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Microwave assisted reactionswith gas reagents

ELENA PETRICCIMAURIZIO TADDEI

ABSTRACT

Controlled microwave heating has found many importantapplications in organic synthesis. Almost all kinds ofreactions have been tested using microwaves. Majorsuccesses in carrying out rapid organic transformationshave been achieved when high temperatures are requiredand substrates or reagents do not survive to prolongedheating. On the other hand, very few reports deal withthe use of gas as reagent inside a microwave oven, eventhough many organic transformations that employs gasare carried out under heating and could take advantageof the use of microwaves. This review collects all thecontributions reported until now on microwave-assistedreaction using gas reagents. Except for a few examples,all the reactions selected have been carried out usingcommercially available instruments for synthesis withminor modifications.

INTRODUCTION

The use of microwaves to heat organic reactions hasattracted considerable interest in the last 15 years. Thistechnique allows to reduce the time of chemicaltransformations and consequently the formation of byproducts is reduced, often with improved yields and purityof the products. Practically any kind of transformation hasbeen tested under microwave irradiation, in manyinstances giving better results than conventional heating (1).Although microwave irradiation might seem simply analternative for introducing energy into reactions, the useof this technology has launched a new concept in organicsynthesis because the transmission and absorption ofenergy is different from conventional thermal heating (2-5). Moreover, several reaction types can be carried outsuccessfully under solvent-free conditions, in which casethe energy is not dispersed in the solvents, but directlyabsorbed by the reagents. This last possibility is alsoattractive in offering reduced pollution and low costtogether with the simplicity of processing and handling(6-8). The temperature profiles achieved by microwaveheating cannot easily be duplicated with traditionalheating and allow kinetic control (9). Moreover, severalreactions have been reported in which the chemo-, regio- and stereo-selectivity changed under microwaveconditions in comparison to conventional heating in an oilbath (1, 10). The success of this technique is confirmed bythe number of scientific publications (and patents) thatincreases every year. Amongst different reaction conditions tested inside amicrowave cavity, the use of gas has been scarcelyinvestigated and only in the latest years some manuscriptsappeared in the literature. As most of the reactors formicrowaves are designed to work under the pressure

developed by the solvent under heating, the microwavereaction tube can be considered as a potential smallautoclave that could be used for reaction with gasreagents. However, only few examples of reactions thatuse gases have been tried in microwave-ovens. Probably,the major concern is the safety of using gases (oftenflammable) in a microwave cavity that is know to produce“hot spot” with potential risks of explosion, besides it isnot so trivial to preload some of the commerciallyavailable microwave vessels with gas. From the reportsreviewed in this article, it seems that the techniques couldbe applied safely and that microwave ovens can be usedalso as small lab-top autoclaves with the possibility tospeed up the reactions. The examples reported deal with hydrogenation(including hydrodechlorination), carbonylation,carboxylation and hydroformylation reactions carried outin previously pressurized vessels containing the reactiongas. However, it must be point out that several groupshave also described the use of solid sources of hydrogenor CO to carry out this kind of reactions.

CARBONYLATION REACTIONS

Carbonylation is an important industrial process for thepreparation of a wide range of products includingamides, esters and carboxylic acids (11). It is widely usedin organic synthesis and represents a useful method forthe preparation of a variety of cyclic compounds (12, 13). With the aim of applying microwaves to this chemistry,several approaches have been developed to circumventthe problem of working with gaseous carbon monoxide.Even if thermal decomposition of DMF in highly basicconditions has been employed, Mo(CO)6 was the mostrepresented source of CO applied to the synthesis ofamides, esters and carboxylic acids starting from aryliodides (14-16). Advantages of using Mo(CO)6 as areplacement for gaseous CO include the fact that it issolid and can be used on a small scale in commercialmonomode microwave ovens with no modificationrequired. However, Mo(CO)6 is toxic and its stechiometricuse results in metal waste; this being a particular problemif the reaction is to be scale-up.Leadbeater and Kormos firstly reported microwave-promoted hydroxy- and alkoxycarboxylation of aryl

