Substitution 1,2-disubstituted

The student when preparing disubstituted benzenes should bear in mind VorlSnder s Rules of aromatic substitution, which form the most convenient modification of Crum Brown s earlier rules. Vorl5nder stated that if a substance... 

A brief account of aromatic substitution may be usefully given here as it will assist the student in predicting the orientation of disubstituted benzene derivatives produced in the different substitution reactions. For the nitration of nitrobenzene the substance must be heated with a mixture of fuming nitric acid and concentrated sulphuric acid the product is largely ni-dinitrobenzene (about 90 per cent.), accompanied by a little o-dinitrobenzene (about 5 per cent.) which is eliminated in the recrystallisation process. On the other hand phenol can be easily nitrated with dilute nitric acid to yield a mixture of ortho and para nitrophenols. It may be said, therefore, that orientation is meta with the... 

The last group of reactions uses ring opening of carbonyl or 1-hydroxyalkyl substituted cyclopropanes, which operate as a -synthons. d -Synthons, e.g. hydroxide or halides, yield 1,4-disubstituted products (E. Wenkert, 1970 A). (1-Hydroxyalkyl)- and (1-haloalkyl)-cyclopropanes are rearranged to homoallylic halides, e.g. in Julia s method of terpene synthesis (M. Julia, 1961, 1974 S.F. Brady, I968 J.P. McCormick, 1975). 

The formation of disubstituted alkynes by coupling of terminal alkynes, followed by intramolecular attack of an alcohol or amine, is used for the preparation of benzofurans and indoles. The benzo[il)]furan 356 can be prepared easily by the reaction of o-iodophenol with a terminal alkyne[262]. The 2-substituted indole 358 is prepared by the coupling of 2-ethynylaniline (357) with aryl and alkenyl halides or triflates, followed by Pd(ll)-catalyzed cycliza-tion[263]. 

Pyrrole derivatives are prepared by the coupling and annulation of o-iodoa-nilines with internal alkynes[291]. The 4-amino-5-iodopyrimidine 428 reacts with the TMS-substituted propargyl alcohol 429 to form the heterocondensed pyrrole 430, and the TMS is removed[292]. Similarly, the tryptophane 434 is obtained by the reaction of o-iodoaniline (431) with the internal alkyne 432 and deprotection of the coupled product 433(293]. As an alternative method, the 2,3-disubstituted indole 436 is obtained directly by the coupling of the o-alky-nyltrifluoroacetanilide 435 with aryl and alkenyl halides or triflates(294]. 

Active methylene or methine compounds, to which two EWGs such as carbonyl, alko.xycarbonyl, formyl, cyano, nitro, and sulfonyl groups are attached, react with butadiene smoothly and their acidic hydrogens are displaced with the 2,7-octadienyl group to give mono- and disubstituted compounds[59]. 3-Substituted 1,7-octadienes are obtained as minor products. The reaction is earned out with a /3-keto ester, /9-diketone, malonate, Q-formyl ketones, a-cyano and Q-nitro esters, cya noacetamide, and phenylsulfonylacetate. Di(octadienyl)malonate (61) obtained by this reaction is converted into an... 

Reactions of the 2-amino-4,5-substituted thiazole (52) in acetic acid with ethylene oxide has been reported to give the N-exocyclic disubstitution product (S3) (201) in a 40% yield (Scheme 38). The reactive species in this reaction is probably the carbocation generated in acetic acid by ethvlene oxide. 

Similarly 2- and 4-disubstituted seienazolidines were prepared from 2-methyl- and 2,2-dimethylaziridines (Table X-17i (74) and 2- and 3-disubstituted seienazolidines were obtained from N-substituted aziridines (Table X-18) (74). 

The peak near 3085 cm disappears only for 2.4-disubstituted derivatives. Its frequency is slightly higher for 2- than for 4-substituted compounds. The vC(2)H and vC(4,H vibrations seem to be nearly equivalent and usually give rise to an unique peak, except in the case of 5-bromo-and 5-isopropylthiazoles in CCI4 solution, where this peak is split into two bands. 

