Synthesis of Azomethines

Fig. 21 Reaction scheme for CVD synthesis of azomethine conjugated polymer, poly.

Aziridines in the synthesis of azomethine ylides 89AHC(45)231. Aziridines in the synthesis of natural products 86AHC(39)I81. Azirines as intermediates in pyrrole formation 87KGS1299. 3-Amino-2-//-azirines, synthesis and properties 90KGS867. Ethynylaziridines 87MI6. 

Schmeyers J, Toda F, Boy J, Kaupp G. Quantitative solid-solid synthesis of azomethines. J Ghem Soc Perkin Trans 1998 2 989-93. 

Organic Synthesis in Solid State 209 13.2.16.3 Synthesis of Azomethines... 

In 2011, Goossen and coworkers [38] also reported a one-pot three-component protocol for the synthesis of azomethines, starting from simple, nontoxic precursors - that is, potassium a-oxo car-boxylates, aryl halides, and primary amines (Scheme 3.21). In the presence of the bimetallic system, Cu/phenanthroline, and Pd/l,l -bis(diphenylphosphino)ferreocene (dppf) a wide range of valuable imines were obtained in good yields at 100 °C (Scheme 3.21). Interestingly, all three substituents in the azomethine products could be individually varied. 

SCHEME 3.141 Rhodium-catalyzed synthesis of azomethine yUdes and their use in multicomponent reactions [150]. 

Use of mesoionic ring systems for the synthesis of five-membered heterocycles with two or more heteroatoms is relatively restricted because of the few readily accessible systems containing two heteroatoms in the 1,3-dipole. They are particularly suited for the unambiguous synthesis of pyrazoles as the azomethine imine is contained as a masked 1,3-dipole in the sydnone system. An attractive feature of their use is that the precursor to the mesoionic system may be used in the presence of the cyclodehydration agent and the dipolarophile, avoiding the necessity for isolating the mesoionic system. 

Scheme 12.28 Synthesis of pyrazolo[l, 2-a]pyrazoles from azomethine ylides.

Another example of a microwave-assisted 1,3-dipolar cycloaddition using azomethine ylides and a dipolarophile was the intramolecular reaction reported for the synthesis of hexahydrochromeno[4,3-fo]pyrrolidine 105 [70]. It was the first example of a solvent-free microwave-assisted intramoleciflar 1,3-dipolar cycloaddition of azomethine ylides, obtained from aromatic aldehyde 102 and IM-substituted glycinate 103 (Scheme 36). The dipole was generated in situ (independently from the presence of a base like TEA) and reacted directly with the dipolarophile present within the same molecifle. The intramolecu-... 

Several variations and extensions of this HHT method have recently been reported. The mildness of this reaction was exemplified through the synthesis of glyphosate thiol ester derivatives 35. The requisite thioglycinate HHT 34 was prepared in high yield by a novel, methylene-transfer reaction between r-butyl azomethine and the ethyl thioglycinate... 

Satoh T, see Miura M (2005) 14 1-20 Satoh T, see Miura M (2005) 14 55-84 Savoia D (2005) Progress in the Asymmetric Synthesis of 1,2-Diamines from Azomethine Compoimds. 15 1-58 Schmalz HG, Gotov B, Bottcher A (2004) Natmal Product Synthesis. 7 157-180 Schmidt B, Hermanns J (2004) Olefin Metathesis Directed to Organic Synthesis Principles and Applications. 13 223-267... 

Progress in the Asymmetric Synthesis of 1,2-Diamines from Azomethine Compounds... 

Pandey, G., Bagul, T.D., Sahoo, A.K. (1998) [3 -E 2] Cycloaddition of Non stabilized Azomethine Ylides. 7. Stereoselective Synthesis of Epibatidine and Analognes. Journal of Organic Chemistry, 63, 760-768. 

