Sequential treatment of 2-C₆H₄Br(CHO) with LiC≡CR¹ (R¹=SiMe₃, tBu), nBuLi, CuBr⋅SMe₂ and HC≡CCHClR² [R²=Ph, 4-CF₃Ph, 3-CNPh, 4-(MeO₂C)Ph] at −50 °C leads to formation of an intermediate carbanion (Z)-1,2-C₆H₄{C_A(=O)C≡C_BR¹}{CH=CH(CH⁻)R²} (4). Low temperatures (−50 °C) favour attack at C_B leading to kinetic formation of 6,8-bicycles containing non-classical C-carbanion enolates (5). Higher temperatures (−10 °C to ambient) and electron-deficient R² favour retro σ-bond C−C cleavage regenerating 4, which subsequently closes on C_A providing 6,6-bicyclic alkoxides (6). Computational modelling (CBS-QB3) indicated that both pathways are viable and of similar energies. Reaction of 6 with H⁺ gave 1,2-dihydronaphthalen-1-ols, or under dehydrating conditions, 2-aryl-1-alkynylnaphthlenes. Enolates 5 react in situ with: H₂O, D₂O, I₂, allylbromide, S₂Me₂, CO₂ and lead to the expected C-E derivatives (E=H, D, I, allyl, SMe, CO₂H) in 49–64 % yield directly from intermediate 5. The parents (E=H; R¹=SiMe₃, tBu; R²=Ph) are versatile starting materials for NaBH₄ and Grignard C=O additions, desilylation (when R¹=SiMe) and oxime formation. The latter allows formation of 6,9-bicyclics via Beckmann rearrangement. The 6,8-ring iodides are suitable Suzuki precursors for Pd-catalysed C−C coupling (81–87 %), whereas the carboxylic acids readily form amides under T3P® conditions (71–95 %).

The amidoamines (S)-Ar¹CONHCHRCH₂NHAr² [Ar¹ = o-C₆H₄SO₃H, R = Bn, iBu, iPr; Ar² = 2,6-iPr₂C₆H₄, 2,6-Et₂C₆H₄, 2,4,6-Me₃C₆H₂] cyclise to (S) 1-aryl-substituted 4,5-dihydro-1H-imidazolinium species with HC(OEt)₃ in moderate-to-excellent yields on heating to 150–175 °C (nine examples, four isolated yields of 48 to >97 %). They are attained as their o-C₆H₄(SO₃^–)(CO₂Et) salts. The latter are readily deprotonated to afford analytically pure (S) 1-aryl-substituted 4,5-dihydro-1H-imidazoles (imidazolines). The purification of the intermediate sulfonate salts is not always necessary, and analytically pure imidazolines are isolated by simple kugelrohr distillation (nine examples, 45–95 %) after basification. Imidazoline alkylation provides a library of (S)-N-alkylimidazolinium salts (23 examples, 74–97 %). As the initially required amidoamines are available in simple one-pot reactions, the overall approach constitutes a rather efficient approach to this useful family of chiral N-heterocyclic carbene (NHC) ligand precursors (effectively three steps from commercial N-Boc-α-amino alcohols; BOC = tert-butyloxycarbonyl).

The diesters (E)-RO₂CCH=CHCO₂R [R = Et, CH₂Ph, iPr, iBu, tBu, 2-ethylhexyl, (–)-menthyl, (–)-bornyl] undergo 1,4-trichloromethylation with Me₃SiCCl₃ in 84–95 % yield with Bu₄NX (X = OAc, Cl, F; 0.5–10 mol-%) as an initiator. Optimal catalysis is attained with X = OAc and F; chloride is less effective, bromide is inadequate. Poor regioselectivity but high yields are demonstrated by mixed diesters (2 examples, both > 80 %). Heating of the trichloromethyl adducts, in the presence of Bu₄N(OAc), leads to equilibrating, approximately equimolar, mixtures of RO₂CC(=CCl₂)CHCO₂R and RO₂CCH=CClCHClCO₂R above 100 °C (7 examples). The latter component is produced under thermodynamic control, which can be isolated pure in some cases. The former is the kinetic product of E2 elimination.

