Synthesis of Novel,Chiral Bicyclo[3.1.0]hex‐2‐ene Amino Acid Derivatives as Useful Synthons in Medicinal Chemistry

A short and concise synthesis of novel, chiral bicyclo[3.1.0]hex‐2‐ene amino acid derivatives 13 and 14 has been developed. The key step is a stereo‐ and regioselective allylic amination of exo‐ and endo‐methyl bicyclo[3.1.0]hex‐2‐ene‐6‐carboxylates 8 and 9 , which were prepared from 7,7‐dichlorobicyclo[3.2.0]hept‐2‐en‐6‐one ( 1 ). These amino acid derivatives are useful building blocks in medicinal chemistry and can be prepared as chiral compounds by using either (+)‐ 1 or (?)‐ 1 as starting material.     

Synthesis and Photochromic Properties of New Heterocyclic Derivatives of 1,3‐Diazabicyclo[3.1.0]Hex‐3‐Ene

The facile synthesis of several 1,3‐diazabicyclo[3.1.0]hex‐3‐ene derivatives with varying substitutions such as 2‐methyl‐6‐(4‐nitrophenyl)‐2,4‐diphenyl‐( 1 ), 2‐methyl‐6‐(4‐nitrophenyl)‐4‐phenyl‐2‐(pyridin‐3‐yl)‐( 2 ), 2‐(furan‐2‐yl)‐6‐(4‐nitrophenyl)‐4‐phenyl‐( 3 ), 2‐(furan‐2‐yl)‐6‐(3‐nitrophenyl)‐4‐phenyl‐( 4 ), 6‐(3‐nitrophenyl)‐2,4‐diphenyl‐( 5 ) and 6‐(4‐chlorophenyl)‐4‐(3‐nitrophenyl)‐2‐phenyl‐( 6 ) that all behave as “intelligent materials” are reported.     

Two 1,3‐Diazabicyclo[3.1.0]hex‐3‐enes with a ‘Tripod’ Core

The photochromic 1,3‐diazabiclyclo[3.1.0]hex‐3‐enes 5 and 6 were synthesized from two premade tris‐aldehydes and two premade aziridinyl ketones and characterized (Scheme 1). Their spectra showed structure? photochromic behavior relationships (SPBR), which were analyzed.     

Novel 1,2,3,4‐Tetrahydroquinazolinones via Reaction of 2‐Amino‐N‐substituted Benzamides and Dimethyl Acetylenedicarboxylate

Reaction of 2‐amino‐N‐substituted benzamides and dimethyl acetylenedicarboxylate (DMAD) in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) in H₂O at room temperature led to the formation of novel 1,2,3,4‐tetrahydroquinazolinones.     

Kinetic characterization of a transient reaction by degeneration of the precursor mechanism: Application to the synthesis of 3,4‐diazabicyclo[4.3.0]‐ non‐2‐ene

The rate of the oxidation of N‐amino‐3‐azabicyclo[3.3.0]octane by chloramine has been studied by GC and HPLC between pH 10.5 and 13.5. The second‐order reaction exhibits specific acid catalysis. The formation of N,N′‐azo‐3‐azabicyclo[3.3.0]octane or 3,4‐diazabicyclo[4.3.0]non‐2‐ene is pH, concentration, and temperature dependent. In alkaline media, the exclusive formation of 3,4‐diazabicyclo[4.3.0]non‐2‐ene is observed. Kinetic studies show that the oxidation of N‐amino‐3‐azabicyclo[3.3.0]octane by chloramine is a multistep process with the initial formation of a diazene‐type intermediate, which is converted by hydroxide ions into 3,4‐diazabicyclo[4.3.0]non‐2‐ene. Because it was not possible to follow the rate of change of the intermediate concentration, to determine the kinetics of 3,4‐diazabicyclo[4.3.0]non‐2‐ene formation, a procedure based on the degeneration of the precursor process was adopted. An appropriate mathematical treatment allowed a quantitative interpretation of all the phenomena observed over the given pH interval. The activation parameters were determined. © 2006 Wiley Periodicals, Inc. Int J Chem Kinet 38: 327–338, 2006     

Controlled ROP of β‐Butyrolactone Simply Mediated by Amidine,Guanidine, and Phosphazene Organocatalysts

