Lithium Amide Research Articles

Enantioselective Synthesis of Planar Chiral Ferrocene Triflones

AbstractA multi‐gram scale synthesis of ferrocenetriflone was optimised from ferrocenesulfonyl fluoride and Me3SiCF3 (Ruppert reagent). Enantioselective deprotolithiations were then optimised using alkyllithiums in the presence of catalytic (+)‐sparteine to afford 2‐substituted ferrocene triflones in 79–84% ee. The use of chiral lithium amides in the presence of in situ traps was also optimised and was found to outperform alkyllithium⋅chiral diamine chelates for the first time in the ferrocene series, with 89–93% ee. Crystallisation of derivatives afforded enantiopure compounds that were engaged in deprotolithiation‐electrophilic trapping sequences, a halogen ‘dance’ reaction and transition metal‐promoted coupling to afford a wide range of variously polysubstituted ferrocene triflones.

An N‐Heterocyclic Germylene and Stannylene with a 1,1’‐Ferrocenylene Backbone and Dimesitylboryl N‐Substituents

AbstractThe diaminoferrocene derivative fc[NH(BMes2)]2 (1H2; fc=1,1’‐ferrocenylene, Mes=mesityl) was prepared from fc(NH2)2 and Mes2BCl and used for the preparation of the N‐heterocyclic tetrylenes fc{[N(BMes2)]2E} (1E, E=Ge, Sn) via the sodium amide fc[NNa(BMes2)]2 (1Na2), which was obtained from 1H2 and NaN(SiMe3)2. 1H2 is inert towards LiN(SiMe3)2 or nBuLi. Its reaction with nBuLi in the presence of TMEDA afforded the TMEDA‐coordinated lithium amide 1Li2(TMEDA)2. Crystallisation of 1Na2 from THF furnished the adduct 1Na2(THF)3. The reaction of 1Na2 with Me3SiCl afforded 1(SiMe3)2. Attempts to obtain the thiourea fc{[N(BMes2)]2C=S} (1C=S) from 1Na2 and Cl2C=S were not successful. 1C=S is accessible from fc(NH3)Cl2, which is transformed to fc[(NH)2C=S] (2) by reaction with Cl2C=S and NEt3 (4 equiv.), followed by conversion of 2 to fc{[N(SiMe3)]2C=S} (3) with Me3SiCl and NEt3 (2 equiv.) and subsequent reaction of 3 with Mes2BCl. All new compounds except 1Na2 and 2 were structurally characterised by single‐crystal X‐ray diffraction. The N‐boryl substituents of 1E compete efficiently with the EII atom for nitrogen π‐donation, causing comparatively long EII−N bonds and small EII bond angles. 1C=S contains a four‐membered BNCS ring due to intramolecular adduct formation involving the Lewis basic S atom and a Lewis acidic B atom.

Regioselective α-Phosphonylation of Unprotected Alicyclic Amines.

Unprotected alicyclic amines undergo α-C-H bond phosphonylation via a two-stage one-pot process involving the oxidation of amine-derived lithium amides with simple ketone oxidants, generating transient imines which are then captured with phosphites or phosphine oxides. Amines with an existing α-substituent undergo regioselective α'-phosphonylation. Amine α-arylation and α'-phosphonylation can be combined, generating a difunctionalized product in a single operation.

A Rationally Designed Iron(II) Catalyst for C(sp3)−C(sp2) and C(sp3)−C(sp3) Suzuki–Miyaura Cross‐Coupling

AbstractDespite the paramount importance of the Suzuki–Miyaura coupling (SMC) in academia and industry, and the great promise of iron to offer sustainable catalysis, iron‐catalyzed SMC involving sp3‐hybridized partners is still in its infancy. We herein report the development of a versatile, well‐defined electron‐deficient anilido‐aldimine iron(II) catalyst. This catalyst effectively performed C(sp3)−C(sp2) and C(sp3)−C(sp3) SMC of alkyl halide electrophiles and (hetero)aryl boronic ester and alkyl borane nucleophiles respectively, in the presence of a lithium amide base. These couplings operated under mild reaction conditions and displayed wide functional group compatibility including various medicinally relevant N‐, O‐ and S‐based heterocycles. They also tolerated primary, secondary and tertiary alkyl halides (Br, Cl, I), electron‐neutral, ‐rich and ‐poor boronic esters and primary and secondary alkyl boranes. Our methodology could be directly and efficiently applied to synthesize key intermediates relevant to pharmaceuticals and a potential drug candidate. For C(sp3)−C(sp2) couplings, radical probe experiments militated in favor of a carbon‐centered radical derived from the electrophile. At the same time, reactions run with a pre‐formed activated boron nucleophile coupled to competition experiments supported the involvement of neutral, rather than an anionic, (hetero)aryl boronic ester in the key transmetalation step.

