PTC agent

Spurred by our desire to avoid use of expensive dipolau aprotic solvents in nucleophilic aromatic substitution reactions, we have developed two alternative phase transfer systems, which operate in non-polar solvents such as toluene, chlorobenzene, or dichlorobenzene. Poleu polymers such as PEG are Inexpensive and stable, albeit somewhat inefficient PTC agents for these reactions. N-Alkyl-N, N -Dialkylaminopyridinium salts have been identified as very efficient PTC agents, which are about 100 times more stable to nucleophiles than Bu NBr. The bis-pyridinium salts of this family of catalysts are extremely effective for phase transfer of dianions such as bis-phenolates. 

In a true biphasic system (i.e. with no PTC agent) with toluene as the organic phase, nitrobenzene and nitrotoluene were reduced with high efficiency with CO + H20 catalyzed by RhCl3.3H20, [Rh CO ] or [ RhCl(l,5-hexadiene) 2] (12 mol aniline/mol Rh.h, at room temperature and 1 bar CO) [364], Other nitroarenes reacted similarly, however, no or only negligible reaction took place with nitroaliphatics. Nitrobenzene is the standard substrate in such reactions, its reduction to aniline was also catalyzed by c/s-[Rh(CO)2(2-picoline)2]PF6 [365] and analogous cis-[Rh(CO)2(amine)2]PF6 complexes immobilized on poly(4-vinylpyridine) [366],... 

The chiral PTC agent 63 (Fig. 7) in combination with CsOH as base, have been used for enantioselective additions of iminoglycinates or a-substituted iminoglycinates onto electrophiles for the synthesis of a-amino acids [16]. Although, initially the system was essayed for the Michael-type addition reaction, some effort also was directed to the enantioselective 1,3-DCR between 3 (R = 2-HOCeH4, R = Me) and methyl acrylate. Unfortunately, the enantioselectivity achieved for the corresponding endo-13 (R = H) was quite low (up to 25% ee) and the chemical yield moderate [58]. 

In these studies (6,7,76)/ the intrinsically slow two-phase reactions have been studied. However, Sharma and coworkers (77) have recently studied the alkaline hydrolysis of a variety of formate esters, which are normally also fast, catalysed by PTC agents, such as cetyltrimethyl-, tricaprylmethyl-ammonium bromide etc. They have carried out experiments with this system in a fully baffled mechanically agitated contactors as well as in a constant area cell. The results are truly remarkable so that the presence of PTC results in an increase in the mass transfer rate ranging from 20 to over 200. 

Wittig and Wittig-Horner reactions, classically requiring strictly anhydrous conditions, can be run much more easily in PTC. In these cases, the intermediate operates as a PTC agent, and the presence of catalysts is therefore not necessary. Typical sulfonium and sulfoxonium ylide reactions have been reproduced, yielding oxiranes and cyclopropanes (Table 19)... 

Oxidizing anionic species, transferred into an organic medium by a PTC agent, normally show higher reactivity than under classical conditions. 

In this chapter, a number of reactions effected in the presence of a PTC agent are described. For the sake of simplicity, the usual abbreviations were used for these catalysts ... 

Aqueous media are often used for reactions with hypervalent iodine compounds. A number of mild and selective methods for arylation of acetylenes by diaryliodonium salts have been published. In neat water the reaction is run at room temperature in a heterogeneous system (PdCl2(PPh3)2, Cul, K2CO3, 10 mol % BU3N) and must be assisted by amine base, which possibly additionally serves as PTC agent. ... 

Pha.se-Tra.nsfer Ca.ta.lysts, Many quaternaries have been used as phase-transfer catalysts. A phase-transfer catalyst (PTC) increases the rate of reaction between reactants in different solvent phases. Usually, water is one phase and a water-iminiscible organic solvent is the other. An extensive amount has been pubHshed on the subject of phase-transfer catalysts (233). Both the industrial appHcations in commercial manufacturing processes (243) and their synthesis (244) have been reviewed. Common quaternaries employed as phase-transfer agents include benzyltriethylammonium chloride [56-37-17, tetrabutylammonium bromide [1643-19-2] tributylmethylammonium chloride [56375-79-2] and hexadecylpyridinium chloride [123-03-5]. 

Direction of Extraction. The "normal" PT process involves the transfer of a reactive agent from a soHd or aqueous environment into a nonpolar organic solvent. But the exact opposite can be executed extraction from an organic phase into an aqueous phase, for example, for changing selectivities. This "inverse PTC" is done relatively rarely. 

Other complexing agents sometimes advocated are cryptates, especially the compound dubbed [2.2.2] (Kryptofix 222) [23978-09-8] (see Chelating agents). Crown ethers were originally advocated for reactions in the presence of soHd reagents (Uquid-soHd PTC). It is now known, however, that onium salts are equally suitable in many cases. 

Solid-liquid PTC conditions in which the nucleophilic salts (organic or mineral) are transferred from the solid state (as they are insoluble) to the organic phase by means of a phase-transfer agent. Most often the organic nucleophilic species can be formed by reaction of their conjugated acids with solid bases (sodium or potassium hydroxides, or potassium carbonate) (Scheme 5.1 path b). Another proposed mechanism suggests that interfacial reactions occur as a result of absorption of the liquid phase on the surface of the solid. 

