Research Article pubs.acs.org/journal/ascecg
Microwave-Assisted, Green Synthesis of 4(3H)‑Quinazolinones under CO Pressure in γ‑Valerolactone and Reusable Pd/β-Cyclodextrin Cross-Linked Catalyst Emanuela Calcio Gaudino,† Silvia Tagliapietra,† Giovanni Palmisano,§ Katia Martina,† Diego Carnaroglio,∥,† and Giancarlo Cravotto*,† †
Dipartimento di Scienza e Tecnologia del Farmaco and NIS−Centre for Nanostructured Interfaces and Surfaces, University of Turin, Via P. Giuria 9, 10125 Turin, Italy § Dipartimento di Scienza e Alta Tecnologia, University of Insubria, Via Valleggio, 11-22100 Como, Italy ∥ Milestone srl, Via Fatebenefratelli, 1-5, 24010, Sorisole, Italy S Supporting Information *
ABSTRACT: The development of alternative, green solvents is an important and ongoing challenge. Our latest contribution to the field is the use of γ-valerolactone in aminocarbonylative coupling reactions for the clean synthesis of several 4(3H)-quinazolinones under microwave irradiation. The palladium-catalyzed, four-component carbonylative coupling reactions of o-iodoanilines, trimethyl orthoformate, and a variety of amines have been carried out under CO pressure (2.5 bar). This protocol was found to be highly efficient and selective for 4(3H)-quinazolinones, which were isolated in good yields in the presence of two different, recyclable Pd catalysts which were prepared under ultrasound irradiation; a novel lead-free Pd/boehmite catalyst and a β-cyclodextrin−cross-linked Pd catalyst. KEYWORDS: 4(3H)-Quinazolinones, γ-Valerolactone, Microwaves, Carbon monoxide, Green synthesis
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INTRODUCTION Chemical process sustainability is one of the most significant challenges currently facing environmental science. In particular, the importance of developing new and highly efficient synthetic protocols has been clearly highlighted by the guidelines of the European Association for Chemical and Molecular Sciences (EuCheMS). Catalyst recyclability, the use of alternative reaction media, and waste minimization are crucial targets if chemical processes, particularly in the pharmaceutical field, are to be made greener. The search for safer reaction media has recently led to special attention being directed toward solvents derived from renewable raw materials,1,2 since they have no, or limited, impact on the environment and health. Intensive research activity into biomass conversion3 has led to the development of several new platform chemicals, including γ-valerolactone (GVL), lactic acid, ethyl lactate, gluconic acid, 2-methyltetrahydrofuran, and limonene,4 which could well replace currently used organic solvents. In particular, GVL is a renewable, biobased solvent that is efficiently produced via the hydrogenation of levulinic acid, which is produced together with formic acid via the acid promoted deconstruction of cellulose and starch.5,6 GVL shows comparable polarity to classical polar aprotic solvents, while also exhibiting a higher boiling point and viscosity as well as good stability to acidic and basic environments.7,8 GVL’s very low toxicity,9,10 combined with its eco-friendly, physical and chemical © 2017 American Chemical Society
properties, make it an attractive sustainable solvent even for the pharmaceutical industry. Since it was initially suggested by Horváth, only a few papers have reported using GVL as a solvent,11−13 often to access active pharmaceutical ingredients.14,15 Meanwhile, the broad spectrum of pharmacological activity, including antitumor, antimicrobial, anti-inflammatory and anticonvulsant action,16 presented by 4(3H)-quinazolinones has made them one of the most commonly used heterocycles in medicinal chemistry and has led to their syntheses being widely debated in the literature.17 The most common synthetic procedures for 4 (3H)quinazolinones are the Niementowski reaction, which starts from anthranilic acid or its derivatives,18 the Aza−Wittig/ cyclization strategy, starting from iminophosphoranes,19 and transition-metal catalyzed carbonylation reactions, starting from N-(o-halophenyl)-imidoyl chlorides or imidates.20 All of these procedures suffer from harsh reaction conditions and long reaction times, compounding the fact that they are traditionally conducted in classical organic solvents and without using recyclable catalysts. A great deal of effort has been invested in Received: July 3, 2017 Revised: August 20, 2017 Published: August 25, 2017 9233
DOI: 10.1021/acssuschemeng.7b02193 ACS Sustainable Chem. Eng. 2017, 5, 9233−9243
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adopting a multifaceted strategy that combines eco-compatible reaction media, recyclable heterogeneous catalysts and suitable enabling techniques with a convenient carbon source, such as CO.
