Triarylamine-based porous coordination polymers performing both hydrogen atom transfer and photoredox catalysis for regioselective α-amino C(sp3)-H arylation.
ABSTRACT: Direct functionalization of C(sp3)-H bonds in a predictable, selective and recyclable manner has become a central challenge in modern organic chemistry. Through incorporating different triarylamine-containing ligands into one coordination polymer, we present herein a heterogeneous approach to the combination of hydrogen atom transfer (HAT) and photoredox catalysis for regioselective C-H arylation of benzylamines. The different molecular sizes and coordination modes of the ligands, tricarboxytriphenylamine (H3TCA) and tris(4-(pyridinyl)phenyl)amine (NPy3), in one coordination polymer consolidate the triarylamine (Ar3N) moiety into a special structural intermediate, which enhances the chemical and thermal stability of the polymers and diminishes structural relaxation during the catalytic process. The inherent redox potentials of Ar3N moieties prohibit the in situ formed Ar3N˙+ to earn an electron from C(sp3)-H nucleophiles, but allow the abstraction of a hydrogen atom from C(sp3)-H nucleophiles, enabling the formation of the C(sp3)˙ radical and the cross-coupling reaction to proceed at the most electron-rich sites with excellent regioselectivity. The new heterogeneous photoredox HAT approach skips several interactions between transient species during the typical synergistic SET/HAT cycles, demonstrating a promising redox-economical and reagent-economical heterogeneous platform that has not been reported for α-amino C-H arylation to form benzylamine derivatives. Control experiments based on monoligand coordination polymers suggested that the mixed-ligand approach improved the photochemical and photophysical properties, providing important insight into rational design and optimization of recyclable photocatalysts for rapid access to complex bioactive molecules and late-stage functionalized pharmaceuticals.
Project description:This report describes a highly enantioselective oxidative sp<sup>3</sup> C-H arylation of <i>N</i>-aryltetrahydroisoquinolines (THIQs) through a dual catalysis platform. The combination of the photoredox catalyst, [Ir(ppy)<sub>2</sub>(dtbbpy)]PF<sub>6</sub>, and chiral copper catalysts provide a mild and highly effective sp<sup>3</sup> C-H asymmetric arylation of THIQs.
Project description:A selective, sequential C-O decarboxylative vinylation/C-H arylation of cyclic alcohol derivatives enabled by visible-light photoredox/nickel dual catalysis is described. This protocol utilizes a multicomponent radical cascade process, <i>i.e.</i> decarboxylative vinylation/1,5-HAT/aryl cross-coupling, to achieve efficient, site-selective dual-functionalization of saturated cyclic hydrocarbons in one single operation. This synergistic protocol provides straightforward access to sp<sup>3</sup>-enriched scaffolds and an alternative retrosynthetic disconnection to diversely functionalized saturated ring systems from the simple starting materials.
Project description:Photoredox catalysis has provided many approaches to C(sp<sup>3</sup>)-H functionalization that enable selective oxidation and C(sp<sup>3</sup>)-C bond formation via the intermediacy of a carbon-centered radical. While highly enabling, functionalization of the carbon-centered radical is largely mediated by electrophilic reagents. Notably, nucleophilic reagents represent an abundant and practical reagent class, motivating the interest in developing a general C(sp<sup>3</sup>)-H functionalization strategy with nucleophiles. Here we describe a strategy that transforms C(sp<sup>3</sup>)-H bonds into carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar crossover. The resulting carbocation is functionalized by a variety of nucleophiles-including halides, water, alcohols, thiols, an electron-rich arene, and an azide-to effect diverse bond formations. Mechanistic studies indicate that HAT is mediated by methyl radical-a previously unexplored HAT agent with differing polarity to many of those used in photoredox catalysis-enabling new site-selectivity for late-stage C(sp<sup>3</sup>)-H functionalization.
