Scale reaction, protocols

We found that the optimal reaction protocol was to add a solution of a-bromo ketone in THF to the amidine in aqueous THF in the presence of potassium bicarbonate under vigorous reflux. Using this procedure, 2,4-disubstituted imidazoles were isolated in excellent yields with >95% purity without column chromatography. Aromatic and aliphatic a-halo ketones participate in this reaction with a variety of aromatic amidines, as indicated in Table 1. Particularly noteworthy is that reactions involving pyridylamidines or chloroacetone are substantially more robust using this process (entries 3 and 4). We have successfully used this protocol on a multi-kilogram scale. 

The Anton Paar Synthos 3000 (Fig. 3.16 and Table 3.5) is the most recent multi-mode instrument to come onto the market. It is a microwave reactor dedicated for scaled-up synthesis in quantities of up to approximately 250 g per run and designed for chemistry under high-pressure and high-temperature conditions. The instrument enables direct scaling-up of already elaborated and optimized reaction protocols from single-mode cavities without changing the reaction parameters. 

C. Large-scale oxidation protocol. The large-scale oxidations reactions were carried out in a 300mL Parr autoclave equipped with an injection port, a thermocouple port, a septa sealed addition port and port connected to the volumetric measurement and gas supply module. The module consists of a forward pressure regulator and a calibrated ballast reservoir. The pressure in the reactor and in the ballast reservoir is monitored constantly and the pressure drop in the ballast reservoir is constantly converted into moles of oxygen uptake recorded vs. the time. 

Note The reaction can also be performed at multigram scale. Owing to the CO released in this reaction, a bubbler should be connected to the condenser in the scaled-up protocol rather than an argon-filled balloon.)... 

Oxoammonium salts react with water resulting in the generation of hydrogen peroxide.14 This side reaction is minimized at 0°C. A substantial amount of heat is evolved in oxidations following Anelli s protocol therefore, on multigram scale reactions it may be very difficult to keep a temperature as low as 0°C. In such cases, an efficient oxidation can be achieved at 10-15°C, a temperature in which the decomposition of oxoammonium compounds does not compete substantially with the desired oxidation of alcohols.15... 

Whereas batch synthesis on the small scale is the standard procedure in microwave-assisted synthesis and has been extensively reviewed ( [50-52] and references cited therein), protocols in the 50 mL range are rather rare. In this section, scale-up of volumes > 50 mL in sealed vessels will be discussed. An important issue for the process chemist is the potential of direct scalability of microwave reactions, allowing rapid translation of previously optimized small-scale conditions to a larger scale. Several authors have reported independently the feasibility of directly scaling reaction conditions from small-scale single-mode (typically 0.5-5 mL) to larger scale multimode... 

A comprehensive study on the scalability of optimized small-scale microwave protocols in single-mode reactors to large-scale experiments in a multimode instrument has been presented by Kappe and coworkers [26]. As a model reaction, the classical Biginelli reaction in acetic acid/ethanol (3 1) as solvent was rim in parallel in an eight-vessel rotor system of the Anton Paar Synthos 3000 synthesis platform (Fig. 8) on a 8 x 80 mmol scale [26]. Here, the temperature in one reference vessel was monitored with the aid of a suitable probe, while the surface temperature of all eight quartz reaction vessels was also monitored (deviation less than 10 °C, see Fig. 16). The yield in all eight vessels after 20 min hold-time at 120 °C was nearly identical, resulting in an overall amount of approximately 130 g of the desired dihydropyrimidine. 

Take a dry 10 mL pear-shaped flask filled with argon and stoppered with a septum. To this add 0.5 M solution of bis(tri-/7-butylammonium pyrophosphate in DMF (1.2 mL, 0.6 mmol) prepared in Protocol 9, 2 mL of dry DMF and finally dry tri-/7-butylamine (290 p.L, 1.2 mmol). Vortex/mix this mixture for about 30 s and then add to the reaction immediately in one portion. Triphosphate formation may be monitored by ion exchange FIPLC (Protocol 6) or silica TLC (Protocol 7) but should be complete within 10 min. A typical silica TLC plate is shown in Figure 9.6. (Note In our experience, 3 eq. of the pyrophosphate/tributylamine is generally adequate in this step, although in some circumstances we have used 4 eq., notably for smaller-scale reactions. In this latter case, the triphosphate will probably require HPLC purification following MPLC in order to remove all the excess pyrophosphate—see Protocols 19 and 20). 

This unwanted side reaction can be eliminated by the use of Fmoc-OSu, which was proposed by several groups and is now the long preferred option for the introduction of the group. A typical reaction protocol for the synthesis of Fmoc-Trp-OH on a five-mole scale is given. 