merging the synthetic value of carbonylative transformations and the growing interest in the preparation of bioactive heterocycles.21,22 For instance, palladium-catalyzed carbonylative reactions using CO, one of the cheapest and most readily available C1 sources, have recently been performed for the synthesis of 4(3H)-quinazolinones by Beller23 and Wu.24 They isolated various 4(3H)-quinazolinones, in moderate to excellent yields, by adopting a multicomponent approach to the palladium catalyzed aminocarbonylation reactions of a variety of different ohaloanilines. Despite the advantages of using CO gas as a high affinity palladium ligand (both in (0) and (+2) oxidation states due its dual ability to act as a σ-donor and π-acceptor),25 its true potential as a valuable reagent has not been fully explored because of its well-known toxicity. In fact, a number of papers have reported the use of alternative sources of carbon monoxide. These include work by Roberts et al., in which a rapid, microwave (MW) assisted cyclocarbonylation procedure was used for the synthesis of 4(3H)-quinazolinones from aryl ureas, using Mo(CO)6 as a robust CO-releasing reagent.26,27 Although carbon monoxide protocols are hampered by the need for highpressure equipment, there have been some developments in using MW technology with high pressure gas reagents,28−30 which may even lead to a technological breakthrough in 4(3H)quinazolinone synthesis. Moreover, in the present context of the relentless demand for more highly sustainable chemistry, MW dielectric heating can benefit from the development of new strategies for safe and energy efficient bioactive product synthesis. Its benefits have been well documented in the literature (remarkable reaction time reduction, improved yields, and cleaner reactions compared to those performed under conventional thermal conditions),31 and also apply to aminocarbonylation reactions.32,33 We herein continue our work toward suitable, MW-accelerated aminocarbonylation protocols34 and describe, for the first time, the use of GVL, as a sustainable, biomass-derived reaction medium for 4(3H)quinazolinone synthesis in the presence of CO gas. The present work has been greatly facilitated by our previous experience of promoting MW reactions with gaseous reagents.35−37 The efficient, Pd catalyzed MW aminocarbonylation of o-halo anilines in the presence of a variety of nucleophiles and trimethyl orthoformate (TMOF) was performed, with particular attention placed on catalyst recyclability. Heterogeneous palladium catalysts have been widely exploited in organic reactions,38 as supported on various carriers (active charcoal, zeolites, metal oxides, molecular sieves, and polymers), due to their unique physical and chemical properties and potential recyclability and are therefore candidates for MW-assisted, environmentally benign syntheses. The 4(3H)-quinazolinone synthesis performance of two different, supported Pd catalysts, a Pd/CβCAT system and a novel Pd/boehmite catalyst, was evaluated with the aim of combining nonconventional enabling technologies with the advantages of heterogeneous catalysis. The cross-linked Pd/ CβCAT catalyst was obtained via the sonochemical reticulation of β-cyclodextrin (β-CD) with hexamethylene diisocyanate (HDI) in the presence of a Pd(II) salts solution,39 while Pd/ boehmite (i.e., aluminum oxide hydroxide γ-AlO(OH)) catalyst was produced via a one-pot ultrasound reduction/deposition strategy in a Luviquat aqueous solution of Pd(II) salts.39 Both heterogeneous catalysts displayed particularly efficient MW irradiation adsorption, while their negligible metal leaching (always less than 0.1% as assessed by ICP MS analysis) makes them excellent recyclable catalyst candidates. A truly sustainable quinazolinone synthetic protocol can be efficiently designed by
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EXPERIMENTAL SECTION
