Accessing Polysubstituted Quinazolines via Nickel Catalyzed

Aug 9, 2018 - Accessing Polysubstituted Quinazolines via Nickel Catalyzed Acceptorless Dehydrogenative Coupling. Seuli Parua , Rina Sikari , Suman ...
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Article Cite This: J. Org. Chem. 2018, 83, 11154−11166

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Accessing Polysubstituted Quinazolines via Nickel Catalyzed Acceptorless Dehydrogenative Coupling Seuli Parua, Rina Sikari, Suman Sinha, Gargi Chakraborty, Rakesh Mondal, and Nanda D. Paul* Department of Chemistry, Indian Institute of Engineering Science and Technology, Shibpur, Botanic Garden, Howrah 711103, India

J. Org. Chem. 2018.83:11154-11166. Downloaded from pubs.acs.org by UNIV OF NEW ENGLAND on 09/21/18. For personal use only.

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ABSTRACT: Two environmentally benign methods for the synthesis of quinazolines via acceptorless dehydrogenative coupling of 2-aminobenzylamine with benzyl alcohol (Path A) and 2-aminobenzylalcohol with benzonitrile (Path B), catalyzed by cheap, earth abundant and easy to prepare nickel catalysts, containing tetraaza macrocyclic ligands (tetramethyltetraaza[14]annulene (MeTAA) or 6,15-dimethyl-8,17-diphenyltetraaza[14]annulene (MePhTAA)) are reported. A wide variety of substituted quinazolines were synthesized in moderate to high yields starting from cheap and easily available starting precursors. A few control reactions were performed to understand the mechanism and to establish the acceptorless dehydrogenative nature of the catalytic reactions.

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INTRODUCTION Organo-heterocyclic compounds are one of the major building blocks/structural motifs in the pharmaceutical and agrochemical industries, and almost comprise more than 50% of all drug substances in therapeutic use (Figure 1).1 Among them the quinazoline scaffolds, in particular, are very common structural motifs and are found in a large number of bioactive natural products and pharmacologically relevant compounds having antimicrobial,2 anticonvulsant,3 antiinflammatory,4 antihypertensive,5 antitubercular,6 antimalarial,7 antiviral,8 and anticancer9 activities. Due to the prevalence of these scaffolds in drug discovery and medicinal chemistry, the development of new synthetic approaches for the synthesis of quinazoline derivatives continues to be a active field of research. Over the years, significant advances have been made in developing efficient strategies for the synthesis of quinazoline derivatives. Majority of the synthetic procedures reported until date involves either oxidative condensation or oxidative coupling of two suitable coupling partners.10−12 Among them, the classic approach involves oxidative condensation of 2aminobenzophenones with aldehydes, acyl chloride and ammonium acetate, or benzylamines.10 Condensation of oxime derivatives with aldehydes under oxidative conditions has also been reported for the synthesis of quinazolines.11 Similarly, the oxidative coupling reactions, involving ocarbonyl halobenzenes, ammonia and aldehydes were reported.12 A few Ullmann or Buchwald−Hartwig type coupling followed by intramolecular cyclization reactions were also developed successfully for the synthesis of quinazolines.13,14 These methods mainly involve copper13 or palladium14 catalyzed cyclization of amidines with o-carbonyl halobenzenes, 2-halobenzyl halides/tosylates and 2-halobenzyl © 2018 American Chemical Society

amines, respectively. Some reports are also available involving the oxidative coupling of amidines with benzyl alcohols, benzaldehydes and hypervalent iodine-substituted alkynes, respectively.15 In spite of significant advances on quinazoline synthesis, the synthetic methods developed so far involve multistep reaction sequences, require prefunctionalized starting precursors, and many of them require stoichiometric or excess amounts of strong oxidants. Therefore, development of new, efficient and environmentally benign alternatives for accessing quinazolines from stable and easily available substrates are still a major challenge in catalysis research. In this regard, the acceptorless dehydrogenative coupling of alcohols with suitable coupling partners has emerged as an attractive atom-economic and environment friendly approach for the synthesis of quinazolines and similar heterocycles.16,17 Only H2O and hydrogen gas are produced as chemical waste. The gradual in situ generation of the relatively unstable aldehydes curtails the possibility of decomposition as well as retards the other side reactions which are one of the major drawback during the synthesis of organo-heterocycles via direct coupling of aldehydes with other coupling partners. It can also circumvent the use of toxic oxidants during oxidative cyclization. However, the majority of currently available acceptorless dehydrogenative coupling reactions rely on expensive and relatively scarce heavier transition metal ions.17 Recently, we reported the acceptorless dehydrogenative synthesis of quinazolin-4(3H)-ones and quinolines, catalyzed by a simple nickel catalyst [Ni(MeTAA)], featuring a tetraaza macrocyclic ligand (tetramethyltetraaza[14]annulene Received: July 11, 2018 Published: August 9, 2018 11154

DOI: 10.1021/acs.joc.8b01479 J. Org. Chem. 2018, 83, 11154−11166

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Figure 1. Selected examples of compounds containing quinazoline moiety.

Scheme 1. Synthetic Hypothesis for the Synthesis of Quinazolines via Acceptorless Dehydrogenative Couplinga

a

AAD: acceptorless alcohol dehydrogenation; AD: acceptorless dehydrogenation.

(MeTAA)).18 To further expand the scope of the [Ni(MeTAA)]-catalyzed synthesis of other organo-heterocycles via acceptorless dehydrogenative coupling, we hypothesized that [Ni(MeTAA)] catalyzed acceptorless dehydrogenative coupling of 2-aminobenzylamine with alcohols would form the cyclic 1,2,3,4-tetrahydro-2-phenylquinazoline (A) intermediate which might undergo further dehydrogenation to afford quinazolines (Scheme 1, path A). On the other hand, the acceptorless dehydrogenative coupling of 2-aminobenzyl alcohols with benzonitriles can also afford quinazolines. As reported by Zhang and co-workers,17d this reaction may proceed via the initial nucleophilic addition of the amino group of aminobenzyl alcohol to the benzonitrile to form an amidine intermediate (A′) which upon [Ni(MeTAA)]catalyzed dehydrogenation (alcohol group of (A′)) will produce an o-carbonyl amidine intermediate (B′) which upon intramolecular condensation could afford quinazolines (Scheme 1, path B). Base mediated conversion of benzonitrile to benzamide followed by cyclocondensation

with 2-aminobenzaldehyde, formed via [Ni(MeTAA)] catalyzed acceptorless dehydrogenation, can also produce quinazolines (Scheme 1).19,20 Herein we report two alternative approaches for the onepot synthesis of quinazolines via acceptorless dehydrogenative coupling of (i) 2-aminobenzylamine with alcohols and (ii) 2aminobenzyl alcohols with benzonitriles, catalyzed by square planar Ni(II) complexes featuring tetraaza macrocyclic ligands (Figure 1). Two different Ni(II)-catalysts differing in the ligand functionality were tested: [NiII(MeTAA)] (1a), [Ni II (MePhTAA)] (1b) (Figure 2). The catalyst, [NiII(MeTAA)] (1a), has been found to be more effective affording a wide variety of substituted quinazolines in moderate to good yield.

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RESULTS AND DISCUSSION The nickel(II) tetraaza[14]annulene catalysts, [Ni(MeTAA)] (Ni(II) tetramethyltetraaza[14]annulene) (1a), and [Ni(MePhTAA)] (Ni(II) 6,15-dimethyl-8,17-diphenyltetraaza11155

DOI: 10.1021/acs.joc.8b01479 J. Org. Chem. 2018, 83, 11154−11166

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xylene in the presence of 1.0 equiv of KOtBu and 4.0 mol % catalyst 1a (Table 1, entry 1). Upon lowering base loading and the temperature the yield of quinazoline (4a) decreases significantly; however, no notable improvement of yield was observed with higher base loading at high temperature (>150 °C). Under identical conditions, using 1b as the catalyst, almost comparable yield of 4a was obtained (Table 1, entry 12). Next, we studied the possibility of quinazoline synthesis via acceptorless dehydrogenative coupling of 2-aminobenzylalcohols with benzonitriles, catalyzed by nickel(II) tetraaza[14]annulenes (1a, 1b). Under the preoptimized reaction conditions (optimal conditions for the dehydrogenative coupling of 2-aminobenzylamine (2a) and benzylalcohol (3a), the dehydrogenative coupling of 2-aminobenzylalcohol (2a′) and benzonitrile (3a′), catalyzed by [Ni(MeTAA)] (1a) afforded 85% of desired 2-phenylquinazoline (4a). The reaction even proceeded efficiently at 100 °C, and catalyst loading of 2.5 mol % is sufficient enough to afford the highest yield of (4a) (Table 1, entry 14) in 24 h. Since the complex [Ni(MeTAA)] (1a) is air stable, we studied the catalytic reactions under aerial conditions. 2Phenylquinazoline (4a) was isolated in almost identical yield when the reaction was carried out in the presence of air (Table 2, entry 2). However, the removal of H2 from the reaction mixture is essential for the progress of these dehydrogenative coupling reactions as observed previously during the acceptorless dehydrogenative synthesis of quinolines and quinazolin-4(3H)-ones.18 The yield of the 2phenylquinazoline (4a) decreased significantly when the

Figure 2. Structures of the Ni(II) catalysts used in this study.

