Utilizing a needle as a source of iron in synergistic dual photoredox catalytic generation of alkoxy radicals.

A visible-light mediated alkoxy radical generation is described, which allows for a structurally divergent oxidative C(sp3)-H bond functionalization. This protocol employs a photoredox/iron dual catalysis allowing for an unprecedented chemoselective single-step transformation of alcohol derivatives giving access to two valuable sets of products, tetrahydrofurans and γ-bromoketones, under one set of conditions. Addition of iron, by slow corrosion of a needle, provides superior reaction efficiency as compared to various iron(III) complexes.

Catalytic Iodination of the Aliphatic C-F Bond by YbI3(THF)3: Mechanistic Insight and Synthetic Utility.

A facile iodination protocol of unactivated alkyl fluorides using catalytic amounts of YbI3(THF)3 in the presence of iodotrimethylsilane as a stoichiometric fluoride trapping agent is presented. (1)H NMR spectroscopy demonstrates a two-step catalytic cycle where TMSI regenerates active YbI3(THF)3. Finally, the catalytic reaction is extended into a one-pot procedure to demonstrate a potential application of the method. Overall, the findings present a distinct strategy for C-F bond transformations in the presence of catalytic YbI3(THF)3.

Mild and selective activation and substitution of strong aliphatic C-F bonds.

A procedure for chemoselectively manipulating the strong aliphatic C-F bond with direct transformation into a C-N bond under mild conditions is reported. The activation and subsequent substitution of primary alkyl fluorides is mediated by La[N(SiMe3)2]3, and results in high to excellent yields of tertiary amines. The methodology displays high selectivity towards the C(sp(3))-F bond, and a variety of secondary amines are applicable as nucleophiles. Mechanistic investigations reveal a reaction that is first order with respect to [La[N(SiMe3)2]3], [R(1)R(2)NH], and [alkyl fluoride], and a 6-membered cyclic transition state is proposed. In addition, (1)H NMR spectroscopy shows that La[N(SiMe3)2]3 is the active species involved in the substitution and that protonolysis of the amine, yielding La[NR(1)R(2)]3, lowers the reactivity.

Solvent-dependent substrate reduction by {Sm[N(SiMe3)2]2(THF)2}. An alternative approach for accelerating the rate of substrate reduction by Sm(II).

The impact of solvent on electron transfer from Sm(II) to substrates was measured by determining the rate of reduction of 1-bromo-, 1-chlorododecane, and 3-pentanone in THF and hexanes using the highly soluble reductant {Sm[N(SiMe3)2]2(THF)2}. Rates were found to be 3 orders of magnitude faster in hexanes than THF, and reductions of alkyl halides were inverse first order in THF. These findings show the solvent milieu significantly impacts the rate of substrate reduction, a consideration that may prove useful in synthesis.

Selective cleavage of 3,5-bis-(trifluoromethyl)benzylcarbamate by SmI2-Et3N-H2O.

A novel electron poor protection group for amines has been developed. It undergoes rapid cleavage by SmI2-Et3N-H2O and its orthogonality towards the regular benzyl carbamate group (CBz) under reductive or transfer hydrogenolytic conditions is reported.

Metalated nitriles: N- and C-coordination preferences of Li, Mg, and Cu cations.

(13)C NMR analyses of a series of metalated arylacetonitriles and cyclohexanecarbonitriles with the synthetically relevant metals Li, Mg, and Cu identifies the influence of the carbon scaffold and the nature of the metal on the preference for N- or C-metalation.

Solvent dependent reductive defluorination of aliphatic C-F bonds employing Sm(HMDS)2.

Sm(HMDS)(2) in n-hexane mediates fast cleavage of primary, secondary and tertiary alkyl fluorides in good to excellent yields. In n-hexane Sm(HMDS)(2) exhibits uniquely enhanced reductive ability towards the C-F bond compared to when using THF as solvent.

A computational study of the enantioselective addition of n-BuLi to benzaldehyde in the presence of a chiral lithium N,P amide.

In the presence of a chiral lithium N,P amide, alkylation of benzaldehyde results in an enantioselective formation of 1-phenyl-pentanol. This stereoselective addition reaction has herein been studied using dispersion-corrected density functional theory. For five different chiral ligands originating from amino acids the resulting enantioselectivity has been computationally determined and compared with experimentally available enantiomeric ratios (e.r.). In all cases the experimentally preferred enantiomer could be reproduced by the computational model. The selectivity trend among the ligands was found strongly sensitive to the amount of dispersion correction included. The origin of selectivity in the alkylation reaction is found to be composed of many combined interactions. For the most selective ligand 2A the most important factors found, which are favouring the (R)-TS, are a CH-π interaction between benzaldehyde-dimethyl ether (DME), stronger Li-solvation, and Li-π interactions with the phenyl ring in the backbone of the chiral lithium N,P amide. In addition, solvation by the bulk solvent and the size of the substituent on the nitrogen are also found important factors for the enantioselectivity.

