Boc-protected Amines Research Articles

Toward a Chemical Constructor: A Lego-Like Approach for Formal α-Alkylation of Cyclic Ketones.

A conceptual strategy for a formal α-alkylation of α-methylene ketones was developed. Diverse 1° and 2° alkyl substituents were generated in the α-position of various ketones via synthesis of enaminone (step 1) and treatment with organomagnesium (step 2) with subsequent catalytic hydrogenation (step 3, 1° alkyl) or organocopper reagents (step 4, 2° alkyl). Tolerance toward ester, Boc-protected amine, and α-fluoro-substituted ketone moieties was demonstrated. The suitability of the method for late-stage natural product modification was shown.

Functionalized [2.2]Paracyclophanedienes as Monomers for Poly(p-phenylenevinylene)s.

Poly(p-phenylenevinylene)s (PPVs) featuring complex side-chains, to date, have only been synthesized by nonliving polymerization methods which have no control over PPV molecular weights, dispersities, or end groups. [2.2]Paracyclophane-1,9-diene (pCpd) has gained attention as a monomer for its ability to be ring-opened to PPV in a living fashion. pCpd, an organic cyclic scaffold with planar chirality, has seen minimal structural diversity due to the harsh reaction conditions required to afford the highly strained compound. Herein, we introduce a general method to overcome this by targeting the synthesis of a monohydroxy-pCpd via mono-demethylation of a dialkoxy-pCpd. The monohydroxy-pCpd can then be functionalized easily, which we demonstrate using three distinct side-chains with four moieties commonly incorporated in conjugated polymers: an alkyl bromide, an oligo(ethylene glycol) chain, an enantiomerically pure side-chain, and a Boc-protected amine. These monofunctionalized-pCpds were investigated as monomers in the ring-opening metathesis polymerization (ROMP) to afford functionalized PPVs in a living manner. The functional-group-containing PPVs are synthesized with full control over their end groups, repeat units, and dispersities. The feasibility of post-polymerization modifications to incorporate any desired moiety to PPV fabricated by this method was demonstrated using an azide-alkyne click reaction. All synthesized PPVs were soluble in organic solvents and display the same fluorescent emission, indicating their conjugated backbones are unaltered.

Direct synthesis of carbamates, thiocarbamates, and ureas from Boc-protected amines: a sustainable and efficient approach.

In the quest for sustainable and efficient synthetic methodologies within medicinal chemistry, the synthesis of carbamates and their derivatives holds a pivotal role due to their widespread application in bioactive compounds. This investigation unveils a novel methodology for the straightforward transformation of Boc-protected amines into carbamates, thiocarbamates, and ureas, utilizing tert-butoxide lithium as the sole base. This approach effectively obviates the necessity for hazardous reagents and metal catalysts, presenting marked enhancements compared to traditional synthetic pathways. Notably, the method demonstrates facile scalability to gram-level production. This study contributes to the advancement of sustainable synthetic methodologies, offering a more benign and efficient alternative for the synthesis of key chemical intermediates with implications for broad pharmaceutical and agrochemical applications.

Synthesis of C3-Symmetric Macrocyclic Triimines from Monomers Having Boc-protected Amine and Formyl Group

Abstract A concise access to C3-symmetric macrocyclic triimines was developed. When biphenyls having a formyl group on one phenyl group and an NHBoc group on the other phenyl group were treated with an excess amount of concentrated HCl in 1,4-dioxane, the detachment of the Boc group followed by a trimerization reaction via imine formation proceeded smoothly to afford C3-symmetric imine-linked macrocycles in good chemical yields.

Bisphosphonate-functionalized poly(amido amine) crosslinked 2-hydroxyethyl methacrylate hydrogel as tissue engineering scaffold

