 1H, NH), 6.24 (s, 1H, H-2), 6.14−6.11 (m, 1H, H-10), 5.91 (dd, 3J5,6 = 9.6 Hz, 3J4a,5 = 4.8 Hz, 1H, H-5), 5.80−5.78 (m, 1H, H-4a), 2.60 [s, 3H, Me from C(O)Me] ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 197.4 [CO from C(O)Me], 164.2 (C-3), 152.4 (C-1), 138.9 (C1′ from Ar), 138.7 (C4′ from Ar), 137.1 (C10a), 130.2 (C-6), 129.4 (C-9), 129.3 (C3′,5′ from Ar), 128.2 (C-7), 127.6 (C2′,6′ from Ar), 121.9 (C-6a), 121.6 (C-8), 117.9 (C-5), 117.5 (C-10), 113.5 (C-2), 65.1 (C-4a), 26.9 [Me from C(O)Me] ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H17N2O2+, 317.1285; found, 317.1281. 5-Methyl-1-phenyl-4,4a-dihydro-3H-pyrimido[1,2-a]quinolin-3one (3g). Method A. From a mixture of quinoline 1b (143 mg, 1.0 mmol), acetylene 2a (127 mg, 1.0 mmol), H2O (90 mg, 5.0 mmol), and KOH (12 mg, 20 mol %) (24 h), product 3g (254 mg, 88%) was obtained as yellow powder, mp 280−282 °C (MeCN). IR (microlayer): 1650 (CC, CO) cm−1. 1H NMR (400.13 MHz, CDCl3): δ 7.62−7.60 (m, 2H, Ho from Ph), 7.42−7.35 (m, 3H, Hm,p from Ph), 7.00−6.98 (m, 1H, H-7), 6.81 (br s, 1H, NH), 6.77−6.75 (m, 2H, H-8, H-9), 6.51 (s, 1H, H-6), 6.19 (s, 1H, H-2), 6.18−6.16 (m, 1H, H-10), 5.55 (d, 3J4a,4 = 2.4 Hz, 1H, H-4a), 2.07 (s, 3H, Me) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 165.4 (C-3), 153.8 (C-1), 136.3 (C-10a), 134.6 (Ci from Ph), 130.8 (Cp from Ph), 129.4 (Cm from Ph), 128.1 (C-9), 127.5 (Co from Ph), 127.0 (C-7), 126.5 (C-5), 125.6 (C-6), 122.8 (C-6a), 121.2 (C-8), 117.8 (C-10), 111.7 (C-2), 69.2 (C-4a), 19.5 (Me) ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H17N2O+, 289.1335; found, 289.1335. Also, side 2-phenylquinoline-3-carbonitrile (4a) (12 mg, 5%) was isolated as white powder, mp 197−198 °C (EtOH).22a 1H, 13C NMR and IR spectra are similar to the literature data.27 1-(4-Acetylphenyl)-5-methyl-4,4a-dihydro-3H-pyrimido[1,2-a]quinolin-3-one (3h). Method A. From a mixture of quinoline 1b (72 mg, 0.5 mmol), acetylene 2f (85 mg, 0.5 mmol), H2O (45 mg, 2.5 mmol), and KOH (6 mg, 20 mol %) (24 h), product 3h (77 mg, 47%) was obtained as yellow powder, mp 256−258 °C (MeCN). Initial quinoline 1b was recovered (35 mg, conversion was 51%). IR (microlayer): 1603, 1659 (CC, CO) cm−1. 1H NMR (400.13 MHz, CDCl3): δ 7.96−7.94 (m, 2H, H3′,5′ from Ar), 7.71−7.69 (m, 2H, H2′,6′ from Ar), 7.42 (br s, 1H, NH), 7.01−6.99 (m, 1H, H-7), 6.77−6.76 (m, 2H, H-8, H-9), 6.52 (s, 1H, H-6), 6.25 (s, 1H, H-2), 6.10−6.09 (m, 1H, H-10), 5.56−5.55 (m, 1H, H-4a), 2.59 [s, 3H, Me from C(O)Me], 2.09 (s, 3H, 5-Me) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 197.4 [CO from C(O)Me], 165.2 (C-3), 152.3 (C-1), 138.9 (C1′ from Ar), 138.6 (C4′ from Ar), 135.9 (C-10a), 129.3 (C3′,5′ from Ar), 128.1 (C-9), 127.7 (C2′,6′ from Ar), 127.2 (C6), 126.7 (C-5), 125.4 (C-7), 122.9 (C-6a), 121.5 (C-8), 117.5 (C10), 113.2 (C-2), 69.2 (C-4a), 26.8 [Me from C(O)Me], 19.5 (5-Me) ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H19N2O2+, 331.1441; found, 331.1443. 