Asymmetric deprotonation using s-BuLi or i-PrLi and chiral diamines in THF: the diamine matters.

The solution structures of [(6)Li]-i-PrLi complexed to (-)-sparteine and the (+)-sparteine surrogate in Et(2)O-d(10) and THF-d(8) at -80 °C have been determined using (6)Li and (13)C NMR spectroscopy. In Et(2)O, i-PrLi/(-)-sparteine is a solvent-complexed heterodimer, whereas i-PrLi/(+)-sparteine surrogate is a head-to-tail homodimer. In THF, there was no complexation of (-)-sparteine to i-PrLi until ≥3.0 equiv (-)-sparteine and with 6.0 equiv (-)-sparteine, a monomer was characterized. In contrast, the (+)-sparteine surrogate readily complexed to i-PrLi in THF, and with 1.0 equiv (+)-sparteine surrogate, complete formation of a monomer was observed. The NMR spectroscopic study suggested that it should be possible to carry out highly enantioselective asymmetric deprotonation reactions using i-PrLi or s-BuLi/(+)-sparteine surrogate in THF. Hence, three different asymmetric deprotonation reactions (lithiation-trapping of N-Boc pyrrolidine, an O-alkyl carbamate, and a phosphine borane) were investigated; it was shown that reactions with (-)-sparteine in THF proceeded with low enantioselectivity, whereas the corresponding reactions with the (+)-sparteine surrogate occurred with high enantioselectivity. These are the first examples of highly enantioselective asymmetric deprotonation reactions using organolithium/diamine complexes in THF.

Selective α-defluorination of polyfluorinated esters and amides using SmI2/Et3N/H2O.

SmI(2)/H(2)O promotes selective α-monodefluorinations, while addition of an amine results in complete α-defluorination reactions.

KHMDS enhanced SmI(2)-mediated reformatsky type alpha-cyanation.

A novel combination of SmI(2), KHMDS, and TsCN can be utilized to introduce a cyano group into structurally diverse and highly sensitive 2-alkyl-chroman-4-ones. Subsequent oxidation allows the formed 2-alkyl-3-cyanochromones to be isolated in yields ranging from 49 to 77%. In addition, alpha-bromoketones and esters were found to undergo equally effective alpha-cyanation.

Instantaneous deprotection of tosylamides and esters with SmI(2)/amine/water.

SmI(2)/amine/water mediates instantaneous cleavage of tosyl amides and tosyl esters. Highly hindered, sensitive and functionalized substrates were successfully deprotected in near quantitative yield.

Improved and efficient synthesis of chiral N,P-ligands via cyclic sulfamidates for asymmetric addition of butyllithium to benzaldehyde.

A robust and scaleable route to chiral 1-isopropylamino-2-(diphenylphosphino)ethanes is described via the ring-opening of chiral, cyclic sulfamidates with potassium diphenylphosphide (KPPh(2)). The novel protocol offers a robust access to gram quantities of chiral amino phosphinoethanes in high yields. The Li-amides of the chiral aminophosphines were evaluated as chiral ligands in the asymmetric addition of n-butyllithium (BuLi) to benzaldehyde, yielding 1-phenylpentanol up to 98% ee.

Correlation between the 6Li,15N coupling constant and the coordination number at lithium.

The 6Li,15N coupling constants of lithium amide dimers and their mixed complexes with n-butyllithium, formed from five different chiral amines derived from (S)-[15N]phenylalanine, were determined in diethyl ether (Et2O), tetrahydrofuran (THF) and toluene. Results of NMR spectroscopy studies of these complexes show a clear difference in 6Li,15N coupling constants between di-, tri- and tetracoordinated lithium atoms. The lithium amide dimers with a chelating ether group exhibit 6Li,15N coupling constants of approximately 3.8 and approximately 5.5 Hz for the tetracoordinated and tricoordinated lithium atoms, respectively. The lithium amide dimers with a chelating thioether group show distinctly larger 6Li,15N coupling constants of approximately 4.4 Hz for the tetracoordinated lithium atoms, and the tricoordinated lithium atoms have smaller 6Li,15N coupling constants, approximately 4.9 Hz, than their ether analogues. In diethyl ether and tetrahydrofuran, mixed dimeric complexes between the lithium amides and n-butyllithium are formed. The tetracoordinated lithium atoms of these complexes have 6Li,15N coupling constants of approximately 4.0 Hz, and the 6Li,15N coupling constants of the tricoordinated lithium atoms differ somewhat, depending on whether the chelating group is an ether or a thioether; approximately 5.1 and approximately 4.6 Hz, respectively. In toluene, mixed trimeric complexes are formed from two lithium amide moieties and one n-butyllithium. In these trimers, two lithium atoms are tricoordinated with 6Li,15N coupling constants of approximately 4.6 Hz and one lithium is dicoordinated with 6Li,15N coupling constants of approximately 6.5 Hz.

Estimating the limiting reducing power of SmI2/H2O/amine and YbI2/H2O/amine by efficient reduction of unsaturated hydrocarbons.

