Chun-Yu Ho

Highly Chemoselective Reductive Amination of Carbonyl Compounds Promoted by InCl3/Et3SiH/MeOH System

A new strategy has been developed for reductive amination of aldehydes and ketones with the InCl3/Et3SiH/MeOH system, which is a nontoxic system with highly chemoselective and nonwater sensitive properties. The methodology can be applied to a variety of cyclic, acyclic, aromatic, and aliphatic amines. Functionalities including ester, hydroxyl, carboxylic acid, and olefin are found to be stable under our conditions. The reaction shows a first-order kinetics profile with respect to both InCl3 and Et3SiH. Spectroscopic techniques such as NMR and ESI-MS have been employed to probe the active and resulting species arising from InCl3 and Et3SiH in MeOH, which are important in deriving a mechanistic proposal. In the ESI-MS studies, we have first discovered the existence of stable methanol-coordinated indium(III) species which are presumably responsible for the gentle generation of indium hydride at room temperature. The solvent attribution was crucial in tuning the reactivity of [In-H] species, leading to the establishment of mild reaction conditions. The system is superior in flexible tuning of hydride reactivity, resulting in the system being highly chemoselective.

α‐Olefins as Alkenylmetal Equivalents in Catalytic Conjugate Addition Reactions

First documented over a century ago, conjugate additions are among the most utilized organic reactions. In carbon-carbon bond-forming variants, the nucleophile is typically organometallic in nature. Earlier technology employed enolate, organolithium, Grignard, or organocopper reagents, and more recently organozinc and organoboron compounds have enhanced this transformation significantly.[1,2] Despite increased functional group tolerance, an organometallic or organometalloid is nonetheless required in these powerful methods. Herein we describe a novel conjugate addition reaction in which a simple, unactivated alkene (ethylene, an alpha olefin, or styrene) takes the place of the organometal (eq 1). In other words, although an alkene is not an alkenylmetal reagent per se, it functions as one in this C–C bond-forming process. (1) Catalyzed polymerization of alkenes is one of the most important industrial processes,[3] and Ni-catalyzed two-alkene coupling reactions have also received significant attention, including hydrovinylation.[4] Montgomery has found that nickel complexes catalyze a wide variety of conjugate addition reactions,[5] but the closest precedent to the transformation reported here (catalytic 1,4-addition of simple alkene to unsaturated carbonyl) appears to be Lewis-acid promoted conjugate addition of electron-rich alkenes.[6,7] However, in these cases migration of the double bond of the alkene nucleophile occurs, in contrast to the Ni-catalyzed reactions described below. Ogoshi reported that stoichiometric amounts of Ni(cod)2 and Me3SiOTf effected intramolecular coupling of an alkene and an aldehyde, and shortly thereafter, we reported that alpha olefins are excellent nucleophiles in intermolecular carbonyl addition reactions catalyzed by complex derived from Ni(cod)2 and a phosphine or an N-heterocyclic carbene.[8] Depending on the nature of the ligand, addition at either the terminus or the 2-position of the alkene occurs. The latter provides direct access to allylic alcohol derivatives, and the former yields products of a carbonyl-ene-like reaction. With the aim of broadening the scope of alkenes as nucleophiles in carbon-carbon bond-forming reactions, we turned our attention to electrophiles containing unsaturated carbonyl functional groups. In order to focus on issues of alkene reactivity in initial studies, we selected ethylene as the coupling partner and decided to address issues of regioselectivity in subsequent experiments. As shown in Table 1, Et3SiOTf and catalytic amounts of Ni(cod)2 and Bu3P afford good to excellent yields of the conjugate addition product, isolated as the enolsilane (entries 1–4). Moreover, the stereoselectivity with respect to formation of the enolsilane is at least 92:8. Unsaturated ketones are also effective electrophiles (entries 5–11) but proceed with lower selectivity in some cases. Table 1 Ni-Catalyzed Conjugate Addition Reactions of Alkenes.[a] As demonstrated in entry 9, electron-rich enones are superior electrophiles, and certain heterocycles are also tolerated (entries 10–11). Despite reduced selectivity, reactions with furan- and thiophene-containing enones proceed in high chemical yield. Overall, most of the above cases are highly selective, and thus the transformation represents a direct and stereoselective assembly of tetrasubstituted siloxyalkenes.