Lithium Aluminum Deuteride Research Articles

Synthesis of Tris[2‐(dimethylamino)ethyl]amine with Regiospecific Deuterium Labels

AbstractSimple synthetic routes to regioselectively deuterated tris[2‐(dimethylamino)ethyl]amine (Me6TREN) variants are described. Imine formation with formaldehyde‐d2 from tris(2‐aminoethyl)amine (TREN) and subsequent reductions with NaBD4 afforded N[CH2CH2N(CD3)2]3 or d18‐Me6TREN in 79 % yield. A trisubstitution protocol from 2‐bromo‐N,N‐dimethylacetamide and ammonium carbonate and subsequent reduction of the N(CH2CONMe2)3 intermediate by lithium aluminum deuteride has afforded N[CH2CD2N(CH3)2]3 or (d6‐arm)‐Me6TREN in three steps and 52 % overall yield. A similar protocol from 2‐bromo‐N,N‐dimethyl‐d2‐acetamide, obtained in two steps from d4‐acetic acid, with reduction of the N(CD2CONMe2)3 intermediate by lithium aluminum hydride has afforded N[CD2CH2N(CH3)2]3 or (d6‐cap)‐Me6TREN in four steps and 13 % overall yield from CD3COOD.

Reaction of 11 C-benzoyl chlorides with metalloid reagents: 11 C-labeling of benzyl alcohols, benzaldehydes, and phenyl ketones from [11 C]CO.

In this article, we describe the carbon-11 (11 C, t1/2 =20.4minutes) labeling of benzyl alcohols, benzaldehydes, and ketones using an efficient 2-step synthesis in which 11 C-carbon monoxide is used in an initial palladium-mediated reaction to produce 11 C-benzoyl chloride as a key intermediate. In the second step, the obtained 11 C-benzoyl chloride is further treated with a metalloid reagent to furnish the final 11 C-labeled product. Benzyl alcohols were obtained in moderated to high non-isolated radiochemical yields (RCY, 35%-90%) with lithium aluminum hydride or lithium aluminum deuteride as metalloid reagent. Changing the metalloid reagent to either tributyltin hydride or sodium borohydride, allowed for the reliable syntheses of 11 C-benzaldehydes in RCYs ranging from 58% to 95%. Finally, sodium tetraphenylborate were utilized to obtain 11 C-phenyl ketones in high RCYs (77%-95%). The developed method provides a new and efficient route to 3 different classes of compounds starting from aryl iodides or aryl bromides.

Expeditious syntheses of stable and radioactive isotope‐labeled anticonvulsant agent, JNJ‐26990990, and its metabolites

Syntheses of stable and radioactive isotope-labeled anticonvulsant agent, JNJ-26990990, that is, N-(benzo[b]thien-3-ylmethyl)-sulfamide and its metabolites are described. [(13)C(15)N]Benzo[b]thiophene-3-carbonitrile was first prepared by coupling of 3-bromo-benzo[b]thiophene with [(13)C(15)N]-copper cyanide. The resultant [(13)C(15)N]benzo[b]thiophene-3-carbonitrile was reduced with lithium aluminum deuteride to give [(13)CD2(15)N]benzo[b]thiophen-3-yl-methylamine; which was then coupled with sulfamide to afford [(13)CD2(15)N]-N-(benzo[b]thien-3-ylmethyl)-sulfamide, the stable isotope-labeled compound with four stable isotope atoms. Direct oxidation of [(13)CD2(15)N]-N-(benzo[b]thien-3-ylmethyl)-sulfamide with hydrogen peroxide and peracetic acid gave the stable isotope-labeled sulfoxide and sulfone metabolites. On the other hand, radioactive (14)C-labeled N-(benzo[b]thien-3-ylmethyl)-sulfamide was prepared conveniently by sequential coupling of 3-bromo-benzo[b]thiophene with [(14)C]-copper cyanide, reduction of the carbonitrile to carboxaldehyde, and reductive amination with sulfamide.

Identification of di- and tri-substituted hydroxy and ketone metabolites of delta1-tetrahydrocannabinol in mouse liver.

In vivo liver metabolites of delta1-tetrahydrocannabinol (delta1-THC) were examined with a gas chromatograph--mass spectrometer--computer system as trimethylsilyl (TMS), [2H9]TMS and methyloxime-TMS derivatives. In addition to the reported monohydroxy, acid, and hydroxyacid metabolites, the following multiply substituted metabolites were identified: 2'',7-, 3'', 7-, and 6beta,7-dihydroxy-delta1-THC; 2'',6alpha,7-, and 3'',6alpha,7-trihydroxy-delta1-THC; 2''-, 3''-, and 7-hydroxy-6-oxo-delta1-THC, and 2'',7- and 3'',7-dihydroxy-6-oxo-delta1-THC. The ketones and hydroxyacids were reduced to common alcohols with lithium aluminium deuteride and the number of deuterium atoms in the product was used to distinguish the metabolic alcohols from those produced by reduction.

