Synthesis of 2-substituted-5-halo-2,3-dihydro-4(H)-pyrimidin-4-ones and their derivatization utilizing the Sonogashira coupling reaction in the enantioselective synthesis of alpha-substituted beta-amino acids

A convenient, one-pot procedure for the synthesis of 1-benzoyl-2(S)-substituted-5-iodo-2,3-dihydro-4(H)-pyrimidin-4-ones by tandem decarboxylation/beta-iodination of the corresponding 6-carboxy-perhydropyrimidin-4-ones was developed. In addition, several 1-benzoyl-2(S)-substituted-5-bromo-2,3-dihydro-4(H)-pyrimidin-4-ones were readily prepared by bromination of 1-benzoyl-2(S)-substituted-2,3-dihydro-4(H)-pyrimidin-4-ones. Subsequently, Sonogashira coupling of the halogenated heterocyclic enones with various terminal alkynes produced 1-benzoyl-2(S)-isopropyl-5-alkynyl-2,3-dihydro-4(H)-pyrimidin-4-ones in good yields. Hydrogenation of the unsaturated C-C moieties in the Sonogashira products followed by acid hydrolysis afforded highly enantioenriched alpha-substituted beta-amino acids.     

The Rearrangement of 3, 4-Dihydro-2, 2-Dimethy-2H, 5H-Pyrano [2, 3-b][1] Benzopyran-5-Ones With DDQ

A novel rearrangement of 3, 4-dihydro-2, 2-dimethyl-2H, 5H-pyrano [2, 3-b] [1] benzopyran-5-ones (dihydropyranochromones) has been observed during the dehydrogenation with DDQ. The products obtained are found to be 2, 2-dimethyl-2H, 5H-pyrano [3, 2-c] [1] benzopyran-5-ones (pyranocoumarins).     

Synthesis of [1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-ones through copper-catalyzed tandem reactions of N-(2-haloaryl)propiolamides with sodium azide

A simple and efficient approach for the synthesis of [1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-ones is described. The methodology is based on a tandem reaction of 1-(2-haloaryl)propiolamides with sodium azide through a [3 + 2] azide-alkyne cycloaddition and intramolecular Ullmann-type C-N coupling process.     

Furyl analogs of α-pyrono[2,3-<Emphasis Type="Italic">f</Emphasis>]isoflavones with an azole substituent in the α-pyrone nucleus

The corresponding 9-azolyl-8-imino-4H,8H-pyrano[2,3-f]chromen-4-ones have been synthesized by the condensation of 7-hydroxy-3-(5-methoxycarbonyl-2-methylfuran-3-yl)-8-formylchromones with 2-aza-hetarylacetonitriles. Acid hydrolysis of the products led to the furyl analogs of 9-azolyl-α-pyrono-[2,3-f]isoflavones.     

Ruthenium/TFA-catalyzed coupling of activated secondary propargylic alcohols with cyclic 1,3-diones: furan versus pyran ring formation

A catalytic system consisting of the 16-electron allyl-ruthenium(II) complex [Ru(eta(3)-2-C3H4Me)(CO)(dppf)][SbF6] (dppf = 1,1'-bis(diphenylphosphino)ferrocene) and trifluoroacetic acid (TFA) has been used to promote the coupling between secondary propargylic alcohols and cyclic 1,3-diketones. The nature of the resulting products was found to be dependent on the ring size of the dicarbonyl compound employed. Thus, whereas 6,7-dihydro-5H-benzofuran-4-ones have been selectively obtained starting from 1,3-cyclohexanediones, via furan-ring formation, the use of 1,3-cyclopentanedione leads instead to 6,7-dihydro-4H-cyclopenta[b]pyran-5-ones via a pyran-ring formation process.     

Chemistry of 1,5-diketones: II. Specificity of transformations of polycyclic 1,5-diketones in acid media

2-(1,3-Diaryl-3-oxopropyl)cyclohexan-1-ones underwent carbo-and heterocyclization in a mixture of acetic acid with acetic anhydride in the presence of perchloric acid. The transformation of 2-(1,3-diaryl-3-oxopropyl)cyclohexan-1-ones into 2,4-diaryl-5,6,7,8-tetrahydrochromenylium salts was shown to involve intermediate 2,4-diarylbicyclo[3.3.1]non-2-en-9-ones. The structure of 2,4-diaryl-substituted bicyclo[3.3.1]non-2-en-9-ones and products of their reactions with halogens and hydroxylamine hydrochloride was confirmed by ¹H and ¹³C NMR spectroscopy.     

