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The Diels-Alder reaction that involves a nitrogen atom in the diene or dienophile is termed the aza-Diels-Alder reaction. As well as the powerful all-carbon Diels-Alder reaction, the aza-Diels-Alder reaction has also played an important role in the total synthesis of natural products. Herein, we review various natural products using an aza-Diels-Alder reaction as a key step to their total synthesis, and divide the syntheses into inter- and intra-molecular aza-Diels-Alder reactions and a retro-aza-Diels-Alder reaction. Inter- and intra-molecular aza-Diels-Alder reactions involve an imine as an electron deficient dienophile and an imine as an electron deficient azadiene. The significance of the aza-Diels-Alder reaction for the construction of a six-membered ring containing nitrogen is tremendous, but the development of asymmetric, in particular catalytic enantioselective intramolecular aza-Diels-Alder reaction in the total synthesis of natural products remains highly challenging, and will no doubt see enormous advances in the future.

The carbodiimide 2 , obtained from the aza-Wittig reactions of iminophosphorane 1 with alkyl isocyanates, reacted with primary amino to give 2-alkylamino benzo[b]thieno[3,2- d ]pyrimidin-4(3 H )-ones 4 and 5 . The formation mechanism of the title compounds has been investigated.

In the title compound, C22H23N3O2, the three fused rings of the benzofuro[3,2-d]pyrimidine system are almost coplanar. The packing of the mol­ecules in the crystal structure is mainly due to π–π and inter­molecular C—H⋯O hydrogen-bonding inter­actions.

Aza-Wittig reaction of phosphorane (I) with isocyanates (II) provide carbodiimides which react with amines to give guanidine intermediates.

1H-1,2,4-Triazole reacted with 2-butenal in the presence of diaryl prolinol silyl ether 3 and benzonic acid to give 3-(1H-1,2,4-triazol-1-yl)butanal 4, which was subsequently reduced and then treated with various acyl chloride to generate enantioriched 3-(1H-1,2,4-triazol-1-yl)butyl benzoates 6. Some of triazoles 6 exhibited strong binding interactions with the cytochrome P450-dependent sterol 14alpha-demethylase (CYP51). For example, compound (R)-6f showed the best binding activity with K(d) 0.3381 microM.

1-Aryl-3-[2-(ethoxycarbonyl)benzothien-3-yl]carbodiimides 4, obtained from aza-Wittig reactions of iminophosphorane 3 with aryl isocyanates, reacted with secondary amines, phenols, or alkanols in the presence of a catalytic amount of potassium carbonate or sodium alkoxide to give 2-substituted benzothieno[3,2-d]pyrimidin-4(3H)-ones 6 in good yields. The reaction of carbodiimides 4 with primary amines RNH 2 (R ≠ H, Me) in the presence of sodium ethoxide selectively produced one regioisomer 8 via a base-catalyzed cyclization mechanism. However, a different regioisomer 9 was obtained when primary amines RNH 2 (R = H, Me) were used in the absence of sodium ethoxide via a direct cyclization mechanism.

The carbodiimides 2, obtained from aza-Wittig reactions of iminophosphorane 1 with aromatic isocyanates, reacted with hydrazine to give selectively 6-amino-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones 5. Compounds 5 were further transformed to iminophosphoranes 6 by reaction with triphenylphosphine, hexachloroethane and triethylamine. A tandem aza-Wittig reaction of iminophosphorane 6 with isocyanate or acyl chloride generated previously unreported 3,5-dihydro-1,2,3-triazolo[4,5-d]-1,2,4-triazolo[1,5-a]pyrimidin-9-ones 10 or 12 in satisfactory yield. X-ray structure analysis of 10 g verified the proposed structure and the reaction selectivity.

The bis(carbodiimides) 4, obtained from bis-aza-Wittig reactions of bis(iminophosphorane) 3 with 2 equiv of aromatic isocyanates, were reacted with secondary amine to give symmetrically substituted 2,7-diaminothieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-dione 6 in the presence of a catalytic amount of EtO(-)Na(+). Reactions of 4 with phenols or ROH in the presence of a catalytic amount of potassium carbonate or RO(-)Na(+) gave symmetrically substituted 2,7-diaryl(alkyl)oxythieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-diones 6 in satisfactory yields. However, iminophosphoranes 9 were obtained via reaction of bis(iminophosphorane) 3 with 1 equiv of aromatic isocyanate and subsequent reaction with an amine in the presence of a catalytic amount of EtO(-)Na(+). Further reaction of iminophosphoranes 9 with aromatic isocyanates and various nucleophile generated unsymmetrically substituted thieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-diones 12 in good yields.

In the title compound, C21H21N3OS, the three fused rings of the 1-benzothieno[3,2-d]pyrimidine system are almost coplanar. The crystal packing is stabilized by π–π stacking inter­actions and inter­molecular C—H⋯O hydrogen bonds.

In the title compound, C20H19N3OS, the three fused rings of the benzo[4,5]thieno[3,2-d]pyrimidone system are essentially coplanar. The crystal packing is mainly stabilized by C—H⋯π and π–π inter­actions.

In the crystal structure of the title compound, C21H19N3OS, there are inter­molecular C—H⋯O hydrogen bonds. No π–π stacking inter­actions are observed.

In the crystal structure of the title compound, C21H19N3O2S, there are two crystallographically independent mol­ecules, which are linked by C—H⋯O hydrogen bonds and π–π inter­actions.

The title compound, C15H16N2O2S, contains a five-membered thiophene ring fused to a benzene ring and a substituted pyrimidinone ring. All three rings in each of the independent molecules of the asymmetric unit lie in approximately the same plane. The crystal structure is stabilized by intermolecular C—H...O hydrogen bonding and π–π stacking interactions.

The molecule of the title compound, C15H16N2O2S, has crystallographic mirror symmetry. The crystal structure is stabilized by inter- and intra­molecular C—H⋯O hydrogen-bonding inter­actions.

In the title compound, C17H21N3OS, the propyl and butyl groups are disordered over two positions; site occupation factors are 0.304 (10) and 0.696 (10). The three fused rings are coplanar. In the crystal structure, intermolecular N—H...O and C—H...O hydrogen bonds link the molecules. Further stability is provided by offset π–π stacking interactions. Adjacent thienophene–pyrimidine and pyrimidine–benzene rings have centroid–centroid distances of 3.96 (1) and 3.55 (2) Å, respectively.

In the title compound, C16H14N4OS, the three fused rings of the benzothieno[3,2-d]pyrimidinone unit are essentially coplanar, the maximum deviation from the mean plane being 0.067 (3) Å. The dihedral angle between the mean plane of the fused rings and the imidazole ring is 72.00 (3)°. Offset π–π stacking interactions involving the fused rings are effective in the stabilization of the crystal structure. The centroid–centroid distances between the thienophene and benzene rings, and between the pyrimidine and benzene rings are 3.67 (1) and 3.93 (1) Å, respectively. There are two intramolecular C—H...O interactions.