KHMDS Research Articles

Potassium Hexamethyldisilazide (KHMDS): Solvent-Dependent Solution Structures.

Solution structures of potassium hexamethyldisilazide [KHMDS] and labeled [15N]KHMDS were examined using a number of analytical methods including 29Si NMR spectroscopy and density functional theory computations. A combination of 15N-29Si couplings, 29Si chemical shifts, and the method of continuous variations reveals dimers, monomers, and ion pairs. Weakly coordinating monofunctional ligands such as toluene, N,N-dimethylethylamine, and Et3N afford exclusively dimers. 1,3-Dioxolane, THF, dimethoxyethane, hexamethylphosphoramide, and diglyme provide dimers at low ligand concentrations and monomers at high ligand concentrations. N,N,N',N'-Tetramethylethylenediamine and N,N,N',N'-tetramethylcyclohexanediamine provide exclusively dimers at all ligand concentrations at ambient temperatures and significant monomer at -80 °C. Studies of 12-crown-4 ran into technical problems. Equimolar 15-crown-5 forms a dimer, whereas excess 15-crown-5 affords a putative ion pair. Whereas equimolar 18-crown-6 also affords a dimer, an excess provides a monomer rather than a solvent-separated ion pair. [2.2.2]cryptand affords what is believed to be a contact-ion-paired cryptate. Solvation was probed using largely density functional theory (DFT) computations. Thermally corrected energies are consistent with lower aggregates and higher solvates at low temperatures, but the magnitudes of the computed temperature dependencies were substantially larger than the experimentally derived data.

Ultrafast Halogen Dance Reactions of Bromoarenes Enabled by Catalytic Potassium Hexamethyldisilazide.

Lochmann-Schlosser base, a stoichiometric combination of nBuLi and KOtBu, is commonly used as a superbase for deprotonating a wide range of organic compounds. In the present study, we report that catalytic potassium hexamethyldisilazide (KHMDS) exhibits higher catalytic activity than KOtBu for successive bromine-metal exchanges. Accordingly, 1-10 mol% of KHMDS dramatically enhances halogen dance reactions to introduce various electrophiles to bromopyridine, bromoimidazole, bromothiophene, bromofuran, and bromobenzene derivatives with the bromo group translocated from the original position. A dual catalytic cycle is proposed to explain the ultrafast bromine transfer.

Development of Catalytic Enantioselective Mannich Reactions Using Esters.

Catalytic enantioselective Mannich reactions of simple nonactivated esters proceeded using a chiral potassium strong base catalyst prepared from a chiral bisoxazoline and potassium hexamethyldisilazide. Alkyl acetates, alkyl propionates, and an alkyl butyrate were employed as the simple esters, and the desired reactions proceeded smoothly to afford Mannich products in good to high yields with high enantioselectivities. One of the products was successfully employed in the asymmetric total synthesis of Maraviroc.

Synthesis of 18F-labelled aryl trifluoromethyl ketones with improved molar activity.

A method for the radiosynthesis of 18F-labelled aryl trifluoromethyl ketones starting from widely available Weinreb amides using [18F]fluoroform is presented. The method uses potassium hexamethyldisilazane as base and delivers products in high molar activity (up to 24 GBq μmol-1) and excellent radiochemical conversions. The applicability for PET tracer synthesis is demonstrated by the radiosynthesis of ten (hetero)aryl trifluoromethylketones, bearing electron-withdrawing and -donating substituents including a derivative of bioactive probenecid.

KHMDS/Triglyme Cryptate as an Alternative to Phosphazene Base in Stereodivergent Pentafluoroethylation of N-Sulfinylimines Using HFC-125.

A protocol for the stereodivergent pentafluoroethylation of N-sulfinylimines using HFC-125 with KHMDS/triglyme has been developed. Both diastereomers of the pentafluoroethylated amines can be selectively synthesized based on the presence or absence of triglyme. This additive-controlled protocol allows the KHMDS/triglyme cryptate to be a straightforward and cheap alternative to previously reported base-controlled stereodivergent trifluoromethylation using potassium hexamethyldisilazide (KHMDS) versus P4-tBu.

Aza-Quasi-Favorskii Reaction Mediated by Potassium Hexamethyldisilazide

Aza-Quasi-Favorskii Reaction Mediated by Potassium Hexamethyldisilazide

Construction of 5H‐Dibenzo[c,e]azepine Framework from Dibenzothiophene Dioxides andN‐Benzylimines through SNAr Reactions

AbstractTreatment of a mixture of dibenzothiophene dioxides and benzaldehydeN‐benzylimines with potassium hexamethyldisilazide induces sequential intermolecular and intramolecular SNAr reactions to eventually form the corresponding 5H‐dibenzo[c,e]azepines without any formation of the conceivable five‐membered fluorene derivatives.

