Development of an Efficient Process for the Preparation of Sch 39166:  Aziridinium Chemistry on Scale

Gala, Dinesh; Dahanukar, Vilas H.; Eckert, Jeffery; Lucas, Brian S.; Schumacher, and Doris P.; Zavialov, Ilia A.; Buholzer, Patrik; Kubisch, Peter; Mergelsberg, and Ingrid; Scherer, Dominik

doi:10.1021/op0402026

Cited by 25 publications

(14 citation statements)

References 12 publications

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“…The use of the salt also removes impurities and improves the chiral purity of the reduced product. The use of sulfuric acid in sulfolane had no effect on the oxalate salt (Scheme ) …”

Section: Selected Examples Of Reactions In Sulfolanementioning

confidence: 99%

“…The use of sulfuric acid in sulfolane had no effect on the oxalate salt (Scheme 2). 4 In 1967 Whiting et al found that a 1:1 mixture of polyphosphoric acid (PPA) and sulfolane is a good reaction medium for the cyclization of the tetrahydronaphthol (7) to hexahydrobenzophenanthrene (8) at 125 °C for 1 h (Scheme 3). 5 Wild, et al used a 1:4.2 mixture of sulfolane and PPA to cyclize acid 9 to the dibenzocycloheptadienone (10) at 110 °C for 4 h in 24 volumes of the mixture.…”

Section: ■ Introductionmentioning

confidence: 99%

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Sulfolane: A Versatile Dipolar Aprotic Solvent

Tilstam¹

2012

Org. Process Res. Dev.

157

124

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Sulfolane is a highly stable and attractive alternative to other more common dipolar aprotic solvents such as DMSO, DMF, DMAC, and NMP. Sulfolane is more toxic than the other solvents but has a very low skin penetration in comparison to that of the others. A high skin penetration is not beneficial for organic solvents as dissolved toxic compounds might be transferred through the skin. Sulfolane has a high dipole moment (μ = 4.7 debye), elevated relative permittivity (ευ = 43.4), and a high Hildebrand solubility parameter (δ = 27.2 [MPa]1/2). This means a high solvency power for reactions containing polarizable intermediates. Sulfolane is capable of strong solvation of cations by the oxygens in the sulfone group which increases the nucleophilicity of the corresponding less solvated anions. With its high stability against strong acids and bases as well as its thermal stability sulfolane is a solvent that can be operated within a wide range of reaction conditions. This makes it the solvent of choice for different acid-catalyzed reactions at elevated temperatures. Sulfolane has also found use in halo exchange reactions for the formation of various fluoroaromatic compounds. It has also been used as solvent for oxidations, nitrations, rearrangements, phosphonylations, and condensation reactions.

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“…The use of the salt also removes impurities and improves the chiral purity of the reduced product. The use of sulfuric acid in sulfolane had no effect on the oxalate salt (Scheme ) …”

Section: Selected Examples Of Reactions In Sulfolanementioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Sulfolane: A Versatile Dipolar Aprotic Solvent

Tilstam¹

2012

Org. Process Res. Dev.

157

124

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“…53 The use of b-amino alcohol 147 as the starting material for the synthesis of ecopipam is an interesting example where the rearrangement of a b-amino alcohol C was realized on an industrial scale. 54 The ecopipam precursor 150 was obtained by nucleophilic attack of the arylmagnesium bromide 149 on the benzylic position of the aziridinium 148. The rearrangement of b-amino alcohol 147 was achieved in a wide range of yields (0-84%) by activation of the hydroxy group with phosphorusbased reagents.…”

Section: R 3 = Alkylmentioning

confidence: 99%

Rearrangement of β-amino alcohols via aziridiniums: a review

et al. 2010

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This tutorial review focuses on the rearrangement of b-amino alcohols via aziridinium intermediates. It covers the literature from 1947 to January 2009 (55 references). The rearrangement of b-amino alcohols can be performed by activation of the hydroxy group followed by the addition of nucleophiles (Nu). In most examples, an aziridinium intermediate is involved in the rearrangement. The ratio of amines resulting from the attack of nucleophiles at either the C-1 or C-2 position of the aziridinium intermediate, depends on the nature of the nucleophiles and the R 2 substituent. In some cases, solvent as well as temperature can influence the ratio of amines.Aziridines have been extensively used as useful building blocks. 1,2 The control of the regio-and stereoselectivity in the opening of aziridines provides convenient access to chiral nitrogen-containing compounds. [3][4][5][6] Although N,N-dialkyl aziridiniums are stronger electrophiles than neutral aziridines, their use as key intermediates in organic synthesis is rare. [7][8][9] Aziridiniums, generally obtained through activation of b-amino alcohols, can be opened by a wide range of nucleophiles with or without rearrangement depending on the regioselectivity of the nucleophilic attack.This review covers only the rearrangement of b-amino alcohols of type A, B, and C (Fig. 1) as the rearrangement of prolinols of type D has been recently covered. 10

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“…The safety concerns are minimized with the use of Eaton's reagent since the resultant mixtures are more mobile solutions with temperature requirements much lower than that of PPA. Although the use of Eaton's reagent as a dehydrating agent in various reactions is well documented, Eaton's reagent-mediated cyclization of phenyl acetamide derivatives with formaldehyde was not available in the literature [7][8][9][10][11][12][13][14][15] . Cyclization of phenyl acetamides using Eaton's reagent was broadened to understand the scope and limitation of the process.…”

Section: Discussionmentioning

confidence: 99%