Cooperative Fe/Co-Catalyzed Remote Desaturation for the Synthesis of Unsaturated Amide Derivatives.

Unsaturated amides represent common functional groups found in natural products and bioactive molecules and serve as versatile synthetic building blocks. Here, we report an iron(II)/cobalt(II) dual catalytic system for the syntheses of distally unsaturated amide derivatives. The transformation proceeds through an iron nitrenoid-mediated 1,5-hydrogen atom transfer (1,5-HAT) mechanism. Subsequently, the radical intermediate undergoes hydrogen atom abstraction from vicinal methylene by a cobaloxime catalyst, efficiently yielding ß,γ- or γ,δ-unsaturated amide derivatives under mild conditions. The efficiency of Co-mediated HAT can be tuned by varying different auxiliaries, highlighting the generality of this protocol. Remarkably, this desaturation protocol is also amenable to practical scalability, enabling the synthesis of unsaturated carbamates and ureas, which can be readily converted into various valuable molecules.

Hydrogen Atom Transfer (HAT)-Mediated Remote Desaturation Enabled by Fe/Cr-H Cooperative Catalysis.

An iron/chromium system (Fe(OAc)2, CpCr(CO)3H) catalyzes the preparation of ß,γ- or γ,δ-unsaturated amides from 1,4,2-dioxazol-5-ones. An acyl nitrenoid iron complex seems likely to be responsible for C-H activation. A cascade of three H• transfer steps appears to be involved: (i) the abstraction of H• from a remote C-H bond by the nitrenoid N, (ii) the transfer of H• from Cr to N, and (iii) the abstraction of H• from a radical substituent by the Cr•. The observed kinetic isotope effects are consistent with the proposed mechanism if nitrenoid formation is the rate-determining step. The Fe/Cr catalysts can also desaturate substituted 1,4,2-dioxazol-5-ones to 3,5-dienamides.

Isomerization of Aziridines to Allyl Amines via Titanium and Chromium Cooperative Catalysis.

A Ti/Cr cooperative catalyst isomerizes aziridines to allyl amines under mild conditions. The reaction tolerates a broad range of aziridines with various nitrogen substituents. The titanium catalyst is most successful in opening 1,2-disubstituted aziridines, forming radical intermediates in a highly regioselective manner. The chromium catalyst appears to abstract an H• from these radical intermediates and then return the H• to the titanium system in the form of an H+ and an electron. The reaction is complementary to previous reports on the isomerization of aziridines to allyl amines.

Highly Selective Hydrogenation of C═C Bonds Catalyzed by a Rhodium Hydride.

Under mild conditions (room temperature, 80 psi of H2) Cp*Rh(2-(2-pyridyl)phenyl)H catalyzes the selective hydrogenation of the C═C bond in α,ß-unsaturated carbonyl compounds, including natural product precursors with bulky substituents in the ß position and substrates possessing an array of additional functional groups. It also catalyzes the hydrogenation of many isolated double bonds. Mechanistic studies reveal that no radical intermediates are involved, and the catalyst appears to be homogeneous, thereby affording important complementarity to existing protocols for similar hydrogenation processes.

Generation of α-Boryl Radicals by H. Transfer and their Use in Cycloisomerizations.

Carbon-centered radicals can be stabilized by delocalization of their spin density into the vacant p orbital of a boron substituent. α-Vinyl boronates, in particular pinacol (Bpin) derivatives, are excellent hydrogen atom acceptors. Under H2 , in the presence of a cobaloxime catalyst, they generate α-boryl radicals; these species can undergo 5-exo radical cyclizations if appropriate double bond acceptors are present, leading to densely functionalized heterocycles with tertiary substituents on Bpin. The reaction shows good functional group tolerance with wide scope, and the resulting boronate products can be converted into other useful functionalities.

TEMPO-Mediated Catalysis of the Sterically Hindered Hydrogen Atom Transfer Reaction between (C5Ph5)Cr(CO)3H and a Trityl Radical.

