Letters in Organic Chemistry - Volume 14, Issue 7, 2017

Background: This review focuses on the recent advances in the asymmetric hydrogenation of pro-chiral C=O and C=N double bonds catalyzed by iron-catalysts based on chiral and achiral Knölker type complexes. Method: The bifunctional nature of such complexes made possible the development of two strategies to achieve asymmetric hydrogenation. The first approach is based on the design of chirally modified Fecomplexes, while the second one relies on the cooperative catalysis of an achiral iron-complex and a chiral additive. Forty-two papers are included in the review. Results: A number of chiral iron-complexes have been synthesized and characterized. Such catalysts have been applied in the direct and transfer hydrogenation of various ketones (up to 77% e.e.). Highly stereoselective hydrogenation of imines, benzoxazine and quinoxaline derivatives (up to 94% e.e.) was performed under H2 pressure by using a catalytic combination of the achiral Knölker’s complex and a chiral phosphoric acid which cooperatively act in determining enantioselectivity. Conclusion: The examples reported in the review highlight the great potential of Knölker type complexes in the field of asymmetric hydrogenation. Recent achievements can inspire the design of new catalysts capable of improving the transfer of chiral information to the substrate.

Background: The carbon-dioxide reduction to obtain important chemicals such as fuels is a topic of high current interest. Recently, monomeric thiophenes and terthiophenes linked to a bipyridine ligand were designed and their polymeric films achieved very high turnover numbers during electrocatalytic CO2 reduction. In this paper we improved the protocol to access the ligand that shows the best performances, in view of opening the way to a general method to obtain side-functionalized terthiophenes. Methods: Several reactions were attempted to improve the synthetic pathway. Different approaches were attempted to convert the 3-bromothiophene into its 3-iodo analog and to brominate it to obtain the 2,5-dibromo-3-iodothiophene. The synthetic pathway was completed by using Pd-catalyzed crosscoupling reactions such as Sonogashira and Suzuki. The removal of a trimethylsilyl protection was attempted by common methods. However, with the use of a one-pot reaction, both the alkyne deprotection and the final Sonogashira coupling were performed as the key point of the pathway to obtain the final product. Results: The key intermediate 2,5-dibromo-3-iodothiophene was obtained by a CuI assisted electrophilic aromatic substitution, followed by a bromination with NBS in ethyl acetate. This compound was reacted with TMS-acetylene to obtain the ((2,5-dibromothiophen-3-yl)ethynyl)trimethylsilane which, by a Suzuki reaction, afforded the ([2,2':5',2''-terthiophen]-3'-ylethynyl)trimethylsilane. Using a onepot reaction for the last step, the deprotection of the TMS-protected alkyne and its coupling with 4- bromo-2,2'-bipyridine was accomplished easily. A final 52% yield was achieved over 5 steps. Conclusion: The ligand 4-([2,2':5',2''-terthiophen]-3'-ylethynyl)-2,2'-bipyridine was prepared in a 52% yield, over 5 steps, improving the previous protocol (17% yield over 4 steps). The rhenium complex of this ligand is still under study for CO2 reduction. This novel protocol can be used to produce a series of analog terthiophene monomers bearing side-attached ligands.

Background: Recently, several chemoselective techniques have been developed to modify biomolecules at a single site. Among these, biomimetic transamination reaction through pyridoxal-5- phosphate is able exclusively to convert the N-terminus of protein/peptides into a ketone/aldehyde under mild conditions. The ketone/aldehyde group can be conjugated with another biomolecule, for example, with an aminooxy group via oxime formation. Methods: Conjugation through oxime formation between self-assembling peptides (SAPs) and different bioactive motifs were investigated. Adhesive sequences from Fibronectin (RGD) and Vitronectin (HVP) were synthesized, purified and finally condensed with SAPs carrying an aminooxy group. Each adhesive sequence was prepared with or without the insertion of a flexible spacer to the N-terminus, consisting in an additional sequence H-Gly-7aminoheptanoic acid. The influence of the spacer on both transamination reaction and bioconjugation was evaluated. Results: The addition of a flexible spacer to the peptide improved transamination reaction’s yield (from 27% to 53% for RGD; from 8% to 25% for HVP) and determined a significant increase in oxime yield (from 0÷3% to 37% for RGD and from 0% to 86% for HVP). Conclusion: The introduction of a flexible spacer in the molecule carrying the ketone/aldehyde functional group dramatically improves the yield of chemoselective oxime ligation.

