Sealed-vessel conditions

In modern microwave synthesis, a variety of different processing techniques can be utilized, aided by the availability of diverse types of dedicated microwave reactors. While in the past much interest was focused on, for example, solvent-free reactions under open-vessel conditions [1], it appears that nowadays most of the published examples in the area of controlled microwave-assisted organic synthesis (MAOS) involve the use of organic solvents under sealed-vessel conditions [2] (see Chapters 6 and 7). Despite this fact, a brief summary of alternative processing techniques is presented in the following sections. 

A recent publication by the group of Baran reports the total synthesis of ageli-ferin, an antiviral agent with interesting molecular architecture (Scheme 4.16) [42], Just 1 min of microwave irradiation of sceptrin, another natural product, at 195 °C in water under sealed-vessel conditions provides ageliferin in 40% yield, along with 52% of recovered starting material. Remarkably, if the reaction is performed without... 

Most examples of microwave-assisted chemistry published to date and presented in this book (see Chapters 6 and 7) were performed on a scale of less than 1 g (typically 1-5 mL reaction volume). This is in part a consequence of the recent availability of single-mode microwave reactors that allow the safe processing of small reaction volumes under sealed-vessel conditions by microwave irradiation (see Chapter 3). While these instruments have been very successful for small-scale organic synthesis, it is clear that for microwave-assisted synthesis to become a fully accepted technology in the future there is a need to develop larger scale MAOS techniques that can ultimately routinely provide products on a multi kg (or even higher) scale. 

No specific recommendations can be given about the optimum reaction time. As speeding up reactions is a key motive for employing microwave irradiation, the reaction should be expected to reach completion within a few minutes. On the other hand, a reaction should be run until full conversion of the substrates is achieved. In general, if a microwave reaction under sealed-vessel conditions is not completed within 60 min then it needs further reviewing of the reaction conditions (solvent, catalyst, molar ratios). The reported record for the longest microwave-mediated reaction is 22 h for a copper-catalyzed N-arylation (see Scheme 6.63). The shortest ever published microwave reaction requires a microwave pulse of 6 s to reach completion (ultra-fast carbonylation chemistry see Scheme 6.49). 

Fig. 5.2 Temperature profile for a 30 ml sample ofwater heated under sealed-vessel conditions. Multimode microwave heating with 100 W maximum power for 8 min with temperature control using the feedback from a f ber-optic probe ramp within 120 s to 70 °C hold for 120 s at 70 °C ramp within 120 s to 100 °C hold for 120 s at 100 °C.

A direct addition of cydoethers to terminal alkynes has been discovered by Zhang and Li (Scheme 6.136) [271]. The best results were obtained when the reactions were run without additional solvent and in the absence of additives such as transition metal catalysts, Lewis acids, or radical initiators. Typically, the cycloether was used in large excess (200 molar equivalents) as solvent under sealed-vessel conditions. At a reaction temperature of 200 °C, moderate to good yields of the vinyl cycloether products (as mixtures of as and trans isomers) were obtained. The reaction is proposed to follow a radical pathway. 

In 2001, Linder and Podlech studied the microwave-assisted decomposition of diazoketones derived from a-amino acids [340]. In the presence of imines, the initially formed ketene intermediates reacted spontaneously by [2+2] cydoaddition to form /3-lactams with a trans substitution pattern at positions C-3 and C-4 (Scheme 6.179) [340], In order to avoid the use of the high-boiling solvent 1,2-dichlorobenzene, most transformations were carried out in 1,2-dimethoxyethane under sealed-vessel conditions. Solvent-free protocols, in which the substrates were adsorbed onto an inorganic alumina support, led only to the corresponding homologated /3-amino acids. Evidently, traces of water present on the support trapped the intermediate ketene. 

The final step in the synthesis ofthe pyridopyrimidinones (Scheme 7.10a) involved the release of the products from the solid support by intramolecular cyclisation, whereupon the pure products were obtained in solution. All reaction steps were carried out in a dedicated single-mode microwave instrument under sealed vessel conditions. 

