[4 + 1]- and [4 + 2]-cycloadditions of a thiazole-2-thione-based 1,4-diphosphinine - broadening the scope.

A broad study on [4 + 1]- and [4 + 2]-cycloaddition reactions of a thiazole-2-thione-based 1,4-diphosphinine (1) is reported, with a special focus on reversible reactions. Reactions of 1 with group 13 carbenoids NacNacM (M = Al and Ga) afford [4 + 1] adducts that can be classified as Al and Ga phosphides or as 7-metalla-1,4-norbornadienes. Reactions of 1 with alkynes and alkenes result in [4 + 2]-cycloaddition, affording 1,4-diphosphabarrelenes.

Nalbuphine Potentiates Reversal of Fentanyl Overdose by Naloxone.

Developing an effective antidote for fentanyl-induced overdose to achieve timely reversal is an unmet public health need. Previously, we found that naloxone derivative NX90 with mild κ-opioid agonistic properties was three-fold more effective than the parent naloxone in reversing a fentanyl overdose in rats. To investigate whether κ-agonistic properties could indeed augment the robustness of overdose reversal, we evaluated a κ-agonist/µ-antagonist nalbuphine (NB) as well as its combinations with naloxone (NX) in a fentanyl overdose model in rodents.

Reversible Coupling of Germylone with Isocyanates.

The germylone dimNHCGe (5, dimNHC=diimino N-heterocyclic carbene) undergoes a [2+2] cycloaddition with isocyanates RNCO (R=4-tolyl or 3,5-xylyl) to furnish novel alkyl carboxamido germylenes 7 (R=4-tolyl) and 8 (R=3,5-xylyl), featuring a C-C bond between the former carbene carbon and the isocyanate moiety. Heating a mixture of 8 with 4-tolyl isocyanate to 100 °C results in isocyanate metathesis, demonstrating reversible C-C bond formation on the reduced germanium compound. DFT calculations suggest that this process occurs via the reductive dissociation of isocyanate from 8 that regenerates the parent Ge(0) compound 5.

1,3-C-H bond activation on a transient gallium(I)/isocyanate adduct.

Reaction of NacNacGa with phenylisocyante generates a transient species amenable to unusual 1,3-C-H bond addition of unactivated sp C-H and sp C-H bonds of substrates featuring a hard donor atom. This reaction proceeds for pyridine oxide, dimethylsulfoxide, and dimethylacetamide, but not for pyridine, cyclohexanone, and ethyl acetate. C-H activation was also not observed for reactions with triethylphosphine oxide but, interestingly, in the presence of this compound isocyanate undergoes self-coupling on Ga(I) with a regioselectivity that is different when carried out in the absence of EtPO.

Germanium Analogue of the Parent Phosphine-Borane FLP Compound.

Diimino-carbene-supported germylone dimNHCGe does not react with BPh and does not activate dihydrogen in the FLP mode in the combination with this borane. However, it reacts with B(C F ) to give the zwitterionic borate dimNHCGe-(C F )BF(C F ) . This compound can be converted into the hydroborate dimNHCGe-(C F )BH(C F ) (8) and further into [dimNHCGe-(C F )B(C F ) ] (4).

A Guanidine-Supported π-Complex of Germanium Amenable to Intramolecular C-C Cleavage in Arene and Ge Atom Transfer.

The germylone dimNHCGe (dimNHC=diimino N-heterocyclic carbene) reacts with azides N R (R=SiMe or p-tolyl) to furnish the first examples of germanium π-complexes, i. e. guanidine-ligated compounds (dimNHI-SiMe )Ge (NHI=N-heterocyclic imine, R=SiMe ) and (dimNHI-Tol)Ge (R=p-tolyl).

Base-Stabilized Phosphinidene Oxide, Imide and Sulfide.

Oxidation of a base-stabilized phosphinidene (κ -NNP)P (12, NNP=phosphinoamidinate) with N O afforded a labile phosphinidene oxide (κ -NNP)P=O (16) which was characterized by NMR spectroscopy. Further oxidation of 16 by N O or reaction of 12 with two equivalents of pyridine oxide afforded the isolable dioxide (κ -NNP)PO which was characterized by NMR and SC XRD. Trapping of 16 with tolyl isocyanate resulted in P=O/N=C metathesis, eventually affording a urea-ligated phosphine (κ -NNP)P(NTol) C=O (17) The mechanism of this reaction was elucidated by DFT calculations.

Small Molecule Activation on a Base-stabilized Phosphinidene.

Reduction of (NP)PCl (NP=phosphinoamidinate [PhC(NAr)(=NPPr )] ) with KC affords the phosphinoamidinato-supported phosphinidene (NP)P (9). Reaction of 9 with a N-heterocyclic carbene (MeC(NMe)) C: results in the NHC-adduct NHC→P-P(Pr )=NC(Ph)=NAr featuring an iminophosphinyl group. Reactions of 9 with HBpin and H SiPh led to the metathesis products (NP)Bpin and (NP)SiH Ph, respectively, whereas with HPPh a base-stabilized phosphido-phosphinidene, the product of N-P and H-P bond metathesis, was obtained.

