Synthesis of novel crownophanes containing two phenolic moieties via a tandem claisen rearrangement

A series of crownophanes containing two phenolic moieties within a macrocyclic ring have been successfully synthesized by a one-step thermal reaction from the corresponding macrocyclic polyethers by using a “Tandem Claisen Rearrangement”.     

Spectroscopic characterization and molecular structure of 3,14‐dimethyl‐2,6,13,17‐tetraazapentacyclo[16.4.0.12,17.16,13.07,12]tetracosane

Constrained cyclam derivatives have been found to exhibit anti‐HIV effects. The strength of binding to the CXCR4 receptor correlates with anti‐HIV activity. The conformation of the macrocyclic compound is very important for co‐receptor recognition. Therefore, knowledge of the conformation and crystal packing of macrocycles has become important in developing new highly effective anti‐HIV drugs. Structural modifications of N‐functionalized polyaza macrocyclic compounds have been achieved using various methods. A new synthesis affording single crystals of the title tetraazapentacyclo[16.4.0.1^2,17.1^6,13.0^7,12]tetracosane macrocycle, C₂₂H₄₀N₄, is reported. Formaldehyde reacts readily at room temperature with the tetraazatricyclo[16.4.0.0^2,17]docosane precursor to yield a macropolycycle containing two five‐membered rings. Characterization by elemental, spectroscopic and single‐crystal X‐ray diffraction analyses shows that the asymmetric unit contains half of a centrosymmetric molecule. The molecular structure shows a trans conformation for the two methylene bridges owing to molecular symmetry. The crystal structure is stabilized by intramolecular C—H…N hydrogen bonds. NMR and IR spectroscopic properties support the methylene‐bridged macrocyclic structure.     

2‐[N‐(2,3‐Dimethylphenyl)carbamoyl]benzenesulfonamide and the 3,4‐ and 2,6‐dimethylphenyl analogues

The structures of 2‐[(2,3‐dimethylphenyl)carbamoyl]benzenesulfonamide, 2‐[(3,4‐dimethylphenyl)carbamoyl]benzenesulfonamide and 2‐[(2,6‐dimethylphenyl)carbamoyl]benzenesulfonamide, all C₁₅H₁₆N₂O₃S, are stabilized by extensive intra‐ and intermolecular hydrogen bonds. In all three structures, the sulfonamide and carbamoyl groups are involved in hydrogen bonding. In the 2,3‐dimethyl and 2,6‐dimethyl derivatives, dimeric units and chains of molecules are formed parallel to the c axis. In the 3,4‐dimethyl derivative, the hydrogen bonding creates tetrameric units, resulting in macrocyclic R₄⁴(22) rings that form sheets in the ab plane. The three analogues are closely related to the fenamate class of nonsteroidal anti‐inflammatory drugs.     

4,17,25,26‐Tetraaza‐6,9,12,15‐tetra­oxa‐2,19,21,24‐tetrathiatricyclo[18.4.11,4.117,20]hexacosa‐1(25),20(26)‐diene‐3,5,16,18‐tetraone

The title compound, C₁₄H₁₆N₄O₈S₄, has crystallographic C₂ symmetry with half a molecule in the asymmetric unit and a dihedral angle of 58.7 (1)° between the two planar 1,3,4‐thiadiazole five‐membered rings of the macrocyclic, giving the molecule a twisted conformation.     

3‐[5‐(4‐Chlorophenyl)‐1‐(4‐methoxyphenyl)‐1H‐pyrazol‐3‐yl]propionic acid and the corresponding methyl ester

The synthesis of 3‐[5‐(4‐chlorophenyl)‐1‐(4‐methoxyphenyl)‐1H‐pyrazol‐3‐yl]propionic acid, C₁₉H₁₇ClN₂O₃, (I), and its corresponding methyl ester, methyl 3‐[5‐(4‐chlorophenyl)‐1‐(4‐methoxyphenyl)‐1H‐pyrazol‐3‐yl]propionate, C₂₀H₁₉ClN₂O₃, (II), is regiospecific. However, correct identification of the regioisomer formed by spectroscopic techniques is not trivial and single‐crystal X‐ray analysis provided the only means of unambiguous structure determination. Compound (I) crystallizes with Z′ = 2. The propionic acid groups of the two crystallographically unique molecules form a hydrogen‐bonded dimer, as is typical of carboxylic acid groups in the solid state. Conformational differences between the methoxybenzene and pyrazole rings give rise to two unique molecules. The structure of (II) features just one molecule in the asymmetric unit and the crystal packing makes greater use than (I) of weak C—H...A interactions, despite the lack of any functional groups for classical hydrogen bonding.     

