1. The First Rapid Palladium-Catalyzed Aminations of (Azahetero)aryl Chlorides Under Temperature-Controlled Microwave Heating; Maes, BUW; Loones, KTJ; Lemiere, GLF; Dommisse, RA; Synlett 2003, No. 12, pp.1822-1825 An arylamine is an important entity due to its presence in many biologically active molecules. The most commonly used synthetic route for arylamines is the Pd catalyzed route developed independently by Buchwald and Hartwig. This route was developed for aryl bromide substrates and for a long time was unreactive for the lower cost, widely available aryl chlorides due to the strength of the C-Cl bond. This work reports on a general palladium-catalyzed amination protocol for (azohetero)aryl chlorides in minutes using a temperature controlled microwave irradiation technique. Yields of 75 –91% were obtained using activated and unactivated (azohetero)aryl chlorides with microwave irradiation times of 10 minutes at 150 – 200 o C
Transcript
1. The First Rapid Palladium-Catalyzed Aminations of (Azahetero)aryl Chlorides Under
An arylamine is an important entity due to its presence in many biologically active molecules. The most commonly used synthetic route for arylamines is the Pd catalyzed route developed independently by Buchwald and Hartwig. This route was developed for aryl bromide substrates and for a long time was unreactive for the lower cost, widely available aryl chlorides due to the strength of the C-Cl bond. This work reports on a general palladium-catalyzed amination protocol for (azohetero)aryl chlorides in minutes using a temperature controlled microwave irradiation technique. Yields of 75 –91% were obtained using activated and unactivated (azohetero)aryl chlorides with microwave irradiation times of 10 minutes at 150 – 200 oC
2. Efficient Palladium-Catalyzed Cross-Coupling of beta-Chloroalkylidene/arylidene
Malonates Using Microwave Chemistry; Poondra, RR; Fischer PM; Turner, NJ; J Org Chem 2004, 69, 6920-6922 β-aryl/alkylarylidene malonates are precursors to a wide range of heterocyclic compounds possessing biological activity. Typical approaches to these malonates relied on the Knoevenagel condensation that is limited to methyl ketones and cyclohexanone derivatives. This work reports on an efficient, versatile Suzuki reaction for the synthesis of β-aryl/alkylarylidene malonates from β-chloroalkylidine/arylidene malonates and boronic acids using microwave irradiation for 30 minutes at 100 oC. The reaction was amenable to a wide range of arylboronic acids including electron rich, electron deficient and sterically hindered ones. The use of the microwave system allowed the preparation of a number of analogues in a very short period of time.
3. Microwave-assisted direct addition of cycloethers to alkynes; Li, CJ and Zhang, Y; Tetrahedron
Lett., 2004, 45, 7581 – 7584
There is an interest in developing synthetic routes to prepare 2-vinyl substituted heterocycles in a ‘Green Chemsitry’ approach since they are key components for a large number of natural products showing biological activity. The traditional routes require the preparation of starting materials and involve an addition/elimination step that reduces yield by a minimum of 50%. This work reports on the direct addition of cycloethers with various terminal alkynes using microwave irradiation under neat conditions. Yields of 22-71 % were obtained at a temperature of 200 oC for reaction times of 30 –180 minutes. The addition of initiators or catalysts (either transition-metals or Lewis acids) was found to decrease the overall yield. The presence of an electron withdrawal groups on the aryl group of the aromatic alkyne improved the reaction. Alkynes having hydroxyl groups or amines do not require the addition of a protection group. The authors propose the reaction to proceed via formation of a malonyl radical that will then react with an alkyne.
4. Efficient O- and N-( β -fluoroethylation)s with NCA [18F] β -fluoroethyl tosylate under
In the field of labeling compounds with fluorine-18 (t1/2=109.8 min; β+=96.9%) for positron emission tomography (PET), no-carrier-added (NCA) [18F] β -fluoroethyl tosylate is widely used as a reagent for O- and N- fluoroalkylations. However, applications of this labeling agent are restricted by some disadvantages, including lower reactivity compared to alternative labeling agents (e.g. [18F] β -fluoroethyl triflate) and its sensitivity to some solvents and bases that are used in the labeling reactions. There is a significant desire to use the tosylated compound as it is much easier to synthesize, handle and has a greater shelf-life. Here is reported how improved radiochemical yields and practical convenience derive from the use of microwaves when using [18F] β -fluoroethyl tosylate to prepare [18F]N- β -fluoroethyl-amines, ethers and esters.
