Enantioselective Synthesis of β-Necrodol and of 1-Epi-β-necrodol via Asymmetric 1,4-Addition and Magnesium-Ene Cyclization. Preliminary Communication

Enantiomerically pure β-necrodol ( 1 ) and its 1-epimer 16 have been synthesized starting from aldehyde 5 . The two key steps are an asymmetric conjugate addtion/Mannich reaction tandem ( 10 → 12 ) and a type-II-magnesiumene cyclization/oxidation sequence ( 14 → 1 + 16 ).     

A Convenient and Efficient Method for the Preparation of Unique Fluorophores of Lariat Naphtho‐Aza‐Crown Ethers

New naphtho‐aza‐crown ethers containing different phenolic side‐arms attached through the ortho‐position of the phenol have been prepared under solvent‐free conditions. The starting macrocyclic naphtho‐aza‐crown ether 2 was obtained by treatment of naphthalene dicarboxylic acid diester 1 with diethylenetriamine in EtOH at room temperature for two days without stirring in 77% yield (Scheme 1). Phenolic ligands ( 3 – 14 ) were synthesized by the Mannich reaction of the secondary macrocyclic amine 2 with the substituted phenols using nontoxic and inexpensive CaCl₂. This procedure was applied successfully for the synthesis of Mannich bases from simple secondary amines. The CaCl₂ powder can be reused up to three times after simple washing with dry acetone.     

Reaction of the 5-Azoniafulvene Ion with Enamines: A New Approach to Pyrrolizines

The synthesis of N,N-dimethyl-N-[(pyrro-1-yl)methyl]anilinium chloride ( 14 ) and of the corresponding p-toluidinium salt 15 is described. These salts, when dissolved in polar solvents, are shown to be in equilibrium with 1-(chloromethyl)pyrrole ( 17 ) and thereby potentially with the 5-azoniafulvene ion ( 2 ). Consequently, they react under very mild conditions (MeCN, 60°) with enamines to give pyrrolizine derivatives in acceptable yield (40–50°). The process is rationalized in terms of an initial Mannich-type reaction which is immediately followed by acyclization.     

Chemistry of Phosphorus Ylides. Part 22 [1]. Effect of Newly Synthesized Niclosamide Mannich Bases,Phosphopyranones, Phosphoranylidenes,and Oxaphosphinin on Some Metabolic Aspects of <Emphasis Type="Italic">Biomphalaria Alexandrina</Emphasis>

Summary. Niclosamide reacts with secondary amines and formaldehyde under the condition of Mannich reaction, to give new Mannich bases. The reaction of these niclosamide Mannich bases with active phosphacumulene ylides affords the corresponding phenyliminopyranone, pyranone, and pyranthione, respectively. When Wittig reaction was carried out on the pyranone, using p-nitrobenzaldehyde, a new arylidene and triphenylphosphine oxide were obtained. On the other hand, stabilized phosphonium ylides affect the transylidation of niclosamide Mannich bases to the corresponding phosphoranylidenes. When diphenylmethylenetriphenylphosphorane reacts with a niclosamide Mannich base, an oxaphosphinin was obtained. The molluscicidal potency of the newly synthesized derivatives against Biomphalaria alexandrina was studied, too.     

Chemical Degradation of Lasalocid: (A) The Mannich reaction (B) Baeyer-Villiger oxidation of the retro-aldol ketone

Under Mannich reaction conditions (diethylamine and formaldehyde in toluene under reflux) lasalocid ( 1 ) undergoes a unique transformation in which the carboxyl group is replaced by a diethylaminomethyl group. The resulting Mannich base 2 was converted back to lasalocid, proving that none of the other chemical and stereochemical features of the molecule were disturbed. Like other phenolic Mannich bases, the one derived from lasalocid readily alkylated mercaptans. The known thermal and base-induced retro-aldol degradations of lasalocid both produce a ketone fragment 9 containing the cyclic ether units. Baeyer-Villiger oxidation of this ketone afforded a carboxylic acid fragment which still contained these ether units. The normal regiochemistry involved in oxidizing this ketone (R? CH₂? CO? CHR′R″ type) was cleanly reversed by first converting it into the hydroxymethylidene derivative 10 .     

