Search

Chiral 1,2-diamines are privileged structural motifs in organocatalysis, whereas efficient 1,3-diamine-derived organocatalysts are very rare. Herein we report a highly efficient camphor-1,3-diamine-derived squaramide organocatalyst. Its catalytic activity in Michael additions of 1,3-dicarbonyl nucleophiles to trans-β-nitrostyrene derivatives provides excellent enantioselectivities (up to >99% ee).

Synthesis and catalyst performance of 2,3- (types and ) and 2,8-disubstituted (type ) thiourea bifunctional organocatalysts was attempted. The synthesis of catalyst of type has, so far, not been realized, while catalysts of type , i.e., the 2,3-exo- and the 2-endo-3-exo-thiourea catalysts, were prepared in six steps starting from (+)-camphor. The catalysts of type were prepared from (+)-camphor in eight steps. All the potential catalysts as well as most of the intermediate products were carefully structurally characterized. The thiourea bifunctional organocatalysts were tested in a model reaction of Michael addition of dimethyl malonate to trans-β-nitrostyrene.

A simple and straightforward four-step synthesis of novel diastereomeric L-phenylalanine-derived pyrazolidin-3-ones is described. The absolute configuration of the novel C(5) stereogenic centre has been unambiguously determined by single crystal X-ray analysis and via chemical interconversions. A series of novel thiourea derived pyrazolidinones have been prepared and tested as potential organocatalysts. N(1) un-substituted pyrazolidinones can be used for the construction of a novel type of bicyclic heterocycles and other selective derivatizations. Chirality 25:541–555, 2013. © 2013 Wiley Periodicals, Inc.

Two novel 4-substituted camphidine derivatives 10a,b have been prepared from (+)-camphor (1 )i nfive steps, the Beckmann rearrangement being the bottleneck of the synthe- sis. Isoborneol derivative 5b, formed as a side product during the hydrogenation of arylidene ketone 3b, under Beckmann rearrangement conditions yielded interesting novel rearrangement products 11 and 12 .( 1S)-(+)-Camphorquinone (13) was transformed into diamines 15 and 16 in two steps, the former being cyclized into an imidazoline salt 17 ,a nN-heterocyclic carbene precursor. The structures of all novel compounds have been meticulously characterized using NMR techniques and/or single crystal X-ray analysis. Chirality 24:778-788, 2012. © 2012 Wiley Periodicals, Inc.

N-Protected L-phenylalanines 1a,b were transformed, via the corresponding Weinreb amides 2 and ethynyl ketones 3, into chiral enamino ketones 4 (Scheme 1). Similarly, L-threonine 6 was transformed in four steps into the enamino ketone 10. Cyclocondensations of 4 and 10 with pyrazolamines 11, benzenecarboximidamide (12), and hydrazine derivatives 18 afforded N-protected 1-heteroaryl-2-phenylethanamines 15a–e, 16, 17, and 21a–k and 1-heteroaryl-1-aminopropan-2-ols 23a,b in good yields (Schemes 2 and 3). Finally, deprotection by catalytic hydrogenation furnished free amines 22a–g and 24a,b (Scheme 3).

Reactions of ethyl 3-[(E)-(dimethylamino)methylidene]pyruvate (3) and 3-[(dimethylamino)methyl-idene]-2-oxosuccinate (4) with hydrazine monohydrochloride (5a) and (hetero)arylhydrazines (5b-i) afforded, regioselectively, 1-substituted ethyl 1H-pyrazole-5-carboxylates 9a-f and diethyl 1H-pyrazole-3,4-dicarboxylates, 11a-i, respectively. Upon treatment of 3 with pyridazinylhydrazines 5d-f, the stable intermediates, 1-substituted ethyl 4,5-dihydro-5-hydroxy-1H-pyrazole-5-carboxylates 8d-f, were isolated. Treatment of compounds 8d-f in acetic acid under reflux furnished the pyrazoles 9d-f. On the other hand, reaction of 3 with N,N′-dimethylhydrazine (51) gave ethyl 1-methyl-1H-pyrazole-3-carboxylate (14). The structures of compounds 3, 4, 14 were determined by nmr (noesy and hmbc techniques), while the structures of compounds 8f, 9f, and 11e, f were determined by X-ray diffraction.

