James Sanderson

Iron-catalyzed Kumada cross-coupling reactions of pyrimidin-2-yl phosphates and Grignard reagents are described. The reaction proceeds at room temperature with a short reaction time of 15 minutes, and the corresponding products are obtained with moderate to high yields. A wide array of C2-functionalized pyrimidines has been prepared in moderate to good yields and many functional groups are well tolerated.

Isn't it iron-ic: Iron-catalyzed Kumada cross-coupling reactions of pyrimidin-2-yl phosphates are reported. The substrate scope with respect to Grignard reagents includes alkyl, aryl, and benzyl Grignard reagents. A wide array of 2-substituted pyrimidines has been prepared in moderate to good yields. dppp=1,3-bis(diphenylphosphino)propane.

The direct C(sp²)C(sp³) cross-coupling of diaryl zinc reagents with benzylic, primary, secondary, and tertiary alkyl halides proceeded in the absence of coordinating ethereal solvents at ambient temperature without the addition of a catalyst. The C(sp²)C(sp³) cross-coupling showed excellent functional-group tolerance, and products were isolated in high yields, generally without the requirement for purification by chromatography. This process represents an expedient, operationally simple method for the construction of new C(sp²)C(sp³) bonds.

Zinc and you’ll miss it! Direct C(sp²)C(sp³) cross-coupling of diaryl zinc reagents with alkyl halides proceeded rapidly at ambient temperature without a coordinating ethereal solvent or an added catalyst (see scheme). This versatile, operationally simple approach to C(sp²)C(sp³) bond formation enables the expedient construction of a diverse array of carbon-based structural motifs.

An Fe(III)-catalyzed cross-coupling of N-heteroaromatic tosylates with aryl and alkyl Grignard reagents is presented. The reaction proceeds at −20°C to room temperature with short reaction time (15–30 min.), and the corresponding products are obtained with moderate to high yields. In particular, low-cost and abundantly available FeCl₃ or Fe(acetylacetonate)₃ catalyze the reaction without other special ligands. All tested N-heteroaromatic tosylates that are available including pyridine and pyrimidine derivatives were subject to the reaction, resulting in the expected products. Copyright © 2015 John Wiley & Sons, Ltd.

Fe(III)-catalyzed cross-coupling of N-heteroaromatic tosylates with aryl and alkyl Grignard reagents is presented. The cross-coupling was catalyzed by FeCl₃ or Fe(acac)₃/TMEDA at −20°C to room temperature with short reaction times (15–30 min).

The “curly arrow” of Robinson and Ingold is the primary tool for describing and rationalizing reaction mechanisms. Despite this approach’s ubiquity and stellar success, its physical basis has never been clarified and a direct connection to quantum chemistry has never been found. Here we report that the bond rearrangements expressed by curly arrows can be directly observed in ab initio computations, as transformations of intrinsic bond orbitals (IBOs) along the reaction coordinate. Our results clarify that curly arrows are rooted in physical reality—a notion which has been challenged before—and show how quantum chemistry can directly establish reaction mechanisms in intuitive terms and unprecedented detail.

Curly arrows from ab initio calculations: Curly arrows in reaction mechanisms are shown to correspond to changes in intrinsic bond orbitals (IBOs) along reaction paths. With this quantum chemical basis, even complex reaction mechanisms can be derived and visualized in a simple, direct, and intuitive form.

A new method for titanium-catalyzed reductive umpolung reactions is reported that overcomes the traditional requirement for a stoichiometric metallic reductant. With N,N′-disilylated tetramethyldihydropyrazine as a potent organic reducing agent, reductive carbonyl–nitrile, enone–acrylonitrile and pinacol coupling reactions can be achieved in good yields and stereoselectivities. [Cp₂TiI₂] is a superior catalyst to [Cp₂TiCl₂], which is rationalized by a faster generation of the active catalyst [Cp₂TiI]. A mechanism is proposed that is in agreement with the experimental results.

Replacing zinc: A protocol for titanium(III)-catalyzed reductive umpolung reactions is presented that enables the title reactions in the presence of an N,N′-disilylated tetramethyldihydropyrazine as an organic sacrificial reducing agent. It is successfully applied to carbonyl–nitrile, enone–acrylonitrile and pinacol coupling reactions. A remarkable effect of the titanocene counterion renders titanocene diiodide a superior catalyst.

Pd-mediated Negishi cross-coupling reactions were studied by a combination of kinetic measurements, electrospray-ionization (ESI) mass spectrometry, ³¹P NMR and UV/Vis spectroscopy. The kinetic measurements point to a rate-determining oxidative addition. Surprisingly, this step seems to involve not only the Pd catalyst and the aryl halide substrate, but also the organozinc reagent. In this context, the ESI-mass spectrometric observation of heterobimetallic Pd–Zn complexes [L₂PdZnR]⁺ (L=S-PHOS, R=Bu, Ph, Bn) is particularly revealing. The inferred presence of these and related neutral complexes with a direct Pd–Zn interaction in solution explains how the organozinc reagent can modulate the reactivity of the Pd catalyst. Previous theoretical calculations by González-Pérez et al. (Organometallics­ 2012, 31, 2053) suggest that the complexation by the organozinc reagent lowers the activity of the Pd catalyst. Presumably, a similar effect also causes the rate decrease observed upon addition of ZnBr₂. In contrast, added LiBr apparently counteracts the formation of Pd–Zn complexes and restores the high activity of the Pd catalyst. At longer reaction times, deactivation processes due to degradation of the S-PHOS ligand and aggregation of the Pd catalyst come into play, thus further contributing to the appreciable complexity of the title reaction.

