CHAPTER 1 - Cycloaddition and Cyclization Chemistry of 2H-Azirines

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Azirines are regarded as one of the most simple of all heterocyclic systems. They are characterized, by the presence of two carbon atoms and one nitrogen atom, in a three-membered ring, containing a π-bond. Numerous members of the 2H-azirine ring systems are fully characterized. The stability of the 2H-azirine ring is attributed to the combined effects of bond shortening and angle compression and to the presence of the electron-rich nitrogen atom. This chapter describes the important cyclo-transformations of the azirine system, with emphasis on cycloaddition and cyclization reactions. It outlines the selective sampling of the photochemical cycloaddition and cyclization chemistry of 2H-azirines. It is noted that the chemistry of 2H-azirines is generally regarded as mechanistically complex and synthetically useful. Also, in contrast to their photochemical behavior, the major thermal reaction of 2H-azirines generally involves C(2)–N bond cleavage to form vinyl nitrenes, which further react, by either insertion into an adjacent C–H bond or else undergo addition across a neighboring π-bond.

Introduction

Azirines can be regarded as one of the most simple of all heterocyclic systems, one which is characterized by the presence of two carbon atoms and one nitrogen atom in a three-membered ring containing a π-bond. While numerous members of the 2H-azirine (1) ring systems are known and have been fully characterized, derivatives of the 1H-azirine ring system (2) are known only as transient intermediates. Interest in these nitrogen-containing small rings is due to the general influence of ring strain upon chemical reactivity, to the degree to which the 1H-azirine ring, for example, is destabilized by conjugation of the nitrogen lone pair electrons with the π-bond, and to the potential of derivatives of these compounds to act as precursors to more elaborate heterocyclic molecules. The stabilities and overall profiles of chemical reactivity of these heterocycles are attributable not only to the combined effects of bond shortening and angle compression, but also to the presence of the electron-rich nitrogen atom. With 1H-azirines, cyclic delocalization of the lone pair electrons is believed to destabilize the ring to an extent which precludes isolation but not detection of the 4π-electron containing antiaromatic ring system. Polarization toward the more electronegative nitrogen atom of the 2H-azirine ring results in a shorter C–N bond and a longer C–C bond, consistent with the dimensions of 2H-azirines found by single crystal X-ray data (97CEJ1757). The stability of the 2H-azirine ring can be attributed not only to the combined effects of bond shortening and angle compression, but also to the presence of the electron-rich nitrogen atom. The strain energy associated with these heterocycles is principally due to deformation of the normal bond angles between the atoms of the ring. The total ring-strain energy of 2H-azirine has been estimated at 48 kcal mol−1 (91AG238, 02EJOC1750) although lower values of 44.6 and 46.7 kcal mol−1 have been reported using ab initio calculations at the MP2/6-31G* and B3LYP/6-31G* levels of theory (98JCC912). The chemistry of 2H-azirines is dominated by processes in which the strain of the three-ring system is relieved. They readily participate in cycloaddition reactions as 2π-components and undergo ring cleavage on photochemical excitation to give nitrile ylides. These dipoles then undergo a subsequent 1,3-dipolar cycloaddition reaction with a variety of π-bonds. Thermal ring cleavage produces vinyl nitrenes by cleavage of the N–C2 bond, which then undergo ring expansion reactions. The theoretical, biological applications, and the synthetic chemistry of 2H-azirines have been extensively explored and a number of general reviews have appeared (01EJOC2401, 02OPP219) (Figure 1).

A major and characteristic reaction of the 2H-azirine ring is its reactivity toward a wide variety of reagents, an effect undoubtedly resulting from the necessary compression of bond angles in the three-membered ring. Thus, this system is extremely susceptible toward ring cleavage because of the favorable release of strain energy involved. For this reason, 2H-azirines have been converted to a wide variety of functionalized compounds. 2H-Azirines are capable of acting in reactions as nucleophiles and electrophiles, as 2π-components in thermal cycloadditions, and as 4π-components in photochemical cycloadditions. These reactions can be regarded in general terms as involving the participation of the Cdouble bondN, C–C and C–N bonds of the 2H-azirine ring. The cycloaddition and cyclization reactions of 2H-azirines have invoked considerable interest in recent years. In this chapter, some of the more important “cyclo” transformations of this unique heterocyclic system are described.

Section snippets

Bimolecular [1,3]-dipolar cycloadditions

2H-Azirines undergo irreversible ring opening on electronic excitation to give nitrile ylides 4 as reactive intermediates (Scheme 1) (76ACR371, 77H143, 73JA1954). Nitrile ylides may be classified as nitrilium betaines, a class of 1,3-dipoles containing a central nitrogen atom and a π-bond orthogonal to the 4π-allyl system. They can be intercepted with a wide variety of dipolarophiles to form five-membered heterocyclic rings (e.g., 5).

The photocycloaddition of arylazirines with electron

Thermal Cyclizations of 2H-Azirines

The major thermal reaction of 2H-azirines of type 60 generally involves C(2)–N bond cleavage to form vinyl nitrenes 61. Cleavage of the C–C bond to produce iminocarbenes 62, diradical species 63 or nitrile ylides 64 is also possible at higher temperatures (Scheme 18). Molecular orbital calculations suggest that C–C bond cleavage can actually occur more readily than C(2)–N bond cleavage (78JA6575). Excellent reviews of these processes are available (82MI101-01, 83MI101-02, 84CHEC-1(7)47,

2H-Azirines as Dienophiles or Dipolarophiles in Cycloaddition Reactions

The 2π-electrons of the carbon–nitrogen double bond of 2H-azirines can participate in thermal symmetry-allowed [4+2]-cycloadditions with a variety of substrates such as cyclopentadienones, isobenzofurans, triazines and tetrazines. Cycloadditions also occur with heterocumulenes such as ketenes, ketenimines, isocyanates and carbon disulfide. It is also possible for the 2π-electrons of 2H-azirines to participate in “ene” reactions (73HCA1351).

Concluding Remarks

A selective sampling of the photochemical cycloaddition and cyclization chemistry of 2H-azirines has been outlined in this chapter. Some photochemical sequences increase molecular complexity more than others, but each seems to provide complex heterocyclic structures in a very efficient manner. Indeed, many of these photoreactions rapidly construct hetero-polycyclic systems that are difficult to produce in other ways. In contrast to their photochemical behavior, the major thermal reaction of 2H

Acknowledgment

AP wishes to acknowledge the research support of our program in heterocyclic chemistry by the National Science Foundation (CHE-0742663).

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