An Efficient Synthesis of Pyrido[2,3‐d][6,5‐d]dipyrimidine and 5,5′‐Arylmethylenebis(2,6‐diaminopyrimidinone) Derivatives under Microwave Irradiation

A series of pyrido[2,3‐d][6,5‐d]dipyrimidine and 5,5′‐arylmethylenebis(2,6‐diaminopyrimidinone) derivatives have been synthesized through a rapid reaction of aromatic aldehydes with aminopyrimidines in acetic acid under microwave irradiation. This method has the advantages of simple operation, high yields, short reaction time, and easy work‐up.     

A Highly cis‐Selective and Enantioselective Metal‐Free Hydrogenation of 2,3‐Disubstituted Quinoxalines

A wide range of 2,3‐disubstituted quinoxalines have been successfully hydrogenated with H₂ using borane catalysts to produce the desired tetrahydroquinoxalines in 80–99 % yields with excellent cis selectivity. Significantly, the asymmetric reaction employing chiral borane catalysts generated by the in situ hydroboration of chiral dienes with HB(C₆F₅)₂ under mild reaction conditions has also been achieved with up to 96 % ee, and represents the first catalytic asymmetric system to furnish optically active cis‐2,3‐disubstituted 1,2,3,4‐tetrahydroquinoxalines.     

Regioselective and 1,2‐cis‐α‐Stereoselective Glycosylation Utilizing Glycosyl‐Acceptor‐Derived Boronic Ester Catalyst

Regioselective and 1,2‐cis‐α‐stereoselective glycosylations using 1α,2α‐anhydro glycosyl donors and diol glycosyl acceptors in the presence of a glycosyl‐acceptor‐derived boronic ester catalyst. The reactions proceed smoothly to give the corresponding 1,2‐cis‐α‐glycosides with high stereo‐ and regioselectivities in high yields without any further additives under mild reaction conditions. In addition, the present glycosylation method was successfully applied to the synthesis of an isoflavone glycoside.     

A Catalyst‐Free Aqueous Synthesis of 2‐Amino‐7,9‐dihydrothieno[3′,2′:5,6]pyrido[2,3‐d]pyrimidine‐4,6(3H,5H)‐dione Derivatives

A series of novel 7,9‐dihydrothieno[3′,2′:5,6]pyrido[2,3‐d]pyrimidine‐4,6(3H,5H)‐dione derivatives were synthesized efficiently via the catalyst‐free reaction of aldehyde, ethyl 2,4‐dioxotetrahydrothiophene‐3‐carboxylate, and 2,6‐diaminopyrimidine‐4(3H)‐one through the sequence of deethoxycarbonylation and three‐component condensation in aqueous media. This protocol featured mild reaction conditions, high yields, easy work‐up, and environmentally friendly procedure.     

Five bicyclo[3.3.0]octa‐2,6‐dienes

A series of five compounds containing the bicyclo[3.3.0]octa‐2,6‐diene skeleton are described, namely tetramethyl cis,cis‐3,7‐dihydroxybicyclo[3.3.0]octa‐2,6‐diene‐2,4‐exo,6,8‐exo‐tetracarboxylate, C₁₆H₁₈O₁₀, (I), tetramethyl cis,cis‐3,7‐dihydroxy‐1,5‐dimethylbicyclo[3.3.0]octa‐2,6‐diene‐2,4‐exo,6,8‐exo‐tetracarboxylate, C₁₈H₂₂O₁₀, (II), tetramethyl cis,cis‐3,7‐dimethoxybicyclo[3.3.0]octa‐2,6‐diene‐2,4‐exo,6,8‐exo‐tetracarboxylate, C₁₈H₂₂O₁₀, (III), tetramethyl cis,cis‐3,7‐dimethoxy‐1,5‐dimethylbicyclo[3.3.0]octa‐2,6‐diene‐2,4‐exo,6,8‐exo‐tetracarboxylate, C₂₀H₂₆O₁₀, (IV), and tetramethyl cis,cis‐3,7‐diacetoxybicyclo[3.3.0]octa‐2,6‐diene‐2,4‐exo,6,8‐exo‐tetracarboxylate, C₂₀H₂₂O₁₂, (V). The bicyclic core is substituted in all cases at positions 2, 4, 6 and 8 with methoxycarbonyl groups and additionally at positions 3 and 7 with hydroxy [in (I) and (II)], methoxy [in (III) and (IV)] or acetoxy [in (V)] groups. The conformations of the methoxycarbonyl groups at positions 2 and 4 are exo for all five compounds. Each C₅ ring of the bicyclic skeleton is almost planar, but the rings are not coplanar, with dihedral angles of 54.93 (7), 69.85 (5), 64.07 (4), 80.74 (5) and 66.91 (7)° for (I)–(V), respectively, and the bicyclooctadiene system adopts a butterfly‐like conformation. Strong intramolecular hydrogen bonds exist between the –OH and C=O groups in (I) and (II), with O...O distances of 2.660 (2) and 2.672 (2) Å in (I), and 2.653 (2) and 2.635 (2) Å in (II). The molecular packing is stabilized by weaker C—H...O(=C) interactions, leading to dimers in (I)–(III) and to a chain structure in (V). The structure series presented in this article shows how the geometry of the cycloocta‐2,6‐diene skeleton changes upon substitution in different positions and, consequently, how the packing is modified, although the intermolecular interactions are basically the same across the series.     