[14]annulene) (1b), were synthesized via the straightforward template condensation between 1,2-phenylenediamine and a 2,4-substituted diketone.18 The reaction of 2.0 equiv of 1,2phenylenediamine, 2.0 equiv of 2,4-substituted diketone, and excess nickel(II) acetate tetrahydrate in methanol under refluxing conditions for 48 h afforded complexes 1a and 1b. Our initial studies were focused on the synthesis of quinazolines via acceptorless dehydrogenative coupling of 2aminobenzylamines with alcohols, catalyzed by nickel(II) tetraaza[14]annulenes (1a, 1b) (Scheme 1, path A). At first, 2-aminobenzylamine (2a) and benzylalcohol (3a) were used as the model substrates to optimize reaction conditions including solvents, bases and reaction temperatures using [Ni(MeTAA)] (1a) as the catalyst. The reaction was found to proceed most efficiently in nonpolar solvents like toluene, xylene etc. However, in polar solvents like ethanol, acetonitrile, DMF, the yield of the desired quinazoline decreases significantly. Effect of bases were also investigated (Table 1, entries 1−6), and KOtBu provided the best result (Table 1, entry 1). The reaction did not proceed in absence of base. Highest yield of the 2-phenylquinazoline (4a) was obtained when the reaction was performed at 140 °C in Table 1. Screening for Optimal Reaction Conditionsa−e

entry

Ni-catalyst (mol %)

solvent

base

temperature (°C)

yield (%) (path A)

yield (%) (path B)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

[Ni(MeTAA)] (4 mol %) [Ni(MeTAA)] (4 mol %) [Ni(MeTAA)] (4 mol %) [Ni(MeTAA)] (4 mol %) [Ni(MeTAA)] (4 mol %) [Ni(MeTAA)] (4 mol %) [Ni(MeTAA)] (4 mol %) [Ni(MeTAA)] (4 mol %) [Ni(MeTAA)] (4 mol %) [Ni(MeTAA)] (4 mol %) [Ni(MeTAA)] (4 mol %) [Ni(MePhTAA)] (4 mol %) [Ni(MeTAA)] (4 mol %) [Ni(MeTAA)] (2.5 mol %) − [Ni(MeTAA)] (4 mol %) NiCl2 (10 mol %) Ni(OAc)2 (10 mol %)

xylene xylene xylene xylene xylene xylene toluene acetonitrile ethanol THF DMF xylene xylene xylene xylene xylene xylene xylene

KOtBu NaOtBu KOH NaOH K3PO4 NEt3 KOtBu KOtBu KOtBu KOtBu KOtBu KOtBu KOtBu KOtBu KOtBu − KOtBu KOtBu

140 140 135 140 140 140 140 140 140 140 140 140 100 100 140 140 140 140

66 57 56 52 trace NR 60 trace trace 59 trace 62 55 53 NR NR NR NR

85 70 60 59 trace NR 75 trace trace 65 trace 42 85 85 NR NR trace trace

a

Stoichiometry (Path A): 2-aminobenzylamine (2a) (1.0 mmol), benzylalcohol (3a) (1.0 mmol); (Path B): 2-aminobenzylalcohol (2a′) (1.0 mmol), benzonitrile (3a′) (1.0 mmol); base (1.0 mmol, 1.0 equiv). bSolvent: 5.0 mL. cUnder argon atmosphere. dIsolated yields after column chromatography. eTime: 24 h. 11156

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corresponding benzonitriles having -Cl group at the ortho-, meta-, or para-positions afforded the corresponding quinazolines in 70, 75 and 71% yields respectively (Table 3, entries 9−11). Similarly benzylalcohols/benzonitriles bearing electron withdrawing -F group at the para- position or -Br group at the para-, or meta- positions afforded the corresponding quinazolines in 63, 65, 63% (with benzylalcohols) and 72, 70 and 74% (with benzonitriles) yields respectively (Table 3, entries 12−14). Reaction also proceeded with substrates (benzylalcohols/benzonitriles) bearing multiple electron withdrawing groups; 3,5-difluorobenzylalcohol and the corresponding 3, 5-difluorobenzonitrile afforded the corresponding 2-(3,5-difluorophenyl)quinazoline (4o) in 57% and 75% isolated yields respectively (Table 3, entry 15). Reactions also proceeded with heterocyclic alcohols and nitriles, the corresponding quinazolines were isolated in moderate to good yields. For example, 2-thiophenemethanol, 2-pyridinemethanol, 4-pyridinemethanol or the corresponding nitriles when reacted with 2-aminobenylamine (2a) and 2-aminobenzylalcohol (2a′) separately under the optimized reaction conditions afforded the corresponding quinazolines in 59, 45, 50% (via Path A), and 62, 50, 56% (via Path B) isolated yields respectively (Table 3, entries 17−19). Reactions also proceed with aliphatic alcohols or nitriles as the coupling partner, albeit the yield of the desired quinazoline decreases significantly and require a longer reaction time (Table 3, entry 20). To further expand the substrate scope various substituted 2-aminobenzylamines and 2-aminobenzylalcohols were employed as substrates to test the catalytic formation of quinazolines using benzylalcohol (3a) and benzonitrile (3a′) as the coupling partners, respectively. 2-aminobenzylamines and 2-aminobenzylalcohols bearing either electron donating or electron withdrawing groups were all effective, affording the corresponding quinazolines in good yields (Table 4, entries 1−9). 2-Aminobenzylamines and 2-aminobenzylalcohols bearing both electron donating and withdrawing groups were also found to produce the corresponding quinazoline (4v) in 70% and 80% isolated yields respectively (Table 4, entry 2). Reactions also proceeded with 2-aminobenzylalcohols with the substitution at the benzyl position (Table 4, entries 5, 6). To gain mechanistic insights on the quinazoline forming process via path A, the cyclic 1,2,3,4-tetrahydro-2-phenylquinazoline (4) derivative was synthesized via direct condensation of 2-aminobenzylamine and benzaldehyde (Scheme 2, eq 1) and subjected to dehydrogenation under the optimized catalytic conditions. The desired 1-phenylquinazoline (4a) was formed in 82% yield (Scheme 2, eq 2). A few control reactions were also carried out to understand the possible intermediates involved in the [Ni(MeTAA)] catalyzed dehydrogenative coupling of 2-aminobenzylalcohol and benzonitrile (Path B). KOtBu, other than acting as a deprotonating agent, can convert nitriles to the corresponding amides even in anhydrous reaction medium under nitrogen atmosphere.19 Therefore, the [Ni(MeTAA)]-catalyzed dehydrogenative coupling of 2-aminobenzylalcohol and benzonitrile can proceed via (i) initial nucleophilic addition of the amino group of 2-aminobenzyl alcohol/aldehyde to the benzonitrile to form an amidine intermediate followed by stepwise dehydrogenation and intramolecular condensation as proposed earlier by Zhang and co-workers17d or (ii) dehydrogenation of 2-aminobenzylalcohol to the correspond-

Table 2. Acceptorless Dehydrogenative Coupling of 2Aminobenzylamine (2a) and 2-Aminobenzylalcohol (2a′) with Benzylalcohol (3a) and Benzonitrile (3a′) in Open/ Closed Conditionsa−c entry

open/ closed

1 2 3

open open closed

atmosphere yield (%) (path A) yield (%) (path B) Ar air air/Ar

66 64 45

85 83 56

a

Path A: stoichiometry: 2-aminobenzylamine (2a) (1.0 mmol), benzylalcohol (3a) (1.0 mmol); temperature: 140 °C; [Ni(MeTAA)] loading: 4.0 mol %; KOtBu (1.0 mmol, 1.0 equiv). bPath B: 2aminobenzylalcohol (2a′) (1.0 mmol), benzonitrile (3a′) (1.0 mmol); temperature: 100 °C; [Ni(MeTAA)] loading: 2.5 mol %; KOtBu (1.0 mmol, 1.0 equiv). cIsolated yields after column chromatography.

reaction was carried out in a closed Schlenk tube (Table 2, entry 3). Control experiments showed that no product was obtained in the absence of the catalyst, [Ni(MeTAA)] (Table 1, entry 15). While in the presence of other nickel(II) sources like NiCl2 and Ni(OAc)2 only a trace amount of quinazoline formation was observed (Table 1, entries 17, 18). Once we had the optimized conditions in hand, we set out to investigate the substrate scope and versatility of the above two alternative pathways (Path A and Path B) for the synthesis of quinazolines via acceptorless dehydrogenative coupling reactions, catalyzed by [Ni(MeTAA)] (1a) (Table 3). Initially, 2-aminobenzylamine (2a) and 2-aminobenzylalcohol (2a′) were reacted separately with various substituted benzylalcohols (3a−3t) and benzonitriles (3a′−3t′) respectively, under the optimized reaction conditions. Both benzylalcohols and benzonitriles bearing electron donating and electron withdrawing groups were found to be compatible as coupling partners with 2-aminobenzylamine (2a) and 2-aminobenzylalcohol (2a′) respectively, affording the corresponding quinazolines in good to excellent yields. For example, benzylalcohols having -Me substituents either at ortho-, meta-, or para-positions produced the corresponding 2-o-tolylquinazoline (4b), 2-m-tolylquinazoline (4c) and 2-ptolylquinazoline (4d) in 60, 61 and 64% yields, respectively. On the other hand, benzonitriles bearing -Me substituents either at ortho-, meta-, or para-positions produced the corresponding quinazolines in 65, 69 and 70% yields, respectively. It is noteworthy to mention here that, in path A, during acceptorless dehydrogenative coupling of benzylalcohols bearing electron donating groups, addition of styrene as the sacrificial hydrogen acceptor increases the yields of the desired quinazolines significantly, whereas the acceptorless dehydrogenative coupling of 2-aminobenzylalcohol with benzonitriles did not require any sacrificial hydrogen acceptor. Reactions also proceeded with benzylalcohols bearing electron withdrawing substituents; the desired quinazolines were obtained in slightly higher yields than that of their counterparts containing electron donating groups. On the other hand, benzonitriles bearing electron withdrawing groups were found to be equally effective, affording the corresponding quinazolines in good yields. Benzylalcohols bearing electron withdrawing -Cl group at the ortho-, meta-, or para-positions afforded the corresponding quinazolines in 69, 67 and 65% yields respectively (Table 3, entries 9−11). The 11157

DOI: 10.1021/acs.joc.8b01479 J. Org. Chem. 2018, 83, 11154−11166

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Table 3. Dehydrogenative Coupling of 2-Aminobenzylamine and 2-Aminobenzylalcohol with Various Benzylalcohols and Benzonitriles, Catalyzed by [Ni(MeTAA)] (1a)a−f

a

Stoichiometry (Path A): 2-aminobenzylamine (2a) (1.0 mmol), benzylalcohol (3a) (1.0 mmol); (Path B): 2-aminobenzylalcohol (2a′) (1.0 mmol), benzonitrile (3a′) (1.0 mmol); KOtBu (1.0 mmol, 1.0 equiv). bXylene: 5.0 mL. cUnder argon atmosphere. dIsolated yields after column chromatography. e(*) represents the yield of quinazolines obtained via dehydrogenative coupling of 2-aminobenzylamine (2a) with benzylalcohols (3a−t). f(#) represents the yield of quinazoline obtained via dehydrogenative coupling of 2-aminobenzylalcohol (2a′) with benzonitriles (3a′− 3t′).

