β,β-Difluoro analogs of α-oxo-β-phenylpropionic acid and phenylalanine

Article abstract of DOI:10.1016/j.tet.2004.06.086

A simple three-step procedure converted the readily accessible (2-bromo-1,1-difluoroethyl)arenes (2) into α-aryl-α,α- difluoroacetaldehydes (1). Subsequent hydrocyanation, hydrolysis, oxidation and again hydrolysis afforded β-aryl-β,β-difluoro-α- oxopropionic acids (3). Reductive amination transformed the oxoacids 3 into a separable mixture of α-hydroxyacids 11 and racemic β,β-difluoro- β-phenylalanine derivatives (4). Enantiomerically pure β,β- difluorophenylalanine (L-4a) was obtained when α,α-difluoro-α- phenylacet-aldehyde (1a) was condensed with homochiral 1-phenylethylamine, hydrogen cyanide added to the resulting imine, the diastereomeric mixture thus produced hydrolyzed to the carboxamides (15) which were found to be separable by fractional crystallization or chromatography. The pK_a values of the β-aryl-β,β-difluoroalanines (4) were measured and biological profile of the latter probed. 3-(4-Chlorophenyl)-3,3-difluoro-2-oxopropionic acid (4c) proved to be a potent (K_i 27 μM) and selective inhibitor of arogenate dehydratase, a key enzyme catalyzing the last step of the phenylalanine biosynthesis.

Full text of DOI:10.1016/j.tet.2004.06.086

Tetrahedron 60 (2004) 7731–7742
b,b-Difluoro analogs of a-oxo-b-phenylpropionic acid
and phenylalanine
a
b
b
Manfred Schlosser,a Nadia Bru¨gger, Werner Schmidt and Nikolaus Amrhein
,
*
a
´
´ ´
Institut de Chimie moleculaire et biologique, Ecole federale polytechnique, CH-1015 Lausanne, Switzerland
¨ ¨
Institut fur Pflanzenwissenschaften, ETH, CH-8092 Zurich, Switzerland
b
Received 23 April 2004; revised 4 June 2004; accepted 7 June 2004
Available online 15 July 2004
To Dieter Seebach with congratulations and best wishes
Abstract—A simple three-step procedure converted the readily accessible (2-bromo-1,1-difluoroethyl)arenes (2) into a-aryl-a,a-
difluoroacetaldehydes (1). Subsequent hydrocyanation, hydrolysis, oxidation and again hydrolysis afforded b-aryl-b,b-difluoro-a-
oxopropionic acids (3). Reductive amination transformed the oxoacids 3 into a separable mixture of a-hydroxyacids 11 and racemic
b,b-difluoro-b-phenylalanine derivatives (4). Enantiomerically pure b,b-difluorophenylalanine (L-4a) was obtained when a,a-difluoro-a-
phenylacet-aldehyde (1a) was condensed with homochiral 1-phenylethylamine, hydrogen cyanide added to the resulting imine, the
diastereomeric mixture thus produced hydrolyzed to the carboxamides (15) which were found to be separable by fractional crystallization or
chromatography. The pKa values of the b-aryl-b,b-difluoroalanines (4) were measured and biological profile of the latter probed. 3-(4-
Chlorophenyl)-3,3-difluoro-2-oxopropionic acid (4c) proved to be a potent (Ki 27 mM) and selective inhibitor of arogenate dehydratase, a
key enzyme catalyzing the last step of the phenylalanine biosynthesis.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Years ago, we have disclosed a convenient access to
aryldifluoroacetaldehydes (2). If not commercial, the
starting material, a styrene or a ring-substituted congener,
was usually made by Wittig methylenation of the corre-
sponding benzaldehyde. It was then consecutively subjected
to a vic-bromofluorination, a base-promoted dehydro-
bromination and a second vic-bromofluorination. The
resulting (2-bromo-1,1-difluoroethyl)arene1 (1) was even-
tually oxidized by applying the Pummerer method.1 As we
have recognized in the meantime, the bromo compounds 1
are also readily obtained by the bromination of the
corresponding acetophenone and the subsequent treatment
of the a-bromoketone with diethylaminosulfur trifluoride
Scheme 1.
(‘DAST’) or sulfur tetrafluoride (see Section 6) (Scheme 1).
The erythro- and threo-b-fluorophenylalanines have been
We wanted to explore now how the aldehydes 2 might be
extensively investigated in the past.2–6 b,b-Difluoro-b-
converted into the 3,3-difluoro analogs of 3-aryl-2-oxo-
phenylalanine, one of the few difluorinated amino acids
propionic acids (3-arylpyruvic acids, 2-hydroxycinnamic
known so far, was synthesized by R. Guedj et al. in a fairly
acids; 3) and 3-arylalanines (4). Both types of compounds
laborious multistep sequence.7,8 Biological studies accom-
are physiologically relevant intermediates (Scheme 2).
plished with this compound have not been reported. We felt,
suitably para substituted derivatives of b,b-difluorophenyl-
alanine might exhibit a potential as inhibitors of tyrosine
hydroxylase,9 decarboxylase9 and ammonia lyase.10 We
decided to investigate the ring-unsubstituted parent
Keywords: Cyanhydrines; Fluoroanalogs; Oxidation; Reductive amination;
Separation of diastereomers; Transition state analogs.
*
Corresponding author. Fax: þ41-21-692-39-65;
e-mail address: manfred.schlosser@epfl.ch
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.086

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M. Schlosser et al. / Tetrahedron 60 (2004) 7731–7742
Scheme 4.
Scheme 2.
4. 3-Aryl-3,3-difluoroalanines
structure, along with three analogs carrying fluorine,
chlorine and methoxy at the para position.
The consecutive treatment of an oxoacid 3 with 25%
aqueous ammonia and sodium borohydride invariably led to
a mixture of the a-hydroxyacid 11 and the a-aminoacid 4.
The product separation required the use of an ion exchange
column. The product ratios 11:4 depend critically on the
imine generating step. For example, 62% of the a-hydro-
xyacid 11a and only 1% of the a-aminoacid 4a were formed
when the oxo precursor 3a was exposed to 25% aqueous
ammonia at 100 8C under atmospheric pressure, whereas the
product composition changed to 29% of 11a and 67% of 4a
when the treatment with ammonia was performed at 60 8C
in a hermetically closed pressure vessel under otherwise
identical conditions. In contrast, to shorten the standard
reaction time of 5–3 h or to extend it to 19 h had little effect
on the combined yields of products, nor on the product
ratios (Scheme 5).
2. 2-Aryl-2,2-difluoroacetaldehydes
The (2-bromo-1,1-difluoroethyl)arenes (1) were prepared in
the standard way described above.1 However, their
transformation into the a-aryl-a,a-difluoroacetaldehydes
(2) no longer relied on the Pummerer isomerization of the
sulfoxide 5 but was based on a simplified sequence
consisting of a nucleophilic acetate/bromide displacement,
hydrolysis of the resulting ester 6 to the alcohol 7 and
treatment of the latter with the Swern11,12 or Dess–Martin13,
14 reagent. Under such conditions the aldehydes 2 could be
isolated in almost quantitative yield although they showed a
pronounced tendency to form the hydrate or to polymerize
(Scheme 3).
Scheme 5.
Both the a-aminoacids 4 and their chlorohydrates decom-
pose upon heating above 150 8C. In order to record at least
one reproducible melting range, compound 4a was con-
verted into the N-acetyl ethyl ester 12a (mp 92–93 8C)
(Scheme 6).
Scheme 3.
3. 3-Aryl-3,3-difluoro-2-oxopropionic acids
The cyanhydrines 8 were obtained in satisfactory yield
(62–74%) when the hydrogen sulfite adducts of the
aldehydes 2 were dissolved in an aqueous solution of
sodium cyanide. The hydrolysis was accomplished by
passing gaseous hydrogen chloride into an ethanolic
solution of the cyanhydrines 8 before pouring the mixture
into water. The resulting ethyl 3-aryl-3,3-difluoro-2-hydro-
xypropionates (9; 77–78%) were oxidized to the ethyl
3-aryl-3,3-difluoro-2-oxopropionates (10; 89–98%) using
the Dess–Martin reagent.13,14 Saponification of the esters
10 with sodium hydrogen carbonate in aqueous isopropanol
eventually gave the oxoacids 3 (87–96%) (Scheme 4).
