Samarium diiodide induced ketyl-(het)arene cyclisations towards novel N-heterocycles

In this tutorial review we discuss recent advances in the field of ketyl-(het)arene cyclisations promoted by samarium diiodide and related processes. Couplings of samarium ketyls with carbon-carbon multiple bonds are perhaps the most useful reactions to create carbocycles and heterocycles of various ring sizes. They have also successfully been exploited for the synthesis of biologically active compounds or natural products. In this article we intend to summarise our diversity orientated approaches towards nitrogen heterocycles and emphasize other approaches with SmI(2) as well as electrochemical cyclisation methods providing similar N-heterocycles. We also briefly discuss our recently published formal total synthesis of strychnine employing a new samarium diiodide induced cascade reaction as key step. All these examples demonstrate the high synthetic potential of samarium ketyl-(het)arene cyclisations for the preparation of various types of important heterocyclic compounds.     

Photoinduced metalation of nonactivated C-Cl bonds with samarium diiodide: synthesis of alkenes with high (Z)-selectivity through beta-elimination reactions

[reaction: see text] The photoinduced metalation of nonactivated C-Cl bonds of O-acetyl chlorohydrins is promoted by samarium diiodide. As a result of this, beta-elimination of O-acetyl chlorohydrins is achieved, affording the corresponding (Z)-alkenes with total or high stereoselectivity.     

Selective reductive transformations using samarium diiodide-water

Samarium diiodide (SmI(2)) is one of the most important reductive electron transfer reagents available in the laboratory. Key to the popularity of SmI(2) is the ability of additives and co-solvents to tune the properties of the reagent. Over the last decade water has emerged as a particularly valuable additive, opening up new chemical space and leading to the discovery of unprecedented selectivity and new reactions promoted by SmI(2). In this Feature Article we review recent progress in the application of SmI(2)-H(2)O systems, with an emphasis on mechanistic considerations and the development of new transformations.     

Direct reaction of dibromoacetic acid with aldehydes promoted by samarium diiodide: an easy, efficient, and rapid synthesis of (E)-alpha,beta-unsaturated carboxylic acids with total stereoselectivity

A promoted SmI2 direct reaction of dibromoacetic acid with different aldehydes, followed by an elimination reaction also promoted by samarium diiodide, affords (E)-alpha,beta-unsaturated carboxylic acids 2 with total stereoselectivity. A mechanism to explain this transformation is proposed.     

Beyond Samarium Diiodide: Vistas in Reductive Chemistry Mediated by Lanthanides(II)

Reactions proceeding through open-shell, single-electron pathways offer attractive alternative outcomes to those proceeding through closed-shell, two-electron mechanisms. In this context, samarium diiodide (SmI(2) ) has emerged as one of the most important and convenient-to-use electron-transfer reagents available in the laboratory. Recently, significant progress has been made in the reductive chemistry of other divalent lanthanides which for many years had been considered too reactive to be of value to synthetic chemists. Herein, we illustrate how new samarium(II) complexes and nonclassical lanthanide(II) reagents are changing the landscape of modern reductive chemistry.     

Intramolecular, reductive cyclization of beta-ketoisothiocyanates promoted by using samarium diiodide

A novel samarium diiodide (SmI2) promoted intramolecular cyclization of beta-ketoisothiocyanate, derived from alpha,beta-unsaturated esters and ammonium thiocyanate led to alpha-hydroxythiolactams and/or thiolactams in high yields. Treatment of beta-ketoisothiocyanate with two equivalents of SmI2 gave a mixture of alpha-hydroxythiolactam and thiolactam. Four equivalents of SmI2 afforded only thiolactam in high yields. The intramolecular cyclization took place with high to complete stereoselectivity. A mechanism to explain this transformation is proposed.     

Tripyrrolidinophosphoric acid triamide as an activator in samarium diiodide reductions

The electrochemical and spectrophotometric characterization of the complex formed from samarium diiodide and 4 equiv of tripyrrolidinophosphoric acid triamide (TPPA) is presented. Kinetic studies indicate that the SmI(2)/TPPA complex possesses reactivity greater than the complex formed between samarium diiodide and 4 equiv of HMPA. Examples of the use of SmI(2)/TPPA in synthesis are presented.     

二碘化钐作为预催化剂的有机反应

二碘化钐是二价稀土试剂中的代表化合物,在有机合成中用途广泛.综述了近年来催化量二碘化钐促进的有机反应,介绍了二碘化钐作为预催化剂在催化有机反应方面所体现的反应活性及选择性.     