ing aldehyde followed by the condensation with amides generated in situ from benzonitrile via KOtBu mediated transformation. To eliminate the possibility of KOtBu mediated conversion of nitriles to amide and to check the possibility of amidine formation,17d when benzonitrile was reacted with the sodium salt of the 2-aminobenzylalcohol under the optimized catalytic reaction conditions (in absence of KOtBu) only 4% of 4a was obtained along with 8% of 2-amino-

benzaldehyde, 26% of unreacted benzonitrile and some unidentified products were also isolated (Scheme 3, eq 1). Interestingly, when the same reaction of benzonitrile and the sodium salt of the 2-aminobenzylalcohol was carried out in the presence of one equivalent of KOtBu and [Ni(MeTAA)] (2.5 mol %), the yield of 4a drastically increases to 80% (Scheme 3, eq 2). And on lowering the amount of KOtBu to 0.5 equiv, the yield of quinazoline decreases to 50% indicating the possibility of active involvement of KOtBu, 11158

DOI: 10.1021/acs.joc.8b01479 J. Org. Chem. 2018, 83, 11154−11166

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The Journal of Organic Chemistry Table 4. Dehydrogenative Coupling of Various Substituted 2-Aminobenzylamines and 2-Aminobenzylalcohols with Benzylalcohols and Benzonitriles, Catalyzed by [Ni(MeTAA)] (1a)a−f

a

Stoichiometry (Path A): 2-aminobenzylamine (1.0 mmol), benzylalcohol (1.0 mmol); (Path B): 2-aminobenzylalcohols (1.0 mmol), benzonitrile (1.0 mmol); KOtBu (1.0 mmol, 1.0 equiv). bXylene: 5.0 mL. cUnder argon atmosphere. dIsolated yields after column chromatography. e(*) represents the yield of quinazolines obtained via dehydrogenative coupling of 2-aminobenzylamines (2b−j) with benzylalcohol (3a). f(#) represents the yield of quinazoline obtained via dehydrogenative coupling of 2-aminobenzylalcohols (2a′−h′) with benzonitrile (3a′).

Scheme 2. Control Reactions during [Ni(MeTAA)] Catalyzed Dehydrogenative Coupling of 2-Aminobenzylamine and Benzylalcohol (Path A)

(1.0 equiv) under argon atmosphere in anhydrous xylene 50% of benzamide was isolated from the reaction medium (Scheme 3, eq 6).19 Further reaction of benzamide with 2aminobenzylalcohol under the optimized catalytic conditions afforded 56% of the desired quinazoline (Scheme 3, eq 7). Moreover, the reaction of benzamide with the preformed 2aminobenzaldehyde in absence of [Ni(MeTAA)] afforded the desired quinazoline in 16% yield. The lower yield obtained in this case may be attributed to the instability of 2aminobenzaldehyde (Scheme 3, eq 8).

other than as a deprotonating agent. However, these reactions did not produce any quinazoline 4a in absence of the catalyst [Ni(MeTAA)] (1a). The reaction of benzonitrile with the preformed 2-aminobenzaldehyde or 1-(2-aminophenyl)ethanone in absence of KOtBu also failed to produce the desired quinazoline 4a (Scheme 3, eq 4), further indicating the active involvement of KOtBu during quinazoline formation. To check the possibility of KOtBu mediated benzamide formation, when benzonitrile was reacted alone with KOtBu 11159

DOI: 10.1021/acs.joc.8b01479 J. Org. Chem. 2018, 83, 11154−11166

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Scheme 3. Control Reactions during [Ni(MeTAA)] Catalyzed Dehydrogenative Coupling of 2-Aminobenzylalcohol and Benzonitrile

measured experimentally during the dehydrogenative coupling of 2-aminobenzylamine and 3-methoxybenzylalcohol and 75% of theoretical yield of hydrogen was determined experimentally during direct dehydrogenation of 1,2,3,4-tetrahydro-2phenylquinazoline (4′). On the other hand, 83% hydrogen was quantified for the dehydrogenative coupling of 2aminobenzyalcohol (1a) with benzonitrile (3a′). On the basis of the above experimental results and available literature, a plausible mechanism for the dehydrogenative synthesis of quinazoline either via Path A or Path B is shown in Scheme 5. The first step in both Path A and Path B is the dehydrogenation of the alcohols to the corresponding aldehydes. It is believed to proceed via the initial deprotonation of the alcohols (benzyl alcohol in Path A and 2-aminobenzyl alcohol in Path B) followed by formation of

Finally to confirm the hydrogen evolution during the dehydrogenative synthesis of quinazolines via either Path A or Path B, dehydrogenation reactions were performed in the presence of a sacrificial hydrogen acceptor like, 4-methoxybenzaldehyde under argon atmosphere. When the cyclic 1,2,3,4-tetrahydro-2-phenylquinazoline (4′) intermediate was subjected to dehydrogenation in the presence of 4methoxybenzaldehyde, 4-methoxybenzylalcohol was isolated in 37% (Scheme 4, eq 2). Moreover, Pd/C catalyzed hydrogenation of styrene using the evolved H2 during these dehydrogenation reactions clearly shows the formation ethylbenzene (see Experimental Section for details) (Scheme 4, eq 3 and 4). Quantification of the liberated hydrogen was done using gas buret. A 53% of theoretical yield of hydrogen was 11160

DOI: 10.1021/acs.joc.8b01479 J. Org. Chem. 2018, 83, 11154−11166

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Scheme 5. Plausible Mechanism of Quinazoline Synthesis via Path A and Path B

the nickel-alkoxy intermediate (C) which then undergoes dehydrogenation to produce the corresponding aldehydes. Benzaldehydes, thus formed (Path A) undergoes cyclocondensation with 2-aminobenzylamine to form the intermediate (A) which upon further [Ni(MeTAA)] catalyzed dehydrogenation afforded (4a). On the other hand, in Path B, base promoted cyclocondensation of 2-aminobenzyldehyde (formed via [Ni(MeTAA)]-catalyzed acceptorless dehydrogenation of 2-aminobenzyl alcohol) with benzamide (formed in situ from benzonitrile) produce the desired quinazoline

(4a). The other possible pathway via amidine intermediate seems less likely as no quinazoline (4a) formation was observed even when the preformed 2-aminobenzaldehyde or 1-(2-aminophenyl)ethanone was reacted separately with benzonitrile in absence of KOtBu, however, cannot be ruled out completely.

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CONCLUSION In summary we have developed two simple but efficient alternative methods for the synthesis of quinazolines via 11161

DOI: 10.1021/acs.joc.8b01479 J. Org. Chem. 2018, 83, 11154−11166

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The Journal of Organic Chemistry

2-Aminobenzyamine (2a) with Benzylalcohol (3a). In a typical experimental setup two Schlenk tubes were connected using a rubber tube. Under argon atmosphere, the first Schlenk tube was charged with [Ni(MeTAA)] (4.0 mol %) and KOtBu (1.0 mmol). In the second Schlenk tube styrene and Pd/C (0.5 g) were placed in THF with a magnetic stir bar. Then this tube was capped by using a Teflon screw cap, evacuated, and backfilled with argon. Rubber septum was used in place of screw cap. In the first Schlenk 2aminobenzylamine (2a) (1.0 mmol) and benzylalcohol (3a) (1.0 mmol) dissolved in 5.0 mL of xylene was added via a syringe. Then this Schlenk tube was placed in an oil bath preheated at 130 °C for 24 h. The conversion of styrene to ethylbenzene was confirmed by GC−MS analysis of the reaction mixture present in the second Schlenk containing styrene. During [Ni(MeTAA)] Catalyzed Acceptorless Dehydrogenative Coupling of 2-Aminobenzyalcohol (2a′) with Benzonitrile (3a′). Under argon atmosphere, a mixture of [Ni(MeTAA)] (2.5 mol %) and KOtBu (1.0 mmol) were added to a Schlenk tube connected with another Schlenk tube by a rubber tube in which styrene and Pd/C (0.5 g) were placed in THF with a magnetic stir bar. Then this tube was capped by using a Teflon screw cap, evacuated, and backfilled with argon. Rubber septum was used in place of screw cap. In the first Schlenk 2-aminobenzyl alcohol (2a′) (1.0 mmol) and benzonitrile (3a′) (1.0 mmol) dissolved in 5.0 mL of xylene was added via a syringe. Then this Schlenk tube was placed into an oil bath and then heated at 100 °C for 24 h. The conversion of styrene to ethylbenzene was confirmed by GC−MS analysis of the reaction mixture present in the second Schlenk containing styrene. Estimation of Evolved Hydrogen by Volumetric Measurement. During [Ni(MeTAA)] Catalyzed Acceptorless Dehydrogenative Coupling of 2-Aminobenzyamine (2a) with 3-Methoxybenzylalcohol (3e). A mixture of 2-aminobenzylamine (2a) (1.0 mmol), 3-methoxybenzylalcohol (3e) (1.0 mmol), [Ni(MeTAA)] (4.0 mol %), and KOtBu (1.0 mmol) in 5 mL of xylene were placed in an oven-dried 25 mL Schlenk tube linked to a gas buret. Then the Schlenk tube was placed in an oil bath preheated at 140 °C and the reaction was continued for 24h. To get consistent reading this experiment was repeated several times. Volume of water level displaced was found to be 42.0 mL. The number of moles of hydrogen evolved was calculated by taking into account the vapor pressure of water at 306 K = 37.7 Torr, the atmospheric pressure 761.3126 Torr, R = 62.3635 L Torr K−1 mol−1, n(H2) = [(Patm − Pwater)V]/RT = 0.001593 mol, expected value 0.003 mol.18 During [Ni(MeTAA)] Catalyzed Acceptorless Dehydrogenation of 1,2,3,4-Tetrahydro-2-(3-methoxyphenyl)quinazoline. 1,2,3,4Tetrahydro-2-(3-methoxyphenyl)quinazoline (1.0 mmol), [Ni(MeTAA)] (4.0 mol %), and KOtBu (1.0 mmol) in 5 mL of xylene were placed in an oven-dried 25 mL Schlenk tube linked to a gas buret. The Schlenk tube was then placed in an oil bath preheated at 140 °C. The reaction was continued for 24 h. To get consistent reading this experiment was repeated several times. Volume of water level displaced was found to be 40.0 mL. The number of moles of hydrogen evolved was calculated by taking into account the vapor pressure of water at 307 K = 39.9 Torr, volume of water displaced (52.0 mL), the atmospheric pressure 761.3126 Torr, R = 62.3635 L Torr K−1 mol−1, n(H2) = [(Patm − Pwater)V]/ RT = 0.001507 mol, expected value 0.0020 mol.18 During [Ni(MeTAA)] Catalyzed Acceptorless Dehydrogenative Coupling of 2-Aminobenzyalcohol (2a′) with Benzonitrile (3a′). A mixture of 2-aminobenzylalcohol (1.0 mmol), benzonitrile (1.0 mmol), [Ni(MeTAA)] (2.5 mol %), and KOtBu (1.0 mmol) in 5 mL of xylene were placed in an oven-dried 25 mL Schlenk tube linked to a gas buret. The Schlenk tube was then placed in an oil bath preheated at 100 °C. The reaction was continued for 24 h. To get consistent reading this experiment was repeated several times. Volume of water level displaced was found to be 22.0 mL. The number of moles of hydrogen evolved was calculated by taking into account the vapor pressure of water at 306 K = 37.7 Torr, the atmospheric pressure 761.3126 Torr, R = 62.3635 L Torr K−1