An intramolecular Cannizzaro-type hydride transfer to an in situ prepared allene enables the synthesis of ortho-fused 4-substituted cycloocta-2,5-dien-1-ones with unprecedented technical ease for an eight-ring carboannulation. Various derivatives could be obtained from commercially available (hetero)aryl aldehydes, trimethylsilylacetylene, and simple propargyl chlorides in good yields.

An intramolecular Cannizzaro-type hydride transfer to an in situ prepared allene enables the synthesis of ortho-fused 4-substituted cycloocta-2,5-dien-1-ones with unprecedented technical ease for an eight-ring carboannulation. Various derivatives could be obtained from commercially available (hetero)aryl aldehydes, trimethylsilylacetylene, and simple propargyl chlorides in good yields.

Improved synthetic conditions allow preparation of TMSCCl₃ in good yield (70 %) and excellent purity. Compounds of the type NBu₄X [X=Ph₃SiF₂ (TBAT), F (tetrabutylammonium fluoride, TBAF), OAc, Cl and Br] act as catalytic promoters for 1,4-additions to a range of cyclic and acyclic nitroalkenes, in THF at 0–25 °C, typically in moderate to excellent yields (37–95 %). TBAT is the most effective promoter and bromide the least effective. Multinuclear NMR studies (¹H, ¹⁹F, ¹³C and ²⁹Si) under anaerobic conditions indicate that addition of TMSCCl₃ to TBAT (both 0.13 M) at −20 °C, in the absence of nitroalkene, leads immediately to mixtures of Me₃SiF, Ph₃SiF and NBu₄CCl₃. The latter is stable to at least 0 °C and does not add nitroalkene from −20 to 0 °C, even after extended periods. Nitroalkene, in the presence of TMSCCl₃ (both 0.13 M at −20 °C), when treated with TBAT, leads to immediate formation of the 1,4-addition product, suggesting the reaction proceeds via a transient [Me₃Si(alkene)CCl₃] species, in which (alkene) indicates an Si⋅⋅⋅O coordinated nitroalkene. The anaerobic catalytic chain is propagated through the kinetic nitronate anion resulting from 1,4 CCl₃⁻ addition to the nitroalkene. This is demonstrated by the fact that isolated NBu₄[CH₂NO₂] is an efficient promoter. Use of H₂CCH(CH₂)₂CHCHNO₂ in air affords radical-derived bicyclic products arising from aerobic oxidation.

The copper-catalysed (10 mol-% CuBr·SMe₂, CuCN·LiCl or CuI/PPh₃) addition of RMgBr to the pentafulvene 1-(cyclopenta-2,4-dien-1-ylidenemethyl)-2-methoxybenzene allows the formation of cyclopentadienyl derivatives with α-CHR(2-MeOPh) sidechains (R = Me, Et, nBu, iBu, allyl, Ph) without H^– transfer. The deprotonation of these sec-alkyl-substituted cyclopentadienyls followed by the addition of TiCl₄ allows the isolation of TiCl₂{η⁵-C₅H₄CHR(2-OMePh)} as rac/meso mixtures that show activity against human colon, breast and pancreatic cell lines (GI₅₀ 2.3–42.4 μM).

