The acylation of acetylenes with β, γ-unsaturated acid chlorides: a new sysnthesis of 5,5-disubstituted 2-cyclopentenones

The acylation of acetylenes with α,α-disubstituted, β,γ-unsaturated acid chlorides was found to lead to 5,5-disubstituted 2-cyclopentenones bya novel intramolecular cyclization-rearrangement process.     

Thermische Lactonisierung von Estern γ-Brom-α, β-ungesättigter Carbonsäuren zu Δα-Butenoliden. Direkte γ-Bromierung von α, β-ungesättigten Säuren

By heating with iron powder at 120–150° some γ-bromo-α, β-unsaturated carboxylic methyl esters, and, less smothly, the corresponding acids, were lactonized to Δ^7alpha;-butenolides with elimination of methyl bromide. The following conversions have thus been made: methyl γ-bromocrotonate ( 1c ) and the corresponding acid ( 1d ) to Δ^α-butenolide ( 8a ), methyl γ-bromotiglate ( 3c ) and the corresponding acid ( 3d ) to α-methyl-Δ^α-butenolide ( 8b ), a mixture of methyl trans- and cis-γ-bromosenecioate ( 7c and 7e ) and a mixture of the corresponding acids ( 7d and 7f ) to β-methyl-Δ^α-butenolide ( 8c ). The procedure did not work with methyl trans-γ-bromo-Δ^α-pentenoate ( 5c ) nor with its acid ( 5d ). Most of the γ-bromo-α, β-unsaturated carboxylic esters ( 1c, 7c, 7e and 5c ) are available by direct N-bromosuccinimide bromination of the α, β-unsaturated esters 1a, 7a and 5a ; methyl γ-bromotiglate ( 3c ) is obtained from both methyl tiglate ( 3a ) and methyl angelate ( 4a ), but has to be separated from a structural isomer. The γ-bromo-α, β-unsaturated esters are shown by NMR. to have the indicated configurations which are independent of the configuration of the α, β-unsaturated esters used; the bromination always leads to the more stable configuration, usually the one with the bromine-carrying carbon anti to the carboxylic ester group; an exception is methyl γ-bromo-senecioate, for which the two isomers (cis, 7e , and trans, 7d ) have about the same stability. The N-bromosuccinimide bromination of the α,β-unsaturated carboxylic acids 1b , 3b , 4b , 5b and 7b is shown to give results entirely analogous to those with the corresponding esters. In this way γ-bromocrotonic acid ( 1 d ), γ-bromotiglic acid ( 3 d ), trans- and cis-γ-bromosenecioic acid ( 7d and 7f ) as well as trans-γ-bromo-Δ^α-pentenoic acid ( 5d ) have been prepared. Iron powder seems to catalyze the lactonization by facilitating both the elimination of methyl bromide (or, less smoothly, hydrogen bromide) and the rotation about the double bond. α-Methyl-Δ^α-butenolide ( 8b ) was converted to 1-benzyl-( 9a ), 1-cyclohexyl-( 9b ), and 1-(4′-picoly1)-3-methyl-Δ^α-pyrrolin-2-one ( 9 c ) by heating at 180° with benzylamine, cyclohexylamine, and 4-picolylamine. The butenolide 8b showed cytostatic and even cytocidal activity; in preliminary tests, no carcinogenicity was observed. Both 8b and 9c exhibited little toxicity.     

Reversible,thermische Isomerisierung zwischen α, β-γ, δ-ungesättigten Aldehyden und Alkenylketenen durch [1,5]-H-Verschiebung. Valenzisomerisierung von cis-Dienonen,V [1]

Vapor phase pyrolysis of 2,4-pentadienaldehyde, of 6-oxabicyclo[3.1.0]hex-2-ene or of 3-pentenoic acid chloride at 600° (0.1 s/1 Torr) leads to similar mixtures containing the stereoisomers of 2, 4-pentadienaldehyde and 1-propenylketene. These compounds, and methyl substituted derivatives thereof, equilibrate at 600° (0.1 s) through intramolecular processes involving cis/trans-isomerisations and [1,5]-H-shifts. It is shown that α, β-γ, δ-unsaturated aldehydes can be prepared in high yield through gas phase thermolysis of appropriately substituted acid chlorides.     

