Recent Applications of α-Metalated Isocyanides in Organic Synthesis

Being both nucleophilic and electrophilic, α-metalated isocyanides can add to polar double bonds, forming heterocycles. They are also synthons for α-metalated primary amines. This article describes recent or improved procedures for their use in organic synthesis: (1) In heterocyclic syntheses to give 2-oxazolines, 2-imidazolines, 2-thiazolines, oxazoles and oligooxazoles, thiazoles, triazoles, imidazolinones, pyrroles, 5,6-dihydro-1,3-oxazines and -thiazines, and (via cycloaddition with nitrones) 2-imidazolidinones. (2) In the field of formylaminomethylenation, for example transformation of estrone methyl ether and a keto sugar into the corresponding α-formylaminoacrylic esters, and the conversion of aldehydes and ketones by 3- and 4-pyridyl-methyl isocyanides into N-(1-pyridyl-1-alkenyl)formamides and their hydrolysis to 3- and 4-acylpyridines. (3) In connection with the use of α-metalated isocyanides as synthons for α-metalated primary amines, the author demonstrates how they may be used for preparation of 1,2- and 1,3-amino alcohols, 1,2-diamines, 2,3-diaminoalkanoic acids and for synthesis of higher amino acids starting from simple amino acids.     

Synthesis of 2-amino-5,6-dihydro-4H-1,3-thiazines and related compounds by acid catalyzed cyclization of allylic isothiuronium salts

Several allylic isothiuronium salts 6 have been shown to yield 4-substituted 2-amino-5,6-dihydro-4H-1,3-thiazines ( 2 ; R³ = H) and the 2-phenylimino compound 10 on exposure to trifluoroacetic acid or trifluoroacetic acid-stannic chloride. The overall process constitutes a convenient transformation of readily available ketones or aldehydes 3 into the target hetero-cycles. The scope and limitations of this approach are discussed in terms of carbenium ion intermediates ( 7 ). Whereas this method successfully led to the imidazo[2,l-b][1,3]thiazine 13 (93% from 12 ), its application to the synthesis of 2-amino-2-thiazolines (eg. 14 → 15 ) or imidazo-[2,1-b]thiazoles (eg. 16 → 17 ) was unsuccessful. The 2-acetylimino derivatives 9 were found to be useful for purification of the 2-aminothiazines.     

Phenyliodine(III) Diacetate/I2-Mediated Domino Approach for Pyrrolo[1,4]Thiazines and 1,4-Thiazines by a One-Pot Morin Rearrangement of N,S-Acetals

An efficient domino transformation using a phenyliodine(III) diacetate (PIDA)/I₂ combination towards Morin 1,4-thiazine compounds has been developed starting from N,S-acetals. The latter leads to “one-step” regioselective methylene insertion without the need for traditional sulfoxide intermediates in good yields. The reaction involves easily accessible N,S-acetals obtained from cost-effective basic ketones and cysteamine as starting materials. This process ultimately leads to 1,4-thiazines related to natural product and fused derivatives necessary for further QSAR study.     

Substrate-controlled and highly stereoselective synthesis of 2-aminobut-2-ene-1, 4-diones

2-Methylthio-substituted 1,4-enediones, obtained from readily available aryl methyl ketones, were reacted with primary or secondary amines to afford the desired 1,4-diaryl-2-aminobut-2-ene-1,4-diones in excellent yields with high Z/E-stereoselectivity.     

A simple synthesis of Δ2-oxazolines, Δ2-oxazines, Δ2-thiazolines and Δ2-imidazolines

Carboxylic acids react with amino alcohols, amino mercaptans or diamines in the presence of triphenylphosphine, CCl₄ and tert. bases to afford in 50–75% yield the corresponding Δ²-oxazolines, Δ²-oxazines, Δ²-thiazolines and Δ²-imidazolines.     

Gemeinsame Einwirkung von elementarem Schwefel und Äthylenimin auf Ketone, 3. Mitt.: Über die gemeinsame Einwirkung von elementarem Schwefel und gasförmigem Ammoniak auf Ketone, 74. Mitt.

