pinecone/core-2020-05-10-deduplication huggingface dataset:
Reaction of gamma-Hydroxy-N-[1-(dimethylcarbamoyl)ethyl]butanamides under the ‘Direct Amide Cyclization’ Conditions

The preparation of the title compounds was achieved via the ‘azirine/oxazolone method’ starting from the corresponding gamma-hydroxy acids. Upon subjecting the gamma-hydroxy-N-[1-(dimethylcarbamoyl)-\ud
ethyl]butanamides 4 to the so-called ‘direct amide cyclization’ (DAC) conditions, chlorinated acids 11 or imino lactones 12 were obtained as the sole products instead of the expected cyclodepsipeptides A or their cyclodimers (Scheme 4). Variation of the substituents in 4 did not affect the outcome of the reaction and a mechanism for the formation of both products from the intermediate oxazolone 13 has been proposed. Under the acidic conditions of the DAC, the imino lactones are formed as their HCl salts 12,\ud
which, in polar solvents or on silica gel, reacted further to give the chlorinated acids 11. Stabilization of the imino lactones was achieved by increasing the substitution in the five-membered ring, and their structure, in the form of the hydrochlorides, was established independently by X-ray crystallography (Fig. 4). A derivative 15 of the imino lactone 12a was prepared by the reaction with the 2H-azirin-3-amine 10a; its structure was also established by an X-ray crystal-structure determination (Fig. 3). Furthermore, the structures of the omega-chloro acids 11a and 11b were determined by X-ray crystallography (Fig. 2)
The ‘Azirine/Oxazolone Method’ on solid phase: Introduction of various alpha,alpha-disubstituted alpha-Amino Acids

Peptides containing various alpha,alpha-disubstituted alpha-amino acids, such as alpha-aminoisobutyric acid (Aib), 1-aminocyclopentane-1-carboxylic acid, alpha-methylphenylalanine, and 3-amino-3,4,5,6-tetrahydro-2Hpyran-3-carboxylic acid have been synthesized from the N- to the C-terminus by the ‘azirine/oxazolone method’ under solid-phase conditions. In this convenient method for the synthesis of sterically demanding peptides on solid-phase, 2H-azirin-3-amines are used to introduce the alpha,alpha-disubstituted alpha-amino acids without the need for additional reagents. Furthermore, the synthesis of poly(Aib) sequences has been explored
The first ring-enlargement of a 1-Azabicyclo[1.1.0]butane to a 1-Azabicyclo[2.1.1]hexane

The reactions of 3-phenyl-1-azabicyclo[1.1.0]butane (4) with dimethyl dicyanofumarate ((E)-8) and dimethyl dicyanomaleate ((Z)-8) lead to the same mixture of cis- and trans-4-phenyl-1-azabicyclo[2.1.1]-hexane 2,3-dicarboxylates (cis-11 and trans-11, resp.; Scheme 3). This result of a formal cycloaddition to the central C-N bond of 4 is interpreted by a stepwise reaction mechanism via a relatively stable zwitterionic intermediate 10, which could be intercepted by morpholine to give a 1 : 1 : 1 adduct 12, which undergoes a spontaneous elimination of HCN to yield the fumarate 13 (Scheme 4)
Regio- and stereoselectivity in the Lewis acid- and NaH-induced reactions of thiocamphor with (R)-2-vinyloxirane

