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Synthesis and chemistry of α-iodoperfluoroacid esters
Journal of Fluorine Chemistry 127 (2006) 1137–1145 www.elsevier.com/locate/fluor
Synthesis and chemistry of a-iodoperfluoroacid esters Xudong Chen, David. M. Lemal * Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA Received 21 March 2006; received in revised form 2 June 2006; accepted 2 June 2006 Available online 10 June 2006
Abstract The title compounds have been synthesized by irradiation of acetonitrile solutions of perfluoroacid esters and diesters containing tetrabutylammonium iodide. They are versatile synthetic intermediates from which ketenes, Reformatsky adducts, a,b-unsaturated esters and a-hydroesters can be prepared. # 2006 Elsevier B.V. All rights reserved. Keywords: Iododefluorination; Photoreduction; a-Iodoesters; Perfluoroiodides; Perfluoroketenes; Reformatsky reaction; a,b-Unsaturated esters; a-Hydroesters
1. Introduction
2. Results and discussion
a-Haloperfluoroacid esters are the subject of much interest, as indicated by the many hundreds of patents and journal articles concerning these compounds that have appeared in recent years. One of the most important transformations of these compounds is the Reformatsky reaction, which yields b-hydroxy esters [1]. A variation on this reaction entails prior conversion to O-silylketene acetals [2], from which chiral b-hydroxy esters have been obtained [3]. Ethyl halodifluoroacetates are widely used as building blocks for complex structures incorporating the –CF2COmoiety [4]. Halodifluoroacetate esters are also good difluorocarbene precursors for cyclopropanation [5] and trifluoromethylation [6] reactions. Most of the studies have been focused on halodifluoroacetates, probably in part because of their ready availability, and the only other known a-haloperfluoroacid esters are propionates. Syntheses of these compounds usually start from commercially available fluoroalkenes (Scheme 1) [7]. We have developed a general synthesis of a-iodoperfluoroacid esters from the corresponding perfluoroacids, which enjoy ready availability in a variety of chain lengths.
2.1. Synthesis of a-iodoperfluoroacid esters
* Corresponding author. Tel.: +1 603 646 2989; fax: +1 603 646 3946. E-mail address: [email protected] (D.M. Lemal). 0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2006.06.003
UV/vis irradiation of an acetonitrile solution of a perfluoroacid ester containing tetrabutylammonium iodide (TBAI) yields the corresponding a-iodo derivative (Eq. (1)).1 Reaction of ethyl heptafluorobutyrate (1) to give ethyl aiodohexafluorobutyrate (2) is a representative example. Under our conditions,
(1)
the iododefluorination is about 60% complete after 24 h, but requires 4 days for complete conversion and a 90% yield (by NMR). Because of their solubility in both water and organic solvents, the tetrabutylammonium salts in the reaction mixture complicate the workup. The only suitable procedure we have found involves flash chromatography on silica gel to remove the salts followed by vacuum distillation. The result is moderate isolated yields. Substitution of other iodides for TBAI was not successful because of either insufficient solubility in acetonitrile (NaI, KI or Et4NI) or, in the case of lithium iodide, 1 Other applications of photoreduction by iodide ion include the photoFinkelstein reaction [8] and the functionalization of saturated fluorocarbons [9].
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Scheme 1.
blocking of the light by coating the immersion well with lithium fluoride. Because they slowed dramatically over time, reactions were typically interrupted after 2 days. Reaction times and isolated yields are reported in Table 1. Yields from methyl perfluoropropionate (3), perfluorooctanoate (4), and hexafluoroglutarate (5) were similar to that from 1. Despite its bifunctionality, methyl hexafluoroglutarate (5) gave only the monoiodo derivative. In the case of methyl octafluoroadipate (6), the monoiodo compound was accompanied by minor amounts of the meso- and dl-2,5-diiodo derivatives. The iododefluorination reaction may be useful for desymmetrization of shortchain perfluorodiesters, but selectivity is lost as the chain lengthens. Methyl perfluorosuberate, for example, gave a mixture that was difficult to separate. It is fortunate that ahalodifluoroacetates are readily available via other synthetic methods, as methyl trifluoroacetate reacted reluctantly, affording only a 10% yield (by NMR) after 24 h. This result probably reflects the greater difficulty of eliminating fluoride ion from a CF3 than from a CF2 group2 and/or, as a reviewer suggested, the higher lying LUMO of trifluoroacetate as compared with higher homologs. We propose the mechanism shown in Scheme 2 for the iododefluorination reaction. The initiating event is a CTTS (charge-transfer-to-solvent) transition of the iodide ion (or triiodide ion as iodine is formed in the reaction). The resulting solvated electron invades the LUMO of an ester molecule, forming a radical anion (7) which ejects an a-fluorine as fluoride ion. Transformation of the enoxyl radical 8 into aiodoester 9 may follow any of several pathways. It can attack an iodine molecule or triiodide ion to give 9 directly. Alternatively, it can react with iodide ion to give radical anion 10, which
2
Uneyama has reduced trifluoroacetates with magnesium [10] and electrochemically [11] in the presence of chlorotrimethylsilane to obtain a-trimethylsilyldifluoroacetates, valuable synthetic intermediates.
yields 9 by reducing iodine. Finally, the enoxyl radical can accept an electron, making the enolate ion 11, which gives 9 via attack on an iodine molecule. This scheme results in the net consumption of one iodide ion per molecule of product. Because molecular iodine, required for capturing species 8, 10, and/or 11, is present only in low concentration early in the reaction, yields are improved by adding a small amount at the outset. The selectivity for monoiodination, even in the case of short-chain diesters, is understandable in terms of reversibility in the iodination step(s).3 When a molecule of the product 9 accepts an electron, the weak carbon–iodine bond is broken with ejection of iodide ion in preference to fluoride ion, regenerating the enoxyl radical 8. Reiodination transforms this radical back into 9. A small amount of ester cleavage accompanied the photoreaction, and methyl fluoride was detected as a byproduct. Thus, tetrabutylammonium fluoride (TBAF) formed during the reaction must attack ester and/or methyl iodide in SN2 fashion. Surprisingly, a-fluoroacetonitrile was also identified as a byproduct. Perhaps TBAF occasionally deprotonates an acetonitrile molecule; if so, the anion would be iodinated, and the a-iodoacetonitrile would then be susceptible to displacement by fluoride ion. 2.2. Ketene formation Fluoroketenes were unknown until almost 60 years after the preparation and characterization of the first ketene, diphenylketene, in 1905 [13]. To date, the only fluoroketene to be isolated ‘‘conventionally’’ is bis(trifluoromethyl)ketene 12, first reported in 1963 [14]. Difluoroketene 13 is well known to 3
Perfluoroacid esters can be photoreduced with 254 nm light in HMPA, but both a-mono- and dihydro derivatives result since incorporation of hydrogen, unlike iodine, is irreversible [12].
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Table 1 Iododefluorination of perfluoroacid esters Ester
Rxn. time (h)
Yield (%)
CF3CO2Me CF3CF2CO2Me (3) CF3CF2CF2CO2Et (1) CF3(CF2)6CO2Me (4) MeO2C(CF2)3CO2Me (5) MeO2C(CF2)4CO2Me (6)
24 48 47 48 48 14
(10)a 46 (80) 47 (76) 54 45b (57) 39c
a b c
Parentheses indicate NMR yields. 90% pure. Small amounts of the 2,5-diodo derivatives were also formed.
be unstable at RT, decomposing readily into difluorocarbene and carbon monoxide [15]. Derivatives have been prepared [16], and the ketene itself has been observed in matrix isolation [17].
Scheme 3.
in wet acetonitrile, but evaporation of the solvent reversed the process (Eq. (2)).
(2) Fluorotrifluoromethylketene (14), with only one fluorine on the double bond, is presumably intermediate in stability between the difluoro and bis(trifluoromethyl) compounds. Despite many attempts, 14 has never been isolated, and has only been trapped as derivatives 15 and 16 (Scheme 3) [18,19]. We have prepared and derivatized fluorotrifluoromethylketene as follows. Methyl a-iodotetrafluoropropionate (17) was saponified with potassium hydroxide, and the dried potassium salt was converted to the acid chloride 18 with oxalyl or thionyl chloride. Zinc reduction of 18 in the presence of styrene produced the ketene, captured as the cyclobutanone 19 in 46% yield based on the starting ester (Scheme 4). The [2 + 2] cycloaddition afforded only one of the four possible cyclobutanone regio- and stereoisomers, purified by flash chromatography. Ketone 19 underwent hydration, forming 20,
Scheme 2.
