Fluoro derivatives

Although some nucleophilic fluorinatiuns have been reported in which potassium, caesium, silver or xenon fluorides react with suitably activated 

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Generally, the reactions of halopyrazines and haloquinoxalines with nucleophiles are believed to proceed by way of addition/elimination sequences, although there are clear-cut examples where this is not the case (see Section 2.14.2.2) and, consistent with a mechanism which involves bond forming, rather than bond breaking, reactions in the rate-determining step, fluoro derivatives are considerably more reactive ca. xlO ) than the corresponding chloro derivatives. 

In a series of reactions with potassium amide in liquid ammonia, 6-chloropyrido[2,3-f)]pyrazine gave reduction and ring contraction (Section 2.15.13.3), the 6-bromo analogue underwent only reduction, whilst the 6-fluoro derivative gave only the 6-amino substitution product (79JHC305). 

The marked influence of solvent and temperature on product composition is illustrated by results obtained with 3 5-hydroxy-5a-androstan-17-one (5), which yields in addition to the 3a-fluoro derivative (6) the elimination... 

Without exception the 17-secondary alcohols give three products, the dehydration products with migration of the 13j5-methyl group, the 17a-fluoro derivatives and the 17/5-chlorofluoroacetates. ... 

The addition of HF to the 5,6-double bond in 3-hydroxy-A -steroids has been investigated intensively. Bowers et al. prepared the 5oc-fluoro derivative (32) from pregnenolone acetate (31) in 10 % yield using methylene dichloride-THF as solvent at 0°. Pregnenolone itself is converted in 30%... 

This reaction is commonly achieved by diazotization of the amine in fluoro-boric acid, followed by decomposition of the diazonium salt (Schiemann reaction).Thus, l-amino-4-methylestra-l,3,5(10)-trien-17-one (50) is converted to the fluoro derivative (51) in 29% yield. The synthesis of 3-fluoroestra-l,3,5(10)-triene-17-one (55) from estrone proceeds via (52) and (53)... 

This topic has been reviewed [2, pp 94, 100-111, 130-134] All of the standard approaches to the synthesis of a compound like methyl 2-fluorostearate from methyl 2-bromostearate result mall yield of the 2-fluoro ester and the unsaturated esters. Although silver fluoride is not a new reagent, its use moist in wet acetonitrile to convert methyl 2-bromostearate to its fluoro ester is a departure from the traditional set of anhydrous conditions (Procedure 6, p 194) [71] In contrast, silver tetrafluoroborate converts a-chloroketones to their respective fluoroketones under anhydrous conditions. The displacement of less activated halogen groups by silver tetrafluoroborate to form their respective fluorides is novel Although silver tetrafluoroborate could not be used to convert an aliphatic terminal dichloromethyl or trichloromethyl group to its corresponding fluoro derivative, it is an effective fluorine source in other situations [72] (Table 8)... 

The reaLUons of phenyltetrafluorophosphorane with numerous silylated secondary or tertiary a- or (1-hydroxy esters, ketones, nitriles, ethers, nitro, and trichloromethyl derivatives have been investigated, the corresponding a or p fluoro derivatives are obtained in yields varying from reasonable to nearly quantitative [24, 25, 26, 27 The application of phenyltetrafluorophosphorane for fliiorination of silyloxy steroids has also been reported [28]... 

In contrast to phosphorus esters, sulfur esters are usually cleaved at the carbon-oxygen bond with carbon-fluorine bond formation Cleavage of esteri nf methanesulfonic acid, p-toluenesidfonic acid, and especially trifluoromethane-sulfonic acid (tnflic acid) by fluoride ion is the most widely used method for the conversion of hydroxy compounds to fluoro derivatives Potassium fluoride, triethylamine trihydrofluoride, and tetrabutylammonium fluoride are common sources of the fluoride ion For the cleavage of a variety of alkyl mesylates and tosylates with potassium fluoride, polyethylene glycol 400 is a solvent of choice, the yields are limited by solvolysis of the leaving group by the solvent, but this phenomenon is controlled by bulky substituents, either in the sulfonic acid part or in the alcohol part of the ester [42] (equation 29)... 

Reactions of alcohols with sulfur tetrafluoride, because of decomposition and/or polymerization, usually do not give fluorinated products However, in the presence of a hydrogen fluoride scavenger like triethylamine or pyridine, even such sensitive substrates as benzylic alcohols [555], 2-phenylethanol, and 2-furylmethanol [554] can be fluorinated to give the expected fluoro derivatives (equation 73)... 

Direct bromination readily yields the 6-bromo derivative (111), just as with uracil. Analogous chlorination and iodination requires the presence of alkalies and even then proceeds in low yield. The 6-chloro derivative (113) was also obtained by partial hydrolysis of the postulated 3,5,6-trichloro-l,2,4-triazine (e.g.. Section II,B,6). The 6-bromo derivative (5-bromo-6-azauracil) served as the starting substance for several other derivatives. It was converted to the amino derivative (114) by ammonium acetate which, by means of sodium nitrite in hydrochloric acid, yielded a mixture of 6-chloro and 6-hydroxy derivatives. A modified Schiemann reaction was not suitable for preparing the 6-fluoro derivative. The 6-hydroxy derivative (115) (an isomer of cyanuric acid and the most acidic substance of this group, pKa — 2.95) was more conveniently prepared by alkaline hydrolysis of the 6-amino derivative. Further the bromo derivative was reacted with ethanolamine to prepare the 6-(2-hydroxyethyl) derivative however, this could not be converted to the corresponding 2-chloroethyl derivative. Similarly, the dimethylamino, morpholino, and hydrazino derivatives were prepared from the 6-bromo com-pound. ... 