Functional groups were selectively introduced at the C-2 position of isophorone by epoxide ring-opening by several nucleophiles with active methylene groups. Different behavior was observed depending on the reaction conditions and the nature of the nucleophilic agents [57]. The best experimental systems involved PTC or KF-alumina under solvent-free conditions and MW irradiation (Eq. 37 and Tab. 5.15). 

The choice of the catalyst is an important factor in PTC. Very hydrophilic onium salts such as tetramethylammonium chloride are not particularly active phase transfer agents for nonpolar solvents, as they do not effectively partition themselves into the organic phase. Table 5.2 shows relative reaction rates for anion displacement reactions for a number of common phase transfer agents. From the table it is clear that the activities of phase transfer catalysts are reaction dependent. It is important to pick the best catalyst for the job in hand. The use of onium salts containing both long and very short alkyl chains, such as hexade-cyltrimethylammonium bromide, will promote stable emulsions in some reaction systems, and thus these are poor catalysts. 

Phase transfer catalysis (1,2) has become in recent years a widely used, well-established synthetic technique applied with advantage to a multitude of organic transformations. In addition to a steadily increasing number of reports in the primary literature, there are several reviews (3-6), comprehensive monographs (7-10) and an ACS Audio Course (1 ) which describe the phase transfer process and which provide extensive compilations of phase transfer agents and reaction types. While the list of applications and in many cases the synthetic results are impressive, phase transfer catalysts (PTCs) suffer some of the same disadvantages as more conventional hetero-and homogeneous catalysts — separation and... 

Polyhalogenoalkanes and dihalogenoethanes have been intensively used to prepare, under PTC conditions, poly(pyrazol-l-yl)alkanes (number of pyrazoles = 2,3,4) and l,2-di(pyrazol-l-yl)ethanes (840PP299, 86H(24)2233). The reaction of both nitrogen atoms with a double alkylating agent has been extended to the reaction with cis-1,4-dichlorobutene to afford salt (109) (89KGS497). 

Solid-liquid solvent-free phase-transfer catalysis (PTC) is specific for anionic reactions including base-catalysed isomerisation7. Usually, a catalyst (typically a tetraalky-lammonium salt or a cationic complexing agent) is added to an equimolar mixture of an electrophile and a nucleophile, one of which serves as both a reactant and the... 

When the alcohol possesses no functionality which is susceptible to basic conditions, it may be readily converted into the corresponding methyl ether by treatment with a suitable methylating agent (e.g. methyl iodide or dimethyl sulphate). Typical conditions are described in Expt 5.73, which also include PTC procedures for those alcohols which are water insoluble. Polyols, as for example in the case of carbohydrate derivatives, may also be methylated by this PTC procedure. If the compound to be methylated is base-labile, methylation may be effected by treatment of a mixture of the compound and neutral silica gel in ether solution with diazomethane.75... 

Conversion of phenols into their methyl or ethyl ethers by reaction with the corresponding alkyl sulphates in the presence of aqueous sodium hydroxide affords a method which avoids the use of the more expensive alkyl halides (e.g. the synthesis of methyl 2-naphthyl ether and veratraldehyde, Expt 6.111). Also included in Expt 6.111 is a general procedure for the alkylation of phenols under PTC conditions.38,39 The method is suitable for 2,6-dialkylphenols, naphthols and various functionally substituted phenols. The alkylating agents include dimethyl sulphate, diethyl sulphate, methyl iodide, allyl bromide, epichlorohy-drin, butyl bromide and benzyl chloride. 

Phenylthiosemicarbazones cyclize easily to triazolo derivatives when heated alone or refluxed in high-boiling solvents. Phenylthiosemicarbazones 95 were refluxed in DMF and cyclized into 4,5-dihydro[l,2,4]tria-zolo[3,4-t/][l, 5]benzothiazepine-l(2tf)-thiones (96), which can exist either in the thioamidic or in the iminothiolic form. Infrared spectra showed that the thioamidic form seems to be preferred. By PTC alkylation of 96 with methyl iodide, ethyl chloroformate, or chloroacetic acid, the corresponding -substituted derivatives 97 were obtained (Scheme 28) (91MI1). Many of the compounds were cytotoxic and hence not screened further others were tested as antibacterial, antimycotic, and antiviral agents, but no appreciable activity was observed. 

Besides the glycinate ester derivatives described above, other types of enolate-forming compounds have proved to be useful substrates for enantioselective alkylation reactions in the presence of cinchona alkaloids as chiral PTC catalysts. The Corey group reported the alkylation of enolizable carboxylic acid esters of type 57 in the presence of 25 as organocatalyst [69]. The alkylations furnished the desired a-substituted carboxylate 58 in yields of up to 83% and enantioselectivity up to 98% ee (Scheme 3.23). It should be added that high enantioselectivity in the range 94-98% ee was obtained with a broad variety of alkyl halides as alkylation agents. The product 58c is a versatile intermediate in the synthesis of an optically active tetra-hydropyran. 

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