Practical Asymmetric Synthesis of α-Branched 2-Piperazinylbenzylamines by 1,2-Additions of Organometallic Reagents to N-tert-Butanesulfinyl Imines

Abstract

[reaction: see text] 2-[4-(tert-Butoxycarbonyl)piperazinyl]benzylidene-tert-butanesulfinamides underwent nucleophilic 1,2-addition with different organometallic reagents to give highly diastereomerically enriched adducts. X-ray crystallography of the resulting alpha-branched N-Boc-2-piperazinylbenzyl-tert-butanesulfinamides confirms different mechanisms depending on the organometallic reagent used. Differential deprotection of the N-Boc and the tert-butanesulfinamides was investigated, and the dehydration byproducts have been identified and characterized. To avoid the formation of byproducts in the acidic deprotection step, the N-tert-butanesulfinamide group was converted to the corresponding N-tert-butanesulfonamide (Bus), which allowed for clean orthogonal deprotection. The efficient synthesis and deprotection of the N-Boc-2-piperazinylbenzyl-tert-butanesulfinamides herein described constitutes an attractive method for extensive structure-activity studies in the search for novel ligands of the human melanocortin 4 receptor.

Novel, Versatile Three-Step Synthesis of 1,2,3,4,10,10a-Hexahydro­pyrazino[1,2-a]indoles by Intramolecular Carbene-Mediated C-H Insertion

“…One limitation to the S N Ar reaction was found with the 3-substituted 2-fluorobenzaldehydes, which were poor substrates for the S N Ar possibly due to steric hindrance, and only the 3-chloro analogue was successfully synthesized, albeit in low yields. 12 As expected, another limitation to this S N Ar was the presence of electron-donating groups (EDGs) para to the fluorine leaving group. Weak electron donors, such as a methyl group, had a significant effect on the yields, and stronger electron-donating groups such as a methoxy group significantly inhibited the S N Ar reaction in agreement with literature N H N 1 reports.…”

“…Even though short reaction times for the S N Ar have been reported in the literature, it was not possible to reproduce the literature conditions. [11][12][13] Mostly, the use of DMF has been reported as the preferred solvent for the nucleophilic substitution, but DMSO was reported as an alternative 12,14 and became our preferred solvent, since 2-N,N-dimethylaminobenzaldehyde was formed as a side product, when DMF was used as solvent. One limitation to the S N Ar reaction was found with the 3-substituted 2-fluorobenzaldehydes, which were poor substrates for the S N Ar possibly due to steric hindrance, and only the 3-chloro analogue was successfully synthesized, albeit in low yields.…”

“…Weak electron donors, such as a methyl group, had a significant effect on the yields, and stronger electron-donating groups such as a methoxy group significantly inhibited the S N Ar reaction in agreement with literature N H N 1 reports. 12 The piperazinobenzaldehydes 3a-j were used as substrates for the key step, the carbene-mediated intramolecular C-H insertion forming the Boc-protected tricyclic phenylpiperazines 4a-j (Table 1). The details of the reaction are described in Scheme 2.…”

tert-Butanesulfinimines: structure, synthesis and synthetic applications

“…a-Branched protected amines 23 are then obtained with good yields (46-90%) and fair to high stereoselectivities (1.5 : 1 to 18 : 1 dr) (Scheme 12). 41 Under these conditions, the induction has been postulated to result from the non-chelation controlled )Yamamoto-type* model M2b where the organolithium approaches opposite to the Lewis acid-coordinated-oxygen, i.e. from the re-face of the imine (Scheme 12).…”

Synthesis of Piperazinephen-1-ylethylamines as Potent and Selective Antagonists of the Human Melanocortin-4 Receptor

“…Condensation of 2,5-difluorobenzaldehyde 6b with N-Boc-piperazine under heating in DMF gave the substituted piperazinebenzaldehyde 11 in moderate yield. Reaction of 11 with (R)-tertbutanesulfinamide in the presence of titanium tetraethoxide afforded the imine 12 in excellent yield, which was subjected to a methyllithium addition at low temperature (THF/-78 o C) to give the (R)-configured phen-1-ylethylamine 13 as the predominant product (2:1 ratio), [7] which was purified by column chromatography. The Boc-group in 13 was selectively removed with TFA in dichloromethane at 0 o C to room temperature, followed by a coupling reaction of the resulting free amine with (R)-N-Boc-(2,4-Cl)-dichlorophenylalanine using a standard protocol to give, after TFA treatment, the amine 14.…”