Addition and Cycloaddition Reactions of Phosphinyl- and Phosphonyl-2H-Azirines, Nitrosoalkenes and Azoalkenes

An overview of the use of 2H-azirines, conjugated nitrosoalkenes and conjugated azoalkenes bearing phosphorus substituents in addition and cycloaddition reactions is presented, focused on strategies for the synthesis of aminophosphonate and aminophosphine oxide derivatives.


Introduction
Over recent years we and others have investigated the use of 2H-azirines, conjugated nitrosoalkenes and conjugated azoalkenes in nucleophilic addition and cycloaddition reactions. The structures I, II and III of these three classes are outlined in Figure 1.

OPEN ACCESS
A common feature of all three structures is that they possess a highly electrophilic carbon centre (C-3 in 2H-azirines, C-4 in conjugated nitroso-and azo-alkenes) that allows nucleophilic addition reactions to proceed very readily. In reactions of nucleophiles with 2H-azirines this often leads eventually to opening of the three membered ring. The electrophilic character of these structures also allows cycloaddition reactions, particularly those with nucleophilic olefins, to take place under very mild conditions. Such reactions have provided routes to a variety of novel heterocyclic structures which have proved to be very useful targets, not only due to their eventual biological and pharmacological properties, but especially to their wide and versatile use as synthetic intermediates or useful building blocks for the synthesis of amino acids, pyrroles, proline, indoles, pyrazines, and azasugars derivatives, amongst many other compounds [1][2][3][4][5][6][7][8][9][10][11].
Aminophosphonic and aminophosphinic acid derivatives can be considered as isosteres or surrogates of aminocarboxylic acids and they regulate various important biological functions [12][13][14][15][16]. In this context it is not surprising that organic chemists have been attracted to them and have paid particular attention to the synthesis of these types of compounds. The aim of this review is to illustrate the particular use of above reaction types of 2H-azirines, nitrosoalkenes and azoalkenes bearing phosphinyl or phosphonyl substituents, for the construction of alkyl α-and β-aminophosphonates and aminoalkylphosphine oxides.

Synthesis
Despite all these potential applications, 2H-azirines bearing phosphorus substituents have received comparatively little attention. Photocyclization

Addition reactions
One of the earliest reported reactions of 2H-azirines bearing phosphorus substituents was hydride addition [24,25]. The treatment of azirines 9, 10 with sodium borohydride in ethanol produced cisaziridines exclusively (Scheme 5). The stereochemical assignment was based on the large coupling constant observed for the ring protons and further established by the transformation into enantiopure  Nitrogen heterocycles, in the presence or absence of base, add regioselectively to the azirine nucleus following the general pattern -the attack being from the less hindered face of the azirineyielding functionalized aziridines [29,30] (Schemes 7 and 8).  Oxygen [30] (Scheme 9) and sulfur [29] (Scheme 10) nucleophiles also add in a similar and regioselective mode, to 2H-azirines bearing phosphorus substituents. In the case of the reaction with benzenethiol, if a methyl group is present in the ring of the resulting aziridines, subsequent ring opening reaction leads to a-aminophospine oxide and -phosphonates 33.
The addition of Grignard reagents to 2-phosphinyl-and 2-phosphonyl-2H-azirines is less simple. Early reports with 2,3-diphenyl-2H-azirine revealed that the reaction followed the general pattern of addition of nucleophiles, i.e., the obtained aziridines arise from the attack at the less hindered face of the azirine [31]. These findings are in clear contrast with those obtained with alkyl 2H-azirine-2carboxylates, in which the syn addition -to the more hindered face-is preferred (Scheme 11) [32,33]. These facts have been ascribed to a prechelating effect of the Grignard reagents with carboxylate substituents.
Scheme 11. Addition of Grignard reagents to 2H-azirine-2-carboxylates.  When the carboxylate group was replaced by a phosphoryl group, the reverse preference was observed, i.e., an exclusive attack at the least hindered side was encountered [30] (Table 1).   Carboxylic acids [26], N-protected aminoacids and peptide residues [34] also add to the carbon nitrogen double bond of phosphinyl-and phosphonyl-2H-azirines. The concomitant ring opening leads to ketamides 48 (Scheme 13).
Due to their ambident character, phosphinyl-and phosphonyl-2H-azirines also react as nucleophiles with carboxylic acid derivatives, such as acid chlorides, producing exclusively trans-aziridines 50 [35]. The scope of the reaction is not limited to simple chlorides since other functionalized acyl chlorides will react similarly in good overall yields.

