Dihaloalkanes, alkylation with

Whereas alkylation of activated methylene systems by classical methods produces a mixture of mono- and dialkylated products, with the latter frequently predominating, phase-transfer catalytic procedures permit better control and it is possible to obtain only the monoalkylated derivatives. Extended reaction times or more vigorous conditions with an excess of the alkylating agent lead to dialkylated products or, with dihaloalkanes, carbocyclic compounds as the technique mimics dilute concentration conditions, e.g. the resonance stabilized cyclopentadienyl anion, generated under solidiliquid two-phase conditions, or under liquiddiquid conditions, reacts with 1,2-dihaloethanes to form spiro[2,4]hepta-4,6-diene (70-85%) [1-3]. Reaction with dichloromethane produces bis(cyclopenta-2,4-dien-l-yl)methane (60%) [4],... 

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 The early extractive alkylation methods have been superseded by solidtliquid phase-transfer catalytic methods [e.g. 58] and, combined with microwave irradiation, the reaction times are reduced dramatically [59].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]. 

Selected examples of the alkylation of methylenesulphones with dihaloalkanes... 

BOC-protected 2-aminopyridines undergo o/t, ti-alkylation with a,o -dihaloalkanes followed by an in situ cyclization to give bicyclic adducts in excellent yield (Scheme 24) <2004TL1721>. 

A systematic study of the alkylation of benzene with optically active 1,2-, 1,3-, 1,4-, and 1,5-dihaloalkanes showed that the stereochemical outcome depends on the halogens and the chain length.142 Retention of configuration in alkylation with (S)-1,2-dichloropropane was explained by invoking double inversion and the involvement of a bridged cation such as 27. (S)-l-Bromo-2-chloropropane, in contrast,... 

An important application of alkylation with di- and polyhalides is cyclialkylative ring formation. Of different a,co-dihaloalkanes studied, 1,4-dichlorobutane was shown to react at exceptional rate and with least rearrangement.143 This was rationalized in terms of participation by the cyclic chloronium ion 29 formed with anchimeric assistance by the second chlorine atom in the molecule ... 

The same reactions were also conducted with alkyl bromides 145 and 146, to check if these reactions were also as selective as the ones with dihaloalkanes (Scheme 17). 

A number of distonic halonium-based dications are also known and their properties are often superelectrophilic.81 The chemistiy of halonium ions was thoroughly reviewed, thus only a few aspects are described here. Alkylation of dihaloalkanes with methyl and ethyl fluoroantimonate (CHsF-SbFs-SCF and CHsCE F-SbFs-SCh) gives the monoalkylated halonium ions and/or the dialkylated dihalonium ions, depending on the reaction conditions. Iodine shows an unusual ability to stabilize positive... 

The dianion 43, prepared from 2,4-diphenylquinazoline with sodium in tetrahydrofuran, was alkylated with l,co-dihaloalkanes (m = 2, 3) and gave the pyrrolo(l,2-c]quinazoline 44 ( = 0) and the pyrido[l,2-c]quinazoline 44 (n= 1), respectively. Attempts to fuse a six-membered ring to the quinazoline ring by the use of 1,4-dibromobutane were less satisfactory. 

Friedel-Crafts alkylations with higher dihaloalkanes generally give a mixture of products derived from processes such as isomerization, multiple addition and dehydrogenation (caused by AICI3), as seen from the examples shown in equations (73) and (74). ... 

Diketones. These reagents are acyl anion equivalents. Thus, alkylation with 1, (jo-dihaloalkanes followed by acid hydrolysis leads to diketones. 

Alkylation. Allyl phenyl sulfide undergoes alkylation using DME-activated sodamide. The process is adaptable to a synthesis of phenyl 1-vinylcycloalkyl sulfides by a twofold alkylation with l,(n-dihaloalkanes. 

Alkylation of arylacetonitriles proceeds efficiently with a variety of substituted haloalkanes such as haloethers, esters, and nitriles of haloalkanoic acids, haloamines, etc. The reaction with dihaloalkanes can give cyclic and chain products ... 

Another C—H activation strategy for lactone synthesis involves the ring closure of benzoic acids with dihaloalkanes [111]. Yu and coworkers recently developed a directed C—H functionalization/alkylation approach using Pd catalysts. Direct access to phthalides and 3,4-dihydroisocoumarins was possible using dibromo-methane and 1,2-dichloroethane, respectively (Scheme 2.56). 

C. Synthesis of m- m-Phenoxyalkoxy)henzamidines 4, 5, H6). The preparation of substituted TO-phenoxyalkoxybenzamidines follows a general scheme in which an ,a)-dihaloalkane 86) in large excess is used to monoalkylate m-cyanophenol 34). The resulting a-bromo-ia-(3-cyano-phenyl) alkane 36) is alkylated with an excess of phenol (37) to give an a-phenyl- -(3-cyanophenyl) alkane 38), which is converted to the m-substituted benzamidine 34-36) by the Pinner reaction. When n. = 3, the synthesis is as follows. To 20 mmoles of m-cyanophenol 36) in 10 ml... 