• Bisphosphonate-functionalized poly(amido amine) macromer (PAA-BP) was synthesized. • Crosslinking with PAA-BP adds excellent mineralization ability to 2-hydroxyethyl methacrylate (HEMA) hydrogel. • This hydrogel is biocompatible and facilitates cell adhesion after mineralization. • PAA-BP improves swelling and degradation properties of the hydrogel. • This hydrogel can be used for tissue engineering scaffolds. The first water soluble, bisphosphonate (BP, not bisphosphonic acid)-functionalized poly(amido amine) macromer (PAA-BP) is synthesized and used as a crosslinker for synthesis of a biodegradable and biocompatible hydrogel for tissue engineering scaffolds. The synthesis of PAA-BP is performed in three steps, the first two giving the control macromers (PAA-NHBoc and PAA-NH 2 ): i) Michael addition reaction of N,N’ -methylene bisacrylamide and N -Boc-1,6-hexanediamine (acrylamide/amine ratios of 1.2), ii) deprotection of Boc-protected amine groups, iii) Michael addition reaction of the amine groups with tetraethyl vinylidene bisphosphonate. The degree of BP substitution is 50% and molecular weight of the PAA-BP macromer is found to be 4800 g/mol. These macromers are incorporated into hydrogels by copolymerization with 2-hydroxyethyl methacrylate and the influence of bisphosphonate functionality on hydrogel properties; degradation, swelling, mechanical and mineralization, is investigated. The mineralization abilities, hence the mechanical properties of the hydrogels are strongly influenced by the BP functionality; PAA-BP forming strong (E = 83 ± 1 kPa) hydrogel-apatite composites, PAA-NH 2 also working to a lesser degree (E = 54 ± 3 kPa). Cytocompatibility of the hydrogels is observed on Saos-2 human osteosarcoma, U-2 OS human bone osteosarcoma epithelial, C2C12 mouse myoblast muscle and NIH mouse embryonic fibroblast 3T3 cells. PAA-BP crosslinked hydrogels facilitate adhesion of C2C12 cells after mineralization. In summary, BP-functionalized hydrogel may have a potential impact on bone tissue engineering.

Functionalizable oxanorbornane-based head-group in the design of new Non-ionic amphiphiles and their drug delivery properties.

A new group of non-ionic amphiphiles with short alkyl chains and functionalizable oxanorbornane-based head group for drug delivery application are presented. They can be prepared through a sequence that starts with cycloaddition of Boc-protected furfuryl amine with maleic anhydride and reduction of the resulting adduct with LiAlH4 to get a diol intermediate. Introduction of alkyl chains through these primary hydroxyl groups and subsequent head-group modification via cis-hydroxylation resulted in a number of new amphiphiles in good yields. They were characterized by various spectro-analytical techniques and then subjected to drug-delivery studies using ibuprofen as a model drug. Functionalization of the head group through the amine functionality was also done with an intention to improve lipid packing to get better drug-loading and release properties. Irrespective of the nature of groups attached through this amine unit, all amphiphiles with short alkyl chains were found to assemble into spherical aggregates when drop-casted from various organic solvents. The same assembly preference prevailed in their formulations containing lipid-cholesterol-drug in 1: 0.5:1 ratio as well, and these particles had diameters <300nm. Apart from good drug-loading efficiencies, these amphiphiles exhibited controlled release properties and did not show any indication of toxicity when assayed against NIH3T3 cells. The formulation based on lipid having a phenylalanine unit on the head group (1.10c) turned out to be the best in this series which showed a loading efficiency of 57.6% with a controlled release of ~42% by end of 24h. Because of efficient layering that is facilitated by hydrogen bonding involving well-directed hydroxyl groups on the head group, amphiphiles with alkyl chains as short as C5 are able to act as efficient drug delivery systems, which is one of the highlights of this work.

Metal-Free Route to Carboxylated 1,4-Disubstituted 1,2,3-Triazoles from Methoxycarbonyl-Modified Vinyl Sulfone.

A metal-free alternative to the regioselective synthesis of carboxylated 1,4-disubstituted 1,2,3-triazoles (1,4-cDTs) has been accomplished. A methoxycarbonyl-substituted vinyl sulfone on reactions with organic azides resulted in the formation of 1,4-cDTs in an operationally simple route. The reaction, carried out with a variety of organic azides containing free alcohol, acid, Boc-protected amine, ester, protected sugars, long-chain alkanes, benzyl, 9-methylanthracenyl, and cholesteryl groups, was found to be general in nature, which afforded a plethora of new chemical entities; reactions of diazides generated mostly the desired and a few unexpected products. This article reports for the first time the targeted metal-free synthesis of any 1,4-disubstituted 1,2,3-triazole using the cycloaddition reactions of an appropriately functionalized vinyl sulfone.

Synthesis of Imidazolidinone, Imidazolone, and Benzimidazolone Derivatives through Oxidation Using Copper and Air.

A new synthetic method of urea derivatives using copper and air was developed. These mild conditions provided moderate to very good yields for 15 examples (53-93%), while low yields were obtained with sterically hindered substrates (3 examples). The reaction was found to go through an in situ generated copper- N-heterocyclic carbene, which was then oxidized into cyclic urea derivatives possessing alkyl, benzyl, aryl, hydroxy, Boc-protected, and tertiary amine groups.

Nickel-Catalyzed Kumada Coupling of Boc-Activated Aromatic Amines via Nondirected Selective Aryl C-N Bond Cleavage.