All chemicals were purchased from Sigma-Aldrich and used without further purification. β-CD was kindly provided by Wacker Chemie (Munich, Germany). The details of the Pd/CβCAT,39 and Pd/ Boehmite,40 catalyst preparation methods and characterization are described elsewhere. Reactions were monitored by TLC on Merck 60 F254 (0.25 mm) plates, which were visualized by UV inspection and/or by heating after spraying with 5% H2SO4 in ethanol or phosphomolybdic acid. MWpromoted reactions were carried out in a SynthWAVE multimode MW reactor (Milestone Srl, Italy; MLS GmbH, Germany), equipped with a safe multiple-gas loading system. This instrument is equipped with a high-pressure, stainless steel reaction chamber, which can work up to a maximum of 300 °C and 199 bar, thus enabling MW reactions both in simultaneous small-scale (mL) and large scale (L) manners. Moreover, integrated reactor sensors continuously monitor internal pressure, temperature, and applied power inside the reactor cavity during reaction runs and adjusts applied MW power in real time to follow a predefined temperature profile. Product purification was performed by flash-chromatography (CombiFlash RfsTeledyne ISCO) on appropriate silica cartridges. GC-MS analyses were carried out in a gas chromatograph Agilent 6890 (Agilent Technologies, USA), fitted with a mass detector Agilent Network 5973, which used a capillary column that was 30 m long and had an i.d. of 0.25 mm and a film thickness of 0.25 mm. GC conditions were an injection split of 1:20, injector temperature of 250 °C, and detector temperature of 280 °C. The gas carrier was helium (1.2 mL min−1), and the temperature program was from 70 °C (2 min) to 300 °C at 5 °C min−1. NMR spectra were recorded on a Bruker Avance 300 (300 and 75 MHz for 1H and 13C, respectively) at 25 °C. Chemical shifts were calibrated to the residual proton and carbon resonances of deuterated solvents; CDCl3 (δ H = 7.26, δ C = 77.16), DMSO (δ H = 2.50, δ C = 39.52). ESI mass spectra were acquired using a Waters Micromass ZQ spectrometer equipped with ESI source. The metal content in solution was determined by ICP-MS on a Quadrupole-ICP-MS X Series II (Thermo Fisher Scientific), after sample digestion in HNO3 and aqua regia. The oxidation state of the adsorbed palladium was measured by Xray photoelectron spectroscopy (XPS), with a Quantum 2000 (PHI Co., Chanhassen, MN, USA), and a focused monochromatic Al K source (1486.7 eV), for excitation. General Procedure for Single, MW-Assisted 4(3H)-Quinazolinone Synthesis Using Pd/CβCAT as the Pd Catalytic System. In a typical experiment, o-iodoaniline (1a) (1 mmol), was reacted with aniline (2a) (1.1 equiv), TMOF (1.2 equiv), and triethylamine (TEA) (1.5 equiv), in the presence of 0.1 mol % palladium catalyst (Pd/ CβCAT: 0.65 wt % loading), using either MeCN or GVL as the reaction solvent (3 mL). After the MW reactor was flushed three times with N2, CO pressure (2.5, 5, or 10 bar) was loaded at room temperature and a total pressure of 10 bar was achieved by adding N2. The reactions were performed under magnetic stirring at 125 °C for 60−90 min in the SynthWAVE reactor (60 W average MW power). The internal pressure of the MW reactor was constantly monitored and little variations (mainly related to the temperature) during the reaction course were recorded. Upon completion of the heating stage, the reaction chamber was cooled to 35 °C and the internal residual pressure was released carefully. The palladium catalyst was filtered off on a sintered-glass Buchner funnel and washed twice with the corresponding reaction solvent. Extraction Work up. When traditional organic solvents were used, they were removed under vacuum. The residue was dissolved in EtOAc (20 mL) and washed with 1 N HCl (2 × 20 mL), saturated NaHCO3 (2 × 20 mL), and brine (2 × 20 mL). The organic phase was finally dried 9234
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ACS Sustainable Chemistry & Engineering Scheme 1
Table 1. Optimization of MW-Assisted 4(3H)-Quinazolinone 3a Synthesis under CO Pressurea yield (%)b
reaction conditions entry
solvent
CO (bar)
temperature (°C)
time (h)
Pd/Cc
Pd/boehmited
Pd/CβCATe
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
toluene toluene toluene toluene toluene toluene toluene toluene THF 1,4-dioxane DMF MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN
