Substituted γ-lactones. XXX. Reactions of α-Keto-β-Subtituted-γ-butyrolactones with diamines

The condensation reaction between α-keto-β-aroyl (or acyl) -γ-butyrolactones, 4a-4e and o-phenylenediamine or 2, 3-diaminonaphthalene leads under retrograde aldol condensation involving loss of formaldehyde to formation of 3-substituted-3, 4-dihydro-2 (1H) quinoxalinones or benzo [g] quinoxalinones, 7a-7g , respectively as a new convenient synthesis of this type of heterocyclic systems. The reaction of type 4 compound with 4, 5-diaminopyromidine, 8 , was found to proceed differently. 2-[(4-Amino-5-pyrimidinyl)amine]-4-oxo-3-(hydroxymethyl)-4-phenyl-2-butenoic acid 9 was the only product formed when the reaction between 4a and 8 was run in ethanol. The same reaction in glacial acetic acid proceeds with loss of formaldehyde, to afford 7-phenacylidene-7,8-dihydro-6 (1H)-pteridione 10 . The reaction between type 4 compounds and ethylenediamine or 1, 4-phenylenediamine leads to the formation of the bis-condensation products 13–15 , respectively.     

Cyclization of ylidenemalononitriles. X. Synthesis of benzazapropellane derivatives from α-Cyano-β-chloroalkylcinnamonitriles

The reaction of nucleophilic and non-nucleophilic bases wtih 2-carbamoyl-3-(γ-chloropropyl)-1-indenone ( 5 ) have been investigated. Condensation of γ-chlorobutyrophenone with malono-nitrile afforded α-cyano-β-(3-ehloropropyl)cinnamonitrile which was cyclized in concentrated sulfurie acid to produce 5 . Two other products obtained from the cyclization reaction were 2-carbamoyl-3-(γ-ehloropropylidene)-1-indanone ( 4 ) and α-carbamoyl-β-(3-chloropropyl)cinnam-amide. Treatment of a solution of 4 in ethyl acetate with piperidine resulted in cyclization of the γ-chloropropyl side chain to give 2-carbamoyl-3-cycIopropyl-1-indanone. The same compound was obtained in improved yield by the treatment of 4 or 5 with sodium hydroxide solution. The reaction of dirnethylamine with 5 in benzene gave initial Michael addition of the amine followed by internal alkylation of the carbanion so formed to yield 3a-dimethylamino-2,3,3a,8-tetrahydro-8-oxoeyclopent[a]indene-8a(lH)earboxamide ( 7a ). Similarly addition of ammonia, pyrrolidine, piperidine, benzenethiol, p-toluenethiol, 2-naphthalenethiol and nitromethane to the indenone I gave respective analogs of type 7 . Treatment of 5 with sodium cyanide in aqueous t-butyl alcohol resulted in a similar Michael addition followed by internal alkylation. In addition, cyclization between the nitrile and the carbamoyl functions occurred in the same step to give 2-oxo-4-imino-7,8-benzo-3-aza[3.3.3]-propellan-6-one ( 13a ). Hydrolysis of the iminopyrrolido ring in 13a to the corresponding suecin-irnide gave 2,4-dioxo-7,8-benzo-3-aza[3.3.3]propellan-6-one ( 13b ). Reactión of 13b with methyl iodide, allyl bromide, benzyl bromide, and diethyluminoethyl chloride afforded the corresponding N-alkylated products. A similar sequence starling with δ-ehlorovalerophenone led to 5,6-fused ring systems, including a [4.3.3]propellane. 2,9-Dioxo-4-methyl-7,8-benzo-3-aza[4.3.3]propell-4-ene was obtained by the reaction of 5 with acetone in dilute alkali.     

