Intramolecular 1,2-addition

Intramolecular Michael addition of nitro compounds proceeds in a stereoselective way to give various types of cyclic nitro compounds with high stereoselectivity. The Michael addition of 1-acetylcyclohexene to nitrostyrene followed by treatment with MeONa in MeOH gives 4-nitro-3-phenyldecalone with high stereoselectivity (Eq. 4.128).175 

Double Michael additions of nitro compounds bearing tethered acidic carbons to 3-butyn-2-one under NaH catalysis give nitrocyclohexanes with high stereoselectivity. The products are transformed into traws-fused bicyclic compounds via the Dickmann reaction on treatment with base. (Eq.4.129).176 

Barco and coworkers have reported a more elegant synthesis of the nitrocyclohexanone via the double Michael addition of nitromethane with enones. (Eq. 4.130).178 

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In principle, the direct hydride addition or catalytic hydrogenation, which did not give chlorins, was replaced by an electrocyclic intramolecular addition which is much easier with the above system. Complete regioselectivity was also achieved since electrocyclization did not occur with the resonance-stabilized ring C. 

Amines undergo aminopalladation to alkynes. The intramolecular addition of amines to alkynes yields cyclic imines. The 3-alkynylamine 273 was cyclized to the 1-pyrroline 274, and the 5-alkynylamine 275 was converted into the 2,3,4,5-tetrahydropyridine 276[137]. Cyclization of o-(l-hexynyl)aniline (277)... 

The reaction of propiolic acid or its esters with 2-aminothiazole yields 7H-thiazolo[3.2o]pyTimidine 7-one (109) (Scheme 74) (273), The reaction probably proceeds by initial nucleophilic attack of 2-aminothiazole on the sp C followed by intramolecular addition of ring nitrogen to spC. 

The synthetic application of reactions based upon the intramolecular addition of a carbanion or its enamine equivalent to a carbonyl or nitrile group has been explored extensively. One class of such reactions, namely the Dieckman, has already been discussed in Section 3.03.2.2, since ring closure can often occur so as to form either the C(2)—C(3) or C(3)—C(4) bond of the heterocyclic ring. Some illustrative examples of the application of this type of ring closure are presented in Scheme 46. 

An unusual case of addition of a carbanion to an unconjugated carbon-carbon double bond is shown in Scheme 47a. The subsequent transfer of the amide group is also noteworthy (80CC1042). The intramolecular addition of a carbanion to an aryne is a more widely established process. Such reactions have been applied to the synthesis of indoles (Scheme 47b) (75CC745> and oxindoles (Scheme 47c) (63JOC1,80JA3646). 

In this group of intramolecular additions the reaction apparently proceeds via an intermediate carbocation whose presence was established by NMR data. 

Tl mediated Inter or intramolecular addition of allytic silanes to ouMnsaiurated ketones or to aldehydes. 

These reactions can also be used to achieve cyclization by intramolecular addition. 

Intramolecular addition reactions are quite common when radicals are generated in molecules with unsaturation in a sterically favorable position. Cyclization reactions based on intramolecular addition of radical intermediates have become synthetically useful, and several specific cases will be considered in Section 10.3.4 of Part B. 

In this series of amides, hydrolysis or aminolysis of a simple ester, cleavage of a silyl groups a cis/trans isomerization, or reduction of a quinone to a hydro-quinone exposes an alcohol that then induces deprotection by intramolecular addition to the amide carbonyl. 

The mechanism of the indolization of aniline 5 with methylthio-2-propanone 6 is illustrated below. Aniline 5 reacts with f-BuOCl to provide A-chloroaniline 9. This chloroaniline 9 reacts with sulfide 6 to yield azasulfonium salt 10. Deprotonation of the carbon atom adjacent to the sulfur provides the ylide 11. Intramolecular attack of the nucleophilic portion of the ylide 11 in a Sommelet-Hauser type rearrangement produces 12. Proton transfer and re-aromatization leads to 13 after which intramolecular addition of the amine to the carbonyl function generates the carbinolamine 14. Dehydration of 14 by prototropic rearrangement eventually furnishes the indole 8. 

Taylor has reported a number examples of intramolecular variations directed towards heterocyclic systems.The following two reactions are representative. Intramolecular addition of triazine 79, after loss of nitrogen afforded 80. Alternatively, triazine 81 generated bicyclic systems 82 which could be oxidized to 83. 