Catalytic complexity: The Pd catalyst used in Negishi cross-coupling reactions shows an unexpected heterogeneity and complexity. Among the various species observed in solution, heterobimetallic Pd–Zn complexes are of particular interest (see figure). These species also seem key to understanding the kinetics of Negishi cross-coupling reactions. S-PHOS=2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl.

The radical nature of iron-catalyzed cross-coupling between Grignard reagents and alkyl halides has been studied by using a combination of competitive kinetic experiments and DFT calculations. In contrast to the corresponding coupling with aryl halides, which commences through a classical two-electron oxidative addition/reductive elimination sequence, the presented data suggest that alkyl halides react through an atom-transfer-initiated radical pathway. Furthermore, a general iodine-based quenching methodology was developed to enable the determination of highly accurate concentrations of Grignard reagents, a capability that facilitates and increases the information output of kinetic investigations based on these substrates.

Iron cross: The iron-catalyzed cross-coupling reaction between alkyl halides and Grignard reagents has been investigated by competitive Hammett studies and DFT calculations. The results support the presence of radical intermediates in an Fe^I–Fe^III cycle with an atom-transfer (AT) mechanism as the rate-limiting step (see figure; TM=transmetalation, RE=reductive elimination).

We report a cobalt-catalyzed cross-coupling of di(hetero)arylzinc reagents with primary and secondary alkyl iodides or bromides using THF-soluble CoCl₂⋅2 LiCl and TMEDA as a ligand, which leads to the corresponding alkylated products in up to 88 % yield. A range of functional groups (e.g. COOR, CN, CF₃, F) are tolerated in these substitution reactions. Remarkably, we do not observe rearrangement of secondary alkyl iodides to unbranched products. Additionally, the use of cyclic TBS-protected iodohydrins leads to trans-2-arylcyclohexanol derivatives in excellent diastereoselectivities (up to d.r.=99:1).

Cobalt and zinc—a lovely couple! The soluble CoCl₂⋅2 LiCl complex allows efficient cross-coupling between polyfunctional diaryl- and diheteroarylzinc reagents, obtained by directed zincation using TMP₂Zn⋅2 MgCl₂⋅2 LiCl, and various primary or secondary alkyl iodides or bromides to afford the alkylated products in up to 88 % yield. In no case was rearrangement of the secondary alkyl iodide (to its linear isomer) observed.

The first cross-coupling reaction between aryl silanes and aryl boronic acids is described. This transformation represents one of the very few examples of coupling reactions between two nucleophilic organometallic reagents and provides a new method for the formation of biaryl compounds. The successful development of this reaction was enabled by the use of commercially available 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) as the ligand. A small amount of BINAP (3 mol %) was sufficient to suppress the formation of the homocoupling products, and the reaction yielded the cross-coupling products with high selectivity under mild conditions, even when the ratio of the two coupling partners was 1:1.

Two nucleophiles: The first cross-coupling reaction between aryl silanes and aryl boronic acids is one of the very few examples of coupling reactions between two nucleophilic organometallic reagents and provides access to biaryl compounds. With the commercially available ligand BINAP, the formation of the homocoupling products was suppressed, and the reaction yielded the cross-coupling products with high selectivity.

An iron-catalyzed diboration reaction of alkynes with bis(pinacolato)diboron (B₂pin₂) and external borating agents (MeOB(OR)₂) affords diverse symmetrical or unsymmetrical cis-1,2-diborylalkenes. The simple protocol for the diboration reaction can be extended to the iron-catalyzed carboboration of alkynes with primary and, unprecedentedly, secondary alkyl halides, affording various tetrasubstituted monoborylalkenes in a highly stereoselective manner. DFT calculations indicate that a boryliron intermediate adds across the triple bond of an alkyne to afford an alkenyliron intermediate, which can react with the external trapping agents, borates and alkyl halides. In situ trapping experiments support the intermediacy of the alkenyl iron species using radical probe stubstrates.

Iron-catalyzed diboration and carboboration reactions of internal alkynes have been developed. Diboration takes place through a borylmetalation/electrophilic substitution process and carboboration through a borylmetalation/radical reaction, both providing the products in a highly cis-selective and chemoselective manner.

A base-promoted three-component coupling of carbon dioxide, amines, and N-tosylhydrazones has been developed. The reaction is suggested to proceed via a carbocation intermediate and constitutes an efficient and versatile approach for the synthesis of a wide range of organic carbamates. The advantages of this method include the use of readily available substrates, excellent functional group tolerance, wide substrate scope, and a facile work-up procedure.

Carbene intermediate? No! An unprecedented strategy for the synthesis of a range of organic carbamates through the coupling of carbon dioxide, amines, and N-tosylhydrazones is reported. The base-promoted reaction is proposed to proceed via a carbocation intermediate and is characterized by excellent functional group tolerance and a wide substrate scope.