Basic organocatalysts of the guanidine (1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene, TBD), amidine (1,8‐diazabicyclo[5.4.0]‐undec‐7‐ene, DBU), and phosphazene (2‐tert‐butylimino‐2‐diethylamino‐1,3‐dimethylperhydro‐1,3,2diazaphosphorine, BEMP) type do effectively polymerize β‐butyrolactone (BL). Poly(3‐hydroxybutyrate)s (PHBs) with controlled molecular features, that is, controlled molar masses, narrow molar mass distributions, and well‐defined functional end groups are thus formed at 60 °C from bulk monomer, with up to 21 500 g mol⁻¹. The formation of α,ω‐guanidine/amidine/phosphazene,crotonate functionalized PHBs, as demonstrated by NMR, SEC, and MALDI–ToF mass spectrometry analyses, mechanistically suggests the formation of N‐acyl‐α,β‐unsaturated propagating species that originate from 1:1 guanidine/amidine/phosphazene:BL adducts.     

1,8‐Diazabicyclo[5.4.0]undec‐7‐ene: A Remarkable Base in the Debromination of 4‐ or 5‐Substituted N‐Benzyl α‐Bromo‐α‐p‐Toluenesulfonylglutarimide

Debromination of N‐benzyl 4‐ or 5‐substituted α‐bromo‐α‐p‐toluenesulfonylglutarimides is achieved with 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) to give the N‐benzyl 4‐ or 5‐substituted α‐p‐toluenesulfonylglutarimides. The DBU/THF system is applied to a new methodology for the synthesis of bicyclic glutarimide skeleton in moderate yields.     

6‐(Diazomethyl)‐1,3‐bis(methoxymethyl)uracil,Synthesis and Transformation into Annulated Pyrimidinediones

6‐(Diazomethyl)‐1,3‐bis(methoxymethyl)uracil ( 5 ) was prepared from the known aldehyde 3 by hydrazone formation and oxidation. Thermolysis of 5 and deprotection gave the pyrazolo[4,3‐d]pyrimidine‐5,7‐diones 7a and 7b . Rh₂(OAc)₄ catalyzed the transformation of 5 into to a 2 : 1 (Z)/(E) mixture of 1,2‐diuracilylethenes 9 (67%). Heating (Z)‐ 9 in 12n HCl at 95° led to electrocyclisation, oxidation, and deprotection to afford 73% of the pyrimido[5,4‐f]quinazolinetetraone 12 . The Rh₂(OAc)₄‐catalyzed reaction of 5 with 3,4‐dihydro‐2H‐pyran and 2,3‐dihydrofuran gave endo/exo‐mixtures of the 2‐oxabicyclo[4.1.0]heptane 13 (78%) and the 2‐oxabicyclo[3.1.0]hexane 15 (86%), Their treatment with AlCl₃ or Me₂AlCl promoted a vinylcyclopropane–cyclopentene rearrangement, leading to the pyrano‐ and furanocyclopenta[1,2‐d]pyrimidinediones 14 (88%) and 16 (51%), respectively. Similarly, the addition product of 5 to 2‐methoxypropene was transformed into the 5‐methylcyclopenta‐pyrimidinedione 18 (55%). The Rh₂(OAc)₄‐catalyzed reaction of 5 with thiophene gave the exo‐configured 2‐thiabicyclo[3.1.0]hexane 19 (69%). The analoguous reaction with furan led to 8‐oxabicyclo[3.2.1]oct‐2‐ene 20 (73%), and the reaction with (E)‐2‐styrylfuran yielded a diastereoisomeric mixture of hepta‐1,4,6‐trien‐3‐ones 21 (75%) that was transformed into the (1E,4E,6E)‐configured hepta‐1,4,6‐trien‐3‐one 21 (60%) at ambient temperature.     

Efficient Synthesis of 2‐(2‐Aminophenyl)‐2,3‐dihydropyridin‐4(1H)‐ones Based on a Cyclization/Ring Cleavage Procedure

(Benzyloxycarbonyl)‐protected 3,4‐benzo‐7‐hydroxy‐2,9‐diazabicyclo[3.3.1]non‐7‐enes were prepared by one‐pot cyclizations of 1,3‐bis(silyl enol ethers) with quinazolines. Subsequent hydrogenation resulted in one‐pot deprotection and rearrangement to give 2‐(2‐aminophenyl)‐2,3‐dihydropyridin‐4(1H)‐ones.     