The Insertion of E and E Chlorides (E=Si, Ge) into the Si-Si Bond of Disilylene.

Reactions of silicon and germanium dichlorides L⋅ECl (E=Si, L=IPr; E=Ge, L=dioxane) with the phosphinoamidinato-supported disilylene ({κ (N,P)-NNP}Si) resulted in formal tetrylene insertions into the Si-Si bond. In the case of the reaction with silylene, two products were isolated. The first product ({κ (N,P)-NNP}Si) SiCl , is the formal product of direct SiCl insertion into the Si-Si bond of ({κ (N,P)-NNP}Si) and thus features two separated silylamido silylene centers.

Facile C-H bond activation on a transient gallium imide.

Reaction of NacNacGa with azide NSiMe results in the generation of a transient imide NacNacGa(NSiMe) that can cleave unactivated sp C-H and sp C-H bonds of different substrates, affording gallium amides. Pyridine, cyclohexanone, ethyl acetate, DMSO, and triethylphosphine oxide were activated in this process producing corresponding gallium amides. All new compounds were characterised by multinuclear NMR and X-ray diffraction.

Modifying naloxone to reverse fentanyl-induced overdose.

Developing an effective antidote for fentanyl-induced overdose (OD) is an unmet medical need that requires both lipophilicity comparable to fentanyl and fast onset of overdose reversal. We synthesized and evaluated a bioreversible derivative of naloxone (NX-90) in silico, in vitro and in vivo to yield a robust reversal of fentanyl-induced OD in rats. All monitored reflexes along with the heart rate (HR) and respiratory rate (RR) were fully restored faster in the NX-90 groups than in naloxone groups on equimolar bases when given intranasally.

An Isolable Gallium-Substituted Nitrilimine and its Reactivity with B-H, Si-H and B-B Bonds.

Reaction of the Ga(I) compound NacNacGa (9) with the diazo compound N CHSiMe affords the nitrilimine compound NacNacGa(N-NCSiMe )(CH SiMe ) (10). Carrying out this reaction in the presence of pyridine does not lead to C-H activation on the transient alkylidene NacNacGa=CHSiMe but generates a metallated diazo species NacNacGa(NHN=CHSiMe )(CN SiMe ) (13) that further rearranges into the isonitrile compound NacNacGa(NHN=CHSiMe )(N(NC)SiMe ) (15). Reactions of 10 with the silane H SiPh and the borane HBcat furnished products of 1,3 addition to the nitrilimine moiety NacNacGa{N(ER )NCSiMe }(CH SiMe ), whereas reaction with the diborane B cat gave the product of formal nitrene insertion into the B-B bond.

Generation and reactivity of an elusive base-stabilised phosphinidene.

Reduction of phosphorus dichloride 6, supported by the diaryloxyphenyl group (OCO) featuring two bulky phenoxy wingtips, by PMe, generates a reactive intermediate that behaves as a base-stabilized phosphinidene (OCO)P (5). Warming up a solution of this species in toluene to room temperature results in trimerization to give the isolable cyclic triphosphine [(OCO)P], whereas trapping with 2,3-dimethylbutadiene-1,3 afforded a 3,4-dimethylphospholene-3. Investigation of the reduction of 6 by the phosphine PMe by NMR led to the observation of a persistent species between -10 °C and 10 °C.

Reactivity of a Phosphinoamidinate-Stabilized Disilylene toward H-X Bonds.

An efficient method for the preparation of a phosphinoamidinate-supported disilylene was developed, and its reactivity toward H-E bonds (E = elements from Groups 13-15) was studied. With HBpin, transfer of the ligand from silicon to boron was observed to afford (NP)Bpin. Reaction with a silane (HSiPh) took place only at elevated temperatures, at which point oxidative addition of the N-P bond of the NP-ligand to one of the silicon atoms of the disilylene occurred prior to Si-H addition involving the remaining silylene center.

NB-33, a bioreversible opioid derivative of Nalbuphine, shows enhanced pharmacodynamics.

Developing non-addictive and safer opioids for pain management is unmet medical need. Among a number of bioreversible derivatives of Nalbuphine - an equipotent to morphine opioid without serious side effects - NB-33 was identified in silico and confirmed in vivo as a superior analgesic agent. Apart from enhanced pharmacodynamics profile, NB-33 outperformed the parent compound on equimolar bases in cold ethanol tail-flick and mechanical models of pain in rats.

Selective Cross-Coupling of Unsaturated Substrates on Al.

The Al compound NacNacAl (1, NacNac = [ArNC(Me)CHC(Me)NAr] , Ar = 2,6-iPr C H ) serves as a template for the chemoselective coupling between carbonyls (benzophenone, fenchone, isophorone, p-tolyl benzoate, N,N-dimethylbenzamide, (1-phenylethylidene)aniline) and pyridine. With the CH-acidic ketone (1R)-(+) camphor, the reaction affords a hydrido alkoxide compound of Al, formed as the result of enolization, whereas an enolizable imine, (1-phenylethylidene)aniline, and the bulky ketone isophorone, still chemoselectively couple with pyridine. In contrast, reaction with the ester p-tolyl benzoate results in cleavage of the ester bond together with replacement of the alkoxy group by a hydrogen atom of the pyridine moiety.

