A new method for the successive addition of two different Grignard reagents onto imidate derivatives is presented. The originality lies in the use of a specific organomagnesium reagent, which is not able to directly react with the imidate, but reacts onto the species generated in situ after the addition of another more reactive Grignard reagent. By this route, several sulfonamides are prepared in good yields. The extension to a diastereoselective version is successfully described using chiral N‐sulfinyl imidates.

The reactivity of organoaluminum reagents with acyl cyanohydrins was studied using two methods for preparing nucleophilic species. Mild and chemoselective conditions were developed and an unprecedented double addition of dimethylalkynylaluminum reagents onto nitriles provided access to a wide range of substituted diethynyl carbinamines in good to excellent yields (>20 examples).

Cyclopropylamines are an important subclass of substituted cyclopropanes that combine the unique electronic and steric properties of cyclopropanes with the presence of a donor nitrogen atom. In addition to their presence in a diverse array of biologically active compounds, cyclopropylamines are utilized as important synthetic intermediates, particularly in ring-opening or cycloaddition reactions. Consequently, the synthesis of these compounds has constituted a significant research topic, as evidenced by the abundant published synthetic methods. In addition to the widely used Curtius rearrangement, classical cyclopropanation methods have been adapted to integrate a nitrogen function (Simmons-Smith reaction, metal-catalyzed reaction of diazo compounds on olefins, Michael-initiated ring-closure reactions) with significant advances in enantioselective synthesis. More recently, specific methods have been developed for the preparation of the aminocyclopropane moiety (Kulinkovich reactions applied to amides and nitriles, addition to cyclopropenes, metal-catalyzed reactions involving C-H functionalization, ...). The topic of this review is to present the different methods for the preparation of cyclopropylamine derivatives, with the aim of covering the methodological advances as best as possible, highlighting their scope, their stereochemical aspects and future trends.

The first studies on [Ru]-catalyzed Asymmetric Ring-Closing Ene-Yne Metathesis (ARCEYM) are disclosed in this communication. The desymmetrization of achiral ene-diyne substrates afforded the corresponding exo cyclic compounds in good yields and enantioselectivities (up to 69 % ee). The methodology provided a straightforward access to functionalized scaffolds displaying alkyne and diene useful for further functionalization such as [4+2] cycloaddition reaction. The first studies on [Ru]-catalyzed Asymmetric Ring-Closing Ene-Yne Metathesis (ARCEYM) are disclosed in this communication. The desymmetrization of achiral ene-diyne substrates afforded the corresponding exo cyclic compounds in good yields and enantioselectivities (up to 69 % ee). The methodology provided a straightforward access to functionalized scaffolds displaying alkyne and diene useful for further functionalization such as [4+2] cycloaddition reaction.image

An efficient and mild synthetic methodology of double addition of propargylzinc reagents onto acylcyanohydrins and cyanocarbonates has been developed. After optimization of reaction conditions, dipropargylic alpha,alpha-disubstituted hydroxyamides and N-Boc-protected amino alcohols have been straightforwardly prepared in good yields. The valorization of the so-obtained compounds was undertaken by cobalt-catalyzed [2+2+2] cycloaddition reactions to provide functionalized pyridine derivatives.

New oxazolone‐based heteromultifunctional linkers were synthesized using a zinc‐mediated double functionalization of nitriles as the key step. The orthogonality of the functional groups displayed by this original scaffold was demonstrated by conducting sequential or simultaneous multi‐component reactions with amines (oxazolone ring opening), thiols (thiol‐ene radical reaction) and azides (Cu‐catalyzed azide–alkyne coupling), in respect to the concept of click chemistry.

Allylzinc reagents were used to access highly functionalized tertiary carbinamine derivatives in high yields from cyanoesters and cyanocarbonates. While the monoaddition of organometallics on nitriles is generally observed, in this work the nucleophilic allylation occurs twice, due to an intermediate transfer of the carbonyl moiety onto the nitrogen atom. The chemoselectivity of the reaction allows the presence of various functionalities and in the case of carbonate derivatives, the nature of the final product was modulated by kinetic control, giving selectively hydroxyamides or cyclic carbamates.

