A new 3-methylidenepentane-1,5-dianion synthon: synthesis of perhydropyrano[2,3-b]pyrans and 1,7-dioxaspiro[4.5]decanes

4-Phenylsulfanyl-2-(2-phenylsulfanylethyl)but-1-ene (2) has proved to be an appropriate and new 3-methylidenepentane-1,5-dianion synthon. The reaction of 2 with an excess of lithium powder and a catalytic amount of DTBB (2.5%) in the presence of a carbonyl compound in THF at 0 °C, leads, after hydrolysis, to the expected methylidenic diols 3. These diols when subjected to successive hydroboration-oxidation and final oxidation, undergo spontaneous cyclisation to furnish a series of cis-perhydropyrano[2,3-b]pyrans (4) in a highly diastereoselective manner (>99% de). Additionally, diols 3 also undergo double intramolecular iodoetherification promoted by a silver salt, to furnish the corresponding 1,7-dioxaspiro[4.5]decanes (6) in very high yields.     

A direct synthesis of 1,7-dioxaspiro[4.5]decanes from the new 3-methylidenepentane-1,5-dianion synthon

4-Phenylsulfanyl-2-(2-phenylsulfanylethyl)but-1-ene (2) has proved to be an appropriate and new 3-methylidenepentane-1,5-dianion synthon. The reaction of 2 with an excess of lithium powder and a catalytic amount of DTBB (2.5%) in the presence of a carbonyl compound in THF at 0 °C, leads, after hydrolysis, to the expected methylidenic diols 3. These diols undergo double intramolecular iodoetherification promoted by a silver salt, to furnish the corresponding 1,7-dioxaspiro[4.5]decanes (4) in very high yields. The oxidation of compounds 4 to the corresponding lactones is also studied.     

Arene-promoted lithiation of 1,n-dihaloalkanes (n=2-6): a comparative study

The reaction of 1,n-dichloroalkanes 3a (n=2-6) with an excess of lithium powder and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB; 2.5 mol %) in the presence of different carbonyl compounds [Bu^tCHO, PhCHO, Et₂CO, (CH₂)₄CO, (CH₂)₅CO, (CH₂)₇CO, (−)-menthone], in THF at −78 °C leads, after hydrolysis with water, to the expected 1,(n+2)-diols 4, yields being <25% for n=2, 3 and in the range of 45-79% for n=4-6. When the same protocol is applied to 1,n-bromochloroalkanes 3b and 1,n-dibromoalkanes 3c (n=2-6), diols 4 are obtained in general with lower yields.     

2-Deuterio-1,3-benzodithiolium perchlorate: A useful synthon for the preparation of aldehydes-1-d

2-Deuterio-1,3-benzodithiolium perchlorate reacted with Grignard reagents to give 2-alkyl or 2-aryl-2-deuterio-1,3-benzodithioles, which in turn could be hydrolysed to corresponding aldehydes-1-d.     

1,3-Dipolar cycloaddition of azomethine ylide with ethene and 2-butene: a computational study

B3LYP/6-311 + G(d,p) has been used to calculate the relative energies and geometrical parameters of the respective reactants, transition states, and cycloadducts from the cycloadditions of azomethine ylide and ethene, (Z)-2-butene, and (E)-2-butene. The half-chair (envelope) transition state structures are consistent with a synchronous concerted cycloaddition mechanism.     

Aminotroponiminates: Impact of the NO2 Functional Group on Coordination,Isomerisation, and Backbone Substitution

Aminotroponiminate (ATI) ligands are a versatile class of redox-active and potentially cooperative ligands with a rich coordination chemistry that have consequently found a wide range of applications in synthesis and catalysis. While backbone substitution of these ligands has been investigated in some detail, the impact of electron-withdrawing groups on the coordination chemistry and reactivity of ATIs has been little investigated. We report here Li, Na, and K salts of an ATI ligand with a nitro-substituent in the backbone. It is demonstrated that the NO₂ group actively contributes to the coordination chemistry of these complexes, effectively competing with the N,N-binding pocket as a coordination site. This results in an unprecedented E/Z isomerisation of an ATI imino group and culminates in the isolation of the first “naked” (i. e., without directional bonding to a metal atom) ATI anion. Reactions of sodium ATIs with silver(I) and tritylium salts gave the first N,N-coordinated silver ATI complexes and unprecedented backbone substitution reactions. Analytical techniques applied in this work include multinuclear (VT-)NMR spectroscopy, single-crystal X-ray diffraction analysis, and DFT calculations.     

