Bromination synthesis

The above synthesis, although performed on a small scale, is easily scaled up to industrial size (French Pat. 2,669,922, CA 118 P6734U). It is a general procedure for substituting aryl-Br with -OMe or -OEt, giving us the possibility to produce other compounds from already known substances, e.g bromination of MDA yields 6-Br-MDA. This is converted by the above procedure to MMDA-2, 133, active at 25-50mg, 8-12 hrs. 

Asaronealdehyde (2,4,5-trimethoxy-benzaldehyde) can be produced in the following way Methylate resorcinol. Product is 1,3-di-MeO-benzene. Do a Vilsmeyer aldehyde synthesis with POCI3/N-methylformanilide to obtain 2,4-di-MeO-benzaldehyde. Brominate and treat as described above to obtain asaronaldehyde. 

The high nucleophilicity of sulfur atoms is preserved, even if it is bound to electron withdrawing carbonyl groups. Thiocarboxylales, for example, substitute bromine, e.g. of a-bromo ketones. In the presence of bases the or-acylthio ketones deprotonate and rearrange to episulfides. After desulfurization with triphenylphosphine, 1,3-diketones are formed in good yield. Thiolactams react in the same way, and A. Eschenmoser (1970) has used this sequence in his vitamin B]2 synthesis (p. 261). 

Within the cubane synthesis the initially produced cyclobutadiene moiety (see p. 329) is only stable as an iron(O) complex (M. Avram, 1964 G.F. Emerson, 1965 M.P. Cava, 1967). When this complex is destroyed by oxidation with cerium(lV) in the presence of a dienophilic quinone derivative, the cycloaddition takes place immediately. Irradiation leads to a further cyclobutane ring closure. The cubane synthesis also exemplifies another general approach to cyclobutane derivatives. This starts with cyclopentanone or cyclohexane-dione derivatives which are brominated and treated with strong base. A Favorskii rearrangement then leads to ring contraction (J.C. Barborak, 1966). 

Synthesis of (A) started with the combination of 2,4,6-trimethylphenol and allyl bromide to give the or/Ao-allyl dienone. Acid-catalyzed rearrangement and oxidative bydroboration yielded the dienone with a propanol group in porlactone ring were irons in the product as expected (see p. 275). Treatment with aqueous potassium hydroxide gave the epoxy acid, which formed a crystalline salt with (R)-l-(or-naphthyl)ethylamine. This was recrystallized to constant rotation. 

The 2-anilinoselenazoles follow an analogous reaction path. The entry of bromine into the 5-position is in agreement as seen in Scheme 35. The 2-anilino-4-phenylselenazole gives a 5-bromo derivative by bromination. It is not identical with either of the bromo derivatives prepared by direct synthesis (Scheme 35) (99). 

Bromination of 2-brOmothia2ole leads to 2,5-dibromothiazole (5). 2-Bromothiazole can be used as a substrate in a malonic synthesis (72) starting from phenylacetonitrile the a phenyl-(2-thiazoiyl)-acetonitrile is obtained in high yields (84%) (Scheme 11). 

Acceptors. Most common acceptor molecules such as tetracyanoethylene or tetracyanoqurno dime thane ate commercially available. However, TCNQ can be synthesized in high yield by a two-step synthesis involving a condensation of malonitrile with 1,4-cyclohexanedione followed by treatment with an oxidizing agent such as bromine or A-bromosuccinamide in pyridine solvent (23) (Fig. 6). 

An alternative synthesis of (Z)-l-halo-l-alkenes involves hydroboration of 1-halo-l-alkynes, followed by protonolysis (246,247). Disubstituted ( )-and (Z)-a1keny1 bromides can be prepared from ( )- and (Z)-a1keny1 boronic esters, respectively, by treatment with bromine followed by base (248). 

Potassium bromide is extensively used in photography (qv) and engra ving. It is the usual source of bromine in organic synthesis. In medicine, it is a classic sedative. 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

Halogen-substituted succinimides are a class of products with important appHcations. /V-Bromosuccinimide [128-08-5] mp 176—177°C, is the most important product ia this group, and is prepared by addition of bromine to a cold aqueous solution of succinimide (110,111) or by reaction of succinimide with NaBr02 iu the presence of HBr (112). It is used as a bromination and oxidation agent ia the synthesis of cortisone and other hormones. By its use it is possible to obtain selective bromine substitution at methylene groups adjacent to double bonds without addition reactions to the double bond (113). 

Chemical Intermediates and Reagents. Table 1 Hsts some chemical intermediates and synthesis reagents containing bromine. The references cited in the table generally give a method of synthesis and often some physical properties. Other physical properties are also available (194—196). 

If bromine is used in equation 8, carbon tetrabromide [558-13-4] is formed. With a minor amount of iodine present, and in the absence of iron catalyst, carbon disulfide and chlorine react to form trichioromethanesulfenyl chloride (perchloromethyl mercaptan [594-42-3]), CCI3SCI, which can be reduced with staimous chloride or tin, and hydrochloric acid to form thiophosgene (thiocarbonyl chloride [463-71-8], CSCI2, an intermediate in the synthesis of many organic compounds (see Sulfurcompounds). 

Acylation of 2-methylpyrido[2,3-d]pyrimidines with anhydrides gives 2-acylmethyl derivatives (67), whilst bromination to the 7-bromomethyl derivative has been reported for 7-methylpyrido[3,2-d]pyrimidines (56JCS4433) in a synthesis of potential folic acid antagonists. 

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