Synthesis of deuterium-labeled analogs of the lipid hydroperoxide-derived bifunctional electrophile 4-oxo-2(E)-nonenal.

Lipid hydroperoxides undergo homolytic decomposition into the bifunctional 4-hydroxy-2(E)-nonenal and 4-oxo-2(E)-nonenal (ONE). These bifunctional electrophiles are highly reactive and can readily modify intracellular molecules including glutathione (GSH), deoxyribonucleic acid (DNA) and proteins. Lipid hydroperoxide-derived bifunctional electrophiles are thought to contribute to the pathogenesis of a number of diseases. ONE is an α,β-unsaturated aldehyde that can react in multiple ways and with glutathione, proteins and DNA. Heavy isotope-labeled analogs of ONE are not readily available for conducting mechanistic studies or for use as internal standards in mass spectrometry (MS)-based assays. An efficient onestep cost-effective method has been developed for the preparation of C-9 deuterium-labeled ONE. In addition, a method for specific deuterium labeling of ONE at C-2, C-3 or both C-2 and C-3 has been developed. This latter method involved the selective reduction of an intermediate alkyne either by lithium aluminum hydride or lithium aluminum deuteride and quenching with water or deuterium oxide. The availability of these heavy isotope analogs will be useful as internal standards for quantitative studies employing MS and for conducting mechanistic studies of complex interactions between ONE and DNA bases as well as between ONE and proximal amino acid residues in peptides and proteins.

Synthesis of deuterium‐labeled (24R)‐methyl brassinosteroids

AbstractSynthesis of labeled brassinosteroids (24‐epibrassinolide and its biosynthetic precursors) containing three deuterium atoms in the terminal part of the side chain is reported. Labeling was achieved by three‐step reductive transformation of carbethoxy group into methyl using lithium aluminium deuteride. The proposed method ensured high isotopic purity of (24R)‐methyl brassinosteroids containing a label in a position which is not subjected to its loss. Copyright © 2011 John Wiley & Sons, Ltd.

Microwave‐accelerated synthesis of psychoactive deuterated N,N‐dialkylated‐[α,α,β,β‐d4]‐tryptamines

AbstractA large number of N,N‐dialkylated tryptamines are known to induce psychoactive effects in humans. This has resulted in their increased attention within clinical and forensic communities. Deuterated tryptamines are ideal for use as internal standards during MS bioanalysis or of use in biochemical NMR studies. The present study reports on a microwave‐enhanced synthesis of 22 N,N‐dialkylated‐[α,α,β,β‐d4]‐tryptamines via the reduction with lithium aluminium deuteride of glyoxalylamide precursors obtained by the procedure of Speeter and Anthony. Syntheses were carried out using a single‐mode system under elevated pressure conditions where anhydrous tetrahydrofuran was used as the solvent at 150°C. Good yields were obtained within 5 min. Copyright © 2008 John Wiley & Sons, Ltd.

Convenient synthesis of deuterated aluminium hydrides

We describe the ball-milling synthesis of alkali metal deuterides from commercial lithium aluminium deuteride. This reaction principle was exemplified by the mechanochemical synthesis of NaAlD 4 and KAlD 4 . NaAlD 4 was prepared on the multi-gram scale by this procedure and purified by standard wet-chemical separation. Pure NaAlD 4 was obtained and used for the synthesis of Ca(AlD 4 ) 2 . The formation of all products was verified by X-ray diffraction.

Preparation of 6,6,1′,1′,6′,6′-hexadeutero sucrose

The preparation of 6,6,1′,1′,6′,6′-hexadeutero sucrose is reported. The synthesis is based on a triple oxidation of a protected sucrose 6,1′,6′-triol to the corresponding 6,1′,6′-tricarboxylic acid or ester, followed by reduction with lithium aluminium deuteride. This triple oxidation could be achieved either using cat. TEMPO–NaOCl (to the acid) or PDC–Ac 2O– t-BuOH (to the t-butyl carboxylic ester).