Alkali metal complexes of an unsymmetrical imino–phosphanamidinate (N-P-N) ligand

The syntheses and characterization of alkali metal complexes of an unsymmetrical monoanionic imidazolin-2-imino–phosphanamidinate ligand, {NHIDippP(Ph)N(Dipp)}− {L}− [Dipp = 2,6-diisopropylphenyl] is reported. The protio-ligand [NHIDippP(Ph)NH(Dipp)] (LH) was obtained by the reaction of N-heterocyclic imine (NHI) and [PhP(Cl)NHDipp] in the presence of Et3N in toluene at room temperature. The lithium complex [{NHIDippP(Ph)N(Dipp)}Li(OEt2)] (1) (Et = ethyl) was synthesized by the reaction of the protio ligand LH and one equivalent LiCH2SiMe3 in diethyl ether at room temperature. The reaction of sodium or potassium hexamethyldisilazide [MN(SiMe3)2] (M = Na or K) with LH in 1:1 molar ratio yielded corresponding alkali metal complexes [{NHIDippP(Ph)N(Dipp)}Na(THF)] (2) and [{NHIDippP(Ph)N(Dipp)}K(THF)2] (3) respectively in good yield. The molecular structures of the protio-ligand LH and alkali metal complexes 1 and 3 were established by single-crystal X-ray diffraction analysis. In the solid-state structures of 1 and 3, the lithium and potassium ions are κ2 bonded to the monoanionic ligand moiety through the imine nitrogen and phosphanamidinate nitrogen atoms.

Chiral Metal Salts as Ligands for Catalytic Asymmetric Mannich Reactions with Simple Amides.

Catalytic asymmetric Mannich reactions of imines with weakly acidic simple amides were developed using a chiral potassium hexamethyldisilazide (KHMDS)-bis(oxazoline) potassium salt (K-Box) catalyst system. The desired reactions proceeded to afford the target compounds in high yields with high diastereo- and enantioselectivities. It was suggested that a K enolate interacted with K-Box to form a chiral K enolate that reacted with imines efficiently. In this system, K-Box (potassium salt of Box) worked as a chiral ligand of the active potassium species.

Direct N1-Selective Alkylation of Hydantoins Using Potassium Bases.

Hydantoins, including the antiepileptic drug phenytoin, contain an amide nitrogen and an imide nitrogen, both of which can be alkylated. However, due to the higher acidity of its proton, N3 can be more easily alkylated than N1 under basic conditions. In this study, we explored methods for direct N1-selective methylation of phenytoin and found that conditions using potassium bases [potassium tert-butoxide (tBuOK) and potassium hexamethyldisilazide (KHMDS)] in tetrahydrofuran (THF) gave N1-monomethylated phenytoin in good yield. The applicable scope of this reaction system was found to include various hydantoins and alkyl halides. To explore the function of methylated hydantoins, the effects of a series of methylated phenytoins on P-glycoprotein were examined, but none of methylated products showed inhibitory activity toward rhodamine 123 efflux by P-glycoprotein.

Asymmetric C(sp3)\u2013H functionalization of unactivated alkylarenes such as toluene enabled by chiral Br\xf8nsted base catalysts

Benzylic functionalisation of unactivated alkylarenes remains as a significant challenge in asymmetric catalysis due to their less reactive nature. Here, we show development of catalytic asymmetric C(sp3)–H functionalization of unactivated alkylarenes such as toluene with imines. The reactions proceeded smoothly under proton-transfer conditions using a chiral, strong Brønsted base catalyst system. A chiral Brønsted base prepared from an alkylpotassium and a chiral amine ligand was found to effectively form a promising asymmetric environment around a benzyl anion. Optimization of the reaction conditions revealed that the use of the alkaline metal amide, potassium hexamethyldisilazide (KHMDS), as an additive was most effective, and enantioselective and atom economical carbon–carbon bond-forming reactions at the benzylic positions of unactivated alkylarenes was achieved without using any transition-metal catalyst.

Isocyanate Insertion into a La-P Phosphide Bond: A Versatile Route to Phosphaureate-Bridged Heterobimetallic Lanthanide-Coinage-Metal Complexes.