Synthesis of complex 1. The pentadentate salen catalyst 1 was synthesized as described (9). In short, the tosylated 2-[2-(2-methoxyethoxy)-ethoxy]-ethanol 2 (10) was reacted with 2,4-dihydroxybenzaldehyde 3 to yield 4-alkoxy salicylaldehyde 4 after chromatographic purification (eq. 1). Subsequent condensation of 4 with 1,3-diaminopropanol yielded water-soluble salen ligand 5 in sufficient purity and 89% yield (11). The formation of an azomethine bond is indicated by a shift of the NMR signal for the carbonyl carbon from 194.4 ppm in aldehyde 4 to 166.4 ppm for the imino carbon in 5. The pentadentate ligand 5 was then treated with copper(ll) acetate in methanol to obtain the dinuclear copper(ll) complex 1 as a green solid (eq. 2) (11). 

In addition to nitrones, azomethine ylides are also valuable 1,3-dipoles for five-membered heterocycles [415], which have found useful applications in the synthesis of for example, alkaloids [416]. Again, the groups of both Grigg [417] and Risch [418] have contributed to this field. As reported by the latter group, the treatment of secondary amines 2-824 with benzaldehyde and an appropriate dipolarophile leads to the formation of either substituted pyrrolidines 2-823, 2-825 and 2-826 or oxa-zolidines 2-828 with the 1,3-dipole 2-827 as intermediate (Scheme 2.184). However, the yields and the diastereoselectivities are not always satisfactory. 

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

Intramolecular cycloadditions are among the most efficient methods for the synthesis of fused bicyclic ring systems [30]. From this perspective, the hetisine skeleton encompasses two key retro-cycloaddition key elements. (1) a bridging pyrrolidine ring accessible via a [3+2] azomethine dipolar cycloaddition and (2) a [2.2.2] bicyclo-octane accessible via a [4+2] Diels-Alder carbocyclic cycloaddition (Chart 1.4). While intramolecular [4+2] Diels—Alder cycloadditions to form [2.2.2] bicycle-octane systems have extensive precedence [3+2], azomethine dipolar cycloadditions to form highly fused aza systems are rare [31-33]. The staging of these two operations in sequence is critical to a unified synthetic plan. As the proposed [3+2] dipolar cycloaddition is expected to be the more challenging of the two transformations, it should be conducted in an early phase in the forward synthetic direction. As a result, a retrosynthetic analysis would entail initial consideration of the [4+2] cycloaddition to arrive at the optimal retrosynthetic C-C bond disconnections for this transformation. 

Hynninen and coworkers <99JCS(PT1)2403> used a similar approach to prepare phytochlorin-C6o diad 38 (Scheme 11). The protocol employed the pyrolysis of the natural chlorophyll a molecule 35, followed by transesterification and demetallation to furnish derivative 36. Subsequent oxidation of 36 with OsCU and NaI04 has allowed the synthesis of the formyl derivative 37, which was further used as precursor of the azomethinic ylide intermediate in the 1,3-DC reaction with Cm leading to the formation of diad 38. Photochemical studies revealed that this diad underwent a fast intramolecular photoinduced electron transfer in polar solvents such a benzonitrile <99JACS9378>. 

Reaction of porphyrins with nitrones has also been studied and the results obtained showed that this is a versatile approach leading to the synthesis of isoxazolidine fused-chlorins (Scheme 26). For instance, chlorin 74 was successfully prepared from the reaction of the jV-methylnitrone, generated in situ from JV-methyl hydroxylamine and paraformaldehyde, with porphyrin Id . It is important to note that bis-addition also took place, yielding exclusively bacteriochlorin type derivatives 76 and 77 (Figure 6). This result contrasts with those obtained in 1,3-DC reactions with azomethinic ylides where isobacteriochlorins were obtained preferentially. 

Type Ilbd pyrrole syntheses fall into three general categories (1) Hinsberg-type (2) azomethine ylide cycloadditions and (3) isocyanide-based cyclocondensations. The Hinsberg pyrrole synthesis, the cyclocondensation between iminodiacetates and oxalates, has been further exploited in the total synthesis of the lamellarins <06T594,06TL3755>. 

A short review has been published on the utilization of chiral enaminones and azomethine imines in the synthesis of functionalized pyrazoles <06ARK35>. 

---