Mono- and disubstituted N,N-dialkylcyclopropylamines from dialkylformamides via ligand-exchanged titanium-alkene complexes

Dibenzylformamide was treated with cyclohexylmagnesium bromide in the presence of either titanium tetraisopropoxide or methyltitanium triisopropoxide and a variety of cyclic and acyclic alkenes and alkadienes to give new mono- and disubstituted as well as bicyclic dialkylcyclopropylamines (Tables 1-3) in yields ranging from 18 to 90 % (in most cases around 55 %). 3-Benzyl-6-(N,N-dibenzylamino)-3-azabicyclo[3.1.0]hexane (10 a) and the orthogonally bisprotected 3-tert-butoxycarbonyl-6-(N,N-dibenzyl)-3-azabicyclo[3.1.0]hexane (10 d) as well as the analogous 6-(N,N-dibenzylamino)bicyclo[3.1.0]hexane (12) were obtained as pure exo diastereomers in particularly high yields (87, 90, and 88 %, respectively) from N-benzylpyrroline (15 a), N-Boc-pyrroline (15 d; Boc=tert-butyloxycarbonyl) and cyclopentene (19). 1,3-Butadiene (52) and substituted 1,3-butadienes were also aminocyclopropanated quite well to give 2-ethenylcyclopropylamines in good yields (51-64 %). Except for alkenyl- and aryl-substituted compounds, N,N-dibenzylcyclopropylamines can be debenzylated by catalytic hydrogenation to the primary cyclopropylamines as demonstrated for 10 a and 10 d to yield the fully deprotected 10 e (93 %) and mono-Boc-protected 10 f (98 %), respectively. The latter are interesting templates for combinatorial syntheses of libraries of small molecules with a well defined distance of 4.3 A between two nitrogen atoms.     

Titanium-mediated syntheses of cyclopropylamines

The transformations of N,N-dialkylcarboxamides and nitriles with 1,2-dicarbanionic organometallics in situ generated from organomagnesium (Grignard) as well as organozinc reagents in the presence of stoichiometric or substoichiometric (semi-catalytic) quantities of a titanium alkoxide derivative of type XTi(OR)₃ with X=OR, Cl, Me and OR=OiPr, OEt are described. The key step in the transformation of a monocarbanionic into a 1,2-dicarbanionic organotitanium species is a disproportionation of a dialkyltitanium intermediate to form an alkane and a titanium alkene complex which has the reactivity of a titanacyclopropane derivative. The latter are able to undergo insertion of the carbonyl group of an N,N-dialkylcarboxamide or a cyano group to furnish, after ring contraction and hydrolysis, dialkylcyclopropylamines or cyclopropylamines, respectively. The titanium alkene complexes can also undergo ligand exchange with alkenes to afford new titanacyclopropanes, which subsequently react as 1,2-dicarbanionic equivalents. In many cases, these titanium-mediated formations of a wide range of synthetically and/or pharmacologically important cyclopropylamines proceed in good to very good yields (from 20% to 98% for dialkylcyclopropylamines from N,N-dialkylcarboxamides and from 27% to 73% for primary cyclopropylamines from nitriles) and with high chemo- and stereoselectivity. These circumstances in conjunction with the simplicity of the experimental handling and inexpensiveness of the reagents favor these reactions for an ever increasing range of applications in organic synthesis.     

Dehalogenation of alkyl halides catalyzed by single-enantiomer complexes of titanium

Racemic alkyl bromides were dehalogenated with a stoichiometric quantity of a main group alkyl metal reductant in the presence of a chiral, single-enantiomer titanium catalyst. The reaction was monitored by chiral gas chromatography of samples from the reaction mixture. The chiral titanium compounds examined proved to be effective catalysts. However, there was no detectable difference in the rate of reduction between the two enantiomers of the alkyl halide. An enantiomerically pure secondary bromide was reduced under the same conditions without racemization during the course of the reaction. This indicates that the secondary alkyl bromide is stereochemically stable to the reaction conditions. Radical probe reactions suggest a radical mechanism.     