Synthesis of [19- [formula omitted]]-analogs of dehydroepiandrosterone and pregnenolone and their sulfates

Deuterated analogs of pregnenolone and pregnenolone sulfate with three atoms of deuterium in position 19 were prepared. The synthetic approach was developed on derivatives of dehydroepiandrosterone, where initial intermediates were well characterized, and then applied to the pregnenolone series. Starting 19-hydroxy compounds were transformed into 3α,5-cycloderivatives to simplify the Jones oxidation into the corresponding 19-oic acids. After oxidation, rearrangement to 3-hydroxy-5-enes, and suitable protection, two deuterium atoms were introduced by lithium aluminum deuteride reduction. Mesylate exchange by iodide in the presence of zinc and deuterium oxide added third deuterium atom. Deprotection gave title analogs with about 93–95% content of d 3-derivative, the rest was mainly not fully deuterated d 2-analogue as followed from the mass spectra analysis. Thus, 3β-hydroxy[19- 2 H 3 ]androst-5-en-17-one was prepared in 14 steps from 19-hydroxy-17-oxoandrost-5-en-3β-yl acetate in 8.9% yield, the analogous sequence in the pregnenolone series gave 3β-hydroxy[19- 2 H 3 ]pregn-5-en-20-one in 7.3% yield. Corresponding sulfates were prepared via pyridinium salts in 53 and 57% yields, respectively. Fully assigned NMR data of selected pregnenolone derivatives were given.

Synthesis of [26-2H(3)]brassinosteroids.

A number of [26-2H(3)]brassinosteroids were prepared for biochemical studies. The parent, nondeuterated compounds were considered to be biosynthetic intermediates in brassinosteroid biosynthesis. Claisen rearrangement was used to construct the steroidal side chain. Deuterium was introduced by reducing the corresponding intermediates with lithium aluminium deuteride.

Quantitative determination of sulfur containing wine odorants at sub-ppb levels. 1. Synthesis of the deuterated analogues.

[2H10]-4-Sulfanyl-4-methylpentan-2-one (d10-SMP), [2H2]-3-sulfanylhexan-1-ol (d2-3SH), and [2H5]-3-sulfanylhexyl acetate (d5-3SHAc), the labeled analogues of impact odorants of wines and other foods, were synthesized to be used for the quantitative determination of the natural compounds in white and red wines by stable isotope dilution assay. The sulfidation was achieved by Michael addition, on mesityl oxide or ethyl hex-2-enoate, respectively, of the sulfhydryl anion generated in situ from triphenylsilanethiol and potassium fluoride under phase transfer conditions. The labeling of 4-sulfanyl-4-methylpentan-2-one (SMP) was obtained from the commercial starting material, [2H6]acetone, so that this method could be used to synthesize 13C-labeled SMP from 13C-labeled acetone. The labeling of 3-sulfanylhexan-1-ol (3SH) and 3-sulfanylhexyl acetate (3SHAc) was obtained from reduction with lithium aluminum deuteride of the Michael adduct ethyl 3-sulfanylhexanoate and [2H3]-acetylation. During the synthesis, 3SH and 3SHAc were partially oxidized to their disulfide, which were reduced back to the thiols by an additional reduction step; the tertiary thiol SMP was less sensitive to this oxidation.

Synthesis of trans-4,5-epoxy-(E)-2-decenal and its deuterated analog used for the development of a sensitive and selective quantification method based on isotope dilution assay with negative chemical ionization.

The volatile compound trans-4,5-epoxy-(E)-2-decenal (1) was synthesized in two steps with good overall yields. The newly developed method is based on trans-epoxidation of (E)-2-octenal with alkaline hydrogen peroxide followed by a Wittig-type chain elongation with the ylide formylmethylene triphenylphosphorane. For the synthesis of [4,5-2H2]-trans-4,5-epoxy-(E)-2-decenal (d-1), [2,3-2H2]-(E)-2-octenal was prepared by reduction of 2-octyn-1-ol with lithium aluminum deuteride and subsequent oxidation of [2,3-2H2]-(E)-2-octen-1-ol with manganese oxide. Compound d1 was used as internal standard for the quantification of 1 by isotope dilution assay. Among various mass spectrometry (MS) ionization techniques tested, negative chemical ionization with ammonia as reagent gas gave best results with respect to both sensitivity and selectivity. The detection limit was found to be at about 1 pg of the analyte introduced into the gas chromatography-MS system.

ChemInform Abstract: Reactions of Saturated and Unsaturated Tertiary Alkyl Halides and Saturated Secondary Alkyl Iodides with Lithium Aluminum Deuteride. Convincing Evidence for a Single‐Electron‐Transfer Pathway.

