Morpholines and Piperidines

The first SBI fungicides to be introduced as agricultural fungicides were, chemically, morpholines such as dodemorph and tridemorph, which had already entered the market at the end of the 1960s (Table 17.21). Whereas dodemorph was mainly developed in ornamentals, tridemorph gained importance in cereal crops and bananas [97]. 

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Enamines are not easily formed from 17-ketones. A pyrrolidine enam-ine is obtained by acid catalysis accompanied by azeotropic removal of water whereas the morpholine and piperidine enamines do not form under these forcing conditions. 

Unlike the pyrrolidine enamine of 2-methylcyclohexanone (7), which consists predominantly of the trisubstituted isomer, the morpholine and piperidine enamines of 2-methylcyclohexanone (20 and 21) were shown by... 

The increase in the proportion of the tetrasubstituted isomer in the cases of the morpholine and piperidine enamines of 2-methylcyelohexanone has been ascribed to both steric and electronic factors. The authors propose that the overlap of the electron pair on the nitrogen atom and the v electrons of the double bond is much more important in the case of the pyrrolidine enamines and much less with the others. Support for this postulate was provided by the NMR spectra of these enamines, wherein the chemical shifts of the vinylic protons of the pyrrolidine enamines were at a higher field than those of the corresponding morpholine and piperidine enamines by 20-27 Hz. The greater amount of overlap or electron delocalization, in the case of pyrrolidine enamine, is in accord with the postulate of Brown et al. (7- ) that the double bond exo to the five-membered ring is more favored than the double bond exo to the six-membered ring. 

Steroidal a,j8-unsaturated ketones such as /l -3-ketones undergo a facile reaction with pyrrolidine to give the corresponding, d - -dienamines (111) (40,53). The reaction is much slower with morpholine and piperidine, which is undoubtedly due to the generation of the double bond exocyclic to the six-membered hetero rings in the step involving the dehydration of the intermediate carbinolamine (112) to the corresponding iminium ion (113). 

The reactions of dichlorocarbene with morpholine and piperidine enamines derived from cyclopentanone and cyclohexanone have been reported to lead to ring expanded and a-chloromethylene ketone products (355,356). Similarly a-chloro-a, -unsaturated aldehydes were obtained from aldehyde derived enamines (357). Synthesis of aminocyclopropanes (353,359) could be realized by the addition of diphenyldiazomethane (360) and the methylene iodide-zinc reagent to enamines (367). 

The reaction was found to be general and was extended to the preparation of a large range of phosphorodiamidic fluorides, e.g-from diethylamine, butylamine, methylaniline, benzylamine, cycfohexylamine, morpholine and piperidine. The method was patented. 

Rappoport and Topol investigated the displacement of the halogen of bromo- and chloromethylenemalonates (287 X= Br, Cl) by several substituted anilines and that of the brosyloxy group of (4-nitrophenyl)(4-bromo-phenylsulfonyloxy)methylenemalonate (289) by morpholine and piperidine, in acetonitrile. A rate-determining nucleophilic addition of the amines was suggested as the mechanism for these reactions. Activation parameters (AH, AS ) were determined [72JCS(P2)1823]. 

Values of N+ for morpholine and piperidine in methanol solution were obtained by taking the average value of N+ determined by fitting the rate constants for the reactions of these nucleophiles with 2,4-dinitrofluorobenzene, 2,4-dinitrochlorobenzene, 2,4-dinitrobromobenzene and 2,4-dinitroiodobenzene, to plots of log k against N+ (using the data reported in Reference 80c). Data for the reactions of these substrates with azide ion were excluded from the correlation lines for the purpose of calculating these N+ values. 

Since morpholine and piperidine are stereochemically similar but exhibit different pKa values, the difference between their rates in the reactions of the fluoro-substrates in acetonitrile could be also due to a change in mechanism, whereby proton transfer from the intermediate 1 in equation 1 becomes rate-limiting when the reagent is morpholine. The change from an uncatalysed to a base-catalysed reaction with decrease in basicity of the nucleophile is well known in ANS for both primary and secondary amines1 200. 

The most common 2° amines used for the preparation of enamines are pyrrolidine, morpholine and piperidine. 

In the first studies of isotope exchange of the haloforms, general base catalysis could not be clearly observed [164]. In more recent studies of the detritiation of chloroform in aqueous morpholine and piperidine buffers, general base catalysis could not be detected and the reaction was dominated by hydroxide ion catalysis [114]. In this latter study it was assumed that the mechanism of isotope exchange consisted of a slow triton transfer to base (99), viz. 

J The di-n-propyl, diethyl, dimethyl, and di-n-butyl derivatives are all very soluble in cold water. The less soluble morpholine and piperidine derivatives can be freed from ammonium chloride by washing with water. 

Tropinone enamines (28) have been prepared, with morpholine and piperidine respectively, and cyanoethylation of (28) gives the 2-j8-cyanoethyl derivative (29). On the other hand, quaternization with methyl iodide of (28) gave the quaternary salt showing adrenolytic and antihistaminic activity. 

An isolated complex with 1 2 ratio of palladium to NITC was also reported to catalyze the reaction of aryl chlorides with secondary amines. Caddick, Cloke and coworkers93 recently reported the use of isolated bis(l,3-di-lV-r-butylimidazol-2-ylidne)palladium(0) as a catalyst for the reactions of 4-chlorotoluene with morpholine and piperidine to give 95% and 70% yields, respectively, at 100 °C. 

Similarly, morpholine and piperidine reacted with tricyclo[2.2.1.0 ]heptan-3-one (10) to yield bicyclo[2.2.1]heptane-2-one derivatives 11 and 12. The reactions were catalyzed by acids such as /7-toluenesulfonic acid. 

Ring opening of the primary adducts is often encountered. For example, the adducts 134 of the dioxides 133 with morpholine and piperidine further react with these amines to give amides 135 in good yields (Scheme 73) [201]. The reaction of 136 with hydrazine under forcing conditions affords the sulfone 137 in 77% yield (Scheme 74) [202]. The ring opening reaction of thiophene 1,1-di-oxides is discussed later. 

Aliphatic primary and secondary amines react with C q and C70 rather efficiently, typically forming multiple addition products [76,115,116], One of a few examples in which the reaction products are well characterized is the nucleophilic additions of morpholine and piperidine to Cjo in the presence of oxygen, resulting in the formation of products 11-13 [76],... 

The Michael addition of amines to a,p-unsaturated thioamides has been carried out [43]. The reaction of tertiary a,p-unsaturated thioamides 59 with cyclic amines such as pyrrolidine, morpholine, and piperidine proceeds slowly (Eq. 19). After five days, the adducts 60 are obtained as stable compounds in moderate yields. On the other hand, the products derived from the addition of pyrrolidine to secondary a,p-unsaturated thioamides 61 are unstable. The stereochemistry of the Michael addition to cyclic a,p-unsaturated thioamides 62 is dependent on the substituents on the nitrogen atom. 

ECF of morpholines and piperidines yields the corresponding perfluorinated compounds. However, isomerization and fragmentation of the intermediate radical species can slightly decrease the efficiency of this process. 

Table 17.21 Most important morpholine and piperidines compounds launched before 1990. 

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