Microwave-assisted, green synthesis of 4(3H)-quinazolinones under

Subscriber access provided by University of Texas Libraries

Article

Microwave-assisted, green synthesis of 4(3H)quinazolinones under CO pressure in #-valerolactone and reusable Pd/#-cyclodextrin cross-linked catalyst Emanuela Calcio Gaudino, Silvia Tagliapietra, Giovanni Palmisano, Katia Martina, Diego Carnaroglio, and Giancarlo Cravotto ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.7b02193 • Publication Date (Web): 25 Aug 2017 Downloaded from http://pubs.acs.org on August 28, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

ACS Sustainable Chemistry & Engineering is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 33

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

ACS Sustainable Chemistry & Engineering

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,ǂ Silvia Tagliapietra,ǂ Giovanni Palmisano,§ Katia Martina,ǂ Diego Carnaroglio∥,ǂ, Giancarlo Cravotto*,ǂ ǂ

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). Corresponding Author E-mail: [email protected]

§

Dipartimento di Scienza e Alta Tecnologia, University of Insubria, Via Valleggio, 11 - 22100 Como (Italy). ∥ Milestone

srl, Via Fatebenefratelli, 1-5, Sorisole 24010, Italy.

KEYWORDS: 4(3H)-Quinazolinones, γ-valerolactone, microwaves, carbon monoxide, green synthesis.

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-

ACS Paragon Plus Environment

1


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

Page 2 of 33

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.

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 towards 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 conversion,3 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, bio-based 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 ecofriendly, physical and chemical properties, make it an attractive sustainable solvent even for


2

Page 3 of 33

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


pharmaceutical industry. Since it was initially suggested by Horváth, only a few papers have reported using GVL as a solvent,11,12,13 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 merging the synthetic value of carbonylative transformations and the growing interest in the preparation of bio-active 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 Beller,23 and Wu.24 They isolated various 4(3H)-quinazolinones, in moderate to excellent yields, by adopting a multi-component approach to the palladium catalyzed aminocarbonylation reactions of a variety of different o-haloanilines. 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 Robert et al., in which


3


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

Page 4 of 33

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 high-pressure equipment, there have been some developments in using MW technology with high pressure gas reagents,28,29,30 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 bio-active 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 aminocarbonylation reactions.32,33

and also apply to

We herein continue our work towards suitable, MW-

accelerated aminocarbonylation protocols,34 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.35,36,37 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


4

Page 5 of 33

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


combining non-conventional 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 LuviquatTM 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 adopting a multi-faceted strategy that combines ecocompatible reaction media, recyclable heterogeneous catalysts and suitable enabling techniques with a convenient carbon source, such as CO.

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. MW-promoted reactions were carried out in a SynthWAVE multimode MW reactor (Milestone Srl, Italy; MLS GmbH, Germany), equipped with a safe multiple-gas loading system.


5


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

Page 6 of 33

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, 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 MHz 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 X-ray photoelectron spectroscopy (XPS), with a Quantum 2000 (PHI Co., Chanhassen, MN, USA), and a focused monochromatic Al K source (1486.7 eV), for excitation.


6

Page 7 of 33

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


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 1N HCl (2 x 20 mL), saturated NaHCO3 (2 x 20 mL), and brine (2 x 20 mL). The organic phase was finally dried over Na2SO4 and the solvent removed by distillation. Product purification was performed using flashchromatography (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).


7


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

Page 8 of 33

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, or 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 (1L 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). Procedure for Palladium heterogeneous catalyst recycling


8

Page 9 of 33

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


The previous reaction procedure was followed and the filtered off catalysts were washed with a Petroleum Ether 40-60/EtOAc (1:1) mixture (3 x 20 mL), dried under vacuum and reused in the next run under the same reaction conditions. 4(3H)-quinazolinones (3a) were obtained using the same work up protocols in yields of 97%, 93%, 89%, 85% and 79% respectively, after each recycle. Procedure for GVL recycling After reaction completion, solid catalyst was removed by simple filtration. The reaction product (3a) was recovered by filtration after precipitation in water and the residual GVL- water mixture was dried under vacuum. The recovered GVL was reused without further purification and the following runs gave 4(3H)-quinazolinone (3a) in good to acceptable yields (93%, 89%, 85%, 79% and 61% ).

