Allylmagnesium Chloride Research Articles

Assessment of the strength of grignard reagent for the synthesis of secondary and tertiary alcohols of terpenes using metal plate flow reactor

The secondary and tertiary alcohols of terpenes were synthesized from aldehydes, and ketones using allyl magnesium chloride by the continuous metal flow reactor method. The flow process was conducted using metal plate reactors of 10 ml capacity in the presence of solvent mixtures, instead of large amounts of pure solvent like tetrahydrofuran. The products were isolated, and confirmed using gas chromatography and Nuclear magnetic resonance techniques respectively. Subsequently, the optimization studies were conducted to obtain mild, and economical reaction conditions, by varying the amount of allyl magnesium chloride, temperature, pressure, retention time, and flow rates. A comparison between batch processes and flow processes proved the advantages of the flow process in terms of reproducibility and product yield without the requirement of excess reagents compared to the batch process. The product yield was found to be excellent (60–97 %) and reproducible at (1–50) gram scale through flow process. The scope of the reaction was studied by synthesizing terpene alcohols using different carbonyl compounds at optimized reaction conditions, which resulted in high product yield. This research addresses a crucial gap in terpene alcohol synthesis, offering a scalable and environmentally friendly approach with broad applicability.

Synthesis and Magnetic Properties of Bis-Halobenzene Decamethyldysprosocenium Cations.

The decamethyldysprosocenium cation, [Dy(Cp*)2]+ (Cp* = {C5Me5}), was a target single-molecule magnet (SMM) prior to the isolation of larger dysprosocenium cations, which have recently shown magnetic memory effects up to 80 K. However, the relatively short Dy···Cp*centroid distances of [Dy(Cp*)2]+, together with the reduced resonance of its vibrational modes with electronic states compared to larger dysprosocenium cations, could lead to more favorable SMM behavior. Here, we report the synthesis and magnetic properties of a series of solvated adducts containing bis-halobenzene decamethyldysprosocenium cations, namely [Dy(Cp*)2(PhX-κ-X)2][Al{OC(CF3)3}4] (X = F or Cl) and [Dy(Cp*)2(C6H4F2-κ2-F,F)(C6H4F2-κ-F)][Al{OC(CF3)3}4]. These complexes were prepared by the sequential reaction of [Dy(Cp*)2(μ-BH4)]∞ with allylmagnesium chloride and [NEt3H][Al{OC(CF3)3}4], followed by recrystallization from parent halobenzenes. The complexes were characterized by powder and single crystal X-ray diffraction, NMR and ATR-IR spectroscopy, elemental analysis, and SQUID magnetometry; experimental data were rationalized by a combination of density functional theory and ab initio calculations. We find that bis-halobenzene adducts of the [Dy(Cp*)2]+ cation exhibit highly bent Cp*···Dy···Cp* angles; these cations are also susceptible to decomposition by C-X (X = F, Cl, Br) activation and displacement of halobenzenes by O-donor ligands. The effective energy barrier to reversal of magnetization measured for [Dy(Cp*)2(PhF-κ-F)2][Al{OC(CF3)3}4] (930(6) cm-1) sets a new record for SMMs containing {Dy(Cp*)2} fragments, though all SMM parameters are lower than would be predicted for an isolated [Dy(Cp*)2]+ cation, as expected due to transverse ligand fields introduced by halobenzenes and the large deviation of the Cp*···Dy···Cp* angle from linearity promoting magnetic relaxation.

Comparison of group 4 and thorium M(IV) substituted cyclopentadienyl silanide complexes.

