Kevin R. Campos

Direct sp3 C–H bond activation adjacent to nitrogen in heterocycles

Activation of sp(3) C-H bonds adjacent to nitrogen in heterocycles is an attractive transformation that is emerging as a practical method in organic synthesis. This tutorial review aims to summarize the key examples of direct functionalization of nitrogen-containing heterocycles via metal-mediated and metal-catalyzed processes, which is meant to serve as a foundation for future investigations into this rapidly developing area of research. The review covers functionalization of N-heterocycles via alpha-lithiation with alkyllithium/diamine complexes, alpha-amino radical formation, metal-catalyzed direct C-H activation, C-H oxidations and oxidative couplings, and metal-catalyzed carbene insertions.

Asymmetric deprotonation of N-boc piperidine: react IR monitoring and mechanistic aspects.

The high yielding asymmetric deprotonation trapping of N-Boc piperidine is successfully realized using s-BuLi and a (+)-sparteine surrogate. Monitoring of the lithiation by in situ React IR allowed the direct observation of a prelithiation complex.

Enantioselective, Palladium-Catalyzed α-Arylation of N-Boc Pyrrolidine: In Situ React IR Spectroscopic Monitoring, Scope, and Synthetic Applications

A comprehensive study of the enantioselective Pd-catalyzed α-arylation of N-Boc pyrrolidine has been carried out. The protocol involves deprotonation of N-Boc pyrrolidine using s-BuLi/(-)-sparteine in TBME or Et(2)O at -78 °C, transmetalation with ZnCl(2) and Negishi coupling using Pd(OAc)(2), t-Bu(3)P-HBF(4) and the aryl bromide. This paper reports several new features including in situ React IR spectroscopic monitoring of the process; use of (-)-sparteine and the (+)-sparteine surrogate to access products with opposite configuration; development of a catalytic asymmetric lithiation-Negishi coupling reaction; extension to a wide range of heteroaromatic bromides; total synthesis of (R)-crispine A, (S)-nicotine and (S)-SIB-1508Y via short synthetic routes; and examples of α-vinylation of N-Boc pyrrolidine using vinyl bromides exemplified by the total synthesis of naturally occurring (+)-maackiamine (thus establishing its configuration as (R)). In this way, the full scope and limitations of the methodology are delineated.

Reversal in enantioselectivity of tert-butyl versus phenyl-substituted bis(oxazoline) copper(II) catalyzed hetero Diels-Alder and ene reactions. Crystallographic and mechanistic studies

Abstract X-Ray crystal structures of the Cu[(S,S)-tert-Bu-bis(oxazoline)](H2O)2(SbF6)2 (6), Cu[(S,S)-Ph-bis(oxazoline)](H2O)2(SbF6)2 (7), and Cu[(S,S)-iso-Pr-bis(oxazoline)](H2O)2(SbF6)2 (8) complexes are presented. Implications of the structural details are considered in the context of the opposite enantiofacial biases conferred by complexes Cu[(S,S)-tert-Bu-bis(oxazoline)](X)2 (1, X = OTf or SbF6) and Cu[(S,S)-Ph-bis(oxazoline)](X)2 (2) in hetero Diels-Alder and glyoxylate ene reactions. Structural and mechanistic studies suggest that a change in geometry at the metal center is not necessarily responsible for the reversal in enantioselectivity.

An Experimental and in Situ IR Spectroscopic Study of the Lithiation–Substitution of N-Boc-2-phenylpyrrolidine and -piperidine: Controlling the Formation of Quaternary Stereocenters

A general and enantioselective synthesis of 2-substituted 2-phenylpyrrolidines and -piperidines, an important class of pharmaceutically relevant compounds that contain a quaternary stereocenter, has been developed. The approach involves lithiation-substitution of enantioenriched N-Boc-2-phenylpyrrolidine or -piperidine (prepared by asymmetric Negishi arylation or catalytic asymmetric reduction, respectively). The combined use of synthetic experiments and in situ IR spectroscopic monitoring allowed optimum lithiation conditions to be identified: n-BuLi in THF at -50 °C for 5-30 min. Monitoring of the lithiation using in situ IR spectroscopy indicated that the rotation of the tert-butoxycarbonyl (Boc) group is slower in a 2-lithiated pyrrolidine than a 2-lithiated piperidine; low yields for the lithiation-substitution of N-Boc-2-phenylpyrrolidine at -78 °C can be ascribed to this slow rotation. For N-Boc-2-phenylpyrrolidine and -piperidine, the barriers to rotation of the Boc group were determined using density functional theory calculations and variable-temperature (1)H NMR spectroscopy. For the pyrrolidine, the half-life (t(1/2)) for rotation of the Boc group was found to be ∼10 h at -78 °C and ∼3.5 min at -50 °C. In contrast, for the piperidine, t(1/2) was determined to be ∼4 s at -78 °C.

Diamine-free lithiation-trapping of N-Boc heterocycles using s-BuLi in THF.

A diamine-free protocol for the s-BuLi-mediated lithiation-trapping of N-Boc heterocycles has been developed. In the optimized procedure, lithiation is accomplished using s-BuLi in THF at -30 °C for only 5 or 10 min. Subsequent electrophilic trapping or transmetalation-Negishi coupling delivered a range of functionalized pyrrolidines, imidazolidines, and piperazines in 43-83% yield.

Enantioselective Pd-Catalyzed α-Arylation of N-Boc-Pyrrolidine: The Key to an Efficient and Practical Synthesis of a Glucokinase Activator

A short and practical synthesis of glucokinase activator 1 was achieved utilizing a convergent strategy involving S(N)Ar coupling of activated aryl fluoride 11 with hydroxypyridine 9. The key to the success of the synthesis was the development of a novel method for enantioselective formation of alpha-arylpyrrolidines during the course of the project. In this method, (-)-sparteine-mediated enantioselective lithiation of N-Boc-pyrrolidine was followed by in situ transmetalation to zinc and Pd-catalyzed coupling with aryl bromide 3, proceeding in 92% ee. This transformation allowed the preparation of compound 1 in a 31% overall yield over six steps.

Enantioselective Synthesis of Hemiaminals via Pd-Catalyzed C–N Coupling with Chiral Bisphosphine Mono-oxides

A novel approach to hemiaminal synthesis via palladium-catalyzed C-N coupling with chiral bisphosphine mono-oxides is described. This efficient new method exhibits a broad scope, provides a highly efficient synthesis of HCV drug candidate elbasvir, and has been applied to the synthesis of chiral N,N-acetals.

Enantioselective, biocatalytic reduction of 3-substituted cyclopentenones: application to the asymmetric synthesis of an hNK-1 receptor antagonist.

A convergent and enantioselective route to the hNK-1 receptor antagonist (1) is described, which sets all six stereogenic centers with high diastereoselectivity and delivers 1 in only 11 steps and 23% overall yield. The process was enabled by the development of the enantioselective enzymatic reduction of 3-functionalized cyclopentenones and stereospecific Pd-catalyzed etherification coupling of fragments 6 and 7.

A general method for the highly diastereoselective, kinetically controlled alkylation of (+)-nopinone

Abstract A general method for the monoalkylation of (+)-nopinone was developed for a variety of carbon and heteroatom electrophiles to afford the kinetically controlled product 2 with high diastereoselectivity (98% d.e.) and excellent yield (75–90%).