Amines tetrasubstituted, formation

The reactions of nucleophilic substitution with participation of reactive clathrochelates are very sensitive to the donor properties of an attacking amine. With aromatic amines, as well as secondary and primary sterically hindered amines in acceptor solvents, and hexachloride precursors, the reaction stops with the formation of disubstituted products. When secondary and sterically hindered primary aliphatic amines are used in donor solvents and sterically unhindered primary aliphatic amines in acceptor solvents, the reaction terminates at trisubstituted products. In the case of sterically unhindered aliphatic amines, tetrasubstituted clathrochelates are formed. With dichloride precursor FeBd2(C12Gm)(BF)2, the primary aliphatic amines in donor solvents form diamine clathrochelates, whereas the secondary amines (diethylamine or piperazine) give only monoamine complexes both in acceptor and donor solvents. 

Intramolecular rhodium-catalyzed carbamate C-H insertion has broad utility for substrates fashioned from most 1° and 3° alcohols. As is typically observed, 3° and benzylic C-H bonds are favored over other C-H centers for amination of this type. Stereospecific oxidation of optically pure 3° units greatly facilitates the preparation of enantiomeric tetrasubstituted carbinolamines, and should find future applications in synthesis vide infra). Importantly, use of PhI(OAc)2 as a terminal oxidant for this process has enabled reactions with a class of starting materials (that is, 1° carbamates) for which iminoiodi-nane synthesis has not proven possible. Thus, by obviating the need for such reagents, substrate scope for this process and related aziridination reactions is significantly expanded vide infra). Looking forward, the versatility of this method for C-N bond formation will be advanced further with the advent of chiral catalysts for diastero- and enantio-controlled C-H insertion. In addition, new catalysts may increase the range of 2° alkanol-based carbamates that perform as viable substrates for this process. 

Tetrasubstituted pyrroles could be obtained by skeletal rearrangement of 1,3-oxazolidines, a reaction that is substantially accelerated by microwave irradiation. Dielectric heating of a 1,3-oxazolidine 7, absorbed on silica gel (1 g silica gel/mmol) for 5 min in a household MW oven (900 W power) cleanly afforded the 1,2,3,4-tetrasubstituted pyrrole 8 in 78% yield, thus reducing the reaction time from hours to minutes (Scheme 5) [24], 1,3-Oxazolidines are accessible in one-pot, two-step, solvent-free domino processes (see also Sect. 2.6). The first domino process, a multi-component reaction (MCR) between 2 equivalents of alkyl propiolate and 1 equivalent of aldehyde furnished enol ethers 9 (Scheme 5). Subsequent microwave-accelerated solvent-free reactions of enol ethers 9 with primary amines on silica support afforded intermediate 1,3-oxazolidines, which in situ rearranged to the tetrasubstituted pyrroles (2nd domino process). Performed in a one-pot format, these... 

Polysubstituted 1,3-oxazolidines were prepared in a one-pot diversity oriented four-component reaction (4-MCR), comprising two linked domino processes. Thus, domino synthesis of enol ethers 9 was followed by a sequential amine addition-cyclization sequence [74]. While strong microwave irradiation (900 W) of silica-gel absorbed conjugated alkynoates 9 and amines afforded tetrasubstituted pyrroles (via the skeletal rearrangement of 1,3-oxazolidines, see Sect. 2.1 and Scheme 5) [24], the use of milder microwave conditions (160 W power, 90 min) furnished 1,3-oxazolidines. Under these mild conditions the 1,3-oxazolidines did not rearrange to pyrroles and with respect to diastereoselectivity, the 1,3-oxazolidines were obtained as mixtures of syn/anti isomers. Overall, the formation of one C-C bond, one C-0 bond, two C - N bonds and a ring in this MCR required less than 3 hours and utilized simple and commercially available reagents (Scheme 26). 

The reactions of phenyl-, i-butyl- and fluoroboron-capped hexachloride iron(II) precursors with aliphatic amines proceeded under steady-state conditions of the solvent, temperature, and reaction time to produce clathrochelates of only one type irrespective of the nature of the substituent at the boron atom (Scheme 18). Therefore, the reactions of the phenylboronic Fe(Cl2Gm)3(BC6H5)2 precursor were studied. The reaction of precursor with n.-butylamine in DMF, benzene, THF, and /i-butylamine as the solvent led to the formation of only tetrasubstituted clathrochelate, whereas the reaction in chloroform unexpectedly resulted in trisubstituted clathrochelate, which underwent further functionalization in DMF with re-butylamine and cyclohexylamine but did not react with diethylamine (Scheme 18). 

In the case of primary aliphatic amines, the reaction products are dramatically affected by the solvent employed. For instance, in the presence of solvents apt to produce a specific solvation of amines (chloroform, and an amine chlorohydrate solution in methylene dichloride), the reaction with hexachloride precursors terminates to yield the trisubstituted product DD D" formed via route A. At the same time, the use of some other solvents (such as benzene, 1,4-dioxane, THF, methylene dichloride, DMF, and alcohols, or the corresponding amine media) led to the formation of the sole tetrasubstituted product (DD"D"). In addition, in the case of sterically unhindered primary amines an alternative isomer (D D D") is not isolated, which indicates reaction route A and a specific control of the tie reaction in the transition state by solvation interactions and intramolecular hydrogen bonds. In the case of the dichloride FeBd2(C12Gm)(BF)2 precursor, with both primary (cyclohexylamine) and secondary (diethylamine and piperazine) aliphatic amines, only a monosubstituted product of the Bd2D type is formed in chloroform, whereas in some other solvents, a diamine clathrochelate of the Bd2D" type is obtained with both sterically hindered and unhindered primary aliphatic amines. 

R. Bossio and co-workers developed a novel method for the synthesis of tetrasubstituted furan derivatives. The Passerini reaction between arylglyoxals, isocyanides, and cyanoacetic acids led to the formation of A/-substituted 3-aryl-2-cyanoacetoxy-3-oxopropionamides, which in the presence of amine bases underwent a Knoevenagei condensation providing A/-substituted 3-aryl-cyano-2,5-dihydro-5-oxofuran-2-carboxamides. 

SCHEME 29 Formation of tetrasubstituted imidazoles from benzils, aldehydes, amines, and ammonium acetate. 

The palladium-catalyzed cross-coupling of vinyl halides with secondary amines leads to the formation of tertiary enamines (Scheme 3.114) [120]. The catalyst system was comprised of a soluble source of Pd(0) along with a bisphosphine hgand as well as a base to consume the acid generated in the reaction. Several secondary amines were successfully used along with a host of vinyl bromides to afford the enamines in moderate to good yields. Even the use of tetrasubstituted alkenes such as 2-bromo-3-methyl-2-butene participated in the N-vinylation reaction. 

Alkynyl substituted ketones react with primary amines in the presence of iron(lll) chloride to form tetrasubstituted and pentasubstituted pyrroles as well as fused pyrrole derivatives in good to excellent yields (Scheme 4—287). The reaction probably proceeds via enamine formation and subsequent intramolecular 5-exo-dig aminoferration of the triple bond (Scheme 4-288). Protonation of the T -alkenyliron complex and isomerization affords the pyrrole. Iron(Ill) chloride is released to initiate a new catalytic cycle. ... 

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