Continuous-flow methylations

The anomalous behavior of quinazoline was first discovered by Albert et who made the surprising observation that 4-methyl-quinazoline 2.5) was a weaker base than quinazoline (pA 3.5). Mason then observed that the ultraviolet spectrum of the quinazoline cation was abnormal but that the spectrum of 4-methylquin-azoline was normal (see Fig. 2). These anomalies led to the suggestion that water adds covalently to the cation of quinazoline to give 12 (R = H). The occurrence and position of hydration were confirmed by a detailed study of the ultraviolet and infrared spectra of the anhydrous and hydrated hydrochlorides and by mild oxidation of the cation to 4(3 )-quinazolinone. Using the rapid-reaction technique (the continuous-flow method), the spectrum of the unstable... 

In this short initial communication we wish to describe a general purpose continuous-flow stirred-tank reactor (CSTR) system which incorporates a digital computer for supervisory control purposes and which has been constructed for use with radical and other polymerization processes. The performance of the system has been tested by attempting to control the MWD of the product from free-radically initiated solution polymerizations of methyl methacrylate (MMA) using oscillatory feed-forward control strategies for the reagent feeds. This reaction has been selected for study because of the ease of experimentation which it affords and because the theoretical aspects of the control of MWD in radical polymerizations has attracted much attention in the scientific literature. 

Current single-mode continuous-flow microwave reactors allow the processing of comparatively small volumes. Much larger volumes can be processed in continuous-flow reactors that are housed inside a multimode microwave system. In a 2001 publication, Shieh and coworkers described the methylation of phenols, indoles, and benzimidazoles with dimethyl carbonate under continuous-flow microwave conditions using a Milestone ETHOS-CFR reactor (see Fig. 3.11) [104]. In a typical procedure, a solution containing the substrate, dimethyl carbonate, 1,8-diazabicy-clo[5.4.0]undec-7-ene (DBU) base, tetrabutylammonium iodide (TBAI), and a solvent was circulated by a pump through the microwave reactor, which was preheated to 160 °C and 20 bar by microwave irradiation (Scheme 4.31). Under these condi-... 

Scheme 4.31 Methylation of phenols, indoles, and benzimidazoles in a multimode continuous-flow microwave reactor.

A continuous-flow reactor with a fixed catalyst bed was employed at pressurized conditions. Gaseous dimethyl ether was supplied to the reactor at its vapor pressure with carbon monoxide while liquid reactants such as methyl acetate, methyl iodide, and water were fed with microfeeders. Methyl acetate used in this experiment was dehydrated by Molecular Sieve 5A before use. A part of the reaction mixture was sampled with a heated syringe and was analyzed by gas chromatography. 

A continuous-flow reactor with a fixed catalyst bed was employed under pressurized conditions. The reactor was made of stainless steel with an inner diameter of 6 mm. All products and unreacted feed materials were withdrawn in the gaseous state from the reactor through a heated pressure let-down valve, A quantitative analysis of the products was carried out by gas chromatography. The time factor, which corresponds to contact time, is expressed by W/F, where W is the weight of catalyst (g) and F is the total flow rate of feed (mol/hr). Chemisorption of H2, CO and methyl iodide (Mel) were measured by a conventional glass vacuum system. 

FAB ionization has been used in combination with LC/MS in a technique called continuous-flow FAB LC/MS (Schmitz et al., 1992 van Breemen et al., 1993). Although any standard HPLC solvent can be used, including methyl-ferf-butyl ether and methanol, the mobile phase should not contain nonvolatile additives such as phosphate or Tris buffers. Volatile buffers such as ammonium acetate are compatible at low concentrations (i.e., <10 mM). Continuous-flow FAB has also been used in combination with MS/MS (van Breemen et al., 1993). The main limitationsof continuous-flow FAB compared to other LC/MS techniques for carotenoids, such as ESI and APCI, are the low flow rates and the high maintenance requirements. During use, the 3-nitrobenzyl alcohol matrix polymerizes on the continuous-flow probe tip causing loss of sample signal. As a result, the continuous-flow probe must be removed and cleaned approximately every 3 hr. 

Extraction in liquid/liquid segmented flow has been developed. A continuous-flow extraction system coupled online with an RP-HPLC with C-l 8 and a UV detector was used to study the extraction of fenthion and azinphos methyl in water (82). 

The other five molecules which were identified using continuous-flow HPLC-1 H NMR spectroscopy at an observation frequency of 400 MHz were a-tocoenol with a mass of 428 (a double bond at Cl 1 ), a-tocotrienol with a mass of 424 (double bonds at C3, Cl and Cll ), (3-tocotrienol with a mass of 410 (double bonds at C3, Cl and Cl V, but with loss of a methyl on the phenyl ring), y-tocotrienol, also with a mass of 410 (like (3-tocotrienol but with loss of a different methyl group on the phenyl ring) and 8-tocotrienol with a mass of 396 (like (3-tocotrienol but with the loss of two methyl groups from the phenyl ring). 

In an application-focused work, Gmbbs and coworkers developed a microreactor for the continuous-flow ethenolysis of methyl oleate [59], This... 

Employing a stainless-steel continuous flow reactor, Zhang et al. (2004) described the synthesis of gram to kilogram quantities of material for use in early clinical studies. One reaction reported by the authors was the exothermic synthesis of N-methoxycarbonyl-L-ferf-leucine 210, as illustrated in Scheme 61. By continuously adding a solution of methyl chlor-oformate 211 to i-tod-leucine 212, in the presence of aq. NaOH 26, at a reactor temperature of —40°C afforded the target compound 210 in 91% yield with a throughput of 83.0 gh... 

By conducting the reaction in a flow reactor, where the heat of reaction can be rapidly dissipated, the authors were able to maintain a reaction temperature of 90 °C as a result of adding the nitrating mixture continuously. Coupled with a residence time of 35 min, the authors were able to attain a throughput of 5.5 gh 1 with an overall yield of 73% 219. In addition to the dramatic reduction in residence time (10h-35min) and the increased process safety, the continuous flow methodology afforded a facile route to the chemoselective synthesis of 2-methyl-4-nitro-5-propyl-2H-pyrazole-3-carboxylic acid 219. 

From the boiler, the chlorination products continuously flow into container 16. From container 16, the mixture is periodically fed into tank 14 to distil methyl(chloromethyl)dichlorosilane in vacuum. 

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