Microwave-Assisted Biginelli Reaction: an Old Reaction, a New Perspective 2.05

569 Send Orders for Reprints to [email protected]

Current Organic Synthesis, 2016, 13, 569-600

ISSN: 1570-1794 eISSN: 1875-6271 Current Organic Synthesis

Impact Factor: Microwave-Assisted Biginelli Reaction: An Old Reaction, a New Perspective 2.05

BENTHAM SCIENCE

Majid M. Heravi*, Mahdieh Ghavidel and Bahareh Heidari

Department of Chemistry, School of Sciences, Alzahra University, Vanak, Tehran, Iran

Abstract: In this review, we tried to highlight the recent advances in the Biginelli reaction, leading to the synthesis of 3,4-dihydropyrimidin-2(1H)-ones, albeit only those conducted under microwave irradiation. The merits and drawbacks of these reactions are compared and discussed with those performed under conventional heating.

Dedicated to kazem Kargosha, in the occasion of his honorable retirement as a Professor in Analytical Chemis- try. I would like to open this essay by paying homage to Professor Kargosha, who was much inspirational to the establishment of the Iranian Chemical &Chemical Engineering Society (then, Iranian Chemical Society). Keywords: Biginelli reaction, dihydropyrimidines, DHPMs microwave irradiation, brønsted acid, lewis acid, ionic liquid, catalysis, multicomponent reactions, (MCRs).

1. INTRODUCTION vinylpyridineco- divinylbenzene)–Cu(II) complex was also found A multicomponent reaction (MCR), occasionally in organic to be promisingly developed [31]. chemistry referred to as a "Multi-component Assembly Process" Dihydropyrimidinones (DHPMs), the products of the Biginelli (MCAP), is a chemical transformation in which three or more com- reaction, exhibit a wide range of biological activities. They are pounds in a one pot fashion are combined in sequential manner to found, acting as calcium channel antagonists. Furthermore, some of generate a single product often in high yield. Multicomponent reac- them are known as anti-hypertensive, anti-bacterial, alpha-1-a- tions are desirable as far as atom economy is concerned. Majority antagonists and anti-inflammatory [32-37]. of MCRs often yield highly selective product, which contain great As a matter of fact, the majority of organic chemical transfor- number of atoms of the starting materials [1]. mations are conducted under conventional heating, typically involv- Multicomponent reactions have been recognized for over 160 ing the use of a furnace, oil or water bath and other different types years. In 1850, the first multicomponent reaction was reported by of heater, which heat the walls of vessel in both laboratory attempts Strecker, for the synthesis of -amino cyanides, which are useful or the reactors in chemical industries by either convection or con- precursors for the synthesis of -amino acids. Nowadays a great duction. Under the conventional heating, the core of the sample number of MCRs are known. Among them, isocyanide -based takes much longer to achieve the required temperature for comple- MCRs are the most renowned and documented [2]. Several num- tion of the reactions [38]. bers of name reactions have also practically proceeded to comple- From the discovery of the Biginelli reaction, it has attracted the tion, providing the desired products via MCRs. The examples are, attention of organic chemists just only for years. However, it has Biginelli reaction, Bucherer–Bergs reaction [3], Gewald reaction been overlooked for many years until few decades ago [39]. Espe- [4], Grieco three-component coupling reaction [5], Hantzsch dihy- cially, over the past few years, remarkable and numerous attempts dropyridine synthesis [6,7], Kabachnik–Fields reaction [8], have been made to develop the first procedure reported by Biginelli Mannich reaction [9], Passerini reaction [10], Pauson–Khand reac- to obtain DHPMs with superiority and merits from different points tion [11], Ugi reaction [12] and Asinger reaction [13]. of view in comparison with the original strategy. 1.1. Biginelli Reaction In spite of several advances, and advantages over the initial re- A one-pot, three-component reaction of an aromatic aldehyde 1, port by Biginelli, there are still some drawbacks, realized [40] at the -keto ester 2 and urea 3 resulting in the synthesis of functionalized practical levels. Most of the Biginelli reactions need tedious work- 3,4-dihydropyrimidin-2(1H)-ones 4 was initially reported by Italian up procedures and column chromatography is required for isolation chemist Pietro Biginelli (July 25, 1860 –January 15, 1937) in 1893 and purification of the desired products, which naturally leads to the (Scheme 1) [14]. decreased yields [41]. Although the original reaction was catalyzed by hydrochloric The chief disadvantage of this methodology is requiring long acid, it has been developed by using other Brønsted acids and/or by reaction times, relatively high temperatures (reflux conditions), obtaining low yields of the desired products especially when substi- Lewis acids such as NiCl2. 6H2O, p-TsOH, LaCl3. 7H2O, BF3. O- Et , InBr , LiClO , FeCl , InCl , and metal triflates [15-18]. tuted aldehydes are used and protection of some susceptible func- 2 3 4 3 3 tional groups are needed throughout the reaction. Thus, after the Remarkably, in the Biginelli reactions, HCl, which was initially first report a wave of interests were directed to develop and im- used by Biginelli has been replaced with Lewis acids [19-23], vari- prove this strategy. From the early days, after the first report till ous metal triflates [24, 25] silica sulfuric acid [26]. L-proline [27] date, numerous developed protocols and improved procedures have and ion exchange resin [28] as a more suitable catalyst, for develop- been accomplished and reported. ing this important name reaction. Use of supported catalysts for example, KAl(SO ) .12H O supported on silica gel [29] alumina Perhaps the most valuable development of this reaction is utili- 4 2 2 zation of microwave irradiation (MWI) as source of heating, which supported MoO3 [30] has also improved this name reaction from different points of view, drastically. The applications of metal com- normally decreases the reaction times significantly and improves plex immobilized on various polymer supports, i.e. poly (4- the yield of the reaction, drastically [41, 42].

Current Organic Synthesis 1.2. Microwave-Assisted Organic Reaction *Address correspondence to this author at the Department of Chemistry, School of Sciences, Alzahra University, Vanak, Tehran, Iran; Tel: +98 912 1329147; Fax: +98 21 On the other hand, MWI is gifted source of heating to transfer 88041344; E-mail: [email protected] the heat to the reaction mixture directly, resulting in saving time

O Ar O O O O 2 H, EtOH R O NH Ar H R1 OR2 H N NH + + 2 2 ! R1 N O 1 2 3 H 4

Scheme 1. The first example of a Biginelli reaction, reported by Pietro Biginelli in 1893. and energy required for the completion of the process .MWI is also leading to design and production of several kinds of specific MW a suitable source to heat adequately tiny substances through their ovens, installed with accessories, to alter in a way to make them volume instead of throughout its outer surface. Thus, in theory suitable and useful source of heating for chemical reactions [43]. MWI provides more uniform heating. From past few decades, MW- When MWI is applicable to organic reactions, a number of assisted method as a non-conventional heating, has attracted much variations such as a catalyst, MW power and time of reaction attention of organic and inorganic chemists [38]. should be examined to select the most appropriate combination for In general, MW-assisted reactions may be gifted by some cer- obtaining higher yields in shortest reaction times [49]. tain profits over conventional heating such as, acceleration of reac- We are interested in heterocyclic chemistry and heterocycles tion rate, requiring milder reaction conditions, giving higher [50-56], especially those synthesized via MCRs [57-60], and in chemical yields, lower energy usage and providing different selec- particular by Biginelli reaction [61-66]. We have also been engaged tivities for some reactions [43]. with development of various organic transformations by conducting The first MW oven was designed in 1955, assembled and pre- them under MWI in order to accelerate the reactions and thus com- sented by Tappan. However it was used extensively, during 1970s plete them in shorter reaction times and improve the reaction yields and 1980s for domestic purpose in the kitchens .The first applica- [67-76]. tion of domestic MW oven and use of MWI as a non-conventional Thus, in continuation of our attempts to update the applications source of heating in chemical synthesis was appeared in chemical of name reactions [77-86], in this review, we tried to underscore the literature in 1986. conduction of a well-known and applicable reaction, namely Bigi- This use of green source of energy actually leads to use of less nelli reaction which is also one of the most useful MCRs for the amount of catalysts or non-catalyzed reactions, being done in a construction of pyrimidine derivatives under MWI as a non- solventless system, along with easy recovery and recycling the conventional heating source. catalysts. Moreover, the yields of the obtained products were often higher than those obtained from being done under conventional 1.3. Catalysis heating. The most important feature is noticed, perhaps was the Catalysis is in fact an increase in rate of a chemical reaction due significant decrease of reaction times. Thus, microwave irradiation to the contribution of an additional substance to starting materials. has gained popularity in the past decade as a powerful tool for rapid In this case, the reactions proceed more rapidly and often less en- and efficient synthesis of a variety of compounds because of selec- ergy is required. Basically, catalysts are not consumed and there- tive absorption of microwave energy by polar molecules. fore, their separation and reuse in an easy and efficient way is de- The application of Microwave irradiation to provide enhanced sirable. These desirable qualities are more operational by using reaction rate and improved product field in chemical synthesis is heterogeneous catalysts which act in a different phase than that of quite successful in the formation of a variety of carbon-heteroatom the reactants. Most heterogeneous catalysts are solids that catalyze bonds. the chemical reactions in a liquid or gaseous mixture. Remarkably, they can be recovered by simple filtration and effectively reused Due to the importance of environmental concerns nowadays in with or without further activation, frequently in several runs [87, every aspect and issues of our life, the extension of this green 88]. A combination of heterogeneous catalysis with MWI has at- source of heating to chemistry and its applications in chemical reac- tracted much attention [89]. tions are much in demands [43]. Catalyzed reactions being performed under solvent-free condi- Generally, MW-assisted chemical transformations have been tions are a kind of heterogeneous catalysis [90]. The catalyzed broadly classified into two categories: a) microwave-assisted reac- MW–induced reactions under solvent free conditions have a mani- tions using solvents [44-47]; b) microwave-assisted reactions using fold advantage, especially when green chemistry is considered as solvent-free conditions [48]. main concern. During the years the application, MW-assisted organic reactions have shown both merits and drawbacks. The intrinsic worth involv- 2. BIGINELLI REACTION UNDER MICROWAVE IRRA- ing, rapid reactions, high purity of products, less side- DIATION product,improved yields, wider usable range of temperature, higher MWI has been found to act as a more sustainable medium in energy efficiency, simplified and improved synthetic procedure, comparison with conventional heating. It is also considered as a sophisticated measurement and safety technology, modular systems more eco-friendly source of heating. enable changing from mg to kg scale, useful being applied in large scale operations. The disadvantages including are the difficult heat Several one-pot, multicomponent reactions have been success- force control, water evaporation and use of sealed vessel is risky fully examined under MWI in order to minimize the reaction time, since it could be burst [43]. Due to these disadvantages, nowadays to decrease the number of steps, save energy, decrease the waste domestic micro oven is not often used for providing heat for chemi- production, and to increase the synthetic efficiency along with pro- cal reactions. In domestic micro oven, heat and force control are viding environmental benignity. Delightfully, it has also been ascer- difficult, water evaporation is inevitable and use of sealed vessel is tained that the Biginelli reaction, as a multicomponent reaction, risky since it could be burst [43]. proceeds smoothly under MWI and in shorter reaction times to give better yields of the corresponding products in comparison with the To circumvent these problems, the MW ovens has been modi- same reactions conducted under conventional heating [66, 49, 91, fied, accordingly. The development of MW was rapidly growing, 92]. Microwave-Assisted Biginelli Reaction Current Organic Synthesis, 2016, Vol. 13, No. 4 571

O R1 O O X

1 2 R CHO + 2 + R O NH Me OR H2N NH2 5 6 7 Me N X H 8, 9

1 8a, R = 3-O2NC6H4, Isolated yield under MWI= 66 % 2 1 8, MW, Solvent- and catalyst-free R = CH3 8b, R = 4-ClC6H4, 68 % 1 X = O 8c, R = 2,4-ClC6H4, 48 % 1 8d, R = 2,6-ClC6H4, 51 %

1 9a, R = 3-ClC6H4, X = S, Isolated yield under MWI = 78 % 1 9b, R = 2-CH3OC6H4, X = S, 84 % 1 2 9c, R = 4-O2NC6H4, X = S, 80 % 9, MW(CEM), 10 W, 130 °C, 18 min R = C2H5 9d, R1= 4-ClC H , X = O, 79 % Solvent- and catalyst-free 6 4 1 9e, R = 4-CH3OC6H4, X = O, 82 % 1 9f, R = 3-O2NC6H4, X = O, 77 %

Scheme 2. MW-assisted catalyst- and solvent-free Biginelli reaction.

2 O R OEt MW (53 W), 5-10 min COOEt O X 150 ˚C HN O2 S 2 + + H R H2N NH2 X N R1 O 1 Refluxed in EtOH SO2 R H 12 13 10 11

1 2 13a, R = 4-MeC6H4, R = 4-MeOC6H4, X = O, MW = 93 %, 10 min, CONV = 45 %, 8 hr 1 2 13b, R = 4-ClC6H4, R = 4-FC6H4, X = O, MW = 80 %, 10 min, CONV = 55 %, 8 h, 8 hr 1 2 13c, R = 4-ClC6H4, R = 4-MeOC6H4, X = S, MW = 78 %, 10 min, CONV = 44 %, 8 hr 1 2 13d, R = 4-ClC6H4, R = 4-MeOC6H4, X = O, MW = 88 %, 10 min, CONV = 45 %, 8 hr 1 2 13e, R = 4-ClC6H4, R = 4-ClC6H4, X = S, MW = 75 %, 10 min, CONV = 48 %, 8 hr

MW % = Isolated yield under MWI CONV % = Isolated yield under conventional heating

Scheme 3. Preparation of ethyl 2-oxo/thio-4-aryl-6-(arylsulfonylmethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylates 13.

2.1. Uncatalyzed Reactions bined with grindstone machinery. The same reactants in refluxing MWI has been employed to accelerate the Biginelli reaction in ethanol also afforded the corresponding compounds (17a–f). In the absence of any catalyst, affording the desired dihydropyrimidi- comparison with using conventional heating, this reaction could be nones in high yields (Scheme 2, 8a-d) [93], (Scheme 2, 9a-f) [94]. conducted under milder conditions; needing a shorter reaction time, it afforded higher yields, and ensued the green chemistry disci- Several new ethyl 2-oxo/thio-4-aryl-6-(arylsulfonylmethyl)- plines, when performed under MWI in a solventless system 1,2,3,4-tetrahydropyrimidine-5-carboxylates 13 were regioselec- (Scheme 4) [97]. tively synthesized via the one-pot MCR of ethyl 3-oxo-4- (arylsulfonyl)butanoate, aromatic aldehyde and urea/thiourea fol- 2.2. Catalyzed Reaction lowing the Biginelli protocol under MWI in the absence of any 2.2.1. Brønsted Acid solvent and catalyst at 150 ºC [95]. For the sake of comparison, the above reactions were also conducted under classical thermal condi- Nanomagnetic-supported sulfonic acid has been introduced as a tions in refluxing EtOH to give 13. The results disclosed that the new, active, powerful, and recyclable heterogeneous catalyst for the yields of 13 under MWI were remarkably higher than those ob- efficient and fast synthesis of 3,4-dihydropyrimidin-2-(1H)-ones tained under conventional heating conditions (Scheme 3) [96]. under both conventional heating and MWI. This is the first report regarding the combination of magnetic Fe nanoparticles and MWI Several multifunctional 2-amino-5-cyano-4-[(2-aryl)-1H-indol- in a multicomponent reaction. These conditions give higher yields 3-yl]-6-hydroxypyrimidines (17a–f) were prepared by MCR of 3- of products in a shorter time in comparison with the Biginelli reac- formylindole (14), cyanoethylacetate (15), and guanidine hydro- tions 22a-h, 23a-f and 29a-f and Biginelli reactions like 53 and chloride (16) in the presence of NaOH by employing MWI com- 54a-j performed under conventional heating. 572 Current Organic Synthesis, 2016, Vol. 13, No. 4 Heravi et al.

NH HO H2N NH2.HCl N NH2 16 (i) MW (800 W), 6-7 min NC (ii) Refluxing in EtOH N CHO + R NaOH R CNCH2COOC2H5 N N H 15 H 17 14 17a, R = 2-F, 5-CH3, MW = 90 %, 7.5 min, CONV = 82 %, 5 hr

17b, R = 4-CH3, MW= 90 %, 6.5 min, CONV = 80 %, 4 hr 17c, R = 4-Br, MW = 90 %, 8 min, CONV = 86 %, 4 hr 17d, R= 4-Cl, MW = 92 %, 7 min, CONV = 82 %, 5 hr 17e, R = 4-F, MW = 89 %, 7 min, CONV = 83 %, 4.5 hr 17f, R = H, MW = 87 %, 7.5 min, CONV = 84 %, 5 hr

Scheme 4. Synthesis of 2-amino-5-cyano-4[(2-aryl)-1H-indol-3-yl]-6-hydroxypyrimidines. O O R X Bronsted acids R C H O C H O NH 2 5 21-30 2 5 + + H2N NH2 O H H C O 3 20 H3C N X 18 H 19 21-30

21a, R = 4-HOC6H4, MW = 96 %, 30 sec, CONV = 89 %, 2:30 hr

21b, R = 4-O2NC6H4, MW = 95 %, 30 sec, CONV = 82 %, 3:30 hr 21: Nano-g -Fe2O3-SO3H, Solvent-free or MW (250) W, 60 °C for both method 21c, R = 4-CH3C6H4, MW = 89 %, 3 min, CONV = 74 %, 3 hr 21d, R = 4-ClC6H4, MW = 96 %, 2 min, CONV = 65 %, 4 hr X = O 21e, R = C6H5, MW = 97 %, 3 min, CONV = 95 %, 3 hr Scheme 5. A Biginelli reaction under different Bronsted acids.

22a, R = 4-CH3OC6H, X = O, Isolated yield = 89 %

22b, R = 4-O2NC6H4, X = O, 78 %

22c, R = 4-O2NC6H4, X = S, 77 % 22d, R = 4-CH OC H, X = S, 89 % 22: PEG-SO3H, Solvent-Free, MW, 100 °C, 6 min 3 6 22e, R= 4-HOC6H4, X = S, 83 %

22f, R= 4-HOC6H4, X = O, 85 %

22g, R = C6H5, X = O, 91 %

22h, R = C6H5, X = S, 88 %

As illustrated in Scheme 5, the MW-induced catalyzed reac- An MW-promoted facile and effective process for a one-pot tions are superior to those performed under conventional heating three-component Biginelli reaction of substituted aldehydes, - (Scheme 5, 21a-e) [98, 99]. ketoesters, and urea / thiourea in a solventless system using a solid Sulfonic acid immobilized on various polymer-supports has at- silica-based sulfonic acid as an efficient and new heterogeneous tracted much attentions as an efficient solid acid catalyst [100-102]. reusable catalyst was accomplished and reported. In comparison to An effective and environmentally benign approach, utilizing a the conventionally heated Biginelli reaction, this approach showed poly(ethylene glycol)-bound sulfonic acid (PEG-SO3H) as a cata- the advantages of better yields, short reaction times, and being ex- lyst under MWI has successfully been achieved and employed in perimentally simple. It was also found that the Lewis acids could the synthesis of 3,4-dihydropyrimidones via a Biginelli-type cyclo- stimulate the reaction; however, the yields were not as good as condensation. Significantly, the functionalized poly(ethylene glycol) sulfonic acid has simultaneously played a dual role of acting as those of other catalyzed reactions. The use of 3-mol% solid silica- a catalyst and as being a suitable solvent in this cyclocondensation. based sulfonic acid significantly increased the reaction yield up to The desired Biginelli products have been obtained in high purity 95 % under the MWI (900 W) in only 7 min. (Scheme 5, 23a-f) and satisfactory yields (Scheme 5, 22a-h) [103]. [104]. Microwave-Assisted Biginelli Reaction Current Organic Synthesis, 2016, Vol. 13, No. 4 573

O 23a, R = 4-CH3OC6H4, X = S, Isolated yield = 91 %

O Si N SO3H 23b, R = 4-O2NC6H4, X = O, 92 % O H 23c, R = 3-O2NC6H4, X = S, 87 % 23: 23d, R = 4-ClC6H4, X = O, 89 % MW (900 W), Solvent-free, 6-7 min, 80 °C 23e, R = C4H4N, X = O, 85 %

23f, R = C6H5, X = S, 89 %

24: HCl / Ethanol, 24a, R = 3,4-CH3OC6H4, X = O, MW = 96 %, 3 min, CONV = 46.9 %, 120 min Method A: MW (200-400 W), 3-11 min, 24b, R = C6H5, X = O, MW = 90 %, 3.5 min, CONV = 78.5 %, 180 min Method B: reflux, 80 °C, 2-24 hr 24c, R = C6H5, X = S, MW = 90 %, 3 min, CONV = 42 %, 120 min

24d, R = 4-O2NC6H4, X = S, MW = 78.4 %, 4 min, CONV = 24 %, -

1 25a, R = 4-CH3OC6H4, MW = 88 %, 12 min, CONV = 71 %, 12 hr 25: Method A: Dry acetic acid, MW (650 W), 1 min 1 25b, R = 4-O2NC6H4, MW = 88 %, 4 min, CONV = 79 %, 15 hr Method B: Refluxed in toluene in the presence 25c, R1 = b-Naphthyl, MW = 88 %, 3 min, CONV = 77 %, 11 hr of either Amberlyst-15 or Nafion-15 as catalyst 25d, R1 = 2-Thienyl, MW = 97 %, 2 min, CONV = 83 %, 6 hr 1 25e, R = C6H5, MW = 86 %, 2 min, CONV = 80 %, 12 hr X = O

Unconventional MWI has been employed in a classic Biginelli Nafion, as a superacid, is a potential catalyst for organic trans- reaction. Gupta et al. [105] and Dandia and co-workers [106] inde- formations. Studies have demonstrated its catalytic activities in pendently reported the synthesis of a wide variety of different Bigi- alkylation, isomerization, oligomerization, acylation, ketalization, nelli products employing an MW-assisted reaction in solution esterification, hydrolysis of sugars and ethers, and oxidation. New phase. Both group employed ethyl acetoacetate, (thio) ureas (X = O, applications are constantly being discovered [109]. S), and a wide range of different aromatic aldehydes to manipulate In general, K-catalysts are used in reactions where acidity of a an MCR acid-catalyzed Biginelli reaction. Interestingly, all these catalyst is essential. For example, they catalyze esterification or reactions were performed in an open glass pot placed inside a do- etherification reactions, which are also catalyzed by Bronsted acids. mestic MW oven and imposed to MWI. As usual, the reaction pro- Catalysis by Lewis-acids leads to alkylation or acylation of aro- gress was monitored by TLC. This monitoring was conducted in matic compounds in the presence of alcohols, olefins and organic parallel with the same reactions performed under the same reaction acids, respectively. The K-catalysts also catalyze these reactions. conditions but with conventional heating. The observations vividly Notably, the K-catalysts possess Bronsted- as well as Lewis-acidic showed the shorter reaction times under MWI in comparison with properties [110]. those performed under conventional heating [105, 106]. Interest- ingly, even the yields obtained from the reactions conducted under Using ion exchange-resins such as Amberlyst-15 and Nafion-H MWI were found to be higher for DHPMs 24 in comparison with for Biginelli reactions, it was found that generally, the reaction the same previously reported reactions conducted under conven- yields are increased and the time of reactions are decreased. The tional heating. As examples of the MW-assisted Biginelli reactions reaction was carried out by refluxing the reactants in toluene in the claimed by Gupta and Dandia [105, 106], four representatives (24a- presence of either Amberlyst-15 or Nafion-H for 6 to 15 h to d) were chosen and investigated carefully. Noticeably, in all four achieve the corresponding products in satisfactory yields [111]. cases increases in the yields were observed under MWI signifi- Solid acids like Amberlyst-15, Nafion-H and KSF clay afforded cantly when compared with those four reactions done under the good yields of Biginelli reaction products in high purity but the conventional heating 24a-c (Scheme 5, 24a-d) [107]. These Bigi- implemented isolation procedures were cumbersome due to the nelli products were obtained in higher yields than those of 28a-d as insolubility of the products in most of the organic solvents except in well as the Biginelli-like products 41a-d and 45 a-d. DMSO or hot methanol. In summary, the results indicate the gener- Dihydropyrimidines were synthesized in high yields by one-pot ality and wide scope of the reaction for various substituted alde- cyclocondensation reactions of aldehydes, acetoacetates and urea hydes (Scheme 5, 25a-e) [111]. using various acid catalysts like Amberlyst-15, Nafion-H, KSF clay 3,4-Dihydropyrimidin-2(1H)-one derivatives were synthesized and dry acetic acid under MWI. in high yields by the Biginelli reaction under MWI using oxalic Amberlyst-15 is an important catalyst in synthetic organic acid Oxalic acid is proven to act as an efficient and environmentally chemistry. It promotes reactions such as esterification, transesterifi- benign catalyst for MW-assisted synthesis of DHPM derivatives cation, Michael addition, aza-Michael addition, Prins cyclization, (Scheme 5, 26a-d) [112]. Friedel-Crafts alkylation, acylation, metal-free hydroarylation, hy- A series of DHPs was synthesized employing the catalytic ac- droalkylation, halogenation, protection of carbonyls, amines, depro- tivity of TsOH under MWI in the presence of glacial acetic acid in tection of acetals and acetates, Boc-protection of amines, cleavage shorter reaction times. Compounds 91a-f were also obtained in of epoxides, crossed-aldol condensation, as well as synthesis of satisfactory yields and short reaction times via Biginelli-like reac- quinolines, pyrazolines, indolinones, acridines, calix[4]pyrroles, tions under MWI in a solventless system, (Scheme 5, 27 a-d) [113]. xanthenes, coumarins, benzopyrans theaspirane, furans, and substituted phosphonates. Applications of this catalyst allow mild and The Biginelli reaction of ethyl acetoacetate, thiourea and an ap- highly selective transformations in a facile and environmentally propriate aromatic aldehyde in ethanol in the presence of a catalytic friendly manner. The catalyst can be regenerated and recycled amount of hydrochloric acid was performed under MWI to [108]. afford ethyl 4-aryl-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine- 574 Current Organic Synthesis, 2016, Vol. 13, No. 4 Heravi et al.

