Gabriel Synthesis Research Articles

A new synthesis of primary aliphatic amines by N,N-didebenzylation. Synthesis of a pirmenol (CI-845) metabolite

We have described a new and useful alternative to the Gabriel synthesis for making primary aliphatic amines. The method allows reactions to be carried out with the dibenzylamine intermediates that may not work with the corresponding phthalimides. It also makes use of mild deprotection conditions that avoid the high temperatures and strong acid or base, or the strongly nucleophilic hydrazine, required to remove the phthaloyl moiety

A Convenient Synthesis of Primary Amines Using Sodium Diformylamide as A Modified Gabriel Reagent

Sodium diformylamide (1) was used as a convenient substitute for phthalimide in the Gabriel synthesis of primary amines. Reagent 1 undergoes smooth N-alkylation with alkyl halides or p-toluene-sulfonates 2 in acetonitrile or dimethylformamide to give the corresponding N,N-diformylalkylamines 3 in good yeilds, except with alkylating agents which are susceptible to base-catalyzed elimination. The formyl group of 3 can be easily removed by hydrochloric acid to give the corresponding alkylamine hydrochlorides 5 or free alkylamines 4

ChemInform Abstract: Synthesis and Antiarrhythmic Activity of N‐Aryl Alkylenediamines.

AbstractThe amines (I) are converted to the chlorides (III), which undergo Gabriel synthesis to give the alkylene diamines (VI) and (VII).

An Unusual Aminal Derivative from a Misdirected Gabriel Synthesis

Abstract N-(2-Bromoethyl)phthalimide (1) was reacted with sodium imidazolate in DMF to give the novel aminal N-[1-(1H-imidazol-1-yl)ethyl]phthalimide (4a) as well as N-vinylphthalimide (3) and the desired Gabriel intermediate 2. Aminal 4a as well as heterologues 4b - d form directly from reaction of 3 with the appropriate heterocyclic sodium salt.

In vivo covalent binding of retronecine-labelled [ 3H]seneciphylline and [ 3H]senecionine to dna of rat liver, lung and kidney

Retronecine-labelled [3H]seneciphylline ([3H]SPH) and [3H]senecionine ([3H]SON) of high specific radioactivity (22 and 49 mCi/mmol, respectively) were prepared biosynthetically with seedlings of Senecio vulgaris L. using [2,3-3H]putrescine as precursor. [2,3-3H]Putrescine was synthesized by Gabriel synthesis of 1,4-diamino-2-butene from 1,4-dibromo-2-butene and catalytic hydrogenation of the product with tritium gas. Rats of both sexes were treated with the labelled pyrrolizidine alkaloids (PAs) (75-215 microCi SPH or 40-485 microCi SON/kg body wt.) and killed after 6 h or 4-5 days. SON-treated females excreted 83.4 +/- 0.2% of applied radioactivity in faeces and urine within 4 days whereas equally treated males excreted 90.9 +/- 3.2% in the same time. Excretion of 3H-activity from SPH-treated females was completed within 5 days (104.7 +/- 6.4%). Corresponding with these results, tissue levels were highest in SON-treated females. DNA and proteins were isolated from liver, lungs and kidneys and covalent binding of the alkaloids to DNA was determined. A Covalent Binding Index (CBI, mumol alkaloid bound per mol nucleotides/mmol alkaloid administered per kg body wt.) of 210 +/- 12 was found for the liver from SON-treated females whereas binding to liver DNA of males was lower by a factor of 4. The DNA damage determined six hours after treatment persisted during the following 4 days. Administration of [3H]SPH to female and male rats resulted in a CBI of 69 +/- 7 and 73/92, respectively, for the liver DNA. Furthermore we found binding of both alkaloids to DNA of lungs and kidneys in male and female rats. The in vivo formation of [3H]SON derived DNA adducts could be proved by HPLC analysis of hydrolyzed DNA.

Synthesis of Primary Amines via Alkylation of the Sodium Salt of Trifluoroacetamide: An Alternative to the Gabriel Synthesis

L'alkylation par des halogenures d'alkyle ou des mesylates d'alkyle conduit aux N-alkyl trifluoroacetamides (I). L'hydrolyse (KOH) ou la reduction (NaBH 4 ) de (I) conduit aux alkylamines

ChemInform Abstract: A FACILE ONE‐POT SYNTHESIS OF N‐SUBSTITUTED PHTHALIMIDES USING A CATALYTIC AMOUNT OF CROWN ETHER

N-Substituted phthalimides, intermediates of the Gabriel synthesis, were obtained in high yields (84–100%) by the addition of a catalytic amount of 18-crown-6 to the reaction of potassium phthalimide and alkyl halides in toluene.