Zusammenfassung Bei der Einwirkung von Äthylenimin und Schwefel auf Methyläthylketon, Methylisopropylketon und Äthylisopropylketon entstehen strukturisomere 5,6-Dihydro-1,4-thiazine (1–6) und als Nebenprodukte die dem jeweiligen Keton entsprechenden Thiazolidine (7–9).Die 5,6-Dihydro-1,4-thiazine werden mit Ameisensäure in N-Formylthiomorpholine (10–15) übergeführt, die mit verd. HCl glatt zu den entsprechenden Thiomorpholinen (16–21) hydrolysiert werden.Das Verhältnis der Thiomorpholin-Isomerenpaare wird gaschromatographisch quantitativ bestimmt.

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Concomitant action of elementary sulfur and gaseous ammonia upon ketones, LXXIV: Concomitant action of elementary sulfur and ethylenimine upon ketones, III

The reaction of ethylenimine and sulfur with methyl ethyl ketone, methyl isopropyl ketone and ethyl isopropyl ketone, resp., yields the structurally isomeric 5.6-dihydro-1.4-thiazines (1–6) and as by-products the thiazolidines (7–9) derived from the corresponding ketones.The 5.6-dihydro-1.4-thiazines are converted with formic acid to the N-formyl thiomorpholines10–15, which are easily hydrolyzed with dilute hydrochloric acid to the corresponding thiomorpholines (16–21). The ratio of the pairs of structurally isomeric thiomorpholines is determined by quantitative gas chromatography.

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2. Mitt.:F. Asinger, H. Offermanns, K. H. Lim undD. Neuray, Mh. Chem.101, 1281 (1970).

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73. Mitt.:F. Asinger, H. Offermanns undD. Neuray, Ann. Chem.739, 72 (1970).

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Teil der DissertationK. H. Lim, Techn. Hochschule Aachen, 1969.     

Nitrogen and sulfur heterocycles. 45. Dual reactivity of 1,2-dioxo-3a-alkyl-7-chloroimidazolidino[3,2-f]-pyrido[2,3-b]-1,4-thiazines

1,2-Dioxo-3a-alkyl-7-chloroimidazolidino[3,2-f]pyrido[2,3-b]-1,4-thiazines react with o- and p-nitroanilines, alkyl and acyl halides, and heterocyclic amines to give C₍₂₎- and N₍₃₎-substituted 3a-alkyl-7-chloroimidazolidino[3,2-f]pyridol[2,3-b]-1,4-thiazines.For Communication 44, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1688–1693, December, 1987.     

Palladium catalyzed oxidation of Δ2, Δ3, and Δ4-unsaturated alcohols

Palladium (0.6~3 mol%) catalyses the oxidation of Δ², Δ³, and Δ₄ -unsaturated aloohols to the copresponding ketones in good yields, where bromomesitylene or bromobenzene ie used as an oxidant.     

Selective carbophilic addition of organolithiums to thioamides. A novel synthesis of unsymmetrical ketones and α-alkylated amines

Thioamides, readily available from aldehydes, sulfur and secondary amines, can be converted to unsymmetrical ketones by the carbophilic addition of organolithiums to the thiocarbonyl group. Reduction of the intermediates with lithium aluminum hydride gives α-alkylated or α-arylated amines.     

The reaction of 2,2,4,4-tetramethyl-1,3-cyclobutanedione with o-aminophenols,o-aminothiophenol and with aliphatic 2- and 3-hydroxy- and -mercaptoamines

Studies of the reaction of the dione dimer of dimethylketene ( 1 ) with a series of o-aminophenols and with o-aminothiophenol have been carried out. These reactions give 2-[2-(2,4-dimethyl-3-oxopentyl)]benzoxazoles and -benzothiazole, respectively. Aliphatic 2- and 3-hydroxy- and 2- and 3-mercaptoamines yield 2-substituted 2-oxazolines, 5,6-dihydro-4H-1,3-oxazines, 2-thiazolines and 5,6-dihydro-4H-1,3-thiazines.     

