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Regioselectivity of bromofluorination of functionalized 1-alkenes
Journal of Fluorine Chemistry 102 (2000) 125±133
Regioselectivity of bromo¯uorination of functionalized 1-alkenes Martin LuÈbke, Rolf Skupin, GuÈnter Haufe*
Organisch-Chemisches Institut, WestfaÈlische Wilhelms-UniversitaÈt, Corrensstraûe 40, D-48149 MuÈnster, Germany Received 22 June 1999; received in revised form 30 June 1999; accepted 27 August 1999 Dedicated to Professor Paul Tarrant on the occasion of his 85th birthday
Abstract The regiochemistry of bromo¯uorinations of 1-alkenes with the combination of N-bromosuccinimide and amine/HF reagents mainly depends on the character of functional groups in the neighborhood of the double bond and only weakly from the ¯uorinating agent. While mono-substituted terminal alkenes mainly yield Markovnikov-oriented products, electron withdrawing groups in allylic or homoallylic position to the double bond destabilize carbenium centers in 2-position. Consequently, the part of anti-Markovnikov-oriented bromo¯uorides increases. Besides, with dropping reactivity of alkenes, the formation of dibromides becomes a competitive side reaction of bromo¯uorination. The extent of this process depends on the nature of the amine/HF reagent. This reaction is most important in case of the more nucleophilic trimethylamine bishydro¯uoride, while this process is neglectible with pyridinium poly(hydrogen ¯uoride) (Olah's reagent). # 2000 Elsevier Science S.A. All rights reserved. Keywords: 1-Alkenes; Bromo¯uorination; Regioselectivity; Amine/HF reagents; Electrophilic addition; Mechanism
1. Introduction Halo¯uorination of unsaturated compounds is an important method to place ¯uorine into organic molecules. Several of the commonly used protocols have been reviewed recently [1±5]. One of the most versatile procedures for bromo¯uorination has proved the combination of N-bromosuccinimide (NBS) as the source of the bromonium ion and triethylamine trishydro¯uoride (Et3N3HF) as the ¯uoride equivalent [6,7]. Among others also N-bromoacetamide [8,9] or 1,3-dibromo-5,5-dimethylhydantoin [10] have been applied as donors of the electrophile. Alternative ¯uoride sources such as liquid hydrogen ¯uoride [11,12] or ammonium- [13±16], pyridinium- [17,18], polymeric pyridinium poly(hydrogen ¯uorides) [19±21] or potassium ¯uoride in poly(hydrogen ¯uorides) [22], tetrabutyl-phosphonium dihydrogen tri¯uoride [23] and several others [15,24] have also been used. The poly(hydrogen ¯uorides) are relatively acidic and do attack glassware. So, they have to be applied in Te¯onTM or polypropylene ¯asks. Moreover, susceptible alkenes can oligomerize or isomerize prior to bromo¯uorination [25]. Recently, a comparison of several methods of generation of intermediary interhalogen ¯uorides in halo¯uorinations has been published [26].
The mechanism of bromo¯uorination involves the electrophilic, acid catalyzed attack of a positive bromine species to give a p-complex followed by generation of a cationic scomplex in the rate determining step. Finally, the backside attack of a nucleophilic ¯uoride species yields the bromo¯uorides (Scheme 1). Mechanistic alternatives have also been discussed [27]. The regiochemistry of bromo¯uorinations of ole®ns depends on the structure of the s-complex. The ¯uoride equivalent attacks non-symmetrically bridged species mainly at the position of better charge stabilization and
* Corresponding author. Fax: 49-251-83-39772. E-mail address: [email protected] (G. Haufe).
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved. PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 2 3 0 - 4
Scheme 1. Mechanism of bromofluorination.
M. LuÈbke et al. / Journal of Fluorine Chemistry 102 (2000) 125±133
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the Markovnikov-orientation is found in the main product. With aliphatic terminal ole®ns the ratio of regioisomers varies between 94:6 and 86:14 [7], while reactions of 2,2dialkyl- or aryl-substituted 1-alkenes show almost exclusive Markovnikov-orientation. Moreover, enolesters on bromo¯uorination with NBS/Et3N3HF showed exclusive Markovnikov-orientation, too [28].
Scheme 4. Bromofluorination of allylphenyl ether.
2. Results and discussion Bromo¯uorination of I- or M-substituted terminal unsaturated compounds as mentioned above are well known in literature. However, reactions of ole®ns bearing ÿIsubstituents in allylic or homoallylic position are rarely investigated. The in¯uence on the regioselectivity of bromo¯uorination of a hydroxyl group or an acetate or trichloro acetate function in b-position to the double bond was found relatively small. From allylic alcohol with NBS/Et3N3HF a 90:10 mixture of 3-bromo-2-¯uoropropanol and its regioisomer was formed (52% yield) [29] (Scheme 2), while from propene under the same conditions a 94:6 mixture of regioisomers was obtained [7]. For the corresponding reactions of allylic alcohol or its acetate with NBS (or NBA) and HF or pyridine/HF in ether formation of the primary bromide was reported as the sole product, however, in very low yields [29,30] while treatment of allylic trichloroacetate with NBA/HF in ether/pyridine gave the corresponding Markovnikov product in 69% yield [31] (Scheme 3). Interestingly, the reaction of 2-methylbut-3-en-2-ol with NBS/Et3N3HF gave no Markovnikov product at all, but yielded an 1:1 mixture of 3-bromo-4-¯uoro-2-methylbutan2-ol (anti-Markovnikov-orientation) and 4-bromo-3-¯uoro2-methylbutan-3-ol, a rearranged product [29]. The portion of the anti-Markovnikov product increases in case when an electron withdrawing substituent like a phenyl group is placed at the oxygen function. The bromo¯uorination of allylphenyl ether, which is only weakly-dependent on the ¯uorinating agent, gave 63:37 or 67:33 mixtures of the regioisomers in the presence of Et3N3HF or Olah's reagent, respectively, (Scheme 4). Besides, p-bromination
Scheme 5. Bromofluorination of vinyl oxirane.
of the aromatic ring was obtained to some extent (11% or 13%, respectively) [32]. Bromo¯uorination of vinyl oxirane with NBS/Et3N3HF gave a 73:27 mixture of the regioisomers (55% yield) in favor of the Markovnikov adduct (Scheme 5). Both regioisomers were formed as approximate 1:1 mixtures of erythro- and threo-isomers [33]. In contrast the product bearing the bromine next to the hydroxyl function was mainly formed when the positive charge can be stabilized by a methyl group in g-position to an oxygen. By way of example in the reaction of trans-but3-enol with NBS/Et3N3HF mainly 2-bromo-3-¯uorobutan1-ol was found [28] (Scheme 6). Similar results have also been reported for reactions of other allylic alcohols [29,34]. Allylic chloride on the other hand on reaction with NBS/ HF in THF gave a 80:20 mixture of the trihalopropanes in 35% yield in favor of the Markovnikov product [35,36] (Scheme 7). This means that there is not a big difference in the in¯uence of the hydroxy function, an epoxy function, a phenoxy group or a chlorine-substituent in allylic position of a terminal alkene in cases when no other stabilizing substituents are acting. In contrast allylic bromide under similar conditions led to a 41:59 mixture of regioisomers in favor of the anti-Markovnikov product [37] (Scheme 8).
Scheme 6. Bromofluorination of trans-but-3-enol. Scheme 2. Bromofluorination of allylic alcohol.
Scheme 3. Bromofluorination of allylic trichloroacetate.
Scheme 7. Bromofluorination of allylic chloride.
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Scheme 8. Mechanism of bromofluorination of allylic bromide.
One possible explanation for this ratio of regioisomers is the formation of a symmetrically bridged cationic intermediate I including two bromine atoms. Sterically hindered attack of the nucleophilic ¯uoride equivalent at the secondary carbon atom by two bromine substituents and better accessibility of the primary position in the mesomeric cationic structure II may determine the preferred formation of the anti-Markovnikov product. In order to examine the in¯uence of other electron withdrawing substituents on the regioselectivity of bromo¯uorinations of terminal ole®ns we investigated N-allylic imides and several other allylic and homoallylic systems. Moreover, in several cases under the conditions of bromo¯uorination the formation of 1,2-dibromides was obtained (wide infra). Factors in¯uencing this process have also been evaluated. The reaction of N-allylphthalic imide with NBS/ Et3N3HF gave 28:72 mixture of the Markovnikov product and its regioisomer. N-Allylsuccinic and N-allylmaleic imides behave analogously. Obviously the strong electron withdrawing effect of the imide moiety disfavors a potential secondary cationic center. Thus, the intermediate cation is mainly attacked in terminal position. In addition approximately 2% of vicinal dibromides have been isolated (Scheme 9).
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The extent of the formation of dibromides under the conditions of bromo¯uorination seems to depend on the reactivity of the ole®n as on the nature of the ¯uorinating reagent. Consequently, for the following experiments with several terminal alkenes bearing electron withdrawing functional groups in allylic or homoallylic position (in all cases the electronegative element is tied at carbon 4 in relation to the terminal unsaturated carbon atom), two different amine/ HF reagents have been used in combination with NBS as the electrophilic reagent. Trimethylamine bishydro¯uoride (Me3N2HF) which is known to be a source of a relatively nucleophilic ¯uoride equivalent [38] or Olah's reagent (Py9HF), a more acidic but less nucleophilic ¯uorinating reagent, have been applied. Bromo¯uorination of but-3-en-1-ol (homoallylic alcohol) with NBS/Me3N2HF gave a 83:17 mixture of 4-bromo-3¯uoro- and 3-bromo-4-¯uorobutanols contaminated with 5% of 3,4-dibromobutanol. The corresponding reaction with Olah's reagent yielded the bromo¯uorides in the same ratio, however, no traces of the dibromide have been detected by GC. Similarly, the reaction of 1-chloropent-4-en-2-ol under the mentioned conditions gave the regioisomeric bromo¯uorides in 79:21 or 85:15 ratio, respectively, as mixtures of diastereomers. In the ®rst case also 6% of the diastereomeric dibromides was formed (Scheme 10). Compared to the corresponding reactions of allylic alcohol (90:10) and 1butene (94:6), the regioselectivity of bromo¯uorination unexpectedly dropped only slightly. In case of 4-bromobut-1-ene (homoallylic bromide) a 3:1 mixture of regioisomers was formed independently from the ¯uorinating agent. The crude product of the reaction with Me3N2HF contained 4% of the tribromide (Scheme 11). In contrast, allylic bromide gave mainly the anti-Markovnikov product [37]. In comparison to the reaction of 1butene the regioselectivity of bromo¯uorination of homoallylic bromide dropped as expected. Reactions of vinylacetic acid under the conditions of bromo¯uorination gave mainly 3-bromobutyrolactone. Besides, some traces of ¯uorinated compounds were formed which have not been identi®ed. On the other hand, the
Scheme 9. Bromofluorination of N-allylphthalic imide.
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Scheme 10. Bromofluorination of but-3-ene-1-ol and 1-chloropent-4-ene-2-ol.
Scheme 11. Bromofluorination of 4-bromobut-1-ene.
