By Direct Alkylation or Arylation

Direct alkylation of unsubstituted qumoxaline has been discussed in Section 2.1.3. Such alkylation or arylation of other quinoxalines is apparently seldom satisfactory, but the following recent examples contain some procedures that may prove useful. 

6-Nitro-2(l//)-quinoxalinone (38) underwent 3,4-addition by /V,/V-dimethylani-line to give 3-(p-dimethylaminophenyl)-6-nitro-3,4-dihydro-2(l //)-quinoxa-linone (39) (AcOH, reflux, 4h 80%) 753 2-chloroqumoxaline and aniline gave several separable products, including 2-p-aminophenyl-3-anilinoqui-noxaline (40) (neat PI1NH2, 150°C, 2h 16% aerial aromatization ).630 

2(17/)-Quinoxalinone and acetone gave 3-acetonyT2( 1 //)-quinoxalinone (41) [Me2SC 4 (as catalyst), reflux until complete by tic 91% aerial aromatization ) homologs likewise.572 cf 335 431 

2-Methoxy-3-phenylquinoxaline and benzaldehyde gave a separable mixture of 5-(a-hydroxybenzyl)-2-methoxy-3-phenyl- (42) and 5-(a-hydroxybenzyl)-3-methoxy-2-phenylquinoxaline (43) [LiN(CMe2CH2)2CH2 (made in situ), 

1 h 44% and 19% analogs likewise].661 In contrast, 2,3-dimethoxyquinoxaline with butyllithium and acetaldehyde gave only 2,2-dibutyl-3-methoxy-l,2-dihydroquinoxaline (44) (BuLi, THF, A, —78°C, 10 min then MeCHO, -78°C, 30 min 88%).661 

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These substances are very promising for the synthesis of organochloro-silanes with various radicals at the silicon atom, i.e. by direct alkylation (or arylation) of hydrideorganochlorosilanes with chlorine derivatives of unsaturated and aromatic hydrocarbons. 

The nature of alkyl halide and the environment of the phosphorus atom make a substantial contribution to the direction of the reaction. Thus, cyclic phosphites [108], like trialkyl phosphites [110], react with preservation of the coordination of the P(III) phosphorus atom (126-132 ppm). If the alkoxyl group is substituted by amide, alkyl, or aryl, the nucleophilicity of the phosphorus atom in the corresponding amidophosphite (phosphonite) increases in comparison with the trialkyl phosphite. This probably promotes attack by 1 -haloalkyl-2-pyrrolidone at the phosphorus atom and not the oxygen, and this was confirmed experimentally. As a result of the investigated reactions amidophosphonates or ethyl phenyl phosphinates llOa-c were isolated compounds with P(III) were not detected in these cases. 

The alkyllithium reagents to be used in tandem reactions can be prepared by direct alkylation or by an aldol reaction involving nucleophilic addition of the alkyllithium as the first step. Several complex heteroaromatic compounds, which can serve as pivotal intermediates in synthetic strategy of biologically active species, could be synthesized by this procedure. The preparation of polysubstituted pyridines has been an active research area for many years181. The synthesis of 2-alkyl- or 2-aryl-5-hydrazinopyridines 327 has never been performed directly from pyridine. The reported methods involve several steps... 

Information on the initiation reaction is restricted to the solvent tetrahydrofuran, in conjunction with the monomers a-methylstyrene and 1,1,-diphenylethylene which can only form oligomers, at least at room temperature. Initiation may once again be produced by metal alkyls or aryls, by direct contact of the olefin with an alkali metal film, or by use of the addition products of alkali metals to condensed aromatic ring compounds. 

Direct alkylation or arylation of metals by alkyl or aryl halides in accord with the general equation ... 

Thiazolium salts can be obtained successfully by a modification of the Hantzsch s thiazole synthesis. This method is particularly valuable for those thiazolium compounds in which the substituent on the ring nitrogen cannot be introduced by direct alkylation, for example, aryl or heteroaryl thiazolium salts (Scheme 42). 

These preceding properties imply that the thiazole has to be introduced in various molecules, by direct cyclization or with precursors already bearing the thiazole ring. Among these last products the clomethiazole. nitrothiazole, and aryl or alkylthiazoles with the functional group on the aryl or alkyl substituent have been widely used. 

Among the compounds of As can be noted the complete series R5 AsX (n = 0-5) where R can be alkyl or aryl. Thus AsPhs (mp 150°) can be prepared by direct reaction of LiPh on either [AsPlu] , Ph3AsCl2 or Ph3As=0. Similarly, AsMes has been prepared as a colourless, volatile, mobile liquid (mp —6°) ... 