Project description:The use of sp(3) C-H bonds--which are ubiquitous in organic molecules--as latent nucleophile equivalents for transition metal-catalyzed cross-coupling reactions has the potential to substantially streamline synthetic efforts in organic chemistry while bypassing substrate activation steps. Through the combination of photoredox-mediated hydrogen atom transfer (HAT) and nickel catalysis, we have developed a highly selective and general C-H arylation protocol that activates a wide array of C-H bonds as native functional handles for cross-coupling. This mild approach takes advantage of a tunable HAT catalyst that exhibits predictable reactivity patterns based on enthalpic and bond polarity considerations to selectively functionalize ?-amino and ?-oxy sp(3) C-H bonds in both cyclic and acyclic systems.
Project description:We present the first example of an unprecedented and fast aryl C(sp<sup>2</sup>)-X reductive elimination from a series of isolated Pt(IV) aryl complexes (Ar = <i>p</i>-FC<sub>6</sub>H<sub>4</sub>) LPt<sup>IV</sup>F(py)(Ar)X (X = CN, Cl, 4-OC<sub>6</sub>H<sub>4</sub>NO<sub>2</sub>) and LPt<sup>IV</sup>F<sub>2</sub>(Ar)(HX) (X = NHAlk; Alk = <i>n</i>-Bu, PhCH<sub>2</sub>, cyclo-C<sub>6</sub>H<sub>11</sub>, <i>t</i>-Bu, cyclopropylmethyl) bearing a bulky bidentate 2-[bis(adamant-1-yl)phosphino]phenoxide ligand (L). The C(sp<sup>2</sup>)-X reductive elimination reactions of all isolated Pt(IV) complexes follow first-order kinetics and were modeled using density functional theory (DFT) calculations. When a difluoro complex LPt<sup>IV</sup>F<sub>2</sub>(Ar)(py) is treated with TMS-X (TMS = trimethylsilyl; X= NMe<sub>2</sub>, SPh, OPh, CCPh) it also gives the corresponding products of the Ar-X coupling but without observable LPt<sup>IV</sup>F(py)(Ar)X intermediates. Remarkably, the LPt<sup>IV</sup>F<sub>2</sub>(Ar)(HX) complexes with alkylamine ligands (HX = NH<sub>2</sub>Alk) form selectively either mono- (ArNHAlk) or diarylated (Ar<sub>2</sub>NAlk) products in the presence or absence of an added Et<sub>3</sub>N, respectively. This method allows for a one-pot preparation of diarylalkylamine bearing different aryl groups. These findings were also applied in unprecedented mono- and di-N-arylation of amino acid derivatives (lysine and tryptophan) under very mild conditions.
Project description:The allylation reaction is a highly versatile transformation in chemical synthesis. While many elegant direct C(sp<sup>2</sup>)-H allylation reactions have been developed, the direct allylation of unactivated C(sp<sup>3</sup>)-H bonds is underdeveloped. By applying photoredox catalysis and a [1,5]-HAT process, herein we report a direct allylation of unactivated C(sp<sup>3</sup>)‒H bonds. This photocatalyzed transformation is tolerant of several functional groups in the amide and allylic chloride substrates. Various allyl-substituted amide products were obtained with good yields and high δ-selectivity.
Project description:While strategies involving a 2e<sup>-</sup> transfer pathway have dictated glycosylation development, the direct glycosylation of readily accessible glycosyl donors as radical precursors is particularly appealing because of high radical anomeric selectivity and atom- and step-economy. However, the development of the radical process has been challenging owing to notorious competing reduction, elimination and/or S<sub>N</sub> side reactions of commonly used, labile glycosyl donors. Here we introduce an organophotocatalytic strategy through which glycosyl bromides can be efficiently converted into corresponding anomeric radicals by photoredox mediated HAT catalysis without a transition metal or a directing group and achieve highly anomeric selectivity. The power of this platform has been demonstrated by the mild reaction conditions enabling the synthesis of challenging α-1,2-<i>cis</i>-thioglycosides, the tolerance of various functional groups and the broad substrate scope for both common pentoses and hexoses. Furthermore, this general approach is compatible with both sp<sup>2</sup> and sp<sup>3</sup> sulfur electrophiles and late-stage glycodiversification for a total of 50 substrates probed.
