Transition metal carbene chemistry. 4. Nucleophilic attachment of DABCO to fischer carbene complexes in MeCN

Rate constants for the attachment of DABCO (1,4-diazabicyclo[2.2.2]octane) to Fischer carbene complexes of the type (CO)(5)Cr=C(XR)C(6)H(4)Z (X = O and S) in dry MeCN at 25 degrees C are reported. Hammett rho values are 2.18 +/- 0.13 and 0.89 +/- 0.07 for DABCO reactions with (CO)(5)Cr=C(OMe)C(6)H(4)Z (10-Cr-Z) and (CO)(5)Cr=C(SMe)C(6)H(4)Z (11-Cr-Z), respectively. The rho values for the reaction of 10-Cr-Z and 11-Cr-Z with CH(CN)(2)(-) in 50% MeCN-50% H(2)O (v/v) are comparable to the present reactions. The reaction of DABCO with 10-Cr-Z is more closely related to the reaction of (n-Bu)(3)P with (CO)(5)W=C(OMe)C(6)H(5)-Z (23) which also provided a rho value 2.22. The much higher rho values and hence much higher reactivity of methoxy carbene complexes over the corresponding thiomethyl derivatives fit a pattern observed previously for alkoxide ion, OH(-), amine, and thiolate ion nucleophiles, and a rational explanation comes from the consideration of the substituent effects not only on the transition state but also on the reactant. A major difference between 10-Cr-Z and 11-Cr-Z is that the pi-donor effect of the methoxy group is much stronger than that of thiomethyl group. This leads to a substantial contribution of the zwitterionic form to the structure of 10-Cr-Z with much more localized positive charge on the methoxy group than the negative charge on the (CO)(5)Cr moiety. This leads to overall destabilization by an electron-withdrawing phenyl substituents resulting an increase in reactivity. The ethoxycarbene complexes are somewhat less reactive than their methoxy counterparts due to the somewhat more ground state stabilization through its stronger pi donor effect and partly due to steric crowding exerted by the slightly larger ethoxy group in the transition state. Higher k(1)(W)/k(1)(Cr) ratios for (thiomethyl)carbene complexes than methoxy or ethoxycarbene complexes are related to the intrinsic rate constant which is higher for ((thiomethyl)carbene)tungsten complexes than the corresponding Cr ones resulting in an enhanced ratio.     

Total synthesis of the calphostins: application of fischer carbene complexes and thermodynamic control of atropisomers

The total syntheses of the potent protein kinase C inhibitors calphostins A, B, C, and D as well as a variety of structural analogues are reported. An aminobenzannulation reaction of an enantiopure chromium Fischer carbene complex is utilized to prepare a pentasubstituted naphthylamine. After optimization of side-chain substituents, conversion of the naphthylamine to an o-naphthoquinone was followed by biomimetic oxidative dimerization using trifluoroacetic acid and air yielding a 1:2 P/M mixture of atropisomeric perylenequinones. Thermal equilibration to a 3:1 P:M atropisomeric ratio and separation of the perylenequinones followed by side chain desymmetrization and functionalization led to the total synthesis of enantio- and diastereomerically pure calphostin C in only twelve steps from commercially available starting materials. In addition, calphostins A, B, D, and several structural analogues were prepared to evaluate biological activities.     

Novel synthesis of lactam from alkyne having amide in a tether using fischer chromium carbene complex

A novel lactam synthesis from alkyne having amide in a tether was developed. The reaction proceeds via a vinylketene complex generated from alkyne and Fischer chromium carbene complex, and the lactam ring was formed from carbon monoxide, alkyne carbon and nitrogen of tosylamide. The four-,five-, six-, and seven-membered lactams having a substituent at the -position were obtained in good yields.     

Total synthesis of carbazoquinocin C: application of the o-benzannulation of Fischer carbene complexes to carbazole-3,4-quinone alkaloids

[reaction: see text] The photoinduced o-benzannulation of 3-(2-vinyl)indolylcarbene complexes provides a direct route to carbazole derivatives that are oxygenated in the 3- and 4-positions. This reaction is quite efficient and provides for a unique synthesis of the lipid peroxidation inhibitor carbazoquinocin C.     

Coupling of propargylsilanes with Fischer carbene chromium complexes: a new synthesis of conjugated dienes

The reaction of propargylsilanes with Fischer carbene complexes has been examined. If the silane-containing carbon is secondary the predominant pathway involves formation of conjugated dienes through a 1,2-silicon shift process of the initially formed vinylcarbene complex intermediate. If a primary propargylsilane is employed, the silicon does not shift and normal alkyne-Fischer carbene coupling processes are observed. The process is moderately stereoselective, resulting in the E enol ether and Z alkenylsilane.     