Scheme 6.
It was never a main objective of the present work to make
enantiomerically pure fluoro analogs of a-aminoacids
available, the more as the kinetic racemate resolution by
enzymatic hydrolysis of methyl phenylalaninates8 appears
to be a generally applicable method. Thus, it was merely for
curiosity if we wanted to explore a new approach. The
aldehyde 2a was condensed with (S)-1-phenylethylamine
and the resulting imine 13a was heated with trimethylsilyl
cyanide in the presence of zinc iodide.15,16 The aminonitrile

M. Schlosser et al. / Tetrahedron 60 (2004) 7731–7742
7733
14a, existing as a roughly 1:1 diastereomeric mixture, was
immediately hydrolyzed to provide the carboxamide 15a,
one component of which crystallized readily. Removal of
the chiral auxiliary by catalytic hydrogenation to afford 16a
and acid-mediated hydrolysis of the carboxamide 16a to the
free amino acid (L)- or (R)-b,b-difluoroalanine (4a),
concluded the reaction sequence. Unfortunately, the
hydrolysis was accompanied by extensive racemization.
We should have searched for a milder amide cleavage
method but ran out of time (Scheme 7).
Scheme 8.
dictated. The introduction of a geminal pair of fluorine
atoms into the b-position of alanine lowers the pKIa and pKaII
values by 0.8 and 1.5 units, whereas the same structural
modification of phenylalanine does hardly affect the pKaI
value (þ0.1), but decreases the pKIaI number by 2.4 units
(Table 3), as potentiometric measurement have now
revealed. The acidity differences between the p-chloro and
p-methoxy substituted phenylalanines and their b,b-
difluoro congeners are quite similar (DpKIa þ0.2 to þ0.3;
DpKIa 22.3 to 22.5).
Scheme 7.
5. Physical and biological properties
A preliminary screening of the b-aryl-b,b-difluoroalanines
5 as inhibitors of the tyrosine metabolism ended disappoint-
ingly. No binding appeared to occur at low concentrations.
The introduction of fluorine atoms into organic lead
compounds is a favorite tool for the modulation of
molecular properties in the life science arena.17,18 The
changeofthepKa valuecausedbysuchahalogensubstituentis
of course a key issue in this respect. It is plausible to expect the
inductive effect to level off with distance, decreasing for
example to one third of the former magnitude with each
additional methylene group inserted between the substituent-
produced perturbation and the monitoring functional group.
One might further suppose fluorine effects to be cumulative, in
other words to increase proportionally if there are two or three
halogen atoms in the same chemical environment rather than a
single one. At least the last assumption is naive and invalid, as
we shall see in a minute.
Table 1. Negative logarithmic of dissociation constants (pKaacid) of
propanoic acid and its 3-fluoro substituted derivatives24–29 X00X0XC–
CH2–COOH
X00
X0
X
(pKaacid
)
H
F
F
F
H
H
F
H
H
H
F
4.8
2.6
1.3
0.2
F
Table 2. Negative logarithmic of dissociation dissociation constants
(pKaamine) of the N-protonated ethylamine and 2-fluoro substituted
derivatives30–33 X00X0XC–CH2–NH2
b-Fluoroamino acids are particularly instructive model
compounds to test the additivity or non-additivity of
substituent effects on acidity.19 Ideally, they would behave
as a super-position of 3-fluorinated propanoic acids and
2-fluorinated ethylamines. This means, the first dissociation
constant of the amino acid (KIa) should approximate that of
the corresponding propanoic acid (Kaacid) and the second one
(KIaI) should mirror that of the corresponding promoted
amine (Kaamine) (Scheme 8).
X00
X0
X
(pKaamine
)
H
F
F
F
H
H
F
H
H
H
F
10.7
8.8
7.1
5.6
F
Table 3. Negative logarithmic of dissociation constants (pKIa and pKaII) of
alanine, phenylalanine and its b-fluoro substituted derivatives24,30,34–36
X00X0XC–CH(NH2)–COOH
This view is oversimplified and not supported by the reality.
Due to cross-interactions between the two functional
groups, the pKa values of amino acids deviate considerably
from that of their structural subcomponents (Tables 1–3).
More importantly, the acidity does not increase mono-
tonously with the number of fluorine substituents. In fact,
the first one does little or even may slightly raise the pKa
value. In this context, it should be recalled that halogen
effects on the acidity of acetic acids in aqueous solution,20,21
but not in the gas phase,22,23 are rather entropy than enthalpy
X00
X0
X
pKIa
pKIaI
H
F
F
F
H5C6
H5C6
H5C6
H
H
F
F
H
F
H
H
H
F
H
H
F
2.3
2.4
1.5
1.2
2.2
n.r
9.9
9.8
8.4
5.3
9.2
n.r
F
2.3
6.8
n.r., not yet reported.

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M. Schlosser et al. / Tetrahedron 60 (2004) 7731–7742
On the other hand, the 3-aryl-3,3-difluoro-2-oxopropionic
acids display all the structural features of a successful
‘transition state analog’.37–39 The keto group being flanked
by two electron-withdrawing entities, the carboxy function
and the difluoromethylene unit, is exceptionally electro-
philic. If water is not rigorously excluded, the oxo
compound spontaneously metamorphoses to the corre-
sponding hydrate. This held the promise of 3-aryl-3,3-
difluoro-2-oxopropionic acids to act as potential inhibitors
of plant metabolism. Its structure suggesting possible
interference with the biosynthesis of phenylalanine, the
oxoacid 3c was considered to be particularly attractive and
was, therefore, selected for a series of tests. Only bacteria,
fungi and plants are capable of synthesizing the three
proteinogenic aromatic amino acids, that is, phenylalanine,
tyrosine, and tryptophan, along the shikimate pathway,40
and phenylalanine in particular is the biosynthetic precursor
of a large number of aromatic natural plant products, such as
flavonoids, lignins, coumarins, etc. En route to these
compounds, phenylalanine is deaminated by phenylalanine
ammonia-lyase (PAL) to yield (E)-cinnamic acid. Among
the flavonoids, anthocyanins are coloured intensely red or
blue, and inhibitors of the synthesis of phenylalanine and
cinnamic acid can be easily identified by their interference
with anthocyanin pigment formation in vivo. When testing
the effect of oxoacid 3c on light-induced anthocyanin
synthesis in buckwheat hypocotyls,41 we found inhibition
with an IC50 value of ca. 200 mM. Unlike known inhibitors
of PAL, oxoacid 3c did not cause an increase, but rather a
decrease in the concentration of the endogenous soluble
phenylalanine, suggesting an interference of oxoacid 3c
with phenylalanine biosynthesis. The number of potential
sites of interference of oxoacid 3c with phenylalanine
biosynthesis was narrowed down by experiments in which
oxoacid 3c was applied simultaneously with the herbicidal
compound glyphosate (N-[phosphonomethyl]-glycine),
which is known to inhibit the shikimate pathway at the
level of the enzyme 5-enolpyruvylshikimate-3-phosphate
(EPSP) synthase, thereby causing the accumulation of large
amounts of shikimate in planta. As oxoacid 3c did not affect
glyphosate-induced shikimate accumulation in buckwheat
hypocotyls, we suspected one of the enzymes catalyzing a
step between EPSP and phenylalanine as the target of
oxoacid 3c. As we had, for the first time, succeeded in the
cloning and heterologous expression of the ultimate enzyme
in phenylalanine biosynthesis, that is, arogenate dehydra-
tase, from the higher plant Arabidopsis thaliana, we tested
oxoacid 3c as a potential inhibitor of this enzyme and found
it to be strongly inhibitory (Ki¼27 mM, mixed-type
inhibition). Reduction of the 2-oxo group of oxoacid 3c
led to the loss of the inhibitory action on arogenate
dehydratase. Thus, a presumably specific inhibitor of this
poorly characterized plant enzyme has been uncovered and
may serve as a lead in the identification of more potent
compounds with possible herbicidal activity.