We have demonstrated the ability of TEMPO to catalyze H· transfer from (C5Ph5)Cr(CO)3H to a trityl radical (tris( p- tert-butylphenyl)methyl radical). We have measured the rate constant and activation parameters for the direct reaction, and for each step in the catalytic process: H· transfer from (C5Ph5)Cr(CO)3H to TEMPO and H· transfer from TEMPO-H to the trityl radical. We have compared the measured rate constants with the differences in bond strength, and with the changes in the Global Electrophilicity Index determined with high accuracy for each radical using state of the art quantum chemical methods. We conclude that neither is a major factor in determining the rates of these H· transfer reactions and that the effectiveness of TEMPO as a catalyst is largely the result of its relative lack of steric congestion compared to the trityl radical.

Catalysis of Radical Cyclizations from Alkyl Iodides under H2: Evidence for Electron Transfer from [CpV(CO)3H].

Radical cyclizations are most often achieved with Bu3SnH in the presence of a radical initiator, but environmental considerations demand that alternative reagents be developed-ones that can serve as a synthetic equivalent to the hydrogen atom. We have revisited [CpV(CO)3H]-, a known replacement for Bu3SnH, and found that it can be used catalytically under H2 in the presence of a base. We have carried out tin-free catalytic radical cyclizations of alkyl iodide substrates. The reactions are atom-efficient, and the conditions are mild, with broad tolerance for functional groups. We have, for example, achieved the first 5-exo radical cyclization involving attack onto a vinyl chloride. We suggest that the radicals are generated by an initial electron transfer.

Insertion of Isonitriles into the M-C Bonds of Group 4 Dialkyl Complexes.

The 2,3-dimethylbutadiene complexes of Group 4 metals with constrained geometry (cg) ligands have been prepared and found to adopt a supine orientation with σ2,π bonding. Treatment of cgTi(2,3-dimethylbutadiene) (1-Ti) with tBuNC leads to the formation of a titana-aziridine (3) with a coordinated cyclopentenimine that arises from the formal [4+1] addition of the diene to the isonitrile. In contrast, the reactions of cgZr(2,3-dimethylbutadiene) (1-Zr) or cgHf(2,3-dimethylbutadiene) (1-Hf) with 2 equiv of tBuNC or XyNC proceeded in a more sophisticated manner to yield unsymmetrical 2,5-diazametallacyclopentane derivatives (4, 6-Zr, and 6-Hf) or symmetrical 2,5-diazametallacyclopentene complexes (7-Zr and 7-Hf). The unsymmetrical products contain coordinated cyclopropanes; the strength of the interaction is measured by the reduction in the 1 JCC of the C-C bond that is coordinated. A detailed mechanistic analysis has been possible with the related cgM(Me)2 (M = Ti and Hf) complexes. The first insertion is too fast to monitor, but allows complete conversion to an alkyl iminoacyl intermediate. The second isonitrile (RNC) may react with that intermediate by either of two different mechanisms, reductive elimination and coordination/insertion. In the first mechanism (Ti), rate-determining C-C coupling gives a titana-aziridine, followed by fast coordination of the isonitrile. In the second mechanism (Hf), coordination is the slow step; insertion to form a bis(iminoacyl) Hf complex is rapid.

Transition-Metal Hydride Radical Cations.

Transition-metal hydride radical cations (TMHRCs) are involved in a variety of chemical and biochemical reactions, making a more thorough understanding of their properties essential for explaining observed reactivity and for the eventual development of new applications. Generally, these species may be treated as the ones formed by one-electron oxidation of diamagnetic analogues that are neutral or cationic. Despite the importance of TMHRCs, the generally sensitive nature of these complexes has hindered their development. However, over the last four decades, many more TMHRCs have been synthesized, characterized, isolated, or hypothesized as reaction intermediates. This comprehensive review focuses on experimental studies of TMHRCs reported through the year 2014, with an emphasis on isolated and observed species. The methods used for the generation or synthesis of TMHRCs are surveyed, followed by a discussion about the stability of these complexes. The fundamental properties of TMHRCs, especially those pertaining to the M-H bond, are described, followed by a detailed treatment of decomposition pathways. Finally, reactions involving TMHRCs as intermediates are described.

Cationic Copper Hydride Clusters Arising from Oxidation of (Ph3P)6Cu6H6.