Although the dialkoxytitanacyclopropanes are presented as important reagents in organic synthesis, the mechanism of their generation from dialkyltitanium species is not firmly established, as shown by the various propositions cited in the literature. An ab initio study of these transformations was investigated, namely, β-H elimination, β-H abstraction, epimetalation, as well as the related α-H abstraction. The results tend to show that the formation of a titanium hydride intermediate is unlikely, but, most probably, a direct hydrogen transfer (β-H abstraction) would occur. Compared to titanocene analogues, the α-H and β-H abstraction reactions were less favorable with dialkoxytitanium complexes. The overall reaction was found to be more favorable in the case of dialkoxydialkyltitanium complexes by the prior formation of bimetallic intermediates, underlining the importance of titanium ate complexes in this chemistry. A prior agostic interaction between the ethyl moiety and the metal was found to facilitate the hydrogen transfer and the formation of the metallacyclopropane. This phenomenon was illustrated by an easier β-H abstraction from a complex bearing an agostic interaction in its ground state. The intrinsic bond orbital method was used throughout this work to better visualize the electronic processes involved in these transformations.

A convenient access to 2-hydroxycyclopentenones was designed from acylcyanohydrins, by using titanacyclopropane complexes as nucleophilic partners and an intramolecular aldol condensation in basic conditions. The development of a one-pot procedure allows a step- and atom-economic process, and the use of Grignard reagents other than ethylmagnesium bromide provided valuable 3,4-disubstituted 2-hydroxycyclopentenones. The utility of the hydroxy group was illustrated by further functionalization of the α-position using palladium-mediated cross-coupling reactions.

Vinyl nosylates, readily obtained from β-dicarbonyl derivatives, could be efficiently engaged in Sonogashira cross-coupling reactions, either cocatalyzed by copper or silver salts. The para-nitrobenzenesulfonate (nosylate) group allows this coupling to be performed under very mild conditions (room temperature). These new leaving group and mild conditions could be applied to the synthesis of acetylenic coumarinyl derivatives and to the total synthesis of an acetylenic monoterpene natural product, named cleviolide.

The titanium-catalyzed asymmetric cyclopropanation of cyanoesters­ with Grignard reagents was investigated for the first time. Particularly, the study of the efficiency of Taddol-based titanium complexes­ has shown that the prior preparation of Taddol titanium complexes was not required and a large panel of ligands was evaluated by using this approach. The spirocyclopropanelactams were obtained with good diastereoselectivity and with moderate enantioselectivities from the main diastereoisomer (up to 32%).

The successive addition of two different Grignard reagents to acyl cyanohydrins was performed with success by using alkynyl Grignard reagents.

BACKGROUND 2-Aminochromene derivatives display important pharmacological properties, including mainly antibiotic and anticancer activities. OBJECTIVE The study aims to synthesize new chromene derivatives via a new approach using Grignard reagents, for the evaluation of their antibiotic and antifungal properties. METHOD A series of novel 3-cyano-4-aminochromene derivatives bearing alkyl substituents at the 4-position was prepared for biological evaluation. RESULTS These compounds were obtained by the addition of various Grignard reagents into Nethoxycarbonyl- 3-cyanoiminocoumarines in moderate to good yields (72-96%). The reaction is completely regioselective. The new chromene derivatives were screened for their in vitro antimicrobial activities against a panel of six bacterial and three fungal strains using agar dilution method. CONCLUSION The antibacterial activity of the chromene derivatives was more pronounced on Gram-positive bacteria than on Gram-negative bacteria with a significant activity observed against Staphylococcus aureus. An interesting antifungal activity against Fusarium sp. and Fusarium oxysporum was also noticed.

As depicted in many textbooks, the addition of organometallics to nitriles is generally limited to a single addition, providing ketones after acidic hydrolysis. However, the double addition, leading to tertiary carbinamines is also possible, as demonstrated as early as 1939 by the double addition of allyl Grignard reagents to alpha-ethoxyacetonitrile. Since this seminal result, and stimulated by the biological importance of the so-obtained carbinamines, efforts were devoted to expand the scope of the double addition of organometallics to nitriles. This review presents these different approaches which have led to short accesses to tertiary carbinamine derivatives. Particularly interesting is the double addition of different organometallics, which opens the way towards the straightforward asymmetric synthesis of tertiary carbinamines from nitriles.