Reaction of cyclic imidates with α,β‐unsaturated esters: Synthesis of new pyrrolo[2,1‐b]‐1,3‐oxazine and pyrido[2,1‐b]‐1,3‐oxazine derivatives

The cycloaddition reaction of cyclic imidates, 2‐benzyl‐5,6‐dihydro‐4H‐1,3‐oxazines 1a , 1b , 1c , 1d , 1e , 1f , with dimethyl acetylenedicarboxylate 2 , trimethyl ethylenetricarboxylate 4 , or dimethyl 2‐(methoxymethylene)malonate 6 afforded new fused heterocyclic compounds, such as methyl (6‐oxo‐3,4‐dihydro‐2H‐pyrrolo[2,1‐b]‐1,3‐oxazin‐7‐ylidene)acetates 3a , 3b , 3c , 3d , 3e , 3f (71–79%), dimethyl 2‐(6‐oxo‐3,4,6,7‐tetrahydro‐2H‐pyrrolo[2,1‐b]‐1,3‐oxazin‐7‐yl)malonates 5b , 5c , 5d , 5e , 5f (43–71%), or methyl 6‐oxo‐3,4‐dihydro‐2H,6H‐pyrido[2,1‐b]‐1,3‐oxazine‐7‐carboxylates 7a , 7b , 7c , 7d , 7e , 7f (32–59%), respectively. In these reactions, 1a , 1b , 1c , 1d , 1e , 1f (cyclic imidates, iminoethers) functioned as their N,C‐tautomers (enaminoethers) 2 to α,β‐unsaturated esters 2 , 4, and 6 to give annulation products 3 , 5 , and 7 following to the elimination of methanol, respectively. J. Heterocyclic Chem., (2011).     

Synthesis of 1‐Methyl‐3‐aryl‐substituted Titanocene and Zirconocene Dichlorides and Crystal Structure of Bis[η5‐1‐methyl‐3‐(α, α‐dimethylbenzyl) cyclopentadienyl] titanium Dichloride

The syntheses of a series of l‐methyl‐3‐aryl‐substituted titanocene and zirconocene dichlorides are reported. These complexes are synthesized by the reaction of 2‐ and 3‐methyl‐6, 6‐dimethylfulvenes (1:4) with aryllithium, followed by the reaction with TiCl₄·2THF, ZrCl₄ and (CpTiCl₂)₂O respectively, to give complexes 1–5. The complex [η⁵‐1‐methyl‐3‐(α, α‐dimethylbenzyl) cyclopentadienyl] titanium dichloride has been studied by X‐ray diffraction. The red crystal of this complex is monoclinic, space group P2_t/C with unit cell parameters: a =6.973(6) × 10^?1 nm, b =36.91(2) × 10^?1 nm, c = 10.063(4) × 10^?1 nm, α=β= γ = 93.35(5)°, V = 2584(5) × 10^?3 nm³ and Z = 4. Refinement for 1004 observed reflections gives the final R of 0.088. There are four independent molecules per unit cell.     

Reaction of Cα,O-dilithiooximes with functionalized carbonyl compounds. Part 2 . Reaction with α-chloroketones and α,β-unsaturated aldehydes and ketones

The reaction of Cα,O-Dilithiooximes 2 and α-chloroketones afforded 5-(hydroxymethyl)-Δ²-soxazolines 4 . α,β-Unsaturated aldehydes and ketones reacted with 2 to give the corresponding acyclic 1,2-addition products 5 . The latter were cyclized with phosphorus pentoxide to 5-vinyl-Δ²-isoxazolines 6 .     

Efficient Synthesis of α‐Benzylidene‐γ‐methyl‐γ‐butyrolactones

A concise synthesis of α‐benzylidene‐γ‐methyl‐γ‐butyrolactones 5a – g from substituted benzaldehydes is described. Compounds 1a – g on reaction with phosphorane 2 , provide the pentenoates 3a – g , which can be hydrolyzed to the acids 4a – g . The latter are cyclized to the corresponding butyrolactones 5a – g in excellent yields. The pentenoates 3a – g , on acid catalyzed cyclization, also provide 5a – g in very high yields.     