26a, R = 4-OH, 3-OCH3C6H3, Isolated yield = 88 %

26: Oxalic acid, Solvent-free, MW (20 W), 2-5 min 26b, R = 3-O2NC6H4, 94 %

26c, R = 4-OCH3C6H3, 85 % X = O 26d, R = C6H5, 87 %

27a, R = 3,4-OCH2OC6H3, Isolated yield = 93 % 27: TsOH /Glacial acetic acid, MW, 4-7 min 27b, R = 4-NO2C6H6, 89 % 27c, R = 4-OHC H , 89 % X = O 6 4 27d, R = C6H5, 97 %

28: Method A: EtOH, conc. HCl , reflux, 3 hr, 28a, R = 4-(CH3)2NC6H4 , MW = 82 %, 5 min, CONV = 55 %, 3 hr

Method B: EtOH, conc. HCl, MW, 140 °C, 5 min 28b, R = 2-CH3OC4H3 , MW = 62 %, 5 min, CONV = 35 %, 3 hr

28c, R = 4-CH3OC6H4 , MW = 87 %, 5 min, CONV = 58 %, 3 hr X = S 28d, R =2-HOC6H4, MW = 70 %, 5 min, CONV = 42 %, 3 hr

29a, R = 4-OCH3, X = O, Isolated yield = 88 %

29b, R = 4-OCH3, X = S, 87 % 29: PSSA/H O, 80 °C, MW 2 29c, R = 4-NO2, X = S, 86 %

29d, R = 4-NO2, X = O, 88 % 29e, R = 4-Cl, X = O, 91 % 29f, R = 4-Cl, X = S, 88 %

30a, R = 3,4,5-CH3OC6H4, Isolated yield = 85 %

30b, R = 4-CH3OC6H4, 95 % 30: ZrO2-pillared clay (Zr-PILC), MW (630 W), 5 min 30c, R = 3-O2NC6H4, 90 %

X = O 30d, R = 4-O2NC6H4, 95 %

30e, R = 4-ClC6H4, 97 %

5-carboxylates 28. The aforementioned reactions were also per- The acid catalyzed condensation of fluorinated aromatic alde- formed under conventional heating. Comparison of the results ob- hydes with ethyl acetoacetate and urea/fluorinated phenylthiourea tained from both conditions revealed the superiority of the MW- 40 in open borosilicate glass vessels using ethanol as an energy assisted method. The reactions are completed in shorter times and transfer medium, afforded ethyl 4-aryl-6-methyl-1,2.3,4-tetrahydro- the better yields of products are obtained, when performed under pyrimidine-2-one/ thione-5-carboxylates 41. MWI as a suitable MWI (Scheme 5, 28a-d) [114]. source of energy have been found to drastically accelerate this Biginelli synthesis of fluorine containing ethyl 4-aryl-6-methyl- An environmentally benign aqueous Biginelli protocol for the 1,2,3,4-tetrahydropyrimidin-2-one/thione-5-carboxylates in open synthesis of substituted 3,4 dihydropyrimidin-2(1H)-ones catalyzed vessels. In this reaction, ethanol is generally used as an energy by polystyrenesulfonic acid (PSSA) under MWI in aqueous phase transfer medium. Results obtained from this reaction conducted has been reported. Initially, the reaction was examined in the ab- under MWI were compared with those obtained from the reaction sence of the catalyst under MWI conditions in an aqueous medium performed under conventional heating to show the superiority of the and no reaction (NR) was observed even at 80 and 100 °C. Using a utilization of MWI. Lewis acid [115] and Nafion-H [116] as catalysts led to only poor yields of the products whereas employing acetic acid (AcOH) as the In order to prove the possible specific effect of MWI as com- catalyst gave moderate yields [115, 117] Delightfully, it was ob- pared with the conventional heating source, two reactions with served that PSSA could efficiently catalyze this reaction to afford same reaction conditions and staring materials, one under MWI and high yields of the desired products in short reaction times (Scheme the other under conventional thermal were studied. Remarkably, the latter afforded lower yield even after prolonged heating (10 h), 5, 29a-f) [118]. which proved the significant effect of MWI, Scheme 6) [120]. A new strategy utilizing ZrO -pillared clay (Zr-PILC) has been 2 A facile and effective approach was developed and reported for developed. This Zr composite acts as a mild, recoverable and reus- the synthesis of several 4-aryl-1,3,4,5- tetrahydro-2H-indeno[1,2- able solid acid catalyst in a solventless, one-pot, three-component d]pyrimidine-2-thiones 45 via a one-pot multicomponent Biginelli synthesis of dihydropyrimidinones both by conventional heating reaction under MWI. For the purpose of comparison, these reac- and under MWI. Interestingly, in accordance with the suggested tions were also performed under conventional heating. The products mechanism (Fig. 1) the Zr composite, Zr-PILC, enjoys both Bron- (45a-d) were obtained via the reaction of an equimolar mixture of sted and Lewis acidic properties to impose its excellent catalytic 1-indanone, thiourea and various substituted aldehydes, in the pres- activity. ence of 3–4 drops of conc. HCl and ethanol as a solvent, in an open It is obvious from the results that the method under solvent-free vessel under MWI as well as via conventional heating. In the case conditions by MWI using Zr-PILC gave the best results in terms of of using MWI, the reactions were completed in 5-8 min. From yields and reaction times (Scheme 5, 30a-e) [119]. Scheme 7, it was established that MWI was generally a heating Microwave-Assisted Biginelli Reaction Current Organic Synthesis, 2016, Vol. 13, No. 4 575

O OH

H2NNH2 32 N NH2 H H R H2O 33 O

O H 31 ZrO -PILC 2 R R Exploitation of Bronsted acidity

Exploitation of Lewis acidity H H R

R HN NH N NH2 O 2 O O C2H5O NH + H2O H O 34 ZrO2 H C N O PILC 3 H C2H5O NH 37 ZrO2 O H3C O OO

H2N 36 H3C OC2H5 35

Fig. (1). A plausible mechanism for zirconium-catalyzed Bigenelli reactions. Ar C H OOC X C H OOC Ar 2 5 2 5 MW (360 W), 6 min NH CHO + + H2N NHR O Me N X 38 Me 40 C2H5OH, H R 39 41

41a, X = S, R = 2-F3CC6H4, Ar = C6H5, MW = 86.4 %, 11 min, CONV = 64 %, 10 hr

41b, X = O, R = H, Ar = 4-FC6H4, MW = 86 %, 6 min, CONV = 70 %, 7 hr

41c, X = S, R = 4-FC6H4, Ar = 4-CH3OC6H4, MW = 75.2 %

41d, X = S, R = 4-FC6H4, Ar = 3-O2NC6H4, MW = 70.2 %

41e, X = S, R = 2-F3CC6H4, Ar = 4-FC6H4 , MW = 65 %

41f, X = S, R = 4-FC6H4, Ar = C6H5, MW = 82.4 %

41g, X = S, R = C6H5, Ar = 4-FC6H4, MW = 87.9 %

41h, X = O, R = H, Ar = 3-FC6H4, MW = 87.4 %

Scheme 6. Synthesis of ethyl 4-aryl-6-methyl-1,2.3,4-tetrahydropyrimidine-2-one/ thione-5-carboxylates (IV). source superior to the conventional heating in the synthesis of the Ketoesters, aryl aldehydes, and urea or thiourea in a heat bath gave above compounds in terms of shorter reaction times, higher yields high yields of the desired products, especially when reactions are and decrease in the amount of side products (Scheme 7) [121]. performed at low temperature. Noticeably, potsherd and ceramic Several pyrimidine derivatives 49a–e were prepared via the were found better heat sinks for the synthesis of these cycloconden- Biginelli reaction under MWI. The efficiency of various baths or sation products under MWI. vessels including molecular sieves, ceramic, silica gel, potsherd, In conclusion, it was found that potsherd and ceramic sinks are and alumina, as heat pools in conveying the MWI for the formation more suitable mediators for Biginelli condensation reactions under of 49a–e has been reported. The one-pot condensations of - MWI. Varma and co-workers reported the use of a ceramic sink, 576 Current Organic Synthesis, 2016, Vol. 13, No. 4 Heravi et al.

S 30 % MW CHO O HN S 2-8 min NH EtOH R + + H2N NH2 H Reflux A R 44 42 43 4-6 hrs 45

45a, R = 2,3-(O-CH2-O), MW = 75 %, 5. 30 min, CONV = 30 % , 4.30 hr

45b, R = 4-OH, 3-OCH3, MW = 67 %, 5 min, CONV = 48 %, 5 hr

45c, R = 4-OCH3, MW = 48 %, 8 min, CONV = 43 %, 5. 30 hr

45d, R = 3-NO2, MW = 92 %, 4.30 min, CONV = 72 %, 5 hr

Scheme 7. Synthesis of indeno[1,2-d]pyrimidine-2-thinones.

O H O Ar X few drops of EtOH R or Solvent-free R NH ArCHO + + H2N NH2 46 O MW (900 W) N X 48 H 47 49

49a, R = EtO, Ar = 2,5-dimethoxyphenyl, X= O, Potsherd (66a °C, 91b %), Ceramic (67a °C, 92b %) 49b, R = t-BuO, Ar = 4-Chlorophenyl, X= O, Potsherd (59a °C, 87b %), Ceramic (66a °C, 93b %) 49c, R = EtO, Ar = Ph, X= O, Potsherd (71a °C, 96b %), Ceramic (83a °C, 93b %) 49d, R = EtO, Ar = Ph, X= S, Potsherd (74a °C, 89b %), Ceramic (85a °C, 92b %) 49e, R = Me, Ar = Ph, X= S

a T ( °C) b Isolated yield under MWI

Scheme 8. Synthesis of several Biginelli products. which allowed the rapid synthesis of the desired products in the This approach not only affords products in satisfactory yields, absence of polyphosphate esters as a catalyst (Scheme 8) [122, but also avoids problems due to using solvents, e.g. their cost, han- 123]. dling, safety, pollution, and more importantly, the reaction times, The three-component condensation of 3-amino-5-alkylthio- which are decreased from several hours to only a few minutes. 1,2,4-triazoles with an appropriate aromatic aldehyde and a - This protocol was also used for the preparation of 58 in the ketoester was successfully accomplished and reported. The ob- presence of acetic acid and NaHSO4. In this case, the yields were tained results clearly exhibited that the reaction solvent and the increased by around 6-13%. The reaction was also repeated in the properties of the -ketoester components had a significant effect on absence of catalyst, which gave moderate yields with the identical the regioselectivity of this reaction. When the reaction is conducted reaction times (Scheme 10) [127]. in H2O, using TSA as a catalyst, the reaction proceeded initially A fast and facile synthesis of 5-unsubstituted 3,4- with the participation of N2 or 3-NH2 of the 3-amino-5-alkylthio- dihydropyrimidin-2-ones and thiones via a Biginelli-like reaction 1,2,4-triazoles to give ethyl-7-aryl-2-alkylthio-4,7-dihydro-1,2,4- has successfully been achieved. This reaction comprises a one-pot, triazolo-[1,5-a]pyrimidine-6-carboxylate (53) or ethyl-7-hydroxy-7- three-component reaction between oxalacetic acid, thiourea/urea, alkyl-5-aryl-2-alkylthio-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a] and differently substituted aldehydes under MWI. It affords the pyrimidine-6-carboxylate (54) depending on the nature of the sub- products in good to high yields and much shorter reaction times in stituent on the aromatic aldehyde. When ethyl trifluoroacetoacetate comparison with those performed under conventional heating. It was actually used as the -ketoester component, either 53 or 54 was was found that under the influence of MWI, the reaction time was obtained. When ethyl acetoacetate or ethyl chloroacetoacetate was drastically decreased from 12 h to 15 min. This result not only chosen and employed as the -ketoester component, the reaction shows the effects of MWI in the Biginelli reaction but further re- always afforded a mixture of the two isomers 53 and 54 (Scheme 9) veals the worth of the MW-assisted synthesis in terms of growing [124]. yield, decreasing reaction time and reorganisation of high output of Biginelli-like reactions, [125, 126] using aldehydes, urea and any other selected organic synthesis. To find optimal reaction con- Meldrum's acid or barbituric acid derivatives have been conducted ditions, the reactions were performed under MWI in diverse reac- under MWI in a solventless system. In these modified reactions, the tion conditions (Scheme 11) [128]. aforementioned acids act as a CH-acid, instead of open-chain cyclic A series of 5-indolylpyrimido[4,5-d]pyrimidinones (66a-h) -dicarbonyl compounds. was obtained by a multi-component reaction of 3-formylindole 63, Microwave-Assisted Biginelli Reaction Current Organic Synthesis, 2016, Vol. 13, No. 4 577

O O O R1

C2H5 1 C2H5 O O R O NH C2H5 51 TSA / H2O O NH N + N + HO HN N N R1 N N R2CHO 2 H N R3 R R3 N 2 N 53a-j 3 50 52 54a-j R

1 2 3 a b 53, 54a, R = ClCH2, R = 4-CH3OC6H4, R = SCH3 , MW = 31 , MW =5 1 2 3 a b 53, 54b, R = ClCH2, R = 4-ClC6H4, R = SCH2Ph , MW = 28 , MW = 35 1 2 3 a b 53, 54c, R = CH3, R = 4-CH3C6H4, R = SCH2Ph, MW = 32 , MW =19 1 2 3 a b 53, 54d, R = CH3, R = 4-CH3OC6H4, R = SCH3, MW = 34 , MW = 35 1 2 3 a b 53, 54e, R = ClCH2, R = 4-ClC6H4, R = SCH3, MW = 43 , MW = 5 1 2 3 b 53, 54f, R = CF3, R = 4-ClC6H4, R = SCH2Ph, MW = 49a, MW = 0 1 2 3 a b 53, 54g, R = CF3, R = 4-CH3C6H4, R = SCH3, MW = 0 , MW = 60 1 2 3 a b 53, 54h, R = CH3, R = 4-ClC6H4, R = SCH3, MW = 36 , MW = 5 1 2 3 a b 53, 54i, R = CF3, R = O2NC6H4, R = SCH3, MW = 55 , MW = 0 1 2 3 a b 53, 54j, R = CF3, R = C6H5, R = SCH3, MW = 0 , MW = 80

aMW % = Isolated yield for pruduct 53 bMW % = Isolated yield for pruduct 54

Scheme 9. The Biginelli-like reaction in an H2O solution using TSA as a catalyst. O H Y XX Y O XX Solvent-free O O + 4 -R C H C H 4-R + H N NH 6 4 6 4 O O 2 2 MW, 4min H H HN N H 57 R 56 O 55 a b c 58a, X-Y-X = MeN-CO-NMe, R= Me, 63 %, 70 %, 80 % 58 58b, X-Y-X = MeN-CO-NMe, R= F, 59a %, 74b %, 83c % a b c 58c, X-Y-X = O-C(Me)2-O, R = Me, 48 %, 61 %, 70 % 58d, X-Y-X = HN-CO-NH, R = Me, 59a %, 71b %, 81c % a b c 58e, X-Y-X = O-C(Me)2-O, R = Cl, 54 %, 63 %, 74 % 58f, X-Y-X = HN-CO-NH, R = Cl, 63a %, 75b %, 82c %

a Isolated yield in the absence of catalyst. b Isolated yield in the presence of NaHSO4. c Isolated yield in the presence of HOAc (reaction time 4 min).

Scheme 10. Synthesis of spiro-fused heterocycles under solvent-free conditions. X O O X R1 TFA / THF NNH 2 1 R CHO + HO2C OH + H2N NHR MW HO C R2 59 60 61 95 °C for 15 min 2 62

1 2 1 2 62a, X = O, R = CH3, R = 2,4-(CH3O)2C6H3, 76 % 62f, X = O, R = H, R = 4-FC6H4, 73 % 1 2 a b 1 2 62b, X = S, R = H, R = C6H5, 82 % (64 %) 62g, X = S, R =H, R = 4-FC6H4, 83 % 62c, X = S, R1 = allyl, R2 = 2-naphthyl, 79 % 62h, X = S, R1 = H, R2 = 2-furyl, 93 % 62d, X = O, R1 = allyl, R2 = 2-naphthyl, 81 % 62i, X = O, R1 = H, R2 =2-furyl, 83 % 1 2 62e, X = S, R = CH3, R = 4-FC6H4, 84 %

a Isolated yield under MWI b Using the conventional heating method as reported by Bussolari et al. (Ref. 211)

Scheme 11. Synthesis of 5-unsubstituted 3,4-dihydropyrimidin-2-ones and thiones. 578 Current Organic Synthesis, 2016, Vol. 13, No. 4 Heravi et al.

Y Y HN NH HN NH Method A = CH3CH2OH, conc. HCl O NH O O (3-4 drops), refluxed for 5-6 hours N X CHO 64 H X Method B = CH3CH2O, acidic Al2O3 + HN 1 MW (800 W), 4-6 mins, 110-120 °C R H2NCNH2 N H 65 66 63 1 R1 66a, R = CH3, Y = S, X = O, MW = 88 %, 5 min, CONV = 62 % , 360 min 1 66b, R = CH3, Y = S, X= S, MW = 90 %, 5.5 min, CONV = 55 %, 360 min 1 66c, R = CH3, Y = O, X = O, MW = 90 %, 5 min, CONV = 58 %, 360 min 1 66d, R = CH3, Y = O, X = S, MW = 85 %, 4 min, CONV = 65 %, 350 min 66e, R1 = H, Y = O, X = O, MW = 86 %, 4 min, CONV = 62 %, 320 min 66f, R1 = H, Y = S, X = O, MW = 84 %, 4.5 min, CONV = 65 %, 350 min 66g, R1 = H, Y = O, X = S, MW = 90 %, 4 min, CONV = 60 %, 340 min 66h, R1 = H, Y = S, X = S, MW = 88 %, 4 min, CONV = 64 %, 350 min

Scheme 12. Synthesis of 5-indolylpyrimido[4,5-d] pyrimidinones 66a-h.

R1 O O2N OH NH R1 O THF N O + + H O NO2 H2N NH2 H OH Etidronic acid MW (360 W) 67 69 68 70

1 1 70a, R = 3,4-di-CH3OC6H3, Isolated yields = 93 % 70e, R = 3-ClC6H5, 86 % 1 1 70b, R = 4-CH3OC6H4, 91 % 70f, R = 3-BrC6H5, 86 % 1 1 70c, R = 4-O2NC6H5, 93 % 70g, R = C6H5, 93 % 1 70d, R = 3-HOC6H4, 86 %

Scheme 13. Etidronic acid catalyzed the one-pot synthesis of nitro derivatives of dihydropyrimidines under MWI. thiobarbituric acid/barbituric acid 64, and thiourea/urea in ethanol explore the usefulness of these catalysts in the Biginelli reaction in adsorbed on acidic alumina (no HCl) under MWI in a solventless THF under MWI. The results were disappointing. Bisphosphonic system to afford the corresponding products in good to high yields acid linked with alkyl amines or with heterocyles exhibited very (80-90%) in comparison with Biginelli like products 41a-d and inefficient catalytic activity in comparison with EDA (Scheme 13) 45a-d; however, lower yields were obtained in comparison with [130]. those of 49a-e. In the conventional strategy, the reaction proceeds to completion by giving moderate yields (55-65%) after prolonged O refluxing in ethanol. In an effort to increase the yield of the reaction and considering the merits of ‘green chemistry’, the same reaction HO P OH R was conducted under MWI conditions (Scheme 12) [129]. OH A one-pot, three-component Biginelli reaction of 1-(2- HO P OH hydroxyphenyl)-2- nitroethanone 68, differently substituted arylal- dehydes and urea catalyzed by etidronic acid (EDA) to provide O nitro derivatives of dihydropyrimidine 70 has been accomplished in 71 THF under MWI. Etidorinc acid in this reaction was used as a novel homogenous catalyst. From this novel approach, a wide variety of dihydropyrimidines was synthesized. In this developed Biginelli Fig. (2). Bisphophonic acid. reaction, differently substituted x-nitro acetophenone was used instead of aldehydes. Actually, cyclocondensation of the 1-(2- A new MCR offering an efficient strategy to the synthesis of hydroxyphenyl)-2-nitroethanone with benzaldehyde and urea, cata- hitherto 2-amino-5-benzoyl-5,6-dihydro-6-aryl pyrimidine- 4(3H)- lyzed by EDA in THF, occurred cleanly and smoothly leading to ones under MWI and solvent-free conditions has been reported. the formation of dihydropyrimidine 70g in very high yield. This Guanidine 74 was used instead of urea in a similar reaction with strategy showed the advantage of giving excellent yields of the ethylbenzoylacetate 73 as -ketoester and benzaldehyde 72a medi- desired products in short reaction times. Alternatively, under these ated by NaHCO3 to provide ethyl-2-amino-4-phenyl-1,4-dihydro-6- optimal conditions, the reactions of 68 with benzaldehyde and urea phenylpyrimidine-5-carboxylate 75a under MWI in a solventless with different bisphosphonic acids 71 (Fig. 2) were also tested to system. Microwave-Assisted Biginelli Reaction Current Organic Synthesis, 2016, Vol. 13, No. 4 579

O Ar O NH EtO N Ar H H N NH 2 2 N NH Ph 2 72 74 H + NaHCO3, Solvent-free 75 O O O O MW (180 W) Ph OEt 120 °C, 12-27 min Ph NH 73 N NH Ar 2 76

76a, Ar = C6H5, Isolated yield = 96 % 75d, Ar = 4-BrC6H4, 91 %

76b, Ar = 2-MeOC6H4, 80 % 75e, Ar = 4-ClC6H4, 92 %

76c, Ar = 4-HOC6H4, 81 % 75f, Ar = 2-O2NC6H4, 86 %

Scheme 14. The reaction leading to the synthesis of 2-aminopyrimidines. R

O CHO X O VBI / Solvent free R + + NH H2N NH2 MW (360 W) O N X 79 H 77 78 80

80a, R = 4- CH3OC6H4, X = O, Isolated yield = 86 % 80d, R = 3-ClC6H4, X = S, MW = 85 %

80b, R = 4-CH3OC6H4, X = S, MW = 83 % 80e, R = C6H5, X = O, MW = 89 % % 80c, R = 4-FC6H4, X = O, MW = 88 % 80f, R = C6H5, X = S, MW = 87

Scheme 15. Synthesis of octahydroquinazolinone.