1H, (1H-decoupled) 13C and 19F NMR spectra were recorded
at 400, 101 and 376 MHz, respectively, chemical shifts
being given relative to tetramethylsilane and
trichlorofluoromethane as the internal standards. The
samples were dissolved in deuterochloroform or, if marked
by an asterisk, in hexadeuteroacetone unless stated other-
wise. Mass spectra were obtained at 70 eV ionization
potential while a source temperature of 200 8C was applied.
Whenever no molecular peak was observed under such
conditions, chemical ionization (‘c.i.’) in an ammonia
atmosphere at 100 8C source temperature was applied. To
avoid redundant information, only the [35Cl] and [79Br]
containing fragments, and not the [37Cl] or [81Br]
isotopomers, are listed. For the pKa measurements, an
automatic titrator model PCA101 (Sirius Analytical
Instruments Ltd, East Sussex, UK) was employed.
6.2. (2-Bromo-1-fluoroethyl)benzenes
6.2.1. (2-Bromo-1-fluoroethyl)benzene. At 0 8C, triethyl-
amine tris(hydrofluoride) (46 mL, 45 g, 0.28 mol) was
added dropwise over 30 min to a solution of styrene
(28 mL, 25 g, 0.24 mol) and N-bromosuccinimide (50 g,
0.28 mol) in dichloromethane (0.15 L). The mixture was
stirred for 15 h at 25 8C before being washed with water
(3£50 mL), a saturated aqueous solution of sodium hydro-
gen carbonate (3£50 mL) and brine (2£50 mL). Distillation
afforded a colorless oil; bp 69–72 8C/2 mm Hg; (Ref. 45: bp
53 8C/0.05 mm Hg); nD20 1.5433; d240 1.473; yield: 39.5 g
(81%). 1H NMR: d 7.5 (5H, m), 5.60 (1H, ddd, J¼47.1, 7.8,
4.1 Hz), 3.66 (1H, ddd, J¼15.3, 11.3, 7.8 Hz), 3.58 (1H,
ddd, J¼26.0, 11.3, 4.2 Hz). 13C NMR: d 137.1 (d,
J¼20 Hz), 129.2 (s), 128.7 (s), 125.7 (d, J¼6 Hz), 92.7 (d,
J¼126 Hz), 34.3 (d, J¼28 Hz). 19F NMR: d 2175.0 (ddd,
J¼47.0, 26.0, 15.4 Hz). MS: 202 (3%, Mþ), 127 (3%), 109
(100%), 89 (1%).
6.2.2.
1-(2-Bromo-1-fluoroethyl)-4-fluorobenzene.
Analogously from 4-fluorostyrene (29 mL, 29 g,
0.24 mol); colorless oil; bp 70–72 8C/2 mm Hg; mp 11–
13 8C; n2D0 1.5223; d240 1.552; yield: 44.0 g (83%). 1H NMR:
d 7.33 (2H, dd, J¼8.4, 5.7 Hz), 7.09 (2H, t, J¼8.4 Hz), 5.60
(1H, ddd, J¼46.5, 7.5, 4.5 Hz), 3.67 (1H, ddd, J¼15.2, 11.3,
7.5 Hz), 3.58 (1H, ddd, J¼24.2, 11.3, 4.5 Hz). 13C NMR: d
163.1 (d, J¼248 Hz), 133.0 (dd, J¼21, 3 Hz), 127.8 (t,
J¼7 Hz), 115.8 (d, J¼22 Hz), 92.1 (d, J¼178 Hz), 34.0 (d,
J¼29 Hz). 19F NMR: d 2112.4 (symm. m), 2172.2 (ddd,
J¼46.3, 24.2, 15.3 Hz). MS: 220 (10%, Mþ), 201 (3%), 140
(9%), 127 (100%). Anal. Calcd for C8H7BrF2 (221.04) C
43.47, H 3.19; found C 43.64, H 2.88%.
6.2.3. 1-(2-Bromo-1-fluoroethyl)-4-chlorobenzene. Ana-
logously from 4-chlorostyrene (31 mL, 33 g, 0.24 mol);
slightly yellow oil; bp 92–98 8C/2 mm Hg; mp 9–11 8C;
n2D0 1.5564; d240 1.576; yield: 45.7 g (80%). 1H NMR: d 7.41
(2H, dm, J¼7.3 Hz), 7.32 (2H, dm, J¼7.3 Hz), 5.62 (1H,
ddd, J¼46.6, 7.3, 4.5 Hz), 3.68 (1H, ddd, J¼16.2, 11.3,
7.3 Hz), 3.61 (1H, ddd, J¼24.4, 11.3, 4.4 Hz). 13C NMR: d
135.5 (d, J¼21 Hz), 135.1 (s), 128.9 (s), 127.1 (d, J¼6 Hz),
91.9 (d, J¼179 Hz), 33.9 (d, J¼29 Hz). 19F NMR: d 2174.5
(1 F, ddd, J¼46.6, 23.8, 15.8 Hz). MS: 236 (42%, Mþ), 219
(2%), 157 (3%), 143 (100%). Anal. Calcd for C8H7BrClF
(237.50) C 40.46, H 2.97; found C 40.43, H 2.84%.
6. Experimental
6.1. Generalities
Details regarding standard operations and abbreviations can
be found in previous publications from this laboratory.42–44

M. Schlosser et al. / Tetrahedron 60 (2004) 7731–7742
7735
6.3. (1-Fluorovinyl)benzenes
(t, J¼35 Hz). 19F NMR: d 298.2 (2F, t, J¼13.8 Hz). MS:
220 (45%, Mþ), 169 (19%), 127 (100%), 109 (37%), 77
(25%).
6.3.1. 1-(Fluorovinyl)benzene. 1-(2-Bromo-1-fluoroethyl)-
benzene (26 mL, 39 g, 0.19 mol) was added to a solution of
potassium tert-butoxide (21 g, 0.19 mol) in tetrahydrofuran
(80 mL). The mixture was stirred 2 h at 25 8C and filtered.
The solvent was evaporated and the residue distilled;
colorless liquid; bp 61–64 8C/40 mm Hg (Ref. 46: bp
45.0–45.4 8C/14 mm Hg); mp 229 to 227 8C; nD20
6.4.2. 1-(2-Bromo-1,1-difluoroethyl)-4-fluorobenzene
(1b). Analogously from 1-fluoro-4-(1-fluorovinyl)benzene
(19 mL, 21 g, 0.15 mol); slightly yellow liquid; bp 82–
84 8C/15 mm Hg; mp 25 to 23 8C; n2D0 1.4943; d420 1.602;
yield: 27.9 g (78%). 1H NMR: d 7.50 (2H, dd, J¼8.6,
5.1 Hz), 7.13 (2H, t, J¼8.5 Hz), 3.74 (2H, t, J¼13.5 Hz).
13C NMR: d 164.0 (d, J¼251 Hz), 130.4 (td, J¼27, 3 Hz),
127.7 (q, J¼6 Hz), 118.4 (t, J¼245 Hz), 115.8 (d,
J¼22 Hz), 33.6 (t, J¼36 Hz). 19F NMR: d 296.9 (2F, t,
J¼13.4 Hz), 2110.2 (1F, symm. m). MS: 238 (13%, Mþ),
220 (2%), 145 (100%), 125 (2%), 109 (9%), 95 (4%). Anal.
Calcd for C8H6BrClF2 (255.49) C 40.20, H 2.53; found C
40.12, H 2.89%.