acceptorless dehydrogenative coupling reactions, catalyzed by a cheap, earth abundant and easy to prepare Ni(II)-catalyst [Ni(MeTAA)]. A wide variety of substituted quinazolines were obtained in moderate to good isolated yields starting from cheap and easily available starting precursors. Overall, these synthetic approaches are operationally simple, straightforward, and proceed with high atom efficiency and do not require expensive heavier transition metals like ruthenium or iridium.

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EXPERIMENTAL SECTION

General Information. Unless otherwise stated all the reactions were carried out under argon atmosphere using standard Schlenk techniques. Tetrahydrofuran (THF), toluene, xylene, 1,4-dioxane, were refluxed over sodium/benzophenone and distilled under argon atmosphere, and then stored over molecular sieves of 4 Å. All other chemicals used in this work were purchased from commercial suppliers and used as received without any further purification. Analytical TLC was performed by using Merck 60 F254 silica gel plate of 0.25 mm thickness and column chromatography was performed by using Merck 60 silica gel of 60−120 mesh. Bruker DPX-300 (300 MHz), and Bruker DPX-400 (400 MHz) spectrometers was used for 1H NMR spectra measurement. TMS (tetramethylsilane) was used as the internal standard. ESI mass were recorded on a mass spectrometer of micromass Q-TOF (serial no. YA 263). PerkinElmer CLARUS 680 instrument was used for GC− MS. Caution! Reactions should be handled with care with appropriate safety precautions where hydrogen evolution occurs at high temperature. Synthesis of Ni(II)-Catalysts. [Ni(MeTAA)] and [Ni(MePhTAA)] were synthesized following the known literature methods.18 General Procedure for Acceptorless Dehydrogenative Coupling of 2-Aminobenzylamine with Benzylalcohol. Under argon atmosphere a 10 mL process vial fitted with a magnetic stir bar was charged with 2-aminobenzylamine (1.0 mmol), benzylalcohol (1.0 mmol), [Ni(MeTAA)] (4.0 mol %), KOtBu (1.0 mmol) and 5.0 mL xylene. The vial was then closed and placed in an oil bath preheated at 140 °C for a given time. After the reaction was complete, the reaction mixture was concentrated under vacuum and the products were purified by flash column chromatography (silica gel) using EtOAc/petroleum ether (1:24) as the eluent. General Procedure for Acceptorless Dehydrogenative Coupling of o-Aminobenzylalcohol with Benzonitrile. A oven-dried Schlenk tube fitted with a magnetic stir bar was charged with 2-aminobenzyl alcohol (1.0 mmol), [Ni(MeTAA)] (2.5 mol %) and KOtBu (1.0 mmol). The Schlenk tube was then capped with a rubber septum, evacuated and backfilled with argon three times. A long neck needle connected with a balloon filled with argon was then inserted to the Schlenk tube. To it 1.0 mmol of the corresponding benzonitriles dissolved in 5.0 mL of degassed xylene was added through a syringe. The Schlenk tube was then placed in an oil bath preheated at 100 °C for a given time. After the reaction was complete, the reaction mixture was concentrated under vacuum and the products were purified by flash column chromatography (silica gel) using EtOAc/petroleum ether (1:24) as the eluent. General Procedure for the Synthesis of 1,2,3,4-Tetrahydro2-phenylquinazoline. A oven-dried Schlenk tube fitted with a magnetic stir bar was charged with 2-aminobenzyl amine (1.0 mmol). The Schlenk tube was then capped with a rubber septum, evacuated and backfilled with argon three times. A long neck needle connected with a balloon filled with argon was then inserted to the Schlenk tube. To it 1.0 mmol of benzaldehyde dissolved in 5.0 mL of EtOH was added through a syringe. The Schlenk tube was the stirred for 24 h. After the reaction was complete, the reaction mixture was concentrated under vacuum and the products were purified by flash column chromatography (silica gel) using EtOAc/ petroleum ether (1:2) as the eluent. Hydrogenation of Styrene by Evolved Hydrogen. During [Ni(MeTAA)] Catalyzed Acceptorless Dehydrogenative Coupling of 11162

DOI: 10.1021/acs.joc.8b01479 J. Org. Chem. 2018, 83, 11154−11166

Article

The Journal of Organic Chemistry mol−1, n(H2) = [(Patm − Pwater)V]/RT = 0.00083 mol, expected value 0.001 mol.18 Characterization Data of the Isolated Compounds. (*) Represents the yield of Path A and (#) represents the yield of Path B. 2-Phenylquinazoline (4a).10f,13h,17d Eluent: petroleum ether/ ethyl acetate (24:1). White solid (*66% and #85%, *136 and #175 mg). mp 97−98 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 9.47 (s, 1H), 8.67−8.65 (m, 2H), 8.10 (d, J = 8.8 Hz, 1H), 7.92−7.88 (m, 2H), 7.61−7.53 (m, 4H). 13C NMR (100 MHz, CDCl3) δ (ppm) = 160.9, 160.4, 150.6, 138.0, 134.0, 130.5, 128.5 (2C), 128.5, 127.1, 127.0, 123.5. 2-o-Tolylquinazoline (4b).10f Eluent: petroleum ether/ethyl acetate (24:1). colorless oil (*60% and #65%, *132 and #143 mg). mp 44−45 °C; 1H NMR (300 MHz, CDCl3) δ (ppm) = 9.52 (s, 1H), 8.12 (d, J = 9 Hz, 1H), 7.99−7.90 (m, 3H), 7.70−7.65 (m, 1H), 7.39−7.34 (m, 3H), 2.62 (s, 3H).13C (75 MHz, CDCl3) δ (ppm) = 164.2, 160.2, 150.5, 138.7, 137.5, 134.2, 131.4, 130.7, 129.4, 128.7, 127.6, 127.1, 126.0, 122.9, 20.9. 2-m-Tolylquinazoline (4c).17f Eluent: petroleum ether/ethyl acetate (24:1). White solid (*61% and #69%, *134 and #152 mg). mp 101−102 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 9.49 (s, 1H), 8.46−8.43 (m, 2H), 8.12 (d, J = 8.5 Hz, 1H), 7.96−7.91 (m, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 2.52 (s, 3H). 13C (100 MHz, CDCl3) δ (ppm) = 161.1, 160.3, 150.7, 138.2, 137.9, 134.0, 131.3, 129.0, 128.5, 128.5, 127.1, 127.0, 125.7, 123.5, 21.4. 2-p-Tolylquinazoline (4d).13g,h Eluent: petroleum ether/ethyl acetate (24:1). White solid (*64% and #70%, *141 and #154 mg). mp 107−109 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 9.45 (s, 1H), 8.54 (d, J = 8.0 Hz, 2H), 8.10 (d, J = 8.6 Hz, 1H), 7.95−7.92 (m, 2H), 7.64−760 (m, 1H), 7.36 (d, J = 7.9 Hz, 2H), 2.47 (s, 3H). 13C (100 MHz, CDCl3) δ 161.1, 160.3, 150.7, 140.7, 135.2, 133.9, 129.3, 128.5, 128.4, 127.0, 126.9, 123.4, 21.4. 2-(3-Methoxyphenyl)quinazoline (4e).17f Eluent: petroleum ether/ethyl acetate (24:1). White solid (*66% and #74%, *156 and #175 mg). mp 93−95 °C; 1H NMR (300 MHz, CDCl3) δ (ppm) = 9.47 (s, 1 H), 8.21 (t, J = 7.74 Hz, 2 H), 8.10 (d, J = 8.25 Hz, 1 H), 7.93 (d, J = 6.06 Hz, 2 H), 7.62 (t, J = 6.84 Hz, 1 H), 7.45 (t, J = 7.80 Hz, 1 H), 7.07 (d, J = 5.73 Hz, 1 H), 3.96 (s, 3 H). 13C (100 MHz, CDCl3) δ (ppm) = 160.8, 160.5, 160.0, 150.7, 139.5, 134.1, 129.7, 128.7, 127.3, 127.1, 123.7, 121.2, 117.3, 113.0, 55.5. 2-(4-Methoxyphenyl)quinazoline (4f).13g,h Eluent: petroleum ether/ethyl acetate (24:1). White solid (*64% and #67%, *151 and #158 mg). mp 87−89 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 9.43 (s, 1H), 8.60 (d, J = 8.5 Hz, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.91−7.87 (m, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 3.92 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) = 161.7, 160.7, 160.3, 150.7, 133.9, 130.6, 130.1, 128.3, 127.0, 126.7, 123.2, 113.9, 55.3. 2-(2,4-Dimethoxyphenyl)quinazoline (4g). Eluent: petroleum ether/ethyl acetate (5:1). White solid (*60% and #69%, *160 and # 184 mg). mp 90−91 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 9.39 (s, 1H, (H1)), 8.01 (d, J = 8.4 Hz, (1H, H5)), 7.85−7.75 (m, 3H, (H2, H3, H4)), 7.54 (d, J = 7.6 Hz, (1H, H6)), 6.58−6.54 (m, 2H, (H7, H8)), 3.80 (br s, 6H, (H9A-C), (H10A-C)). 13C NMR (100 MHz, CDCl3) δ (ppm) = 162.2, 162.1, 160.0, 159.2, 150.7, 134.0, 133.2, 128.4, 127.2, 127.1, 122.9, 121.8, 105.0, 99.4, 56.0, 55.5. HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H15N2O2+ 267.1133, found 267.1100. 2-(4-tert-Butylphenyl)quinazoline (4h).10d Eluent: petroleum ether/ethyl acetate (24:1). White solid (*62% and #68%, *162 and #178 mg). mp 82−84 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 9.45 (s, 1H), 8.56 (d, J = 8.2 Hz, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.95−7.89 (m, 2H), 7.64−7.58 (m, 3H), 1.42 (s, 9H). 13C NMR (100 MHz, CDCl3) δ (ppm) = 161.0, 160.3, 153.8, 150.7, 135.2, 133.9, 128.5, 128.2, 127.0, 126.9, 125.5, 123.4, 34.8, 31.2. 2-(2-Chlorophenyl)quinazoline (4i).12b Eluent: petroleum ether/ ethyl acetate (24:1). yellow solid (*69% and #70%, *166 and #168