Titanium-catalyzed enantioselective alkynylation of aldehydes

A simple and practical method to make chiral propargylic alcohols has been developed: in the presence of a titanium alkoxide catalyst prepared in situ from titanium tetraisopropoxide and (R)-H8-binaphthol, a variety of aromatic aldehydes were converted to the corresponding chiral propargylic alcohols with very good enantioselectivities (up to 96.2% e.e.) and yields.     

Diastereoselective titanium-mediated construction of cis-2,3-ring annelated 1-(2'-chloroethyl)cyclopropanols

Titanium(IV)-mediated cyclopropanation induced by reaction of cycloalkylmagnesium bromides 1a-e in the presence of titanium tetraisopropoxide with ethyl beta-chloropropionate 2 yielded cis-fused 1-(2'-chloroethyl)cyclopropanols 3b-e with diastereoselectivity highly depending on the ring size. Unexpected rearrangement products 5d,e were isolated in some cases.     

A Convenient Procedure for Preparation of 1-(1-Aminoalkyl)-1-cyclopropanols from N-Benzyl α-Amino Acid Esters

The reaction of N-benzyl -amino acid ethyl esters with ethylmagnesium bromide in the presence of a catalytic amount of titanium tetraisopropoxide leads to formation of the corresponding 1-aminoalkyl- 1-cyclopropanols in high yields. Hydrogenation of the latter over palladium catalyst ensures selective removal of one or two protecting benzyl groups from the nitrogen atom.     

Effect of Heat Treatment Temperature on Surface Topography and Hydrophobicity of Polydimethylsiloxane/Titanium Oxide Hybrid Films

Hydrophobic thin films of polydimethylsiloxane (PDMS) - titamium (hydrous) oxide hybrid material were deposited on glass substrate by dip coating from the precursor containing hydroxyl-terminated PDMS and titanium tetraisopropoxide (TIP), as well as small amounts of water and ethyl acetoacetate. Film's hydrophobicity was evaluated by performing contact angle measurement, while surface topography was analyzed by using an atomic force microscope (AFM). Effects of heat treatment temperature and TIP:PDMS ratio on film's hydrophobicity are described.     

trans-1-Sulfonylamino-2-isoborneolsulfonylaminocyclohexane derivatives: excellent chiral ligands for the catalytic enantioselective addition of organozinc reagents to ketones

The catalytic enantioselective addition of different organozinc reagents (such as alkyl and aryl derivatives or in situ generated aryl, allyl alkenyl, and alkynyl derivatives obtained through different transmetallation processes) to simple ketones has been accomplished by using titanium tetraisopropoxide and chiral ligands derived from substituted trans-1-sulfonylamino-2-isoborneolsulfonylaminocyclohexane, producing the corresponding tertiary alcohols with enantiomeric excesses (ee) up to >99 %. A simple and efficient procedure for the synthesis of the chiral ligands used in these reactions is described.     

Polymer supported trans-1-phenylsulfonylamino-2-isoborneolsulfonylaminocyclohexane ligand for the titanium catalyzed organozinc addition to ketones

The catalytic enantioselective addition of different organozinc reagents, such as diethylzinc, or in situ generated phenylzinc derivatives to simple ketones was accomplished using titanium tetraisopropoxide and supported chiral ligands derived from trans-1-phenylsulfonylamino-2-isoborneolsulfonylamidocyclohexane, to give the corresponding tertiary alcohols with enantioselectivities up to >99%. A simple and efficient procedure for the synthesis of the disulfonamide monomeric ligand and the corresponding polymerization is described.     

Beiträge zur Chemie der Alkylverbindungen von Übergangsmetallen. IV Über Darstellung und Eigenschaften von Alkyl- und Aryltitantrihalogeniden

Titanium(IV)chloride and bromide react with zinc dialkyls forming the corresponding titanium trihalides. In detail the preparation and charakterisation of methyltitanium trichloride, methyltitanium tribromide, phenyltitanium trichloride and of complexes of proypl-, pentyl- and phenyltitanium trichloride are described. Furthermore some considerations are made on the stabilities of organotitanium compounds.     