Direct synthesis of methyl 2-diazo-4-aryl-3-butenoates and their application to the enantioselective synthesis of 4-aryl-4-(1-naphthyl)-2-butenoates

An improved one-flask synthesis of various methyl 2-diazo-4-aryl and 4-heteroaryl-3-butenoates, precursors to donor/acceptor substituted carbenoids, is described. Their Rh₂(S-DOSP)₄ catalyzed reaction with 1-acetoxy-3,4-dihydronaphthalene, via a combined C–H activation/Cope rearrangement pathway followed by elimination of acetic acid affords a highly enantioselective (98–99% ee) entry to methyl 4-aryl- and 4-heteroaryl-4-(1-naphthyl)-2-butenoates.     

Direct one-pot synthesis of primary 4-amino-2,3-diaryl-quinolines via Suzuki-Miyaura cross-coupling of 2-aryl-4-azido-3-iodoquinolines with arylboronic acids

Palladium-catalyzed Suzuki-Miyaura cross-coupling of 2-aryl-4-azido-3-iodo-quinolines with arylboronic acids afforded the corresponding primary 4-amino-2,3-diarylquinolines in a single-pot operation along with symmetrical biaryls and traces of the 2,3-diaryl-4-azidoquinolines. A plausible mechanism, which implicates palladium hydride species in the reduction of the incipient 2,3-diaryl-4-azidoquinolines to afford the 4-amino-2,3-diarylquinolines is proposed.     

Polymer-supported haloarene chromium dicarbonyl isonitrile complexes: a study of their synthesis and reactivity

Different arene Cr(CO)(3) complexes were supported on a polystyrene isonitrile resin by photochemical-promoted replacement of a chromium carbonyl ligand by the NC group. The supported complexes proved to be stable and were successfully used for further transformations. In particular, the reactivity of dichlorobenzene complexes to different nucleophiles was investigated and found to be comparable with that of the parent Cr(CO)(3) complexes.     

From dicarbonylallene to 1-aryl-3,6-dimethyl-4-aminoaryl-2-pyridones: a one-pot versatile and uncatalyzed synthesis

Reaction of amines with an allenic precursor leads to new 1-aryl-3,6-dimethyl-4-aminoaryl-2-pyridones in good yields. These syntheses can be performed in two distinct steps, allowing the possibility to introduce different substituents in the positions 1 and 4. By using o-aminopyridine, a new pyridopyrimidone is easily obtained.     

The synthesis and characterisation of immobilised palladium carbene complexes and their application to heterogeneous catalysis

Silica supported palladium NHC complexes have been prepared by two different routes: one involving the reaction of silica-supported imidazolium salts with palladium acetate and a direct immobilisation of a pre-formed complex by reacting a (trimethoxysilylpropyl)-N-aryl-imidazolylidene palladium complex with surface hydroxyl groups. A small range of catalysts of varying steric bulk were prepared in order to evaluate the effect on catalytic conversion. The activity of the palladium catalysts in Suzuki cross-coupling reactions has been established. The catalysts prepared by immobilising pre-formed palladium complexes gave superior results for the conversion of aryl bromides and aryl chlorides. In addition, use of sterically bulky NHCs (such as the N-2,6-(diisopropyl)phenyl-substituted ligand) resulted in increased catalytic activity, which is analogous to the trends noted in homogeneous catalysis.     

Copper-catalyzed dimerization of chromium Fischer carbene complexes: synthesis of dialkoxytrienes and their Nazarov-type cyclization to 2-alkoxy-2-cyclopentenones

Fischer carbene complexes 1 underwent a clean ligand dimerization reaction yielding functionalized olefins and trienes 4 in the presence of copper (I) catalysts. If treated with trifluoroacetic acid (TFA), trienes 4c, d, f undergo a cyclization process (Nazarov reaction) which furnishes cyclopentenone derivatives 6c, d, 7c, d and 8 in good yields. Finally, the Fischer aminocarbene 9 efficiently cyclodimerizes to the substituted arene 10 in the presence of CuBr.     

An efficient and fast synthesis of 4-aryl-3,4-dihydrocoumarins by (CF3SO3)3Y catalysis under microwave irradiation

A new and efficient synthesis of eleven 4-aryl-3,4-dihydrocoumarins, in which six are new compounds, was performed using (CF₃SO₃)₃Y as catalyst under microwave irradiation. The target compounds were obtained in good yields (68-80%) and remarkable time (7-20 min) when compared to the literature reports (1-40 h).     