Chemistry of Phosphorus Ylides. Part 22 [1]. Effect of Newly Synthesized Niclosamide Mannich Bases, Phosphopyranones, Phosphoranylidenes, and Oxaphosphinin on Some Metabolic Aspects of Biomphalaria Alexandrina

Niclosamide reacts with secondary amines and formaldehyde under the condition of Mannich reaction, to give new Mannich bases. The reaction of these niclosamide Mannich bases with active phosphacumulene ylides affords the corresponding phenyliminopyranone, pyranone, and pyranthione, respectively. When Wittig reaction was carried out on the pyranone, using p-nitrobenzaldehyde, a new arylidene and triphenylphosphine oxide were obtained. On the other hand, stabilized phosphonium ylides affect the transylidation of niclosamide Mannich bases to the corresponding phosphoranylidenes. When diphenylmethylenetriphenylphosphorane reacts with a niclosamide Mannich base, an oxaphosphinin was obtained. The molluscicidal potency of the newly synthesized derivatives against Biomphalaria alexandrina was studied, too.     

Diastereoselektive synthese neuartiger Mannich-Basen mittels titanderivaten,vorläufige mitteilung

Diastereoselective Synthesis of Novel Mannich (Bases¹) through Titanium Reagents Trichlorotitanium dialkylamino-alkoxides ( 2 ; titanates of N, O-hemiacetals) are generated either from the corresponding lithium alkoxides and titanium tetrachloride (Scheme 1) or by addition of trichloro-dialkuylamino-titanium to aldehydes. The electrophilic (dialkylamino) alkylating reagents 2 are used to convert lithium enolates to β-dialkylamino-ketones and -esters 5 (Mannich bases), see Scheme 2 and Table. One diastereoisomer of the products 5g–5p thus obtained with cyclohexenolate is formed preferentially (66-84%). The configuration of the products of this first diastereoselective version of the Mannich reaction could not yet be determined. A typical procedure for carrying out the reaction is given.     

Benzimidazole, 7. Mitt.:Mannichbasen-artige Stickstoffloste aus Benzimidazolderivaten

Zusammenfassung Eine derMannichreaktion ähnliche Umsetzung zwischen Bis(2-chloräthyl)amin, Formaldehyd und verschiedenen Benzimidazolen wurde untersucht. Bis(2-chloräthyl)amin kondensiert sich in alkohol. Formaldehydlösung mit einfachen und substituierten 1H-Benzimidazolen unter Bildung der entsprechendenMannichbasen-Stickstoffloste. 2-Benzylbenzimidazol reagiert auf einem anderen Weg unter Bildung von -[Bis(2-chloräthyl)-aminomethyl]-2-benzylbenzimidazol (6).

---

AMannich type reaction involving bis(2-chloroethyl)amine, formaldehyde and various benzimidazoles has been investigated. Bis(2-chloroethyl)amine was shown to condense in ethanol-formaldehyde solution with simple as well as substituted 1H-benzimidazoles to yield the correspondingMannich base nitrogen mustards. The reaction of 2-benzyl-benzimidazole was found to follow another course yielding -[bis(2-chloroethyl)aminomethyl]-2-benzylbenzimidazole (6).

     