The reaction of the enolizable thioketone (1R,4R)-thiocamphor (=(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-thione; 1) with (R)-2-vinyloxirane (2) in the presence of a Lewis acid such as SnCl4 or SiO2 in anhydrous CH2Cl2 gave the spirocyclic 1,3-oxathiolane 3 with the vinyl group at C(4’), as well as the isomeric enesulfanyl alcohol 4. In the case of SnCl4, an allylic alcohol 5 was obtained in low yield in addition to 3 and 4 (Scheme 2). Repetition of the reaction in the presence of ZnCl2 yielded two diastereoisomeric 4-vinyl-1,3-oxathiolanes 3 and 7 together with an alcohol 4, and a ‘1 :2 adduct’ 8 (Scheme 3). The reaction of 1 and 2 in the presence of NaH afforded regioselectively two enesulfanyl alcohols 4 and 9, which, in CDCl3 , cyclized smoothly to give the corresponding spirocyclic 1,3-oxathiolanes 3, 10, and 11, respectively (Scheme 4). In the presence of HCl, epimerization of 3 and 10 occurred to yield the corresponding epimers 7 and 11, respectively (Scheme 5). The thio-Claisen rearrangement of 4 in boiling mesitylene led to the allylic alcohol 12, and the analogous [3,3]-sigmatropic rearrangement of the intermediate xanthate 13, which was formed by treatment of the allylic alcohol 9 with CS2 and MeI under basic conditions, occurred already at room temperature to give the dithiocarbonate 14 (Schemes 6 and 7). The presented results show that the Lewis acid-catalyzed as well as the NaH-induced addition of (R)-vinyloxirane (2) to the enolizable thiocamphor (1) proceeds stereoselectively via an SN2-type mechanism, but with different regioselectivity
Synthesis of Enniatin-like Cyclic Depsipeptides via direct Amide Cyclization

The synthesis of several 18-membered cyclodepsipeptides with an alternating sequence of a,a-disubstituted a-amino acids and a-hydroxy acids (compounds 14a–14e) is described. The ring closure via macrolactonization\ud
was accomplished by treatment of a diluted suspension of the corresponding linear precursors 12a–12e in toluene with HCl gas, i.e., the so-called 'direct amide cyclization'. The incorporation of the a,a-disubstituted a-amino acids was achieved via the 'azirine/oxazolone method' with 2H-azirin-3-amines of type 6 and 9 as building blocks. The structure of the cyclic depsipeptide 14a was established by X-ray crystallography
Reactions of 2-unsubstituted 1H-Imidazole 3-Oxides with 2,2- Bis(trifluoromethyl)ethene-1,1-dicarbonitrile: A stepwise 1,3-dipolar Cycloaddition

The reaction of 1,4,5-trisubstituted 1H-imidazole-3-oxides 1 with 2,2-bis(trifluoromethyl)ethene-1,1-dicarbonitrile (7, BTF) yielded the corresponding 1,3-dihydro-2H-imidazol-2-ones 10 and 2-(1,3-dihydro-\ud
2H-imidazol-2-ylidene)malononitriles 11, respectively, depending on the solvent used. In one example, a 1 : 1 complex, 12, of the 1H-imidazole 3-oxide and hexafluoroacetone hydrate was isolated as a second product. The formation of the products is explained by a stepwise 1,3-dipolar cycloaddition and subsequent fragmentation. The structures of 11d and 12 were established by X-ray crystallography
Novel N-(2,2-Dimethyl-2H-azirin-3-yl)-L-prolinates as Aib-Pro Synthons

The syntheses of phenacyl N-(2,2-dimethyl-2H-azirin-3-yl)-L-prolinate and allyl N-(2,2-dimethyl-2H-azirin-3-yl)-L-prolinate are reported. Reactions of these 2H-azirin-3-amine derivatives with Z-protected amino acids have shown them to be suitable synthons for the Aib-Pro unit in peptide synthesis. After incorporation into the peptide by means of the 'azirine/oxazolone method', the C-termini of the resulting peptides were deprotected selectively with Zn in AcOH or by a mild Pd0-promoted procedure, respectively
1,5-Dipolar electrocyclizations in reactions of alpha-Thioxo Ketones and alpha-Thioxo Thioamides with Diazo compounds

Several reactions of a-thioxo ketones and a-thioxo thioamides with diazo compounds were investigated. Most of them proceeded via a reactive thiocarbonyl ylide, which underwent a [2+3] cycloaddition with the a-thioxo ketone to give the 'Schönberg products' 17–19 or a 1,5-dipolar electrocyclization to give the corresponding five membered 1,3-oxathioles (i.e., 13, 20a, 20b, 21, and 25) and 1,3-dithioles (i.e., 33, 34, and 35), respectively. In the case of thioamide 32, the thiocarbonyl ylides underwent a competitive 1,3-dipolar electrocyclization to yield the corresponding thiiranes. In these cases, spontaneous desulfurization led to the corresponding alkenes 36 and 37. The nature of the employed thiocarbonyl\ud
or diazo compounds seem to be decisive for the reaction pathway. When the diazo compound bears at least one H-atom in the b-position to the diazo group (i.e., diazocyclohexane 15f), no products of an electrocyclization\ud
could be isolated in the reactions with a-thioxo ketones or a-thioxo thioamides. The only products which were isolated in these cases were 2-[(cyclohex-1-enyl)sulfanyl]-1,2-diphenylethanone (22) and 2-[(cyclohex-1-enyl)sulfanyl]-N,N-dimethyl-2-phenylthioacetamide (38), which were formed\ud
by a [1,4]-H shift of the corresponding thiocarbonyl ylides
Reactions of alpha,beta-unsaturated Thioamides with Diazo compounds

