Jan W. Bats

Organocatalytic Asymmetric Domino Reactions: A Cascade Consisting of a Michael Addition and an Aldehyde α-Alkylation†

The development of asymmetric reactions using small organic molecules as catalysts, which are often nontoxic, environmentally friendly, and stable under aerobic and aqueous reaction conditions, has attracted much attention in recent years. Domino reactions provide an efficient means to construct complex molecules in a single process, while minimizing the number of manual operations and the generation of chemical waste and easing purification. Organocatalytic domino reactions can combine these advantages, and many interesting reactions have been developed during the past few years. The asymmetric secondary-amine-catalyzed Michael addition of aldehydes and ketones to nitroalkenes is a direct entry to g-nitroaldehydes and -ketones, which has been applied by our group in organocatalytic triple-cascade reactions. In 2004, List and Vignola reported the first catalytic asymmetric intramolecular a-alkylation of aldehydes. Asymmetric organocatalytic domino reactions consisting of a Michael addition and an alkylation have been recently developed to form enantioenriched and highly functionalized cyclopropane and cyclopentane derivatives. These reactions involve iminium–enamine activation and utilize a,b-unsaturated aldehydes and bromomalonates or bromo-b-ketoesters. We envisaged aldehydes A and the wiodonitroalkene B as potential substrates for a domino reaction made up of Michael addition and intramolecular alkylation, leading to either the cyclopentanecarbaldehydesC or the classical Michael-initiated ring-closure (MIRC) products D (Scheme 1). While the MIRC compounds D are not observed, the cyclic g-nitro-substituted aldehydes C are synthetically useful compounds, which may be converted into cyclic g-amino acids containing an all-carbon-substituted quaternary stereogenic center considered as a challenging task. g-Aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system of mammals, and many of its derivatives show biological activity. For example, Gabapentin, Pregabalin, and Vigabatrin have been commercialized as drugs to treat neurological disorders. Thus, the efficient stereoselective synthesis of gamino acids is of great interest, and many asymmeric auxiliary-based and metal-catalyzed methods have been developed. Recently, organocatalytic asymmetric syntheses of acyclic g-amino acids have been reported. Herein we report an organocatalytic domino Michael addition/alkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene (B) involving enamine–enamine activation. The process is highly stereoselective and leads to the g-nitroaldehydes C, which contain an all-carbonsubstituted quaternary stereogenic center. Furthermore, a novel cyclic g-amino acid was easily synthesized from the domino product in two steps. Diphenylprolinol silyl ether 1 shows good catalytic activity and gives excellent levels of asymmetric induction in the Michael addition of aldehydes to nitroalkenes. Therefore, we initially investigated its use as a catalyst in the reaction between propanal (4a) and nitroolefins bearing different leaving groups in the w position (OMs, Br, I; Ms= mesyl). In the case of the bromo and mesylate derivatives, the initial Michael addition occurred in good yield (70–80%); however, the desired cyclopentane product 6a was not formed. Using the w-iodonitroalkene 5 the domino reaction occurred and cyclopentane 6a was obtained in a low yield of 20% (entry 1, Table 1). Although the diastereoselectivity was only moderate (d.r. 70:30), the enantiomeric excess was excellent (trans : 94% ee, cis : 95% ee). Encouraged by this initial result, we undertook a detailed optimization study. Scheme 1. Secondary-amine-catalyzed domino reaction consisting of a Michael addition and an intramolecular alkylation proceeding by tandem enamine–enamine activation.

Cyclization of Propargylic Amides: Mild Access to Oxazole Derivatives

The substrate scope, the mechanistic aspects of the gold-catalyzed oxazole synthesis, and substrates with different aliphatic, aromatic, and functional groups in the side chain were investigated. Even molecules with several propargyl amide groups could easily be converted, delivering di- and trioxazoles with interesting optical properties. Furthermore, the scope of the gold(I)-catalyzed alkylidene synthesis was investigated. Further functionalizations of these isolable intermediates of the oxazole synthesis were developed and chelate ligands can be obtained. The use of Barluengas reagent offers a new and mild access to the synthetically valuable iodoalkylideneoxazoles from propargylic amides, this reagent being superior to other sources of halogens.

Gold-catalyzed synthesis of chroman, dihydrobenzofuran, dihydroindole, and tetrahydroquinoline derivatives.

Different furans containing an ynamide or alkynyl ether moiety in the side chain were prepared. The gold-catalyzed transformation of these compounds delivered dihydroindole, dihydrobenzofuran, chroman, and tetrahydroquinoline derivatives at room temperature through very fast reactions. Furthermore, the stabilizing effect of the heteroatom directly attached to the intermediate arene oxides led to highly selective reactions, even in the case of only mono-substituted furans, which is quite different from previous results obtained with non-heteroatom-substituted alkynes.

