Synthesis and chemistry of α-iodoperfluoroacid esters

Article abstract of DOI:10.1016/j.jfluchem.2006.06.003

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, α,β-unsaturated esters and α-hydroesters can be prepared.

Full text of DOI:10.1016/j.jfluchem.2006.06.003

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 –CF2CO-
moiety [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].
2.1. Synthesis of a-iodoperfluoroacid esters
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 a-
iodohexafluorobutyrate (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 acetoni-
trile (NaI, KI or Et4NI) or, in the case of lithium iodide,
We have developed a general synthesis of a-iodoperfluor-
oacid esters from the corresponding perfluoroacids, which
enjoy ready availability in a variety of chain lengths.
1
* Corresponding author. Tel.: +1 603 646 2989; fax: +1 603 646 3946.
Other applications of photoreduction by iodide ion include the photo-
E-mail address: david.m.lemal@dartmouth.edu (D.M. Lemal).
Finkelstein reaction [8] and the functionalization of saturated fluorocarbons [9].
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.06.003

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X. Chen, D.M. Lemal / Journal of Fluorine Chemistry 127 (2006) 1137–1145
Scheme 1.
blocking of the light by coating the immersion well with lithium
fluoride.
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.
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 perfluor-
opropionate (3), perfluorooctanoate (4), and hexafluorogluta-
rate (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 iododefluorina-
tion reaction may be useful for desymmetrization of short-
chain 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 a-
halodifluoroacetates 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.
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.
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 a-
iodoester 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
2.2. Ketene formation
Fluoroketenes were unknown until almost 60 years after the
preparation and characterization of the first ketene, diphenylk-
etene, 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
2
3
Uneyama has reduced trifluoroacetates with magnesium [10] and electro-
Perfluoroacid esters can be photoreduced with 254 nm light in HMPA, but
chemically [11] in the presence of chlorotrimethylsilane to obtain a-trimethyl-
silyldifluoroacetates, valuable synthetic intermediates.
both a-mono- and dihydro derivatives result since incorporation of hydrogen,
unlike iodine, is irreversible [12].

X. Chen, D.M. Lemal / Journal of Fluorine Chemistry 127 (2006) 1137–1145
1139
Table 1
Iododefluorination of perfluoroacid esters
Ester
Rxn. time (h)
Yield (%)
CF3CO2Me
24
48
47
48
48
14
(10)a
46 (80)
47 (76)
54
45b (57)
39c
CF3CF2CO2Me (3)
CF3CF2CF2CO2Et (1)
CF3(CF2)6CO2Me (4)
MeO2C(CF2)3CO2Me (5)
MeO2C(CF2)4CO2Me (6)
a
Parentheses indicate NMR yields.
b
ꢀ90% pure.
Scheme 3.
c
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].
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 fluorotrifluoromethyl-
ketene 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,
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 2.
Scheme 4.

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X. Chen, D.M. Lemal / Journal of Fluorine Chemistry 127 (2006) 1137–1145
Fig. 1. (a) Proton NMR assignments for adduct 19; (b) schematic representa-
tion 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 b-
lactone 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].
Scheme 6.
less hindered 21 could be formed as the major adduct,
meaning reversed, albeit low stereoselectivity.
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: À0.45 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
2.3. Reformatsky reaction
a-Iodoperfluoroacid ester 2 reacts with zinc and benzalde-
hyde 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
Metal
Temperature
Solvent
Adducts:alkene
26:27
Zn
Zn
Zn
Zn
In
RT
MeCN
MeCN
Diglyme
THF
1.3:1
1.5:1
2:1
1:1
0 8C
0 8C
RT
1:1
1.4:1
1.4:1
0.5:1
5.2:1
8:1
RT
THF
Scheme 5.

