Intramolecular SN reactions

Step 1 of the Edman degradation is the addition of the NH2 group of the N-ter-minal amino acid to the C=N double bond of phenyl isothiocyanate. Step 2 (B —> C) is an intramolecular SN reaction of an S nucleophile on the carboxyl carbon of a pro-tonated amide. It follows the substitution mechanism shown in Figure 6.5. The substitution product C is a heterocyclic derivative of the N-terminal amino acid. The simultaneously formed second reaction product, the oligopeptide D, which has been shortened by one amino acid, is ejected as the leaving group. 

If an acceptor-substituted C=C double bond is attacked in the first step of these ylide reactions and a zwitterion is formed whose anionic moiety is an enolate, then a cyclopropane is produced in the ensuing intramolecular SN reaction. On the other hand, if a C=0 double bond is attacked in the first step and an alkoxide results, then the subsequent SN reaction gives an epoxide. 

It is well known that enolates act as O-nucleophiles in Sisr -type cyclizations to furnish alkylidene tetrahydrofurans (Equation 72) <2004JOC6715>. A double intramolecular Sn reaction with O-nucleophiles to yield bis-tetrahydro-furan cores of acetogenins has been achieved <1999JOC2259>. 

An effective approach to condensed heterocyclic systems is the use of intramolecular nucleophilic substitution of hydrogen. The key role of the Sn step has been demonstrated by the synthesis of quinoxalines condensed with five- and six-membered heterocycles starting firom 2-aminoquinoxaline [166] or quinoxaline-2-carbaldehyde [167, 168], correspondingly. Indeed, 2-aminoquinoxaline can be condensed with acetylacetone or other p-dicarbonyl compounds to give after oxidative intramolecular Sn reaction pyrrolo[2,3-i>]quinoxalines in good yields (Scheme 52) [166]. Also condensation of quinoxaline aldehyde with ethyl... 

The ring-closure involves an intramolecular Sn reaction. Thus, piperidines are also formed by cychzing 1,5-dihalogenoalkanes with primary amines. 

Scheme 3.88 Activation through eneyne-allene conversion by an intramolecular Sn reaction (Shibuya) [26, 342]. TFA.

A SN reaction-based domino route to clerodane diterpenoid tanabalin (2-488) [258] has been described by Watanabe s group (Scheme 2.111) [259]. This natural product is interesting as it exhibits potent insect antifeedant activity against the pink bollworm, Pectinophora gossypiella, a severe pest of the cotton plant The domino sequence towards the substituted trans-decalin 2-487 as the key scaffold is induced by an intermolecular alkylation of the (5-ke toes ter 2-484 with the iodoalkane 2-483 followed by an intramolecular Michael addition/aldol condensation (Robin-... 

The following example completes the section of threefold anionic domino processes initiated by a SN-type reaction. As discussed earlier in Section 2.2, the reaction of a five-membered cyclic phosphonium ylide with enones, a, 3-unsaturated esters, and a, 3-unsaturated thioesters provides cycloheptene or hydroazulene derivatives in a domino Michael/intramolecular Wittig reaction. This sequence... 

Stereochemical investigation on the vinylogous 1,5-elimination reactions of 16 to give cyclopropylalkenes has revealed highswi stereoselectively of the intramolecular SN process (equation 18)30. The stereoselectivity of the cyclization reaction of 17 to give the ( )-isomer is improved by the increase in steric bulkiness of the sulfonyl substituent (equation 19)31. 

The Sn(Oct)2 catalyst is generally active at elevated temperatures, leading to some intermolecular and intramolecular transesterification reaction [140]. Recently, a new catalyst system for the ROP of lactones has been reported, based on tin(II) or scandium(III) trifluoromethanesulfonate [141,142]. These catalysts are very versatile, and highly selective, and they can be used under mild conditions. 

Figure 2.6 shows several methylations, which in each case take place as one-step SN reactions. The nucleophile is in each case a sulfonyl anion a methyl (arenesulfonate) reacts as electrophile. These classic experiments were carried out to clarify whether these methylations take place inter- or intramolecularly. 

The intramolecular methylation of the substrate of Figure 2.6, which was not observed, would have had to take place through a six-membered cyclic transition state. In other cases, cyclic, six-membered transition states of intramolecular reactions are so favored that intermolecular reactions usually do not occur. Why then is a cyclic transition state not able to compete in the SN reactions in Figure 2.6 ... 

In the SN reactions of Figure 2.6, the endocyclic restriction would therefore impose a geometry in an intramolecular substitution that is energetically disfavored relative to the... 

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.

According to this equation, the product is indeed produced by an SN reaction because the nucleophile displaces an oxyanion as a leaving group from the attacked C atom. Nonetheless this oxyanion is still a part of the reaction product. In this respect this reaction can also be considered to be an addition reaction. An intermolecular addition reaction is one that involves the combination of two molecules to form one new molecule. An intramolecular addition reaction is one that involves the combination of two moieties within a molecule to form one new molecule. 

An interesting sequence based on an intermolecular Michael addition and a subsequent transition metal-catalyzed carbocyclization was recently explored. Much of the development of this strategy relies on recent studies related to the intramolecular carbometalation reaction of stabilized carbanions bearing an unactivated alkynyl group. Several transition metal complexes such as Cu [52], Pd [53], Ti [54], Zn [55], Co [56] and Sn [57] have been reported to catalyze this reaction (Scheme 17). 

FeCls is superior to Al, Sn, and Zn Lewis acids in the intramolecular ene reaction of the Knoevenagel adduct from citronellal and dimethyl malonate (Sch. 61) [207]. 

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