Gold Catalysis: Deuterated Substrates as the Key for an Experimental Insight into the Mechanism and Selectivity of the Phenol Synthesis

The second phase of the gold-catalyzed phenol synthesis, the ring opening of the intermediate arene oxide, follows general acid catalysis. The product selectivity is determined by the substrate only and can be explained by the stability of the intermediate arenium ions. Thus, even remote substitutents can be used to control the chemoselectivity of the overall reaction by electronic influences and their influence is stronger than the steric influence of neighboring substituents. This is supported by quantum chemical calculations of the intermediates. The lack of exchange of deuterium labels excludes even equilibria with acetylide or vinylidene intermediates and the observed deuterium distribution in the final products is in accord with the NIH-shift reaction. In addition, these findings now explain previously obtained results.

Gold Catalysis: Switching the Pathway of the Furan‐Yne Cyclization

The use of gold compounds as homogeneous catalysts for the conversion of many organic substrates is one of the fastest growing areas in organic chemistry today. Among these transformations, the cyclization of ene–ynes is playing a major role. We developed the gold-catalyzed synthesis of highly substituted phenols, starting from furan–alkyne systems. In this case, as in most of the common ene–yne systems, the first step of the reaction is also initiated by a 5-exo-dig cyclization, but because of the furan moiety, a series of subsequent steps (ring opening of the furan system, oxepine-formation, and rearrangement) finally leads to phenolic systems. Recently, we investigated the use of ynamideand alkynylether moieties in the side chain of these systems, which led to a dramatic increase in reaction rates and to higher selectivities (see Scheme 2, left side). 5] These effects stem from the highly polarized triple bond that can be formulated as the ketene-like mesomer B in Scheme 1.

Rapid and Highly Sensitive Dual-Channel Detection of Cyanide by Bis-heteroleptic Ruthenium(II) Complexes

Two new ruthenium complexes [Ru(bipy)(2)(PDA)](2+) (1) and [Ru(phen)(2)(PDA)](2+) (2) (PDA = 1,10-phenanthroline-4,7-dicarboxaldehyde) have been synthesized to detect cyanide based on the well-known formation of cyanohydrins. Both 1[PF(6)](2) and 2[PF(6)](2) were fully characterized by various spectroscopic techniques and their solid state structures determined by single-crystal X-ray diffraction. Their anion binding properties in pure and aqueous acetonitrile were thoroughly examined using two different channels, i.e., UV-vis absorption and photoluminescence (PL). After addition of only 2 equiv of CN(-), the PL intensity of 1[PF(6)](2) and 2[PF(6)](2) was enhanced ∼55-fold within 15 s along with a diagnostic blue shift of the emission by more than 100 nm. PL titrations of 1[PF(6)](2) and 2[PF(6)](2) with CN(-) in CH(3)CN furnished the very high overall cyanohydrin formation constants log β([CN(-)]) = 15.36 ± 0.44 (β([CN(-)]) = 2.3 × 10(15) M(-2)) and log β([CN(-)]) = 16.37 ± 0.53 (β([CN(-)]) = 2.3 × 10(16) M(-2)), respectively. For both probes, the second constant, K(2), is about 57-84 times less than K(1), suggesting that the cyanohydrin reaction is stepwise. The stepwise mechanism is further supported by results of a (1)H NMR titration of 2[PF(6)](2) with CN(-). The high selectivity of 2[PF(6)](2) for CN(-) was established by PL in the presence of other competing anions. Furthermore, the color change from orange-red to yellow and the appearance of a orange luminescence, which can be observed by the naked eye, provides a simple real-time method for cyanide detection. Finally, theoretical calculations were carried out to elucidate the details of the electronic structure and transitions involved in the ruthenium probes and their cyanide adducts.

Homogeneous gold-catalyzed synthesis of biphenyls and furfuryl-substituted arenes

Abstract The synthesis of phenyl- and furfuryl-substituted furans and their unique gold-catalyzed transformation to biaryl compounds and furfuryl arenes was investigated. With the aryl-substituted substrates the reactions proceeded very well, and in the case of a chloro-substituent in o -position of the phenyl group a minor side-product, that might be explained by a neighboring-group participation of that chloro-substituent, was isolated. In the case of the furfuryl-substitution the side reactions become more relevant, the two side-products provide evidence for a carbeniumion as intermediate that is transformed into a more stable furfuryl cation by a C–C bond cleavage.

Gold catalysis: enantiotopos selection.