6-Methyl-1-phenyl-4,4a-dihydro-3H-pyrimido[1,2-a]quinolin-3one (3i). Method A. From a mixture of quinoline 1c (72 mg, 0.5 mmol), acetylene 2a (64 mg, 0.5 mmol), H2O (45 mg, 2.5 mmol), and KOH (6 mg, 20 mol %) (24 h), product 3i (43 mg, 30%) was obtained as light-beige powder, mp 229−235 °C (washed with Et2O, MeCN). IR (microlayer): 1651 (CC, CO) cm−1. 1H NMR (400.13 MHz, CDCl3): δ 7.62−7.61 (m, 2H, Ho from Ph), 7.43−7.36 (m, 3H, Hm,p from Ph), 7.26−7.23 (m, 1H, H-7), 6.85−6.82 (m, 2H, H-8, H-9), 6.24−6.22 (m, 1H, H-10), 6.18 (s, 1H, H-2), 6.16 (br s, 1H, NH), 5.74−5.69 (m, 2H, H-5, H-4a), 2.19 (s, 3H, Me) ppm. 13 C{1H} NMR (100.62 MHz, CDCl3): δ 164.9 (C-3), 154.0 (C-1), 137.6 (C-10a), 135.5 (C-6), 134.6 (Ci from Ph), 130.8 (Cp from Ph), 129.4 (Cm from Ph), 128.9 (C-9), 127.4 (Co from Ph), 124.5 (C-7), E

DOI: 10.1021/acs.joc.9b01482 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry 123.4 (C-6a), 121.0 (C-8), 118.2 (C-10), 115.2 (C-5), 112.0 (C-2), 64.9 (C-4a), 19.0 (Me) ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H17N2O+, 289.1335; found, 289.1333. 8-Methyl-1-phenyl-4,4a-dihydro-3H-pyrimido[1,2-a]quinolin-3one (3j). Method A. From a mixture of quinoline 1d (72 mg, 0.5 mmol), acetylene 2a (64 mg, 0.5 mmol), H2O (45 mg, 2.5 mmol), and KOH (6 mg, 20 mol %) (24 h), product 3j (96 mg, 67%) was obtained as yellow powder, mp 213−216 °C (MeCN). IR (KBr): 1629, 1651 (CC, CO) cm−1. 1H NMR (400.13 MHz, CDCl3): δ 7.62−7.60 (m, 2H, Ho from Ph), 7.42−7.36 (m, 3H, Hm,p from Ph), 6.87 (s, 1H, H-7), 6.75 (d, 3J5,6 = 10.5 Hz, 1H, H-6), 6.63 (d, 3J9,10 = 7.6 Hz, 1H, H-9), 6.48 (br s, 1H, NH), 6.14 (s, 1H, H-2), 6.08 (d, 3 J9,10 = 7.6 Hz, 1H, H-10), 5.88 (dd, 3J5,6 = 10.5 Hz, 3J4a,5 = 5.0 Hz, 1H, H-5), 5.75−5.74 (m, 1H, H-4a), 2.16 (s, 3H, Me) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 164.8 (C-3), 153.9 (C-1), 135.1 (C10a), 134.7 (Ci from Ph), 130.8 (Cp from Ph), 130.6 (C-8), 130.2 (C9), 129.8 (C-6), 129.3 (Cm from Ph), 128.5 (C-7), 127.5 (Co from Ph), 121.8 (C-6a), 118.0 (C-10), 117.7 (C-5), 111.5 (C-2), 65.1 (C4a), 20.4 (Me) ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H17N2O+, 289.1335; found, 289.1344. 8-Chloro-1-phenyl-4,4a-dihydro-3H-pyrimido[1,2-a]quinolin-3one (3k). Method B. From a mixture of quinoline 1e (163 mg, 1.0 mmol), acetylene 2a (127 mg, 1.0 mmol), H2O (90 mg, 5.0 mmol), and KOH (12 mg, 20 mol %) in 0.2 mL of MeCN (16 h), product 3k (48 mg, 16%) was obtained as light-beige powder, mp 264−266 °C (MeCN, EtOH). Initial quinoline 1e was recovered (58 mg, conversion was 64%). IR (KBr): 1634 (CC), 1656 (CO) cm−1. 