Mechanochemical Synthesis of Silylcyclopentenes via Ball Milling.

The development of innovative methods for synthesizing silylcyclopentene compounds is particularly important for enriching and improving the synthetical toolbox of organosilicon compounds. Herein, a facile approach has been developed for the synthesis of silylcyclopentenes promoted by mechanochemically generated organolithium species as silicon nucleophiles under ball milling conditions, avoiding the requirement of large amounts of bulk solvent. This operationally simple method demonstrates good functional group compatibility, which provides a great opportunity for further exploration of the synthetic applications of silylcyclopentenes. Density functional theory calculations indicated that the transient lithiosilole intermediates undergo a stepwise nucleophilic addition process, which governs this mechanic-force-promoted [4+1] cycloaddition reaction.

Mechanistic Insights into the Metal-Free Deoxygenative Borylation of Ketones and Aldehydes with Bis(catecholato)diborane.

The mechanisms of direct deoxygenative borylation of acetone and benzaldehyde with bis(catecholato)diborane (B2 cat2 ) in the solvent N,N-dimethylacetamide (DMA) are investigated through detailed density functional theory calculations. These calculations show that the isomer 1,2-B2 cat2 in situ generated from 1,1-B2 cat2 induced by DMA is the reactive boron intermediate for the reactions. The addition of the B-B bond of 1,2-B2 cat2 to the C=O bond of acetone or benzaldehyde via a concerted [2σ+2π]-cycloaddition-like transition state is the rate-limiting step for both the triboration reaction of acetone and the monoboration reaction of benzaldehyde. DMA not only acts as the solvent but also promotes the structural isomerization of B2 cat2 , the deoxygenation of acetone to form the vinyl boronate intermediate and subsequent diboration of vinyl boronate with 1,2-B2 cat2 , as well as the protodeboronation of the gem-diboronate intermediate in the deoxygenative borylation of benzaldehyde. The presented computational results can explain the observed experimental facts and provide insight into the roles of the isomeric 1,2-B2 cat2 and the solvent DMA in related reactions.

Combined molecular dynamics and coordinate driving method for automatically searching complicated reaction pathways.

The combined molecular dynamics and coordinate driving (MD/CD) method is updated and generalized in this work to broaden its applications in automatically searching reaction pathways for complicated reactions. In this updated version, MD simulations are performed with the GFN's family of methods to systematically sample conformers for almost any systems with atomic numbers Z ≤ 86. The improved CD procedure is greatly accelerated by applying a pre-screening stage at the semiempirical GFN2-xTB level. An automatic module based on the Marcus theory and its improved version (the Wolynes theory) is designed to include single electron transfer (SET) processes into reaction pathways. The capabilities of this method are demonstrated by exploring the most possible reaction pathways of three experimentally reported reactions: the organophosphine-catalyzed trans phosphinoboration, the Fe(II) complex-mediated C(sp2)-H borylation reaction, and the SET-triggered deaminative radical cross-coupling reaction. Comprehensive reaction networks are obtained for all three reactions with reasonable computational costs. Detailed mechanisms for these reactions can account for the reported experimental facts.

Mechanistic Insight into Hydroboration of Imines from Combined Computational and Experimental Studies.

Boron Lewis acid-catalyzed and catalyst-free hydroboration reactions of imines are attractive due to the mild reaction conditions. In this work, the mechanistic details of the hydroboration reactions of two different kinds of imines with pinacolborane (HBpin) are investigated by combining density functional theory calculations and some experimental studies. For the hydroboration reaction of N-(α-methylbenzylidene)aniline catalyzed by tris[3,5-bis(trifluoromethyl)phenyl]borane (BArF 3 ), our calculations show that the reaction proceeds through a boron Lewis acid-promoted hydride transfer mechanism rather than the classical Lewis acid activation mechanism. For the catalyst- and solvent-free hydroboration reaction of imine, N-benzylideneaniline, our calculations and experimental studies indicate that this reaction is difficult to occur under the reaction conditions reported previously. With a combination of computational and experimental studies, we have established that the commercially available BH3 ⋅ SMe2 can serve as an efficient catalyst for the hydroboration reactions of N-benzylideneaniline and similar imines. The hydroboration reactions catalyzed by BH3 ⋅ SMe2 are most likely to proceed through a hydroboration/B-H/B-N σ-bond metathesis pathway, which is very different from that of the reaction catalyzed by BArF 3 .

Iodoperfluoroalkylation of unactivated alkenes via pyridine-boryl radical initiated atom-transfer radical addition.