Diazoalkane complexes of tungsten from the condensation of hydrazido Complexes with Ketones

Hydrazido(2?) and hydrazido(1?) complexes of tungsten condense with ketones, R¹R²CO, in the presence of catalytic amounts of acid to yield complexes containing the groups W = NN = CR¹R² and WNHN =CR¹R² respectively. The other ligands are halide ions and monotertiary phosphines. These new complexes yield secondary amines and ammonia on reduction with LiAlH₄; acids produce nitrogen-free tungsten materials, hydrazine and azines.     

The structure of 2-arylamino-2-thiazolines,analogous thiazines and their amides—X. An IR and NMR investigation of the N-methyl derivatives

The isomer-pairs of the 2-arylamino-2-thiazolines and -thiazines, carrying a methyl substituent on the nitrogen atom of the ring and outside the ring were synthesised by unambiguous routes. An IR and NMR investigation of these compounds revealed the fact that the NMR signal of the 2,6-symmetrically substituted aryl group can be used advantageously for the determination of the isomeric structures. The AB₂ multiplet of the aromatic protons is shifted towards the AX₂ pattern in the b isomer—containing a conjugated C?N bond outside the ring—as compared to the a isomers. The structure of this multiplet does not depend on the size of the hetero-ring.     

Aromatic derivatives of 2H-pyrimidino[5,6-b]-1,4-thiazine

5-R¹3-(4-R-Phenyl)-2H-pyrimidino[5,6-b]-1,4-thiazines [R¹=N(CH₃)₂ or OCH₃], which exist primarily in the 2H form, were synthesized by the reaction of -bromoacetophenones with 4-R¹-5-amino-6-thiopyrimidines.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 275–277, February, 1987     

Gemeinsame Einwirkung von elementarem Schwefel und Äthylenimin auf Ketone, 2. Mitt.

Zusammenfassung Bei der gemeinsamen Einwirkung von Schwefel und Äthylenimin auf 4-Heptanon, Cyclopentanon, Cyclohexanon und Cyclooctanon bilden sich in glatter Reaktion 5,6-Dihydro-4H-1,4-thiazine (3–6). Als Nebenprodukte von3, 4 und5 fallen die dem jeweiligen Keton zugrunde liegenden 2,2-dialkylierten Thiazolidine (7–9) an. Bei Einsatz von Phenylisopropylketon in diese Reaktion wird dagegen das 2-Isopropyl-2-phenylthiazolidin (12) zum Hauptprodukt, während das entsprechende 5,6-Dihydro-2H-1,4-thiazin (11) nur in untergeordnetem Maße entsteht.Die Reaktionsmechanismen sowohl der 5,6-Dihydro-1,4-thiazin-als auch der Thiazolidin-Bildung werden diskutiert.Die Umsetzung der 5,6-Dihydro-1,4-thiazine (1, 3–5, 11) mit überschüss. Ameisensäure führt zu N-Formylthiomorpholinen (13–17), die sich mit verd. HCl glatt zu den entsprechenden Thiomorpholinen (18–22) verseifen lassen.

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Concomitant action of elementary sulfur and gaseous ammonia upon ketones, LXXI. Concomitant action of elementary sulfur and ethylenimine upon ketones, II

The interaction of sulfur and ethylenimine with 4-heptanone, cyclopentanone, cyclohexanone, and cyclooctanone leads to 5.6-dihydro-4H-1.4-thiazines (3–6) in good yields. As byproducts of3, 4 and5 2.2-dialkylated thiazolidines (7–9, resp.) are isolated. When this reaction is carried out with phenyl isopropyl ketone, however, the main product is 2-isopropyl-2-phenylthiazolidine (12), the corresponding 5.6-dihydro-2H-1.4-thiazine (11) is but formed in a small quantity.The mechanisms of the formation of 5.6-dihydro-1.4-thiazines, as well as the formation of the thiazolidines are discussed.Reaction of 5.6-dihydro-1.4-thiazines (1, 3–5, 11) with excess formic acid leads to N-formylthiomorpholines (13–17) which can be easily saponified with dil. HCl to the corresponding thiomorpholines (18–22).

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Herrn Prof. Dr.O. Hromatka mit herzlichen Grüßen zum 65. Geburtstag gewidmet

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70. Mitt.:F. Asinger, H. Offermanns, D. Neuray undF. Abo Dagga, Mh. Chem.101, 500 (1970)

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Teil der DissertationK. H. Lim, Techn. Hochschule Aachen, 1969.