On the chance that it would decarbonylate to give a cyclopropane, the ketone was subjected to UV irradiation, but the result was decomposition to an unidentified mixture. The structure and stereochemistry of cyclobutanone 19 was assigned with the help of 1H NMR and FH-NOESY spectra. Ha (d 4.21) was assigned as vicinal and cis to the tertiary fluorine, as it is the only proton strongly coupled (J = 14 Hz) to that fluorine (Fig. 1a). Such coupling is characteristic of fluorine cis to methine hydrogen on a four-membered ring, and trans coupling is generally negligible [20]. The FH-NOESY spectrum showed weak interaction of the CF3 group with phenyl protons and Hc at 3.64 ppm, as well as strong interaction of the tertiary fluorine with Ha. The regiochemistry of the cycloaddition leading to ketone 19 is as expected, for the dominant frontier orbital interaction is between the ketene LUMO, with largest coefficient at the carbonyl carbon, and the alkene HOMO, with largest coefficient at the terminal carbon [21a]. Stereochemistry of 19 is correctly predicted by the Woodward–Hoffmann perpendicular model for ketene cycloadditions (Fig. 1b) [22,23]. The least hindered perpendicular approach of the reactants gives the adduct with the larger substituents cis to one another. In a study of the cycloaddition of fluorine-substituted
Scheme 4.
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Fig. 1. (a) Proton NMR assignments for adduct 19; (b) schematic representation of the transition state leading to 19.
ketenes with cyclopentadiene, Dolbier et al. found only one adduct in each case, and the stereochemistry of the adducts was consistent with the Woodward–Hoffmann model [20]. Reaction of ketene 14 with aldehydes can yield b-lactones and, via subsequent decarboxylation, fluoroalkenes. Adding acid chloride 18 to a mixture of zinc and benzaldehyde gave blactone adducts 21 and 22 in the ratio 1.5:1. Both lost carbon dioxide spontaneously at RT, but at very different rates. Adduct 21 yielded alkene 23 quickly, but formation of alkene 24 was observed only after several days (Scheme 5). The 19F NMR chemical shifts and coupling constants of alkenes 23 and 24 agreed with literature values [24]. Decarboxylation of b-lactones is a stereospecific syn elimination [25,26]. Thus, the stereochemical assignments for lactones 21 and 22 follow from the respective alkene configurations. Not only is there little stereoselectivity in this cycloaddition, but it is also reversed compared with the [2 + 2] reaction of the ketene with styrene that gave only the cis adduct 19. Generally, for addition of ketenes to carbonyl compounds, the key interaction takes place between the ketene HOMO and the carbonyl LUMO, with C2 of the ketene attacking the carbonyl carbon [27]. In the case of the very electron-deficient ketene 14, the ketene HOMO–aldehyde LUMO gap is greater than the ketene LUMO–aldehyde HOMO gap. Nonetheless, the dominant frontier orbital interaction occurs between the former pair of orbitals, according to AM1 calculations [28]. The frontier orbital interactions are not great, and the strong coulombic attraction between the aldehyde oxygen and the ketene carbonyl carbon (electrostatic charges: 0.45 and +0.74, respectively) could result in formation of a well stabilized zwitterion (25) [21b,29]. If the reaction proceeds in this stepwise fashion, the
Scheme 6.
less hindered 21 could be formed as the major adduct, meaning reversed, albeit low stereoselectivity.
2.3. Reformatsky reaction a-Iodoperfluoroacid ester 2 reacts with zinc and benzaldehyde to give b-hydroxy adducts 26 and 27, together with 28, a byproduct resulting from elimination of fluoride from the zinc enolate intermediate (Scheme 6). Diastereomers 26 and 27 were easily separated by column chromatography. Solvent and temperature influence the ratio of adducts to byproduct and the diastereomeric ratio (Table 2). Lowering the temperature improves the adducts/byproduct ratio a bit, as does changing the solvent from acetonitrile to diglyme. THF increases the ratio much more, and the use of indium in place of zinc in THF gives the best result, a 78% yield of adducts with just 10% of the byproduct. Selectivity between 26 and 27 ranges from none to modest under the various reaction conditions, but it is interesting that the switch from zinc to indium in THF reverses the selectivity. Both H–H coupling constants and 13C NMR chemical shifts have been employed in the determination of stereostructure of b-hydroxycarbonyl compounds [30]. Erythro isomers have been reported to have a considerably smaller H(C2)–H(C3) coupling constant than their threo counterparts. Isomer 26 Table 2 Reformatsky reaction of 2 with benzaldehyde
Scheme 5.
Metal
Temperature
Solvent
Adducts:alkene
26:27
Zn Zn Zn Zn In
RT 0 8C 0 8C RT RT
MeCN MeCN Diglyme THF THF
1.3:1 1.5:1 2:1 5.2:1 8:1
1:1 1:1 1.4:1 1.4:1 0.5:1
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Scheme 8.
Scheme 7.
3. Conclusions (J = 23 Hz) was assigned as threo (2R, 3S and 3R, 2S) and 27 (J = 18 Hz) as erythro according to this rule. The rule has been rationalized on the basis that b-hydroxycarbonyl compounds exist in intramolecularly hydrogen-bonded form [31], and there can be an equilibrium between two chair-like conformers for each diastereomer, as illustrated in Scheme 7. Here F substitutes for H at C2. The equilibrium for the threo isomer favors conformer 26b, in which F(C2)–H(C3) are anti with a relatively large coupling constant. In the two conformers of the erythro isomer 27, these nuclei are in a gauche relationship, resulting in a smaller coupling constant. It was found that erythro isomers consistently showed an upfield shift for C2 and C3 as compared with the threo isomers. This relationship was rationalized on the basis of the same model. Chemical shifts for C2 and C3 in isomer 26 are 97.2 and 73.8 ppm, respectively, while those of 27 are 93.3 and 73.5 ppm. Thus, the configurational assignment based on 13C chemical shifts accords with that based on H–F coupling constants. Coe et al. used the same method to tentatively assign the configurations of the diastereomeric b-hydroxyesters 29 and 30 [32], which have structures very similar to those of 26 and 27.
2.4. a,b-Unsaturated and a-hydroester formation a,b-Unsaturated perfluoroacid esters have attracted interest recently as building blocks for monomers of photoresist polymers [33]. Zinc reduction of a-iodoperfluoroacid ester 2 without trapping agent in acetonitrile generated unsaturated ester 28 and its Z isomer 31, ratio 5:1, in 91% crude yield (Scheme 8) [34]. Roughly 12% of hydro compound 32 was present as a byproduct, presumably arising from a trace of moisture in the reaction system. When the reaction with zinc was carried out in acetic acid, a-hydroester 32 was isolated in 94% yield [12,35].
A method for selective introduction of a single iodine at the a-position of a perfluoroacid ester or diester has been developed. We have shown that the iodo derivatives can be transformed into ketenes, Reformatsky adducts, a,b-unsaturated esters and a-hydroesters. Perfluoroiodides are among the most versatile intermediates in fluoroorganic synthesis, and we have only scratched the surface of the synthetic potential these iodoesters possess. Alkylation, acylation, dimerization, heterocoupling, and addition to alkenes are some of the kinds of transformation remaining to be explored. 4. Experimental NMR spectra were taken on Varian Unity Plus 300 and 500 MHz machines. 19F NMR spectra were recorded at 282.2 and 470.3 MHz, using an internal standard of trichlorofluoromethane. In spectra of certain complex spin systems, line spacings reported as Js may not be true coupling constants. 13C NMR spectra were recorded at 125.7 MHz. GC was performed on a Hewlett-Packard 5750 gas chromatograph, and GC/MS on a Hewlett-Packard 5890A gas chromatograph with a HewlettPackard 5971 series mass detector. IR spectra were measured on a Perkin-Elmer 599 FTIR instrument. The UV source for photoreaction was a Vycor-filtered 450 W Hanovia mediumpressure mercury arc contained in a quartz water jacket. The 150 mL pyrex reaction vessel surrounding the jacket had a sidearm connecting the top with the bottom, and it was warmed with a heating tape to effect circulation by convection. Elemental analyses were done by Atlantic Microlab, Inc., Atlanta, GA. High resolution mass spectra were obtained from the Mass Spectrometry Center, University of Massachusetts, Amherst, MA. THF was distilled from potassium benzophenone ketyl, and acetonitrile from calcium hydride. 4.1. Perfluoro-2-iodobutyrate (2) Ethyl heptafluorobutyrate (1) (14.5 g, 60 mmol), tetrabutylammonium iodide (22.16 g, 60 mmol), iodine (0.76 g,
