Open vessel microwave synthesis

Nyutu, E.K., Chen, C., Sithambaram, S., Crisostomo, V.M.B. and Suib, S.L. (2008) Systematic control of particle size in rapid open-vessel microwave synthesis of K-OMS-2 nanofibers. Journal of Physical Chemistry C, 112, 6786-6793. 

Another example of the necessity to perform open-vessel microwave synthesis in specific cases is outlined in Scheme 4.11, namely the formation of 4-hydroxyquino-lin-2-(lH)-ones from anilines and malonic esters. The corresponding conventional... 

NMP), or ethylene glycol have frequently been used in open-vessel microwave synthesis [16, 17]. 

One of the most common approaches to pyrrole synthesis is the Paal-Knorr reaction, in which 1,4-dicarbonyl compounds are converted to pyrroles by acid-mediated dehydrative cyclization in the presence of a primary amine. The group of Taddei has reported a microwave-assisted variation of the Paal-Knorr procedure, whereby a small array of tetrasubstituted pyrroles was obtained (Scheme 6.181) [342], The pyrroles were effectively synthesized by heating a solution of the appropriate 1,4-dicarbonyl compound in the presence of 5 equivalents of the primary amine in acetic acid at 180 °C for 3 min. The same result was obtained by heating an identical mixture under open-vessel microwave conditions (reflux) for 5 min. Interestingly, the authors were unable to achieve meaningful product yields when attempting to carry out the same transformation by oil-bath heating. 

The ten membered N-heterocycles have also attracted a lot of interest due to their structural appearance with various biologically interesting molecules like the alkaloid Dysazecine (Aladesanmi et al., 1983), Protopine (Xiao et al., 2008) (a potent antimalarial lead compound) as well as the nanomolar dopamine receptor antagonist LE300 (Mohr et al., 2006). Dunkel et al. (2010) reported a straight forward, microwave-assisted synthesis of tribenzo[b,d,f]- and pyridazino[d]dibenzo[b,f] azecines, employing the tert-amino effect. The desired compounds were furnished via an open-vessel microwave-assisted cyclization of corresponding triphenyl intermediates at 100-200 °C for 2-150 min. 

Benzothiazepines belong to the three classes of calcium channel blockers which are important cardiovascular drugs in the management of angina pectoris and hypertension. A diastereoselective one-pot synthesis of the trans-and ds-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-l,5-benzothiazepin-4-one nucleus, a key intermediate in the preparation of the calcium channel blocker Diltiazem, was carried out under microwave irradiation in an open vessel (Scheme 25). Control of the diastereoselectivity was achieved by vary-... 

Fig. 14 Microwave-assisted synthesis of pyrazoles and isoxazoles on cellulose. Reagents and conditions a Camphorsulfonic acid, DMF, MW 80 °C, 15 min, open vessel b NH2XH, MW 82 °C, 15 min, open vessel. X = N,0 Y = NH, NEt, O R = Me, i-Pr, BUCH2, PhCH2, Et(Ph)CH, R = alkyl, aUyl, and aryl groups...

Fig. 15 Microwave-assisted isoxazole synthesis via on resin [3-1-2] cycioaddition. Reagents and conditions a 1-nitrobutane, DMTMM, DMAP, MeCN, THE, MW 80 °C, 5 min, open vessel b TEA CH2CI2 (5 95), rt, 20 min...

Fig. 19 Synthesis and cyclative cleavage of 2,4,6-trisubstituted pyrimidines using microwave-assisted solid-phase protocol. Reagents and conditions a DMF, camphorsul-phonic acid, MW 80 °C, 30 min, open vessel b EtONa, EtOH/THF (4/1), MW 130 °C, to min, closed vessel. Y = O, NEt2 R = Me, i-Pr R = Et R" = H, alkyl, cycloalkyl, aryl, benzyl R" = H, Me, Et...

Alternatively, microwave-assisted synthesis has been carried out using standard organic solvents under open-vessel conditions. If solvents are heated by microwave irradiation at atmospheric pressure in an open vessel, the boiling point of the solvent typically limits the reaction temperature that can be achieved. In order to none-... 

In modern microwave synthesis, a variety of different processing techniques can be utilized, aided by the availability of diverse types of dedicated microwave reactors. While in the past much interest was focused on, for example, solvent-free reactions under open-vessel conditions [1], it appears that nowadays most of the published examples in the area of controlled microwave-assisted organic synthesis (MAOS) involve the use of organic solvents under sealed-vessel conditions [2] (see Chapters 6 and 7). Despite this fact, a brief summary of alternative processing techniques is presented in the following sections. 

An example of solid-phase microwave synthesis where the use of open-vessel technology is essential is shown in Scheme 4.10. The transesterification of /3-keto esters with a supported alcohol (Wang resin) is carried out in 1,2-dichlorobenzene (DCB) as a solvent under controlled microwave heating conditions [22], The temperature is kept constant at 170 °C, ca. 10 degrees below the boiling point of the solvent, thereby allowing safe processing in the microwave cavity. In order to achieve full conversion to the desired resin-bound /3-keto ester, it is essential that the methanol formed can be removed from the equilibrium [22]. 