The pyridine/bis(pinacolate)diboron combination has been found to be able to initiate the iodoperfluoroalkylation of unactivated alkenes with perfluoroalkyl iodides. Theoretical calculations and control experiments indicate that the atom transfer radical addition mechanism is responsible for the formation of iodoperfluoroalkylation products. This metal-free and photo-free strategy is applicable to a wide range of perfluoroalkyl iodides and unactivated alkenes with good functional group tolerance. Further applications in iodoperfluoroalkylation of organic semiconductor-relevant or bioactive molecules demonstrate the synthetic potential of this method.

Rational design of the nickel-borane complex for efficient hydrogenation of styrene.

The Ni-B complex 1BCF with a facilely accessible monophosphine (Pt Bu3 ) unit was theoretically designed, which was found to be more active than that with an ambiphilic ligand for hydrogenation of styrene. Substituting Pt Bu3 with a stronger electron donating ligand N-heterocyclic carbene largely improves the activity of the Ni-B complex.

Catalytic Dehydrogenation of Ammonia Borane Mediated by a Pt(0)/Borane Frustrated Lewis Pair: Theoretical Design.

A new efficient metal-based frustrated Lewis pair constructed by (Pt Bu3 )2 Pt and B(C6 F5 )3 was designed through density functional theory calculations for the catalytic dehydrogenation of ammonia borane (AB). The reaction was composed by the successive dehydrogenation of AB and H2 liberation, which occurs through the cooperative functions of the Pt(0) center and the B(C6 F5 )3 moiety. Two equivalents of H2 were predicted to be liberated from each AB molecule. The generation of the second H2 is the rate-determining step, with a Gibbs energy barrier and reaction energy of 27.4 and 12.8 kcal/mol, respectively.

Photoredox-Controlled ß-Regioselective Radical Hydroboration of Activated Alkenes with NHC-Boranes.

In this Communication, we report an unprecedented ß-regioselective radical inverse hydroboration (compared with ionic hydroboration) of α,ß-unsaturated amides with NHC-BH3 enabled by photoredox catalysis. Density functional theory (DFT) calculations show that the unique photoredox cycle is a key factor to control the ß-regioselective radical hydroboration, by lowering the energy barrier in comparison with other pathways. This protocol provides a general and convenient route to construct a wide range of structurally diverse ß-borylated amides in synthetically useful yields under mild conditions.

How intermolecular interactions influence electronic absorption spectra: insights from the molecular packing of uracil in condensed phases.

The photoexcitation mechanism in photochemistry and photophysics is a key to understanding the photostability and photoreaction of nucleobases. Using a combination of the generalized energy-based fragmentation (GEBF) and quantum mechanical and molecular mechanical (GEBF-QM/MM) approach and the QM/MM approach, we have investigated the electronic absorption spectra for the π-π* transition of uracil in aqueous solution, amorphous solid, and crystal. Our results indicate that the intermolecular interactions in terms of molecular packing are crucial for the investigation of the absorption spectra of uracil in different environments. There is a large red-shift (relative to uracil in the gas-phase) for uracil in the amorphous phase, which arises from hydrogen-bonding (HB) and close π-π stacking interactions. In contrast, the relatively smaller red-shift of uracil in aqueous solution can be attributed to the cooperative HB and long-range electrostatic and polarization interactions. Due to the HB and weak π-π interactions, the red-shift of the crystal is smaller than that of amorphous uracil. Furthermore, the results suggest that a large system is required to obtain the accurate absorption spectra of solutions, whereas small electrostatically embedded cluster models could be used to obtain the corresponding results for amorphous solids and molecular crystals.

Chemoselective Borane-Catalyzed Hydroarylation of 1,3-Dienes with Phenols.

A B(C6 F5 )3 -catalyzed hydroarylation of a series of 1,3-dienes with various phenols has been established through a combination of theoretical and experimental investigations, affording structurally diverse ortho-allyl phenols. DFT calculations show that the reaction proceeds through a borane-promoted protonation/Friedel-Crafts pathway involving a π-complex of a carbocation-anion contact ion pair. This protocol features simple and mild reaction conditions, broad functional-group tolerance, and low catalyst loading. The obtained ortho-allyl phenols could be further converted into flavan derivatives using B(C6 F5 )3 with good cis diastereoselectivity. Furthermore, this transformation was applied in the late-stage modification of pharmaceutical compounds.

Metal-Free Synthesis of C-4 Substituted Pyridine Derivatives Using Pyridine-boryl Radicals via a Radical Addition/Coupling Mechanism: A Combined Computational and Experimental Study.

Density functional theory investigations revealed that the pyridine-boryl radical generated in situ using 4-cyanopyridine and bis(pinacolato)diboron could be used as a bifunctional "reagent", which serves as not only a pyridine precursor but also a boryl radical. With the unique reactivity of such radicals, 4-substituted pyridine derivatives could be synthesized using α,ß-unsaturated ketones and 4-cyanopyridine via a novel radical addition/C-C coupling mechanism. Several controlled experiments were conducted to provide supportive evidence for the proposed mechanism. In addition to enones, the scope could be extended to a wide range of boryl radical acceptors, including various aldehydes and ketones, aryl imines and alkynones. Lastly, this transformation was applied in the late-stage modification of a complicated pharmaceutical molecule.