Electrochemical Amination in the System Ti(IV)–NH2OH–C6H6: The Efficiency of the Process in a Sulfuric Acid Solution Containing an Organic Solvent

Electrolysis of the system Ti(IV)–NH₂OH–C₆H₆ in an 11 M H₂SO₄ solution shows that using an organic solvent (acetic acid, acetonitrile) during cathodically initiated amination of aromatic substrates permits the production of aromatic amines with the overall yield by hydroxylamine reaching 91%. Due to a chain mechanism of radical substitution, the benzene amination in electrolytes containing 5 M CH₃COOH and 5.5 M CH₃CN terminates largely upon consuming 70–75 and 50–55% of the charge required theoretically for a one-electron process. The maximum efficiency of electrochemical amination is observed at low hydroxylamine conversions and the overall current efficiency for mono- and disubstituted products of the benzene amination may exceed in these conditions 750%.     

Iodine-alumina as an efficient and useful catalyst for the regeneration of carbonyl functionality from the corresponding 1,3-oxathiolanes and 1,3-dithiolanes in aqueous system

A simple and useful method has been demonstrated for the deprotection of 1,3-oxathiolanes and 1,3-dithiolanes to the corresponding carbonyl compounds in excellent yield by employing catalytic amount (30 mol %) of iodine supported on neutral alumina in ethanol-water or water. The major advantages of this protocol are mild reaction conditions, less reaction time, easy to handle, high yields, inexpensive reagent and environmentally benign.     

5,7-Dichloro-1,3-dithiolo[4,5-d]pyrimidine-2-thione and -2-Selone: Synthesis, Crystal Structure, Solvatochromism, and Reactions with Nucleophiles

We have obtained for the first time the halo derivatives of a novel heterocyclic system, 1,3-dithiolo[4,5-d]pyrimidine-2-thione and -2-selone, by reaction of 5,7-dioxo(4H,6H)-1,3-dithiolo[4,5-d]pyrimidine-2-thione and -2-selone with POCl₃. The crystal structure of thione confirms that we had obtained the desired compound. The electronic absorption spectra reveal an interesting solvatochromism connected with the appearance of low-intensity n transitions from selenium and sulfur atoms in the visible region of the spectrum. The chlorine atoms in the studied compounds have significant mobility in reactions with nucleophiles (amines, thiourea, azidione), which ensures that new derivatives of 1,3-dithiolo[4,5-d]pyrimidine-2-selone are obtained, and specifically 7-N,N-dialkylamino, 7-N-alkyl-N-arylamino derivatives and 7-isothiuronium salts. The 2-selones obtained can be used in synthesis of new tetrathiafulvalenes.     

The first example of the generation of azomethine ylides from a fluorocarbene: 1,3-cyclization and 1,3-dipolar cycloaddition

The reaction of Schiff bases with fluorocarbene, generated by reduction of dibromofluoromethane with active lead in the presence of Bu₄NBr under ultrasound irradiation, involves the formation of fluoro-substituted azomethine ylides which undergo cyclization into aziridines. 1,3-Cyclization of ylides, generated from N-arylimines of benzaldehyde, proceeds stereoselectively. When carrying out the reaction of Schiff bases with fluorocarbene in the presence of dimethyl maleate or dimethyl acetylenedicarboxylate, the products of dehydrofluorination of the primary adducts of the 1,3-dipolar cycloaddition of fluoro-substituted azomethine ylides to multiple bonds of dipolarophiles were obtained. In the case of the reaction of N-alkylimines of benzaldehyde the cycloaddition of ylides to dimethyl maleate completely suppressed the cyclization to aziridines.     