mg). mp 69−70 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 9.50 (s, 1H), 8.11 (t, J = 8.8 Hz, 1H), 7.97−7.90 (m, 2H), 7.45(d, J = 8.0 Hz, 2H), 7.39−7.32 (m, 2H). 2-(3-Chlorophenyl)quinazoline (4j).12b,17f Eluent: petroleum ether/ethyl acetate (24:1). White solid (*67% and #75%, *161 and #181 mg). mp 148−150 °C; 1H NMR (300 MHz, CDCl3) δ (ppm) = 9.46 (s, 1H), 8.64 (s, 1H), 8.53−8.51 (m, 1H), 8.09 (d, J = 9 Hz, 1H), 7.95−7.90 (m, 2H), 7.64 (t, J = 9 Hz, 1H), 7.50−7.44 (m, 2H) . 13C (75 MHz, CDCl3) δ (ppm) = 160.7, 159.8, 150.7, 139.9, 134.8, 134.4, 130.6, 129.9, 128.7, 128.7, 127.7, 127.2, 126.7, 123.8. 2-(4-Chlorophenyl)quinazoline (4k).12b,17d Eluent: petroleum ether/ethyl acetate (24:1). White solid (*65% and #71%, *156 and #171 mg). mp 133−135 °C; 1H (400 MHz, CDCl3) δ (ppm) = 9.47 (s, 1H), 8.60 (d, J = 8.2 Hz, 2H), 8.09 (d, J = 8.3, 1H), 7.96− 7.92 (m, 2H), 7.65 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 8.6 Hz, 2H). 13 C (100 MHz, CDCl3) δ (ppm) = 160.4, 159.9, 150.6, 136.7, 136.4, 134.1, 129.8, 128.7, 128.5, 127.3, 127.0, 123.5. 2-(4-Fluorophenyl)quinazoline (4l).12b,13h,17f Eluent: petroleum ether/ethyl acetate (24:1). White solid (*63% and #72%, *141 and # 161 mg). mp 122−123 °C; 1H NMR (300 MHz, CDCl3) δ (ppm) = 9.43(s, 1H), 8.64−8.59(m, 2H), 8.06(d, J = 8.2 Hz, 1H), 7.91(d, J = 7.6 Hz, 2H), 7.60(t, J = 6.8 Hz, 1H), 7.32−7.17(m, 2H). 13C NMR (100 MHz, CDCl3) δ (ppm) = 165.9, 163.4, 160.5, 160.1, 150.7, 134.2, 130.7, 130.6, 128.5, 127.3, 127.2, 123.5, 115.7, 115.5. 2-(3-Bromophenyl)quinazoline (4m).12b,17f Eluent: petroleum ether/ethyl acetate (24:1). White solid (*63% and #74% and *180 and #211 mg). mp 153−155 °C; 1H NMR (300 MHz, CDCl3) δ (ppm) = 9.47(d, J = 4.98 Hz, 1H), 8.79(s, 1H), 8.55(d, J = 6.45 Hz, 1H), 8.09(d, J = 6.12 Hz, 1H), 7.94(d, J = 6.4 Hz, 2H), 7.65(d, J = 5.79 Hz, 2H), 7.40(t, J = 5.94 Hz, 1H). 13C (100 MHz, CDCl3) δ (ppm) = 160.5, 159.5, 150.6, 140.1, 134.3, 133.5, 131.6, 130.1, 128.7, 127.7, 127.2, 127.1, 123.7, 122.9. 2-(4-Bromophenyl)quinazoline (4n).17f Eluent: petroleum ether/ ethyl acetate (24:1). White solid (*65% and #70%, *185 and #200 mg). mp 120−121 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 9.45 (s, 1H), 8.51 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.6 Hz, 1H), 7.94−7.90 (m, 2H), 7.68−7.61 (m, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) = 160.4, 160.0, 150.6, 136.9, 134.1, 131.7, 130.0, 128.5, 127.4, 127.0, 125.3, 123.5. 2-(3,5-Difluorophenyl)quinazoline (4o). Eluent: petroleum ether/ethyl acetate (24:1). White solid (*57% and #75%, *138 and #182 mg). mp 137−138 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) = 9.46 (s, 1H, (H1)), 8.20−8.14 (m, 2H, (H4, H5)), 8.09 (d, J = 8.0 Hz, 1H, (H2)), 7.94 (t, J = 7.6 Hz, 2H, (H6, H8)), 7.66 (t, J = 7.6 Hz, 1H, (H3)), 6.97−6.91(m, 1H, (H7)). 13C NMR (100 MHz, CDCl3) δ (ppm) = 164.5 (d, J = 10.0 Hz), 162.5 (d, J = 10.0 Hz), 160.7 (d, J = 23.0 Hz), 159.0, 150.7, 141.8 (t, J = 7.0 Hz), 134.6 (d, J = 20.0 Hz), 128.9 (d, J = 19.0 Hz), 128.1 (d, J = 18.0 Hz), 127.3 (d, J = 20.0 Hz), 124.1, 111.7−111.3 (m), 106.1− 105.6 (m). HRMS (ESI-TOF) m/z [M + H]+ calcd for C14H9F2N2+ 243.0734, found 243.0754. 2-(4-(Trifluoromethyl)phenyl)quinazoline (4p).10h Eluent: petroleum ether/ethyl acetate(24:1) white solid (*59% and #49%, *162 and #134 mg). mp 146−147 °C; 1H NMR (CDCl3, 400 MHz) δ (ppm) = 9.37 (s, 1H), 8.64 (d, J = 8.0 Hz, 2H), 8.00 (d, J = 8.8 Hz, 1H), 7.83 (t, J = 8.0 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.55 (t, J = 8.4 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ (ppm) = 160.6, 159.6, 150.6, 141.3, 134.4, 132.3, 131.9, 128.8, 128.8, 127.9, 127.2, 125.5 (q, JC−F = 4.0 Hz), 123.8. 2-(Thiophen-2-yl)quinazoline (4q).13h Eluent: petroleum ether/ ethyl acetate (5:1). White solid (*59% and #62%, *125 and #132 mg). mp 137−138 °C; 1H NMR (CDCl3, 400 MHz) δ (ppm) = 9.32 (s, 1H), 8.14(d, J = 3.6 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.85 (t, J = 6.8 Hz, 2H), 7.55−7.50 (m, 2H), 7.18 (t, J = 4.0 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ (ppm) = 160.6, 157.8, 150.6, 143.9, 134.4, 130.0, 129.3, 128.4, 128.2, 127.3, 127.0, 123.4. 2-(Pyridin-2-yl)quinazoline (4r).15d Eluent: petroleum ether/ethyl acetate (5:1). White solid (*45% and #50%, *93 and #104 mg). mp 90−92 °C; 1H NMR (CDCl3, 400 MHz) δ (ppm) = 9.98 (s, 1H), 11163