A Facile One-pot Synthesis of N-Substituted Phthalimides Using a Catalytic Amount of Crown Ether

Abstract N-Substituted phthalimides, intermediates of the Gabriel synthesis, were obtained in high yields (84–100%) by the addition of a catalytic amount of 18-crown-6 to the reaction of potassium phthalimide and alkyl halides in toluene.

Sythesis of deuterium and tritium labeled psoralens

AbstractDeuterium and tritium labeled 4,5′,8‐trimethylpsoralen (), psoralen (), and angelicin (), have been prepared by D2O and T2O exchange with specific activities of 228‐253 mCi/mmol. Tritium labeled 4,5′,8‐trimethylpsoralen () with a specific activity of 17.6 Ci/mmol was prepared by catalytic reduction with tritium gas followed by dehydrogenation. Tritiated 4′‐hydroxymethyl‐4,5′,8‐trimethylpsoralen () with a specific activity of 12.0 Ci/mmol was obtained by reduction of the corresponding aldehyde with sodium borotritide and elaborated to 4′‐aminomethyl‐4,5′,8‐trimethylpsoralen () (12.0 Ci/mmol) by conversion of to the chloromethyl derivative followed by the Gabriel synthesis. Tritium labeled 8‐methoxypsoralen () was prepared by demethylation of unlabeled to the phenol followed by methylation with tritiated methyl iodide.

Reinvestigation of the stevens rearrangement of 1‐benzyl‐1,3,4‐trimethyl‐1,2,5,6‐tetrahydropyridinium salts. II. Synthesis of 2‐aryl‐3‐isopropenyl‐1,3‐dimethylpyrrolidines

Abstractcis‐2‐Aryl‐3‐isopropenyl‐1,3‐dimethylpyrrolidines Ha and IIb have been synthesized by an unambiguous way, thus confirming the structure of the methylene derivatives obtained as by‐products in the Stevens rearrangement of 1‐benzyl‐1,3,4‐trimethyl‐1,2,5,6‐tetrahydropyridinium salts Ia and Ib. The synthesis is based on the acid‐induced intramolecular cyclization between an iminium salt and the α‐position of a ketal group. Thus, condensation between amino ketal XXI, prepared via Gabriel synthesis from 5‐chloro‐3‐methyl‐2‐pentanone, and the appropriate aldehyde afforded imines XXI. Their treatment with dry hydrogen chloride followed by acid hydrolysis and methylation gave 3‐acetylpyrrolidines IV, which were transformed into the isopropenyl derivatives II by reaction with methyl‐lithium and further dehydration.

Absolute configuration of glycerol derivatives. 7. Enantiomers of 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-1,4-benzodioxane (WB-4101), a potent competitive alpha-adrenergic antagonist.

The enantiomers of 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-1,4-benzodioxane (4) were prepared from the chiral 2-[(tosyloxy)methyl]-1,4-benzodioxanes [(2S)- and (2R)-5]. The corresponding (2R)- and (2S)-2-(aminoethyl)-1,4-benzodioxanes [2R)- and (2S)-7] were prepared by a modified Gabriel synthesis and converted to the enantiomers of 4 by condensation with 2,6-dimethoxyphenoxyacetaldehyde (8) and reduction of the intermediate imine with NaBH4. The enantiomer (2S)-4 was 40--50 times as potent as the enantiomer (2R)-4 in antagonizing the alpha-adrenergic response of methoxamine-induced contraction of rabbit aortic strips, showing a pA2 = 9.0. This result is consistent with the previous observation that S enantiomers of 2-[(alkylamino)methyl]benzodioxanes are more potent antagonists at a alpha-adrenergic receptors than the R enantiomers.

