Di-tert-butyl Dicarbonate Research Articles

A facile and economic method for the synthesis of (S)-N-Boc-3′-hydroxyadamantylglycine

(S)-N-Boc-3′-hydroxyadamantylglycine (I) is an important intermediate of saxagliptin for type 2 diabetes mellitus (T2DM). It was prepared from 1-adamantanecarboxylic acid(1) via mild reaction with sulfuric acid/nitric acid, VHA reagent (SOCl2/DMF) and sodium diethyl malonate, then was treated with hydrolysis, decarboxylation, alkalization and oxidation to give 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid (4), then through oximation, reduction and (Boc)2O protection to give the N-Boc-3′-hydroxyadamantylglycine(6), then was treated with quinidine to get (S)- N-Boc-3′-hydroxyadamantylglycine(I) and quinine to get (R)–N-Boc-3′-hydroxyadamantylglycine(II). Finally, Compound II was racemized by dicyclohexylcarbodiimide (DCC) and sodium hydride (NaH) to afford compound 6. In this route, the overall yield of preparing compound I was about 35 % and the enantiomeric excess (ee) reach to 99 %. This route provided a novel idea for the preparation of (S)-N-Boc-3′-hydroxyadamantylglycine.

ChemInform Abstract: Intramolecular Cyclization of Alkylimidazoles.

Abstract1,2‐Dialkylimidazoles are converted to nucleophilic 2‐alkylidene imidazoles upon treatment with Boc2O.

ChemInform Abstract: BF3‐Mediated cis‐Selective Cycloaddition of O‐Silyloxime with Alkenes.

AbstractO‐Silyloxime (I) reacts with alkenes (II) and Boc2O to the Boc‐protected isoxazolidin‐3‐carboxamides (IV) and (V) favouring the cis‐isomer (IV).

Synthetic and Crystallographic Studies of (9-Ethyl-9H-carbazol-3-yl)-carbamic acid tert-butyl ester

The title compound (9-ethyl-9H-carbazol-3-yl)-carbamic acid tert-butyl ester was prepared from 3-amino-9-ethylcarbazole and di-tert-butyldicarbonate (Boc anhydride) in good yield. It was characterized by elemental analysis, FT-NMR, FT-IR spectroscopy and subjected to single crystal X-ray diffraction studies. The compound crystallizes in monoclinic space group P21/c with unit cell dimensions are a = 13.5218(8) A, b = 12.7624(7) A, c = 10.1352(6) A, β = 100.784(6)°, V = 1718.15(17) A3, D x = 1.200 Mg m−3, and Z = 4. According to X-ray diffraction studies the molecule is in a non planar conformation except for the carbazole moiety and having a dihedral angle of 30.239(89)° between the plane of the carbazole and amide moieties. The molecules are packed in a zig-zag manner and strong N–H···O [C(4) motif] intermolecular hydrogen bonding, weak C–H···π [C(5) motif] and π–π stacking interaction stabilize the crystal packing. The thermal analysis of single crystal was determined by DSC and TGA.

Novel one-component positive-tone chemically amplified i-line molecular glass photoresist based on tannic acid

Molecular glass resist has been considered as one of the best choices for a new generation of lithography. In this work, a new type of photoactive compound was obtained by the esterification of tannic acid with 2-diazo-1-naphthoquinone-4-sulfonyl chloride(2,1,4-DNQ-Cl) and ditertbutyl dicarbonate. The new obtained compound possessed both a photosensitive group of diazonaphthoquinone sulfonate(2,1,4-DNQ) and a group of acidolytic protection. Upon the irradiation of the compound under 365 nm light, the former group was photolyzed and converted into indene carboxylic acid along with a small amount of sulfonic acid, which could lead to the deprotection of the latter group. As a result, a novel i-line molecular glass photoresist was formed with the chemical modification of tannic acid. The experimental results show that the modificated compound had a fair solubility in many organic solvents. The lithographic performance of the resist was evaluated on an i-line exposure system with high photosensitivity and resolution as well.