Synthesis of 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones: selective antagonists of muscarinic (M3) receptors

Two approaches to tetrahydro-[1H]-2-benzazepin-4-ones of interest as potentially selective, muscarinic (M(3)) receptor antagonists have been developed. Base promoted addition of 2-(tert-butoxycarbonylamino)methyl-1,3-dithiane with 2-(tert-butyldimethylsiloxymethyl)benzyl chloride gave the corresponding 2,2-dialkylated 1,3-dithiane which was taken through to the dithiane derivative of the parent 2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one by desilylation, oxidation and cyclisation via a reductive amination. After conversion into the N-tert-butyloxycarbonyl, N-toluene p-sulfonyl and N-benzyl derivatives , hydrolysis of the dithiane gave the N-protected tetrahydro-[1H]-2-benzazepin-4-ones . However, preliminary attempts to convert these into 5-cycloalkyl-5-hydroxy derivatives were not successful. In the second approach, ring-closing metathesis was used to prepare 2,3-dihydro-[1H]-2-benzazepines which were hydroxylated and oxidized to give the required 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones. Following preliminary studies, ring-closing metathesis of the dienyl N-(2-nitrophenyl)sulfonamide gave the dihydrobenzazepine which was converted into the 2-butyl-5-cyclobutyl-5-hydroxytetrahydrobenzazepin-4-one by hydroxylation and N-deprotection followed by N-alkylation via reductive amination, and oxidation. This chemistry was then used to prepare the 2-[(N-arylmethyl)aminoalkyl analogues , , and . N-Acylation followed by amide reduction using the borane-tetrahydrofuran complex was also used to achieve N-alkylation of dihydrobenzazepines and this approach was used to prepare the 5-cyclopentyl-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one and the 5-cyclobutyl-8-fluoro-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one . The structures of 2-tert-butyloxycarbonyl-4,4-propylenedithio-2,3,4,5-tetrahydro-[1H]-2-benzazepine and (4RS,5SR)-2-butyl-5-cyclobutyl-4,5-dihydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepine were confirmed by X-ray diffraction. The racemic 5-cycloalkyl-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones were screened for muscarinic receptor antagonism. For M(3) receptors from guinea pig ileum, these compounds had log(10)K(B) values of up to 7.2 with selectivities over M(2) receptors from guinea pig left atria of approximately 40.     

Synthesis of highly substituted furans by the electrophile-induced coupling of 2-(1-alkynyl)-2-alken-1-ones and nucleophiles

[reaction: see text] The coupling of 2-(1-alkynyl)-2-alken-1-ones with nucleophiles, either catalyzed by AuCl3 or induced by an electrophile, provides highly substituted furans in good to excellent yields under very mild reaction conditions. Various nucleophiles, including functionally substituted alcohols, H2O, carboxylic acids, 1,3-diketones, and electron-rich arenes, and a range of cyclic and acyclic 2-(1-alkynyl)-2-alken-1-ones readily participate in these cyclizations. Iodine, NIS, and PhSeCl have proven successful as electrophiles in this process. The resulting iodine-containing furans can be readily elaborated to more complex products using known organopalladium chemistry.     

Palladium-Catalyzed [3+2] and [2+2+2] Annulations of 4-Iodo-2-quinolones with Activated Alkynes through Selective C−H Activation

The palladium-catalyzed reaction of 4-iodo-2-quinolones with activated alkynes was investigated. Cyclopenta[de]quinoline-2(1 H)-ones and/or phenanthridine-6(5 H)-ones were obtained through [3+2] annulation involving aromatic C−H activation or [2+2+2] annulation involving vinylic C−H activation, respectively. Reasonable mechanisms for the formation of these annulation products have been proposed based on density functional theory calculations.     

