Tandem Catalytic Allylic Amination and [2,3]-Stevens Rearrangement of Tertiary Amines

Abstract

We have developed a catalytic allylic amination involving tertiary aminoesters and allylcarbonates, which is the first example of the use of tertiary amines as intermolecular nucleophiles in metal-catalyzed allylic substitution chemistry. This process is employed in a tandem ammonium ylide generation/[2,3]-rearrangement reaction, which formally represents a palladium-catalyzed Stevens rearrangement. Low catalyst loadings and mild reaction conditions are compatible with an unprecedented substrate scope for the ammonium ylide functionality, and products are generated in high yields and diastereoselectivities. Mechanistic studies suggested the reversible formation of an ammonium intermediate.

Isothiourea-catalysed chemo- and enantioselective [2,3]-sigmatropic rearrangements of N,N-diallyl allylic ammonium ylides

“…This process generates functionalized α-amino esters 6 with high diastereocontrol but in racemic form. 5 Building upon this work, we demonstrated an isothiourea-promoted 6,7 catalytic enantioselective [2,3]rearrangement of allylic ammonium ylides, leading to a range of α-amino acid derivatives 8 bearing either N,N-dimethyl or cyclic-N-alkyl substituents (Scheme 1c). 8 This process allows for the synthesis of a variety of α-amino ester derivatives and the incorporation of pharmacological relevant amine motifs such as the morpholine unit, although the preparation of free α-amino esters was not possible as suitable N-substituents amenable to facile deprotection were not incorporated.…”

“…1e The most common approach utilizes an intermediate metal carbenoid to generate the reactive ylide intermediate as shown by Doyle (Scheme 1a), 4 yet catalytic enantioselective variants have remained elusive. 1b In 2011, Tambar and co-workers 5 reported an alternative strategy in the catalytic [2,3]-rearrangements of allylic ammonium ylides through Pd-catalysed allylic substitution of allylic carbonates 5 with tertiary amino esters 4 and in situ rearrangement (Scheme 1b). This process generates functionalized α-amino esters 6 with high diastereocontrol but in racemic form.…”

“…9 Notable previous work by Tambar has shown that treatment of N-methyl-N-allyl amine 9 with cinnamyl carbonate 10 in the presence of Pd 2 (dba) 3 ·CHCl 3 , P(2-furyl) 3 and Cs 2 CO 3 gave ammonium ylide 11, bearing a stereogenic nitrogen. 5 [2,3]-Rearrangement of ammonium ylide 11 proceeded through the N-cinnamyl unit and the N-allyl unit, resulting in non-chemoselective [2,3]-rearrangement to give a 4:1 mixture of N-cinnamyl rearranged product 12 and N-allyl rearranged product 13 in a combined 78% yield (Scheme 2a). 5 We report herein that isothiourea-mediated catalysis of N,Ndiallyl allylic ammonium ylides proceeds chemoselectively, generating N,N-diallyl amino esters 15 with high diastereo-and enantiocontrol that can be readily bis-deprotected to generate free α-amino esters (Scheme 2b).…”

“…Crude dr 90:10. The residue was purified by flash column chromatography on silica gel (5% EtOAc/hexanes) to give the title product (92 mg, 69%, 90:10 dr) as a yellow oil; Enantiopurity determined after derivatisation to 39 and N-Boc protection, 96% ee; [α] ୈ ଶ +54.7 (c 1, CHCl 3 ); υ max (film, cm −1 ) M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT Tetrahedron 10 2980Tetrahedron 10 , 1724Tetrahedron 10 , 1518Tetrahedron 10 , 1343Tetrahedron 10 , 1155; 1 H NMR (500 MHz, CDCl 3 ) δ H 1.34 (3H, t, J 7.1, OCH 2 CH 3 ), 2.81 (2H,dd,J 14.4,8.4,NCHH),3.35 (2H,ddt,J 14.4,4.0,1.9,NCHH),3.82 (1H,d,J 11.7,C(2)H), 3.98 (1H, dd, J 11.7, 7.9, C(3)H), 4.24 (2H, dddd, J 18.0, 10.8, 7.1, 3.7, OCH 2 CH 3 ), 4.98-5.16 (6H, m, C(5)H 2 + diallyl-C(3)H 2 ), 5.36 (2H, dddd, J 16.9, 10.3, 8.3, 4.1, diallyl-C(2)H), 5.86 (1H, ddd, J 17.0, 10.3, 7.9, C(4)H), 7.33 (2H,d,J 8.8,Ar(2,6)H), 8.19 (2H,d,J 8.8,Ar(3,5) …”

“…Crude dr 94:6. The residue was purified by flash column chromatography on silica gel (5% EtOAc/hexanes) to give the title product (222 mg, 85%, 95:5 dr) as a colourless oil; HPLC analysis, Chiralpak AD-H (0.5% IPA/hexane, flow rate 1.5 mL/min, 211 nm, 40 °C) t R Major 3.3 min, Minor 4.3 min, 96% ee; [α] 2.79 (2H,dd,J 14.5,8.3,NCHH),3.34 (2H,ddt,J 14.5,4.0,1.9,NCHH),m,C(2)H + C(3)H), 4.09-4.34 (2H, m, OCH 2 CH 3 ), 4.86-5.14 (6H, m, C(5)H 2 + diallyl-C(3)H 2 ), 5.26-5.50 (2H, m, diallyl-C(2)H), 5.85 (1H, ddd, J 17.1, 10.2, 7.6, C(4)H), 6.98 (2H,t,J 8.7,Ar(3,5)H), 7.09 (2H,ddt,8.3,5.2,2.5,Ar(2,6) (−3.1 ppm).…”