Yield, phase transfer catalytic reactions

A typical phase transfer catalytic reaction of the liquid/liquid type is the cyanation of an alkyl halide in an organic phase using sodium or potassium cyanide in an aqueous phase. When these phases are stirred and heated together very little reaction occurs. However, addition of a small amount of crown ether (or cryptand) results in the reaction occurring to yield the required nitrile. The crown serves to transport the cyanide ion, as its ion pair with the complexed potassium cation, into the organic phase allowing the reaction to proceed. 

A series of methods has been published for the preparation of dialkyl carbonates from CO2 and carbonate salts using alkyl halides. Carbonic esters can be prepared in a phase-transfer catalytic reaction from primary alkyl halides and a mixture of dry potassium hydrogen carbonate and dry potassium carbonate in non-polar solvents. Yields of dialkyl carbonates obtained are 67-83%. The conversion is ineffective in the absence of the hydrogen carbonate and or a phase-transfer catalyst (PTC) [709]. 

Reaction of organic halides with alkenes catalyzed by palladium compounds (Heck-type reaction) is known to be a useful method for carbon-carbon bond formation at unsubstituted vinyl positions. The first report on the application of microwave methodology to this type of reaction was published by Hallberg et al. in 1996 [86], Recently, the palladium catalyzed Heck coupling reaction induced by microwave irradiation was reported under solventless liquid-liquid phase-transfer catalytic conditions in the presence of potassium carbonate and a small amount of [Pd(PPh3)2Cl2]-TBAB as a catalyst [87]. The arylation of alkenes with aryl iodides proceeded smoothly to afford exclusively trans product in high yields (86-93%) (Eq. 61). 

The yields of arenesulphonic acids (-80%) via the reaction of activated haloarenes with potassium sulphite under phase-transfer catalytic conditions [62, 63] are no better than conventional non-catalytic methods, although reaction conditions are less severe. There is evidence that indicates the initial attack by the sulphite anion is at C-5. Surprisingly, tri-n-butylamine is a better catalyst, producing higher yields (>90%). 

Terminal alkynes are converted in high yield (70-80%) into 1-iodoalkynes by their copper-catalysed reaction with iodine under phase-transfer catalytic conditions... 

The application of phase-transfer catalysis to the Williamson synthesis of ethers has been exploited widely and is far superior to any classical method for the synthesis of aliphatic ethers. Probably the first example of the use of a quaternary ammonium salt to promote a nucleophilic substitution reaction is the formation of a benzyl ether using a stoichiometric amount of tetraethylammonium hydroxide [1]. Starks mentions the potential value of the quaternary ammonium catalyst for Williamson synthesis of ethers [2] and its versatility in the synthesis of methyl ethers and other alkyl ethers was soon established [3-5]. The procedure has considerable advantages over the classical Williamson synthesis both in reaction time and yields and is certainly more convenient than the use of diazomethane for the preparation of methyl ethers. Under liquidrliquid two-phase conditions, tertiary and secondary alcohols react less readily than do primary alcohols, and secondary alkyl halides tend to be ineffective. However, reactions which one might expect to be sterically inhibited are successful under phase-transfer catalytic conditions [e.g. 6]. Microwave irradiation and solidrliquid phase-transfer catalytic conditions reduce reaction times considerably [7]. 

The highly hydrophilic alcohols, pentaerythritol and 2-ethyl-2-hydroxymethyl-propan-l,3-diol, can be converted into their corresponding ethers in good yields under phase-transfer catalytic conditions [12]. Etherification of pentaerythritol tends to yield the trialkoxy derivative and kinetics of the reaction have been shown to be controlled by the solubility of the ammonium salt of the tris-ether in the organic phase and the equilibrium between the tris-ether and its sodium salt [13]. Total etherification of the tetra-ol is attained in good yield when reactive haloalkanes are used, and tetra-rt-octylammonium, in preference to tetra-n-butylammonium, bromide [12, 13]. 