A simple, metal-free method for the synthesis of the title pyridines is developed, which complements the existing methods of 2-pyridine synthesis by coupling reactions of organometallic reagents.

(NH3OH)2MnF4 (I) and (NH3OH)3ScF6 (II) crystals are prepared by reacting NH3OHF with solutions of Mn2O3 or ScF3 in aqueous HF followed by solvent evaporation.

N-protected α-amino acids can be converted to enaminones [e.g. compound (III)], which can be isolated, but in many cases easily transform into 4-hydroxypyrroles and their 4-oxo-tautomers [e.g. compounds (IV) and (V)].

A novel simple five-step synthesis of 1,6-disubstituted tetrahydropyrazolo[1,5- c ]pyrimidine-2,7(1 H ,3 H )-diones has been developed. The synthetic protocol starts with ‘ring switching’ transformation of commercially available 5,6-dihydro-2 H -pyran-2-one into the 5-(2-hydroxyethyl)pyrazolidin-3-one, followed by addition of the latter to isocyanates, Appel bromination, cyclization, and N(1)-alkylation with alkyl halides to give the title compounds. In comparison to a 12-step synthesis reported recently, the present method is clearly superior with respect to the number of synthetic steps and versatility of substituents at position 6.

The 5,5-dimethylpyrazolidin-3-one (4), prepared from ethyl 3-methylbut-2-enoate (3) and hydrazine hydrate, was treated with various substituted benzaldehydes 5a – i to give the corresponding (1Z)-1-(arylmethylidene)-5,5-dimethyl-3-oxopyrazolidin-1-ium-2-ide azomethine imines 6a – i. The 1,3-dipolar cycloaddition reactions of azomethine imines 6a – h with dimethyl acetylenedicarboxylate (=dimethyl but-2-ynedioate; 7) afforded the corresponding dimethyl pyrazolo[1,2-a]pyrazoledicarboxylates 8a – h, while by cycloaddition of 6 with methyl propiolate (=methyl prop-2-ynoate; 9), regioisomeric methyl pyrazolo[1,2-a]pyrazolemonocarboxylates 10 and 11 were obtained. The regioselectivity of cycloadditions of azomethine imines 6a – i with methyl propiolate (9) was influenced by the substituents on the aryl residue. Thus, azomethine imines 6a – e derived from benzaldehydes 5a – e with a single substituent or without a substituent at the ortho-positions in the aryl residue, led to mixtures of regioisomers 10a – e and 11a – e. Azomethine imines 6f – i derived from 2,6-disubstituted benzaldehydes 5f – i gave single regioisomers 10f – i.

An on-line estimation of the specific growth rate of an aerobic fermentation batch process was conducted based on measurements of oxygen or carbon dioxide concentrations in exhaust gas, or the concentrations of dissolved oxygen in the liquid phase in the fermentor. A simple linear model used was upgraded with a mechanism for a time-varying forgetting factor to enable good tracking of estimated parameters as well during rapid and large changes in the process. Because the measuring methods used are independent of each other and can identify the process well, mutual control of individual sensors is also possible in industrial reactors. The results from the model agree well with experimentally obtained values for bacitracin fermentation in an 80-m3 and 1.5-m3 batch bioreactor. The model provides a good basis for robust adaptive regulation of aerobic batch processes.

4(R)-(6-Chloro-s-triazolo[4,3-b]pyridazinyl-3)-1,4-furanoses 10 and 11, 5(R)-(6-chloro-s-triazolo[4,3-b]pyridazinyl-3)-1,5-pyranose 13, and 2(S),3(R)-dihydro-5-(6-chloro-s-triazolo[4,3-b]pyridazinyl-3)-2,3-O-isopropylidenefuran (12) were prepared by cyclization of hydrazones 6–9 obtained from 6-chloro-3-hydrazinopyridazine (1) and aldofuranoses 2, 3 and 4, and aldopyranose 5.

The synthesis of ethyl 2-(2-acetyl-2-benzoyl-1-ethenyl)amino-3-dimethylarninopropenoate (4) from benzoylacetone (1) via 3-dimethylarninomethylenebenzoylacetone (2) and ethyl N-(2-acetyl-2-benzoyl-1-ethenyl)glycinate (3) and its transformation into 4-benzoyl-2-ethoxycarbonyl-3-methylpyrrole (9) is described. Cyclization of 4 into 9 represents a new synthesis of polysubstituted pyrroles.