Asymmetric ring-opening of cyclohexene oxide with trimethylsilyl azide in the presence of titanium isopropoxide/chiral ligand

trans-2-Azidocyclohexanol of enantiomeric excess up to 24% is obtained in the ring opening of cyclohexene oxide by use of trimethylsilyl azide in the presence of stoechiometric amount of titanium tetraisopropoxide and chiral diols or aminoalcohols.     

Asymmetric alkylation of aldehydes catalyzed by novel dinuclear bis-BINOLate titanium(IV) complexes

Bis-BINOLs 1a,b in which two BINOL units are tethered by o- and m-phenylenebis(ethynyl) groups form stable dinuclear bis-BINOLate titanium(IV) complexes 2a,b by treatment with titanium tetraisopropoxide. In the presence of excess titanium tetraisopropoxide, 2a and 2b (2–20 mol %) catalyze diethylzinc addition to aromatic and aliphatic aldehydes in an efficient manner to give the ethylation products with high enantioselectivities. While more than 1 equiv of titanium tetraisopropoxide (with respect to a substrate aldehyde) is generally employed for obtaining high turnover frequency and selectivity in reactions catalyzed by a parent (BINOLate)Ti(OⁱPr)₂, the amount can be reduced as low as 0.2 equiv in the reactions catalyzed by 2a,b.     

Titanium(IV) chloride and quaternary ammonium salt promoted Baylis-Hillman reaction.

The Baylis-Hillman reaction of aldehydes with alpha,beta-unsaturated ketones can be drastically affected by the reaction temperature and Lewis bases. When the reaction was carried out at -78 degrees C using catalytic amounts of quaternary ammonium salts (R4N+X-, X = Cl, Br, I) as Lewis bases, in the presence of titanium(IV) chloride, the chlorinated aldol adduct 1 was obtained as the major product. Quaternary ammonium bromides and iodides (R4N+X-, X = Br, I) have higher catalytic activity than corresponding chlorides (R4N+Cl-). Quaternary ammonium fluorides (R4N+F-) do not have activity at all. The amounts of Lewis acid and quaternary ammonium salts used affect the reaction rate and product. A plausible reaction mechanism is proposed. If the reaction was carried out at room temperature (about 20 degrees C) in the presence of titanium(IV) chloride and quaternary ammonium salts (R4N+X-, X = Cl, Br, I), the elimination product 3, derived from 1, was formed as the major product.     

Achiral tetrahydrosalen ligands for the synthesis of C(2)-symmetric titanium complexes: a structure and diastereoselectivity study

Achiral tetrahydrosalen ligands have been employed in the synthesis of chiral C(2)-symmetric titanium complexes. When combined with tetrahydrosalen ligands 2a and 2b, titanium tetraisopropoxide liberated 2 equiv of isopropyl alcohol and generated the (tetrahydrosalen)Ti(O-i-Pr)(2) complexes 3a and 3b. These complexes were shown to be C(2)-symmetric by (1)H and (13)C[(1)H] NMR spectrometry and X-ray crystallography. X-ray structures of 3a and 3b indicate that the bonding of the tetrahydrosalen ligand to titanium is different than the bonding of salen ligands to titanium. Whereas salen ligands usually bind to titanium in a planar arrangement, the tetrahydrosalen is bonded with the phenoxide oxygens mutually trans. When bound in this fashion, the nitrogens of the tetrahydrosalen ligand and the titanium become stereogenic centers. The use of titanium complexes of high enantiopurity in the generation of tetrahydrosalen titanium adducts resulted in a maximum diastereoselectivity of 2:1. The diastereoselectivity obtained using chiral titanium alkoxide complexes was greater than the diastereoselectivity observed when a tetrahydrosalen ligand derived from (S,S)-trans-diaminocyclohexane was employed.     

