Current Organocatalysis (v.3, #3)

Meet Our Editorial Board Member by Chuan-Feng Chen (221-221).

Background: The organocatalytic asymmetric aza-Henry (nitro-Mannich) reaction is a powerful tool for the synthesis of enantiopure compounds containing a 1,2-arrangement of stereogenic nitrogen-bearing carbon centers. The products are useful synthetic intermediates which may be easily transformed into a variety of useful substances, with applications in medicine, agriculture and even as ligands or organocatalysts for asymmetric synthesis. Given the usefulness of this reaction and the large body of information published, this review aims to provide readers with an up-to-date account of the latest developments in the field.
Methods: The research published on the organocatalytic aza-Henry reaction during approximately the last two years is reviewed. The last comprehensive review dedicated exclusively to this subject was published in March 2013.
Results: The main developments which took place during this period were the design of novel catalysts which broadened the scope of the reaction, including some anchored to solid supports, novel activating groups and access to novel targets up to now inaccessible via this route: non-symmetric cis-stilbene diamines, chiral ?-amino-?-nitroesters, ?-amino-?- nitrophosphonates and functionalized isatin-derived ketimines to name a few. Umpolung chemistry was used to afford peptides bearing aliphatic side chains and it even became possible to carry out asymmetric aza-Henry reactions in the presence of water. The development of new multi-component reactions and domino processes which provided nitrogen heterocycles bearing multiple chiral centers with very high degrees of stereoselectivity continued to be an important addition to the chemist's repertoire.
Conclusion: The developments achieved during this period continue to show the enormous potential of asymmetric organocatalysis and should inspire further work in this area.

Proline Based Organocatalysis: Supported and Unsupported Approach by Praveenkumar Upadhyay, Vivek Srivastava (243-269).
Background: This review article, mainly focuses on the proline-based supported and unsupported organocatalysis. Organocatalysis, where low molecular weight organic molecules such as ?- amino acids, ?-hydroxy acids, nucleic acids and carbohydrates are used as catalysts (in stoichiometric amounts) to catalyze various organic transformations such as Aldol, Mannich and Michael reactions in a rapidly expanding segment of organic synthesis. Easy operational process, easy availability of the catalysts, selectivity, productivity and low price make such organocatalyzed organic transformations an attractive alternative to metal-mediated reactions.
Methods: Although organocatalysts have many striking features, but this catalytic system also suffers from poor solubility in conventional solvent systems, high catalyst loading and catalyst recycling. Recently ionic liquids, PEG, montmorillonite clays silica and cyclodextrine were identified as good supports to overcome partly these boundaries. The supported systems offer often good compromises in terms of selective product with the added benefits of catalysts recyclability.
Results: In this review, heterogenized organocatalysts will be discussed in detail, which are immobilized/ supported on organic as well as inorganic supports to effectively catalyze chiral organic transformations of topical interests. We also compared various supported and non-supported aminocatalysts, particularly focusing on the C-C bond forming reactions. The review offers critical views on the future scope, research advices, and academic as well as industrial benefits out of proline-based supported organocatalysis.
Conclusion: Immobilization of organocatalysts may provide answers at least partly to the at tents. They may allow low catalyst loading improved selectivity, recyclability and easy separation of the catalyst. The often observed lower catalyst activity and the required multistep preparation are often mentioned difficulties. The examples covered in review article have explained the significant application of supported and unsupported strategies on asymmetric organocatalysis, to improve easy handling and good applicability in a number of useful examples. In some of them, a surprising, enhanced efficiency and selectivity were achieved on the basis of the proper choice of immobilization protocol and type of supports type. Surprisingly, in most of the cases the supported proline catalyst was recovered and recycled for the limited number times still suffers with limited substrate scope. We can say no covalent immobilization represents one of the feasible methods to be further reconnoitered. Further studies will certainly improve the availability of these systems, in particular, for industrial applications.

