Synthesis of Functionalized Diethyl (pyrrolidin-2-yl)Phosphonate and Diethyl (5-oxopyrrolidin-2-yl)Phosphonate

Short and efficient syntheses of functionalized (pyrrolidin-2-yl)phosphonate and (5-oxopyrrolidin-2-yl)phosphonate have been developed. The synthetic strategy involved the diastereospecific 1,3-dipolar cycloaddition of N-benzyl-C-(diethoxyphosphoryl)nitrone to cis-1,4-dihydroxybut-2-ene and dimethyl maleate, respectively. O,O-Diethyl 3-carbamoyl-4-hydroxy(5-oxopyrrolidin-2-yl)phosphonate was obtained from O,O-diethyl 2-benzyl-4,5-dimethoxycarbonyl(isoxazolidin-3-yl)phosphonate by hydrogenation and subsequent treatment with ammonia, whereas transformation of O,O-diethyl 2-benzyl-4,5-dihydroxymethyl(isoxazolidin-3-yl)phosphonate into O,O-diethyl 3-aminomethyl-4-hydroxy(pyrrolidin-2-yl)phosphonate was accomplished by mesylation followed by hydrogenolysis to undergo intramolecular cyclization and the introduction of amino group via ammonolysis. Stereochemistry of the isoxazolidine cycloadducts, as well as the final functionalized (pyrrolidin-2-yl)- and (5-oxopyrrolidin-2-yl)phosphonates were established based on conformational analyses using vicinal H–H, H–P, and C–P couplings and supported by the observed diagnostic NOESY correlation signals.

3-Benzylbenzothiazolylidene Carbene Catalyzed Isomerization of Dimethyl Maleate to Dimethyl Fumarate: Experimental and Theoretical Results

Background: N-Heterocyclic Carbenes (NHCs) have emerged as ubiquitous species having applications in a broad range of fields, including organocatalysis and organometallic chemistry. Since Arduengo and co-workers first isolated a bottlable NHC, namely imidazol-2-ylidene derivative, these nucleophilic species have attained a prominent place in synthetic organic chemistry. The NHC-induced non-asymmetric catalysis has turned out to be a really fruitful area of research in recent years. Methods and Results: The quantitative aspects of the experimental and theoretical investigation of isomerization of dimethyl maleate to dimethyl fumarate catalyzed by an N-heterocyclic carbene (NHC), namely 3-benzylbenzothiazolylidene are being reported for the first time. Dimethyl maleate on treating with 3-benzylbenzothiazolylidene carbene (10 mol%), generated in situ from the reaction of 3- benzylbenzothiazolium bromide with triethylamine in diethyl ether at room temperature under nitrogen atmosphere isomerizes quantitatively to dimethyl fumarate. Theoretical investigation of a model reaction scheme at the wB97XD/6-31+G(d) level reveals that initial attack of the carbene, which is the ratedetermining step, is followed by rotation about the C-C bond in preference to a higher activation free energy path involving proton abstraction. The species so formed splits off the carbene to yield dimethyl fumarate. Eyring equation has been used to rationalize the effect of temperature on the isomerization rate. Conclusions and Perspective: 3-Benzylbenzothiazolylidene carbene catalyzes the isomerization of dimethyl maleate to its trans-isomer. This carbene can be used in other catalytic reactions, such as acyloin condensation and Stetter reaction.

Synthesis of Unsaturated Esters by Cross-Metathesis of Terpenes and Natural Rubber Using Ru-Alkylidene Catalysts

This study reports the cross-metathesis of bicyclic β-pinene, acyclic cis-3- methylpent-2-ene terpenes and the natural rubber with functionalized olefins, a route for the functionalization of the carbon-carbon double bond of natural products to obtain aliphatic unsaturated esters. The production of unsaturated esters from β-pinene and cis-3- methylpent-2-ene via cross-metathesis reaction with dimethyl maleate and diethyl maleate in the presence of the ruthenium-alkylidene [Ru(Cl)2(=CHPh)(1,3-bis(2,4,6- trimethylphenyl)-2-imidazolidinylidene)(PCy3)] (I), [Ru(Cl)2(=CH(o-isopropoxyphenylmethylene))( 1,3-bis(2,4,6-trimethylphenyl) -2-imidazolidinylidene)] (II) and rutheniumvinylidene [RuCl2(=C=CH(p-C6H4CF3))(PCy3)2] (III) was carried out. Results showed that the reaction of β-pinene with diethyl maleate using II catalyst produced unsaturated esters with 43 % selectivity. I and III catalysts showed low activity toward the cross-metathesis of β-pinene and dimethyl maleate. A survey about the cross-metathesis of acyclic cis-3-methylpent-2-ene with diethyl maleate by II catalyst was also studied. The formation of ethyl but-2-enoate and ethyl-3-methylpent-2-enoate products was highly selective by 63 %. The unsaturated esters formation from the cross-metathesis degradation of natural rubber (99.9 % cis-polyisoprene) with dimethyl maleate and diethyl maleate using I-III catalysts was accomplished as well. I and II catalysts showed high activity in the degradation of natural rubber with diethyl maleate to produce the low molecular weight of oligomers unsaturated ester products (Mn = 1 x 103 g mol-1) with isoprene units of m = 10 – 27 and yields ranging from 68 to 94 %.

