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

Graeme Barker, Julia L. McGrath, Artis Klapars, Darren Stead, George Zhou, Kevin R. Campos, Peter O'Brien

Research output: Contribution to journalArticle

Abstract

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 Et2O at −78 °C, transmetalation with ZnCl2 and Negishi coupling using Pd(OAc)2, t-Bu3P-HBF4 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.
Original languageEnglish
Pages (from-to)5936-5953
JournalJournal of Organic Chemistry
Volume76
Issue number15
Early online date29 Jun 2011
DOIs
Publication statusPublished - 5 Aug 2011

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Sparteine
Palladium
Bromides
Nicotine
N-Boc-pyrrolidine

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Barker, Graeme ; McGrath, Julia L. ; Klapars, Artis ; Stead, Darren ; Zhou, George ; Campos, Kevin R. ; O'Brien, Peter. / Enantioselective, Palladium-Catalyzed α-Arylation of N-Boc Pyrrolidine: In Situ React IR Spectroscopic Monitoring, Scope, and Synthetic Applications. In: Journal of Organic Chemistry. 2011 ; Vol. 76, No. 15. pp. 5936-5953.
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abstract = "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 Et2O at −78 °C, transmetalation with ZnCl2 and Negishi coupling using Pd(OAc)2, t-Bu3P-HBF4 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.",
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Enantioselective, Palladium-Catalyzed α-Arylation of N-Boc Pyrrolidine: In Situ React IR Spectroscopic Monitoring, Scope, and Synthetic Applications. / Barker, Graeme; McGrath, Julia L.; Klapars, Artis; Stead, Darren; Zhou, George; Campos, Kevin R.; O'Brien, Peter.

In: Journal of Organic Chemistry, Vol. 76, No. 15, 05.08.2011, p. 5936-5953.

Research output: Contribution to journalArticle

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AB - 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 Et2O at −78 °C, transmetalation with ZnCl2 and Negishi coupling using Pd(OAc)2, t-Bu3P-HBF4 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.

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