Synthesis and chemical modification of hyperbranched polyethers with terminal hydroxy groups by the anionic ring‐opening polymerization of 3‐alkyl‐3‐hydroxymethyl oxetanes

The anionic ring‐opening polymerization of oxetanes containing hydroxyl groups was carried out with potassium tert‐butoxide as an initiator in the presence of 18‐crown‐6‐ether in N‐methylpyrrolidinone at 180 °C; it yielded corresponding multifunctional hyperbranched polymers: poly(3‐ethyl‐3‐hydroxymethyloxetane)s, with number‐average molecular weights of 2200–4100 in 83–95% yields, and poly(3‐methyl‐3‐hydroxymethyloxetane)s, with number‐average molecular weights of 4600–5200 in 70–95% yields. The synthesized poly(3‐ethyl‐3‐hydroxymethyloxetane)s and poly(3‐methyl‐3‐hydroxymethyloxetane)s were hyperbranched polyethers containing an oxetane moiety and many hydroxy groups at the ends. The postpolymerization of poly(3‐ethyl‐3‐hydroxymethyloxetane)s was performed in the presence of potassium tert‐butoxide and 18‐crown‐6‐ether in N‐methylpyrrolidinone at 180 °C; it yielded corresponding polymers with higher molecular weights in good yields. The cationic polymerization of poly(3‐ethyl‐3‐hydroxymethyloxetane) derivatives was carried out with boron trifluoride etherate as an initiator and was followed by alkaline hydrolysis; this yielded a new branched polymer, a poly(hyperbranched polyether), with many pendant hydroxy groups. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 3739–3750, 2004     

A One‐Pot Biginelli Synthesis of 6‐Unsubstituted 5‐Aroylpyrimidin‐2(1H)‐ones and 6‐Acetyl‐1,2,4‐triazin‐3(2H)‐ones

The three‐component Biginelli‐like cyclocondensation reaction of enamines 1 , urea, and aldehydes in dioxane/acetic acid efficiently afforded the corresponding 6‐unsubstituted 3,4‐dihydropyrimidin‐2(1H)‐ones 2 in good yields (Scheme 1, Table). The corresponding reaction of azaenamine (=hydrazone) 7 with benzaldehyde and urea afforded 6‐acetyl‐1,2,4‐triazin‐3(2H)‐ones in good yields (Scheme 3).     

On the chemistry of 5‐aryl‐2‐hydrazino‐benzo[6,7]cyclohepta[1,2‐b]pyrido[2,3‐e] pyrimidin‐4‐one

Several pyrido[2,3‐e]pyrimidine fused with other rings have been prepared by intramolecular cyclization of 5‐(4‐chlorophenyl)‐2‐hydrazino‐benzo [6,7]cyclohepta‐[1,2‐b]pyrido[2,3‐e]pyrimidine‐4‐one ( 1 ) with acids, carbon disulfide to form triazole derivatives ( 2,4 ), halo‐ketones to give triazine derivative ( 5 ), β‐ketoesters, β‐cyanoesters, and β‐diketones to yield 2‐(1‐pyrazolyl) derivatives ( 7,9,10 ), and aldehydes to form arylhydrazone derivatives ( 11a,b ) which cyclized to form triazoles ( 12a,b ). Also, acyclic N‐nucleosides are prepared by heating under reflux 2‐hydrazino‐benzo[6,7]cyclohepta[1,2‐b]pyrido[2,3‐e] pyrimidin‐4‐one ( 1 ) with xylose and glucose to give the corresponding acyclic N‐nucleosides ( 13a,b ) which are cyclized to afford the corresponding protected tetra and penta–O‐acetate C‐nucleosides ( 14a,b ). Deacetylating of the latter nucleosides afforded the free acyclic C‐nucleosides ( 15a,b ). © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:34–43, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20248     

New diazadi(and tri)thia‐21‐crown‐7 ethers containing 8‐hydroxyquinoline side arms