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3 mmol), and acetonitrile (120 mL) were added to the photoreaction vessel. After 48 h of irradiation, ethyl perfluoro-2-iodobutyrate (2) was present in 77% yield, as measured by 19F NMR with trifluorotoluene as internal standard. Solvent was removed by distillation, and then tetrabutylammonium salts were removed by flash chromatography (100 g silica gel, 300 mL ether). After removal of ether, a reduced pressure distillation (20 Torr, 58–60 8C) gave pure 2. Yield: 9.90 g, 47%. 1H NMR (CDCl3): d 4.41 (q, J = 6.9 Hz, CH2), 1.35 (t, J = 6.9 Hz, CH3). 19F NMR (CDCl3): d 79.2 (m, poorly resolved, 3F, C4), 111.7, 112.6 (AB q, J = 279 Hz, subsplit, d, J = 17 Hz, 2F, C3), 137.8 (m, 1F, C2). 13C NMR (19F decoupled, CDCl3): d 162.9 (C1), 116.2 (C4), 109.8 (C3), 70.7 (C2), 64.4 (t, J = 149 Hz, CH2), 13.5 (q, J = 128 Hz, CH3). IR (neat, cm 1): 2990, 1767, 1471, 1449, 1372, 1326, 1200, 1128, 1075, 1014. HRMS: 349.9239 found, 349.9243 calculated for C6H5F6O2I. 4.2. Methyl perfluoro-2-iodopropionate (17) Methyl pentafluoropropionate (3) (10.7 g, 60 mmol), tetrabutylammonium iodide (22.16 g, 60 mmol), iodine (0.76 g, 3 mmol), and acetonitrile (120 mL) were placed in the photoreactor. Methyl perfluoro-2-iodopropionate (17) was formed in 80% yield after 48 h, as measured by 19F NMR with trifluorotoluene as internal standard. Solvent was removed by distillation, and then tetrabutylammonium salts were removed by flash chromatography (100 g silica gel, 300 mL ether). After removal of ether, reduced pressure distillation (30 Torr, 40 8C) gave pure 17. Yield: 7.9 g, 46%. 1 H NMR (CDCl3): d 3.97 (s, CH3). 19F NMR (CDCl3): d 76.3 (d, J = 11.8, 3F, C3), 140.7 (q, J = 11.8 Hz, 1F, C2). 13 C NMR (19F decoupled, CDCl3): d 163.5 (C1), 120.7 (C3), 67.8 (C2), 54.8 (q, J = 149 Hz, CH3). IR (neat, cm 1): 2963, 1765, 1440, 1290, 1219, 1188, 1124, 1027, 1002, 941, 793,730, 667. HRMS: 285.9124 found, 285.9114 calculated for C4H3F4O2I. 4.3. Methyl perfluoro-2-iodooctanoate Methyl perfluorooctanoate (4) (9.00 g, 21 mmol), tetrabutylammonium iodide (12.0 g, 32.5 mmol), iodine (0.50 g, 2 mmol), and acetonitrile (120 mL) were placed in the photoreactor. After 48 h, methyl perfluoro-2-iodooctanoate was present in good yield, as revealed by 19F NMR. Solvent was removed by distillation, and then product was purified by flash chromatography (100 g silica gel, 250 mL ether). Yield: 6.03 g, 54%. 1H NMR (CDCl3): d 3.96 (s, CH3). 19F NMR (CDCl3): d 81.3 (s, 3F, C8), 107.1, 107.6 (AB q, J = 282 Hz, 2F), 119.6 (br s, 2F), 122.4 (s, broad, 2F), 122.9, 123.4 (AB q, J = 303 Hz, 2F), 126.4, 126.9 (AB q, J = 298 Hz, 2F), 137.5 (m, 1F, C2). 13C NMR (19F decoupled, CDCl3): d 163.9 (C1), 118.4, 116.3, 112.2, 110.8, 110.4, 108.6 (C3–8), 72.0 (C2), 54.8 (q, J = 150 Hz, CH3). IR (neat, cm 1): 2964, 1769, 1442, 1360, 1239, 1205, 1144, 1080, 1017. HRMS: 535.8983 found, 535.8954 calculated for C9H3F14O2I.
4.4. Dimethyl 2-iodoperfluoroglutarate Dimethyl hexafluoroglutarate (5) (8.04 g, 30 mmol), tetrabutylammonium iodide (22.2 g, 60 mmol), iodine (0.50 g, 2 mmol), and acetonitrile (120 mL) were added to the photoreactor. Dimethyl 2-iodoperfluoroglutarate was formed in 57% yield after 48 h, as measured by 19F NMR with trifluorotoluene as internal standard. Solvent was removed by distillation, and then one-half of the product was purified by flash chromatography (100 g silica gel, 250 mL ether; then 20 g silica gel, hexane/ether 3:1). Yield: 2.55 g, 41% (45.2% crude, 90% pure). 1H NMR (CDCl3): d 3.97 (s, CH3), 3.94 (s, CH3). 19F NMR (CDCl3): d 108.0, 108.8 (AB q, J = 281 Hz, A subsplit, dd, J = 4.7, 17 Hz, B subsplit, d, J = 18 Hz, 2F, C3 or 4), 116.4, 116.9 (AB q, J = 275 Hz, A subsplit, d, J = 14 Hz; B subsplit, m; 2F, C3 or 4), 136.8 (m, 1F, C2). 13C NMR (19F decoupled, CDCl3): d 163.8 (q, J = 3.8 Hz, C1 or 5), 159.3 (q, J = 4.7 Hz, C1 or 5), 111.4 (C3 or 4), 107.4 (C3 or 4), 71.8 (C2), 54.5 (q, J = 149 Hz, CH3), 54.5 (q, J = 150 Hz, CH3). IR (neat, cm 1): 2963, 1775, 1441, 1324, 1275, 1177, 1140, 1035, 980, 800, 780. HRMS: 375.9216 found, 375.9231 calculated for C7H6F5O4I. 4.5. Dimethyl 2-iodoperfluoroadipate Dimethyl octafluoroadipate (0.58 g, 1.8 mmol), tetrabutylammonium iodide (0.80 g, 1.2 equiv.), iodine (0.050 g), and acetonitrile (10 mL) were added to a 25 mL quartz tube. It was sealed with a septum, and attached to the UV source. The whole assembly was immersed in water contained in a large beaker. Cooling water was introduced to the beaker continuously, and a large pan with a draining hose was used to collect the running water. The mixture was irradiated for 14 h. Formation of dimethyl 2-iodoperfluoroadipate and dimethyl 2,5-diiodoperfluoroadipates was observed by NMR. Solvent was removed by rotary evaporation, and the iodoesters were separated by flash chromatography (20 g silica gel, 100 mL methylene chloride to remove tetrabutylammonium salts; then 30 g silica gel, hexane/ ether 8:1 to separate esters). Yield of dimethyl 2-iodoperfluoroadipate: 0.30 g, 39%. 1H NMR (CDCl3): d 3.98 (poorly resolved d, J = 2.5 Hz, CH3), 3.94 (poorly resolved d, J = 3.0 Hz, CH3). 19F NMR (CDCl3): d 106.3, 107.8 (AB q, J = 286 Hz, 2F, C3), 118.8, 119.5 (AB q, J = 280 Hz, each part poorly resolved m, 2F, C4), 120.5, 120.9 (AB q, J = 292 Hz, A part poorly resolved m, 2F, C5), 137.2 (poorly resolved m, 1F, C2). 13C NMR (19F decoupled, CDCl3): d 163.9 (q, J = 3.6 Hz, C1 or 6), 159.2 (q, J = 3.6 Hz, C1 or 6), 112.1 (CF2, C3, 4 or 5), 109.9 (CF2, C3, 4 or 5), 108.1 (CF2, C3, 4 or 5), 72.1 (C2), 54.7 (q, J = 150 Hz, CH3), 54.6 (q, J = 149 Hz, CH3). IR (neat, cm 1): 3019, 2964, 1768, 1441, 1331, 1273, 1180. Yield of dimethyl 2,5-diiodoperfluoroadipate: 0.062 g, 6%. m.p. 105.0–107.0 8C. 1H NMR (CDCl3): d 3.94 (s, CH3). 19 F NMR (CDCl3): d 103.1, 104.3 (AB q, J = 282 Hz, each part poorly resolved m, 4F, C3 and 4), 137.7 (m, 2F, C2 and 5). 13C NMR (19F decoupled, CDCl3): d 164.0 (C1 and 6), 111.6 (C3 and 4), 72.5 (C2 and 5), 54.5 (q, J = 149 Hz, CH3). IR (neat, cm 1): 2962, 1763, 1438, 1289, 1254, 1155, 1118. The other
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isomer of dimethyl 2,5-diiodoperfluoroadipate (smaller Rf on silica gel) was contaminated with dimethyl 2-iodoperfluoroadipate. 1H NMR (CDCl3): d 3.95 (s, CH3). 19F NMR (CDCl3): d 102.4, 106.2 (AB q, J = 137 Hz, each part poorly resolved m, 4F, C3 and 4), 136.1 (m, 2F, C2 and 5). Dimethyl octafluoroadipate (0.040 g, 7%) was recovered. 4.6. 2-Fluoro-2-trifluoromethyl-3-phenylcyclobutanone (19) Methyl perfluoro-2-iodopropionate (17) (1.0 g, 3.5 mmol) was dissolved in ethanol/water solution (1:1, 5 mL). Potassium hydroxide (0.23 g, 3.5 mmol) was dissolved in the same solvent (5 mL), and it was added dropwise to the ester solution. Formation of potassium perfluoro-2-iodopropionate (92) was very clean, as observed by NMR. After 0.5 h, solvent was removed by rotary evaporation, and the salt was dried by azeotropic distillation with benzene (10 mL). The resulting white solid was dissolved in freshly dried acetonitrile (5 mL). The solution was cooled in a dry ice–ethylene glycol slush bath, while oxalyl chloride (0.57 g, 1.3 equiv.) was added dropwise. After the addition, the mixture was warmed to room temperature and then heated to 50 8C for 0.5 h. As judged by NMR, acid chloride 18 was formed in good yield. When the mixture had cooled, nitrogen pressure was used to transfer 18 slowly through a Teflon tube to a 25 mL round-bottom flask containing zinc (0.677 g, 3 equiv.) and styrene (1.08 g, 3 equiv.). The mixture was stirred for 1 h in an ice bath. After solvent was removed by rotary evaporation, flash chromatography (silica gel, 30 g, ether/ hexane, 1:3) gave pure 2-fluoro-2-trifluoromethyl-3-phenylcyclobutanone (19). Yield: 0.37 g, 46% based on 17 m.p. 41.0– 42.0 8C. 1H NMR (CDCl3): d 7.36–7.46 (m, 5H, phenyl), 4.21 (ddd, J = 6.6, 7.5, 14 Hz, 1H, C3), 3.64 (ddd, J = 2.7, 7.5, 10.8 Hz, 1H, C4, cis to CF3), 3.54 (ddd, J = 3.9, 6.6 10.8 Hz, 1H, C4, trans to CF3). 19F NMR (CDCl3): d 74.5 (d, J = 10 Hz, 3F, CF3), 157.8 (m, 1F, C2). 13C NMR (1H decoupled, CDCl3): d 193.4 (d, J = 16 Hz, subsplit, d, poorly resolved, C1), 131.9 (Ph, ipso), 128.9, 128.5, 128.1 (Ph, o, m, p), 120.7 (dq, J = 30, 285 Hz, CF3), 103.8 (qd, J = 32, 244 Hz, CF, C2), 44.6 (qd, J = 1.4, 12.8 Hz, C3), 41.8 (d, J = 18.8 Hz, C4). IR (neat, cm 1): 3035, 1809, 1183. HRMS: 232.0516 found, 232.0511 calculated for C11H8F4O. Anal. calculated for C11H8F4O: C, 56.90; H, 3.47; F, 32.73. Found for C, 56.61; H, 3.45; F, 32.48.
