Intramolecular bonds, formation

The selectivity, functional group tolerance, and mild reaction conditions of the various Pd° cross-coupling reactions have made them invaluable tools for carbon-carbon bond formation. Intramolecular variations to construct macrocycles have also been described. 

The scope aromatic C-N bond formation extends beyond simple amine substrates. For example, selected imines, sulfoximines, hydrazines, lactams, azoles, and carbamates give useful products from intermolecular aromatic C-N bond formation. Intramolecular formation of aryl amides has been reported. In addition, allylamine undergoes arylation, providing a readily cleaved amine alternative to the ammonia surrogates benzylamine, t-butylcarbamate, or benzophenone imine. Although it is an amine substrate, the reaction of this reagent is included here because of its special purpose. 

Figure 21 Attempts to clipping by covalent bond formation. Intramolecular cycli2ation of (50) provided only the extraannual isomer (51). The intraannular isomer (52) was not isolated [42].

Abstract Direct sp C-H bond functionalization is an efficient, straightforward, and powerful method to construct new C-X (X=C, N, F, S) bonds from nonfunctionalized aliphatic motif of organic molecules, which has been used in late-stage modification of complex molecules. In this chapter, the recent developments of silver-mediated direct sp C-H functionalizations are reviewed, categorized by C-C bond formation (C-H insertion), C-N bond formation (intramolecular and intermolecular amination/amidation), C-F bond formation, and C-S bond formation. 

Quinazolinones can be accessed using a similar intermolecular C—N bond formation/intramolecular condensation-cyclization strategy. For example, the Fu research group reported an elegant synthesis using o-bromobenzoic acid substrates and amidines under particularly mild conditions (Scheme 24.26) [101]. The use of such conditions can be attributed to the formation of a chelated... 

Syntheses of alkenes with three or four bulky substituents cannot be achieved with an ylide or by a direct coupling reaction. Sterical hindrance of substituents presumably does not allow the direct contact of polar or radical carbon synthons in the transition state. A generally applicable principle formulated by A. Eschenmoser indicates a possible solution to this problem //an intermolecular reaction is complex or slow, it is advisable to change the educt in such a way. that the critical bond formation can occur intramolecularly (A. Eschenmoser, 1970). 

Although a variety of oxidizing agents are available for this transformation it occurs so readily that thiols are slowly converted to disulfides by the oxygen m the air Dithiols give cyclic disulfides by intramolecular sulfur-sulfur bond formation An example of a cyclic disulfide is the coenzyme a lipoic acid The last step m the laboratory synthesis of a lipoic acid IS an iron(III) catalyzed oxidation of the dithiol shown... 

Construct molecular models of the gauche and anti conformations of 1 2 ethanediol and explore the possibility of intramolecular hydrogen bond formation in each one... 

Oxidative Ring Closure Reactions 4.03.4.1.1 C—N bond formation N—N bond formation C—S bond formation N—S bond formation O—C bond formation O—N bond formation S—S, S—Se and Se—Se bond formation Electrophilic Ring Closures via Acylium Ions and Related Intermediates Ring Closures via Intramolecular Alkylations... 

Carbon-Carbon Bond Formation 4.03.8.3.1 Intramolecular reactions... 

The first benzazetidine (243) was isolated from the photolysis of 3-phenyldihydroben-zotriazine (242) (66JA1580). Another route to benzazetidines involving formation of the N to aryl-C bond utilizes intramolecular nucleophilic substitution via aryne (287). It is not general, however, and is only satisfactory when R and/or are alkoxy groups. The reaction also fails for iV-alkylamines (78LA608). 

GOMBERG - BACHMANN - GRAEBE - ULLMANN Arylatwn Atykaryl bond formation via diazonium salts Carbazole synthesis by intramolecular aryl-aryl bond formation. 

One-bond formation through (5+0) atoms intramolecular heterocyclization of pyrimidines having an -N-N-C appendage at Nl(3) and a leaving group at C4(6) (Scheme 6). 

Double ring-closure comprising two-bond formation by intramolecular heterocyclrzation of (9-10) atoms open structures consisting of five carbons and four nitrogens (C5N4) (Scheme 32). 

Intramolecular Pd(0)-catalyzed Stille reaction of organotin reagents with electrophiles leading to C—C a-bond formation in synthesis of heterocycles, particularly, macrocyclic lactones 99JCS(P1)1235. 

For reactions of A-acyliminium ions with alkenes and alkynes one has to distinguish between A-acyliminium ions locked in an s-trans conformation and those which (can) adopt an s-cis conformation. The former type reacts as a (nitrogen stabilized) carbocation with a C —C multiple bond. Although there are some exceptions, the intramolecular reaction of this type is regarded as an anti addition to the 7t-nucleophile, with (nearly) synchronous bond formation, the conformation of the transition state determining the product configuration. 

Microwave-assisted intramolecular C - N bond formations have also been studied. Substituted benzimidazoles were easily prepared from the corresponding M-(2-bromophenyl)imidoformamides by Brian et al. (Scheme 102) [ 104]. The protocol involved the use of a combination of Pd2 (dba)3 and PPha in a mixture of DME and water using NaOH as the base at 160 °C. It was apphca-ble for electron poor, neutral and rich as well as sterically hindered amidines. The fastest reactions were obtained with an electron withdrawing substituent... 

Cyclic structures can form as a result of side reactions. One of the most common examples is the formation of diketopiperazines during the coupling of the third amino acid onto the peptide chain (Fig. 7). Intramolecular amide bond formation gives rise to a cyclic dipeptide of a six-membered ring structure, causing losses to the sequence and regeneration of the hydroxyl sites on the resin. The nucleophilic group on the resin can lead to fiuther unwanted reactions [14]. 

In the preceding sub-section it was shown that one reason for increased values in pyridinocrowns [9] was the possibility of intramolecular hydrogen bond formation. In macrocycles containing more than one pyridine unit, such stabilization is even more hkely. Table 11 lists pK values for a number of polypyridinocrowns [25]-[26]. 

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