A Rationally Designed Iron(II) Catalyst for C(sp3)-C(sp2) and C(sp3)-C(sp3) Suzuki-Miyaura Cross-Coupling.

Despite the paramount importance of the Suzuki-Miyaura coupling (SMC) in academia and industry, and the great promise of iron to offer sustainable catalysis, iron-catalyzed SMC involving sp3-hybridized partners is still in its infancy. We herein report the development of a versatile, well-defined electron-deficient anilido-aldimine iron(II) catalyst. This catalyst effectively performed C(sp3)-C(sp2) and C(sp3)-C(sp3) SMC of alkyl halide electrophiles and (hetero)aryl boronic ester and alkyl borane nucleophiles respectively, in the presence of a lithium amide base. These couplings operated under mild reaction conditions and displayed wide functional group compatibility including various medicinally relevant N-, O- and S-based heterocycles. They also tolerated primary, secondary and tertiary alkyl halides (Br, Cl, I), electron-neutral, -rich and -poor boronic esters and primary and secondary alkyl boranes. Our methodology could be directly and efficiently applied to synthesize key intermediates relevant to pharmaceuticals and a potential drug candidate. For C(sp3)-C(sp2) couplings, radical probe experiments militated in favor of a carbon-centered radical derived from the electrophile. At the same time, reactions run with a pre-formed activated boron nucleophile coupled to competition experiments supported the involvement of neutral, rather than an anionic, (hetero)aryl boronic ester in the key transmetalation step.

Development of Sterically Hindered and Basic Sodium Amides for Catalytic Hydrogen Isotope Exchange

AbstractSodium amides are gaining momentum in synthetic chemistry, emerging not only as more sustainable alternatives to lithium amides but also as superior reagents in synthesis and catalysis. Despite recent advances in sodium organometallics, the information available about the constitution of these reagents is very limited. Advancing the understanding on structure/reactivity correlations in sodium amide chemistry, here, we report the synthesis and characterisation of four new sodium amides, with different sterically demanding substituents (adamantyl/trimethylsilyl and dicyclohexyl groups at the nitrogen atom) and different polyamine donors as well as investigate their ability to promote catalytic hydrogen isotope exchange using deuterated benzene as deuterium source. These studies have revealed that sodium dicyclohexylamide in combination with PMDETA (N,N,N’,N’’,N’’‐pentamethyldiethylentriamine) offers only slightly lower deuterium incorporation for non‐activated arenes than sodium 2,2,6,6‐tetramethylpiperidide, which is significantly more expensive and less available.

Behavior of Lithium Amide Under Argon Plasma.

Alkali and alkaline earth metal amides are a type of functional materials for hydrogen storage, thermal energy storage, ion conduction, and chemical transformations such as ammonia synthesis and decomposition. The thermal chemistry of lithium amide (LiNH2), as a simple but representative alkali or alkaline earth metal amide, has been well studied previously encouraged by its potentials in hydrogen storage. In comparison, little is known about the interaction of plasma and LiNH2. Herein, we report that the plasma treatment of LiNH2 in an Ar flow under ambient temperature and pressure gives rise to distinctly different reaction products and reaction pathway from that of the thermal process. We found that plasma treatment of LiNH2 leads to the formation of Li colloids, N2, and H2 as observed by UV-vis absorption, EPR, and gas products analysis. Inspired by this very unique interaction between plasma and LiNH2, a chemical loop for ammonia decomposition to N2 and H2 mediated by LiNH2 was proposed and demonstrated.