Oxidative Fragmentations of the 5α‐ and 5β‐Hydroxy‐B‐norcholestan‐ 3β‐yl Acetates

Oxidations of 5α‐hydroxy‐B‐norcholestan‐3β‐yl acetate ( 8 ) with Pb(OAc)₄ under thermal or photolytic conditions or in the presence of iodine afforded only complex mixtures of compounds. However, the HgO/I₂ version of the hypoiodite reaction gave as the primary products the stereoisomeric (Z)‐ and (E)‐1(10)‐unsaturated 5,10‐seco B‐nor‐derivatives 10 and 11 , and the stereoisomeric (5R,10R)‐ and (5S,10S)‐acetals 14 and 15 (Scheme 4). Further reaction of these compounds under conditions of their formation afforded, in addition, the A‐nor 1,5‐cyclization products 13 and 16 (from 10 ) and 12 (from 11 ) (see also Scheme 6) and the 6‐iodo‐5,6‐secolactones 17 and 19 (from 14 and 15 , resp.) and 4‐iodo‐4,5‐secolactone 18 (from 15 ) (see also Scheme 7). Oxidations of 5β‐hydroxy‐B‐norcholestan‐3β‐yl acetate ( 9 ) with both hypoiodite‐forming reagents (Pb(OAc)₄/I₂ and HgO/I₂) proceeded similarly to the HgO/I₂ reaction of the corresponding 5α‐hydroxy analogue 8 . Photolytic Pb(OAc)₄ oxidation of 9 afforded, in addition to the (Z)‐ and (E)‐5,10‐seco 1(10)‐unsaturated ketones 10 and 11 , their isomeric 5,10‐seco 10(19)‐unsaturated ketone 22 , the acetal 5‐acetate 21 , and 5β,19‐epoxy derivative 23 (Scheme 9). Exceptionally, in the thermal Pb(OAc)₄ oxidation of 9 , the 5,10‐seco ketones 10, 11 , and 22 were not formed, the only reaction being the stereoselective formation of the 5,10‐ethers with the β‐oriented epoxy bridge, i.e. the (10R)‐enol ether 20 and (5S,10R)‐acetal 5‐acetate 21 (Scheme 8). Possible mechanistic interpretations of the above transformations are discussed.     

Photochemie von tricyclischen β, γ-γ′, δ′-ungesättigten Ketonen. 50. Mitteilung über Photoreaktionen

Photochemistry of tricyclic β, γ-γ′, δ′-unsaturated ketones The easily available tricyclic ketone 1 (cf. Scheme 1) with a homotwistane skeleton yielded upon direct irradiation the cyclobutanone derivative 3 by a 1,3-acyl shift. Further irradiation converted 3 into the tricyclic hydrocarbon 4 . However, acetone sensitized irradiation of 1 gave the tetracyclic ketone 5 by an oxa-di-π-methane rearrangement. Again with acetone as a sensitizer the ketone 5 was quantitatively converted to the pentacyclic ketone 6 . The conversion 5 → 6 represents a novel photochemical 1,4-acyl shift. The possible mechanisms are discussed (see Scheme 7). The tricyclic ketone 2 underwent similar types of photoreactions as 1 (Scheme 2). Unlike 5 the tetracyclic ketone 9 did not undergo a photochemical 1,4-acyl shift. The epoxides 10 and 14 derived from the ketones 1 and 2 , respectively, underwent a 1,3-acyl shift upon irradiation followed by decarbonylation, and the oxa-di-π-methane rearrangement (Schemes 3 and 4). The diketone 18 derived from 1 behaved in the same way (Scheme 5). The tetracyclic diketone 21 cyclized very easily to the internal aldol product 22 under the influence of traces of base (Scheme 5). Upon irradiation the γ, δ-unsaturated ketone 24 underwent only the Norrish type I cleavage to yield the aldehyde 25 (Scheme 6).     

