A Convenient Dehydration Procedure for the Synthesis of Enantiomerically Pure Cyanohydrins

Abstract

Starting from protected a-hydroxy amides, cyanohydrins (a-hydroxy nitriles) are obtained through dehydration by cyanuric chloride/DMF in excellent yield. The advantages of the procedure are the extremely mild reaction conditions that prevent racemization.Cyanohydrins (a-hydroxy nitriles) are commonly synthesized by the addition of hydrocyanic acid to an aldehyde, as described in several standard textbooks of organic chemistry. 1 Naturally, this method yields racemic mixtures of a-hydroxy nitriles. Starting from an aldehyde, enantiomerically pure a-hydroxynitriles can be obtained using an enzyme (oxynitrilase) 2,3 or by the chiral Lewis acid-catalyzed addition of hydrocyanic acid (or cyanotrimethylsilane) (M = Ti, 4 B, 5 Sn, 6 Re 7 ). Cyanohydrins are of particular interest as intermediates since they can readily be converted into a variety of valuable starting materials for synthesis (b-amino alcohols, a-hydroxy ketones, ahydroxy carboxylic acids).An alternative method to prepare a-hydroxy nitriles is the dehydration of a-hydroxy amides. We became interested in alternative dehydration methods since all the established procedures give rise to insurmountable problems when conducted on an industrial scale, e.g. expensive reagents, large excess of the cyano component, painstaking workup, toxic solvents, waste problems, etc. The mixture cyanuric chloride/DMF was introduced by Olah and coworkers for the dehydration of aliphatic and aromatic amides to the corresponding nitriles. 8 The potential of this method has so far not been exploited with the notable exception of the synthesis of heterocyclic carbonitriles. 9,10 At around the same time, Rodrigues and Maetz described the preparation of N-protected chiral a-amino nitriles from N-protected a-amino acid amides using cyanuric chloride/DMF. 11Based on our experience with the synthesis of heterocyclic amides we decided to extend our methodology to the dehydration of functionalized amides. We chose cyanohydrins as target molecules for two reasons: on the one hand, there exists a vast experience with enantiomerically enriched cyanohydrines concerning synthesis and analytics, and on the other hand the hydroxy amide precursors are readily available as starting materials. In our model study, the enantiopure a-hydroxy amide was obtained by aminolysis of D-and L-pantolactone (1), respectively (Scheme 1). The hydroxy groups were protected with isopropenyl methyl ether (IPM). 12 Standard procedures for the introduction of a protecting group for the hydroxy functionalities did not yield satisfactory results. Protection with acetone/p-TsOH gave only a yield of 35% of the dioxane 3, while the alternative acetone/orthoester procedure led to only a slight increase of product yield (55%). Scheme 1The crucial step, the dehydration of the 1,3-dioxane-4-carboxamide 3 to the nitrile 4, could be conducted in excellent yields by means of the reaction conditions outlined in Scheme 1. Standard acid-catalyzed deprotection gives the desired cyanohydrin 5. The key question was whether or not the D...

Copper-Mediated Synthesis ofN-Acyl Vinylogous Carbamic Acids and Derivatives: Synthesis of the Antibiotic CJ-15,801

“…Substrate scope was next investigated employing Cu(CH 3 CN) 4 PF 6 , 9b as ligand, Rb 2 CO 3 as base, and DMA as solvent (Table ). Amidation of vinyl iodide 4 with ( R )-2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamide ( 10 ) afforded N -acyl vinylogous carbamate 5c (entry 3), a precursor to CJ-15,801, in excellent yield. However, other primary amides afforded only moderate yields of the desired coupling products.…”

Fine Tuning of Pyrene Excimer Fluorescence in Molecular Beacons by Alteration of the Monomer Structure

“…The key aminodiol 2, previously described only in the form of protected derivatives, was synthesized using two-step procedure from commercially available d -(−)-pantolactone with 75% overall yield in multigram scale. ( R )-2,4-Dihydroxy-3,3-dimethylbutanamide ( 1 ) was reduced with borane-dimethyl sulfide complex (BMS) in THF followed by sorption on an ion-exchange resin, wash out of admixtures and selective product elution with triethylamine in ethanol. This straightforward procedure can be extended to the synthesis and isolation of other amino polyols without additional protection.…”

“…One L three necked round bottomed flask equipped with a mechanical stirrer, a reflux condenser, and a dropping funnel was purged with argon and charged with ( R )-2,4-dihydroxy-3,3-dimethylbutanamide ( 1 ) (29.4 g, 0.2 mol) in absolute THF (600 mL). Borane dimethyl sulfide complex (BMS) (57.0 mL, 0.6 mol) was transferred via cannula into a dropping funnel, then solution in THF was cooled to 0–5 °C and BMS was added dropwise to amide solution for 40 min with stirring.…”

Facile and Racemization-Free Conversion of Chiral Nitriles into Pyridine Derivatives

“…2,2,5,5-Tetramethyl-1,3-dioxane-4-carbonitrile ( 1a ) has been converted into the corresponding pyridine as a racemate ( rac - 1b ) as well as in the form of its ( S )-enantiomer (−)- 1b [(−)-( S )-2-(2,2,5,5-tetramethyl-1,3-dioxan-4-yl)pyridine]. Furthermore, through cyanethylation enantiomerically pure nitriles could be prepared from ( + ) - as well as ( − ) -3-(2-isopropyl-5-methylcyclohexyloxy)propionitrile [ ( + )- and (−)- 2a ] and were converted into the corresponding enantiomerically pure 2-[2-(2-isopropyl-5-methylcyclohexyloxy)ethyl]pyridine [(+)- and (−)- 2b ].…”