We report the synthesis and characterisation of a series of M(IV) substituted cyclopentadienyl hypersilanide complexes of the general formula [M(CpR)2{Si(SiMe3)3}(X)] (M = Hf, Th; CpR = Cp', {C5H4(SiMe3)} or Cp'', {C5H3(SiMe3)2-1,3}; X = Cl, C3H5). The separate salt metathesis reactions of [M(CpR)2(Cl)2] (M = Zr or Hf, CpR = Cp'; M = Hf or Th, CpR = Cp'') with equimolar K{Si(SiMe3)3} gave the respective mono-silanide complexes [M(Cp')2{Si(SiMe3)3}(Cl)] (M = Zr, 1; Hf, 2), [Hf(Cp'')(Cp'){Si(SiMe3)3}(Cl)] (3) and [Th(Cp'')2{Si(SiMe3)3}(Cl)] (4), with only a trace amount of 3 presumably formed via silatropic and sigmatropic shifts; the synthesis of 1 from [Zr(Cp')2(Cl)2] and Li{Si(SiMe3)3} has been reported previously. The salt elimination reaction of 2 with one equivalent of allylmagnesium chloride gave [Hf(Cp')2{Si(SiMe3)3}(η3-C3H5)] (5), whilst the corresponding reaction of 2 with equimolar benzyl potassium yielded [Hf(Cp')2(CH2Ph)2] (6) together with a mixture of other products, with elimination of both KCl and K{Si(SiMe3)3}. Attempts to prepare isolated [M(CpR)2{Si(SiMe3)3}]+ cations from 4 or 5 by standard abstraction methodologies were unsuccessful. The reduction of 4 with KC8 gave the known Th(III) complex, [Th(Cp'')3]. Complexes 2-6 were characterised by single crystal XRD, whilst 2, 4 and 5 were additionally characterised by 1H, 13C{1H} and 29Si{1H} NMR spectroscopy, ATR-IR spectroscopy and elemental analysis. In order to probe differences in M(IV)-Si bonds for d- and f-block metals we studied the electronic structures of 1-5 by density functional theory calculations, showing M-Si bonds of similar covalency for Zr(IV) and Hf(IV), and less covalent M-Si bonds for Th(IV).

Synthesis of heterocyclic enamine-zinc complexes as precursors of stereocontrolled substitution of nitrogen α-position

In the presence of ZnCl2, chiral protected amino-ketones and amino-aldehydes gave zinc enamino-complexes. Both enamine and iminium structures of these complexes were observed in 1H and 13C NMR spectra depending on the solvent. Introduction of either an allyl or a hydrogen substituent was performed using allylmagnesium chloride or NaBH4 in excess leading to various heterocycles. With the amino-ketones diastereoselectivity (de = 50) was observed respectively. Homoconiine and coniine precursors were prepared by this strategy.

A Bridging bis-Allyl Titanium Complex: Mechanistic Insights into the Electronic Structure and Reactivity.

Treatment of the dinuclear compound [{Ti(η5-C5Me5)Cl2}2(μ-O)] with allylmagnesium chloride provides the formation of the allyltitanium(III) derivative [{Ti(η5-C5Me5)(μ-C3H5)}2(μ-O)] (1), structurally identified by single-crystal X-ray analysis. Density functional theory (DFT) calculations confirm that the electronic structure of 1 is a singlet state, and the molecular orbital analysis, along with the short Ti-Ti distance, reveal the presence of a metal-metal single bond between the two Ti(III) centers. Complex 1 reacts rapidly with organic azides, RN3 (R = Ph, SiMe3), to yield the allyl μ-imido derivatives [{Ti(η5-C5Me5)(CH2CH═CH2)2}2(μ-NR)(μ-O)] [R = Ph(2), SiMe3(3)] along with molecular nitrogen release. Reaction of 2 and 3 with H2 leads to the μ-imido propyl species [{Ti(η5-C5Me5)(CH2CH2CH3)2}2(μ-NR)(μ-O)] [R = Ph(4), SiMe3(5)]. Theoretical calculations were used to gain insight into the hydrogenation mechanism of complex 3 and rationalize the lower reactivity of 2. Initially, the μ-imido bridging group in these complexes activates the H2 molecule via addition to the Ti-N bonds. Subsequently, the titanium hydride intermediates induce a change in hapticity of the allyl ligands, and the nucleophilic attack of the hydride to the allyl groups leads to metallacyclopropane intermediates. Finally, the proton transfer from the amido group to the metallacyclopropane moieties affords the propyl complexes 4 and 5.

