A Strategy for the Formal C-N Cross-Coupling of Tertiary Amines.

We report a strategy for the C-N cross-coupling of tertiary amines via the in situ generation and displacement of N-acyl ammonium species. Specifically, treatment of diverse tertiary amines with TFAA or choroformates in the presence of NaI leads to the efficient generation of alkyl iodides, which can be engaged directly in Ni-catalyzed cross-couplings. The protocol is applicable to acyclic and cyclic systems, including highly hindered variants. Applications to the late-stage modification of complex heterocycles are presented.

(±)-Polysiphenol and Other Analogues via Symmetrical Intermolecular Dimerizations: A Synthetic, Spectroscopic, Structural, and Computational Study.

We report an improved total synthesis of 4,5-dibromo-9,10-dihydrophenanthrene-2,3,6,7-tetraol, (±)-polysiphenol, via intermolecular McMurray dimerization of 5-bromovanillin and subsequent intramolecular oxidative coupling as the key steps. The synthetic route is applicable to 4,5-dichloro- and 4,5-difluoro-halologues (as well as a 4,5-dialkyl-analogue). Distinctive AA'BB' multiplets in their 1H NMR spectra for the dimethylene bridges of the dibromo and dichloro compounds reveal them to be room-temperature stable atropisomers, while for the difluoro compound they present as a singlet. X-ray crystal structure determinations of their tetramethylated synthetic precursors show atropisomeric twist angles of 48°, 46°, and 32°, respectively, with the former representing the largest yet observed in any 4,5-disubstituted-9,10-dihydrophenanthrene. DFT computational studies reveal an unprecedented two-stage atropisomeric interconversion process involving time-independent asynchronous rotations of the dimethylene bridge and the biaryl axis for halologues containing chlorine or bromine, but a more synchronous rotation for the difluoro analogue.

Looking deep into C-H functionalization: the synthesis and application of cyclopentadienyl and related metal catalysts.

Metal catalyzed C-H functionalization offers a versatile platform for methodology development and a wide variety of reactions now exist for the chemo- and site-selective functionalization of organic molecules. Cyclopentadienyl-metal (CpM) complexes of transition metals and their correlative analogues have found widespread application in this area, and herein we highlight several key applications of commonly used transition-metal Cp-type catalysts. In addition, an understanding of transition metal Cp-type catalyst synthesis is important, particularly where modifications to the catalyst structure are required for different applications, and a summary of this aspect is given.

Relay Cross Metathesis for the Iterative Construction of Terpenoids and Synthesis of a Diterpene-Benzoate Macrolide of Biogenetic Relevance to the Bromophycolides.

We report a relay cross metathesis (ReXM) reaction for the construction of terpenoids in an iterative protocol. The protocol features the cross metathesis of a relay-actuated Δ6,7-functionalized C10-monoterpenoid alcohol with C10-monoterpenoid citral to form a C15-sesquiterpene. Subsequent functional group manipulation allows for the method to be repeated in an iterative fashion. The method is used for the synthesis of a diterpene-benzoate macrolide of biogenetic relevance to the bromophycolide family of natural products.

A Relay Strategy Actuates Pre-Existing Trisubstituted Olefins in Monoterpenoids for Cross-Metathesis with Trisubstituted Alkenes.

A retrosynthetic disconnection-reconnection analysis of epoxypolyenes-substrates that can undergo cyclization to podocarpane-type tricycles-reveals relay-actuated Δ6,7-functionalized monoterpenoid alcohols for ruthenium benzylidene catalyzed olefin cross-metathesis with homoprenyl benzenes. Successful implementation of this approach provided several epoxypolyenes as expected (E/Z, ca. 2-3:1). The method is further generalized for the cross-metathesis of pre-existing trisubstituted olefins in other relay-actuated Δ6,7-functionalized monoterpenoid alcohols with various other trisubstituted alkenes to form new trisubstituted olefins. Epoxypolyene cyclization of an enantiomerically pure, but geometrically impure, epoxypolyene substrate provides an enantiomerically pure, trans-fused, podocarpane-type tricycle (from the E-geometrical isomer).

Kinetic Benchmarking Reveals the Competence of Prenyl Groups in Ring-Closing Metathesis.

A series of prenyl-containing malonates are kinetically benchmarked against the standard allyl-containing congeners using a ruthenium benzylidene precatalyst for ring-closing metatheses. The prenyl grouping is found to be a superior acceptor olefin compared to an allyl group in RCM processes with ruthenium alkylidenes derived from terminal alkenes. The prenyl group is also found to be a highly competent acceptor for a ruthenium alkylidene derived from a 1,1-disubstituted olefin in a RCM process.

Metal-free, hydroacylation of C=C and N=N bonds via aerobic C-H activation of aldehydes, and reaction of the products thereof.

In this report, a thorough evaluation of the use of aerobically initiated, metal-free hydroacylation of various C=C and N=N acceptor molecules with a wide range of aldehydes is presented. The aerobic-activation conditions that have been developed are in sharp contrast to previous conditions for hydroacylation, which tend to use transition metals, peroxides that require thermal or photochemical degradation, or N-heterocyclic carbenes. The mildness of the conditions enables a number of reactions involving sensitive reaction partners and, perhaps most significantly, allows for α-functionalised chiral aldehydes to undergo radical-based hydroacylation with complete retention of optical purity. We also demonstrate how the resulting hydroacylation products can be transformed into other useful intermediates, such as γ-keto-sulfonamides, sultams, sultones, cyclic N-sulfonyl imines and amides.