Zhulin Tan

Copper Catalyzed Asymmetric Propargylation of Aldehydes

The highly enantio- and regioselective copper catalyzed asymmetric propargylation of aldehydes with a propargyl borolane reagent is reported. The methodology demonstrated broad functional group tolerance and provided high enantioselectivities for aliphatic, vinyl, and aryl aldehydes. The utility of the TMS homopropargylic alcohols was demonstrated by the facile conversion to a chiral dihydropyranone.

Room Temperature Palladium-Catalyzed Cross Coupling of Aryltrimethylammonium Triflates with Aryl Grignard Reagents

Aryltrimethylammonium triflates and tetrafluoroborates were found to be highly reactive electrophiles in the Pd-catalyzed cross coupling with aryl Grignard reagents. The coupling reactions proceed at ambient temperature with a nearly stoichiometric quantity of Grignard reagent, and diverse functionality is tolerated. Competition experiments established the reactivity of PhNMe(3)OTf relative to PhCl, PhBr, PhI, and PhOTf.

Copper-catalyzed annulation of 2-formylazoles with o-aminoiodoarenes.

In the presence of catalytic CuI and sparteine, 2-formylpyrroles can be annulated with o-aminoiodoarenes to give substituted pyrrolo[1,2-a]quinoxalines and related heterocycles. The reaction also works for annulation of 2-formylindoles, 2-formylimidazole, 2-formylbenzimidazole, and a 3-formylpyrazole.

N-Heterocyclic Carbene-Catalyzed Silyl Enol Ether Formation†

N-Heterocyclic carbenes (NHCs) were found to catalyze the silyl transfer from trialkylsilyl ketene acetals to ketones. In the presence of a catalytic amount of NHC 3 (IAd, 0.1 to 5 mol %), a series of enolizable ketones as well as cyclohexanecarboxaldehyde were efficiently converted into the corresponding silyl enol ethers at 23 degrees C in THF.

Zinc catalyzed and mediated propargylations with propargyl boronates.

The utility of allenyl and propargyl boronates for the propargylation of aldehydes and ketones mediated by zinc is presented. The reaction is catalytic in zinc with allenyl or propargyl borolanes. The propargylation with crystalline and air-stable propargyl diethanolamine boronates was also achieved. A catalytic cycle is proposed, and preliminary mechanistic studies are discussed.

Zinc Catalyzed and Mediated Asymmetric Propargylation of Trifluoromethyl Ketones with a Propargyl Boronate

The development of zinc-mediated and -catalyzed asymmetric propargylations of trifluoromethyl ketones with a propargyl borolane and the N-isopropyl-l-proline ligand is presented. The methodology provided moderate to high stereoselectivity and was successfully applied on a multikilogram scale for the synthesis of the Glucocorticoid agonist BI 653048. A mechanism for the boron-zinc exchange with a propargyl borolane is proposed and supported by modeling at the density functional level of theory. A water acceleration effect on the zinc-catalyzed propargylation was discovered, which enabled a catalytic process to be achieved. Reaction progress analysis supports a predominately rate limiting exchange for the zinc-catalyzed propargylation. A catalytic amount of water is proposed to generate an intermediate that catalyzes the exchange, thereby facilitating the reaction with trifluoromethyl ketones.

Highly Diastereoselective Zinc-Catalyzed Propargylation of tert-Butanesulfinyl Imines

A zinc-catalyzed diastereoselective propargylation of t-butanesulfinyl imines is presented. The methodology provided both aliphatic and aryl homopropargylic amines in up to 98:2 and 99.8:0.2 dr, respectively. The utility of the homopropargylic amines was demonstrated by the application to the synthesis of a cis-substituted pyrido-indole through a diastereoselective Pictet-Spengler cyclization.

Direct Titanium‐Mediated Conversion of Ketones into Enamides with Ammonia and Acetic Anhydride