10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 7.5 5 2.5 1 2.5 2.5
95 110 125 125 125 125 140 160 125 125 125 125 125 125 125 125 125 125 125 110 95
3 3 3 1.5 1 0.5 1.5 1.5 3 3 3 3 1.5 1.0 0.5 1 1 1 1 1 1
25 58 87 65 35 15 73 82 45 60 57 76 72 68 55 68 70 69 56 67 53
33 63 90 68 42 22 79 87 61 68 68 82 81 81 67 79 78 78 65 73 59
37 65 94 73 48 26 85 92 68 74 72 97 94 90 74 91 90 91(74)f 76 84 72
a Reactions were performed simultaneously in the SynthWAVE reactor multirack position on a 1 mmol scale of o-iodoaniline (1a), with 3 mL solvent, using 1.1 equiv of (2), 1 mol % of Pd catalyst (Pd/C, Pd/boehmite, or Pd/CβCAT), 2 equiv of TMOF, and 3 equiv of DiPEA in the presence of CO and N2 atmosphere up to 10 bar. bDetermined by GC−MS (yields are based on area percentage). cPd/C (5 wt % loading). dPd/ boehmite (0.75 wt % loading). ePd/CβCAT (0.65 wt % loading). fReaction performed under conventional heating (24 h) using a Parr device (40 mL scale) keeping constant the reaction concentration used for microwave procedure.
over Na2SO4, and the solvent removed by distillation. Product purification was performed using flash chromatography (CombiFlash RfsTeledyne ISCO), on appropriate silica cartridges (petroleum ether 40-60/EtOAc = 7:3 v/v), yielding 4(3H)-quinazolinone (3a) in a 94% yield (when using MeCN). Precipitation Work up. When using GVL as the reaction solvent, water (5 mL) was added to the reaction mixture after catalyst filtration and then cooled to 0 °C. The so-obtained precipitate was filtered off, washed twice with water, and finally dried under vacuum. Product purification was performed via flash-chromatography (CombiFlash RfsTeledyne ISCO) on appropriate silica cartridges (petroleum ether 40-60/EtOAc = 7:3 v/v), yielding 4(3H)-quinazolinone (3a) in a 97% yield. General Procedure for Simultaneous MW-Assisted Aminocarbonylation of o-Iodoanilines with Different Anilines Using the Pd/CβCAT Catalytic System. All reagents and catalyst were added to each of ten, magnetic-stir-bar-equipped reaction vessels (15 mL capacity), placed into a multiple-position rack: o-iodoanilines (1a,
1b, or 1c, 1 mmol), the various anilines (2a or 2d−m; 1.1 equiv), TMOF (1.2 equiv), TEA (1.5 equiv), and 0.1 mol % Pd/CβCAT (0.65 wt % loading), while either MeCN or GVL were used as the reaction solvent (3 mL). The multiple-position rack was immersed in 250 mL of ethylene glycol, present in the reactor cavity (1 L Teflon vessel) as a moderating fluid. The vessel was loaded and purged three times with N2, then loaded with 2.5 bar CO and further pressurized with N2 up to10 bar. A standard condition to compare all the reactions at the same total pressure. The heating program was identical to that used in the previous single experiments (MW heating at 125 °C for 60 min). The internal pressure was monitored and recorded. Each product mixture was worked up individually after reaction completion using the protocol previously described for the single reaction procedure, thus obtaining 4(3H)quinazolinones (3a−m), in good to excellent yields. The crude products did not require further purification for metal contamination, as shown by ICP-MS analysis (Pd content < 6−8 ppm in all cases). 9235
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ACS Sustainable Chemistry & Engineering Table 2. Optimization of MW-Assisted 4(3H)-Quinazolinone 3a Synthesis under CO Pressure reaction conditionsa entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
base (equiv) DiPEA Na2CO3 K2CO3 Cs2CO3 DMAP 2,6-lutidine Et3N Et3N Et3N Et3N − Et3N Et3N Et3N Et3N Et3N Et3N Et3N Et3N
TMOF
Pd/CβCAT (mol %)
yield (%)b
2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 1.6 1.2 0.8
1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 0.75 0.5 0.25 0.1 0.1 0.1 0.1 0.1
91 (71)c 65 69 83 85 56 98 97 97 52 0 96 96 95 94 (62)c (0)d (0)e 93 92 43 0 (65%) of 3a were even obtained under the same reaction conditions, but at a reduced MW irradiation time of 90 min (Table 1, entry 4). All three heterogeneous palladium catalysts (Pd/C, Pd/ Boehmite and Pd/CβCAT), showed good catalytic activity when used at 1 mol % palladium content.
