Olefins azide 1,3-dipolar cycloadditions

Dipolar cycloaddition of azides with olefins provides a convenient access to triazolines, cyclic imines, and aziridines and hence is a valuable technique in heterocyclic synthesis. For instance, tricyclic -lactams 273 - 276 have been synthesized using the intramolecular azide-olefin cycloaddition (lAOC) methodology (Scheme 30) [71]. 

The thermal cycloaddition of azides to acetylenes is the most versatile route to 1,2,3-triazoles, because of the wide range of substituents that can be incorporated into the acetylene and azide components. The accepted mechanism for the reaction is a concerted 1,3-dipolar cycloaddition. The rates of addition of phenyl azide to several acetylenes have been measured the rates of formation of the aromatic triazoles are not appreciably different from the rates of cycloaddition to the corresponding olefins, indicating that the transition-state energy is not lowered significantly by the incipient generation of an aromatic system. 

Aryl azide, acyl azide, sulfonyl azides, and azidoformate add to olefins by a 1,3-dipolar cycloaddition mechanism to yield triazoline. This addition also occurs with other unsaturated systems such as a,/S-unsaturated olefins, enam-ines, and cynamines [48]. 

Sulfonyl azides react with olefins at a temperature which is much lower than the decomposition temperature of the azides (120-150°). The isolated products are aziridines and anils. The addition can be conceived as a result of two consecutive reactions, namely a 1,3-dipolar cycloaddition of the azide to the olefin immediately followed by decomposition of the formed unstable triazoline. As no triazolines can be detected, these reactions can also be regarded as a concerted addition with concomitant loss of nitrogen. 

Azide addition to enolizable ketones is regiospecific and may be considered as a 1,3-dipolar cycloaddition occurring at the double bond of the enolate, similar to the addition of azides to electron-rich olefins. However, a stepwise reaction appears more probable because glycosyl azides exhibit anomerism when they react with activated methylene compounds, thus indicating the presence of a triazene intermediate.264 On the other hand, the formation of the triazene intermediate may be considered as a limited case of 1,3-dipolar cycloaddition where one of the bonds is formed completely before the other one starts,2 such a limited case being observed for the Diels-Alder reaction.265... 

To use 1,3 dipolar cycloadditions in a retrosynthetic sense, it is necessary to know what 1,3 dipoles are available. The list on pages 319-320 is representative of die more common and useful examples, although many others have been reported. Azides, diazo compounds, and nitrones are normally isolable compounds which can be added to a solution of an olefin. Other 1,3 dipolar species such as nitrile oxides and azomethine ylides are not stable molecules they must be generated in the reaction mixture in the presence of the olefin. As might be expected, many different ways to generate 1,3 dipoles have been developed. 

The addition of nitrogen across a double bond to form a fused-ring aziridine of type II generally takes one of two forms. The simplest is the dipolar cycloaddition of an azide across a double bond followed by loss of dinitrogen to provide an aziridine. A second and operationally more complex approach is the generation of a nitrene, which then adds to the olefin to directly provide the aziridine. 

The most common addition reaction of azides in general is the 1,3-dipolar cycloaddition to double and triple bonds. These reactions have been reviewed in this series of books as well as elsewhere, primarily by Huisgen and lately by L abbe, and their mechanism has been discussedThe 1,3-dipolar cycloaddition of azides is generally understood as a concerted process in which the terminal nitrogen of the azido group binds to the atom that is more negative in the olefin, if the olefin happens to be electronically unsymmetric. As a consequence of its concerted nature, it is a stereospecific cis addition. 

Sustmann164 has also collected data for 1,3-dipolar cycloadditions. Phenyl azide (197) reacts fast with electron-poor and with electron-rich olefins, but slowly with a simple olefin. A plot of the rate constant against the energy of the... 

Shea et al. investigated whether strain involved in alkenes affects reactivity and regiochemistry of the intermolecular 1,3-dipolar cycloaddition reaction [14]. Therefore, the addition of picryl azide (18) with a series of mono-and bicyclic olefins including frans-cycloalkenes and bridgehead alkenes was studied (Scheme 5). In the cases of czs-cyclooctene (16) and ci5-cyclononene (17), decomposition of the initially formed cycloadducts 19 and 20 followed... 

