Imines formation, intramolecular

As a benzodiazepine-type drug, alprazolam is used to treat anxiety and panic disorders. The synthesis starts with a hydrazine benzodiazepine derivative followed by the imine formation, intramolecular cyclization, and oxidation to obtain alprazolam. ... 

Another type of bifunctional catalysis has been noted with a,cn-diamines in which one of the amino groups is primary and the other tertiary. These substituted diamines are from several times to as much as 100 times more reactive toward imine formation than similar monofunctional amines. This is attributed to a catalytic intramolecular proton transfer. 

Two possible mechanisms exist for the Friedlander reaction. The first involves initial imine formation followed by intramolecular Claisen condensation, while the second reverses the order of the steps. Evidence for both mechanisms has been found, both... 

An interesting reaction ensues when the intermediate synthetic precursor (65) to synthon 60 is heated with phenylenediamine. The reaction can be rationalized as involving initial enamine-imine formation (66), followed by intramolecular attack on the ester carbonyl groups resulting in carbamate formation (67), which carbamate undergoes intramolecular trans-amidation to give urea 66. Other scenarios can be proposed and defended, but the net result is formation... 

Fig. 11.20. Examples of intramolecular imine formation in the metabolism of U-54494A... 

Imine formation is an important reaction. It generates a C-N bond, and it is probably the most common way of forming heterocyclic rings containing nitrogen (see Section 11.10). Thns, cycliza-tion of 5-aminopentanal to A -piperideine is merely intramolecular imine formation. A further property of imines that is shared with carbonyl groups is their susceptibility to reduction via complex metal hydrides (see Section 7.5). This allows imines to be... 

A general and efficient synthesis of 5-oxygenated indoles 126 and 128 has been reported by Kita et al. (92H503). The method involves intramolecular imine formation from p-benzoquinones 125 and p-benzoquinone monoacetals 127 bearing the 2-aminoethyl side chain. Compounds 125 and 127 are prepared by the oxidation of 124 with IBTA in acetonitrile in the presence of water and methanol, respectively (Scheme 35). 

When DHAP-dependent aldolases are used as catalyst of the aldol reaction, a phosphorylated azido or amino polyhydroxyketone is obtained. The phosphate may be cleaved enzymatically or reductively cleaved under the hydrogenation conditions of the next step in which the azide is reduced to the amine. Intramolecular imine formation occurs spontaneously when the azide is reduced. The intramolecular reductive amination is the second key step of the aldolase-mediated synthesis of iminocyclitols. In general, delivery of hydrogen onto five- and six-membered ring imines occurs from the face opposite to the C4 hydroxyl group. 

Intramolecular imine formation has also been successfully applied to the synthesis of bicyclic iV-sulfonylketeni-mines 105 and 97 (Scheme 27) <2002HCA1973, 1997JOC3625>. In these cases, cyclization occurs under either basic or acidic conditions from the primary iV-sulfonamides 200 and 201 in high yield. 

Intramolecular imine formation between a coordinated aminate ion and a 2-oxo acid has been utilized to synthesize the two racemic amino acids 2-cyclopropylglycine and proline.463 Thus anation of [Co(NH3)5OH2]3+ by Br(CH2)3C0C02H at pH 5 gives two major products (145) and (146). Both are converted to tetraammineiminocarboxylato chelates by attack of an adjacent deprotonated ammonia. The cyclopropylimine complex can, for example, be reduced by alkaline BH4 to give the (RS)-2-cyclopropylglycine complex. 

In a very significant development, the parent 277-azepine 85 was prepared for the first time (Scheme 10) <1995AGE1469>. A ring construction was adopted involving A-BOC deprotection of 84 followed by treatment with strong base to afford 85 after intramolecular imine formation and base-induced elimination of acetate. While the yield was only 1%, the azepine was sufficiently stable at 25 °C for 48 h to allow for H and 13C NMR spectroscopic characterization. 

A sequence comprising an Oppenauer-type oxidation, intramolecular imine formation, and reduction, a process mediated by the iridium catalyst [Cp hG 2]2 and K2C03 in toluene at 120 °C for several days, afforded the structurally simple l-methyl-2,3,4,5-tetrahydro-177-benzo[l,4]diazepine in 68% yield from iV-(2-aminophenyl)-(Af-methylamino)propan-l-ol (Scheme 68) <2006TL6899>. 