Homogeneous gold catalysis has made a major contribution to organic synthesis in the past decade and, apart from significant methodology work in the meantime, it has become an efficient tool in total synthesis. It has almost been forgotten that enantioselective gold catalysis was the origin of homogenous gold catalysis. After significant initial success, stereoselective gold catalysis was neglected for some time. As recently predicted, enantioselective gold catalysis revived in the last years and significant success has been achieved with a number of different enantiomerically pure gold complexes and even enantiomerically pure counterions. Common for these enantioselective reactions is that the new stereocenters are formed by the transformation of a sp center of a C=C double bond (in an allene or alkene 1, Scheme 1) to a chiral center with sp hybridization in the product 2. Alternatively, a C=O double bond (in an aldehyde) is transformed. So far only an enantiofacial selection in the selectivity determining step has been exploited for enantioselective homogeneous gold catalysis. With mono-alkynes, such a facial selection is not possible—the typical addition reactions initially form alkenes that do not possess a stereocenter. Dialkynes 3 with symmetry equivalent, enantiotopic alkynyl groups would allow stereoselective conversions. If, after the coordination (an intermolecular process) of the alkyne to the enantiomerically pure gold catalyst, the subsequent intramolecular addition is fast for both diastereomeric p complexes (leading to the two enantiomeric products 4 and ent-4 ; in general, gold-catalyzed reactions are fast compared to other catalysts). The stereoselection would be quite difficult, as the p coordination of one of the two alkynes to the gold catalyst would become the selectivity determining step (in general, the subsequent addition reactions are not reversible). Here we report our findings with regard to this concept in the gold-catalyzed phenol synthesis. As the test substrate for this investigation, we used the furyldialkyne 8. It was easily prepared from 5-methylfurfural (5) by an aldol condensation with tert-butyl acetate to deliver the furylacrylate 6, followed by chemoselective transfer hydrogenation to give 7 and twofold addition of propargyl magnesium bromide to the ester group (Scheme 2). With 5 mol % AuCl3 this substrate 8 readily and chemoselectively underwent cycloisomerization to the phenol rac-9

A Modular Approach to Structurally Diverse Bidentate Chelate Ligands for Transition Metal Catalysis

A modular approach to a new class of structurally diverse bidentate P/N, P/P, P/S, and P/Se chelate ligands has been developed. Starting from hydroquinone, various ligands were synthesized in a divergent manner via orthogonally bis-protected bromohydroquinones as the central building block. The first donor functionality (L1) is introduced to the aromatic (hydroquinone) ligand backbone either by Pd-catalyzed cross-coupling (Suzuki coupling) with hetero-aryl bromides, by Pd-catalyzed amination, or by lithiation and subsequent treatment with electrophiles (e.g., chlorophosphanes, disulfides, diselenides, or carbamoyl chlorides). After selective deprotection, the second ligand tooth (L2) is attached by reaction of the phenolic OH functionality with a chlorophosphane, a chlorophosphite, or a related reagent. Some of the resulting chelate ligands were converted into the respective PdX2 complexes (X = Cl, I), two of which were characterized by X-ray crystallography. The methodology developed opens an access to a broad variety of new chiral and achiral transition metal complexes and is generally suited for the solid-phase synthesis of combinatorial libraries, as will be reported separately.

Unsymmetrically Substituted 9,10-Dihydro-9,10-diboraanthracenes as Versatile Building Blocks for Boron-Doped π-Conjugated Systems

The targeted hydrolysis of the 9,10-dihydro-9,10-diboraanthracene adduct (Me(2)S)HB(C(6)H(4))(2)BH(SMe(2)) (1) with 0.5 equiv of H(2)O leads to formation of the borinic acid anhydride [(Me(2)S)HB(C(6)H(4))(2)B](2)O (2) and thereby provides access to the field of unsymmetrically substituted 9,10-dihydro-9,10-diboraanthracenes. Compound 2 reacts with tBuC≡CH to give the corresponding vinyl derivative in an essentially quantitative conversion. Subsequent cleavage of the B-O-B bridge by LiAlH(4) with formation of hydridoborate functionalities is possible but is accompanied by partial B-C(vinyl) bond degradation. This situation changes when the related mesityl derivative [MesB(C(6)H(4))(2)B](2)O (7) is employed, which can be synthesized from BrB(C(6)H(4))(2)BBr (6) by treatment with 1 equiv of MesMgBr and subsequent hydrolysis. The reaction of 7 with LiAlH(4) in tetrahydrofuran (THF) furnishes Li[MesB(C(6)H(4))(2)BH(2)] (8); hydride elimination with Me(3)SiCl leads to formation of the THF adduct MesB(C(6)H(4))(2)BH(THF) (9·THF). Alternatively, 7 can be transformed into the bromoborane MesB(C(6)H(4))(2)BBr (10) by treatment with BBr(3). A Br/H-exchange reaction between 10 and Et(3)SiH yields the donor-free borane MesB(C(6)H(4))(2)BH (9), which forms B-H-B bridged dimers (9)(2) in the solid state. The vinyl borane MesB(C(6)H(4))(2)BC(H)=C(H)Mes (14) is accessible from MesC≡CH and either 9·THF or 9. Compared with the related compound Mes(2)BC(H)=C(H)Mes, the electronic absorption and emission spectra of 14 reveal bathochromic shifts of Δλ(abs)=17 nm and Δλ(em)=74 nm, which can be attributed to the rigid, fully delocalized π framework of the [MesB(C(6)H(4))(2)B] chromophore.