Dimethylaminomethylene compounds

Depending upon the reaction conditions, Vilsmeier-Haack formylation of the pyrido [1,2-a] pyrimidines (63 R = H, Me) yielded the 3-formyl derivatives (222 and 223) or the 3-dimethylaminomethylene compounds (224).98,285,296 298 Under vigorous conditions, 2-methoxy-4-oxo-4//-pyrido... 

The substrate 139, which is readily available by reaction of glycine with the corresponding dimethylaminomethylene compound, underwent cyclization to the unusual pyrrole 140 in a useful yield (Equation 39). A similar strategy could also be employed for instance in syntheses of isoindoles <2002J(P1)2799>. 

The dimethylaminomethylene compound 468 was converted to arylamino-methylene derivatives 471 with anilines in acetic acid, and to the phenylhy-drazone 472 with phenyldiazonium chloride (83JCR(S)161 84JMC1253). The ester group of compounds 471 and 472 could be hydrolyzed to a carboxylic group under alkaline conditions (84JMC1253). 

The five-membered homolog of 390 (R = R = H, = 0) gave the dimethylaminomethylene derivative 381 upon treatment with dimethyl-amine. The formyl compounds 390 = 0,1) and the dimethylaminomethylene derivatives 392 were transformed by amines, hydrazines, and hydroxylamine into the corresponding 3-aminomethylene derivatives of type 394. - ° The dimethylaminomethylene compound 381 and the formyl derivative 390 (R = R = H, = 0) afforded cyano derivatives 395 on treatment with acetone cyanohydrin. - Compound 395 (R = NMe2) was hydrolyzed to the acetic acid derivative 396 in concentrated hydrochloric acid. Treatment of the (dimethylaminomethylene) pyrrolo-[2,l-i ]quinazoline 381 with formic acid furnished the bis derivative 397. The formyl and dimethylaminomethylene groups of compounds... 

These observations indicated that an intermolecular double condensation to give a bis N-(methylene-4-oxocoumarinyl)-l,4 aromatic diamine had occurred. Data from the elemental analysis indicated that the calculated and observed values were within the acceptable limits ( 0.4%) and in conformity with the assigned structure. In the addition of molar equivalents of 1,4-aromatic binucleophilic compounds to compound 72 we did not observe any heterocyclic compounds resulting from the further intermolecular nucleophilic attack on the single condensation product. Since the condensation of 3-(dimethylaminomethylene)-chromane-2,4-dione with aromatic binucleophilic compounds is the only route to the new coumarinic compounds, this represents a useful synthetic method. 

Mannschreck and Kolle examined various systems in which the dipolar structure 28 was stabilized by delocalization of the negative charge to the other end of enamines. The highest barrier to rotation in their work in 1967 (71) was obtained with 2,3-diformyl-6-dimethylaminofulvene (30). The H NMR spectrum of the compound did not change up to 185°C, and the barrier to rotation was estimated to be >25 kcal/mol. Another candidate that provided stable retainers was 4-(dimethylaminomethylene)-l,2-diphenyldiazolidine-3,5-dione (31). 

In attempts to formylate the bicyclic compound 5-methyl-9-phenylhy-drazono-6,7,8,9-tetrahydro-4-oxo-4//-pyrido[l,2- z]pyrimidine 3-carboxy-late (129) with dimethylformamide-phosphoroxychloride at 90-100°C, a degenerate ring rearrangement took place, resulting in the formation of 7-(o -chloroethyl)-8-chloro-9-(A,A-dimethylaminomethylene)amino-6,7,8,9-tetrahydro-4-oxo-4H-pyrido[l,2-a]pyrimidine-3-carboxylate (131)... 

Similarly, reaction of 2-dimethylaminomethylene-3-oxoalkanoates or 2-di-methylaminomethylene-1,3-cyclohexanediones with 2-phenyl-5(4/7)-oxazolone 146, generated in situ from hippuric acid, affords 6-substituted 3-(benzoyl-amino)-2-oxo-2//-pyran-5-carboxylates 204 and 3-(benzoylamino)-7,8-dihydro-2//-l-benzopyran-2,5(6//)-diones 206, respectively. These compounds showed strong local anesthetic activity (Scheme 7.62). ... 