The second step in the above sequence, deprotonation followed by silylation of the resulting enolate, was not successful under standard lithium diisopropylamide (LDA) conditions, presumably because silylation of the lithium enolate was slow. The deprotonation/silylation can be carried out effectively using KHMDS, which is available from Aldrich Chemical Company, Inc., as a 0.5 M solution in toluene. This protocol is quite general for the preparation of various dienes containing different silyl and amino groups as illustrated in Table I.5-7 For preparative scale reactions, such as that described above, the use of NaHMDS was preferred as it is available from Aldrich Chemical Company, Inc., as 1.0 M solution in THF. The procedure described here also provides a convenient and high-yielding preparation of Danishefsky s diene (1-methoxy-3-trimethylsiloxy-1,3-butadiene).8... 

The hydrovinylation of styrene has been carried out at -60 C on an 8.26 kg (79.6 mol) scale by the Wilke group using the azaphospholene hgand 8. The yield (41%) and enantioselectivity (87.4% ee) are lower than what is observed for small-scale reactions, and further developmental efforts are needed before the reaction can be practiced on an industrial scale. The low temperature and the esoteric nature of the ligand may also limit further apphcations of this chemistry. Discovery of new protocols which yield nearly quantitative yields [12] on a laboratory scale, the use of other metals (especially palladium), and a new generation of ligands that are under investigation in several laboratories may ultimately overcome the current problems. 

However, the approach we outlined in this work allows us to assess the magnitude of the driving force attributable to [1] and [2] in a way that provides a safe and efficient reaction protocol for scale-up, even in the absence of detailed mechanistic information. We do this by changing the value... 

After analyzing this reaction protocol, two primary differences between a small scale and a large scale reaction were considered that could potentially account for the problems in the 5 g experiment. 

Porco has reported the gold(III)-catalyzed cydization of o-alkynylbenzaldehydes as a route to azaphilones and related compounds [40]. Toward this goal, treatment of o-alkynylbenzaldehyde 26 with a catalytic amount of Au(OAc)3 in a 10 1 DCE/TFA mixture led to quantitative formation of the benzopyrylium salt 27 within 1 min at room temperature (Scheme 12.7). In a preparative-scale reaction, gold(III)-catalyzed cydization of 26 followed by oxidation with IBX led to isolation of azaphilone 28 in 84% yield (Scheme 12.7). Similarly, the two-step cyclization/oxidation protocol was applied to the synthesis of a number of unnatural azaphilones. 

The use of hydrophilic sulfonated phosphines TPPMS and particularly TPPTSf allowed development of a very mild procedure for Heck reactions of iodoarenes and iodoalkenes, though this protocol requires a large amount of expensive catalyst, which makes this scheme unsuitable for large-scale reactions. The method showed unusual selectivity trends for example, in the reactions with cycloalkenes no migration of double bond was reported. "" Also, a very rare endo-trig-mode of cyclization is favored in the aqueous phosphine-assisted method compared to the normal exo-trig-mode observed in nonaqueous methods (Scheme 35). "" " ... 

In 2002, Zhu reported an example of oxidative carbon-carbon coupling catalysed by a gold(iii) complex where air was the sole oxidant (Scheme 16.39). Tertiaiy amines were coupled with nitroalkanes or ketones in the presence of 3 mol% of complex XXm. The reaction was carried out using the corresponding nitroalkane or ketone as solvent and in some cases a small amount of methanol was added. In the case of the coupling with ketones, the addition of 4 A molecular sieves and small amounts of acid were proven to be beneficial for the reaction. Remarkably, this protocol could be scaled up and one of the products was successfully prepared on a 1 g scale. The protocol was expanded to the coupling of tertiary amines and phosphine oxides in a later report by the same group. ... 

Cool the zirconacycle solution prepared in Protocol la to -78°C and then evacuate the reaction flask through stopcock B. There will be some bubbling as gases are removed. Close stopcock B and open stopcock A to admit carbon monoxide. For larger scale reactions this evacuate/refill cycle should be repeated. 

Scale-up Protocol for Homogeneous Reactions. Chemists report a yield of R of 68% for a reaction in which they added reagent B to A in the ratio 1.05 A/B in a round-bottomed flask with paddle impeller over a 1 h period with cooling to control the temperature at 50°C. A and B are both dissolved in solvents that are miscible in all proportions. B is consumed completely. The amounts of unreacted A and by-product S in the final reaction mixture were determined analytically to be 19% and 14%, respectively. Evaluation of the effectiveness of mixing in the round-bottomed flask can be useful but is difficult to characterize, as the types of impellers often used provide good circulation but low shear. The small scales involved may mask mixing effects. 

Scale-up Protocol for Solid-Liquid Reactions. Refer to Section 13-4.3.1 and change reagent B from being dissolved in a miscible solvent to being added as a fine powder, all other factors remaining unchanged. 

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