A one-pot reaction of Boc-protected amino alcohols and 2-sulfobenzoic anhydride followed by the addition of a wide variety of primary amines has allowed rapid access to diverse libraries of amidosulfonates 1,2-C₆H₄(SO₃^–)(COCHR¹CH₂NH₂⁺R²) (R¹ = Bn, iPr, Ph; R² = aryl, CHMePh, 1-adamantyl), of which two examples have been characterised by X-ray crystallography. These reactions proceed by S_N2 opening of unisolated oxazoline intermediates. The amidosulfonates have been converted to imidazolinium sulfonate zwitterions (N-heterocyclic carbene precursors) in a two-step process, which involved reduction with BH₃·SMe₂ and cyclisation with HC(OEt)₃. Two examples (R¹ = Bn, R² = 2,6-iPrC₆H₃ and R¹ = iPr, R² = 3,5-Me₂C₆H₃) have been crystallographically characterised, the latter as a PF₆ salt. The imidazolinium sulfonate zwitterions (1 mol-%) catalysed additions of RMgBr (R = alkyl) to (E)-ArC(R)=CHCH₂Br (R = H, Me). Additions to cinnamyl bromides showed high γ (S_N2′) selectivity (up to 18.4:1) and provided significantly enantiomerically enriched products (up to 82 % ee).

Bis-sulfamyl imines are shown to be potentially ideal substrates for rhodium-catalysed asymmetric additions of arylboron nucleophiles as they show: (i) near perfect enantioselectivities (11 examples, 98–99+% ee), (ii) good to excellent diastereoselectivities (10–32:1 rac:meso), and (iii) high functional group tolerance in removal of the low molecular weight protecting group via mild heating in aqueous pyridine.

A practical asymmetric 1,2-addition of functionalised arylzinc halides to aromatic and aliphatic aldehydes is described by the use of aminoalcohol catalysis in the presence of AlMe₃. The process is simple to carry out, uses only commercially available reagents/ligands and provides moderate to good (80–96 % ee) enantioselectivities for a wide range of substrates. Either commercial ArZnX reagents or those prepared in situ from low cost aryl bromides can be used. In the latter case electrophilic functional groups are tolerated (CO₂Et, CN). The reaction relies on rapid exchange between ArZnX and AlMe₃ to generate mixed organometallic species that lead to the formation of a key intermediate that is distinctly different from the classic “anti” transition states of Noyori. NMR monitoring and related experiments have been used to probe the validity of the proposed selective transition state.

Reaction of the cyclic thioacetal (RS)₂CHCHO [R=1/2×(CH₂)₃] with HCCCOMe, followed by treatment with TsCl/DABCO (Ts=tosyl, DABCO=1,4-diazabicyclo[2.2.2]octane) affords the mono-protected 1,4-benzoquinone dithioacetal. The reactivity of this SR-protected 1,4-benzoquinone has been compared with the behavior of the analogous OR-protected acetal in copper-catalyzed additions of ZnMe₂ by using chiral phosphoramidite ligands. The activation energy for 1,4-methylation of the latter OR-acetals with ZnMe₂ (>95 % ee) has been determined for two CuX₂ pre-catalysts (X=OAc, 12.2 kcal mol⁻¹; X=OTf, 6.7 kcal mol⁻¹; Tf=triflate). The dithioacetal SR aromatizes in the presence of Cu^I/ZnMe₂ giving 1,4-HOC₆H₄S(CH₂)₃SMe through CS bond formation. The disparate behavior of these two very closely related substrates is in accordance with the formation of closely related cuprate intermediates that were optimized by DFT calculations, supporting the synthetic and kinetic studies and thus defining the mechanisms of both pathways.

A new catalytic method for the synthesis of α-hydroxyallenes is described. Efficient S_N2′ substitution of propargylic dioxolanones has been achieved with a copper(I)/P(OBu)₃ catalyst using Grignard reagents as the nucleophiles. The reaction tolerates a wide variety of propargylic dioxolanones, the corresponding primary and secondary α-hydroxyallenes are obtained in good to excellent yields and excellent diastereoselectivity. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Enantioselective Ni-catalysed methylation of Baylis–Hillman-derived allylic electrophiles in the presence of ferrophite ligands has been investigated computationally and experimentally. The sense and degree of enantioselectivity attained is independent of both the leaving group and the isomeric structure of the initial allylic halide. DFT studies support the selective formation of a limited number of energetically favoured anti and syn π-allyl intermediates. The observed regio- and enantioselectivity can be rationalised based on the energetics of these structures. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)