4- Chloropyrimidine

Submitted by Irving C. Kogon, Ronald Minin, and C. G. Overberger.1 

Caution This procedure should be carried out in a good hood. 

In a 3-1. three-necked round-bottomed flask fitted with a stirrer and a low-temperature thermometer is placed 500 ml. of concentrated hydrochloric acid (6.0 moles), and the solution is cooled to 0°. To the cooled solution, 142 g. (1.5 moles) of 2-amino-pyrimidine (Note 1) is added portionwise with stirring until a homogeneous solution is obtained. The solution is cooled to — 15° (Note 2), and a 500-ml. dropping funnel is fitted to the flask. A cold solution of 207 g. (3.0 moles) of sodium nitrite in 375 ml. of water is then added dropwise with stirring over a period of 55 minutes, the reaction temperature being maintained at —15° to —10° (Note 3). The solution is stirred an additional hour, and the temperature is allowed to rise to —5°. The mixture is then carefully neutralized to about pH 7 with a 30% solution of sodium hydroxide (about 3.0 moles), care being taken not to allow the temperature to rise above 0° (Note 4). The solid which forms, consisting of 2-chloropyrimidinc and sodium 

Purchased from the Matheson, Coleman and Bell Company, Norwood, Ohio. 

Care should be exercised since at this point nitrogen oxides are being evolved. Addition should be started cautiously, as there tends to be a rapid initial rise in temperature. 

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Aryl and alkenyl phenyl sulfides are prepared by the reaction of aryl and alkenyl halides and inflates with tributylstannyl phenyl sulfide. 2-Chloropyrimidine (737) is used for the coupling[606,607]. The diaryl or divinyl sulfide 739 is prepared by the reaction of distannyl sulfide (738)[548], N,N-Diethylaminotributyltin (740) reacts with aryl halides to give arylamines[608]. 

Better results were obtained when a mixture of chloroform and either pyrazole or C-methylpyrazoles was heated at 555 °C in a continuous-flow vapour phase reactor (79JCS(P1)2786). 2-Chloropyrimidines were obtained in high yields (51-89%). Indazole similarly gave only 2-chloroquinazoline (68%). 

From the standpoint of geometrical considerations, the major difference is in the far greater steric requirements of the nitro group. This could result in either primary or secondary steric effects. Nevertheless, primary steric effects do not seem to be necessarily distinguishable by direct kinetic comparison. A classic example is the puzzling similarity of the activation parameters of 2-chloropyrimidine and 2,6-dinitrochlorobenzene (reaction with piperidine in ethanol), which has been described by Chapman and Rees as fortuitous. However, that nitro groups do cause (retarding) primary steric effects has been neatly shown at peri positions in the reaction with alkoxides (see Section IV,C, l,c). 

The.effect of the entropy of activation was noted above for the quaternary pyridine salts (280 and 281). In future work, it may also be found to reflect the electrostatic or hydrogen-bonding interactions in transition states of amination reactions and the effect of reversible cationization of an azine-nitrogen. Brower et observed a substantial rate difference between piperidino-dechlorinations of 2-chloropyrimidine in petroleum ether and in alcohol due partly to the higher entropy of activation in the latter solvent (Table III, lines 3 and 4). 

The 2- and 4-chloro derivatives readily react with sodium methoxide in methanol at reflux (and probably at 25°) to yield 2-methoxy- and 4-methoxy-pyrimidine. The high order of reactivity of the 4-position is evident from the fact that 4-methoxy-2-chloropyrimidine (299) is the sole product formed on treatment of 2,4-dichloropyrimidine in methanol with one mole of sodium methoxide at 25° cf. 

Chloropyrimidine is aminated with alcoholic ammonia at 130° while 4-chloro-2-methyl- and 4-chloro-6-methyl-pyrimidine yield the corresponding 4-amino derivatives at 100°. 4-Aminopyrimi-dine is not prepared from the chloro analog because of facile self-quatemization (see Section III, B, 2 for comments on factors involved) of the latter. 

Amino group of 7-aminomethyl-2-substituted perhydropyrido[l,2-u]pyr-azines were reacted with 2-bromopyridine and 2-chloropyrimidines to give 7-(hetarylamino)methyl derivatives in the presence of Na2C03 in DMF at 100-120°C for 18h in 13-51% yields (00MIP15). An aminomethyl group of... 

Brompheniramine maleate Chlorpheniramine meleate Methyl phenidate HCI Tranzodone HCI 2-Chloropyrimidine Piribedil... 

The synthesis of 2-substituted pyrimidines from 1,3-dicarbonyl compounds and urea derivatives was first described by Evans2 and was later improved by Hunt, McOmie, and Sayer3 for the preparation of 2-mercapto-4,6-dimethylpyrimidine. Burness4 employed 3-ketobutyraldehyde acetal in this procedure to give 2-mercapto-4-methylpyrimidine. 2-Mercaptopyrimidine has been prepared from 1,1,3,3-tetraethoxypropane and thiourea by variations of this basic method 3 6 6 as well as by the reaction of 2-chloropyrimidine with thiourea 1 or sodium hydrosulfide.8... 

Nucleophilic substitution of leaving groups is probably the most important area in pyrimidine reactivity and, in particular, the differential reactivity of C-2 and C-4 is the most investigated topic. The displacement of 2- and 4-sulfide and sulfone groups is referred to in the synthesis section. The selective hydrolysis of 4-amino-2-chloropyrimidines under acidic conditions has been studied in great detail by a process research group <06OPRD921>. 

This trend is also observed in palladium chemistry where the general order for oxidative addition often correlates with that of nucleophilic substitution. Not only are 2-, 4- and 6-chloropyrimidines viable substrates for Pd-catalyzed reactions, but 4- and 6-chloropyrimidines react more readily than 2-chloropyrimidines. 

Chloropyrimidine was coupled with diethyl (3-pyridyl)borane in the presence of Pd(Ph3P)4, Bt NBr, and KOH to afford 3-(2 -pyrimidinyl)pyridine [23]. Likewise, the Suzuki coupling of 2-bromopyrimidine with diethyl (4-pyridyl)borane (47) led to 4-(2 -pyrimidinyl)pyridine (48) in 50% yield, whereas 2-chloropyrimidine produced 48 in only 20% yield under the same conditions [24], Diethyl (4-pyridyl)borane (47), on the other hand, was readily accessible from sequential treatment of 4-bromopyridine with n-BuLi and diethylmethoxyborane. 

Pd(dppb)Cl2 possessed greater effectiveness than Pd(Ph3P)4 for the coupling of 2-chloropyrimidine 49 and arylboronic acid 50 to afford 2-arylpyrimidine 51 [26,27],... 

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