Condensed isoquinolines 28*. Synthesis and properties of 10a,15b-diazadibenzo[a,e]-pleiaden-11-ones

The reaction of 7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones with o-xylidene dibromide leads to 11-oxo-4bH,5H,10H,11H,16H-10a-aza-15b-azoniadibenzo[a,e]pleiadene bromides, which are converted to 11-oxo-10H,11H,16H-10a-aza-15b-azoniadibenzo[a,e]pleiadene salts upon oxidation using nitrobenzene. The reaction of these salts with benzylamine leads to 6-{2-[(benzylimino)methyl]phenyl}-7,12-dihydroisoquino[3,2-b][2]benzazepin-14(6H)-ones, which recyclize to 11-oxo-5H,10H,11H-10a-aza-15b-azoniadibenzo[a,e]pleiadene perchlorates upon the action of perchloric acid. The reactions of the 10a,15b-diazadibenzo[a,e]pleiadene salts obtained with NaBH₄ were studied and the structures of the reduction products were determined by spectral methods. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 280–292, February, 2008.     

The Lewis acid-catalyzed nazarov reaction of 2-(n-methoxycarbonylamino)-1,4-pentadien-3-ones

[reaction: see text] A highly efficient carbonylative Suzuki-Miyaura coupling reaction of lactam-derived vinyl triflates and alkenylboronic acids afforded 2-(N-methoxycarbonylamino)-1,4-pentadien-3-ones as suitable substrates for the Nazarov reaction. The most competent Lewis acids for the Nazarov reaction were Cu(OTf)(2) (2 mol %) and Sc(OTf)(3) (3 mol %) in DCE, which provided the Nazarov products in excellent yield. As both the carbonylative coupling and the subsequent Nazarov reaction were high yielding, the overall methodology is a concise and efficient route to [1]pyrindine systems.     

Tandem versus single C-C bond forming reaction under palladium-copper catalysis: regioselective synthesis of α-pyrones fused with thiophene

We herein report a highly convenient protocol for rapid construction of α-pyrone fused with thiophene. This includes one-pot and regioselective synthesis of 4,5-disubstituted and 5-substituted thieno[2,3-c]pyran-7-ones, 6,7-disubstituted and 6-substituted thieno[3,2-c]pyran-4-ones. The synthesis of thieno[2,3-c]pyran-7-ones involves palladium mediated cross coupling of 3-iodothiophene-2-carboxylic acid with terminal alkynes in a simple synthetic operation. The coupling-cyclization reaction was initially studied in the presence of Pd(PPh₃)₂Cl₂ and CuI in a variety of solvents. 5-Substituted 4-alkynylthieno[2,3-c]pyran-7-ones were isolated in good yields when the reaction was performed in DMF. Similarly, 6-substituted 7-alkynylthieno[3,2-c]pyran-4-ones were synthesized via palladium-catalyzed cross coupling of 2-bromothiophene-3-carboxylic acid with terminal alkynes. A tandem C-C bond forming reaction in the presence of palladium catalyst rationalizes the formation of coupled product in this apparently three-component reaction. The cyclization step of this coupling-cyclization-coupling process occurs in a regioselective fashion to furnish products containing six-membered ring only. This sequential C-C bond forming reaction however, can be restricted to the formation of single C-C bond by using 10% Pd/C-Et₃N-CuI-PPh₃ as catalyst system in the cross coupling reaction. 5-Substituted thieno[2,3-c]pyran-7-ones were obtained in good yields when the coupling reaction was performed under this condition. Some of the compounds synthesized were tested in vitro for their anticancer activities.     

Chemical behaviour of N-(2-hydroxybenzyl)anthranilic acids in the presence of acyclic anhydrides

The synthesis of 11-acyl-11,12-dihydrodibenz[bf][1,5]oxazocin-6-ones 9-13 is reported by reaction of N-(2-hydroxybenzyl)anthranilic acids 1 with acetic, isobutyric, 2-ethylbutyric anhydrides. The structures of the obtained 6,8,6 products are proved with the use of ir, mass spectrometry, ¹H and ¹³C nmr spectra, homo-and heteronuclear two-dimensional nmr experiments. The formation of 9-13 is discussed in relation to the obtainment of 12H-quino[2,1-b][1,3]benzoxazin-5-ones 2-8 and 6a,12-dihydro[3,1]benzoxazino[2,1-b][1,3]-benzoxazin-5-ones 14-19 from the same starting products 1 with suitable anhydrides under controlled reaction conditions.     