1H NMR (400.13 MHz, DMSO-d6): δ 8.18 (s, 1H, NH), 7.61 (m, 2H, Ho from Ph), 7.46 (m, 3H, Hm,p from Ph), 7.29 (s, 1H, H-7), 6.91 (m, 1H, H-6), 6.85−6.84 (m, 1H, H-9), 6.18 (s, 1H, H-2), 6.06 (m, 2H, H-5, H-10), 5.75 (m, 1H, H-4a) ppm. Because of poor solubility of 3k in any solvents, there is no chance to check the 13C NMR spectrum. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H14ClN2O+, 309.0789; found, 309.0790. Also, side 6-chloro-2-phenylquinoline-3-carbonitrile (4k) (47 mg, 18%) was isolated as white powder, mp 197−198 °C (EtOH).22a 1H, 13 C NMR and IR spectra are similar to the literature data.27 8-Methoxy-1-phenyl-4,4a-dihydro-3H-pyrimido[1,2-a]quinolin3-one (3l). Method A. From a mixture of quinoline 1f (159 mg, 1.0 mmol), acetylene 2a (127 mg, 1.0 mmol), H2O (90 mg, 5.0 mmol), and KOH (12 mg, 20 mol %) (24 h), product 3l (172 mg, 57%) was obtained as yellow powder, mp 243−245 °C (EtOH). Initial quinoline 1f was recovered (28 mg, conversion was 82%). IR (microlayer): 1655 (CC, CO) cm−1. 1H NMR (400.13 MHz, CDCl3): δ 7.62−7.60 (m, 2H, Ho from Ph), 7.44−7.36 (m, 3H, Hm,p from Ph), 6.74 (d, 3J9,10 = 9.8 Hz, 1H, H-9), 6.63 (d, 4J6,7 = 2.8 Hz, 1H, H-7), 6.45 (s, 1H, NH), 6.39 (dd, 4J6,7 = 2.8 Hz, 3J5,6 = 9.4 Hz, 1H, H-6), 6.13 (s, 1H, H-2), 6.11 (d, 3J9,10 = 9.8 Hz, 1H, H-10), 5.93 (dd, 3J5,6 = 9.4 Hz, 3J4a,5 = 4.9 Hz, 1H, H-5), 5.74−5.72 (m, 1H, H4a), 3.67 (s, 3H, OMe) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 164.9 (C-3), 154.2 (C-8), 154.0 (C-1), 134.7 (Ci from Ph), 131.1 (C-10a), 130.8 (Cp from Ph), 130.1 (C-6), 129.4 (Cm from Ph), 127.6 (Co from Ph), 122.8 (C-6a), 119.1 (C-9), 118.6 (C-10), 114.5 (C-5), 113.3 (C-7), 111.2 (C-2), 65.0 (C-4a), 55.7 (OMe) ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H17N2O2+, 305.1285; found, 305.1283. Also, side 6-methoxy-2-phenylquinoline-3-carbonitrile (4l) (23 mg, 9%) was isolated as white powder, mp 169−170 °C (EtOH). IR (microlayer): 2216 (CN) cm−1. 1H NMR (400.13 MHz, CDCl3): δ 8.51 (s, 1H, H-4), 8.07 (d, 3J7,8 = 9.2 Hz, 1H, H-8), 7.97−7.95 (m, 2H, Ho from Ph), 7.56−7.50 (m, 3H, Hm,p from Ph; 1H, H-7), 7.10 (d, 4J5,7 = 2.6 Hz, 1H, H-5), 3.96 (s, 3H, OMe) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 159.0 (C-6), 155.9 (C-2), 145.2 (C-8a), 142.6 (C-4), 137.9 (Ci from Ph), 131.5 (C-8), 129.9 (Cp from Ph), 126.2 (Co from Ph), 128.8 (Cm from Ph), 126.4 (C-4a), 126.2 (C-7), 118.3 (CN), 105.9 (C-3), 104.7 (C-5), 55.9 (OMe) ppm. Anal. Calcd for C17H12N2O: C, 78.44; H, 4.65; N, 10.76. Found: C, 78.38; H, 4.55; N, 10.85. 8-(Methylthio)-1-phenyl-4,4a-dihydro-3H-pyrimido[1,2-a]quinolin-3-one (3m). Method A. From a mixture of quinoline 1g (88