In 2001, researchers at Wyeth-Ayerst described the preparation of RFI-641, a potent and selective inhibitor of the respiratory syncytial virus (RSV) [251], The final key step in the synthesis involved the coupling of a diaminobiphenyl with two equivalents of a chlorotriazine derivative under microwave irradiation (Scheme 6.123). The reaction was carried out in dimethyl sulfoxide/phosphate buffer/sodium hydroxide in an open vessel at 105 °C. This protocol provided RFI-641 in 10% isolated yield. 

Toma and coworkers have described the solvent-free synthesis of salicylanilides from phenyl salicylate or phenyl 4-methoxysalicylate and substituted anilines (Scheme 6.155) [302]. By exposing an equimolar mixture of the ester and the amine to microwave irradiation at 150-220 °C for 4—8 min under open-vessel conditions, good yields of the corresponding salicylanilides were obtained. This synthesis was carried out on a multigram scale (0.1 mol). 

In Scheme 6.230, the multistep synthesis of 2,3-dihydro-4-pyridones is highlighted [411]. The pathway described by Panunzio and coworkers starts from a dioxin-4-one precursor, which is readed with 2 equivalents of benzyl alcohol under solvent-free microwave conditions to furnish the corresponding /1-diketo benzyl esters. Subsequent treatment with 1 equivalent of N,N-dimethylformamide dimethyl acetal (DMFDMA), again under solvent-free conditions, produces an enamine, which is then cyclized with an amine building block (1.1 equivalents) to produce the desired 4-pyridinone produds. All microwave protocols were conducted under open-vessel conditions using power control. 

The Friedlander reaction is the acid- or base-catalyzed condensation of an ortho-acylaniline with an enolizable aldehyde or ketone. Henichart and coworkers have described microwave-assisted Friedlander reactions for the synthesis of indoli-zino[l,2-b]quinolincs, which constitute the heterocyclic core of camptothecin-type antitumor agents (Scheme 6.238) [421], The process involved the condensation of ortho-aminobenzaldehydcs (or imines) with tetrahydroindolizinediones to form the quinoline structures. Employing 1.25 equivalents of the aldehyde or imine component in acetic acid as solvent provided the desired target compounds in 57-91% yield within 15 min. These transformations were carried out under open-vessel conditions at the reflux temperature of the acetic acid solvent. 

These examples of Knoevenagel condensations illustrated that reaction times could be reduced from 1-2 days to 30-60 min by employing parallel microwave-promoted synthesis in open vessels, without affecting the purity of the resin-bound products. 

A method for microwave-assisted transesterifications has been described by Van-den Eynde and Rutot [73], The authors investigated the microwave-mediated deriva-tization of poly(styrene-co-allyl alcohol) as a key step in the polymer-assisted synthesis of heterocycles. Several /i-ketoesters were employed in this procedure and multigram quantities of products were obtained when neat mixtures of the reagents in open vessels were subjected to microwave irradiation utilizing a domestic micro-wave oven (Scheme 7.65). The successful derivatization of the polymer was confirmed by IR, 1H NMR, and 13C NMR spectroscopic analyses. The soluble supports... 

Numerous reactions in organic synthesis can be achieved under solid-liquid PTC and with microwave irradiation in the absence of solvent, generally under normal pressure in open vessels. Increased amounts of reactants can be used to ensure better compatibility between the in-depth penetrability of materials and the radiation wavelength. 

In microwave-assisted synthesis, a homogeneous mixture is preferred to obtain a uniform heating pattern. For this reason, silica gel is used for solvent-free (open-vessel) reactions or, in sealed containers, dipolar solvents of the DMSO type. Welton (1999), in a review, recommends ionic liquids as novel alternatives to the dipolar solvents. Ionic liquids are environmentally friendly and recyclable. They have excellent dielectric properties and absorb microwave irradiation in a very effective manner. They exhibit a very low vapor pressure that is not seriously enhanced during microwave heating. This makes the process not so dangerous as compared to conventional dipolar solvents. The polar participants of organic ion-radical reactions are perfectly soluble in polar ionic liquids. 

Quiroga and co-workers55 have described a facile three-component microwave assisted, one-pot synthesis of 5-aryl-6-cyano-7-phenyl-5,8-dihydropyrido[2,3-d]pyrimidin-4 (3/f)-ones suitable also in a combinatorial set-up, Scheme 5.36. Equimolar quantities of the starting compounds were placed in open vessels and irradiated in a domestic microwave oven for 15-20 min at 600 W. When irradiation was complete, the resulting solid was treated with ethanol and filtered to give the products in 70-75% yield. Under reflux in ethanol, a much longer reaction time (40-48 h) was required to provide the product in very modest yields (21-25%). 

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