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Teil der DissertationD. Neuray, Techn. Hochschule Aachen, 1969

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1. Mitt.:F. Asinger, H. Offermanns, W. Pürschel, K. H. Lim undD. Neuray, Mh. Chem.99, 2090 (1968).     

Reaction of hexafluoro-N-(4-N,N-dialkylaminophenyl)-1,4-naphthoquinon-4-imines with primary amines

Amination of 2,3,5,6,7,8-hexafluoro-N-(4-N,N-dialkylaminophenyl)-1,4-naphthoquinon-4-imines with primary amines led to the formation of 3-amino derivatives, which further underwent cyclization into 7-alkyl(aryl)-1,2,3,4,6-pentafluoro-5H-benzo[a]phenazin-5-ones. The spectral properties of compounds obtained were examined.     

Réactivité des liaisons σ uranium-carbone: réactions du méthyltris(hexaméthyldisilylamido)uranium

The uranium-carbon σ bond of the methyltris(hexamethyldisilylamido)uranium, [(SiMe₃)₂N]₃UCH₃, was poorly reactive towards carbon monoxide insertion, but reacted readily with isocyanides, aliphatic nitriles and carbonyl compounds (aldehydes and ketones).“Acidic” hydrogens reacted under mild conditions; secondary amines gave the tetraamido compounds [(SiMe₃)₂N]₃UNR₂ and metallic hydrides gave the binuclear compounds with an isocarbonyl linkage.     

REACTION OF AROMATIC NITRO COMPOUNDS WITH ELEMENTAL SULFUR IN LIQUID AMMONIA AND AMINES

Abstract

Aromatic nitro compounds were reduced with elemental sulfur in liquid ammonia and in amines, yielding the corresponding anilines. However, introduction of a substituent on the benzene ring or variation of the amine changed somewhat the pattern of this reaction. For example, 4-nitrotoluene (3) and 4-cyanonitrobenzene (6) were found to give not only the corresponding reduced products but also 4,4′-dicyanodiphenyl disulfide (10), formed by replacement of the nitro group, in addition to 4-cyanoaniline (9) in the reaction with elemental sulfur in liquid ammonia. Probable mechanisms of these reactions are discussed in the light of new knowledge on the similar reactions of elemental sulfur.     

Über die flüchtigen Anteile der Ananas

A gas chromatographic investigation of the volatile part of a pineapple concentrate led to the identification of 59 substances, 35 of which were not previously found in pineapple. The identifications and syntheses of some esters (Δ³- and Δ⁴-unsaturated, β-hydroxy, β-acetoxy, and δ-acetoxy) and of a new sulfur compound are given.     

Amination of [60]fullerene by ammonia and by primary and secondary aliphatic amines--preparation of amino[60]fullerene peroxides

Ammonia and aliphatic amines react readily in the oxygen-rich regions of the Cs symmetric fullerene peroxides C60(O)(OOtBu)4 (1) and C60(OH)(Br)(OOtBu)4 (2 c). Michael addition-type hydroamination of the 1,4-diene moiety on the central skew-pentagon was observed when 1 was treated with ammonia or with nonbulky primary amines, while sterically demanding primary amines opened the epoxy moiety to form vicinal aminohydroxy fullerene compounds with the amino group on the central pentagon. In 2 c the bromo group was replaced under similar conditions by ammonia and primary amines. Cyclic secondary amines showed different reaction patterns, forming hydrogenation products or aminoketal-fullerenes when treated with 1 and 2 c, respectively. Single-electron transfer (SET) is the key step in all the proposed mechanisms. The compounds were characterized by their spectroscopic data, and in addition, three single-crystal X-ray structures were obtained.     

Acetylene derivatives Communication 183. New method for the synthesis of 4-piperidones; action of ammonia or primary amines on 1-alkenyl 2-dialkylaminoethyl ketones

Summary A new simple method was developed for the synthesis of 4-piperidones by the action of ammonia or primary amines on 1-alkenyl 2-diethylaminoethyl ketones, which are readily obtained from hydrocarbons derived from 1-buten-3-yne.