Current Organic Synthesis - Volume 8, Issue 5, 2011

Over the past decade, 2-isoxazolines (Δ2-isoxazolines, 4,5-dihydroisoxazoles) have seen a vast increase in their use, both as intermediates in the synthesis of natural and unnatural products, and as bioisosteric functionalities in medicinal compounds. As a result, a number of new methods and expansions in traditional techniques have emerged for the preparation and derivatization of 2-isoxazolines. Considering the burgeoning use of these versatile synthetic compounds since the 1990s, few reviews have appeared in the literature addressing the copious and significant developments in this area. This issue aims to provide the most thorough, updated guide to the chemistry of 2-isoxazolines since Grunager's 1991 volume in The Chemistry of Heterocyclic Compounds (John Wiley and Sons, Inc.: New York, 1991). Nitrile oxide cycloaddition (NOC) reactions remain the most common method for the preparation of 2-isoxazolines, and Digamber Rane and Mukund Sibi address current trends in intermolecular reactions towards these compounds. Intramolecular nitrile oxide cycloadditions receive separate treatment in my article. Notably, a number of asymmetric NOC reactions have emerged in the past decade, which receive special attention in both Drs. Rane and Sibi's as well as my reviews. As the scope of NOC approaches to 2-isoxazolines has broadened, additional non-cycloaddition methods have emerged for the preparation of these compounds. As explored by Michael Mosher, these include C-O and C-N bond-forming reactions, as well as reductions of the related 2-isoxazoline N-oxides. Finally, the utility of 2-isoxazolines owes much to the many methods for their selective cleavage, including oxidative and reductive cleavage as well as thermal, photochemical, and hydrolysis processes. Jaipal R. Nagireddy, Mohammed- Abdul Raheem, Jamie Haner and William Tam have painstakingly compiled the extensive literature in this area. While we wish to have covered every aspect of modern 2-isoxazoline chemistry, the preparation of 2-isoxazolines through solid-phase and combinatorial approaches, as well as the use of 2-isoxazolines as intermediates in the synthesis of natural products and drug compounds are notably absent from this issue. We anticipate reviews on these topics to appear elsewhere in the near future. This Special Issue of Current Organic Synthesis would not be possible without the hard work and dedication of each of the contributors. I am particularly grateful for the insightful comments provided by the referees, and wish to thank my colleagues at Northern Arizona University for their support and assistance in preparing and compiling these articles. Most importantly, the efforts of Ms. Humaira Hashmi, Sr. Manager Publications and Ms. Maria Baig, Asst. Manager Publications (Current Organic Synthesis, Bentham Science Publishers) were invaluable in developing and coordinating this issue.

Synthesis of novel heterocyclic compounds continues to be an important and challenging task. Isoxazolines are one such class of heterocyclic molecules of significance, since they are frequently found in many compounds that show significant biological activity. They are also of importance since they can be easily transformed into important functional groups. Nitrile oxide cycloaddition with carbon dipolarophiles represents an easy route to the synthesis of these molecules. Research groups over the past decades have established novel protocols and methods for the synthesis of isoxazolines via dipolar cycloaddition. This review will highlight the success that has been achieved in this field since 2000.

The utility of 2-isoxazolines (Δ2-isoxazolines, 4,5-dihydroisoxazoles) in the preparation of natural products and other compounds of medicinal and materials interest is growing because the 2-isoxazoline serves both as a desirable functional group and a versatile synthetic intermediate. Nitrile oxide cycloaddition (NOC) to alkenes is the most common method for the preparation of 2- isoxazolines, and the intramolecular version of this reaction provides a powerful entry into complex polycyclic systems. This review is the first to compile studies on the intramolecular nitrile oxide cycloaddition (INOC) reaction, with an emphasis on studies from 2000 to 2009. Trends in stereo- and regioselectivity are discussed from observations made in the formation of a wide variety of polycyclic 2- isoxazoline compounds.

Methods for the synthesis of 2-isoxazolines and 2-isoxazoline N-oxides that do not involve the [3+2] cycloaddition of a nitrile oxide are reviewed.

This review details the numerous methods of cleavage of 2-isoxazolines and the application of these methods in the synthesis of natural products. 2-Isoxazolines can be cleaved to provide a vast array of functionalities depending on the cleavage conditions used and nature of the substrate. Several cleavage reactions of 2-isoxazolines are covered, including, reductive cleavage by hydrogenolysis using various metal catalysts and under various conditions; oxidative cleavage using ozonolysis, Br2 and ethylene glycol, and peracids; cleavage using Mo(CO)6 or Mo(CO)3(MeCN)3, thermolysis, photolysis, flash vacuum thermolysis, I2, DBU, sodium alkoxides, Et3N, EtMgBr, and mineral acids.

The review deals with the chemistry of bimetallic systems containing boron and one of group 14 metalloids or metals attached to the aromatic nucleus. Synthetic approaches to these compounds are described. This is followed by an overview on various applications of these compounds in organic synthesis, supramolecular and material chemistry.

In this review, the recent progress in the use of room temperature ionic liquids (RTILs) as reaction media and/or catalysts for the synthesis of various biologically privileged compounds, mainly heterocycles and nucleoside derivatives, is described.

Pyrimidine derivatives have played an important role in the chemistry of biological systems. This review focuses on recent work of our studies on the synthesis and biological activity of fused pyrimidine derivatives including pyrido[4,3-d]pyrimidine-4(3H)- ones; 3,4-dihydro-pyrido[4,3-d]pyrimidine-8-carbonitriles; pyrazolo[3,4-b]pyrido[4,3-d]-pyrimidine-4-ones; thieno[3',2'-5,6]pyrido [4,3- d]pyrimidin-4(3H)-ones; 1,2,3-triazolo[4,5-d]pyrimidin-7-ones; 1,2,4-triazolo[1,5-a]pyrimidin-10(3H)-ones; thiazolo[4,5-d]pyrimidin- 4(3H)-ones and pyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidin-4(3H)-ones. The different approaches for the syntheses of these fused pyrimidine derivatives are described and reviewed. Parts of other researchers' most relevant work were also included in this review.

The present state of art on the application of carbene-rhodium complexes as stable catalysts for hydroformylation reaction is described. A critical analysis of the influence of pressure and temperature on the hydroformylation of non-modified rhodium complexes and those ones described in the presence of carbenes is also done. Finally, a set of experiments using NHCs prepared by us at different reactions conditions is presented and discussed.