Unpredictably, it was found that when the aforementioned mix- solvent-free conditions. Encouraged by these results, the authors ture was irradiated in an MW oven, the spectral data of isolated studied the efficiency of this catalyst in different solvents with the product was totally different from that of the desired derivative 75a. aforementioned strategy for the synthesis of octahydroquinazoli- It was revealed that the reaction proceeded via a different mecha- none and compared the results obtained with those provided from nism. In fact, the data were in good agreement with the structure of the reaction conducted under solvent-free conditions (Scheme 15) a unique compound, 2-amino-5-benzoyl-5,6-dihydro-6-phenyl [135]. pyrimidine-4-(3H)-one 76a (Scheme 14) [131]. Thiamine hydrochloride (VB ) (Fig. 3) has been employed suc- 1 NH cessfully as an acid catalyst in organic synthesis [132-134]. It has Cl 3 Cl also been used as 10 mol% in a one-pot, MCR Biginelli reaction of N N dimedone, urea or thiourea and several differently substituted aro- S matic aldehydes catalyzed by 10 mol% of thiamine hydrochloride H C N H C (VB1) under MWI in a solventless system. The yields of the Bigi- 3 3 nelli products obtained using this protocol were reported as good to excellent. 81 OH Thiamine hydrochloride (VB1) is commercially available and is relatively inexpensive. It is also easily accessible. Thus, it can be used as a non-toxic catalyst for the preparation of octahydroquina- Fig. (3). The structure of thiamine hydrochloride (VB1). zolinone derivatives via a Biginelli-type reaction under MWI. This A Biginelli-type reaction [136, 137] involving a one-pot, three- reaction is completed rapidly giving the desired products in short component cyclocondensation of salicylaldehyde or different sub- reaction times via a convenient work up procedure for isolation of stituted salicylaldehyde, -ketoester and urea/ thiourea catalyzed by the desired products in high yields. sodium hydrogen sulphate under MWI in a solventless system has Recently, thiamine hydrochloride has been used as a greener been reported. NaHSO4 is known as a non-toxic chemical and an catalyst in the synthesis of octahydroquinazolinone under MWI in inexpensive commercially available. 580 Current Organic Synthesis, 2016, Vol. 13, No. 4 Heravi et al.

R2 R1 OHC R1 O O X NaHSO4 / Solvent-free O + 3 HO + H2N NHR MW, 85°C Me NH R2 O 83 84 82 Me N X R3 1 2 3 85 85a R = C(CH3)3, R = C(CH3)3, R = H, X = S, Isolated yield = 90 % 1 2 3 85b, R = NO2, R = H, R = Ph, X = O, 82 % 1 2 3 85c, R = NO2, R = H, R = H, X = S, 87 % 85d, R1 = H, R2 = H, R3 = Ph, X = O, 86 % 85e, R1 = Br, R2 = H, R3 = Ph, X = O, 82 % 85f, R1 = H, R2 = H, R3 = H, X = S, 91 %

Scheme 16. Biginelli cyclocondensation reaction with NaHSO4 as a catalyst. O

Ar O O Me NH 89 TsOH / Solvent-free Ar X MW (500 W), 55 °C, 30 min X N Me H + H O 91 H2N NH2

88 90

91a, Ar = 3,4-Cl2C6H3, X = S, Isolated yield = 95 % 91d, Ar = 3-O2NC6H4, X =O, 93 %

91b, Ar =3,4-Cl2C6H3, X = O, 92 % 91e, Ar = 4-IC6H4, X = O, 81 %

91c, Ar = 4-MeOC6H4, X = S, 85 % 91f, Ar = C6H5, X = S, 92 %

Scheme 17. The synthesis of 5-(4-toluoyl)-3,4-dihydropyrimidin-2(1H)-ones(or-thiones).

Depending on the ester alkyl group, the reaction gives two dis- The synthesis of C(5)-(p-toluoyl)-3,4-dihydropyrimidin-2(1H)- tinct products. They are 4-(2-hydroxyphenyl) pyrimidines 86 and ones (or -thiones) via the Biginelli reaction from the reaction of oxygenbridged pyrimidine derivatives, 9 methyl-11-oxo(or thioxo)- aldehydes, p-toluoylacetone, and urea or thiourea catalyzed with 2,7 8-oxa-10,12-diazatricyclo[7.3.1.0 ]trideca-2,4,6-triene 87 (Fig. 4). TsOH under MWI in a solventless system has been achieved. Satis- Characterization of the structures of oxygen-bridged products factory yields and high purities without using cost-effective chro- encouraged the same research group to go ahead with synthesizing matographic separations have been claimed as advantages for this a series of oxygen-bridged compounds via the reaction of substi- strategy (Scheme 17) [139]. tuted salicylaldehydes, acetylacetone and urea (thiourea, pheny- The MW-assisted synthesis of 5-benzoyl-4,6-diphenyl-1,2,3,4- lurea) catalyzed by NaHSO under MWI in a solventless systems 4 tetrahydro-2-thioxopyrimidine 95a and 5-benzoyl-4-(2-chlorophen- (Scheme 16) [138]. The comparison of this reaction with the reac- yl)-6-phenyl-1,2,3,4-tetrahydro-2-thioxopyrimidine 95b using the tion in Scheme 10 reveals that this reaction gives products in higher yields. Biginelli three-component cyclocondensation reaction of a - diketone, arylaldehyde, and thiourea was reported. These reactions were conducted under MWI and conventional heating in the pres- R1 1 R ence of glacial acetic acid containing a few drops of conc. HCl. The results from the reaction performed under MWI as well as conven- O OH O tional heating are listed and can be compared (Scheme 18) [140].

2 2.2.2. Lewis Acids R O NH R2O O NH An MW-assisted multi-component reaction in the presence of H C N X 3 H3C N X Cu(OTf)2 in catalytic amounts is a facile, efficient, clean, and envi- 3 ronmentally benign strategy to create DHPMs in high yields; the R R3 reaction proceeds under mild reaction conditions, and column 86 87 chromatography for the purification of products is non-required. Moreover, the reaction times were remarkably decreased while the Fig. (4). The structure of 4-(2-hydroxyphenyl) pyrimidines 86 and 9 methyl- product yields increased when the reaction conducted under MWI 11-oxo(or thioxo)-8-oxa-10,12-diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene 87. (Scheme 19, 99a-f) [41]. Microwave-Assisted Biginelli Reaction Current Organic Synthesis, 2016, Vol. 13, No. 4 581

O Ar H O O O S CH3COOH / conc.HCl Ph NH Ar + + H N NH H Ph Ph 2 2 reflux, 8 hr Ph N S 92 93 94 MW, 5 min H

95 a,b 95a, R1 = Ph, MW = 75 %, 5 min, CONV = 93 %, 480 min 95b, R1 = 2-(Cl)-Ph, MW = 80 %, 5 min, CONV = 90 %, 480 min

Scheme 18. Synthesis of 1,2,3,4-tetrahydro-2-thioxopyrimidine derivative. O R O O X Lewis acids H C2H5O N RCHO 99-128 + Me OEt + H2N NH2 H3C N X 96 97 98 H

99-128

99a, R = C6H5, Isolated yield = Quantitative %

99b, R = 4-O2NC6H4, 90 %

99: Cu(OTf)2 / EtOH, 100 ˚C,1 hr, MW (200 W) 99c, R = 2-F3CC6H4, 95 %

99d, R = 3-HOC6H4, 95 % X = O 99e, R = 4-BrC6H4, 96 % 99f, R = 2-Furyl, 90 %

Scheme 19. Biginelli reaction, catalyzed by different Lewis acids.

100a, R =4-CH3OC4H6, Isolated yield = 56 %

100: FeCl3/Nanopore Silica, Solvent-free, MW 100b, R = 1H-indole-3-carbaldehyde, 60 %

(400W), 15 min 100c, R = 2,4,6-(CH3O)3C6H4, 36 %

100d, R = (CH3)2NC6H4, 60 % X = O 100e, R = 4-O2NC6H4, 73 %

100f, R = HOC6H4, 51 %

101a, R = C6H5, X = O, Catalyst = SnCl2, Isolated yield = 89 %

101b, R = 3-(CH3O)-C6H4 , X = S, conc. HC1, 96 % 101c, R = C H , X = O or S, CuCl .2H O, 92 % 101: ZnCI2, SnCl2, FeCl3.6H2O, CuCl2.2H2O 6 5 2 2 or conc. HC1 ( 1-2 drops), Solvent-free, MW (150 W) 101d, R = 4-O2NC6H4, X = O, conc. HC1, 78 %

101e, R = C6H5, X = S, FeCl3.6H2O, 93 %

101f, R = C6H5, X = S, SnCl2, 92 %

101g, R = C6H5, X = S, ZnCl2 , 95 %

Porous materials or Lewis-acid supported porous materials, e.g. Lewis acids, e.g. ZnCI2, SnCl2, FeCl3.6H2O, and CuCl2.2H2O MCM-41, SBA-15, VSB-5, nanopore silica, FeCl3/MCM-41, were utilized as effective catalysts under MWI for the synthesis of FeCl3/nanopore silica, CeCl3/nanopore silica and InCl3/ nanopore dihydropyrimidinones via the Biginelli reaction. The experiments silica are examined in a classical Biginelli reaction. It has been revealed that the addition of one or two drop of conc. HC1 afforded found that catalytic activity of nanopore silica is enhanced upon virtually identical high yields under MWI in a solventless system treatment with Lewis acids, particularly with FeCl3. (Scheme 19, 101a-g) [142]. When Nanopore silica was used as a catalyst, the yield of the Ethyl 4-aryl-6-methyl-1,2,3,4-tetrahydropyrimidin-2-one-5- Biginelli products was in the range of 27–56%. However, when carboxylates were synthesized by a one-pot, three-component con- FeCl3/Nanopore silica was used as a catalyst, the yield of the Bigi- densation of aromatic aldehydes, ethyl acetoacetate and urea, cata- nelli product was increased dramatically. Thus the use of lyzed by ferric chloride hexahydrate supported on silica gel as a FeCl3/Nanopore Silica as a heterogeneous catalyst in the Biginelli carrier under MWI in a solventless system. The reactions were reaction provides green conditions while being very cost effective completed in 4–6 min giving 87–92% yields for the corresponding (Scheme 19, 100a-f) [141]. products (Scheme 19, 102a-d) [143]. 582 Current Organic Synthesis, 2016, Vol. 13, No. 4 Heravi et al.

102a, R = 3,4-(OCH2O)C6H3, Isolated yield = 94 %, 5 min 102: FeCl3. 6H2O, on silica gel, Solvent -free, 102b, R = 4-CH3OC6H4, 95 %, 6 min MW (650 W) 102c, R = 3-O2NC6H4, 89 %, 5 min

102d, R = 4-HOC6H4, 87 %, 4 min X = O

103a, R = C6H5, Isolated yield = 38 %, 20 sec 103: FeCl3.6H2O, solvent-free, MW (900 W) 103b, R = 4-CH3OC6H5, 55 %, 20 sec 103c, R = 4-HOC H , 68 %, 20 sec X = O 6 5 103d, R = C6H3S, 56 %, 20 sec

104a, R = C6H5, Isolated yield = 89 %

104b, R = 4-CH3OC6H4, 85 % 104: FeCl3/Si-MCM-41, MW (700 W), 3.0 to 5.0 min 104c, R = 4-O2NC6H4, 76 % 104d, R = 2,3-ClC H , 79 % X = O 6 4 104e, R = CH3OC6H4, 70%

104f, R = 2-ClC6H4, 94 %

105a, R = C6H5, X = O, Isolated yield = 98 %

105b, R = 3-O2NC6H4, X =O, 94 %

105c, R = 3-O2NC6H4, X = S , 87 % 105d, R = 4-OHC H , X = S, 89 % 105: Ni NPs, Solvent-free, MW (360 W) 6 4 105e, R = 4-ClC6H4, X =O, 95 % 105f, R = 4-Pyridyl, X =O, 95 % 105g, R = 2-Furyl, X = O, 95 %

105h, R = n-C4H9, X = S , 80 %

105i, R = C6H5, X =S, 95 %

106: Yb(OTf)3 , AcOH/EtOH (3:1), MW (0 -300 W), 10 min R = C6H5,Temp = 120 °C, Yield = 92 % X = O

Moreover, an efficient synthesis of 3,4-dihydropyrimidinones to products in high yields using a convenient and simple work-up from the cyclocondensation of an appropriate aromatic aldehyde, a procedure (Scheme 19, 105a-i) [146]. ketoester, and urea or thiourea using a catalytic amount of ferric A library of 48 dihydropyrimidine derivatives was synthesized chloride hexahydrate is described. MWI has been used to accelerate using the automated addition of a framework and subsequent se- the synthesis of the Biginelli compounds under solvent-free condi- quential MWI of each process vial. For most frameworks, combina- tions (Scheme 19, 103a-d) [144]. This reaction was performed in a tions of 10 min of MWI and heating at 120 °C utilizing shorter reaction time but with a lower yield in comparison with the AcOH/EtOH (3:1) and 10 mol% Yb(OTf)3 as the solvent/ catalyst yields obtained for 100a-f, 102a-d and 104a-e. system gave successfully the desired products resulting an average The Si-MCM-41 or montmorillonite K-10 clay supported isolated yield of 52% of DHPMs with excellent purity (Scheme 19, ZnCl2, AlCl3, GaCl3, InCl3 and FeCl3 were used as Lewis acid cata- 106) [147]. lysts. Among them, FeCl3/Si-MCM-41 showed the best activity for Graphite-supported lanthanum chloride can effectively catalyze the MW-assisted synthesis of dihydropyrimidinones via a classic the classical Biginelli reaction under MWI. The catalytic system Biginelli reaction involving a multicomponent condensation of an was impregnated by LaCl3 on the graphite support as a strong MWI appropriate aromatic aldehyde, ethyl acetoacetate and urea in absorbent and increases the reaction temperature rapidly and conse- EtOH. It was found as an ideal catalyst for the MW-assisted reac- quently enhances the yield of products (Scheme 19, 107a-g) [148]. tion affording high product yields in a short reaction time (few minutes) (Scheme 19, 104a-e) [145]. Nano-crystalline zirconium oxide with a high surface area has been prepared via employing alanine as a fuel through the solution Nickel nanoparticles (Ni NPs) has shown good catalytic activity combustion method. Recently, it was used as an effective catalyst in in the Biginelli reaction for the synthesis of 3,4-dihydropyrimidine- the synthesis of DHPMs under MWI in a solventless system. Using 2(1H)-ones via a one-pot MCR reaction of a wide variety of alde- this strategy, 3,4-dihydropyrimidin-2(1H)-ones/-thiones with a wide hydes, urea or thiourea and ethyl acetoacetate under the influence of variety of substitutions could be synthesized in short times (10-20 MWI. This approach needs mild reaction conditions, and low cata- min) and excellent yields (85%-96%). Significantly, the catalyst lyst loading. It tolerates several different functional groups leading Microwave-Assisted Biginelli Reaction Current Organic Synthesis, 2016, Vol. 13, No. 4 583

107a, R = C6H5, X = O, Isolated yield = 85 %

107b, R = 4-O2NC6H4, X = O, 75 %

107c, R = 4-O2NC6H4, X = S, 80 % 107: LaCl3-graphite, Solvent free, MW (180 W) 107d, R = 4-CH3C6H4, X = O, 80 %

107e, R = 4-CH3C6H4, X = S, 84 %

107f, R = 2-ClC6H4, X = O, 65 %

107g, R = 4-ClC6H4, X = S, 80 %

108a, R = C6H4, X = O, Isolated yield = 96 %

108b, R = C6H4CH=CH, X = O, 91 %

108c, R = 4-CH3OC6H4, X = O, 87 % 108: Nano-ZrO2, Solvent-free, MW (300 W),10-20 min 108d, R = 4-CH3OC6H4, X = S, 90 %

108e, R = 4-O2NC6H4, X = O, 90 %

108f, R = 4-O2NC6H4, X = S, 88 %

108g, R = 4-ClC6H4, X = S, 92 % 108h, R = 2-furyl, X = O, 91 %

109a, R = Cinnamyl, X = O, Isolated yield = 73 %

109b, R = 4-CH3OC6H4, X = S, 58 %

109: I2-Al2O3, Solvent-free, MW, 1 min, 90 °C 109c, R = 4-CH3OC6H4, X = O, 74 %

109d, R = 4-ClC6H4, X = O, 87 %

109e, R = C6H5, X = S, 65 %

109f, R = C6H5, X = O, 90 %

110a, R = C6H5, Isolated yield = 95 %

110b, R = 4-CH3OC6H4 , 92 % 110: I2, Solvent-free, MW (600 W), 60 °C, 15–30 min 110c, R = 3-O2NC6H4, 95 %

X = S 110d, R = 3-HOC6H4, 89 %

110e, R = 4-FC6H4, 94 % 110f, R = 2-Furyl, 90 %

111a, R = 4-HO-3-MeO-C6H3, Isolated yield = 86 %

111b, R = 3,4-Me2OC6H3, 84 % 111: ZnI2, Solvent-free, MW (600 W) 111c, R = 4-O2NC6H4, 86 %

X = O 111d, R = 2-HOC6H4, 78 %

111e, R = C6H5, 88 % can be recovered easily and reused at least for five runs with no A practical route for the cyclocondensation reaction under MWI significant change in its catalytic activity (Scheme 19, 108a-h) and solvent-free conditions using zinc iodide as a mild catalyst is [149]. reported. Compared to the other methods, the present one is rapid A rapid and effective one-pot procedure for the three- (3-7 min), mild (room temperature), environmentally friendly (sol- component condensation in the presence of 10% iodine adsorbed on vent-free) and high yielding (78-88%). It has also been found that neutral alumina as the catalyst under solvent-free conditions and one or two drops of conc. HCl gave comparable high yields under MWI has been reported (Scheme 19, 109a-f) [150]. solvent-free, MWI conditions (Scheme 19, 111a-e) [152]. A convenient, facile and effective approach has been accom- A green approach for the synthesis of DHPMs via the Biginelli plished and reported for the synthesis of 3,4-dihydropyrimidin-2- reaction has been achieved and reported. In this strategy, silica- thiones 110. The reaction of various aldehydes, acetoacetates, and immobilized nickel was used as a catalyst in an MW-assisted reac- thiourea catalyzed by iodine under MWI and solvent-free condition. Reduced reaction times, high yields of products, absence of tions gave the desired Biginelli products in good yields (Scheme 19, 110a-f) [151]. This MW-assisted reaction in comparison with 109a- solvent and recyclability of this catalyst add it to the valuable sys- f gives products in higher yields and longer reaction times. tem of previously reported catalysts. 584 Current Organic Synthesis, 2016, Vol. 13, No. 4 Heravi et al.