mg, 0.5 mmol), acetylene 2a (64 mg, 0.5 mmol), H2O (45 mg, 2.5 mmol), and KOH (6 mg, 20 mol %) (120 h), product 3m (93 mg, 58%) was obtained as light-yellow powder, mp 265−267 °C (EtOH). Initial quinoline 1g was recovered (19 mg, conversion was 78%). IR (microlayer): 1656 (CC, CO) cm−1. 1H NMR (400.13 MHz, CDCl3): δ 7.61−7.59 (m, 2H, Ho from Ph), 7.42−7.37 (m, 3H, Hm,p from Ph), 7.35 (d, 3J5,6 = 10.0 Hz, 1H, H-6), 6.79−6.73 (m, 2H, H-8, H-9), 6.57 (br s, 1H, NH), 6.20 (s, 1H, H-2), 6.06 (d, 3J9,10 = 7.6 Hz, 1H, H-10), 5.95 (dd, 3J5,6 = 10.0 Hz, 3J4a,5 = 5.0 Hz, 1H, H-5), 5.75− 5.73 (m, 1H, H-4a), 2.41 (s, 3H, SMe) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 164.8 (C-3), 153.8 (C-1), 138.0 (C-7), 136.5 (C10a), 134.5 (Ci from Ph), 130.8 (Cp from Ph), 129.4 (Cm from Ph), 128.9 (C-9), 127.3 (Co from Ph), 126.5 (C-6), 120.2 (C-6a, C-8), 117.7 (C-10), 116.0 (C-5), 112.5 (C-2), 64.6 (C-4a), 16.8 (SMe) ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H17N2OS+, 321.1056; found, 321.1044. Also, side 6-(methylthio)-2-phenylquinoline-3-carbonitrile (4m) (10 mg, 7%) was isolated as light-beige powder, mp 157−160 °C (EtOH). IR (microlayer): 2219 (CN) cm−1. 1H NMR (400.13 MHz, CDCl3): δ 9.08 (s, 1H, H-4), 7.97 (d, 3J7,8 = 8.0 Hz, 1H, H-8), 8.01− 7.95 (m, 2H, Ho from Ph ), 7.79 (t, 3J6,7 = 8.0 Hz, 3J7,8 = 8.0 Hz, 1H, H-7), 7.58−7.52 (m, 3H, Hm,p from Ph), 7.49 (d, 3J6,7 = 8.0 Hz, 1H, H-6), 2.63 (s, 3H, SMe) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 158.2 (C-2), 149.2 (C-8a), 141.1 (C-4), 137.7 [Ci from C(2)-Ph], 137.6 (C-5), 132.8 [Cp from C(2)-Ph], 130.3 (C-7), 129.3 [Co from C(2)-Ph], 128.9 [Cm from C(2)-Ph], 127.3 (C-8), 125.4 (C-6), 124.2 (C-4a), 118.2 (CN), 105.3 (C-3), 16.6 (SMe) ppm. Anal. Calcd for C17H12N2S: C, 73.89; H, 4.38; N, 10.14; S, 11.60. Found: C, 73.92; H, 4.36; N, 10.11; S, 11.63. 4-Phenyl-1,11b-dihydro-2H-pyrimido[2,1-a]isoquinolin-2-one (6a). Method A. From a mixture of isoquinoline (5) (129 mg, 1.0 mmol), acetylene 2a (127 mg, 1.0 mmol), H2O (90 mg, 5.0 mmol), and KOH (12 mg, 20 mol %) (24 h), product 6a (252 mg, 92%) was obtained as yellow powder, mp 215−216 °C (EtOH). IR (microlayer): 1650 (CC, CO) cm−1. 1H NMR (400.13 MHz, CDCl3): δ 7.55−7.54 (m, 2H, Ho from Ph), 7.50−7.42 (m, 3H, Hm,p from Ph), 7.34−7.32 (m, 1H, H-9), 7.30−7.28 (m, 1H, H-11), 7.27−7.23 (m, 1H, H-10), 7.09−7.07 (m, 1H, H-8), 6.39 (s, 3J1,11b = 0.2 Hz (theoretical), 1H, H-11b), 6.23 (d, 3J6,7 = 7.8 Hz, 1H, H-6), 5.74 (s, 1H, H-3), 5.70 (br s, 1H, NH), 5.55 (d, 3J6,7 = 7.8 Hz, 1H, H-7) ppm. 13 C{1H} NMR (100.62 MHz, CDCl3): δ 164.1 (C-2), 154.0 (C-4), 132.9 (Ci from Ph), 131.0 (Cp from Ph), 130.6 (C-7a), 129.7 (C-6), 129.2 (Co from Ph), 129.0 (Cm from Ph), 127.1 (C-9), 127.0 (C-11), 126.2 (C-10), 125.6 (C-11a), 125.3 (C-8), 104.5 (C-3), 102.2 (C-7), 66.3 (C-11b) ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H15N2O+, 275.1179; found, 275.1179. 