Synthesen von 2-Pyronen aus α, β-ungesättigten Säurechloriden und tertiären Aminen

A new synthesis of 2-pyrones has been developed. Two molecules of α, β-unsaturated acid chlorides ( 8 , 12 and 18 ) condense, with loss of two molecules hydrogen chloride, to pairs of substituted 2-pyrones ( 9 and 10 , 13 and 14 , 19 and 20 ) when treated with triethyl amine in chloroform or methylene chloride at room temperature. In the case of 18 , two additional products were obtained, namely the resorcinol derivative 21 and traces of the 1, 3-cyclobutanedione derivative 22 . Under the same conditions the α, β-unsaturated acid chlorides 8 , 15 , 18 and 41 were condensed with trichloroacetyl chloride to give 6-trichloromethyl-2-pyrones ( 42 , 43 , 44 and 46 ). These 2-pyrones are valuable intermediates for the synthesis of 6-carboxy-2-pyrones and 6-methyl-2-pyrones. A methyl group in β-position of the α, β-unsaturated acid chloride appears to be essential for the described condensations, for the acid chlorides 16 and 17 did not yield defined products and the acid chloride 40 reacted with trichloroacetyl chloride in a very low yield. It is considered that the described reactions proceed via the 1, 4-addition of an acid chloride to a vinyl ketene or through the acylation of an intermediate anion by an acyl derivative as outlined in reaction scheme 1. The structures of the 2-pyrones were confirmed by their spectroscopic properties, summarized in table 3, and by some of their chemical transformations.     

Über einen neuartigen synthetischen Zugang zu β,γ-ungesättigten α-Aminocarbonsäuren

A New Synthetic Route to β,α-Unsaturated α-Amino Acids A versatile new synthetic pathway for the preparation of βγ-unsaturated α-amino acids ( 1 ) is presented. Cu(I)-catalyzed addition of ethyl isocyanoacetate ( 2 ) to α-chloro carbonyl compounds ( 3 ) gives 5-chloroalkyl-2-oxazolin-4-carboxylates ( 4 ) in high yields. A reductive elimination on 4 by means of zinc yields the N-formyl derivatives of βγ-unsaturated α-amino carboxylates ( 5 ), which on acid hydrolysis lead to the free amino acids 1 . The five different βγ-dehydro-α-amono acids 1b-1f have been prepared by this method.     

Thermische Cyclisierung von α-Alkinonen zu 2-Cyclopentenonen

Thermal Cyclization of α-Alkynones to 2-Cyclopentenones Gas phase thermolysis at 600–740° of substituted 1-pentyn-3-ones (α-alkynones), which are easily prepared by acylation of trimethylsilyl acetylenes, leads to substituted 2-cyclopentenones. The intramolecular formation of a new C, C-bond between an acetylenic and a non-activated carbon atom is accompanied by a [1,2]-migration of one of the substituents at the triple bond. This novel ‘-alkynone cyclization’ reaction may be explained by postulating an alkylidene carbene intermediate which inserts into a C,H-bond five carbon atoms away at the non-acetylenic part of the ketone. Several examples demonstrate that the α-alkynone cyclization offers a simple tool for the preparation of certain monocyclic, bicyclic and spiro compounds containing a 2-cyclopentenone moiety.     

Konformationsanalysen von Modell-Tripeptiden: Der Einfluss von α,α-disubstituierten α-Aminosäuren auf die Sekundärstruktur. Teil II. Röntgenstrukturanalyse und Konformationsenergie-Berechnungen

Conformational Analysis of Tripeptide Models: The Influence of α,α-disubstituted α-Amino Acids on the Secondary Structure. X-Ray Analysis and Conformational Energy Calculations The X-ray analysis of tripeptide Z-Ile-Val(2-Me)-benzocaine ( 1f ) reveals the presence of a type-III β-turn. Moreover, MMP2 calculations on tripeptides, e.g. Z-Ile-Aib-benzocaine ( 1c ), Z-Ile-D -Val(2-Me)-benzocaine ( 1g ), Z-Ile-Gly(2,2-Pr₂)-benzocaine ( 1h ), Z-Ile-Gly-benzocaine ( 1a ), and 1f , fit well into the frame of NMR and CD investigations. They allow considerations on the relative stability of different types of β-turns depending on the peptide sequence, e.g. the kind of α,α-disubstituted amino-acid moieties.     