Shedding Light on the Diverse Reactivity of NacNacAl with N-Heterocycles.

The aluminum(I) compound NacNacAl (NacNac=[ArNC(Me)CHC(Me)NAr] , Ar=2,6-iPr C H , 1) shows diverse and substrate-controlled reactivity in reactions with N-heterocycles. 4-Dimethylaminopyridine (DMAP), a basic substrate in which the 4-position is blocked, induces rearrangement of NacNacAl by shifting a hydrogen atom from the methyl group of the NacNac backbone to the aluminum center. In contrast, C-H activation of the methyl group of 4-picoline takes place to produce a species with a reactive terminal methylene.

Ge(0) Compound Stabilized by a Diimino-Carbene Ligand: Synthesis and Ambiphilic Reactivity.

The germylone dimNHCGe (, dimNHC = diimino N-heterocyclic carbene) was successfully prepared via the reduction of the germanium cation [dimNHCGeCl] with KC. The molecular structure of was unambiguously established by both NMR spectroscopy and single-crystal X-ray diffraction. The reactivity of was investigated, revealing that it undergoes oxidative addition of HCl, CHI, and PhI, accompanied by an unusual migration of the H, Me, and Ph groups from germanium to the carbene ligand.

Sequential Oxidation and C-H Bond Activation at a Gallium(I) Center.

In situ oxidation of the Ga compound NacNacGa by either N O or pyridine oxide results in the generation of a labile monomeric oxide, NacNacGa(O), which can easily cleave the C-H bonds of aliphatic and aromatic substrates featuring good donor sites. The products of this reaction are gallium organyl hydroxides. DFT calculations show that these reactions start with the formation of NacNac-Ga(O)(L) adducts, the oxo ligand of which can easily abstract protons from nearby C-H bonds, even for sp -hybridized carbon centers.

Adduct of NacNacAl with Benzophenone and Its Coupling Chemistry.

Reaction of NacNacAl (NacNac=[DippNC(Me)CHC(Me)NDipp] ) with one equivalent of benzophenone affords a ketylate species NacNacAl(η (C,O)-OCPh ) that undergoes easy cyclization reactions with unsaturated substrates. The scope of substrates included benzophenone, aldimine (PhNC(Ph)H), quinoline, phenyl nitrile, trimethylsilyl azide, and a saturated cyclic thiourea. The latter substrate reacted by an unusual C-N cleavage that left the C=S functionality intact.

Ligand Effect in Alkali-Metal-Catalyzed Transfer Hydrogenation of Ketones.

This work unveils the reactivity patterns, as well as ligand and additive effect on alkali-metal-base-catalyzed transfer hydrogenation of ketones. Crucially to this reactivity is the presence of a Lewis acid (alkali cation), as opposed to a simple base effect. With aryl ketones, the observed reactivity order is Na >Li >K , whereas for aliphatic substrates it follows the expected Lewis acidity, Li >Na >K .

Interaction of Multiple Bonds with NacNacGa: Oxidative Cleavage vs Coupling and Cyclization.

The reactivity of the gallium(I) compound NacNacGa (4) to a variety of unsaturated compounds has been studied. Whereas 4 proved surprisingly unreactive toward olefins, ketones, guanidines, and thioureas, it reacts with isocyanates and carbodiimides to furnish the products of coupling of two heterocumulenes. With isothiocyanate, the C═S cleavage occurs, leading to the dimer (NacNacGa)(μ-S)(μ-CNPh) and the cyclization product NacNacGa(SC═NPh).

7-Metalla-1,4-diphosphanorbornadienes: cycloaddition of monovalent group 13 NacNac complexes to a stable 1,4-diphosphinine.

This work presents the first example of a dienophilic property of the monovalent group-13 NacNac complexes, which are well-known for their carbene-like reactivity, e.g., addition to multiple bonds, insertion into single bonds, and oxidative cleavage of some multiple bonds.

Imino-stabilised phosphinidene (or azaphosphole?) and some of its derivatives.

Diiminophenyl (dimph) proved to be an excellent ligand platform to stabilise a low-valent phosphorus centre. The resultant compound dimphP (3), which can be rationalized as an imino-stabilised phosphinidene or benzoazaphosphole, shows remarkable chemical stability: it withstands treatment with water and oxidizers (O2 and pyridine oxide) and only reacts with excess strong acid (e.g.

Oxidative Addition and Reductive Elimination at Main-Group Element Centers.

Oxidative addition and reductive elimination are key steps in a wide variety of catalytic reactions mediated by transition-metal complexes. Historically, this reactivity has been considered to be the exclusive domain of d-block elements. However, this paradigm has changed in recent years with the demonstration of transition-metal-like reactivity by main-group compounds.