Intramolecular substitution intermediates

Beak and coworkers accomplished the asymmetric deprotonation of several Ai-Boc-iV-(3-chloropropyl)arylmethylamines (240) with enantiomeric excesses up to 98 2 (equation 56). The intermediate lithium compound 241 cyclizes to form pyrrolidines 242 in good yields and enantioselectivities. The rapid intramolecular substitution step conserves the originally achieved high kinetic differentiation in the deprotonation step. 

Among dichloro bis-electrophiles, malonyl chloride with enamine 183b affords pyridone 189, probably resulting from C-alkylation and cyclocondensation followed by aromatization (02T2821). Finally, o-chloro-benzoylchloride leads to C-benzoylation and subsequent intramolecular substitution of the isolable intermediate to yield quinoline 190 (03ARK (is.2)146). 

In summary, it would appear that the oxidation of a catecholamine probably first involves the formation of a semi-quinone radical (this can be brought about by an one-electron transfer, e.g. from Cu++ ions,14 or by photoactivation 1) which rapidly undergoes further oxidation (e.g. with atmospheric oxygen) to an intermediate open-chain quinone (such as adrenaline-quinone) and then cyclizes by an oxidative nucleophilic intramolecular substitution to the amino-chrome molecule. Whilst the initial formation of a leucoaminochrome by non-oxidative cyclization of the intermediate open-chain quinone in some cases cannot be entirely excluded at the moment (cf. Raper s original scheme for aminochrome formation72), the... 

Doyle et al.344 and Wee and Liu345 have reported the ring-closing transformation of a-diazoacetamides 108 and 109 to yield 2(3//)-indolinones over Nafion-H [Eq. (5.136)]. In the transformation of compounds 109 the electrophilic intramolecular substitution is followed by decarboxylation.345 Small amounts of 2-azetidinone derivatives (4—10%) formed through a carbene intermediate were also detected. The yield of products from compounds 108 are even higher than observed in the presence of Rh(OAc)2 often applied in the decomposition of diazo compounds.344... 

The aminonitrile 207 was condensed with carbon disulfide and base, leading to an intermediate dithiocarboxylate, which underwent intramolecular substitution. After alkylation of the remaining thiolate function, pyridothiazepi-nones 208 were formed (Equation 15) <1998EJO 237>. 

There have been several reports of the use of intramolecular displacements of nitro groups in the synthesis of heterocyclic compounds. Thus, reaction16 of the intermediate (2) with a strong base in DMF results in the substitution of a nitro group by the amide function to yield a dibenzothiazepinone derivative (3). Nucleophilic addition across the double bond of 2,4,6-trinitrostyrene may occur with thiophenol, aniline, and aliphatic amines. The adducts so formed with primary amines may undergo intramolecular substitution of an o-nitro group to give IV-substituted 4,6-dinitroindoles.17... 

There is continued expansion in the use of metals as catalysts in substitution reactions. Copper iodide in the presence of /V./V -dimcthylcthylcncdiamine has been shown to be effective in the intramolecular substitution of aryl bromides carrying an o-l,3-dicarbonyl substituent reaction may involve either an oxygen centre or a carbon centre of the dicarbonyl moiety.26 The reaction of aryl halides with sodium trifluoroacetate in the presence of copper iodide may lead to the formation of the tri-fluoromethylated derivatives, possibly via CF3CuI as an intermediate.27 There have been theoretical calculations, PM3 and ab initio, on complexes formed from copper... 

Calculations at the B3LYP and MP2 levels of theory with the 6-31+G basis set were used to model the S 2 reactions of the intermediates formed when alkyllithiums were reacted with several 1,1-dibromo- and 1,1-dichloro-alkenes.118 The calculations showed, correctly, that the most sterically constrained halogen was attacked in the first step of the reaction and that the intramolecular substitution reaction in the second step of the reaction occurred by an SN2 mechanism. 

Poor nucleophiles react with acyl isoureas B so slowly that the latter start to decompose. In some sense they acylate themselves. The N atom designated with the positional number 3 intramolecularly substitutes the O-bound leaving group that is attached to the carboxyl carbon Cl. A four-membered cyclic tetrahedral intermediate is formed. When the Cl -Ol bond in this intermediate opens up, the N-acyl urea E is produced. Because compound E is an amide derivative it is no longer an acylating agent (cf. Section 6.2). 