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RESULTS AND DISCUSSION According to the literature, 4(3H)-quinazolinone synthesis through cyclocarbonylation usually involves long heating times (hours/days) and traditional organic solvents.17 We describe herein our approach to an environmentally sustainable synthesis for 4(3H)-quinazolinone moieties, which combines the advantages of dielectric heating with recently introduced biobased solvents that are suitable for heterogeneous catalysis. The syntheses of the desired 4(3H)-quinazolinones (3a−3m), were performed in one step MW-assisted carbonylative reactions from a variety of o-haloanilines and either aliphatic or aromatic amines under carbon monoxide pressure in the presence of different heterogeneous palladium catalysts (Scheme 1). Heterogeneous catalysis prevents metal leaching into reaction products, which is especially important when those products exhibit biological activity. This strategy was inspired by our recent findings on MW aminocarbonylation in the presence of CO gas37 and Pd/ CβCAT. In fact, Pd/CβCAT could well be a valid alternative for use in MW 4(3H)-quinazolinone syntheses,23 due to its proven recyclability and ability to absorb MW, provided by the polar nature of its cyclodextrin network.39,41 9236
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Table 3. MW-Assisted 4(3H)-Quinazolinone Synthesis Starting from o-Iodo Anilines (1a−c) with Different Amines (2a−m)
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ACS Sustainable Chemistry & Engineering Table 3. continued
a
Reactions were performed simultaneously in the SynthWAVE reactor multirack position on a 1 mmol scale of o-iodoaniline (1a) and solvent (3 mL) using 1.1 equiv of (2a−m), 0.1 mol % of Pd/CβCAT (0.65 wt % loading), 1.2 equiv of TMOF, and 1.5 equiv of TEA in the presence of a CO (2.5 bar) and N2 (7.5 bar) atmosphere (125 °C, 60 min). bDetermined by GC-MS (yields are based on area percentage). cReaction performed on a 10 mmol scale of o-iodoaniline (1a), using 1.1 equiv of (2a). dReaction conditions; 150 °C, 3 h. eReaction time: 90 min.
It is notoriously difficult to completely avoid the formation of side products in palladium catalyzed carbonylations and this MW-assisted 4(3H)-quinazolinone synthesis also produced a small amount (always less than 4−5%) of compounds 4, 5, and 6, which were identified by GC-MS.