Scheme 1

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iodides using heavy-walled quartz reaction vessels pre-pressurized with CO in the presence of Pd(OAc)2 ascatalyst (17, 18). The reactor used is a multimodemicrowave (Anton Paar Synthos 3000) equipped with agas-loading interface, allowing the vessels to be pre-pressurized to up to 20 bar prior to placing in themicrowave cavity (19). Different conditions for theconversion of 4-iodoanisole into 4-methoxybenzoic acidand esters have been tested. A CO pressure of 14 bar, 1mol% of Pd(OAc)2, Na2CO3 as base, H2O as the solventand microwave irradiation at 165°C for 20 minutes havebeen selected as the best conditions forhydroxycarbonylation. On the other handalkoxycarbonylation of aryl iodides gives good resultswith lower pressure of CO (10 bar) and with loweramounts of Pd(OAc)2 (0.1 mol%). The methodology hasbeen applied to a wide range of substrates withinteresting results (Table 1).Different aryl iodides were converted to thecorresponding benzoic acids including o-substitutedcompounds. Generally product yields are higher usinghigher catalyst loading, heterocyclic iodide gave onlymoderate yields of carboxylic acid (Table 1, entry 9)because of competitive decomposition as well as difficultyin isolating the acidic product from the reaction mixture.Aryl bromides proved to be completely inactive underthese conditions (Table 1, entry 2). It is interesting to notethat the expected alkoxy products are obtained in higheryield than the corresponding carboxylic acids probablybecause carbon monoxide is significantly more soluble inshort chain alcohols than in water.

HYDROGENATION AND HYDROGENOLYSIS

Hydrogenation and hydrogenolysis are processes ofmajor industrial importance. These transformations oftenrequired long reaction times, high pressures andtemperatures. Hydrogenation and hydrogenolysisreactions carried out inside microwave reactors havebeen usually driven using reagents that generate thehydrogen gas in situ or transfer hydrogen directly to thesubstrate even if H2 is the best hydrogen donor, especially

in terms of atom economy. Hydrogen donors used inmicrowave-assisted hydrogenations included ammoniumformate (20-23), solid supported formats (24, 25),sodium formate (26) or isopropanol (27, 28). Microwave-assisted hydrogenation of olefins, aromaticsand azide, as well as debenzylation have been optimizedin a dedicated reactor constructed by MLS/Milestone(29). The reactor consists of a polyetrafluoroethylene(PTFE) tube which is covered by a polyetheretherketone(PEEK) tube to protect the system from explosions (30).The gas inlet, including a back pressure valve preventingthe back flow of the reaction mixture is on the bottom sideof the microwave oven and outside of the reaction room.A pressure sensor, a temperature sensor, an excesspressure valve (30 bar) and an outlet valve are located onthe top of this tube. With this apparatus, pyperidine-2-carboxylicacid wastrasformedinto (racemic)pipecolicacid usingPtO2 ascatalyst, inEtOH at 25 bar of H2, at 125°C (Scheme 2). Theexpected product was obtained in quantitative yields after1 h instead of 12-24 h required by the classicalprocedure (60 bar, 160 °C).In the same paper, Pd-C has been tested for microwave-assisted debenzylation, and for azide and alkenehydrogenation in high yields (Scheme 3).Another generally applicable method for the introductionof gaseous hydrogen into a sealed reaction system formicrowave assisted organic synthesis has been proposedby CEM (31). The system uses a dedicated glassware thatcan be inserted inside the standard microwavemonomode cavity and allow the contemporaryregistration of internal pressure and temperature.Different products are easily reduced using Pd-C in shortreaction times with moderate temperature between 80°Cand 100°C at a relatively low H2 pressure (3.4 bar). Thechemistry reported in that paper seems to benefit fromuse of simultaneous cooling (Table 2, entry 7-9) inreactions thatrequire higherpower levels toachieve completehydrogenation. Allthe examplesreporteddemonstrate thathydrogenationsunder microwavesled to substantiallyshorter reactiontimes and oftenbetter yields thantraditional heating.A possibleexplanation of thisperformance canbe the possibilitythat microwavesmay interact withthe surface of theheterogeneouscatalyst and createactive “hot sopts”on the catalystsurface.