4-(4-Ethoxyphenyl)-1,11b-dihydro-2H-pyrimido[2,1-a]isoquinolin-2-one (6b). Method A. From a mixture of isoquinoline (5) (65 mg, 0.5 mmol), acetylene 2c (78 mg, 0.5 mmol), H2O (45 mg, 2.5 mmol), and KOH (6 mg, 20 mol %) (24 h), product 6b (75 mg, 50%) was obtained as mustard powder, mp 214−216 °C (MeCN). Initial isoquinoline (5) was recovered (29 mg, conversion was 55%). IR (microlayer): 1649 (CC, CO) cm−1. 1H NMR (400.13 MHz, CDCl3): δ 7.47−7.45 (m, 2H, H2′,6′ from Ar), 7.33− 7.22 (m, 5H, H-9, H-10, H-11, H3′,5′ from Ar), 7.08 (d, 3J8,9 = 7.4 Hz, 1H, H-8), 6.38 (s, 1H, H-3), 6.26 (d, 3J6,7 = 7.8 Hz, 1H, H-6), 5.73 (s, 1H, H-11b), 5.57 (br s, 1H, NH), 5.54 (d, 3J6,7 = 7.8 Hz, 1H, H-7), 2.69 (q, 3JH,H = 7.8 Hz, 2H, CH2 from Et), 1.26 (t, 3H, Me from Et) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 164.3 (C-2), 154.3 (C-4), 147.9 (C4′ from Ar), 130.8 (C-7a), 130.3 (C1′ from Ar), 129.8 (C-6), 129.4 (C2′,6′ from Ar), 128.7 (C3′,5′ from Ar), 127.4 (C-9), 127.1 (C-11), 126.3 (C-10), 125.8 (C-11a), 125.4 (C-8), 104.1 (C3), 102.2 (C-7), 66.4 (C-11b), 22.9 (CH2 from Et), 15.4 (Me from Et) ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H19N2O+, 303.1492; found, 303.1493. 4-(4-Acetylphenyl)-1,11b-dihydro-2H-pyrimido[2,1-a]isoquinolin-2-one (6c). Method A. From a mixture of isoquinoline (5) (65 mg, 0.5 mmol), acetylene 2c (85 mg, 0.5 mmol), H2O (45 mg, 2.5 mmol), and KOH (6 mg, 20 mol %) (24 h), product 6c (113 mg, 72%) was obtained as yellow powder, mp 227−229 °C (MeCN). F

DOI: 10.1021/acs.joc.9b01482 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

Reaction. Org. Lett. 2007, 9, 571−574. (b) Cho, H. Dihydropyrimidine. Heterocycles 2013, 87, 1441−1479. (c) Panday, A. K.; Mishra, R.; Jana, A.; Parvin, T.; Choudhury, L. H. Synthesis of Pyrimidine Fused Quinolines by Ligand-Free Copper-Catalyzed Domino Reactions. J. Org. Chem. 2018, 83, 3624−3632. (d) Aparna, E. P.; Devaky, K. S. Advances in the Solid-Phase Synthesis of Pyrimidine Derivatives. ACS Comb. Sci. 2019, 21, 35−68. (2) Hermecz, I.; Vasvari-Debreczy, L.; Matyus, P. Bicyclic 6-6 Systems with One Ring Junction Nitrogen Atom:One Extra Heteroatom 1:0. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: London, 1996; Vol. 8, Chapter 23, pp 563−595. (3) Hermecz, I. Chemistry of Benzologs of Pyrido[1,2-a]pyrimidines: Part V of Series on Pyrido-oxazines, -diazines, and thiazines. In Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press, 1999; Vol. 73, pp 177−274. (4) (a) Suri, O. P.; Suri, K. A.; Gupta, B. D.; Satti, N. K. An Unequivocal Synthesis of 4-Methyl-2-oxo-(2H)-pyrido-[1,2-a]pyrimidines. Synth. Commun. 