Alkyl (E,Z)-2-(2-benzoyl-2-ethoxycarbonyl-1-ethenyl)amino-3-dimethylaminopropenoates 1a,b react with het-eroarylamines 2 to give alkyl 2-(2-benzoyl-2-ethoxycarbonyl-1-ethenyl)amino-3-heteroarylaminopropenoates 3-13. These were cyclized into fused 3-(2-benzoyl-2-ethoxycarbonyl-1-ethenyl)amino-4H-azolo- (or azino)-pyrim-idin-4-ones 14-18. 2-Benzoyl-2-ethoxycarbonyl-1-ethenyl group can be easily removed from 3-(2-benzoyl-2-ethoxycarbonyl-1-emenyl)amino-8-memyl-4H-pyrido[1,2-a]pyrimidin-4-one (14) to give 3-amino-8-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (19). The structure of 1a was confirmed by X-ray analysis.

In connection with our studies on potential bioactive compounds some new polysubstituted 3-thiocarbamoylthiazolidines 5, 6, 7, 9 and 10 were prepared in the reaction between 2-(2-methoxy-phenyl)iminothiazolidine (2) and sulfamoylphenyl isothiocyanates 3 and 4a-c. The structures for compounds 2 and 5 were established by X-ray analyses, showing that the reaction is taking place at the endo-cyclic nitrogen atom of thiazolidine ring.

A series of tetrahydropyrazolo[1,5- c ]pyrimidine-2,7(1 H ,3 H )-diones 3a – h as the first representatives of the so far unexplored saturated heterocyclic system have been synthesized, formally in 12 steps from methyl acrylate ( 4 ). The synthesis comprises a four-step preparation of methyl N -Cbz-5-alkylamino-3-oxopentanoates 9a–c , their three-step transformation into 5-{2-[(alkyl)(benzyloxycarbonyl)amino]ethyl}pyrazolidin-3-ones 12a – c , three-step selective alkylation of the amidic N-2 to give 2-alkyl-5-{2-[(alkyl)(benzyloxycarbonyl)amino]ethyl}pyrazolidin-3-ones 16b – h , followed by hydrogenolytic Cbz-deprotection and subsequent cyclization of the intermediate 1,4-diamine with CDI to furnish the title compounds 3 . Most of the synthetic steps were performed as a one-pot transformation.

Eleven (S)-1,6-dialkylpiperazine-2,5-diones and five (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones were prepared in three steps from the corresponding (S)-α-amino acid esters comprising of reductive N-alkylation, N-acylation and cyclisation. The synthesis of (S)-1,6-dialkylpiperazine-2,5-diones has a broad scope allowing preparation of diketopiperazines with primary and secondary alkyl groups at N(1), while the synthesis of (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones is limited to compounds with primary alkyl groups at N(1). Reductive alkylation of amino acid ester hydrochlorides by catalytic hydrogenation in the presence of a carbonyl compound proved to be a simple, efficient and general method for the preparation of stable (storable) α-alkylamino acid ester hydrochlorides. The structures of the novel compounds were determined by NMR and X-ray diffraction.

In connection with our studies on potential bioactive compounds some new polysubstituted 3-thiocarbamoylthiazolidines 5, 6, 7, 9 and 10 were prepared in the reaction between 2-(2-methoxy-phenyl)iminothiazolidine (2) and sulfamoylphenyl isothiocyanates 3 and 4a-c. The structures for compounds 2 and 5 were established by X-ray analyses, showing that the reaction is taking place at the endo-cyclic nitrogen atom of thiazolidine ring.

Alkyl (E,Z)-2-(2-benzoyl-2-ethoxycarbonyl-1-ethenyl)amino-3-dimethylaminopropenoates 1a,b react with het-eroarylamines 2 to give alkyl 2-(2-benzoyl-2-ethoxycarbonyl-1-ethenyl)amino-3-heteroarylaminopropenoates 3-13. These were cyclized into fused 3-(2-benzoyl-2-ethoxycarbonyl-1-ethenyl)amino-4H-azolo- (or azino)-pyrim-idin-4-ones 14-18. 2-Benzoyl-2-ethoxycarbonyl-1-ethenyl group can be easily removed from 3-(2-benzoyl-2-ethoxycarbonyl-1-emenyl)amino-8-memyl-4H-pyrido[1,2-a]pyrimidin-4-one (14) to give 3-amino-8-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (19). The structure of 1a was confirmed by X-ray analysis.

