The preparation and properties of polyfluoro aromatic and heteroaromatic compounds

Kinetics of nucleophilic substitution reactions of polyfluoroaromatic compounds

Publisher Summary This chapter presents various developments that took place in Fluorine-19 nuclear magnetic resonance (NMR) spectroscopy between 1976 and 1978. The major part of the chapter consists of tables containing chemical shift and spin-spin coupling constant information for compounds in the liquid state or in solution. The remainder part of the chapter cover studies in solids and liquid crystals, together with biological applications and theoretical studies involving F-19 NMR. The tables are arranged according to the type of carbon (or element) to which the fluorine nucleus is bound. The appearance of a compound, with more than one type of fluorine-bonded carbon, in a particular table is according to which fluorine has its chemical shift reported and/or comes higher in the list of tables found above. Most of the tables consist of (a) the molecular formula of the compound, (b) the structure of the compound, (c) the F-19 chemical shift data, (d) the F-19 spin-spin coupling constant data, and (e) the literature reference number with the reference compound index. The other tables are arranged according to the index of the molecular formulae, and the convention adopted for priority of the elements is C, F, H, and then the other elements in alphabetical order. Only the relevant nuclei in the molecule are numbered and in cases where only one number is given but the system shows two chemical shifts, they are distinguished by letters following the number.

Fluorine- 19 Nuclear Magnetic Resonance Spectroscopy (1976–1978)

Irradiation of isoquinolinium hydroxytris(pentafluorophenyl)borate, 1, and phenanthridium hydroxytris(pentafluorophenyl)borate, 2, in either CH2Cl2 or CH3CN resulted in C6F5 transfer to the isoquinolinium and phenanthridium cations, generating 2-methyl-1-(2,3,4,5,6- pentafluorophenyl)-1,2-dihydroisoquinoline, 3, and 2-methyl-1-(2,3,4,5,6-pentafluorophenyl)-1,2-dihydrophenanthridine, 4, respectively. In addition, photogeneration of H2O·B(C6F5)3 resulted from 1. Photogeneration of C6F5−C6F4H from HO−B(C6F5)3- and of C6H5−C6F4H from C6H5−B(C6F5)3- was discovered.

Pentafluorophenyl Transfer: A New Group-Transfer Reaction in Organoborate Salts

Bromopentafluorobenzene (PFPBr) is an important building block for the preparation of polyfluorophenyl containing compounds.[1] Under different conditions, the PFP–Br bond can be cleaved in a diverse manner (Scheme 1). Through metallation reactions with alkali metals, alkyl lithium reagents, or oxidative additions to Pd (0), PFPBr serves as an equivalent of the PFP anion[2] (Mode I), which participates in reactions with diverse electrophiles or in cross-coupling reactions. On the other hand, there have been reports on the Br+ abstraction from PFPBr by nucleophiles (Mode II).[3] Herein, we report an unprecedented mode III, in which PFPBr works as an equivalent of both Br+ and PFP− in the same transformation: a one-pot arylative epoxidation of ketones into pentafluorophenyloxiranes (Mode III).



Scheme 1

Diverse Reactivity of PFPBr.



Our group has recently reported that alkynyl bromides and cyanogen bromide can act as equivalents of both Br+ and alkynyl- or cyanide anions in a highly efficient one-pot conversion of ketones into fully substituted alkynyl or cyanoepoxides.[4,5] Since the amphoteric reactivity of PFPBr as an equivalent of either Br+ or PFP− has been reported (Scheme 1), we hypothesized that it may also serve as a competent reagent for the one-pot cascade epoxidation reaction of ketones (Scheme 2). It was expected that an enolate would abstract Br+ from PFPBr to produce an α-bromoketone i and a PFP anion. Following nucleophilic addition of the latter at the carbonyl group would generate an alkoxide v, which, upon intramolecular SN2 reaction would produce the oxirane 2.



Scheme 2

Proposed Reaction Path for Epoxidation of Ketones with PFPBr.



To test the above hypothesis, the reaction of isobutyrophenone (1a) and PFPBr (3a) has been examined (Table 1). Gratifyingly, it was found that employment of LiHMDS in THF led to 23% yield of the epoxide 2a (entry 3)! Further brief optimization of the reaction conditions revealed that isobutyrophenone in the presence of NaHMDS in 1,4-dioxane almost quantitatively was converted into tetrasubstituted epoxide 2a (entry 9). Under these reaction conditions, 1-bromoperfluorobutane and 1-iodoperfluorobutane did not undergo this cascade transformation.[6]



Table 1

Screening of Reaction Conditions.