X. Chen, D.M. Lemal / Journal of Fluorine Chemistry 127 (2006) 1137–1145
1141
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.
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-unsatu-
rated 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, hetero-
coupling, and addition to alkenes are some of the kinds of
transformation remaining to be explored.
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.
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 trichlorofluor-
omethane. In spectra of certain complex spin systems, line
spacings reported as Js may not be true coupling constants. 13
C
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 Hewlett-
Packard 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 medium-
pressure 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.
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].
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), tetrabuty-
lammonium iodide (22.16 g, 60 mmol), iodine (0.76 g,

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X. Chen, D.M. Lemal / Journal of Fluorine Chemistry 127 (2006) 1137–1145
3 mmol), and acetonitrile (120 mL) were added to the
photoreaction vessel. After 48 h of irradiation, ethyl per-
fluoro-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 chromato-
graphy (100 g silica gel, 300 mL ether). After removal of ether,
a reduced pressure distillation (20 Torr, 58–60 8C) gave pure 2.
4.4. Dimethyl 2-iodoperfluoroglutarate
Dimethyl hexafluoroglutarate (5) (8.04 g, 30 mmol), tetra-
butylammonium 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 À108.0, 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), À116.4, À116.9 (AB q, J = 275 Hz, A subsplit, d,
1
Yield: 9.90 g, 47%. H NMR (CDCl3): d 4.41 (q, J = 6.9 Hz,
CH2), 1.35 (t, J = 6.9 Hz, CH3). 19F NMR (CDCl3): d À79.2 (m,
poorly resolved, 3F, C4), À111.7, À112.6 (AB q, J = 279 Hz,
subsplit, d, J = 17 Hz, 2F, C3), À137.8 (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, cmÀ1): 2990, 1767, 1471, 1449, 1372, 1326, 1200,
1128, 1075, 1014. HRMS: 349.9239 found, 349.9243
calculated for C6H5F6O2I.
J = 14 Hz; B subsplit, m; 2F, C3 or 4), À136.8 (m, 1F, C2). 13
C
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, cmÀ1): 2963, 1775, 1441, 1324, 1275, 1177,
1140, 1035, 980, 800, 780. HRMS: 375.9216 found, 375.9231
calculated for C7H6F5O4I.
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%.
1H NMR (CDCl3): d 3.97 (s, CH3). 19F NMR (CDCl3): d
À76.3 (d, J = 11.8, 3F, C3), À140.7 (q, J = 11.8 Hz, 1F, C2).
13C NMR (19F decoupled, CDCl3): d 163.5 (C1), 120.7 (C3),
67.8 (C2), 54.8 (q, J = 149 Hz, CH3). IR (neat, cmÀ1): 2963,
1765, 1440, 1290, 1219, 1188, 1124, 1027, 1002, 941,
793,730, 667. HRMS: 285.9124 found, 285.9114 calculated
for C4H3F4O2I.
4.5. Dimethyl 2-iodoperfluoroadipate
Dimethyl octafluoroadipate (0.58 g, 1.8 mmol), tetrabuty-
lammonium 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-diiodoper-
fluoroadipates 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-iodoper-
4.3. Methyl perfluoro-2-iodooctanoate
1
fluoroadipate: 0.30 g, 39%. H NMR (CDCl3): d 3.98 (poorly
Methyl perfluorooctanoate (4) (9.00 g, 21 mmol), tetra-
butylammonium 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:
resolved d, J = 2.5 Hz, CH3), 3.94 (poorly resolved d,
J = 3.0 Hz, CH3). 19F NMR (CDCl3): d À106.3, 107.8 (AB
q, J = 286 Hz, 2F, C3), À118.8, À119.5 (AB q, J = 280 Hz,
each part poorly resolved m, 2F, C4), À120.5, À120.9 (AB q,
J = 292 Hz, A part poorly resolved m, 2F, C5), À137.2 (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, cmÀ1): 3019, 2964, 1768, 1441, 1331, 1273,
1180. Yield of dimethyl 2,5-diiodoperfluoroadipate: 0.062 g,
1
6.03 g, 54%. H NMR (CDCl3): d 3.96 (s, CH3). 19F NMR
(CDCl3): d À81.3 (s, 3F, C8), À107.1, 107.6 (AB q,
J = 282 Hz, 2F), À119.6 (br s, 2F), 122.4 (s, broad, 2F),
À122.9, À123.4 (AB q, J = 303 Hz, 2F), À126.4, À126.9 (AB
q, J = 298 Hz, 2F), À137.5 (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, cmÀ1): 2964, 1769, 1442, 1360, 1239, 1205, 1144, 1080,
1017. HRMS: 535.8983 found, 535.8954 calculated for
C9H3F14O2I.
1
6%. m.p. 105.0–107.0 8C. H NMR (CDCl3): d 3.94 (s, CH3).
19F NMR (CDCl3): d À103.1, 104.3 (AB q, J = 282 Hz, each
part poorly resolved m, 4F, C3 and 4), À137.7 (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,
cmÀ1): 2962, 1763, 1438, 1289, 1254, 1155, 1118. The other

