Standard Carbonyl chloride

The reaction between 6-aminopenicillanic acid (6.5 g) and 3-o-chlorophenyl-5-methyllsoxa2ole-4-carbonyl chloride (7.66 g) gave the sodium salt of 3-o-chlorophenyl-5-methyl4-isoxa2olyl-penicillin (9.9Bg) asa pale yellow solid. Colorimetric assay with hydroxy lamina against a ben2-ylpenicillin standard indicated a purity of 6B%. 

Electrophilic additions to 7t-deficient heterocycles are less common than those to 7t-excessive heterocycles. However, intramolecular electrophilic cyclizations have been used to access the heterocycles of interest in this chapter <1996CHEC-II(7)49>. Recent examples include the preparation of a pyrrolo[2,3-f]pyrazole 165 by acid-catalyzed condensation of 163 and 164 (Equation 37) <1999SC311> and the reaction of 3-(4-pyrazolyl)acrylic acids 166 with excess thionyl chloride in the presence of benzyltriethylammonium chloride (BTEAC) to afford 4-chlorothieno[2,3-f]pyrazole-5-carbonyl chlorides 167 (Equation 38) <2003RJ0893, 2003ZOK942>. In the latter case, the reaction products were readily manipulated to prepare corresponding carboxylic acids, esters, and amides using standard procedures. 

For the analyst it is important to note that carbonyl chloride is an extremely acute toxic substance (irritant capable of producing delayed pulmonary edema) and is gaseous at room temperature (b.p. 7.5°C/1013 mbar).Therefore, all processes in which carbonyl chloride may be liberated must be carried out in a fume cupboard. Skin and eye contact with carbonyl chloride solutions and especially the inhalation of carbonyl chloride vapour must be avoided. It is recommended not to work with pure carbonyl chloride but with commercially available solutions, for instance 20 % carbonyl chloride in toluene (density at 20 °C 0.935 kg/1) corresponding to a concentration of 1.93 Mol per litre or 191 g/1. Stock solutions and standard solutions should be prepared and stored in closed containers. 

Whereas carbonyl chloride itself is very moisture sensitive and requires the corresponding precautions such as efficiently dried glassware and solvents, the Box derivative is very stable and can be analysed by high performance liquid chromatography (HPLC) with ultra violet (UV) detection at 270 nm. Quantification is achieved by the standard addition procedure spiking carbonyl chloride into the test polymer solution. However, since Box is a commercially available chemical, it is advisable to work also with Box standards, especially when the method is used for the first time and when problems are experienced in the HPLC determination or the derivation procedure. The standards of the carbonyl chloride derivative are particularly useful to establish the analytical system and to check linearity of detector response as well as for the recovery check. 

For illustration purposes, in the following the determination of carbonyl chloride in test sample is described in detail. From the measurements of the calibration samples prepared according to the standard addition procedure a calibration graph is obtained as depicted in Fig. 10-9. 

In addition, testing scope and limitations of this sequence and the conditions, ferrocenyl substituted isoxazoles 23 were synthesized from ferrocenyl carbonyl chloride (R = ferrocenyl) and/or ethynyl ferrocene (R = ferrocenyl), and were often obtained as red crystals [99]. Unfortunately, standard conditions of the cycloaddition step failed, which had to be conducted at room temperature (Scheme 16). 

Whereas the original Moffat-Pfitzner oxidation employs dicyclohexylcarbodiimide to convert DMSO into the reactive intermediate DMSO species 1297, which oxidizes primary or secondary alcohols via 1298 and 1299 to the carbonyl compounds and dicyclohexylurea [78-80], subsequent versions of the Moffat-Pfitzner oxidation used other reagents such as S03/pyridine [80a, 83] or oxalyl chloride [81-83] to avoid the formation of dicyclohexylurea, which is often difficult to remove. The so-called Swern oxidation, a version of the Moffat-Pfitzner oxidation employing DMSO/oxalyl chloride at -60°C in CH2CI2 and generating Me2SCl2 1277 with formation of CO/CO2, has become a standard reaction in preparative organic chemistry (Scheme 8.31). 

Decarboxylation of 16 using the previously described NMP, lithium chloride method provided the dione 32. Selective reduction of the least hindered carbonyl was readily effected using sodium borohydride providing 33. Hydroxymethylenation followed by O-alkylation of the butenolide unit by standard procedures provided the A-B-D-ring analog 34a,b (racemic mixture of epimers). 

This method is of quite general applicability and the carbonyl compound may be an aldehyde, a ketone, or an ester. Similarly, the halide may be chloride, bromide, or iodide although yields are generally lower with iodides. Alkyl and aryl halides react with equal facility and the alkyl halide may be primary, secondary, or tertiary. A few examples of the yields obtained with a variety of reagents are given in Table I (the yields quoted are obtained by g.l.c. analysis of the reaction mixture using an internal standard ). 

Benzo[e]thieno[3,2- ]thiepin-10(5Ef)-one 388 can be smoothly reduced with sodium borohydride to the corresponding alcohol, which forms the chloro substituted compound under standard treatment with thionyl chloride (1991CPB2564). Dihydro derivatives of pyrrolo-benzothiazepine 377 have been reported starting from ketone 373 by a carbonyl reduction, bromination and amination sequence (Scheme 76, Section 5.1.1 (1998JMC3763, 2002JMC344, 2004JMC143)). 

The synthesis of AFP-07 is shown in Scheme 9 [107], The enone 59 prepared from the Corey lactone was reduced with aluminum reagent and protected with f-butyidimethylsilyl chloride. Fluorination of the lactone 60 under the standard conditions gave the difluorolactone 61. The carbonyl group of the difluorolactone... 

In the absence of the activating second carbonyl functionality, it is necessary to use more ingenious methods to produce the same net effect. These procedures more often than not involve radical reactions. Among them is the thermolysis of tert-butyl esters of peroxyacids 437, which are readily synthesized in a standard esterification of tert-butyl hydroperoxide with an acid chloride. Decarboxylation proceeds via an initial homolytic cleavage of the 0-0 bond, elimination of CO2, and reduction of the incipient alkyl radical by an added hydrogen atom donor such as 438 (Scheme 2.143). Examples showing the exceptional synthetic importance of this decarboxylation procedure will be presented later. 

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