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Yield: 6.45 g, 90%. 19F NMR (CDCl3): d 75.0 (d, J = 13.6 Hz, 3F, C3), 132.8 (q, J = 13.6 Hz, 1F, C2). 4.8. Ethyl 2-fluoro-2-pentafluoroethyl-3-hydroxy-3phenylbutyrate (26, 27) Ethyl perfluoro-2-iodobutyrate (2) (1.0 g, 2.9 mmol) was added dropwise to a mixture of THF (5 mL), indium powder (0.26 g, 2.3 mmol), and benzaldehyde (0.91 g, 8.7 mmol) in a 10 mL vial. The mixture was stirred for 0.5 h, then quenched with hydrochloric acid (5%, 10 mL) and extracted with ether (3 5 mL). The organic layers were combined and dried over sodium sulfate. After solvent was removed by rotary evaporation, flash chromatography (silica gel, 30 g, pentane/ ether 3:1) gave b-hydroxyesters 26 and 27, both in pure form. Yield: threo isomer, 0.25 g; erythro isomer, 0.49 g; 0.74 g total, 78%. Threo isomer: m.p. 70.5–71.5 8C. 1H NMR (CDCl3): d 7.20 (m, 5H), 5.44 (dd, J = 6.6, 23 Hz, 1H, CH), 4.04 (m, 2H, CH2), 2.55 (d, J = 6.6 Hz, 1H, OH), 1.07 (t, J = 7.0 Hz, 3H, CH3). 19F NMR (CDCl3): d 81.3 (d, J = 8.9 Hz, 3F, CF3), 119.2, 122.3 (AB q, J = 287 Hz, B subsplit, d, J = 10 Hz, 2F, CF2), 189.9 (m, 1F). 13C NMR (1H decoupled, CDCl3): d 163.1 (dd, J = 6.0, 23.5 Hz, C1), 135.9 (Ph, ipso), 129.8, 128.8, 128.3 (Ph, o, m, p), 118.4 (tq, J = 35, 288 Hz, CF3), 115.5 (dqdd, J = 30, 39, 265, 270 Hz, CF2), 94.2 (ddd, J = 22, 27, 211 Hz, C2), 73.8 (d, J = 18.4 Hz, CH), 63.4 (s, CH2), 13.7 (s, CH3). IR: 3471 (br), 2988, 1766, 1455, 1216. Anal. calculated for C13H12F6O3: C, 47.28; H, 3.66; F, 34.52. Found for C, 47.49; H, 3.67; F, 34.63. Erythro isomer: m.p. 65.5–66.5 8C. 1H NMR (CDCl3): d 7.40 (m, 5H, Ph), 5.38 (dd, J = 7.8, 18 Hz, each peak a poorly resolved d, 1H, CH), 4.32 (q, J = 6.9 Hz, 2H, CH2), 2.97 (d, J = 7.8 Hz, 1H, OH), 1.27 (t, J = 6.9 Hz, 3H, CH3). 19F NMR (CDCl3): d 81.6 (d, J = 10 Hz, 3F, CF3), 119.6, 122.9 (AB q, J = 288 Hz, B subsplit, d, J = 14 Hz, 2F, CF2), 184.0 (br s, 1F). 13C NMR (1H decoupled, CDCl3): d 164.1 (dd, J = 6.4, 24 Hz, C1), 136.4 (Ph, ipso); 129.6, 128.7, 127.9 (Ph, o, m, p), 118.3 (tq, J = 35, 288 Hz, CF3), 111.0 (dqdd, J = 29, 38, 266, 269 Hz, CF2), 93.3 (td, J = 24, 210 Hz, C2), 73.5 (d, J = 21 Hz, CH), 63.7 (s, CH2), 13.9 (s, CH3). IR: 3484 (br), 2988, 1752, 1450, 1200. Anal. calculated for C13H12F6O3: C, 47.28; H, 3.66; F, 34.52. Found for C, 47.40; H, 3.71; F, 33.77.
4.7. 2-Iodoperfluoropropionyl chloride (18) 4.9. Ethyl 2H-perfluorobutyrate (32) Potassium perfluoro-2-iodopropionate (7.6 g, 21 mmol) was added to an oven-dried 10 mL round-bottom flask, with a condenser installed. Thionyl chloride (2.7 mL, 4.4 g, 37 mmol) was added to the flask while it was cooled in a dry ice–acetone bath under nitrogen. A large stirring bar was used in order to mix the relatively large amount of solid with the small amount of liquid. The mixture was warmed up to room temperature first, and then refluxed for 8 h. Excess thionyl chloride was removed by distillation. A vacuum transfer afforded acid chloride 18 slightly contaminated with thionyl chloride, as determined by GC.
Ethyl perfluoro-2-iodobutyrate (2) (0.40 g, 1.1 mmol) dissolved in acetic acid (1 mL) was added dropwise to a mixture of zinc (0.16 g, 2.4 mmol) and acetic acid (1 mL) in a 5 mL vial with stirring. After 1 h, the mixture was transferred to a 15 mL centrifuge tube, and washed with water/brine (1:1, 5 mL), then with brine (3 mL). A vortex stirrer was used to mix the organic and aqueous layer, and centrifuging was done to separate the two layers. After the aqueous layer was removed, anhydrous magnesium sulfate (100 mg) was added to dry the organic layer. A vacuum transfer afforded quite
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pure ethyl 2H-perfluorobutyrate (32). Yield: 0.24 g, 94%. 1H NMR (CDCl3): d 5.21 (ddd, J = 5.7, 16, 46 Hz, 1H, C2), 4.39 (dq, J = 1.2, 7.2 Hz, 2H, CH2), d 1.36 (t, J = 7.2 Hz, 3H, CH3). 19F NMR (CDCl3): d 82.8 (d, J = 10 Hz, 3F, C4), 122.4, 127.4 (AB q, J = 286 Hz, subsplit; A, dd, J = 5.7, 11 Hz; B, dd, J = 14, 16 Hz; 2F, C3), 205.8 (subsplit d, J = 46 Hz, 1F, C2). 4.10. Ethyl pentafluorobut-2-enoate (28, 31) Ethyl perfluoro-2-iodobutyrate (2) (1.00 g, 2.86 mmol) was added dropwise to a mixture of zinc (0.22 g, 3.4 mmol) and acetonitrile (1 mL) in a 5 mL vial with stirring. After 2 h, the mixture was transferred to a 15 mL centrifuge tube and washed with water/brine (1:1, 5 mL), then with brine (3 mL). A vortex stirrer was used to mix the organic and aqueous layer, and centrifuging was done to separate the two layers. After the aqueous layer was removed, anhydrous magnesium sulfate (100 mg) was added to dry the organic layer. A vacuum transfer afforded ethyl pentafluorobut-2-enoate (28, 31). Yield: 0.53 g, 91% (trans/cis ratio, 5:1; 12% of hydro compound 32 present). 1H NMR (CDCl3, trans): d 4.42 (q, J = 7.2 Hz, 2H, CH2), d 1.40 (t, J = 7.2 Hz, 3H, CH3). 19F NMR (CDCl3, trans): d 68.9 (dd, J = 8.5, 21 Hz, 3F, CF3), 151.7 (qd, J = 8.5, 138 Hz, 1F), 153.7 (qd, J = 21, 138 Hz, 1F). Acknowledgement The National Science Foundation is gratefully acknowledged for support of this research. References
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Synthesis and chemistry of a-iodoperfluoroacid esters Xudong Chen, David. M. Lemal * Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA Received 21 March 2006; received in revised form 2 June 2006; accepted 2 June 2006 Available online 10 June 2006
Abstract The title compounds have been synthesized by irradiation of acetonitrile solutions of perfluoroacid esters and diesters containing tetrabutylammonium iodide. They are versatile synthetic intermediates from which ketenes, Reformatsky adducts, a,b-unsaturated esters and a-hydroesters can be prepared. # 2006 Elsevier B.V. All rights reserved. Keywords: Iododefluorination; Photoreduction; a-Iodoesters; Perfluoroiodides; Perfluoroketenes; Reformatsky reaction; a,b-Unsaturated esters; a-Hydroesters
1. Introduction
2. Results and discussion
a-Haloperfluoroacid esters are the subject of much interest, as indicated by the many hundreds of patents and journal articles concerning these compounds that have appeared in recent years. One of the most important transformations of these compounds is the Reformatsky reaction, which yields b-hydroxy esters [1]. A variation on this reaction entails prior conversion to O-silylketene acetals [2], from which chiral b-hydroxy esters have been obtained [3]. Ethyl halodifluoroacetates are widely used as building blocks for complex structures incorporating the –CF2COmoiety [4]. Halodifluoroacetate esters are also good difluorocarbene precursors for cyclopropanation [5] and trifluoromethylation [6] reactions. Most of the studies have been focused on halodifluoroacetates, probably in part because of their ready availability, and the only other known a-haloperfluoroacid esters are propionates. Syntheses of these compounds usually start from commercially available fluoroalkenes (Scheme 1) [7]. We have developed a general synthesis of a-iodoperfluoroacid esters from the corresponding perfluoroacids, which enjoy ready availability in a variety of chain lengths.