A straightforward synthesis of symmetrically ,-disubstituted -amino acids is presented. The key step of this process relies on the efficient double addition of Grignard reagents to acyl cyanohydrins to provide N-acyl amino alcohols selectively in good yields. The chemoselectivity of the reaction was modulated by the nature of the acyl moiety. Eleven amino acids were prepared, including the particularly simple divinylglycine, which is not easily accessible by using conventional methods.

Titanium is employed in a wide range of important enantioselective reactions, including epoxidations, reductions, nucleophilic additions, and cycloadditions. This chapter summarises the most important catalytic systems employed in these reactions and the sustainable aspects developed thereof. In particular, efforts to reduce the amount of catalyst (or the ligand) or the use of supported heterogeneous and homogeneous catalysts are described.

A comparative study of the titanium-mediated cyclopropanation of (benzyloxy)acetonitrile and Boc-protected cyanohydrin using unsaturated Grignard reagents (but-3-enyl- and pent-4-enylmagnesium bromides) is described. The best conditions to provide the cis and trans isomers of cyclopropylamines bearing unsaturation were identified and the alkene moiety was subjected to chemical modifications, as shown by the synthesis of orthogonally protected cis- and trans-2,3-methanolysine, cis-2,3-methanoornithine, and cis-2,3-methanohomolysine.

The first synthesis of a triazolium salt with ferrocene-based planar chirality is described. It was obtained from enantiopure Kagan's acetal, via the construction of a lactam intermediate. The corresponding 1,2,4-triazolylidene-Cu(I) complex was prepared. Its structure as well as the parent triazolium salt were characterized by X-ray diffraction analysis.

ChemInformVolume 45, Issue 26 Preparative Organic Chemistry ChemInform Abstract: Titanium-Mediated Addition of Grignard Reagents to Acyl Cyanohydrins: Aminocyclopropane versus 1,4-Diketone Formation. Paul Setzer, Paul Setzer Inst. Mol. Materiaux Mans, CNRS, Univ. Maine, F-72085 Le Mans, Fr.Search for more papers by this authorGwenael Forcher, Gwenael Forcher Inst. Mol. Materiaux Mans, CNRS, Univ. Maine, F-72085 Le Mans, Fr.Search for more papers by this authorFabien Boeda, Fabien Boeda Inst. Mol. Materiaux Mans, CNRS, Univ. Maine, F-72085 Le Mans, Fr.Search for more papers by this authorMorwenna S. M. Pearson-Long, Morwenna S. M. Pearson-Long Inst. Mol. Materiaux Mans, CNRS, Univ. Maine, F-72085 Le Mans, Fr.Search for more papers by this authorPhilippe Bertus, Philippe Bertus Inst. Mol. Materiaux Mans, CNRS, Univ. Maine, F-72085 Le Mans, Fr.Search for more papers by this author Paul Setzer, Paul Setzer Inst. Mol. Materiaux Mans, CNRS, Univ. Maine, F-72085 Le Mans, Fr.Search for more papers by this authorGwenael Forcher, Gwenael Forcher Inst. Mol. Materiaux Mans, CNRS, Univ. Maine, F-72085 Le Mans, Fr.Search for more papers by this authorFabien Boeda, Fabien Boeda Inst. Mol. Materiaux Mans, CNRS, Univ. Maine, F-72085 Le Mans, Fr.Search for more papers by this authorMorwenna S. M. Pearson-Long, Morwenna S. M. Pearson-Long Inst. Mol. Materiaux Mans, CNRS, Univ. Maine, F-72085 Le Mans, Fr.Search for more papers by this authorPhilippe Bertus, Philippe Bertus Inst. Mol. Materiaux Mans, CNRS, Univ. Maine, F-72085 Le Mans, Fr.Search for more papers by this author First published: 12 June 2014 https://doi.org/10.1002/chin.201426056Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume45, Issue26July 1, 2014 RelatedInformation

The 1,2-dianion reactivity of the reagent generated from EtMgBr and titanium isopropoxide was illustrated when N-acyl cyanohydrins were used as substrates (>20 examples), giving both aminocyclopropane derivatives and 1,4-dicarbonyl compounds. When the reaction was performed in diethyl ether, 5-hydroxy-1,4-diketones were the main product. Under specific conditions (use of tetrahydrofuran and a bulky carboxylic moiety), the cyclopropane derivatives were obtained in good yields. The observed dichotomy may be explained by a ring-opening of the five-membered titanacycle intermediate followed by a nonselective acyl addition.