η3-Allyl Coordination at Pb(II)

Allylmagnesium chloride and methyl-propenyl-magnesium bromide were reacted with bulky substituted organolead and organotin halides (Ar*PbBr)2, (Ar′PbBr)2, (Ar*SnCl)2 (Ar* = 2,6-trip2C6H3-, trip = 2,4,6-triisopropylphenyl, Ar′ = 2,6-mes2C6H3-, mes = 2,4,6-trimethylphenyl). The allyl ligand coordinates in an η3-coordination mode at organoplumbylene fragments. In the solid state as well as in solution, η3-coordination was characterized by crystal structure analysis and Saunders’ isotopic perturbation technique. For the plumbylene Ar*Pb(C3H5), a solid state 207Pb magic angle spinning (MAS) NMR spectrum could be obtained. The isotropic chemical shift is −435 ppm, and the magnitude of the 207Pb chemical shift tensor of 7000(500) ppm is among the greatest observed experimentally. The methylallyl ligand coordinated at a plumbylene fragment exhibits two short and one long Pb–C interaction. In reaction with aniline, the allyl ligand reacts as a leaving group to give amidoplumbylenes.

An Effective Route to Dinuclear Niobium and Tantalum Imido Complexes.

Thermal treatment of the trichloro complexes [MCl3(NR)py2] (R = tBu, Xyl; M = Nb, Ta) (Xyl = 2,6-Me2C6H3) under vacuum affords the dinuclear imido species [MCl2(μ-Cl)(NR)py]2 (R = tBu, Xyl; M = Nb 1, 3; Ta 2, 4) with loss of pyridine. Complexes 1-4 can be easily transformed to the mononuclear starting materials [MCl3(NR)py2] (R = tBu, Xyl; M = Nb, Ta) upon reaction with pyridine. While reactions of compounds 1 and 2 with a series of alkylating reagents render the mononuclear peralkylated imido complexes [MR3(NtBu)] (R = Me, CH2Ph, CH2CMe3, CH2CMePh, CH2SiMe3), the analogous treatment with allylmagnesium chloride results in the formation of the dinuclear niobium(IV) derivative [(NtBu)(η3-C3H5)M(μ-C3H5)(μ-Cl)2M(NtBu)py2] (5). Additionally, the treatment of the starting materials 1 and 2 with the organosilicon reductant 1,4-bis(trimethylsilyl)-1,4-diaza-2,5-cyclohexadiene yields the pyridyl-bridged dinuclear derivatives [M2Cl2(μ-Cl)2(NtBu)2py2]2(μ-NC4H4N)2 (M = Nb 6, Ta 7). Controlled hydrolysis reaction of 1 and 2 affords the oxo chlorido-bridged products [MCl(μ-Cl)(NtBu)py]2(μ-O) (M = Nb 8, Ta 9) in a quantitative way, while the treatment of these latter with one more equivalent of pyridine led to complexes [MCl2(NtBu)py2]2(μ-O) (M = Nb 10, Ta 11). Structural study of these dinuclear imido derivatives has been also performed by X-ray crystallography.

Synthesis and reductive chemistry of bimetallic and trimetallic rare-earth metallocene hydrides with (C5H4SiMe3)1− ligands

The reductive chemistry of [Cp'2Ln(μ–H)(THF)x]y [Ln = Y, Dy, Tb; Cp' = (C5H4SiMe3)1−; x = 2, 0 and y = 2, 3] was examined to determine if these hydrides would be viable precursors for 4fn5d1 Ln2+ ions that could form 5d1-5d1 metal–metal bonded complexes. The hydrides were prepared by reaction of the chlorides, [Cp'2Ln(μ–Cl)]2, 1-Ln, with allylmagnesium chloride to form the allyl complexes, [Cp'2Y(η3–C3H5)(THF)], 2-Ln, which were hydrogenolyzed. The solvent-free reaction of solid 2-Ln with 60 psi of H2 gas in a Fischer-Porter apparatus produced, in the Y case, the trimetallic species, [Cp'2Y(μ–H)]3, 3-Y, and in the Dy and Tb cases, the bimetallic complexes [Cp'2Ln(μ–H)(THF)]2, 4-Ln (Ln = Dy, Tb). The latter complexes could be converted to 3-Dy and 3-Tb by heating under vacuum. Isopiestic data indicate that 3-Y solvates to 4-Y in THF. Reductions of 4-Y, 4-Dy, and 4-Tb with KC8 in the presence of a chelate such as 2.2.2-cryptand or 18-crown-6 all gave reaction products with intense dark colors characteristic of Ln2+ ions. In the yttrium case, with either chelating agent, the dark green product gives a rhombic EPR spectrum (g1 = 2.01, g2 = 1.99, g3 = 1.98, A = 24.1 G) at 77 K. However, the only crystallographically-characterizable products obtainable from these solutions were Ln3+ polyhydride anion complexes of composition, [K(chelate)]{[Cp'2Ln(μ–H)]3(μ–H)}. Reduction of 1-Y with KC8 in the presence of 2.2.2-cryptand also yields an intensely colored product with an axial EPR spectrum (gx = gy = 2.05, Ax = Ay = 35.5 G; gz = 2.07, Az = 34.5) similar to that of (Cp'3Y)1− ion, but crystals were not obtained from this system.