Synthesis of Some Novel Phenyl Substituted Oxothiazolidin- 1’’,3’’,4’’-thiadiazolo-[3’,4’-b]thiazoline of 3β-Substituted Cholestane

Three title compounds 4a—4c have been synthesized by the cyclodehydration of 1’-benzylidine-4’-(3β-substituted-5α-cholestane-6-yl)thiosemicarbazones 2a—2c with thioglycolic acid followed by the treatment with cold conc. H2SO4 in dioxane. The compounds 2a—2c were prepared by condensation of 3β-substituted-5α-cholestan- 6-one-thiosemicarbazones 1a—1c with benzaldehyde. These thiosemicarbazones 1a—1c were obtained by the reaction of corresponding 3β-substituted-5α-cholestan-6-ones with thiosemicarbazide in the presence of few drops of conc. HCl in methanol. The structures of the products have been established on the basis of their elemental, analytical and spectral data.     

Synthesis of dihydrofuro[2,3‐b]pyridines by the reaction of 2‐amino‐4,5‐dihydro‐3‐furancarbonitriles with α,β‐unsaturated carbonyl compounds

The reactions of 2‐amino‐4,5‐dihydro‐3‐furancarbonitriles 1a‐d with α,β‐unsaturated carbonyl compounds in the presence of sodium ethoxide (0.1 equivalent) gave the corresponding Michael adducts 2a‐d , 3a‐d and 4a‐d. Compounds 2a‐d and 3a‐c reacted with sodium alkoxide (1 equivalent) to yield the corresponding 7a‐alkoxyhexahydrofuro[2,3‐b]pyridines 5a‐d, 6a‐d, 7a‐c and 8a‐c . Treatment of 5a‐d, 6a‐d, 7a‐c and 8a‐c with potassium tert‐butoxide produced the corresponding dihydrofuro[2,3‐b]pyridines 9a‐d and 10a‐c . The reaction of 4a‐c with sodium ethoxide (1 equivalent) afforded the corresponding dihydro‐furo[2,3‐b]pyridines 11a‐c .     

Synthesis of β‐Arylacyl/β‐Heteroarylacyl‐β‐alkylidene Malonates and Their Application in Substituted Pyridone Synthesis

A novel approach has been developed for the synthesis of β‐arylacyl/β‐heteroarylacyl‐β‐alkylidine malonates in moderate to good yields by the reaction of Stork aryl and heteroaryl enamine with β‐chloroalkylidene malonates. The reaction involves conjugate (Michael) addition of Stork enamine on β‐chloroalkylidene malonates and elimination of chloride ion. These Michael adducts were utilized as intermediates for the synthesis of highly substituted 1,4‐dialkyl‐2‐oxo‐6‐aryl/hetreoaryl‐1,2‐dihydro‐pyridine‐3‐carboxylic acid ethyl esters via 5 + 1 ring annulation protocol.     

Synthesis and isolation of bromo‐β‐carbolines obtained by bromination of β‐carboline alkaloids

β‐Carbolines ( 1–5 ) undergo electrophilic aromatic substitution with N‐bromosuccinimide under different experimental conditions. Although 6‐bromo‐nor‐harmane ( la ) obtained by bromination of nor‐harmane ( 1 ) was isolated and fully characterized sometime ago, the other bromoderivatives of nor‐harmane ( 1b‐1e ) and harmane ( 2a‐2e ) were partially described as part of the reaction mixtures. The preparation and subsequent isolation, purification and full characterization of 1b, 1c, 1d, 1e, 2a, 2b, 2c, 2d, 2e are reported (mp, R _f, ¹H‐nmr, ¹³C‐nmr and ms) together with the preparation, isolation and charaterization, for the first time, of the bromoderivatives obtained from harmine ( 3a‐3e ), harmol ( 4a, 4b ) and 7‐acetylharmol ( 5a‐5c ). As brominating reagent N‐bromosuccinimide and N‐bromosuccinimide‐silica gel in dichloromethane and in chloroform as well as the β‐carboline ‐ N‐bomosuccinimide solid mixture have been used and their uses have been compared. Semiempirical AMI and PM3 calculations have been performed in order to predict reactivity in terms of the energies of HOMO, HOMO‐LUMO difference and in terms of the charge density of β‐carbolines ( 1–5 ) and bromo‐β‐carbolines ( 1a‐1e, 2a‐2e, 3a‐3e, 4a, 4b, 5a, 5b and 5c ) (Scheme 1). Theoretical and experimental results are discussed briefly.     