Scheme 12. Bromofluorination of vinylacetic acid benzyl ester.
benzylic ester of this acid gave 3:1 mixtures of the bromo¯uorides, independently from the ¯uorinating agent. Applying the more basic Me3N2HF the yield was quite low and 14% of the dibromide was found, while no traces of this compound have been detected in the product mixture of the reaction with Olah's reagent (Scheme 12). Bromo¯uorination with BrF (generated in situ from the elements) of the methyl ester of vinylacetic acid gave a 63:37 mixture of the Markovnikov and the anti-Markovni-
kov products in high yield [39] (Scheme 13). Formation of a dibromide has not been reported. Finally, the reaction of allylic cyanide with NBS and Me3N2HF gave less than 2% of a 46:54 mixture of bromo¯uorides, while 3,4-dibromobutyronitril was the main product (>98%, GC). In contrast with Olah's reagent this compound was not detected, but a 45:55 mixture of 4bromo-3-¯uoro- and 3-bromo-4-¯uorobutyronitrile was isolated (Scheme 14).
Scheme 13. Bromofluorination of vinylacetic acid methyl ester.
Scheme 14. Bromofluorination of allylic cyanide.
M. LuÈbke et al. / Journal of Fluorine Chemistry 102 (2000) 125±133
Scheme 15. Mechanism of the formation of bromine by reaction of NBS and HFÿ 2 [40].
The formation of dibromides as minor side products has already been observed in some cases during our ®rst studies of bromo¯uorination of alkenes with NBS/Et3N3HF [40]. Also in reactions with HF pyridine with excess NBS [10] and in reactions of several ole®ns with NBS=Bu4 N H2 Fÿ 3 dibromides have been formed [16]. Since the part of dibromides in our reactions [6,40] never extended 5% (GC) we believed, that a small amount of elemental bromine which is usually present in NBS was responsible. However, in 1989 Guerrero and coworkers [41] showed that in reactions of ole®ns with NBS and tetrabutylammonium hydrogen di¯uoride (Bu4 N HFÿ 2 ) bromine can be formed according to the chain-mechanism shown in Scheme 15. In an initial step the reaction of NBS with HFÿ 2 (Scheme 15) gives the interhalogen, HF and a succinimidyl anion. Succeeding reactions of this anion with NBS produce bromide which gives elemental bromine by reaction with a third molecule of NBS. Assuming a hydrogendi¯uoride anion as ¯uorinating species of Me3N2HF this mechanism could operate in the considered reactions as well. Consequently, in case of less reactive ole®ns the reduction of NBS to form elemental bromine is faster than bromo¯uorination. Since two molecules of NBS are consumed for this process the relatively low chemical yield of the reaction could be explained. Calculated on consumed NBS the yield of the dibromide is almost quantitative in the reaction with allylic cyanide. Formation of dibromides has also been observed in bromo¯uorinations with NBS/Et3N3HF of other less reactive alkenes such as 1,2-di¯uoro-1,2-di(p-tolyl)ethene and 1,2,3,4-tetra¯uoro-1,4-di(p-tolyl)butadiene [5] or 2methylene-1,3-propanediol and its mono or bisalkyl ethers [42]. 3. Experimental 1
H NMR (300.13 MHz), 13 C NMR (75.48 MHz) and 19 F NMR (282.37 MHz) were recorded on a Bruker WM 300. Chemical shifts are reported as d values in units of ppm related to the internal standards TMS (d 0.0 ppm, 1 H NMR), CDCl3 (d 77.0 ppm, 13 C NMR) and CFCl3
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(d 0.0 ppm, 19 F NMR). Multiplicities of signals in 13 C NMR spectra were determined by DEPT operation, 19 F NMR chemical shifts of signals were obtained from decoupled spectra. Abbreviations mean m multiplet, s singlet, d doublet, t triplet, q quartet, dm doublet of multiplet, dd doublet of doublet, dt doublet of triplet, etc. GC investigations were done with a Hewlett±Packard GC 6890 (quartz capillary column HP 5 (0.11 mm) dimensions 25 m, 10.2 mm). Mass spectra (70 eV) were recorded by GC/MS technique using a combination of a Varian GC 3400 (quartz capillary column DB 5 (0.33 mm) dimensions: 25 m, 10.2 mm) and Saturn II (Ion Trap) or a Varian GC 3400 (quartz capillary column HP 1 (0.52 mm) dimensions: 50 m, 10.2 mm) and Finnigan MAT 8230; main peaks and speci®c fragmentations are listed. Column chromatography was done with silica gel (Merck 60, 70±230 mesh) and combinations of solvents, which are speci®ed for the corresponding experiments. Elemental analyses were carried out by the Mikroanalytisches Laboratorium, Organisch-Chemisches Institut, UniversitaÈt MuÈnster with a Perkin±Elmer 240 Elemental Analyzer. Olah's reagent (Py9HF) was obtained from Aldrich and has a 65±70% share of HF. Triethylamine trishydro¯uoride and trimethylamine bishydro¯uoride (Et3N3HF) (Me3N2HF) were kindly disposed by Hoechst [45]. The latter reagent contains 2.2 mol HF per mole trimethylamine. Cyclohexane and ethyl acetate for column chromatography were puri®ed by distillation, pentane and ether were used without puri®cation. CH2Cl2 was dried by distillation over Ê ). The ratio of P2O5 and stored over molecular sieves (4 A ¯uorinated regio and stereoisomers was determined by integration of 19 F NMR signals or by GC of the crude product mixture. 3.1. Bromofluorinations 3.1.1. General procedure for bromofluorination with NBS and Me3N2HF Method A. To a solution of the ole®n (10 mmol) and Me3N2HF (4.7 ml, 46 mmol) in CH2Cl2 (50 ml) NBS (1.96 g, 11 mmol) is added in portions at 08C. The mixture is stirred at 08C for 30 min and at room temperature for 4± 6 h, poured into ice-water (100 ml) and neutralized with concentrated ammonia. The organic phase is separated and the aqueous phase is extracted with ether (3 20 ml). The combined organic extracts are washed with 0.1 N HCl, 5% aq. solution of NaHCO3 and dried (MgSO4). After removing the solvent the products are isolated by column chromatography to give mixtures of the regioisomeric bromo¯uorides and occasionally the dibromide as light yellow liquids. 3.1.2. General procedure for bromofluorination with NBS and Py9HF Method B. To a solution of the ole®n (10 mmol) and Py9HF (2.6 ml, 11 mmol) in CH2Cl2 (50 ml) NBS (1.96 g, 11 mmol) is added in portions at 08C. The mixture is stirred
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at 08C for 30 min and at room temperature for 2 h. The work-up is done as mentioned above. After puri®cation by column chromatography mixtures of the regioisomers are obtained as light yellow liquids. 3.1.3. Bromofluorination of N-allylic imides with NBS/Et3N3HF To a solution of the N-allylic imide (15 mmol) and Et3N3HF (5 ml, 30 mmol) in CH2Cl2 (20 ml) NBS (3.94 g, 16.5 mmol) is added in portions under stirring at room temperature. After 18 h the reaction mixture is worked up as mentioned above. According to this procedure from N-allylphthalic imide a 28:72 mixture of N-(2-bromo-3-¯uoropropyl)-phthalic imide and its regioisomer was obtained (19 F NMR). Additionally a small amount of N-(2,3-dibromopropyl)-phthalic imide was isolated by chromatography (CH2Cl2). 3.1.3.1. N-(2,3-dibromopropyl)-phthalic imide. Yield: 0.1 g (2%), m.p. 1088C (CH2Cl2), [46]: m.p. 112±1148C (ethanol). 1 H NMR d: 3.73 (dd, 1H, 2 JHH 10.7 Hz, 3 JHH 8.6 Hz, 3-Ha), 3.86 (dd, 1H, 2 JHH 10.7 Hz, 3 JHH 4.8 Hz, 3-Hb), 4.15 (dd, 2 JHH 14.3 Hz, 3 JHH 8.6 Hz, 1-Ha), 4.25 (dd, 1H, 2 JHH 14.3 Hz, 3 JHH 5.3 Hz, 1-Hb), 4.62±4.68 (m, 1H, 2-H), 7.72±7.80 (m, 2H, Harom), 7.85±7.93 (m, 2H, Harom). 13 C NMR d: 33.7 (t, C-3), 43.2 (t, C-1), 47.5 (d, C-2), 123.6 (d, Carom), 131.8 (s, Carom), 134.2 (d, Carom), 168 (s, C=O). MS m/z (%): 349/ 347/345 (0.01, M), 268/266 (11, M ÿ Br), 267/265 (82, 186 (23, M ÿ Br ÿ HBr), 160 M ÿ HBr), (100,C9 H6 NO2 ). 1
