Umpolung Amide Synthesis (UmAS) provides direct access to amides from an α-bromo nitroalkane and an amine. Based on its mechanistic bifurcation after convergent C–N bond formation, depending on the absence or presence of oxygen, UmAS using substoichiometric N-iodosuccinimide (NIS) under aerobic conditions has been developed. In combination with the enantioselective preparation of α-bromo nitroalkane donors, this protocol realizes the goal of enantioselective α-amino amide and peptide synthesis based solely on catalytic methods.

The mechanism of umpolung amide synthesis was probed by interrogating potential sources for the oxygen of the product amide carbonyl that emanates from the α-bromo nitroalkane substrate. Using a series of 18 O-labeled substrates and reagents, evidence is gathered to advance two pathways from the putative tetrahedral intermediate. Under anaerobic conditions, a nitro-nitrite isomerization delivers the amide oxygen from nitro oxygen. The same homolytic nitro-carbon fragmentation can be diverted by capture of the carbon radical intermediate with oxygen gas (O 2 ) to deliver the amide oxygen from O 2 . This understanding was used to develop a straightforward protocol for the preparation of 18 O-labeled amides in peptides by simply performing the umpolung amide synthesis reaction under an atmosphere of .

The g-nitrogen of phenylsulfonyl azide can be readily labeled with 15 N by treating benzenesulfonyl hydrazide with Na 15 NO 2 . The resulting g-15 N-labeled sulfonyl azide reacts with carbon-centered free radicals to produce alkyl azides exclusively containing a C-15 N bond. This chemistry provides valuable insight into the free-radical azidation mechanism as well as providing a mild method for the production of 15 N-amines.Free-radical azidation has been used successfully to form carbon-nitrogen bonds under relatively mild reaction conditions. 1-7 The reaction has been shown to proceed smoothly using both phenylsulfonyl azide (1) and ethanesulfonyl azide (2) with great success. Free-radical azidation has also been explored in systems where diastereocontrol was at issue. 8,9 The early reports by Renaud et al. suggested that radical addition to the sulfonyl azide could occur at either the a-nitrogen or the g-nitrogen of the sulfonyl azide (Scheme 1) and that nucleophilic radicals produced the best yields. 2 Scheme 1 Mechanistic possibilities for radical addition to sulfonyl azide 2We devised an experiment aimed at determining which nitrogen of the sulfonyl azide functions as the radical trap. We selectively introduced a 15 N atom in the g-position of phenylsulfonyl azide as illustrated in Scheme 2. 10 Commercially available benzenesulfonyl hydrazide was dissolved in 1.2 M HCl and placed in an ice bath. One equivalent of Na 15 NO 2 was then added slowly as a solid over 15 minutes. The resulting solution was allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was worked up in the normal manner by extraction providing a 96% yield of g-15 N phenylsulfonyl azide (Scheme 2). (1) Free-radical azidation was performed using a variety of substrates in order to determine the generality of the reaction mechanism. A free-radical azidation reaction was performed by slow infusion of Barton ester 3 into a solution of 1 under photolysis conditions. 9 The azide product 4 was isolated by preparative TLC and 4 (60% yield by 1 H NMR of crude mixture) was characterized by 1 H NMR and 13 C NMR. The NMR spectra of compound 4 showed exclusive C-15 N bond formation as evidenced by the observed 1 H-15 N coupling observed in the 1 H NMR spectrum (Scheme 3). Scheme 2 Preparation of g-15 N-labeled phenyl sulfonyl azide Scheme 3 Free-radical azidation with 1The result illustrated in Scheme 3 suggests that the freeradical addition occurs exclusively at the g-nitrogen atom of the phenylsulfonyl azide. Substrate 3 is relatively bulky and we could not rule out that we were simply observing addition to the g-nitrogen atom due to steric considerations. In order to address the steric issue we decided to try substrates with varying steric requirements (i.e. 2° and 3° radical centers).It is well known that electrophilic radicals do not undergo radical addition to sulfonyl azides and that 1° free radicals react with sulfonyl azides in poor yield. 2,3 We decided that we would generate electrophilic radicals that ...

Achiral pyrazolidinone auxiliaries have been investigated in exo-and enantioselective Diels-Alder reactions. The effect of pyrazolidinone N-1 substitution and chiral ligand identity were studied in Yb(OTf) 3 -catalyzed exo-selective Diels-Alder reactions. An appropriate choice of pyrazolidinone auxiliary and Yb(OTf) 3 / Pybox chiral Lewis acid led to moderate exo selectivity and high enantioselectivity for the exo-cycloadduct.

Umpolung Amide Synthesis Using Substoichiometric N-Iodosuccinimide (NIS) and Oxygen as a Terminal Oxidant. -Reaction of -bromo-nitroalkanes with amines using O 2/NIS as oxidative catalytic system gives the respective amides with high stereoselectivity (dr >20:1). Amino acids as well as peptides can also be used as amine source. -(SCHWIETER, K. E.; SHEN, B.; SHACKLEFORD, J. P.; LEIGHTY, M. W.; JOHNSTON*, J. N.; Org. Lett. 16 (2014) 18, 4714-4717, http://dx.doi.org/10.1021/ol502089v ; Dep. Chem., Vanderbilt Univ., Nashville, TN 37235, USA; Eng.) -M. Tismer 10-056