Background: One-Pot three component preparation of α-aminophosphonates in the presence of o-benzenedisulfonimide as efficient acidic organocatalyst has been described. The catalyst can be recovered for further reactions and reused without any loss of efficiency. Methods: A very simple protocol was followed in the reaction process. Initially, we attempted a three component coupling of benzaldehyde with aniline and trimethylphosphite using o-benzenedisulfonimide (5 mol%). The reaction proceeded smoothly at r.t under solvent free conditions and the desired product. Results: The reactions worked well with almost all the aldehydes, heteroaryl aldehydes and ketones; at the end of the reaction, the product could be separated by usual work up. Finally, the water tolerant catalyst may be recycled from water, because of its good solubility in water. Conclusion: The catalyst is a safe, nonvolatile, and noncorrosive Brønsted acid; it is readily recovered at the end of the reactions simply by evaporating the aqueous washings. The products are generally obtained in good yields and short time under simple and mild reaction conditions.

Background: The synthesis of octahydroquinazolin-2,5-dione derivatives via multi-component condensation reaction of aromatic aldehydes, dimedone and urea in the presence of catalytic amounts of acidic ionic liquids such as 2-pyrrolidonium hydrogensulfate, N-methyl-2-pyrrolidonium hydrogensulfate, N-methyl-2 pyrrolidonium dihydrogenphosphate and 1,3-disulfonic acid imidazolonium chloride is described. This protocol includes some advantages, such as reusability of ionic liquids with high activity, excellent yields of product, short reaction times (11-23 min). In addition to these, reactions were performed at room temperature. Method: The mixture of the aldehyde (1 mmol), dimedone (0.14g, 1 mmol), urea (0.1g, 1.5 mmol) and ILs containing [H-NMP][HSO4] (0.03gr, 15 mol%), [H-NMP][H2PO4] (0.03 gr, 15 mol%), [H-NHP] [HSO4] (0.027gr, 15 mol%), and [Dsim]Cl (0.04gr, 15 mol%) as catalyst was stirred at 25oC under solvent- free conditions for the specific time. After completion of the reaction (11-23 min), 5 mL of water were added to the mixture. The IL was dissolved in water, and the solution was filtered for separation of the crude product. The separated product was washed twice with water (2×5 mL). The solid product was purified by recrystallization in ethanol (96 %). All the desired products were characterized by comparison of their physical data with those of known compounds. Results: We studied the effect of catalyst loading and temperature in the three-component condensation reaction for the synthesis of 4-Phenyl-7,7-dimethyl-1,2,3,4,5,6,7,8-octahydro-quinazoline-2,5-dione in the presence of the IL, N-methyl-2-pyrrolidonum hydrosulfate ([H-NMP]HSO4 was selected as a model (Table 1). The generality of the reaction was investigated by using diverse aryl aldehydes under optimized conditions (Table 2). The wide ranges of substituted and structurally diverse aryl aldehydes synthesize the corresponding products in high to excellent yields using the four Brønsted acidic ILs as catalysts. Conclusion: In this research, four acidic ILs [H-NMP][HSO4], [H-NMP][H2PO4], [H-NHP][HSO4] and [Dsim]Cl were used for the preparation of octahydroquinazolin-2,5-diones under solvent-free conditions for the first time. The attractive features of this protocol are simple procedure, cleaner reaction and use of inexpensive and reusable ILs as catalysts. Satisfactory yields of products, as well as a simple experimental, isolation and purification of the products make it a useful protocol for the green synthesis of these compounds.