Phosphole tetramer 193, obtained by the pyrolysis of 1-phenyl-3,4-dimethyl-phosphole, incorporates two 2,2 -biphospholyl units linked by two P-P bonds. The P-P bonds could be reductively cleaved to form dianions containing one or two (194) 2,2 -biphospholyl units. Alkylation of those dianions with dihaloalkanes lead to the cyclophanes 195-197 (Scheme 12.67) [166]. 

In view of the ready availabiUty of optically pure lactic acid derivatives this reaction offers an attractive general method for the preparation of optically pure aromatic ester derivatives (41). Stereoselective alkylation (15—60% inversion) of ben2ene with optically active 1,2- 1,3- and 1,5-dihaloalkanes was also reported (42). 

This reaction gives fair-to-good yields of monoorganotin tribromides and trichlorides when quaternary ammonium or phosphonium catalysts are used (149). Better yields are obtained with organic bromides and staimous bromide than with the chlorides. This reaction is also catalyzed by tri alkyl antimony compounds at 100—160°C, bromides are more reactive than chlorides in this preparation (150,151). a,C0-Dihaloalkanes also react in good yield giving CO-haloalkyltin trihaHdes when catalyzed by organoantimony compounds (152). 

This reaction is illustrative of a general procedure for the alkylation of active methylene functions in the presence of concentrated aqueous alkali catalyzed by tetraalkylammonium salts. This catalytic method has been used to alkylate arylacetonitriles with monohaloalkanes,2 dihaloalkanes,3 a-chloroethers,4 chloronitriles,.5 haloacetic acid esters,6 and halonitro aromatic compounds.7 It has also been used to alkylate ketones,8 lf/ indene,9 9i/-fluorene,ll) and the Reissert compound.11 The reaction is inhibited by alcohols and by iodide ion.2... 

Thermolysis of the dicarbamic acid silyl ester (CH2 N[SiMe3]C02SiMe3)2) gives the 1,3-diazetane derivative 26 <96JOM93>. Alkylation of the 1,3-dithietane tetraoxide 27 with a,co-dihaloalkanes yields the dispiro compounds 28 (n = 1-4) <95ZOR589>. The first 1,2-dithiete S-oxide 29 is reported <95TL8583>. 

Attempts to exploit the reaction of the dianion with alkyl halides to produce a c/.v-dialkyl complex by using 1,2- or 1,3-dihaloalkanes did not indeed give this result. The reaction of Ru(Por) " with 1,2-dibromoethane was sucessful, but the resulting metallacyclopropane product is better formulated as a /r-complex of ethene, and will be discussed below in the section on alkenc and alkyne complexes. The corresponding reaction of the diiinion with 1,3-dichloropropane gave no evidence for a metallacyclobutane. but instead free cyclopropane was detected by GC analysis and the porphyrin product was Ru(TTP)(THF)2. ... 

Several syntheses of l,3-dioxoperhydropyrrolo[l,2-c]imidazoles have been developed using different strategies. a-Substituted bicyclic proline hydantoins were prepared by alkylation of aldimines 135 of resin-bound amino acids with a,tu-dihaloalkanes and intramolecular displacement of the halide to generate cr-substituted prolines 136 and homologs (Scheme 18). After formation of resin-bound ureas 137 by reaction of these sterically hindered secondary amines with isocyanates, base-catalyzed cyclization/cleavage yielded the desired hydantoin products <2005TL3131>. 

The catalysed A/-alkylation of the potassium salt of sulphoximines in l, 2-dimethoxyethane produces yields in excess of 90% [48]. Similarly, azacrown ethers have been synthesized by alkylation of bis(tosyIamino)alkyl ethers under catalysed basic two-phase conditions [49] (Scheme 5.12). The yields of the cyclic products (Table 5.24) are influenced by the choice of the alkali metal hydroxide employed, suggesting that there is a degree of template control in the ring closure step. This is not the case in the analogous reaction of p-toluenesulphonamide with a, co-dihaloalkanes [50], which leads to the formation of a mixture of l l and 2 2 cyclic products... 

Phosphonates and related compounds, which can subsequently be used in the Wittig-Homer reaction (see Section 6.5), are readily alkylated in good yield (Table 6.8) [67-71], Mono-alkylation is observed with mildly basic conditions at 45°C [67] and dialkylation under stronger basic conditions at 60°C [70], Reaction of a,to-dihaloalkanes with phosphonocarboxylates leads to cycloalkylphosphonates [72], The methylenebisphosphonate reacts in a similar manner. 

Silver nitrite gives significantly higher yields of nitro compounds from primary alkyl halides, and consequently, the synthesis of Q, ty-dinitroalkanes from the reaction of o, )-dihaloalkanes with sodium nitrite is inferior to the same reaction with silver nitrite (Table 1.2). However, the use of a solvent system composed of DMSO and MEK is reported to considerably improve the yields of Q , y-dinitroalkane when using sodium nitrite. ... 

---