Reactions were rapid (2-10 minutes) and efficient (51-89% conversion). An otherwise sluggish reaction in acetonitrile, a low boiling point and medium polar solvent, became possible by using microwave as opposed to thermal heating. The use of high boiling point solvents, such as DMSO and DMF, which are difficult to remove, is avoided. RCYs for these reactions are at least 20% greater under microwave-enhanced condition than under thermal heating at similar temperatures and reaction times. For reaction with a bi-functional compound, such as DL-pipecolinic acid, [18F] β -fluoroethyl tosylate reacts exclusively with the amino group.
The second part of this article goes on to explain how the reaction can be chemioselective. By varying the base (or extending the reaction time), the authors found they could direct the formation of either the mono-substituted ester or the di-substituted compound (reaction at both the carboxylic acid and the amine).
5. Microwave-Assisted Preparation of Aryltetrazoleboronate Esters; Schulz, MJ, Coats, SJ
and Hlasta, DJ; Org. Lett., Vol. 6, No. 19, 2004.
The tetrazole functional group is of particular interest in medicinal chemistry due to its potential role as a bioisostere of the carboxyl group. Generally, a more favorable pharmacokinetic profile (i.e., increased biological absorption and greater metabolic stability) can be obtained by the bioisosteric replacement of carboxylic acids with tetrazoles while still retaining the desired pharmacological effect. Most methods for the preparation of tetrazoles from nitriles require long reaction times measured in hours or days.
This work discusses the development of a fast, efficient route for the preparation and isolation of aryltetrazoleboronates using a two-step microwave heating process at 150 oC for a total time of 20 minutes. The protection of the boronic acid functionality as the pinacol ester greatly increased preparative efficiency. Furthermore, this rapid method was scaled up to 15 mmol using a sealed 80 mL vessel and conducted under identical microwave conditions, giving the desired product, 3-tetrazolephenylboronic acid, in nearly quantitative yield.
6. Aqueous N-alkylation of amines using alkyl halides: direct generation of tertiary amines under microwave irradiation; Ju, Y and Varma, R; Green Chem., 2004, 6, 219-221. Amines are widely used as intermediates to prepare solvents, fine chemicals, agrochemicals, pharmaceuticals and catalysts for polymerization. The nucleophilic attack of alkyl halides by primary and secondary amines is useful for the preparation of tertiary amines but the reaction requires long reaction times and gives rise to a mixture of secondary and tertiary amines. This work reports on an environmentally-friendly synthesis of tertiary amines via direct N-alkylation of primary and secondary amines by alkyl halides under microwave irradiation that proceeds in water without phase transfer reagent.
A direct comparison of thermal and microwave heating was performed using mixtures of alkyl halides and amines in the presence of 1 equivalent of aqueous NaOH at atmospheric conditions. The microwave irradiated reactions went to completion in 1/60th of the time if the thermal reaction without side reactions. The reaction is general in nature and is applicable to aliphatic halides and both aromatic and aliphatic amines as summarized in Table 2. Interestingly, the intramolecular double-alkylation of primary amines occurs in reaction with dihalides such as 1,6-dibromohexane thus providing a potentially useful approach to assemble cyclic amines in a single step (entries 8 and 10, Table2)
7. Microwave-assisted N-arylation of a sulfoximine with aryl chlorides; Michael Harmata,
Xuechuan Hong and Sunil K. Ghosh ; Tetrahedron Letters 45 (2004) 5233–5236.