N‐Heterocyclic Carbene‐Catalysed Direct Synthesis of Cyano Esters via Cyanation‐Esterification Reaction of α‐Keto Esters

The cyanation‐esterification reaction of α‐keto esters catalysed by N‐heterocyclic carbenes (NHCs) is developed. Under the catalysis of 10 mol% 1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene, aromatic and aliphatic α‐keto esters reacted with ethyl cyanoformate or acetyl cyanide to produce the corresponding cyano esters with a tetrasubstituted carbon center in high yields.     

Cycloaromatization Reaction of 4‐Alkoxy‐1,1,1‐trifluoroalk‐3‐en‐2‐ones with 2,6‐Diaminotoluene: The Unexpected Regioselective Synthesis of 2,4,7,8‐Tetrasubstituted Quinolines

This article reports a convenient and general method for the regioselective synthesis of a new series of 2‐alkyl(aryl)‐8‐methyl‐4‐trifluoromethyl‐7‐aminoquinolines in 86–93% yields, from cycloaromatization reactions of N‐(oxotrifluoroalkenyl)‐2,6‐diaminotoluenes in a strongly acidic medium polyphosphoric acid and absence of solvent. The enaminoketone intermediates were easily isolated from the reaction of 4‐alkoxy‐4‐alkyl(aryl)‐1,1,1‐trifluoroalk‐3‐en‐2‐ones [CF₃C(O)CH═C(R)OR¹, where R = H, Me, Ph, 4‐FPh, 4‐BrPh, 4‐MePh, and R¹ = Me, Et] with 2,6‐diaminotoluene (2,6‐DAT) in methanol under mild conditions, in 46–70% yields. Another synthetic route also allowed the regioselective synthesis of 2‐aryl(heteroaryl)‐4‐methyl‐4‐trifluoromethyl‐7‐aminoquinolines from direct cyclocondensation reactions of 4‐alkoxy‐4‐aryl(heteroaryl)‐1,1,1‐trifluoroalk‐3‐en‐2‐ones with 2,6‐diaminotoluene in methanol under mild conditions, in 21–36% yields.     

Enzyme‐Mediated Preparation of (+)‐ and (−)‐β‐Irone and (+)‐ and (−)‐cis‐γ‐Irone from Irone alpha®