3.1.3.2. N-(2-bromo-3-fluoropropyl)-phthalic imide. H NMR d: 4.07±4.26 (m, 2H, 1-H2), 4.45±4.82 (m, 3H, 2-H and 3-H2), 7.70±7.75 (m, 2H, Harom), 7.82±7.90 (m, 2H, Harom). 13 C NMR d: 41.2 (t, C-1), 45.3 (dd, 1 JCF 20.35 Hz, C-2), 83.8 (td, 1 JCF 178.0 Hz, C-3), 123.6 (d, Carom), 131.8 (s, Carom), 134.3 (d, Carom), 167.7 (s, C=O). 19 F NMR d: ÿ213.69 (dt, 2 JHF 45.7 Hz, 3 JHF 17.2 Hz). MS m/z (%): 288/286 (0.24, M 1), 287/285 (0.03, M), 286/284 (0.27, M ÿ 1), 206 (5, M ÿ Br), 186 (17, 206 ÿ HF), 185 (92), 162 (26) 160 (100, C9 H6 NO 2 ), 133 (11), 130 (9), 105 (10, 133 ÿ CO), 104 (22, 132 ÿ CO), 77 (17, C6 H 5 ), 76 (26, C6 H4 ). 3.1.3.3. N-(3-bromo-2-fluoropropyl)-phthalic imide. 19 F NMR d: ÿ184.0 (m). MS m/z (%): 287/285 (0.01, M), 207 (2), 206 (12, M ÿ Br), 186 (4, 206 ÿ HF), 185 (24), 162 (2), 161 (10) 160 (100, C9 H6 NO 2 ), 133 (4), 130 (3), 105 (4, 133 ÿ CO), 104 (10, 132 ÿ CO), 77 (10, C6 H 5 ), 76 (11, C 6 H ). 4 3.1.3.4. N-(2-bromo-3-fluoropropyl)-succinic imide and N(3-bromo-2-fluoropropyl)-succinic imide. According to the above mentioned procedure a 71:29 mixture (19 F NMR) of N-(2-bromo-3-fluoropropyl)-succinic imide (19 F NMR d:
ÿ212.4 (dt, 2 JHF 45.8 Hz, 3 JHF 15.3 Hz)) and N-(3bromo-2-fluoropropyl)-succinic imide (19 F NMR d: ÿ184.4 (m)) was obtained. 3.1.3.5. N-(2-bromo-3-fluoropropyl)-maleic imide and N(3-bromo-2-fluoropropyl)-maleic imide. According to the above mentioned procedure a 70:30 mixture (19 F NMR) of N-(2-bromo-3-fluoropropyl)-maleic imide (19 F NMR d: ÿ213.4 (dt, 2 JHF 45.8 Hz, 3 JHF 15.3 Hz)) and N-(3bromo-2-fluoropropyl)-maleic imide (19 F NMR d: ÿ184.0 (m)) was obtained. 3.1.4. Bromofluorination of 4-buten-1-ol Method A. 960 mg (52%) of a 83:17 mixture (GC) of 4bromo-3-¯uorobutan-1-ol, 3-bromo-4-¯uorobutan-1-ol and 3,4-dibromobutan-1-ol (5%) was isolated by chromatography (pentane/ether 2:1). Method B. 790 mg (39%) of a 84:16 mixture (GC) of 4bromo-3-¯uorobutan-1-ol and 3-bromo-4-¯uorobutan-1-ol was isolated by chromatography (pentane/ether 2:1). 3.1.4.1. 4-Bromo-3-fluorobutan-1-ol. 1 H NMR d: 1.85± 2.04 (m, 2H, 2-H2), 3.45±3.64 (m, 2H, 4-H2), 3.78±3.83 (m, 2H, 1-H2), 4.90 (dddt, 1H, 2 JHF 47.9 Hz, 3 JHH 6.2 Hz, 3 JHH 4.5 Hz, 3-H). 13 C NMR d: 33.7 (td, 2 JCF 22.9 Hz, C-2), 36.1 (td, 2 JCF 20.3 Hz, C-4), 58.4 (td, 3 JCF 5.1 Hz, C-1), 89.7 (dd, 1 JCF 173.0 Hz). 19 F NMR d: ÿ180.6 (m). MS m/z (%): 172/170 (<0.01, M), 153/151 (0.2, M 1 ÿ HF), 122/120 (36, M ÿ HF ÿ CH2O), 71 (74, 153/151 ÿ HBr), 41 (100, C3 H 5 ). 3.1.4.2. 3-Bromo-4-fluorobutan-1-ol. 1 H NMR d: 1.83± 2.02 (m, 2H, 2-H2), 3.42±3.61 (m, 2H, 1-H2), 4.27±4.40 (m, 1H, 3-H), 4.46±4.74 (dm, 2H, 1 JHF 47.0 Hz, 4-H2). 13 C NMR d: 36.8 (t, C-2), 47.8 (dd, 2 JCF 20.3 Hz, C-3), 59.7 (t, C-1), 85.5 (td, 1 JHF 178.0 Hz, C-4). 19 F NMR d: ÿ211.3 (dt, 2 JHF 45.8 Hz, 3 JHF 15.3 Hz). MS m/z (%): 172/170 (0.5, M), 152/150 (1.1, M ÿ HF), 122/120 (22, M ÿ HF ÿ CH2O), 71 (60, 152/150 ÿ Br), 41 (100, C3 H 5 ). 3.1.5. Bromofluorination of 1-chloro-4-penten-2-ol Method A. 1.21 g (55%) of a 79:21 mixture (GC) of 5bromo-1-chloro-4-¯uoropentan-2-ol, 4-bromo-1-chloro-5¯uoropentan-2-ol and 4,5-dibromo-1-chloropentan-2-ol (6%) was isolated by chromatography (pentane/ether 9:1). Method B. 0.96 g (44%) of a 85:15 mixture (GC) of 5bromo-1-chloro-4-¯uoropentan-2-ol and 4-bromo-1chloro-5-¯uoropentan-2-ol was isolated chromatographically (pentane/ether 9:1). 3.1.5.1. 4,5-Dibromo-1-chloropentan-2-ol. MS m/z (%): 233/231/229 (18, M ÿ CH2Cl), 203/201/199 (3, M ÿ CH2Cl ÿ CH2O), 151/149 (14, M ÿ CH2Cl ÿ HBr), 123/121 (12, 151/149 ÿ CO), 121/119 (10, 151/ 149 ÿ CH2O), 79 (47), 41 (100).
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3.1.5.2. 5-Bromo-1-chloro-4-fluoropentan-2-ol. 19 F NMR d: ÿ177.9 and ÿ180.4 (m, two diastereomers). MS m/z (%): 222/220/218 (0.07, M), 171/169 (75, M ÿ CH2Cl), 151/149 (64, 171/169 ÿ HF), 123/121 (23, 151/149 ÿ CO), 121/119 (24, 151/149 ÿ CH2O), 105/103 (6), 89 (4, 171/ 169 ÿ HBr), 79 (48, 150 ÿ HBr), 41 (100). 3.1.5.3. 4-Bromo-1-chloro-5-fluoropentan-2-ol. 19 F NMR d: ÿ211.6 and ÿ211.9 (ddd, 2 JHF 46.7 Hz, 3 JHF 17.2 Hz, 3 JHF 15.2 Hz, two diastereomers). MS m/z (%): 222/220/218 (<0.01, M), 184/182 (4, M ÿ HCl), 171/169 (100, M ÿ CH2Cl), 164/162 (8, 184/182 ÿ HF), 151/149 (78, 171/169 ÿ HF); 123/121 (30, 151/149 ÿ CO), 121/119 (35, 151/149 ÿ CH2O), 105/103 (11), 89 (5, 171/ 169 ÿ HBr), 79 (47), 69 (10, 150 ÿ HBr), 41 (70). 3.1.6. Bromofluorination of 4-bromo-1-butene Method A. 930 mg (40%) of a 75:25 mixture (GC) of 1,4dibromo-2-¯uorobutane, 2,4-dibromo-1-¯uorobutane and 1,2,4-tribromobutane (4%) was isolated chromatographically (pentane/ether 1:1). Method B. 820 mg (35%) of a 78:22 mixture (GC) of 1,4dibromo-2-¯uorobutane and 2,4-dibromo-1-¯uorobutane was isolated chromatographically (pentane/ether 1:1). Spectroscopic data were taken from the mixture of regioisomers. 3.1.6.1. 1,4-Dibromo-2-fluorobutane. 1 H NMR d: 2.20± 2.46 (m, 2H, 3-H2), 3.48±3.57 (m, 4H, 1-H2 and 4-H2), 4.89 (ddddd, 1H, 2 JHF 47.7 Hz, 3 JHH 5.0 Hz, 3 JHH 4.8 Hz, 3 JHH 3.3 Hz, 3 JHH 3.1 Hz, 2-H). 13 C NMR d: 27.6 (td, 3 JCF 4.5 Hz, C-4), 32.8 (td, 2 JCF 25.1 Hz, C-3), 36.5 (td, 2 JCF 20.4 Hz, C-1), 89.4 (dd, 1 JCF 175.5 Hz, C-2). 19 F NMR d: ÿ182.4 (m). MS m/z (%): 236/234/232 (4, M), 155/153 (28, M ÿ Br), 154/152 (42, M ÿ HBr), 135/133 (4, 216/ 214/212 ÿ HBr), 109/107 (22, BrCH2 CH2 ), 95/93 (12, BrCH 2 ), 73 (100, 155/153 ÿ HBr), 53 (39, 73 ÿ HF), 47 (30). 3.1.6.2. 2,4-Dibromo-1-fluorobutane. 1 H NMR d: 2.09± 2.20 (m, 2H, 3-H2), 3.45±3.58 (m, 2H, 4-H2), 4.27±4.40 (m, 1H, 2-H), 4.55 (ddd, 2 JHF 47.0 Hz, 3 JHH 9.8 Hz, 3 JHF 6.4 Hz, 1-H), 4.65 (ddd, 2 JHF 47.0 Hz, 3 JHH 9.8 Hz, 3 JHF 4.8 Hz, 1-H). 13 C NMR d: 30.1 (t, C-4), 37.1 (t, C-3), ca. 48 (dd, C-2), 84.9 (td, 1 JCF 178.0 Hz, C-1). 19 F NMR d: ÿ211.7 (dt, 2 JHF 46.7 Hz, 3 JHF 16.2 Hz). MS m/z (%): 236/234/ 232 (16, M), 216/214/212 (14, M ÿ HF), 155/153 (28, M ÿ Br), 154/152 (42, M ÿ HBr), 135/133 (11, 216/214/ 212 ÿ HBr), 109/107 (17, BrCH2 CH 2 ), 95/93 (5, BrCH2 ), 73 (100, 155/153 ÿ HBr), 53 (27, 73 ÿ HF), 47 (16). 3.1.7. Bromofluorination of benzyl 3-butenoate Method A. 470 mg (14%) of benzyl 3,4-dibromobutanoate (spectroscopic data correspond to those reported in literature [47]) and 610 mg (22%) of a 3.6:1 mixture
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(GC) of benzyl 4-bromo-3-¯uorobutanoate and benzyl 3bromo-4-¯uorobutanoate were isolated by chromatography (cyclohexane/ethyl acetate 15:1). Method B. 1.40 g (51%) of a 74:26 mixture (GC) of benzyl 4-bromo-3-¯uorobutanoate and benzyl 3-bromo-4¯uorobutanoate was isolated by chromatography (cyclohexane/ethyl acetate 15:1). 3.1.7.1. Benzyl 4-bromo-3-fluorobutanoate. 1 H NMR d: 2.81±2.90 (m, 2H, 2-H2), 3.50±3.61 (m, 2H, 4-H2), 4.99± 5.20 (m, 1H, 3-H), 5.16 (s, 2H, 5-H2), 7.25±7.47 (m, 5H, 7-H bis 11-H). 13 C NMR d: 33.1 (td, 2 JCF 25.7 Hz, C-2), 38.2 (td, 2 JCF 24.9, C-4), 66.8 (t, C-5), 87.8 (dd, 1 JCF 178.1 Hz, C-3), 128.2 (d, 1C, C-9), 128.4 (d, 2C, C-8, C-10), 128.6 (d, 2C, C-7, C-11), 135.4 (s, C-6), 169.0 (s, C-1). 19 F NMR d: ÿ177.4 (dtt, 2 JHF 45.8 Hz, 3 JHF 21.0 Hz, 3 JHF 17.2 Hz). MS m/z (%): 276/274 (20, M), 174 (5, M ÿ HF ÿ Br), 170/168 (4, M ÿ C6H5CH2O), 141/139 (2, M ÿ C6H5CH2CO2), 108 (100, C6H5CH2OH), 91 (41, C6 H5 CH 2 ), 59 (4, CH2 CFCH 2 ). C11H12BrFO2 (275.1): ca. C, 48.02; H, 4.40; found C, 48.64; H, 4.64%. 3.1.7.2. Benzyl 3-bromo-4-fluorobutanoate. 1 H NMR d: 2.84 (dd, 1H, 2 JHH 16.6 Hz, 3 JHH 8.3 Hz, 2-H, ABXsystem), 3.06 (dd, 1H, 2 JHH 16.6 Hz, 3 JHH 5.0 Hz, 2-H, ABX-system), 4.32±4.50 (m, 1H, 3-H), 4.50±4.67 (m, 2H, 4-H2), 5.10 (s, 2H, 5-H2), 7.17±7.35 (m, 5H, 7-H bis 11-H). 13 C NMR d: 39.7 (t, C-2), 43.1 (dd, 2 JCF 21.9 Hz, C-3), 67.0 (t, C-5), 84.3 (td, 1 JCF 178.1 Hz, C-4); 128.3 (d, C9), 128.4 (d, 2C, C-8, C-10), 128.6 (d, 2C, C-7, C-11), 135.4 (s, C-6), 169.4 (s, C-1). 19 F NMR d: ÿ211.5 (dt, 2 JHF 47.7 Hz, 3 JHF 13.3 Hz). MS m/z (%): 276/274 (24, M), 194 (5, M ÿ HBr), 170/168 (4, M ÿ C6H5CH2O), 141/139 (5, M ÿ C6H5CH2CO2), 108 (100, C6H5CH2OH), 91 (48, C6 H5 CH 2 ), 87 (9, FCH2CHCHCO), 59 (5, FCH2CHCH). 3.1.8. Bromofluorination of allylic cyanide Method A. 960 mg (42%) of 3,4-dibromobutyronitrile isolated by chromatography (pentane/ether 1:1). Minor amounts of a 46:54 mixture of 4-bromo-3-¯uorobutyronitril and 3-bromo-4-¯uorobutyronitril were not isolated. Method B. 480 mg (29%) of a 45:55 mixture of 4-bromo3-¯uorobutyronitrile and 3-bromo-4-¯uorobutyronitrile (GC) was isolated chromatographically (pentane/ether 1:1). Elemental analysis and NMR spectra were recorded from the mixture of regioisomers. 3.1.8.1. 3,4-Dibromobutyronitrile [48]. 1 H NMR d: 3.22 (d, 2H, 3 JHH 5.2 Hz, 2-H2), 3.72 (dd, 1H, 2 JHH 10.7 Hz, 3 JHH 10.5 Hz, 4-H, ABX system), 3.91 (dd, 1H, 2 JHH 10.7 Hz, 3 JHH 4.1 Hz, 4-H, ABX system), 4.26±4.34 (m, 1H, 3-H). 13 C NMR d: 26.1 (t, C-2), 33.6 (t, C-4), 41.8 (d, C-3), 115.4 (s, C-1). MS m/z (%): 229/ 227 (0.3, MH), 189/187 (1.8, MH ÿ CH2CN), 148/146
