Aromatic multicomponent reaction

An interesting observation was made when o-aminophenol (2-411) was employed in the reaction with carbethoxypiperidone 2-410 and acrolein (Scheme 2.98). In this case, the spirocydic scaffold 2-412 was exclusively formed in 67% yield. This result can be explained by invoking a stereoelectronic control due to the presence of the aromatic ring which prevents the formation of the corresponding fused tetracyclic isomer. Moreover, both reactive sites can simultaneously be functionalized using 2-amino-1,3-propanediol (2-413) as partner in the multicomponent reaction. This leads to the formation of three new cycles... 

One-pot condensation of an aromatic aldehyde, urea, and ethyl acetoacetate in the acidic ethanolic solution and expansion of such a condensation thereof. It belongs to a class of transformations called multicomponent reactions (MCRs). 

The most common methods suitable for the synthesis of different azolium compounds will be discussed here. Two routes are particularly useful for the preparation of the imidazolium salts (1) substitution reactions at the nitrogen atoms of imidazole [25] and (2) multicomponent reactions for the generation of an Af,Af -substituted heterocycle which are particularly useful for the synthesis of imidazolium salts bearing aromatic, very bulky, or particularly reactive N,N -sub-stituents (Fig. 3a,b) [26]. Both methods offer the opportunity to produce unsym-metrically substituted imidazolium salts of type 1 either by stepwise alkylation of imidazole or by the synthesis of an W-arylated imidazole derivative followed by 77 -alkylation [27]. Nevertheless, the method of choice for the preparation of the imidazolium salts 1 is the 77,77 -substitution of imidazole. Several other methods for the preparation of imidazolium salts with previously unattainable substitution patterns have also been described [28, 29]. 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

In view of the complicated reaction kinetics of multicomponent systems, it was not clear whether or not the diffusional effects would also affect the relative rate of conversion of feed molecules in a mixture. To answer this question we studied the hydrocracking of three multicomponent systems. The first was a C5-C8 mixture, a C5 360° C boiling range midcontinent reformate which contained 12.5 wt % n-paraffins including 4.2% n-pentane, 4.3% n-hexane, 2.9% n-heptane, l.l%n-octane, and <1% C9+ n-paraffins, with the remainder isoparaffins and aromatics. The reaction was carried out at 400 psig, 2 H2/HC, 2 LHSV, and 800°F. Secondly, a Cg-Cie mixture... 

Acetamido ketones have been prepared in a multicomponent reaction from aromatic aldehydes, enolizable ketones (acetophenone and propiophenone), and acetyl chloride in acetonitrile over Nafion-H1002 [Eq. (5.363)]. High yields are achieved under mild conditions and the catalyst proved to be recyclable. 

Unlike amidines, the multicomponent reaction of a,(3-unsaturated ketones 96 (aliphatic [94] or aromatic [95, 96]) with carbonyl compounds 97 and ammonia, which are the synthetic precursors of amidines, yielded 1,2,5,6-tetrahydropyrimidines 98 instead of dihydroheterocycles. When R3 is not the same as R4 tetrahydropyrimidines 98 were mixtures of diastereomers A and B, in which the relative configurations of stereogenic centers were also established [95, 96]. In contrast to conventional mechanical shaking requiring about 48 h [95], sonicated reactions were completed within 90 min at room temperature and provided the target heterocycles in high yields and purities [96]. Ultrasonic irradiation also significantly expanded the possibilities of such three-component reactions (Scheme 3.29). 

For 3-aryl-5-aminopyrazoles 222 the direction of the multicomponent reaction with cyclic P-diketones and aromatic aldehydes is not so unequivocal. Quiroga et al. [190] found that during refluxing of these starting materials in ethanol, the reaction products were only derivatives of pyrazoloquinoline 227,... 

A regioselective synthesis of pyrazoloquinolines 225 by the multicomponent reaction of 3-aryl-5-aminopyrazole 222 with 1,3-diketones and aromatic aldehydes in ethanol in the presence of Et3N under microwave irradiation at 150°C (Scheme 3.62, reaction i) was described in [193,194]. In the presence of a strong base such as EtONa (KOH), the three-component treatment proceeded via a different pathway and led to novel and unusual reaction products—quinolizi-nones 226 (Scheme 3.62, reaction ii) [193]. The formation of only one diaster-eomeric pair from two possible ones with trans relative configuration of the... 

Chebanov et al. [202] noted that condensation of the unsaturated acids 236 with 5-aminopyrazoles 220-222 never yielded isomers with opposite location of the aryl and carboxyl groups on the pyridine or pyrimidine rings, respectively. In the case of the multicomponent reaction of aminopyrazoles 220-222 with pyruvic acid 239 and aromatic aldehydes a different direction was observed. Refluxing of the starting materials in acetic acid led exclusively to pyrazolo[3,4-Z ]pyridine-4-carboxylic acids 249-251 instead of the anticipated carboxylic acids 243-248 (Scheme 3.69). The three-component procedures led only to the formation of heteroaromatized compounds even under a nitrogen atmosphere [202]. 

These disadvantages were avoided in the procedure proposed in [187]. The authors synthesized target pyrimido[4,5-Z>]quinolines in 90-98% yields and high purity (without any crystallization) by the multicomponent reaction of 6-ami-nouracil derivatives, aromatic aldehydes and cyclic 1,3-diketones under micro-wave irradiation in ethanol with Et3N as the catalyst. 