The First Synthesis of 3-epi-Xestoaminol C

A new 1-deoxysphingoid, 3-epi-xestoaminol C (1), isolated from the New Zealand brown alga Xiphophora chondrophylla was firstly synthesized for the identification of its absolute stereochemistry via stereoselective reduction of 2-acylaziridine followed by hydrogenolysis. Sphingosine as a class of lipid described almost two centuries ago 1 was characterized structurally as 2-amino-1,3diol in long alkyl chain most of which participate in cell structure and its regulation. 2 Up to now hundreds of sphingosines were isolated and their structures were identified and some of them showed important biological activities to lead for a new drug development program. 2,3 Most of them have different number of carbon backbones, position of double bonds and the stereochemistry of olefin and other functionalities in alcohol and amine. Due to the same biosynthetic origin of sphingosine from serine and fatty acids most of them have 2-amino-1,3-diols as the common functionalities even though their carbon backbones are different. However, few isolated natural products including spisulosine, 4 clavaminol, 5 xestoaminol 5a,6 and obscuraminol 7 have only 2-amino-3-ol functionalities without one alcohol at the end of the backbone as 1-deoxysphingoid. The absolute stereochemistries of two functional groups are important for their biological actives. The epimer of the previously isolated xestoaminol C (2), 5a,6 3-epi-xestoaminol C (1), was isolated for the first time from a brown alga Xiphophora chondrophylla by bioassay-guided isolation method last year. 8 Its structure was identified by extensive 1 H NMR analysis including NOE correlations of its oxazolidinone derivative. To confirm its chemical structure and absolute stereochemistry we decided to synthesize both isomers, xestoaminol C and 3-epi-xestoaminol C, starting from chiral aziridine. At first we prepared 2-acylaziridine (3) from (2S)-aziridine-2-carboxylate 9 by the known method whose 2S configuration should be ended at the C2 of the final product bearing amine functional group. The hydroxy groups at C3 of the target molecules are 2R in xestoaminol C and 2S in 3-epi-xestoaminol C. Thereby we decided to reduce the ketone in 2-acylaziridine (3) in stereoselective manner which we already established well. Reduction with L-Selectride yielded the threo product (4) while NaBH4 with ZnCl2 gave erythro product (5) by different transition states. 4a Hydrogenolysis with H2 in the presence of catalyst Pd(OH)2 yielded the product 3-epi-xestoaminol C and xestoaminol C with concomitant aziridine ring opening in regioselective manner and the removal of the α-methylbenzyl group at the amine. However, we were not able to get the final products in analytically pure forms by single operation. We decided to get the products as their Boc-protected forms by performing hydrogenolysis in the presence of 1.1 equiv. of (Boc)2O to afford analytically pure products 6 and 7 from 4 and 5, respectively. Once we had Boc-protected forms of the 3

Efficient N-Boc protection of amines by a reusable heterogeneous solid acid nanocatalyst at room temperature

An efficient and rapid protocol for chemoselective N-Boc protection of various structurally different aryl, aliphatic, and heterocyclic amines is reported with (Boc)2O using mesoporous silica phenylsulfonic acid (SBA-15-Ph-SO3H) as a recyclable and heterogeneous solid acid nanocatalyst under solvent-free condition at ambient temperature. The catalyst can be easily recovered and reused for ten reaction cycles for protection of amines without considerable loss of activity. The advantages of this green method are simplicity, easy workup, chemoselectivity, short reaction time, and excellent yield.

ChemInform Abstract: Synthesis of 3‐(ω‐Hydroxyalkoxy)isobenzofuran‐1(3H)‐ones by Trifluoroacetic Acid‐Mediated Lactonization of tert‐Butyl 2‐(1,3‐Dioxol‐2‐yl)‐ or 2‐(1,3‐Dioxan‐2‐yl)benzoates.

An efficient two-step method for the preparation of 3-(2-hydroxyethoxy)- or 3-(3-hydroxypropoxy)isobenzofuran-1(3H)-ones 3 has been developed. Thus, the reaction of 1-(1,3-dioxol-2-yl)- or 1-(1,3-dioxan-2-yl)-2-lithiobenzenes, generated in situ by the treatment of 1-bromo-2-(1,3-dioxol-2-yl)- or 1-bromo-2-(1,3-dioxan-2-yl)benzenes 1 with BuLi in THF at −78°, with (Boc)2O afforded tert-butyl 2-(1,3-dioxol-2-yl)- or 2-(1,3-dioxan-2-yl)benzoates 2, which can subsequently undergo facile lactonization on treatment with CF3COOH (TFA) in CH2Cl2 at 0° to give the desired products in reasonable yields.

Synthesis and Anti-microbial Activity of Novel Phosphatidylethanolamine-N-amino Acid Derivatives.