A nickel-catalyzed Kumada coupling of aniline derivatives was developed by selective cleavage of aryl C-N bonds under mild reaction conditions. Without preinstallation of an ortho directing group on anilines, the cross-coupling reactions of Boc-protected aromatic amines with aryl Grignard reagents afforded unsymmetric biaryls. Mechanistic studies by DFT calculations revealed that the nickel-mediated C-N bond cleavage is the rate-limiting step.

Metal-Templated Assembly of Cyclopropane-Fused Diazepanones and Diazecanones via exo- trig Nucleophilic Cyclization of Cyclopropenes with Tethered Carbamates.

A strain-release-driven, cation-templated nucleophilic 7- and 8- exo-trig-cyclization of tethered Boc-protected amines to cyclopropenes is described. The featured reaction proceeds in diastereo- and regioselective fashion and allows for preparation of the corresponding 2,5-diazabicyclo[5.1.0]octan-6-ones and 2,6-diazabicyclo[6.1.0]nonan-7-ones as sole products in high yields. Preliminary studies on anticancer activities of these novel cyclopropane-fused medium heterocycles were performed.

Functionalized 3D Architected Materials via Thiol-Michael Addition and Two-Photon Lithography.

Fabrication of functionalized 3D architected materials is achieved by a facile method using functionalized acrylates synthesized via thiol-Michael addition, which are then polymerized using two-photon lithography. A wide variety of functional groups can be attached, from Boc-protected amines to fluoroalkanes. Modification of surface wetting properties and conjugation with fluorescent tags are demonstrated to highlight the potential applications of this technique.

Solvent-Free Mechanochemical Deprotection of &amp;lt;i&amp;gt;N&amp;lt;/i&amp;gt;-Boc Group

Boc protection group could be readily removed in a very mild mechanochemical conditions. In a short reaction time, ball milling of Boc-protected amines with p-toluenesulfonic acid in solvent-free conditions affords corresponding amine p-TsOH salts.

One-pot synthesis of carbamates and thiocarbamates from Boc-protected amines

A highly efficient one-pot procedure for the synthesis of carbamates and thiocarbamates has been described. In the presence of 2-chloropyridine and trifluoromethanesulfonyl anhydride, the isocyanate intermediates were generated in situ for further reactions with alcohols and thiols to afford the desired carbamates and thiocarbamates in high yields.

New Insight of Tetraphenylethylene-based Raman Signatures for Targeted SERS Nanoprobe Construction Toward Prostate Cancer Cell Detection.

We have designed and synthesized novel tetraphenylethylene (TPE) appended organic fluorogens and unfold their unique Raman fingerprinting reflected by surface-enhanced Raman scattering (SERS) upon adsorption on nanoroughened gold surface as a new insight in addition to their prevalent aggregation-induced emission (AIE) and aggregation-caused quenching (ACQ) phenomena. A series of five TPE analogues has been synthesized consisting of different electron donors such as (1) indoline with propyl (TPE-In), (2) indoline with lipoic acid (TPE-In-L), (3) indoline with Boc-protected propyl amine (TPE-In-Boc), (4) benzothaizole (TPE-B), and (5) quinaldine (TPE-Q). Interestingly, all five TPE analogues produced multiplexing Raman signal pattern, out of which TPE-In-Boc showed a significant increase in signal intensity in the fingerprint region. An efficient SERS nanoprobe has been constructed using gold nanoparticles as SERS substrate, and the TPE-In as the Raman reporter, which conjugated with a specific peptide substrate, Cys-Ser-Lys-Leu-Gln-OH, well-known for the recognition of prostate-specific antigen (PSA). The designated nanoprobe TPE-In-PSA@Au acted as SERS "ON/OFF" probe in peace with the vicinity of PSA protease, which distinctly recognizes PSA expression with a limit of detection of 0.5 ng in SERS platform. Furthermore, TPE-In-PSA@Au nanoprobe was efficiently recognized the overexpressed PSA in human LNCaP cells, which can be visualized through SERS spectral analysis and SERS mapping.

Probing Supramolecular Interactions between a Crown Ether Appended Zinc Phthalocyanine and an Ammonium Group Appended to a C60 Derivative.