1
1.5223; d240 1.026; yield: 18.9 g (81%). H NMR: d 7.6
(5H, m), 5.02 (1H, dd, J¼49.8, 3.4 Hz), 4.84 (1H, dd,
J¼17.9, 3.4 Hz). 13C NMR: d 163.0 (d, J¼250 Hz), 132.0
(d, J¼29 Hz), 129.4 (s), 128.5 (s), 124.6 (d, J¼7 Hz), 89.5
(d, J¼26 Hz). 19F NMR: d 2108.5 (1 F, dd, J¼49.8,
17.8 Hz). MS: 122 (100%, Mþ), 109 (50%), 96 (20%).
6.3.2. 1-Fluoro-4-(1-fluorovinyl)benzene. Analogously
from 1-(2-bromo-1-fluoroethyl)-4-fluoro-benzene (27 mL,
42 g, 0.19 mol); colorless liquid; bp 144–146 8C; mp 230
to 228 8C; n2D0 1.4976; d240 1.126; yield: 21.3 g (80%). H
NMR: d 7.52 (2H, dd, J¼8.9, 5.2 Hz), 7.05 (2H, t,
J¼8.9 Hz), 4.95 (1H, dd, J¼49.6, 3.6 Hz), 4.82 (1H, dd,
J¼17.9, 3.6 Hz). 13C NMR: d 163.4 (d, J¼249 Hz), 162.2
(d, J¼250 Hz), 128.53 (dd, J¼30, 3 Hz), 126.6 (t, J¼8 Hz),
115.6 (d, J¼22 Hz), 89.3 (d, J¼23 Hz). 19F NMR: d 2107.5
(1F, dd, J¼49.6, 17.9 Hz), 2119.9 (1F, symm. m). MS: 140
(100%, Mþ), 120 (17%), 114 (18%), 96 (11%). Anal. Calcd
for C8H6F2 (140.13) C 68.57, H 4.32; found C 68.60, H
4.40%.
6.4.3. 1-(2-Bromo-1,1-difluoroethyl)-4-chlorobenzene
(1c). Analogously from 1-chloro-4-(1-fluorovinyl)benzene
(20 mL, 24 g, 0.15 mol); colorless liquid; bp 82–84 8C/
2 mm Hg; mp 24 to 22 8C; n2D0 1.5287; d420 1.621; yield:
31.8 g (83%). 1H NMR: d 7.44 (4H, s), 3.74 (2H, t,
J¼13.5 Hz). 13C NMR: d 136.8 (s), 132.8 (t, J¼26 Hz),
128.9 (s), 126.9 (t, J¼6 Hz), 118.4 (t, J¼245 Hz), 33.4 (t,
J¼35 Hz). 19F NMR: d 297.7 (2F, t, J¼13.6 Hz). MS: 254
(34%, Mþ), 237 (4%), 161 (100%), 125 (15%), 111 (9%).
Anal. Calcd for C8H6BrClF2 (255.49) C 37.61, H 2.37;
found C 37.59, H 2.14%.
1
6.3.3. 1-Chloro-4-(1-fluorovinyl)benzene. Analogously
from 1-(2-chloro-1-fluoroethyl)-4-chloro-benzene (29 mL,
45 g, 0.19 mol); colorless liquid; bp 72–73 8C/12 mm Hg;
mp 229 to 228 8C; nD20 1.5442; d240 1.189; yield: 25.0 g
(84%). 1H NMR: d 7.42 (2H, dm, J¼8.7 Hz), 7.33 (2H, dm,
J¼8.7 Hz), 5.00 (1H, dd, J¼49.4, 3.7 Hz), 4.86 (1H, dd,
J¼17.8 Hz, 3.7).13C NMR: d 162.0 (d, J¼250 Hz), 135.3
(s), 130.5 (d, J¼30 Hz), 128.7 (s), 125.9 (d, J¼7 Hz), 90.1
(d, J¼22 Hz). 19F NMR: d 2108.6 (1F, dd, J¼49.4 Hz,
17.6). MS: 156 (100%, Mþ), 136 (2%), 121 (39%), 101
(28%), 91 (8%). Anal. Calcd for C8H6ClF (156.59) C 61.36,
H 3.86; found C 61.49, H 3.99%.
6.4.4. 1-(2-Bromo-1,1-difluoroethyl)-4-methoxybenzene
(1d). A solution of 2-bromo-1-(4-methoxyphenyl)ethanone
(80 g, 0.35 mol) and diethylaminosulfur trifluoride (46 mL,
56 g, 0.35 mol) in dichloromethane (0.35 L) was heated
under reflux for 50 h. The mixture was cautiously poured
onto ice (0.10 L) and the organic phase washed with a
saturated aqueous solution of sodium hydrogen carbonate
(3£0.10 L), water (2£0.10 L) and brine (0.10 L). Distilla-
tion in the presence of some potassium carbonate (0.1 g)
gave a yellow oil; bp 92–94 8C/2 mm Hg; mp 15–17 8C;
n2D0 1.5253; d240 1.516; yield: 33.2 g (38%). 1H NMR: d 7.42
(2H, d, J¼7.7 Hz), 6.94 (2H, d, J¼7.7 Hz), 3.73 (2H, t,
J¼13.8 Hz). 13C NMR: d 161.2 (s), 126.9 (t, J¼6 Hz), 126.4
(t, J¼27 Hz), 118.4 (t, J¼244 Hz), 113.9 (s), 55.4 (s), 34.0
(t, J¼36 Hz). 19F NMR: d 296.7 (2F, t, J¼13.8 Hz). MS:
250 (75%, Mþ), 233 (53%), 157 (100%), 135 (62%). Anal.
Calcd for C9H9BrF2O (251.07) C 43.06, H 3.61; found C
43.11, H 3.63%.
6.4. (2-Bromo-1,1-difluoroethyl)benzenes
The (2-bromo-1,1-difluoroethyl)benzenes were made from
(1-fluorovinyl)benzenes following exactly the same proto-
col as described for the preparation of (2-bromo-1-
fluoroethyl)-benzenes from styrenes. Due to the chemical
lability of 1-(2,bromo-1-fluoroethyl)-4-methoxy-benzene,
the p-methoxy derivative 1d was prepared on a different
route (see below).
6.5. 2-Aryl-2,2-difluoroethyl acetates
6.5.1. 2,2-Difluoro-2-phenylethyl acetate (6a). A mixture
containing (2-bromo-1,1-difluoroethyl)benzene (1a; 17 mL,
27 g, 0.12 mol), anhydrous potassium acetate (47 g,
0.48 mol) and 1,4,7,10,13,16-hexaoxacyclooctadecane
(3.2 g, 12 mmol) in anhydrous N,N-dimethylformamide
(0.12 L) was heated to 150 8C for 15 h. The mixture was
diluted with water (0.10 L) and extracted with diethyl ether
(3£50 mL). The combined organic layers were evaporated
and the product was isolated by distillation as a colorless
liquid; bp 57–59 8C/1 mm Hg; mp 232 to 230 8C; nD20
1.4655; d240 1.188; yield: 20.6 g (86%). 1H NMR: d 7.5 (5H,
m), 4.50 (2H, t, J¼13.3 Hz), 2.09 (3H, s). 13C NMR: d 169.9
6.4.1. (2-Bromo-1,1-difluoroethyl)benzene (1a). From
(1-fluorovinyl)benzene (18 mL, 18 g, 0.15 mol) using
N-bromosuccinimide (32 g, 0.18 mol) and triethylamine
tris(hydrofluoride) (49 mL, 48 g, 0.30 mol) in dichloro-
methane (0.12 L). Upon distillation a faintly yellow oil was
collected; bp 55–56 8C/2 mm Hg (Ref. 1: bp 62–
63 8C/5 mm Hg); mp 226 to 224 8C; n2D0 1.5131; d420
1
1.534; yield: 30.2 g (91%). H NMR: d 7.5 (5H, m), 3.75
(2H, t, J¼13.9 Hz). 13C NMR: d 134.4 (t, J¼26 Hz), 130.6
(s), 128.6 (s), 125.4 (t, J¼6 Hz), 118.5 (t, J¼244 Hz), 33.8

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M. Schlosser et al. / Tetrahedron 60 (2004) 7731–7742
(s), 134.1 (t, J¼25 Hz), 130.5 (s), 128.6 (s), 125.4 (t,
J¼6 Hz), 119.2 (t, J¼244 Hz), 65.1 (t, J¼33 Hz), 20.5 (s).
19F NMR: d 2105.0 (2F, t, J¼13.4 Hz). MS: 200 (13%,
Mþ), 158 (2%), 140 (6%), 127 (100%), 109 (6%). Anal.