N-Functionalized sulfoximine derivatives exhibit therapeutic characteristics in multiple areas, possess antitumor activity, and are important synthetic intermediates for heterocyclic compounds. A common method for the preparation of N-arylated sulfoximines is to couple aryl bromides with NH-sulfoximines using palladium as a catalyst. This work investigates the use of microwave irradiation of the reaction using aryl chlorides as a substitute for aryl bromides to prepare N-arylated sulfoximines. The results are summarized in Table 1A process with a two-irradiation cycles at 135 oC for 90 minutes each with 5 equivalents of the aryl chloride provided yields of 43-94%
8. Microwave-Assisted Parallel Synthesis of a 4,6-Diamino-2,2-dimethyl-1,2-dihydro-1-phenyl-s-
Phenyl dihydrotriazines have been used therapeutically as antimalarial, anticancer, and antiparasitic agents. The phenyl dihydrotriazines are typically synthesized using a “one-pot-three-component” method for parallel synthesis of a library producing clean compounds in reasonable yields, but have reaction times of over 22 hours.
This work compares microwave assisted and conventional synthesis of a library of 20 phenyl dihydrotriazines with the aim of reducing reaction time and producing purer compounds in higher yields. The optimized microwave conditions were 90 oC for 35 minutes that were applied to all compounds made in the library, significantly reducing the overall time to make the library. In addition to shortened reaction times, the microwave technique provided purer products with the yields being comparable. This indicates that less time would be needed for the synthetic and purification processes.
9. A Highly Efficient Microwave-Assisted Suzuki Coupling Reaction of Aryl
Perfluorooctylsulfonates with Boronic Acids ; Zhang,W, Chen, CH-T, Lu, Y, and Nagashima, T.; Org Lett, 2004, 6(9); 1473-1476.
The palladium-catalyzed cross-coupling of aryl halides with aryl boronic acids (Suzuki coupling) is a powerful reaction for the construction of biaryls. The fluorous Suzuki coupling reaction employs aryl perfluorooctylsulfonates (ArOSO2(CF2)7CF3) as precursors that act as halide equivalents. The combination of microwave-assisted synthesis with a fluorous tagged reagents is shown to be a powerful tool to accelerate reaction with simplified purification for the synthesis of biaryls via a C-C bond.
A literature procedure was adapted for the fluorous Suzuki coupling reactions using [Pd(dppf)Cl2] (dppf ) 1,1¢-bis(diphenylphosphino) ferrocene) as a catalyst, K2CO3 as a base, and 4:4:1 toluene/acetone/H2O as a cosolvent. The reactions were conducted in a sealed-tube under single-mode microwave irradiation at 100-130 °C for 10 min. This general condition is compatible with a range of functionalized aryl perfluorooctylsulfonates with methoxy, aldehyde, ketone, and heterocyclic groups. It is also compatible with a broad range of boronic acids, including sterically hindered ortho-isopropoxy- substituted boronic acid and electron-deficient 3,4- dichlorophenylboronic acid (Table 1). After F-SPE, biaryl compounds were isolated in 75-95% yields with purity greater than 90%.
10. A method for generating nitrile oxides from nitroalkanes: a microwave assisted route
for isoxazoles; Giampaolo Giacomelli,* Lidia De Luca and Andrea Porcheddu; Tetrahedron 59 (2003) 5437–5440
Nitrile oxides undergo 1,3-dipolar cycloadditions with olefins and acetylenes to provide isoxazolines and isoxazoles, respectively. These products, besides being potential pharmaceutical agents, are also precursors to useful intermediates such as γ-amino alcohols and β-hydroxy ketones. Conventional synthetic methods suffer from limitations owing to the presence of some functional groups (dehydrogenation of aldoximes) or the relatively high reaction temperature may cause polymerization of the forming nitrile oxide (reaction of primary nitroalkanes with a dehydrating agent).This work reports on the use of 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) in the presence of DMAP as catalyst converting nitroalkanes to nitrile oxide and consequently can be used for their transformation into isoxazolines or isoxazoles under very mild conditions and in good yields. The procedure is based on treatment of DMTMM with four equivalents of the dipolarophile in acetonitrile at 20oC and 0.1 equiv of DMAP, followed after 15 min by addition of the nitroalkane (Scheme 1). After 8–10 h the reaction mixture is quenched with water and worked up to yield the heterocyclic compound.
