Iminoether

A series of 4-methyleneisoxazolin-5-ones was produced by the reaction of hydroxylamine with iminoether (508) (77ACH(94)403) or with a /3-ketoester and triethyl orthoformate (Scheme 147) (65CI(L)36). 

WASSERMANN BORMANN Maciocydiclactamsynttwsis Ring expansion sequence of lactams by reaction with cyclic Iminoethers followed by reductive ring opening to a macrocyclic lactam. 

Cyclic enamines with an isomeric position of the double bond have been obtained by the addition of Grignard reagents to five- (78-81), six- (82-86), seven- (87-90), and thirteen- (89-91) membered lactams, whereas other medium-sized (92,93) lactams furnished amino ketones. The reaction has been extended to substituted lactams (94-98), and iminoethers (99,100). 

As part of a strategy for adding rings to system 4 the cyanide 232 was converted into the iminoether and treated with amines to give tricycle 233 (96JHC319). 

In this context, the treatment of the AT-phosphinyl iminoethers 15 with methyl iodide furnish the P-methyl phosphonium iodides, which by heating experience an 0-dealkylation, reminiscent of the Arbuzov reaction, for yielding the iV-acylphosphazenes 16 [45] (Scheme 16). 

An enantiopure bicyclic triazolium salt was prepared by a three step conversion of the oxazolidinone 31 (Scheme 18). The first step was a methylation affording an iminoether which was transformed into the phenylhydrazone 32. A final cyclization gave the salt 33 as a cristalline solid [25]. 

Neutral tertiary and secondary amides react with very reactive alkylating agents, such as triethyloxonium tetrafluoroborate, to give O-alkylation.63 The same reaction occurs, but more slowly, with tosylates and dimethyl sulfate. Neutralization of the resulting salt provides iminoethers. 

While screening for p-lactam antibiotics stable to p-lactamases, a strain of Streptomyces lactamdurans was found to contain several such agents which have a 6-a-methoxy group whose electronic and steric properties protect the antibiotic from enzymatic attack. Cephamycin C (29a), one of these substances, is not of commercial value, but side chain exchange has led to much more potent materials. Of the various ways of effecting this transformation, one of the more direct is to react cephamycin C with nitrous acid so that the aliphatic diazo product (29b) decomposes by secondary amide participation giving cyclic iminoether 30. The imino ether moiety solvolyzes more readily than the p-lactam to produce 7-aminocephamycinic... 

Cyclocondensation of the iminoethers 157 with anthranilic acid was utilized in the synthesis of compounds 158a, 158b <2004TA3045> and 158 (R2 = indol-3-ylmethyl R1 = (A )-Me, (R)-Me (A)-Pr R4 = H, (A)-Me) resulting in moderate yields with retention of configuration at all stereocenters (Equation 16) <1998T969>. 

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 4(5)-amino-2-substituted imidazoles (45) and (46) have been prepared (50JCS2775) by condensation of aminoacetonitrile (30) with the thio-iminoether hydrochloride salts (40) and (41), respectively. These 4(5)-aminoimidazoles (45, 46) were isolated as their hydrochloride salts in yields of 36 and 90% (Scheme 3). 

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. 

Fig. 8. X-ray crystal structure of the raras-Pt(II)-iminoether anticancer complex 18. Adapted from (129). 

In both cases the intermediate product, the enol form , is unstable, but alkyl derivatives, the so-called iminoethers, are known. 

Iminoether hydrochloride (536) was condensed with 2 mol of Meldrum s acid (421) in the presence of triethylamine in boiling chloroform overnight to give isopropylidene (2-oxo-5-methylpiperidin-6-ylidene)malonate (537) in 40% yield (86JST319). 

The reaction of EtO- with chloro compounds in ethanol is actually not an entirely satisfactory system for studying the activating effect of CN on aromatic nucleophilic substitution, because there is a tendency for CN itself to react, forming the conjugate base of iminoether, —C(OEt)=NH209. 

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