Preparation of (R)-Fluoropyruvaldehyde N,S-Ketals by Highly Stereospecific Tandem Pummerer Rearrangement/1,2-p-Tolylthio Group Migration of (R)-α-(Fluoroalkyl)-β-sulfinylenamines

Abstract

Fluoropyruvaldehyde N,S-ketals (R)-2 have been prepared in good yields (up to 88%) and ee (up to 79%) from alpha-(fluoroalkyl)-beta-sulfinylenamines (R)-(Z)-1, through a new self-immolative tandem sequential process, consisting of a Pummerer reaction, promoted by trifluoroacetic anhydride, followed by a 1,2-migration of the p-tolylthio group, triggered by addition of silica gel or aqueous base. Each transfer of stereogenic center, from sulfur to the alpha-carbon and then to the beta-carbon, occurs with an average degree of enantioselectivity up to 94:6. Cis geometry between the sulfinyl and the amino groups of the starting enamine (R)-1 is necessary for achieving high level of stereocontrol, since neighboring group participation by the N-Cbz amino group prevents the sulfinyl center from racemization promoted by trifluoroacetic anhydride. NMR studies have shown that imines 3 are intermediate products of the Pummerer rearrangement, which are stable in the reaction environment.

1,2‐Migration of the Thio Group in Allenyl Sulfides: Efficient Synthesis of 3‐Thio‐Substituted Furans and Pyrroles

“…2) The migration is triggered by attack of the sulfur atom at the sp 2 carbon atom of the iminium2a,b or imine2c moiety of D to form the thiiranium species E . The latter either produces sulfide F through nucleophilic attack2c or gives the thioenamine G as a result of a deprotonation/ring‐opening process [R 1 =H, Eq. (2)] 2a,b.…”

(R)-Trifluoro- and Difluoropyruvaldehyde N,S-Ketals: Chiral Synthetic Equivalents of β-Trifluoro and β-Difluoro α-Amino Aldehydes

“…Condensation of lithiated ( R )-methyl p -tolyl sulfoxide and fluoroacetic esters afforded high yields of the corresponding α-fluoro α‘-sulfinyl ketones ( R )- 2a − c , which were transformed in good yields into geometrically homogeneous cis -α-(fluoroalkyl)-β-sulfinyl enamines ( R )- 3a − c by reaction with N -Cbz iminotriphenylphosphorane . A highly enantioselective tandem Pummerer reaction/1,2-migration of the p -tolylthio group, which produced in one-pot the target fluoropyruvaldehyde N , S -ketals ( R )- 1a − c from the enamines ( R )- 3a − c , through the intermediate imine ( R )- 4a − c , is the last step of the sequence . This tandem reaction is operatively simple, fast, and requires nonexotic and inexpensive reagents, namely 1 equiv of trifluoroacetic anhydride, which promotes the Pummerer rearrangement (step 1), and silica gel or aqueous NaHCO 3 , which trigger the suprafacial migration of the p -tolylthio residue to give the desired fluoropyruvaldehyde N , S -ketals ( R )- 1a − c (step 2).…”

Stereoselective Synthesis of Enantiopure Amino Compounds, via Mitsunobu Azidation of (2S,RS)-1-(p-Tolylsulfinyl)butan-2-ol

“…General Procedure.ÐThe instrumentation and general experimental and analytical procedures were recently described in detail. 9 The -sul®nyl alcohol (2S,R S )-1 was prepared according to a literature procedure. 4 -Sul®nyl Azide (2R,R S )-2.ÐMethod A.…”