1,8‐Diazabicyclo[5.4.0]undec‐7‐ene: A Highly Efficient Catalyst for One‐Pot Synthesis of Substituted Tetrahydro‐4H‐chromenes,Tetrahydro[b]pyrans,Pyrano[d]pyrimidines,and 4H‐Pyrans in Aqueous Medium

We have reported 1,8‐diazabicyclo[5.4.0]undec‐7‐ene catalyzed one‐pot synthesis of tetrahydro‐4H‐chromenes, tetrahydro[b]pyrans, pyrano[d]pyrimidines and 4H‐pyrans from aldehydes, active methylene compounds malononitrile/ethyl cyanocacetate and activated C–H acids such as dimedone, 1,3‐cyclohexanedione, 1,3‐cyclopentanedione, 1,3‐dimethylbarbituric acid, and ethyl acetoacetate in water under reflux. The attractive features of this process are mild reaction conditions, reusability of the reaction media, short reaction times, easy isolation of products, and excellent yields. Copyright © 2013 HeteroCorporation     

Cytotoxicities and Topoisomerase I Inhibitory Activities of 2‐[2‐(2‐Alkynylphenyl)ethynyl]benzonitriles, 1‐Aryldec‐3‐ene‐1,5‐diynes,and Related Bis(enediynyl)arene Compounds

The activities of a series of acyclic enediynes, 2‐(6‐substituted hex‐3‐ene‐1,5‐diynyl)benzonitriles ( 1 – 5 ) and their derivatives 7 – 23 were evaluated against several solid tumor cell lines and topoisomerase I. Compounds 1 – 5 show selective cytotoxicity with Hepa cells, and 2‐[6‐phenylhex‐3‐ene‐1,5‐diynyl]benzonitrile ( 5 ) reveals the most‐potent activity. Analogues 8 – 10 and 13 – 22 also have the same effect with DLD cells; 1‐[(Z)‐dec‐3‐ene‐1,5‐diynyl)‐4‐nitrobenzene 21 shows the highest activity among them. Moreover, 1‐[(Z)‐dec‐3‐ene‐1,5‐diynyl]‐2‐(trifluoromethyl)benzene ( 20 ) exhibits the strongest inhibitory activity with the Hela cell line. Derivatives 9, 10, 18 , and 23 display inhibitory activities with topoisomerase I at 87 μM . The cell‐cycle analysis of compound 5 , which induces a significant blockage in S phase, indicates that these novel enediynes probably undergo other biological pathways leading to the cytotoxicity, except the inhibitory activity toward topoisomerase I.     

Intramolecular Radical Aziridination of Allylic Sulfamoyl Azides by Cobalt(II)‐Based Metalloradical Catalysis: Effective Construction of Strained Heterobicyclic Structures

Cobalt(II)‐based metalloradical catalysis (MRC) has been successfully applied for effective construction of the highly strained 2‐sulfonyl‐1,3‐diazabicyclo[3.1.0]hexane structures in high yields through intramolecular radical aziridination of allylic sulfamoyl azides. The resulting [3.1.0] bicyclic aziridines prove to be versatile synthons for the preparation of a diverse range of 1,2‐ and 1,3‐diamine derivatives by selective ring‐opening reactions. As a demonstration of its application for target synthesis, the metalloradical intramolecular aziridination reaction has been incorporated as a key step for efficient synthesis of a potent neurokinin 1 (NK₁) antagonist in 60 % overall yield.     

Heterocyclization reaction of 2‐(2‐methylaziridin‐1‐yl)‐3‐ureidopyridines under appel's conditions

The reaction of 2‐(2‐methylaziridin‐1‐yl)‐3‐ureidopyridines 12 with triphenylphosphine, carbon tetra‐chloride, and triethylamine (Appel's conditions) led to the corresponding carbodiimides 13 , which underwent intramolecular cycloaddition reaction with aziridine under the reaction conditions to give the pyridine‐fused heterocycles, 2,3‐dihydro‐1H‐imidazo[2′,3′:2,3]imidazo[4,5‐b]pyridines 16 and 12,13‐dihydro‐5H‐1,3 ‐benzodiazepino [2′,3′:2,3] imidazo[4,5‐b]pyridines 17 .     