Scheme 2

Scheme 3

Table 1

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sThe use of an H2 atmosphere has been also successfullyapplied to microwave assisted hydrodechlorination ofchlorobenzenes using Pd/Al2O3 as catalyst (32). Thisreaction was carried out at atmospheric pressure in acontinuous phase microwave reactor (CEM, Model-Voyager) equipped with a pressure pump (for feedingthe substrate), a stirrer and a fiber optic temperaturesensor as shown in scheme 4. The catalyst was packedin a 15 mL quartz U-tube (1.1 cm i.d, 12.5 cm long)placed in the microwave chamber. Chlorobenzene wasfed to the reactor at an adjustable flow rate by thepressure pump along with a controlled flow of hydrogenfrom a cylinder. The reactor was subjected to microwaveirradiation at 100 W power for a given time. Thetemperature of the system was monitored by a fiber optictemperature sensor attached to the U tube reactor andwas maintained constant at a predetermined value byautomatic variation of the MW power. The outlet of thereactor flowed through a pre-cooled collector where theproducts were recovered.It has been observed that hydrochlorination reaction canbe significantly improved by conducting the reactionunder microwave irradiation conditions rather thanconventional heating. Moreover, catalyst poisoning bychlorine ions may be minimized especially at elevatedtemperature which facilitates their relatively easy removal

from the catalyst surface. In terms of energy utilization,the authors measured a significant reduction in the powerconsumption during the microwave reaction comparedwith conventional heating reactions (32).

MICROWAVE-ASSISTED REACTIONS INATMOSPHERE OF ETHYLENE

Ethylene have been used as dienophile in microwaveassisted Diels–Alder reaction of variously functionalized2(1H)-pyrazinones giving cyclic products (Scheme 5)(33). Under conventional heating, these reactions have tobe carried out in an autoclave applying 25-40 bar ofethylene pressure heating to 110°C for several hours oreven days. Some studies on how a pressurised microwaveprotocol can speed up these transformation have beendone using a prototype, bench-top multimode microwavereactor (19, 34). Different reaction conditions andsubstrates have been tested; best results have beenobtained by microwave irradiation of a solution of thepyperazinone 30 in DCB under pressure of ethylene (10bar) at 190°C for 20 minutes and hydrolyzing the adduct31 by treatment with NaOH in THF under microwaveirradiation at 70°C for 5 minutes. A camparison is madewith conventional heating conditions, revealing that noimprovement in the yields wasobserved using microwaveirradiation. However, the use of microwave dramaticallyspeed up the overall process. The nature of the substituentat C3 position of the 2(1H)-pyrazinone also influences therate of the reaction (Table 3).Gaseous ethylene was also used in a microwave-assistedintermolecular ene-yne methatesis (EYM). The synthesis ofenantiomerically enriched 2-(N-1-acetyl-1-arylmethyl)-1,3-butadienes, important building blocks for synthesis ofpotential biologically active compounds, has been

Table 2 Table 3

Scheme 4

Scheme 5

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reported starting from chiral 1-arylpropargyl amides andethylene using an unmodified CEM Discover Unit. Thebest conversion of (R)-33 with ethylene under microwaveirradiation was achieved using 10 mol% of secondgeneration Grubbs’ catalyst, in toluene at 80°C for 20minutes at atmospheric pressure of ethylene (Scheme 6)(35, 36).