[Design, synthesis, antibacterial and anti-cell proliferation activities of [1,2,4]triazino[3,4-h] [1,8]naphthyridine-8-one-7-carboxylic acid derivatives].

To discover novel fluoroquinolone lead compounds as possible anti-infective or/and antitumor chemotherapies, combination principle of pharmacophore-based drug design, a series of novel tricyclic fluoroquinolone title compounds, [1,2,4]triazino[3,4-h][1,8]naphthyridine-8-one-7-carboxylic acid derivatives ( 5a-5p), were designed and synthesized with a fused [1,2,4]-triazine ring unit. Their structures were characterized by spectral data and elemental analysis and the in vitro antibacterial and anti-cell proliferation activities were also evaluated. The results showed that the titled compounds exhibited more significant inhibitory activities against drug-resistant bacteria (Methicillin-resistant Staphylococcus aureus and multi drug-resistant Escherichia coli strains) and three tested cancer cell lines (human hepatoma SMMC-7721, murine leukemia L1210 and human murine leukemia HL60 cells). Interestingly, SAR showed that compounds with electron-donating groups attached to benzene ring had stronger antibacterial activity than antitumor activity, but electron-withdrawing compounds displayed more potential antitumor activity than antibacterial activity, especially antitumor activity of nitro compounds was comparable to comparison doxorubicin. Thus, novel triazine-fused tricyclic fluoroquinolones as potent anti-infective or/and antitumor lead compounds are valuable to pay attention and for further development.

[Synthesis and anti-proliferative activity of fluoroquinolone (rhodanine unsaturated ketone) amide derivatives].

To discover novel antitumor rhodanine unsaturated ketones, a series of fluoroquinolone (rhodanine α, ß-unsaturated ketone) amine derivatives (5a-5r) were designed and synthesized with fluoroquinolone amide scaffold as a carrier. The structures of eighteen title compounds were characterized by elemental analysis, 1H NMR and MS. The in vitro anti-proliferative activity against Hep-3B, Capan-1 and HL60 cells was evaluated by MTT assay. The results showed that the title compounds not only had more significant anti-proliferative activity against three tested cancer cell lines than that of the parent ciprofloxacin 1, but also exhibited the highest activity against Capan-1 cells. The SAR revealed that some compounds carrying aromatic heterocyclic rings or phenyl attached to an electron-withdrawing carboxyl or sulfonamide substituent were comparable to or better than comparison doxorubicin against Capan-1 cells. As such, it suggests that fluoroquinolone (rhodanine α, ß-unsaturated ketone) amines are promising leads for the development of novel antitumor fluoroquinolones or rhodanine analogues.

[Synthesis and antitumor activity of fluoroquinolon-3-yl-s-triazole sulfide ketones and their derivatives from ciprofloxacin].

To discover an efficient strategy for the conversion of the antibacterial activity of fluoroquinolones into the antitumor activity, the three series of C-3 s-triazole-based derivatives including sulfide ketones (6a-6g), thiosemicarbazones (7a-7g) and fused heterocyclic thiazolotriazoles (8a-8g) were synthesized from ciprofloxacin (1), respectively. The structures were characterized by elemental analysis and spectral data. The antitumor activity was tested against three tumor cell lines (Hep-3B, Capan-1 and HL60) using the MTT assay. The three types of compounds all exhibited stronger anti-proliferative activities than ciprofloxacin in the test. The order of their activities was in compounds 7>8>6, and the order of selectivity against cancer cell lines was Capan-1, Hep-3B and HL60. Meanwhile, the SAR revealed that some compounds with electron-drawing group substituted such as fluoro- and nitro-phenyl compounds (6f, 7f, 8f) and (6g, 7g, 8g) displayed more significant activity than the control compounds, especially the IC50 values of thiosemicarbazone compounds 7f and 7g against Capan-1 was comparable to doxorubicin. Thus, a five-membered triazole as the C-3 bioisostere modified with the functionalized side-chain of sulfide-ketone thiosemicarbazone warrants special attention and further investigation.

[Synthesis, antitumor activity and SAR of C-3 oxadiazole sulfanylacetylhydrazone-substituted fluoroquinolone analogues].