2002, 32, 741−746. (b) Jadhav, A. G.; Halikar, N. K. Synthesis and Biological Activity of Pyrimido[1,2a]quinoline Moiety and Its 2-Substituted Derivatives. J. Phys.: Conf. Ser. 2013, 423, 012007. (c) Elattar, K. M.; Rabie, R.; Hammouda, M. M. Recent Progress in the Chemistry of Bicyclic 6−6 Systems: Chemistry of Pyrido[1,2-a]pyrimidines. Monatshefte Chem. 2017, 148, 601−627. (d) Chen, L.; Huang, R.; Kong, L.-B.; Lin, J.; Yan, S.-J. Facile Route to the Synthesis of 1,3-Diazahetero-Cycle-Fused [1,2a]Quinoline Derivatives via Cascade Reactions. ACS Omega 2018, 3, 1126−1136. (5) Vartale, S. P.; Halikar, N. K.; Pawar, Y. D. Design Synthesis, Reactions and Pharmacological Properties of Some Novel Fused Pyrimido[1,2-a]quinolines Moiety. J. Pharm. Res. 2012, 5, 2672− 2675. (6) Mogle, P. P.; Hese, S. V.; Kamble, R. D.; Hebade, M. J.; Ambhore, A. N.; Kadam, S. N.; Kadam, S. S.; Kamble, S. S.; Gacche, R. N.; Dawane, B. S. Synthesis and Evaluation of 7,8,9,10-Tetrahydro1H-pyrimido[1,2-a]quinoline-2,5-dicarbonitrile Derivatives as a Antimicrobial Agents. J. Chem. Pharm. Res. 2015, 7, 894−900. (7) Kadin, S. B. 2-Amino-4-hydroxyquinolines. Ger. Offen. DE 2801248, Jul. 20, 1978. Chem. Abstr. 1978, 89, 146784. (8) (a) De, P.; Baltas, M.; Bedos-Belval, F. Cinnamic Acid Derivatives as Anticancer Agents-a Review. Curr. Med. Chem. 2011, 18, 1672−1703. (b) Peperidou, A.; Pontiki, E.; Hadjipavlou-Litina, D.; Voulgari, E.; Avgoustakis, K. Multifunctional Cinnamic Acid Derivatives. Molecules 2017, 22, 1247. (9) Baumann, M.; Baxendale, I. R. An Overview of the Synthetic Routes to the Best Selling Drugs Containing 6-Membered Heterocycles. Beilstein J. Org. Chem. 2013, 9, 2265−2319. (10) Flores Toque, H. A.; Priviero, F. B. M.; Teixeira, C. E.; Perissutti, E.; Fiorino, F.; Severino, B.; Frecentese, F.; Lorenzetti, R.; Baracat, J. S.; Santagada, V.; Caliendo, G.; Antunes, E.; De Nucci, G. Synthesis and Pharmacological Evaluations of Sildenafil Analogues for Treatment of Erectile Dysfunction. J. Med. Chem. 2008, 51, 2807− 2815. (11) Kleemann, A.; Engel, J.; Kutscher, B.; Reicher, D. Pharmaceutical Substances (Syntheses, Patents, Applications); Thieme: Stuttgart, NY, 2001; Vol. 1, p 31. (12) Di Braccio, M.; Roma, G.; Leoncini, G. 1,2-Fused Pyrimidines VII. 3-(Dialkylamino)-1H-pyrimido[1,2-a]quinolin-1-ones and 2(Dialkylamino)-4H-pyrimido[2,1-a]isoqiunolin-4-ones as Antiplatelet Compounds. Eur. J. Med. Chem. 1995, 30, 27−38. (13) Adib, M.; Mollahosseini, M.; Yavari, H.; Sayahi, M. H.; Bijanzadeh, H. R. Simple One-Pot Three-Component Synthesis of 2Oxo-1,11b-dihydro-2H-pyrimido[2,1-a]isoquinolines. Synthesis 2004, 2004, 861−864. (14) Chen, D.-Q.; Li, C.-M.; Tu, S.-J. 6-(4-Chlorophenyl)-9,9dimethyl-3,7-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-pyrimido[1,2-a]quinoline-5-carbonitrile. Acta Crystallogr., Sect. E: Struct. Rep. Online 2007, 63, o3931.