Synthesis of a New Odourant, 2-Mercapto-4-Heptanol

2-Mercapto-4-heptanol is a relatively new flavour compound that was recently approved as an ingredient by the Flavour and Extract Manufacturers’ Association in 2013. Its synthesis, which we have accomplished in four-steps, involved firstly a Grignard reaction of n-butanal with allylmagnesium chloride to prepare 1-hepten-4-ol. This was epoxidised and then converted to 1,2-epithio-4-heptanol, reduction of which with LiAlH4 gave the target compound in an overall yield of about 54%.

Highly Stereoselective Nucleophilic Addition of Difluoromethyl‐2‐pyridyl Sulfone to Sugar Lactones and Efficient Synthesis of Fluorinated 2‐Ketoses

AbstractNucleophilic addition of difluoromethyl‐2‐pyridyl sulfone to sugar lactones proceeded with good yield and excellent stereoselectivity. The hitherto unknown direct addition intermediates are stable and capable of useful conversions: Formal elimination of the anomeric hydroxy and sulfonyl groups yielded a 1‐deoxy‐1‐difluoromethylene mannopyranose derivative. Directly from sugar lactones, by nucleophilic addition and subsequent one‐pot reduction with allylmagnesium chloride, unprecedented fluorinated 2‐ketose analogues were prepared efficiently.

Steric Factors in the Single‐Electron Transfer Carbolithiation and Transannular Reduction of 6,12‐Diphenyldibenzo[b,f]­[1,5]­diazocine by Organolithium Reagents

AbstractThe puckered tricyclic heterocycle 6,12‐diphenyldibenzo[b,f][1,5]diazocine, a novel probe for revealing single‐electron transfer (SET) reactions, is here employed as a model substrate for investigating the carbolithiation of imines and the stereochemistry, the regiochemistry, and the electronic nature (polar or SET) of such R–Li additions. The chemical behavior of the following organolithium reagents (mainly in THF) toward the diazocine was studied: benzyl‐, methyl‐, phenyl‐, n‐butyl‐, and phenylethynyllithiums, as well as the reactive allylmagnesium chloride and the typical tert‐butylmagnesium chloride. The only reagent that failed to carbometalate or to reduce the diazocine transannularly was phenylethynyllithium. The tert‐butyl Grignard reagent could not carbometalate but did reduce the diazocine with photocatalysis. The other five organometallics yielded both carbometalation of the diazocine and, upon hydrolysis, transannular SET reduction to 4b,9b‐diphenyl‐4b,5,9b,10‐tetrahydroindolo[3,2‐b]indole (“indoloindole”) in varying proportions. Three types of carbometalation products were observed in such hydrolyzed reactions: (1) exo‐1,2‐addition to a C=N bond by C6H5CH2Li, H2C=CHCH2MgCl, and CH3Li, as established by spectral and XRD data; (2) 1,4‐addition to the ortho‐phenyl carbon Co=C‐C=N linkage by phenyllithium with the subsequent elimination of LiH; and (3) 1,4‐addition, as in type 2, by n‐butyllithium but without the elimination of LiH. The foregoing modes of reactivity, the concomitant formation of the telltale SET reduction product, “indoloindole”, and the failure of PhC≡CLi to react at all with the diazocine are marshaled to support the conclusion that the organometallics reacting with the diazocine, by carbometalation and by transannular reduction, do so by SET processes and not by straightforward nucleophilic attack. The relative stabilities of sp3‐, sp2‐, and sp‐hybridized carbon radicals possibly involved were assessed in concluding that PhC≡CLi is incapable of reacting through any SET pathway.