An interesting preparation of alkyl carboxylates in high yield (Table 3.14) from the sodium salt of the carboxylic acids under mild phase-transfer catalytic conditions involves their reaction with alkyl chlorosulphate [50] and has been used with success in the preparation of alkyl esters derived from p-lactam antibiotics. The procedure is also excellent for the production of chloromethyl esters, particularly where the carboxylic acids will not withstand the classical Lewis acid-catalysed procedure using an acid chloride and formaldehyde, or where the use of iodochloromethane [51] results in the formation of the bis(acyloxy)methane. The procedure has been applied with some success to the synthesis of chloromethyl A-protected a-amino carboxylates [52],... 

Dialkyl hydrogen phosphites are alkylated in high yield under basic liquiddiquid phase-transfer catalytic conditions via the Michaelis-Becker reaction to yield dialkyl alkylphosphonates without serious side reactions [16, 17]. 

A -(4-Toluenesulphonyl)sulphilimines, which are useful precursors in the synthesis of oxiranes and in alkylidene transfer reactions, have been prepared under solidiliquid phase-transfer catalytic conditions from Chloramine-T [2], Comparable yields are obtained irrespective of whether the reaction is catalysed by Adogen or by benzyltriethylammonium chloride (Table 4.31). The procedure is an improvement on the liquiddiquid two-phase method [3]. 

Alkylation of 2-hydroxyanilides with 1,2-dibromoethane under soliddiquid phase-transfer catalytic conditions leads to the formation of A-acyl 3,4-dihydro-2//-l,4-benzoxazines (Scheme 5.11) and optimum yields are obtained when a mixed organic phase of acetonitrile dichloromethane (4 6) is used [43]. No reaction occurs in dichloromethane and a complex mixture of products results, when acetonitrile is used alone. 

It has been reported that the reaction of 2-(2-pyridyl)indole with benzene-sulphonyl chloride, under phase-transfer catalytic conditions, yields three products, which have been recorded as being the 3-, 4- and 6-benzenesulphonylindoles [56], or 3-chloro-l-benzenesulphonyl-2-(2-pyridyl)indole, as the major product, with the 1-benezenesulphonyl- and l,3-bis(benzenesulphonyl) derivatives, as the minor products [55]. In the light of the earlier discussion, the latter structural assignments appear to be more likely to be correct. 

Arylamines and hydrazines react with tosyl azide under basic conditions to yield aryl azides [1] and arenes [2], respectively, by an aza-transfer process (Scheme 5.25). Traditionally, the reaction of anilines with tosyl azides requires strong bases, such as alkyl lithiums, but acceptable yields (>50%) have been obtained under liquidiliquid phase-transfer catalytic conditions. Not surprisingly, the best yields are obtained when the aryl ring is substituted by an electron-withdrawing substituent, and the yields for the corresponding reaction with aliphatic amines are generally poor (-20%). Comparison of the catalytic effect of various quaternary ammonium salts showed that tetra-/i-butylammonium bromide produces the best conversion, but differences between the various catalysts were minimal [ 1 ]. 

Although aliphatic azides can be prepared under liquidrliquid phase-transfer catalytic conditions [3-5], they are best obtained directly by the reaction of a haloalkane with sodium azide in the absence of a solvent [e.g. 6, 7]. Iodides and bromides react more readily than chlorides cyclohexyl halides tend to produce cyclohexene as a by-product. Acetonitrile and dichloromethane are the most frequently used solvents, but it should be noted that prolonged contact (>2 weeks) of the azide ion with dichloromethane can produce highly explosive products [8, 9] dibromomethane produces the explosive bisazidomethane in 60% yield after 16 days [8]. 

V-(p-Toluenesulphonyl)sulphilimines have been prepared under solidtliquid phase-transfer catalytic conditions from the reaction of sulphides with Chloramine-T [25] (see Section 4.5). Osmium-catalysed oxyamination of alkenes by Chloramine-T under two-phase conditions is aided by the addition of benzyltriethylammonium chloride. p-Aminoalkanols are obtained in good yields (60-75%) [26]. 