The (−)‐ and (+)‐β‐irones ((−)‐ and (+)‐ 2 , resp.), contaminated with ca. 7 – 9% of the (+)‐ and (−)‐trans‐α‐isomer, respectively, were obtained from racemic α‐irone via the 2,6‐trans‐epoxide (±)‐ 4 (Scheme 2). Relevant steps in the sequence were the LiAlH₄ reduction of the latter, to provide the diastereoisomeric‐4,5‐dihydro‐5‐hydroxy‐trans‐α‐irols (±)‐ 6 and (±)‐ 7 , resolved into the enantiomers by lipase‐PS‐mediated acetylation with vinyl acetate. The enantiomerically pure allylic acetate esters (+)‐ and (−)‐ 8 and (+)‐ and (−)‐ 9 , upon treatment with POCl₃/pyridine, were converted to the β‐irol acetate derivatives (+)‐ and (−)‐ 10 , and (+)‐ and (−)‐ 11 , respectively, eventually providing the desired ketones (+)‐ and (−)‐ 2 by base hydrolysis and MnO₂ oxidation. The 2,6‐cis‐epoxide (±)‐ 5 provided the 4,5‐dihydro‐4‐hydroxy‐cis‐α‐irols (±)‐ 13 and (±)‐ 14 in a 3 : 1 mixture with the isomeric 5‐hydroxy derivatives (±)‐ 15 and (±)‐ 16 on hydride treatment (Scheme 1). The POCl₃/pyridine treatment of the enantiomerically pure allylic acetate esters, obtained by enzymic resolution of (±)‐ 13 and (±)‐ 14 , provided enantiomerically pure cis‐α‐irol acetate esters, from which ketones (+)‐ and (−)‐ 22 were prepared (Scheme 4). The same materials were obtained from the (9S) alcohols (+)‐ 13 and (−)‐ 14 , treated first with MnO₂, then with POCl₃/pyridine (Scheme 4). Conversely, the dehydration with POCl₃/pyridine of the enantiomerically pure 2,6‐cis‐5‐hydroxy derivatives obtained from (±)‐ 15 and (±)‐ 16 gave rise to a mixture in which the γ‐irol acetates 25a and 25b and 26a and 26b prevailed over the α‐ and β‐isomers (Scheme 5). The (+)‐ and (−)‐cis‐γ‐irones ((+)‐ and (−)‐ 3 , resp.) were obtained from the latter mixture by a sequence involving as the key step the photochemical isomerization of the α‐double bond to the γ‐double bond. External panel olfactory evaluation assigned to (+)‐β‐irone ((+)‐ 2 ) and to (−)‐cis‐γ‐irone ((−)‐ 3 ) the strongest character and the possibility to be used as dry‐down note.     

Chiral Induction by Elimination‐Coupled Lithium–Ene Reaction: Synthesis of (+)‐(3R,4R)‐1,2‐Dihydromultifidene

Cyclization of the alkadienyl carbamates 1 to the cis‐divinylcyclopentanes 2 with high enantioselectivity and diastereoselectivity has been successfully achieved by (−)‐sparteine‐induced asymmetric deprotonation. The conversion may be described as a hybrid of a lithium–ene reaction and an S_n ′ reaction.     

Diastereo‐ and Regioselective Addition of Thioamide Dianions to Imines and Aziridines: Synthesis of N‐Thioacyl‐1,2‐diamines and N‐Thioacyl‐1,3‐diamines

Addition reactions of thioamide dianions that were derived from N‐arylmethyl thioamides to imines and aziridines were carried out. The reactions of imines gave the addition products of N‐thioacyl‐1,2‐diamines in a highly diastereoselective manner in good‐to‐excellent yields. The diastereomeric purity of these N‐thioacyl‐1,2‐diamines could be enriched by simple recrystallization. The reduction of N‐thioacyl‐1,2‐diamines with LiAlH₄ gave their corresponding 1,2‐diamines in moderate‐to‐good yields with retention of their stereochemistry. The oxidative‐desulfurization/cyclization of an N‐thioacyl‐1,2‐diamine in CuCl₂/O₂ and I₂/pyridine systems gave the cyclized product in moderate yield and the trans isomer was obtained as the sole product. On the other hand, a similar cyclization reaction with antiformin (aq. NaClO) as an oxidant gave the cis isomer as the major product. The reactions of N‐tosylaziridines gave the addition products of N‐thioacyl‐1,3‐diamines with low diastereoselectivity but high regioselectivity and in good‐to‐excellent yields. The use of AlMe₃ as an additive improved the efficiency and regioselectivity of the reaction. The stereochemistry of the obtained products was determined by X‐ray diffraction.     

A Convenient Synthesis of Functionalized Indenopyrazolones from Indan‐1,2,3‐trione,Benzaldehydes, and Phenylhydrazine

A synthesis of cis‐3‐aryl‐3a,8b‐dihydro‐3a,8b‐dihydroxy‐1‐phenylindeno[1,2‐c]pyrazol‐4(1H)‐ones in good yields from the sequential reaction between benzaldehydes, phenylhydrazine, and indan‐1,2,3‐trione in MeCN is described (Scheme 1).     