RCM Approach to Complex Polycyclic α‐Hydroxy γ‐Lactams: Synthesis of Indolizinones and Pyrroloazepinones

AbstractThe allylmagnesium chloride addition/RCM sequence on N‐alkenyl‐substituted imides provides a mild access to indolizinone and pyrroloazepinone derivatives with the α‐hydroxy‐γ‐lactam framework. The procedure can be applied to the asymmetric synthesis of this type of derivatives, by employing a 2‐exo‐hydroxy‐10‐bornylsulfinyl group as a chiral auxiliary. Further functionality can be introduced at the angular position through an α‐amidoalkylation reaction.

Half-sandwich rare-earth-metal derivatives bearing pyrrolidinyl-functionalized cyclopentadienyl ligand: synthesis, characterization and catalysis in syndiospecific polymerization of styrene

One-pot reaction of LnCl3 with 1 equivalent of C5Me4SiMe2NC4H8Li followed by addition of 2 equivalents of allylmagnesium chloride C3H5MgCl or LiN(SiHMe2)2 in THF at room temperature afforded the half-sandwich rare-earth-metal bis(η3-allyl) complexes (C5Me4SiMe2NC4H8)Ln(η3-C3H5)2 (Ln = Sc (1), Y (2), Lu (3)) and the half-sandwich rare-earth-metal bis(silylamide) complexes (C5Me4SiMe2NC4H8)Ln[N(SiHMe2)2]2 (Ln = Sc (4), Y (5), Lu (6)), respectively. All these complexes were well-characterized by elemental analysis, FT-IR spectroscopy, NMR spectroscopy and X-ray crystallography. The binary catalyst systems 1–3/[Ph3C][B(C6F5)4] and the ternary catalyst systems 1–6/[Ph3C][B(C6F5)4]/AliBu3 in toluene at room temperature showed activity toward the syndiospecific polymerization of styrene.

Monitoring and Control of a Continuous Grignard Reaction for the Synthesis of an Active Pharmaceutical Ingredient Intermediate Using Inline NIR spectroscopy

Inline near-infrared (NIR) spectroscopy has been used to monitor a continuous synthesis of an active pharmaceutical ingredient (API) intermediate by a Grignard alkylation reaction. The reaction between a ketone substrate and allylmagnesium chloride may form significant impurities with excess feeding of the Grignard reagent beyond the stoichiometric ratio. On the other hand, limiting this reagent would imply a loss in yield. Therefore, accurate dosing of the two reactants is essential. A feedforward–feedback control loop was conceived in order to maintain the reaction as closely as possible to the stoichiometric ratio, leading the path to full process automation. The feedback control loop relies on NIR transmission measurements performed in a flow cell where, in contrast to labor-intensive offline HPLC analytical methods, the whole reaction product can be scanned in real time without sample dilution. A robust PLS (projection to latent structures) model was developed with a satisfactory standard error of pr...

Design and operation of a filter reactor for continuous production of a selected pharmaceutical intermediate

A novel filter reactor system for continuous production of selected pharmaceutical intermediates is presented and experimentally verified. The filter reactor system consists of a mixed flow reactor equipped with a bottom filter, to retain solid reactant particles, followed by a conventional plug flow reactor, where residual reactant is converted by titration. A chemical case study, production of the pharmaceutical intermediate allylcarbinol by a reaction between allylmagnesium chloride and 2-chloro-thioxanthone, in the presence of a side reaction is considered. The synthesis is conducted in tetrahydrofuran solvent. The use of the filter reactor design was explored by examining the transferability of a synthesis step in a present full-scale semi-batch pharmaceutical production into continuous processing. The main advantages of the new continuous minireactor system, compared to the conventional semi-batch operation, are reduced impurity formation and the use of much lower reactor volumes (factor of 1000 based on the laboratory reactor) and less solvent consumption (from 5.8 to 2.3L/kg reactant). Added challenges include handling of continuous solid powder feeding, stable pumping of reactive slurries, and a possibility of continuous control.