Conjugate addition of grignard reagents to N-(α,β-unsaturated)acylpyrazoles. Diastereoselective β-alkylation using 3-phenyl-l-menthopyrazole

The conjugate additions of N-(α,β-unsaturated)acylpyrazoles were carried out by the treatment with Grignard reagents in the presence of cuprous halides. The reaction of 2-(α,β-unsaturated)acyl-3-phenyl-l-menthopyrazoles 3a-h occurred in higher chemical yields and with asymmetric inductions on β-position, where the addition of magnesium bromide as a Lewis acid influenced to the yields and the diastereoselectivities. In the case of α-methylated 2-(α,β-unsaturated)acyl-3-phenyl-l-menthopyrazoles 3i-n , the excellent asymmetric induction on the α-position was also observed through the diastereofacial protonation.     

Highly Substituted Spiro[4.4]nonatrienes from a β-Amino-Substituted α,β-Unsaturated Fischer Carbene Complex and Three Molecules of an Arylalkyne

A novel mode of reaction towards arylethynes is shown by the β-trimethylsilyl-substituted α,β-unsaturated Fischer carbene complexes 1 . A mixture of the isomeric, highly substituted spiro[4.4]nonatrienes 2 and 3 is formed by the formal insertion of three alkyne molecules and subsequent cyclization (see scheme). Such selective triple insertions of alkynes into ethenylcarbene complexes have not been previously observed.     

Kupplung von Peptiden mit C-terminalen α,α-disubstituierten α - Aminosäuren via Oxazol-5(4H)-one

Peptide-Bond Formation with C-Terminal α,α-Disubstituted α - Amino Acids via Intermediate Oxazol-5(4H)-ones The formation of peptide bonds between dipeptides 4 containing a C-terminalα,α-disubstituted α-amino acid and ethyl p-aminobenzoate ( 5 ) using DCC as coupling reagent proceeds via 4,4-disubstituted oxazol-5(4H)-ones 7 as intermediates (Scheme 3). The reaction yielding tripeptides 6 (Table 2) is catalyzed efficiently by camphor-10-sulfonic acid (Table 1). The main problem of this coupling reaction is the epimerization of the nonterminal amino acid in 4 via a mechanism shown in Scheme 1. CSA catalysis at 0° suppresses completely this troublesome side reaction. For the coupling of Z-Val-Aib-OH ( 11 ) and Fmoc-Pro-Aib-OH ( 14 ) with H-Gly-OBu¹ ( 12 ) and H-Ala-Aib-NMe₂ ( 15 ), respectively, the best results have been obtained using DCC in the presence of ZnCl₂ (Table 3).     

Photochemische Reaktionen. 85. Mitteilung [1]. Zur Photochemie von α, β-Epoxy-eucarvon

Photochemistry of α,β-epoxy-eucarvone . On π,π^*-excitation (λ = 254 nm) 4 isomerizes to the bicyclic ketoaldehyde 5 ; on n,π^*-excitation (λ ? 280 nm) 4 gives 5 , the β,γ-unsaturated ketone 6 , the enone 7 and the cyclobutanone 8 . Scission of the (C—C)-bond of the oxirane 4 would give the dihydrofurane e , which could isomerize to the ketoaldehyde 5 . On the other hand, 4 is assumed to isomerize to the β,γ-unsaturated aldehyde c , which could yield 6 and 7 by photodecarbonylation. The cyclo-butanone 8 is shown to be a photoisomer of the ketone 6 . Furthermore, eucarvol ( 18 ) rearranges by a thermal [1,5]-H-shift to dihydro-eucarvone ( 20 ); on UV.-irradiation 18 gives the bicyclic isomers 27 and 28 .     

Acid-Catalysed Rearrangements of α-Vinylcyclobutanones

The BF₃ · Et₂O- and the CH₃SO₃H-catalysed rearrangements of 10 α-vinylcyclobutanones have been examined. With little acid, the β,β-dialkyl derivatives 1 were transformed into linear dienones 2 and 3 ; with more acid, they were converted into cyclopentenones 4 by Nazarov cyclisation of initially formed 2/3 . The β-monoalkyl (including the β,γ-dialkyl) derivatives 7 rearranged only with a high acid concentration to afford the cyclopentenones 8 by 1,2-acyl migration. In the case of 7a , the cyclopentenone 8a was accompanied by the unexpected constitutional isomer 9a , which is explained by a reversible interconversion of the cyclobutanone 7a with its isomer 19 via a cyclopropane intermediate like 18 . In the case of the β,β-dialkyl derivative 5 , which contains an α-isobutenyl (instead of an α-vinyl) group, the acid-catalysed rearrangement product was the bicyclo[3. 1. 0]hexanone derivative 6 .     