Benzo‐fused Nitrogen Heterocycles by Asymmetric Ring Expansion and Stereochemically Retentive Re‐contraction of Cyclic Ureas

AbstractBenzo‐fused nitrogen heterocycles are common features of bioactive molecules, and the enantioselective synthesis of their substituted analogues is an important goal. In this paper we demonstrate a practical and mechanistically intriguing approach to the enantioselective synthesis of 1‐arylbenzazepines and their analogues. The reaction sequence starts with an asymmetric migratory ring expansion of indoline, tetrahydroquinoline, or tetrahydrobenzazepine ureas on treatment with a chiral lithium amide base. Treatment of the ring‐expanded ureas with acid triggers a two‐atom ring contraction—an ‘azatropic shift’ in which one urea nitrogen displaces the other—with almost complete retention of stereochemistry. Aminolysis of the urea products provides enantioenriched 1‐aryl‐tetrahydrobenzazepine derivatives and their congeners, including an analogue of an intermediate in the synthesis of the drug solifenacin. Deuteration, in situ IR, and DFT studies provide evidence for the mechanisms of the reaction steps.

Benzo-fused Nitrogen Heterocycles by Asymmetric Ring Expansion and Stereochemically Retentive Re-contraction of Cyclic Ureas.

Benzo-fused nitrogen heterocycles are common features of bioactive molecules, and the enantioselective synthesis of their substituted analogues is an important goal. In this paper we demonstrate a practical and mechanistically intriguing approach to the enantioselective synthesis of 1-arylbenzazepines and their analogues. The reaction sequence starts with an asymmetric migratory ring expansion of indoline, tetrahydroquinoline, or tetrahydrobenzazepine ureas on treatment with a chiral lithium amide base. Treatment of the ring-expanded ureas with acid triggers a two-atom ring contraction-an 'azatropic shift' in which one urea nitrogen displaces the other-with almost complete retention of stereochemistry. Aminolysis of the urea products provides enantioenriched 1-aryl-tetrahydrobenzazepine derivatives and their congeners, including an analogue of an intermediate in the synthesis of the drug solifenacin. Deuteration, in situ IR, and DFT studies provide evidence for the mechanisms of the reaction steps.

Chiral Lithium Amide Improves Stereoselectivity and Yield of Tuberculosis Drug Bedaquiline

Chiral Lithium Amide Improves Stereoselectivity and Yield of Tuberculosis Drug Bedaquiline

BN-Embedded Aromatic Hydrocarbon Synthesis via Nucleophilic Diboration Reactions.

Activation of bis(pinacolato)diboron with aromatic lithium amide promotes diboration of the proximal C-C triple bond, leading to BN-embedded aromatic compounds. In situ treatment of the initially generated spirocyclic borate intermediate with aqueous acid or organometallic reagents enables ligand installation on the endocyclic boron atom.

Application of Chiral Transfer Reagents to Improve Stereoselectivity and Yields in the Synthesis of the Antituberculosis Drug Bedaquiline.

Bedaquiline (BDQ) is an important drug for treating multidrug-resistant tuberculosis (MDR-TB), a worldwide disease that causes more than 1.6 million deaths yearly. The current synthetic strategy adopted by the manufacturers to assemble this molecule relies on a nucleophilic addition reaction of a quinoline fragment to a ketone, but it suffers from low conversion and no stereoselectivity, which subsequently increases the cost of manufacturing BDQ. The Medicines for All Institute (M4ALL) has developed a new reaction methodology to this process that not only allows high conversion of starting materials but also results in good diastereo- and enantioselectivity toward the desired BDQ stereoisomer. A variety of chiral lithium amides derived from amino acids were studied, and it was found that lithium (R)-2-(methoxymethyl)pyrrolidide, obtained from d-proline, results in high assay yield of the desired syn-diastereomer pair (82%) and with considerable stereocontrol (d.r. = 13.6:1, e.r. = 3.6:1, 56% ee), providing BDQ in up to a 64% assay yield before purification steps toward the final API. This represents a considerable improvement in the BDQ yield compared to previously reported conditions and could be critical to further lowering the cost of this life-saving drug.

