Base-assisted substitution

A practical synthesis of 2-arylamino-6-alkylaminopurines from 2,6-dichloropurine by base-assisted substitution of the 6-chloro substituent with cyclobutylamine followed by a new trimethylsilyl chloride-catalyzed displacement of the 2-chloro group in the intermediate purine with an aromatic amine has been published <06OPRD799>. 

The base-assisted substitution of a-amidoalkyl sulfones by the nitromethane anion has been studied in detail and shown not to involve SET. ... 

The first expeditious solid-phase procedure for the preparation of optically active quaternary r/.v- 3-lactams with an innovative substitution pattern is reported by Gonzalez-Muniz et al. [214]. They describe an operationally simple four-step procedure for the solid-phase synthesis of chiral (3S,4S)-l,3,4,4-tetrasubstituted p-lactams. Taking into account the recurrence of 1,3,4-trisubstituted pattern in bioactive monocyclic (3-lactams, the development of an environment friendly method for the synthesis of this 1,3,4,4-analogues may be of major interest. The key step to the four-member ring formation is the enantioselective phosphazene base-assisted cyclization of the resin-bound /V-(alky 1)-W- [(5)-2-ch Ioropropiony 1 ]... 

The action of a catalytic amount of MeONa on methoxymethyldisilane gives o,a>-dimethoxypermethylpolysilanes or cyclic polysilanes, depending on the reaction time (55b). It was concluded that the mechanism involves a concerted nucleophilic substitution with base-assistance or stepwise substitution by silyl anion a silylene mechanism is ruled out. 

Base-assisted cyclization of l-[3-[hydroxy(substituted methyl)]propargyl]benzotriazoles, which are available from lithiated 1-propargylbenzotriazole and aromatic aldehydes, gives 2-arylfurans (Equation (13)) <93JOC3038>. 

These data can be accommodated by a simultaneous addition of the hydride and proton to form an alcohol that is initially hydrogen bonded to the amine and forms the alkoxide without dissociation of free alcohol or by a transition state with a structure resembling those proposed for the direct, simultaneous transfer of the hydride and proton, but leading to the alkoxide complex directly. After this transfer of the hydride to form an alkoxide, a base-assisted elimination of the alkoxide to form the amide complex is proposed to occur. This step parallels the classic conjugate-base mechanism for dissociative Hgand substitution discussed in Chapter 5. 

It was found that the overall reaction follows the stereochemical pathways of related aminoacetoxylation reactions [87] and consists of a base-assisted syn-nucleopaUadation from paUadium(II) amidato intermediate AF to AG in the first step, and an anti-C-N bond formation in the second step. The first step was found to be rate-determining, while the second one was suggested to involve a paUa-dium(IV) catalyst state AH, which was generated by rapid, irreversible oxidation with iodine(III) [97]. Subsequent intramolecular nucleophiHc substitution through AI furnishes the diamination product and regenerates the paUadium(ll) catalyst (Figure 16.7). 

The mechanism of direct arylation has been studied experimentally and computationally and possible pathways include electrophilic aromatic substitution, Heck-type coupling and concerted metalation-deprotonation (CMD). The reaction pathway is dependent on the substrate and the catalytic system employed,however, most electron-rich (hetero)arenes seem to follow a base-assisted CMD pathway. Two catalytic cycles for the coupling of bromo-benzene and thiophene are shown in Schemes 19.5 and 19.6. Scheme 19.5 depicts a carboxylate-mediated process where C-H activation occurs... 

Electrophilic aromatic substitution is an important reaction that allows the introduction of many different functional groups onto an aromatic ring. A general form of the reaction is given by Equation 15.1, where Ar-H is an aromatic compound, an arene, and represents an electrophile that replaces an H on the ring. This equation is oversimplified because the electrophile is usually generated during the reaction, and a Lewis base assists in the removal of... 

The observation of general base catalysis in some substitutions by amines is additional evidence for the presence of an intermediate. It is particularly significant that plots of the second-order rate constant versns the concentration of added base may be curved. Examples reported early on are in the reactions of 4-nitrophenylphosphate with secondary amines in water [22] and of 2,4-dinitrophe-nyl ether with piperidine [23]. At low concentrations of the base catalyst, the base-assisted second step is rate determining so that increases in catalyst concentration result in rate increases. However, a point is reached at high base concentrations, when the second step is sufficiently rapid, that the first step becomes rate limiting. 

For the hydride elimination in Heck reactions of substituted thiophenes, where the iyn-mechanism is structurally precluded (from the 2-position), three mechanistic pathways can be envisaged (i) isomerization followed by syn-/i-H elimination (ii) a-H elimination, and 1,2-H shift and (iii) anti-P-H elimination. According to DFT calculations, the base-assisted anti-P-H elimination (third pathway) is the most energetically... 