Alkyl and glycosyl isocyanates and isothiocyanates are produced in good yield under phase-transfer catalytic conditions using either conventional soluble catalysts or polymer-supported catalysts [32, 33]. Acyl isothiocyanates are obtained under similar conditions [34]. A-Aryl phosphoramidates are converted via their reaction with carbon disulphide under basic conditions into the corresponding aryl isothiocyanates, when the reaction is catalysed by tetra-n-butylammonium bromide [35]. 

Aroyl cyanides, which have low stability in the presence of water, can be prepared under phase-transfer catalytic conditions in yields >60% [24], A major byproduct of the reaction with benzoyl chloride is a,a-dicyanobenzyl benzoate, resulting from reaction of the benzoyl cyanide with the cyanide ion and subsequent esterification. 

In the main, the original extractive alkylation procedures of the late 1960s, which used stoichiometric amounts of the quaternary ammonium salt, have now been superseded by solid-liquid phase-transfer catalytic processes [e.g. 9-13]. Combined soliddiquid phase-transfer catalysis and microwave irradiation [e.g. 14-17], or ultrasound [13], reduces reaction times while retaining the high yields. Polymer-supported catalysts have also been used [e.g. 18] and it has been noted that not only are such reactions slower but the order in which the reagents are added is important in order to promote diffusion into the polymer. 

Methylenesulphones are more acidic than the simple esters, ketones and cyano compounds and are more reactive with haloalkanes [e.g. 48-57] to yield precursors for the synthesis of aldehydes [53], ketones [53], esters [54] and 1,4-diketones [55] (Scheme 6.4). The early extractive alkylation methods have been superseded by solidtliquid phase-transfer catalytic methods [e.g. 58] and, combined with microwave irradiation, the reaction times are reduced dramatically [59]. The reactions appear to be somewhat sensitive to steric hindrance, as the methylenesulphones tend to be unreactive towards secondary haloalkanes and it has been reported that iodomethylsulphones cannot be dialkylated [49], although mono- and di-chloromethylsulphones are alkylated with no difficulty [48, 60] and methylenesulphones react with dihaloalkanes to yield cycloalkyl sulphones (Table 6.5 and 6.6). When the ratio of dihaloalkane to methylene sulphone is greater than 0.5 1, open chain systems are produced [48, 49]. Vinyl sulphones are obtained from the base-catalysed elimination of the halogen acid from the products of the alkylation of halomethylenesulphones [48]. 

The Ramberg-Backland rearrangement of a-halosulphones to alkenes (Scheme 6.8), for which the choice of base and solvent for optimum yield by classical methods is not trivial, is extremely conveniently conducted under phase-transfer catalytic conditions [66]. The reaction is particularly facile for benzylsulphones and generally gives high yields in relatively short reaction times for a range of systems. In the absence of the catalyst no reaction occurs under the mildly basic conditions. 

The Darzens reaction between aldehydes and ketones with activated halomethyl compounds is an effective route to oxiranes under phase-transfer catalytic conditions and the catalyst has a profound stereochemical control of the substituents (see Chapter 12). The reaction has been conducted in high yield under liquidtliquid and solidrliquid two-phase conditions with a range of halomethyl compounds [e.g. 25-30], Ketones tend to be much slower in their reaction and benzylic ketones undergo alkylation with chloroacetonitrile in preference to the Darzens reaction [25]. 

The reactivity of phenylacetic esters with electron-deficient alkenes is generally fairly poor, even under phase-transfer catalytic conditions. The reaction with cinnamic esters is often accompanied by hydrolysis and the yield of the adduct with chalcone is generally <60% [10]. The activity of the methylene group towards alkylation has been enhanced by the initial complexation of the phenyl ring with chromium tricarbonyl (see Section 6.2), but this procedure has not been applied to the Michael reaction. 