Synthesis of (E)-alpha,beta-unsaturated amides with high selectivity by using samarium diiodide

Stereoselective beta-elimination of 2-chloro-3-hydroxyamides 1 is achieved by using samarium diiodide to yield alpha,beta-unsaturated amides 2, in which the C=C bond is di- tri-, or tetrasubstituted. The starting compounds 1 are easily prepared by reaction of the corresponding lithium enolates of alpha-chloroamides with aldehydes or ketones at - 78 degrees C. The influence of the reaction conditions and the structure of the starting compounds on the stereoselectivity of the beta-elimination reaction is also discussed.     

Mechanistic evidence for intermolecular radical carbonyl additions promoted by samarium diiodide

In this work, mechanistic studies were performed to understand the SmI2/H2O-mediated coupling of N-acyl oxazolidinones with acrylates and acrylamides, providing gamma-keto esters and amides, respectively. Our results provide experimental evidence that C-C bond formation via intermolecular radical addition reactions to carbonyl substrates can be promoted by samarium diiodide. Coupling reactions with N-cyclopropylcarbonyl-2-oxazolidinone suggest the alpha,beta-unsaturated esters/amides are reduced by the low-valent lanthanide reagent and not the N-acyl oxazolidinones, as originially proposed (J. Am. Chem. Soc. 2005, 127, 6544). Rate measurements support the preferred reduction of an acrylate or acrylamide by SmI2/H2O in the presence of an N-acyl oxazolidinone. In the absence of the N-acyl oxazolidinone, SmI2/H2O promotes dimerization of the acrylates, whereas the C=C bond of the acrylamides is reduced. In addition, coupling of the Pfp ester of Cbz-protected phenylalanine with an acrylamide leads only to reduction of the acrylamide and recovered ester, whereas the same coupling with the N-acyl oxazolidinone derivative provides the gamma-keto amides. These results imply that a pathway involving nucleophilic acyl substitution cannot take place and that a radical mechanism must be invoked to explain the C-C bond formation. We propose that the acrylate/acrylamide is reduced to a conjugated ketyl radical that adds to the exocyclic carbonyl group of the N-acyl oxazolidinone, activated through bidentate coordination to a lanthanide ion.     

A Samarium "Soluble" Anode: A New Source of SmI(2) Reagent for Electrosynthetic Application

An electrochemical method to prepare solutions of samarium diiodide in THF is reported. The simple electrolysis of a samarium rod provides a rapid and straightforward in situ synthesis of SmI(2) . The electrogenerated complex catalyzes various C?C bond formations. The reagent is produced continuously and leads to efficient organic electrosynthesis with significantly smaller amounts of solvent than usually required.     

Synthesis of ferrocenyl alkenes, dienes, and enynes via samarium diiodide promoted tandem addition and dehydration of ferrocenyl carbonyls with halides

A practical method for preparation of ferrocenyl alkenes, dienes, and enynes from ferrocenyl carbonyls was explored. A one-pot operation using samarium diiodide to promote the condensation reactions of ferrocenecarboxaldehyde, acetylferrocene, benzoylferrocene, and butanoylferrocene with benzyl bromides, allyl bromide, propargyl bromide, and 1-bromo-3-chlorobutane gave the olefinic products in very high yields. The condensation reactions were also achieved by using catalytic amounts of SmI(2) with magnesium to regenerate the divalent samarium reducing agent.     

Application of samarium diiodide (SmI2)-induced reduction of gamma-acetoxy-alpha,beta-enoates with alpha-specific kinetic electrophilic trapping for the synthesis of amino acid derivatives

Gamma-acetoxy-alpha,beta-enoates were easily reduced by samarium diiodide (SmI2) in THF to generate samarium dienolates which were kinetically trapped with ease at their alpha-positions by electrophiles (proton, aldehydes or ketones) to yield (E)-alkene dipeptide isosteres or gamma-amino acid derivatives in high chemical yields.     

First direct evidence of radical intermediates in samarium diiodide induced cyclization by ESR spectra

The mechanism of samarium diiodide (SmI(2))-induced cyclization of α,β-unsaturated esters and ketones to bicyclic compounds was examined using ESR spectroscopy. This is the first report of direct evidence of the radical intermediates in the SmI(2) reaction. The preferential reduction of the α,β-unsaturated carbonyl part in some substrates should be recognized as a main route.     

Facile synthesis of substituted phenanthroline ligands by samarium-promoted coupling of phenanthroline with ketones

[formula: see text] 1,10-Phenanthroline undergoes coupling with ketones promoted by samarium diiodide to produce 2-(1-hydroxyalkyl)-1,10-phenanthrolines. O-Methylation of these derivatives provides the corresponding 2-(1-methoxyalkyl)phenanthrolines. Demethoxylation with samarium diiodide then affords 2-alkylphenanthrolines. This process may be repeated to obtain 2,9-disubstituted phenanthrolines. A variety of new, substituted phenanthrolines are thus obtained. These compounds have numerous potential applications as ligands in metal-promoted reactions, including asymmetric catalysis.     

