The synthesis of 1,2-azaphospholes, 1,2-azaphosphorines and 1,2-azaphosphepines

1,2-Azaphospholes, 1,2-azaphosphorines and 1,2-azaphosphepines are prominent phosphorus heterocycles and are of interest due to their potent pharmacological activities. In this review, we provide the available literature data on the synthesis of 1,2-azaphospholes, 1,2-azaphosphorines and 1,2-azaphosphepines.


Introduction
0][21][22] Ifosfamide and cyclophosphamide are two important examples of phosphorus heterocycles that were launched on the market more than 30 years ago and are still used in treatment of cancer. 23,246][27][28][29][30][31] Among these phosphorus heterocycles, 1,2-azaphospholes, 1,2-azaphosphorines and 1,2-azaphosphepines are of interest in several laboratories due to their potent pharmacological activities such as antitumor, 32 complexing agents, 33,34 and inhibitor of mammalian dihydroorotase. 35The present review is focused on the most methodologies for the construction of 1,2-azaphospholes, 1,2-azaphosphorines and 1,2-azaphosphepines up to the end of 2019 and to supplement the information available in literature.In addition, there is discussion of mechanisms.

Scheme 12
N-Benzyl-N-methyl-dinaphthylphosphinamide (29) underwent cyclization by using n-BuLi in THF then adding acetic anhydride to isolate the azaphosphole 38 as the major product in the presence or absence of the co-solvent HMPA (Scheme 13).The acylation then deprotonation of the methyl group of the CH 3 CO moiety and trapping gave the product of O-acetylation 37, or C-acetylation 39 with low yields (Scheme 13). 45

Scheme 14
The reaction of starting material 29 with n-BuLi in THF followed by addition of 2-cyclopenten-1-one or 2-cyclohexen-1-one took place with good yield and low selectivity to form a mixture of tricyclic 1,2-azaphospholes 45 and 46 with a cis-junction in a ratio of 1:1.6 (Scheme 15).Other products (47 and 48)  were also formed due to the dearomatization of the two naphthalene rings (Scheme 15). 45cheme 15

Scheme 20
Similarly, the ring-opening of the 1,2-azaphosphirene complex 68 in benzonitrile in the presence of dimethyl acetylenedicarboxylate as a trapping reagent afforded the 1,2-azaphosphole complex 69.When the reaction was performed with Ph 3 P=NCN in dry toluene, the 1,2-azaphosphole complex 70 was formed in high yield (Scheme 21). 33,55

Reaction of adduct of phosphaalkynes and imidovanadium with acetylenes
The cycloadduct 84 was generated in situ by addition of an equimolar amount of a phosphaalkynes 83 to the imidovanadium complexes 82 (Scheme 25).The cycloadduct 84 was treated with an excess of disubstituted acetylenes in toluene at -78 o C to form the tetrasubstituted 1,2-azaphospholes 85 in 31-71% yields (Scheme 25). 58Scheme 25

Reaction of chlorophosphenium triflate with potassium metal
Treatment of chlorophosphenium triflate 100 with potassium metal in toluene at 25 o C resulted in a pale yellow crystalline 1,2-azaphospholidine 104 (Scheme 29).It was assumed that the two-electron reduction of the idealized chlorophosphenium ion 100 proceeded in two steps; addition of the first electron would generate the monoradical 101.Addition of the second electron would then generate the triplet diradical phosphinidene 102.The conversion of 102 to 103 took place by an intramolecular P-C bond formation to afford the derivative 103.Finally, the latter 103 underwent N-C bond cleavage and hydrogen transferred from β-methyl group to the nascent imido nitrogen center forming the isolated 1,2-azaphospholidine isomer 104 (Scheme 29). 63

Cyclization of phosphinamides using various bases
Cyclization of different phosphinamides 105 using various bases at the boiling point of the used solvent furnished 2-oxido-1,2-azaphosphinanes 106 in different yields through removal of ethanol or hydrogen halide (Scheme 30). 64,65heme 30

Conclusions
In conclusion, this survey has presented the synthetic methods for 1,2-azaphospholes, 1,2-azaphosphorines and 1,2-azaphosphepines.Most of these synthetic methods require special reaction conditions and specific starting materials that are not available in some laboratories.However, cyclization of amino-and hydrazino compounds with phosphorus reagents or cyclization of aminophosphorus compounds with simple electrophiles are convenient and easy to perform.We hope that this review may encourage scientists to create new routes towards these ring systems with important biological activity.