O 112a, R = 4-H3CC6H4, X = O, Isolated yield = 95 % O Si N 112: 112b, R = C H CH=CH, X = O, 80 % O N 6 5 112c, R = 4-O NC H , X = O, 93 % Ni 2 6 4 Cl 112d, R = 4-HOC H , X = O, 93 % Cl 6 4 112e, R = 4-BrC6H4, X = S, 95 %

MW (100W), Solvent-free 112f, R = C6H5, X = S, 96 %

113a, R= C6H5, X = O , Isolated yield = 94 %

113: TMSCl, MeCN, MW, 120 °C, 10 min 113b, R = 3,4-(CH3O)2C6H3 , X = S , 76 %

113c, R = 2-F3CC6H4, X = S, 66 %

113d, R = 3-BrC6H4, X = S , 86 %

113e, R = C6H5, X = S , 90 %

114a, R = 4-CH3OC6H4, X = O, MW = 93 %, 1.5 min, CONV = 94 %, 60 min

114: 5 mol% GaCl3 or GaBr3, solvent-free, 114b, R = 4-O2NC6H4, X = O, MW = 96 %, 1 min, CONV = 92 %, 55 min

MW (220 W), = 90 °C 114c, R = 4-ClC6H4, X = S, MW = 85 %, 1.5 min, CONV = 86 %, 70 min 114d, R = 2-Thienyl, X = S, MW = 83 %, 1.5 min, CONV = 81 %, 75 min 114e, R = 2-Furyl, X = O, MW = 88 %, 1.5 min, CONV = 87 %, 65 min

114f, R = C6H5, X = O, MW = 96 %, 1 min, CONV = 94 %, 55 min

115a, R = CH3OC6H4, CONV = 80 %, 10 mol % catalyst, 2 mL anhydrous THF, 6 hr

115b, R = C6H5, MW = 98 %, 2 mol % catalyst, under MWI in the CEM Discover Lab-Mate microwave, Solventless, 4.5 min 115: Bi(NO3)3 115c, R = C6H5, CONV = 96 %, 10 mol % catalyst, 2 mL anhydrous ethanol, 5 hr X = O 115d, R = C6H5, CONV = 85 % , 10 mol % catalyst, 2 mL anhydrous THF, 6 hr

115e, R = C6H5, MW = 88 %, 2 mol % catalyst, MW, Solventless, under in a domestic microwave, 5 min

115f, R = C6H5, CONV = 23 %, 10 mol % catalyst, 2 mL ice water, 6 hr

Silica gel is an ideal solid support due to its flexible pore sizes Although the reaction proceeded cleanly and smoothly, it is com- and springy surface area, high thermal and mechanical stability. It pleted in about 1.0 hr (Scheme 19, 114a-f) [162]. can be readily immobilized and make the surfaces ready for func- An enormously fast (4-5min) synthesis of 4-aryl-3,4- tionalization [153-159]. Thus, it was selected for immobilization of dihydropyrimidones via a three-component Biginelli reaction cata- catalysts in this protocol. A combination of silica gel immobilized lyzed by bismuth nitrate under MWI has been developed. This Ni with MWI (100W) was used for a successful Biginelli reaction novel catalytic and cost-effective reaction occurs under solvent-free (Scheme 19, 112a-f) [160]. conditions to afford 4-aryl-3,4-dihydropyrimidones in excellent yields [163]. It is worthy to mention that bismuth nitrate is an inex- A two-step strategy for the MW-assisted synthesis of several 5- pensive commercially available compound. It is a quite stable and aroyl-3,4-dihydropyrimidine-2-ones, combining a trimethylsilyl non-toxic crystalline solid. Using this strategy, the synthesis of chloride-mediated Biginelli multicomponent approach with the several differently substituted dihydropyrimidones has been transition metal-catalyzed Liebeskind-Srogl ketone has been devel- achieved. It is worthy to note that this reaction is completed to af- oped. In the first step, commercially available aldehydes, boronic ford the desired products even using as low as 0.1 mol% of bismuth acids, and ureas were used to create diversity on the 5-aroyl-DHPM nitrate (Scheme 19, 115a-f) [164]. backbone (Scheme 19, 113a-e) [161]. Trichloroisocyanuric acid [1,3,5-trichoro-1,3,5-triazine-2,4,6- A combination of gallium(III) halides as a catalyst MWI accel- (1H,3H,5H)-trione or TCCA] (Fig. 5) has been used as a mild, ef- erates a one-pot MCR of various aldehydes, 1,3-dicarbonyl com- fective and neutral catalyst for a one-pot, three-component synthesis of 3,4-dihydropyrimidinones following the Biginelli protocol in pounds and urea / thiourea in a solventless system to provide 3,4- either ethanol or DMF under reflux and MWI conditions. Although dihydropyrimidin-2-(1H )-ones in high yields. Noticeably, the reac- the reactions are catalyzed homogeneously, the work up procedure tion time is drastically diminished to 11.5 min upon the effects of is easy and the yields are high to excellent conducted under either MWI. Moreover, this protocol is eco-friendly. In this non- of the two conditions. hazardous reaction, low boiling solvents, e.g. acetonitrile have not TCCA is a relatively stable, neutral, non-volatile, inexpensive been used. commercially available, and safe reagent (initially used as a disin- For sake of direct comparison, the same reactions have also fectant and deodorant) which has been largely overlooked as a cata- been performed using conventional heating in solventless systems. lyst in organic chemistry (Scheme 19, 116a-g) [165-167]. Microwave-Assisted Biginelli Reaction Current Organic Synthesis, 2016, Vol. 13, No. 4 585

116a, R = 4-CH3OC6H4, X = O, CONV = 93 %, 12 hr, MW = 89 %, 3 min

116b, R = 4-O2NC6H4, X = O, CONV = 94 %, 12 hr, MW = 93 %, 3 min

116c, R = 4-ClC6H4, X = O, CONV = 95 %, 10 hr, MW = 90 %, 3 min 116: TCCA (15 mol%) / EtOH, MW (600 W), 3 min 116d, R = C6H5, X = O, CONV = 94 %, 12 hr, MW = 92 %, 3 min

116e, R = C6H4CH=CH2, X = O, CONV = 90 %, 8 hr, MW = - , -

116f, R = 4-CH3C6H4 , X = S, CONV = 89 %, 10 hr, MW = - , -

116g, R = C6H5, X = S, CONV = 94 %, 10 hr, MW = - , -

118a, R = C6H5, X = S, Isolated yield = 96 %

118b, R = 4-CH3OC6H4, X = O, 91 % 118: Co(OAc) .4H O / TMSCl, DMF, MW (300 W), 7 min 2 2 118c, R = 3-O2NC6H4, X = O, 97 %

118d, R = 3-O2NC6H4, X =S, 94 %

118e, R = 3-ClC6H4, X = O, 95 %

118f, R = C6H5, X = O, 94 %

119a, R = 4-CH3OC6H4, Isolated yeild = 91 %

119b, R = 3-CH3OC6H4, 94 % 119: CaCl2, MW (850 W), 2.0 min, Solvent-free 119c, R = 2-O2NC6H4, 86 %

X = O 119d, R = 2-F3CC6H4, 70 %

119e, R = 4-ClC6H4, 88%

a b a b 120a, R = 2-CH3OC6H4, CuY = 30.2 %, 48.2 %, CoY = 28.4 %, 43.0 %, MnY = 26.1a %, 40.8b %, NiY = 28.3a %, 41.2b %, FeY = 10.0a %, 40.5b %

a b a b 120: Method A: metal/Y zeolite, Aqa, 120b, R = 2-ClC6H4, CuY = 22.4 %, 32.1 %, CoY = 19.0 %, 29.1 %, a b a b a b Method B: metal/Y zeolite, MW (900), 10-20 min MnY = 17.4 %, 25.0 %, NiY = 18.0 %, 26.8 %, FeY = 5.4 %, 26.0 % a b a b 120c, R = C6H5, CuY = 34.2 %, 38.1 %, CoY = 24.2 %, 37.0 %, X = O MnY = 23.8a %, 32.5b %, NiY = 21.7a %, 34.2b %, FeY = 5.3a %, 32.5b %

Aqa = Aqueous solution MWb = Solid state

laboratory bench-top chemical under MWI in solvent-free condi- Cl tions has been reported. It has been found that 0.1 equiv. of CaCl2 O N O with respect to the aldehyde and 2.0 min irradiation is good enough for most of the aldehydes to produce excellent yields of DHPMs NN without production of any side product. Cl Cl In order to compare the microwave influence in the rate en- O hancement of Biginelli reaction, similar reactions were carried out 117 in an oil bath at 120 °C, where the reaction took longer time and gave low yields (Scheme 19, 119a-e) [169]. Fig. (5). TCCA. Zeolites are microporous, aluminosilicate minerals are frequently used as catalysts in some organic reactions [170-172]. Zeo- New 3,4-dihydropyrimidin-2-ones having a phenyl moiety at C- lites can catalyze the multicomponent one-pot Bignelli reaction 5 and C-6 have been prepared by an MW-assisted Biginelli–like under environmentally benign conditions. In a successful attempt, reaction through a one-pot, three-component, condensation of an initially transition metal/Y zeolites were provided via an MW solid- aromatic aldehyde, deoxybenzoin and urea, or thiourea using state and ion-exchange methods in aqueous solutions. The yield of TMSCl and Co(OAc)2.4H2O as an efficient Lewis acid catalyst the reactions was found to increase in two different orders. In the under MWI. TMSCl was used successfully to accelerate the Bigi- solid-state zeolite ion exchange, the order was CuY> CoY> NiY> nelli–like reaction. MnY ~ FeY> VY> CrY> ZnY whereas in the aqueous solution ion Short reaction time, high yield, a simple procedure for isolation exchange, the order was found to be CuY> CoY> NiY> MnY> of the by-product, and the use of low amounts of catalyst were the CrY> VY> ZnY> FeY. Interestingly, the solid-state ion-exchange advantages of this protocol. Optimized microwave power and the zeolite under MWI exhibited a higher activity compared to the irradiation time were found to be 300 W and 7 min, respectively aqueous solution exchange. The yield of the product in the presence (Scheme 19, 118a-f) [168]. of CuY zeolite was in the range of 22–50%. A rapid and efficient synthesis of Biginelli reaction catalyzed Various kinds of zeolites were used for the synthesis of 3,4- by calcium chloride, as an inexpensive, neutral and eco-friendly Dihydropyrimidin-2(1H)-ones 120(a-c) via the reaction of differ- 586 Current Organic Synthesis, 2016, Vol. 13, No. 4 Heravi et al.

121a, R = 4-CH3OC6H4, X = S, MW = 94 %, 8 min, CONV = 81 %, 80 min

121: Method A: Nickel (II) oxide, solvent-free, 121b, R = 4-CH3OC6H4, X = O, MW = 91%, 6 min, CONV = 89 %, 90 min

70 °C, 60-90 min, Method B: Nickel (II) oxide, 121c, R = 4-O2NC6H4, X = O, MW = 91%, 8 min, CONV = 92 %, 70 min

MW (200 W), 4-8 min 121d, R = 4-HOC6H4, X = S, MW = 91%, 6 min, CONV = 82 %, 70 min

121e, R = C6H5, X = O, MW = 96 % 4 min, CONV = 96 %, 60 min

121f, R = 4-HO-3-CH3OC6H3, X = O, CONV = 95 %, 60 min

121g, R = 4-CH3O-3-HOC6H3, X = O, MW = 94 %, 6 min

122a, R = CH3OC6H4, X = O, CONV = 92 %,70 min, MW = 94 %, 1.5 min

122b, R = CH3OC6H4, X = S, CONV = 81 %, 65 min, MW = 91 %, 2 min 122: Method A: SbCl -Al O , Solvent-free, MW 3 2 3 122c, R = O NC H , X = O, CONV = 88 %, 60 min, MW = 90 %, 2 min = 2 6 4 Method B: SbCl3-Al2O3, 100 °C, Solvent-free 122d, R = FC6H4, X = O, CONV = 91 %, 75 min, MW = 92 %, 1.5 min

122e, R = C6H5, X = O, CONV = 95 %, 55 min, MW = 96 %, 1 min

122f, R = C6H5, X = S, CONV = 89 %, 80 min, MW = 95 %, 2 min

123a, R = 1-CH3O-4-CH3C6H4, CONV = 86 %, 2.45 hr, MW = 80 %, 18 min 123: Method A: SiO2 / CuCl2 / Diphenic acid 123b, R = 1-CH3-2-O2NC6H4, CONV =80 %, 3.5 hr, MW = 82 %, 15 min Solvent-free, 40 °C, Method B: SiO2 / CuCl2 , 123c, R = 2-CH C H O, CONV = 82 %, 2.5 hr, MW = 90 %, 55 min MW, acetonitrile , 80 °C 3 4 3 123d, R = toluene, CONV = 94 %, 2 hr, MW = 90 %, 15 min X = O 123e, R = n-Bu, CONV = Trace, 6.30 hr, MW = - , -

124a, R = C6H5, X = O, Isolated yield = 96 %

124b, R = 2,4-Cl2-C6H4, X = O, 85 % 124c, R = 4-CH OC H , X = O, 80 % 124: TiO2–MWCNTs, Solvent-free, MW (600 W), 5 min 3 6 4 124d, R = 2-CH3OC6H4, X = S, 80 %

124e, R = 4-O2NC6H4, X = O, 90 %

124f, R = 3-O2NC6H4, X = S, 89 %

124g, R = 4-BrC6H4, X = S, 70 % ently substituted aldehydes, ethyl acetoacetate and urea under two different conditions were compared. Both of them enjoy using MWI. The yields of these reactions were found to be higher under the heterogeneous green catalyst, i.e. silica supported CuCl2 which MWI, when a solid ion-exchanged metal zeolite was used (Scheme takes advantages of green and economical natures of copper under 19, 120a-c) [173]. mild reaction conditions and easy work-up. However, the reactions Nickel(II) oxide was used under solvent free conditions and performed under MW needed less reaction times, giving higher MWI resulted in Biginelli product in short time and in comparison yields as well as tolerating more different functional groups with 105a-e and 112a-f, it gave a higher yield (Scheme 19, 121a-g) (Scheme 19, 123a-e) [176]. [174]. The catalytic potency of transition metal oxide–MWCNT nano- The antimony(III) chloride impregnated on alumina efficiently composites was also examined in the Biginelli multicomponent catalyses a one-pot, three-component condensation reaction of an one-pot reaction of aldehydes, -dicarbonyl compounds and urea aldehyde, a -ketoester, and urea or thiourea to afford the corre- (thiourea) in a solventless system under MWI as non-conventional sponding dihydropyrimidinones in good to excellent yields. The energy source. The experimental outcomes revealed that TiO2– reactions are probed in MWI, ultrasonic, and thermal conditions MWCNTs were the most effective nanocatalyst for the Biginelli and the best results are found using MWI under solvent-free condi- reaction among the other examined transition metal oxide– tions. MWCNT. Encouraged by these results and to establish the versatility of In this line, initial attempts were made to optimize the power of antimony(III) chloride impregnated on alumina, the authors used the MWI to reveal its effect on the reaction. As illustrated, the various substrates under optimized reaction conditions. The results highest yield of the product was provided when the power of the are depicted in (Scheme 19, 122a-f) [175]. oven was fixed to 600 W (Scheme 19, 124a-g) [177]. Several important biologically and pharmaceutically 3,4- Syntheses of some novel DHPMs using sodium sulphate solid dihydropyrimidin-2(1H)-ones were synthesized using silica- support catalyzed indium triflate have been reported. The MWI- supported copper(II) chloride as a heterogeneous and green catalyst induced fast synthesis gave high yields of DHPMs. The substrates under MW in acetonitrile as well as thermal conditions in a sol- and In(OTf)3 on the solid support, under MWI gave the desired ventless system. It was found that the reactions conducted under products in high yields (Scheme 19, 125a-f) [178]. conventional heating in a solventless system at 40 ºC need a co- A one-pot condensation of aryl aldehydes, -diketones and urea catalyst such as diphenic acid whereas under MWI at 80 ºC in ace- derivatives catalyzed by phosphotungstic acid/sulfated zirconia was tonitrile no co-catalyst is required. The results obtained from the performed under MWI. This reaction was rapidly completed to give Microwave-Assisted Biginelli Reaction Current Organic Synthesis, 2016, Vol. 13, No. 4 587

125a, R = 6-Methoxy-3-chromonyl, Isolated yeild = 81 % 125b, R = 2-Chloro-3-quinolyl, 76 % 125: mol % In(OTf) , Sodium sulfate, 30 % MW 3 125c, R = 1-Naphthyl, 84 % X = O 125d, R = Phenyl, 91 % 125e, R = 2-pyridyl, 83 % 125f, R = Thienyl, 85 %

a b 126a, R = 4-CH3OC6H4, 89 %, 79 % 126b, R = 4-O NC H , 89a %, 94b % 126: Phosphotungstic acid, Sulfated zirconia, 2 6 4 126c, R = 4-ClC H , 95a %, 91b % MW (900 W), Solvent-free 6 4 a b 126d, R = 3-O2NC6H4, 92 %, 91 % a b X = O 126e, R = C6H5, 92 %, 86 %

a Isolated yield under PWA catalyst b Isolated yield under sulfated zirconia catalyst

127a, R = 4-ClC6H4, X = O, Isolated yield under SnCl2 = 97 %

127b, R = 4-ClC6H4, X = S, 95 %

127c, R = C6H5, X = O, 95 % 127: SnCl2 / SnI2, Solvent-free, MW (800W) 127d, R = C6H5, X = S, 97 %

127e, R = 4-Cl-C6H4, X = O, Isolated yield under SnI2 = 96 %

127f, R = C6H5, X = S, 95.5 %

127g, R = C6H5, X = O, 97 %

128a, R =3,5-(CH3O)2-C6H3, X = O, CONV = 98 %, 20 min, MW = 99 %, 4 min

128b, R = 3-O2N-C6H4, X = O, CONV = 97 %, 30 min, MW = 98 %, 4 min 128: MNP-ILs , Solvent-free, Method A = 128c, R = 4-CH3C6H4, X = S, CONV = 90 %, 40 min, MW = 95 %, 4 min MW (90 W), 4 min, Method B = 100 °C 128d, R =2-Tiophen, X = O, CONV = 98 %, 25 min, MW = 98 %, 4 min 128e, R = 2-Tiophen, X = S, CONV = 95 %, 25 min, MW = 95 %, 4 min

128f, R = C6H5, X = O, CONV = 95 %, 30 min, MW = 97 %, 4 min

128g, R = C6H5, X = S, CONV = 96 %, 35 min, MW = 97%, 4 min pure substituted 3,4-dihydropyrimidin-2(1H)-ones in excellent the one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones under yields. The both components of the catalyst system are commer- MWI in a solventless system in excellent yields. The Biginelli reac- cially available in relatively low prices. In addition, it shows a sig- tion between benzaldehyde, ethyl acetoacetate and urea was per- nificant reactivity and reusability for this particular synthesis. Using formed as the model reaction under various conditions. this catalyst system under MWI decreased the reaction time of a Encouraged with the above-optimized results, the authors went mixture including aryl aldehyde, urea and ethyl acetoacetate to 30 further to study the effects of the MWI power and the irradiation seconds (Scheme 19, 126a-e) [179]. time on the Biginelli reaction. They found out in spite of obtaining A simple, economic and efficient one-pot synthesis of some better yields in some reactions, the use of MWI is unquestionably substituted 2-oxo-1,2,3,4-tetrahydropyrimidines [3,4-dihydropyrim- vital for this conversion in terms of the reaction times and when idin-2(1H)-ones] and 2-thioxo-1,2,3,4-tetrahydropyrimidines under conventional heating fails (Scheme 19, 128a-g) [182]. solvent-free conditions and MWI catalyzed by tin(II) chloride dihy- 3-(1,3-Dioxobutan-1-yl)-2H-chromen-2-one (131), aromatic al- drate and tin(II) iodide has been reported . Aromatic aldehydes dehydes and urea were employed in the Biginelli reaction. The react efficiently with urea (or thiourea) and -dicarbonyl com- reaction was performed in both classical one-pot variation via re- pounds to give excellent yields of substituted 3,4-dihydro fluxing in ethanol in the presence of HCl, and in a solventless sys- pyrimidin-2 (1H)-ones (or 3,4-dihydropyrimidin-2(1H)-thiones] tem by 700 Watt MWI and zinc chloride as a catalyst (Scheme 20) (Scheme 19, 127a-g) [180]. [183]. This Biginelli-like reaction in both conditions gives a lower The magnetic Fe3O4 has recently attracted much attention as an yield in comparison with the Biginelli reaction 101g. easily separable catalyst [181]. The magnetic Fe O nanoparticles 3 4 Ammonium metavanadate (NH4VO3) has been found to be a supported by imidazolium-based ionic liquids (MNPs–IILs), 1- mild, non-toxic metal, effective and commercially available catalyst methyl-3-(3-trimethoxysilylpropyl) imidazolium hydrogen sulphate for the one-pot Biginelli-like synthesis of octahydroquinazolinone (MNPs–IIL–HSO4), 1-methyl-3-(3-trimethoxysilylpropyl) imida- derivatives. It catalyzes the reaction of dimedone, urea/thiourea, zolium acetate (MNPs–IIL–OAc) and 1-methyl-3-(3-trimethoxy- and differently substituted aromatic aldehydes under MWI and silylpropyl) imidazolium chloride (MNPs–IIL–Cl) have recently solvent-free conditions. The reactions are fast and give the high been used as an effective, new generation of catalysts for achieving yields of products (Scheme 21, 136a-g) [184]. 588 Current Organic Synthesis, 2016, Vol. 13, No. 4 Heravi et al.

O R

H2N NH2 130 O O O

+ ZnCl / solvent-free CHO Me 2 NH MW (700) O O O N O R OH H 131 129 R = H 132 R = OMe yield (43-85%)

Scheme 20. Synthesis of chromenoquinazolines. R

CHO O O X Lewis acids O 136-139 NH + + H2N NH2

2 3 R1 R R 135 N X H 133 134 136-139

136a, R1 = H, X = O, Isolated yield = 94 % 1 136b, R = 3- OCH3, X = O, 86 % 136c, R1 = 4-OCH , X = S, 83 % 136, NH4VO3, Solvent-free condition, MW (360 W) 3 1 136d, R = 3-NO2, X = O, 92 % 2 3 R , R = CH3 136e, R1 = 3-Cl, X = O , 85 % 136f, R1 = 3-Cl, X = S, 85% 136g, R1 = H, X = S, 87 % Scheme 21. Biginelli- Like reaction using cyclic 1,3- dicarbonyl compounds.

1 2 3 137a, R = 4-Cl4, R = CH3, R = CH3, 96 % 137, Iodine, Solvent-free, MW, 4.0–4.5mins 1 2 3 137b, R = H, R = CH3, R = CH3, 95% X = O 137c, R1 = H, R2 = H, R3 = H, 86 %

A pseudo four-component reaction involving an aldehyde, urea reported, which makes use of an effective catalyst under MWI in a / thiourea, and cyclic 1,3-dicarbonyl compounds can be considered solventless system. The merits noticed from this approach are a as a modification of the Biginelli cyclocondensation. Interestingly, solventless system, short reaction times, ease of product isolation, this reaction can be performed using non-toxic molecular iodine as and obtaining high yields of products. In general, aromatic alde- a mild and green Lewis acid under MWI in a solventless system to hydes, dimedone, urea/ thiourea, and molybdenum oxide are mixed provide a wide range of symmetric spiro heterobicyclic rings in appropriately using a glass rod and irradiated in an MW oven at 360 very high yields. This modified Biginelli reaction provides a novel W (Scheme 21, 138a-h) [186]. and facile methodology for the synthesis of a wide variety of sym- A facile, effective and inexpensive approach for the preparation metrical spiro heterobicyclic compounds. of octahydroquinazolinone derivatives employing dimedone, Moreover, its practical simplicity, high selectivity, ability to urea/thiourea and aromatic aldehydes and catalyzed by lanthanum tolerate differently substituted aldehydes and conditions are other oxide under MWI in a solventless system has been achieved and noticeable features of this reaction. These advantages make this reported. In this strategy, no hazardous organic solvents were used. Biginelli-type reaction a useful alternative to the frequently applied The catalyst used offered unprecedented features for a reaction, i.e. procedures. Following this strategy, diverse substituted aldehydes, a short reaction time, excellent yields, ease of isolation, purity of barbituric acids or substituted barbituric acids, and urea / thiourea products and avoiding expensive chromatographic methodologies. were reacted to give the respected spiroheterocycles in good to high This simple procedure uses a solventless system along with facile yields and shorter reaction times in comparison to the times for the recovery and reuse of the catalyst, which make this method eco- production of compounds 110a-f (Scheme 21, 137a-c) [185]. nomically feasible and environmental friendly process. This proto- An efficient protocol for the synthesis of octahydroquinazoli- col presents a simple route for the synthesis of octahydroquinazolinone derivatives employing molybdenum oxide nanoparticles was none derivatives, which were found to be biological active. The Microwave-Assisted Biginelli Reaction Current Organic Synthesis, 2016, Vol. 13, No. 4 589

138a, R1 = H, X = O, Isolated yield = 97 % 1 138b, R = C6H5-CH=CH, X = S, 91 % 1 138c, R = C6H5-CH=CH, X = O, 93 % 138, MoO3 NPs, Solvent-free, MW (360 W) 138d, R1 = 3-OMe, X = O, 86 % R2, R3 = CH 1 3 138e, R = 4-NO2, X = O, 94 % 138f, R1 = 4-OMe, X = S, 83 % 138g, R1 = 4-F, X = O, 96 % 138h, R1 = 4-Cl, X = S, 90 %

139a, R1 = 3,4,5-(CH3O)-C6H2, X = S, Isolated yield = 90 % 139b, R1 = H, X = O, 96% 1 139c, R = C6H5-CH=CH, X = O, 94 % 139, La2O3, Solvent-free, MW (480 W), 35-80 sec 1 139d, R = C6H5-CH=CH, X = S, 91 % 2 3 R , R = CH3 1 139e, R = 4-CH3O, X = O, 92 % 1 139f, R = 4-CH3O, X = S , 90 % 1 139g, R = 3-NO2, X = O, 98 % 1 139h, R = 3-NO2, X = S, 94 %

R O Lewis acids R O 143, 144 + + H2N NH2 NH

H O 142 N O 141 H 140 143, 144

143a, R = 4-OMe, 94a %, 68b % a b 143b, R = 2,6-Cl2 , 89 %, 58 % 143c, R = 4-Me, 90a %, 61b % 143: MnO2-CNTs, Solvent free, MW (80 W) 143d, R = 4-OH, 87a %, 50b % 143e, R = 3-Br, 96a %, 73b % 143f, R = H, 97a %, = 70 b %

a Isolated yield using MnO2-CNTs b Isolated yield using MnO2

Scheme 22. Biginelli-like reactions using acetophenone.

best result has been reported for the reaction of benzaldehyde, di- ZnI2 was used as a Lewis acid catalyst in the Biginelli-type re- medone, urea/thiourea catalyzed by La2O3 at 480 W (Scheme 21, action of aryl aldehyde, acetophenone and urea under MWI in a 139a-h) [187]. solventless system. These Biginelli-type reactions in comparison with 111a-e the original Biginelli reaction give products in a higher A facile and efficient approach for the synthesis of dihydro- yield (Scheme 22, 144a-f) [190]. pyrimidinone derivatives via a fast condensation of differently substituted aromatic aldehydes, ketones and urea in the presence of An outstanding modified Biginelli cyclocondensation of an unprotected aldose as a bio-recycble aldehyde and 2-phenyl-1,3- effective and easily available MnO2–CNT nanocomposites as a catalyst under MWI and solvent-free conditions was accomplished oxazol-5-one as a new active methylene building block were re- and reported. It is worthwhile to mention that even ketones can acted with urea or thiourea. This reaction was successfully catalyzed with cerium(III) salts under MWI in a solventless system to fruitfully participate in such reactions providing unconventional afford iminosugar-annulated polyfuntionalized perhydropyrimidi- Biginelli products in excellent yields [188]. nes, stereoselectively through ring transformation of an isolable For this reaction, the effect of the MWI power, and the irradia- intermediate with subsequent cyclodehydration. The strategy re- tion time were examined on a Biginelli-like reaction. Using higher ported was successfully conducted under MWI of an intimate sol- powers resulted in degradation of products and naturally lower vent-free mixture of 2-phenyl-1,3-oxazol-5-one 145, D-xylose/D- yields were resulted (Scheme 22, 143a-f) [189]. glucose 146, urea/thiourea and Ce(III) salt (Scheme 23) [191]. 590 Current Organic Synthesis, 2016, Vol. 13, No. 4 Heravi et al.