Three-component coupling of acylphosphonates and two carbonyl compounds promoted by low-valent samariums: one-Pot synthesis of beta-hydroxyphosphonates

Three-component coupling of acylphosphonates and two carbonyl compounds leading to beta-hydroxyphosphonates has been achieved with low-valent samariums. Thus, acylphosphonates reacted with aldehydes in the presence of semicatalytic amounts of samarium metal or SmI(2) to give acyloxyphosphonates in good yields. The second coupling reaction of the acyloxyphosphonates with aldehydes or ketones promoted by SmI(2) afforded beta-hydroxyphosphonates instead of olefins. Moreover, these two reactions could be carried out in one pot.     

Samarium diiodide-catalyzed diastereoselective pinacol couplings

A complex of samarium diiodide (SmI(2)) with tetraglyme catalyzes the intermolecular pinacol coupling of aromatic or aliphatic aldehydes at loadings of 10 mol % in the presence of Me(2)SiCl(2) and Mg. Diastereoselectivity of up to 95/5 (+/-/meso) has been achieved for aliphatic aldehydes and up to 19/81 (+/-/meso) for aromatic aldehydes. De values of up to 99% have been achieved in intramolecular pinacol coupling reactions using the SmI(2)/tetraglyme/Mg/Me(2)SiCl(2) catalytic system.     

A highly stereoselective samarium diiodide-promoted aldol reaction with 1'-phenylseleno-2'-keto nucleosides. Synthesis of 1'alpha-branched uridine derivatives

Since 1'-branched nucleosides are biologically important targets in medicinal chemistry, more efficient methods for preparing them are required. The 1'alpha-branched uridine derivatives were successfully synthesized via a samarium diiodide (SmI(2))-promoted aldol reaction. Treatment of the 1'alpha-phenylseleno-2'-ketouridine derivative 6, readily prepared from uridine, with SmI(2) at -78 degrees C in THF reductively cleaved the anomeric Se-C bond to generate the corresponding samarium enolate, which was highly stereoselectively condensed with aldehydes, such as PhCHO, MeCHO, i-PrCHO, or (CH(2)O)(n)(), to give the corresponding 1'alpha-1' 'S-branched products 12a-d. This is the first time an enolate has been generated by reductively cleaving a C-Se bond. The highly selective stereochemical results suggest that the aldol reaction proceeds via a chelation-controlled transition state. When an excess of aldehyde was used and the reaction mixture was gradually warmed, the tandem aldol-Tishchenko reaction proceeded to give the "arabino-type" nucleosides 14a-c, having a 2'-"up" hydroxyl and 1'alpha-1' 'S-branched chain. 1'alpha-Hydroxymethyluridine (21), which is the uracil version of the antitumor antibiotic angustmycin C, was synthesized from the aldol reaction product 10.     

Preparation of samarium(II) iodide: quantitative evaluation of the effect of water, oxygen, and peroxide content, preparative methods, and the activation of samarium metal

Samarium(II) iodide (SmI(2)) is one of the most important reducing agents in organic synthesis. Synthetic chemistry promoted by SmI(2) depends on the efficient and reliable preparation of the reagent. Unfortunately, users can experience difficulties preparing the reagent, and this has prevented realization of the full synthetic potential of SmI(2). To provide synthetic chemists with general and reliable methods for the preparation of SmI(2), a systematic evaluation of the factors involved in its synthesis has been carried out. Our studies confirm that SmI(2) is a user-friendly reagent. Factors such as water, oxygen, and peroxide content in THF have little influence on the synthesis of SmI(2). In addition, the use of specialized glovebox equipment or Schlenk techniques is not required for the preparation of SmI(2). However, our studies suggest that the quality of samarium metal is an important factor and that the use of low quality metal is the main cause of failed preparations of the reagent. Accordingly, we report a straightforward method for activation of "inactive" samarium metal and demonstrate the broad utility of this protocol through the electron transfer reductions of a range of substrates using SmI(2) prepared from otherwise "inactive" metal. An investigation into the stability of SmI(2) solutions and an evaluation of commercially available solutions of the reagent is also reported.     

A convenient pathway to Sm(II)-mediated chemistry in acetonitrile

In this communication we show that the instability of samarium diiodide (SmI(2)) in acetonitrile is a consequence of ionization of the reductant in this solvent. Samarium triflate (Sm(OTf)(2)) is exceptionally stable in acetonitrile for periods over six months and can be used with appropriate additives to initiate a ketyl-olefin coupling reaction in high yield.