Ferrocenium Boronic Acid Catalyzed Deoxygenative Coupling of Alcohols with Carbon- and Nitrogen-Based Borate and Silane Nucleophiles.

A boronic acid catalyzed carbon-carbon and carbon-nitrogen bond-forming reaction for the functionalization of various π-activated alcohols has been developed. Ferrocenium boronic acid hexafluoroantimonate salt was identified as an effective catalyst in the direct deoxygenative coupling of alcohols with a variety of potassium trifluoroborate and organosilane nucleophiles. In a comparison between these two classes of nucleophiles, the use of organosilanes leads to higher reaction yields, increased diversity of the alcohol substrate scope, and high E/Z selectivity. Furthermore, the reaction proceeds under mild conditions and yields up to 98%. Computational studies provide a rationalization for a mechanistic pathway for the retention of E/Z stereochemistry when E or Z alkenyl silanes are used as nucleophiles. This methodology is complementary to existing methodologies for deoxygenative coupling reactions involving organosilanes, and it is effective with a variety of organosilane nucleophile sub-types, including allylic, vinylic, and propargylic trimethylsilanes.

Unsymmetrical Diarylmethanes by Ferroceniumboronic Acid Catalyzed Direct Friedel-Crafts Reactions with Deactivated Benzylic Alcohols: Enhanced Reactivity due to Ion-Pairing Effects.

The development of general and more atom-economical catalytic processes for Friedel-Crafts alkylations of unactivated arenes is an important objective of interest for the production of pharmaceuticals and commodity chemicals. Ferroceniumboronic acid hexafluoroantimonate salt (1) was identified as a superior air- and moisture-tolerant catalyst for direct Friedel-Crafts alkylations of a variety of slightly activated and neutral arenes with stable and readily available primary and secondary benzylic alcohols. Compared to the use of classical metal-catalyzed alkylations with toxic benzylic halides, this methodology employs exceptionally mild conditions to provide a wide variety of unsymmetrical diarylmethanes and other 1,1-diarylalkane products in high yield with good to high regioselectivity. The optimal method, using the bench-stable ferroceniumboronic acid salt 1 in hexafluoroisopropanol as cosolvent, displays a broader scope compared to previously reported catalysts for similar Friedel-Crafts reactions of benzylic alcohols, including other boronic acids such as 2,3,4,5-tetrafluorophenylboronic acid. The efficacy of the new boronic acid catalyst was confirmed by its ability to activate primary benzylic alcohols functionalized with destabilizing electron-withdrawing groups like halides, carboxyesters, and nitro substituents. Arene benzylation was demonstrated on a gram scale at up to 1 M concentration with catalyst recovery. Mechanistic studies point toward the importance of the ionic nature of the catalyst and suggest that factors other than the Lewis acidity (pKa) of the boronic acid are at play. A SN1 mechanism is proposed where ion exchange within the initial boronate anion affords a more reactive carbocation paired with the non-nucleophilic hexafluoroantimonate counteranion.

A surprising substituent effect provides a superior boronic acid catalyst for mild and metal-free direct Friedel-Crafts alkylations and prenylations of neutral arenes.

The development of more general and efficient catalytic processes for Friedel-Crafts alkylations is an important objective of interest toward the production of pharmaceuticals and commodity chemicals. Herein, 2,3,4,5-tetrafluorophenylboronic acid was identified as a potent air- and moisture-tolerant metal-free catalyst that significantly improves the scope of direct Friedel-Crafts alkylations of a variety of slightly activated and neutral arenes, including polyarenes, with allylic and benzylic alcohols. This method also provides a simple alternative for the direct installation of prenyl units commonly found in naturally occurring arenes. Alkylations with benzylic alcohols occur under exceptionally mild conditions.

Transition-metal-free access to primary anilines from boronic acids and a common (+)NH2 equivalent.

Diversely substituted anilines are prepared by treatment of functionalized arylboronic acids with a common, inexpensive source of electrophilic nitrogen (H2N-OSO3H, HSA) under basic aqueous conditions. Electron-rich substrates are found to be the most reactive by this method. However, even moderately electron-poor substrates are well tolerated under the room temperature conditions. Sterically hindered substrates appear to be equally effective compared to unhindered ones. Highly electron-deficient substrates afford product in very low yields at room temperature, but moderate to good yields are obtained at refluxing temperatures. Our method is also amenable to electrophilic amination of several common boronic acid derivatives (e.g., pinacol esters). We demonstrate that it can be combined with metal-halogen exchange reactions or a variety of directed ortho metalation protocols in a "one-pot" sequence for the synthesis of aromatic amines with unique substitution patterns. DFT studies, in combination with experimental results, suggest that the reaction occurs via base-mediated activation of HSA, followed by 1,2 aryl B-N migration. This mode of activation appears to be critical for the success of the reaction and allows, for the first time, a general, electrophilic amination of boronic acids at ambient temperature.