Several reactions of the a,b-unsaturated thioamide 8 with diazo compounds 1a–1d were investigated. The reactions with CH2N2 (1a), diazocyclohexane (1b), and phenyldiazomethane (1c) proceeded via a 1,3-dipolar cycloaddition of the diazo dipole at the C=C bond to give the corresponding 4,5-dihydro-1H-pyrazole-3-carbothioamides 12a–12c, i.e., the regioisomer which arose from the bond formation between the N-terminus of the diazo compound and the C(alpha)-atom of 8. In the reaction of 1a with 8, the initially formed cycloadduct, the 4,5-dihydro-3H-pyrazole-3-carbothioamide 11a, was obtained after a short reaction time. In the case of 1c, two tautomers 12c and 12c’ were formed, which, by derivatization with 2-chlorobenzoyl chloride 14, led to the crystalline products 15 and 15’. Their structures were established by X-ray crystallography. From the reaction of 8 and ethyl diazoacetate (1d), the opposite regioisomer 13 was formed. The monosubstituted thioamide 16 reacted with 1a to give the unstable 4,5-dihydro-1H-pyrazole-3-carbothioamide 17
Reactions of Thioketones possessing a conjugated C=C bond with Diazo compounds

The reactions of several thioketones containing a conjugated C=C bond with diazo compounds were investigated. All of the selected compounds reacted via a 1,3-dipolar cycloaddition with the C=S group and subsequent N2 elimination to yield thiocarbonyl ylides as intermediates, which underwent a 1,3-dipolar electrocyclization to give the corresponding thiirane 25, or, by a subsequent desulfurization, to give the olefins 33a and 33b. None of the intermediate thiocarbonyl ylides reacted via 1,5-dipolar electrocyclization.\ud
If the a,b-unsaturated thiocarbonyl compound bears an amino group in the b-position, the reactions with diazo compounds led to the 2,5-dihydrothiophenes 40a–40d. In these cases, the proposed mechanism of the reactions led once more to the thiocarbonyl ylides 36 and thiiranes 38, respectively. The thiiranes reacted via an SNi’-like mechanism to give the corresponding thiolate/ammonium zwitterion 39, which underwent a ring closure to yield the 2,5-dihydrothiophenes 40. Also in these cases, no 1,5-\ud
dipolar electrocyclization could be observed. The structures of several key products were established by X-ray crystallography
1,5-Dipolar electrocyclizations of Thiocarbonyl Ylides bearing C=N groups: Reactions of N-[(Dimethylamino)methylene]thiobenzamide and 2-(Dimethylhydrazono)-1-phenylethane-1-thione with Diazo compounds

The reactions of thiobenzamide 8 with diazo compounds proceeded via reactive thiocarbonyl ylides as intermediates, which underwent either a 1,5-dipolar electrocyclization to give the corresponding five-membered heterocycles, i.e., 4-amino-4,5-dihydro-1,3-thiazole derivatives (i.e., 10a, 10b, 10c, cis-10d, and trans-10d) or a 1,3-dipolar electrocyclization to give the corresponding thiiranes as intermediates, which underwent a SNi’-like ring opening and subsequent 5-exo-trig cyclization to yield the isomeric 2-amino-2,5-dihydro-1,3-thiazole derivatives (i.e., 11a, 11b, 11c, cis-11d, and trans-11d). In general, isomer 10 was formed in higher yield than isomer 11. In the case of the reaction of 8 with diazo(phenyl)methane (3d), a mixture of two pairs of diastereoisomers was formed, of which two, namely cis-10d and trans-10d, could be isolated as pure compounds. The isomers cis-11d and trans-11d remained as a mixture. In the reactions of the thioxohydrazone 9 with diazo compounds 3b and 3d, the main products were\ud
the alkenes 18 and 23, respectively. Their formation was rationalized by a 1,3-dipolar electrocyclization of the corresponding thiocarbonyl ylide and subsequent desulfurization of the intermediate thiiran. As minor products, 2,5-dihydro-1,3-thiazol-5-amines 21 and 24 were obtained, which have been formed by 1,5-dipolar electrocyclization of the thiocarbonyl ylide, followed by a 1,3-shift of the dimethylamino group
5-Morpholino-1,2,3,4-thiatriazole as a Sulfur-Transfer reagent in the reactions with Thioketones