Total Synthesis of (+)‐β‐Himachalene

An enantioselective synthesis of (+)‐β‐himachalene ( 2 ) was accomplished starting from (1S,2R)‐1,2‐epoxy‐p‐menth‐8‐ene ( 3 ) in 15 or 16 steps with an overall yield of ca. 6% (Schemes 3, 5, and 6). Key transformations include an Ireland–Claisen rearrangement, a Corey oxidative cyclization, and a ring expansion.     

5-雄烯-3β, 7α, 17β-三醇和5-雄烯-3β, 7β, 17β-三醇的合成

以5-雄烯二醇为原料,用微生物转化的方法合成了两个重要的神经甾体5-雄烯-3β, 7α, 17β-三醇和5-雄烯-3β, 7β, 17β-三醇。所用菌种总枝毛霉为我们自己筛选,并首次应用于5-雄烯-3β, 7α, 17β-三醇和5-雄烯-3β, 7β, 17β-三醇的合成中。     

Synthesis and Evaluation of α-Methylidene-γ-butyrolactone bearing flavone and xanthone moieties

In a search for inhibitors of platelet aggregation, a number of α-methylidene-γ-butyrolactones 5 and 6 bearing flavone or xanthone moieties, respectively, were synthesized and evaluated for their antiplatelet activity against thrombin(Thr)-, arachidonic-acid(AA)-, collagen(Col)?, and platelet-activating-factor(PAF)-induced aggregation in washed rabbit platelets. These compounds were synthesized from 7-hydroxyflavone ( 1 ) or 3-hydroxyxanthone ( 2 ) via O-alkylation (→ 3 and 4 , resp.) and Reformatsky-type condensation (Scheme). Most of the flavone-containing α-methylidene-γ-butyrolactones 5a – d showed potent antiplatelet effects on AA- and Col-induced aggregation, while xanthone derivatives 6c – e were found to have the same pharmacological profile than aspirin in which only AA-induced aggregation was inhibited (Table 1). However, 6c – e were approximately three to ten times more potent than aspirin (Table 2). For the vasorelaxing effects, 5a was the only compound which exhibited significant inhibitory activity on the high-K⁺ medium, Ca²⁺-induced vasoconstriction (Table3). Both 5a and 6a , with an aliphatic Me substituent at C(γ) of the lactone, were active against norepinephrine-induced phasic and tonic constrictions while their γ-aryl-substituted counterparts 5b – f and 6b – f were inactive.     