First application of hexaaquaaluminium(III) tetrafluoroborate as a mild, recyclable, non-hygroscopic acid catalyst in organic synthesis: a simple and efficient protocol for the multigram scale synthesis of 3,4-dihydropyrimidinones by Biginelli reaction

For the first time hexaaquaaluminium(III) tetrafluoroborate has been used as a mild acid catalyst in organic synthesis. A simple method of its preparation based on the reaction of aluminium triisopropoxide and tetrafluoroboric acid in isopropanol afforded catalyst of high purity and activity. The three-component Biginelli condensation of acetoacetate esters, urea and aldehydes catalyzed by 10 mol % of [Al(H₂O)₆](BF₄)₃ in refluxing acetonitrile afforded 3,4-dihydropyrimidonones in good to high yields on multigram scales. The tolerance to acid sensitive reactants such as thienyl and furyl carbaldehydes, applicability to sterically hindered β-ketoesters and simple recyclability without losing catalytic activity make this catalyst as good replacement to literature methods. The mechanism of the reaction includes formation of the so called ‘ureido-crotonate’ rather than corresponding acylimino intermediate as found with Brønsted type catalysts.     

Dowex-promoted general synthesis of N,N′-disubstituted-4-aryl-3,4-dihydropyrimidinones using a solvent-free Biginelli condensation protocol

Dowex-50W ion exchange resin-promoted solvent-free heating of an intimate mixture of an aldehyde, an active methylene compound and N,N′-dimethylurea furnished the title compounds in moderate to good yields.     

Metalation of Biginelli compounds. A general unprecedented route to C-6 functionalized 4-aryl-3,4-dihydropyrimidinones

4-Aryl-6-methyl-3,4-dihydro-2(1H)-pyrimidinone esters (DHPMs) readily undergo metalation at the C-6 methyl (vinylogous ester) position on treatment with lithium diisopropylamide at -10 degrees C. The resulting anion intermediates can be treated with electrophilic reagents to afford functionalized DHPMs that have been chemically elaborated mainly at the C-6 position. Di- and trianion formation is also possible at both the vinylogous methyl and NH positions when reactions are performed with excess equivalents of the base.     

Oxaziridine-mediated amination of primary amines: scope and application to a one-pot pyrazole synthesis

Electrophilic amination of primary aliphatic and aromatic amines is reported using a diethylketomalonate-derived oxaziridine to afford the corresponding N-Boc hydrazines in good to excellent yields. The method allows a one-pot synthesis of pyrazoles from primary amines. [Reaction: see text]     

Reaction of 4-oxo-2,3,5,6-tetrafluorocyclohexa-2,5-dienylidene with acetylene: a carbene to carbene reaction.

The EPR spectrum of triplet 4-oxo-2,3,5,6-tetrafluorocyclohexa-2,5-dienylidene 1 was recorded in solid argon at 15 K. Carbene 1 reacts with acetylene under the conditions of matrix isolation yielding triplet vinylmethylene 4, which was characterized by its IR, UV-vis, and EPR spectrum. Carbene 4 is photolabile and is converted to spiro compound 5 on irradiation with lambda > 515 nm. The reaction of triplet carbene 1 with acetylene to produce triplet carbene 4 is predicted to be exothermic by 55 kcal mol(-1) at the B3LYP/6-31G(d,p) level of theory. The cis isomer is calculated to be only 0.4 kcal mol(-1) less stable than trans-4 at this level of theory. According to our calculations, singlet carbene S-4 is not a minimum on the C(8)F(4)H(2)O potential energy surface; however, at the T-4 geometry, the lowest lying singlet state is predicted to be 20.7 kcal mol(-1) higher in energy. The subsequent photochemical cyclization of T-4 yielding spiro compound 5 is exothermic by 10.3 kcal mol(-1) relative to T-4 and by 31.1 kcal mol(-1) relative to S-4. 4-Ethinyl-2,3,5,6-tetrafluorocyclohexa-2,5-dienone 9, the C-H insertion product of 1 and acetylene, was not observed experimentally, although it is favored energetically by 4.3 kcal mol(-1) over 5.     

Green chemistry approaches to the synthesis of 5-alkoxycarbonyl-4-aryl-3,4- dihydropyrimidin-2(1H)-ones by a three-component coupling of one-pot condensation reaction: comparison of ethanol,water, and solvent-free conditions

A general and practical green chemistry route to the Biginelli cyclocondensation reaction using cerium(III) chloride as the catalyst (25% mol) is described under three different sets of reaction conditions. This method provides an efficient and much improved modification of original Biginelli reaction reported in 1893, in terms of high yields, short reaction times, and simple work-up procedure, and it has the ability to tolerate a wide variety of substitutions in all three components, which is lacking in existing procedures.