The variable frequencies of suites V and VIII on one side, and VI and VIII on the other, correspond to oscillations resulting from the coupling of the v(C-X) vibration with the cjf mode in the case of 2- or 5-substituted derivatives and with the mode in the case of 4-substituted derivatives. For 2,5-disubstituted thiazoles the ojf, vibration is only slightly different from that of thiazole itself and the 5 oscillation is coupled with both v(C(2iX) and vfC(5,X or Y) modes, giving rise to three frequencies, two of which are higher and classified in suites V and V, the third, being lower, is assigned to suite VIII. 

The cyclization of -halocarbonyl compounds is carried out with a great variety of reactants including thioamides, thioureas, their mono- or disubstituted derivatives, and salts and esters of monothiocar-bamic acid, leading to variously substituted thiazoles. 

In the reverse reaction, thioheteroaryl amides reacted under reflux in alcohol with haloketones or aldehydes to give the corresponding 2-heteroarylthiazole derivatives (238, 271, 482, 550, 751, 765, 776, 781). 2,2 -Bithiazoles (4,4 -disubstituted) have been obtained in 80 to 90% yield by cyclocondensation of 1 mole rubeanic acid with 2 moles of a-bromoketones in polyphosphoric acid at 95 to 135 C (780). Some multiheteroaryl substituted thiazoles have been also reported (704). 

Various 4-, 5-, or 4,5-disubstituted 2-aryIamino thiazoles (124), R, = QH4R with R = 0-, m-, or p-Me, HO C, Cl, Br, H N, NHAc, NR2, OH, OR, or OjN, were obtained by condensing the corresponding N-arylthiourea with chloroacetone (81, 86, 423), dichloroacetone (510, 618), phenacyichloride or its p-substituted methyl, f-butyl, n-dodecyl or undecyl (653), or 2-chlorocyclohexanone (653) (Method A) or with 2-butanone (423), acetophenone or its p-substituted derivatives (399, 439), ethyl acetate (400), ethyl acetyl propionate (621), a- or 3-unsaturated ketones (691), benzylidene acetone, furfurylidene acetone, and mesityl oxide in the presence of Btj or Ij as condensing agent (Method B) (Table 11-17). 

Degree of substitution We classify double bonds as monosubstituted, disubstituted,... 

All the entries above the broken line in Table 2.3 are disubstituted, and those below, with the exception of poly (dimethyl siloxane), are mono-substituted. Those in the former category consistently have larger values of f than the latter. 

Chiral separations are concerned with separating molecules that can exist as nonsupetimposable mirror images. Examples of these types of molecules, called enantiomers or optical isomers are illustrated in Figure 1. Although chirahty is often associated with compounds containing a tetrahedral carbon with four different substituents, other atoms, such as phosphoms or sulfur, may also be chiral. In addition, molecules containing a center of asymmetry, such as hexahehcene, tetrasubstituted adamantanes, and substituted aHenes or molecules with hindered rotation, such as some 2,2 disubstituted binaphthyls, may also be chiral. Compounds exhibiting a center of asymmetry are called atropisomers. An extensive review of stereochemistry may be found under Pharmaceuticals, Chiral. 

Researchers at Du Pont used hydroquinone asymmetrically substituted with chloro, methyl, or phenyl substituents and swivel or nonlinear bent substituted phenyl molecules such as 3,4- or 4,4 -disubstituted diphenyl ether, sulfide, or ketone monomers. Eor example,... 

Dibromoborane—dimethyl sulfide is a more convenient reagent. It reacts directly with alkenes and alkynes to give the corresponding alkyl- and alkenyldibromoboranes (120—123). Dibromoborane differentiates between alkenes and alkynes hydroborating internal alkynes preferentially to terminal double and triple bonds (123). Unlike other substituted boranes it is more reactive toward 1,1-disubstituted than monosubstituted alkenes (124). 