Vilsmeier formylation has attracted much attention as a route to cyclazines (see Section III,B,6). Jessep and Leaver have obtained the Vilsmeier salt 263 from 1 by using dimethylformamide and phosphoryl chloride at — 65°C, but the formylpyrrolizine was very unstable, and a second Vilsmeier reaction has not been achieved.128 The salt 263 could be converted to the 3,5-bisaldehyde equivalent 264a by treatment with dimethylthioformamide and acetic anhydride. Flitsch et al. prepared l-chloro-3H-pyrrolizine and treated it in situ at — 60°C with the Vilsmeier reagent to obtain the chloro derivative 259 of compound 263. 7 They also obtained the bis(dimethylaminomethylene) derivative 264b and, at room temperature, the tris(dimethylaminomethylene) derivative 265, which was hydrolyzed to give the dialdehyde 266. Reactions... 

Compounds with structure 80 can be synthesized by intra or intermolecular cyclization of substituted 3,4-diaminothieno[2,3-Z>]pyridines. For example, heating (A,A-dimethylaminomethylene)amines 82 affords tricyclic pyrimidine derivatives 83 via intramolecular cyclocondensation (1993KFZ40). 

Treatment of 4-dimethylaminomethylene-2//-thiopyran-3,5(4//,6//)-dione (575) with hydroxyl-amine hydrochloride in refluxing MeOH gives compound (576) in good yield (Equation (56)) (84JHC1437). 

The synthesis of dimethylaminomethylene derivatives of steroidal ketones and lactones such as (127), (128), (129), and (130) has been described. Some compounds of this type possess high anabolic activity. 

The V-dimethylaminomethylene derivatives (81) of HAA were prepared by heating these compounds with N, ACdi methyl formarn idc dimethyl acetal (80), as shown in equation 6. The reaction was applied for derivatizing HAA listed in Table 2.B-C, with end analysis by GC-MS or GC-NPD170. 

Formerly, a GC method with nitrogen-phosphorus selective detector (NPD) was developed for the determination of HCAs with the advantage of the high response of these compounds in the detector due to the nitrogen atoms present in the structure of the HCAs. Kataoka and Kijima developed a simple and rapid derivatiza-tion method for GC analysis of HCAs. Ten HCAs were converted into their A-dimethylaminomethylene derivatives with A,A-dimethylformamide dimethylac-etal and measured by GC with NPD using two connected fused silica capillary columns in order to improve the separation of HCAs [115]. The structures of the HCAs derivatives were confirmed by GC-MS. 

This type of reaction is essentially similar to that of replacement of an aromatic halogen by a thiolate group. Halogen compounds studied include 3,4-dimethyl-5-bromo-2(N,N-dimethylaminomethylene)-2H-pyrrole and chlorofuro-[2,3-d]pyridazines . Copper(i) alkylthiolates have been used to form thioethers with 2-bromothiophene, 2-bromopyridine and 2-bromofuroic acid, the latter with concomitant decarboxylation . 

A considerable number of triarylethylene type estrogens have been prepared in the laboratories of the Richardson, Merrell Company. One of the earliest hypoHpidemic compounds reported in this series was Mer. 13 (XXXIV). When added to the diet of cholesterol-fed cockerels, compound XXXIV inhibited the development of hypercholesterolemia, as well as aortic and coronary atherosclerosis [131]. Interestingly enough, introduction of a dimethylaminomethylene group in trianisylethylene afforded the drug myordil, (Win. 5494, XXXV),... 

After a detailed study of the structure of the reaction product, it was concluded that it is not the compound 104, which is noncharacteristic for the dimethylcar-bamoyl group but its isomer-1-IVW-dimethylaminomethylene-l,2-dihydrofuro [2,3-fo]quinoxalin-2-one 108 (Scheme 6.35). 

Acetyltetronic acid derivatives (94) are formed during base-catalysed rearrangement of 4-ethoxycarbonyl-3(2//)-furanones (93). 3-(Arylmethylene)-furandiones (95) can be obtained in fair yield froni tetronic acid itself (for which an improved preparation has been found) by condensation with aromatic aldehydes (three equivalents ) in the presence of concentrated hydrochloric acid. Butyrolactones are transformed into their 2-keto analogues upon dye-sensitized photo-oxygenation of their readily available 2-dimethylaminomethylene derivatives, the overall yield for the two steps, with model compounds, being about 60%. °"... 

Bristol-Myers Company has reported on the use of TBA as a solvent for the in-vial deposition of 7 (dimethylaminomethylene) amino-9a-methoxymitosane in sterile unit dosage form. This compound is not stable in water. It is introduced into a sterile vial in a TBA solution. Then the TBA is removed by lyophilization. The deposited material contains up to 0.5 mole equivalent of TBA as a hemi-solvate and is very stable to heat. 

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