Background: A facile, effective, new and green methodology has been developed for the synthesis of 3,3-di(indolyl)indolin-2-one through electrophilic condensation reaction of indole derivatives with various isatins in the presence of 1,4-diazabicyclo[2.2.2]octanium diacetate as an efficient homogeneous media under grinding. This work consistently has advantages as excellent yields, short reaction time, mild condition and simple work-up procedures. The catalyst could be easily recovered and reused for six cycles with almost consistent activity. All of the synthesized compounds were characterized by their physical constant, comparison with authentic samples, IR, 1H NMR, 13C NMR spectroscopy and elemental analysis. Methods: A mixture of isatin derivatives (1 mmol) or synthesized bis isatin (0.5 mmol), indole derivatives (2 mmol) and [DABCO] dihydroacetate (0.5 mmol) were added to a mortar and the mixture was pulverized with a pestle for the required reaction time. After completion of the reaction, as indicated by TLC, the reaction mixture was dissolved in 20mL of H2O. The product was separated by filtration and recrystallized from EtOH and dried to afford powdery compounds 3a-n. The filtrate was concentrated under reduced pressure and washed with diethyl ether. Then, it was dried in a vacuum evaporator to recover the ionic liquid for subsequent use. Results: In continuation of our ongoing studies to synthesize heterocyclic and pharmaceutical compounds under mild and practical protocols, herein we wish to report our experimental results on the synthesis of 3,3-di(indolyl)indolin-2-one using various isatins and indoles in the presence of novel ionic liquid ([DABCO]diactate). After the reaction, the used ionic liquid was separated and recycled to use for the next reaction run. Our experiments also indicated that after five runs, the catalytic activities of the reagents were almost the same as those of fresh catalysts. Conclusion: In conclusion, we have investigated DABCO-diacetate as a mild and efficient catalyst for the synthesis of oxindoles. This method should be useful from the industrial point of view because it is high yielding and time saving under solvent free condition. DABCO-diacetate is inexpensive, nontoxic, easy to handle, and can act as a green medium. Simple work-up procedure, short reaction times, high yields of product with better purity, and green aspect due to the recyclability of media are major advantages of this protocol.

Background: Earlier we found that the reaction of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene- 2,3-dione (1) with primary aromatic amines, secondary aliphatic amines and N,N′-dinucleophiles such as 1-aminoguanidine, guanidine, urea, and 1,2-phenylenediamine in ethanol or acetic acid at high temperature gave the substituted thiophenes, amide and heterocyclic derivatives that have Nphenylthiocarbamoyl group, respectively. As a part of our studies on the intermediate 1 in relation to the synthesis of thioamides in aqueous medium, we now report the reactions of 1 with amines at room temperature in the THF–H2O (1:1) system. The reaction of 1 with primary and secondary aliphatic amines, N,N′-dinucleophiles such as hydrazine and guanidine and tertiary aromatic and aliphatic amines led to 3-N-phenylthiocarbamoyl-2-butenamides 2a-n. Method: In general, to a stirred solution of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione (1) (1.0 mmol) in THF/H2O (1:1) was added each of the amines (1.0 mmol) (piperazine and DABCO 0.5 mmol) at room temperature. The reaction mixture was then stirred for 3-6 h. The progress of the reaction was monitored by TLC (eluent AcOEt/hexane 2:1). The resulting solid was separated by filtration and was recrystallized from a suitable solvent to give 2a-n. The structures of 2a-n were deduced from their elemental analyses and IR, 1H, 13C NMR spectroscopic and mass spectrometric data. Results: Reactions of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione (1) with primary aliphatic amines, N,N′-dinucleophiles such as hydrazine and guanidine and secondary aliphatic amines under mild conditions in THF/H2O (1:1) afforded the corresponding N-alkyl and N,N-dialkyl 3-N-phenylthiocarbamoyl- 2-butenamides (2a-g and 2h-j) and 1,4-bis(3-N-phenylthiocarbamoyl-2-butenoyl)piperazine (2k). In addition, the reaction of 1 with tertiary aromatic and aliphatic amines in the same conditions led to stable 1,4-diionic nitrogen betaines 2l-n. These showed the nucleophilic attacks of primary and secondary aliphatic amines, N,N′-dinucleophiles and tertiary aromatic and aliphatic amines on thioesteric carboxyl group (C-2) of the thiophene-2,3-dione ring (1), due to the extremely high reactivity of the thioesteric carboxyl group. Conclusion: In conclusion, we have described a convenient route for the synthesis of 3-N-phenylthiocarbamoyl- 2-butenamide derivatives (2a-n) from 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3- dione (1) with primary and secondary aliphatic amines, N,N′-dinucleophiles and tertiary aromatic and aliphatic amines in medium to good yields. The advantage of the present procedure is that the reaction is performed in aqueous medium at room temperature by simple mixing of the starting materials.