The thermal decomposition of 5-morpholino-1,2,3,4-thiatriazole (7), which leads to the extrusion of an active form of sulfur, in the presence of different thioketones is described. The interception of the S-atom by the C=S bond leads to in situ formation of an elusive thiocarbonyl S-sulfide of type 5. This\ud
intermediate is a prone 1,3-dipole, which undergoes effectively [2+3] cycloadditions with thioketones to yield 1,2,4-trithiolane derivatives in a regioselective manner. Unexpectedly, 3,3-dichloro-2,2,4,4-tetramethyl-3-thioxocyclobutanone (1c) does not lead to the expected symmetrical 1,2,4-trithiolane. This result can be explained by the reduced stability of the corresponding thiosulfine 5c. Three-component reactions, which were carried out in the presence of equimolar amounts of two different thioketones, result in the formation of 'mixed' 1,2,4-trithiolanes of type 8
Selenium-Containing heterocycles from isoselenocyanates: synthesis of 5-Amino-2,4-dihydro-3H-1,2,4-triazole-3-selones

The reaction of S-methylisothiosemicarbazide hydroiodide (= S-methyl hydrazinecarboximidothioate hydroiodide; 1), prepared from thiosemicarbazide by treatment with MeI in EtOH, and aryl isoselenocyanates 5 in CH2Cl2 affords 3H-1,2,4-triazole-3-selone derivatives 7 in good yield (Scheme 2, Table 1). During attempted crystallization, these products undergo an oxidative dimerization to give the corresponding bis(4H-1,2,4-triazol-3-yl) diselenides 11 (Scheme 3). The structure of 11a was established by X-ray crystallography
Reactions of polycyclic ketones with Dimethoxycarbene; a convenient route for a  one-pot preparation of some alpha-hydroxycarboxylic acid esters

Polycyclic 'cage' ketones, such as pentacyclo[5.4.0.02,6.03,10.05,9]undecan-8-one (10), pentacyclo[5.4.0.02,6.03,10.05,9]undecane-8,11-dione (11), and adamantan-2-one (16) were treated with the nucleophilic dimethoxycarbene (DMC; 1), which was generated thermally from 2,5-dihydro-2,2-dimethoxy-5,5-dimethyl-1,3,4-oxadiazole (4a) in boiling toluene. In this 'one-pot' procedure, the ahydroxycarboxylic\ud
acid ester 12 or a corresponding derivative 15 or 17 was obtained (Schemes 4 – 7).\ud
Additionally, 'cage' thione 21 was treated with DMC under the same conditions yielding dimethoxythiirane 22 (Scheme 8). Subsequent hydrolysis or desulfurization (followed by hydrolysis on silica gel) of 22 gave alpha-mercaptocarboxylate 25 and the corresponding desulfurized ester 24, respectively. In all cases, the addition of DMC occurred stereoselectively, and the addition from the exo-face is postulated to explain the structures of the isolated products
The first reaction of Dimethoxycarbene with an imine moiety

The nucleophilic dimethoxycarbene (DMC; 2) generated by thermal decomposition of 2,5-dihydro-1,3,4-oxadiazole derivative 1 in boiling toluene reacts smoothly with N-(9H-fluoren-9-ylidene)-4-methylbenzenesulfonamide (7b) to yield carbonimidoate derivative 10. A multi-step reaction pathway, initiated by the attack of DMC onto the C=N bond and followed by the migration of the sulfonyl group (or via a sulfinate anion) is proposed to explain the formation of the final product. In contrast to the formal ketimine 7b, N-benzylidene-4-methylbenzenesulfonamide (7a), a formal aldimine, does not react with DMC under comparable conditions
Synthesis of new Bis-imidazole derivatives

