Constantin G. Daniliuc

6‐Trifluoromethyl‐Phenanthridines through Radical Trifluoromethylation of Isonitriles

The trifluoromethyl group can be found in many drugs or drug candidates. Chemical and physical properties of biologically active compounds are altered upon incorporation of the CF3 group. The higher solubility and lipophilicity exerted by the fluorinated methyl group lead to better membrane permeability and increased bioavailability. Importantly, because of the higher resistance toward oxidative degradation, fluorinated compounds generally have higher metabolic stability. Therefore, development of new methods for C CF3 bond formation has caught great attention from the synthetic community during the past few years and different methods for the trifluoromethylation of arenes have been developed. Transition-metal-catalyzed and radical aromatic trifluoromethylation have been studied intensively (Scheme 1).

6-Phosphorylated Phenanthridines from 2-Isocyanobiphenyls via Radical C–P and C–C Bond Formation

A C-P bond and a C-C bond are formed in the synthesis of 6-phosphorylated phenanthridines starting with readily prepared 2-isocyanobiphenyls and commercially available P-radical precursors. The radical cascade reaction comprises addition of an oxidatively generated P-centered radical to the isonitrile functionality and subsequent homolytic aromatic substitution. Various 6-phosphorylated phenanthridines are formed in moderate to excellent yield. In contrast to the currently intensively investigated direct arene phosphorylation, the arene core is constructed with concomitant phosphorylation using this approach.

6-Aroylated Phenanthridines via Base Promoted Homolytic Aromatic Substitution (BHAS)

Readily accessible 2-isocyanobiphenyls react with aromatic aldehydes via base promoted homolytic aromatic substitution (BHAS) to give 6-aroylated phenanthridines. Reactions occur via addition of acyl radicals to the isonitrile functionality and subsequent intramolecular BHAS of the intermediate imidoyl radicals. Initiation of the radical chain reaction is best achieved with small amounts of FeCl3 (0.4 mol %), and the commercially available and cheap tBuOOH is used as the oxidant.

N,N-addition of frustrated Lewis pairs to nitric oxide: an easy entry to a unique family of aminoxyl radicals.

The intramolecular cyclohexylene-bridged P/B frustrated Lewis pair [Mes(2)P-C(6)H(10)-B(C(6)F(5))(2)] 1b reacts rapidly with NO to give the persistent FLP-NO aminoxyl radical 2b formed by P/B addition to the nitrogen atom of NO. This species was fully characterized by X-ray diffraction, EPR and UV/vis spectroscopies, C,H,N elemental analysis, and DFT calculations. The reactive oxygen-centered radical 2b undergoes a H-atom abstraction (HAA) reaction with 1,4-cyclohexadiene to give the diamagnetic FLP-NOH product 3b. FLP-NO 2b reacts with toluene at 70 °C in an HAA/radical capture sequence to give a 1:1 mixture of FLP-NOH 3b and FLP-NO-CH(2)Ph 4b, both characterized by X-ray diffraction. Structurally related FLPs [Mes(2)P-CHR(1)-CHR(2)-B(C(6)F(5))(2)] 1c, 1d, and 1e react analogously with NO to give the respective persistent FLP-NO radicals 2c, 2d, and 2e, respectively, which show similar HAA and O-functionalization reactions. The FLP-NO-CHMePh 6b derived from 1-bromoethylbenzene undergoes NO-C bond cleavage at 120 °C with an activation energy of E(a) = 35(2) kcal/mol. Species 6b induces the controlled nitroxide-mediated radical polymerization (NMP) of styrene at 130 °C to give polystyrene with a polydispersity index of 1.3. The FLP-NO systems represent a new family of aminoxyl radicals that are easily available by N,N-cycloaddition of C(2)-bridged intramolecular P/B frustrated Lewis pairs to nitric oxide.

Reactions of phosphorus/boron frustrated Lewis pairs with SO2

The frustrated Lewis pair tBu3P/B(C6F5)3 (1) readily adds SO2 to yield the zwitterionic adduct tBu3P+–S(O)–OB−(C6F5)3 (3). A series of intramolecular vicinal P/B FLPs Mes2P–(X)–B(C6F5)2 [X = –CH2–CH2– (2a), –CHMe–CH2– (2b), cyclo-C6H10 (5)] add SO2 at −78 °C to yield the corresponding six-membered addition products 4a, 4b, 6. The adducts contain a chiral sulfur center. The [B]–O–(O)S–[P] addition products 3, 4b and 6 were characterized by X-ray diffraction.