Synthesis of Metal Catalysts from Industrial Waste Effluents and its Catalytic Application in Biginelli Reaction by Rashmi B. Patel, Rajesh H. Vekariya, Kinjal D. Patel, Hitesh D. Patel (270-276).
Background: Industries are using various metals containing salts, for various purposes. However, some amount of metal salts is leached, which creates environmental pollution. Removal of these pollutants is essential. Various groups are working to remove them by different techniques, but here we have applied simple techniques to extract and then these materials are used as a catalyst for the synthesis of organic compounds. Presently, as per our knowledge, this type of approach is adopted by us.
Method: The ligand pyrazole-thiosemicarbazide was prepared by green chemistry method, which was well characterized by various analytical techniques. This ligand is used for the extraction of various salts of metal from the effluent. The metal salts are converted into metal complexes. The metal complexes from the waste are used for the preparation of important biologically active derivatives.
Results: The ligand extracts the metals very fast. We have also studied the metal - ligand ratio and found that it is 1:1. These complexes are used as a catalyst for Biginalli reaction and in the presence of the catalysts the reaction is faster as compared to the absence of a catalyst.
Conclusion: Based on a study we conclude that the ligand can work efficiently for the extraction of metal from the waste water. The formed complexes are the efficient catalysts for the preparation of dihydropyrimidines and its recycle and reuse.

Background: The Diels-Alder reaction is one of the important and highly applicable reactions in the area of organic synthesis. It is useful to obtain six membered cyclic compounds using onestep inter- or intra-molecular reaction protocol. The high degree of regio- as well as stereoselectivity can be easily obtained by this reaction. The aim of this proposed work is to increase the efficiency of MacMillan catalyst using ionic liquid medium to obtain the Diels-Alder reaction product in good yield and selectivity.
Methods: MacMillan's catalyst was used in pyridinium based ionic liquids to promote Diels-Alder reaction. After completion the reaction product was isolated by simple ether washing and the catalytic system was reused for the next reaction cycle.
Results: A highly enantio- and diastereoselective Diels-Alder reaction was obtained by using MacMillan's catalyst in ionic liquid medium. Surprisingly, Ionic liquid mediated MacMillan's catalyst was found highly active in term of yield and selectivity for the Diels -Alder reaction with the added advantage of 8 times catalyst recycling. Synthesis of steroid, is the major outcome of our developed protocol.
Conclution: MwacMillan's catalyst was found highly active in terms of yield and selectivity. We also extended the application of our proposed protocol and successfully synthesized the biologically active steroid.

Metalloporphyrins-Catalyzed Synthesis of 2-Carboxybenzothiazole from 2-Methylbenzothiazole Using Molecular Oxygen as Oxidant by Jinquan Bai, Weiwei Hou, Cuimin Wu, Ruimei Guo, Yabo Xie, Jianrong Li (283-290).
Background: Heterocyclic compounds containing two or more hetero atoms can represent the most important class of key structural units in a large number of bioactive molecules. Among them, benzothiazole derivatives are often investigated as antitumor, antiviral, and antimicrobial agents, and as important building blocks in pharmaceuticals, agrochemicals and natural products. As one of benzothiazole derivatives, 2-carboxybenzothiazole is an important organic intermediate and taking it as a parent, we can synthesize dipeptide protease inhibitor, it can also be used for the synthesis of anticancer, anti-inflammatory drugs or medicine for treating neural cardiovascular disease. So far, the methods to synthesize 2-carboxybenzothiazole have some defects such as tedious steps, harsh reaction conditions and poor environmental performance. While the biomimetic catalysis of metalloporphyrins (MPs) has increasingly attracted considerable attention, and many processes with the catalysis of metalloporphyrins have been developed. The aims of this paper are to find a simple and green procedure for the synthesis of 2-carboxybenzothiazole from 2-methylbenzothiazole using the metalloporphyrins as biomimetic catalysts and molecular oxygen as oxidant.
Methods: 2-Carboxybenzothiazole was prepared according to a typical oxidation procedure: 2-methylbenzothiazole (3.9 mmol), NaOH (0, 0.82, 0.99, 1.31, 1.48, 1.64, 1.8 and 2.05 mol·L-1), and 10-200 ppm different kinds of metalloporphyrins were dissolved in 30 mL solvent, which were added into a 200 mL autoclave with a magnetic stirrer. Oxygen of 0, 1.0, 1.2, 1.4, 1.6 and 1.8 MPa was inflated into the autoclave. The reaction proceeded for different hours (2, 4, 6, 7, 8, 9, 10 and 12 h) under different temperatures (60, 80, 100, 110, 120, 130 and 140 °C). The reaction liquid was cooled to room temperature, and 5 mol·L-1 of HCl was added to adjust pH value to 5-6. Then the product was obtained and was analyzed by HPLC.
Result: The type of solvents, kinds of metalloporphyrins, temperature, reaction time, oxygen pressure, concentration of NaOH and concentration of metalloporphyrin have important influences on the reaction effects. According to a series of experiments, the optimal conditions for the synthesis of 2-carboxybenzothiazole from 2-methyl benzothiazole are as follows: 2-methylbenzothiazole (0.13 mol·L-1), NaOH (1.64 mol·L-1), and T(p-OCH3)PPFe (4.1x10-5 mol·L-1 ) are placed in a 200 mL autoclave with a magnetic stirrer in 30 mL ethanol, then 1.4 MPa of O2 is inflated into the autoclave and the reaction liquid is heated to 120 °C and keep reaction for 8 hours, the selectivity and conversion can reach 59.1% and 39.2% respectively.
Conclusion: A simple and green procedure for the synthesis of 2-carboxybenzothiazole from 2-methylbenzothiazole has been successfully realized by using the metalloporphyrins as biomimetic catalysts and molecular oxygen as oxidant. The catalytic properties of metalloporphyrins and optimum reaction conditions have been explored. Clearly, the central metal ions in the metalloporphyrins have a remarkable effect on their own activities, and metalloporphyrins with Fe2+ as central metal ions have higher catalytic effect than those with Mn2+ and Co2+ as central metal ions. This strategy opens a new opportunity for the preparation of 2-substituted benzothiazole derivatives. Further application of this catalytic system and the amplification experiment are under progress.

