Nucleophilic substitution positional selectivity

Tetrafluoropyrimidine Perfluorinated diazines (pyrimidine, pyrazine, and pyridazine) are typically 1000 times more reactive toward nucleophiles than pentafluoropyridine. Various reactions of tetrafluoropyrimidine with a small range of nucleophiles have been reported (Fig. 8.15) and, in all cases, nucleophilic substitution occurs selectively at the 4-position, consistent with the mechanistic principles discussed above. 

As in the pyridopyrimidines, selective nucleophilic substitution reactions at reactive ring positions have been a fruitful source of pyridopyridazines. 

The selective reaction of anionic 3,6-dichloro-4-sulfanilamidopy-ridazine with excess methanolic methoxide at the 3-position is another indication of the absence of major steric effects in most nucleophilic substitutions, as a result of the direction of nucleophilic attack (cf. Section II, A, 1). The selectivity at the 3-position is an example of the interaction of substituent effects. The sulfonamide anion deactivates both the 3-chloro (ortho direct deactivation) and... 

The selective activation of the methyl group in the 5-position is of considerable importance. This may be compared with the preceding activation of the nucleophilic substitution at C-5 by the substituent at C-4 (Section IV,B). 

The overall conclusion from the reaction of BP and 6-substituted BP radical cations with nucleophiles of various strengths is that weak nucleophiles display higher selectivity toward the position of highest charge localization. Thus another important factor in the chemical reactivity of radical cations is represented by the strength of the nucleophile. 

Additions to quinoline derivatives also continued to be reported last year. Chiral dihydroquinoline-2-nitriles 55 were prepared in up to 91% ee via a catalytic, asymmetric Reissert-type reaction promoted by a Lewis acid-Lewis base bifunctional catalyst. The dihydroquinoline-2-nitrile derivatives can be converted to tetrahydroquinoline-2-carboxylates without any loss of enantiomeric purity <00JA6327>. In addition the cyanomethyl group was introduced selectively at the C2-position of quinoline derivatives by reaction of trimethylsilylacetonitrile with quinolinium methiodides in the presence of CsF <00JOC907>. The reaction of quinolylmethyl and l-(quinolyl)ethylacetates with dimethylmalonate anion in the presence of Pd(0) was reported. Products of nucleophilic substitution and elimination and reduction products were obtained . Pyridoquinolines were prepared in one step from quinolines and 6-substituted quinolines under Friedel-Crafts conditions <00JCS(P1)2898>. 

Selective generation of 2-aza-l,5-diradicals 146 through nucleophilic addition to the less substituted positions of the cation radicals 145 arising by intramolecular electron transfer was attributed to the cyclization regiochemistry (equation 66). 

The synthesis of deoxysepiapterin (82) has been recently achieved by homo-lytic nucleophilic substitution of the pteridine nucleus by acyl radicals (505). Since this substitution arises preferentially at the most electron-deficient 7 position, protection at 7 position is necessary for nucleophilic attack at the 6 position. 2,4-Diamino-7-methylthiopteridine (597) and 2-amino-4- -pentyloxy-7-n-pro-pylthiopteridine (600), protected by the thio function, can be used as starting materials. Homolytic acylation of 597 with the system propionalde-hyde/Fe2+//ert-butylhydroperoxide afforded 6-propionylpteridine (598) in good yields, which could be transformed to deoxysepiapterin (82) by selective hydrolysis followed by deprotection of the thio function (Scheme 75). Deoxysepiapterin (82) can also be prepared by a similar procedure from 600. 

Z- and 4-alkoxyquinazolines are readily prepared by nucleophilic substitution reactions, and 2,4-dialkoxyquinazolines can simply be prepared by boiling 2,4-dichloroquinazolines with 2 equiv of an alkoxide in the appropriate alcohol solvent <1996HC(55)1>. The first substitution is in the more reactive 4-position, so it is possible to isolate both 4-alkoxy and 4-phenoxy monosubstitution products <1977EJM325, 2005BMC3681>, and this selectivity has been used to attach both 2,4,6- and 2,4,7-trichloroquinazoline to a solid support, via the 4-position, for subsequent solid-phase synthesis of 2,6- and 2,7-diamino-4(377)-quinazolinones <2003TL7533>. 

The introduction of substituents into position 7 of a 2,4-disubstituted pteridine can be effected very cleanly by the use of acyl radicals typically and has been known for many years. Treatment of aldehydes with /-butyl hydroperoxide and iron(ll) generates acyl radicals which add selectively to the 7-position. A recent exploitation of this chemistry has provided a large number of new examples including both aryl and alkyl acyl radicals as reagents <2004PTR129> pA , data have been compiled (Section 10.18.4) and many nucleophilic substitution reactions of the 7-acylated pteridines and functional group modifications have been described (Section 10.18.7.2). 

The point of the change from a stepwise to a concerted mechanism for nucleophilic substitution at X-l-Cl may be detected as an upward break in the observed nucleophile selectivity nu/ s with decreasing stability of the putative intermediate X-1 (Fig. 2.2). Figure 2.5 shows that the position of this break and the change in mechanism shifts to more electron-withdrawing X as the reactivity of the nucleophile is decreased, from X = 4-F for... 

Free-radical bromination of toluene is selective for the benzylic position. Benzyl bromide cannot undergo elimination, and so nucleophilic substitution of bromide by hydroxide will work well. 

Chlorinated cyclopenta-l,2,3-dithiazole 44 is susceptible to nucleophilic substitution with amines, and in all cases only the 5-chlorine atom of dithiazole 44 is substituted (Scheme 24). The selectivity in these reactions is apparently due to the activation of the c/r-position to the cyano group of the dithiazole 44, which is a unique feature of this compound <2005EJ05055>. 

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