Iodine‐Catalyzed Highly Diastereoselective Synthesis of trans‐2,6‐Disubstituted‐3,4‐Dihydropyrans: Application to Concise Construction of C28–C37 Bicyclic Core of (+)‐Sorangicin A

A novel iodine‐catalyzed highly diastereoselective synthesis of trans‐2,6‐disubstituted‐3,4‐dihydropyrans have been achieved from δ‐hydroxy α,β‐unsaturated aldehydes by treating with allyltrimethyl silane in THF at room temperature with good to excellent yields. This methodology has been successfully implemented for a concise asymmetric synthesis of C28–C37 dioxabicyclo[3.2.1]octane ring system of (+)‐sorangicin A in 8 steps with 21 % overall yield.     

SmI2‐induced cyclizations and their applications in natural product synthesis

Since the isolation of brevetoxin‐B, a red tide toxin, many bioactive marine natural products featuring synthetically challenging trans‐fused polycyclic ether ring systems have been reported. We have developed SmI₂‐induced cyclization of β‐alkoxyacrylate with aldehyde, affording 2,6‐syn‐2,3‐trans‐tetrahydropyran (THP) or 2,7‐syn‐2,3‐trans‐oxepane with complete stereoselection, as a key reaction of efficient iterative and bi‐directional strategies for the construction of these polycyclic ethers. This reaction is also applicable to the synthesis of 3‐, 5‐, and 6‐methyl‐THPs and 3,5‐dimethyl‐THP. The synthesis of 2‐methyl‐ and 2,6‐dimethyl‐THPs was accomplished by means of a unique methyl insertion. Recently, the SmI₂‐induced cyclization was extended to similar reactions using β‐alkoxyvinyl sulfone and sulfoxide. Reaction of (E)‐ and (Z)‐β‐alkoxyvinyl sulfone‐aldehyde afforded 2,6‐syn‐2,3‐trans‐ and 2,6‐syn‐2,3‐cis‐ THPs, respectively. Reaction of (E)‐β‐alkoxyvinyl (R)‐ and (S)‐sulfoxides gave 2,6‐anti‐2,3‐cis‐ and 2,6‐syn‐2,3‐trans‐THPs, respectively. Reaction of (Z)‐β‐alkoxyvinyl (R)‐sulfoxides gave 2,6‐syn‐2,3‐cis‐THP and an olefinic product, while that of (Z)‐β‐alkoxyvinyl (S)‐sulfoxide afforded a mixture of many products. These SmI₂‐induced cyclizations have been applied to the total syntheses of various natural products, including brevetoxin‐B, mucocin, pyranicin, and pyragonicin. Synthetic studies on gambierol and maitotoxin are also introduced. © 2010 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 10: 159–172; 2010: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.200900027     

A simple synthesis of 5‐ethoxycarbonyl‐6‐phenyl‐1,3‐dioxin‐4‐ones and ethyl 3‐benzoyl‐4‐oxo‐2,6‐diphenylpyran‐5‐carboxylate

4‐Ethoxycarbonyl‐5‐phenyl‐2,3‐dihydrofuran‐2,3‐dione 1 reacts with aldehydes via the acylketene intermediate 2 giving the 1,3‐dioxin‐4‐ones 3a‐e and the 1,4‐bis(5‐ethoxycarbonyl‐4‐oxo‐6‐phenyl‐4H‐1,3‐dioxin‐2‐yl)benzene 4 , and a one step reaction between dibenzoylmethane and oxalylchloride gave 3,5‐dibenzoyl‐2,6‐diphenyl‐4‐pyrone 7 . The reaction of 1 with dibenzoylmethane, a dicarbonyl compound, provided ethyl 3‐benzoyl‐4‐oxo‐2,6‐diphenylpyran‐5‐carboxylate derivative 9 . Compound 9 was converted into the corresponding ethyl 3‐benzoyl‐4‐hydroxy‐2,6‐diphenylpyridine‐5‐carboxylate derivative 10 via its reaction with ammonium hydroxyde solution in 1 ‐butanol.     

An efficient strategy for synthesis of 2,6‐dimethyl‐1,3‐diarylpyrano[4,3‐b]pyrrol‐4(1H)‐one derivatives in water

An efficient approach for the synthesis of 2,6‐dimethyl‐1,3‐diarylpyrano[4,3‐b]pyrrol‐4(1H)‐one derivatives has been established. The reaction was performed in aqueous media using readily available and inexpensive 6‐methyl‐4‐(phenylamino)‐2H‐pyran‐2‐one and nitroolefin as substrates. The present methodology shows many attractive advantages, such as using water as green reaction media, inexpensive and environmentally friendly acetic acid as catalyst, easy work‐up procedure, and good to excellent yields.     