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(96, MH ÿ HBr), 121/119 (4, 148/146 ÿ HCN), 107/105 (6, 148/146 ÿ CH3CN), 95/93 (18, BrCH 2 ), 66 (100, 148/ ). 146 ÿ HBr), 39 (40, C3 H 3 3.1.8.2. 4-Bromo-3-fluorobutyronitrile. 1 H NMR d: 2.93 (dd, 2H, 3 JHF 19.6 Hz, 3 JHH 5.5 Hz, 2-H2), 3.57±3.64 (m, 2H, 4-H2), 4.94 (dtt, 1H, 2 JHF 46.0 Hz, 3 JHH 5.5 Hz, 3 JHH 5.2 Hz, 3-H). 13 C NMR d: 22.4 (td, 2 JCF 25.4 Hz, C-2), 30.6 (td, 2 JCF 25.4 Hz, C-4), 86.2 (dd, 1 JCF 183.1 Hz, C-3), 114.8 (s, C-1). 19 F NMR d: 2 3 JHF 45.8 Hz, JHF 19.1 Hz, ÿ174.8 (dtt, 3 JHF 17.2 Hz). MS m/z (%): 168/166 (2, MH), 167/ 165 (20, M), 147/145 (3, M ÿ HF), 127/125 (30, M ÿ CH2CN), 107/105 (15, 127/125 ÿ HF), 95/93 (10, BrCH 2 ), 86 (14, MH ÿ HBr, M ÿ Br), 72 (100, M ÿ BrCH2), 45 (24, 72 ÿ HCN), 41 (71). C4H5BrFN (166.0): ca. C, 28.94; H, 3.04; N, 8.44; found C, 29.15%; H, 3.06%; N, 8.14% (obtained for the mixture of the isomers). 3.1.8.3. 3-Bromo-4-fluorobutyronitrile. 1 H NMR d: 3.06± 3.11 (m, 2H, 2-H2); 4.18±4.31 (m, 1H, 3-H); 4.44±4.80 (m, 2H, 4-H2). 13 C NMR d: 23.8 (td, 3 JCF 5.1 Hz, C-2); 40.4 (dd, 2 JCF 22.9 Hz, C-3); 83.0 (td, 1 JCF 180.6 Hz, C-4); 115.7 (s, C-1). 19 F NMR d: ÿ210.4 (dt, 2 JHF 45.8 Hz, 3 JHF 13.3 Hz). MS m/z (%): 168/166 (2, M 1); 167/ 165 (24, M); 134/132 (4, M ÿ FCH2); 127/125 (8, M ÿ CH2CN), 107/105 (8, 127/125 ÿ HF), 86 (100, MH ÿ HBr, M ÿ Br), 85 (8, M ÿ HBr), 66 (30, 86 ÿ HF), 59 (44, 86 ÿ HCN). 4. Conclusion Regioselectivity of bromo¯uorination of terminal alkenes depends on the different electronic effects of substituents in allylic or homoallylic positions which also in¯uence the reactivity of the double bond. Electron donating groups such as alkyl substituents, which are able to stabilize a positive charge in 2-position, as expected favor the formation of Markovnikov-oriented products, while electron withdrawing substituents in allylic position destabilize corresponding secondary cationic centers. Hence, an increasing amount of anti-Markovnikov products is formed in the latter case. This is consistent with the observations made in ring opening reactions of epoxides with Olah's reagent [43]. The effect is quite weak in case of hydroxyl, epoxide, phenoxy or chlorine substituents. However, the effect becomes more important in reactions of carboxylic esters. After all bromo¯uorination of allylic imides and of allylic cyanide gave the primary ¯uorides even as the main product. Similar regioselectivity was found also in reactions with allylic bromide which in this special case seems to be caused mostly by the bridging effect of the bromine substituent. Hydroxyl groups in homoallylic position have a stronger in¯uence than in allylic position, while the reverse effect was observed for the bromine substituent.
The nature of the amine/HF reagent does not strongly in¯uence the regioselectivity of bromo¯uorination, but in¯uences the extent of side reactions, namely the formation of dibromides. While in reactions with the more acidic Olah's reagent dibromides were not found, these products were formed in all reactions with the less acidic, but more nucleophilic [38] Me3N2HF. The portion of these products increases with decreasing reactivity of the double bond and becomes almost the exclusive reaction with allylic cyanide. Thus, application of the combination NBS/Et3N3HF or NBS/Me3N2HF is recommended for bromo¯uorinations of reactive alkenes, while NBS/Olah's reagent can also be applied for less reactive alkenes which, however, should not be susceptible against cationic oligomerization or isomerization [25,40,44]. Acknowledgements Financial support by the Fonds der Chemischen Industrie is gratefully acknowledged. We are grateful to the Hoechst AG, Frankfurt/Main and the Bayer AG, Leverkusen for the kind donation of chemicals. References [1] G.A. Olah, X.-Y. Li, in: G.A. Olah, R.D. Chambers, G.K.S. Prakash (Eds.), Synthetic Fluorine Chemistry, Wiley, New York, 1992, pp. 163±204. [2] S. Rozen, in: S. Patai, Z. Rappoport (Eds.), The Chemistry of Halides, Pseudo-halides and Azides, Suppl. D2, Wiley, Chichester, 1995, pp. 629±708. [3] A.-E. Feiring, in: M. HudlickyÂ, A. E. Pavlath (Eds.), Chemistry of Organo Fluorine Compounds II, ACS Monograph 187, American Chemical Society, Washington, DC, 1995, pp. 61±69. [4] R. Miethchen, D. Peters, in: B. Baasner, H. Hagemann, J. C. Tatlow (Eds.), Houben-Weyl, Methods of Organic Chemistry, vol 10e, Thieme, Stuttgart, 1999, pp. 95±157. [5] M.M. Kremlev, G. Haufe, J. Fluorine Chem. 90 (1998) 121. [6] G. Alvernhe, A. Laurent, G. Haufe, Synthesis (1987) 562. [7] G. Haufe, G. Alvernhe, A. Laurent, T. Ernet, O. Goj, S. KroÈger, A. Sattler, Org. Synth. 76 (1998) 159. [8] A. Bowers, L.C. IbaÂnez, E. Denot, R. Becerra, J. Am. Chem. Soc. 82 (1960) 4001. [9] F.H. Dean, D.R. Marshall, E.W. Warnhoff, F.L.M. Pattison, Can. J. Chem. 45 (1967) 2279. [10] D.Y. Chi, D.O. Kiesewetter, J.A. Katzenellenbogen, M.R. Kilbourn, M.J. Welch, J. Fluorine Chem. 31 (1986) 99. [11] E. Forche, in: E. MuÈller (Ed.), Houben-Weyl, Methoden der Organischen Chemie, Vol. 5/3, Thieme, Stuttgart, 1962, pp. 117± 118. [12] M. HudlickyÂ, Chemistry of Organofluorine Compounds, 2nd (revised) ed., 1976, Ellis Horwood, Chichester, 1992, pp. 52±56. [13] M. Maeda, M. Abe, M. Kojima, J. Fluorine Chem. 34 (1987) 337. [14] J. Ichihara, K. Funabiki, T. Hanafusa, Tetrahedron Lett. 31 (1990) 3167. [15] M. Kuroboshi, T. Hiyama, Bull. Chem. Soc. Jpn. 68 (1995) 1799, and references cited therein. [16] D. Albanese, D. Landini, M. Peuso, M. Pratelli, Gazz. Chim. Ital. 121 (1991) 537.
M. LuÈbke et al. / Journal of Fluorine Chemistry 102 (2000) 125±133 [17] G.A. Olah, M. Nojima, I. Kerekes, Synthesis (1973) 779, 781. [18] G.A. Olah, J.T. Welch, Y.D. Vankar, M. Nojima, I. Kerekes, J.A. Olah, J. Org. Chem. 44 (1979) 3872. [19] A. Gregorcic, M. Zupan, J. Fluorine Chem. 24 (1984) 291. [20] A. Gregorcic, M. Zupan, Bull. Chem. Soc. Jpn. 60 (1987) 3083. [21] G.A. Olah, X.-Y. Li, Q. Wang, G.K.S.Prakash, Synthesis (1993) 693. [22] M. Tamura, M. Shibakami, A. Sekiya, Synthesis (1995) 515. [23] Y. Uchibori, M. Umeno, H. Seto, H. Yoshioka, Chem. Lett. (1993) 673. [24] O.A. Mascaretti, Aldrichim. Acta 26 (1993) 47. [25] S. Hamman, J. Fluorine Chem. 45 (1989) 377. [26] D.F. Shellhamer, M.J. Horney, B.J. Pettus, T.L. Pettus, J.M. Stringer, V.L. Heasley, R.G. Syvret, J.M. Dobrolsky Jr., J. Org. Chem. 64 (1999) 1094. [27] A. Gregorcic, M. Zupan, J. Org. Chem. 49 (1984) 333, and references cited therein. [28] D. Limat, Y. Guggisberg, M. Schlosser, Liebigs Ann. Chem. (1995) 849. [29] I. Chehidi, M. Chaabouni, A. Baklouti, Tetrahedron Lett. 30 (1989) 3167. [30] J. Jindrich, H. DvoraÂkovaÂ, A. HolyÂ, Collect. Czech. Chem. Commun. 57 (1992) 1466. [31] F.H. Dean, F.L.M. Pattison, Can. J. Chem. 43 (1965) 2415. [32] U. Weûel, G. Haufe, Unpublished, 1992. [33] A. Hedhli, A. Baklouti, J. Org. Chem. 59 (1994) 5277.