144a, R1 = H, Isolated yield = 94% 1 144b, R = 3-CH3O-4-OH, 80 % 1 144c, R = 3-CH3O, 89 % 144: ZnI2, Solvent-free, MW (750 W), 8 min 1 144d, R = 4-CH3, 92 % 144e, R1 = 3-Br, 88 % 144f, R1 = 4-Cl, 93 % 144g, R1 = 4-CHO, 96 %

PhOCHN OH O OH n = 3 NN R OH

CHO X X N 148 O (CHOH)n + + NH2CNHR MW, Solvent-free O Ph CH2OH Ce(III) salt PhOCHN OH 147 145 146 -H2O O OH D-xylose D-glucose NN n = 4 R OH X OH 148a, X = O, R = H, Isolated yield = 74 % 149a, X = O, R = 2-MeC6H4, 79 % 149 148b, X = O, R = 2-MeC6H4, 77 % 149b, X = O, R = H, 78 % 148c, X = O, R = Ph, 82 % 149c, X = O, R = Ph, 87 % 148d, X = S, R = H, 81 % 149d, X = S, R = H, 89 % 148e, X = S, R = Ph, 79 % 149e, X = S, R = Ph, 81 % 148f, X = O, R = Et, 80 % 149f, X = O, R = Et, 85 %

Scheme 23. Synthesis of iminosugar-annulated perhydropyrimidines.

R O O X O R NiO-CNTs / Solvent- free + + H N OMe 2 NH2 MW (300 W) HN OMe CHO 151 152 X N 150 H 153a, R = 3-OMe, X = O, 90 % 153e, R = 4-OH, X = S, 87 % 153 153b, R = 4-NMe2 , X = S, 89 % 153f, R = 4-Br, X = S, 93 % 153c, R = 4-NO2, X = O, 95 % 153g, R = 4-Cl, X = O, 92 % 153d, R = 4-OMe, X =S, 92 % 153h, R = H, X = O, 98 %

Scheme 24. Microwave-mediated multi-component synthesis of dihydropyrimidinones (thiones).

A simple protocol to synthesize 3,4- dihydropyrimidin-2(1H)- MWI as the energy source. This new method has the advantage of ones/thiones via the MWI promoted the cyclocondensation of an giving excellent yields of the desired products (90-95%). This pro- aromatic aldehyde, -dicarbonyl compound and urea or thiourea is cedure will offer an easy access to substituted 3,4-dihydro- mediated by nickel oxide supported on multi-walled carbon nano- pyrimidin-2(1H)-ones/-thiones with a varied substitution pattern in tubes as a heterogeneous catalyst has been achieved and reported very high yields. The use of TBAB preserved the classical simplic- (Scheme 24) [192]. In addition, this Biginelli-like reaction, in the ity of the Biginelli one-pot synthesis and remarkably improved the presence of nickel oxide, gives products in excellent yields similar yield profile and time to complete the reactions in shorter span (3-4 to the original Biginelli compounds 121a-g. min) than the reported longer times (Scheme 25, 157a-g) [193].

2.2.3. Ionic Liquid Carboxy functionalized IL [cmmim][BF4] was found as an effective and environmentally benign catalyst for the one-pot, three- Simple and improved conditions have been found to perform component synthesis of 3,4-dihydropyrimidin-2-(1H)-ones via the the Biginelli reaction for the synthesis of 3,4- dihydropyrimidin- Biginelli reaction under MWI. A combination of IL-MWI strategy 2(1H)-one derivatives. This synthesis was performed in the pres- has been proved as simple way for a convenient access to the Bigi- ence of tetra-n-butylammonium bromide (TBAB) as a catalyst. nelli products in high purity and yields. An appropriate mixture of These reactions were performed under solvent-free conditions using Microwave-Assisted Biginelli Reaction Current Organic Synthesis, 2016, Vol. 13, No. 4 591

O R

O O O X Iion liquids EtO NH 157-164 R H + OEt + H N NH 2 2 N X 154 155 156 H

157-164

157a, R = Ph, X = O, Isolated yield = 95 %

157b, R = 4-CH3OC6H4, X = O, 94 %

157c, R = 4-CH3OC6H4, X = S, 94 % 157: TBAB, Solvent- free, MW (300W) , 3-4 min 157d, R = 4-O2NC6H4, X = O, 92 %

157e, R = 4-CH3C6H4, X = O, 90 %

157f, R = 4-FC6H4, X = O, 93 % 157g, R = 4-FC H , X = S, 95 % 6 4 Scheme 25. Biginelli reaction under different Ionic liquid.

158a, R = 3,4,5-(CH3O)3-C6H2, X = S, CONV = 79 %, 270 min, MW = 91 %, 3 min

158b, R = 4-CH3OC6H4, X = O, CONV = 86 %, 150 min, MW = 97 %, 1.5 min

158c, R = 4-HOC6H4, X = O, CONV = 88 %, 150 min, MW = 96 %, 1.5 min 158: [cmmim][BF4 ], Method A: MW 158d, R = 4-CH3OC6H4, X = S, CONV = 84 %, 150 min, MW = 95 %, 3 min (280 W), 1-3 min, Method B: (80 °C) 158e, R = 4- O2NC6H4, X = O, CONV = 88 %, 240 min, MW = 96 %, 3 min

158f, R = 3-ClC6H4, X = O, CONV = 90 %, 150 min, MW = 96 %, 2.5 min

158g, R = C6H5, X = O, CONV = 92 %, 90 min, MW = 97 %, 1.5 min

158h, R = C6H5, X = S, CONV = 86 %, 120 min, MW = 92 %, 2.5 min

159a, R = C6H5, X = O, Isolated yield = 92 % NN H CH3 159b, R = 4-CH3OC6H4, X = S, 95 %

159: 159c, R = 4-CH3OC6H4, X = O, 94 % CF3COO (1 mmol) 159d, R = 4-O2NC6H4, X = O, 93 % MW (630 W), 2 min 159e, R = 4-ClC6H4, X = O, 90 %

159f, R = 4-ClC6H4, X = S, 94 % the components of the classical Biginelli reaction was stirred gently A mild, effective, and MW-assisted classical Biginelli reaction with a spatula for a few seconds and subjected to MWI for the indi- using nitrite ionic liquid (IL-ONO) for the synthesis of 3,4- cated time (Scheme 25, 158a-h) [194]. dihydropyrimidin-2(1H)-(thio)ones has been achieved and reported. The ionic liquid used is a weak Lewis base acting as an efficient [Hmim][Tfa] has been employed as an efficient catalyst for the catalyst in this reaction. Remarkably, this IL can be readily recov- Biginelli reaction under MWI. Unexpectedly, low catalyst loading ered and reused in several cycles (Scheme 25, 160a-g) [196]. increased the rate of reaction, while decreasing the reaction time and making the separation practically simple. Encouraged by this A facile and eco-friendly approach for the synthesis of dihydro- result, the same research group studied four other different types of pyrimidinones via an MWI-activated Biginelli reaction catalyzed by IL for this reaction. They initially conducted a one-pot, three- heteropolyanion-based ILs in a solventless system has been accom- component reaction of benzaldehydes, ethylacetoacetate and urea to plished and disclosed. The reaction was found to be well suited obtain optimized reaction conditions. They examined already with different structurally diverse starting materials. Obtaining satisfactory to excellent yields, short reaction times and ease of known ILs such as [Hmim][HSO4], [Bmim][BF4] and [Bmim][PF6] diversely as a catalyst under MWI and successfully obtained operation are the chief merits of this strategy. In addition, the DHPMs. For the sake of comparison, the [Hmim][Tfa] was used as HPAILs are recyclable and reusable for more than five successive a catalyst in the above reaction, which was found to be fruitful, both cycles, while no appreciable loss in its catalytic activity is observed under conventional heating and MWI. (Scheme 25, 161a-i) [197]. The results clearly show that [Hmim][Tfa] under MWI is highly An efficient and cost-effective strategy for the Biginelli reaction active and it effectively acts as a superior catalyst, leading to the using inexpensive ILs amino acid ionic under MWI has been devel- best yields and shortest reaction times. As a thermal source, the oped. Among amino acid ILs used, glycine nitrate with less toxicity superiority of using MWI over conventional heating for the synthe- and better biodegradability is frequently used. A positive effect in sis of 3,4-dihydropyrimidin-2(1H)-ones 95 using the above catalyst terms of remarkable reduction of the reaction time (10 min) was was also observed in terms of yields and reaction times. Under observed as an advantage of conducting the reaction under MWI. MWI, the reaction is completed only in 2 min. giving the desired To evaluate the potency of the above amino acid ILs as cata- products virtually in quantitative yields (Scheme 25, 159a-f) [195]. lysts in a one-pot, three-component Biginelli cyclocondensation, the 592 Current Organic Synthesis, 2016, Vol. 13, No. 4 Heravi et al.

160a: R = C6H5, X = O, Isolated yield = 90 %

160b: R = 4-CH3OC6H4. X = O, 91 %

160c: R = 4-CH3OC6H4, X = S, 90 % 160: IL-ONO, Solvent-free, MW (60 W), 80 °C 160d: R = 4-O2NC6H4, X = O, 89 %

160e: R = 3-O2NC6H4, X = S, 88 %

160f: R = 4-ClC6H4, X = S, 89 % 160g: R = 2-Furyl, X = O, 89 %

161a, R = C6H5, X = O, Isolated yield = 95 % 161: catalyst (3 mol %), Solvent-free, MW, 120°C, 5-10min 161b, R = 4-CH3OC6H4, X = O, 96 % 161c, R = 4-O2NC6H4, X = O, 93 % 161d, R = 4-CH3C6H4, X = S, 91 % 161e, R = 4-O2NC6H4, X = S, 90 % 161f, R = 4-ClC H , X = O, 92 % cat. 3- 6 4 PW12O40 N SO3H 161g, R = 4-ClC6H4, X = S, 92 % + 161h, R = 2-Furyl, X = O, 88 % 3 161i, R = i-Pr, X = O, 83 % [PyPS]3PW12O40

162a, R = 3-BrC6H4, X = O, Isolated yield = 88 %

162b, R = 4-(HO), 3-(CH3O)C6H3, X = S, 80 %

162c, R = 4-N,N(CH3)2C6H4, X = O, 84 % 162: GlyNO3 / EtOH, MW (100 W), 10 min 162d, R = 4-CH3OC6H4, X = O, 88 %

162e, R = 4-O2NC6H4, X = O, 85 %

162f, R = 3-HOC6H4, X = S, 74 %

162g, R = 4-ClC6H4, X = S, 83 %

163a, R = 4-CH3OC6H5, X = O, MW = 90 %, 4 min, CONV = 87 %, 5 hr

163b, R = 4-HOC6H5, X = O, MW = 80 %, 5 min, CONV = 78 %, 5.5 hr 163: Method A: IL, 90 °C, 5-8 h, 163c, R = 4-CH3C6H5, X = S, MW = 74 %, 6 min, CONV = 72%, 6.5 hr Method B: IL, 200 W, 4-8 min 163d, R = 3-O2NC6H5, X = O, MW = 73 %, 7 min, CONV = 70 %, 8 hr

163e, R = 3-O2NC6H5, X = S, MW = 67 %, 8 min, CONV = 66 %, 8 hr

163f, R = C6H5, X = O, MW = 90 %, 4 min, CONV = 88 %, 5 hr

163g, R = C6H5, X = S, MW = 80 %, 5 min, CONV = 78 %, 5.5 hr

reaction of benzaldehyde, ethyl acetoacetate and urea was con- An acidic IL [bmim]HSO4 [200] has been used as a catalyst for ducted with 1 equiv. quantity of catalyst in EtOH. The results the simple, green and efficient synthesis of an array of 3,4- dihy- showed that among all the three ILs examined, GlyNO3 gave better dropyrimidin-2-(1H)-ones via the Biginelli reaction, using both results in terms of yields and reaction times (Scheme 25, 162a-g) thermal and MWI as sources of energy. Products have been ob- [198]. tained in high levels of purity and good yields using this one-pot methodology. The reaction has been carried out both thermally and A facile, effective and environmentally benign approach using a under microwave conditions to provide pure products in very good new generation of ionic liquid (IL), tri-(2-hydroxyethyl) ammonium yields. acetate has been reported. The ionic liquid plays a dual role as both solvent and catalyst in this process leading to an efficient synthesis Easy product isolation, pure product formation, solvent-free of 3,4-dihydropyrimidinones using a one-pot, three-component conditions, enhanced reaction rate, milder reaction conditions and Biginelli reaction of aromatic aldehydes, -dicarbonyl compounds, compatibility with various functional groups are the main advan- and urea/thiourea. Thus, a green and cost-effective protocol was tages of this methodology for the synthesis of dihydropyrimidi- performed using both conventional heating and MWI. This reaction nones. It has also been demonstrated that simple non-acidic ILs do is an example of combination of IL with MWI energy. It provides not catalyze this reaction (Scheme 25, 164a-e) [201]. an interesting and rapid alternative strategy to the orthodox acid- A facile and efficient Biginelli synthesis of several 3,4- base catalyzed thermal routes. It was observed that in case of using dihydropyrimidin-2(1H)-ones and 3,4-dihydropyrimidine- 2(1H)- thiourea, the yields were slightly lower in comparison to using urea. thiones has been developed. A one-pot, three-component of substituted aromatic and heterocyclic aldehydes, methyl acetoacetate, and The reactions were also examined practically for diverse start- urea / thiourea, catalyzed by 10 mol% ([C mim][HSO ]) as an ing materials using the combination of MWI and IL. It was found 4 4 acidic task-specific ionic under MWI in the solvent-free conditions that the use of MWI drastically decreased the reaction times from gave the corresponding dihydropyrimidones. This strategy warrants 58 h to 48 min (Scheme 25, 163a-g) [199]. Microwave-Assisted Biginelli Reaction Current Organic Synthesis, 2016, Vol. 13, No. 4 593

164a, R = 4-(HO), 3-(CH3O)C6H3, MW = 90 %, 2 min, CONV = 96 %, 15 min 164: [bmim]HSO , Solvent-free, Method A: 4 164b, R = 3,5-(CH3O)C6H3, MW = 78 %, 3 min, CONV = 87 %, 20 min MW (130 W), Method B: (90 °C) 164c, R = 3-O2NC6H5, MW = 91 %, 1 min, CONV = 95 %, 10 min 164d, R = 2-ClC H , MW = 91 %, 2 min, CONV = 97 %, 15 min X = O 6 5 164e, R = C6H5, MW = 92 % , 2 min, CONV = 94 %, 10 min

O R O O X [C mim][HSO ] 4 4 MeO NH Solvent-free RCHO + Me OMe + H N NH 2 2 Me N X MW (150 W), 140°C H 165 166 167 168

168a, R = 4-MeOC6H4, X = O, 85 % 168e, R = pyridin-3-yl, X = O, 76 %

168b, R = 4-MeOC6H4, X = S, 82 % 168f, R = 4-HOC6H4, X = O, 83 %

168c, R = 4-O2NC6H4, X = S, 79 % 168g, R= 4-ClC6H4, X = S, 80 %

168d, R = 4-O2NC6H4, X = O, 82 %

Scheme 26. Catalytic effect of ionic liquid [C4mim][HSO4] in the Biginelli reaction.

N N R IL: SO3H O X TS NH

RCHO + Acidic IL + NH2 NH2 N X H 169 171 MW (250 W), 5 min R 172 170 90 °C, neat

172a, R = 4-O2NC6H4, X = S, 75 %, 18 min 172e, R = 4-MeC6H4, X = O, 73 %, 8 min

172b, R = 4-MeO-C6H4, X = O, 64 %, 5 min 172f, R = Ph, X = S, 82 %, 10 min

172c, R = 4-O2NC6H4, X = O, 83 % , 5 min 172g, R = Ph, X = O, 82 %, 5 min

172d, R = 4-MeC6H4, X = S, 64 %, 12 min

Scheme 27. Ion liquid promoted, MW-assisted, one-pot synthesis of pyrimidinone. short reaction times (4.4-8 min) as well as giving the products in strategy can be better understood by comparison of some of the high yields and pure enough not needing costly column chromatog- results illustrated, which underlines and compares the reaction con- raphy. All the products were purified by crystallization. Having this ditions, yields and reaction times (Scheme 27) [203]. ideal catalyst, [C4mim][HSO4] available, the effect of the quantity of [C4mim][HSO4] was investigated. The reaction of 4- 2.3. Miscellaneous methoxybenzaldehyde with methyl acetoacetate and urea was cho- A mixture of ethyl acetoacetate, thiourea,, benzaldehyde, and sen and performed under MWI at 120 and 140°C in a solventless commercially available N-bromosuccinimide was subjected to system, while varying the amount of catalyst. MWI. It was found that the best yield could be achieved under irra- Considering this result, further study was contemplated. To es- diation at a power of 150 W in 3–5 min with a 30-min break after tablish the generality of methodology, utilizing [C4mim][HSO4] as every one minute of heating. The product was purified by recrystal- a catalyst in the Biginelli reactions, differently substituted aromatic lization from ethanol to give the desired products in 75% yield aldehydes were used and several Biginelli products were obtained (Scheme 28, 176a,b) [204]. in satisfactory yields and short reaction times. An efficient synthesis of 3,4-dihydropyrimidin-2-(1H)-ones and Generally speaking, it has been realized that all MWI- pro- the corresponding thioxo derivatives using 1,3-dibromo-5,5-dime- moted reactions require short reaction times. For the aforemen- thylhydantoin (DBU) as a catalyst has been successfully achieved. tioned catalyst, MWI also increased its catalytic activity, particu- The DBH catalysis of a one-pot, three-component Biginelli reaction larly when it was used in the Biginelli reaction (Scheme 26) [202]. of aldehydes, ethyl acetoacetate, and urea or thiourea under MWI An effective Brønsted acidic IL-catalyzed, one-pot, three- gives the desired Biginelli reaction products in high yields. component Biginelli-type reaction of differently substituted aro- DBH is an inexpensive and commercially available reagent matic aldehydes, cyclopentanone, and urea / thiourea was accom- used for analytical purposes [205]. The effect of the MWI power in plished for the preparation of arylidene heterobicyclic pyrimidi- this reaction was investigated. The highest yields of the products nones under MWI in solventless conditions. The competence of this were obtained at the power of 800 W (Scheme 28, 177a-h) [206]. 594 Current Organic Synthesis, 2016, Vol. 13, No. 4 Heravi et al.

O R O O O X Miscellaneous catalysts 176-178 EtO NH R H + OEt + H2N NH2 N X 173 174 175 H

176-178

176: Method A: NBS, Solvent- free, MW (150 W), 176a, R = C H , Isolated yield under MWI using Silica gel = 75 % 3-5 min, Method B: Silica gel / conc. H2SO4 and 6 5 EtOH, MW (800 W), 30 sec 176b, R = C6H5, Isolated yield under MWI using NBS = 65 %

X = S

Scheme 28. Biginelli reaction under miscellaneous catalysts.