Self-assembly driven by crown ether complexation of zinc phthalocyanines equipped with one 18-crown-6 moiety and fullerenes bearing an ammonium head group afforded a novel donor-acceptor hybrid. In reference experiments, fullerenes containing a Boc-protected amine functionality have been probed. The circumvention of zinc phthalocyanine aggregation is important for the self-assembly, which required the addition of pyridine. From absorption and fluorescence titration assays, which provided sound and unambiguous evidence for mutual interactions between the electron donor and the electron acceptor within the hybrids, association constants in the order of 8.0×105 m-1 have been derived. The aforementioned is based on 1:1 stoichiometries, which have been independently confirmed by Job's plot measurements. In the excited state, which has been examined by transient absorption experiments, intermolecular charge separation evolves from the photoexcited zinc phthalocyanine to the fullerene subunit and leads to short-lived charge-separated states. Interestingly, photoexcitation of zinc phthalocyanine dimers/aggregates can also be followed by an intermolecular charge separation between vicinal phthalocyanines. These multicomponent supramolecular ensembles have also been shown by in-depth electrospray ionization mass spectrometry (ESI-MS) studies, giving rise to the formation and detection of a variety of non-covalently linked species.

Orthogonally Protected Oxadiazole-Based Building Blocks: Synthesis and Characterization

We present a straightforward route for the preparation of orthogonally protected oxadiazole-based building blocks in high yields. Their structures contain a Boc-protected amine and an ester group, thus rendering the compounds amenable to functionalization or integration into larger structures. Thus, we provided access to interesting and innovative building blocks/decorated scaffolds for drug discovery. Keywords: 1, 2, 4-oxadiazole, 1, 3, 4-oxadiazole, building block, privileged structure, scaffold.

Disulfonimide-Catalyzed Asymmetric Reduction of N-Alkyl Imines.

A chiral disulfonimide (DSI)-catalyzed asymmetric reduction of N-alkyl imines with Hantzsch esters as a hydrogen source in the presence of Boc2 O has been developed. The reaction delivers Boc-protected N-alkyl amines with excellent yields and enantioselectivity. The method tolerates a large variety of alkyl amines, thus illustrating potential for a general reductive cross-coupling of ketones with diverse amines, and it was applied in the synthesis of the pharmaceuticals (S)-Rivastigmine, NPS R-568 Hydrochloride, and (R)-Fendiline.

Carbonyl-11C]4-Fluoro-N-methyl-N-(4-(6-(methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide ([11C]FIMX) is an effective radioligand for PET imaging of metabotropic glutamate receptor 1 (mGluR1) in monkey brain

IntroductionMetabotropic glutamate subtype receptor 1 (mGluR1) is implicated in several neuropsychiatric disorders and is a target for drug development. [18F]FIMX ([18F]4-fluoro--N-methyl-N--(4-(6-(methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide) is an effective radioligand for imaging brain mGluR1 with PET. A similarly effective radioligand with a shorter half-life would usefully allow PET studies of mGluR1 at baseline and after pharmacological or other challenge on the same day. Here we describe the preparation of [11C]FIMX for evaluation in monkey with PET. Methods[11C]FIMX was prepared via Pd-promoted carbonylation of 1-fluoro-4-iodobenzene with [11C]carbon monoxide, aminolysis of the [11C]acyl-palladium complex with the requisite Boc-protected amine, and deprotection with HCl in THF. PET scans of [11C]FIMX injected into a monkey were performed at baseline and after preblock of mGluR1 with measurement of the arterial input function. ResultsThe radiosynthesis required 42min and gave [11C]FIMX in about 5% overall decay-corrected radiochemical yield and with a specific activity of about 100GBq/μmol. PET in rhesus monkey at baseline showed that radioactivity peaked high in receptor-rich cerebellum and much lower in receptor-poor occipital cortex. Radioactivity in cerebellum declined to 32% of peak at 85min. VT at baseline appeared stable in all brain regions after 60min. Under mGluR1 pre-blocked condition, radioactivity uptake in all regions declined more rapidly to a low level. Receptor pre-block reduced VT from 13.0 to 1.5 in cerebellum and from 2.9 to 1.4 in occipital cortex. Conclusion[11C]FIMX is an effective radioligand for imaging mGluR1 in monkey with PET.

ChemInform Abstract: Ligand‐Controlled α‐ and β‐Arylation of Acyclic N‐Boc Amines.

AbstractA sequence of directed α‐lithiation, transmetalation with zinc, and Pd‐catalyzed cross‐coupling leads to either α‐ or β‐arylated Boc‐protected amines.

One-pot synthesis of ureas from Boc-protected amines.

A practical one-pot synthesis of ureas is described. Boc-protected amines can be transformed into nonsymmetrical and symmetrical disubstituted and trisubstituted ureas utilizing 2-chloropyridine and trifluoromethanesulfonyl anhydride for the in situ generation of an isocyanate, which reacts with an amine. A variety of amines can be employed successfully, leading to high yields of isolated ureas.