Transfer of the first electron from (Ph3P)6Cu6H6 to Cp*2Fe+ is fast (k > 106 L·mol-1·s-1). Transfer of a second electron to the same oxidant has a much lower thermodynamic driving force and is considerably slower, with k = 9.29(4) × 103 L·mol-1·s-1. The second oxidation leads to the formation of [(Ph3P)6Cu6H5]+. The structure of [(Ph3P)6Cu6H5]+ has been confirmed by its conversion back to (Ph3P)6Cu6H6 and by microanalysis; X-ray diffraction shows that the complex is a bitetrahedron in the solid state. [(Ph3P)6Cu6H5]+ can also be prepared by treating (Ph3P)6Cu6H6 with MeOTf. With less than 1 equiv of Cp*2Fe+ as oxidant, (Ph3P)6Cu6H6 gives [(Ph3P)7Cu7H6]+ as the major product; X-ray diffraction shows a Cu6 octahedron with one face capped by an additional Cu. [(Ph3P)7Cu7H6]+ can also be prepared by treating (Ph3P)6Cu6H6 with [Cu(CH3CN)4]+ (along with 1 equiv of Ph3P), and can be converted back to (Ph3P)6Cu6H6 with base/H2.

Radical Isomerization and Cycloisomerization Initiated by H• Transfer.

Under H2 pressure, Co(II)(dmgBF2)2L2 (L = H2O, THF) generates a low concentration of an H• donor. Transfer of the H• onto an olefin gives a radical that can either (1) transfer an H• back to the metal, generating an isomerized olefin, or (2) add intramolecularly to a double bond, generating a cyclized radical. Transfer of an H• back to the metal from the cyclized radical results in a cycloisomerization. Both outcomes are favored by the low concentration of the cobalt H• donor, whereas hydrogenation and cyclohydrogenation are more likely with other catalysts (when the concentration of the H• donor is high).

Direct generation of oxygen-stabilized radicals by H• transfer from transition metal hydrides.

Transition-metal hydrides generate α-alkoxy radicals by H• transfer to enol ethers. We have measured the rate constant for transfer from CpCr(CO)3H to n-butyl vinyl ether and have examined the chemistry of radicals generated by such transfers. Radicals from appropriate substrates undergo 5-exo cyclization, with higher diastereoselectivity than the analogous all-carbon radicals. From such radicals it is straightforward to make substituted tetrahydrofurans.

Reaction of Cp*(Cl)M(Diene) (M = Ti, Hf) with Isonitriles.

We have investigated the reaction of isonitriles (RNC) with electronically unsaturated diene complexes of Ti and Hf. Cp*(Cl)Ti(2,3-dimethylbutadiene) (1) reacts with 2 equiv of RNC to give η(1),η(2)-diimine complexes 2 (R = (t)Bu) and 3 (R = 1-adamantyl). Cp*(Cl)Ti(N,N-di-(t)Bu-η(1),η(2)-diimine) (2), in the presence of pyridine, fragments to Cp*(Cl)Ti(N(t)Bu)(NC5H5) (10) and an α-methylene cyclopent-3-enimine (11). The hafnium analogue of 1, Cp*(Cl)Hf(2,3-dimethylbutadiene) (14), has been reported to give a cyclic amidine complex when treated with 2 equiv of 2,6-dimethylphenyl isonitrile. By X-ray crystallography, however, we find that 14 and 2,6-dimethylphenyl isonitrile give instead a 2,5-diazahafnacyclopentane that features a σ-interaction between the C-C bond of a cyclopropane ring and the Hf.

Kinetics and thermodynamics of H-/H•/H+ transfer from a rhodium(III) hydride.

The thermodynamics and kinetics of all three cleavage modes for Rh-H, the transfer of H(-), H(+), or H•, have been studied for the Rh(III) hydride complex Cp*Rh(2-(2-pyridyl)phenyl)H (1a). The thermodynamic hydricity, ΔG°H(-), for 1a has been measured (49.5(1) kcal/mol) by heterolytic cleavage of H2 with Et3N in CH3CN. The transfer of H(-) from 1a to 1-(1-phenylethylidene)pyrrolidinium is remarkably fast (kH(-) = 3.5(1) × 10(5) M(-1) s(-1)), making 1a a very efficient catalyst for the ionic hydrogenation of iminium cations. The pKa of 1a in CH3CN has been measured as 30.3(2) with (tert-butylimino)tris(pyrrolidino)phosphorane (12), and the rate constant for H(+) transfer from 1a to 12 has been estimated (kH(+) = 5(1) × 10(-4) M(-1) s(-1)) from the half-life of the equilibration. Thus, 1a is a poor H(+) donor both thermodynamically and kinetically. However, 1a transfers H• to TEMPO smoothly, forming a stable Rh(II) radical Cp*Rh(2-(2-pyridyl)phenyl)• (14a) that can activate H2 at room temperature and 1 atm. The metalloradical 14a has a g value of 2.0704 and undergoes reversible one-electron reduction at -1.85 V vs Fc(+)/Fc in benzonitrile, implying a bond-dissociation enthalpy for the Rh-H bond of 1a of 58.2(3) kcal/mol--among the weakest Rh(III)-H bonds reported. The transfer of H• from 1a to Ar3C• (Ar = p-(t)BuC6H4) is fast, with kH• = 1.17(3) × 10(3) M(-1) s(-1). Thus, 1a is a good H(-) and H• donor but a poor H(+) donor, a combination that reflects the high energy of the Rh(I) anion [Cp*Rh(2-(2-pyridyl)phenyl)](-).