O 177a, R = C6H5, X = O, Isolated yield = 82 % 177b, R = 3-CH3O-C6H4, X = O, 83 % Br Br N N 177c, R = 3-MeO-C6H4, X = O, 90 % 177: / solvent-free 177d, R = 3-O2NC6H4, X = S, 88% O 177e, R = 2-HOC6H4, X = O, 98 % 177f, R = 2-ClC6H4, X = O, 70 % MW (800 W), 3-7 min 177g, R = 4-ClC6H4, X = O, 94 % 177h, R = C6H5, X = S, 81 %

178a, R = C6H5CH = CH, MW = 85 %, min2.5, CONV = 81 %, 4 hr

178b, R = 4-O2NC6H4, MW = 88 %, 2.5 min, CONV = 84 %, 3 hr CoCl2.6H2O / MW 178c, R = 4-CH OC H , MW = 99 %, 2 min, CONV = 92 %, 4 hr 178 a-f 3 6 4 178d, R = 4-HOC H , MW = 88 %, 2 min, CONV = 80 %, 3 hr X = O 6 4 178e, R = 2-Furyl, MW = 85 %, 3 min, CONV = 76 %, 3.5 hr

178f, R = C6H5, MW = 98 %, 2 min, CONV = 92 %, 3.5 hr

178g, R = 4-CH3OC6H4, MW = 88 %, 2.5 min, CONV = 82 %, 4 hr

178h, R = 4-O2NC6H4, MW = 82 %, 2.5 min, CONV = 80 %, 3.5 hr MnCl .4H O / MW 178 g-l 2 2 178i, R = 2-Furyl, MW = 78 %, 3.5 min, CONV = 67 %, 3.5 hr X = O 178j, R = 4-ClC6H4, MW = 85 %, 2 min, CONV = 74 %, 3 hr

178k, R = C6H5, MW = 87 %, 3 min, CONV = 80 %, 3.5 hr 178l, R = n-Bu, MW = 76 %, 3 min, CONV = 68 %, 4 hr

178m, R = C6H5CH = CH, MW = 84 %, 4 min, CONV = 80 %, 7 hr

178n, R = 4-HOC6H4, MW = 86 %, 3 min, CONV = 80 %, 5.5 hr

178p, R = 4-CH3OC6H4, MW = 88 %, 4min, CONV = 80 %, 7 hr SnCl2.2H2O / MW 178 m-s 178q, R = 4-O2NC6H4, MW = 92 %, 3 min, CONV = 85 %, 5 hr X = O 178r, R = 2-Furyl, MW = 85 %, 3.5 min, CONV = 80 %, 6 hr

178s, R = C6H5, MW = 96 %, 3.5 min, CONV = 90 %, 6 hr

An efficient, facile Biginelli reaction using relatively non-toxic Under MWI, a one-pot, three-component reaction of various and inexpensive CoCl2.6H2O or MnCl2.4H2O or SnCl2.2H2O as a aromatic aldehydes, substituted acetophenones and urea in DMF led catalyst under MWI has been performed. The yield of the DHPMs to the synthesis of 4,6-diaryl-3,4-dihydro-pyrimidin-2(1H)-ones in was increased from 20-50% [207] to 75-99%. In addition, delight- good to high yields (68%84%). In the presence of chlorotrimeth- fully, the reaction times were significantly decreased from 18-48 ylsilane, the above Biginelli-like reaction gave the respective dehy- hrs to 2-3 min. To establish the generality of this reaction differ- drogenated 4,6-diarylpyrimidin- 2(1H)-ones in also good to high ently substituted aldehydes and acetates were reacted with urea yields (66%-87%). This protocol, using MWI for the synthesis of under optimized conditions to give the desired products in satisfac- 4,6-diaryl pyrimidin-2(1H)-ones, was facile, effective and most tory yields (Scheme 28, 178 a-s) [208]. importantly time-saving (Scheme 29) [209]. Microwave-Assisted Biginelli Reaction Current Organic Synthesis, 2016, Vol. 13, No. 4 595

O R R1 HN NH O + + NH2CNH2

R R1 CHO COCH3 181 182

179 180

1 1 182a, R = Cl, R = Cl, Isolated yield = 84 % 182g, R = Cl, R = CH3, Isolated yield = 84 % 1 182h, R = CH , R1 = OCH , 73 % 182b, R = CH3, R = OCH3, 77 % Me 3SiCl 3 3 1 1 DMF 182c, R = OCH3, R = Cl, 80 % DMF 182i, R = OCH3, R = Cl, 66 % 1 1 MW (75 W) 182d, R = Cl, R = CH3, 75 % MW (75 W) 182j, R = OCH3, R = H, 87 % 1 1 182e, R = H, R = CH3, 81 % 182k, R = H, R = Cl, 81 % 182f, R = H, R1 =H, 68 % 182l, R = H, R1 = H, 80 %

Scheme 29. Synthesis of 4,6-diaryl-3,4-dihydro-pyrimidin-2(1H)-ones. OH

OH S' O OH n = 3 NNH R 188 X CHO S X MW, 9-13 min Ph O CHOH 90 °C , Solvent-free n + O + NH2CNHR HO CH OH Me OH 2 K-10 185 187 clay OH 186 S' O D-xylose OH D-glucose n = 4 NNH n = 3,4 R X 189

188a, X = O, R = H, Isolated yield = 83 %, cis: transs ratio = 96:4 189a, X = S, R = 2-CH3C6H4, 81 %, 98:2 188b, X = O, R = 2-CH3C6H4, 80 %, 97:3 189b, X = O, R = Ph, 78 %, 97:3 188c, X = O, R = Ph, 76 %, 97:3 189c, X = S, R = Ph, 84 %, 96:4 188d, X = S, R = Ph, 85 %, 96:4 189d, X = O, R = H, 89 %, 98:2 188e, X = O, R = Et, 82 %, 96:4 189e, X = S, R = H, 77 %, 96:4 189f, X = S, R = Et, 80 %, 97:3 188f, X = S, R = H, 79 %, 98:2

Scheme 30. Synthesis of thiosugar-annulated dihydropyrimidines 188 and 189.

A new Biginelli-type reaction employing an unprotected aldose pyrimidines 188 and 189 under MWI in a solventless system. Iso- as a bio-renewable aldehyde component and 2-methyl-2-phenyl- lated products were purified by crystallization from ethanol to ob- 1,3-oxathiolan-5-one 185 as a mercaptoacetylating active methyl- tain 188 and 189 in satisfactory yields with >95% de (Scheme 30) ene building block with urea/thiourea has been accomplished and [210]. reported. This nanoclay-catalyzed, swift reaction was performed under MWI in a solventless system in a one-pot fashion to give the O S diastereoselectively, thiosugar-annulated multifunctionalized dihy- LiBr Ph O dropyrimidines. This reaction is believed to proceed via an in- + HSCH2COOH Ph Me -H O O tramolecular domino cyclocondensation reaction. Noticeably, the 2 Me 184 generated intermediate can also be isolated. Compound 185 was 183 185 synthesized using LiBr in accordance with the previously reported method (Fig. 6). The protocol was followed for the envisioned diastereoselective Fig. (6). Formation of the mecaptoacetyl transfer agent 2-methyl-2-phenyl- synthesis of thiosugar-annulated multifunctionalized dihydro- 1,3-oxathiolan-5-one 185. 596 Current Organic Synthesis, 2016, Vol. 13, No. 4 Heravi et al.

CONCLUSION REFERENCES Chief, frequently-encountered disadvantages of the Biginelli re- [1] Armstrong, R.W.; Combs, A.P.; Tempest, P.A.; Brown, S.D; Keating, T.A. action are long reaction times and elevated temperatures, giving Multiple-Component Condensation Strategies for Combinatorial Library Synthesis. Acc. Chem. Res. 1996, 29, 123-131. low yields of the desired products, especially in case of substituted [2] Sadjadi, S.; Heravi, M.M. Recent application of isocyanides in synthesis of aldehydes and sometimes elimination of fragile functional groups heterocycles. Tetrahedron, 2011, 67, 2707-2752. during the reaction. DHPMs have a wide scope of biological activi- [3] Heravi, M.M.; Ahmadi, T.; Azadeh, F.; Kalkhorani, M.N. Recent Advances ties: They generally act as calcium channel antagonists, anti- in the Application of the Burgess Reagent in Organic Synthesis. Curr. Org. Synth. 2015, 12, 327-356. hypertensive, anti-bacterial, and anti-inflammatory agents, while [4] Puterová, Z.; Krutoíková, A.; Végh, D. Gewald reaction: synthesis, proper- also possessing cytotoxic activity. The use of MWI has circum- ties and applications of substituted 2-aminothiophenes. Arkivoc. 2010, 2010, vented most of the aforementioned drawbacks. Generally, when the 209-246. Biginelli reaction is performed under MWI, a rapid reaction occurs [5] Greico, P.A.; Bahsas, A. Role reversal in the cyclocondensation of cyclopen- tadiene with heterodienophiles derived from aryl amines and aldehydes: Syn- giving the desired product in high purity, less by-products, and thesis of novel tetrahydroquinolines. Tetrahedron Lett. 1988, 29, 5855-5858. improved yields. Performing the Biginelli reaction under MWI in a [6] Heravi, M.M.; Oskooie, H.A.; Malakooti, R; Alimadadi, B.; Alinejad, H.; solventless system can be considered as a green reaction. It also Behbahani, F.K. Oxidative aromatization of Hantzsch 1,4-dihydropyridines simplifies and modifies the synthetic procedure, giving an opportu- in the presence of a catalytic amount of Mn(pbdo)2Cl2/MCM-41 or Mn(pbdo)2Cl2/Al-MCM-41 as reusable and green catalysts. Catal. Commun. nity for a wider usable range of reaction temperature, along with 2009, 10, 819-822. sophisticated measurements, safety and also a modular system op- [7] Heravi, M.M.; Derikvand, F.; Hassan-Pour, S.; Bakhtiari, K.; Bamoharram, erationally changing from mg to kg scale. F.F.; Oskooie, H.A. Oxidative aromatization of Hantzsch 1,4- dihydropyridines in the presence of mixed-addenda vanadomolybdophos- phate heteropolyacid, H6PMo9V3O40. Bioorg. Med. Chem. Lett. 2007, 17, CONFLICT OF INTEREST 3305-3309. The authors confirm that this article content has no conflict of [8] Zefirov, N.S.; Matveeva, E.D. Catalytic Kabachnik-Fields reaction: New horizons for old reaction. Arkivoc. 2008, 2008, 1-17. interest. [9] Heravi, M.M.; Zadsirjan, V; Savadjani, Z.B. Applications of Mannich Reac- tion in Total Synthesis of Natural Products. Curr. Org. Chem. 2014, 18, ACKNOWLEDGEMENTS 2857-2891. [10] Banfi, L.; Riva, R. Organic Reactions || The Passerini Reaction; Wiley MMH is thankful to Alzahra University Research Council for Blackwell (John Wiley & Sons), 2005, Vol. 65, pp.1-140. partial financial assistance. [11] Blanco-Urgoiti, J.; Añorbe, L.; Pérez-Serrano, L.; Domínguez, G.; Pérez- Castells, J. The Pauson-Khand reaction, a powerful synthetic tool for the synthesis of complex molecules. Chem. Soc. Rev. 2004, 33, 32-42. ABBREVIATIONS [12] Soleymanifard, B.; Heravi, M.M.; Shiri, M.; Zolfigol, M.A.; Rafiee, M.; Kruger, H.G.; Naicker, T .; Rasekhmanesh, F. Synthesis of arylidenepyruvic MCR = Multi-component reaction amide derivatives via Ugi-four component condensation. Tetrahedron Lett. MCAP = Multi-component Assembly Process 2012, 53, 3546-3549. [13] Wang, Z. Comprehensive Organic Name Reactions and Reagents, Asinger DHPMs = Dihydropyrimidin-2(1H)-ones Reaction.; Wiley & Sons. 2010. [14] Biginelli, P. Aldehyde- Urea Derivatives of Aceto- and Oxaloacetic Acids. MW = Microwave Gazz. Chim. Ital. 1893, 23, 360-413. [15] (a) Fu, N.Y.; Yuan, Y.F.; Cao, Z.; Wang, S.W.; Wang, J.T.; Peppe, C. In- MWI = Microwave irradiation dium(III) bromide-catalyzed preparation of dihydropyrimidinones: improved protocol conditions for the Biginelli reaction. Tetrahedron. 2002, 58, 4801- PEG-SO3H = poly(ethylene glycol)-bound sulfonic acid 4807; (b) Hu, E.H.; Slider, D.R.; Dolling, U.H. Hu, E.H., D.R. Slider and PHA = Phosphotungstic acid U.H. Dolling, 1998. Unprecedented Catalytic Three Component One-Pot Condensation Reaction: An Efficient Synthesis of 5-Alkoxy-carbonyl-4-aryl- PSSA = Polystyrenesulfonic acid 3,4-dihydropyrimidin-2(1H)-ones, J. Org. Chem. 1998, 63, 3454-3457. TBAB = Tetra-n-butylammonium bromide [16] (a) Jiang, J.; Yu, J.; Sun, X.X.; Rao, Q.Q.; Gong, L.Z. Organocatalytic asymmetric three-component cyclization of cinnamaldehydes and primary HPAIL = heteropolyanion-based ionic liquid amines with 1,3-dicarbonyl compounds: Straightforward access to enanti- omerically enriched dihydropyridines. Angew. Chem., Int. Ed. 2008, 47, VB1 = Thiamine hydrochloride 2458-2462. (b) Khabazzadeh, H.; Saidi, K.; Sheibani, H. Microwave-assisted synthesis of dihydropyrimidin-2(1H)-ones using graphite supported lantha- TCCA = Trichloroisocyanuric acid [1,3,5-trichoro-1,3,5- num chloride as a mild and efficient catalyst .Bioorg. Med. Chem.Lett. 2008, triazine- 2,4,6-(1H,3H,5H)-trione] 18, 278-280; (c) Varala, R.; Alam, M. M.; Adapa, S. R. Bismuth triflate catalyzed one-pot synthesis of 3,4-dihydropyrimidin-2 (1H)-ones: An improved ILs = Ionic liquids protocol for the Biginelli reaction. Synlett. 2003, 1, 67-70; (d) Paraskar, A.S.; DBH = 1,3-dibromo-5,5-dimethylhydantoin Dewkar, G. K.; Sudalai, A. Cu(OTf)2: a reusable catalyst for high-yield synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Tetrahedron Lett. 2003, 44, TSA = p-toluene sulfonic acid 3305-3308; (e) Ma, Y.; Qian, C.; Wang, M. Lanthanide triflate catalyzed Biginelli reaction. One-pot synthesis of dihydropyrimidinones under solvent- EDA = etidronic acid free conditions. J. Org. Chem. 2000, 65, 3864-3868; (f) Ranu, B.; Hajra, A.; Jana, U. Indium(III) chloride-catalyzed one-pot synthesis of dihydro- TFA = Trifluoroacetic acid pyrimidinones by a three-component coupling of 1,3-dicarbonyl compounds, TMS = Trimethylsilane aldehydes, and urea: An improved procedure for the Biginelli reaction. J. Org. Chem. 2000, 65, 6270-6272; (g) Yadav, J.S.; Reddy, B.V.S.; Srinivas, MNPs = magnetic nanoparticles R.; Venugopal, C.; Ramalingam, T. LiClO4-catalyzed one-pot synthesis of dihydropyrimidinones: An improved protocol for Biginelli reaction. CNTs = Carbon nanotubes Synthesis. 2001, 1341-1345. [17] (a) Li, N.; Chen, X.H.; Song, J.; Luo, S.W.; Fan, W.; Gong, L.Z. Highly TBAB = Tetra-n-butylammonium bromide Enantioselective Organocatalytic Biginelli and Biginelli-Like Condensations: IL-ONO = Nitrite ionic liquid Reversal of the Stereochemistry by Tuning the 3,3 '-Disubstituents of Phos- phoric Acids. J. Am. Chem. Soc. 2009, 131, 15301-15310; (b) Chen, X. H.; NPs = Nanoparticles Xu, X.Y.; Liu, H.; Cun, L.F.; Gong, L.Z. Highly enantioselective organocatalytic Biginelli reaction . J. Am. Chem. Soc. 2006, 128, 14802-14803. PWA = Phosphotungstic acid [18] Song, D.; Wang, R.; Chen, Y.; Zhang, S.; Liu, C.; Luo, G. Copper (II) trifluoroacetate catalyzed synthesis of 3,4- dihydropyrimidin-2(1H)-ones un- [Hmim]Tfa = 1-Methylimidazolium trifluoroacetate der solvent-free conditions. React. Kinet. Catal. L. 2008, 95, 385-390. [19] Liu, C.; Wang, J.; Li, Y. One-pot synthesis of 3,4-dihydropyrimidin-2(1H)- [Bmim][BF4] = 1-Butyl-3-methylimidazolium tetrafluoroborate (thio)ones using strontium(II) nitrate as a catalyst, J. Mol. Catal. A: Chem. DMF = N,N-dimethyl formamide 2006, 258, 367-370. Microwave-Assisted Biginelli Reaction Current Organic Synthesis, 2016, Vol. 13, No. 4 597

[20] Ahmed, N.; Lier, J.E.V. TaBr5-catalyzed Biginelli reaction: one-pot synthesis unsubstituted-3,4-dihydropyrimidin-2(1H)-ones under solvent-free condi- of 3,4-dihydropyrimidin-2-(1H)-ones/thiones under solvent-free conditions. tions, Tetrahedron. 2007, 63, 1981-1986. Tetrahedron Lett. 2007, 48, 5407-5409. [43] Surati, M.A.; Jauhari, S.; Desai, K.R. A brief review: Microwave assisted [21] Ranu, B.C.; Hajra, A.; Jana, U. Indium(III) Chloride-Catalyzed One-Pot organic reaction. Arch. Appl. Sci. Res. 2012, 4, 645-661. Synthesis of Dihydropyrimidinones by a Three-Component Coupling of 1,3- [44] Breslow, R. Hydrophobic Effects On Simple Organic-Reactions In Water. Dicarbonyl Compounds, Aldehydes, and Urea: An Improved Procedure for Acc. Chem. Res. 1991, 24, 159-164. the Biginelli Reaction. J. Org. Chem. 2000, 65, 6270-6272. [45] Bose, Ak.; Manhas, Ms.; Banik, Bk.; Robb, Ew. Microwave-Induced Or- [22] Sun, Q.; Ge, Y.; Wang, Z.; Cheng, T.; Li, R. A highly efficient solvent-free ganic-Reaction Enhancement (More) Chemistry - Techniques For Rapid, synthesis of dihydropyrimidinones catalyzed by zinc chloride. Synthesis. Safe And Inexpensive Synthesis Res. Chem. Intermed. 1994, 20, 1-11. 2004, 2004, 1047-1051. [46] Bose, A.K.; Banik, B.K.; Lavlinskaia, N.; Manhas. More chemistry in a [23] Salitha, G.; Reddy, G.S.K.K.; Reddy, K.B.; Yadav, J.S. Vanadium(III) microwave. Chem. Tech. 1997, 27, 18-24. chloride catalyzed Biginelli condensation: solution phase library generation [47] Lubineau, A.; Auge, J.; Queneau, Y. Water-Promoted Organic-Reactions. of dihydropyrimidin-(2H)-ones. Tetrahedron Lett. 2003, 44, 6497-6499. Synthesis. 1994, 1994, 741-760. [24] Ma, Y.; Qian, C.; Wang, L.; Yang, M. Lanthanide triflate catalyzed biginelli [48] Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Microwave assisted reaction. one-pot synthesis of dihydropyrimidinones under solvent-free con- organic synthesis - a review Tetrahedron. 2001, 57, 9225-9283. ditions. J. Org. Chem. 2000, 65, 3864-3868. [49] Panda, S.S.; Khanna, P.; Khanna, L. Biginelli Reaction: A Green Perspec- [25] Paraskar, A.S.; Dewkar, G.K.; Sudalai, A.; Cu(OTf)2: a reusable catalyst for tive. Curr. Org. Chem. 2012, 16, 507-520. high- yield synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Tetrahedron Lett. [50] Heravi, M.M. Vavsari, V. F. In: Advances in Heterocyclic Chemistry; Alan 2003, 44, 3305-3308. Katritzky, Ed.; Elsevier : USA, 2015; Vol. 114, pp. 77-145. [26] Salehi, P.; Dabiri, M.; Zolfigolc, M.A.; Fard, M.A.B. Silica sulfuric acid: an [51] Heravihttp://www.sciencedirect.com/science/article/pii/S0065272515000021 efficient and reusable catalyst for the one-pot synthesis of 3,4- - cor1, M.M.; Talaei, B. In: Advances in Heterocyclic Chemistry; Alan Ka- dihydropyrimidin-2(1H)-ones. Tetrahedron Lett. 2003, 44, 2889-2891. tritzky, Ed.; Elsevier: USA, 2015; Vol. 114, pp. 147-225. [27] Yadav, J.S.; Kumar, S.P.; Kondaji, G.; Rao, R.S.; Nagaiah, K. A novel L- [52] Heravihttp://www.sciencedirect.com/science/article/pii/S0065272515000021 proline catalyzed biginelli reaction: one-pot synthesis of 3,4- - cor1, M.M.; Khaghaninejad, S.; Mostofi, M. In: Advances in Heterocyclic dihydropyrimidin-2(1H)- ones under solvent-free conditions. Chem. Lett. Chemistry; Alan Katritzky, Ed.; Elsevier: USA, 2014; Vol. 112, pp. 1-50. 2004, 33, 1168-1169. [53] Heravi, M.M.; Alishiri. T. In: Advances in Heterocyclic Chemistry; Alan [28] Joseph, J.K.; Jain, S.L.; Sain, B. Ion exchange resins as recyclable and het- Katritzky, Ed.; Elsevier: USA, 2014, vol. 113, pp. 1-66. erogeneous solid acid catalysts for the Biginelli condensation: An improved [54] Heravi, M.M.; Khorasani, M.; Derikvand, F.; Oskooie, A.H.; Bamoharram, protocol for the synthesis of 3,4-dihydropyrimidin-2-ones. J. Mol. Catal. A: F.F. Highly efficient synthesis of coumarin derivatives in the presence of Chem. 2006, 247, 99-102. H14[NaP5W30O110] as a green and reusable catalyst. Catalysis Commun. 2007, [29] Azizian, J.; Mohammadi, A.A.; Karimi, A.R.; Mohammadizadeh, M.R. 8, 1886-1890. KAl(SO4)2.2H2O supported on silica gel as a novel heterogeneous system- [55] Heravi, M.M.; Sadjadi, S; Oskooie, H.A.; Hekmat S.R .; F. Bamoharram, catalyzed biginelli reaction: One-pot synthesis of di-hydropyrimidinones un- F.mailto:[email protected] The synthesis of coumarin-3- der solvent-free conditions, Appl. Catal. A: Gen. 2006, 300, 85-88. carboxylic acids and 3-acetyl-coumarin derivatives using heteropolyacids as [30] Jai, S.L.; Prasad, V.V.D.N.; Sain, B. Alumina supported MoO3: an efficient heterogeneous and recyclable catalysts. Catalysis Commun. 2008, 9, 470- and reusable heterogeneous catalyst for synthesis of 3,4-dihydropyridine- 474. 2(1H)-ones under solvent free conditions. Catal. Commun. 2008, 9, 499-503. [56] Heravi, M.M.; Rajabzadeh, G.; Bamoharram, F.F.; Seifi, N. An eco-friendly [31] Yarapathi, R.V.; Kurya, S.; Tammishetti, S. Synthesis of 3,4- catalytic route for synthesis of 4-amino-pyrazolo[3,4-d]pyrimidine deriva- dihydropyrimidin-2(1H) ones using reusable poly(4-vinylpyridineAco- tives by Keggin heteropolyacids under classical heating and microwave irra- divinylbenzene)-Cu(II)complex. Catal. Commun. 2004, 5, 511-513. diation. J. Mol. Catal. A: Chem. 2006, 256, 238-241. [32] Rovnyak, G.C.; Atwal, K.S.; Hedberg, A.; Kimball, S.D.; Moreland, S.; [57] Heravi, M.M.; Faghihi, Z. Applications of heteropoly acids in multi- Gougoutas, J.Z.; O'Reilly, B.C.; Schwartz, J.; Malley, M.F. Dihydro- component reactions. J. Iran Chem. Soc . 2014, 11, 209-224. pyrimidine calcium channel blockers. 4. Basic 3-substituted-4-aryl-1,4- [58] Heravi, M.M.; Moghimi, S. An efficient synthesis of thiazol-2-imine deriva- dihydropyrimidine-5-carboxylic acid esters. Potent antihypertensive agents. tives via a one-pot, three-component reaction. Tetrahedron Lett, 2012, 53, J. Med. Chem. 1992, 35, 3254-3263. 392-394. [33] (a) Singh, K.; Arora, D.; Poremsk, E.; Lowery, J.; Moreland, R.S. N1- [59] Heravi, M.M.; Moghimi, S. Catalytic Multicomponent Reactions Based on Alkylated 3,4-dihydropyrimidine-2(1H)-ones: Convenient one-pot selective Isocyanides. J. Iran Chem. Soc. 2011, 8, 306-373. synthesis and evaluation of their calcium channel blocking activity. Eur. J. [60] Heravi, M.M.; Hashemi, E; Beheshtiha, Y.S; Kamjou, K.; Toolabi, M.; Med. Chem. 2009, 44, 1997-2001; (b) Jauk, B.; Pernat, T.; Kappe, C.O. Hosseintash, Nastaran. Solvent-free multicomponent reactions using the Design and synthesis of a conformationally rigid mimic of the dihydro- novel N-sulfonic acid modified poly(styrene-maleic anhydride) as a solid pyrimidine calcium channel modulator SQ 32,926. Molecules. 2000, 5, 227- acid catalyst . J. Mol. Catal. A: Chem. 2014, 392, 173-180. 239; (c) Kappe, C.O. 4-aryldihydropyrimidines via the Biginelli condensa- [61] Heravi, M.M.; Asadi, S; Lashkariani, B.M. Recent progress in asymmetric tion: Aza-analogs of nifedipine-type calcium channel modulators. Molecules. Biginelli reaction. Mol. Diversity. 2013, 17, 389-407. 1998, 3, 1-9; (d) Kettmann, V.; Drimal, J.; Svetlik, J. Radioligand binding [62] Heravi, M.M.; Mousavizadeh, F.; Ghobadi, N.; Tajbakhsh, Mahgol . A green studies on some dihydropyridine analogues as probes of the dihydropyridine and convenient protocol for the synthesis of novel pyrazolopyranopyrimidi- receptor. Pharmazie. 1996, 51, 747-750. nes via a one-pot, four-component reaction in water. Tetrahedron Lett. 2014, [34] Rovnyak, G.C.; Atwal, K.S.; Hedeberg, A.; Kimball, S.D.; Moreland, S.; 55, 1226-1228. Gougoutas, J. Z.; O’Reilly, B. C.; Schwart, J.; Malley, M.F. [63] Heravi, M.M.; Bakhtiari, K; Oskooie, H.A.; Taheri, S. Synthesis of 2,4,5- Dihydropyrimidine Calcium-Channel Blockers .4. Basic 3-Substituted-4- triaryl-imidazoles catalyzed by NiCl2 center dot 6H2O under heterogeneous Aryl-1,4-Dihydropyrimidine-5-Carboxylic Acid-Esters - Potent Antihyper- system . J. Mol. Catal. A: Chem. 2007, 263, 279-281. tensive Agents. J. Med. Chem. 1992, 35, 3254-3263. [64] Heravi, M.M.; Bakhtiari, K; Bamoharram, F.F. 12-molybdophosphoric acid: [35] Deshmukh, M.B.; Salunkhe, S.M.; Patil, D.R.; Anbhule, P.V.A novel and A recyclable catalyst for the synthesis of Biginelli-type 3,4- efficient one step synthesis of 2-amino-5-cyano-6-hydroxy-4-aryl pyrimidi- dihydropyrimidine-2(1H)-ones. Catal. Commun. 2006, 7, 373-376. nes and their anti-bacterial activity. Eur. J. Med. Chem. 2009, 44, 2651-2654. [65] Heravi, M.M; Derikvand, F; Bamoharram, F.F. A catalytic method for syn- [36] Mayer, T.U.; Kapoor, T.M.; Haggarty, S.J.; King, R.W.; Schreiber, S.L.; thesis of Biginelli-type 3,4-dihydropyrimidin-2 (1H)-one using 12- Mitchison, T.J. Small molecule inhibitor of mitotic spindle bipolarity identi- tungstophosphoric acid. J. Mol. Catal. A: Chem. 2005, 242, 173-175. fied in a phenotype-based screen. Science. 1999, 286, 971-974. [66] Tajbakhsh, M; Mohajerani, B; Heravi, M.M; Ahmadi, A. Natural HEU type [37] Azizian, J.; Mohammadi, M.K.; Firuzi, O.; Mirza, B.; Miri, R. Microwave- zeolite catalyzed Biginelli reaction for the synthesis of 3,4-dihydropyrimidin- Assisted Solvent-Free Synthesis of Bis(dihydropyrimidinone)benzenes and 2(1H) one derivatives. J. Mol. Catal. A: Chem. 2005, 236, 216-219. Evaluation of their Cytotoxic Activity. Chem. Biol. Drug. Des. 2010, 75, [67] Heravi, M.M.; Fazeli. A.; Oskooie, H.A.; Beheshtiha, Y.S.; Matloubi 375-380. Moghaddam, F.; Koushki Foroushani, B. Synthesis of 1,4-Disubstituted [38] Kappe, C.O. Controlled Microwave Heating in Modern Organic Synthesis. 1,2,3-Triazoles from Aromatic a-Bromoketones, Sodium Azide and Terminal Angew. Chem. Int Ed. 2004, 43, 6250-6284. Acetylenes via Cu/Cu(OTf)2-catalyzed Click Reaction under Microwave Ir- [39] Kappe, C.O. Recent Advances in the Biginelli Dihydropyrimidine Synthesis. radiation. Z. Naturforsch. B: Chem. Sci. 2013, 68, 391-396. New Tricks from an Old Dog. Acc. Chem. Res. 2000, 33, 879-888. [68] Heravi, M.M.; Moghimi, S. Solid-supported Reagents in Organic Synthesis [40] Lu, J.; Bai, Y. Catalysis of the Biginelli reaction by ferric and nickel chloride Using Microwave Irradiation. Curr. Org. Chem. 2013, 17, 504-527. hexahydrates. One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Syn- [69] Valizadeh, H; Heravi, M.M.; Amiri, M. Unexpected synthesis of N- thesis. 2002, 2002, 466-470. methylbenzo[d]isoxazolium hydroxides under microwave irradiation condi- [41] Pasunooti, K.K.; Chai,H.; Jensen, C.N.; Gorityala, B.K.; Wang, S.; Liu, tions. Mol. Divers. 2010, 14, 575-579. X.W. A microwave-assisted, copper-catalyzed three-component synthesis of [70] Valizadeh, H.; Heravi, M.M.; Amiri, M. Conventional and Microwave- dihydropyrimidinones under mild conditions. Tetrahedron Lett. 2011, 52, 80- Assisted Facile One-Pot Synthesis of N-Substituted Pyrrole-2,3,4,5- 84. tetracarboxylates Under Neat Conditions. Synthetic Commun. 2010, 40, [42] Liang, B.; Wang, X.; Wang, J.X.; Dua, Z. New three-component cyclo- 3699-3706. condensation reaction: microwave assisted one-pot synthesis of 5- [71] Heravi, M.M.; Rajabzadeh, G.; Bamoharram, F.F.; Seifi, N. An eco-friendly catalytic route for synthesis of 4-amino-pyrazolo[3,4-d]pyrimidine deriva- 598 Current Organic Synthesis, 2016, Vol. 13, No. 4 Heravi et al.