A series of macrocyclic diazadi(and tri)thiacrown ethers containing two 5‐substituent‐8‐hydroxyquinoline side arms have been synthesized from the corresponding macrocyclic diazadi(and tri)thiacrown ethers. The crown ethers were obtained by reduction of the proper macrocyclic di(and tri)thiadiamides by borane‐tetrahydrofuran or by sodium borohydride‐boron trifluoride ethyl etherate‐tetrahydrofuran. The yields for the reduction of diamides by sodium borohydride‐boron trifluoride ethyl etherate‐tetrahydrofuran were higher than those by borane‐tetrahydrofuran. The following four methods were used to prepare macrocycles bearing two 8‐hydroxyquinoline side arms: (1) Mannich reaction with 8‐hydroxyquinoline; (2) Reductive animation with 8‐hydroxyquinoline‐2‐carboxaldehyde using sodium triacetoxyborohydride as the reducing agent; (3) Cyclization of N,N'‐bis(8‐hydroxyquinolin‐2‐ylmethyl)‐1,2‐bis(2‐aminoethoxy)ethane (38) with bis(α‐chloroamide) 5 ; and ( 4 ) A step‐by‐step process wherein macrocyclic trithiadiamide 11 was reduced by lithium aluminum hydride‐tetrahydrofuran to the cyclic monoamide 36 , which smoothly reacted with 5‐chloro‐8‐hydroxyquinoline to produce monosubstituted‐macrocyclic monoamide 39 .     

Investigation of Some Functionalization Reactions of 4‐Benzoyl‐5‐phenyl‐1‐(4‐methoxyphenyl)‐1H‐pyrazole‐3‐carbonyl Chloride and Their Antimicrobial Activity

The 1H‐pyrazole‐3‐carboxylic acid 1 was converted via reactions of its acid chloride 3 with various asymmetrical disubstituted urea and alcohol derivatives into the corresponding novel 4‐benzoyl‐N‐(N′,N′‐dialkylcarbamyl)‐1‐(4‐methoxyphenyl)‐5‐phenyl‐1H‐pyrazole‐3‐carboxamide 4a , b and alkyl 4‐benzoyl‐1‐(4‐methoxyphenyl)‐5‐phenyl‐1H‐pyrazole‐3‐carboxylate 7a‐c , respectively, in good yields (57%‐78%). Friedel‐Crafts reactions of 3 with aromatic compouns for 15 min.‐2 h led to the formation of the 4‐3‐diaroyl‐1‐(4‐hydroxyphenyl)‐5‐phenyl‐1H‐pyrazoles 9a‐c , 4‐benzoyl‐1‐(4‐methoxyphenyl)‐3‐aroyl‐5‐phenyl‐1H‐pyrazoles 10a , b and than from the acylation reactions of 9a‐c were obtained the 3,4‐diaroyl‐1‐(4‐acyloxyphenyl)‐5‐phenyl‐1H‐pyrazoles 13a‐d . The structures of all new synthesized compounds were established by NMR experiments such as ¹H, and ¹³C, as well as 2D COSY and IR spectroscopic data, and elemental analyses. All the compounds were evaluated for their antimicrobial activities (agar diffusion method) against eight bacteria and two yeasts.     

4‐Hydroxy‐1‐phenylquinolin‐2(1H)‐one in One‐pot Synthesis of Pyrimidoquinolines and Related Compounds under Microwave Irradiation and Conventional Conditions

Biginelli condensation reactions of 4‐hydroxy‐1‐phenylquinolin‐2(1H)‐one, aryl aldehydes and urea, or thiourea, 5‐amino‐1H‐1,2,4‐triazole, or 2‐amine‐1H‐benzimidazole ( 9 ) under microwave irradiation afforded the corresponding pyrimido[5,4‐c]quinolin‐5‐one derivatives in high yields. One‐pot synthesis of 2H‐pyrano[3,2‐c]quinolines is also reported.     

