Positive schemes

The action of formaldehyde on 2-acetamido-4-inethylselenazole can lead to dimerization in the 5-position (Scheme 17) (4),... 

Mechanistically, the reaction results from the mesomeric donor effect of the 2-hydrazino group. The coupling between the two molecules takes place in the 5-position (Scheme 48). 

A radically different course is followed when the reaction of 2-alkyl-substituted thiazoles is periormed in methanol or acetonitrile (335), 2 1 adducts containing seven-membered azepine rings (91) are being formed in which two of the original activated hydrogen atoms have altered positions (Scheme 55). A similar azepine adduct (92) was obtained by... 

Erlenmeyer et al. also examined the behavior of 4-methyl-, 4,5-dimethyl-, and 5-methylthiazole in the reaction with benzaldehyde at 160°C in the presence of ZnClj (439, 510) they were able to show that neither the 4- nor 5-methyl groups reacted under these conditions and that the condensation occurred at the sole unsubstituted 2-position (Scheme 114). 

Treatment of a-thiocyanatoketones at low temperature with dry hydrogen chloride in ether solution gives satisfactory yields of 2-chloro-thiazole derivatives (188). The use of phosphorus pentachloride leads to the same results, but in this case chlorination can also occur at the 5-position (Scheme 97) (18, 68). 

Carbon disulfide readily reacts with a-aminonitriles giving 2-mercapto-5-aminothiazoles (213), (271, 293) which can be converted to 5-aminothiazoles unsubstituted in the 2-position (Scheme 110 and Table II-34a). If this reaction is carried out in the presence of benzyl chloride in phosphorus tribromide, a 2-S-substituted thiazole derivative (214) is obtained in quantitative yield (Scheme 111), with R = hydrogen or phenyl (68, 304). 

Azidopyridazine 2-oxides give on thermolysis either maleonitrile (19), /3-cyanoacrylate (20) or 2-cyano-l-hydroxypyrazole (21), dependent on the substituent at the 6-position (Scheme 4) <75CC703>. 

Interesting results have been obtained in intramolecular acylation reactions involving pyrrole and thiophene derivatives. A muscone synthesis involves selective intramolecular acylation at a vacant a-position (Scheme 18) (80JOC1906). In attempts to prepare 5,5-fused systems via intramolecular acylation reactions on to a jS-position of a thiophene or a pyrrole, in some cases ipso substitution occurs with the result that rearranged products are formed (Scheme 19) (82TH30200). 

By using an aromatic aldehyde carrying an electron-releasing group the intermediate cation can be stabilized. This is the basis of the widely-used Ehrlich colour reaction for pyrroles, indoles and furans which have a free reactive nuclear position (Scheme 21). 

Neutral azoles are readily C-lithiated by K-butyllithium provided they do not contain a free NH group (Table 6). Derivatives with two heteroatoms in the 1,3-orientation undergo lithiation preferentially at the 2-position other compounds are lithiated at the 5-position. Attempted metallation of isoxazoles usually causes ring opening via proton loss at the 3-or 5-position (Section 4.02.2.1.7.5) however, if both of these positions are substituted, normal lithiation occurs at the 4-position (Scheme 21). 

The quaternization of 5iT-imidazoles occurs at the 1-position (Scheme 39) (64AHC(3)1). 4//-Pyrazoles are also readily monoquaternized. 

Substituents in the indazole ring may direct a given reaction towards another position either by their R and I electronic properties or simply by protecting the most reactive position. Examples of both types are found in sulfonation studies (67HC(22)l). As indicated before (Section 4.04.2.3.2(i)), sulfonation takes place at position 7. However, the presence of an amino group at positions 5 or 7 directs the attack towards the 4-position (Scheme 40). To obtain the indazole-5-sulfonic acid a more complicated procedure has been used but it is still based on the same ideas. 

Amines normally have no effect on the isothiazole ring, but 3-chloro-4-nitroisothiazole (49) reacts with cyclic amines such as morpholine at 0 °C to give the enamine (50) (75JOC955). The mechanism may involve attack either at sulfur or at the 5-position (Scheme 6). 

When 1-methyl-, 1,2- and 1,3-dimethyl-indoles were oxidized on a platinum electrode in methanolic ammonium bromide solution, in addition to the oxidation products, products of nuclear bromination at the 3-and 5-positions were observed. 1,2- Dimethylindole (20) gave 3-bromo-1,2-dimethylindole (81CCC3278) [bromine in chloroform gave the same product (85CHE786)]. In acidic conditions the amidinium cation formed from 20 was brominated in the 5-position (Scheme 14). Acylated 2-aminoindoles reacted similarly in neutral media to give 3-bromo derivatives and when protonated to give 5-bromo products. Bromine in chloroform transformed l-methyl-2-dimethylaminoindole (21) into the 3-bromo derivative (85CHE782) (Scheme 15). 