Asymmetric aldol reactions using catalytic d(+)-proline: a new, economic and practical approach to a commonly employed C1-C6 keto-acid synthon of the epothilones

A new approach to ketoacid 4, a common C1-C6 fragment used in the total synthesis of epothilones was initiated by direct aldol reaction of acetone with a pivaldehyde-like substance 5, catalyzed with d-proline, leading to a 2,6-diketoalcohol with better than 99% ee. Further intramolecular closure of the diketone 8 followed by oxidation of the silyl protected hydroxycyclohexenone 14 led to the desired product 4. None of the steps have been optimized, yet the overall yield for the four-step process is 31%. The use of commercially available d-proline to construct the chiral center of 4 under very mild reaction conditions provided an economical and practical method for its construction.     

Substituent and solvent effects in the 1,3-dipolar cycloadditions for synthesis of anti-influenza agent peramivir and its analog

Influenza remains a health problem to humans. Peramivir is a FDA approved anti-influenza drug targeting the virus neuraminidase. The (3 + 2) cycloaddition reaction of 2-ethylbutanenitrile oxide with the cyclopentene dipolarophile derived from Vince lactam is a key step in the conventional synthesis of peramivir. Our study showed that conducting the (3 + 2) cycloaddition reactions with either aliphatic or aromatic nitrile oxide in hexane solution provided high percentage of the desired regioisomer, and the N-substituent having electron-withdrawing property is also beneficial to the regioselectivity. This study also demonstrated an alternative synthetic pathway of (−)-peramivir and the analog having a phenyl group in place of the 3-pentyl moiety.     

Highly diastereoselective 1,3-dipolar cycloaddition reactions of trans-2-methylene-1,3-dithiolane 1,3-dioxide with 3-oxidopyridinium and 3-oxidopyrylium betaines: a route to the tropane skeleton

The C2-symmetric vinyl sulfoxide, trans-2-methylene-1,3-dithiolane 1,3-dioxide, was found to react with a range of 3-oxidopyridinium betaines (bearing different substituents on nitrogen) in high yield and with total diastereoselectivity. A 2.3:1 mixture of regioisomers was formed with all of the 3-oxidopyridinium betaines but the ratio was found to change over prolonged periods of time due to reversibility of the minor regioisomer. 3-Oxidopyridinium betaines bearing methyl substituents at either the 2- or 6-position were also tested in the cycloaddition process. Improved regioselectivity (8:1) and again high diastereoselectivity were observed with the betaine having an additional substituent at the 2-position, but with betaines having a substituent in the 6-position although high regioselectivity was observed (9.9:1), the major isomer was formed with low diastereoselectivity (5.5:4.4). The origin of the regio- and diastereo-selectivity with all the betaines is discussed. Finally, the C2-symmetric vinyl sulfoxide, trans-2-methylene-1,3-dithiolane 1,3-dioxide was reacted with an oxidopyrylium betaine in moderate yield. Good regioselectivity and moderate diastereoselectivity were observed.     

2-(2-Nitroethyl)-1,3-dioxolane as reagent for 3-oxopropyl anion synthon : a new route to jasmonoid and prostaglandin intermediates

2-(2-Nitroethyl)-l,3-dioxolane 18 a versatile reagent for 3-oxopropyl anion synthon. New methodology, based on nitro- aldol condensation, oxidation and direct or indirect denitration sequence is developed for the conversion of 2-(2-nitroethyl)-l,3 dioxolane into (Z)-l,4-dioxodec-7-ene, (Z)-2-(2-pentenyl)-2-cy clopenten-l-one, methyl 9,12-dioxododecanoate and methyl 7-(5- oxocyclopentenyl)heptanoate, which are popular Intermediates for syntheses of (Z)-jasmonolds and prostaglandins.     