Intramolecular addition of the amide group to the triple bond in pyrazoles is more difficult, and results in closure of the 5-lactam rather than the y-lactam ring. The reaction time of the 4-phenylethynylpyrazole-3-carboxylic acid amide under the same conditions is extended to 42 h (Scheme 129) (Table XXVII). The cyclization of l-methyl-4-phenylethynyl-l//-pyrazole-3-carboxylic acid amide, in which the acetylene substituent is located in the 7r-electron-rich position of the heterocycle, is the only one complete after 107 h (Scheme 130) (90IZV2089). 

The reaction of the carbinol 198 with acetone leads to dienic 1,3-dioxolanes 200 as a result of the intramolecular addition of the hydroxyl group of the intermediate hemiacetal 199 to its triple bond (73ZOR1594). 

Further intramolecular addition of the C8 carbocation to the 13,14 double bond occurs with nonHMarkovnikov regio-chemistry and gives a tricyclic secondary carbocation at Cl3. 

Vinyl radical formation by intramolecular addition of a carbon-centered radical to an alkyne... 

This section describes Michael-analogous processes in which, mostly under electrophilic conditions, ally - or alkynylsilanes undergo addition to enones or dienones (Sakurai reactions). The intramolecular addition of allylsilanes is an extremely useful reaction especially for the construction of carbocyclic ring systems, which occurs in a diastereoselective manner, in many cases with complete asymmetric induction. 

For 10 years, attention has been focused on the intramolecular additions ofallylic and alkynyl-silanes to enones. In early studies, a variety of Lewis acids were tested and reaction conditions were optimized to make this reaction a powerful tool in the synthesis of spiro-annulated, and 1,2-fused ring systems, which can be utilized in the total synthesis of natural products34,35. 

Analogous to the allylsilane cyclizations, alkynylsilanes can also be used to synthesize 1,2-fused bicyclic compounds. The intramolecular addition of 4-[5-(trimethylsilyl)-3-pentynyl]-2-cyclo-hexenone proceeded smoothly in the presence of various Lewis acids, yielding functionalized cw-fused octahydro-5/f-inden-5-ones containing the synthetically useful terminal allene unit45. 

The 1,6-intramolecular addition of unsymmetrical allylsilanes to conjugated dienones proceeded to give a trans relation between the angular substituents and the vinyl groups (complete 1,3-asymmetric induction). Ethylaluminum dichloride has been most successfully used in all reactions described35-53. 

The intramolecular Michael addition of acyclic systems is often hampered by competing reactions, i.e., aldol condensations. With the proper choice of Michael donor and acceptor, the intramolecular addition provides a route to tram-substituted cyclopentanones, and cyclopentane and cyclohexane derivatives. Representative examples are the cyclizations of /3-oxo ester substituted enones and a,/J-unsaturated esters. 

The rate of radical addition is most dramatically affected by substituents either at the site of attack or at the radical center. Remote substituents generally have only a small influence on the stereochemistry and regiospecificity of addition unless these groups are very bulky or the geometry of the molecules is constrained (e.g. intramolecular addition - Section 1,2.4). 

Geometric considerations in cyclopolymerization are optimal for 1,6-dienes (see 4.4.1.1). Instances of cyclopolymerization involving formation of larger rings have also been reported (see 4.4.1.4), as have examples where sequential intramolecular additions lead to bicyclic structures within the chain (see 4.4.1.2). Various 1,4- and 1,5-dienes are proposed to undergo cyclopolymerization by a mechanism involving two sequential intramolecular additions (see 4.4.1.3). 

The explanation proposed involved sequential inter- and intramolecular addition steps. The presence of cyclic structures within the polymer chain was soon confirmed by degradation experiments.106 However, these experiments did... 

It has also been proposed that the ring-opened radicals may undergo ring-closure to a cyclobutane (Scheme 4.23).202,2 8 At this stage the only evidence for this pathway is observation of signals in the NMR spectrum of the polymer that cannot be rationalized in terms of the other structures. There is no precedent for 1,4-ring-closure of a 3-butenyl radical in small molecule chemistry and the result is contrary to expectation based on stcrcoclcctronic requirements for intramolecular addition (Section 2.3.4). However, an alternate explanation has yet to be proposed. The possibility of carbonium ion intermediates should not be discounted. 

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