Microwave‐induced Stereoselectivity in Synthesis of trans‐4‐Aryl‐3‐methyl‐6‐oxo‐4,5,6,7‐tetrahydro‐2H‐pyrazolo[3,4‐b]pyridine‐5‐carbonitriles

A facile synthesis of trans isomers of 4‐aryl‐3‐methyl‐6‐oxo‐4,5,6,7‐tetrahydro ‐ 2H ‐ pyrazolo[3,4‐b]pyridine‐5‐carbonitriles via three‐component condensation reaction of an aldehyde, 3‐amino‐5‐methylpyrazole and ethyl cyanoacetate in acetonitrile has been developed under microwave irradiation. This one‐pot reaction proceeds without any catalyst in short times and gives the product in high selectivities and high yields.     

A Synthetic Study of Chiral α‐Hydroxy‐H‐Phosphinates Based on Proline Catalysis

A highly enantioselective synthesis of α‐hydroxyphosphinates was achieved based on the L ‐proline‐catalyzed aldol reaction of α‐acylphosphinates and acetone. Due to the preexisting chirality at the phosphorus center, mixtures of two diastereomers of the α‐hydroxyphosphinates were obtained in moderate to good yields, with simultaneously high enantioselectivity for both diastereomers. The products could be converted into α‐hydroxy‐H‐phosphinates with satisfactory yields. Furthermore, an unprecedented oxidation–reduction reaction of the α‐hydroxyphosphinates or α‐hydroxy‐H‐phosphinates to form phosphonates was observed, and the mechanism involved in such a chemical transformation is discussed.     

One Pot Synthesis of Medicinally Important cis‐2‐Methyl‐4‐amino substituted‐1,2,3,4‐tetrahydroquinolines

A simple synthesis of medicinally important cis‐2‐methyl‐4‐azapan‐2‐one‐1,2,3,4‐tetrahydroquinolines/cis‐9‐(2‐methyl‐1,2,3,4‐tetrahydroquinolin‐4‐yl)‐9H‐carbazole was reported. Multicomponent one pot synthesis with anilines and N‐vinylcaprolactam/N‐vinyl carbazole via imino Diels‐Alder reaction by using antimony trichloride as catalyst and acetonitrile as solvent was employed. NMR technique (2D) was used to study the regio‐ and stereo‐chemistry of newly synthesized compounds. The cis diastereo‐selectivity of the products was predicted by COSY and NOESY studies.     

The Thermal Instability of 2,4 and 2,6‐N‐Alkylamino‐disubstituted and 2‐N‐Alkylamino‐substituted Nitrobenzenes in Weakly Alkaline Solution: sec‐Amino Effect

We report herein the preparation of two families of secondary amines by the reactions of two equivalents of monoamines with either 2,4 or 2,6‐difluoronitrobenzenes in N,N‐dimethylacetamide in the presence of anhydrous potassium carbonate, as precursors of biologically important nitric oxide donating N‐nitrosamines. In both instances, these compounds could be prepared in quantitative yield when the reaction temperature was held below 130°C. Above this reaction temperature, an unexpected cyclization reaction between the nitro and newly formed adjacent secondary amine group leads to the formation of benzimidazole or quinoxaline rings in low yields. Reasonable reaction mechanisms for the cyclization reaction are proposed.     

Synthesis of 11‐cis‐Retinoids by Hydrosilylation–Protodesilylation of an 11,12‐Didehydro Precursor: Easy Access to 11‐ and 12‐Mono‐ and 11,12‐Dideuteroretinoids

An expeditious, highly efficient approach to 11‐cis‐retinoids was achieved by semihydrogenation of a readily available 11‐yne precursor through a hydrosilylation–protodesilylation protocol. The complete chemo‐, regio‐, and syn‐stereoselectivity of the method also allowed direct access to 11‐ and 12‐monodeutero‐, and 11,12‐dideutero‐11‐cis‐retinoids. The analogous trans series was not accessible by this route, and was synthesized by means of Hiyama coupling.