Birch Reduction Conditions Research Articles

Improved Synthesis of the Amine Fragment of FR901464 and Thailanstatins through the Development of a Convenient N-Detosylation Method.

FR901464 and thailanstatins are potent cytotoxic natural products that share an amine-containing tetrahydropyran ring. We previously reported the synthesis of the tetrahydropyran component. Here, we changed the protecting group for the amine from Boc to tosyl, improving yields and the time economy. A highlight of the revised synthetic scheme is the use of lithium, t-butanol, and ethylenediamine in THF (nontraditional Birch reduction conditions) for the N-detosylation.

C2‐(1 N/2 N‐Methyl‐tetrazole)methyl Ether (MeTetMe) as a Stereodirecting Group for 1,2‐trans‐β‐O‐Glycosylation

AbstractDevelopment of stereoselective synthetic methods for O‐glycosides is of paramount importance in the field of glycochemistry. Therefore, we report herein (1 N/2 N)‐methylated tetrazole methyl (MeTetMe) ethers as a C2‐directing group for the formation of 1,2‐trans‐β‐O‐glycosides. The synthesis of the tetrazole moiety was readily achieved by a 3+2 cycloaddition reaction on nitrile functionality. The tethered thioglycoside donors were found to deliver the β‐O‐glycosides when activated by PIFA‐TfOH reagent system. The reactions were performed with six newly synthesized phenyl and ethyl thioglycosides to obtain the glycosylated adducts in moderate to high yields and excellent to exclusive β‐selectivity. The glycosylation method was easily scalable up to grams without affecting the yield and stereoselectivity. The MeTetMe group was efficiently removed under Birch reduction conditions without affecting the benzyl ethers or isopropylidene acetal protection.

Enantioselective Formal Total Synthesis of (-)-Quinagolide.

The enantioselective formal total synthesis of (-)-quinagolide has been accomplished in a linear sequence of 8 purification steps from pyridine. The key steps are (a) organocatalyzed Diels-Alder reaction for fixing all three stereocenters on piperidine ring; (b) protecting group enabled deoxygenation of isoquinuclidine skeleton under Birch reduction condition; (c) Lewis acid (TiCl4) catalyzed intramolecular Friedel-Crafts cyclization of dicarboxylic acid; and (d) one-pot diastereoselective ketone reduction-intramolecular cyclization to form oxazolidinone which enables trans-geometry installation. During the course of the synthesis, an interesting reductive cleavage of the C-N bond in the electron-deficient isoquinuclidine skeleton under the Birch reduction conditions has been observed. This is the first synthetic effort to access the core skeleton of (-)-quinagolide.

Adverse Effect of PTFE Stir Bars on the Covalent Functionalization of Carbon and Boron Nitride Nanotubes Using Billups-Birch Reduction Conditions.

The functionalization of nanomaterials has long been studied as a way to manipulate and tailor their properties to a desired application. Of the various methods available, the Billups–Birch reduction has become an important and widely used reaction for the functionalization of carbon nanotubes (CNTs) and, more recently, boron nitride nanotubes. However, an easily overlooked source of error when using highly reductive conditions is the utilization of poly(tetrafluoroethylene) (PTFE) stir bars. In this work, we studied the effects of using this kind of stir bar versus using a glass stir bar by measuring the resulting degree of functionalization with 1-bromododecane. Thermogravimetric analysis studies alone could deceive one into thinking that reactions stirred with PTFE stir bars are highly functionalized; however, the utilization of spectroscopic techniques, such as Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy, tells otherwise. Furthermore, in the case of CNTs, we determined that using Raman spectroscopy alone for analysis is not sufficient to demonstrate successful chemical modification.

L‐Menthol‐Assisted Synthesis of P‐Stereogenic Phosphinous Acid Amides and Phosphine‐Boranes

Diastereomerically pure phenylphosphonous acid‐borane l‐menthyl ester N,N‐diethylamide was obtained through the fractional crystallization of a diastereomeric mixture of compounds synthesized from PhPCl2, l‐menthol, diethylamine, and BH3·THF. Treatment of racemic or diastereomerically pure phenylphosphonous acid‐borane derivatives with sodium in liquid ammonia followed by the addition of an electrophile led to the formation of phosphinous acid‐amides. Surprisingly, these compounds undergo preferential P–N bond cleavage under Birch reduction conditions.

ChemInform Abstract: The Reactivity of Arylphosphorus Acid Amides under Birch Reduction Conditions.

AbstractArylphosphorus acid amides undergo generally two processes under Birch reduction conditions ‐ Birch reduction or cleavage of the P‐aryl bond.