Phase-transfer catalytic conditions provide an extremely powerful alternative to the use of alkali metal hydrides for the synthesis of cyclopropanes via the reaction of dimethyloxosulphonium methylides with electron-deficient alkenes [e.g. 54-56] reaction rates are increased ca. 20-fold, while retaining high yields (86-95%). Dimethylphenacylsulphonium bromide reacts in an analogous manner with vinyl-sulphones [57] and with chalcones [58] and trimethylsulphonium iodide reacts with Schiff bases and hydrazones producing aziridines [59]. 

Compared with the classical procedures, which employ chloroform and dry potassium /ert-butoxide, Makosza s method is several magnitudes superior, in spite of the normally recognized requirements that the dichlorocarbene should be produced under totally anhydrous conditions. Several early reports of the reactions of dichlorocarbene, generated by Makosza s procedure, led to suggestions that the activity of the carbene was considerably greater than that of the classically produced carbenes. This assumption was based on the overall higher yields of dichlorocyclopropanes derived from the reaction with alkenes, and upon the observation that weakly activated alkenes reacted with Makosza carbenes, but not with the classically produced carbenes. A consideration of the mechanism of formation of the carbenes under phase-transfer catalytic conditions exposes the fallacies in the assumptions. 

Difluorocarbene cannot be generated (<1%) under liquiddiquid phase-transfer catalytic conditions [29] owing to the rapid hydrolysis of the carbene at the interface [30], although it has been indicated that it is possible to obtain low yields of 1,1-difluorocyclopropanes under soliddiquid conditions [1]. More successful is the reaction of dibromomethane and dibromodifluoromethane under basic conditions. It is assumed that the initially formed dibromomethyl anion is transported into the organic phase where an equilibrium reaction with dibromodifluoromethane produces the bromodifluoromethyl anion and, subsequently, the difluorocarbene [31]. 

When sodium ethoxide is used in place of sodium hydroxide in the carbonylation reaction of benzyl halides with dicobalt octacarbonyl, ethyl esters are produced instead of the acids [15], Esters are also produced directly from iodoalkanes through their reaction with molybdenum hexacarbonyl in the presence of tetra-/i-butylammo-nium fluoride [16]. Di-iodoalkanes produce lactones [16]. The reaction can be made catalytic in the hexacarbonyl by the addition of methyl formate [16]. t-Butyl arylacetic esters are produced in moderate yield (40-60%) under phase-transfer catalytic conditions in the palladium promoted carbonylation reaction with benzyl chlorides [17]. 

Primary and secondary alcohols are oxidized slowly at low temperatures by benzyltriethylammonium permanganate in dichloromethane primary alcohols produce methylene esters (60-70%), resulting from reaction of the initially formed carboxylate anion with the solvent, with minor amounts of the chloromethyl esters and the carboxylic acids. Secondary alcohols are oxidized (75-95%) to ketones [34] the yields compare favourably with those obtained using potassium permanganate on a solid support. 1,5-Diols are oxidized by potassium permanganate under phase-transfer catalytic conditions to yield 8,8-disubstituted-8-valerolactones [35] (Scheme 10.1). 

Methylbenzenes are oxidized to the corresponding benzoic acids in very high yield under phase-transfer catalytic conditions by sodium hypochlorite in the presence of ruthenium trichloride, which is initially oxidized to ruthenium tetroxide [5]. Absence of either the ruthenium or the quaternary ammonium salt totally inhibits the reaction. 

During these reactions, nitriles are also formed as by-products and it is probable that they result from dehydration of the oxime by the carbon disulphide under the phase-transfer catalytic conditions [9] (see Chapter 9). Under modified conditions, it is possible to carry out a one-pot high-yielding conversion of the nitro compounds into the nitriles [10]. 

Asymmetric induction has been noted [64] when ethyl glycine, protected as its imine by (S)-menthone, is allowed to react with ethyl acrylate under phase-transfer catalytic conditions using tetra-n-butylammonium bromide. An overall yield of 43% was achieved with 46% ee. The stereoselectivity of the reaction was not enhanced when A-benzylquininium or cinchoninium chloride were used and, unlike reactions catalysed by chiral catalysts, the enantiomeric excess increased, when a more polar solvent was used. 

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