The mixture of samarium diiodide, amine, and water (SmI2/H2O/Et3N) is known to be a particularly powerful reductant, but until now the limiting reducing power has not been determined. A series of unsaturated hydrocarbons with varying half-wave reduction potentials (E(1/2) = -1.6 to -3.4 V, vs SCE) have been treated with SmI2/H2O/Et3N and YbI2/H2O/Et3N, respectively. All hydrocarbons with potentials of -2.8 V or more positive were readily reduced with SmI2/H2O/Et3N, whereas all hydrocarbons with potentials of -2.3 V or more positive were readily reduced using YbI2/H2O/Et3N. This defines limiting values of the chemical reducing power of SmI2/H2O/Et3N to -2.8 V and of YbI2/H2O/Et3N to -2.3 V vs SCE.

Kinetic and NMR spectroscopic studies of chiral mixed sodium/lithium amides used for the deprotonation of cyclohexene oxide.

The mixed-metal complex formed from n-butylsodium, n-butyllithium, and a chiral amino ether has been studied by NMR spectroscopy. Three different mixed-metal amides were used as chiral bases for the deprotonation of cyclohexene oxide. The selectivity and initial rate of reaction were compared for sodium-amido ethers, lithium-amido ethers, and mixtures of sodium and lithiumamido ethers in diethyl ether and tetrahydrofuran, respectively. The mixed sodium/lithium amides are more reactive than the single sodium and lithium amides, whereas the stereoselectivities are higher when lithium amides are used. The alkali-metal/gamma-amido ethers exhibit both higher initial reaction rates and stereoselectivities than their beta-amido ether analogues. NMR spectroscopic studies of mixtures of n-butylsodium (nBuNa), n-butyllithium (nBuLi), and the gamma-amino ethers in diethyl ether show the exclusive formation of dimeric mixed-metal amides. In diethyl ether, the lithium atom of the mixed-metal amide is internally coordinated and the sodium atom is exposed to solvent; however, in tetrahydrofuran, both metals are internally coordinated.

Mechanistic study of the SmI2/H2O/amine-mediated reduction of alkyl halides: amine base strength (pKBH+) dependent rate.

The kinetics of the SmI(2)/H(2)O/amine-mediated reduction of 1-chlorodecane has been studied in detail. The rate of reaction is first order in amine and 1-chlorodecane, second order in SmI(2), and zero order in H(2)O. Initial rate studies of more than 20 different amines show a correlation between the base strength (pK(BH+) of the amine and the logarithm of the observed initial rate, in agreement with Bronsted catalysis rate law. To obtain the activation parameters, the rate constant for the reduction was determined at different temperatures (0 to +40 degrees C, DeltaH++ = 32.4 +/- 0.8 kJ mol(-1), DeltaS++ = -148 +/- 1 J K(-1) mol(-1), and DeltaG++(298K) = 76.4 +/- 1.2 kJ mol(-1)). Additionally, the (13)C kinetic isotope effects (KIE) were determined for the reduction of 1-iododecane and 1-bromodecane. Primary (13)C KIEs (k(12)/k(13), 20 degrees C) of 1.037 +/- 0.007 and 1.062 +/- 0.015, respectively, were determined for these reductions. This shows that cleavage of the carbon-halide bond occurs in the rate-determining step. A mechanism of the SmI(2)/H(2)O/amine-mediated reduction of alkyl halides is proposed on the basis of these results.

Exploring SmBr2-, SmI2-, and YbI2-mediated reactions assisted by microwave irradiation.

The use of microwave heating in lanthanide(II) halide (LnX2 = SmBr2, SmI2, and YbI2) mediated reduction and coupling reactions has been investigated for a variety of functional groups including alpha,beta-unsaturated esters, aldehydes, ketones, imines, and alkyl halides. Good to quantitative transformations were obtained within a few minutes without the addition of any co-solvents, such as hexamethyl phosphoramide (HMPA). The redox potential of YbI2 in tetrahydrofuran (THF) has been determined as -1.02+/-0.05 V (versus Ag/AgNO3) by cyclic voltammetry. A large selectivity difference in various reactions was observed depending on the redox potential of the LnX2 reagent. The more powerful reductant, SmBr2, afforded mainly pinacol-coupling products of ketones whereas the weaker reductant YbI2 afforded mainly reduction products. The results indicate that the reducing power of LnX2 has a large impact on not only the pinacol coupling/reduction product ratio of ketones but also on other substrates in which there are competing coupling and reduction reactions. The use of in situ generated LnX2 has also been explored and proven useful in many of these reactions.

Reduction of beta-hydroxyketones by SmI2/H2O/Et3N.

Reduction of a series of beta-hydroxyketones by SmI2/H2O/Et3N provided 1,3-diols in quantitative yields. The reactions were exceedingly clean with no byproduct formation, negating the need for further purification. Most reactions provided moderate to excellent diastereoselectivity with syn-diols as the major isomer in most instances.