Oxidation. As a 7t-excessive heterocycle, indole is susceptible to oxidation a variety of oxidation intermediates and products have been observed. With oxygen as the oxidant, the key intermediate is normally a 3-hydroperoxy-3ff-indole. These intermediates ate observable for 2,3-disubstituted indoles but are unstable for less substituted derivatives. Figure 1 indicates typical reactivity patterns toward oxygen. 

Although there are a wide variety of indole ring syntheses (25), most of the more useful examples fall within a small number of groups. Indole syntheses usually start with an aromatic compound, either monosubstituted or ortho-disubstituted. Those which begin with a monosubstituted starting material must at some point effect a substitution of the benzene ring. 

Substituted Nickel Carbonyl Complexes. The reaction of trimethyl phosphite and nickel carbonyl yields the monosubstituted colorless oil, (CO)2NiP(OCH )2 [17099-58-0] the disubstituted colorless oil, (CO)2Ni[P(OCH )2]2 [16787-28-3] and the trisubstituted white crystalline soHd,... 

Substituted Amides. Monosubstituted and disubstituted amides can be synthesized with or without solvents from fatty acids and aLkylamines. Fatty acids, their esters, and acid halides can be converted to substituted amides by reaction with primary or secondary aLkylamines, arylamines, polyamines, or hydroxyaLkylamines (30). Di- -butylamine reacts with oleic acid (2 1 mole ratio) at 200—230°C and 1380 kPa (200 psi) to produce di-A/-butyloleamide. Entrained water with excess -butylamine is separated for recycling later (31). 

Amyl alcohol describes any saturated aliphatic alcohol containing five carbon atoms. This class consists of three pentanols, four substituted butanols, and a disubstituted propanol, ie, eight stmctural isomers four primary, three secondary, and one tertiary alcohol. In addition, 2-pentanol,... 

FrielA,nderSynthesis. The methods cited thus far all suffer from the mixtures which usually result with meta-substituted anilines. The use of an ortho-disubstituted benzene for the subsequent constmction of the quinoline avoids the problem. In the FrieWider synthesis (52) a starting material like 2-aminoben2aldehyde reacts with an CX-methyleneketone ia the presence of base. The difficulty of preparing the required anilines is a limitation ia this approach, but 2-nitrocarbonyl compounds and the subsequent reduction of the nitro group present a usehil modification (53). 

Extension of the Phosphorane Route. Ample evidence of the versatihty of the phosphorane synthesis strategy is provided by the proliferation of penems that followed. Nucleophilic displacement of the acetate function of the acetoxy-azetidinone (51, R = OCOCH ) [28562-53-0] (86) provided azetidinones where R = SCOCH, SCSSC2H, and SCSOC2H, which on elaboration gave the penems (52, R = CH ) (87), (52, R = SC2H ) (88), (52, R = 0C2H ) (89). Similar treatment of 3-substituted (or disubstituted) acetoxyazetidinones allowed the synthesis of a number of 2-substituted- 6-alkyl-and 6,6-dialkylpenems (90). 

Chlorine or bromine react with benzene in the presence of carriers, such as ferric halides, aluminum halides, or transition metal halides, to give substitution products such as chlorobenzene or bromobenzene [108-86-17, C H Br occasionally para-disubstitution products are formed. Chlorobenzene [108-90-7] ... 

Hydroxyl Group. The OH group of cyanohydrins is subject to displacement with other electronegative groups. Cyanohydrins react with ammonia to yield amino nitriles. This is a step in the Strecker synthesis of amino acids. A one-step synthesis of a-amino acids involves treatment of cyanohydrins with ammonia and ammonium carbonate under pressure. Thus acetone cyanohydrin, when heated at 160°C with ammonia and ammonium carbonate for 6 h, gives a-aminoisobutyric acid [62-57-7] in 86% yield (7). Primary and secondary amines can also be used to displace the hydroxyl group to obtain A/-substituted and Ai,A/-disubstituted a-amino nitriles. The Strecker synthesis can also be appHed to aromatic ketones. Similarly, hydrazine reacts with two molecules of cyanohydrin to give the disubstituted hydrazine. 

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