X. Chen, D.M. Lemal / Journal of Fluorine Chemistry 127 (2006) 1137–1145
1143
isomer of dimethyl 2,5-diiodoperfluoroadipate (smaller Rf on
silica gel) was contaminated with dimethyl 2-iodoperfluor-
oadipate. 1H NMR (CDCl3): d 3.95 (s, CH3). 19F NMR
(CDCl3): d À102.4, 106.2 (AB q, J = 137 Hz, each part poorly
resolved m, 4F, C3 and 4), À136.1 (m, 2F, C2 and 5). Dimethyl
octafluoroadipate (0.040 g, 7%) was recovered.
Yield: 6.45 g, ꢀ90%. 19F NMR (CDCl3): d À75.0 (d,
J = 13.6 Hz, 3F, C3), À132.8 (q, J = 13.6 Hz, 1F, C2).
4.8. Ethyl 2-fluoro-2-pentafluoroethyl-3-hydroxy-3-
phenylbutyrate (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 Â 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%.
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
azeotropicdistillationwithbenzene(10 mL).Theresultingwhite
solid was dissolved in freshly dried acetonitrile (5 mL). The
solution was cooled in a dry ice–ethyleneglycol slushbath, 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 pressurewas 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-phenylcy-
clobutanone (19). Yield: 0.37 g, 46% based on 17 m.p. 41.0–
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). 19
F
NMR (CDCl3): d À81.3 (d, J = 8.9 Hz, 3F, CF3), À119.2,
À122.3 (AB q, J = 287 Hz, B subsplit, d, J = 10 Hz, 2F, CF2),
À189.9 (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.
1
Erythro isomer: m.p. 65.5–66.5 8C. H NMR (CDCl3): d
1
42.0 8C. H NMR (CDCl3): d 7.36–7.46 (m, 5H, phenyl), 4.21
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 À81.6 (d, J = 10 Hz, 3F, CF3), À119.6, À122.9
(AB q, J = 288 Hz, B subsplit, d, J = 14 Hz, 2F, CF2), À184.0
(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.
(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 À74.5 (d, J = 10 Hz, 3F,
CF3), À157.8 (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, cmÀ1): 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.
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

1144
X. Chen, D.M. Lemal / Journal of Fluorine Chemistry 127 (2006) 1137–1145
1
P. Meffre, R.H. Dave, J. Leroy, B. Badet, Tetrahedron Lett. 42 (2001)
8625–8627;
pure ethyl 2H-perfluorobutyrate (32). Yield: 0.24 g, 94%. H
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 À82.8 (d, J = 10 Hz, 3F, C4),
À122.4, À127.4 (AB q, J = 286 Hz, subsplit; A, dd, J = 5.7,
11 Hz; B, dd, J = 14, 16 Hz; 2F, C3), À205.8 (subsplit d,
J = 46 Hz, 1F, C2).
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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,
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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
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The National Science Foundation is gratefully acknowl-
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