The reaction of aldimines with alpha-(hydroxyimino) ketones of type 10 (1,2-diketone monooximes) was used to prepare 2-unsubstituted imidazole 3-oxides 11 bearing an alkanol chain at N(1) (Scheme 2, Table 1). These products were transformed into the corresponding 2H-imidazol-2-ones 13 and 2H-imidazole-2-thiones 14 by treatment with Ac2O and 2,2,4,4-tetramethylcyclobutane-1,3-dithione, respectively (Scheme 3). The three-component reaction of 10, formaldehyde, and an alkane-1,omega-diamine\ud
15 gave the bis[1H-imidazole 3-oxides] 16 (Scheme 4, Table 2). With Ac2O, 2,2,4,4-tetramethylcyclobutane-1,3-dithione or Raney-Ni, the latter reacted to give the corresponding bis[2H-imidazol-2-ones] 19 and 20, bis[2H-imidazol-2-thione] 21, and bis[imidazole] 22, respectively (Schemes 5 and 6).\ud
The structures of 11a and 16b were established by X-ray crystallography
Selenium-containing heterocycles from isoselenocyanates: Base-catalyzed reaction of malononitrile with phenyl isoselenocyanate and bromoacetonitrile or alpha-halogenated ketones

The reaction of phenyl isoselenocyanate (1a) with malononitrile (= propanedinitrile) in DMF in the presence of Et3N leads to the intermediate ketene N,Se-hemiacetal 6a, which can be trapped with bromoacetonitrile or a-halogenated ketones 12a and 12b (Scheme 3). The products are [(alkylseleno)-(phenylamino)methylene]malononitriles 10 and 13, which are obtained in good yield. In the case of the (2-oxoalkyl)seleno derivatives 13, they are in equilibrium with the cyclic hemiacetals 14. Chemical and spectroscopic evidence for the structures of the new compounds are described. The structure of 14a was\ud
established by X-ray crystallography
Reactions of dimethoxycarbene with N-tosylated imines

The reactions of dimethoxycarbene (DMC; 2), which was generated in situ by thermal decomposition of 2,5-dihydro-2,2-dimethoxy-5,5-dimethyl-1,3,4-oxadiazole (1), with N-tosylated imines of xanthone and 2,3 : 6,7 dibenzosuberenone, 3a and 3d, respectively, led to different adducts with rearranged skeletons. In the case of 3a, the 1 :1 adduct 5 as well as the 2 : 1 adduct 6 were obtained (Scheme 2). The formation of both products can be explained by a migration of a MeO group of the DMC fragment in a zwitterionic intermediate. On the other hand, migration of a Me group of DMC is necessary for the formation of the two 1 :1 adducts 13 and 14 of 2 and 3d (Scheme 5). The structures of all products have been established by X-ray crystallography
Thermolysis of imidates: A new method for the generation of carbonyl ylides

Thermolysis of dimethyl 2-[(3-oxo-3H-isoindol-1-yl)oxy]malonate (8) promotes a [1,4]-H shift in the imidic  N¼C O CH  fragment of the starting molecule, which leads to a reactive carbonyl ylide. This carbonyl ylide can be trapped by the C¼N bond of imidates and imines, as well as the C¼O bond of\ud
benzaldehyde. The corresponding cycloadducts 11, 14, and 16 are formed regioselectively in good yields (60 – 95%) and with high stereoselectivity. In the case of 11, the minor cycloadduct in solution undergoes an isomerization to give the more stable stereoisomer. The structures of two cycloadducts, i.e., 11a and\ud
14a, have been established by X-ray crystallography
Selenium-containing heterocycles from isoselenocyanates:5-methylselenazole derivatives from the reaction with malononitrile and propargyl chloride

Aryl isoselenocyanates 1 react with malononitrile (6a) and propargylchloride (8) in DMF in the presence of Et3N to give the corresponding 2-(3-aryl-2,3-dihydro-4-methyl-1,3-selenazol-2-ylidene)malononitriles 12 as major products. The analogous reaction takes place with benzoylacetonitrile (6b) instead of 6a. In some cases, the corresponding non-cyclic 2-[(arylamino)(prop-2-ynylselanyl)methylidene]malononitriles 9 were obtained as minor products. The structures of 9e and 11a have been established by X-ray crystallography
Synthesis of optically active 1-(1-phenylethyl)imidazoles eerived from 1-phenylethylamine