A new route to heterobimetallic lanthanide–coinage-metal complexes is disclosed. The selective insertion of organic substrates such as phenyl iso(thio)cyanate into the La–P bond of the primary phosphido complex (PN)2La(PHMes) (1) (with PN– = (N-(2-(diisopropylphosphanyl)-4-methylphenyl)-2,4,6-trimethylanilide) yields the phospha(thio)ureate complexes (PN)2La(OC(NPh)(PHMes)) (2) and (PN)2La(SC(NPh)(PHMes)) (3) with retention of the PH protons. Subsequent deprotonation of the phosphaureate complex 2 with potassium hexamethyldisilazide (KHMDS, K[N(SiMe3)2]) leads to the polymeric complex [K{(PN)2La(OC(NPh)(PMes))}]n (4). Complex 4 was found to be an excellent precursor for salt metathesis reactions with copper(I) and gold(I) chlorides supported by an N-heterocyclic carbene (NHC, 5 and 6) or a cyclic alkyl amino carbene (CAAC, 7 and 8). This resulted in the unprecedented formation of heterobimetallic lanthanum–coinage-metal complexes, containing the first example of a μ,κ2(O,N):κ1(P)-phosphaureate bridging ligand. For an alternative route to complex 8 a direct protonolysis protocol between a new basic gold(I) precursor, namely (MeCAAC)Au(HMDS), and 2 was also investigated. The complexes have been characterized by multinuclear NMR spectroscopy, IR spectroscopy, and X-ray crystallography (except for 8).

One‐Pot Generation of Benzynes from Phenols: Formation of Primary Anilines by the Deoxyamination of Phenols

Benzynes were selectively generated in-situ from phenols and trapped regioselectively by potassium hexamethyldisilazide to form primary anilines following acidic workup. The direct conversion of a phenolic hydroxyl group to a free amino group is a useful method for the preparation of primary aryl amines that are hard to synthesize using coupling reactions involving phenol derivatives with ammonia. While reactions of ortho - and meta -substituted phenols produced meta-substituted anilines exclusively, those of para -substituted phenols provided ortho -silylanilines.

Rearrangement of N-tert-Butanesulfinyl Enamines for Synthesis of Enantioenriched α-Hydroxy Ketone Derivatives.

Treating chiral N-tert-butanesulfinyl ketimines with potassium hexamethyldisilazide (or potassium tert-butoxide) and methyl triflate gives N-methylated N-tert-butanesulfinyl enamine intermediates that undergo stereoselective [2,3]-rearrangement to afford α-sulfenyloxy ketones with excellent enantiopurities. This cascade of enamination-N-methylation-rearrangement was even used to generate acyclic tertiary α-hydroxy ketones bearing two α-substituents showing negligible differences in bulkiness, such as methyl and ethyl groups.

Nucleophilic 5-endo-trig cyclization of 2-(trifluoromethyl)allylic metal enolates and enamides: Synthesis of tetrahydrofurans and pyrrolidines bearing exo-difluoromethylene units

Ketones and imines bearing a 2-(trifluoromethyl)allylic moiety successfully underwent nucleophilic 5-endo-trig cyclization via their metal enolates and enamides. O- or N-Cyclization proceeded exclusively in each case to afford the corresponding five-membered heterocycles with both exo-difluoromethylene and exo-alkylidene units. On treatment with potassium hexamethyldisilazide (KHMDS) or lithium diisopropylamide (LDA), 2-(trifluoromethyl)allylic ketones or imines provided the corresponding tetrahydrofurans or pyrrolidines bearing a Z-alkylidene group with perfect or substantial stereoselectivity, respectively.

Synthesis and Properties of Tribenzocarbazoles via an Acid-Promoted Retro (2+2)-Cycloaddition of Azapropellanes.

We describe herein the development of a new method to synthesize tribenzocarbazoles via an acid-promoted retro (2+2)-cycloaddition of azapropellanes, which were prepared by potassium hexamethyldisilazide (KHMDS)-promoted (2+2)-cycloaddition. The tribenzocarbazoles showed strong fluorescence both in solution and the solid state. The structural, electronic, and optical properties of the synthetic tribenzocarbazoles are also described.

An Improved Approach to the Direct Construction of 2-Deoxy-β-Linked Sugars: Applications to Oligosaccharide Synthesis.

A next-generation reagent-controlled approach for the synthesis of 2,6-dideoxy and 2,3,6-trideoxy sugar donors in good yield and high β-selectivity is reported. The use of p-toluenesulfonyl chloride and potassium hexamethyldisilazide (KHMDS) greatly simplifies deoxy-sugar glycoside construction, and can be used for gram-scale glycosylation reactions. The development of this approach and its application to the construction of β-linked deoxy-sugar oligosaccharides are described.