Heating the reaction mixture at the reflux temperature (82oC) did not increase significantly the rate and the yields decreased drastically, because of formation of by-products. With the goal of reducing the reaction times, all reactions were repeated under microwave irradiation.
Reactions were performed using a flask equipped with a reflux condenser mounted outside the apparatus. In this case, the use of microwaves was crucial for the success of the reaction. A MeCN solution of DMTMM, 4 equiv. of the dipolarophile, 0.1 equiv. of DMAP and of the nitroalkane were completely converted and pure products 1 and 2 could be recovered after usual work-up.
11. Facile Syntheses of Oxazolines and Thiazolines with N-Acylbenzotriazoles under
Microwave Irradiation; Katritzky, AR; Cai, C; Suzuki, K and Singh, SK; J. Org. Chem. 2004, 69, 811-814.
Oxazolines and thiazolines are important heterocycles. Well known applications of 2-oxazolines include their use as synthetic intermediates, protecting groups, and chiral auxiliaries. Thiazoline derivatives possess anti HIV- 1,antimitotic, and bioluminescent activities,and have recently found applications as building blocks in pharmaceutical drug discovery. Limitations associated with standard synthetic methods include: high temperatures, low yields, long reaction times, use of complex reagents and/or use of strongly acidic conditions. This work reports on the use of N-acylbenzotriazoles in a mild, two step procedure for the direct synthesis of 2-substituted 2-oxazolines and 2-substituted 2-thiazolines under microwave irradiation in a reproducible and safe means with simplicity in processing and handling. The microwave reaction conditions were applied to the synthesis of a variety of 2-substituted 2-oxazolines 3a-j (Table 1).
The microwave procedure was also successfully applied to the preparation 2-substituted 2-thiazolines 5a-f,h,i in excellent yields (Table 2).
12. Microwave-Assisted Paal-Knorr Reaction. A Rapid Approach to Substituted Pyrroles
and Furans; Giacomo Minetto, Luca F. Raveglia, and Maurizio Taddei; Org. Lett., Vol. 6, No. 3, 2004.
Tetrasubstituted pyrroles are an extremely important class of heterocyclic compounds, displaying antibacterial, antiviral, anticonvulsant, and antioxidant activities and inhibiting cytokine-mediated diseases. A common approach to pyrrole synthesis is the Paal-Knorr reaction in which 1,4 dicarbonyl compounds are converted to pyrrole via acid-mediated dehydrative cyclization in the presence of a primary amine. The main limitations to intensive use of this reaction are the strong reaction conditions and the low availability of nonsymmetrical substituted 1,4-dicarbonyl compounds. This work describes a new rapid and versatile approach to tetrasubstituted pyrroles starting from commercially available β-ketoesters in few highly efficient steps, which conclude with a microwave assisted Paal-Knorr cyclization.
A series of differently substituted 1,4-dicarbonyl compounds were produced by reacting commercially available β-ketoesters with aldehydes followed by oxidation (Scheme 2).
This synthetic sequence has general application for the substrates seen in Table 1, providing yields of 86-92% for the 1,4 dicarbonyl compounds.
The tetrasubstituted pyrrole 14 was effectively obtained (see scheme 4) by microwave heating of a solution of the 1,4 dicarbonyl 4 in the presence of benzylamine and acetic acid in a sealed tube to180 oC for 3 min. It is worth noting that, when the reaction was conducted under traditional heating at 110 °C (external oil bath 150°C) for 12 hours, the starting material was still present in the reaction medium that had begun to become very dark with formation of less than 15% of the desired product.
Microwave-assisted Paal-Knorr cyclization was carried out on different 1,4-diketoesters in the presence of different amines and always gave the expected pyrroles 14-22 in good yields (see Table 2).
Table 2. 1,2,3,5-Tetrasubstituted Pyrroles Prepared as
