Bicyclic malonate

SCHEME 8 Model for anticipated diastereoselectivity during alkylation of the bicyclic malonate. 

The stereoselectivity displayed during the alkylation of 43 (Scheme 25) was quite surprising, considering that formation of the major diastereomer (endo-44) requires the electrophile to approach bicyclic malonate anion 69 firom what appears to be the more crowded endo (concave) face. This is cotmter to what is commonly perceived as a reliable strategy for stereoinduc-tion. At the time, we had tried several experiments attempting to alter the diastereoselectivity, but to no avail. In the end, we reluctantly accepted the... 

Our studies of the alkylation reaction clearly indicated that bicyclic malonates like 23 have an inherent bias to undergo alkylation on the undesired endo face and that it will be difficult to overcome this bias with small electrophiles. Because of this bias, we carried out several exploratory reactions aimed at... 

Dhimane et al. studied the flash vacuum pyrolysis of isopropylidene [l-(a>-chloroalkyl)-l-azacycloalk-2-ylidene]malonates (1274) at 570°C and 1CT4 torr (87TL885 89T6161) (Scheme 52). They obtained bicyclic esters (1276) in 35-45% yields when the pyrolytic products were condensed on a cold finger at -196°C, covered with methanol, and triethylamine was introduced at the end of the reaction. Pyrolysis of the pyrrrolidine derivative (1274, n = 0, m = 1) without methanol on the cold finger afforded the bicyclic carboxylic chloride (1275, n = 0, m = 1), which was converted to ester (1276, n - 0, m = 1) by treatment with a mixture of methanol and triethylamine. 

The flash vacuum pyrolysis of isopropylidene (1-ally 1-1-azacycloalk-2-ylidene)malonate (1277) at 460-680°C and 10 5-10 3 torr yielded a mixture of bicyclic azepines (1278) and pyrrolinones (1279) (85TL833) (Scheme 53). The ratio of 1278 and 1279 shifted towards the lower homologue (1279) at higher reaction temperature. 

The large literature on cyclization reactions of aminoalkylidene-malonates is surveyed in order of the various ring systems that are formed. Of particular importance are the preparations of 4-hydroxyquino-line derivatives and of the corresponding naphthyridines. But a wide variety of other bicyclic heterocycles has also been prepared by methods of this type, as have tri- and polycyclic analogs. 

The reaction with monomethyl malonate in acetic acid, which does not occur at 0-10°C, proceeds smoothly when sonication is applied (Allegretti et al. 1993). From cyclohexene, only the cis ring fusion in bicyclic lactone is observed the product is formed at 80% yield for 15 min at 10°C. The overall transformation, in brief, is shown in Scheme 6.16. The stereoselectivity of the sonochemical process probably reflects the enhanced reaction rate, which does not allow equilibration processes to take place. 

The scope of electrophiles was explored with malonates and p-ketoesters, providing chiral amine adducts in high yield and enantioselectivities (Scheme 57) [109]. Addition of cyclic P-ketoesters was also explored with hydrazines, providing cyclic and bicyclic chiral amines with quaternary centers in high enantiomeric ratios (Scheme 58). 

The most reactive Michael acceptors, such as alkylidene malonates, gem-dicyanoalkenes and nitroalkenes, react with a-halozinc esters in a conjugate fashion. Beautiful examples were offered by two stereocontrolled conjugate additions to piperidinone 102 and pyrro-lidinone 104 leading to optically active bicyclic lactams 103147 (equation 60) and 105 (equation 61)148. With these electron-poor alkenes a Grignard two-step protocol is to be adopted in order to avoid the single electron transfer reactions from the metal to the Michael acceptor, which should afford olefin dimers. The best solvent is found to be a... 

Here too there is an enol that tautomerizes to the product. The mechanism is illustrated for the case of p-keto acids,475 but it is likely that malonic acids, a-cyano acids, a-nitro acids, and p,y-unsaturated acids476 behave similarly, since similar six-membered transition states can be written for them. Some a,p-unsaturated acids are also decarboxylated by this mechanism by isomerizing to the p,7-isomers before they actually decarboxylate.477 Evidence is that 36 and similar bicyclic p-keto acids resist decarboxylation.47" In such compounds the... 

The reaction of 2-aminopyridines and diethyl malonate was studied in detail by Lappin et til.91 and Ingalls and Popp.98 Lappin et al. carried out the reaction in the melt at 210-220 C or in a high-boiling solvent (Dowtherm A) at 240-250°C. Depending on the substituents of the starting material noncyclized products of type 64 and/or 65 and/or bicyclic products, the pyrido[l,2- ]pyrimidines (63) or the naphthyridines (66) were isolated.97... 

A palladium-cataly/ed C-C coupling reaction—the Heck reaction — is used in the construction of bicyclic system 13. Cyclization leads to a q3-alIyl-Pd complex, which undergoes nucleophilic attack by malonic ester anion 12. This in turn leads to formation of the C4 side chain The mechanism of this reaction therefore differs from that of a normal Heck reaction. 

When the bicyclic dienone 142 was treated with dimethyl malonate and potassium t-butoxide in t-butanol at 25°C for 10 days, the axial isomer 143 was obtained in 51% yield. None of the equatorial isomer 144 was isolated. When the reaction was carried out at reflux, a mixture of 143 and 144 was isolated in which the more stable equatorial isomer predominated (50). 