Pd Catalyzed C-N Bond Forming Reactions of 6-Bromo-2- cyclopropyl-3-(pyridyl-3-ylmethyl)-4-quinazolin-(3H)-one at Room Temperature by Narender Pottabathini, Ramesh Garlapati, Venkateshwarlu Gurram, Suresh Poudapally, Pavan K. Machiraju, Somesh Sharma (291-300).
Background: Quinazolinones are important subunits of many compounds that are of biological and pharmaceutical interest including anticancer, antimicrobial, anti-inflammatory, antitubercular, anti-HIV, and as an analgesic. Quinazolin[3H]-4-one systems were found to have distinctive biological functions. On the other hand, 2,3-disubstituted quinazolin[3H]-4-one derivatives substitution with various heterocyclic moieties displayed conspicuous anti-tubercular activity. Considering the much broder range of pharmacological properties, several useful approaches to the construction of modified quinazolinones have been developed with the help of Pd/L systems.
Methods: Various amines, Pd(OAc)2, Pd2(dba)3, Pd(dba)2, ligands, PtBu3, DavePhos, XantPhos, triphenylphosphine and dppf, were utilised to assess the C-N reaction results. For analysis 1H NMR, LCMS and HRMS were used.
Results: After screening different conditions, Pd(dba)2, PtBu3, NaOtBu in THF was proved to be the best catalyst/ligand system for Pd-catalyzed amination at room temperature. We evaluated the generality of the methodology with variety of amines (aryl, heteroaryl and alkyl amines) participated in the Pd-catalyzed amination reactions. We reported the synthesis of twenty four analogues utilizing these conditions. We have also investigated what cycle differences might exist in the usage of two different Pd sources, Pd(dba)2 and Pd2(dba)3. It is known that dba (dibenzylideneacetone) can competitively inhibit the catalytic cycles, also were interested to find out if in these cases it is inhibiting the catalytic cycle and assess that dba is responsible for the difference in yields. In silico analysis is utilized to evaluate the diversity of the set of compounds against shape space (PMI), polar surface area (PSA) calculations and relevant drug like properties (viz. HBA, HBD, PSA, mol. wt., log P and Log D).
Conclusion: In summary, we have developed a room temperature C-N bond formation reaction with simple catalyst system. We have thoroughly investigated the effect of dba in the amination reactions.