To explore an efficient strategy for the conversion of antibacterial fluoroquinolones into antitumor fluoroquinolones, an azole heterocyclic ring of oxadiazole instead of the C-3 carboxylic acid group with a functionalized hydrazone group as a modified side-chain, fifteen novel 2-(fluoroquinolon-3-yl)-oxadiazole-5- sulfanylacetylhydrazone derivatives 7a-7o were designed and synthesized on the basis of the pharmacophore hybridization principle from pefloxacin, separately. The structures for fifteen title compounds were characterized by elemental analysis, 1H NMR and MS, and their in vitro antitumor activity against Hep-3B cell line was evaluated by a MTT assay. The results showed that the title compounds exhibited more significantly inhibitory activity than that of the parent pefloxacin, in which compounds with electron-withdrawing group attached on aryl ring had more potency than that of compounds with electron donating group, especially compounds with a carboxylic substituent were comparable to comparison doxorubicin. It suggests that it is favorable for an improvement of antitumor activity to remain a carboxylic acid unit at the aromatic ring.

Base-mediated C-B bond activation of benzylic boronate for the rapid construction of ß-silyl/boryl functionalized 1,1-diarylalkanes from aromatic alkenes.

The effect of tBuOK on the existing state of benzylic boronates in the solution phase has been investigated in detail by NMR analysis and DFT calculations. It was determined that simply using an excess of tBuOK (2.0 equivalents) can result in the full deborylation of benzylic boronates to afford free benzyl potassium species. These mechanistic insights were leveraged for the facile construction of ß-silyl/boryl functionalized 1,1-diarylalkanes from aromatic alkenes via the combination of base-mediated silylboration or diborylation of aromatic alkenes and nucleophilic-type reactions with various electrophiles. Based on further machine-learning-assisted screening, the scope of electrophiles for this transformation can be generalized to the challenging aromatic heterocycles. Late-stage functionalization performed on several drug-relevant molecules generates the highly valuable 1,1-diaryl framework.

1,2-Silylpyridylation Reaction of Aryl Alkenes with Silylboronate.

A metal-free silyl-pyridylation of alkenes using silyl boronates and B2pin2 through a pyridine-mediated B-interelement activation has been demonstrated, which provides a practical strategy for a variety of C4-silylalkylated pyridines. DFT calculations and control experiments show that the reaction proceeds through a silyl radical addition/radical-radical coupling sequence. This protocol features a broad substrate scope and excellent functional group compatibility, and thus it showcases great potential in the late-stage modification of bioactive molecules.

Mechanistic insights into the dearomative diborylation of pyrazines: a radical or non-radical process?

The mechanisms of the dearomative diborylation of pyrazines were investigated via a combination of density functional theory (DFT) calculations and experimental studies. DFT calculations revealed that a non-radical mechanism involving two successive [3,3]-σ-rearrangement-type processes is responsible for the diborylation of pyrazine with bis(pinacolato)diboron (B2pin2). However, this non-radical process is highly unfavorable for the diborylation reaction of sterically hindered pyrazine (2,3-dimethylpyrazine). For the diboration reaction of 2,3-dimethylpyrazine with B2pin2 in the presence of 2,6-dichloro-4,4'-bipyridine as the catalyst, 4,4'-bipyridine-mediated radical pathway proceeding through a B-B homolytic cleavage/boryl radical addition is preferred. Control experiments combined with kinetic studies provided supportive evidence for the proposed mechanism.

Borane-catalyzed selective dihydrosilylation of terminal alkynes: reaction development and mechanistic insight.

Here, we describe simple B(C6F5)3-catalyzed mono- and dihydrosilylation reactions of terminal alkynes by using a silane-tuned chemoselectivity strategy, affording vinylsilanes and unsymmetrical geminal bis(silanes). This strategy is applicable to the dihydrosilylation of both aliphatic and aryl terminal alkynes with different silane combinations. Gram-scale synthesis and conducting the reaction without the exclusion of air and moisture demonstrate the practicality of this methodology. The synthetic utility of the resulting products was further highlighted by the structural diversification of geminal bis(silanes) through transforming the secondary silane into other silyl groups. Comprehensive theoretical calculations combined with kinetical isotope labeling studies have shown that a prominent kinetic differentiation between the hydrosilylation of alkynes and vinylsilane is responsible for the chemoselective construction of unsymmetrical 1,1-bis(silanes).

B(C6F5)3-Catalyzed Sequential Additions of Terminal Alkynes to para-Substituted Phenols: Selective Construction of Congested Phenol-Substituted Quaternary Carbons.

We have developed a borane-catalyzed sequential addition of terminal alkynes to para-substituted phenols, which affords a wide range of ortho-propargylic alkylated phenols bearing congested quaternary carbons. Control experiments combined with DFT calculations suggest that the reaction undergoes a sequential phenol alkenylation/hydroalkynylation process. Further extension of this strategy to the construction of triaryl-substituted quaternary carbons demonstrates the broad utility of this method.