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[34] M. Fujita, H. Ishizuka, K. Ogura, Tetrahedron Lett. 32 (1991) 6355. [35] W.R. Dolbier Jr., T.A. Gray, J.J. Keaffaber, L. Celewicz, H. Koroniak, J. Am. Chem. Soc. 112 (1990) 363 [36] P.B.D. de la Mare, P.G. Naylor, D.L.H. Wiliams, J. Chem. Soc. (1963) 3429. [37] F.H. Dean, F.L.M. Pattison, D.A.V. Peters, F.H. Dean, Can. J. Chem. 43 (1965) 1689. [38] M.B. Giudicelli, D. Picq, B. Veyron, Tetrahedron Lett. 31 (1990) 6527. [39] S. Rozen, M. Brand, J. Org. Chem. 50 (1985) 3342. [40] G. Alvernhe, D. Anker, A. Laurent, G. Haufe, C. Beguin, Tetrahedron 44 (1988) 3551. [41] F. Camps, E. Chanorro, V. Gasol, A. Guerrero, J. Org. Chem. 54 (1989) 4294. [42] A. Burchardt, Ph. D Dissertation MuÈnster, 1998. [43] R. Skupin, G. Haufe, J. Fluorine Chem. 92 (1998) 157. [44] G. Haufe, G. Alvernhe, A. Laurent, Tetrahedron Lett. 27 (1986) 4449. [45] R. Franz, J. Fluorine Chem. 15 (1980) 423. [46] J.A. Lamberton, Aust. J. Chem. 8 (1955) 289. [47] G. Sun, P.S. Sarle, R.D. Gandour, N.N. a'Bhaird, R.R. Ramsay, F.R. Fronczek, J. Org. Chem. 60 (1995) 6688. [48] J.P. Schroeder, L. Braxton Tew, V.M. Peters, J. Org. Chem. 35 (1970) 3181.
Regioselectivity of bromo¯uorination of functionalized 1-alkenes Martin LuÈbke, Rolf Skupin, GuÈnter Haufe*
Organisch-Chemisches Institut, WestfaÈlische Wilhelms-UniversitaÈt, Corrensstraûe 40, D-48149 MuÈnster, Germany Received 22 June 1999; received in revised form 30 June 1999; accepted 27 August 1999 Dedicated to Professor Paul Tarrant on the occasion of his 85th birthday
Abstract The regiochemistry of bromo¯uorinations of 1-alkenes with the combination of N-bromosuccinimide and amine/HF reagents mainly depends on the character of functional groups in the neighborhood of the double bond and only weakly from the ¯uorinating agent. While mono-substituted terminal alkenes mainly yield Markovnikov-oriented products, electron withdrawing groups in allylic or homoallylic position to the double bond destabilize carbenium centers in 2-position. Consequently, the part of anti-Markovnikov-oriented bromo¯uorides increases. Besides, with dropping reactivity of alkenes, the formation of dibromides becomes a competitive side reaction of bromo¯uorination. The extent of this process depends on the nature of the amine/HF reagent. This reaction is most important in case of the more nucleophilic trimethylamine bishydro¯uoride, while this process is neglectible with pyridinium poly(hydrogen ¯uoride) (Olah's reagent). # 2000 Elsevier Science S.A. All rights reserved. Keywords: 1-Alkenes; Bromo¯uorination; Regioselectivity; Amine/HF reagents; Electrophilic addition; Mechanism
1. Introduction Halo¯uorination of unsaturated compounds is an important method to place ¯uorine into organic molecules. Several of the commonly used protocols have been reviewed recently [1±5]. One of the most versatile procedures for bromo¯uorination has proved the combination of N-bromosuccinimide (NBS) as the source of the bromonium ion and triethylamine trishydro¯uoride (Et3N3HF) as the ¯uoride equivalent [6,7]. Among others also N-bromoacetamide [8,9] or 1,3-dibromo-5,5-dimethylhydantoin [10] have been applied as donors of the electrophile. Alternative ¯uoride sources such as liquid hydrogen ¯uoride [11,12] or ammonium- [13±16], pyridinium- [17,18], polymeric pyridinium poly(hydrogen ¯uorides) [19±21] or potassium ¯uoride in poly(hydrogen ¯uorides) [22], tetrabutyl-phosphonium dihydrogen tri¯uoride [23] and several others [15,24] have also been used. The poly(hydrogen ¯uorides) are relatively acidic and do attack glassware. So, they have to be applied in Te¯onTM or polypropylene ¯asks. Moreover, susceptible alkenes can oligomerize or isomerize prior to bromo¯uorination [25]. Recently, a comparison of several methods of generation of intermediary interhalogen ¯uorides in halo¯uorinations has been published [26].
The mechanism of bromo¯uorination involves the electrophilic, acid catalyzed attack of a positive bromine species to give a p-complex followed by generation of a cationic scomplex in the rate determining step. Finally, the backside attack of a nucleophilic ¯uoride species yields the bromo¯uorides (Scheme 1). Mechanistic alternatives have also been discussed [27]. The regiochemistry of bromo¯uorinations of ole®ns depends on the structure of the s-complex. The ¯uoride equivalent attacks non-symmetrically bridged species mainly at the position of better charge stabilization and
* Corresponding author. Fax: 49-251-83-39772. E-mail address: [email protected] (G. Haufe).
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved. PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 2 3 0 - 4
Scheme 1. Mechanism of bromofluorination.
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the Markovnikov-orientation is found in the main product. With aliphatic terminal ole®ns the ratio of regioisomers varies between 94:6 and 86:14 [7], while reactions of 2,2dialkyl- or aryl-substituted 1-alkenes show almost exclusive Markovnikov-orientation. Moreover, enolesters on bromo¯uorination with NBS/Et3N3HF showed exclusive Markovnikov-orientation, too [28].
Scheme 4. Bromofluorination of allylphenyl ether.
2. Results and discussion Bromo¯uorination of I- or M-substituted terminal unsaturated compounds as mentioned above are well known in literature. However, reactions of ole®ns bearing ÿIsubstituents in allylic or homoallylic position are rarely investigated. The in¯uence on the regioselectivity of bromo¯uorination of a hydroxyl group or an acetate or trichloro acetate function in b-position to the double bond was found relatively small. From allylic alcohol with NBS/Et3N3HF a 90:10 mixture of 3-bromo-2-¯uoropropanol and its regioisomer was formed (52% yield) [29] (Scheme 2), while from propene under the same conditions a 94:6 mixture of regioisomers was obtained [7]. For the corresponding reactions of allylic alcohol or its acetate with NBS (or NBA) and HF or pyridine/HF in ether formation of the primary bromide was reported as the sole product, however, in very low yields [29,30] while treatment of allylic trichloroacetate with NBA/HF in ether/pyridine gave the corresponding Markovnikov product in 69% yield [31] (Scheme 3). Interestingly, the reaction of 2-methylbut-3-en-2-ol with NBS/Et3N3HF gave no Markovnikov product at all, but yielded an 1:1 mixture of 3-bromo-4-¯uoro-2-methylbutan2-ol (anti-Markovnikov-orientation) and 4-bromo-3-¯uoro2-methylbutan-3-ol, a rearranged product [29]. The portion of the anti-Markovnikov product increases in case when an electron withdrawing substituent like a phenyl group is placed at the oxygen function. The bromo¯uorination of allylphenyl ether, which is only weakly-dependent on the ¯uorinating agent, gave 63:37 or 67:33 mixtures of the regioisomers in the presence of Et3N3HF or Olah's reagent, respectively, (Scheme 4). Besides, p-bromination
Scheme 5. Bromofluorination of vinyl oxirane.
of the aromatic ring was obtained to some extent (11% or 13%, respectively) [32]. Bromo¯uorination of vinyl oxirane with NBS/Et3N3HF gave a 73:27 mixture of the regioisomers (55% yield) in favor of the Markovnikov adduct (Scheme 5). Both regioisomers were formed as approximate 1:1 mixtures of erythro- and threo-isomers [33]. In contrast the product bearing the bromine next to the hydroxyl function was mainly formed when the positive charge can be stabilized by a methyl group in g-position to an oxygen. By way of example in the reaction of trans-but3-enol with NBS/Et3N3HF mainly 2-bromo-3-¯uorobutan1-ol was found [28] (Scheme 6). Similar results have also been reported for reactions of other allylic alcohols [29,34]. Allylic chloride on the other hand on reaction with NBS/ HF in THF gave a 80:20 mixture of the trihalopropanes in 35% yield in favor of the Markovnikov product [35,36] (Scheme 7). This means that there is not a big difference in the in¯uence of the hydroxy function, an epoxy function, a phenoxy group or a chlorine-substituent in allylic position of a terminal alkene in cases when no other stabilizing substituents are acting. In contrast allylic bromide under similar conditions led to a 41:59 mixture of regioisomers in favor of the anti-Markovnikov product [37] (Scheme 8).
Scheme 6. Bromofluorination of trans-but-3-enol. Scheme 2. Bromofluorination of allylic alcohol.
Scheme 3. Bromofluorination of allylic trichloroacetate.
Scheme 7. Bromofluorination of allylic chloride.
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Scheme 8. Mechanism of bromofluorination of allylic bromide.
One possible explanation for this ratio of regioisomers is the formation of a symmetrically bridged cationic intermediate I including two bromine atoms. Sterically hindered attack of the nucleophilic ¯uoride equivalent at the secondary carbon atom by two bromine substituents and better accessibility of the primary position in the mesomeric cationic structure II may determine the preferred formation of the anti-Markovnikov product. In order to examine the in¯uence of other electron withdrawing substituents on the regioselectivity of bromo¯uorinations of terminal ole®ns we investigated N-allylic imides and several other allylic and homoallylic systems. Moreover, in several cases under the conditions of bromo¯uorination the formation of 1,2-dibromides was obtained (wide infra). Factors in¯uencing this process have also been evaluated. The reaction of N-allylphthalic imide with NBS/ Et3N3HF gave 28:72 mixture of the Markovnikov product and its regioisomer. N-Allylsuccinic and N-allylmaleic imides behave analogously. Obviously the strong electron withdrawing effect of the imide moiety disfavors a potential secondary cationic center. Thus, the intermediate cation is mainly attacked in terminal position. In addition approximately 2% of vicinal dibromides have been isolated (Scheme 9).