Ciufolini and co-workers demonstrated the use of 1,3-dipolar azide-olefin cycloaddition reactions in the total synthesis of ( )-FR66979 (52) [25], an antitiunor agent which is structurally related to the mitomycins [26]. Thus, the triazoline 50 was obtained as a single diastereomer by smooth cycloaddition of the activated double bond and the dipole in 49 by heating in toluene. Brief photolysis of 50 provided aziridine 51, which fragmented to 52 (Scheme 8B). Other intramolecular azide-alkene cycloaddition in natural product synthesis is illustrated by a munber of examples [27-32]. 

Rondan, N. G., Paddon-Row, M. N., CarameUa, R, Houk, K. A. (1981). Nonplanar Alkenes and Carbonyls A Molecular Distortion which Parallels Addition Steroselectivity. J. Am. Chem. Soc., 103,2436. Ess, D. H. Houk, K. N. (2007). Distortion/Interaction Energy Control of 1,3-Dipolar Cycloaddition Reactivity. J. Am Chem. Soc., 129, 10646-10647. Lopez, S. A., Houk, K. N. (2013). Alkene Distortion Energies and Torsional Effects Control Reactivities, and Stereoselectivities of Azide Cycloadditions to Norbomene and Substituted Norbomenes. J. Org. Chem., 78(5), 1778-1783. Hong, X., Liang, Y, Griffith, A. K., et al. (2013). Distortion-Accelerated Cycloadditions and Strain-Release-Promoted Cycloreversions in the Organocatalytic Carbonyl-Olefin Metathesis. Chem. Sci., 5(2), 471-475. 

Mann and coworkers recently demonstrated the synthesis of the pyrro-hzidine alkaloid amphorogynine C 122 using an azido-olefin dipolar cycloaddition as the key step (2012EJO4347). Heating a sample of azide 119 in toluene at 140 °C for 24 h produced triazohne 120 which subsequendy lost nitrogen to give imine 121 along with lesser quantities of an aziridine by-product. Imine 121 was eventually converted into the natural product 122 in several additional steps (Scheme 28). 

Further examples of this reaction have been observed when highly electrophilic arylnitrenes are produced by azide decomposition or deoxygenation of nitrosoperfluorobenzene in olefinic solvents which bear electron-donating substituents. The highly stereospecific nature of these additions confirmed the involvement of a singlet arylnitrene and the possibility of a 1,3-dipolar cycloaddition was ruled out. 

A /j-TsOH (p-toluenesulfonic acid)-mediated 1,3-dipolar cycloaddition of nitro olefins 45 and NaNa (sodium azide) for the synthesis of 4-aryl-NH-1,2,3-triazoles 46 has been presented by Guan and co-workers (Scheme 7.26) [86]. p-TsOH proved to be a vital additive in this reaction. This novel cycloaddition reaction tolerates a wide range of functional groups and is a reliable method for the rapid elaboration of readily available nitro olefins and NaN3 into a variety of NH-1,2,3-triazoles in high yields under mild conditions, which is complementary for the well-known 1,3-dipolar cycloaddition. 

Azides can partake in stereoselective dipolar cycloaddition reactions with olefins. The unstable resulting triazolines typically expel N2 under the conditions of the cycloaddition reaction, leading to the corresponding stable azir-idines. Cha has reported that heating of azide 32 leads directly to aziridine 33 as a single diastereomer (Scheme 18.8) [55]. The allylic stereocenter resident in 32 thus effectively controls the stereochemical outcome of the transformation. The product aziridine 33 was subsequently elaborated into 6,7-di-epi-castanospermine (34). 

Intramolecular dipolar azide-olefin cycloaddition of 723 took place upon heating in benzene to afford 724 (83JA3273). An alternative rearrangement process can take place upon photolysis of 724 to give 725. Mesylation of 4-(3-hydroxypropyl)-2,4,6-trimethyl-2,5-cyclohexadiene-l-one (78JA4618) and subsequent treatment with sodium azide in DMF afforded the respective azide 726 which underwent intramolecular cycloaddition to afford the triazoline 727 (83JOC2432). Irradiation of 727 gave the triazole derivative 728 (Scheme 126). 

An example of intramolecular azide addition to the olefinic bond of an enol ether is provided by the synthesis of a heptacyclic steroidal triazoline (Scheme 63).253 The dipolar aprotic solvent that is used is considered to facilitate the cycloaddition.11 182... 

---