The design of polydentate ligands containing imines has exercised many minds over many years, and imine formation is probably one of the commonest reactions in the synthetic co-ordination chemist s arsenal. Once again, the chelate effect plays an important role in stabilising the co-ordinated products and the majority of imine ligands contain other donor atoms that are also co-ordinated to the metal centre. The above brief discussion of imine formation will have shown that the formation of the imine from amine and carbonyl may be an intra- or intermolecular process. In many cases, the detailed mechanism of the imine formation reaction is not fully understood. In particular, it is not always clear whether the nucleophile is metal-co-ordinated amine or amide. Some intramolecular imine formation reactions at cobalt(m) are known to proceed through amido intermediates. A particularly useful intermediate (5.24) in metal-directed amino acid chemistry is... 

This is one of the finest single-step transformations in the chemical literature. Note that five reactions are achieved in one pot hydrogenation of two double bonds, Cbz deprotection, intramolecular imine formation, and convex-face alkene hydrogenation that establishes the n-Pr stereocenter. 

Thus, it is likely, that after imine formation a second catalyst precoordination occurs and an intramolecular imine hydrogenation takes place. Such an intramolecular process should be kinetically favored compared to a corresponding intermolecular reaction pathway. Hence, the catalyst-directing o-DPPB group may be acting within one sequential transformation in... 

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. 

As mentioned previously, the cyclization of phenethyl ketone oximes with [Bu4N]Re04 and CF3SO3H and the cyclic imine formation from 0-sulfonyl oximes both proceed by intramolecular S 2-type reaction on the nitrogen atom of the oximes (Scheme 33). ° In contrast, both of the E- and Z-isomers cyclized smoothly and only 8-hydroxyquinoline was obtained regioselectively without forming 6-hydroxy derivatives. These phenomena are not consistent with a nucleophilic substitution reaction, and the cyclization of 0-2,4-dinitrophenyloxime 80a seemed to proceed by another reaction pathway (Scheme 37). To check isomerization of the 0-2,4-dini-trophenyloxime 84, the Z-isomer was treated with NaH and m-cresol. The isomerization of (Z)-84 hardly occurred, but 4-phenylbutan-2-one azine (85) and 4-phenyl-2-butanone (86) were obtained in 27 and 11%... 

Although cyclization can take place in many ways, according to Kallen [11] the most preferred pathway involves imine formation followed by intramolecular cyclization. During the course of cyclization a new chiral center at C-2 is created thereby giving rise to a diastereomeric mixture namely 2R, 4R and 2S, 4R. An interesting situation arises when the reactant aldehyde is also chiral. The stereochemistry at the newly formed center is controlled by the stereochemistry of the aldehyde [12]. In view of the biological importance of thiazolidine, Patek et al. reported a solid-phase synthesis protocol (Scheme 4) [13]. This enables the synthesis of compound libraries for quick lead optimization. 

The alkaloid (+)-pinidine81 (4) is obtained as a single a s-stereoisomer in a one-pot transformation of the chiral methyl sulfide 3 via oxidative amination, rearrangement, intramolecular imine formation and stereoselective reduction. 

The nitrogen atom is more nucleophilic than the oxygen atom so we should start with the amine attacking the carbonyl group. The first product will be an imine and addition of the alcohol to that gives the product. Imine formation is acid-catalysed but occurs quite rapidly at neutral pHs and the intramolecular second step is fast. The whole system is under equilibrium but the other product, water, is driven off as an azeotrope with benzene so the equilibrium is driven over to give the... 

The following example is an intramolecular reaction similar to the aldol reaction. A deprotonated nitrile (nitrile enolate) acts as a nucleophile and adds via an AdN to another nitrile. The acidic water workup is the reverse of imine formation. Section 10.5.2. 

Imine formation. An example of this route is Echavarren and Stille s use of a simple intramolecular imine formation between a quinone moiety and an amino group to complete the nucleus (Scheme 25) of amphi-medine 105 (88JA4051). The quinone 159 was prepared by a palladium-catalyzed cross-coupling of 5,8-dimethoxyquinolin-4-yl triflate 157 (from... 

Lactacystin 97 inhibits cell proliferation and induces neurite outgrowth as a result of proteosome-mediated peptidase inhibition. In one approach to this target, the a,a-disubstituted a-amino acid contained in this molecule was assembled using an intramolecular asymmetric Strecker reaction.43 Esterification of a-hydroxyketone 93 with Boc-Z,-Phe afforded ester 94. Deprotection of the Boc group and intramolecular imine formation preceeded the addition of cyanide to produce 95. Ozonolysis and treatment with cone. HC1 gave rise to the desired amino acid 96. This advanced intermediate constituted a formal total synthesis of lactacystin 97. 

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