Photochemische Reaktionen 49. Mitteilung [1] Spezifisch π → π*-induzierte Keton-Photoreaktionen: Die Doppelbindungsverschiebung von O-Acetyl-10α-testosteron Protonisierung der Doppelbindung seines δ5-Isomeren

The α,β-unsatured ketone 10α-testosterone has been reported previously [6] to photoisomerize in t-butanol solution to the β,γ-unsaturated ketone. The irradiation had been carried out using a high-pressure mercury lamp in a quartz vessel. For structural reasons this double bond shift cannot proceed through a photoenolization mechanism involving an intramolecular hydrogen transfer from the γ-position to the enone oxygen as has been suggested to operate in several formally analogous cases of aliphatic enone isomerizations. In the present reinvestigation, O-acetyl 10α-testosterone ( 1 ) was used, employing selectively either excitation of its n → π* (with wavelengths > 300 nm) or its π → π* absorption band (with 253,7 nm). In t-butanol solution the doublebond shift 1 → 2 could be effected with π→* excitation only. Experiments in deuterated solvent (t-BuOD) resulted in deuterium in corporation in both the δ5-ketone in the C(4)-position, cf.( 3 ) and in the conjugated ketone. These results indicate that the reactions is initiated either in the, S_π,π* state or in a high vibrational mode of the S₀ or t_ππ*state. n→ π* Excitation of 1 in t-butanol gave essentially no over-all chemical change, while in benzene solution it resulted again in a double bond isomerization ( 1 → 2 ). In analogy to results with similar enones [28] under identical conditions the deconjugation in benzene may be the consequence of an intermolecular hydrogen abstraction of the T_n,π* excited state of the enone. Another specifically π →π* induced photoreaction was observed on irradiation of the β, γ-unsaturated ketone 2 in t-BuOD with 253,7 nm. The olefinic hydrogen at C-6 of 2 was exchanged with deuterium and, to a small extent, isomerization to the conjugated ketone 1 with concomitant deuterium incorporation occurred. It is concluded that from the higher excited state of the β, γ-unsaturated ketone, but not from its S_n,π* state, an activation mode of the double bond is accessible to effect D+ addition at C-6 followed by deprotonation to 4 and to deuterated 1 , respectively.     

Photochemische Reaktionen 111. Mitteilung [1] Zur Photochemie α, β-ungesättigter γ, δ-Epoxyester I: Singulett- versus Triplettreaktivität

On triplet excitation (E)- 2 isomerizes to (Z)- 2 and reacts by cleavage of the C(γ), O-bond to isomeric δ-ketoester compounds ( 3 and 4 ) and 2,5-dihydrofuran compounds ( 5 and 19 , s. Scheme 1). - On singulet excitation (E)- 2 gives mainly isomers formed by cleavage of the C(γ), C(δ)-bond ( 6–14 , s. Scheme 1). However, the products 3–5 of the triplet induced cleavage of the C(γ), O-bond are obtained in small amounts, too. The conversion of (E)- 2 to an intermediate ketonium-ylide b (s. Scheme 5) is proven by the isolation of its cyclization product 13 and of the acetals 16 and 17 , the products of solvent addition to b . - Excitation (λ = 254 nm) of the enol ether (E/Z)- 6 yields the isomeric α, β-unsaturated ε-ketoesters (E/Z)- 8 and 9 , which undergo photodeconjugation to give the isomeric γ, δ-unsaturated ε-ketoesters (E/Z)- 10 . - On treatment with BF₃O(C₂H₅)₂ (E)- 2 isomerizes by cleavage of the C(δ), O-bond to the γ-ketoester (E)- 20 (s. Scheme 2). Conversion of (Z)- 2 with FeCl₃ gives the isomeric furan compound 21 exclusively.     