Highly enantioselective (-)-sparteine-mediated lateral metalation-functionalization of remote silyl protected ortho-ethyl N,N-dialkyl aryl O-carbamates.

We report the enantioselective, lateral deprotonation of ortho-protected or functionalized tertiary N,N-dialkyl aryl O-carbamates 5-7 (Scheme 2 ) and meta-protected carbamates 14, 15, and 20 (Schemes 5 and 7 ) by s-BuLi/(-)-sparteine and subsequent quench with a variety of electrophiles to give products 11-13 and 16, 17, and 21 in yields up to 96% and enantiomeric ratios up to 99:1. The influence of organolithium reagents, ratio of organolithium/(-)-sparteine pair versus N,N-dialkyl aryl O-carbamate starting materials, temperature, solvents, electrophiles, substituents located ortho or meta to the O-carbamate moiety, and O-carbamate N-substituents was investigated. The identical absolute configuration of the stereogenic center of the major enantiomers of the products, as established by single-crystal X-ray analysis for substrates (S)-11c, (S)-19, and (S)-21a, provides evidence for a consistent stereochemical course in the enantioselective deprotonation. Mechanistic investigations, including an estimate of the configurational stability of the benzyllithium species 9 (starting from 12e; Scheme 8 ) and 23 (starting from 17e; Scheme 9 ), both derived by tin-lithium exchange, and 24 (starting from 20; Scheme 9 ) are reported. The experimental results, together with semiempirical molecular orbital calculations (PM3/SMD), are consistent with a process in which enantioinduction occurs in the deprotonation step (Scheme 11 ).

Mild and tunable benzoic acid catalysts for rearrangement reactions of allylic alcohols.

An efficient and simple catalytic method for the isomerization of readily prepared allylic alcohols is described. We focus particularly on cyclic examples and the synthesis of unusual enyne and dienols. The benzoic acid catalysts employed are commercially available and very inexpensive and can be tuned for reactivity and substrate sensitivity.

Boronic Acid catalyzed friedel-crafts reactions of allylic alcohols with electron-rich arenes and heteroarenes.

Pentafluorophenylboronic acid catalyzes the regioselective coupling of structurally diverse allylic alcohols with a variety of electron-rich aromatic and heteroaromatic substrates under ambient conditions. The commercially available catalyst is recoverable and air and moisture stable, and the reaction produces water as the only byproduct.

Palladium-catalyzed direct heck arylation of dual pi-deficient/pi-excessive heteroaromatics. Synthesis of C-5 arylated imidazo[1,5-a]pyrazines.

A general and efficient synthesis of 5-aryl imidazo[1,5- a]pyrazines by palladium-catalyzed coupling of the corresponding 8-substituted derivatives with aryl halides is described. The scope of this new reaction for the imidazo[1,5- a]pyrazine ring system was explored using three readily available 8-substituted precursors, X = NH2, NMe2, and OMe, as well as 8-aryl derivatives, X = Ar'. On the basis of these results as well as studies using a deuterated derivative, a Heck-like mechanism is proposed for this transformation.

Total synthesis of cryptophycin analogues via a scaffold approach.

[reaction: see text] Allylation of in situ generated beta,gamma-unsaturated aldehydes affords rapid access to vinyl halide analogues of fragment A of the cryptophycins. Three scaffolds are prepared in gram quantities by a ring-closing metathesis approach. Derivatization via a variety of cross-coupling protocols is possible, which affords novel analogues of these potent antimitotic agents.

Directed metalation route to ferroelectric liquid crystals with a chiral fluorenol core: the effect of restricted rotation on polar order.

A new series of smectic C* (SmC*) mesogens containing a chiral (R)-2-octyloxy side chain and either a fluorenone (2a-e) or chiral fluorenol (3a-e) core were synthesized using a combined directed ortho metalation-directed remote metalation strategy. The SmC phase formed by the fluorenol mesogens is more stable and has a wider temperature range than that formed by the fluorenone mesogens, which may be ascribed to intermolecular hydrogen bonding according to variable-temperature FT-IR measurements. The C11 fluorenol mesogens (R,R)-3d and (S,R)-3d were obtained in diastereomerically pure form and gave reduced polarization (Po) values of +106 and +183 nC/cm2, respectively, at 10 K below the SmA*-SmC* phase transition temperature. The difference in Po values suggests that the chiral fluorenol core contributes to the spontaneous polarization of the SmC* phase. This is ascribed to the bent shape of the fluorenol core, which should restrict its rotation with respect to the side chains in the SmC* phase and favor one orientation of its transverse dipole moment along the polar axis, and to steric coupling of the core to the chiral 2-octyloxy side chain.