Fig. 6.15. Carboxylic acid activation with DCC. [1,3] means the intramolecular substitution of the oxygen atom 01 by the N atom "3" via a cyclic four-membered tetrahedral intermediate. From the point of view of the heteroatoms, this SN reaction corresponds to a migration of the acyl group R-C=0 from the oxygen to the nitrogen. (Examples for amino acid activations in the form of the pentafluorophenyl ester C or the benzotriazolyl ester D are given in Figure 6.32 (oligopeptide synthesis) and Figure 6.31 (dipeptide synthesis), respectively.

Another intramolecular substitution has been used for the synthesis of an intermediate in a proposed route to 3-substituted benzofurans. A / -methylene-dihydrobenzofuran complex was obtained upon fluoride-induced removal of the SiR3 protecting group from complex 37 (Scheme 16) in an ipso SnAr process. Desilylation resulted in spontaneous cyclization to the stable methylene complex 38 in 89 % yield. No isomerization occurred and the 3-methyl benzofuran complex was not detected [21]. 

The treatment of 4-chlorobutyronitrile, 3-chloropropyl phenyl sulfone, and other related compounds with a base affords 7-halocarbanions which are usually prone to undergo intramolecular substitution to produce substituted cyclopropanes. However, these carbanionic intermediates can be trapped with external electrophilic partners, such as aldehydes, to give alcoholate anions, which then cyclize to produce 2,3-disubstituted tetrahydrofurans in excellent yields (Scheme 78) <2002CEJ4234>. 

The reactive intermediate in a base catalyzed reaction is the deproto-nated substrate. Deprotonation of an alcohol or phenol leads to the formation of an anion which is a stronger nucleophile than the substrate itself. This is of particular interest if the anion may undergo an intramolecular substitution. An example of such a mechanism is the base catalyzed formation of an epoxide... 

A betaine intermediate is formed, the fragmentation of which leads to formation of an oxirane ring by intramolecular substitution by the anionic oxygen (Eq. 89). The sulfonium ylides also react with other types of compounds containing an electrophilic unsaturated bond (C=C, C=N), giving cyclopropane derivatives and aziridines. 

The neighbouring group effect can lead to a retention of configuration, due to two sequential inversions. The reaction proceeds via an intramolecular SN2 reaction to form a cyclic intermediate, which is then opened up by the attack of the nucleophile to form the final product. The intramolecular substitution reaction is favoured over the intermolecular substitution reaction due to the smaller decrease in entropy that such a route necessitates. This intramolecular attack can proceed via three-, five- or six-membered rings, but not four-membered rings. 

Extensive studies by Griitzmacher and co-workers94- 96> clearly established that the elimination of ortho substituents X (X = hydrogen, halide) from 88 is not the result of a one step intramolecular substitution reaction. Instead of this, an addition/ dissociation mechanism operates leading to 90 (18). The rate determining step of the reaction sequence is the formation of the a-complex, 89, which itself has the typical characteristics of a reactive intermediate. 

The cisjtrans ratio of the cyclopropanes formed in this transformation depends to some extent on the nature of the salts and the solvent. A particularly high cisitram ratio was obtained when copper(II) acetate, calcium chloride, and ethanol were employed (no values given). Cyclopropane synthesis from active methylene compounds and nonactivated alkenes was also possible with the help of iodine and a base under phase-transfer conditions. Intra-and intermolecular reactions to give 6 and 5, respectively, have been carried out. The intramolecular reaction is nonstereospecific with respect to the C-C double bond. Although an iodo-substituted intermediate has been isolated in one case, all the details of the reaction mechanism are not yet clear. 

A synthesis of 3 starting from a conformationally flexible D-mannitol A-Boc bis-aziridine derivative 81 has been reported (Scheme 14). The cyclic carbamate-protected pyrrolidine 82 was obtained from 81 via the regioselective bis-aziridine ring opening with Li2NiBr4, followed by Ag+-promoted intramolecular substitution of the bromide by the N -Boc group in 75% overall yield. Nitrous acid deamination of 82 with isoamyl nitrite led, in 50% yield, to a 1 1 mixture of cyclic carbamate protected pyrrolidines 84 and 85 via the intermediate... 

Aldehydes and ketones react with diazomethane with evolution of nitrogen. Diazonium betaines are assumed to be intermediates, and in them electron-attracting groups R such as trichloromethyl or / -nitrophenyl favor intramolecular substitution which affords epoxides in other cases, however, the removal of nitrogen is coupled with 1,2-shifts of hydrogen or alkyl or aryl groups ... 

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