2.1. Synthesis of a-iodoperfluoroacid esters
* Corresponding author. Tel.: +1 603 646 2989; fax: +1 603 646 3946. E-mail address: [email protected] (D.M. Lemal). 0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2006.06.003
UV/vis irradiation of an acetonitrile solution of a perfluoroacid ester containing tetrabutylammonium iodide (TBAI) yields the corresponding a-iodo derivative (Eq. (1)).1 Reaction of ethyl heptafluorobutyrate (1) to give ethyl aiodohexafluorobutyrate (2) is a representative example. Under our conditions,
(1)
the iododefluorination is about 60% complete after 24 h, but requires 4 days for complete conversion and a 90% yield (by NMR). Because of their solubility in both water and organic solvents, the tetrabutylammonium salts in the reaction mixture complicate the workup. The only suitable procedure we have found involves flash chromatography on silica gel to remove the salts followed by vacuum distillation. The result is moderate isolated yields. Substitution of other iodides for TBAI was not successful because of either insufficient solubility in acetonitrile (NaI, KI or Et4NI) or, in the case of lithium iodide, 1 Other applications of photoreduction by iodide ion include the photoFinkelstein reaction [8] and the functionalization of saturated fluorocarbons [9].
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Scheme 1.
blocking of the light by coating the immersion well with lithium fluoride. Because they slowed dramatically over time, reactions were typically interrupted after 2 days. Reaction times and isolated yields are reported in Table 1. Yields from methyl perfluoropropionate (3), perfluorooctanoate (4), and hexafluoroglutarate (5) were similar to that from 1. Despite its bifunctionality, methyl hexafluoroglutarate (5) gave only the monoiodo derivative. In the case of methyl octafluoroadipate (6), the monoiodo compound was accompanied by minor amounts of the meso- and dl-2,5-diiodo derivatives. The iododefluorination reaction may be useful for desymmetrization of shortchain perfluorodiesters, but selectivity is lost as the chain lengthens. Methyl perfluorosuberate, for example, gave a mixture that was difficult to separate. It is fortunate that ahalodifluoroacetates are readily available via other synthetic methods, as methyl trifluoroacetate reacted reluctantly, affording only a 10% yield (by NMR) after 24 h. This result probably reflects the greater difficulty of eliminating fluoride ion from a CF3 than from a CF2 group2 and/or, as a reviewer suggested, the higher lying LUMO of trifluoroacetate as compared with higher homologs. We propose the mechanism shown in Scheme 2 for the iododefluorination reaction. The initiating event is a CTTS (charge-transfer-to-solvent) transition of the iodide ion (or triiodide ion as iodine is formed in the reaction). The resulting solvated electron invades the LUMO of an ester molecule, forming a radical anion (7) which ejects an a-fluorine as fluoride ion. Transformation of the enoxyl radical 8 into aiodoester 9 may follow any of several pathways. It can attack an iodine molecule or triiodide ion to give 9 directly. Alternatively, it can react with iodide ion to give radical anion 10, which
2
Uneyama has reduced trifluoroacetates with magnesium [10] and electrochemically [11] in the presence of chlorotrimethylsilane to obtain a-trimethylsilyldifluoroacetates, valuable synthetic intermediates.
yields 9 by reducing iodine. Finally, the enoxyl radical can accept an electron, making the enolate ion 11, which gives 9 via attack on an iodine molecule. This scheme results in the net consumption of one iodide ion per molecule of product. Because molecular iodine, required for capturing species 8, 10, and/or 11, is present only in low concentration early in the reaction, yields are improved by adding a small amount at the outset. The selectivity for monoiodination, even in the case of short-chain diesters, is understandable in terms of reversibility in the iodination step(s).3 When a molecule of the product 9 accepts an electron, the weak carbon–iodine bond is broken with ejection of iodide ion in preference to fluoride ion, regenerating the enoxyl radical 8. Reiodination transforms this radical back into 9. A small amount of ester cleavage accompanied the photoreaction, and methyl fluoride was detected as a byproduct. Thus, tetrabutylammonium fluoride (TBAF) formed during the reaction must attack ester and/or methyl iodide in SN2 fashion. Surprisingly, a-fluoroacetonitrile was also identified as a byproduct. Perhaps TBAF occasionally deprotonates an acetonitrile molecule; if so, the anion would be iodinated, and the a-iodoacetonitrile would then be susceptible to displacement by fluoride ion. 2.2. Ketene formation Fluoroketenes were unknown until almost 60 years after the preparation and characterization of the first ketene, diphenylketene, in 1905 [13]. To date, the only fluoroketene to be isolated ‘‘conventionally’’ is bis(trifluoromethyl)ketene 12, first reported in 1963 [14]. Difluoroketene 13 is well known to 3
Perfluoroacid esters can be photoreduced with 254 nm light in HMPA, but both a-mono- and dihydro derivatives result since incorporation of hydrogen, unlike iodine, is irreversible [12].
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Table 1 Iododefluorination of perfluoroacid esters Ester
Rxn. time (h)
Yield (%)
CF3CO2Me CF3CF2CO2Me (3) CF3CF2CF2CO2Et (1) CF3(CF2)6CO2Me (4) MeO2C(CF2)3CO2Me (5) MeO2C(CF2)4CO2Me (6)
24 48 47 48 48 14
(10)a 46 (80) 47 (76) 54 45b (57) 39c
a b c
Parentheses indicate NMR yields. 90% pure. Small amounts of the 2,5-diodo derivatives were also formed.
be unstable at RT, decomposing readily into difluorocarbene and carbon monoxide [15]. Derivatives have been prepared [16], and the ketene itself has been observed in matrix isolation [17].
Scheme 3.
in wet acetonitrile, but evaporation of the solvent reversed the process (Eq. (2)).
(2) Fluorotrifluoromethylketene (14), with only one fluorine on the double bond, is presumably intermediate in stability between the difluoro and bis(trifluoromethyl) compounds. Despite many attempts, 14 has never been isolated, and has only been trapped as derivatives 15 and 16 (Scheme 3) [18,19]. We have prepared and derivatized fluorotrifluoromethylketene as follows. Methyl a-iodotetrafluoropropionate (17) was saponified with potassium hydroxide, and the dried potassium salt was converted to the acid chloride 18 with oxalyl or thionyl chloride. Zinc reduction of 18 in the presence of styrene produced the ketene, captured as the cyclobutanone 19 in 46% yield based on the starting ester (Scheme 4). The [2 + 2] cycloaddition afforded only one of the four possible cyclobutanone regio- and stereoisomers, purified by flash chromatography. Ketone 19 underwent hydration, forming 20,
Scheme 2.