Scale-up as defined for this chapter covers batch reactions in closed vessels at the > 50 mL scale, flow systems employing flow cells > 5 mL, and SF containers of > 50 mL volume. Microwave-mediated scale-up reactions under open vessel conditions are not discussed in detail as up to date only a few examples have been published [33-37] and most of the beneficial rate enhancements have been reported under sealed vessel conditions. 

Similar to the CEM equipment, Milestone offers the modular MicroSYNTH platform, which is based on the ETHOS digestion instrument [40]. The diversity of different rotor and vessel systems enables reactions from 3 to 500 mL under open and sealed vessel conditions in batch/parallel manner up to 50 bar of pressure. The START package offers simple laboratory glassware for reactions at atmospheric pressure under reflux conditions (Fig. 6). A protective... 

With those single-mode reactors that do not require a minimum filling volume (CEM Discover platform temperature measurement is performed from the bottom and not from the side by an external IR sensor) even volumes as low as 50 xL can be processed [57]. With the commercially available singlemode cavities of today, the largest volumes that can be processed under sealed vessel conditions are ca 50 mL, with different vessel types being available to upscale in a linear fashion from 0.05 to 50 mL. Under open vessel conditions higher volumes (> 1000 mL) have been processed under microwave irradiation conditions, without presenting any technical difficulties as, e.g., described for the synthesis of various ionic liquids on a 2 mol scale [35]. 

To decrease the probability of explosion during a microwave assisted synthesis under sealed vessel condition, involving volatile products, the chemists have used open vessel solvent-free conditions [4, 18]. 

The [2+2+1] cycloaddition of an alkene, an alkyne, and carbon monoxide is often the method of choice for preparation of cyclopentenones [118]. Groth et al. have demonstrated that such Pauson-Khand reactions can be performed very efficiently under the action of microwaves (Scheme 11.60) [119]. A small quantity, 20 mol%, of [Co2(CO)8] was sufficient to drive the reactions to completion under sealed vessel conditions, without the need for additional carbon monoxide. Under carefully optimized reaction conditions with 1.2 equiv. cydohexylamine as an additive in toluene, microwave exposure for 5 min at 100 °C provided good yields of the desired cycloadducts. Similar results were published independently by Evans et al. (Scheme 11.61) [120]. 

MW-assisted MCRs can also be conducted in standard organic solvents under both open and sealed vessel conditions. If solvents are heated in an open vessel, the boiling point of the solvent typically limits the reaction temperature that can be reached. The recent availability of modern monomode MW reactors [23] with on-line monitoring of both temperature and pressure has meant that MAOS in sealed vessels are increasingly commonly employed and this will be the method of choice for performing MW-assisted MCRs in the future, essentially if coupled with solvent-free procedures (cf Chapters 4 and 8). 

A sealed-vessel batch approach represents an attractive choice in the scale up of microwave-promoted reactions. The primary advantage is that most small-scale reactions are developed under sealed-vessel conditions in monomode equipment thus, scale up is potentially straightforward with little or no reoptimization needed. Disadvantages to this approach are the limits of reaction volume that can be irradiated as well as the safety requirements when working with vessels under pressure. 

There are many examples of the successful application of MW-assisted chemistry to organic synthesis these include the use of benign reaction media, solvent-free conditions, and application of solid supported and reusable catalysts. Over the past few years, it was demonstrated that many transition-metal-catalyzed bond transformations can be significantly enhanced by employing MW heating under sealed-vessel conditions, in most cases without requiring an inert atmosphere. 

The organozinc reagents for the Negishi couplings could be prepared by insertion of activated Rieke zinc dust into aryl bromides (or iodides). This transformation normally requires several hours under reflux conditions in THF (Zhu et al., 1991). This process was accelerated by the use of controlled microwave irradiation under sealed vessel conditions to 5-30 min. 

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