The three-component reaction of (R)- or (S)-1-phenylethylamine (6), formaldehyde, and an -(hydroxyimino) ketone 5, i.e., 3-(hydroxyimino)butan-2-one (5a) or 2-(hydroxyimino)-1,2-diphenylethanone (5b), yields the corresponding enantiomerically pure 1-(1-phenylethyl)-1H-imidazole 3-oxide 7 in high yield (Schemes 2 and 3). The reactions are carried out either in MeOH or in AcOH. Smooth transformations of the N-oxides into optically active 1-(1-phenylethyl)-1H-imidazoles 10 and 2,3-dihydro-1-(1-phenylethyl)-1H-imidazole-2-thiones 11 are achieved by treatment of 7 with Raney-Ni and 2,2,4,4-tetramethyl-3-thioxocyclobutanone (12), respectively (Scheme 4)
Synthesis and conformational analysis of pentapeptides containing enantiomerically pure 2,2-disubstituted glycines

The synthesis and conformational analysis of model pentapeptides with the sequence Z-Leu-Aib-Xaa-Gln-Valol is described. These peptides contain two 2,2-disubstituted glycines (α,α-disubstituted α-amino acids), i.e., Aib (aminoisobutyric acid) and a series of unsymmetrically substituted, enantiomerically pure amino acids Xaa. These disubstituted amino acids were incorporated into the model peptides via the ‘azirine/oxazolone method’.\ud
Conformational analysis was performed in solution by means of NMR techniques and in the solid state by X-ray crystallography. Both methods show that the backbones of thesemodel peptides form helical conformations, as is expected for 2,2-disubstitued glycinecontaining peptides
Substituted pyrazolo[3,4-d]pyrimidines : microwave assisted, solvent free synthesis and biological evaluation

A simple and efficient method has been developed for the synthesis of various pyrazolo[3,4-d]pyrimidines using microwave irradiation under solvent-free conditions. The advantages of applying microwave irradiation compared with the classical method were demonstrated. The structures of all the compounds were confirmed by the usual techniques and in two cases by X-ray analysis. The compounds did not display appreciable ability to inhibit xanthine oxidase activity. Screening for antifungal activity showed that some derivatives were active against four fungi, with more significant results for Botrytis.FEDERFundação para a Ciência e Tecnologia (FCT) - I&D 226/2003, POCTI-SFA-3-686), SFRH/BPD/20816/ 2004)Xunta de Galicia - PGIDIT05PXIB26201PR,PR405A098/59-
The azirine/oxazolone approach to the synthesis of Aib-Pro endothiopeptides

The reaction of methyl N-(2,2-dimethyl-2H-azirin-3-yl)-l-prolinate (2a) with thiobenzoic acid at room temperature gave the endothiopeptide Bz AibY[CS]-Pro-OMe (7) in high yield. In an analogous manner, (benzyloxy)carbonyl (Z)-protected proline was transformed into the thioacid, which was reacted with 2a to give the endothiotripeptide Z-Pro-AibY[CS]-Pro-OMe (12). The corresponding thioacid of 7 was prepared in situ via saponification, formation of a mixed anhydride, and treatment with H2S. A second reaction with 2a led to the endodithiotetrapeptide 9, but extensive epimerization at Pro2 was observed. Similarly, saponification of 12 and coupling with either 2a or H-Phe-OMe and 2-(1Hbenzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxy-1H-benzotriazole (TBTU/HOBt) gave the corresponding endothiopeptides as mixtures of two epimers. The synthesis of the pure diastereoisomer BzY[CS]-Aib-Pro-AibY[CS]-N(Me)Ph (21) was achieved via isomerization of 7 to BzY[CS]-Aib-Pro-OMe (16), transformation into the corresponding thioacid, and reaction with N,2,2-trimethyl-N-phenyl-2H-azirin-3-amine (1a). The structures of 12 and 21 were established by X-ray crystallography