Enhancement of the Catalytic Activity of Lithium Amide towards Ammonia Decomposition by Addition of Transition Metals

The catalytic decomposition of ammonia to hydrogen is a vital process in the use of ammonia as a zero-carbon energy store. However, the viability of current catalyst systems in terms of operating conditions, versatility, and cost efficiency has proven an issue. Catalytic and gravimetric studies were conducted considering mechanistic uncertainty surrounding the enhanced catalytic activity reported for lithium amide and imide composited with transition metals (Cr, Mn, Fe). Gas flow in excess of ammonia decomposition was quantified and used to differentiate the extent of formation of non-stoichiometric lithium imide amide from other competing processes. This analysis showed the initial compositional transition from lithium amide to an imide-rich phase was reduced in temperature by compositing with Mn and Cr, but not with Fe. The system is, therefore, best considered as promoted lithium imide, with Cr and Mn acting to reduce the formation temperature of the active imide-rich phase such that the catalytic activity is enhanced.

Synthesis, structure, and reactivity of the ferrocene-based N-heterocyclic stannylene [Fe{(η 5-C5H4)NC6H3-2,6-iPr2}2Sn

Abstract The N-heterocyclic stannylene [Fe{(η 5-C5H4)NC6H3-2,6-iPr2}2Sn] (1) has been synthesised from SnCl2 and the lithium amide [Fe{(η 5-C5H4)NC6H3-2,6-iPr2}2Li2]. Compound 1 is inert towards H2, CO, CO2, and MeI under ambient conditions. Immediate hydrolysis and ammonolysis was observed with H2O and NH3, respectively. While oxidation reactions of 1 with chalcogens (O2, S8, Se8) afforded only intractable material, the reaction with Ph2Se2 cleanly furnished [Fe{(η 5-C5H4)NC6H3-2,6-iPr2}2Sn(SePh)2] (2). Compounds 1 and 2 have been structurally characterised by single-crystal X-ray diffraction. Compound 2 exhibits an intramolecular CH⋯Se contact compatible with a weak hydrogen bond.

Enantioselective [2,3]-Wittig Rearrangement of Carboxylic Acid Derived Enolates by Tetradentate Chiral Lithium Amide

AbstractA chiral lithium amide mediated enantioselective [2,3]-Wittig rearrangement of carboxylic acid enolate has been developed. The reaction proceeds through the formation of a chiral mixed aggregate that shields one enantioface of enolate anion to give a highly functionalized chiral α-hydroxycarboxylic acid.

Enantioselective Intramolecular α‐Arylation of Benzylamine Derivatives: Synthesis of a Precursor to Levocetirizine

AbstractA practical, transition metal‐free method allows the enantioselective synthesis of α,α‐diarylmethylamines by asymmetric α‐arylation of benzylamines. Enantioselective lithiation of N′‐aryl‐N‐benzyl‐N‐isopropyl ureas using a chiral lithium amide base generates a benzyllithium that undergoes an unactivated stereospecific intramolecular nucleophilic aromatic substitution to generate an α,α‐diarylmethylamine in the form of its urea derivative, in up to >99 % ee. Treatment with acid induces an “azatropic shift” with retention of configuration, the product of which may be hydrolysed to the target amine.

Enantioselective Intramolecular α-Arylation of Benzylamine Derivatives: Synthesis of a Precursor to Levocetirizine.

A practical, transition metal-free method allows the enantioselective synthesis of α,α-diarylmethylamines by asymmetric α-arylation of benzylamines. Enantioselective lithiation of N'-aryl-N-benzyl-N-isopropyl ureas using a chiral lithium amide base generates a benzyllithium that undergoes an unactivated stereospecific intramolecular nucleophilic aromatic substitution to generate an α,α-diarylmethylamine in the form of its urea derivative, in up to >99 % ee. Treatment with acid induces an "azatropic shift" with retention of configuration, the product of which may be hydrolysed to the target amine.