DOI: 10.1021/acs.joc.8b01479 J. Org. Chem. 2018, 83, 11154−11166

Article

The Journal of Organic Chemistry 8.94 (d, J = 8.4 Hz, 1H), 8.74 (dd, J = 4.0 Hz, 0.8 Hz, 1H), 8.23 (dd, J = 8.0, 0.8 Hz, 1H), 7.89−7.82 (m, 3H), 7.69 (dd, J = 7.6, 1.2 Hz, 1H), 7.45−7.42 (m, 1H). 2-(Pyridin-4-yl)quinazoline(4s).15d Eluent: petroleum ether/ethyl acetate (5:1). Gray solid (*50% and #56%, *104 and #116 mg). mp 134−138 °C; 1H NMR (CDCl3, 400 MHz) δ (ppm) = 9.52(s, 1H), 8.82 (d, J = 5.6 Hz, 2H), 8.47 (t, J = 4.4 Hz, 2H), 8.14 (d, J = 8.0 Hz, 1H), 8.00−7.96 (m, 2H), 7.71 (t, J = 8.0 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ (ppm) = 161.0, 159.0, 150.6, 150.6, 145.6, 134.8, 128.6, 128.4, 127.4, 124.4, 122.6. 2-Butylquinazoline (4t).10e Eluent: petroleum ether/ethyl acetate (24:1). yellow oil (*25% and #30%, *47 and #56 mg). 1H NMR (CDCl3, 400 MHz) δ (ppm) = 9.37 (s, 1H), 7.97−7.91 (m, 1H), 7.84−7.81 (m, 2H), 7.52−7.50 (m, 1H), 3.58 (t, J = 5.6 Hz, 2H), 1.97 (t, J = 7.2 Hz, 2H), 1.63−1.51 (m, 2H) 0.81 (t, J = 6.4 Hz, 3H). 6-Methyl-2-phenyl quinazoline (4u).11a,17d Eluent: petroleum ether/ethyl acetate (24:1). White solid (*74% and #86%, *163 and # 189 mg). mp 130−132 °C ; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 9.38 (d, J = 3.72 Hz, 1H), 8.60 (s, 2H), 7.98 (d, J = 7.92 Hz, 1H), 7.71 (t, J = 9.09 Hz, 2H), 7.53 (s, 3H), 2.57 (d, J = 3.69 Hz, 3H). 13C NMR (CDCl3, 100 MHz) δ (ppm) = 160.4, 159.8, 149.4, 138.2, 137.5, 136.4, 130.4, 128.6, 128.4, 128.3, 125.8, 123.6, 21.7. 8-Bromo-6-methyl-2-phenylquinazoline (4v). Eluent: petroleum ether/ethyl acetate (24:1). White solid (*70% and #80%, *209 and # 239 mg). mp 98−100 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 9.30 (s, 1H, (H1)), 8.69−8.67 (m, 2H, (H4, H8)), 8.02 (s, 1H, (H3)), 7.59−7.51 (m, 4H, (H2, H5, H6, H7)), 2.51 (s, 3H, (H9AC)). 13C NMR (CDCl3, 100 MHz) δ (ppm) = 161.0, 160.2, 146.6, 139.4, 138.2, 137.7, 130.9, 128.7, 128.7, 125.6, 124.6, 123.8, 21.4. HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H12N2Br+ 299.0309, found 299.0313. 7-Chloro-2-phenyl quinazoline (4w).10k Eluent: petroleum ether/ethyl acetate (24:1). White solid (*69% and #84%, *166 and #202 mg). mp 137−138 °C; 1H NMR (CDCl3, 400 MHz) δ (ppm) = 9.40 (s,1H), 8.59 (d, J = 4.8 Hz, 2H), 8.07 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 5.6 Hz, 4H). 13C NMR (CDCl3, 100 MHz) δ (ppm) = 161.9, 160.2, 151.3, 140.3, 137.6, 131.0, 128.7, 128.5, 128.4, 127.8, 121.9. 6,7,8-Trimethoxy-2-phenylquinazoline (4x). Eluent: petroleum ether/ethyl acetate (24:1). pale yellow oil (*60% and #81%, 178 and 240 mg). 1H NMR (CDCl3, 400 MHz) δ (ppm) = 9.21 (s,1H (H1)), 8.53 (d, J = 6.8 Hz, 1H (H7)), 7.47−7.41 (m, 4H (H3− H6)), 6.89 (s, 1H (H2)), 4.25 (s, 3H (H10A-C)), 4.06 (s, 3H (H8A-C)), 3.95 (s, 3H (H9A-C)). 13C NMR (CDCl3, 100 MHz) δ (ppm) = 158.2, 153.8, 146.7, 138.2, 130.2, 128.5, 128.2, 120.8, 100.1, 61.7, 60.5, 56.2. HRMS (ESI-TOF) m/z [M + H]+ calcd for C17H17N2O3+ 297.1239, found 297.1269. 4-Methyl-2-phenylquinazoline (4y).10j Eluent: petroleum ether/ ethyl acetate (24:1). pale yellow solid (#55%, #121 mg). mp 73−75 °C; 1H NMR (CDCl3, 400 MHz) δ (ppm) = 8.55−8.53 (m, 2H), 8.08−8.00 (m, 2H), 8.81−7.78 (m, 1H), 7.65−7.40 (m, 4H). 13C NMR (CDCl3, 100 MHz) δ (ppm) = 168.5, 160.3, 150.6, 138.6, 133.6, 130.5, 129.5, 128.7, 128.7, 127.0, 125.1, 21.2. 4-Methyl-2-p-tolylquinazoline (4z). Eluent: petroleum ether/ ethyl acetate (24:1). pale yellow solid; (#50%, #117 mg). mp 68−69 °C; 1H NMR (CDCl3, 400 MHz) δ (ppm) = 8.44 (d, J = 8.0 Hz, 2H), 7.99 (t, J = 8.8 Hz, 2H), 7.79−7.75 (m, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 2.93 (s, 3H), 2.37 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ (ppm) = 168.2, 160.5, 150.7, 140.7, 135.8, 133.5, 129.4, 129.4, 128.7, 126.7, 125.1, 123.1, 22.1, 21.6. HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H15N2+ 235.1235, found 235.1240. 7-Chloro-2-p-tolylquinazoline (4z′). Eluent: petroleum ether/ ethyl acetate (24:1). White solid (*68% and #83%, *173 and #211 mg). mp 156−158 °C; 1H NMR (CDCl3, 400 MHz) δ (ppm) = 9.39 (s, 1H (H1)), 8.48 (d, J = 8.0 Hz, 2H (H5, H8)), 8.05 (s, 1H (H4)), 7.83 (d, J = 8.0 Hz, 1H (H3)), 7.53−7.51 (m, 1H (H2)), 7.34 (d, J = 8.0 Hz, 2H (H6, H7)), 2.45 (s, 3H (H9A-C)). 13C NMR (CDCl3, 100 MHz) δ (ppm) = 162.1, 160.2, 151.5, 141.4,

140.4, 135.0, 129.6, 128.8, 128.5, 128.3, 127.8, 122.0, 21.7. HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H12ClN2+ 255.0689, found 255.0691. 2-(4-Bromophenyl)-7-chloroquinazoline (4z″). Eluent: petroleum ether/ethyl acetate (24:1). White solid (*67% and #80%, *214 and #256 mg). mp 162−165 °C; 1H NMR (CDCl3, 400 MHz) δ (ppm) = 9.39 (s, 1H (H1)), 8.46 (d, J = 8.0 Hz, 2H (H5, H8)), 8.05 (s, 1H (H4)), 7.85 (d, J = 8.0 Hz, 1H (H3)), 7.65 (d, J = 8.0 Hz, 2H (H6, H7)), 7.57−7.54 (m, 1H (H2)). 13C NMR (CDCl3, 100 MHz) δ (ppm) = 160.3, 151.3, 140.7, 136.8, 132.0, 130.4, 128.8, 128.5, 127.9, 126.0, 122.1. HRMS (ESI-TOF) m/z [M + H]+ calcd for C14H9BrClN2+ 318.9638, found 318.9650. 2-(4-Chlorophenyl)-6-methylquinazoline (4z‴).17d Eluent: petroleum ether/ethyl acetate (24:1). White solid (*70% and #83%, *178 and #211 mg). mp 150−152 °C; 1H NMR (CDCl3, 400 MHz) δ (ppm) = 9.34 (s, 1H), 8.53 (d, J = 8.0 Hz, 2H), 7.95 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz,1H), 7.66 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 2.56 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ (ppm) = 159.8, 159.4, 149.3, 137.7, 136.7, 136.6, 129.7, 128.8, 128.2, 125.8, 123.6, 21.7. 1,2,3,4-Tetrahydro-2-phenylquinazoline (4).17f Eluent: petroleum ether/ethyl acetate (2:1). White solid (80% and 168 mg). 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.49 (t, J = 6.8 Hz, 2H), 7.39−7.31 (m, 3H), 7.03 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 7.2 Hz, 1H), 6.72−6.68 (m, 1H), 6.54 (d, J = 8.0 Hz, 1H), 5.18 (s, 1H), 4.24 (s, 1H), 4.20 (brs, NH, 1H), 3.94 (d, J = 16.8 Hz, 1H), 1.92 (brs, NH, 1H). 13C NMR (CDCl3, 100 MHz) δ (ppm) = 143.8, 141.6, 128.8, 128.6, 127.3, 126.7, 126.3, 121.3, 118.2, 115.1, 69.6, 46.5. 1,2,3,4-Tetrahydro-2-(3-methoxyphenyl)quinazoline (4′).17f Eluent: petroleum ether/ethyl acetate (2:1). White solid (65% and 156 mg). 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.31−7.24 (m, 1H), 7.09−7.02 (m, 3H), 6.93 (d, J = 7.6 Hz, 1H), 6.89−6.87 (m, 1H), 6.71 (t, J = 7.2 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 5.18 (s, 1H), 4.24 (d, J = 16.8 Hz, 1H), 3.97 (d, J = 16.8 Hz, 1H), 3.81 (d, J = 4.4 Hz, 3H).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01479. 1 H and 13C NMR spectral data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Nanda D. Paul: 0000-0002-8872-1413 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The research was supported by CSIR, New Delhi (Project: 01(5234)/15) and DST (Project: YSS/2015/001552). S.P. thanks CSIR, R.S. thanks RJNF, S.S. thanks IIETS, G.C. thanks UGC, and R.M. thanks CSIR for fellowship support. Financial assistance from IIESTS is acknowledged.