Condensed isoquinolines 30. Acylation and alkylation of 5,13-dihydro-11H-isoquino-[3,2-<Emphasis Type="Italic">b</Emphasis>]quinazolin-11-one

It was shown that 6-acyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-ones are formed when 5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-one is heated with the chlorides and anhydrides of carboxylic acids in the presence of bases (pyridine, NaOAc) while 5-acyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-ones are formed in the presence of NaH. In the presence of NaH 6-acyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-ones form the products from acylation and alkylation at position 5. The action of heat on 5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-one in oxalyl chloride leads to 7H,8H-2a,7a-diazacyclopenta[fg]naphthacene-1,2,8-trione. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 741–750, May, 2008.     

Expeditious entry to novel 2-methylene-2,3-dihydrofuro[3,2-c] chromen-2-ones from 6-chloro-4-hydroxychromen-2-one and propargylic alcohols

A catalytic system consisting of the ruthenium(II) complex [Ru(η3-2-C3H4Me)(CO)(dppf)][SbF6] (dppf=1,1'-bis(diphenylphosphino)ferrocene) and trifluoroacetic acid has been used to promote the coupling of secondary propargylic alcohols with 6-chloro-4-hydroxychromen-2-one. The reactions afforded unusual 2-methylene-2,3-dihydrofuro[3,2-c]chromen-2-ones in good yields.     

Chemoselectivities in the platinum-catalyzed hydrative carbocyclizations of oxo-alkyne-nitrile functionalities

Two new hydrative carbocyclizations of oxa-alkyne-nitrile functionalities are reported to produce distinct nitrogen-containing heterocycles. Protracted heating of oxoalkynyl nitrile substrates with PtCl(2)/CO/H(2)O in hot 1,4-dioxane gave 2,3-dihydro-1H-pyrido[1.2-b]-isoquinolin-4(6H)-ones. In this hydration reaction, dicarbonyl nitrile intermediates were isolated efficiently after a brief period, and they were subjected to an NHC-based crossed benzoin coupling to give spiro alcohols that further reacted with TfOH to give spiro[indene-2,2'-piperidine]-1,6'(3H)-diones.     

Unusual reactions of 5,5-dimethyl-2-(indenyl-2)-3-pyrazolidinone with acetylenedicarboxylates

[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.     

Synthesis and biological activities of novel furo[2,3,4-jk][2]benzazepin-4(3H)-one derivatives

A novel seven-membered lactam formation method has been established by intramolecular ring closure reaction of 4-bromo-(E)-3-[(2-alkylvinyl)carbonylamino]benzo[b]furans under Heck coupling conditions. A number of furo[2,3,4-jk][2]benzazepin-4(3H)-ones, tricyclicbenzo[b]furans, have been prepared by this method and evaluated for their leukotriene B(4) (LTB(4)) receptor and poly(ADP-ribose)polymerase-1 (PARP-1) inhibitory activities.     

Syntheses of spiro[indazole-3,3′-indolin]-2′-ones and spiro[indazole-3,3′-indolin]-2′-imines via 1,3-dipolar cycloadditions of arynes and studies on their isomerization reactions

A 1,3-dipolar cycloaddition reaction of arynes with 3-diazoindolin-2-ones under mild conditions in excellent yields has been developed, which allows facile access to a library of labile spiro[indazole-3,3′-indolin]-2′-ones. Spiro[indazole-3,3′-indolin]-2′-imines could be obtained as well following the same protocol. The isomerization reaction of spiro[indazole-3,3′-indolin]-2′-ones under thermal or acidic conditions has been efficiently achieved to afford a wide range of indazolo-[2,3-c]quinazolin-6(5H)-ones and the one-pot synthesis of indazolo-[2,3-c]quinazolin-6(5H)-ones from arynes and 3-diazoindolin-2-ones is also described. Whereas, spiro[indazole-3,3′-indolin]-2′-imines could not undergo the same rearrangement.     

Palladium-catalyzed reaction of 2-alkynylhalobenzene with 2-alkynylbenzamide: an efficient approach to indeno[1,2-c]azepin-3(2H)-ones

A novel and efficient route for rapid access to indeno[1,2-c]azepin-3(2H)-ones is described, which proceeds through a palladium-catalyzed tandem reaction of 2-alkynylhalobenzene with 2-alkynylbenzamide in the presence of PPh(3) or PCy(3). The indeno[1,2-c]azepin-3(2H)-ones which incorporate both indene and unsaturated seven-membered ring lactam skeletons are obtained in good to excellent yields.