Calcd for C10H10F2O2 (200.19) C 60.00, H 5.04; found C
59.89, H 4.93%.
J¼13.6 Hz). MS: 158 (7%, Mþ), 127 (100%), 109 (2%), 91
(10%), 77 (28%). Anal. Calcd for C8H8F2O (158.15) C
60.76, H 5.10; found C 60.61, H 5.11%.
6.6.2.
2,2-Difluoro-2-(4-fluorophenyl)ethanol
(7b).
Analogously from 2,2-difluoro-2-(4-fluorophenyl)ethyl
acetate (6b; 16 mL, 20 g, 90 mmol); the product was
purified by crystallization rather than distillation; colorless
needles (from diethyl ether and hexanes); mp 41–42 8C;
yield: 14.7 g (93%). 1H NMR: d 7.50 (2H, dd, J¼8.8,
5.4 Hz), 7.12 (2H, t, J¼8.8 Hz), 3.93 (2H, t, J¼13.3 Hz),
2.40 (1H, broad s). 13C NMR: d 163.9 (d, J¼250 Hz), 130.5
(t, J¼25 Hz), 127.8 (q, J¼7 Hz), 120.3 (t, J¼244 Hz), 115.7
(d, J¼22 Hz), 65.9 (t, J¼33 Hz). 19F NMR: d 2106.5 (2F, t,
J¼13.0 Hz), 2110.9 (1F, symm. m). MS: 176 (9%, Mþ),
157 (1%), 145 (100%), 125 (4%), 109 (7%), 95 (6%). Anal.
Calcd for C8H7F3O (176.14) C 54.55, H 4.01; found C
54.42, H 3.87%.
6.5.2. 2,2-Difluoro-2-(4-fluorophenyl)ethyl acetate (6b).
Analogously from 1-(2-bromo-1,1-difluoroethyl)-4-fluoro-
benzene (1b; 18 mL, 29 g, 0.12 mol); colorless liquid; bp
40–42 8C/0.5 mm Hg; mp 8–9 8C; n2D0 1.4529; d420 1.260;
yield: 21.2 g (81%). 1H NMR: d 7.51 (2H, dd, J¼8.8,
5.1 Hz), 7.13 (2H, t, J¼8.8 Hz), 4.47 (2H, t, J¼13.1 Hz),
2.07 (3H, s). 13C NMR: d 169.8 (s), 164.0 (d, J¼250 Hz),
130.2 (td, J¼26, 3 Hz), 127.8 (q, J¼7 Hz), 119.0
(t, J¼244 Hz), 115.8 (d, J¼22 Hz), 65.0 (t, J¼34 Hz),
20.5 (s). 19F NMR: d 2103.8 (2F, t, J¼13.0 Hz), 2110.4
(1F, symm. m). MS: 218 (28%, Mþ), 215 (7%), 199 (5%),
158 (16%), 145 (100%), 109 (8%). Anal. Calcd for
C10H9F3O2 (218.17) C 55.05, H 4.16; found C 55.37, H
3.91%.
6.6.3. 2-(4-Chlorophenyl)-2,2-difluoroethanol (7c). Ana-
logously from 2-(4-chlorophenyl)-2,2-di-fluoroethyl acetate
(6c; 16 mL, 21 g, 90 mmol); colorless needles (from
chloroform and hexanes); mp 38–39 8C; yield: 16.2 g
(94%). 1H NMR: d 7.42 (4H, symm. m), 3.92 (2H, t,
J¼13.4 Hz), 2.48 (1H, broad s). 13C NMR: d 136.5 (s),
132.9 (t, J¼26 Hz), 128.9 (s), 127.1 (t, J¼6 Hz), 120.3 (t,
J¼244 Hz), 65.7 (t, J¼33 Hz). 19F NMR: d 2107.5 (t,
J¼13.4 Hz). MS: 192 (45%, Mþ), 161 (100%), 125 (21%),
111 (10%). Anal. Calcd for C8H7ClF2O (192.59) C 49.89, H
3.66; found C 49.60, H 3.90%.
6.5.3. 2-(4-Chlorophenyl)-2,2-difluoroethyl acetate (6c).
Analogously from 1-(2-bromo-1,1-difluoroethyl)-4-chloro-
benzene (1c; 19 mL, 31 g, 0.12 mol); colorless liquid; bp
90–92 8C/2 mm Hg; mp 27 to 25 8C; n2D0 1.4851; d420
1.298; yield: 22.1 g (78%). 1H NMR: d 7.42 (4H, symm. m),
4.47 (2H, t, J¼13.0 Hz), 2.08 (3H, s). 13C NMR: d 169.6 (s),
136.7 (s), 132.6 (t, J¼26 Hz), 128.8 (s), 127.0 (t, J¼6 Hz),
118.9 (t, J¼244 Hz), 64.8 (t, J¼34 Hz), 20.3 (s). 19F NMR:
d 2104.7 (2F, t, J¼13.0 Hz). MS: 234 (100%, Mþ), 215
(7%), 174 (7%), 161 (70%), 125 (14%), 111 (7%). Anal.
Calcd for C10H9ClF2O2 (234.63) C 51.19, H 3.87; found C
51.13, H 3.97%.
6.6.4. 2,2-Difluoro-2-(4-methoxyphenyl)ethanol (7d).
Analogously from 2,2-difluoro-2-(4-methoxyphenyl)ethyl
acetate (6d; 17 mL, 21 g, 90 mmol); colorless needles (from
diethyl ether and hexanes); mp 57–58 8C; bp 122–125 8C/
4 mm Hg; yield: 16.1 g (95%). H NMR: d 7.44 (2H, d,
J¼7.7 Hz), 6.95 (2H, d, J¼7.7 Hz), 3.94 (2H, td, J¼13.4,
6.5 Hz), 3.83 (3H, s), 2.09 (1H, broad t, J¼6.1 Hz). 13C
NMR: d 161.0 (s), 127.0 (t, J¼6 Hz), 126.6 (t, J¼26 Hz),
120.8 (t, J¼243 Hz), 113.9 (s), 66.0 (t, J¼33 Hz), 55.4 (s).
19F NMR: d 2106.1 (2F, t, J¼13.4 Hz). MS: 188 (21%,
Mþ), 169 (1%), 157 (100%), 142 (4%), 114 (16%). Anal.
Calcd for C9H10F2O2 (188.18) C 57.45, H 5.36; found C
57.96, H 5.32%.
6.5.4. 2,2-Difluoro-2-(4-methoxyphenyl)ethyl acetate
(6d). Analogously from 1-(2-bromo-1,1-difluoroethyl)-4-
methoxybenzene (1d, 20 mL, 30 g, 0.12 mol); bp 102–
104 8C/1 mm Hg; mp 11–13 8C; n2D0 1.4914, d420 1.226;
1
yield: 22.3 g (81%). H NMR: d 7.43 (2H, d, J¼7.7 Hz),
6.94 (2H, d, J¼7.7 Hz), 4.46 (2H, t, J¼13.2 Hz), 3.82 (3H,
s), 2.08 (3H, s). 13C NMR: d 169.6 (s), 161.2 (s), 127.0 (t,
J¼6 Hz), 126.2 (t, J¼26 Hz), 119.4 (t, J¼244 Hz), 113.9
(s), 65.1 (t, J¼34 Hz), 55.3 (s), 20.5 (s). 19F NMR: d 2103.3
(2F, t, J¼13.2 Hz). MS: 230 (83%, Mþ), 211 (17%), 157
(100%), 114 (38%). Anal. Calcd for C11H12F2O3 (230.21) C
57.39, H 5.25; found C 57.35, H 5.30%.