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REFERENCES

(1) (a) DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow, J. W.; Pippin, D. A. Privileged Structures: Applications in Drug Discovery. Comb. Chem. High Throughput Screening 2004, 7, 473− 493. (b) Leeson, P. D.; Springthorpe, B. The Influence of Drug-like Concepts on Decision-making in Medicinal Chemistry. Nat. Rev. Drug Discovery 2007, 6, 881−890. (c) Craig, P. N. In Comprehensive Medicinal Chemistry; Drayton, C. J., Ed.; Pergamon Press: New York, 11164

DOI: 10.1021/acs.joc.8b01479 J. Org. Chem. 2018, 83, 11154−11166

Article

The Journal of Organic Chemistry 1991; Vol. 8. (d) Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Eds.; Elsevier: Oxford, 1996. (e) Fairlamb, I. J. S. Regioselective (site-selective) Functionalisation of Unsaturated Halogenated Nitrogen, Oxygen and Sulfur Heterocycles by PdCatalysed Cross-couplings and Direct Rrylation Processes. Chem. Soc. Rev. 2007, 36, 1036−1045. (2) (a) Grover, G.; Kini, S. G. Synthesis and Evaluation of New Quinazolone Derivatives of Nalidixic Acid as Potential Antibacterial and Antifungal Agents. Eur. J. Med. Chem. 2006, 41, 256−262. (b) Van Horn, K. S.; Burda, W. N.; Fleeman, R.; Shaw, L. N.; Manetsch, R. Antibacterial Activity of a Series of N 2,N4Disubstituted Quinazoline-2,4-diamines. J. Med. Chem. 2014, 57, 3075−3093. (c) Parhi, A. K.; Zhang, Y.; Saionz, K. W.; Pradhan, P.; Kaul, M.; Trivedi, K.; Pilch, D. S.; LaVoie, E. Antibacterial Activity of Quinoxalines, Quinazolines, and 1,5-Naphthyridines. Bioorg. Med. Chem. Lett. 2013, 23, 4968−4974. (3) (a) Ugale, V. G.; Bari, S. B. Quinazolines: New Horizons in Anticonvulsant Therapy. Eur. J. Med. Chem. 2014, 80, 447−501. (b) Abbas, S. E.; Awadallah, F. M.; Ibrahim, N. A.; Said, E. G.; Kamel, G. Design and Synthesis of Some 3-Substituted-2-[(2,4dichlorophenoxy)- methyl]quinazolin-4(3H)-one Derivatives as Potential Anticonvulsant Agents. Chem. Pharm. Bull. 2013, 61, 679−687. (4) (a) Khan, I.; Ibrar, A.; Abbas, N.; Saeed, A. Recent Advances in the Structural Library of Functionalized Quinazoline and Quinazolinone Scaffolds: Synthetic Approaches and Multifarious Applications. Eur. J. Med. Chem. 2014, 76, 193−244. (b) Smits, R. A.; Adami, M.; Istyastono, E. P.; Zuiderveld, O. P.; van Dam, C. M. E.; de Kanter, F. J. J.; Jongejan, A.; Coruzzi, G.; Leurs, R.; de Esch, I. J. P. Synthesis and QSAR of Quinazoline Sulfonamides As Highly Potent Human Histamine H4 Receptor Inverse Agonists. J. Med. Chem. 2010, 53, 2390−2400. (5) Mendes da Silva, J. F.; Walters, M.; Al-Damluji, S.; Ganellin, C. R. Molecular Features of the Prazosin Molecule Required for Activation of Transport-P. Bioorg. Med. Chem. 2008, 16, 7254−7263. (6) Waisser, K.; Gregor, J.; Dostal, H.; Kunes, J.; Kubicova, L.; Klimesova, V. Kaustova, Influence of the Replacement of the Oxo Function with the Thioxo Group on the Antimycobacterial Activity of 3-aryl-6,8-dichloro-2H-1,3-benzoxazine-2,4(3H)-diones and 3arylquinazoline-2,4(1H,3H)-diones. Farmaco 2001, 56, 803−807. (7) (a) Madapa, S.; Tusi, Z.; Mishra, A.; Srivastava, K.; Pandey, S. K.; Tripathi, R.; Puri, S. K.; Batra, S. Search for New Pharmacophores for Antimalarial Activity. Part II: Synthesis and Antimalarial Activity of New 6-ureido-4-anilinoquinazolines. Bioorg. Med. Chem. 2009, 17, 222−234. (b) Verhaeghe, P.; Azas, N.; Gasquet, M.; Hutter, S.; Ducros, C.; Laget, M.; Rault, S.; Rathelot, P.; Vanelle, P. Synthesis and Antiplasmodial Activity of New 4-aryl2-trichloromethylquinazolines. Bioorg. Med. Chem. Lett. 2008, 18, 396−401. (8) (a) Schleiss, M.; Eickhoff, J.; Auerochs, S.; Leis, M.; Abele, S.; Rechter, S.; Choi, Y.; Anderson, J.; Scott, G.; Rawlinson, W.; Michel, D.; Ensminger, S.; Klebl, B.; Stamminger, T.; Marschall, M. Protein Kinase Inhibitors of the Quinazoline Class Exert Anticytomegaloviral Activity in vitro and in vivo. Antiviral Res. 2008, 79, 49−61. (b) Chien, T.-C.; Chen, C.-S.; Yu, F.-H.; Chern, J.-W. Nucleosides XI. Synthesis and Antiviral Evaluation of 5-Alkylthio-5deoxy Quinazolinone Nucleoside Derivatives as S-AdenosylLhomocysteine Analogs. Chem. Pharm. Bull. 2004, 52, 1422−1426. (c) Herget, T.; Freitag, M.; Morbitzer, M.; Kupfer, R.; Stamminger, T.; Marschall, M. Novel Chemical Class of pUL97 Protein Kinasespecific Inhibitors with Strong Anticytomegaloviral Activity. Antimicrob. Antimicrob. Agents Chemother. 2004, 48, 4154−4162. (9) (a) Henderson, E. A.; Bavetsias, V.; Theti, D. S.; Wilson, S. C.; Clauss, R.; Jackman, A. L. Targeting the α-folate Receptor with Cyclopenta[g]quinazoline-based Inhibitors of Thymidylate Synthase. Bioorg. Med. Chem. 2006, 14, 5020−5042. (b) Doyle, L.; Ross, D. D. Multidrug Resistance Mediated by the Breast Cancer Resistance Protein BCRP (ABCG2). Oncogene 2003, 22, 7340−7358. (c) Wang, H. Lapatinib for the Treatment of Breast Cancer in

the People’s Republic of China. OncoTargets Ther. 2014, 7, 1367− 1373. (10) (a) Zhang, Z.-H.; Zhang, X.-N.; Mo, L.-P.; Li, Y.-X.; Ma, F.-P. Catalyst-free Synthesis of Quinazoline Derivatives Using Low Melting Sugar−Urea−Salt Mixture as a Solvent. Green Chem. 2012, 14, 1502−1506. (b) Zhang, J.; Yu, C.; Wang, S.; Wan, C.; Wang, Z. A novel and Efficient Methodology for the Construction of Quinazolines Based on Supported Copper Oxide Nanoparticles. Chem. Commun. 2010, 46, 5244−5246. (c) Chatterjee, T.; Kim, D. I.; Cho, E. J. Base-Promoted Synthesis of 2-Aryl Quinazolines from 2-Aminobenzylamines in Water. J. Org. Chem. 2018, 83, 7423−7430. (d) Yamaguchi, T.; Sugiura, Y.; Yamaguchi, E.; Tada, N.; Itoh, A. Synthetic Method for the Preparation of Quinazolines by the Oxidation of Amines Using Singlet Oxygen. Asian J. Org. Chem. 2017, 6, 432−435. (e) Zhang, Z.; Wang, M.; Zhang, C.; Zhang, Z.; Lu, J.; Wang, F. The Cascade Synthesis of Quinazolinones and Quinazolines Using an α-MnO2 Catalyst and tert-butyl hydroperoxide (TBHP) as an Oxidant. Chem. Commun. 2015, 51, 9205− 9207. (f) Zhang, L.; Li, J.; Hu, Z.; Dong, J.; Zhang, X.-M.; Xub, X. Silver-Catalyzed Isocyanide Insertion into N−H Bond of Ammonia: [5 + 1] Annulation to Quinazoline Derivatives. Adv. Synth. Catal. 2018, 360, 1938. (g) Chen, Z.; Chen, J.; Liu, M.; Ding, J.; Gao, W.; Huang, X.; Wu, H. Unexpected Copper-Catalyzed Cascade Synthesis of Quinazoline Derivatives. J. Org. Chem. 2013, 78, 11342−11348. (h) Peng, Y.-Y.; Zeng, Y.; Qiu, G.; Cai, L.; Pike, V. W. A Convenient One-pot Procedure for the Synthesis of 2-Aryl Quinazolines Using Active MnO2 as Oxidant. J. Heterocycl. Chem. 2010, 47, 1240−1245. (i) Xu, C.; Jia, F.-C.; Zhou, Z.-W.; Zheng, S.J.; Li, H.; Wu, A.-X. Copper-Catalyzed Multicomponent Domino Reaction of 2-Bromoaldehydes, Benzylamines, and Sodium Azide for the Assembly of Quinazoline Derivatives. J. Org. Chem. 2016, 81, 3000−3006. (j) Karnakar, K.; Shankar, J.; Murthy, S. N.; Ramesh; Nageswar, Y. V. D. An Efficient Protocol for the Synthesis of 2Phenylquinazolines Catalyzed by Ceric Ammonium Nitrate (CAN). Synlett 2011, 2011, 1089−1096. (k) Yamaguchi, T.; Sakairi, K.; Yamaguchi, E.; Tada, N.; Itoh, A. Magnesium Iodide-catalyzed Synthesis of 2-Substituted Quinazolines Using Molecular Oxygen and Visible Light. RSC Adv. 2016, 6, 56892−56895. (11) (a) Wang, H.; Chen, H.; Chen, Y.; Deng, G.-J. PalladiumCatalyzed One Pot 2-Arylquinazoline Formation via Hydrogentransfer Strategy. Org. Biomol. Chem. 2014, 12, 7792−7799. (b) Portela-Cubillo, F.; Scott, J. S.; Walton, J. C. 2-(Aminoaryl)alkanone O-Phenyl Oximes: Versatile Reagents for Syntheses of Quinazolines. Chem. Commun. 2008, 2935−2937. (c) PortelaCubillo, F.; Scott, J. S.; Walton, J. C. Microwave-Promoted Syntheses of Quinazolines and Dihydroquinazolines from 2-Aminoarylalkanone O-Phenyl Oximes. J. Org. Chem. 2009, 74, 4934−4942. (12) (a) Ju, J.; Hua, R. M.; Su, J. Copper-Catalyzed ThreeComponent One-pot Synthesis of Quinazolines. Tetrahedron 2012, 68, 9364−9370. (b) Han, B.; Yang, X.-L.; Wang, C.; Bai, Y.-W.; Pan, T.-C.; Chen, X.; Yu, W. CuCl/DABCO/4-HO-TEMPO-Catalyzed Aerobic Oxidative Synthesis of 2-Substituted Quinazolines and 4H3,1-Benzoxazines. J. Org. Chem. 2012, 77, 1136−1142. (13) (a) Tang, X.; Wu, W.; Zeng, W.; Jiang, H. Copper-Catalyzed Oxidative Carbon−Carbon and/or Carbon−Heteroatom Bond Formation with O2 or Internal Oxidants. Acc. Chem. Res. 2018, 51, 1092−1105 and references therein. (b) 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. (c) Guo, S.; Wang, F.; Tao, L.; Zhang, X.; Fan, X. Solvent-Dependent CopperCatalyzed Indolyl C3-Oxygenation and N1-Cyclization Reactions: Selective Synthesis of 3H-Indol-3-ones and Indolo[1,2-c]quinazolines. J. Org. Chem. 2018, 83, 3889−3896. (d) Liu, J.-Q.; Ma, Y.-G.; Zhang, M.-M.; Wang, X.-H. Consecutive Sonogashira Coupling and Hydroamination Cyclization for the Synthesis of Isoindolo[1,2-b]quinazolin-10(12H)-ones Catalyzed by CuI/l-Proline. J. Org. Chem. 2017, 82, 4918−4923. (e) Wang, X.; He, D.; Huang, Y.; Fan, Q.; Wu, W.; Jiang, H. Copper-Catalyzed Synthesis 11165