Intramolecular Glycosidation by Click Reaction Mediated Spacer Generation Followed by Spacer Cleavage

Abstract2‐O‐Propargyl‐substituted glycosyl donors and O‐(2‐azidobenzyl)‐substituted acceptors having a vicinal hydroxy group readily underwent the click reaction. Intramolecular glycosidation with N‐iodosuccinimide/trifluoromethansulfonic acid as the activating system afforded β‐(1–3)‐ and α‐(1–2)‐linked disaccharides as part of 14‐membered macrocycles. Descriptors for these reactions are proposed that consider the donor and acceptor attachment sites and the stereochemistry of the functional groups. Investigation of the influence of 2‐O‐linked 1‐aryl‐1,2,3‐triazol‐4‐ylmethyl groups, as contained in the spacer, on the anomeric selectivity exhibited no anchimeric assistance. In addition, it was shown that the spacer group can be readily cleaved under Birch reduction conditions.

Two-Fold Modification of the Phenyl Substituent in Phenylphosphonic Acid Monoester Monoamides

Phenylphosphonic acid ethyl ester N,N-diethylamide was subjected to a double modification of its phenyl substituent through directed ortho-metalation followed by dearomatization of the aryl substituent under Birch reduction conditions. Application of the same methodology to a diastereomerically pure phenylphosphonic acid monoester monoamide led to the formation of P-stereogenic cyclohexadienyl-phosphonic acid derivatives. The method offers a simple and efficient modification of phenyl substituent in organophosphorus compounds.

In Situ Dearomatisation/Alkylation of Arylphosphane Derivatives

AbstractThe dearomatisation of aryldialkylphosphane–boranes and aryldialkylphosphane oxides under Birch reduction conditions, followed by treatment with reactive alkyl halides, provides the corresponding α‐functionalised (cyclohexa‐1,4‐dien‐3‐yl)phosphane derivatives. This reaction offers a method of choice for the synthesis of bulky (cyclohexadienyl)phosphanes.

Ammonia-free Birch reductions with sodium stabilized in silica gel, Na–SG(I)

Ammonia-free Birch reduction conditions were developed based upon sodium stabilized in silica gel for a variety of substrates. In general, the yields were similar to those reported for lump sodium in liquid ammonia.

The partial reduction of electron-deficient pyrroles: procedures describing both Birch (Li/NH3) and ammonia-free (Li/DBB) conditions

The partial reduction of electron-deficient pyrroles using either Birch (Li/NH(3)) or ammonia-free (Li/di-tert-butyl biphenyl) conditions allows formation of pyrroline compounds in good yield and, when combined with a reductive alkylation or similar approach, leads to highly functionalized, synthetically useful compounds. This methodology has been proven in the syntheses of several complex natural products, all of which show interesting biological activity. This protocol describes in detail the following stages of the partial reduction procedure: formation of the reducing solution, partial reduction of the pyrrole compound and finally quench of the resulting anion/dianion using either protonating agents or an aldehyde. The ammonia-free conditions described herein are particularly useful for reactions requiring the use of reactive electrophiles, such as acid chlorides or enolizable aldehydes, which are incompatible with the standard Birch reduction conditions. The reaction procedure for the ammonia Birch reduction (procedure A) takes about 9.5 h to complete. Those described for the ammonia-free reductions, procedure B and procedure C, can be expected to take approximately 33 and 8 h, respectively.

An Enzymatic Approach to the Desymmetrization of Disubstituted Pyrrolines

The enzymatic desymmetrization of 2,2- and 2,5-disubstituted pyrroline compounds is reported in a procedure which gives access to both enantiomers in excellent enantiomeric excess and good yield. The enzyme reaction precursors are formed easily from two readily available substituted pyrroles using both ammonia (Na/NH3) and ammonia-free (Li/DBB) Birch reduction conditions.

Synthesis of clastro-Lactacystin β-Lactone

The highlight in this total synthesis of clastro-lactacystin β-lactone is the anti-selective reductive aldol reaction of electron-deficient pyrrole A under ammonia-free Birch reduction conditions to construct key intermediate C. The Donohoe group has applied this methodology to the synthesis of other natural products including Nemorensic acid (T. J. Donohoe, J.-B. Guillermin, D. S. Walter J. Chem. Soc., Perkin Trans. 1 2002, 1369-1375) and Secosyrin 1 (T. J. Donohoe, H. O. Sintim Org. Lett. 2004, 6, 2003-2006).

Selective Partial Reduction of Various Heteroaromatic Compounds with Bridgehead Nitrogen via Birch Reduction Protocol

[reaction: see text] For the first time various heteroaromatic compounds with bridgehead nitrogen, including indolizines, bispyrrolopyrimidines, pyrroloquinolines, pyrroloisoquinolines, and bispyrrolopyrazines, were selectively partially reduced under Birch reduction conditions. It was found that the double bond in the fused heterocycles which possesses the highest LUMO density can be selectively reduced under these conditions. Indolizine 6, containing an ester group at C-6, was reductively alkylated to give dihydroindolizines 8 and 9 possessing a quaternary carbon center in good yield. It was found that ambident substrate 12, under Birch reduction conditions, underwent smooth partial reduction to give 4,5-dihydroquinoline 14 as a sole product with no evidence of reduction of the side chain olefin. It was also shown that electron-rich pyrroloisoquinoline 15, which cannot be reduced via catalytic hydrogenation conditions, was efficiently transformed into its dihydrocounterpart 16 by using the Birch reduction protocol. Finally, it was shown that various fused diazines were smoothly and stereoselectively reduced under Birch reduction conditions to give trans-4,5-disubstituted dihydropyrimidines 30 and 32 in virtually quantitative yields.