Structural characterization of the 1-metallo-2-t-butyl-1,2-dihydropyridyl rubidium and caesium complexes

With recent reports of alkali metal amides used in homogeneous catalytic chemistry where the reactivity down group one is dependent on the metal identity, esoteric rubidium and caesium amides are finding new admirers amongst chemists who usually study lithium, sodium, and potassium utility amides. Here, as a forerunner to their exploitation in catalysis, we report the X-ray crystallographic and NMR solution structures of the 1-metallo-2-t-butyl-1,2-dihydropyridyl (DHP) complexes of rubidium and caesium, thereby completing the homologous alkali metal series. Crystallized as monosolvated {[Rb(tBuDHP)·THF]2}∞ and hemisolvated {[Cs(tBuDHP)]2·THF}∞, both form spectacular supramolecular structures. While each shares a plethora of metallo-π-contacts with the DHP anion, their subunits differ. The former dimerizes in a ‘slipped’ fashion via interactions between the symmetrically-equivalent Rb centres and the π-system of the adjacent DHP ring, but the latter has distinct Cs centres within its dinuclear subunit, with one Cs engaging in σ-bonding to two tBuDHP anions, whereas the other Cs binds in a more side-on fashion to the π-system of the ring.

(S)-N1,N3-Dibenzyl-1-cyclohexyl-N1,N3-bis((R)-1-phenylethyl)propane-1,3-diamine

(S)-N1,N3-dibenzyl-1-cyclohexyl-N1,N3-bis((R)-1-phenylethyl)propane-1,3-diamine was prepared in good yield by the reduction of the corresponding amide, which was obtained by the addition of a chiral lithium amide to an α,β-unsaturated ester. The target compound was fully characterized by NMR (1H and 13C), high-resolution mass spectrometry and polarimetry.

Density functional theory on reaction mechanism between p-doped LiNH<sub>2</sub> clusters and LiH and a new hydrogen storage and desorption mechanism

Hydrogen energy is considered a clean energy with great development prospects. In the field of hydrogen energy applications, the solid-state chemical hydrogen storage method using hydrogen storage materials as media has received widespread attention due to its safety and high hydrogen storage density. In the research on metal-N-H system hydrogen storage materials, current studies focus on improving the kinetic conditions for hydrogen storage. In this study, the B3LYP hybrid functional method of density functional theory is used to investigate the reaction mechanism between P-doped LiNH<sub>2</sub> clusters and LiH at a cluster level, and explore the effects of doping, in addition a new hydrogen storage mechanism called “secondary hydrogen transfer” is proposed. The full-geometry optimization of (LiNH<sub>2</sub>)<sub><i>n</i></sub> (<i>n</i> = 1–4) clusters and their P-doped clusters at the 6-31G(d,p) basis set level are carried out, and their corresponding most stable configurations are obtained. The distribution and stability of the frontier orbitals of the relevant reactants are calculated. Using the same method and basis set, the theoretical calculation and analysis of the reaction mechanism between P-doped (LiNH<sub>2</sub>)<sub><i>n</i></sub> (<i>n</i> = 1–4) clusters and LiH are conducted, including the configuration optimization of the stationary points in each reaction path, and the correctness of the connection between the stationary points is determined through frequency and intrinsic reaction coordinate calculations. The results show that P doping has a small effect on the lowest unoccupied molecular orbital, while the highest occupied molecular orbital has a significant transition towards the doping atom, and the electron-deficient region is concentrated at the P atom. P doping reduces the stability of the lithium amide clusters and enhances their ability to participate in chemical reactions and reaction activity, and the reaction dehydrogenation energy barrier decreases. The reaction dehydrogenation energy barrier between P-doped LiNH<sub>2</sub> clusters and LiH is significantly lower than that between LiNH<sub>2</sub> and LiH, which is consistent with the analysis of reactant stability. Additionally, it is found that the reaction between P-doped LiNH<sub>2</sub> clusters and LiH tends to dehydrogenate through the —PH<sub>2</sub> functional group and store hydrogen at the —NH<sub>2</sub> functional group. Therefore, a new idea of “secondary hydrogen transfer” is proposed, in which effective transfer of hydrogen between —NH<sub>2</sub> and —PH<sub>2</sub> functional groups takes place during the cyclic hydrogen storage process, thus the reversibility of hydrogen storage is further improved and the hydrogen desorption energy barrier of the material is reduced.