DOI: 10.1021/acs.joc.8b01479 J. Org. Chem. 2018, 83, 11154−11166

Article

The Journal of Organic Chemistry of Substituted Quinazolines from Benzonitriles and 2-Ethynylanilines via Carbon−Carbon Bond Cleavage Using Molecular Oxygen. J. Org. Chem. 2018, 83, 5458−5466. (f) Wang, X.; Jiao, N. Rh- and Cu-Cocatalyzed Aerobic Oxidative Approach to Quinazolines via [4 + 2] C−H Annulation with Alkyl Azides. Org. Lett. 2016, 18, 2150− 2153. (g) Malakar, C. C.; Baskakova, A.; Conrad, J.; Beifuss, U. Copper-Catalyzed Synthesis of Quinazolines in Water Starting from o-Bromobenzylbromides and Benzamidines. Chem. - Eur. J. 2012, 18, 8882−8885. (h) Wang, C.; Li, S.; Liu, H.; Jiang, Y.; Fu, H. Copper-Catalyzed Synthesis of Quinazoline Derivatives via UllmannType Coupling and Aerobic Oxidation. J. Org. Chem. 2010, 75, 7936−7938. (14) (a) Ruiz-Castillo, P.; Buchwald, S. L. Applications of Palladium-Catalyzed C−N Cross-Coupling Reactions. Chem. Rev. 2016, 116, 12564−12649 and references therein. (b) Hu, K.; Zhen, Q.; Gong, J.; Cheng, T.; Qi, L.; Shao, Y.; Chen, J. PalladiumCatalyzed Three-Component Tandem Process: One-pot Assembly of Quinazolines. Org. Lett. 2018, 20, 3083−3087. (c) Xu, L.; Li, H.; Liao, Z.; Lou, K.; Xie, H.; Li, H.; Wang, W. Divergent Synthesis of Imidazoles and Quinazolines via Pd(OAc)2-Catalyzed Annulation of N-Allylamidines. Org. Lett. 2015, 17, 3434−3437. (d) McGowan, M. A.; McAvoy, C. Z.; Buchwald, S. L. Palladium-Catalyzed NMonoarylation of Amidines and a One-pot Synthesis of Quinazoline Derivatives. Org. Lett. 2012, 14, 3800−3803. (e) Sadig, J. E. R.; Foster, R.; Wakenhut, F.; Willis, M. C. Palladium-Catalyzed Synthesis of Benzimidazoles and Quinazolinones from Common Precursors. J. Org. Chem. 2012, 77, 9473−9486. (15) (a) Zhang, W.; Guo, F.; Wang, F.; Zhao, N.; Liu, L.; Li, J.; Wang, Z. H. Synthesis of Quinazolines via CuO Nanoparticles Catalyzed Aerobic Oxidative Coupling of Aromatic Alcohols and Amidines. Org. Biomol. Chem. 2014, 12, 5752−5756. (b) Ohta, Y.; Tokimizu, Y.; Oishi, S.; Fujii, N.; Ohno, H. Direct Synthesis of Quinazolines through Copper-Catalyzed Reaction of Aniline-Derived Benzamidines. Org. Lett. 2010, 12, 3963−3965. (c) Ambethkar, S.; Kalaiselvi, M.; Ramamoorthy, J.; Padmini, V. I2-Catalyzed Oxidative Cross-Coupling Reaction of Methyl Ketones and 2-(2-Aminophenyl) Benzimidazole: Facile Access to Benzimidazo[1,2-c]quinazoline. ACS Omega 2018, 3, 5021−5028. (d) Li, C.; An, S.; Zhu, Y.; Zhang, J.; Kang, Y.; Liu, P.; Wang, Y.; Li, J. Coppercatalyzed Intermolecular Cyclization of Nitriles and 2-Aminobenzylamine for 3,4-Dihydroquinazolines and Quinazolines Synthesis via Cascade Coupling and Aerobic Oxidation. RSC Adv. 2014, 4, 49888−49891. (16) (a) Crabtree, R. H. Homogeneous Transition Metal Catalysis of Acceptorless Dehydrogenative Alcohol Oxidation: Applications in Hydrogen Storage and to Heterocycle Synthesis. Chem. Rev. 2017, 117, 9228−9246 and references therein. (b) Gunanathan, C.; Milstein, D. Metal.Ligand Cooperation by AromatizationDearomatization: A New Paradigm in Bond Activation and “Green” Catalysis. Acc. Chem. Res. 2013, 44, 588−602. (c) Werkmeister, S.; Neumann, J.; Junge, K.; Beller, M. Pincer-Type Complexes for Catalytic (De)Hydrogenation and Transfer (De)Hydrogenation Reactions: Recent Progress. Chem. - Eur. J. 2015, 21, 12226−12250. (d) Chelucci, G. Metal-Catalyzed Dehydrogenative Synthesis of Pyrroles and Indoles from Alcohols. Coord. Chem. Rev. 2017, 331, 37−53. (e) Siddiki, S. M. A. H.; Toyao, T.; Shimizu, K. Acceptorless Dehydrogenative Coupling Reactions with Alcohols over Heterogeneous Catalysts. Green Chem. 2018, 20, 2933. (f) Shee, S.; Ganguli, K.; Jana, K.; Kundu, S. Cobalt Complex Catalyzed AtomEconomical Synthesis of Quinoxaline, Quinoline and 2-Alkylaminoquinoline Derivatives. Chem. Commun. 2018, 54, 6883. (g) Daw, P.; Ben-David, Y.; Milstein, D. Direct Synthesis of Benzimidazoles by Dehydrogenative Coupling of Aromatic Diamines and Alcohols Catalyzed by Cobalt. ACS Catal. 2017, 7, 7456−7460. (h) EspinosaJalapa, N. A.; Kumar, A.; Milstein, D. Synthesis of Cyclic Imides by Acceptorless Dehydrogenative Coupling of Diols and Amines Catalyzed by a Manganese Pincer Complex. J. Am. Chem. Soc. 2017, 139, 11722−11725. (i) Daw, P.; Chakraborty, S.; Garg, J. A.; Ben-David, Y.; Milstein, D. Direct Synthesis of Pyrroles via

Dehydrogenative Coupling of Diols and Amines Catalyzed by Cobalt Pincer Complexes. Angew. Chem., Int. Ed. 2016, 55, 14373− 14377. (17) (a) Srimani, D.; Ben-David, Y.; Milstein, D. Direct Synthesis of Pyridines and Quinolines by Coupling of Gamma-AminoAlcohols With Secondary Alcohols Liberating H2 Catalyzed by Ruthenium Pincer Complexes. Chem. Commun. 2013, 49, 6632− 6634. (b) Srimani, D.; Ben-David, Y.; Milstein, D. Direct Synthesis of Pyrroles by Dehydrogenative Coupling of -Aminoalcohols With Secondary Alcohols Catalyzed by Ruthenium Pincer Complexes. Angew. Chem., Int. Ed. 2013, 52, 4012−4015. (c) Li, F.; Lu, L.; Liu, P. Acceptorless Dehydrogenative Coupling of o-Aminobenzamides with the Activation of Methanol as a C1 Source for the Construction of Quinazolinones. Org. Lett. 2016, 18, 2580−2583. (d) Chen, M.; Zhang, M.; Xiong, B.; Tan, Z.; Lv, W.; Jiang, H. A Novel Ruthenium-Catalyzed Dehydrogenative Synthesis of 2Arylquinazolines from 2-Aminoaryl Methanols and Benzonitriles. Org. Lett. 2014, 16, 6028−6031. (e) Maji, M.; Chakrabarti, K.; Paul, B.; Roy, B. C.; Kundu, S. Ruthenium(II)-NNN-Pincer-ComplexCatalyzed Reactions Between Various Alcohols and Amines for Sustainable C-N and C-C Bond Formation. Adv. Synth. Catal. 2018, 360, 722−729. (f) Fang, J.; Zhou, J.; Fang, Z. Synthesis of 2Substituted Quinazolines via Iridium Catalysis. RSC Adv. 2013, 3, 334−336. (18) (a) Parua, S.; Das, S.; Sikari, R.; Sinha, S.; Paul, N. D. Onepot Cascade Synthesis of Quinazolin-4(3H)-ones via NickelCatalyzed Dehydrogenative Coupling of o-Aminobenzamides with Alcohols. J. Org. Chem. 2017, 82, 7165−7175. (b) Parua, S.; Sikari, R.; Sinha, S.; Das, S.; Chakraborty, G.; Paul, N. D. Nickel Catalyzed Acceptorless Dehydrogenative Approach to Quinolines. Org. Biomol. Chem. 2018, 16, 274−284. (19) Midya, G. C.; Kapat, A.; Maiti, S.; Dash, J. Transition-MetalFree Hydration of Nitriles Using Potassium tert-Butoxide under Anhydrous Conditions. J. Org. Chem. 2015, 80, 4148−4151. (20) From the TLC check of the reaction mixture, a small amount of unreacted amines were found in all the cases. However, we believe that the reactions were complete after 24 h, as we have not observed any noticeable increase of yields after 24 h. Moreover, the yields reported here are all isolated yields. So, during workup of the reaction mixture the possibility of loss of products also cannot be excluded.

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DOI: 10.1021/acs.joc.8b01479 J. Org. Chem. 2018, 83, 11154−11166