Nickel, Ruthenium, and Rhodium NCN-Pincer Complexes Featuring a Six-Membered N-Heterocyclic Carbene Central Moiety and Pyridyl Pendant Arms

NCN pincer ligand precursor 1·HX (X = Cl, PF6), having a six-membered N-heterocyclic carbene central moiety and pyridyl pendant arms, was prepared via N–C cross-coupling of 2-bromo-6-tert-butylpyridine with propane-1,3-diamine, followed by ring closure with triethylorthoformate. The free ligand 1 was not accessible via deprotonation, yet its copper(I) complex 2 was prepared by reacting 1·HCl with CuI and potassium hexamethyldisilazide. It was used further as a transmetalation agent to prepare nickel(II) and ruthenium(II) dihalide NCN-pincer complexes 3a, 4a, and 4b, featuring a distorted square-pyramidal geometry at the metal, with the carbene ligand in the axial position. The rhodium(III) NCN-pincer complex 6b was obtained from 2 and [Rh(cod)Cl]2 via transmetalation followed by oxidation with Cu(I) in THF. The rhodium(III) NCC-pincer complex 9b was prepared under similar conditions in acetonitrile, where a spontaneous rollover cyclometalation occurred. Complex 9b has a distorted octahedral geometry, with the acetonitrile ligand trans to the carbene. Very short Ru–CNHC and Rh–CNHC bonds were measured in complexes 4a, 4b, and 9b. Halogen exchange was observed by 1H and 13C NMR spectroscopy in both ruthenium and rhodium systems during the transmetalation stage, and the purification was accomplished by pushing the respective equilibrium with excess halide.

Borenium and boronium ions of 5,6-dihydro-dibenzo[c,e][1,2]azaborinine and the reaction with non-nucleophilic base: trapping of a dimer and a trimer of BN-phenanthryne by 4,4′-di-tert-butyl-2,2′-bipyridine

Abstract 6-Chloro-5,6-dihydro-dibenzo[c,e][1,2]azaborinine (1) reacts with pyridine derivatives to borenium or boronium ions. The boronium ion obtained from reaction with an excess of pyridine could be characterized structurally and transforms into the borenium ion in solution. The reaction of 1 with 2,2′-bipyridine (a) and derivatives (b: 6,6′-dimethyl; c: 4,4′-di-tert-butyl) results in spirocyclic boronium ions 8a–c of which 8b could be characterized by X-ray crystallography. Despite the chelate effect, the spirocyclic boronium ions readily undergo hydrolysis or alcoholysis. Treatment of the spirocyclic boronium ion 8c with potassium hexamethyl disilazide (KHMDS) results in neutral products that are monomers, dimers, or trimers of dibenzo[c,e][1,2]azaborinine (“BN-phenanthryne”) trapped with 4,4′-di-tert-butyl-2,2′-bipyridine by formation of B–C, B–N, or dative B–N bonds, indicative of deprotonation of NH and CH bonds of the boronium ion by KHMDS.

Synthesis and characterization of polymer linked copper(I) bis(N‐heterocyclic carbene) mechanocatalysts

ABSTRACTIn this paper, the synthesis and characterization of a series of latent polymeric bis(N‐heterocyclic carbene) (NHC) copper(I) complexes is reported, which can be activated for the copper(I)‐catalyzed azide/alkyne cycloaddition (CuAAC) via ultrasound. To prove the influence of chain length and nature of the polymer towards the activation, poly(isobutylene) (PIB), poly(styrene) (PS) and poly(tetrahydrofuran) (PTHF) are synthesized via living polymerization techniques (LCCP, ATRP, CROP) obtaining different chain lengths (from 2500 to 9000 g/mol), followed by quaternization with N‐methylimidazole, generating the corresponding N‐methylimidazolium‐telechelic polymers. The deprotonation of these macroligands via strong bases like sodium tert‐butoxide (NaOtBu) or potassium hexamethyldisilazide (KHMDS) yields the free N‐heterocyclic carbenes (NHCs), which are used to coordinate to tetrakis(acetonitrile)copper(I) hexafluorophosphate, forming the final polymer‐based mono‐ and bis(N‐methylimidazole‐2‐ylidene) copper(I)X complexes. The structural proof of these complexes is accomplished via 1H‐NMR spectroscopy, MALDI‐TOF‐MS and GPC‐techniques. The activation of the copper(I) biscarbene catalysts by ultrasound is studied by GPC, revealing the cleavage of one shielding NHC‐ligand. The initial catalytic latency and the via ultrasound introduced catalytic activation is successfully demonstrated monitoring a CuAAC “click” reaction of benzyl azide and phenylacetylene by in situ 1H‐NMR spectroscopy introducing thus “click” conversions up to 97%. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 3893–3907