Weygand/Hilgetag Preparative Organic Chemistry

Replacement of OH, OR, or =O by halogen 2 41
The reaction may also be carried out in the presence of a tertiary amine.
2,6,8-Trichloropurine is obtained from 2,6-dichloro-8-hydroxypurine by means
of POCI3 and dimethylaniline, 1065 and the preparation of 3-chloroindazole
from 0.2 mole of dry indazolone, 0.2 mole of dry pyridine, and 0.3 mole of
POCI3 is detailed in Organic Syntheses. 1066
The POCI3 may be replaced by PC15 or a mixture of the two. 1062 ' 1067 For
instance, 1,4-dichlorophthalazine is formed when phthalodihydrazide (32 g) is
heated with PC15 (100 g) for 4 hours at 150°. 1068
3,6-DicMoropyridazine: 1069 ' 1070 3,6-Pyridazinediol (25 g; from hydrazine dihydrochloride
and maleic anhydride 1069 ) is boiled in POC13 (300 ml) for 5 h under reflux. The excess of
POCI3 is distilled off in a vacuum and the residue is cooled, poured on ice, and made weakly
alkaline to litmus with ammonia. The precipitated product is dried in a vacuum and the
filtrate therefrom is extracted with CHC13. A further amount of crude product is obtained
from the dried CHC13 extract, the total yield being 87 %. Purification by vacuum-distillation
(b.p. 89-91 °/l -2 mm) or by recrystallization from hexane gives a product of m.p. 69-70°.
2-Chloropyrimidine: 1061 2-Pyrimidinol hydrochloride (5.3 g), PC15 (15 g), and POC13
(4 ml) are heated for 45min at 140-150°. Part of the POC13 is removed and the residual
solution is poured on ice and made alkaline with NaOH. NaCl is added and the 2-chloropyrimidine
is extracted in ether. Removal of the ether and recrystallization from light petroeum
give the product, m.p. 65°, in 93 % yield.
It is particularly easy to replace the OH of picric acid by Cl, although this
compound reacts with POC13 only when present as pyridine picrate.
Picryl chloride: 1071 Pyridine (7.9) is added to a hot solution of picric acid (22.9 g) in 95 %
alcohol (200 ml); on cooling, pyridine picrate (30.1 g, 98%), m.p. 166°, separates. Dry
pyridine picrate (1 mole), POC13 (0.67 mole), and benzene (250 ml) are boiled under reflux
for 15min; the benzene layer and the oil that separates are washed separately with hot
water; after removal of the benzene, the benzene layer affords 73 % and the oil 25 % of picryl
chloride, m.p. 79-81°.
4-Hydroxypyridine [4(l/f)-pyridone] and PC15-POC13 give 75% of 4-chloropyridine,
but heating with PBr5 at 110° gives only 47% of 4-bromopyridine,
3,4,5-tribromopyridine being a by-product. 1067
General directions for substitution of Br for OH in heterocycles by means of PBr5 or POBr3:
The hydroxy compound (1 mole) is mixed with PBr5 (1.05 mole) and heated at 100° for
6-8Jh with exclusion of water. The mixture is decomposed with ice and made alkaline with
Na2CO3 or NaOH solution; it is worked up by distillation in steam or extraction with a
suitable solvent. See, for example, the preparation of 3-bromo-6-methylpyridazine. 1072
,POBr3
OH
Br OH
3,4-Di br omopyr idazine
1065 J. Davoll, B. Lythgoe, and A. R. Todd, /. Chem. Soc, 1946, 833.
1066 E F M stephenson, Org. Syn., 29, 54 (1949).
1067 J. P. Wibaut and F. W. Broekman, Rec. Trav. Chim., 58, 885 (1939).
1068 H. D. K. Drew and H. H. Hatt, /. Chem. Soc, 1937, 16.
1069 R. H. Mizzoni and P. E. Spoerri, /. Amer. Chem. Soc, 73, 1874 (1951).
1070 E. A. Steck, R. P. Brundage, and L. T. Fletcher, /. Amer. Chem. Soc, 76, 3226
(1954).
1071 R. Boyer, E. V. Spencer, and G. F. Wright, Can. J. Res., 24 B, 200 (1946).
1072 C. Grundmann, Chem. Ber., 81, 7 (1948).