Мulticomponent Reactions of NH4Cl,CH2O and SH‐acids in Water as Effective Synthesis of Biologically Active Heterocycles

Multicomponent reactions of ammonium chloride in water with formaldehyde and SH‐acids (H₂S, ethane‐1,2‐dithiol) proceed with selective formation of such heterocycles as 3,7‐dithia‐1,5‐diazabicyclo[3.3.1nonane, 3‐(1,5,3‐dithiazepan‐3‐ylmethyl)‐1,5,3‐dithiazepanе and 1,6‐bis‐(1,5,3‐dithiazepan‐3‐yl)‐2,5‐disulphanylhexane. With participation of 1,3‐propanedithiol, this reaction leads to the formation of three‐dimensional hetero(S,N)‐chain polymer. The antifungal activity of 3,7‐dithia‐1,5‐diazabicyclo[3.3.1]nonane against microscopic fungi Bipolaris sorokiniana, Fusarium oxysporum and Aspergillus niger and same for 1,6‐bis‐(1,5,3‐dithiazepan‐3‐yl)‐2,5‐disulphanylhexane against Botrytis cinerea and Rhizoctonia solani was evaluated.     

Mass spectrometric studies of cis‐ and trans‐1a,3‐disubstituted‐1,1‐dichloro‐4‐formyl‐1a, 2,3,4‐tetrahydro‐lH‐azirino[1,2‐a]1,5]benzodiazepines

The mass spectrometric behaviour of four cis‐ and trans‐1a,3‐disubstituted‐1,1‐dichloro‐4‐formyl‐1a,2,3,4‐tetrahydro‐1H‐azirino [1, 2‐a][1,5]benzodiazepines has been studied with the aid of mass‐analysed ion kinetic energy spectrometry and exact mass measurements under electron impact ionization. All compounds show a tendency to eliminate a chlorine atom from the aziridine ring, and then eliminate a neutral propene or styrene from the diazepine ring to yield azirino [1,2‐b][1,3] benzimidazole ions. These azirino [1,2‐a][1,5]‐benzodiazepimes can also eliminate HCl, or Cl plus HCl simultaneously to undergo a ring enlargement rearrangement to yield 1,6‐benzodiazocine ions, which further lose small molecular fragments, propyne or phenylacetylene, with rearrangement to give quinoxaline ions.     

Oligonucleotides Containing 7‐Deaza‐2′‐deoxyxanthosine: Synthesis,Base Protection,and Base‐Pair Stability

Oligonucleotides incorporating 7‐deaza‐2′‐deoxyxanthosine ( 3 ) and 2′‐deoxyxanthosine ( 1 ) were prepared by solid‐phase synthesis using the phosphoramidites 6 – 9 and 16 which were protected with allyl, diphenylcarbamoyl, or 2‐(4‐nitrophenyl)ethyl groups. Among the various groups, only the 2‐(4‐nitrophenyl)ethyl group was applicable to 7‐deazaxanthine protection being removed with 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) by β‐elimination, while the deprotection of the allyl residue with Pd⁰ catalyst or the diphenylcarbamoyl group with ammonia failed. Contrarily, the allyl group was found to be an excellent protecting group for 2′‐deoxyxanthosine ( 1 ). The base pairing of nucleoside 3 with the four canonical DNA constituents as well as with 3‐bromo‐1‐(2‐deoxy‐β‐D ‐erythro‐pentofuranosyl)‐1H‐pyrazolo[3,4‐d]pyrimidine‐4,6‐diamine ( 4 ) within the 12‐mer duplexes was studied, showing that 7‐deaza‐2′‐deoxyxanthosine ( 3 ) has the same universal base‐pairing properties as 2′‐deoxyxanthosine ( 1 ). Contrary to the latter, it is extremely stable at the N‐glycosylic bond, while compound 1 is easily hydrolyzed under slightly acidic conditions. Due to the pK_a values 5.7 ( 1 ) and 6.7 ( 3 ), both compounds form monoanions under neutral conditions (95% for 1 ; 65% for 3 ). Although both compounds form monoanions at pH 7.0, pH‐dependent T_m measurements showed that the base‐pair stability of 7‐deaza‐2′‐deoxyxanthosine ( 3 ) with dT is pH‐independent. This indicates that the 2‐oxo group is not involved in base‐pair formation.     