Electrochemical Asymmetric Diacetoxylation of Styrenes Mediated by Chiral Iodoarene Catalyst**

Organocatalysis with chiral iodoarenes has emerged as a powerful approach for performing enantioselective transformations. However, it suffers from the need to utilize stoichiometric amounts of peroxy acids or similar high energy oxidants. Electrosynthesis enables eliminating stoichiometric redox reagents by replacing them with electric stimuli. In this context, an electrochemically-promoted variant of the chiral iodoarene-catalyzed asymmetric diacetoxylation of styrenes was evaluated. The screening of reaction parameters established a set of conditions under which, for the first time, an enantioselective electrochemical oxidation mediated by a chiral iodoarene achieving a catalytic turnover has been accomplished. The reaction was applied for the synthesis of an array of products in 15–60 % yields and 0–84 % ee. The modest efficiency of the electrocatalysis was traced to a partial direct oxidation of styrene substrates leading to racemic products and undesired dimeric side-products. Cyclic voltammetry measurements demonstrated that such outcome originates from a somewhat difficult electrochemical oxidation of the applied iodoarene catalyst. Present work provides important insights and implications for the design of more efficient electrocatalytic systems employing chiral iodoarenes as mediators.     

Reduction of Secondary Alkyl Bromides by Palladium Catalysts Containing Chelating Diphosphine Ligands

Secondary alkyl bromides were reduced by diisobutylaluminum hydride and ethylmagnesium chloride in the presence of catalysts derived from chelating diphosphine complexes of palladium. Traditional palladium(0) diphosphine complexes generated by other means were not viable catalysts for the reaction in the absence of diisobutylaluminum hydride and ethylmagnesium chloride. Deuterium labeling experiments indicate that the reaction does not take place via halogen metal exchange.     

Chiral tertiary alcohols from a trans-1-arenesulfonyl-amino-2-isoborneolsulfonylaminocyclohexane-catalyzed addition of organozincs to ketones

The catalytic enantioselective addition of different organozinc reagents, such as alkyl, or in situ generated aryl, allyl, alkenyl and alkynyl derivatives to simple aryl ketones, was accomplished using titanium tetraisopropoxide and chiral ligands derived from 1-arenesulfonylamino-2-isoborneolsulfonylamidocyclohexane, giving the corresponding tertiary alcohols with enantioselectivities up to >99%. A simple and efficient procedure for the synthesis of the disulfonamide ligands used is described.     

Stereoselectivity of Grignard Reaction in the Presence of Chiral Podands and Crown Ethers

Reactions of ethylmagnesium bromide with benzaldehyde and acetophenone in toluene proceed stereoselectively in the presence of catalytic amounts of chiral podands and crown ethers. Under catalytic conditions theyield of the corresponding alcohols is nearly quantitative. The optical yield varies in the range 9-86% depending     

NaIO4-mediated asymmetric bromohydroxylation of α,β-unsaturated carboxamides with high diastereoselectivity: a short route to (−)-cytoxazone and droxidopa

The NaIO₄-mediated asymmetric bromohydroxylation of α,β-unsaturated carboxamides was achieved using lithium bromide as the bromine source under acidic conditions at rt to afford the corresponding chiral α-bromo-β-hydroxy carboxamides. Excellent yields (77-90%) and diastereoselectivities (up to 10:1) along with exclusive control over regio- as well as anti-selectivity are the main features with a good scope of substrates. The method has successfully been applied in the enantioselective syntheses of two biologically important molecules, viz (−)-cytoxazone and l-threo-DOPS (droxidopa).     

Asymmetric synthesis using enantiomerically pure 2-(p-anisylsulfinyl)-2-cycloalkenones

Conjugate additions of many organometallic reagents to 2-(p-anisylsulfinyl)-2-cycloalkenones, 2 proceed with much greater diastereoselectivity than additions to the corresponding 2-(p-tolylsulfinyl)-2-cycloalkenones, 7. Complexation of 2 with zinc dibromide followed by addition of various Grignard reagents lead, after reductive removal of the sulfoxide, to 3-substituted cycloalkanones of higher optical purity than those obtained from 7. Addition of methyltitanium triisopropoxide to 2-(p-anisylsulfnyl)-2-cyclohexenone, 2b, in the absence of zinc dibromide, proceeds with virtually complete asymmetric induction.