Facile Carbon Monoxide Reduction at Intramolecular Frustrated Phosphane/Borane Lewis Pair Templates†

Finding novel pathways for the reduction of carbon oxides is important for the ongoing search for new systematic entries to hydrocarbon feedstocks. The CO to formyl conversion with readily available hydrides represents an important step along this way. Using boranes as the reducing reagents is desirable and potentially useful. Reactions of trialkylboranes with carbon monoxide are synthetically established. H. C. Brown had shown that R3B systems readily react with CO at 100 to 125 8C at normal pressure to yield the respective tertiary alcohols after oxidative workup. They modified this procedure to achieve the synthesis of ketones and aldehydes. In the latter case lithium aluminium hydride reagents were added. However, carbon monoxide is surprisingly reluctant to be reduced with [B]H boranes. Carbon monoxide is reported to react with B2H6 at 100 8C and 20 atm to give “borane carbonyl” [H3B-CO], a gas (b.p. 64 8C) that dissociates at atmospheric pressure. We have now found that B H borane reduction of carbon monoxide can be carried out with a suitable borane at a frustrated phosphane/borane Lewis pair (FLP) template. We stirred a mixture of the bulky cyclopentenylphosphane 1 with the hydroboration reagent [HB(C6F5)2] [9] for about 15 minutes at RT and then subjected the resulting mixture to an atmosphere of carbon monoxide (2 bar). Workup after 12 h at RT eventually gave the reduction product 2 as a colorless solid in 63% yield (see Scheme 1). Single crystals of 2 were obtained from dichloromethane/n-pentane. In the crystal compound 2 contains a “h-formyl” B(C6F5)2 subunit that is bonded through the acyl carbon atom (C1) to the phosphorus atom and through the acyl oxygen atom (O1) to the boron center (B1) of the FLP framework (see Figure 1 and Table 1). The resulting six-membered heterocycle fea-

N-Aminopyridinium Salts as Precursors for N-Centered Radicals – Direct Amidation of Arenes and Heteroarenes

Readily prepared N-aminopyridinium salts are valuable precursors for the generation of N-centered radicals. Reduction of these salts by single electron transfer allows for clean generation of amidyl radicals. It is shown that direct radical C-H amination of heteroarenes and arenes can be achieved with N-aminopyridinium salts under mild conditions by using photoredox catalysis.

Asymmetric synthesis of highly substituted β-lactones through oxidative carbene catalysis with LiCl as cooperative Lewis acid.

The reaction of enals with β-diketones, β-ketoesters, and malonates bearing a β-oxyalkyl substituent at the α-position by oxidative NHC catalysis to provide highly substituted β-lactones is described. Reactions occur with excellent diastereo- and enantioselectivity. The organo cascade comprises two CC bond formations and one CO bond formation. Up to four contiguous stereogenic centers including two fully substituted stereocenters are formed in the cascade.

Enantioselective, desymmetrizing bromolactonization of alkynes.

Asymmetric bromolactonizations of alkynes are possible using a desymmetrization approach. The commercially available catalyst (DHQD)2PHAL promotes these cyclizations in combination with cheap NBS as a bromine source to give bromoenol lactones in high yield and with high enantioselectivity. The bromoenol lactone products, containing a tetrasubstituted alkene and a quaternary stereocenter, are valuable building blocks for synthetic chemistry.

N-Heterocyclic Carbene Catalyzed Formal [3+2] Annulation Reaction of Enals: An Efficient Enantioselective Access to Spiro-Heterocycles†

A highly enantioselective N-heterocyclic carbene (NHC) catalyzed formal [3+2] annulation of α,β-unsaturated aldehydes with azaaurones or aurone generating spiro-heterocycles has been developed. The protocol represents a unique NHC-activation-based approach to access spiro-heterocyclic derivatives bearing a quaternary stereogenic center with high optical purity (up to 95% ee).