Iminoether formation

Thiomethyl iminoether formation, 289 Thiophene formation, cycloaddition, thioglycolate, 583 Thiophenodiazepine formation, 622 Thiophenol formation, 527 sulfonyl chloride, 527 Thiourea formation... 

In the case of complexes such as (21) and (23) which have an extended planar ligand, a significantly higher proportion of interstrand cross-links in DNA is formed in comparison to either cis- or trans-platin.172 The steric effects of these planar ligands result in the formation of structurally unique 1,2-interstrand cross-links like those formed by cisplatin, a unique example of how steric effects may alter a nonactive lesion into an active one (Figure 13).173,174 Model studies predicted this outcome by preparation of the monofunctional models trans-[PtCl(9-ethylguanine) (NH3)(quinoline)] and comparison of substitution rates of the Pt—Cl bond by G or C mononucleotides.175 176 Interestingly, the iminoether compound (25) appears to form predominantly monofunctional adducts with DNA.177... 

The biological significance of long-lived monofunctional adducts on DNA remains to be determined, but these alone may be sufficient to kill cells if they are not repaired, which seems to be the case for the active trans iminoether complex 18 (60). Long-lived monofunctional adducts may also promote the formation of DNA-protein cross-links. 

Whereas the reactions of Meldrum s acid (421) and iminoether hydrochlorides (538, n = 3,4) in the presence of triethylamine in boiling benzene afforded (l-amino-w-chloroalkylidene)malonate [454, R = (CH2) C1 n = 3,4]. The reaction in chloroform under the previous conditions resulted in the formation of isopropylidene 2-azacycloalkylidenemalonates (468, n = 0, 1 R2, R4 = H) in low yields (81S130, 81TL2255). 

Condensation of anthrandic acid (77-1) with an iminoether represents another method for preparing quinazolones. The reaction with the iminoether (77-2) from 2-cyano-5-nitrofuran and ethanohc acid can be visualized as proceeding through the formation of the amidine from addition-elimination of anthranilic acid cycliza-tion then affords the observed product (77-3). This is then converted to chloride (77-4) in the usual way. Displacement of the newly introduced chlorine with diethanolamine leads to the formation of nifurquinazol (77-5) [86], one of the antibacterial nitrofmans (see Chapter 8). 

The more challenging task of direct C-N bond formation has recently been accomplished by utilization of the oxazoline ring as the nitrogen donor [76 - 78]. This approach was demonstrated by the preparation of spirolactams such as 17 from oxazoline derivatives of tyrosine and related phenolic acids by oxidation with BAIB in trifluoroethanol (Scheme 25), and similar conversions of indole-tethered oxazalones to tetracyclic products through spirolactam intermediates. It is noteworthy that phenolic amides, amines, and iminoethers were not useful for this purpose [78]. 

In 2001, Magnus and co-workers reported a straightforward synthesis of racemic rhazinilam by initial construction of the pyrrole ring from a piperidone, Fig. (33) [154]. The sequential alkylation of piperidone 155 with iodoethane and allyl bromide furnished piperidone 156, having the requisite C-20 substitution of rhazinilam. After formation of the thiophenyl iminoether 157, A-alkylation with allyl bromide 158 furnished the corresponding iminium intermediate which underwent 1,5-... 

Azole approach. The substituted isothiazole (142) can be reacted with an ortho ester to form a methyleneamine which reacts with hydroxylamine to yield the 5-oxide (143). With amidines, (142) yields 4-amino derivatives (75JHC883). The reaction of 5-amino-4-ethoxycar-bonylisothiazole with iminoethers results in pyrimidine annulation, as in the formation of... 

The chemical synthesis of 7-ACA (Fig. 3) is a classical organic route, which uses equimolar amounts of chemicals. A preferred process is the so-called iminoha-lide/iminoether deacylation route, involving formation of the iminochloride by reaction with PCI5, conversion into the iminoether by treatment with alcohol and hydrolysis with water [7]. Highly purified cephalosporin C, isolated, for example as the zinc salt, is required as a dried solid as the starting material. 

Considerable effort has been expended in exploring the scope of ke-tenimine formation as it pertains to the introduction of 7(6)-methoxy substituents. Carrol et al. (1974) reported the facile construction of ke-tenimines derived from penicillin G and demonstrated deuterium incorporation at C-6 by base-catalyzed exchange of a related imino chloride. Workers at Sankyo later reported a method (Sugimura et al., 1976) by which an imine 145 was produced from an a-haloimino chloride (144) via base-catalyzed 1,4-elimination. The resulting imine was stereospe-cifically converted to methoxyketenimine 146 by the addition of meth-oxide anion (—78°C). Exposure to lithium methoxide at -20°C then led to iminoether 147, which was transformed to amide 148 by a new reaction with trimethylchlorosilane and I equiv of quinoline. 

---