[9,10] Several observations regarding the optimum reaction conditions are noteworthy. Increasing either the ethylene pressure from 1 atm to 2 atm or the scale of the reaction fourfold resulted in only a marginal reduction in yield (entries 2 and 6). Out of 25 additives investigated (see Supporting Information), Bu3P was by far the most effective for coupling reactions of ethylene. Toluene is the superior solvent; for example, ethereal solvents such as Et2O, THF, and 1,4-dioxane completely suppress the coupling reaction. Significant effort was expended to reduce the rather high catalyst loading (30 mol%); however, small decreases in the amount of Ni(cod)2 resulted in significantly reduced yield. For example, 2b was afforded in 49% yield when 15 mol% Ni(cod)2 was used (76% yield under standard conditions). Similarly, a 63% yield of 2f was obtained at 20% loading, down from 94% yield at 30% loading. Other critical variables are the amounts of Et3N and Et3SiOTf employed. Decreasing or increasing the former lowered the yield or completely suppressed the reaction, and reducing the amount of silyl triflate from 1.75 to 1.25 equiv decreased the yield of 2b from 76% to 47% under otherwise identical conditions. It should also be noted that Me3SiOTf can be used in place of Et3SiOTf, but this substitution tends to diminish the product yield. Unactivated monosubstituted olefins are also good coupling partners in this reaction. For example, 1-octene and 2-hexylacrolein are united in 67% yield, and with very high enolsilane E/Z selectivity (entry 12). Coupling occurs with approximately 4:1 regioselectivity, favoring coupling at the 2-position of the alkene. Since there are comparatively a greater number of general methods for the preparation of 1-alkenyl organometallics (e.g., hydrometalation of terminal alkynes), the fact that 1-octene functions as a 2-alkenyl organometallic reagent highlights a particularly useful aspect of this reaction. Aryl alkenes, on the other hand, afford the opposite alkene regioselectivity (entries 13–14). Coupling at the 2-position of styrene is not observed; carbon-carbon bond formation at 1-position occurs exclusively, whether the electrophile is an enal or an enone. These trends and observations noted above suggest a basic mechanistic framework (Scheme 1). The proposed sequence of events is based largely on a crystal structure of a complex derived from Ni(cod)2, Cy3P, a 1,3-diene, and PhCHO reported recently by Ogoshi.[11] We believe that the alkene (ethylene shown) and the electrophile (enal or enone, 1) afford an oxa-π-allyl nickel complex (A) during the formation of the carbon-carbon bond. The silyl triflate reacts with this species, giving an enolsilane and a Ni(II) complex (B) that undergoes rapid β-H elimination. Product (2) release and Et3N abstraction of TfOH from complex C affords a Ni(0) species (not shown), completing the catalytic cycle. Scheme 1 Proposed Mechanistic Framework The E/Z selectivity thus appears to be dictated by two factors that in most cases reinforce each other. The placement of R2 and R3 away from each other and the chair-like chelation of Ni in complex A are consistent with the observed sense of alkene geometry. The superior performance of electron-rich enals and enones is consistent with the fact that reaction with silyl triflate is a critical step in the cycle. Mackenzie has reported Ni-catalyzed conjugate addition reactions between alkenyltributyltin reagents and α,β-unsaturated aldehydes that are assisted by chlorotrialkylsilanes and likely proceed via 1-((trialkylsilyl)oxy)allyl]nickel(II) intermediates.[7] In this vein, it is possible that the silyl triflate and enal (or enone) first combine, and that the resulting species then undergoes coupling with the alkene. Morken has proposed a similar sequence of events in Ni-catalyzed coupling reactions between allylboron reagents and enones.[12] With the caveat that different ligands are used in coupling reactions of alpha olefins (CyPPh2) and styrene (P(cyclopentyl)3), our working hypothesis for the complementary regioselectivity in these two cases is as follows: It is possible that the regioselectivity observed for styrene (coupling at the alkene 1-position) is due primarily to an electronic consideration, specifically, the formation of a benzylic Ni species. On the other hand, the sense of selectivity in alpha olefin cases is that resulting from avoidance of steric repulsion between the Ni-ligand complex and the alkene substituent. We have proposed an explanation similar to the latter for the behavior of alpha olefins in other Ni-catalyzed coupling reactions that we have developed.[8b–f] Several aspects of this transformation are noteworthy. First, it is a rare example of selective conjugate addition of an alkenyl equivalent to an unsaturated aldehyde. Typically in such reactions 1,2-addition is favored, or complex mixtures are afforded.[1] The high E/Z selectivity in most cases also merits further comment. Enolsilanes are starting materials in a wide range of enantioselective transformations leading to carbonyl compounds with quaternary stereogenic centers in the α-position, in many cases with very high enantioselectivity.[13,14] The double bond configuration is generally critical for high facial selectivity, and thus the nickel-catalyzed conjugate addition reaction provides rapid access to important tri-and tetrasubstituted enolsilanes that would otherwise be difficult to prepare with high selectivity via enolization of an aldehyde or ketone[9] (cf. Table 1, entry 2, (allyl vs. n-hexyl). Finally, the products derived from ethylene possess a monosubstituted alkene that is an excellent substrate for catalytic olefin cross-metathesis.[15] This combination therefore affords products that are regiocomplementary to those of the nickel-catalyzed conjugate addition reaction with aliphatic, monosubstituted alkenes (e.g., 1-octene). Our current efforts expanding the scope and utility of the conjugate addition of monosubstituted alkenes to unsaturated carbonyl compounds. More broadly, we continue to explore catalytic reactions that utilize simple, widely available chemical feedstocks, including alpha olefins, and provide important synthetic intermediates in a single operation.