Initial isoquinoline (5) was recovered (16 mg, conversion was 75%). IR (microlayer): 1567, 1653, 1676 (CC, CO) cm−1. 1H NMR (400.13 MHz, CDCl3): δ 8.03−8.01 (m, 2H, H3′,5′ from Ar), 7.67− 7.65 (m, 2H, H2′,6′ from Ar), 7.35−7.26 (m, 3H, H-9, H-10, H-11), 7.09 (d, 3J8,9 = 7.4 Hz, 1H, H-8), 6.41 (s, 1H, H-3), 6.16 (d, 3J6,7 = 7.8 Hz, 1H, H-6), 5.80 (s, 1H, H-11b), 5.77 (br s, 1H, NH), 5.59 (d, 3J6,7 = 7.8 Hz, 1H, H-7), 2.63 [s, 3H, Me from C(O)Me] ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 197.3 [CO from C(O)Me], 163.8 (C-2), 152.8 (C-4), 139.0 (C1′ from Ar), 137.3 (C4′ from Ar), 130.5 (C-7a), 129.9 (C-6), 129.6 (C3′,5′ from Ar), 129.0 (C2′,6′ from Ar), 127.3 (C-9), 126.8 (C-11), 126.3 (C-10), 125.7 (C-11a), 125.6 (C8), 105.9 (C-3), 103.0 (C-7), 66.5 (C-11b), 26.9 [Me from C(O)Me] ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H17N2O2+, 317.1285; found, 317.1284. Dehydrogenation of the 5-Methyl-1-phenyl-4,4a-dihydro-3Hpyrimido[1,2-a]quinolin-3-one (3g) to 5-Methyl-1-phenyl-3Hpyrimido[1,2-a]quinolin-3-one (7). A mixture of dihydropyrimido[1,2-a]quinolin-3-one 3g (100 mg, 0.3 mmol), DDQ (79 mg, 0.3 mmol), and CH2Cl2 (1 mL) was stirred at 20−25 °C during 4 h. Solvent was evaporated at the reduced pressure. The solid was extracted with MeCN (10 × 0.5 mL); then, solvent was removed, and the crude product was passed through the chromatography column deliver to pyrimido[1,2-a]quinolin-3-one 7 (37 mg, 43%) as brown oil. Initial compound 3g was recovered (43 mg, conversion was 57%). IR (microlayer): 1631 (CC, CO) cm−1. 1H NMR (400.13 MHz, CDCl3): δ 7.69 (s, 1H, H-6), 7.59 (d, 3J7,8 = 7.6 Hz, 1H, H-7), 7.45− 7.43 (m, 1H, Hp from Ph), 7.41−7.37 (m, 2H, Hm from Ph), 7.33− 7.30 (m, 1H, H-9), 7.28−7.24 (m, 2H, Ho from Ph), 7.03−7.01 (m, 1H, H-8), 6.89 (d, 3J9,10 = 8.6 Hz, 1H, H-10), 6.56 (s, 1H, H-2), 2.49 (s, 3H, Me) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 169.5 (C3), 154.0 (C-4a), 151.0 (C-1), 135.4 (C-10a), 135.1 (C-6), 134.0 (C5), 131.7 (Ci from Ph), 130.4 (Cp from Ph), 129.5 (Cm from Ph), 128.0 (C-9), 127.5 (Co from Ph), 127.3 (C-7), 126.1 (C-8), 124.5 (C-6a), 122.3 (C-10), 113.6 (C-2), 18.5 (Me) ppm. HRMS (ESITOF) m/z: [M + H]+ calcd for C19H15N2O2+, 287.1179; found, 287.1180.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b01482. 1 H and 13C NMR spectra for all new compounds (PDF) Crystallographic data of 6a (CIF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: boris_trofi[email protected]. ORCID

Andrei V. Afonin: 0000-0001-7916-2421 Boris A. Trofimov: 0000-0002-0430-3215 Author Contributions

All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The main results were obtained with Baikal analytical centre of collective using SB RAS. Mass spectra were performed by A. V. Kuzmin in Shared Research Facilities for Physical and Chemical Ultramicroanalysis LIN SB RAS.