Chemo‐Enzymatic Synthesis of 3‐Deoxy‐β‐D‐ribofuranosyl Purines

9‐(3‐Deoxy‐β‐D ‐erythro‐pentofuranosyl)‐2,6‐diaminopurine ( 6 ) was synthesized by an enzymatic transglycosylation of 2,6‐diaminopurine ( 2 ) with 3′‐deoxycytidine ( 1 ) as a donor of 3‐deoxy‐D ‐erythro‐pentofuranose moiety. This transformation comprises i) deamination of 1 to 3′‐deoxyuridine ( 3 ) under the action of whole cell (E. coli BM‐11) cytidine deaminase (CDase), ii) the phosphorolytic cleavage of 3 by uridine phosphorylase (UPase) giving rise to the formation of uracil ( 4 ) and 3‐deoxy‐α‐D ‐erythro‐pentofuranose‐1‐O‐phosphate ( 5 ), and iii) coupling of the latter with 2 catalyzed by whole cell (E. coli BMT‐4D/1A) purine nucleoside phosphorylase (PNPase). Deamination of 6 by adenosine deaminase (ADase) gave 3′‐deoxyguanosine ( 7 ). Treatment of 6 with NaNO₂ afforded 9‐(3‐deoxy‐β‐D ‐erythro‐pentofuranosyl)‐2‐amino‐6‐oxopurine (3′‐deoxyisoguanosine; 8 ). Schiemann reaction of 6 (HF/HBF₄+NaNO₂) gave 9‐(3‐deoxy‐β‐D ‐erythro‐pentofuranosyl)‐2‐fluoroadenine ( 9 ).     

Base‐Catalyzed Highly Stereoselective Conversion of γ‐Hydroxy‐α,β‐acetylenic Esters to γ‐Acetoxy Dienoates

A convenient route with high stereo control to γ‐acetoxy dienoates is provided by the reaction of methyl propiolate with aldehydes in the presence of ZnEt₂ and N‐methylimidazole at room temperature, followed by the catalytic conversion of the resulting γ‐hydroxy‐α,β‐acetylenic esters with p‐N,N‐dimethylaminopyridine (DMAP) in acetic anhydride (see scheme).

     

Diazoaldehyde Chemistry. Part 1. Transdiazotization of Acylacetaldehydes in Neutral-to-Acidic Medium. A Direct Approach to the Synthesis of α-Diazo-β-oxoaldehydes

First ever non-deformylating transdiazotization of acylacetaldehydes was achieved: the reactions of 2-azido-l-ethylpyridinium tetrafluoroborate ( 4 ) with acylacetaldehydes 3 proceeded partially without deformylation to yield 16 new α-diazo-β-oxoaldehydes 1 along with diazomethyl ketones 2 , especially in the presence of NaOAc (Scheme 1, Tables 1 and 2). The product distribution was substituent-dependent and could be correlated quantitatively. This new diazotization reaction appears as an alternative, direct, and more general method for the synthesis of these diazooxoaldehydes. α-Oxocycloalkanecarbaldehydes 5 gave only traces (if any) of α-diazocycloalkanones 7 , and rearrangement products 6 were isolated (Scheme 2). Mechanisms of the reactions are discussed (Schemes 4 and 5).     

Synthesis of heterocyclic compounds VIII. 4H-Pyrans from α-benzoylcinnamonitriles

A new synthesis of substituted 4H-pyrans is reported. The base catalyzed reaction of substituted α-benzoy]cinnamonitri]es (I) with malononitrile yields 6-amino-2,4-diaryl-3,5-dieyano-4H-pyrans (III). Similarly, 6-amirio-2,4-diaryl-5-carbethoxy-3-cyano-4H-pyrans (IV) have been prepared Irom ethyl cyanoacetate.     

金属参与的N-酰基腙的偕二氟烯丙基化反应：高效合成偕二氟高烯丙基胺

金属铟参与醛衍生的N-酰基腙 1a-1q,4a-4g与3-溴-3,3-二氟丙烯 2 的反应,分别高效得到α, α-二氟高烯丙基肼 3a-3q,5a-5g。该反应条件温和,操作简便。硝基,酚羟基,苄氧基,α, β-不饱和醛的碳-碳双键等官能团对该反应具有良好的官能团兼容性。通过用锌粉代替铟粉, 酮衍生的N-酰基腙 6a-6d 也能发生偕二氟烯丙基化反应,以中等产率得到α, α-二氟高烯丙基肼 7a-7d。裂解肼3a的 N-N键顺利得到偕二氟高烯丙基胺 8,化合物 8 经丙烯酰化,随后进行RCM关环反应,可以方便的转化为偕二氟-γ-取代α, β-不饱和内酰胺 11。