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The extent of the formation of dibromides under the conditions of bromo¯uorination seems to depend on the reactivity of the ole®n as on the nature of the ¯uorinating reagent. Consequently, for the following experiments with several terminal alkenes bearing electron withdrawing functional groups in allylic or homoallylic position (in all cases the electronegative element is tied at carbon 4 in relation to the terminal unsaturated carbon atom), two different amine/ HF reagents have been used in combination with NBS as the electrophilic reagent. Trimethylamine bishydro¯uoride (Me3N2HF) which is known to be a source of a relatively nucleophilic ¯uoride equivalent [38] or Olah's reagent (Py9HF), a more acidic but less nucleophilic ¯uorinating reagent, have been applied. Bromo¯uorination of but-3-en-1-ol (homoallylic alcohol) with NBS/Me3N2HF gave a 83:17 mixture of 4-bromo-3¯uoro- and 3-bromo-4-¯uorobutanols contaminated with 5% of 3,4-dibromobutanol. The corresponding reaction with Olah's reagent yielded the bromo¯uorides in the same ratio, however, no traces of the dibromide have been detected by GC. Similarly, the reaction of 1-chloropent-4-en-2-ol under the mentioned conditions gave the regioisomeric bromo¯uorides in 79:21 or 85:15 ratio, respectively, as mixtures of diastereomers. In the ®rst case also 6% of the diastereomeric dibromides was formed (Scheme 10). Compared to the corresponding reactions of allylic alcohol (90:10) and 1butene (94:6), the regioselectivity of bromo¯uorination unexpectedly dropped only slightly. In case of 4-bromobut-1-ene (homoallylic bromide) a 3:1 mixture of regioisomers was formed independently from the ¯uorinating agent. The crude product of the reaction with Me3N2HF contained 4% of the tribromide (Scheme 11). In contrast, allylic bromide gave mainly the anti-Markovnikov product [37]. In comparison to the reaction of 1butene the regioselectivity of bromo¯uorination of homoallylic bromide dropped as expected. Reactions of vinylacetic acid under the conditions of bromo¯uorination gave mainly 3-bromobutyrolactone. Besides, some traces of ¯uorinated compounds were formed which have not been identi®ed. On the other hand, the
Scheme 9. Bromofluorination of N-allylphthalic imide.
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Scheme 10. Bromofluorination of but-3-ene-1-ol and 1-chloropent-4-ene-2-ol.
Scheme 11. Bromofluorination of 4-bromobut-1-ene.
Scheme 12. Bromofluorination of vinylacetic acid benzyl ester.
benzylic ester of this acid gave 3:1 mixtures of the bromo¯uorides, independently from the ¯uorinating agent. Applying the more basic Me3N2HF the yield was quite low and 14% of the dibromide was found, while no traces of this compound have been detected in the product mixture of the reaction with Olah's reagent (Scheme 12). Bromo¯uorination with BrF (generated in situ from the elements) of the methyl ester of vinylacetic acid gave a 63:37 mixture of the Markovnikov and the anti-Markovni-
kov products in high yield [39] (Scheme 13). Formation of a dibromide has not been reported. Finally, the reaction of allylic cyanide with NBS and Me3N2HF gave less than 2% of a 46:54 mixture of bromo¯uorides, while 3,4-dibromobutyronitril was the main product (>98%, GC). In contrast with Olah's reagent this compound was not detected, but a 45:55 mixture of 4bromo-3-¯uoro- and 3-bromo-4-¯uorobutyronitrile was isolated (Scheme 14).
Scheme 13. Bromofluorination of vinylacetic acid methyl ester.
Scheme 14. Bromofluorination of allylic cyanide.
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Scheme 15. Mechanism of the formation of bromine by reaction of NBS and HFÿ 2 [40].
The formation of dibromides as minor side products has already been observed in some cases during our ®rst studies of bromo¯uorination of alkenes with NBS/Et3N3HF [40]. Also in reactions with HF pyridine with excess NBS [10] and in reactions of several ole®ns with NBS=Bu4 N H2 Fÿ 3 dibromides have been formed [16]. Since the part of dibromides in our reactions [6,40] never extended 5% (GC) we believed, that a small amount of elemental bromine which is usually present in NBS was responsible. However, in 1989 Guerrero and coworkers [41] showed that in reactions of ole®ns with NBS and tetrabutylammonium hydrogen di¯uoride (Bu4 N HFÿ 2 ) bromine can be formed according to the chain-mechanism shown in Scheme 15. In an initial step the reaction of NBS with HFÿ 2 (Scheme 15) gives the interhalogen, HF and a succinimidyl anion. Succeeding reactions of this anion with NBS produce bromide which gives elemental bromine by reaction with a third molecule of NBS. Assuming a hydrogendi¯uoride anion as ¯uorinating species of Me3N2HF this mechanism could operate in the considered reactions as well. Consequently, in case of less reactive ole®ns the reduction of NBS to form elemental bromine is faster than bromo¯uorination. Since two molecules of NBS are consumed for this process the relatively low chemical yield of the reaction could be explained. Calculated on consumed NBS the yield of the dibromide is almost quantitative in the reaction with allylic cyanide. Formation of dibromides has also been observed in bromo¯uorinations with NBS/Et3N3HF of other less reactive alkenes such as 1,2-di¯uoro-1,2-di(p-tolyl)ethene and 1,2,3,4-tetra¯uoro-1,4-di(p-tolyl)butadiene [5] or 2methylene-1,3-propanediol and its mono or bisalkyl ethers [42]. 3. Experimental 1
H NMR (300.13 MHz), 13 C NMR (75.48 MHz) and 19 F NMR (282.37 MHz) were recorded on a Bruker WM 300. Chemical shifts are reported as d values in units of ppm related to the internal standards TMS (d 0.0 ppm, 1 H NMR), CDCl3 (d 77.0 ppm, 13 C NMR) and CFCl3
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(d 0.0 ppm, 19 F NMR). Multiplicities of signals in 13 C NMR spectra were determined by DEPT operation, 19 F NMR chemical shifts of signals were obtained from decoupled spectra. Abbreviations mean m multiplet, s singlet, d doublet, t triplet, q quartet, dm doublet of multiplet, dd doublet of doublet, dt doublet of triplet, etc. GC investigations were done with a Hewlett±Packard GC 6890 (quartz capillary column HP 5 (0.11 mm) dimensions 25 m, 10.2 mm). Mass spectra (70 eV) were recorded by GC/MS technique using a combination of a Varian GC 3400 (quartz capillary column DB 5 (0.33 mm) dimensions: 25 m, 10.2 mm) and Saturn II (Ion Trap) or a Varian GC 3400 (quartz capillary column HP 1 (0.52 mm) dimensions: 50 m, 10.2 mm) and Finnigan MAT 8230; main peaks and speci®c fragmentations are listed. Column chromatography was done with silica gel (Merck 60, 70±230 mesh) and combinations of solvents, which are speci®ed for the corresponding experiments. Elemental analyses were carried out by the Mikroanalytisches Laboratorium, Organisch-Chemisches Institut, UniversitaÈt MuÈnster with a Perkin±Elmer 240 Elemental Analyzer. Olah's reagent (Py9HF) was obtained from Aldrich and has a 65±70% share of HF. Triethylamine trishydro¯uoride and trimethylamine bishydro¯uoride (Et3N3HF) (Me3N2HF) were kindly disposed by Hoechst [45]. The latter reagent contains 2.2 mol HF per mole trimethylamine. Cyclohexane and ethyl acetate for column chromatography were puri®ed by distillation, pentane and ether were used without puri®cation. CH2Cl2 was dried by distillation over Ê ). The ratio of P2O5 and stored over molecular sieves (4 A ¯uorinated regio and stereoisomers was determined by integration of 19 F NMR signals or by GC of the crude product mixture. 3.1. Bromofluorinations 3.1.1. General procedure for bromofluorination with NBS and Me3N2HF Method A. To a solution of the ole®n (10 mmol) and Me3N2HF (4.7 ml, 46 mmol) in CH2Cl2 (50 ml) NBS (1.96 g, 11 mmol) is added in portions at 08C. The mixture is stirred at 08C for 30 min and at room temperature for 4± 6 h, poured into ice-water (100 ml) and neutralized with concentrated ammonia. The organic phase is separated and the aqueous phase is extracted with ether (3 20 ml). The combined organic extracts are washed with 0.1 N HCl, 5% aq. solution of NaHCO3 and dried (MgSO4). After removing the solvent the products are isolated by column chromatography to give mixtures of the regioisomeric bromo¯uorides and occasionally the dibromide as light yellow liquids. 3.1.2. General procedure for bromofluorination with NBS and Py9HF Method B. To a solution of the ole®n (10 mmol) and Py9HF (2.6 ml, 11 mmol) in CH2Cl2 (50 ml) NBS (1.96 g, 11 mmol) is added in portions at 08C. The mixture is stirred