ChemInform Abstract: The Synthesis of Some Carbohydrate-Derived Precursors to Tylonolide, the Aglycon of the Antibiotic Tylosin.

Treatment of methyl 2,3-anhydro-4,6-O-benzylidene-α-D-alloside with the anion derived from trimethyl(prop-1-ynyl)silane, allylmagnesium chloride or isobutenylmagnesium chloride introduces a three- or four- carbon substituent at C2 of the sugar. In each case, a hydroboration-oxidation sequence helps convert the centre of unsaturation in the new substituent into a carboxylic acid residue. Subsequent manipulations allow the introduction ofanother carbon at C6 of the sugar to give a highly functionalized precursor to the C1-C9 fragment of tylonolide, the aglycon of the antibiotic tylosin. Attempts at the introduction of an axial methyl group at C4 of the extended sugar also described.

Synthesis, Structure, and Density Functional Theory Analysis of a Scandium Dinitrogen Complex, [(C5Me4H)2Sc]2(μ-η2:η2-N2)

Investigation of the bis(tetramethylcyclopentadienyl) metallocene chemistry of scandium has revealed that the method involving reduction of trivalent salts with alkali metals used with lanthanides can also be applied to scandium to make a dinitrogen complex of the first member of the transition metal series. ScCl(3) reacts with 2 equiv of KC(5)Me(4)H to form (C(5)Me(4)H)(2)ScCl(THF), 1, which reacts with allylmagnesium chloride to make (C(5)Me(4)H)(2)Sc(eta(3)-C(3)H(5)), 2. Complex 2 reacts with [HNEt(3)][BPh(4)] to yield [(C(5)Me(4)H)(2)Sc][(mu-Ph)BPh(3)], 3, which has just one primary Sc-C(phenyl) contact connecting the tetraphenylborate anion and the metallocene cation. Treatment of 3 with KC(8) in THF under N(2) generates [(C(5)Me(4)H)(2)Sc](2)(mu-eta(2):eta(2)-N(2)), which has a coplanar arrangement of scandium and nitrogen atoms within a square planar array of tetramethylcyclopentadienyl rings. Density functional calculations explain the bonding that results in the 1.239(3) A N-N bond distance in the (N=N)(2-) moiety.

Stereo-controlled approach to pyrrolidine iminosugar C-glycosides and 1,4-dideoxy-1,4-imino- l-allitol using a d-mannose-derived cyclic nitrone

Intramolecular N-alkylation of 2,3- O-isopropylidene-5- O-methanesulfonyl-6- O- t-butyldimethylsilyl- d-mannofuranose-oxime 7 afforded a five-membered cyclic nitrone 9, which on N– O bond reductive cleavage followed by deprotection of –OTBS and acetonide functionalities gave 1,4-dideoxy-1,4-imino- l-allitol (DIA) 3. Addition of allylmagnesium chloride to nitrone 9 afforded α-allylated product 10a in high diastereoselectivity providing an easy entry to N-hydroxy-C1-α-allyl-substituted pyrrolidine iminosugar 4a after removal of protecting group, while N– O bond reductive cleavage in 10a afforded C1-α-allyl-pyrrolidine iminosugar 4b.

An Efficient Double 1,2-Addition Reaction of 2,3-Allenoates with Allyl Magnesium Chloride

In this paper, it was reported that double 1,2-addition reaction of 2,3-allenoates with allyl magnesium chloride at room temperature in the absence of any transition metal catalyst provides an efficient method for the synthesis of tertiary alpha-allenols. The optically active allenol could be prepared from the reaction of the optically active 2,3-allenoate without obvious racemization of the axial chirality. Under different reaction conditions, cyclization reactions of alpha-allenol 2i prepared have been studied for the synthesis of different 2,5-dihydrofuran derivatives.

A Stereoselective Approach for the Total Synthesis of Clonostachydiol

A stereoselective synthesis of clonostachydiol is accomplished using readily available (±)-epichlorohydrin as a precursor. The synthesis involves direct and straightforward reactions such as Sharpless asymmetric epoxidation, iodination, stereoselective opening of epoxide with allylmagnesium chloride and Sharpless asymmetric dihydroxylation.