Next, the generality of the cascade transformation of different ketones with PFPBr was examined (Table 2). It was found that α,α-disubstituted methyl aryl ketones are suitable substrates for this transformation. Thus, isopropyl, cyclobutyl, cyclopentyl and cyclohexyl phenyl ketones (1a-d) smoothly reacted with PFPBr to produce epoxides 2a-d in good to excellent yields. Pyran-4-yl ketone 1e was also successfully converted to the corresponding product 2e. Diverse substituents at the phenyl ring, such as 4-methoxy (1f) and 4-cyano (1g, h), were tolerated in this reaction (entries 6–8). Moreover, different heteroaryl ketones, including pyridin-3-yl ketone (1j, j) and N-tosyl-indole-3-yl ketone (1k), were converted into the corresponding epoxides 2i-k in good yields (entries 9–11). Importantly, in contrast to the epoxidation reaction with alkynyl bromides[4] and cyanogen bromide,[5] PFPBr smoothly reacted with propiophenone 1l and butyrophenone 1m producing the corresponding trisubstituted oxiranes (2l, m) in good yield and very high diastereoselectivity[7] (entries 12, 13). It should be mentioned that this reaction is easily scalable, as 10 mmol scale reaction of propiophenone 1l with PFPBr resulted in outcome similar to that for 0.5 mmol reaction (entry 12).



Table 2

Synthesis of Pentafluorophenyl Oxiranes.



Next, the scope of bromopolyfluroarenes was tested. It was found that 1-bromo-4-trifluoromethytetrafluorolbenzene 3b, 1,4-dibromotetrafluorobenzne 3c, and 4-bromotetrafluoropyridine 3d were all competent reactants in this cascade transformation, producing the corresponding polyfluoroaryl (hetaryl) epoxides in good yields (2n-t). Although the reactions of 3b-d with propiophenone and butyrophenone produced good yields of the trisubstituted epoxides 2q-t, the diastereoselectivity was lower (entries 4–7) compared to that of the analogous reactions with PFPBr (Table 1, entries 12, 13).

The synthetic usefulness of the obtained polyfluorophenyl oxiranes was showcased by their further transformations. First, it was demonstrated that oxiranes 2b and 2l in the presence of stoichiometric amount of FeCl3 undergo a facile semipinacol rearrangement[8] to produce the ring expansion product 4a and a H-migration product 4b, respectively, in good to excellent yields (Scheme 3). Secondly, it was shown that the obtained polyfluorophenyl oxiranes are excellent substrates for SNAr reactions[9] (Scheme 4). Thus, 2l underwent efficient substitution reaction with piperidine and sodium methylthiolate to produce the corresponding N- and S-containing products 5a and 5b in excellent yields with no oxirane ring opening[10] products detected.



Scheme 3

Semipinacol Rearrangement of Oxiranes.





Scheme 4

SNAr on Pentafluorophenyl Ring.



In conclusion, we have demonstrated that amphoteric bromopolyfluoroarenes(heteroarenes) could serve as equivalents of both Br+ and aryl(hetaryl) anions in the same cascade transformation. Thus, reaction of enolizable ketones with bromopolyfluoroarenes leads to a variety of valuable tri- and tetrasubstituted epoxides[11] in good to excellent yields and diastereoselectivity. A synthetic usefulness of the obtained polyfluorophenyl-containing oxiranes was further demonstrated in their transformations, including a semipinacol rearrangement and SNAr reactions.

One‐Pot Arylative Epoxidation of Ketones by Employing Amphoteric Bromoperfluoroarenes

Nucleophilic displacement in polyhalogenoaromatic compounds. Part X. Transmission of substituent effects in polyfluorobiphenyl derivatives

Homolytic reactions of polyfluoroaromatic compounds Part VI. The mechanism of the phenylation of hexafluorobenzene

Homolytic reactions of polyfluoroaromatic compounds Part VII. Products and relative rates of phenylation of pentafluorobenzene, bromopentafluorobenzene and octafluorotoluene with benzoyl peroxide

John P.B. Sandall

Papers

Nucleophilic displacement in polyhalogenoaromatic compounds. Part X. Transmission of substituent effects in polyfluorobiphenyl derivatives

Homolytic reactions of polyfluoroaromatic compounds Part VI. The mechanism of the phenylation of hexafluorobenzene

Homolytic reactions of polyfluoroaromatic compounds Part VII. Products and relative rates of phenylation of pentafluorobenzene, bromopentafluorobenzene and octafluorotoluene with benzoyl peroxide

Homolytic reactions of polyfluoroaromatic compounds. Part XII. Aryldehydrogenation and aryldefluorination in polyfluorobenzenes

Homolytic reactions of polyfluoroaromatic compound. Part XI. Confirmation of the proposed mechanism of phenylation of polyfluoroaromatic substrates