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at 08C for 30 min and at room temperature for 2 h. The work-up is done as mentioned above. After puri®cation by column chromatography mixtures of the regioisomers are obtained as light yellow liquids. 3.1.3. Bromofluorination of N-allylic imides with NBS/Et3N3HF To a solution of the N-allylic imide (15 mmol) and Et3N3HF (5 ml, 30 mmol) in CH2Cl2 (20 ml) NBS (3.94 g, 16.5 mmol) is added in portions under stirring at room temperature. After 18 h the reaction mixture is worked up as mentioned above. According to this procedure from N-allylphthalic imide a 28:72 mixture of N-(2-bromo-3-¯uoropropyl)-phthalic imide and its regioisomer was obtained (19 F NMR). Additionally a small amount of N-(2,3-dibromopropyl)-phthalic imide was isolated by chromatography (CH2Cl2). 3.1.3.1. N-(2,3-dibromopropyl)-phthalic imide. Yield: 0.1 g (2%), m.p. 1088C (CH2Cl2), [46]: m.p. 112±1148C (ethanol). 1 H NMR d: 3.73 (dd, 1H, 2 JHH 10.7 Hz, 3 JHH 8.6 Hz, 3-Ha), 3.86 (dd, 1H, 2 JHH 10.7 Hz, 3 JHH 4.8 Hz, 3-Hb), 4.15 (dd, 2 JHH 14.3 Hz, 3 JHH 8.6 Hz, 1-Ha), 4.25 (dd, 1H, 2 JHH 14.3 Hz, 3 JHH 5.3 Hz, 1-Hb), 4.62±4.68 (m, 1H, 2-H), 7.72±7.80 (m, 2H, Harom), 7.85±7.93 (m, 2H, Harom). 13 C NMR d: 33.7 (t, C-3), 43.2 (t, C-1), 47.5 (d, C-2), 123.6 (d, Carom), 131.8 (s, Carom), 134.2 (d, Carom), 168 (s, C=O). MS m/z (%): 349/ 347/345 (0.01, M), 268/266 (11, M ÿ Br), 267/265 (82, 186 (23, M ÿ Br ÿ HBr), 160 M ÿ HBr), (100,C9 H6 NO2 ). 1
3.1.3.2. N-(2-bromo-3-fluoropropyl)-phthalic imide. H NMR d: 4.07±4.26 (m, 2H, 1-H2), 4.45±4.82 (m, 3H, 2-H and 3-H2), 7.70±7.75 (m, 2H, Harom), 7.82±7.90 (m, 2H, Harom). 13 C NMR d: 41.2 (t, C-1), 45.3 (dd, 1 JCF 20.35 Hz, C-2), 83.8 (td, 1 JCF 178.0 Hz, C-3), 123.6 (d, Carom), 131.8 (s, Carom), 134.3 (d, Carom), 167.7 (s, C=O). 19 F NMR d: ÿ213.69 (dt, 2 JHF 45.7 Hz, 3 JHF 17.2 Hz). MS m/z (%): 288/286 (0.24, M 1), 287/285 (0.03, M), 286/284 (0.27, M ÿ 1), 206 (5, M ÿ Br), 186 (17, 206 ÿ HF), 185 (92), 162 (26) 160 (100, C9 H6 NO 2 ), 133 (11), 130 (9), 105 (10, 133 ÿ CO), 104 (22, 132 ÿ CO), 77 (17, C6 H 5 ), 76 (26, C6 H4 ). 3.1.3.3. N-(3-bromo-2-fluoropropyl)-phthalic imide. 19 F NMR d: ÿ184.0 (m). MS m/z (%): 287/285 (0.01, M), 207 (2), 206 (12, M ÿ Br), 186 (4, 206 ÿ HF), 185 (24), 162 (2), 161 (10) 160 (100, C9 H6 NO 2 ), 133 (4), 130 (3), 105 (4, 133 ÿ CO), 104 (10, 132 ÿ CO), 77 (10, C6 H 5 ), 76 (11, C 6 H ). 4 3.1.3.4. N-(2-bromo-3-fluoropropyl)-succinic imide and N(3-bromo-2-fluoropropyl)-succinic imide. According to the above mentioned procedure a 71:29 mixture (19 F NMR) of N-(2-bromo-3-fluoropropyl)-succinic imide (19 F NMR d:
ÿ212.4 (dt, 2 JHF 45.8 Hz, 3 JHF 15.3 Hz)) and N-(3bromo-2-fluoropropyl)-succinic imide (19 F NMR d: ÿ184.4 (m)) was obtained. 3.1.3.5. N-(2-bromo-3-fluoropropyl)-maleic imide and N(3-bromo-2-fluoropropyl)-maleic imide. According to the above mentioned procedure a 70:30 mixture (19 F NMR) of N-(2-bromo-3-fluoropropyl)-maleic imide (19 F NMR d: ÿ213.4 (dt, 2 JHF 45.8 Hz, 3 JHF 15.3 Hz)) and N-(3bromo-2-fluoropropyl)-maleic imide (19 F NMR d: ÿ184.0 (m)) was obtained. 3.1.4. Bromofluorination of 4-buten-1-ol Method A. 960 mg (52%) of a 83:17 mixture (GC) of 4bromo-3-¯uorobutan-1-ol, 3-bromo-4-¯uorobutan-1-ol and 3,4-dibromobutan-1-ol (5%) was isolated by chromatography (pentane/ether 2:1). Method B. 790 mg (39%) of a 84:16 mixture (GC) of 4bromo-3-¯uorobutan-1-ol and 3-bromo-4-¯uorobutan-1-ol was isolated by chromatography (pentane/ether 2:1). 3.1.4.1. 4-Bromo-3-fluorobutan-1-ol. 1 H NMR d: 1.85± 2.04 (m, 2H, 2-H2), 3.45±3.64 (m, 2H, 4-H2), 3.78±3.83 (m, 2H, 1-H2), 4.90 (dddt, 1H, 2 JHF 47.9 Hz, 3 JHH 6.2 Hz, 3 JHH 4.5 Hz, 3-H). 13 C NMR d: 33.7 (td, 2 JCF 22.9 Hz, C-2), 36.1 (td, 2 JCF 20.3 Hz, C-4), 58.4 (td, 3 JCF 5.1 Hz, C-1), 89.7 (dd, 1 JCF 173.0 Hz). 19 F NMR d: ÿ180.6 (m). MS m/z (%): 172/170 (<0.01, M), 153/151 (0.2, M 1 ÿ HF), 122/120 (36, M ÿ HF ÿ CH2O), 71 (74, 153/151 ÿ HBr), 41 (100, C3 H 5 ). 3.1.4.2. 3-Bromo-4-fluorobutan-1-ol. 1 H NMR d: 1.83± 2.02 (m, 2H, 2-H2), 3.42±3.61 (m, 2H, 1-H2), 4.27±4.40 (m, 1H, 3-H), 4.46±4.74 (dm, 2H, 1 JHF 47.0 Hz, 4-H2). 13 C NMR d: 36.8 (t, C-2), 47.8 (dd, 2 JCF 20.3 Hz, C-3), 59.7 (t, C-1), 85.5 (td, 1 JHF 178.0 Hz, C-4). 19 F NMR d: ÿ211.3 (dt, 2 JHF 45.8 Hz, 3 JHF 15.3 Hz). MS m/z (%): 172/170 (0.5, M), 152/150 (1.1, M ÿ HF), 122/120 (22, M ÿ HF ÿ CH2O), 71 (60, 152/150 ÿ Br), 41 (100, C3 H 5 ). 3.1.5. Bromofluorination of 1-chloro-4-penten-2-ol Method A. 1.21 g (55%) of a 79:21 mixture (GC) of 5bromo-1-chloro-4-¯uoropentan-2-ol, 4-bromo-1-chloro-5¯uoropentan-2-ol and 4,5-dibromo-1-chloropentan-2-ol (6%) was isolated by chromatography (pentane/ether 9:1). Method B. 0.96 g (44%) of a 85:15 mixture (GC) of 5bromo-1-chloro-4-¯uoropentan-2-ol and 4-bromo-1chloro-5-¯uoropentan-2-ol was isolated chromatographically (pentane/ether 9:1). 3.1.5.1. 4,5-Dibromo-1-chloropentan-2-ol. MS m/z (%): 233/231/229 (18, M ÿ CH2Cl), 203/201/199 (3, M ÿ CH2Cl ÿ CH2O), 151/149 (14, M ÿ CH2Cl ÿ HBr), 123/121 (12, 151/149 ÿ CO), 121/119 (10, 151/ 149 ÿ CH2O), 79 (47), 41 (100).
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3.1.5.2. 5-Bromo-1-chloro-4-fluoropentan-2-ol. 19 F NMR d: ÿ177.9 and ÿ180.4 (m, two diastereomers). MS m/z (%): 222/220/218 (0.07, M), 171/169 (75, M ÿ CH2Cl), 151/149 (64, 171/169 ÿ HF), 123/121 (23, 151/149 ÿ CO), 121/119 (24, 151/149 ÿ CH2O), 105/103 (6), 89 (4, 171/ 169 ÿ HBr), 79 (48, 150 ÿ HBr), 41 (100). 3.1.5.3. 4-Bromo-1-chloro-5-fluoropentan-2-ol. 19 F NMR d: ÿ211.6 and ÿ211.9 (ddd, 2 JHF 46.7 Hz, 3 JHF 17.2 Hz, 3 JHF 15.2 Hz, two diastereomers). MS m/z (%): 222/220/218 (<0.01, M), 184/182 (4, M ÿ HCl), 171/169 (100, M ÿ CH2Cl), 164/162 (8, 184/182 ÿ HF), 151/149 (78, 171/169 ÿ HF); 123/121 (30, 151/149 ÿ CO), 121/119 (35, 151/149 ÿ CH2O), 105/103 (11), 89 (5, 171/ 169 ÿ HBr), 79 (47), 69 (10, 150 ÿ HBr), 41 (70). 3.1.6. Bromofluorination of 4-bromo-1-butene Method A. 930 mg (40%) of a 75:25 mixture (GC) of 1,4dibromo-2-¯uorobutane, 2,4-dibromo-1-¯uorobutane and 1,2,4-tribromobutane (4%) was isolated chromatographically (pentane/ether 1:1). Method B. 820 mg (35%) of a 78:22 mixture (GC) of 1,4dibromo-2-¯uorobutane and 2,4-dibromo-1-¯uorobutane was isolated chromatographically (pentane/ether 1:1). Spectroscopic data were taken from the mixture of regioisomers. 3.1.6.1. 1,4-Dibromo-2-fluorobutane. 1 H NMR d: 2.20± 2.46 (m, 2H, 3-H2), 3.48±3.57 (m, 4H, 1-H2 and 4-H2), 4.89 (ddddd, 1H, 2 JHF 47.7 Hz, 3 JHH 5.0 Hz, 3 JHH 4.8 Hz, 3 JHH 3.3 Hz, 3 JHH 3.1 Hz, 2-H). 13 C NMR d: 27.6 (td, 3 JCF 4.5 Hz, C-4), 32.8 (td, 2 JCF 25.1 Hz, C-3), 36.5 (td, 2 JCF 20.4 Hz, C-1), 89.4 (dd, 1 JCF 175.5 Hz, C-2). 19 F NMR d: ÿ182.4 (m). MS m/z (%): 236/234/232 (4, M), 155/153 (28, M ÿ Br), 154/152 (42, M ÿ HBr), 135/133 (4, 216/ 214/212 ÿ HBr), 109/107 (22, BrCH2 CH2 ), 95/93 (12, BrCH 2 ), 73 (100, 155/153 ÿ HBr), 53 (39, 73 ÿ HF), 47 (30). 3.1.6.2. 2,4-Dibromo-1-fluorobutane. 1 H NMR d: 2.09± 2.20 (m, 2H, 3-H2), 3.45±3.58 (m, 2H, 4-H2), 4.27±4.40 (m, 1H, 2-H), 4.55 (ddd, 2 JHF 47.0 Hz, 3 JHH 9.8 Hz, 3 JHF 6.4 Hz, 1-H), 4.65 (ddd, 2 JHF 47.0 Hz, 3 JHH 9.8 Hz, 3 JHF 4.8 Hz, 1-H). 13 C NMR d: 30.1 (t, C-4), 37.1 (t, C-3), ca. 48 (dd, C-2), 84.9 (td, 1 JCF 178.0 Hz, C-1). 19 F NMR d: ÿ211.7 (dt, 2 JHF 46.7 Hz, 3 JHF 16.2 Hz). MS m/z (%): 236/234/ 232 (16, M), 216/214/212 (14, M ÿ HF), 155/153 (28, M ÿ Br), 154/152 (42, M ÿ HBr), 135/133 (11, 216/214/ 212 ÿ HBr), 109/107 (17, BrCH2 CH 2 ), 95/93 (5, BrCH2 ), 73 (100, 155/153 ÿ HBr), 53 (27, 73 ÿ HF), 47 (16). 3.1.7. Bromofluorination of benzyl 3-butenoate Method A. 470 mg (14%) of benzyl 3,4-dibromobutanoate (spectroscopic data correspond to those reported in literature [47]) and 610 mg (22%) of a 3.6:1 mixture