This result should be compared to the cydization of the more advanced intermediate 49 (4 1 mixture of isomers at the acetal position Scheme 9.25), which afforded the bicyclic oxepane 50 as the sole product in excellent yield. It was suggested that this result was due to the presence of a trans-fused five-membered ring, which restricts the rotation around the C7-C8 bond and thus promotes the 7-endo cydization. 

Danshefsky s diene [19] is the 1,3-butadiene with amethoxy group at the 1-position and a trimethylsiloxy group at the 3-position (Scheme 18). This diene and Lewis acids extended the scope of hetereo-Diels-Alder reactions with aldehydes [20], This diene reacts with virtually any aldehyde in the presence of Lewis acids whereas dienes usually react with only selected aldehydes bearing strongly electron accepting a-substituents. There are two (Diels-Alder and Mukaiyama aldol) reaction pathways (Scheme 18) identified for the Lewis acids catalyzed reactions of Danishefsky diene with aldehydes [21, 22]. The two pathways suggest that these reactions occur on the boundary between the delocahzation band (the pericyclic... 

The orbital mixing rule was recently applied to the prediction and design of cyclopentadienes having substituents of tr-system at 5-positions (Scheme 8) [13,14],... 

In addition, another computational study in the frame of DFT, using the hybrid functional MPW1K,53 had suggested that o-QM may be an intermediate in the reaction of the peroxy radical (HO2") with the benzyl radical at the ortho-position (Scheme 2.16),54 which should be significant in atmospheric processes and low-temperature combustion systems (T < 1500 K). 

When -elimination is impossible, e.g., Me2Zn and Ph2Zn, Me and Ph groups are introduced at the distal allylic terminus of an intermediate 46 via czs-reductive elimination, overall establishing difunctionahzation of dienes at Cl and C4 positions (Scheme 19). The following equations summarize examples demonstrating 1,4-difunctionalization of dienes currently developed [45-57]. The reaction shown in Eq. 25 is stoichiometric with respect to Ni, and the other examples are all catalytic with respect to Ni. 

Oxygen functionalities, such as alcohols, ethers, and acetate groups, and halogens at the allylic position, deshield when the fluorine is at the terminal position and shield when it is at the internal 2-position (Scheme 3.43). 

For both pyridines and quinolines, it is easy to distinguish between the 2- and the 4-substituted isomers, since the trifluoromethyl group at the 2-position absorbs at somewhat higher field than that at the 4-position (Scheme 5.45). CF3 at the 3-position appears at a still lower field. 

Similarly, the fluorines of a trifluoromethyl group in the 3-position of thiophenes absorb at a higher field than those of one at the 2-position (Scheme 5.49). 

Knolker and coworkers also used a domino [3+2] cycloaddition for the clever formation of a bridged tetracyclic compound 4-172, starting from a cyclopentanone 4-168 and containing two exocydic double bonds in the a-positions (Scheme 4.36) [57]. The reaction of 4-168 with an excess of allylsilane 4-169 in the presence of the Lewis acid TiCLj led to the spiro compound 4-170 in a syn fashion. It follows a Wag-ner-Meerwein rearrangement to give a tertiary carbocation 4-171, which acts as an electrophile in an electrophilic aromatic substitution process. The final step is the... 

The first spirophosphorane with an azaphosphetidine ring 63 was prepared from the intramolecular cyclization and dehydration of phosphane oxides with DEAD/PPh3 <1996AGE1096, 1996PS489>. Dissolution of 63 in [r/8]-toluene led to some isomerization to the pseudorotamer 64, where the electronegative nitrogen occupies the equatorial position (Scheme 32). Such rotamers were previously unknown for the analogous oxaphosphetanes. 

The estrogenic properties of isoflav-3-enes are well known and consequently, several derivatives of these chromene heterocycles have been the target of medicinal chemists. Varma and coworkers uncovered a useful enamine-mediated pathway to this class of compounds [142-144], Now the group has discovered a facile and general method for the MW-expedited synthesis of isoflav-3-enes substituted with basic moieties at the 2-position (Scheme 6.42) [145], These promising results are especially appealing in view of the convergent one-pot approach to 2-substituted isoflav-3-enes... 

Unlike the 3-position, the 5-position is very susceptible to nucleophilic substitutions and additions. Thus, a series of publications report that 5-fluoroalkyl-l,2,4-oxadiazoles 94 undergo reaction with hydrazine or hydroxylamine to furnish 3-fluoroalkyl-l,2,4-triazoles 95 (X = NH) and 3-fluoroalkyl-1,2,4-oxadiazoles 95 (X = 0), a reaction that proceeds via addition of the nitrogen nucleophile to the 5-position (Scheme 9) <2005JOC3288, 2004EJ0974, 2003JOC605>. 

In 1981, it was demonstrated (70) that anions of nitro compounds can be involved in C,C-coupling with allyl acetates at the allylic carbon atom with the use of metal complex catalysis. For many years, this observation did not come to the attention of chemists interested in the synthesis of cyclic nitronates. However, Trost demonstrated (71) that this process can be used in the synthesis of five-membered cyclic nitronates from olefins (18) containing two acyl groups in the different allylic positions (Scheme 3.21). 

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