6.7. 2-Aryl-2,2-difluoroacetaldehydes
6.7.1. 2,2-Difluoro-2-phenylethanal (2a). At 275 8C,
anhydrous dimethyl sulfoxide (13 mL, 14 g, 0.18 mol) was
added to a solution of oxalyl chloride (7.6 mL, 11 g,
88 mmol) in dichloromethane (0.30 L). The mixture was
kept at 260 8C for 30 min, before 2,2-difluoro-2-phenyl-
ethanol (7a; 10 mL, 13 g, 80 mmol) in dichloromethane
(0.10 mL) was added, then stirred vigorously at 260 8C for
30 min, before triethylamine was added (50 mL, 36 g,
0.36 mol). After having waited 6 h at 25 8C, the mixture was
washed with water (5£0.10 L), dried and evaporated. The
residue cannot be stored for a longer period of time,
undergoing polymerization or decomposition; yellow oil; bp
60–64 8C/5 mm Hg (Ref. 1: bp 66–69 8C/5 mm Hg); yield:
6.6. 2-Aryl-2,2-difluoroethanol
6.6.1. 2,2-Difluoro-2-phenylethanol (7a). A solution of
2,2-difluoro-2-phenylethyl acetate (6a; 15 mL, 28 g,
90 mmol) and sodium hydroxide (7.2 g, 0.18 mol) in 80%
aqueous ethanol (0.10 L) was left for 2 h at 25 8C. The
mixture was diluted with water and the product extracted
with diethyl ether (3£50 mL). The combined organic layers
were washed with brine (3£50 mL) and evaporated. The
product was isolated by distillation; colorless liquid; bp 69–
72 8C/2 mm Hg; mp 19–21 8C; n2D0 1.4890; d420 1.232; yield:
13.8 g (97%). 1H NMR: d 7.5 (5H, m), 3.98 (2H, t,
J¼13.6 Hz), 2.68 (1H, broad s). 13C NMR: d 134.5 (t,
J¼26 Hz), 130.3 (s), 128.5 (s), 125.5 (t, J¼6 Hz), 120.7 (t,
J¼244 Hz), 65.7 (t, J¼32 Hz). 19F NMR: d 2107.9 (t,
1
12.4 g (99%). H NMR: d 9.55 (1H, t, J¼3.2 Hz), 7.4 (5H,
m). 19F NMR: d 2111.7 (2F, t, J¼3.1 Hz), 2113.0 (2F, t,
J¼5.5 Hz).

M. Schlosser et al. / Tetrahedron 60 (2004) 7731–7742
7737
6.7.2. 2,2-Difluoro-2-(4-fluorophenyl)ethanal (2b). Ana-
logously from 2,2-difluoro-2-(4-fluoro-phenyl)ethanol (7b;
14 g, 80 mmol); yellowish oil; bp 49–54 8C/1 mm Hg; nD20
1.4668; d240 1.276; unstable compound; yield: 23.8 g (99%).
1H NMR: d 7.56 (2H, dd, J¼8.6, 5.1 Hz), 7.17 (2H, t,
J¼8.5 Hz), 4.79 (1H, t, J¼8.4 Hz), 3.67 (1H, broad s). 13C
NMR: d 165.5 (d, J¼252 Hz), 128.5 (q, J¼7 Hz), 127.1 (t,
J¼26 Hz), 117.7 (t, J¼251 Hz), 116.0 (t, J¼22 Hz), 115.2
(s), 65.7 (t, J¼38 Hz). 19F NMR: d 2104.7 (1F, dd,
J¼253.5, 7.5 Hz), 2106.4 (1F, dd, J¼253.5, 8.5 Hz),
2108.8 (1F, symm. m). MS: 201 (1%, Mþ), 155 (1%),
145 (100%), 127 (3%), 95 (4%). Anal. Calcd for C8H5F3O
(174.12) C 55.19, H 2.89; found C 55.87, H 3.09%.
(71%). 1H NMR: d 7.5 (5H, m), 4.81 (1H, dd, J¼9.6,
8.0 Hz), 3.87 (1H, broad s). 13C NMR: d 131.4 (s), 131.2 (t,
J¼25 Hz), 128.7 (s), 126.1 (t, J¼6 Hz), 118.0 (t,
J¼251 Hz), 115.2 (s), 65.6 (t, J¼37 Hz). 19F NMR: d
2105.7 (1F, dd, J¼252.2, 7.8 Hz), 2107.7 (1F, dd,
J¼252.2, 9.6 Hz). MS: 183 (1%, Mþ), 127 (100%), 109
(5%), 77 (18%). Anal. Calcd for C9H7F2NO (183.16) C
59.02, H 3.85; found C 58.96, H 4.00%.
6.8.2. 3,3-Difluoro-3-(4-fluorophenyl)-2-hydroxypropio-
nitrile (8b). Analogously from 2,2-difluoro-2-(4-fluoro-
phenyl)ethanal (2b; 10.4 g, 60 mmol); yellow oil; bp 99–
102 8C/2 mm Hg; nD20 1.4769; d240 1.388; yield: 7.51 g
(62%). 1H NMR: d 7.56 (2H, dd, J¼8.6, 5.1 Hz), 7.17
(2H, t, J¼8.5 Hz), 4.79 (1H, t, J¼8.4 Hz), 3.67 (1H, broad
s). 13C NMR: d 165.5 (d, J¼252 Hz), 128.5 (q, J¼7 Hz),
127.1 (t, J¼26 Hz), 117.7 (t, J¼251 Hz), 116.0 (t,
J¼22 Hz), 115.2 (s), 65.7 (t, J¼38 Hz). 19F NMR: d
2104.7 (1F, dd, J¼253.5, 7.5 Hz), 2106.4 (1F, dd,
J¼253.5, 8.5 Hz), 2108.8 (1F, symm. m). MS: 201 (1%,
Mþ), 155 (1%), 145 (100%), 127 (3%), 95 (4%). Anal.
Calcd for C9H6F3NO (201.15) C 53.74, H 3.01; found C
53.76, H 2.94%.
6.7.3. 2-(4-Chlorophenyl)-2,2-difluoroethanal (2c). Ana-
logously from 2-(4-chlorophenyl)-2,2-difluoroethanol (7c;
15 g, 80 mmol); yellow oil; bp 49–51 8C/1 mm Hg; nD20
1.4995; yield: 15.0 (99%). 1H NMR: d 9.56 (1H, t,
J¼2.7 Hz), 7.44 (4H, s). 13C NMR: d 188.0 (t, J¼40 Hz),
137.9 (s), 129.4 (s), 128.6 (t, J¼25 Hz), 127.4 (t, J¼6 Hz),
114.3 (t, J¼251 Hz). 19F NMR: d 2110.8 (2F, t, J¼2.7 Hz).
MS: 190 (8%, Mþ), 171 (2%), 161 (100%), 143 (5%), 125
(13%), 111 (10%). Anal. Calcd for C8H5ClF2O (190.58) C
50.42, H 2.64; found C 50.02, H 2.92%.
6.8.3. 3-(4-Chlorophenyl)-3,3-difluoro-2-hydroxypropio-
nitrile (8c). Analogously from 2-(4-chlorophenyl)-2,2-
difluoroethanal (2c; 11.4 g, 60 mmol); yellow oil; bp 99–
102 8C/2 mm Hg; nD20 1.5055, d240 1.595; yield: 8.55 g
6.7.4. 2,2-Difluoro-2-(4-methoxyphenyl)ethanal (2d). A
solution containing 2,2-difluoro-2-(4-methoxyphenyl)-
ethanol (7d; 15 g, 80 mmol) and 1,1,1-triacetoxy-1,1-
1
dihydro-1,2-benziodoxol-3(1H)-one13,14
(‘Dess–Martin
(69%). H NMR: d 7.49 (4H, symm. m), 4.79 (1H, dd,
reagent’; 34 g, 80 mmol) in dichloromethane (0.16 L) was
kept at 25 8C for 4 h. The suspension formed was diluted
with diethyl ether (0.60 L) before being slowly poured into a
saturated solution of sodium hydrogen carbonate (0.60 L) in
which beforehand sodium thiosulfate pentahydrate (40 g,
0.16 mol) had been dissolved. After 15 min of vigorous
stirring, the organic phase was collected and the aqueous
one extracted with diethyl ether (3£0.10 L). The combined
organic layers were dried and evaporated. Distillation of the
residue provided an unstable colorless oil; bp 49–
51 8C/1 mm Hg; nD20 1.4995; d240 1.280; yield: 11.0 g
J¼8.9, 7.9 Hz), 3.70 (1H, broad s). 13C NMR: d 137.8 (s),
129.5 (t, J¼25 Hz), 129.1 (s), 127.7 (t, J¼6 Hz), 117.6 (t,
J¼251 Hz), 114.8 (s), 65.5 (t, J¼37 Hz). 19F NMR: d
2105.4 (1F, dd, J¼253.8, 7.6 Hz), 2107.4 (1F, dd,
J¼253.8, 9.0 Hz). MS: 217 (1%, Mþ), 190 (2%), 161
(100%), 143 (5%), 125 (10%), 111 (6%). Anal. Calcd for
C9H6ClF2NO (206.62) C 49.68, H 2.78; found C 49.40, H
3.09%.