Cosford and coworkers presented a simple microreador setup for enabling multi-step synthesis of bis-substituted 1,2,4-oxadiazoles that required differential and controlled thermal treatments (between 0 and 200 °C) (Scheme 5.24) [34]. A base-assisted reaction between arylnitrile and hydroxylamine hydrochloride at 150°C in the first reactor produced amidoxime, which was quickly cooled to 0 °C before it was mixed with the add chloride. This mixture was then warmed and maintained at room temperature for 2 min in the connected tube before it entered a superheated chip-microreador where the high temperature (200 °C) and pressure (7.5-9.0 bar) accelerated the reaction leading to 40-63% of differently functionalized oxadiazoles within 30 min of total process time. Relativdy inferior yields were obtained from over three-day-long reaction in a sealed tube for the same products. 

Of note, substitution of unsaturated NHC ligands by their saturated analogues, such as 19, doubled the activity but left the branched/linear ratios unaffected." An increase in activity was also observed upon addition of one equivalent of triethyl-amine with no appreciable loss of selectivity. This increase in activity might be attributed to a base-assisted generation of the active catalyst, which is thought to be a rhodium hydride species. Many other rhodium complexes of the general formula [(NHQRh(COD)X] 20 were tested and usually displayed reasonable activity." " ... 

Bromination has been shown not to exhibit a primary kinetic isotope effect in the case of benzene, bromobenzene, toluene, or methoxybenzene. There are several examples of substrates which do show significant isotope effects, including substituted anisoles, JV,iV-dimethylanilines, and 1,3,5-trialkylbenzenes. The observation of isotope effects in highly substituted systems seems to be the result of steric factors that can operate in two ways. There may be resistance to the bromine taking up a position coplanar with adjacent substituents in the aromatization step. This would favor return of the ff-complex to reactants. In addition, the steric bulk of several substituents may hinder solvent or other base from assisting in the proton removal. Either factor would allow deprotonation to become rate-controlling. 

It is clear from the results that there is no kinetic isotope effect when deuterium is substituted for hydrogen in various positions in hydrazobenzene and 1,1 -hydrazonaphthalene. This means that the final removal of hydrogen ions from the aromatic rings (which is assisted either by the solvent or anionic base) in a positively charged intermediate or in a concerted process, is not rate-determining (cf. most electrophilic aromatic substitution reactions47). The product distribution... 

The Suzuki reaction has been successfully used to introduce new C - C bonds into 2-pyridones [75,83,84]. The use of microwave irradiation in transition-metal-catalyzed transformations is reported to decrease reaction times [52]. Still, there is, to our knowledge, only one example where a microwave-assisted Suzuki reaction has been performed on a quinolin-2(lH)-one or any other 2-pyridone containing heterocycle. Glasnov et al. described a Suzuki reaction of 4-chloro-quinolin-2(lff)-one with phenylboronic acid in presence of a palladium-catalyst under microwave irradiation (Scheme 13) [53]. After screening different conditions to improve the conversion and isolated yield of the desired aryl substituted quinolin-2( lff)-one 47, they found that a combination of palladium acetate and triphenylphosphine as catalyst (0.5 mol %), a 3 1 mixture of 1,2-dimethoxyethane (DME) and water as solvent, triethyl-amine as base, and irradiation for 30 min at 150 °C gave the best result. Crucial for the reaction was the temperature and the amount of water in the... 

This transformation can also be carried out under solvent-free conditions in a domestic oven using acidic alumina and ammoniiun acetate, with or without a primary amine, to give 2,4,5-trisubstituted or 1,2,4,5-tetrasubstituted imidazoles, respectively (Scheme 15A) [69]. The automated microwave-assisted synthesis of a library of 2,4,5-triarylimidazoles from the corresponding keto-oxime has been carried out by irradiation at 200 ° C in acetic acid in the presence of ammonium acetate (Scheme 15B) [70]. Under these conditions, thermally induced in situ N - O reduction occurs upon microwave irradiation, to give a diverse set of trisubstituted imidazoles in moderate yield. Parallel synthesis of a 24-membered library of substituted 4(5)-sulfanyl-lff-imidazoles 40 has been achieved by adding an alkyl bromide and base to the reaction of a 2-oxo-thioacetamide, aldehyde and ammonium acetate (Scheme 15C) [71]. Under microwave-assisted conditions, library generation time was dramatically re-... 

Microwave-assisted Heck reaction of (hetero)aryl bromides with N,N-dimethyl-2-[(2-phenylvinyl)oxy]ethanamine, using Herrmann s palladacycle as a precatalyst, yielded the corresponding /3-(hetero)arylated Heck products in a good EjZ selectivity (Scheme 79) [90]. The a/yd-regioselectivity can be explained by the chelation control in the insertion step. This selectivity is better than 10/90 when no severe steric hindrance is introduced in the (hetero)aryl bromides. The process does not require an inert atmosphere. There is evidence that a Pd(0)/Pd(II)- and not Pd(II)/Pd(IV)-based catalytic cycle is involved. Similarly, other j6-amino-substituted vinyl ethers such as... 

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