Iminonitroso ene reactions: experimental studies on reactivity, regioselectivity, and enantioselectivity

Abstract

Ene reactions of iminonitroso agents with olefins were investigated in both solution and solid phase. Reactions afforded allyl hydroxylamine products in up to 99% yield and with high regioselectivity. A Cu(I)-mediated enantioselective nitroso ene reaction gave an ene product with up to 40% ee.The nitroso ene reaction with alkenes constitutes a mild, valuable method for generation of allylamines, versatile and fundamental building blocks in organic synthesis, in an atom economical fashion (Scheme 1). 1 However, this method has received relatively little attention compared to ene reactions with other enophiles such as singlet oxygen ( 1 O 2 ) 2 , azo compounds 3 and carbonyl functionalities, 4 presumably due to the labile nature of the resulting hydroxylamine products. 5 To minimize such problems, a frequently employed strategy involves the introduction of electron-withdrawing groups at the nitroso functionality to not only increase the enophilic reactivity, but also afford relatively stable hydroxylamine products that are useful for further transformation. In this regard, electron-poor enophiles, such as pentafluoronitrosobenzene, 6 α-chloronitroso agents, 7 acylnitroso agents 8 and pnitronitosobenzene 9 are often used.Enantioselective nitroso ene reactions would offer an attractive pathway to valuable, optically active amines from readily available olefins. However, only limited examples of asymmetric nitroso ene reactions have been reported, either by use of a chiral auxiliary for stereo control, 10 or using a-choronitroso sugar derivatives as chiral nitrosyl reagents. 7 Recently, iminonitroso agents have attracted a great deal of interest. Unlike the transient acylnitroso species, most iminonitroso agents, in particular, pyridinylnitroso derivatives, can be synthesized from commercially available amine precursors and stored in pure form. 11 Their successful application in Diels-Alder reactions, including enantioselective versions, 12 encouraged us to examine their reactivity in ene chemistry, which, surprisingly, has not been disclosed. Herein, we report studies of the reactivity and regioselectivity of iminonitroso agents with various olefins in ene reactions. We also describe preliminary results from solid phase supported nitroso ene reactions as well as enantioselective nitroso ene reactions.To begin our investigation, a panel of iminonitroso agents 1a-e were synthesized based on a literature reported procedure. 11 The unsymmetrical alkene, 2-methyl-2-butene 2a, was used as a model olefin substrate to examine the reactivity of enophiles 1a-e in the ene reaction. The Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and ...

N–O Chemistry for Antibiotics: Discovery of N-Alkyl-N-(pyridin-2-yl)hydroxylamine Scaffolds as Selective Antibacterial Agents Using Nitroso Diels–Alder and Ene Chemistry

“…24–26 Several important and highly biologically active compounds ( 7 , 9 , and 11 ) from this library were resynthesized according to the previously described methods (Scheme 1). Separable isomers 7a and 7b were prepared using an indium(III) triflate-mediated nucleophilic ring opening of 5-bromo-2-nitrosopyridine Diels-Alder cycloadduct 6 with methanol.…”

“…24 Compounds 9 and 11a , b were synthesized using nitroso ene reactions with 2-methyl-2-butene and geraniol, respectively. 26 The major isomer from the ene reaction with geraniol ( 11a ) was readily obtained in pure form by standard chromatographic methods, while the minor isomer ( 11b ) was always isolated as a mixture with 11a .…”

“…26 These methodologies were an extension of our Modular Enhancement of Nature’s Diversity (MEND) natural product derivatization program into a DOS strategy for rapidly producing structurally complex small molecules from simple starting materials. 27–31 Biological screening of the hydroxylamine-containing compounds revealed selective and potent antibacterial activity against Micrococcus luteus ATCC 10240 for compounds with pyridyl or isoxazole heterocycles.…”

“…Our group recently published new synthetic methodologies for the syntheses of highly functionalized hydroxylamine-containing compounds using Lewis acid-mediated nucleophilic ring-opening reactions of nitroso Diels–Alder cycloadducts with alcohols , and nitroso ene reactions with substituted alkenes . These methodologies were an extension of our Modular Enhancement of Nature’s Diversity (MEND) natural product derivatization program into a DOS strategy for rapidly producing structurally complex small molecules from simple starting materials. − Biological screening of the hydroxylamine-containing compounds revealed selective and potent antibacterial activity against Micrococcus luteus ATCC 10240 for compounds with pyridyl or isoxazole heterocycles.…”

A Bridge to Alkaloid Synthesis

“…However, asymmetric nitroso-ene reactions remain a formidable subject, with sporadic examples applicable to achieve good results. [42] The extremely short lifetime of nitroso species in general makes this objective even more challenging. [43] Moreover, application of the aza-Wacker reaction in bioactive substance synthesis is still underscored despite that it has been carried out with good enantiomeric control in several precedents to form one ring or fused ring systems.…”