Daniele Addis

Zinc-Catalyzed Reduction of Amides: Unprecedented Selectivity and Functional Group Tolerance

A novel zinc-catalyzed reduction of tertiary amides was developed. This system shows remarkable chemoselectivity and substrate scope tolerating ester, ether, nitro, cyano, azo, and keto substituents.

A convenient and general iron-catalyzed reduction of amides to amines.

Amines constitute an important class of compounds in chemistry and biology. They are widely used in the pharmaceutical industry for crop protection and natural product synthesis, as well as for the preparation of advanced materials. Among the different procedures for their synthesis, the reduction of amides is one of the most fundamental methods. In general, reactive alkali metal hydrides or boron hydrides are used for such reduction processes. However, their air and moisture sensitivty, their low functional group tolerance, and tedious purification procedures are drawbacks. Interestingly, Cole-Hamilton and co-workers showed that catalytic hydrogenation of amides using molecular hydrogen constitutes a highly attractive access to amines, but the vigorous reaction conditions, that is, high pressures and elevated temperature, limit this methodology. During the last decade, metal-catalyzed hydrosilylations of amides have received considerable interest. Although various catalyst systems including Rh, Ru, Pt, Pd, Ir, Os, Re, Mn, Mo, In, and Ti have proven to be effective for this reduction, the development of cost-efficient and environmentally benign catalysts for this transformation is still desirable. In addition, most of the known catalyst systems either require expensive silanes or have limited functional group tolerance. During our recent studies on iron-catalyzed dehydrations of primary amides in the presence of hydrosilanes, we isolated the corresponding secondary amine as a by-product. Thus, our attention focused on this side-reaction of reducing carboxamides to amines. The abundant availability of iron makes it a highly attractive candidate for catalysis and a “cheap metal for noble tasks”. 7] Herein we report the first general iron-catalyzed hydrosilylation of amides to generate amines. Initially, the reaction of N,N-dimethylbenzamide (1 a) with PhSiH3 in toluene was investigated as a model system to identify and optimize critical reaction parameters (Table 1). As expected the reaction did not occur in the absence of any catalyst (Table 1, entry 1). In contrast, when using 2 mol% of cheap [Fe3(CO)12], an excellent yield (97%) of N,N-dimethylbenzylamine (2a) was obtained (Table 1, entry 3). Other iron sources, such as [Fe2(CO)9], Fe(OAc)2, [Fe(acac)2], and [Fe(acac)3] are also reactive but resulted in lower product yields (Table 1, entries 2 and 4–9). Next, we investigated the influence of different silanes on the reaction. To our delight the reduction also took place in the presence of inexpensive polymethylhydrosiloxane (PMHS) to give the desired product in 93 % yield (Table 1, entry 16). Advantageously, this silane is also easily separated from the reaction mixture. Additional studies revealed that the reduction proceeded best in the presence of an excess of four equivalents of Si H (Table 1, entry 17). Among the different solvents tested, toluene and di-n-butyl ether gave the best results (Table 1, entries 17 and 19). With respect to the mechanism, we propose that the ironcatalyzed reduction of tertiary amides proceeds somewhat similarly to the ruthenium-catalyzed procedure reported by Nagashima and co-workers. Reaction of the hydrosilane with the iron precursor should yield an activated species, Table 1: Iron-catalyzed reduction of N,N-dimethylbenzamide.

Selective Reduction of Carboxylic Acid Derivatives by Catalytic Hydrosilylation

In the last decade, an increasing number of useful catalytic reductions of carboxylic acid derivatives with hydrosilanes have been developed. Notably, the combination of an appropriate silane and catalyst enables unprecedented chemoselectivity that is not possible with traditional organometallic hydrides or hydrogenation catalysts. For example, amides and esters can be reduced preferentially in the presence of ketones or even aldehydes. We believe that catalytic hydrosilylations will be used more often in the future in challenging organic syntheses, as the reaction procedures are straightforward, and the reactivity of the silane can be fine-tuned. So far, the synthetic potential of these processes has clearly been underestimated. They even hold promise for industrial applications, as inexpensive and readily available silanes, such as polymethylhydrosiloxane, offer useful possibilities on a larger scale.

Enantioselective Synthesis of Amines: General, Efficient Iron‐Catalyzed Asymmetric Transfer Hydrogenation of Imines

Chiral amines find numerous applications in the pharmaceutical and agrochemical industries. Notable examples of established drugs and their areas of application include Zoloft (depression), Cinacalcet (secondary hyperparathyroidism), Flomax (prostate), and Rivastigmine (Alzheimer s and Parkinson s disease) as well as the chiral herbicide Metolachlor (Scheme 1). The most direct and efficient syn-

A general and convenient catalytic synthesis of nitriles from amides and silanes.

A new and convenient protocol for the catalytic dehydration of aromatic and aliphatic amides using silanes in the presence of catalytic amounts of fluoride is presented. The synthesis of aliphatic and aromatic nitriles proceeds with high selectivity under mild conditions. Notably, a wide substrate range is converted in good to excellent yields.

Zinc‐Catalyzed Chemoselective Reduction of Tertiary and Secondary Amides to Amines

General and convenient procedures for the catalytic hydrosilylation of secondary and tertiary amides under mild conditions have been developed. In the presence of inexpensive zinc catalysts, tertiary amides are easily reduced by applying monosilanes. Key to success for the reduction of the secondary amides is the use of zinc triflate and disilanes with dual Si-H moieties. The presented hydrosilylations proceed with excellent chemoselectivity in the presence of sensitive ester, nitro, azo, nitrile, olefins, and other functional groups, thus making the method attractive for organic synthesis.

Chemo- and stereoselective iron-catalyzed hydrosilylation of ketones.

The reduction of ketones with polymethylhydrosiloxane (PMHS) gives the corresponding alcohols in good to excellent yield applying iron-based catalyst systems. In the case of prochiral ketones, the use of Fe(OAc)(2)/(S,S)-Me-DuPhos leads to high enantioselectivity up to 99% ee. The reaction proceeds in the presence of several functional groups such as esters, halides as well as conjugated double bonds, with high chemoselectivity. The advantage of this protocol is that the reaction requires no activating agents or additives.

A Practical and Benign Synthesis of Primary Amines through Ruthenium‐Catalyzed Reduction of Nitriles

The catalytic hydrogenation of nitriles represents an atom-economic and valuable route to amines. In the present study, the ruthenium-catalyzed hydrogenation of various organic nitriles to give primary amines has been examined in detail. Straightforward ruthenium complexes modified by cheap and widely available triphenylphosphine allow for the efficient and general reduction of various aryl, alkyl, and heterocyclic nitriles. By using a practical in situ catalyst composed of [Ru(cod)(methylallyl(2))] and PPh(3), excellent yields and chemoselectivity were achieved. Moreover, the catalyst system displays broad functional group tolerance.

Synthesis of Enantiomerically Pure 1,2,3,4-Tetrahydro-β-carbolines and N-Acyl-1-aryl Ethylamines by Rhodium-Catalyzed Hydrogenation

The rhodium-catalyzed asymmetric hydrogenation of different enamides, in particular, dihydro-beta-carboline derivates, was investigated in the presence of chiral phosphorus ligands. Enantioselectivities of up to 99 % ee were obtained after ligand screening and optimization of the reaction conditions. The scope and limitation of the catalysts were shown in the synthesis of optically active tetrahydro-beta-carbolines and other benchmark N-acyl-1-aryl ethylamines.