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Harnessing Alkyl Pyridinium Salts as Electrophiles in Deaminative Alkyl-Alkyl Cross-Couplings Shane Plunkett, Corey H. Basch, Samantha O. Santana, and Mary P. Watson J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00111 • Publication Date (Web): 25 Jan 2019 Downloaded from http://pubs.acs.org on January 25, 2019
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Journal of the American Chemical Society
Harnessing Alkyl Pyridinium Salts as Electrophiles in Deaminative Alkyl-Alkyl Cross-Couplings Shane Plunkett, Corey H. Basch, Samantha O. Santana, Mary P. Watson* Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716, United States Supporting Information Placeholder ABSTRACT: A Negishi cross-coupling of alkyl pyridinium
salts and alkylzinc halides has been developed. This is the first example of alkyl–alkyl bond formation via cross-coupling of an alkyl amine derivative with an unactivated alkyl group, and allows both primary and secondary alkyl pyridinium salts to react with primary alkylzinc halides with high functional group tolerance. When combined with formation of the pyridinium salts from primary amines, this method enables the noncanonical transformation of NH2 groups into a wide range of alkyl substituents with broad functional group tolerance.
veloped Minisci arylation, alkynylation, and borylations.9 These exciting reports demonstrate the potential of alkyl pyridinium salts in synthesis, and offer avenues to convert ubiquitous NH2 groups into C(sp2) and C(sp) substituents. However, no current methods enable C(sp3)–C(sp3) formation via cleavage of these unactivated alkyl pyridinium salts.10 Scheme 1. Alkyl amine derivatives in cross-coupling reactions. A. Alkyl amine derivatives used in cross-couplings O R
[N] Ar
OR [N] Wang
R
[N]
[N]
Ar Doyle Jamison strain-activated
Tian
Watson Tian electronically activated
Alkyl amines are abundant molecules ranging from simple starting materials to complex natural products and drug candidates.1 As an example of their prevalence, a search of Pfizer’s internal chemical store revealed over 47,000 alkyl primary amines vs. about 28,000 primary and secondary alkyl halides.2 In addition, the use of alkyl amines as intermediates is advantageous, because they can be prepared directly and convergently with simultaneous formation of the amine and C–C bonds via classic reactions, such as Mannich, Petasis, Strecker, and others.3 Due to their ubiquity, methods that allow alkyl amines to be converted into electrophiles for cross-coupling reactions present an exciting opportunity for development. However, the utilization of amine-derived alkyl electrophiles remains limited with cross-couplings largely restricted to alkyl amine derivatives with electronic or strain activation of the C(sp3)–N bond (Scheme 1A).4,5,6 We recently overcame this limitation by developing a Suzuki–Miyaura arylation of Katritzky pyridinium salts, which are easily and selectively prepared from primary alkyl amines (Scheme 1B).7,6m, 6n,5b, 8 This reaction was the first crosscoupling of an alkyl amine derivative with an unactivated alkyl group. Recognizing that our proposed alkyl radical intermediate could also be formed via photoredox catalysis, Glorius, Gryko, Aggarwal, Li and Shi then de-
B. Alkyl pyridinium salts with unactivated alkyl groups Ph Ph BF4 R1
NH2 Ph
O
BF4
Ar–B(OH)2 cat. Ni(OAc)2·4H2O/BPhen
Ph Ph
R2
N
R1 R2 Alkyl Radical Intermediate
Ph
R1
KOtBu Watson C(sp3)–C(sp2)
R1 R2 1, Katritzky pyridinium salts
Ar R2
C: This work: Alkyl–alkyl cross-couplings Ph BF4 R1
NH2 R2
1° or 2° alkyl
Ph
O
Ph BF4
Ph Ph
N R1
1
Ph
Alkyl–ZnX cat. [Ni] C(sp3)–C(sp3)
R1
Alkyl R2
R2
The prevalence of C(sp3)–C(sp3) bonds in bioactive molecules has led to intense efforts to develop methods to incorporate fully saturated C–C bonds in complex products.11 In particular, Negishi cross-couplings have emerged as a reliable and functional group tolerant method.6a, 6d, 12 Motivated by the myriad advantages of alkyl amine derivatives as alkyl electrophiles, we envisioned a Negishi cross-coupling for the generation of C(sp3)–C(sp3) bonds from alkyl pyridinium salts (Scheme 1C). However, despite the precedent with other alkyl electrophiles, we were concerned that competitive nucleophilic addition of the organozinc to the pyridinium ring and/or deprotonation of the acidic a-proton of the
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alkyl pyridinium salts would prevent the desired crosscoupling. Overcoming these challenges, we have developed the first example of alkyl–alkyl bond formation via cross-coupling of an alkyl amine derivative with an unactivated alkyl group. This method allows both primary and secondary alkyl pyridinium salts to react with primary alkylzinc halides with high functional group tolerance. In combination with efficient pyridinium formation, this reaction enables the non-canonical transformation of amino groups into alkyl substituents, providing unprecedented entry to complex, saturated organic frameworks via versatile and attractive amine intermediates. We selected the cross-coupling of phenethyl pyridinium salt 1a and commercially available (2-(1,3-dioxolan2-yl)ethyl)zinc bromide for our initial studies. We prioritized the use of alkyl zinc halides, as opposed to dialkyl zinc reagents, due to their greater commercial availability, higher functional group tolerance, and ease of handling.13 Using bathophenanthroline (BPhen), the optimal ligand for our Suzuki–Miyaura arylation, resulted in