Effects of Basic Promoters on the Catalytic Performance of Cu/SiO2 in the Hydrogenation of Dimethyl Maleate

Continuous hydrogenation of dimethyl maleate (DMM) toγ-butyrolactone (GBL), 1,4-butanediol (BDO) and tetrahydrofuran (THF) is a promising process in industry. In this study, Cu-M/SiO2 catalysts modified by basic promoters (M = Mg, Ca, Sr, Ba, La) were prepared, and characterized by physical adsorption of N2, in situ XRD, H2-TPR, CO2-TPD. With the addition of basic promoters, the basicity of Cu-M/SiO2 catalysts was improved. The particle size of CuO on Cu-M/SiO2 catalyst was increased after modified by Mg, Ca, Sr, Ba. However, the CuO particle was decreased on the Cu-La/SiO2 catalyst. The series of Cu-M/SiO2 catalyst was applied to the hydrogenation of DMM. The addition of basic promoters increased the selectivity of GBL during the hydrogenation for the basic promoters improved the dehydrogenation of BDO to GBL in alkaline sites. Furthermore, Cu-La/SiO2 presented a higher activity in the hydrogenation of DMM, due to its higher dispersion of Cu.

Design, Synthesis and Chemical Hydrolysis Study of Codrugs of Metoprolol with Metformin

In the present study we have synthesized ester prodrugs (Pa-i) of Metoprolol (I) by using pthalic anhydride and derivatives of succinic and maleic anhydride. Different codrugs (COa-i) were synthesized from prodrugs of metoprolol. All the codrugs were characterized by melting point, FTIR, NMR and Mass Spectroscopy. The chemical hydrolysis of COa-i were investigated at the pH 1.2, 6.8 and 7.4. Presence of maleate, methyl maleate, dimethyl maleate and succinate group as linker were found to possess good hydrolysis when compared to that of other substitutes. Among the synthesized codrugs, COf is found to be the best one among the series

[3+2] Cycloaddition of Trifluoromethylated N-Acylhydrazones with Maleates: Synthesis of Trifluoromethylated Pyrazolidines

An efficient [3+2] cycloaddition reaction of trifluoromethylated N-acylhydrazones with dimethyl maleate has been developed under basic conditions. This protocol provides an easy access to potentially bioactive trifluoromethylated pyrazolidines in moderate to excellent yields. It also illustrates that the trifluoromethylated N-acylhydrazones are useful trifluoromethyl building blocks for the synthesis of trifluoromethylated N-heterocycles.

First Total Synthesis of (±)-Rhodoconferimide

Starting from vanillin and dimethyl maleate, a concise and efficient racemic total synthesis of the potent antioxidant marine natural product (±)-rhodoconferimide has been carried out via the Wittig reaction, catalytic hydrogenation, selective brominations, and imide formation. An appropriate regioselective double bromination of the aromatic ring was a key step in the synthesis.

Synthesis and crystal structures of three novel benzimidazole/benzoindolizine hybrids

Three benzoindolizine derivatives, 1, 2, and 3, were obtained via 1,3-dipolar cycloaddition. The reaction of 1-(2′-benzimidazolylmethyl)isoquinolinium ylides with dimethyl acetylenedicarboxylate gave a mixture of pyrrolo[2,1-a]isoquinoline-1,2-dicarboxylate (1) and 1,10b-dihydropyrrolo[2,1-a]isoquinoline-1,2-dicarboxylate (2) derivatives containing a benzimidazole moiety. The reaction of this isoquinolinium N-ylide with dimethyl maleate gave an unexpected 2,3-dihydropyrrolo[2,1-a]isoquinoline-1,2-dicarboxylate (3). The structures of all reported compounds have been examined by X-ray crystallography, mass spectrometry, and NMR spectroscopy.