6.8.4. 3,3-Difluoro-2-hydroxy-3-(4-methoxyphenyl)pro-
pionitrile (8d). Analogously from 2,2-difluoro-2-(4-meth-
oxyphenyl)ethanal (2d; 11.2 g, 60 mmol); yellow oil; bp
99–102 8C/2 mm Hg; nD20 1.5043, d240 1.272; yield: 9.46 g
1
(74%). H NMR: d 9.52 (1H, t, J¼3.4 Hz), 7.45 (2H, d,
J¼8.7 Hz), 6.97 (2H, d, J¼8.7 Hz), 3.82 (3H, s). 13C NMR:
d 188.2 (t, J¼41 Hz), 162.0 (s), 127.6 (t, J¼6 Hz), 122.0 (t,
J¼26 Hz), 115.0 (t, J¼251 Hz), 114.5 (s), 55.4 (s). 19F
NMR: d 2110.6 (2F, s). MS (c.i.): 204 (5%, MþþNH4), 186
(29%, Mþ), 167 (53%), 157 (100%), 114 (62%). Anal.
Calcd for C9H8ClF2O2 (186.16) C 58.07, H 4.33; found C
58.07, H 4.24%.
1
(74%). H NMR: d 7.48 (2H, d, J¼8.6 Hz), 6.97 (2H, d,
J¼8.6 Hz), 4.76 (1H, t, J¼8.3 Hz), 3.83 (3H, s), 4.7 (1H,
broad m). 13C NMR: d 161.8 (s), 127.7 (t, J¼6 Hz), 123.1 (t,
J¼25 Hz), 118.2 (t, J¼250 Hz), 115.2 (s,), 114.2 (s), 65.9 (t,
J¼38 Hz), 55.5 (s). 19F NMR: d 2104.8 (1F, dd, J¼250.4,
8.6 Hz), 2105.9 (1F, dm, J¼250 Hz). MS (c.i.): 231 (4%,
MþþNH4), 213 (6%, Mþ), 186 (6%), 164 (100%), 157
(47%). Anal. Calcd for C10H9F2NO2 (213.19) C 56.32, H
4.26; found C 56.31, H 4.27%.
6.8. Cyanhydrines
6.8.1. 3,3-Difluoro-2-hydroxy-3-phenylpropionitrile (8a).
2,2-Difluoro-2-phenylethanal (2a; 9.4 g, 60 mmol) was
added to a solution of sodium metabisulfite (11 g,
60 mmol) in water. The mixture was vigorously stirred for
2 h at 25 8C and, after the addition of a solution of sodium
cyanide (5.9 g, 0.12 mol) in water (25 mL), again for 1 h.
The mixture was extracted with diethyl ether (3£50 mL).
The product was absorbed on silica gel (30 mL) and eluted
from a column filled with more silica (0.35 L) with a 1:4
(v/v) mixture of diethyl ether and hexanes to afford a
yellowish oil, bp 99–100 8C/1 mm Hg (Ref. 47: bp 109–
110 8C/1.3 mm Hg); nD20 1.4875; d240 1.312; yield: 7.82 g
6.9. Ethyl 3-aryl-3,3-difluoro-2-hydroxypropionates
6.9.1. Ethyl 3,3-difluoro-2-hydroxy-3-phenylpropionate
(9a). Gaseous hydrogen chloride was slowly bubbled into a
mixture of 3,3-difluoro-2-hydroxy-3-phenylpropionitrile
(8a; 6.4 g, 35 mmol) and ethanol (4.1 mL, 3.2 g,
70 mmol), whereupon a precipitate formed. After 4 h at
25 8C, water (20 mL) was added and the suspension was
stirred until it became clear. The product was extracted with
diethyl ether (4£25 mL) and, after washing (2£25 mL of
brine), drying and evaporation of the combined organic

7738
M. Schlosser et al. / Tetrahedron 60 (2004) 7731–7742
layers, crystallized from diethyl ether and hexanes; colorless
needles; mp 59–60 8C (Ref. 47: mp 59–60 8C); yield:
6.76 g (84%). 1H NMR: d 7.5 (5H, m), 4.56 (1H, dt, J¼12.8,
7.8 Hz), 4.28 (2H, q, J¼7.2 Hz), 3.29 (1H, broad d,
J¼8.2 Hz), 1.27 (3H, t, J¼7.2 Hz). 13C NMR: d 169.5 (s),
133.5 (t, J¼25 Hz), 130.5 (s), 128.3 (s), 125.8 (t, J¼6 Hz),
119.3 (t, J¼251 Hz), 73.7 (t, J¼33 Hz), 62.8 (s), 13.9 (s).
19F NMR: d 2104.0 (1F, dd, J¼252.8, 7.6 Hz), 2108.3 (1F,
dd, J¼252.8, 13.0 Hz). MS: 230 (3%, Mþ), 210 (1%), 149
(3%), 127 (100%), 109 (15%), 91 (12%), 77 (18%).
dihydro-1,2-benziodoxol-3(1H)-one13,14 (16 g, 38 mmol)
were conjointly dissolved in dichloromethane (0.12 L) and
kept at 25 8C for 5 h. After dilution with diethyl ether
(0.30 L), the mixture was slowly poured into a concentrated
aqueous solution of sodium hydrogen carbonate (0.30 L),
which also contained sodium thiosulfate pentahydrate (19 g,
75 mmol). After 15 min of vigorous stirring, the organic
phase was collected and the aqueous one extracted with
diethyl ether (3£0.10 L). The combined organic layers were
evaporated and the residue absorbed on silica gel (30 mL).
The product was eluted from a column filled with more
silica (0.32 L) using a 1:1 (v/v) mixture of diethyl ether and
hexanes. The product was recrystallized from the same
mixture; colorless needles; mp 48–50 8C (Ref. 47 mp 55–
6.9.2. Ethyl 3,3-difluoro-3-(4-fluorophenyl)-2-hydroxy-
propionate (9b). Analogously from 3,3-difluoro-3-(4-
fluorophenyl)-2-hydroxypropionitrile
(8b;
7.0 g,
1
35 mmol); colorless needles; mp 43–44 8C; yield: 7.12 g
(82%). 1H NMR: d 7.49 (2H, dd, J¼8.7, 5.2 Hz), 7.11 (2H,
t, J¼8.6 Hz), 4.51 (1H, dt, J¼13.1, 7.5 Hz), 4.27 (2H, q,
J¼7.1 Hz), 3.37 (1H, broad d, J¼7.9 Hz), 1.27 (3H, t,
J¼7.1 Hz). 13C NMR: d 169.4 (s), 164.0 (d, J¼250 Hz),
129.5 (t, J¼25 Hz), 128.1 (q, J¼7 Hz), 118.9 (t, J¼251 Hz),
115.5 (d, J¼22 Hz), 73.6 (t, J¼33 Hz), 63.0 (s), 14.0 (s). 19F
NMR: d 2102.5 (1F, dd, J¼253.5, 7.1 Hz), 2107.3 (1F, dd,
J¼253.4, 13.1 Hz), 2110.6 (1F, symm. m). MS: 248 (2%,
Mþ), 145 (100%), 127 (26%), 107 (4%). Anal. Calcd for
C11H11F3O3 (248.20) C 53.23, H 4.47; found C 53.36, H
4.89%.