Geometry‐Retentive C‐Alkenylation of Lithiated α‐Aminonitriles: Quaternary α‐Alkenyl Amino Acids and Hydantoins

α‐Amino nitriles tethered to alkenes through a urea linkage undergo intramolecular C‐alkenylation on treatment with base by attack of the lithionitrile derivatives on the N′‐alkenyl group. A geometry‐retentive alkene shift affords stereospecifically the E or Z isomer of the 5‐alkenyl‐4‐iminohydantoin products from the corresponding starting E ‐ or Z ‐N ′‐alkenyl urea, each of which may be formed from the same N ‐allyl precursor by stereodivergent alkene isomerization. The reaction, formally a nucleophilic substitution at an sp² carbon atom, allows the direct regioselective incorporation of mono‐, di‐, tri‐, and tetrasubstituted olefins at the α‐carbon of amino acid derivatives. The initially formed 5‐alkenyl iminohydantoins may be hydrolyzed and oxidatively deprotected to yield hydantoins and unsaturated α‐quaternary amino acids.     

Two derivatives of 5‐amino­tetrazole: 5‐amino‐1‐phenyl­tetrazole and 5‐amino‐1‐(1‐naphthyl)­tetrazole

In the mol­ecules of 5‐amino‐1‐phenyl­tetrazole, C₇H₇N₅, (I), and 5‐amino‐1‐(1‐naphthyl)­tetrazole, C₁₁H₉N₅, (II), the tetrazole rings and aryl fragments are not coplanar; corresponding dihedral angles are 50.58 (5) and 45.19 (7)° for the two independent mol­ecules of (I), and 64.14 (5)° for (II). Intermolecular N—H⋯N hydrogen bonds between the amino groups and tetrazole N atoms are primarily responsible for formation of two‐dimensional networks extending parallel to the bc plane in both compounds. The presence of the amino group has a distinct effect on the geometry of the tetrazole rings in each case.     

(1R*,11R*)‐Bi­cyclo­[9.4.1]­hexa­decane‐12,16‐dione

The title compound, C₁₆H₂₆O₂, (I), prepared by oxidation of (1R*,11R*)‐12‐hydroxy­bi­cyclo­[9.4.1]­hexa­decan‐16‐one using pyridinium dichromate, has a trans configuration of the two fused rings and represents an interesting precursor for the synthesis of macrocyclic structures.     

Regioselective Synthesis of the 5,6‐Dihydro‐4H‐furo[2,3‐c]pyrrol‐4‐one Skeleton: A New Class of Compounds

We hereby report the first preparation of the 5,6‐dihydro‐4H‐furo[2,3‐c]pyrrol‐4‐one ( 3 ) and its derivatives starting from methyl 3‐(methoxycarbonyl)furan‐2‐acetate ( 8 ). The ester functionality connected to the methylene group was regiospecifically converted to the desired monohydrazide 9 . Conversion of 9 into the acyl azide 10 followed by Curtius rearrangement gave the corresponding isocyanate derivative 11 (Scheme 2). Reaction of 11 with different nucleophiles produced urethane and urea derivatives (Scheme 3). Intramolecular cyclization reactions provided the target compounds (Scheme 5). Removal of the amine‐protecting group formed the title compound 3 .     

Crystallographic study of self‐organization in the solid state including quasi‐aromatic pseudo‐ring stacking interactions in 1‐benzoyl‐3‐(3,4‐dimethoxyphenyl)thiourea and 1‐benzoyl‐3‐(2‐hydroxypropyl)thiourea

1‐Benzoylthioureas contain both carbonyl and thiocarbonyl functional groups and are of interest for their biological activity, metal coordination ability and involvement in hydrogen‐bond formation. Two novel 1‐benzoylthiourea derivatives, namely 1‐benzoyl‐3‐(3,4‐dimethoxyphenyl)thiourea, C₁₆H₁₆N₂O₃S, (I), and 1‐benzoyl‐3‐(2‐hydroxypropyl)thiourea, C₁₁H₁₄N₂O₂S, (II), have been synthesized and characterized. Compound (I) crystallizes in the space group P , while (II) crystallizes in the space group P 2₁/c . In both structures, intramolecular N—H…O hydrogen bonding is present. The resulting six‐membered pseudo‐rings are quasi‐aromatic and, in each case, interact with phenyl rings via stacking‐type interactions. C—H…O, C—H…S and C—H…π interactions are also present. In (I), there is one molecule in the asymmetric unit. Pairs of molecules are connected via two intermolecular N—H…S hydrogen bonds, forming centrosymmetric dimers. In (II), there are two symmetry‐independent molecules that differ mainly in the relative orientations of the phenyl rings with respect to the thiourea cores. Additional strong hydrogen‐bond donor and acceptor –OH groups participate in the formation of intermolecular N—H…O and O—H…S hydrogen bonds that join molecules into chains extending in the [001] direction.     