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Insect Desaturases as Unique Analytical Tools To Unravel the Stereochemical Course of the Reduction of Vicinal Ditosylates with Lithium Aluminum Deuteride

Care is advisable in the reduction of vicinal sulfonate esters with LiAlD4, since the reaction takes an unexpected stereochemical course: whereas in the substitiution of one of the tosylate (Ts) groups an inversion of configuration at the C atom occurs, the other is substituted with retention of configuration. The latter can best be explained by a double inversion with participation of the neighboring group (see scheme). Ts= toluene-4-sulfonyl.

Convenient Labeling of Sterols with Eight Deuterium Atoms :

For quantitative and metabolic examination of sitosterol in plants, deuterio-labeled sitosterol and related steroids were synthesized from stigmasterol. The base-catalyzed enolization of a 3, 6-diketone group and reduction of the diketone with lithium aluminum deuteride were conducted as key reactions for the introduction of deuterium atoms into the steroidal A/B-ring. [2, 2, 3, 4, 4, 6, 7, 7-2H8] Sitosterol was obtained at 89% isotopic purity. The present labeling method for introducing eight deuterium atoms would appear, based on the present results, to be applicable to other sterols. Possible biosynthetic intermediate steroids from sitosterol to sitostanol were also prepared in deuterio-labeled form.

Reactions of Saturated and Unsaturated Tertiary Alkyl Halides and Saturated Secondary Alkyl Iodides with Lithium Aluminum Deuteride. Convincing Evidence for a Single-Electron-Transfer Pathway

Reactions of saturated secondary and tertiary alkyl halides with LiAlH4 (LAH) and LiAlD4 (LAD) have been carried out, and convincing evidence for a single-electron-transfer (SET) pathway has been obtained. Reactions involving saturated alkyl halides with LAD provide a model system in which a halogen-atom radical chain process is not possible, and therefore, the observation of large quantities (in some cases >90%) of protium in the reduction product provides strong evidence for a radical intermediate and a SET pathway. Specifically, the reaction of 2-iodooctane (10) with LAD produced octane with a deuterium content as low as 21%. Also, the reaction of the tertiary halide 2-iodo-2-methylheptane (15) with LAD produced 2-methylheptane (16) with a deuterium content as low as 8%. The effect of stoichiometry, halogen type, and reaction vessel surface on these reactions was studied. Reaction of the unsaturated tertiary halide 6-iodo-6-methyl-1-heptene (25) with LAD was also studied and was found to proceed predom...

Evidence for Single-Electron Transfer in the Reactions of Unhindered Saturated Primary Alkyl Iodides with Lithium Aluminum Hydride. Reactions of 1-Halooctanes with Lithium Aluminum Deuteride

Evidence for single-electron transfer (SET) in the reactions of lithium aluminum hydride (LAH) with unhindered, saturated primary alkyl halides has not been available. In this study, experiments have been carried out that provide convincing evidence that the unhindered, saturated primary alkyl iodide 1-iodooctane reacts with lithium aluminum deuteride (LAD) in a 1:0.2 ratio to form 1-deuteriooctane with up to 38% incorporation of protium. Since the protium incorporation increased as the reaction proceeded, studies involving the reaction of 1-iodooctane with AlD3 (one of the byproducts in the reaction of LAD with alkyl halides) were carried out in order to determine the effect of AlD3. With AlD3, protium incorporations as high as 84% were observed, indicating that the reaction of AlD3 with 1-iodooctane proceeds via a pathway that involves at least 84% radical formation. The study also included the effect of reaction vessel surface, concentration, and leaving group on the course of the reaction. Factors pre...

The effect of reactor surfaces on single electron transfer reactions. The reaction of 1-Iodo-2,2-dimethylhexane with lithium aluminum deuteride

Reactions of 1-iodo-2,2-dimethylhexane (4) with LiAlD 4 have been carried out in a variety of reaction vessels. In vessels of used pyrex, teflon, and stainless steel, the surface of the reactor plays a role in the product distribution. However, treated pyrex, new pyrex and quartz vessels yield consistent data that support single electron transfer as the major reaction pathway in the reduction of 4 with LiAlD 4.

Synthesis of 1,2,3‐trideutero amines, alcohols and hydrocarbons from tricarbonyliron(0) complexes of 1‐heterodienes and homodiens

AbstractA simple procedure for the synthesis of 1,2,3‐trideutero amines, alcohols and hydrocarbons from the reaction between lithium aluminiumdeuteride and tricarbonyliron(0) complexes of 1‐heterodienes and homo‐dienes is reported.