The study involved synthesis of five novel amino acid derivatives of phosphatidylethanolamine isolated from egg yolk lecithin employing a three step procedure i) N-protection of L-amino acids with BOC anhydride in alkaline medium ii) condensation of - CO2H group of N-protected amino acid with free -NH2 of PE by a peptide linkage and iii) deprotection of N-protected group of amino acids to obtain phosphatidylethanolamine-N-amino acid derivatives in 60-75% yield. The five L-amino acids used were L glycine, L-valine, L-leucine, L-isoleucine and L-phenylalanine. The amino acid derivatives were screened for anti-baterial activity against B. subtilis, S. aureus, P. aeroginosa and E. coli taking Streptomycin as reference compound and anti-fungal activity against C. albicans, S. cervisiae, A. niger taking AmphotericinB as reference compound. All the amino acid derivatives exhibited extraordinary anti-bacterial activities about 3 folds or comparable to Streptomycin and moderate or no anti-fungal activity against Amphotericin-B.

Combining two-directional synthesis and tandem reactions. Part 21: Exploitation of a dimeric macrocycle for chain terminus differentiation and synthesis of an sp3-rich library

The application of a tandem condensation/cyclisation/[3+2]-cycloaddition/elimination reaction gives an sp3-rich tricyclic pyrazoline scaffold with two ethyl esters in a single step from a simple linear starting material. The successive hydrolysis and cyclisation (with Boc anhydride) of these 3-dimensional architectures, generates unprecedented 16-membered macrocyclic bisanhydrides (characterised by XRD). Selective amidations could then be achieved by ring opening with a primary amine followed by HATU-promoted amide coupling to yield an sp3-rich natural product-like library.

Synthesis of 3‐(ω‐Hydroxyalkoxy)isobenzofuran‐1(3H)‐ones by Trifluoroacetic Acid‐Mediated Lactonization of tert‐Butyl 2‐(1,3‐Dioxol‐2‐yl)‐ or 2‐(1,3‐Dioxan‐2‐yl)benzoates

AbstractAn efficient two‐step method for the preparation of 3‐(2‐hydroxyethoxy)‐ or 3‐(3‐hydroxypropoxy)isobenzofuran‐1(3H)‐ones 3 has been developed. Thus, the reaction of 1‐(1,3‐dioxol‐2‐yl)‐ or 1‐(1,3‐dioxan‐2‐yl)‐2‐lithiobenzenes, generated in situ by the treatment of 1‐bromo‐2‐(1,3‐dioxol‐2‐yl)‐ or 1‐bromo‐2‐(1,3‐dioxan‐2‐yl)benzenes 1 with BuLi in THF at −78°, with (Boc)2O afforded tert‐butyl 2‐(1,3‐dioxol‐2‐yl)‐ or 2‐(1,3‐dioxan‐2‐yl)benzoates 2, which can subsequently undergo facile lactonization on treatment with CF3COOH (TFA) in CH2Cl2 at 0° to give the desired products in reasonable yields.

A New, Efficient, and Catalyst-free Microwave-assisted Approach for Formation of O-tert-Butoxy Carbonates

Abstract A new simple, efficient, greener, and catalyst-free chemoselective protocol for the O-tert-butoxycarbonylation of various structurally diverse hydroxy compounds was carried out with (Boc)2O under microwave radiation. The corresponding O-tert-butoxy carbonates were obtained in good to excellent yields in a short reaction time without any side reactions.

A facile synthesis of saxagliptin intermediate N-Boc-3-hydroxyadamantylglycine

Commercial-scale synthesis of (S)-N-Boc-3-hydroxyadamantylglycine (I), which is the key intermediate of saxagliptin, can be achieved from 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid (6) by reductive amination with phenylalanine dehydrogenase. The biological enzyme used in the original medicinal chemistry route is expensive and not easily obtained, making it unsuitable for further development. In this work, we developed a conventional chemical approach to give the corresponding oxime from oxoacetic acid followed by reduction of oxime and protected amino with (Boc)2O to afford the racemic mixture of N-Boc-3-hydroxyadamantylglycine (III). Utilizing this route, N-Boc-3-hydroxyadamantylglycine was prepared in six linear chemical steps with 38 % overall yield.

Metal-free (Boc)2O-mediated C4-selective direct indolation of pyridines using TEMPO

Direct metal-free C-4-selective indolation of pyridines is achieved for the first time using TEMPO and (Boc)2O. A variety of substituents on both indoles and pyridines are tolerated to give 3-(pyridin-4-yl)-1H-indole derivatives in moderate to excellent yields. This finding provides a novel approach for developing metal-free C-H functionalization of pyridines.