Enantioselective Allylations of Selected α,β,γ,δ-Unsaturated Aldehydes by Axially Chiral N,N'-dioxides. Synthesis of the Left-hand Part of Papulacandin D by Klára Vlašaná, Robert Betík, Irena Valterová, David Ne|as, Martin Kotora (301-305).
Background: Catalytic asymmetric allylation of aldehydes is a synthetically useful method for preparation of chiral homoallylic alcohols that may serve as convenient synthetic building blocks. The catalysis can be brought about with Lewis acid or Lewis bases, and Bronsted acids.
Objective: The main aim was to evaluate enantioselective allylation of variously substituted α,β,γ,δ- aldehydes with allyltrichlorosilane catalyzed by axially chiral Lewis bases with bis(tetrahybis( tetrahydroisoquinoline) N,N'-dioxide scaffold.
Method: Allylations of several structurally different α,β,γ,δ-aldehydes were carried out in various solvents in the presence of a catalytic amount of an N,N'-dioxide to access conditions leading to the highest symmetric induction.
Results: Out of screening of several reaction conditions the highest asymmetric induction (up to 98% ee) was achieved in THF. A higher asymmetric induction was observed with substrates bearing additional substituents on ?-carbon atom. Allylation of (S)-(2E,4E)-2,8-dimethyldecadienal gave rise to the corresponding homoallylic alcohol (an intermediate for synthesis of papulacandin D) with a high asymmetric induction of 92% ee.
Conclusion: Enantioselective allylation of α,β,γ,δ-aldehydes with allyltrichlorosilane catalyzed by an axially chiral Lewis base gave rise to the corresponding homoallylic alcohols with a good enantioselection. This method could be used for synthesis of valuable building block for organic synthesis as it was demonstrated by a synthesis of a papulacandin D intermediate.

Asymmetric Aldol and Michael Reactions in Water Using Organocatalysts Immobilized on a Thermoresponsive “Linear” Block Copolymer by Noriyuki Suzuki, Ryuji Akebi, Takahiro Inoue, Masahiro Rikukawa, Yoshiro Masuyama (306-314).
Background: Conducting organic reactions in water as a solvent have attracted chemists because of its environmentally benign property. However, it often suffers practical difficulties since most of organic compounds are insoluble in water. One promising methodology to improve the reactivity in water is to use surfactants that emulsify the organic/water mixture. Efficient extraction from the emulsified mixture is necessary to reduce the usage of organic solvent.
Methods: We designed polymer micelle that can be turned on and off by temperature-stimuli. Poly(Nisopropyl acrylamide), known as thermoresponsive polymer, was copolymerized with the acrylate ester of 4-hydroxy-Lproline using a reversible addition/fragmentation chain transfer polymerization (RAFT) reagent that contains a poly(ethylene glycol) (PEG) chain to obtain a polymer-tethered organocatalyst. The L-proline moieties were immobilized on a thermoresponsive amphiphilic diblock copolymer that consists of poly(N-isopropyl acrylamide) (PNIPAAm) and linear PEG fragments. The copolymer dissolved in water to form clear solution at room temperature, whereas the solution turned opaque at 50 °C, indicating the micelle formation.
Results: The aldol reaction of 4-nitrobenzylaldehyde and cyclohexanone was catalyzed with the copolymer micelles, and the product was obtained in good yield with excellent diastereo- and enantioselectivity. Both the yield and stereoselectivity were superior to those obtained by using our previously developed proline-immobilized “broom”-type PNIPAAm-b- PEG copolymer catalysts. The Michael reaction was also catalyzed by the “linear”-type PNIPAAm-b-PEG catalyst and resulted in moderate yields with good stereoselectivity.
Conclusion: We have synthesized a series of “linear” thermoresponsive block copolymers on which L-proline moieties were immobilized. The polymer catalyst formed micelles at 50 °C. The aldol reaction was catalyzed by the copolymer in water with high diastereo- and enantioselectivity. The catalytic performance of the linear copolymer was superior to that of the similar “broom”-type copolymer. The polymer catalyst also catalyzed the enantioselective Michael addition reaction.