Microwave-assisted organic synthesis may also be used for carrying out the multicomponent reactions of ketones and 1,2-diamines [20, 21, 92, 100]. For example, the three-component reaction of o-PDA 1 with acetoacetic acid ethyl ester 83 and a series of aromatic and heteroaromatic aldehydes 84 proceeds under microwave irradiation with very high yields of diazepines 85 (up to 95%) [100]. Reaction of 2 equiv of cyclohexanone 86 with o-PDA 1 was also realized in a microwave field on a basic alumina surface in 4 min [92] (Scheme 4.27). 

Procedure for multicomponent reaction Polymer-bound thiouronium salt 111 was prepared under standard conditions [132] by reacting thiourea with Merrifield resin in DMF at 80 °C. Resin 111 (0.8 mmol was treated with ethyl cyanoacetate (8 mmol) and various substituted aromatic aldehydes (8 mmol) and K2CO3 (10 mmol) in DMF at 80 °C for 24 h, under shaking in an Advanced Chemtech (Advanced ChemTech, Inc., LouisviUe, KY,... 

The reactions that have been illustrated should give an idea of the potential of a methodology which combines the criterion of multicomponent reactions with that of selectivity, usually difficult to reconcile. One key feature is the use of an olefin as a scaffold for the construction of a palladacycle that is able to direct aromatic functionalization selectively and can be easily removed at the end of the process. Another important feature is the use of different oxidation states of palladium to control reactivity. The combination of an inorganic catalyst (palladium) with an organic one (norbornene) leads to a variety of syntheses in one-pot reactions, which represent only the beginning of what may be expected to be a very fruitful development. Needless to say, any advancement in this area requires a thorough study of the reactivity of the organometallic species involved. 

A library of pyrazoloquinolizinones has been prepared via a multicomponent reaction between 5-aminopyrazoles, cyclic 1,3-diketones, and aromatic aldehydes. Under the strongly basic conditions used, the initial product formed undergoes a subsequent ring-opening/recyclization process to give the pyrazoloquinolizinones (Scheme 4.14). 

An aryne multicomponent reaction involving isoquinoline and 5-bromo-1-methylisatin resulted in spirooxazino isoquinolines (Scheme 66).The reaction occurs with a number of iV-substituted isatins. Quinoline can replace the isoquinoline as well. Carbonyls other than the isatins can trap the anion as well. A variety of aromatic, aliphatic, and heteroaromatic aldehydes can function as the electrophile. When pyridine replaces isoquinoUne as the nucleophilic trap, the reaction forms an oxindole but not an oxazino pyridine derivative (14SL608). 

An efficient approach to fused pyrimidine derivatives 154 was developed by Singh and coworkers [85]. This multicomponent reaction was performed with 69, 6-amino-l,3-dimethyluracil 153, and 33a, and promoted by p-TsOH in water (Scheme 12.61). The protocol avoided the use of expensive catalysts, toxic solvents, and chromatographic separation. Both aromatic and aliphatic aldehydes could be utilized for this reaction. 

The synthesis of 2-aminochromes by Vaddula and Gonzalez [77] is an example of a multicomponent reaction performed within a single pass of a continuous-flow ThalesNano H-Cube Pro reactor. Using this reactor the authors demonstrated that various chromene derivatives could be obtained with a simple and rapid one-step continuous-flow synthesis route from the reaction of aromatic aldehydes, a-cyano-methylene compounds, and naphthols. The efficient, safer, faster, and modular reaction proceeded to completion with very high yields and residence times of less than 2 min at a slightly elevated pressure of approximately 25 bar. 

Neuenfeldt et al. (2011) used ultrasonic power to promote the synthesis of thi-azolidinones (91). 2-Aryl-3-(piperonylmethyl)-l,3-thiazolidin-4-ones (91) were obtained in good yields (60%-92%) from the multicomponent reaction of aromatic... 

Imidazo[l,2-(j]pyridines can be prepared from a multicomponent reaction of alcohols, 2-aminopyridines, and isocyanides (Scheme 53) (13TL95). The alcohols are oxidized by DMSO and propylphosphonic anhydride, which also catalyzes the nucleophilic addition with isocyanides. Aromatic alcohols with electron-donating and electron-withdrawing groups can provide the desired... 

Recent significant advance in the area of the transition metal-mediated aromatic ring construction reactions enables the construction of substituted benzenoid aromatic rings with efficient and convenient manners [1], These aromatic ring constrnction reactions provide promising new routes to the complex benzenoid aromatic compounds. In this chapter, I snmmarize the intermolecular multicomponent reactions and the intramolecnlar single-component reactions, which are able to construct benzenoid aromatic rings. 

As the intermolecular multicomponent reactions, three-component cycloaddition reactions (21.2 [2+2-1-2] cycloaddition and 21.3 [3+2+1] cycloaddition) and two-component cycloaddition reactions (21.4 [4+2] cycloaddition) are described. As the intramolecnlar single-component reactions, cycloaromatization reactions (21.5 intramolecular hydroarylation of alkynes and cychzation via transition metal vinybdenes) are described. Aromatic ring constrnction reactions involving aryne reactions (Chapter 12), rearrangement reactions (Chapters 16 and 18), metathesis reactions (Chapter 17), and coupling reactions (Chapters 19 and 20) are described in these different chapters. 

Recently, in 2013, Lin and coworkers reported a one-pot multicomponent reaction of aromatic aldehydes 4, anilines 51, and p-ketoesters 91 catalyzed by the spirocyclic phosphoric... 

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