A Convenient One-Pot Synthesis of N-Alkylanilines from Benzanilides

Abstract The direct synthesis of secondary amines from the corresponding primary amines by alkylation has been widely used. The major drawback, however, consists of polyalkylation. Several procedures exist for the solution of the problem. Some of the early methods involve reduction3, or alkylative hydrolysis4 of Schiff base. Other methods include acid hydrolysis of alkylated formanilides prepared from primary aromatic amine and trialkyl orthoformate5, or acid hydrolysis of N-alkylated phosphinamides6, or zinc cleavage of N-alkylated phenacylsulfonamides7, or reductive deprotection of N-alkylated trifluoromethanesulfonamides7. This latter method is analogous to the Gabriel synthesis of

Synthesis of new dibenzo[b,e]thiepin derivatives related to the antidepressant agent prothiadene

A reaction of dibenzo[b,e]thiepin-11(6H)-one with cyclopropylmagnesium bromide afforded the carbinol VII giving by treatment with hydrogen bromide the bromo derivative IV. Application of the Gabriel synthesis led to the primary amine III postulated earlier to be a metabolite of the antidepressant agent prothiadene (I). Demethylation of 2-methoxy-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]thiepin (X) with boron tribromide or hydrobromic acid gave mixtures of geometric isomers of the phenol IX from which either the trans- or cis-form could be isolated; trans-IX is another potential metabolite of prothiadene (I). Attempts at preparing prothiadene N-oxide yielded as the main product the nitrogen-free diene XI which was apparently formed by a Cope elimination. The analogous sulfone XII was obtained as a by-product of the preparation of prothiadene S,S-dioxide (XV). Treatment of dibenzo[b,e]thiepin-11(6H)-one with methoxymethylmagnesium chloride opened the access to the aldehyde XVI which was further used for the preparation of the nitrile XVIII, alcohol XIX, carboxylic acid XX and acrylic acid XXI.

The Gabriel synthesis of benzylamine: An undergraduate organic experiment

The Gabriel synthesis involves the reaction of the conjugate base of phthalimide and an alkyl halide to give an alkyl phthalimide which is subsequently hydrolyzed to the primary alkyl amine; the reaction is important historically for the synthesis of pure primary amines uncontaminated by secondary or tertiary by-products.

New “Gabriel” syntheses of amines

The Gabriel synthesis is generalized as monoalkylation of an ammonia or primary amine derivative with subsequent removal of the derivatizing group(s) from nitrogen. Two new derivatives for this purpose are introduced: phenacylsulfonamides and triflamides, with discussion of their generality and effectiveness.

Triflamides for protection and monoalkylation of amines and a new gabriel synthesis.

Triflamides for protection and monoalkylation of amines and a new gabriel synthesis.

An investigation of the synthesis of 3-amino-4-ethoxycarbonylaminotetrahydrothiophene

Methods of synthesis of 3-amino-4-ethoxycarbonylaminotetrahydrothiophene (VIII), and of other diamines, from 4-ethoxycarbonylaminotetrahydro-3-hydroxyiminothiophene (I), 2-benzylidene-4-ethoxycarbonylaminotetrahydro-3-hydroxyiminothiophene (III) and 4-ethoxycarbonylaminotetrahydro-3-hydroxythiophene (V) were investigated. Chlorination of V followed by the Gabriel synthesis gave VIII.

Five-membered rings. II. Inter and intramolecular reactions of simple amines with N-substituted phthalimides. Methylamine as a reagent for removal of a phthaloyl group from nitrogen

A reexamination of the literature on inter and intramolecular reactions of amines with N-substituted phthalimides has led to the demonstration that methylamine is a convenient reagent for removal of a phthaloyl protecting group from nitrogen at room temperature. Application of this procedure (first described in 1896) to the Gabriel synthesis of primary amines and to peptide synthesis is recommended. The simplicity of the reaction is a consequence of the consecutive occurrence of two unexpectedly rapid processes: (1) methylaminolysis of one of the imide bonds; (2) intramolecular catalysis, by an N-methylamido group, of the hydrolysis or aminolysis of an adjacent phthalamido linkage.Some unsuccessful attempts to prepare 2-aminoethylphthalimide are also described.

The Gabriel Synthesis of Primary Amines

AbstractReaction of potassium phthalimide with halogenoalkanes and with a variety of other alkylating agents leads to the N‐alkylphthalimide. N‐Substituted phthalimides may be converted into the corresponding primary amine by hydrolysis or hydrazinolysis. The scope and limitations of these reactions, which together constitute the Gabriel Synthesis of primary amines, are reviewed.

Syntheses of 3-Aminopropylguanidine Derivatives

The fourteen compounds of 3-(substituted amino)propylguanidine were synthesized by reacting S-methylisothiourea sulfate with 3-(substituted amino)propylamine : 3-(substituted amino) propylamine having an aliphatic substituent group at 3-position were synthesized by reacting the aliphatic amine with acrylonitrile and by reducting with lithium aluminum hydride, while 3-(substituted amino)propylamine having an aromatic substituent group at 3-position, synthesized by the Ing-Manske modification of the Gabriel synthesis of primary amines.