On the chance that it would decarbonylate to give a cyclopropane, the ketone was subjected to UV irradiation, but the result was decomposition to an unidentified mixture. The structure and stereochemistry of cyclobutanone 19 was assigned with the help of 1H NMR and FH-NOESY spectra. Ha (d 4.21) was assigned as vicinal and cis to the tertiary fluorine, as it is the only proton strongly coupled (J = 14 Hz) to that fluorine (Fig. 1a). Such coupling is characteristic of fluorine cis to methine hydrogen on a four-membered ring, and trans coupling is generally negligible [20]. The FH-NOESY spectrum showed weak interaction of the CF3 group with phenyl protons and Hc at 3.64 ppm, as well as strong interaction of the tertiary fluorine with Ha. The regiochemistry of the cycloaddition leading to ketone 19 is as expected, for the dominant frontier orbital interaction is between the ketene LUMO, with largest coefficient at the carbonyl carbon, and the alkene HOMO, with largest coefficient at the terminal carbon [21a]. Stereochemistry of 19 is correctly predicted by the Woodward–Hoffmann perpendicular model for ketene cycloadditions (Fig. 1b) [22,23]. The least hindered perpendicular approach of the reactants gives the adduct with the larger substituents cis to one another. In a study of the cycloaddition of fluorine-substituted
Scheme 4.
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Fig. 1. (a) Proton NMR assignments for adduct 19; (b) schematic representation of the transition state leading to 19.
ketenes with cyclopentadiene, Dolbier et al. found only one adduct in each case, and the stereochemistry of the adducts was consistent with the Woodward–Hoffmann model [20]. Reaction of ketene 14 with aldehydes can yield b-lactones and, via subsequent decarboxylation, fluoroalkenes. Adding acid chloride 18 to a mixture of zinc and benzaldehyde gave blactone adducts 21 and 22 in the ratio 1.5:1. Both lost carbon dioxide spontaneously at RT, but at very different rates. Adduct 21 yielded alkene 23 quickly, but formation of alkene 24 was observed only after several days (Scheme 5). The 19F NMR chemical shifts and coupling constants of alkenes 23 and 24 agreed with literature values [24]. Decarboxylation of b-lactones is a stereospecific syn elimination [25,26]. Thus, the stereochemical assignments for lactones 21 and 22 follow from the respective alkene configurations. Not only is there little stereoselectivity in this cycloaddition, but it is also reversed compared with the [2 + 2] reaction of the ketene with styrene that gave only the cis adduct 19. Generally, for addition of ketenes to carbonyl compounds, the key interaction takes place between the ketene HOMO and the carbonyl LUMO, with C2 of the ketene attacking the carbonyl carbon [27]. In the case of the very electron-deficient ketene 14, the ketene HOMO–aldehyde LUMO gap is greater than the ketene LUMO–aldehyde HOMO gap. Nonetheless, the dominant frontier orbital interaction occurs between the former pair of orbitals, according to AM1 calculations [28]. The frontier orbital interactions are not great, and the strong coulombic attraction between the aldehyde oxygen and the ketene carbonyl carbon (electrostatic charges: 0.45 and +0.74, respectively) could result in formation of a well stabilized zwitterion (25) [21b,29]. If the reaction proceeds in this stepwise fashion, the
Scheme 6.
less hindered 21 could be formed as the major adduct, meaning reversed, albeit low stereoselectivity.
2.3. Reformatsky reaction a-Iodoperfluoroacid ester 2 reacts with zinc and benzaldehyde to give b-hydroxy adducts 26 and 27, together with 28, a byproduct resulting from elimination of fluoride from the zinc enolate intermediate (Scheme 6). Diastereomers 26 and 27 were easily separated by column chromatography. Solvent and temperature influence the ratio of adducts to byproduct and the diastereomeric ratio (Table 2). Lowering the temperature improves the adducts/byproduct ratio a bit, as does changing the solvent from acetonitrile to diglyme. THF increases the ratio much more, and the use of indium in place of zinc in THF gives the best result, a 78% yield of adducts with just 10% of the byproduct. Selectivity between 26 and 27 ranges from none to modest under the various reaction conditions, but it is interesting that the switch from zinc to indium in THF reverses the selectivity. Both H–H coupling constants and 13C NMR chemical shifts have been employed in the determination of stereostructure of b-hydroxycarbonyl compounds [30]. Erythro isomers have been reported to have a considerably smaller H(C2)–H(C3) coupling constant than their threo counterparts. Isomer 26 Table 2 Reformatsky reaction of 2 with benzaldehyde
Scheme 5.
Metal
Temperature
Solvent
Adducts:alkene
26:27
Zn Zn Zn Zn In
RT 0 8C 0 8C RT RT
MeCN MeCN Diglyme THF THF
1.3:1 1.5:1 2:1 5.2:1 8:1
1:1 1:1 1.4:1 1.4:1 0.5:1
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Scheme 8.
Scheme 7.
3. Conclusions (J = 23 Hz) was assigned as threo (2R, 3S and 3R, 2S) and 27 (J = 18 Hz) as erythro according to this rule. The rule has been rationalized on the basis that b-hydroxycarbonyl compounds exist in intramolecularly hydrogen-bonded form [31], and there can be an equilibrium between two chair-like conformers for each diastereomer, as illustrated in Scheme 7. Here F substitutes for H at C2. The equilibrium for the threo isomer favors conformer 26b, in which F(C2)–H(C3) are anti with a relatively large coupling constant. In the two conformers of the erythro isomer 27, these nuclei are in a gauche relationship, resulting in a smaller coupling constant. It was found that erythro isomers consistently showed an upfield shift for C2 and C3 as compared with the threo isomers. This relationship was rationalized on the basis of the same model. Chemical shifts for C2 and C3 in isomer 26 are 97.2 and 73.8 ppm, respectively, while those of 27 are 93.3 and 73.5 ppm. Thus, the configurational assignment based on 13C chemical shifts accords with that based on H–F coupling constants. Coe et al. used the same method to tentatively assign the configurations of the diastereomeric b-hydroxyesters 29 and 30 [32], which have structures very similar to those of 26 and 27.
2.4. a,b-Unsaturated and a-hydroester formation a,b-Unsaturated perfluoroacid esters have attracted interest recently as building blocks for monomers of photoresist polymers [33]. Zinc reduction of a-iodoperfluoroacid ester 2 without trapping agent in acetonitrile generated unsaturated ester 28 and its Z isomer 31, ratio 5:1, in 91% crude yield (Scheme 8) [34]. Roughly 12% of hydro compound 32 was present as a byproduct, presumably arising from a trace of moisture in the reaction system. When the reaction with zinc was carried out in acetic acid, a-hydroester 32 was isolated in 94% yield [12,35].
A method for selective introduction of a single iodine at the a-position of a perfluoroacid ester or diester has been developed. We have shown that the iodo derivatives can be transformed into ketenes, Reformatsky adducts, a,b-unsaturated esters and a-hydroesters. Perfluoroiodides are among the most versatile intermediates in fluoroorganic synthesis, and we have only scratched the surface of the synthetic potential these iodoesters possess. Alkylation, acylation, dimerization, heterocoupling, and addition to alkenes are some of the kinds of transformation remaining to be explored. 4. Experimental NMR spectra were taken on Varian Unity Plus 300 and 500 MHz machines. 19F NMR spectra were recorded at 282.2 and 470.3 MHz, using an internal standard of trichlorofluoromethane. In spectra of certain complex spin systems, line spacings reported as Js may not be true coupling constants. 13C NMR spectra were recorded at 125.7 MHz. GC was performed on a Hewlett-Packard 5750 gas chromatograph, and GC/MS on a Hewlett-Packard 5890A gas chromatograph with a HewlettPackard 5971 series mass detector. IR spectra were measured on a Perkin-Elmer 599 FTIR instrument. The UV source for photoreaction was a Vycor-filtered 450 W Hanovia mediumpressure mercury arc contained in a quartz water jacket. The 150 mL pyrex reaction vessel surrounding the jacket had a sidearm connecting the top with the bottom, and it was warmed with a heating tape to effect circulation by convection. Elemental analyses were done by Atlantic Microlab, Inc., Atlanta, GA. High resolution mass spectra were obtained from the Mass Spectrometry Center, University of Massachusetts, Amherst, MA. THF was distilled from potassium benzophenone ketyl, and acetonitrile from calcium hydride. 4.1. Perfluoro-2-iodobutyrate (2) Ethyl heptafluorobutyrate (1) (14.5 g, 60 mmol), tetrabutylammonium iodide (22.16 g, 60 mmol), iodine (0.76 g,