Cycloadditions
Simple alkyl-and aryl-2H-azirines, although being more reactive than acyclic imines, participate in Diels-Alder reactions only with highly reactive dienes, such as cyclopentadienones and 1,3-diphenylisobenzofuran in refluxing toluene [36], or with acyclic dienes and cyclopentadiene under Lewis acid catalysis [37,38]. 2H-Azirines with an alkoxy-, aryl-, amino-carbonyl [8,39] or heteroaromatic [40] substituent on the C=N bond are particularly good dienophiles in Diels-Alder reactions with a great variety of dienes, as a consequence of the conjugated effect of ring strain and extra activation by the electron-withdrawing group.
Similarly enantiomerically enriched 2H-azirine-3-phosphonates 51 when stirred with 100 equiv of 2,3-dimethylbutadiene or trans-piperylene for 2-4 days at room temperature or with Danishefsky's diene for 8 The stereochemistry of cycloadducts 53 was consistent with exclusive addition of the diene to the less hindered face of the azirine 51. The longer reaction times, when compared with 2H-azirine-3carboxylates, may suggest that 2H-azirine-3-phosphonates are less reactive than carboxylates.
Recently an azirine bearing both ethoxycarbonyl and phosphonate groups, was generated in situ and intercepted with a number of nucleophilic dienes [41]. With open chain dienes bicyclic functionalized six-membered ring fused aziridines were produced; although cyclic dienes afforded tryciclic structures. The presence of a trimethylsilyloxy group at the conjugated system, induced hydrolysis of cycloadduct 56f and 56c to 57 and 58 respectively (Scheme 16).
Scheme 16. Cycloaddition reactions of 2H-azirine 55 with nucleophilic dienes. The products were isolated as single isomers, presumed to be formed by endo selective processes, as clearly indicated by the low field resonance of H-3 in the tricyclic structure 56d, attributed to the anisotropy of the backside double bond over H-3, due to constrain of the tricyclic structure [42]. To the poor stability of azirine 55 was ascribed the low to moderate yields of cycloadducts (Scheme 16).

Nitroso-and Azo-alkenes
Nitrosoalkenes and azoalkenes, used either as Michael-type acceptors in conjugate 1,4-additions, or as heterodienes in cycloaddition reactions with a range of nucleophiles, alkenes and heterocycles, have proved to be invaluable tools for the synthetic organic chemists.

Synthesis or generation
Electron-deficient nitrosoalkenes are, generally, very unstable species and for this reason, they are usually generated and intercepted in situ. Depending on the substituents, azoalkenes are sometimes stable enough to be isolated. Anyway, being isolated or generated "in situ", the most common, general and broad scope method for the obtention of nitroso-and azo-alkenes is the base induced 1,4-dehydro elimination from oximes and hydrazones bearing a suitable halogen or ester leaving group at the

Reactions with nucleophiles
Although in reactions involving nitroso-and azo-alkenes generated and intercepted in situ, the distinction between nucleophilic substitution of the original α-halogenated oxime or hydrazone and 1,4-conjugate (or Michael type) addition, is sometimes an intricate decision, the following reactions are thought to proceed via this latter process. The primary literature reference to azoalkenes bearing phosphorus substituents [43] reported their use at the synthesis of 1-aminopyrroles substituted with a phosphine oxide or phosphonate group in the 3-position.
In this context, Palacios and co-workers [70] found that the reactions of nitrosoalkenes, bearing a phosphinyl or phosphonyl substituent at the terminal carbon, with enamines 99 did not proceed by [4+2] cycloaddition reactions producing the expected 1,2-oxazines, but N-hydroxypyrroles were instead isolated, presumably by a mechanism involving an initial conjugate addition of the enamine followed by a formal [3+2] dipolar cycloaddition (Scheme 26).

Cycloadditions
Cycloaddition reactions of nitroso-and azo-alkenes with electron rich carbon-carbon double bonds and heterocycles are important and powerful synthetic tools, as demonstrated by the enormous impetus of the chemistry of these compounds over the last decades.
Azoalkenes with a phosphinyl or phosphonyl substituent at the 4-position were generated by triethylamine induced dehydrohalogenation of chlorohydrazones [71]. Its interception with acyclicstyrene and cyclic-cyclopentadiene and norbornadiene alkenes and di-hydrofuran gave regio-and stereo-selectivelly endo cycloadducts, except in the case of the strained norbornadiene, which produced an exo cycloadduct (Scheme 27). Attempts to bring about some degree of diastereoselectivity to the reaction, induced by the use of an optically active (-)-menthyl ester, were unsuccessful, since a diasteroisomeric ratio of 1:1 was found.
Cycloadducts were also obtained in regioselective fashion in reactions of azoalkenes bearing a phosphonate substituent at the 3-position with electron rich olefins [51] (Scheme 28).  (Table 2), assumed to be the result of rearomatization of the primarily formed cycloadducts [72]. The yields were, in general, lower than those obtained in similar reactions with azoalkenes bearing the same alkoxycarbonylazo substituent, but having an ethoxycarbonyl group at the 3-position [73], pointing out that eventually the ethoxycarbonyl group may play a more effective role than the phosphonate moiety. Nitrosovinylphosphonates generated from the corresponding chlorooximes were intercepted by electron-rich alkenes and heterocycles [74]. The yields, although not optimised, were fair and the reactions were found to be completely regioselective: no other isomers were detected or isolated from the reaction medium (Scheme 29).

Concluding Remarks
Synthetic applications of 2H-azirines, nitroso-and azo-alkenes bearing phosphinyl or phosphonyl substituents, emphasised towards the synthesis of αand β-amino-phosphonates and -phosphine oxides have been addressed in this review. Established methods of aziridine ring opening [17,75] and reductive transformations at the C=N bond [76][77][78] will further broaden the scope and importance of these strategies that surely will be further developed and attract the attention and interest of synthetic chemists.