The usual order found with halogenonitrobenzenes is F > Cl Br I, the order of Cl and Br being variable, just as in heteroaromatic reactivity. The position of fluorine is of interest the available data indicate that it is usually the same as for nitrobenzene derivatives. Thus, in acid hydrolysis the order F > Cl for 2-halogeno-quinolines can be deduced beyond doubt since the fluoro derivative appears to react in the non-protonated form and the chloro derivative to resist hydrolytic attack even in the protonated form under appropriate conditions (Section II,D, l,d). Furthermore, in the benzo-thiazole ring, fluorine is displaced by the CHgO reagent at a rate 10 times that for chlorine. ... 

In an extensive investigation of the behavior of halogeno-pyridines and -quinolines towards potassium amide in liquid ammonia, tendencies to react according to the hetaryne type and other mechanisms were compared. The following results may be mentioned. 3-Fluoropyridine does not react via 3,4-pyridyne, but yields fluoro derivatives of 4,4 - and 2,4 -bipyridine. 3,6-Dibromopyridine is converted first into 6-bromo-3,4-pyridyne and not into 6-amino-3-bromopyridine. 2-Bromoquinoline yields 2-methylquinazoline together with 2-aminoquinohne. ... 

Synthesis of coordination compounds and catalysis with participation of fluoro derivatives of alkaloids 98KK3. 

Methylsulfonyl-9-(4-methylpiperazinyl)-3-methyl-2,3-dihydro-7-oxo-7//-pyrido[l,2,3- /e]-l,4-benzoxazine-6-carboxylic acid was obtained from 9-fluoro-lO-methylsulfonyl derivative with 1-methylpiperazine in MeCN at 60 °C for 16h. The boron chelate of lO-methoxylsulfonyl-9-fluoro derivatives gave the same result (99H(51)1563). 

Derivatives of 11 //-dibenz[6,e]azepine (morphanthridines) and 5/2-dibenz[Z>,/]azepine are valuable, commercial pharmaceutical products. The most important derivatives are the antidepressant, Depramine (16),30 the antiepileptic, Carbamazepin (17),62 the hypnotic agents Perlapine (18),63-64 and its 2-fluoro derivative (Fluperlapine),65 and Opipramol (19), an antidepressant and antipsychotic agent.66... 

Most recent syntheses of fluorinated benzothiazoles make use of nucleophilic substitution. Potassium fluoride in acetonitrile converted 40 into the 2-fluoro derivative (R = 6-nitro) in 99% yield. When the solvent was dimethylformamide the 2-dimethylamino derivative was formed instead [80JCS(P1)2358], and similar behavior was reported earlier (77BSF171). 

Fluorination. Attention has been focused on the direct fluorination of isoquinolines activated by conversion into 2-methylisocarbostyril (80). With gaseous fluorine (diluted to 10% with argon) in acetic acid a 54% yield of the 4-fluoro derivative was obtained. (Scheme 40). With methylene chloride as the solvent, only the 4-chloro analogue was formed [82H( 17)429]. Fluoroisoquinolines have also been made by displacement of nitro groups, and from diazonium fluoroborates (87JHC181). Hepta-chloroisoquinoline was converted into a perfluoro derivative by heating it in an autoclave with anhydrous potassium fluoride [66JCS(C)2328]. 

Moderate yields of the 1- (47%) and 4- (51%) fluoro derivatives of benzo[c]cinnoline were obtained by fluorodenitration of the nitro precursors using tetrabutylammonium fluoride. The 2- and 3-fluoro isomers have been made by Schiemann reactions, though yields were only 25 and 35%, respectively (92SC545). 

Preparation of 2-fluorofuranoses is also important in relation to the synthesis of biologically active 2 -fluoro derivatives of nucleosides (see Section 111,4). Su and coworkers prepared the 2-triflates 236 and 239 through acid-catalyzed methanolysis of 3,5-di-O-benzyl-1,2-(9-isopropylidene-a-D-ribofuranose [to give 235 (major) and 238] and subsequent triflylation. On treatment with fluoride ion, the anomer 236 afforded exclusively the furan derivative 237, whereas the a anomer 239 gave the 2-fluoro compound 240... 

The 4-triflates 277, 279, and 281 of benzyl 2,3-anhydro-o -D- and -) -L-ri-bopyranosides and -a-D-lyxopyranoside gave, - readily, on reaction with BU4NF [CgHg (24 h) or MeCN (5-8 h), r.t.], the respective 2,3-anhydro-4-deoxy-4-fluoro derivatives 278,280, and 282 in good yields. The conformation ( //s) of the starting compounds remained the same after fluorination. Methyl 2,3-anhydro-4-deoxy-4-fluoro-a-L-lyxopyranoside (284, 86%) was prepared from the 4-triflate 283 by treatment with EtjN- 3HF (CH2CI2-EtjN, 40°, 5 h). 

Direct conversion of the 6-sulfonates of D-galactopyranosides into their 6-deoxy-6-fluoro derivatives is usually hindered, because of the polar field-effect exerted by the lone electron pairs of the axial 0-4 (Ref. 158). Thus, the 6-0-mesylgalactoside 294 gave ° the 3,6-anhydro derivative 297 (23%) as the only isolated product on reaction with CsF in boiling ethanediol. How-... 

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