tives by Keggin heteropolyacids under classical heating and microwave irra- [99] Kolvari, E.; Koukabi, N.; Armandpour, O. A simple and efficient synthesis diation. J. Mol. Catal. A: Chem. 2006, 256, 238-241. of 3,4-dihydropyrimidin-2-(1H)- ones via Biginelli reaction catalyzed by [72] Oskooie, H.A.; Alimohammadi, Z.; Heravi, M.M. Microwave-assisted solid- nanomagnetic-supported sulfonic acid. Tetrahedron. 2014, 70, 1383-1386. phase synthesis of 2,4,5-triaryl imidazoles in a solventless system: An im- [100] Heravi, M.M.; Hashemi, E.; Beheshtiha, Y.S.; Kamjou, K .; Toolabi, M .; proved protocol. Heteroat. Chem. 2006, 17, 699-702. Hosseintash, N. Solvent-free multicomponent reactions using the novel N- [73] Heravi, M.M.; Ajami, D.; Mohajerani, B.; Tabar-Hydar, K.; Ghassemzadeh, sulfonic acid modified poly(styrene-maleic anhydride) as a solid acid cata- Mitra. Zeofen, An Eco-Friendly Catalyst For Deoximation Under Microwave lyst. J. Mol. Catal. A: Chem. 2014, 392, 173-180. Irradiation In Solventless System. Synthetic Commun. 2002, 32, 3325-3330. [101] Heravi, M.M.; Hashemi, E.; Azimian, F. N-Sulfonic acid modified [74] Heravi, M.M.; Montazeri, N.; Rahimizadeh, M.; Bakavoli, M.; Ghas- poly(styrene-co-maleic anhydride): an efficient and recyclable solid acidcata- semzadeh, M. Solid acid induced heterocyclization under microwave irradia- lyst for the synthesis of a wide range of spiropyrans. J. Iran. Chem. Soc. tion. Highly selective synthesis of condensed thiazole. J. Chem. Res. 2000, 2015, 12, 647-653. 2000, 464-465. [102] Nemati, Firouzeh; Heravi, M.M.; Rad, Raheleh Saeedi. Nano-Fe3O4 Encap- [75] Heravi, M.M.; Beheshtiha, Y.S.; Ghasemzadeh, M.; shoar, R. H.; Sarmad, sulated-Silica Particles Bearing Sulfonic Acid Groups as a Magnetically Nooshin. Solid state deoximation with clay supported ammonium chloro- Separable Catalyst for Highly Efficient Knoevenagel Condensation and Mi- chromate: Regeneration of carbonyl compounds using microwaves in a sol- chael Addition Reactions of Aromatic Aldehydes with 1,3-Cyclic Diketones. ventless system. Monatsh. Chem. 2000, 131, 187-190. Chinese. J. Catal. 2012, 33, 1825-1831. [76] Heravi, M.M.; Ajami, D.; Mojtahedi, M.M.; Ghassemzadeh, M.A convenient [103] Wang, X.; Quan, Z.; Wang, F.; Wang, M.; Zhang, Z.; Li, Z. PEG-SO3H as oxidative deprotection of tetrahydropyranyl ethers with iron(III) nitrate and Catalyst for 3,4-Dihydropyrimidones via Biginelli Reaction Under Micro- clay under microwave irradiation in solvent free conditions. Tetrahedron wave and Solvent-Free Conditions. Synth. Commun. 2006, 36, 451-456. Lett. 1999, 40, 561-562. [104] Jetti, S.R .; Upadhyaya, A .; Jain, S. 3,4-Hydropyrimidin-2-(1H)one derivati- [77] Heravi, M.M.; Bakhtiari, A.; Faghihi, Z., Applications of Barton-McCombie ves: solid silica-based sulfonic acid catalyzed microwave-assisted synthesis reaction in total synthesis. Curr. Org. Syn. 2014, 11, 787-823. and their biological evaluation as antihypertensive and calcium channel blo- [78] Heravi, M.M.; Hajiabbasi, P.; Hamidi, H., Recent Development in the cking agents. Med. Chem. Res. 2014, 23, 4356-4366. Asymmetric Michael Addition for Carbon-Carbon Bond Formation. Curr. [105] Gupta, R.; Gupta, A.K.; Paul, S.; Kachroo, P. L.Improved Synthesis Of Org. Chem. 2014, 18, 489-511. Some Ethyl 4-Aryl-6-Methyl-1,2,3,4-Tetrahydropyrimidin-2-One/Thione-5- [79] Heravi, M.M.; Hashemi, E., Recent applications of the Suzuki reaction in Carboxylates By Microwave Irradiation . Indian J. Chem., Sect B. 1995, 34, total synthesis. Tetrahedron. 2012, 68, 9145-9178. 151-152. [80] Heravi, M.M.; Faghihi, Z., McMurry coupling of aldehydes and ketones for [106] Dandia, A.; Saha, M.; Taneja, H. Synthesis of fluorinated ethyl 4-aryl-6- the formation of heterocyles via olefination. Curr. Org. Chem. 2012, 16, methyl-1,2,3,4-tetrahydropyrimidin-2-one/thione-5-carboxylates under mi- 2097-2123. crowave irradiation . J. Fluorin.e Chem. 1998, 90, 17-21. [81] Heravi, M.M.; Asadi, S.; Lashkariani, B.M., Recent progress in asymmetric [107] Stadler, A.; Kappe, C.O. Microwave-mediated Biginelli reactions revisited. Biginelli reaction. Mol. div. 2013, 17, 389-407. On the nature of rate and yield enhancements. J. Chem. Soc. 2000, 2, 1363- [82] Heravi, M.M.; Hashemi, E.; Azimian, F., Recent developments of the Stille 1368. reaction as a revolutionized method in total synthesis. Tetrahedron. 2014, 70, [108] Pal, R.; Sarkar, T.; Khasnobis, S. Amberlyst-15 in organic synthesis. 7-21. Arkivoc. 2012. 2012, 570-609. [83] Heravi, M.M.; Hashemi, E.; Nazari, N., Negishi coupling: an easy progress [109] Gelbard, G. Organic Synthesis by Catalysis with Ion-Exchange Resins. Ind. for C-C bond construction in total synthesis. Mol. div. 2014, 18, 441-472. Eng. Chem. Res. 2005, 44, 8468-8498. [84] Heravi, M.M.; Hajiabbasi, P., Recent advances in Kumada-Tamao-Corriu [110] Dasgupta, S.; Torok, B. Application of clay catalysts in organic synthesis. a cross-coupling reaction catalyzed by different ligands. Monatsh. Chem. 2012, review. Org. Prep. Proced. Int. 2009, 40, 1-65. 143, 1575-1592. [111] Yadav, J.S.; Reddy, B.V.S.; Reddy, E. J.; Ramalingam, T. Microwave- [85] Heravi, M.M.; Hashemi, E., Recent advances in application of intramolecular assisted efficient synthesis of dihydro pyrimidines: improved high yielding Suzuki cross-coupling in cyclization and heterocyclization. Monatsh. Chem. protocol for the Biginelli reaction. J. Chem. Res (S). 2000, 2000, 354-355. 2012, 143, 861-880 . [112] Gangwar, N.; Kasana, V.K. 3,4-Dihydropyrimidin-2(1H)-one derivatives: [86] Heravi, M.M.; Fazeli, A., Recent advances in the application of the Heck Organocatalyzed microwave assisted synthesis and evaluation of their anti- reaction in the synthesis of heterocyclic compounds. Heterocycles. 2010, 81, oxidant activity. Med. Chem. Res. 2012, 21, 4506-4511. 1979-2026. [113] Shu-Jiang, T.; Fang, F.; Chm-Bao, M.; Hong, J.; Da-Qing, S. One-pot [87] Heravi, M.M.; Sadjadi, S.; Oskoole, H.A.; Bamoharram, F.F. The synthesis Synthesis of 3,4-Dihydropyrimidin-2(1H)-one Using TsOH as a Catalyst of coumarin-3-carboxylic acids and 3-acetyl-coumarin derivatives using het- under Microwave Irradiation. Chin. J. Chem . 2003, 21, 706-709. eropolyacids as heterogeneous and recyclable catalysts. Catal. Commun. [114] Youssef, M.M.; Amin, M.A. Microwave Assisted Synthesis of Some New 2008, 9, 470-474. Thiazolopyrimidine,Thiazolodipyrimidine and [88] Heravi, M.M.; Tajbakhsh, M.; Ahmadi, A.N.; Mohajerani, B. Zeolites. Thiazolopyrimidothiazolopyrimidine Derivatives with Potential Antioxidant Efficient and eco-friendly catalysts for the synthesis of benzimidazoles. and Antimicrobial Activity. Molecules. 2012, 17, 9652-9667. Monatsh. Chem. 2006, 137, 175-179. [115] Suzuki, I.; Suzumura, Y.; Takeda, K. Metal triflimide as a Lewis acid cata- [89] Heravi, M.M.; Rajabzadeh, G.; Bamoharram, F.F.; Seifi, N. An eco-friendly lyst for Biginelli reactions in water. Tetrahedron Lett. 2006, 47, 7861-7864. catalytic route for synthesis of 4-amino-pyrazolo[3,4-d]pyrimidine deriva- [116] Lin, H.; Zhao, Q.; Xu, B.; Wang, X. J. Nafion-H catalyzed cyclocondensa- tives by Keggin heteropolyacids under classical heating and microwave irra- tion reaction for the synthesis of octahydroquinazolinone derivatives. Mol. diation. J. Mol. Catal. A: Chem. 2006. 256, 238-241. Catal. A: Chem. 2007, 268, 221-226. [90] Heravi, M.M; Aghapoor, K; Nooshabadi, M.A; Mojtahedi, M.M. Regioselec- [117] Yu, Y.; Liu, D.; Liu, C.; Luo, G. One-pot synthesis of 3,4-dihydropyrimidin- tive annelation of 3-(prop-2-ynylsulfanyl)-1,2,4-benzotriazine to thia- 2(1,H)-ones using chloroacetic acid as catalyst. Bioorg. Med. Chem. Lett. zolo[2,3-c][1,2,4]benzotriazine. Monatsh. Chem. 1997, 128, 1143-1147. 2007, 17, 3508-3510. [91] (a) Roberts, B.A.; Strauss, C.R. Toward rapid, "green", predictable micro- [118] Polshettiwar, V.; S. Varma, R. Biginelli reaction in aqueous medium: a wave-assisted synthesis. Acc. Chem. Res. 2005, 38, 653-661; (b) De La Hoz, greener and sustainable approach to substituted 3,4-dihydropyrimidin-2(1H)- A.; Diaz-Ortiz, A.; Moreno, A. Microwaves in organic synthesis. Thermal ones. Tetrahedron Lett. 2007, 48, 7343-7346. and non-thermal microwave effects. Chem. Soc. Rev. 2005, 34, 164-178. [119] Singh, V.; Sapehiyia, V.; Srivastava, V.; Kaur, S. ZrO2-pillared clay: An [92] Dömling, A.; Ugi, I. Multicomponent reactions with isocyanides. Angew. efficient catalyst for solventless synthesis of biologically active multifunctio- Chem., Int. Ed. 2000, 39, 3169-3210. nal dihydropyrimidinones. Catal. Commun. 2006, 7, 571-578. [93] Stefani, A.H.; Gatti, M.P. 3,4-Dihydropyrimidin-2(1H)-Ones: Fast Synthesis [120] Dandia, A.; Saha, M.; Taneja, H. Synthesis of fluorinated ethyl 4-aryl-6- Under Microwave Irradiation in Solvent Free Conditions. Synth. Commun. methyl-1,2,3,4- tetrahydropyrimidin-2-one/thione 5carboxylates under mic- 2000, 30, 2165-2173. rowave irradiation. J. Fluorine. Chem. 1998, 90, 17-21. [94] Zhan, H.W.; Wang, J.X.; Wang, X.T. Solvent- and catalyst-free synthesis of [121] Kaur, R.; Bansal, M.; kaur, B.; Mishra, T.; Bhatia, A. Synthesis of 4-aryl- dihydropyrimidinthiones in one-pot under focused microwave irradiation 4,5-dihydro-1H-indeno[1,2-d]pyrimidines by Biginelli condensation and conditions. Chin. Chem. Lett. 2008, 19, 1183-1185. their antibacterial activities. J. Chem. Sci. 2011,123, 443-451. [95] Suresh, A.; Sandhu, J.S. Past, present and future of the Biginelli reaction: a [122] Kappe, C.O.; Kumar, D.; Varma, R. S. Microwave-assisted high-speed critical perspective. Arkivoc. 2011, 2012, 66-133. parallel synthesis of 4-aryl-3,4-dihydropyrimidin-2(1H)-ones using a sol- [96] Harikrishnan, P.S.; Rajesh, S.M.; Perumal, S.; I. Almansour, A. A micro- ventless Biginelli condensation protocol. Synthesis. 1999, 1999, 1799- 1803. wave-mediated catalyst- and solvent-free regioselective Biginelli reaction in [123] Mobinikhaledi, A.; Foroughifar, N.; Jirandehi, H. F. Investigation Of The the synthesis of highly functionalized novel tetrahydropyrimidines. Tetrahe- Effects Of Some Heat Sinks In Microwave-Assisted Synthesis Of Some dron Lett. 2013, 54, 1076-1079. Biginelli Compounds. Phosphorus, Sulfur Silicon Relat. Elem. 2004, 179, [97] Gupta, R.; Jain, A.; Madan, Y.; Menghanib, E.A “One Pot,” Environmentally 2259-2263. Friendly, Multicomponent Synthesis of 2-Amino-5-cyano-4-[(2-aryl)-1H- [124] Chen, Q.; Jiang, L.L, Chen, C.N.; Yang, G.F. The First Example of a Re- indol-3-yl]-6-hydroxypyrimidines and Their Antimicrobial Activity. J. gioselective Biginelli-Like Reaction Based on 3-Alkylthio-5-amino-1,2,4- Heterocycl. Chem. 2014, 51, 1395 -1403. triazole. J. Heterocycl. Chem. 2009, 46, 139-148. [98] Polshettiwar, V.; Nano-organocatalyst: magnetically retrievable ferrite- [125] Shaabani, A. Bazgir, A. Bijanzadeh, H. A reexamination of Biginelli-like anchored glutathione for microwave-assisted Paal-Knorr reaction, aza- multicomponent condensation reaction: One-pot regioselective synthesis of Michael addition, and pyrazole synthesis. Tetrahedron. 2010, 66, 1091-1097. spiro heterobicyclic rings. Mol. Divers. 2004, 8, 141-145. Microwave-Assisted Biginelli Reaction Current Organic Synthesis, 2016, Vol. 13, No. 4 599