Total Synthesis of Cyclothialidine

A total synthesis of cyclothialidine ( 1 ), a new DNA gyrase inhibitor isolated from Streptomyces filipinensis, is described. The synthetic concept was tested by preparing the lactone 13 (Scheme 2) which contains the characteristic bicyclic core entity of 1 . Key features of the synthesis of 1 are: preparation of 3,5-dihydroxy-2,6-dimethylbenzoic acid ( 23 ) from 3,5-dihydroxybenzoic acid ( 19 ) by two consecutive Mannich aminomethylation/hydrogenation sequences; benzylic N-bromosuccinimide bromination of an ester derivative 25 thereof and its subsequent coupling with Boc-Ser-Cys-OMe ( 11 ); cyclization of the ω-hydroxy acid 29 29 to the 12-membered lactone 30 using preferably Mitsunobu conditions; completion of the peptidic side chains of 1 using Boc strategy (Scheme 4). Optically pure cis-N-(tert-butoxycarbonyl)-3-hydroxy-L -proline ((–)- 14 ) was obtained by resolution of the racemate via an efficient reaction sequence containing a lipase-catalyzed enantiospecific acetate hydrolysis (Scheme 3). The structure of natural 1 was confirmed by comparison with the synthetic material. The synthetic route described provides also easy access to analogues of 1 , e.g., via the intermediate 30 .     

Pictet-Spengler reactions of Tryptamine and tryptophan with cycloalkanones and ketonicMannich bases

APictet-Spengler reaction of Tryptamine (1) with cyclopentanone under physiological conditions gave 3-(cyclopentylideneaminoethyl)indole (3), which was cyclized to the 1-spirocyclic 1,2,3,4-tetrahydro-2-carboline (4). Treatment of (±)-tryptophan with cyclopentanone and cyclohexanone in acidic medium afforded the spirocyclic systems5 and6, respectively. ThePictet-Spengler reaction was extended further using ketonic bis-Mannich bases, to give compounds7 and8. The possibility of using other types of ketonic bases was investigated.

---

DiePictet-Spengler-Reaktion von Tryptamin and Tryptophan mit Cycloalkanonen und Keto-Mannich-Basen

Zusammenfassung DiePictet-Spengler-Reaktion von Tryptamin (1) mit Cyclopentanonen ergab unter physiologischen Bedingungen 30(Cyclopentylidenaminoethyl)indole (3), die zu den spirocyclischen Tetrahydro-2-carbolinen4 cyclisiert wurden. Die Behandlung von (±)-Tryptophan mit Cyclopentanon oder Cyclohexanon in saurem Milieu ergab die spirocyclischen Systeme5 oder6. DiePictet-Spengler-Reaktion wurde auch auf Keto-Bis-Mannich-Basen zur Synthese der Verbindungstypen7 und8 ausgeweitet. Die Möglichkeiten zur Nutzung anderer Keto-Basen wurde untersucht.

     

A study on the doubleMannich reaction with 1,3-diphenylacetone

DoubleMannich reaction of the title compound1 with morpholine acetate in ethanol gave the symmetrical bis-base2, whereas such reaction in acetic acid afforded the vinyl-ketonic base3. Reactions of3 with morpholine, piperidine, thiophenol and dimethyl phosphite were investigated.Mannich reaction of2 with primary amines gave di-basically substituted -piperidones6a-b. Compound1 reacts with ethylenediamine and formaldehyde to give the diazatricyclic system7.

---

Untersuchungen zur doppeltenMannich-Reaktion mit 1,3-Diphenylaceton

Zusammenfassung Die Doppel-Mannichreaktion der Titelverbindung1 ergab mit Morpholinacetat in Ethanol die symmetrische Bis-Base2, in Essigsäure erhielt man jedoch die Vinyl-keton-base3. Die Reaktionen von3 mit Morpholin, Piperidin, Thiophenol und Dimethylphosphit wurden untersucht. DieMannich-Reaktion von2 mit primären Aminen ergab di-basisch substituierte -piperidone6a-b. Verbindung1 reagiert mit Ethylendiamin und Formaldehyd unter Ausbildung eines Diaza-tricyclischen Systems7.

     

Elektrophile Substitution und nucleophile Addition an 3,4-Dihydro-5(1H)-pyrromethenonen

3,4-Dihydro-5(1H)-pyrromethenones are easier attacked at themeso-position by electrophiles than 5(1H)-pyrromethenones. This is demonstrated both by aMannich-type-substitution or deuterium-exchange-experiments and by the addition of O-, S-, and N-Nucleophiles to the exocyclic double bond of the model-dihydropyrromethenone (Z)-1 under very mild reaction conditions. Applying these results to the chemistry of 2,3-dihydro-bilatrienes-abc, their chemical characteristics—especially their tautomeric behavior and their dominant C-5-selectivity towards electrophiles—become better understandable.