Nickel-catalyzed coupling reactions of alkenes*

Several reactions of simple, unactivated alkenes with electrophiles under Ni(0) catalysis are discussed. The coupling of olefins with aldehydes and silyl triflates provides allylic or homoallylic alcohol derivatives, depending on the supporting ligands and, to a lesser extent, the substrates employed. Reaction of alkenes with isocyanates yields N-alkyl acrylamides. In these methods, alkenes act as the functional equivalents of alkenyl- and allylmetal reagents.

Catalytic Asymmetric Hydroalkenylation of Vinylarenes: Electronic Effects of Substrates and Chiral N‐Heterocyclic Carbene Ligands

An asymmetric tail-to-tail cross-hydroalkenylation of vinylarenes with terminal olefins was achieved by catalysis with NiH complexes bearing chiral N-heterocyclic carbenes (NHCs). The reaction provides branched gem-disubstituted olefins with high enantioselectivity (up to 94 % ee) and chemoselectivity (cross/homo product ratio: up to 99:1). Electronic effects of the substituents on the vinylarenes and on the N-aryl groups of the NHC ligands, but not a π,π-stacking mechanism, assist the steric effect and influence the outcome of the cross-hydroalkenylation.

Synthesis, biological activity, and biopharmaceutical characterization of tacrine dimers as acetylcholinesterase inhibitors.

Tacrine (THA), as the first approved acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimers disease (AD), has been extensively investigated in last seven decades. After dimerization of THA via a 7-carbon alkyl spacer, bis(7)-tacrine (B7T) showed much potent anti-AChE activity than THA. We here report synthesis, biological evaluation and biopharmaceutical characterization of six THA dimers referable to B7T. According to IC50 values, the in vitro anti-AChE activities of THA dimers were up to 300-fold more potent and 200-fold more selective than that of THA. In addition, the anti-AChE activities of THA dimers were found to be associated with the type and length of the linkage. All studied THA dimers showed much lower cytotoxicity than B7T, but like B7T, they demonstrated much lower absorptive permeabilities than that of THA on Caco-2 monolayer model. In addition, all THA dimers demonstrated significant efflux transport (efflux ratio >4), indicating that the limited permeability could be associated with the efflux transport during absorption process. Moreover, the dimer with higher Log P value was accompanied with higher permeability but lower aqueous solubility. A balanced consideration of activity, solubility, cytotoxicity and permeability should be conducted in selection of the potential candidates for further in vivo investigation.

Intranasal delivery of a novel acetylcholinesterase inhibitor HLS-3 for treatment of Alzheimer's disease

Aim: The present study aims to investigate the pharmacokinetics and pharmacodynamics of HLS‐3, a tacrine dimer with high anti‐acetylcholinesterase activity for the treatment of Alzheimers disease. Main methods: In vitro Calu‐3 and Caco‐2 cell monolayer transport and liver microsomal incubation studies of HLS‐3 were carried out to evaluate its nasal epithelium and intestinal membrane permeability, transporters involved in absorption and hepatic metabolism. In vivo pharmacokinetics of HLS‐3 followed by central and peripheral cholinergic mediated responses and ex vivo AChE activities in rats via oral and intranasal administrations were further investigated and compared. Key findings: Our in vitro studies suggested that HLS‐3 is the substrate of both P‐gp and MRPs with no significant hepatic oxidation and glucuronidation metabolism. Oral administration only delivered trace amount of HLS‐3 in systemic circulation with a high faecal recovery of 70.7%, whereas intranasal administration demonstrated an absolute bioavailability of 28.9% with urinary and faecal recoveries of 1.5% and 34.0%, respectively. In comparison to oral administration of HLS‐3, intranasally delivered HLS‐3 exhibited significant higher central cholinergic mediated responses without obvious peripheral side effect. Significance: Intranasal delivery of HLS‐3 with better pharmacokinetics and pharmacodynamics performances provides a promising approach for treatment of Alzheimers disease.