[4 + 2]-Cycloadditionen von α, β- ungesättigten hydrazonen. Teil3. Isothiazolo[4,5-b]pyridin-3(2H)-on-1,1-dioxide (= 4-azasaccharine)

[4 + 2] Cycloaddition of α, β-Unsaturated Hydrazones: Isothlazolo[4,5-b]pyridin-3(2H)-on 1,1-Dioxides (= 4-Azasaccharine Derivatives) The [4 + 2] cycloaddition of α, β -unsaturated hydrazones of type 1 (1-azabuta-1,3-dienes) with isothiazol-3(2H)-on 1,1-dioxide derivatives 10 affords, depending on the solvent used, picolinamides 15 or 17 , 4,7-dihydro-4-azasaccharine 14 or 4-azasaccharine derivatives 16 (Scheme 4). The course of the reaction is mainly influenced by the substituent R of the dienophile 10 .     

[3+3] Cyclization reactions of β-nitroenamines and β-enaminonitriles with α,β-unsaturated carboxylic acid chlorides

New indolizidines, quinolizidines, and octahydro-pyrido[1,2-a]azepines of lactam type were synthesized from 2-nitromethylene-pyrrolidine, -piperidine, and -hexahydroazepine, respectively, by [3+3] cyclizations with α,β-unsaturated carboxylic acid chlorides. In the case of quinolizidines, a double bond migration was observed, and explained in terms of amidity percentage. Cyanomethylene-pyrrolidine gave indolizidines of lactam type, while transformations of 1-cyanomethylene-tetrahydoisoquinoline resulted in lactams as well as ketones, when simple open-chain acid chlorides or cinnamoyl chloride were used, respectively.     

[4 + 2]-Cycloadditionen von α,β-ungesättigten Hydrazonen. Teil 1. Pyridin-2,3-dicarboximide aus 1-(Dimethylamino)-1,4-dihydropyridin-Derivaten

[4 + 2] Cycloadditions of α,β-Unsaturated Hydrazones to Pyridine-2,3-dicarboximides via 1-(Dimethylamino)-1,4-dihydropyridine Derivatives The [4 + 2] Cycloaddition of α,β-unsaturated hydrazones of type 1 (1-aza-1,3-butadienes) with 2-halogenomaleimides 4 affords 1,4-dihydropyridines 6 which, after treatment with an acid, yield highly substituted pyridine-2,3-dicarboximide derivatives 7 (Scheme 1).     

The Synthesis of β,γ- and α,β-Unsaturated Aldehydes via Polyene Epoxides

A substitute for the Darzens glycidic ester synthesis for converting unsaturated ketones or aldehydes into the homologated β,γ- or α,β-unsaturated aldehydes employing sulfur ylides is described. The carbonyl group is converted into the unsaturated oxirane which is then rearranged to the new aldehyde. High yields of isomerically pure aldehydes are available by this method and the process is of practical importance in the conversion of β-ionone into the β-C₁₄-aldehyde, a key intermediate in the Isler synthesis of vitamin A. The efficient preparation of α- and β-cyclocitral by the novel process is also described.     

Studies on furan derivatives. II. Preparation of α-substituted β-2-(5-nitrofuryl)vinylamines

α-Subslituted β-2-(5-nitrofuryl)viriylamines were synthesized from α-ary]-β-2-(5-nitrofuryl)-aeryloyl azides and N-[α-substituled β-2-(5-nitrofuryl)vinyl] pyridinium bromides.     

Benzo[b] thiophene derivatives. XXII. Synthesis of the isomeric 5-methyl-6-methoxy- and 5-methoxy-6-methylbenzo[b] thiophene-2-carboxylic acids

The two isomeric benzo[b] thiophene-2-carboxylie acids having methyl and methoxy groups at positions 5 and 6 have been prepared and characterized. Both acids have been decarboxylated to the corresponding isomeric 5,6-disubstituted benzo[b]thophenes, and esterified to their methyl esters. The intermediate rhodanines, α-mercaptocinnamic acids and corresponding disulfides are described. An unusual by-product in the oxidative cyclization of β-3-methyl-4-methoxyphenyl-α-mercaptoacrylic acid with iodine is shown to be trans-3-methyl-4-methoxycinnamic acid, which can also be formed directly from the mercaptoacrylic acid by reduction with hydrogen iodide.