Background: The design of biologically-active compounds is a challenging viewpoint in medicinal chemistry, and pyranopyrazoles and pyranopyrimidine play a crucial role as biologicallyactive molecules. Methods: At the moment, a few examples have been reported for the synthesis of pyrazolopyranopyrimidine derivatives. In this work, magnetized water was applied as a green promoting medium for one-pot, practical, efficient, and environmentally benign four-component reaction of an aldehyde, ethyl acetoacetate, hydrazine hydrate, and thiobarbituric acid under catalyst-free conditions. Results: The reactions proceeded rapidly for aromatic aldehydes with the electron-withdrawing or electron-donating groups at different positions of the ring, and heteroaryl aldehydes, and the desired products were isolated in high yields without any side product formation in very short reaction times. Conclusion: An efficient, catalyst-free, green, and convenient method was proposed for the synthesis of pyrazolopyranopyrimidines in magnetized water in good-to-high yields.. This method offers the advantages of short reaction times, low costs, quantitative yields, simple work-up, green, and no need of any organic solvent.

Background: An effective approach to the synthesis of some new (Z)-2-((5-(4- chlorobenzylidene)-4-oxo-4,5-dihydrothiazol-2-yl)amino) substituted acids 7a-l is reported under microwave irradiation as well as conventional conditions. The method provides rapid and easy access to thiazolidinone compounds in good to excellent yields. Methods: In a 100 mL round bottom flask, the compound (Z)-5-(4-chlorobenzylidene)-2-thioxothiazolidin- 4-one 3 (0.5 gm, 1 mmol), triethylamine (0.2 gm, 1.2 mmol) and dichloromethane (1 mL) was added at room temperature. To the stirred reaction mixture with iodomethane (0.3 gm, 1.2 mmol) was added and stirred for 1 h at room temperature. Results: This study synthesized (Z)-5-(4-chlorobenzylidene)-2-(methylthio)thiazol-4(5H)-one 5 (Scheme 2) and screening of model reaction (Z)-2-((5-(4-chlorobenzylidene)-4-oxo-4,5-dihydrothiazol-2-yl)amino) propanoic acid 7a (Scheme 3, Table 1). This study developed the protocol for the synthesis of compound 7a by condensation of compounds 5 and 6a. After the initial success with ethanol, various solvents and bases were screened and the results are shown in Table 1. The reactions of compound 5 (1 mmol) and compound 6a (1.2 mmol), catalyzed by various bases and various solvents were selected as a model reaction to optimize the reaction conditions. Conclusion: In conclusion, we successfully developed an easy access to a new series of (Z)-2-((5-(4- chlorobenzylidene)-4-oxo-4,5-dihydrothiazol-2-yl)amino)substituted acid derivatives. This method provides an easy and rapid access to pharmaceutical important thiazolidinone derivatives. We reported here shorter reaction time, cleaner reaction profile and excellent yield of the products, by MW irradiation as well as conventional method synthesis.

Background: Jatropha curcas oil is a potential feedstock in biodiesel (fatty acid alkyl esters) production due to low acidity, good oxidation stability and excellent cold flow properties. Mg-Al hydrotalcites are potentially interesting for the transesterification, given its characteristics as anion exchangers, solid base catalyst and adsorbents. In this paper, a theoretical and experimental study of the mechanism and the kinetics of the transesterification of Jatropha curcas oil using Mg-Al hydrotalcite is presented. Methods: Design experimental was used to evaluate the influence of operational parameters on conversion of reaction, being concentration of catalyst, followed by alcohol/oil molar ratio and temperature the significant factors. Equations were formulated for predicting the conversion of reaction. Optimum geometries and chemical and physic steps of the reaction mechanism were evaluated using DFT calculation. Results: The experimental study includes catalysts characterization, ANOVA evaluation of transesterification of Jatropha curcas oil and definition of regressions models for reactions using calcined catalysts at different temperature. The stability and chemical reactivity were evaluated by the correlation of energies of the frontier orbitals in theoretical study. The results suggest the possibility of transesterification of jathopha curcas oil occurs on the surface of catalyst of hydrotalcite, specifically on the acid sites of the species of Mg²⁺. Conclusion: Experimental and theoretical results demonstrated that transesterification of Jatropha curcas oil using hydrotalcite Mg-Al as catalyst occur by LHHW mechanism and the chemical reaction is the rate-determining step. These results were also corroborated by frontier molecular orbital theory.