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3 mmol), and acetonitrile (120 mL) were added to the photoreaction vessel. After 48 h of irradiation, ethyl perfluoro-2-iodobutyrate (2) was present in 77% yield, as measured by 19F NMR with trifluorotoluene as internal standard. Solvent was removed by distillation, and then tetrabutylammonium salts were removed by flash chromatography (100 g silica gel, 300 mL ether). After removal of ether, a reduced pressure distillation (20 Torr, 58–60 8C) gave pure 2. Yield: 9.90 g, 47%. 1H NMR (CDCl3): d 4.41 (q, J = 6.9 Hz, CH2), 1.35 (t, J = 6.9 Hz, CH3). 19F NMR (CDCl3): d 79.2 (m, poorly resolved, 3F, C4), 111.7, 112.6 (AB q, J = 279 Hz, subsplit, d, J = 17 Hz, 2F, C3), 137.8 (m, 1F, C2). 13C NMR (19F decoupled, CDCl3): d 162.9 (C1), 116.2 (C4), 109.8 (C3), 70.7 (C2), 64.4 (t, J = 149 Hz, CH2), 13.5 (q, J = 128 Hz, CH3). IR (neat, cm 1): 2990, 1767, 1471, 1449, 1372, 1326, 1200, 1128, 1075, 1014. HRMS: 349.9239 found, 349.9243 calculated for C6H5F6O2I. 4.2. Methyl perfluoro-2-iodopropionate (17) Methyl pentafluoropropionate (3) (10.7 g, 60 mmol), tetrabutylammonium iodide (22.16 g, 60 mmol), iodine (0.76 g, 3 mmol), and acetonitrile (120 mL) were placed in the photoreactor. Methyl perfluoro-2-iodopropionate (17) was formed in 80% yield after 48 h, as measured by 19F NMR with trifluorotoluene as internal standard. Solvent was removed by distillation, and then tetrabutylammonium salts were removed by flash chromatography (100 g silica gel, 300 mL ether). After removal of ether, reduced pressure distillation (30 Torr, 40 8C) gave pure 17. Yield: 7.9 g, 46%. 1 H NMR (CDCl3): d 3.97 (s, CH3). 19F NMR (CDCl3): d 76.3 (d, J = 11.8, 3F, C3), 140.7 (q, J = 11.8 Hz, 1F, C2). 13 C NMR (19F decoupled, CDCl3): d 163.5 (C1), 120.7 (C3), 67.8 (C2), 54.8 (q, J = 149 Hz, CH3). IR (neat, cm 1): 2963, 1765, 1440, 1290, 1219, 1188, 1124, 1027, 1002, 941, 793,730, 667. HRMS: 285.9124 found, 285.9114 calculated for C4H3F4O2I. 4.3. Methyl perfluoro-2-iodooctanoate Methyl perfluorooctanoate (4) (9.00 g, 21 mmol), tetrabutylammonium iodide (12.0 g, 32.5 mmol), iodine (0.50 g, 2 mmol), and acetonitrile (120 mL) were placed in the photoreactor. After 48 h, methyl perfluoro-2-iodooctanoate was present in good yield, as revealed by 19F NMR. Solvent was removed by distillation, and then product was purified by flash chromatography (100 g silica gel, 250 mL ether). Yield: 6.03 g, 54%. 1H NMR (CDCl3): d 3.96 (s, CH3). 19F NMR (CDCl3): d 81.3 (s, 3F, C8), 107.1, 107.6 (AB q, J = 282 Hz, 2F), 119.6 (br s, 2F), 122.4 (s, broad, 2F), 122.9, 123.4 (AB q, J = 303 Hz, 2F), 126.4, 126.9 (AB q, J = 298 Hz, 2F), 137.5 (m, 1F, C2). 13C NMR (19F decoupled, CDCl3): d 163.9 (C1), 118.4, 116.3, 112.2, 110.8, 110.4, 108.6 (C3–8), 72.0 (C2), 54.8 (q, J = 150 Hz, CH3). IR (neat, cm 1): 2964, 1769, 1442, 1360, 1239, 1205, 1144, 1080, 1017. HRMS: 535.8983 found, 535.8954 calculated for C9H3F14O2I.
4.4. Dimethyl 2-iodoperfluoroglutarate Dimethyl hexafluoroglutarate (5) (8.04 g, 30 mmol), tetrabutylammonium iodide (22.2 g, 60 mmol), iodine (0.50 g, 2 mmol), and acetonitrile (120 mL) were added to the photoreactor. Dimethyl 2-iodoperfluoroglutarate was formed in 57% yield after 48 h, as measured by 19F NMR with trifluorotoluene as internal standard. Solvent was removed by distillation, and then one-half of the product was purified by flash chromatography (100 g silica gel, 250 mL ether; then 20 g silica gel, hexane/ether 3:1). Yield: 2.55 g, 41% (45.2% crude, 90% pure). 1H NMR (CDCl3): d 3.97 (s, CH3), 3.94 (s, CH3). 19F NMR (CDCl3): d 108.0, 108.8 (AB q, J = 281 Hz, A subsplit, dd, J = 4.7, 17 Hz, B subsplit, d, J = 18 Hz, 2F, C3 or 4), 116.4, 116.9 (AB q, J = 275 Hz, A subsplit, d, J = 14 Hz; B subsplit, m; 2F, C3 or 4), 136.8 (m, 1F, C2). 13C NMR (19F decoupled, CDCl3): d 163.8 (q, J = 3.8 Hz, C1 or 5), 159.3 (q, J = 4.7 Hz, C1 or 5), 111.4 (C3 or 4), 107.4 (C3 or 4), 71.8 (C2), 54.5 (q, J = 149 Hz, CH3), 54.5 (q, J = 150 Hz, CH3). IR (neat, cm 1): 2963, 1775, 1441, 1324, 1275, 1177, 1140, 1035, 980, 800, 780. HRMS: 375.9216 found, 375.9231 calculated for C7H6F5O4I. 4.5. Dimethyl 2-iodoperfluoroadipate Dimethyl octafluoroadipate (0.58 g, 1.8 mmol), tetrabutylammonium iodide (0.80 g, 1.2 equiv.), iodine (0.050 g), and acetonitrile (10 mL) were added to a 25 mL quartz tube. It was sealed with a septum, and attached to the UV source. The whole assembly was immersed in water contained in a large beaker. Cooling water was introduced to the beaker continuously, and a large pan with a draining hose was used to collect the running water. The mixture was irradiated for 14 h. Formation of dimethyl 2-iodoperfluoroadipate and dimethyl 2,5-diiodoperfluoroadipates was observed by NMR. Solvent was removed by rotary evaporation, and the iodoesters were separated by flash chromatography (20 g silica gel, 100 mL methylene chloride to remove tetrabutylammonium salts; then 30 g silica gel, hexane/ ether 8:1 to separate esters). Yield of dimethyl 2-iodoperfluoroadipate: 0.30 g, 39%. 1H NMR (CDCl3): d 3.98 (poorly resolved d, J = 2.5 Hz, CH3), 3.94 (poorly resolved d, J = 3.0 Hz, CH3). 19F NMR (CDCl3): d 106.3, 107.8 (AB q, J = 286 Hz, 2F, C3), 118.8, 119.5 (AB q, J = 280 Hz, each part poorly resolved m, 2F, C4), 120.5, 120.9 (AB q, J = 292 Hz, A part poorly resolved m, 2F, C5), 137.2 (poorly resolved m, 1F, C2). 13C NMR (19F decoupled, CDCl3): d 163.9 (q, J = 3.6 Hz, C1 or 6), 159.2 (q, J = 3.6 Hz, C1 or 6), 112.1 (CF2, C3, 4 or 5), 109.9 (CF2, C3, 4 or 5), 108.1 (CF2, C3, 4 or 5), 72.1 (C2), 54.7 (q, J = 150 Hz, CH3), 54.6 (q, J = 149 Hz, CH3). IR (neat, cm 1): 3019, 2964, 1768, 1441, 1331, 1273, 1180. Yield of dimethyl 2,5-diiodoperfluoroadipate: 0.062 g, 6%. m.p. 105.0–107.0 8C. 1H NMR (CDCl3): d 3.94 (s, CH3). 19 F NMR (CDCl3): d 103.1, 104.3 (AB q, J = 282 Hz, each part poorly resolved m, 4F, C3 and 4), 137.7 (m, 2F, C2 and 5). 13C NMR (19F decoupled, CDCl3): d 164.0 (C1 and 6), 111.6 (C3 and 4), 72.5 (C2 and 5), 54.5 (q, J = 149 Hz, CH3). IR (neat, cm 1): 2962, 1763, 1438, 1289, 1254, 1155, 1118. The other
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isomer of dimethyl 2,5-diiodoperfluoroadipate (smaller Rf on silica gel) was contaminated with dimethyl 2-iodoperfluoroadipate. 1H NMR (CDCl3): d 3.95 (s, CH3). 19F NMR (CDCl3): d 102.4, 106.2 (AB q, J = 137 Hz, each part poorly resolved m, 4F, C3 and 4), 136.1 (m, 2F, C2 and 5). Dimethyl octafluoroadipate (0.040 g, 7%) was recovered. 4.6. 2-Fluoro-2-trifluoromethyl-3-phenylcyclobutanone (19) Methyl perfluoro-2-iodopropionate (17) (1.0 g, 3.5 mmol) was dissolved in ethanol/water solution (1:1, 5 mL). Potassium hydroxide (0.23 g, 3.5 mmol) was dissolved in the same solvent (5 mL), and it was added dropwise to the ester solution. Formation of potassium perfluoro-2-iodopropionate (92) was very clean, as observed by NMR. After 0.5 h, solvent was removed by rotary evaporation, and the salt was dried by azeotropic distillation with benzene (10 mL). The resulting white solid was dissolved in freshly dried acetonitrile (5 mL). The solution was cooled in a dry ice–ethylene glycol slush bath, while oxalyl chloride (0.57 g, 1.3 equiv.) was added dropwise. After the addition, the mixture was warmed to room temperature and then heated to 50 8C for 0.5 h. As judged by NMR, acid chloride 18 was formed in good yield. When the mixture had cooled, nitrogen pressure was used to transfer 18 slowly through a Teflon tube to a 25 mL round-bottom flask containing zinc (0.677 g, 3 equiv.) and styrene (1.08 g, 3 equiv.). The mixture was stirred for 1 h in an ice bath. After solvent was removed by rotary evaporation, flash chromatography (silica gel, 30 g, ether/ hexane, 1:3) gave pure 2-fluoro-2-trifluoromethyl-3-phenylcyclobutanone (19). Yield: 0.37 g, 46% based on 17 m.p. 41.0– 42.0 8C. 1H NMR (CDCl3): d 7.36–7.46 (m, 5H, phenyl), 4.21 (ddd, J = 6.6, 7.5, 14 Hz, 1H, C3), 3.64 (ddd, J = 2.7, 7.5, 10.8 Hz, 1H, C4, cis to CF3), 3.54 (ddd, J = 3.9, 6.6 10.8 Hz, 1H, C4, trans to CF3). 19F NMR (CDCl3): d 74.5 (d, J = 10 Hz, 3F, CF3), 157.8 (m, 1F, C2). 13C NMR (1H decoupled, CDCl3): d 193.4 (d, J = 16 Hz, subsplit, d, poorly resolved, C1), 131.9 (Ph, ipso), 128.9, 128.5, 128.1 (Ph, o, m, p), 120.7 (dq, J = 30, 285 Hz, CF3), 103.8 (qd, J = 32, 244 Hz, CF, C2), 44.6 (qd, J = 1.4, 12.8 Hz, C3), 41.8 (d, J = 18.8 Hz, C4). IR (neat, cm 1): 3035, 1809, 1183. HRMS: 232.0516 found, 232.0511 calculated for C11H8F4O. Anal. calculated for C11H8F4O: C, 56.90; H, 3.47; F, 32.73. Found for C, 56.61; H, 3.45; F, 32.48.