The synthesis of ethyl 2-(2-acetyl-2-benzoyl-1-ethenyl)amino-3-dimethylarninopropenoate (4) from benzoylacetone (1) via 3-dimethylarninomethylenebenzoylacetone (2) and ethyl N-(2-acetyl-2-benzoyl-1-ethenyl)glycinate (3) and its transformation into 4-benzoyl-2-ethoxycarbonyl-3-methylpyrrole (9) is described. Cyclization of 4 into 9 represents a new synthesis of polysubstituted pyrroles.

4(R)-(6-Chloro-s-triazolo[4,3-b]pyridazinyl-3)-1,4-furanoses 10 and 11, 5(R)-(6-chloro-s-triazolo[4,3-b]pyridazinyl-3)-1,5-pyranose 13, and 2(S),3(R)-dihydro-5-(6-chloro-s-triazolo[4,3-b]pyridazinyl-3)-2,3-O-isopropylidenefuran (12) were prepared by cyclization of hydrazones 6–9 obtained from 6-chloro-3-hydrazinopyridazine (1) and aldofuranoses 2, 3 and 4, and aldopyranose 5.

[reaction: see text] Reaction of 5,5-dimethyl-3-pyrazolidinone (1) with 2-indanone (2) gave 5,5-dimethyl-2-(1H-indenyl-2)-3-pyrazolidinone (3) instead of the expected azomethine imine 4. Although reaction of 2-substituted 3-pyrazolidinones with acetylenedicarboxylates usually gives ring expansion products, such as 1,2-diazepines, treatment of 3 with dialkyl acetylenedicarboxylates (5, R = Me; 6 R = Et) resulted in the formation of rel-(7aR,12aS)-6,7-bis(alkoxycarbonyl)-3,4-dihydro-4,4-dimethyl-7aH-indano[1,2-b]pyrrolo[1,2-a]pyrimidin-2-ones (7, R = Me; 9, R = Et) as major products and 3,4-bis(alkoxycarbonyl)-7,7-dimethyl-2-(indenyl-2)-6,7-dihydro-2H,6H-1,2-diazepin-5-ones (8, R = Me: 10, R = Et) as minor products.

Some new aplysinopsin analogues were prepared by a simple coupling of N , N -(dimethylamino)methylidene substituted hydantoin, thiohydantoin, and thiazolone derivatives, with indole derivatives. Configuration around the exocyclic CC double bond was determined on the basis of long-range heteronuclear coupling constants using 2D HMBC correlation technique.

Ethyl (Z)-2-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-(dimethylamino)propenoate was prepared in one step from ethyl (2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)acetate and bis(dimethylamino)-tert-butoxymethane and treated with various amines and hydrazines to afford the corresponding amino substituted products. Reactions of the titled compound with N,N'-, C,N-, and C,O'-ambident nucleophiles in refluxing acetic acid furnished the corresponding fused pyrimidinones, quinolizinones, and pyranones.

Easily accessible cycloalkenyl-1-diazenes and β-dicarbonyl compounds are converted in one-pot into previously unknown functionalized fused cycloalkenyliden-pyrroles of different sizes. The domino reaction proceeds through a base-catalyzed conjugate addition/cyclization/elimination sequence.

A series of substituted 5-hydroxy-lH-pyrazoles (5) was prepared by treatment of 4-hydroxymethylidene-2-phenyloxazol-5(4H)-one (1) with ethanol followed by reaction with phenylhydrazines and subsequent treatment with NaOH. Structures of the pyrazoles (5p) and (5r) were confirmed by X-ray structure analysis.

A one-pot, three-step regio- and stereoselective synthesis of unknown functionalized oxazoline-fused pyridazines is reported. The approach involves base-assisted 'Michael addition-pyridazine cyclization-oxazoline cyclization' cascade reactions of 4-chloro-1,2-diaza-1,3-butadienes with 3-dimethylaminopropenoates.