Synthesis of [3,3′(4H,4′H)‐Bi‐2H‐1,3‐oxazine]‐4,4′‐diones and Their Hydrolysis

The [3,3′(4H,4′H)‐bi‐2H‐1,3‐oxazine]‐4,4′‐diones 3a – 3i were obtained by [2+4] cycloaddition reactions of furan‐2,3‐diones 1a – 1c with aromatic aldazines 2a – 2d (Scheme 1). So, new derivatives of bi‐2H‐1,3‐oxazines and their hydrolysis products, 3,5‐diaryl‐1H‐pyrazoles 4a – 4c (Scheme 3), which are potential biologically active compounds, were synthesized for the first time.     

Incorporation of an Allene Unit into α‐Pinene via β‐Elimination

The two double‐bond isomers 3‐iodo‐2,6,6‐trimethylbicyclo[3.1.1]hept‐2‐ene ( 6b ) and 3‐iodo‐4,6,6‐trimethylbicyclo[3.1.1]hept‐2‐ene ( 11 ) were synthesized by reacting 2,6,6‐trimethylbicyclo[3.1.1]heptan‐3‐one ( 9 ) with hydrazine, followed by treatment with I₂ in the presence of Et₃N. Treatment of 11 with t‐BuOK as base in diglyme at 220° resulted in the formation of 9 and 6,6‐dimethyl‐4‐methylidenebicyclo[3.1.1]hept‐2‐ene ( 12 ). For the formation of 9 , the cyclic allene 7 is proposed as an intermediate. Treatment of the second isomer, 6b , with t‐BuOK at 170° gave rise to the diene 12 and the dimerization product 17 . The underlying mechanism of this transformation is discussed. On the basis of density‐functional‐theory (DFT) calculations on the allene 7 and the alkyne 15 , the formation of the latter as the intermediate was excluded.     

Reaction of a Dialumene‐Benzene Adduct with Diphenylacetylene: Formation of 3,4‐Dialuminacyclobutene and 5,6‐Dialuminabicyclo[2.1.1]hex‐2‐ene Derivatives

Reaction of a dialumene‐benzene adduct bearing bulky aryl substituents with diphenylacetylene was found to give a novel 5,6‐dialuminabicyclo[2.1.1]hex‐2‐ene derivative in addition to the 3,4‐dialuminacyclobutene derivative, the formal [2+2]cycloadduct of an intermediary dialumene with diphenylacetylene. The molecular structure of the newly obtained 5,6‐dialuminabicyclo[2.1.1]hex‐2‐ene has been elucidated by X‐ray crystallographic analysis.     

Diastereodivergent Asymmetric 1,3‐Dipolar Cycloaddition of Azomethine Ylides and β‐Fluoroalkyl Vinylsulfones: Low Copper(II) Catalyst Loading and Theoretical Studies

A Cu^II‐catalyzed asymmetric 1,3‐dipolar cycloaddition using β‐fluoroalkyl alkenyl arylsulfones as dipolarophiles and glycine/alanine iminoesters as azomethine ylide precursors has been developed. Remarkably, a catalyst loading as low as 0.5 mol % is highly efficient. Accordingly, a wide range of enantioenriched 3‐fluoroalkyl pyrrolidines, as well as Δ²‐pyrroline and pyrrole derivatives, are generated in good to excellent yields with high asymmetric induction. This synthetic approach is diastereodivergent in that exo‐adducts could be converted into the corresponding exo′‐adducts by 1,8‐diazabicyclo[5.4.0]undec‐7‐ene mediated epimerization at C2 of the pyrrolidine core. The free‐energy profiles from DFT calculations suggest the Michael addition of the 1,3‐dipole to be the rate‐ and enantiodetermining step, and the origin of stereoselectivity is studied by means of the noncovalent interaction (NCI) analysis.