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Yield: 6.45 g, 90%. 19F NMR (CDCl3): d 75.0 (d, J = 13.6 Hz, 3F, C3), 132.8 (q, J = 13.6 Hz, 1F, C2). 4.8. Ethyl 2-fluoro-2-pentafluoroethyl-3-hydroxy-3phenylbutyrate (26, 27) Ethyl perfluoro-2-iodobutyrate (2) (1.0 g, 2.9 mmol) was added dropwise to a mixture of THF (5 mL), indium powder (0.26 g, 2.3 mmol), and benzaldehyde (0.91 g, 8.7 mmol) in a 10 mL vial. The mixture was stirred for 0.5 h, then quenched with hydrochloric acid (5%, 10 mL) and extracted with ether (3 5 mL). The organic layers were combined and dried over sodium sulfate. After solvent was removed by rotary evaporation, flash chromatography (silica gel, 30 g, pentane/ ether 3:1) gave b-hydroxyesters 26 and 27, both in pure form. Yield: threo isomer, 0.25 g; erythro isomer, 0.49 g; 0.74 g total, 78%. Threo isomer: m.p. 70.5–71.5 8C. 1H NMR (CDCl3): d 7.20 (m, 5H), 5.44 (dd, J = 6.6, 23 Hz, 1H, CH), 4.04 (m, 2H, CH2), 2.55 (d, J = 6.6 Hz, 1H, OH), 1.07 (t, J = 7.0 Hz, 3H, CH3). 19F NMR (CDCl3): d 81.3 (d, J = 8.9 Hz, 3F, CF3), 119.2, 122.3 (AB q, J = 287 Hz, B subsplit, d, J = 10 Hz, 2F, CF2), 189.9 (m, 1F). 13C NMR (1H decoupled, CDCl3): d 163.1 (dd, J = 6.0, 23.5 Hz, C1), 135.9 (Ph, ipso), 129.8, 128.8, 128.3 (Ph, o, m, p), 118.4 (tq, J = 35, 288 Hz, CF3), 115.5 (dqdd, J = 30, 39, 265, 270 Hz, CF2), 94.2 (ddd, J = 22, 27, 211 Hz, C2), 73.8 (d, J = 18.4 Hz, CH), 63.4 (s, CH2), 13.7 (s, CH3). IR: 3471 (br), 2988, 1766, 1455, 1216. Anal. calculated for C13H12F6O3: C, 47.28; H, 3.66; F, 34.52. Found for C, 47.49; H, 3.67; F, 34.63. Erythro isomer: m.p. 65.5–66.5 8C. 1H NMR (CDCl3): d 7.40 (m, 5H, Ph), 5.38 (dd, J = 7.8, 18 Hz, each peak a poorly resolved d, 1H, CH), 4.32 (q, J = 6.9 Hz, 2H, CH2), 2.97 (d, J = 7.8 Hz, 1H, OH), 1.27 (t, J = 6.9 Hz, 3H, CH3). 19F NMR (CDCl3): d 81.6 (d, J = 10 Hz, 3F, CF3), 119.6, 122.9 (AB q, J = 288 Hz, B subsplit, d, J = 14 Hz, 2F, CF2), 184.0 (br s, 1F). 13C NMR (1H decoupled, CDCl3): d 164.1 (dd, J = 6.4, 24 Hz, C1), 136.4 (Ph, ipso); 129.6, 128.7, 127.9 (Ph, o, m, p), 118.3 (tq, J = 35, 288 Hz, CF3), 111.0 (dqdd, J = 29, 38, 266, 269 Hz, CF2), 93.3 (td, J = 24, 210 Hz, C2), 73.5 (d, J = 21 Hz, CH), 63.7 (s, CH2), 13.9 (s, CH3). IR: 3484 (br), 2988, 1752, 1450, 1200. Anal. calculated for C13H12F6O3: C, 47.28; H, 3.66; F, 34.52. Found for C, 47.40; H, 3.71; F, 33.77.
4.7. 2-Iodoperfluoropropionyl chloride (18) 4.9. Ethyl 2H-perfluorobutyrate (32) Potassium perfluoro-2-iodopropionate (7.6 g, 21 mmol) was added to an oven-dried 10 mL round-bottom flask, with a condenser installed. Thionyl chloride (2.7 mL, 4.4 g, 37 mmol) was added to the flask while it was cooled in a dry ice–acetone bath under nitrogen. A large stirring bar was used in order to mix the relatively large amount of solid with the small amount of liquid. The mixture was warmed up to room temperature first, and then refluxed for 8 h. Excess thionyl chloride was removed by distillation. A vacuum transfer afforded acid chloride 18 slightly contaminated with thionyl chloride, as determined by GC.
Ethyl perfluoro-2-iodobutyrate (2) (0.40 g, 1.1 mmol) dissolved in acetic acid (1 mL) was added dropwise to a mixture of zinc (0.16 g, 2.4 mmol) and acetic acid (1 mL) in a 5 mL vial with stirring. After 1 h, the mixture was transferred to a 15 mL centrifuge tube, and washed with water/brine (1:1, 5 mL), then with brine (3 mL). A vortex stirrer was used to mix the organic and aqueous layer, and centrifuging was done to separate the two layers. After the aqueous layer was removed, anhydrous magnesium sulfate (100 mg) was added to dry the organic layer. A vacuum transfer afforded quite
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pure ethyl 2H-perfluorobutyrate (32). Yield: 0.24 g, 94%. 1H NMR (CDCl3): d 5.21 (ddd, J = 5.7, 16, 46 Hz, 1H, C2), 4.39 (dq, J = 1.2, 7.2 Hz, 2H, CH2), d 1.36 (t, J = 7.2 Hz, 3H, CH3). 19F NMR (CDCl3): d 82.8 (d, J = 10 Hz, 3F, C4), 122.4, 127.4 (AB q, J = 286 Hz, subsplit; A, dd, J = 5.7, 11 Hz; B, dd, J = 14, 16 Hz; 2F, C3), 205.8 (subsplit d, J = 46 Hz, 1F, C2). 4.10. Ethyl pentafluorobut-2-enoate (28, 31) Ethyl perfluoro-2-iodobutyrate (2) (1.00 g, 2.86 mmol) was added dropwise to a mixture of zinc (0.22 g, 3.4 mmol) and acetonitrile (1 mL) in a 5 mL vial with stirring. After 2 h, the mixture was transferred to a 15 mL centrifuge tube and washed with water/brine (1:1, 5 mL), then with brine (3 mL). A vortex stirrer was used to mix the organic and aqueous layer, and centrifuging was done to separate the two layers. After the aqueous layer was removed, anhydrous magnesium sulfate (100 mg) was added to dry the organic layer. A vacuum transfer afforded ethyl pentafluorobut-2-enoate (28, 31). Yield: 0.53 g, 91% (trans/cis ratio, 5:1; 12% of hydro compound 32 present). 1H NMR (CDCl3, trans): d 4.42 (q, J = 7.2 Hz, 2H, CH2), d 1.40 (t, J = 7.2 Hz, 3H, CH3). 19F NMR (CDCl3, trans): d 68.9 (dd, J = 8.5, 21 Hz, 3F, CF3), 151.7 (qd, J = 8.5, 138 Hz, 1F), 153.7 (qd, J = 21, 138 Hz, 1F). Acknowledgement The National Science Foundation is gratefully acknowledged for support of this research. References
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