A phosgene and peroxide-free one-pot tandem synthesis of isatoic anhydrides involving anthranilic acid, Boc anhydride, and 2-chloro-N-methyl pyridinium iodide

A phosgene and peroxide-free approach for the synthesis of isatoic anhydrides has been described. The synthesis involves the carbamate formation with Boc anhydride followed by in situ cyclization to afford the isatoic anhydride. The importance of this synthetic strategy is in the ease of operation, scalability, and preparation from readily available raw materials.

A Mild and Green Method for the N-BOC Protection of Amines without Assistant of Catalyst Under Solvent-free Conditions

A facile, green and versatile method for the Boc protection of amines has been developed by a treatment with (Boc)2O without any additive at room temperature. The method is general for the preparation of N-Boc derivatives of aliphatic (acyclic and cyclic), aromatic, and heteroaromatic amines; primary and secondary amines. The advantages of this method are green, simplicity, short reaction times and excellent yields. Keywords: N-BOC protection, green, catalyst-free, solvent-free

The comparison of protecting methods to the amino group in 2-Aminomethylphenylacetic acid

2-Aminomethylphenylacetic acid is an important intermediate of ceforanide, and this article compared two different protecting agents for protecting the amino group in 2-aminomethylphenylacetic acid by BOC (Di-tert butyl dicarbonate) or acetacetic ester, and compared the deprotection condition. The yield was higher when BOC was used as protecting agent, but when it was deprotected, it was more difficult than when acetacetic ester was used as protecting agent.

Ionic liquid (tetrachlorocobaltate(II) anion with a dicationic counterion) catalyzed N-Boc protection of amines

Ionic liquid (1,1′-hexane-1,6-diylbis(3-methylpyridinium) tetrachlorocobaltate(II) ([C6(mpy)2][CoCl4]2−)) catalyzed N-tert-butyloxycarbonylation (N-Boc) of various amines using (Boc)2O is reported. Halogenated aniline and amino alcohols were converted efficiently to their corresponding N-Boc derivatives without any side products. The reported method is mild, solvent free, uses low amounts of ionic liquid, allows easy product separation and results in high yields of the products. The catalytic efficiency for N-Boc formation in IL is superior to previously reported catalysts.

Regio-specific size, shape and surface chemistry designed dendrimers based on differentiated dendroid templates

Various generations of zero α,ω-alkylenediamine core poly(amidoamine) PAMAM dendrimers (tetra-amine terminated substrates, A4) were allowed to react with sub-stoichiometric amounts (i.e., 2.0 equivalents) of Boc anhydride to give product mixtures consisting of the symmetrical tetra-Boc product (B4) and four partial Boc protected adducts, namely, (1) the tri-(AB3), (2) di-geminal (A2B2), (3) di-vicinal (A2B2) and (4) mono-Boc (A3B) products. These unprecedented, regio-differentiated Boc cores possess emerging dendritic features and intrinsic “protect–deprotect” function. We refer categorically to these newly differentiated branched cores as differentiated dendroid templates (DDT's). These dendroid templates can be well resolved by thin layer chromatography (TLC). Gram quantities of these Boc adducts were purified using single pass silica gel column chromatography. These partial Boc protected, differentiated dendroid templates (AmBn, m/n = 1–3) were used as “protect–deprotect” functionalized starting substrates (i.e., regio-differentiated cores) for synthesizing higher generation libraries of regio-differentiated PAMAM dendrimers. In principle, the use of differentiated dendroid templates (i.e., regio-functionalized star-branched cores) should be expected to offer broad options for the systematic engineering and control of many diverse organic nanostructures as a function of size, shape and regio-chemistry.

Rhodium-Catalyzed Intramolecular Formation of N-Sulfamoyl 2,3-Aziridino-γ-lactones and Their Use for the Enantiospecific Synthesis of α,β-Diamino Acid Derivatives

4-Hydroxymethylbutenolide 4 was transformed into its sulfamoyl derivative 5, which upon treatment with iodosobenzene diacetate and magnesium oxide in the presence of a rhodium catalyst afforded the product of intramolecular aziridination 6. Reaction of 6 with primary or secondary amines in DMA led to regioselective opening of the aziridine ring at C2 to give the corresponding bicyclic derivatives 7a-7g in good to excellent yields. Methanolysis of the lactone ring of the N-benzyl-N-methyl derivative 7c followed by protection of the resulting secondary hydroxy group and treatment of the product with Boc anhydride provided the activated cyclic sulfamates 13 and 14. The latter then reacted with a second nucleophile (azide or thiophenol) to give the corresponding difunctionalized α,β-diamino methyl esters 15-18, 20.