Ring opening polymerization of epoxides with urea‐derivatives of 4‐aminopyridine as thermally latent anionic initiator

In this study, a series of urea‐derivatives of 4‐aminopyridine (4AP) were evaluated as thermally latent initiators for the anionic ring‐opening polymerization of diglycidyl ether of bisphenol A (DGEBA). The urea‐derivatives were synthesized by the reactions of 4AP with the corresponding iso(thio)cyanates (phenyl isocyanate, tert‐butyl isocyanate, methylene diphenyl diisocyanate, and phenyl isothiocyanate). The ability of the urea‐derivatives as latent initiators was investigated with differential scanning calorimetry (DSC): Upon heating formulations comprised of DGEBA and the urea‐derivatives in a heating rate at 10 °C/min, the resulting DSC profiles indicated exothermic peaks to confirm that DGEBA underwent the polymerization efficiently. The corresponding DSC‐peak top temperatures (T_{peak top}) was higher than that observed for the formulation comprised of DGEBA and pristine 4AP, to clarify that the urea are useful initiators with thermal latency. A possible mechanism for the initiation step involves the thermal dissociation of the urea into 4AP and the corresponding isocyanates. 4AP thus generated readily initiated the ring‐opening polymerization of epoxide. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 2518–2522     

1,ω‐Bis(4‐amino‐1,2,4‐triazole‐5(1H)‐thion‐3‐ylsulfanyl)alkanes: Versatile precursors for novel bis(S‐triazolo[3,4‐b][1,3,4]thiadiazines) as well as novel bis(macrocyclic schiff bases)

Two synthetic routes were attempted for the synthesis of the novel bis(5,6‐dihydro‐S‐triazolo[3,4‐b]thiadiazines) 12a,b and 14 . In the first route the bis(aminotriazoles) 4a,b were reacted with the appropriate α‐haloketones or α‐haloesters to give the corresponding bis(S‐triazolo[3,4‐b]thiadiazines) 11a‐d followed by reduction with NaBH₄. In the second route, the bis(Schiff bases) 13d were reacted with the appropriate α‐haloesters in refluxing DMF containing TEA to give the target compound 14 . Cyclocondensation of 4a,b with the appropriate bis(carbonyl) ethers 15a,b in refluxing acetic acid under high dilution conditions afforded the corresponding macrocyclic Schiff bases 16a‐c . The latter underwent alkylation with the appropriate halo compounds to give the corresponding alkylated derivatives 17a‐d .     

N‐tert‐Butyl‐N′‐[5‐cyano‐2‐(4‐methylphenoxy)phenylsulfonyl]urea,a new TXA2 receptor antagonist

The title compound, C₁₉H₂₁N₃O₄S, crystallizes in the space group P2/c with two molecules in the asymmetric unit. The conformation of both molecules is very similar and is mainly determined by an intramolecular N—H...O hydrogen bond between a urea N atom and a sulfonyl O atom. The O and second N atom of the urea groups are involved in dimer formation via N—H...O hydrogen bonds. The intramolecular hydrogen‐bonding motif and conformation of the C—SO₂—NH(C=O)—NH—C fragment are explored and compared using the Cambridge Structural Database and theoretical calculations. The crystal packing is characterized by π–π stacking between the 5‐cyanobenzene rings.     

Macrocyclic 2,7‐Anthrylene Oligomers

A macrocyclic compound consisting of six 2,7‐anthrylene units was successfully synthesized by Ni‐mediated coupling of the corresponding dibromo precursor as a novel π‐conjugated compound. This compound was sufficiently stable and soluble in organic solvents due to the presence of mesityl groups. X‐ray analysis showed that the molecule had a nonplanar and hexagonal wheel‐shaped framework of approximately S₆ symmetry. The dynamic process between two S₆ structures was observed by using the dynamic NMR technique, the barrier being 58 kJ mol^?1. The spectroscopic properties of the hexamer were compared with those of analogous linear oligomers.