SYNTHESIS OF CYCLIC CARBONATES

Carbon dioxide is a renewable resource and can beused as a safe and cheap C1 building block tosynthesize useful organic compounds withoutproducing any co-products (37, 38). The solvent freesynthesis of cyclic carbonates from CO2 and epoxideswas carried out under microwave irradiation withcontrolled temperature and pressure (39). Microwaveassisted reactions were carried out in a IMCR-25003microwave reactor from IDX corporation (40).Different zinc salts, five kind of ionic liquids at differentpressure of CO2 and reaction temperatures wereinvestigated in detail finding that best results can beobtained using ZnPO, Bu4NBr, using 30 bar of CO2,irradiating at 120°C for 15 minutes. A kinetic analysis from the perspective of employingdifferent heating source was attempted by the authorsfinding a first order plots for microwave and thermalactivation as revealed by the values of k calculated forCO2 coupling reaction with PO obtained frommicrowave and oil bath at temperature ranged from70 to 100°C. From the extrapolation of Ea and Avalues it seemed that both parameters weresignificantly influenced by microwave irradiation, anddecreased remarkably compared with that of oil bath.TOF values for the tested catalytic systems werecalculated showing that the catalyst consist of ZnPOand Bu4NBr under microwave irradiation provide thehighest TOFs reported in the literature for this kind ofreaction.

HYDROFORMYLATION

Since its discovery in 1938, hydroformylation of olefinshas evolved into one of the industrially most importantprocesses which rely on homogeneous catalysis (41, 42).Recently we reported a general applicable procedure formicrowave-assisted hydroformylation of terminal olefinsadapting a Discover microwave oven equipped with the80 mL vial for reaction under pressure (43, 44). Several terminal alkenes were submitted to optimised

reaction conditions and all gave high conversion into thelinear aldehydes without notable formation of thebranched isomers with the exception of styrene whichgave a mixture of products respectively (Table 4). Similarresults were observed under standard hydroformylationconditions using Wilkinson catalyst and XANTPHOS.These results suggest that for the hydroformylationreaction no special effects can be ascribed to themicrowaves except for a tremendous increase of thereaction rate. The compatibility of the process withdifferent functional groups is demonstrated by the highyielding transformations carried out successfully (Table 4). Tandem microwave-assisted hydroformylationreductive amination have been also optimizedsubjecting octene and 4-phenyl-1-buten-1ol tohydroformylation in the presence of amines (Scheme9). Different reaction conditions have been testedfinding that using EtOH as solvent is possible to obtainexpected compounds 41a,b,f,g in good yields (70-90percent) starting from secondary ammines. On thecontrary in the presence of primary amines only imineintermediates were isolated in good yields (Table 5).These results show that the hydroformylation reactionruns but the hydrogenation of the intermediate iminedid not occur even changing catalyst, solvent, reactiontemperature and time (45).The possibility to drive tandem hydroformylation andPictet-Spengler’s reaction have been evaluated as well.Intermulecolar Pictet-Spengler’s reaction on indolederivatives gave only intermediate imines. Expectedproduct has been obtained preforming the aldehyde bymicrowave-assisted hydroformylation and successively

Scheme 6

Scheme 8

Table 4

Scheme 7

Table 5

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ELENA PETRICCI, MAURIZIO TADDEI

Università degli Studi di SienaDipartimento Farmaco Chimico TecnologicoVia A. Moro 253100 Siena, Italy

irradiating in the presence of the indol compound at100°C (Scheme 10) (45). On the other hand,Intramolecular tandem hydroformylation and Pictet-Spengler cyclisation was successful applied to botharomatic and protected indol compounds giving tricyclicderivatives in accettable yields (Scheme 11) (45).

CONCLUSIONS

This article has collected the very few examples ofreaction performed inside a microwave cavitywith gases as reagents. Despite potential risk,the reports do not register any accidentoccurred during experiments. Great care mustbe done especially to prevent entrance ofoxygen in the vessel. However, microwavedemonstrates to be able to accelerate alsoreactions with gases, opening new possibility todevelop new reactions and procedure. We hopethat this short review will inspire to moresuccessful research in this area and that the useof gas in microwave chemistry both in batchthan in continuous flow could replace conventionalautoclave chemistry in the future.

ACKNOWLEDGMENT

The authors thank CEM Italia s.r.l. and Siena BiotechS.p.A. for financial support.

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44. www.cem.com/synthesis/index.asp45. Unpublished results from our laboratory.

Scheme 9

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Scheme 11