     

A New and Facile Synthesis of Novel Pyrazolothienopyrimidines and Imidazopyrazolothienopyrimidines

4‐Amino‐3‐methyl‐1‐phenyl‐1H‐thieno[2,3‐c]pyrazole‐5‐carboxamide ( 5 ), which was synthesized by an innovative method, was used as a versatile precursor for synthesizing pyrazolothienopyrimidines and imidazopyrazolothienopyrimidines compounds. Reaction of amino thienopyrazole carboxamide 5 with triethyl orthoformate afforded thienopyrazolopyrimidine 6 . Chlorination of the latter compound, using phosphorus oxychloride afforded the chloro pyrazolothienopyrimidine 7 , which underwent nucleophilic substitution reactions with various primary and secondary amines to give the alkyl (aryl) amino pyrimidine compounds 8a–d . On the other hand, the reaction of chloropyrimidine 7 with thiourea afforded the pyrimidine thione compound 9 , which was alkylated with α‐halogentaed compounds to afford the S‐alkylated derivatives 10a–c . Also, chloroacetylation of the amino carboxamide 5 using chloroacetyl chloride yielded the chloromethyl pyrazolothienopyrimidine 12 , which underwent nucleophilic substitu‐ tion reactions with various primary and secondary amines to afford the alkyl (aryl) aminomethyl compounds 13a–f . The latter Compounds underwent Mannich reaction to give imidazopyrimidothieno‐ pyrazoles 14a–c . The newly synthesized compounds and their derivatives were fully characterized by elemental and spectral analysis.     

Isosteviol?Proline Conjugates as Highly Efficient Amphiphilic Organocatalysts for Asymmetric Three‐Component Mannich Reactions in the Presence of Water

In this work, six isosteviol? amino acid conjugates were designed and synthesized through simple condensation on a large scale without protecting group (Scheme). These amphiphilic organocatalysts mediated asymmetric three‐component Mannich reactions of cyclohexanone and anilines with aromatic aldehydes in the presence of H₂O. Meanwhile, the isosteviol? proline conjugate 3b has been established as a highly efficient catalyst (Table 1), and afforded syn‐Mannich products with excellent diastereoselectivities (syn/anti up to 98 : 2) and enantioselectivities (up to >99% ee; Table 3). The transition state of the reaction in the presence of H₂O is proposed (Fig. 2).     

1-[(Dimethylamino)methyl]pyrrol aus Trimethyl (1-pyrrolyl)-ammonium-Ion

1-[(Dimethylamino)methyl]pyrrole from Trimethyl (1-pyrrolyl)ammonium Ion Trimethyl (1-pyrrolyl)ammonium iodide ( 5a ) and the corresponding p-toluene-sulfonate 5b are transformed by strong bases into 1-[(dimethylamino)methyl]-pyrrole ( 9 ), i.e. into a N-Mannich base, a type of compound novel in the pyrrole series. In this reaction, which is very fast in DMSO, the cation of compounds 5 is deprotonated to form the nitrogen ylide 6 . The latter undergoes a Stevens-type rearrangement to 9 . Several facts, namely the negative outcome of a cross-reaction experiment with 3,4-dimethylpyrrole and of an attempt to obtain 9 from pyrrole and dimethyl (methylidene)ammonium iodide in the presence of one equivalent of sodium methoxide, as well as unsuccessful CIDNP studies point to a rearrangement mechanism via the contact ion pair 12 .     

A New Total Synthesis of dl-Pumiliotoxin-C via an Indanone

dl-Pumiliotoxin-C (4) was synthesized in a practical manner from trans-4-hexenal (9) . The key step 14 → 15 (Scheme 3) involves an intramolecular Diels-Alder reaction giving mainly the cis-fused indanols 15a , which were converted to the cis-fused ketone 16 . After Beckmann-rearrangement of 16 the octahydroquinolinone 7 was transformed to the lactim-ether 23 . (Scheme 7). Reaction of 23 with propylmagnesium bromide followed by hydrogenation furnished dl- 4 in a highly stereoselective fashion.     