1-Oxo-2-hydroxy-1,2-dihydroacronycine: a useful synthon in the acronycine series for the introduction of amino substituents at 6-position and for the conversion into isopropylfuroacridones

Thermic aromatic nucleophilic displacement of the methoxy group at C-6 of (+/-)-1-oxo-2-hydroxy-1,2-dihydroacronycine (2) by an amine is a reaction that gives a facile entry to acronycine derivatives bearing an amino substituent at this position. The introduction of the amino substituents was confirmed with a long-range 1H-15N correlation NMR spectrum at natural abundance. Under basic conditions, compound 2 can also be rearranged to the corresponding isopropylfuroacridone 12, in 80% yield.     

1,2-Diphosphinobenzene as a synthon for the 1,2,3-triphospha- and 2-arsa-1,3-diphosphaindenyl anions and a stable organo derivative of the P8 unit of Hittorf's phosphorus

The electronic structure of the 1,2,3-triphosphaindenyl ligand suggests that it should exhibit enhanced pi-acceptor properties when compared to the eta(5)-indenyl system; this insight encouraged us to develop a simple synthetic pathway from 1,2-diphosphinobenzene to the 1,2,3-C(6)H(4)P(3) and 2-As-1,3-C(6)H(4)P(2) anions, both of which have been structurally characterised by X-ray crystallography; as a bonus from these studies we also obtained the first structurally characterised organo derivative of the P(8) unit present in Hittorf's phosphorus.     

The Ambident Reactivity of 2,4,6‐Tris(trifluoromethanesulfonyl)anisole in Methanol: Using the SO2CF3 Group as a Tool to Reach the Superelectrophilic Dimension in σ‐Complexation Processes

The kinetics of σ complexation of 2,4,6‐tris(trifluoromethanesulfonyl)anisole ( 7 d ) have been investigated over a large pH range of 2–13.70 at T=20 °C in methanol. Two competitive processes associated with the initial addition of MeO^? at the unsubstituted 3‐position of 7 d to give a 1,3‐dimethoxy adduct ( 9 d ‐Me) and a subsequent and slow conversion of this species into a 1,1‐dimethoxy isomer ( 8 d ‐Me) have been identified. Both adducts 8 d ‐Me and 9 d ‐Me are 10⁵–10⁶ times more stable than the related adducts 8 a ‐Me and 9 a ‐Me of 2,4,6‐trinitroanisole ( 7 a ), a conventional reference aromatic electrophile in Meisenheimer complex chemistry. The high stability of 8 d ‐Me and 9 d ‐Me is shown to derive from greater rates of formation and lower rates of decomposition than previously determined for 8 a ‐Me and 9 a ‐Me, thereby emphasising the especially high activation of a benzene ring by SO₂CF₃ group(s). Analysis of the collected rate and equilibrium data for σ complexation in the anisole series 2,4,6‐tris(SO₂CF₃)‐, 2,6‐bis(SO₂CF₃)‐4‐nitro‐, 4‐SO₂CF₃‐2,6‐dinitro‐ and 2,4,6‐trinitro‐ supports the idea that the especially high capacity of resonance stabilisation of the negative charge of the adducts through an F_π‐type (as defined in ref. 49 ) polarisation effect is a major factor that accounts for the strong activation provided by SO₂CF₃ groups. A most significant result is the finding that the 1,1‐dimethoxy adduct 8 d ‐Me is by far the most stable benzene σ adduct so far reported. With a p value of 7.32, this adduct is formed exclusively through methanol addition up to pH≈10. This is consistent with the location of 7 d in the superelectrophilic region defined by p ≤9.5–10.5. For comparison, the solvent contribution is negligible in the formation of the 1,3‐isomer 9 d ‐Me, the p (10.59) of which is situated on the upper limit of the boundary. Taking advantage of the simple relationship linking pK_a values for σ complexation in methanol and water, a ranking of the triflone 7 d on the general thermodynamic scale constructed for Meisenheimer electrophiles in water is informative. An approximate calibration on the electrophilicity scale kinetically derived by Mayr et al. has also been made.