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(GC) of benzyl 4-bromo-3-¯uorobutanoate and benzyl 3bromo-4-¯uorobutanoate were isolated by chromatography (cyclohexane/ethyl acetate 15:1). Method B. 1.40 g (51%) of a 74:26 mixture (GC) of benzyl 4-bromo-3-¯uorobutanoate and benzyl 3-bromo-4¯uorobutanoate was isolated by chromatography (cyclohexane/ethyl acetate 15:1). 3.1.7.1. Benzyl 4-bromo-3-fluorobutanoate. 1 H NMR d: 2.81±2.90 (m, 2H, 2-H2), 3.50±3.61 (m, 2H, 4-H2), 4.99± 5.20 (m, 1H, 3-H), 5.16 (s, 2H, 5-H2), 7.25±7.47 (m, 5H, 7-H bis 11-H). 13 C NMR d: 33.1 (td, 2 JCF 25.7 Hz, C-2), 38.2 (td, 2 JCF 24.9, C-4), 66.8 (t, C-5), 87.8 (dd, 1 JCF 178.1 Hz, C-3), 128.2 (d, 1C, C-9), 128.4 (d, 2C, C-8, C-10), 128.6 (d, 2C, C-7, C-11), 135.4 (s, C-6), 169.0 (s, C-1). 19 F NMR d: ÿ177.4 (dtt, 2 JHF 45.8 Hz, 3 JHF 21.0 Hz, 3 JHF 17.2 Hz). MS m/z (%): 276/274 (20, M), 174 (5, M ÿ HF ÿ Br), 170/168 (4, M ÿ C6H5CH2O), 141/139 (2, M ÿ C6H5CH2CO2), 108 (100, C6H5CH2OH), 91 (41, C6 H5 CH 2 ), 59 (4, CH2 CFCH 2 ). C11H12BrFO2 (275.1): ca. C, 48.02; H, 4.40; found C, 48.64; H, 4.64%. 3.1.7.2. Benzyl 3-bromo-4-fluorobutanoate. 1 H NMR d: 2.84 (dd, 1H, 2 JHH 16.6 Hz, 3 JHH 8.3 Hz, 2-H, ABXsystem), 3.06 (dd, 1H, 2 JHH 16.6 Hz, 3 JHH 5.0 Hz, 2-H, ABX-system), 4.32±4.50 (m, 1H, 3-H), 4.50±4.67 (m, 2H, 4-H2), 5.10 (s, 2H, 5-H2), 7.17±7.35 (m, 5H, 7-H bis 11-H). 13 C NMR d: 39.7 (t, C-2), 43.1 (dd, 2 JCF 21.9 Hz, C-3), 67.0 (t, C-5), 84.3 (td, 1 JCF 178.1 Hz, C-4); 128.3 (d, C9), 128.4 (d, 2C, C-8, C-10), 128.6 (d, 2C, C-7, C-11), 135.4 (s, C-6), 169.4 (s, C-1). 19 F NMR d: ÿ211.5 (dt, 2 JHF 47.7 Hz, 3 JHF 13.3 Hz). MS m/z (%): 276/274 (24, M), 194 (5, M ÿ HBr), 170/168 (4, M ÿ C6H5CH2O), 141/139 (5, M ÿ C6H5CH2CO2), 108 (100, C6H5CH2OH), 91 (48, C6 H5 CH 2 ), 87 (9, FCH2CHCHCO), 59 (5, FCH2CHCH). 3.1.8. Bromofluorination of allylic cyanide Method A. 960 mg (42%) of 3,4-dibromobutyronitrile isolated by chromatography (pentane/ether 1:1). Minor amounts of a 46:54 mixture of 4-bromo-3-¯uorobutyronitril and 3-bromo-4-¯uorobutyronitril were not isolated. Method B. 480 mg (29%) of a 45:55 mixture of 4-bromo3-¯uorobutyronitrile and 3-bromo-4-¯uorobutyronitrile (GC) was isolated chromatographically (pentane/ether 1:1). Elemental analysis and NMR spectra were recorded from the mixture of regioisomers. 3.1.8.1. 3,4-Dibromobutyronitrile [48]. 1 H NMR d: 3.22 (d, 2H, 3 JHH 5.2 Hz, 2-H2), 3.72 (dd, 1H, 2 JHH 10.7 Hz, 3 JHH 10.5 Hz, 4-H, ABX system), 3.91 (dd, 1H, 2 JHH 10.7 Hz, 3 JHH 4.1 Hz, 4-H, ABX system), 4.26±4.34 (m, 1H, 3-H). 13 C NMR d: 26.1 (t, C-2), 33.6 (t, C-4), 41.8 (d, C-3), 115.4 (s, C-1). MS m/z (%): 229/ 227 (0.3, MH), 189/187 (1.8, MH ÿ CH2CN), 148/146
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(96, MH ÿ HBr), 121/119 (4, 148/146 ÿ HCN), 107/105 (6, 148/146 ÿ CH3CN), 95/93 (18, BrCH 2 ), 66 (100, 148/ ). 146 ÿ HBr), 39 (40, C3 H 3 3.1.8.2. 4-Bromo-3-fluorobutyronitrile. 1 H NMR d: 2.93 (dd, 2H, 3 JHF 19.6 Hz, 3 JHH 5.5 Hz, 2-H2), 3.57±3.64 (m, 2H, 4-H2), 4.94 (dtt, 1H, 2 JHF 46.0 Hz, 3 JHH 5.5 Hz, 3 JHH 5.2 Hz, 3-H). 13 C NMR d: 22.4 (td, 2 JCF 25.4 Hz, C-2), 30.6 (td, 2 JCF 25.4 Hz, C-4), 86.2 (dd, 1 JCF 183.1 Hz, C-3), 114.8 (s, C-1). 19 F NMR d: 2 3 JHF 45.8 Hz, JHF 19.1 Hz, ÿ174.8 (dtt, 3 JHF 17.2 Hz). MS m/z (%): 168/166 (2, MH), 167/ 165 (20, M), 147/145 (3, M ÿ HF), 127/125 (30, M ÿ CH2CN), 107/105 (15, 127/125 ÿ HF), 95/93 (10, BrCH 2 ), 86 (14, MH ÿ HBr, M ÿ Br), 72 (100, M ÿ BrCH2), 45 (24, 72 ÿ HCN), 41 (71). C4H5BrFN (166.0): ca. C, 28.94; H, 3.04; N, 8.44; found C, 29.15%; H, 3.06%; N, 8.14% (obtained for the mixture of the isomers). 3.1.8.3. 3-Bromo-4-fluorobutyronitrile. 1 H NMR d: 3.06± 3.11 (m, 2H, 2-H2); 4.18±4.31 (m, 1H, 3-H); 4.44±4.80 (m, 2H, 4-H2). 13 C NMR d: 23.8 (td, 3 JCF 5.1 Hz, C-2); 40.4 (dd, 2 JCF 22.9 Hz, C-3); 83.0 (td, 1 JCF 180.6 Hz, C-4); 115.7 (s, C-1). 19 F NMR d: ÿ210.4 (dt, 2 JHF 45.8 Hz, 3 JHF 13.3 Hz). MS m/z (%): 168/166 (2, M 1); 167/ 165 (24, M); 134/132 (4, M ÿ FCH2); 127/125 (8, M ÿ CH2CN), 107/105 (8, 127/125 ÿ HF), 86 (100, MH ÿ HBr, M ÿ Br), 85 (8, M ÿ HBr), 66 (30, 86 ÿ HF), 59 (44, 86 ÿ HCN). 4. Conclusion Regioselectivity of bromo¯uorination of terminal alkenes depends on the different electronic effects of substituents in allylic or homoallylic positions which also in¯uence the reactivity of the double bond. Electron donating groups such as alkyl substituents, which are able to stabilize a positive charge in 2-position, as expected favor the formation of Markovnikov-oriented products, while electron withdrawing substituents in allylic position destabilize corresponding secondary cationic centers. Hence, an increasing amount of anti-Markovnikov products is formed in the latter case. This is consistent with the observations made in ring opening reactions of epoxides with Olah's reagent [43]. The effect is quite weak in case of hydroxyl, epoxide, phenoxy or chlorine substituents. However, the effect becomes more important in reactions of carboxylic esters. After all bromo¯uorination of allylic imides and of allylic cyanide gave the primary ¯uorides even as the main product. Similar regioselectivity was found also in reactions with allylic bromide which in this special case seems to be caused mostly by the bridging effect of the bromine substituent. Hydroxyl groups in homoallylic position have a stronger in¯uence than in allylic position, while the reverse effect was observed for the bromine substituent.
The nature of the amine/HF reagent does not strongly in¯uence the regioselectivity of bromo¯uorination, but in¯uences the extent of side reactions, namely the formation of dibromides. While in reactions with the more acidic Olah's reagent dibromides were not found, these products were formed in all reactions with the less acidic, but more nucleophilic [38] Me3N2HF. The portion of these products increases with decreasing reactivity of the double bond and becomes almost the exclusive reaction with allylic cyanide. Thus, application of the combination NBS/Et3N3HF or NBS/Me3N2HF is recommended for bromo¯uorinations of reactive alkenes, while NBS/Olah's reagent can also be applied for less reactive alkenes which, however, should not be susceptible against cationic oligomerization or isomerization [25,40,44]. Acknowledgements Financial support by the Fonds der Chemischen Industrie is gratefully acknowledged. We are grateful to the Hoechst AG, Frankfurt/Main and the Bayer AG, Leverkusen for the kind donation of chemicals. References [1] G.A. Olah, X.-Y. Li, in: G.A. Olah, R.D. Chambers, G.K.S. Prakash (Eds.), Synthetic Fluorine Chemistry, Wiley, New York, 1992, pp. 163±204. [2] S. Rozen, in: S. Patai, Z. Rappoport (Eds.), The Chemistry of Halides, Pseudo-halides and Azides, Suppl. D2, Wiley, Chichester, 1995, pp. 629±708. [3] A.-E. Feiring, in: M. HudlickyÂ, A. E. Pavlath (Eds.), Chemistry of Organo Fluorine Compounds II, ACS Monograph 187, American Chemical Society, Washington, DC, 1995, pp. 61±69. [4] R. Miethchen, D. Peters, in: B. Baasner, H. Hagemann, J. C. Tatlow (Eds.), Houben-Weyl, Methods of Organic Chemistry, vol 10e, Thieme, Stuttgart, 1999, pp. 95±157. [5] M.M. Kremlev, G. Haufe, J. Fluorine Chem. 90 (1998) 121. [6] G. Alvernhe, A. Laurent, G. Haufe, Synthesis (1987) 562. [7] G. Haufe, G. Alvernhe, A. Laurent, T. Ernet, O. Goj, S. KroÈger, A. Sattler, Org. Synth. 76 (1998) 159. [8] A. Bowers, L.C. IbaÂnez, E. Denot, R. Becerra, J. Am. Chem. Soc. 82 (1960) 4001. [9] F.H. Dean, D.R. Marshall, E.W. Warnhoff, F.L.M. Pattison, Can. J. Chem. 45 (1967) 2279. [10] D.Y. Chi, D.O. Kiesewetter, J.A. Katzenellenbogen, M.R. Kilbourn, M.J. Welch, J. Fluorine Chem. 31 (1986) 99. [11] E. Forche, in: E. MuÈller (Ed.), Houben-Weyl, Methoden der Organischen Chemie, Vol. 5/3, Thieme, Stuttgart, 1962, pp. 117± 118. [12] M. HudlickyÂ, Chemistry of Organofluorine Compounds, 2nd (revised) ed., 1976, Ellis Horwood, Chichester, 1992, pp. 52±56. [13] M. Maeda, M. Abe, M. Kojima, J. Fluorine Chem. 34 (1987) 337. [14] J. Ichihara, K. Funabiki, T. Hanafusa, Tetrahedron Lett. 31 (1990) 3167. [15] M. Kuroboshi, T. Hiyama, Bull. Chem. Soc. Jpn. 68 (1995) 1799, and references cited therein. [16] D. Albanese, D. Landini, M. Peuso, M. Pratelli, Gazz. Chim. Ital. 121 (1991) 537.
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