Suspension Ring-Opening Metathesis Polymerization: The Preparation of Norbornene-Based Resins for Application in Organic Synthesis

A series of norbornene-based resin beads were obtained by aqueous suspension ring-opening metathesis polymerization (ROMP) and used as polymeric supports for organic synthesis. These resins were prepared from norbornene, norborn-2-ene-5-methanol, and cross-linkers such as bis(norborn-2-ene-5-methoxy)alkanes, di(norborn-2-ene-5-methyl)ether, and 1,3-di(norborn-2-ene-5-methoxy)benzene. The resulting unsaturated ROMP (U-ROMP) resins containing olefin repeat units were chemically modified using hydrogenation, hydrofluorination, chlorination, and bromination reactions to produce saturated ROMP resins with different chemical and physical properties. The hydrogenated ROMP (H-ROMP) resin was found to be highly resistant to acidic, basic, Lewis acid, and Birch reduction conditions and was assessed as a polymeric support in a series of solid-phase synthetic applications. The H-ROMP resin was found to have superior performance compared to polystyrene-divinylbenzene (PS-DVB) copolymers in aromatic nitration and acylation reactions. In a conventional five-step solid-phase synthesis of a hydantoin, similar results were obtained for both the H-ROMP and PS-DVB resins. The U-ROMP resin was also shown to be effective in the solid-phase syntheses of benzimidazoles and benzimidazolones.

Partial reduction of electron-deficient pyridines

The partial reduction of electron-deficient pyridines is described herein. Mono- and disubstituted pyridines can be transformed into functionalized dihydropyridines using either Birch reduction conditions or sodium/naphthalene in THF. The compounds formed by these high-yielding reductive alkylation protocols have potential as synthetic intermediates, and we have shown that bicyclo compounds containing 6,5, 6,6, and 6,7 ring systems can be prepared in one step via a base-promoted cylization.

Chemical Attachment of Organic Functional Groups to Single-walled Carbon Nanotube Material

We have subjected single-walled carbon nanotube materials (SWNTM's) to a variety of organic functionalization reactions. These reactions include radioactive photolabeling studies using diradical and nitrene sources, and treatment with dichlorocarbene and Birch reduction conditions. All of the reactions provide evidence for chemical attachment to the SWNTM's, but because of the impure nature of the staring materials, we are unable to ascertain the site of reaction. In the case of dichlorocarbene we are able to show the presence of chlorine in the SWNT bundles, but as a result of the large amount of amorphous carbon that is attached to the tube walls, we cannot distinguish between attachment of dichlorocarbene to the walls of the SWNT's and reaction with the amorphous carbon.

Polymeric fullerene hydrides. Birch reduction of [60] fullerene polymers from solution-based photopolymerization and free radical polymerization reactions

Fullerene polymers represent a new class of carbon materials for potential hydrogen storage applications. Poly[60]fullerene polymers were obtained by covalently linking [60]fullerene molecules in photochemical reactions. [60]Fullerene polymers were also prepared in free radical reactions of [60]fullerene with radical initiator benzoyl peroxide. The polymeric [60]fullerene materials were hydrogenated under Birch reduction conditions. The hydrides, which contain ≈3.5% (wt/wt) of hydrogen, were characterized by use of gel permeation chromatography, NMR, FT-IR, and elemental analysis. The results are compared with those of monomeric [60]fullerene hydrides.

A New Oxidative Conversion of Carbohydrate Benzyl Ethers to Benzoyl Esters with RuCl3-NaIO

Abstract The benzyl group is often used in organic synthesis, especially in carbohydrate chemistry, as one of the most useful of the hydroxyl protecting groups. Benzyl ethers are stable to basic conditions and the benzyl group is removed easily by hydrogenolysis or under Birch reduction conditions. Alternatively, the benzyl ether group is oxidized to benzoyl ester and removed under basic conditions. A few oxidation methods have been reported using more than a stoichiometric amount of chromium reagents such as CrO3-H2SO4 (Jones reagent)1 or CrO3-AcOH2. Here we report a new and mild oxidation of benzyl ether to benzoyl ester with a catalytic amount of RuO4 derived from RuCl3 and NaIO4. This method has proved effective in removing benzyl ether groups chemoselectively in the presence of benzylidene acetal and benzyl glycosidic functions.

An Efficient Dechlorination Method for 1,2,3,4-Tetrachloro-5,5-dimethoxycyclopentadiene Diels-Alder Adducts: Inverse Addition-Ethereal Birch Reduction Conditions

Modified Birch reduction conditions for the selective dechlorination of title compounds are described. Inverse addition of a suspension of lithium in liquid ammonia to a dilute ethereal solution of the adduct at −78 o C gives clean dechlorination with no accompanying alkene reduction