Poor results were recorded in toluene under shortened reaction times, of less than 90 min (Table 1, entries 5, 6), and at temperatures of less than 125 °C (Table 1, entries 1, 2). Toluene was probably ineffective because of its weak MW absorbing character. In fact, it only gave quantitative conversions 9238
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products were detected in the absence of a base (Table 2, entry 11). Moreover, we were pleased to observe remarkable 4(3H)quinazolinone yields, when using TEA as the reference base, even when reducing the palladium catalyst loading CβCAT to 0.1 mol % (Table 2, entries 12−15), and even when using only 1.2 equiv of TMOF instead of its routinely employed overstoichiometric amount (Table 2, entry 17). Only 2-amino-N-phenyl benzamide intermediate III (Scheme 4) and by product 4 were detected under optimized reaction conditions when TMOF was omitted (Table 2, entry 19), while only formanilide 5a and its o-iodo derivative 6a were recorded when CO gas was omitted (Table 2, entry 15d). Despite acetonitrile now being the most recommended polar aprotic solvent, its high volatility and toxicity do not make it attractive for organic synthesis.43 In order to maximize the sustainability of this process toward the use of renewable solvents, we directed our attention to biomass derived GVL, since it holds the promise of biodegradability and reduced toxicity. The applicability of GVL as a reaction medium for MWassisted 4(3H)-quinazolinone synthesis was verified first in the benchmark reaction between o-iodoaniline 1a and 2a (1.2 equiv). It should be noted that GVL acted as an effective replacement for acetonitrile under the optimized, Pd/CβCAT-catalytic-system based synthetic protocol. Excellent 4(3H)-quinazolinone 3a yields were recorded (97%), in only 60 min of MW irradiation at 125 °C (Table 3, entry 1). GVL was therefore preferred for use in further investigations since the crude product could be efficiently recovered via precipitation by adding a small amount of water after heterogeneous catalyst recovery, minimizing waste production (see the Experimental Section) Encouraged by these results, a wide range of substrates was tested in order to establish the scope and limitations of this heterogeneous Pd catalyzed synthetic protocol in GVL (Scheme 2). Various o-haloanilines were combined with a vast array of nucleophilic partners (including aliphatic and (het)aromatic amines), the simultaneous MW-assisted synthesis of a number of 4(3H)-quinazolinones (3a−m), in reactions that ranged from 1 to 10 mmol in scale (Table 3). A number of different aromatic and aliphatic amines (2a−j) were reacted in GVL with o-iodo aniline (1a) and substituted oiodo anilines (4-chloro-2-iodoaniline (1b) and 4-amino-3iodobenzonitrile (1c), respectively) to yield the desired quinazolinones (3a−j) in good to excellent yields (80−97%), regardless of the of the presence of electron-withdrawing and -donating groups (Table 3, entries 1−10). Unfortunately, lower product yields (69%), where obtained when starting from o-bromo aniline, whereas o-chloro aniline proved to be almost inactive for this purpose, even when reaction
to 4(3H)-quinazolinone 3a in 90 min when the reaction temperature was raised to 160 °C (Table 1, entries 7, 8). Moving on to solvents that are more useful under MW heating (e.g., DMF, THF, 1,4-dioxane, MeCN), acetonitrile was found to be the most favorable, giving very good results (>80%), even in short reaction times (Table 1, entries 12−15). The almost quantitative conversion of o-iodo aniline (1a), into the desired product 3a (90% yield) in MeCN in only 1 h of MW irradiation at 125 °C, when Pd/CβCAT was used as the palladium heterogeneous catalyst instead of Pd/C or Pd/Boehmite (Table 1, entry 14) is certainly worthy of note. Based on our experience, the higher catalytic activity shown by the Pd/CβCAT system in acetonitrile, rather than in toluene, can be explained by its improved swelling capability in highly polar solvents, as a consequence of their better interactions with its cyclodextrin matrix. Further attempts were made to clarify the influence of CO pressure on the overall Pd catalyzed carbonylative process with acetonitrile and Pd/CβCAT as the reference solvent and catalytic system, respectively. A reduction in applied CO pressure, from 10 to 2.5 bar (diluting it up to 10 bar with N2), did not significantly affect overall reaction yields at 125 °C, (Table 1, entries 16−18), while a further reduction did not provide sufficiently good results (Table 1, entry 19). Moreover, an advantageous reduction in side product 4a formation was observed (less than 2%), when 2.5 bar of CO was used instead of a higher pressure. For the sake of comparison, the optimized procedure (2.5 bar CO, 125 °C, MeCN as solvent), was