Sulfonic esters are most frequently prepared by treatment of the corresponding halides with alcohols in the presence of a base. The method is much used for the conversion of alcohols to tosylates, brosylates, and similar sulfonic esters. Both R and R may be alkyl or aryl. The base is often pyridine, which functions as a nucleophilic catalyst, as in the similar alcoholysis of carboxylic acyl halides (10-21). Primary alcohols react the most rapidly, and it is often possible to sulfonate selectively a primary OH group in a molecule that also contains secondary or tertiary OH groups. The reaction with sulfonamides has been much less frequently used and is limited to N,N-disubstituted sulfonamides that is, R" may not be hydrogen. However, within these limits it is a useful reaction. The nucleophile in this case is actually R 0 . However, R" may be hydrogen (as well as alkyl) if the nucleophile is a phenol, so that the product is RS020Ar. Acidic catalysts are used in this case. Sulfonic acids have been converted directly to sulfonates by treatment with triethyl or trimethyl orthoformate HC(OR)3, without catalyst or solvent and with a trialkyl phosphite P(OR)3. ... 

N-Substituted amides can be prepared by direct attack of isocyanates on aromatic rings.The R group may be alkyl or aryl, but if the latter, dimers and trimers are also obtained. Isothiocyanates similarly give thioamides. The reaction has been carried out intramolecularly both with aralkyl isothiocyanates and acyl isothiocyanates.In the latter case, the product is easily hydrolyzable to a dicarboxylic acid this is a way of putting a carboxyl group on a ring ortho to one already there (34 is... 

The reaction has also been used to prepare 1,3-dilithiopropanes" and 1,1-dilithio-methylenecyclohexane" from the corresponding mercury compounds. In general, the equilibrium lies in the direction in which the more electropositive metal is bonded to that alkyl or aryl group that is the more stable carbanion (p. 228). The reaction proceeds with retention of configuration an Sgi mechanism is likely. Higher order cuprates (see Ref. 1277 in Chapter 10) have been produced by this reaction starting with a vinylic tin compound ... 

If the substituents are nonpolar, such as an alkyl or aryl group, the control is exerted mainly by steric effects. In particular, for a-substituted aldehydes, the Felkin TS model can be taken as the starting point for analysis, in combination with the cyclic TS. (See Section 2.4.1.3, Part A to review the Felkin model.) The analysis and prediction of the direction of the preferred reaction depends on the same principles as for simple diastereoselectivity and are done by consideration of the attractive and repulsive interactions in the presumed TS. In the Felkin model for nucleophilic addition to carbonyl centers the larger a-substituent is aligned anti to the approaching enolate and yields the 3,4-syn product. If reaction occurs by an alternative approach, the stereochemistry is reversed, and this is called an anti-Felkin approach. 

The alkylation of 15 (path b, Scheme 15)40 has been performed according to conventional procedures using lithium or Grignard reagents. The preliminary isolation of 15 is not essential thus, the synthesis of the zirconium alkyl or aryl derivatives can be carried out in situ directly from 3 (path a, Scheme 15). The h NMR spectra of 71-74 all imply C2V symmetry, as revealed by the CH2 (one pair of doublets), Bu (two singlets), and MeO (one singlet) patterns. All the alkyl derivatives 71-73 are thermally stable up to 80°C in CgDg. The aryl derivative... 

The catalytic cycles for reduction of alkyl and atyl halides using Ni(o), Co(i) or Pd(o) species are interrupted by added carbon dioxide and reaction between the first formed carbon-metal bond and carbon dioxide yields an alkyl or aryl car-boxylate. These catalyses reactions have the advantage of occuriiig at lower cathode potentials than the direct processes summarised in Table 4.14. Mechanisms for the Ni(o) [240] and Pd(o) [241] catalysed processes have been established. Carbon dioxide inserts into the carbon-metal bond in an intermediate. Once the carboxy-late-metal species is formed, a further electron transfer step liberates the carboxy-late ion reforming the metallic complex catalyst. 

Tetrakis-/i-(carboxylato)-dimolybdenum(II) complexes have been obtained by only one general route, namely by the direct interaction of carboxylic acids with molybdenum hexacarbonyl.8 This reaction requires elevated reaction temperatures and prolonged reaction times. These same compounds are obtained in comparable or better yields by the brief reaction of tetrachloro- or tetrabromotetrakis(tributylphosphine)dimolybdenum(II) with alkyl- or aryl-carboxylic acids in refluxing benzene. The bis-/i-(arylcarboxylato) complexes... 

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