■

REFERENCES

(1) (a) Fu, R.; Xu, X.; Dang, Q.; Chen, F.; Bai, X. Rapid Access to Pyrimido[5,4-c]isoquinolines via a Sulfur Monoxide Extrusion G

DOI: 10.1021/acs.joc.9b01482 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry (15) Tu, S.; Li, C.; Li, G.; Cao, L.; Shao, Q.; Zhou, D.; Jiang, B.; Zhou, J.; Xia, M. Microwave-Assisted Combinatorial Synthesis of Polysubstituent Imidazo[1,2-a]quinoline, Pyrimido[1,2-a]quinoline and Quinolino[1,2-a]quinazoline Derivatives. J. Comb. Chem. 2007, 9, 1144−1148. (16) Abdelmoniem, A. M.; Ramadan, M. A.; Ghozlan, S. A. S.; Abdelhamid, I. A. New Synthesis of N-(1H-pyrazol-5-yl)-hexahydroquinoline-3-carbonitrile and Octahydropyrazolo[4′,3′:5,6]pyrimido[1,2-a]quinoline-6-carbonitrile Derivatives from the Cyclic β-Enaminones. J. Heterocycl. Chem. 2017, 54, 1193−1198. (17) Marjani, A. P.; Khalafy, J. A Short and Efficient Method for the Synthesis of Pyrimido[1,2-a]quinolines. Chem. Heterocycl. Compd. 2011, 47, 96−100. (18) Chanda, A.; Fokin, V. V. Organic Synthesis “On Water”. Chem. Rev. 2009, 109, 725−748. (19) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. “On water”: Unique Reactivity of Organic Compounds in Aqueous Suspension. Angew. Chem., Int. Ed. 2005, 44, 3275−3279. (20) (a) Lipshutz, B. H. When Does Organic Chemistry Follow Nature’s Lead and “Make the Switch”? J. Org. Chem. 2017, 82, 2806− 2816. (b) Kitanosono, T.; Masuda, K.; Xu, P.; Kobayashi, S. Catalytic Organic Reactions in Water toward Sustainable Society. Chem. Rev. 2018, 118, 679−746. (21) For example see: (a) Skvortsov, Y. M.; Mal’kina, A. G.; Volkov, A. N.; Trofimov, B. A.; Oleinikova, E. B.; Kazin, I. V.; Gedymin, V. V. Cyanacetylene and Its Derivatives. I Synthesis of Substituted Cyanacetylenes and Their Interaction with Glycols. Izv. Akad. Nauk SSSR, Ser. Khim. 1978, 4, 872−875. (b) Rong, G.; Mao, J.; Zheng, Y.; Yao, R.; Xu, X. Cu-Catalyzed Direct Cyanation of Terminal Alkynes with AMBN or AIBN as the Cyanation Reagent. Chem. Commun. 2015, 51, 13822−13825. (c) Liu, P.; Clark, R. J.; Zhu, L. Synthesis of 1-Cyanoalkynes and Their Ruthenium(II)-Catalyzed Cycloaddition with Organic Azides to Afford 4-Cyano-1,2,3-triazoles. J. Org. Chem. 2018, 83, 5092−5103. (22) (a) Trofimov, B. A.; Belyaeva, K. V.; Nikitina, L. P.; Mal’kina, A. G.; Afonin, A. V.; Ushakov, I. A.; Vashchenko, A. V. Transition Metal-Free One-Pot Double C-H Functionalization of Quinolines with Disubstituted Electron-Deficient Acetylenes. Chem. Commun. 2018, 54, 5863−5866. (b) Belyaeva, K. V.; Nikitina, L. P.; Afonin, A. V.; Trofimov, B. A. Simultaneous Double C2/C3 Functionalization of Quinoline with p-Nitrobenzoyl(phenyl)acetylene. One-Pot Synthesis of 3-(4-Nitrobenzoyl)-2-phenylquinoline. Russ. J. Org. Chem. 2018, 54, 1845−1847. (23) Belyaeva, K. V.; Nikitina, L. P.; Afonin, A. V.; Vashchenko, A. V.; Trofimov, B. A. Reaction of 2-Methylquinoline with 3-Phenylprop-2-ynenitrile in the KOH-H2O System. Russ. Chem. Bull. 2017, 66, 2258−2263. (24) Trofimov, B. A.; Andriyankova, L. V.; Belyaeva, K. V.; Nikitina, L. P.; Afonin, A. V.; Mal’kina, A. G. Ring-Opening of Pyridines with Acylacetylenes and Water: Straightforward Access to 5-[(Z)Acylethenyl]amino-2,4-pentadienals. Eur. J. Org. Chem. 2015, 7876− 7879. (25) Clarke, P. A.; Santos, S.; Martin, W. H. C. Combining Pot, Atom and Step Economy (PASE) in Organic Synthesis. Synthesis of Tetrahydropyran-4-ones. Green Chem. 2007, 9, 438−440. (26) Zhao, H. Y.; Li, Y. M.; Gong, T. J.; Guo, Q. X. A Highly Selective and Easy-to-Synthesize Zn(II) Fluorescent Probe Based on 6-Methoxyquinolin. Chin. Chem. Lett. 2011, 22, 1013−1016. (27) (a) Tsai, P.-J.; Kao, C.-B.; Chiow, W.-R.; Chuang, C.-P. Manganese(III) Acetate Mediated Oxidative Radical Cyclizations of N-(2-Alkenylaryl)-Substituted Enamines. Synthesis 2013, 46, 175− 182. (b) Lu, C.-Y.; Chuang, C.-P. Copper-Catalyzed Aerobic Oxidative Carbocyclization Reactions of N-[(E)-Stilben-2-yl]amine Derivatives. Synthesis 2015, 47, 3687−3700.

H

DOI: 10.1021/acs.joc.9b01482 J. Org. Chem. XXXX, XXX, XXX−XXX