[126] Shaabani, A.; Bazgir, A.; Teimouri, F. Ammonium chloride-catalyzed one- [151] Liu, Q.; Pan, N.; Xu, J.; Zhang, W.; Kong, F. Microwave-Assisted and pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones under solvent-free condi- Iodine-Catalyzed Synthesis of Dihydropyrimidin-2-thiones via Biginelli tions. Tetrahedron Lett. 2003, 44, 857-859. Reaction Under Solvent-Free Conditions. Synth Commun. 2013, 43, 139-146. [127] Shaabani, A.; Bazgir, A. Microwave-assisted efficient synthesis of spiro- [152] Zhu, K.; Gao,L.; Taibao Wei, Y.; Liu, L.; Li, W. Synthesis of 4-Aryl- fused heterocycles under solvent-free conditions. Tetrahedron Lett. 2004, 45, substituted 3,4-Dihydropyrimidin-2-ones Under Microwave Irradiation and 2575-2577. Solvent-Free Condition. Asian J. Chem. 2007, 19, 2461-2463. [128] Fang, Z.; Lam, Y. A rapid and convenient synthesis of 5-unsubstituted 3,4- [153] Corma, A.; Garcia, H. Organic reactions catalyzed over solid acids. Catal. dihydropyrimidinones and thiones. Tetrahedron. 2011, 67,1294-1297. Today. 1997, 38, 257-308. [129] Gupta, R.; Jain, A.; Joshi, R.; Jain, M. Eco-friendly Solventless Synthesis of [154] Sharma, R.K.; Rawat, D. An Efficient and Recyclable Silica Based Inor- 5 Indolylpyrimido[4,5-d]pyrimidinones and Their Antimicrobial Activity. ganic-Organic Hybrid Zinc Catalyst for Transesterification of -Ketoesters. Bull. Korean. Chem. Soc. 2011, 32, 899-904. J. Inorg. Organomet. Polym. 2011, 21, 619-626. [130] Savant, M.M.; Pansuriya, A.M.; Bhuva, C.V.; Kapuriya, N.P.; Naliapara, [155] Sharma, R.K.; Sharma, C. Oxidative bromination reaction using Cu2+- per- Y.T. Etidronic Acid: a New and Efficient Catalyst for the Synthesis of Novel fluorophthalocyanine-immobilized silica gel catalyst under mild reaction 5-Nitro-3,4-Dihydropyrimidin-2(1H)-ones. Catal. Lett. 2009, 132, 281-284. conditions. Tetrahedron Lett. 2010, 51, 4415-4418. [131] Kefayati, H.; Mirfarhadi, S.M.; Kazemi-Rad, R. Unexpected One-pot Syn- [156] Sharma, R.K.; Rawat, D. Modified silico-tungstate: an easy and recyclable thesis of Novel 2-Aminopyrimidine-4-ones under Microwave Irradiation. J. catalyst for acetylation of amines under solvent-free condition. J. Inorg. Or- Chin. Chem. Soc. 2015, 62, 107-111. ganomet. Polym. 2010, 20, 698-705. [132] Chen, Fanglei.; Lei, Min.; Lihong, H. Thiamine hydrochloride (VB1)- [157] Sharma, R.K.; Sharma, C. A highly efficient synthesis of oxindoles using a catalyzed one-pot synthesis of (E)-Nbenzylidene-2-phenyl-1H- functionalized silica gel as support for indium(III) acetylacetonate catalyst in benzo[d]imidazo[1,2a]imidazol-3-amine derivatives. Tetrahedron. 2013, 69, an aqueous- acetonitrile medium, J. Mol. Catal. A: Chem. 2010, 332, 53-58. 2954-2960. [158] Sharma, R.K.; Sharma, C., Zirconium(IV)-modified silica gel: preparation, [133] Pawar, O. B.; Chavan, F. R.; Suryawanshi, V. S.; Shinde, V. S.; Shinde, N. characterization and catalytic activity in the synthesis of some biologically D. Thiamine hydrochloride: An efficient catalyst for one-pot synthesis of important molecules. Catal. Commun, 2011, 12, 327-331. quinoxaline derivatives at ambient temperature. J. Chem. Sci. 2013, 125, [159] Sharma, R.K.; Rawat, D. Pant, P. Synthesis, characterization and catalytic 159-163. behaviour of silica supported zinc salicylaldimine complex. J. Macromol. [134] Lei, M.; Ma, L.; Hu, L. Thiamine Hydrochloride-Catalyzed One-Pot Synthe- Sci. Part A Pure Appl. Chem. 2008, 45, 394-399. sis of 1,4-Dihydropyridine Derivatives Under Solvent-Free Conditions. [160] Sharma, R. K.; Rawat, D. Silica immobilized nickel complex: An efficient Synth. Commun. 2011, 41, 1969-1976. and reusable catalyst for microwave-assisted one-pot synthesis of dihydro- [135] Badadhe, P.V.; Chate, A.V.; Hingane, D. G.; Mahajan, P. S.; Chavhan, N.M. pyrimidinones. Inorg. Chem. Commun. 2012, 17, 58-63. Gill, C.H. Microwave-Assisted One-Pot Synthesis of Octahydroquinazolino- [161] Pisani, L.; Prokopcova, H.; Kremsner, J.M.; Kappe, C.O. 5-Aroyl-3,4- ne Derivatives Catalyzed by Thiamine Hydrochloride Under Solvent-free dihydropyrimidin-2-one Library Generation via Automated Sequential and Condition. J. Korean. Chem. Soc. 2011, 55, 936-939. Parallel Microwave-assisted Synthesis Techniques . J. Comb. Chem. 2007, 9, [136] Cheng, Q.F.; Xu, X.Y.; Ruan, M.J.; Yao, H.L.; Yang, X. J. Solvent-Free 415-421. Synthesis of Monastrol Derivatives Catalyzed by NaHSO4 . J. Heterocycl. [162] Saini, A.; Kumar, S.; Sandhu, J.S. Gallium(III) halides catalyzed, microwave Chem. 2010, 47, 624-628. enhanced, synthesis of 3,4-dihydropyrimidin-2-(1H)-ones under solvent free [137] Cheng, Q.F.; Xu, X.Y.; Zhang, H.; Ruan, M. J.; Lin, Q.; Yang, X. J. Biginelli condition. Indian J. Chem. Sec B. 2007, 46B, 1886-1889. Reactions by Steric Control under Solvent-free Conditions. Acta. Chimica. [163] Mukhopadhyay, C.; Dutta, A.; Banik, B. K. Dowex 50W in aqueous Sinica. 2009, 67, 996-1000. medium: Highly efficient biginelli condensation procedure for the synthesis [138] Cheng, Q.; Wang, Q.; Tan, T.; Chen, N.; Shuaib, M. One- Pot Synthesis of of 4-aryl-3,4-dihydropyrimidone Heterocycles. 2007, 71, 181-188. 13-Acetyl- 9-methyl-11-oxo(or thioxo) - 8-oxa-10,12-diazatricyclo [164] K. Banik, B.; Reddy, T.A.; Dattab, A.; Mukhopadhyay, C. Microwave- [7.3.1.02,7] trideca-2,4,6-trienes under Microwave Irradiation. J. Heterocycl. induced bismuth nitrate-catalyzed synthesis of dihydropyrimidones via Bigi- Chem. 2012, 49, 1352- 1356. nelli condensation under solventless conditions. Tetrahedron Lett. 2007, 48, [139] Qingjian, L.L.L.; Xueyan, S. Synthesis of C(5)-(p-Toluoyl substituted)-3,4- 7392-7394. dihydropyrimidinones (or -thiones) via Biginelli Reaction Promoted with [165] (a) Tilstam, U.; Weinmann, H. Trichloroisocyanuric acid: A safe and effi- Microwave Irradiation under Solvent-Free Conditions. Chin. J. Org. Chem. cient oxidant . Org. Process Res. Dev. 2002, 6, 384-393; (b) Ye, J. ; Wang, 2014, 34, 1669-1672. Y.; Liu, R.; Zhang, G.; Zhang, Q.; Chen, J.; Liang, X. A highly enantioselec- [140] Akba, E.; Aslanolu, F. Studies on Reactions of Pyrimidine Compounds. tive phase-transfer catalyzed epoxidation of enones with a mild oxidant, 21. Microwave-Assisted Synthesis of 1,2,3,4-Tetrahydro-2-thioxopyrimidine trichloroisocyanuric acid. Chem. Commun. 2003, 7, 2714- 2715; (c) Ye, J.X.; Derivatives. Phosphorus, Sulfur Silicon Relat. Elem. 2008, 183, 82-89. Wang, Y.C.; Chen, J. P.; Liang, X. Trichloroisocyanuric acid: A convenient [141] Ahn, B.J.; Gang, M. S.; Chae, K.; Oh, Y.; Shin, J.; Chang, W. A microwave- oxidation reagent for phase-transfer catalytic epoxidation of enones under assisted synthesis of 3,4-dihydro-pyrimidin-2-(1H)-ones catalyzed by FeCl3- non-aqueous conditions. Adv. Synth. Catal. 2004, 346, 691-696. (d) Firouza- supported Nanopore Silica under solvent-free conditions. J. Ind. Eng. Chem. badi, H.; Iranpoor, N.; Hazarkhani, H. Trichloroisocyanuric acid as a mild 2008, 14, 401-405. and efficient catalyst for thioacetalization and transthio-acetalization reac- [142] Song, X.; yan-Cai, S.; Ya-Li, L.; XiaoMing, S.; Qing-Xiang, G. Synthesis of tions Synlett. 2001, 2001, 1641- 1643; (e) Xiog, Z. X.; Huang, N.P.; Zhong, 4-Aryl-3 4-dihydropyrimidinones Using Microwave assisted Solventless P. A selective and convenient oxidation of sulfides to sulfoxides with Biginelli Reaction. Chin. J. Chem. 2002, 20, 385-389. trichloroisocyanuric acid . Synth. Commun. 2001, 31, 245- 248; (f) Men- [143] Tu, S.J.; Zhou, J.F.; Cai, P.J.; Wang, H.; Feng, J.C. A Convenient Ferric donca, G. F; Sanseverino, A. M; de Mattos, M. C. S. Trichloroisocyanuric Chloride Catalyzed Synthesis Of 5-Alkoxycarbonyl-4-Aryl-3,4- Dihydro- acid as a cohalogenating reagent: An efficient transformation of alkenes into pyrimidin-2(1H)-Ones Under Microwave Irradiation. Synth. Commun. 2002, chlorohydrins, beta-chloroethers and beta-chloroacetates . Synthesis. 2003, 32, 147-151. 34, 45-48. [144] Mirza-Aghayan, M.; Bolourtchian, M.; Hosseini, M. Microwave-Assisted [166] Bigdeli, M.A.; Heravi, M.M.; Mahdavinia, G.H. Wet cyanuric chloride Efficient Synthesis of Dihydropyrimidines in Solvent-Free Condition. Synth. catalyzed simple and efficient synthesis of 14-aryl or alkyl-14-H- Commun. 2004, 34, 3335-3341. dibenzo[a,j]xanthenes. Catalysis Communications. 2007, 8, 1595-1598. [145] Choudhary, V.R.; Tillu, V.H.; Narkhede, V.S.; Borate, H.B.; Wakharkar, [167] Bigdeli, M.; Jafari, S.; Mahdavinia, G. H. Hazarkhani, H. Trichloroisocyanu- R.D. Microwave assisted solvent-free synthesis of dihydropyrimidinones by ric acid, a new and efficient catalyst for the synthesis of dihydropyrimidi- Biginelli reaction over Si-MCM-41 supported FeCl3 catalyst. Catal. Com- nones. Catal. Commun. 2007, 8, 1641-1644. mun. 2003, 4, 449-453 [168] Kefayati, H.; Fakhriyannejad, M.; Mohammadi, A.A. An Efficient Synthesis [146] Sapkal, S.B.; Shelke, K.F.; Shingate, B.B.; Shingare, M.S. Nickel of New 3,4-Dihydropyrimidin- 2(1H)-ones Incorporating a Phenyl Moiety at Nanoparticles: An Ecofriendly and Reusable Catalyst for the Synthesis of C-5 and C-6 Catalyzed by TMSCl and Co(OAc)2.4H2O. Phosphorus, Sulfur 3,4-Dihydropyrimidine-2(1H)-ones via Biginelli Reaction. Bull. Korean Silicon Relat. Elem. 2009, 184, 1796-1804. Chem. Soc. 2010, 31, 351-354. [169] Misra, A.K.; Agnihotri, G.; Madhusudan, S.K. Microwave induced eco- [147] Stadler, A.; Kappe, C.O. Automated Library Generation Using Sequential friendly solvent-free Biginelli reaction catalyzed by calcium chloride. Indian. Microwave-Assisted Chemistry. Application toward the Biginelli Multicom- J. Chem., Sect B. 2004, 43B, 2018-2020. ponent Condensation. J. Comb. Chem. 2001, 3, 624-630. [170] Heravi, M.M.; Tajbakhsh, M.; Ahmadi, A.N.; Mohajerani, B. Zeolites. [148] Khabazzadeh, H.; Saidi, K .; Sheibani, H. Microwave-assisted synthesis of Efficient and eco-friendly catalysts for the synthesis of benzimidazoles. dihydropyrimidin-2(1H)-ones using graphite supported lanthanum chloride Monatshefte. Fur. Chemie. 2006, 137, 175-179. as a mild and efficient catalyst. Bioorg. Med. Chem. Lett. 2008, 18, 278-280. [171] Heravi, M.M.; Rajabzadeh, G.; Bamoharram, F. F.; Seifi, N. An eco-friendly [149] Madhusudana Reddy M,B.; Ashoka, S.; Anandakumar B,S.; Chandrappa catalytic route for synthesis of 4-amino-pyrazolo[3,4-d]pyrimidine deriva- G.T.; Mohamed A.P. Combustion Derived Nanocrystalline-ZrO2 and Its tives by Keggin heteropolyacids under classical heating and microwave irra- Catalytic Activity for Biginelli Condensation under Microwave Irradiation. diation. J. Mol. Catal. A: Chem. 2006, 256, 238-241. Chin. J. Chem. 2011, 29, 1863—1868. [172] Heravi, M.M.; Montazeri, N.; Rahmizadeh, M.; Bakavoli, M.; [150] Saxena, I.; Borah, D.C.; Sarma, J.C. Three component condensations Ghassemzadeh, M. Zeolite-induced heterocyclization: a superior method of catalyzed by iodine-aluminaforthe synthesis of substituted 3,4- synthesis of condensed imidazoles. J. Chem. Res (s). 2000, 12, 584-585. dihydropyrimidin(1H)-onesunder microwave irradiation and solvent-free conditions. Tetrahedron Lett. 2005, 46, 1159-1160. 600 Current Organic Synthesis, 2016, Vol. 13, No. 4 Heravi et al.

[173] Zendehdel, M.; Mobinikhaledi, A.; Asgari, A. Zeolite an efficient catalyst for [192] Safari, J.; Gandomi-Ravandi, S. Decoration of multi-walled carbon nano- the Biginelli condensation reaction. J Incl Phenom Macrocycl Chem. 2008, tubes with NiO nanoparticles and investigation on their catalytic activity to 60, 353-357. synthesize pyrimidinone heterocycles. J. Iran. Chem. Soc. 2015, 12, 147- [174] Lal, J.; Sharma, M.; Sahu, P.K .; Agarwal, D.D. Multi-component One-Pot 154. Synthesis of 4-Aryl Substituted Dihydropyrimidinones and Mechanistic [193] Kadre, T.; Jetti, S.R.; Bhatewara, A.; Paliwal, P.; Jain, S. Green protocol for Study Under Solvent-Free Conditions Using NiO2 as Heterogeneous Recy- the synthesis of 3,4-Dihydropyrimidin-2(1H)- ones/thiones using TBAB as a clable Green Catalyst. Proc. Natl. Acad. Sci., India, Sect. A Phys. Sci. 2013, catalyst and solvent free condition under microwave irradiation. Arch. Appl. 83, 187-193. Sci. Res. 2012, 4, 988-993. [175] Kapoor, K.K.; Ganai, B.A.; Kumar, S.; Andotra, C.S. Antimony(III) chloride [194] Dadhania, A. N.; Patel, V. K.; Raval, D. K. A facile approach for the synthe- impregnated on alumina — An efficient and economical Lewis acid catalyst sis of 3,4-dihydropyrimidin-2-(1H)-ones using a microwave promoted Bigi- for one-pot synthesis of dihydropyrimidinones under solvent-free conditions. nelli protocol in ionic liquid. J. Chem. Sci. 2012,124, 921-926. Can. J. Chem. 2006, 84, 433-437. [195] Srivastava, V. An Improved Protocol for Dihydropyrimidines Synthesis. [176] Kour, G.; Gupta, M.; Paul, S.; Rajnikant.; K. Gupta, V. SiO2-CuCl2: An Natl. Acad. Sci. Lett. 2013, 36, 493-495. efficient and recyclable heterogeneous catalyst forone-pot synthesis of 3,4- [196] Mirzai, M.; Valizadeh, H. Microwave-Promoted Synthesis Of 3,4- dihydropyrimidin-2(1H)-ones. J. Mol. Catal. A: Chem. 2014, 392, 260-269. Dihydropyrimidin-2(1H)-(Thio) Ones Using Il-Ono As Recyclable Base [177] Safari, J.; Gandomi-Ravandi, S. Titanium dioxide supported on MWCNTs as Catalyst Under Solvent-Free Conditions. Synth. Commun. 2012, 42, 1268- an eco-friendly catalyst in the synthesis of 3,4-dihydropyrimidin-2-(1H)-ones 1277. accelerated under microwave irradiation. New. J. Chem. 2014, 38, 3514- [197] Fu, R.; Yang, Y.; Lai, Wenchen.; Ma, Y.; Chen, Z.; Zhou, J.; Chai, Wen.; 3521. Wang, Q.; Yuan, R. Efficient and green microwave-assisted multicomponent [178] G. Annie, P.S.; Perumal, P.T. Synthesis of Novel 3,4-Dihydropyrimidinones Biginelli reaction for the synthesis of dihydropyrimidinones catalyzed by on Water Soluble Solid Support Catalyzed by Indium Triflate. J. Heterocycl. heteropolyanion-based ionic liquids under solvent-free conditions. Synth. Chem. 2003, 40, 879- 883. Commun. 2015, 45, 467-477. [179] Kumar, D.; Mishra, B. G.; Rao, V. S. An environmentally benign protocol [198] Sharma, N.; Sharma, U. K.; Kumar, R.; Kumar Sinha, R and A. Green and for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones using solid acid cata- recyclable glycine nitrate (GlyNO3) ionic liquid triggered multicomponent lysts under solvent-free conditions. Indian J. Chem., Sect B. 2006, 45B, Biginelli reaction for the efficient synthesis of dihydropyrimidinones . RSC 2325-2329. Adv. 2012, 2, 10648-10651. [180] Roy, D. K.; Bordoloi, M. Synthesis of some substituted 2-oxo- 1,2,3,4- [199] Chavan, S.S.; Sharma, Y.O.; Degani, M.S. Cost-effective ionic liquid for tetrahydropyrimidines (3,4-dihydropyrimidin-2(1H)-ones) and 2-thioxo- environmentally friendly synthesis of 3,4-dihydropyrimidin-2(1H)-ones. 1,2,3,4-tetrahydropyrimidines, catalyzed by tin(II) chloride dihydrate and tin Green. Chem. Lett. Rev. 2009, 2, 175-179. (II) iodide under microwave irradiation. Indian J. Chem., Sect B. 2006, 45B, [200] Singh, V.; Kaur, S.; Sapehiyi, V.; Singh, J.; Kad, G.L. Microwave acceler- 1067-1071. ated preparation of [bmim][HSO4] ionic liquid: an acid catalyst for improved [181] Nemati, F.; Heravi, M.M. Elhampour, A. Magnetic nano-Fe3O4@TiO2/Cu2O synthesis of coumarins. Catal. Commun, 2005, 6, 57-60. core-shell composite: an efficient novel catalyst for the regioselective syn- [201] Singh, V.; Kaur, S.; Ratti, R.; Kad, G. L.; Singh, J. Acidic task specific ionic thesis of 1,2,3-triazoles using a click reaction. RSC Adv, 2015, 5, 45775- liquid catalyzed synthesis of dihydropyrimidinones. Indian J. Chem., Sec B. 45784. 2010, 49, 611-616. [182] Zarnegar, Z.; Safari, J. Magnetic nanoparticles supported imidazolium-based [202] Arfan, A.; Paquin, L.; Bazureau, J. P. Acidic Task-Specific Ionic Liquid as ionic liquids as nanocatalyst in microwave-mediated solvent-free Biginelli Catalyst of Microwave-Assisted Solvent-Free Biginelli Reaction. Russ. J. reaction. J. Nanopart. Res. 2014, 16, 2509. Org. Chem. 2007, 43, 1058-1064. [183] Mazhukina, O.A.; Platonova, A.G.; Fedotova, O.V.; Reshetov, P.V. A Novel [203] Rahman, M.; Majee, A.; Hajra, A. Microwave-Assisted Brønsted Acidic Route For The Preparation Of Chromenoquinazolines. Chem. Heterocycl. Ionic Liquid-Promoted One-Pot Synthesis of Heterobicyclic Dihydro- Compd. 2012, 48, 1368-1370. pyrimidinones by a Three-Component Coupling of Cyclopentanone, Alde- [184] Niralwad, K.S.; Shingate, B.B.; Shingare, M.S. Microwave-assisted one-pot hydes, and Urea. J. Heterocycl. Chem. 2010, 47, 1230-1233. synthesis of octahydroquinazolinone derivatives using ammonium metava- [204] Khrustalev, D.P. Biginelli Reaction under Microwave Irradiation Conditions nadate under solvent-free condition. Tetrahedron Lett. 2010, 51, 3616-3618. without a Solvent. Russ. J. Gen. Chem. 2009, 79, 164-165. [185] Prajapati, D.; Bhuyan, D.; Gohain, M.; Hu, W. Green chemistry approaches [205] Hilp, M. Determination of selenium sulfide using 1,3-dibromo-5,5 to the regioselective synthesis of spiro heterobicyclic rings using iodine as a dimethylhydantoin (DBH) Analytical methods of pharmacopeias with DBH new and efficient catalyst under solvent-free conditions. Mol. Divers. 2011, in respect to environmental and economical concern part 11. J. Pharm. 15, 257-261. Biomed. Anal. 2002, 28, 337-343. [186] Jadhav, S.; Anandgaonker, P.L.; Kulkarni, G .; Gaikwad, Suresh T.; Rajbhoj, [206] Abdollahi-Alibeik, M.; Zaghaghi, Z. 1,3-Dibromo-5,5-dimethylhydantoin as A.S. Microwave-Assisted One-Pot Synthesis of Octahydroquinazolinone a useful reagent for efficient synthesis of 3,4-dihydropyrimidin-2-(1H)-ones Derivatives Using Molybdenum Oxide Nanoparticles in Solvent-Free under solvent-free conditions. Chem. Pap. 2009, 63, 97-101. Condition. J. Clust. Sci. 2014, 25, 1389-1399. [207] Hu, E.H.; Sidler, D.R .; Dolling, U.H. Unprecedented catalytic three compo- [187] Kuraitheerthakumaran, A.; Pazhamalai, S.; Manikandan, H.; Gopalakrishnan, nent one-pot condensation reaction: An efficient synthesis of 5- M.Rapid and efficient one-pot synthesis of octahydroquinazolinone alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones . J. Org. Chem . derivatives using lanthanum oxide under solvent-free condition. J. Saudi. 1998, 63, 3454-3457. Chem. Soc. 2011, 18, 920-924. [208] Kumar, S.; Saini, A.; Sandhu, J. S. Cobalt (II) chloride or manganese (II) [188] Baruah, P.P.; Gadhwal, S.; Prajapati, D.; Sandhu, J.S. The Biginelli conden- chloride or tin (II) chloride promoted one pot synthesis of dihydropyrimidin- sation: A novel and efficient regioselective synthesis of dihydropyrimidin- 2(1H)-ones using microwave irradiation Indian Journal of Chemistry. Indian 2(1H)-ones using lithium bromide. Chem. Lett. 2002, 10, 1038-1039. J. Chem., Sec B. 2005, 44B, 762-767. [189] Safari, J.; Gandomi-Ravandi, S. MnO2-MWCNT nanocomposites as efficient [209] Lin, A.; Ling, Z.; Youguang, Z.; Yunsheng, X.; Jie, M.; Ling, L.; Yi, L. catalyst in the synthesis of Biginelli-type compounds under microwave radia- Microwave Irradiation Assisted Selective Synthesis of 4,6-Diaryl-3,4- dihy- tion. J. Mol. Catal. A: Chem. 2013, 373, 72- 77. dropyrimidin-2(1H)-ones and Pyrimidin-2(1H)-ones. Chin. J. Org. Chem. [190] Liang, B.; Wang, X.; Wanga, J.; Dua, Z. New three-component cycloconden- 2012, 32, 1108-1111. sation reaction: microwave assisted one-pot synthesis of 5-unsubstituted-3,4- [210] Yadav, L.D.S.; Awasthi, C.; Rai, V.K; Rai, A. Biorenewable and mercap- dihydropyrimidin-2(1H)-ones under solvent-free conditions. Tetrahedron. toacetylating building blocks in the Biginelli reaction: synthesis of thiosugar- 2007, 63, 1981-1986. annulated dihydropyrimidines. Tetrahedron Lett. 2007, 48, 4899-4902. [191] Rai, A.; Rai, V.K.; Awasthi, C. Biorenewable Resources in the Biginelli [211] Bussolari, J.C.; McDonnell, P.A. A new substrate for the Biginelli cyclocon- Reaction: Cerium(III)-Catalyzed Synthesis of Novel Iminosugar-Annulated densation: Direct preparation of 5-unsubstituted 3,4-dihydropyrimidin- Perhydropyrimidines. Synlett. 2007, 2007, 1905-1908. 2(1H)-ones from a beta-keto carboxylic acid. J. Org. Chem. 2000. 65, 6777- 6779.

Received: August 23, 2015 Revised: November 18, 2015 Accepted: November 18, 2015