The reaction of cobaloximes with hydrogen: products and thermodynamics.

A cobalt hydride has been proposed as an intermediate in many reactions of the Co(dmgBF2)2L2 system, but its observation has proven difficult. We have observed the UV-vis spectra of Co(dmgBF2)2L2 (1) in CH3CN under hydrogen pressures of up to 70 atm. A Co(I) compound (6a) with an exchangeable proton is eventually formed. We have determined the bond dissociation free energy and pK(a) of the new O-H bond in 6a to be 50.5 kcal/mol and 13.4, respectively, in CH3CN, matching previous reports.

Effect of double-bond substituents on the rate of cyclization of α-carbomethoxyhex-5-enyl radicals.

Rate constants have been calculated, and compared with experimental results, for the cyclizations of 1-carbomethoxy-1-methyl-5-hexenyl radicals (2) with various substituents on C6. The calculations have been done by DFT at the B3LYP/6-311++G** level of theory. They show considerable interaction between C5 and the radical centers even in the ground state of all of the radicals 2. Experimentally, the radicals have been generated by H(•) transfer to the corresponding acrylate esters 1 and the yields of cyclized products compared to the calculated rate constants. (The "cyclized products" include those from cyclohydrogenation, 4, and those from cycloisomerization, 9.) Two phenyl substituents on C6 (2i), or a phenyl and a methyl substituent (2g, 2h), increase the rate of cyclization, but a single phenyl substituent on C6 produces a greater increase. The calculations show that the two phenyl substituents are twisted in the transition state for cyclization, while a single phenyl substituent remains flat in that transition state. A methyl substituent on C6 along with a single phenyl causes the phenyl to twist in the transition state and decreases the rate constant for cyclization below that of the H/Ph-substituted 2e, 2f.

Dihydrogen activation by cobaloximes with various axial ligands.

We have investigated the effect of axial ligands on the ability of cobaloximes to catalyze the generation of transferable hydrogen atoms from hydrogen gas and have learned that the active catalyst contains one and only one axial ligand. We have, for example, shown that Co(dmgBF2)2 coordinates only one Ph3P and that the addition of additional Ph3P (beyond 1 equiv) to solvated Co(dmgBF2)2 does not affect its catalytic turnover for H• transfer from H2.

Ti(III)-Catalyzed Anti-Markovnikov Reduction of Epoxides with Borohydride.

We have developed a Ti catalyst that carries out the anti-Markovnikov reduction of a wide range of epoxides; [BH4]- is used as both the electron and the hydrogen atom source. It requires only mild conditions and accommodates a broad range of epoxide substrates. The Ti catalyst is readily available and is environmentally friendly.

Electron transfer from hexameric copper hydrides.

The octahedral core of 84-electron LCuH hexamers does not dissociate appreciably in solution, although their hydride ligands undergo rapid intramolecular rearrangement. The single-electron transfer proposed as an initial step in the reaction of these hexamers with certain substrates has been observed by stopped-flow techniques when [(Ph3P)CuH]6 is treated with a pyridinium cation. The same radical cation has been prepared by the oxidation of [(Ph3P)CuH]6 with Cp*2Fe(+) and its reversible formation observed by cyclic voltammetry; its UV-vis spectrum has been confirmed by spectroelectrochemistry. The 48-electron trimer [(dppbz)CuH]3 has been prepared by use of the chelating ligand 1,2-bis(diphenylphosphino)benzene (dppbz).