Total Synthesis of β-Bulnesene and 1-Epi-β-bulnesene by Intramolecular Photoaddition

dl-β-Bulnesene (1) and dl-1-epi-α-bulnesene (15) have been synthesized starting from the bromide 4 (Schemes 2 and 3). In the key step 9→10 the bonds of the final product were formed by an intramolecular photoaddition. The synthesis was completed by the fragmentation 12→14 and the Wittig reaction 14→15+1 .     

Umlagerung von Vinyl-Cyclopropan-Carbaminalen

Rearrangement of Vinyl-Cyclopropane-Carbaminals Both (c-2, t-3-diphenyl-r-1-cyclopropyl)methylene-dipyrrolidine ( 4 ) and its (t-2, t-3)-isomer 10 underwent a thermal rearrangement to (E)-N-2-benzylidene-1-indanyl-pyrrolidine ( 5 ). Under the conditions of the rearrangement, 5 was partially converted into 2-benzyl-1-indanone ( 6 ) in a base catalysed reaction. The structures of 5 and 6 were derived from spectroscopic data and from degradation reactions.- N,N′-(t-2-Vinyl-r-1-cyclopropyl)methylene-dipyrrolidine ( 11 ) rearranged thermally to N-(2-methylidene-3-cyclopenten-1-yl)pyrrolidine ( 12 ), the structure of which was established from spectroscopic evidence and from a hydrogenation to N-(2-methylcyclopentyl)pyrrolidine ( 13 , cis/trans mixture 3:2). The aminal 4 was reduced with formic acid to give N-(c-2, t-3-diphenyl-r-1-cyclopropyl)methyl-pyrrolidine ( 14 ). If perdeuterio formic acid was used, the mixture product 14-d/14-d ₂ was obtained which contained exactly one deuterium atom in its methylene group and about half a deuterium atom on C(1). This labeling pattern is mechanistically explained with the existence of a fast equilibrium between the iminium ion 19 and the enamine 18 , so that 18 and 19 are considered to be plausible reactive intermediates in the above mentioned thermal rearrangement. - Based on this, several mechanisms for the rearrangements 4 → 5, 10 → 5 and 11 → 12 were considered: A Pictet-Spengler- or Mannich-type reaction, which starts from the iminium ion 23 and is followed by a cyclopropylmethyl-homoallylic rearrangement and by deprotonation (path a, Scheme 5), was judged to be improbable because the postulated intermediates could lead more easily to other stable products than the observed ones. If the reaction is formulated as a [3,3]-sigmatropic shift occurring on exclusively the (E)-isomer 5 suggests a concerted process whose steric course is predominantly controlled by strain factors. Alternatively, the reaction could be formulated via a dipolar ( 27 ) or a diradical ( 26 ) species derived from the enamine 22 (paths c and d, Scheme 5); attempts to trap such species by a number of agents were unsuccessful. - The previously unknown aminals 10 and 11 were synthesized by standard methods.     

Basic Functionalized Ionic Liquid Catalyzed One-pot Mannich-type Reaction: Three Component Synthesis of β-Amino Carbonyl Compounds

Summary. Three-component Mannich-type reaction of cyclohexanone, aromatic aldehydes, and aromatic amines was catalyzed by a basic functionalized ionic liquid, 1-butyl-3-methylimidazolium hydroxide ([bmim][OH]), at room temperature to give various β-amino carbonyl compounds in high yields. The ionic liquid, which is environmentally friendly, can be recycled at least 5 times without significant loss of activity.     

Microwave Assisted Mannich Reaction of Terminal Alkynes on Alumina

Summary.  Terminal alkynes, secondary amines, and formaldehyde undergo a Mannich reaction at room temperature in the presence of CuCl on Al₂O₃ without any organic solvent as reaction medium. The reaction can be promoted by microwave irradiation and is complete within one minute. Received May 2, 2001. Accepted (revised) June 25, 2001