RESULTS AND DISCUSSION According to the literature, 4(3H)-quinazolinone synthesis through cyclocarbonylation usually involves long heating times (hours/days), and traditional organic solvents17. 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 bio-based 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 ohaloanilines 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


9


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

Page 10 of 33

aminocarbonylation in the presence of CO gas,37 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

For the sake of comparison, the activity of Pd/CβCAT in MW 4(3H)-quinazolinone synthesis was compared with that of 5% Pd/C, the benchmark heterogeneous catalyst used,23 and with Pd/Boehmite. Pd/CβCAT has recently been described by our group and successfully used in the selective MW semi-hydrogenation of alkynes and may be a valid alternative to the typical Lindlar catalyst, due to its recyclability and MW absorbing capability.42

Scheme 1

The influence of critical reaction parameters (i.e. temperature, time, base, CO pressure, catalyst loading and solvent), on MW 4(3H)-quinazolinone synthesis was investigated for optimization using o-iodoaniline(1a) (1 mmol scale) and aniline (2a) (1.2 equiv.) as the reagents (Table 1 and Table 2) in the presence of TMOF (2 equiv.). Initial efforts focused on catalyst comparison; the three palladium heterogeneous catalysts mentioned above (Pd/C, Pd/Boehmite, Pd/CβCAT), were used for the synthesis of 3a 4(3H)quinazolinone. In particular, toluene was chosen as the first classical solvent for carbonylations


10

Page 11 of 33

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


and N,N-Diisopropylethylamine (DiPEA) was used as a base to perform the MW assisted synthesis under CO pressure (10 bar).33 The MW reactor was equipped with a pressure control system and a multiple position rack, which proved effective during multiple gas loading (both inert and reactive) and parallel reaction runs. In particular, quinazolinone 3a was obtained in 87%, 90% and 94% yields using the Pd/C, Pd/Boehmite and Pd/CβCAT catalytic systems, respectively (Table 1, entry 3), after three hours of MW irradiation at 125°C in the presence of 10 bar CO gas. It is worth noting that acceptable yields (>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). Table 1. Optimization of MW-assisted 4(3H)-Quinazolinone 3a synthesis under CO pressure. Yield (%)a

1

Reaction conditions Solvent CO Temperature (bar) (°C) Toluene 10 95

2

Toluene

10

110

3

58

63

65

3

Toluene

10

125

3

87

90

94

4

Toluene

10

125

1.5

65

68

73

5

Toluene

10

125

1

35

42

48

6

Toluene

10

125

0.5

15

22

26

7

Toluene

10

140

1.5

73

79

85

8

Toluene

10

160

1.5

82

87

92

9

THF

10

125

3

45

61

68

10

1,4Dioxane

10

125

3

60

68

74

11

DMF

10

125

3

57

68

72

12

MeCN

10

125

3

76

82

97

13

MeCN

10

125

1.5

72

81

94

14

MeCN

10

125

1.0

68

81

90

15

MeCN

10

125

0.5

55

67

74

16

MeCN

7.5

125

1

68

79

91

Entry

Time (h) 3

Pd/Cb

Pd/Boehmitec

Pd/Cβ β CATd

25

33

37


11


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

Page 12 of 33

17

MeCN

5

125

1

70

78

90

18

MeCN

2.5

125

1

69

78

91(74)e

19

MeCN

1

125

1

56

65

76

20

MeCN

2.5

110

1

67

73

84

21

MeCN

2.5

95

1

53

59

72

a

Reactions were performed simultaneously in the SynthWAVE reactor multi-rack 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. a Determined by GC–MS (yields are based on area percentage). bPd/C (5 wt. % loading). cPd/Boehmite (0.75 wt. % loading), dPd/CβCAT (0.65 wt. % loading). eReaction performed under conventional heating (24 h) using a Parr device (40 mL scale) keeping constant the reaction concentration used for microwave procedure.

All three heterogeneous palladium catalysts (Pd/C, Pd/Boehmite and Pd/CβCAT), showed good catalytic activity when used at 1 mol% palladium content. 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 GCMS. 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 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 one hour of MW irradiation at 125 °C, when Pd/CβCAT was used


12

Page 13 of 33

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


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


13


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

Page 14 of 33

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 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 over-stoichiometric 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).

Table 2. Optimization of MW-assisted 4(3H)-quinazolinone 3a synthesis under CO pressure. Reaction conditions a Entry

Base (equiv)

TMOF

Pd/CβCAT (mol %)

Yield (%)b

1

DiPEA

3

2

1.0

91 (71)c

2

Na2CO3

3

2

1.0

65

3

K2CO3

3

2

1.0

69

4

Cs2CO3

3

2

1.0

83

5

DMAP

3

2

1.0

85

6

2,6-lutidine

3

2

1.0

56

7

Et3N

3

2

1.0

98

8

Et3N

2

2

1.0

97

9

Et3N

1.5

2

1.0

97

10

Et3N

1

2

1.0

52

11

--

--

2

1.0

0


14

Page 15 of 33

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


12

Et3N

1.5

2

0.75

96

13

Et3N

1.5

2

0.5

96

14

Et3N

1.5

2

0.25

95

15

Et3N

1.5

2

0.1

94 (62)c (0)d(0)e

16

Et3N

1.5

1.6

0.1

93

17

Et3N

1.5

1.2

0.1

92

18

Et3N

1.5

0.8

0.1

43

19

Et3N

1.5

-

0.1

0 (

Microwave-assisted, green synthesis of 4(3H)-quinazolinones under

Recommend Documents