repeated under conventional heating using a Parr device (40 mL scale) keeping constant the reaction concentration used for microwave procedure. After a reaction time of 24 h, 4(3H)-quinazolinone 3a yields dropped to 74%, compared to 91% after 60 min under MW irradiation (Table 1, entry 18e). Higher reaction temperatures (150 °C) were tested with the aim of completing the reaction in shorter times, but unfortunately, no improvement in quinazolinone yields was reached in 15−30 min. A number of attempts were carried out at 125 °C and decreased CO pressure (Table 3). No reduction in product yields was observed even at 2.5 bar, with additional nitrogen up to a total of 10 bar, while a decrease in yields occurred when reducing pressure below 1 bar (Table 2). The promising results obtained for MW-assisted 4(3H)quinazolinone synthesis using Pd/CβCAT lead us to test it in the presence of a variety of organic and inorganic bases, including 2,6-lutidine, 4-dimethylaminopyridine (DMAP), triethylamine (TEA), K2CO3, Na2CO3, and Cs2CO3 (Table 2). All the bases listed were found to be less effective than DiPEA (Table 2, entries 1−7), with the exception of TEA that furnished excellent results (97% yield for compound 3a), even when present in lower amounts of up to 1.5 equiv (Table 2, entries 7−9). No reaction 9239
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ACS Sustainable Chemistry & Engineering Scheme 3
Scheme 4. Proposed Reaction Mechanism for the MW-Assisted Synthesis of 4(3H)-Quinazolinones
time and temperature were increased to 3 h and 150 °C of MW irradiation reaction yields were less than 5% (Table 3, entry 1). It is interesting to note that a wide range of synthetically useful functional groups, including ethers, halides, nitriles, and trifluoromethyl groups, remained intact over the course of the reaction. In spite of the presence of a −Br substituent in 2f, no byproducts were detected under described reaction condition. Furthermore, notoriously difficult benzylamines23 were successfully converted into the corresponding 4(3H)-quinazolinone 3h (89% yield; Table 3, entry 8). It was also found that alkylamines gave N-alkylquinazolinones 3i−3j in excellent yield (91−98%, entries 9 and 10).
The present system also shows excellent potential for heterocyclic amine transformation (Table 3, entries 11−13). In fact, 4-(1-piperidinyl)aniline (2k), 4-(1-piperazinyl)aniline (2l), and 4-(4-morpholinyl)aniline (2m) were used in a Pd catalyzed carbonylative cyclization. All reactions proceed efficiently and gave products 3k−3m in good yields (70−79%; Table 3, entries 11−13). Finally, the supported Pd/CβCAT system used for 4(3H)-quinazolinone synthesis displayed negligible palladium leaching, as shown by ICP analyses, while its recyclability was proven in GVL (vide inf ra). In order to show the synthetic utility of this protocol, gramscale reactions were carried out under the optimized conditions 9240
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presence of CO gas (reactions performed in GVL at 125 °C for 60 min in the presence of CO (2.5 bar) and N2 (7.5 bar). It should be pointed out that, after reaction completion, used Pd/ CβCAT was easily recovered via filtration, washed with water and a petroleum ether 40−60/EtOAc (1:1) mixture, dried under vacuum and reused under the same reaction conditions. The recovered catalyst was reused at least five times giving consistent 4(3H)-quinazolinone 3a isolated yields (97%, 93%, 89%, 85%, and 79%, respectively) (Figure 1). The slight change may be due
(125 °C, 60 min), by reacting 1a (10 mmol), with 2a (1.2 equiv), in the presence of 2.5 bar CO, 1.5 equiv of TEA, and 1.2 equiv of TMOF. The reaction proceeded well by providing 3a in an 89% isolated yield (Table 3, entry 1c), as expected from the results of our previous smaller-scale trials (Table 1, entry 1). Reaction Mechanism. The MW synthesis of 4(3H)quinazolinone 3a was carried out (Scheme 3) in GVL using the heterogeneous Pd/CβCAT catalysts. The reaction was steadily monitored by GC-MS (by sample withdrawal) in order to provide insight into the reaction mechanism. The reaction between o-iodo aniline (1a) and aniline (2a) under the abovereported optimized MW conditions, proceeded with the rapid generation of an amide intermediate (III), that was subsequently formylated, and cyclized into 4(3H)-quinazolinone structure 3a. A number of control experiments were carried out using the Pd/CβCAT system in toluene. When the benchmark reaction was performed under 2.5 bar of CO in the absence of TMOF, only the aminocarbonylation intermediate (III) was recorded from the fifth minute of MW irradiation and did not undergo the subsequent cyclization to 4(3H)-quinazolinone over the next 60 min at 125 °C (Table 2, entry 19). A small amount of 4(3H)quinazolinone product 3a (