Various aplysinopsin and β -carboline thiohydantoin analogues were prepared starting from ethyl 3-formyl-1H-indole-2-carboxylate by condensation with the active methylene group of 2-thiohydantoin, rhodanine, or thiobarbituric acid derivatives

(S)-3-(Dimethylamino)methylidene-5-benzyltetramic acid derivatives 4a and 4b were prepared in three steps from N-protected (S)-3-phenylalanines la and 1b, respectively. Similarly, N-[N-(benzyloxycarbonyl)glycyl]glycine (1c) was transformed into the enaminone 4c. Acid-catalysed coupling of enaminones 4a-c with aliphatic, aromatic, and heteroaromatic primary amines 5-34 afforded the corresponding N(3')-substituted 3-aminomethylidenetetramic acid derivatives 35-64 in 29-96% yields.

We observed a nucleophilic attack by the ene-amino carbon of 3-dimethylaminopropenoates at the terminal carbon of the azo-ene system of 1,2-diaza-1,3-butadienes. In tetrahydrofuran at 65 degrees C, this attack produced 1-aminopyrrolines with a high degree of cis-stereoselectivity by means of an unusual zwitterionic adduct intermediate followed by intramolecular ring closure. In toluene under reflux, 1-aminopyrrolines produced oxazoline-fused 1-aminopyrrolines. Oxazoline-fused 1-aminopyrrolines were directly obtained by reaction of 1,2-diaza-1,3-butadienes with 3-dimethylaminopropenoates in toluene under reflux. The ring opening of oxazoline-fused 1-aminopyrrolines in acidic or basic media provides highly substituted 1-aminopyrroles. 5-Unsubstituted 1-aminopyrrole derivatives were obtained from 1-aminopyrrolines under basic conditions by loss of dimethylamino and ester groups. We discuss the plausible mechanisms of the ring closure and opening.

Reactions of ethyl 3-[(E)-(dimethylamino)methylidene]pyruvate (3) and 3-[(dimethylamino)methyl-idene]-2-oxosuccinate (4) with hydrazine monohydrochloride (5a) and (hetero)arylhydrazines (5b-i) afforded, regioselectively, 1-substituted ethyl 1H-pyrazole-5-carboxylates 9a-f and diethyl 1H-pyrazole-3,4-dicarboxylates, 11a-i, respectively. Upon treatment of 3 with pyridazinylhydrazines 5d-f, the stable intermediates, 1-substituted ethyl 4,5-dihydro-5-hydroxy-1H-pyrazole-5-carboxylates 8d-f, were isolated. Treatment of compounds 8d-f in acetic acid under reflux furnished the pyrazoles 9d-f. On the other hand, reaction of 3 with N,N′-dimethylhydrazine (51) gave ethyl 1-methyl-1H-pyrazole-3-carboxylate (14). The structures of compounds 3, 4, 14 were determined by nmr (noesy and hmbc techniques), while the structures of compounds 8f, 9f, and 11e, f were determined by X-ray diffraction.

The 5,5-dimethylpyrazolidin-3-one (4), prepared from ethyl 3-methylbut-2-enoate (3) and hydrazine hydrate, was treated with various substituted benzaldehydes 5a – i to give the corresponding (1Z)-1-(arylmethylidene)-5,5-dimethyl-3-oxopyrazolidin-1-ium-2-ide azomethine imines 6a – i. The 1,3-dipolar cycloaddition reactions of azomethine imines 6a – h with dimethyl acetylenedicarboxylate (=dimethyl but-2-ynedioate; 7) afforded the corresponding dimethyl pyrazolo[1,2-a]pyrazoledicarboxylates 8a – h, while by cycloaddition of 6 with methyl propiolate (=methyl prop-2-ynoate; 9), regioisomeric methyl pyrazolo[1,2-a]pyrazolemonocarboxylates 10 and 11 were obtained. The regioselectivity of cycloadditions of azomethine imines 6a – i with methyl propiolate (9) was influenced by the substituents on the aryl residue. Thus, azomethine imines 6a – e derived from benzaldehydes 5a – e with a single substituent or without a substituent at the ortho-positions in the aryl residue, led to mixtures of regioisomers 10a – e and 11a – e. Azomethine imines 6f – i derived from 2,6-disubstituted benzaldehydes 5f – i gave single regioisomers 10f – i.