Slaframine.—Slaframine (37) is produced by the phytopathogen Rhizoctonia leguminicola. It has been known for some time that (37) derives in part from lysine via pipecolic acid (33), which is incorporated intact the earliest bicyclic intermediate identified is (38) (c/. Vol. 5, p. 9 and ref. 2). New results have shown that the two skeletal carbons in (37), and also in the metabolite (36), not accounted for by pipecolic acid, derive from malonate (and acetate).13 The labelling of (37) by, in particular, [2-2H2]acetate was deduced to be of C-2 on the basis of mass spectral evidence (which is not entirely convincing). The acyl-CoA derivative (34) has been suggested as an intermediate in the biosynthesis of (37) and also of (36). It is to be noted that condensation between malonyl-CoA and pipecolic acid (33) to give (34) must be simultaneous with decarboxylation of malonyl-CoA, since two deuterium atoms of acetate are retained at C-2 in (37) (later intermediates with a double-bond to C-2 are also excluded by these results). 

The prochiral triene 16 (Figure 5) is a suitable precursor for the bicyclic core structure 17, and can be obtained in ten steps starting from dimethyl malonate. The intramolecular Diels-Alder cyclization to 17 proceeds with Me2AlCl catalysis in very good yield under mild conditions [12, 18],... 

In a series of publications (75JOC2600, 70JOC1965, 73JOC3087), Potts and coworkers have reported that cyclic amidines (290) readily condense with trichloromethylsulfenyl chloride (329) to yield the sulfenamides (330 Scheme 119). Treatment of the latter compounds with aromatic amines in the presence of triethylamine results in cyclization, possibly via an intermediate such as (331), to produce bicyclic products of type (332). Heterocycles (290) which have been used successfully in this reaction include 2-amino-l,3,4-thiadiazoles, 3-aminopyridazines, 2-aminopyrimidines, 2-aminopyrazines, 2-aminopyridines, 3-aminoisoxazoles and 5-amino-1,2,4-thiadiazoles. The sulfenamide derivative (330) of 2-aminopyridine also was found to react with sodium sulfide and with diethyl malonate to produce (333) and (334) respectively. Attempts to hydrolyze (332) to (295) under acidic conditions failed. 

Recently, a catalytic system consisting of a second generation Grubbs catalyst or an in situ non-carbenic ruthenium complex have allowed a cascade catalytic reaction of cyclopropanation/ring closing metathesis of dienynes containing a malonate or bissulfone moiety. In this reaction, the interaction between the triple bond and one double bond gives a bicyclic product via cyclopropanation, and then the subsequent diene RCM produces the last cyclization step [16] (Scheme 6). 

A variety of bicyclic heterocycles has been obtained from the cyclic enediamine 285. Ethyl phenylacetate and methyl propiolate give derivatives, 286 and 287, respectively, of 1,8-naphthyridine, while hydrogenated quinolizidinones, 288 and 289, are formed from diethyl malonate and ethyl acetoacetate (Scheme 9)145. 

Among the nucleophiles that add exo to coordinated dienes are aUcoxides, amines, azide, acetates, halides, and stabilized carbon enolates, such as malonates and /3-diketones. The alkoxide addition is reversible if the product is treated with HCl. With a few nucleophiles, double addition reactions are observed. Acetate will react with 1,5-cod in the presence of Pb(OAc)4 and palladium salts to give a bicyclic product from addition of two acetate groups, both exo (equation 43). 

A recent synthesis of the tricyclic secoiridoid ( )-sarracenin (98) relied on the Patemo-Biichi addition of acetaldehyde and cyclopentadiene as the initial step. Irradiation of cyclopentadiene and acetaldehyde provided a 5 1 mixture of bicyclic oxetanes (97) and (96) in 5-10% yield. Treatment of the crude photolysate with CSA and methanol followed by tosylation of the cmde product gave (99), which represents the toluenesulfonate ester derived from the major oxetane (97). The tosylate was displaced by the anion prepared from dimethyl 3-styrenylmalonate to afford the substituted malonate (100) in 84% yield (Scheme 10). Attempts to effect ring opening of the oxetane mixture were unsuccessful. Decarboxylation and demethylation gave the alcohol (102) which was subjected to ozonolysis and reductive work-up to afford ( )-sarracenin in 60% yield. The oxetane-based synthesis is noteworthy due to its brevity and use of a biosynthetically postulated trialdehyde equivalent. 

It was shown that an enol intermediate was initially formed in the decarboxylation of l -ketoacids and presumably in the decarboxylation of malonic acids. It was found that the rate of decarboxylation of a,a-dimethylacetoacetic acid equalled the rate of disappearance of added bromine or iodine. Yet the reaction was zero order in the halogen . Qualitative rate studies in bicyclic systems support the need for orbital overlap in the transition state between the developing p-orbital on the carbon atom bearing the carboxyl group and the p-orbital on the i -carbonyl carbon atom . It was also demonstrated that the keto, not the enol form, of p ketoacids is responsible for decarboxylation of the free acids from the observa-tion that the rate of decarboxylation of a,a-dimethylacetoacetic acid k cid = 12.1 xlO sec ) is greater than that of acetoacetic acid (fcacw = 2.68x10 sec ) in water at 18 °C. Enolization is not possible for the former acid, but is permissible for the latter. Presumably this conclusion can be extended to malonic acids. 

Novel bicyclic (92) and tricyclic (93ab) hydrophosphoranes have been synthesized and shown to form complexes with PdCl2(COD), PdCl2(RCN)2, and Pd(allyl)Cl2 containing an open form of the phosphoranes. The Pd-catalyzed alkylation of 1,3-diphenylallyl acetate (94) with dimethyl malonate gave (95) in up to 74% ee using complexes of (92) or (93ab). " ... 

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