N-Acyl enamides are useful compounds in organic synthesis. In the realm of catalytic asymmetric hydrogenation, they are among the most exhaustively studied class of substrates, and provide access to valuable chiral amine building blocks. These substrates have also demonstrated broad utility in catalytic asymmetric C C bond forming processes such as aza–ene, Michael, Friedel–Crafts, cycloaddition, and arylation reactions. Despite the extensive applications of Nacyl enamides, their preparation remains challenging. The direct condensation of acetamide with ketones, while attractive in its simplicity, proceeds either in low yields or not at all for the majority of ketone substrates. The Pd-catalyzed cross-coupling of vinyl electrophiles with amides and the Heck reaction of N-vinylacetamide with aryl halides often require additional steps for preparation of coupling precursors and employ a costly transition metal catalyst. The addition of alkyl magnesium or alkyl lithium reagents to nitriles followed by trapping with Ac2O or AcCl has limited functional-group tolerance and requires low reaction temperatures. By far the most commonly employed procedure is the two-step conversion of ketones through ketoximes (Scheme 1). This reaction was first described in 1975 by Barton and coworkers. After a first step of oxime formation, the ketoxime was then treated with Ac2O and either pyridine at reflux, Cr(OAc)2, or Ti(OAc)3 for reductive acylation. [13] Subsequently, numerous alternative reducing agents were developed. The most commonly employed reductant is Fe powder, which was first demonstrated by Barton and Zard in 1985 and subsequently developed by Burk and Zhang in 1998. From a large scale perspective, the use of highenergy hydroxylamine, generating a high-energy oxime intermediate, and reducing the oxime at high temperatures present safety concerns. In addition, the workup of the Fe process is often tedious, requiring filtration of large amounts of inorganic salts. While several alternatives to Fe metal have emerged recently, these still rely on the same overall two-step process through a ketoxime. Our own requirements for large-scale synthesis of N-acetyl enamides for asymmetric hydrogenation prompted us to develop a more direct and process-friendly alternative in which hydroxylamine is replaced with ammonia. Herein we describe a direct, redoxfree synthesis of enamides from ketones, ammonia, and Ac2O mediated by Ti(OiPr)4. In addition, we introduce the use of edte (N,N,N’,N’-tetrakis(2-hydroxyethyl)ethylenediamine) to effect water solubilization of the Ti and allow a simple extractive workup. Our strategy for enamide synthesis was based on condensation of a ketone with ammonia to give an N-unsubstituted imine or enamine, followed by N-acetylation on addition of Ac2O. The imine formation presented a challenge due to the volatility of ammonia, which excluded the common method for imine formation by azeotropic distillation for removal of water. Therefore the condensation with NH3 at room temperature in the presence of various dehydrating agents was explored. Acetophenone 1 was treated with a dehydrating agent (2 equiv) and an ammonia source at room temperature for 24 h, followed by quenching with Et3N and Ac2O (Table 1). Little or no enamide 2 was observed with conventional desiccants and ammonia (entries 1–4). The use of sodium tetraborate (Na2B4O7) or boric anhydride (B2O3) in THF or NMP gave modest conversion to product (entries 5– 7). This prompted screening of other boron reagents, and the discovery that certain trialkyl borates, in combination with NH4Br/Et3N as the ammonia source, gave moderate conversions to product. The most effective boron reagent was 2isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (entry 11), which gave a 59 % conversion to 2. The best results were obtained by using titanium alkoxides, however, with Scheme 1. Conventional two-step enamide synthesis and the direct Timediated method.

Development of a large scale asymmetric synthesis of the glucocorticoid agonist BI 653048 BS H3PO4.

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H3PO4 (1·H3PO4) is presented. A key trifluoromethyl ketone intermediate 22 containing an N-(4-methoxyphenyl)ethyl amide was prepared by an enolization/bromine-magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone 22 gave the desired diastereomer in 32% yield and with dr = 98:2 from a 1:1 diastereomeric mixture after crystallization. Subsequently, an asymmetric propargylation was developed which provided the desired diastereomer in 4:1 diastereoselectivity and 75% yield with dr = 99:1 after crystallization. The azaindole moiety was efficiently installed by a one-pot cross coupling/indolization reaction. An efficient deprotection of the 4-methoxyphenethyl group was developed using H3PO4/anisole to produce the anisole solvate of the API in high yield and purity. The final form, a phosphoric acid cocrystal, was produced in high yield and purity and with consistent control of particle size.

Carbamoyl anion addition to N-sulfinyl imines: highly diastereoselective synthesis of α-amino amides.

Carbamoyl anions, generated from N,N-disubstituted formamides and lithium diisopropylamide, add with high diastereoselectivity to chiral N-sulfinyl aldimines and ketimines to provide α-amino amides. The methodology enables the direct introduction of a carbonyl group without the requirement of unmasking steps as with other nucleophiles. The products may be converted to α-amino esters or 1,2-diamines. Iterative application of the reaction enabled the stereoselective synthesis of a dipeptide. Spectroscopic and computational studies support an anion structure with η(2) coordination of lithium by the carbonyl group.