Project description:A stepwise build-up of multi-substituted C<sub>sp<sup>3</sup></sub> carbon centers is an attractive, conceptually simple, but often synthetically challenging type of disconnection. To this end, this report describes how <i>gem</i>-α,α-dimetalloid-substituted benzylic reagents bearing boron/silicon or boron/tin substituent sets are an excellent stepping stone towards diverse substitution patterns. These <i>gem</i>-dimetalloids were readily accessed, either by known carbenoid insertion into C-B bonds or by the newly developed scalable deprotonation/metallation approach. Highly chemoselective transformations of either the C-Si (or C-Sn) or the C-B bonds in the newly formed <i>gem</i>-C<sub>sp<sup>3</sup></sub> centers have been achieved through a set of approaches, with a particular focus on exploiting the synthetically versatile polarity reversal in organometalloids by λ<sup>3</sup>-aryliodanes. Of particular note is the metal-free arylation of the C-Si (or C-Sn) bonds in such <i>gem</i>-dimetalloids <i>via</i> the iodane-guided C-H coupling approach. DFT calculations show that this transfer of the (α-Bpin)benzyl group proceeds <i>via</i> unusual [5,5]-sigmatropic rearrangement and is driven by the high-energy iodine(iii) center. As a complementary tool, the <i>gem</i>-dimetalloid C-B bond is shown to undergo a potent and chemoselective Suzuki-Miyaura arylation with diverse Ar-Cl, thanks to the development of the reactive <i>gem</i>-α,α-silyl/BF<sub>3</sub>K building blocks.
Project description:A transition metal-free dehydrogenative method for the direct mono-arylation of a wide range of activated C(sp<sup>3</sup>)-H bonds has been developed. This operationally simple and environmentally friendly aerobic arylation uses <i>tert</i>-BuOK as the base and nitroarenes as electrophiles to prepare up to gram quantities of structurally diverse sets (>60 examples) of ?-arylated esters, amides, nitriles, sulfones and triaryl methanes. DFT calculations provided a predictive model, which states that substrates containing a C(sp<sup>3</sup>)-H bond with a sufficiently low p<i>K</i> <sub>a</sub> value should readily undergo arylation. The DFT prediction was confirmed through experimental testing of nearly a dozen substrates containing activated C(sp<sup>3</sup>)-H bonds. This arylation method was also used in a one-pot protocol to synthesize over twenty compounds containing all-carbon quaternary centers.
Project description:Transition metal-catalysed C-H bond functionalisations have been extensively developed in organic and medicinal chemistry. Among these catalytic approaches, the selective activation of C(sp<sup>3</sup>)-H and C(sp<sup>2</sup>)-H bonds is particularly appealing for its remarkable synthetic versatility, yet it remains highly challenging. Herein, we demonstrate the first example of temperature-dependent selective C-H functionalisation of unactivated C(sp<sup>3</sup>)-H or C(sp<sup>2</sup>)-H bonds at remote positions through palladium catalysis using 7-pyridyl-pyrazolo[1,5-<i>a</i>]pyrimidine as a new directing group. At 120 °C, C(sp<sup>3</sup>)-H arylation was triggered by the chelation of a rare [6,5]-fused palladacycle, whereas at 140 °C, C(sp<sup>2</sup>)-H arylation proceeded instead through the formation of a 16-membered tetramer containing four 7-pyridyl-pyrazolo[1,5-<i>a</i>]pyrimidine-palladium chelation units. The subsequent mechanistic study revealed that both C-H activations shared a common 6-membered palladacycle intermediate, which was then directly transformed to either the [6,5]-fused palladacycle for C(sp<sup>3</sup>)-H activation at 120 °C or the tetramer for C(sp<sup>2</sup>)-H arylation at 140 °C with catalytic amounts of Pd(OAc)<sub>2</sub> and AcOH. Raising the temperature from 120 °C to 140 °C can also convert the [6,5]-fused palladacycle to the tetramer with the above-mentioned catalysts, hence completing the C(sp<sup>2</sup>)-H arylation ultimately.