Morpholine, Michael addition

Figure 6.27 Representative (R,R)-l,2-diaminocyclohexane-derived thiourea derivatives incorporating a phthalimide (Phthal) and tetraphenylphthalimide (TPhP) moiety catalyst screening was performed in the Michael addition of acetophenone-derived morpholine enamine to trans-()-nitrostyrene in toluene as the solvent.

Scheme 6.94 Typical products obtained from the 86-catalyzed Michael addition of aryl methyl-ketone-derived morpholine enamines to various aromatic nitroalkenes and subsequent acidic hydrolysis.

Alternatively, the enamine (3b) may be treated with the morpholine enamine of 2-acetylpyri-dine. The resulting Michael addition product would be a dipyridyl 1,5-diketone, which is not isolated but rather cyclized directly with ammonium acetate to provide tpy in 82% yield.6... 

One specific enol equivalent that works very well for aldehydes is an enamine. Secondary amines such as Me2NH, Et2NH, pyrrolidine, piperidine, or morpholine 34 add cleanly to aldehydes to give enamines 36. These relatively stable nitrogen analogues of enols react well with reactive alkyl halides, such as a-carbonyl halides, and in Michael additions. They were considered in chapter 2 and only a few extra examples will be given here. 

The diketo-aldehyde 37 has four electrophilic carbon atoms (A-D) and three positions for enolisation (1-3). Cyclisation could occur in twelve different ways. Three can be regioselectively realised by different conditions.6 With morpholine catalysis, the aldehyde forms an enamine which does a Michael addition on the enone (B) to give 39. Enamine formation with PhNHMe also gives the aldehyde enamine, but this time it does an aldol condensation with the simple ketone (D) to give 38. 

Seebach and Golinski further examined the Michael addition of the enamines derived from ketones and morpholine to nitroolefins, as shown in Scheme 16 and Table 4 (33,35,36). The structure of the major product of entry 1 (Table 4) was assigned by chemical correlation. The remaining structures were assigned by analogy to entry 1. High levels of syn selectivity were uniformly observed. Control experiments revealed that the geometry of neither the enamine nor the nitroolefin influences the stereochemistry. Indeed, observation of the reaction of isomeric nitrostyrenes and the morpholine... 

Another example of a Michael addition of a pyrazol-3-one onto a,/i-unsaturated derivatives is the reaction of compound 444 with arylidenemalononitriles 445a that gave pyrazol-3-one adducts 446a, carried out in boiling methanol containing a catalytic amount of morpholine (83JOU2291) (Scheme 136). 

Under basic conditions a version of the Michael addition occurred followed by cyclisation in the reaction of resorcinol and 4-bromobenzylidenemalononitrile in ethanol containing morpholine with a brief heating period to produce a 70% yield... 

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. 

The Michael addition of secondary amines to a,)S-unsaturated carbonyl compounds under MWI essentially required the presence of water to drive the amine addition to completion and the presence of at least 10 mole equivalents of the amine. Besides increasing the polarity and possibly some micellar effect, water facilitates protonation of the resulted enolate from amine addition. In a typical procedure, benzalacetophenone was mixed with morpholine (469) and water in a teflon flask and subjected to MWI for 2 min to yield 93% of the 1,4-adduct 471 (Scheme 92). The method was also extended to other morpholine derivatives 472 and 473 in 30% and 100% yields, respectively (00SC643). 

Kinetic studies of Michael addition of alicyclic secondary amines to ethyl propiolate in H2O and MeCN have demonstrated a substantial solvent effect on reactivity and transition-state structure. The amines were found to be less reactive in MeCN, although they are by 7-9 units more basic in the aprotic solvent. The reaction rates for morpholine and deuterated morpholine proved to be identical, which rules out both a stepwise mechanism in which proton transfer would occur in the RLS and a concerted mechanism in which nucleophilic attack and proton transfer would occur through a four-membered cyclic transition state. Consequently, a stepwise mechanism with proton transfer occurring after the RLS is probable. Br0nsted-type plots were found to be linear with = 0.29 and 0.51 in H2O and MeCN, respectively, indicating that bond formation is not advanced significantly in the RLS. The small value is also consistent with the absence of isotope effect. ... 

A library of novel 5-amino-2,7-diaryl-2,3-dihydrobenzo[l)]thiophene-4,6-dicarbonitriles was synthesized by a one-pot domino reaction of 5-aryldihydro-3(2H)-thiophenes, malonitrile, and aromatic aldehydes in the presence of morpholine (13BMCL2101). A mechanism was proposed that involves a sequence of Knovenagel condensation, Michael addition, intramolecular Thorpe-Ziegler cyclization, tautomerization, and elimination. The compounds were evaluated for their AChE (acetylcholinase) activity. The 5-amino-2,7-bis(4-methoxyphenyl)-2,3-dihydrobenzo[l)] thiophene-4,6-dicarbonitrile was found to be the most potent with IC50 4.16 xmol/L. 

The morpholine-promoted reaction of Af-alkyl piperi-dine-4-one with malonodinitrile and p-nitrostyrene derivatives in refluxing EtOH directly led to substituted tetrahydroisoquinoline derivatives in moderate to good yields [121], The reaction is initiated by a Knoevenagel condensation, in which a Michael addition/Thorpe-Ziegler sequence follows. Oxidation by air is the last step to occur providing the desired products. 

On the other hand, reaction of the sulfonyl chloride 397 with excess morpholine, pyrrolidine and piperidine (three equivalents) afforded a mixture of the sulfonamides 400 and 401. The succinimidosulfonamide 401 was formed by simultaneous nucleophilic substitution at sulfur and Michael addition of the amine to the activated alkenic double bond. The pure maleimidosulfonamide 400 could be prepared by column chromatography of the mixture. The reaction of N- p-chlorosulfonylphenyl) maleimide 397 with excess dimethylamine or diethylamine in methanol as solvent resulted in the formation of ring-opened products. For instance, in the reaction with diethylamine, the methyl ester 402 was formed by base-catalysed nucleophilic ring-opening by the solvent (methanol) this ring... 

The Michael reaction with enamines is exemplified in this procedure. In a second (spontaneous) step of the reaction, an aldol-type condensation occurs resulting in cyclization. Finally, the morpholine enamine of the product forms and is hydrolized by the addition of water to yield a mixture of octalones, which is separated by fractional crystallization. J -Octalone-2 can be reduced by lithium in anhydrous ammonia to the saturated tra/i5-2-decalone (Chapter 3, Section III). 

The Michael-type addition of morpholine to propiolic, tetrolic, phenylpropiolic, and acetylenedicarboxylic esters has been described by Postovskii et al.500... 

In addition, they carried out enantioselective Michael-type hydroamination of the alkenoyl-A-oxazolidinone 26 with aniline and obtained the chiral amine 27 with 93 % ee. Furthermore, they reported hydroamination of dihydrofuran (28) and 2,3-dihydropyran (30). Reaction of dihydrofioran (28) with morpholine proceeded at room temperature to give 2-aminotetrahydrofuran 29 regioselectively in high yield. Hydroamination of 2,3-dihydropyran (30) with morpholine proceeded at 80 "C to give 2-morpholinotetrahydropyran (31). For this hydroamination, phosphine-free... 

---