56 8C); yield: 5.85 g (95%). H NMR: d 7.6 (2H, m), 7.5
(3H, m), 4.37 (2H, q, J¼7.2 Hz), 1.37 (3H, t, J¼7.2 Hz). 13C
NMR: d 168.9 (s), 131.6 (t, J¼25 Hz), 130.7 (s), 128.0 (s),
127.2 (t, J¼6 Hz), 118.6 (t, J¼254 Hz), 93.0 (t, J¼34 Hz),
64.0 (s), 13.9 (s). 19F NMR: d 2110.2 (2F, s). MS: 228
(2%, Mþ), 200 (1%), 127 (100%), 109 (6%), 91 (1%), 77
(6%).
6.10.2. Ethyl 3,3-difluoro-3-(4-fluorophenyl)-2-oxo-
propionate (10b) hydrate. Analogously from ethyl 3,3-
difluoro-3-(4-fluorophenyl)-2-hydroxypropionate
(9b;
6.2 g, 25 mmol); colorless needles; mp 44–45 8C; yield:
6.47 g (98%). 1H NMR: d 7.57 (2H, dd, J¼8.8, 5.2 Hz), 7.09
(2H, t, J¼8.6 Hz), 4.37 (2H, s), 4.34 (2H, q, J¼7.1 Hz), 1.33
(3H, t, J¼7.1 Hz). 13C NMR: d 168.9 (s), 164.2 (d,
J¼250 Hz), 129.5 (q, J¼7 Hz), 127.8 (t, J¼26 Hz), 118.4
(t, J¼253 Hz), 115.1 (d, J¼22 Hz), 93.0 (t, J¼35 Hz), 64.1
(s), 13.9 (s). 19F NMR: d 2109.3 (2F, s), 2110.4 (1F,
symm. m). MS: 246 (2%, Mþ), 218 (3%), 171 (7%), 145
(100%), 125 (11%), 95 (22%). Anal. Calcd for C11H11F3O4
(264.20) C 50.01, H 4.20; found C 50.24, H 4.31%.
6.9.3. Ethyl 3-(4-chlorophenyl)-3,3-difluoro-2-hydroxy-
propionate (9c). Analogously from 3-(4-chlorophenyl)-3,3-
difluoro-2-hydroxypropionitrile (8c; 7.2 g, 35 mmol); color-
less needles; mp 45–46 8C; yield: 7.14 g (77%). 1H NMR: d
7.44 (4H, symm. m), 4.51 (1H, dt, J¼13.4, 6.8 Hz), 4.29
(2H, q, J¼7.1 Hz), 3.75 (1H, broad d, J¼6.9 Hz), 1.28 (3H,
t, J¼7.1 Hz). 13C NMR: d 169.4 (s), 136.9 (s), 132.1 (t,
J¼26 Hz), 128.7 (s), 127.5 (t, J¼6 Hz), 118.9 (t,
J¼251 Hz), 73.5 (t, J¼33 Hz), 63.0 (s), 14.0 (s). 19F
NMR: d 2103.1 (1F, dd, J¼253.8 Hz, 6.8), 2108.4 (1F, dd,
J¼253.8 Hz, 13.4). MS: 264 (5%, Mþ), 244 (1%), 161
(100%), 143 (10%), 125 (4%), 111 (3%). Anal. Calcd for
C11H11ClF2O3 (264.66) C 49.92, H 4.19; found C 49.81, H
4.30%.
6.10.3. Ethyl 3-(4-chlorophenyl)-3,3-difluoro-2-oxo-
propionate (10c) hydrate. Analogously from ethyl 3-(4-
chlorophenyl)-3,3-difluoro-2-hydroxypropionate (9c; 6.6 g,
25 mmol); colorless needles; mp 65–67 8C; yield: 6.26 g
1
(89%). H NMR: d 7.53 (2H, d, J¼7.7 Hz), 7.40 (2H, d,
J¼7.7 Hz), 4.39 (2H, q, J¼7.2 Hz), 4.12 (2H, broad m),
1.37 (3H, t, J¼7.2 Hz). 13C NMR: d 168.8 (s), 136.9 (s),
130.2 (t, J¼26 Hz), 128.7 (t, J¼6 Hz), 128.2 (s), 118.2 (t,
J¼253 Hz), 92.8 (t, J¼33 Hz), 64.1 (s), 13.8 (s). 19F NMR:
d 2110.0 (2F, s). MS: 262 (5%, Mþ), 234 (4%), 161
(100%), 143 (4%), 125 (8%), 111 (6%). Anal. Calcd for
C11H11ClF2O4 (280.66) C 47.08, H 3.95; found C 47.13, H
4.16%.
6.9.4. Ethyl 3,3-difluoro-2-hydroxy-3-(4-methoxy-
phenyl)propionate (9d). Analogously from 3,3-difluoro-
2-hydroxy-3-(4-methoxyphenyl)propionitrile (8d; 7.5 g,
35 mmol); colorless needles; mp 54–55 8C; yield: 7.93 g
1
(87%). H NMR: d 7.42 (2H, d, J¼8.8 Hz), 6.93 (2H, d,
J¼8.8 Hz), 4.51 (1H, dt, J¼12.6 Hz, 7.4), 4.27 (2H, q,
J¼7.2 Hz), 3.83 (3H, s), 3.25 (1H, broad d, J¼8.0 Hz), 1.27
(3H, t, J¼7.2 Hz). 13C NMR: d 169.6 (s), 161.1 (s), 127.4 (t,
J¼6 Hz), 125.6 (t, J¼26 Hz), 119.3 (t, J¼251 Hz), 113.7
(s), 73.8 (t, J¼33 Hz), 62.8 (s), 55.3 (s), 14.0 (s). 19F NMR:
d 2102.0 (1F, dd, J¼251.5, 7.1 Hz), 2106.8 (1F, dd,
J¼251.5, 12.6 Hz). MS (c.i.): 278 (100%, MþþNH4), 260
(12%, Mþ), 238 (100%), 157 (75%), 114 (8%). Anal. Calcd
for C12H14F2O4 (260.24) C 55.39, H 5.42; found C 55.49, H
5.36%.
6.10.4. Ethyl 3,3-difluoro-2-oxo-3-(4-methoxyphenyl)-
propionate (10d) hydrate. Analogously from ethyl 3,3-
difluoro-2-hydroxy-3-(4-methoxyphenyl)propionate (9d;
6.5 g, 25 mmol); colorless needles; mp 69–70 8C; yield:
6.38 g (92%). 1H NMR: d 7.50 (2H, d, J¼8.9 Hz), 6.91 (2H,
d, J¼8.9 Hz), 4.34 (2H, q, J¼7.2 Hz), 4.25 (2H, s), 3.80
(3H, s), 1.34 (3H, t, J¼7.2 Hz). 13C NMR: d 169.1 (s), 161.3
(s), 128.7 (t, J¼6 Hz), 123.8 (t, J¼26 Hz), 118.8 (t,
J¼253 Hz), 113.4 (s), 93.1 (t, J¼35 Hz), 64.0 (s), 55.3 (s),
13.9 (s). 19F NMR: d 2109.1 (2F, s). MS (c.i.): 276 (32%,
MþþNH4), 258 (8%, Mþ), 239 (72%), 157 (100%), 114
(23%). Anal. Calcd for C11H11ClF2O4 (280.66) C 52.18, H
5.11; found C 52.20, H 5.10%.
6.10. Ethyl 3-aryl-3,3-difluoro-2-oxopropionates
6.10.1. Ethyl 3,3-difluoro-2-oxo-3-phenylpropionate
(10a) hydrate. Ethyl 3,3-difluoro-2-hydroxy-3-phenyl-
propionate (9a; 5.8 g, 25 mmol) and 1,1,1-triacetoxy-1,1-

M. Schlosser et al. / Tetrahedron 60 (2004) 7731–7742
7739
6.11. 3-Aryl-3,3-difluoro-2-oxopropionic acids
6.12. 3-Aryl-3,3-difluoroalanines
Upon heating or even simple storage, these compounds
may loose partially or completely hydrate water.
Thus melting ranges and analytical data may be a bit
fortuitous.
6.12.1. 2-Amino-3,3-difluoro-3-phenylpropionic acid
(4a). 3,3-Difluoro-2-oxo-3-phenylpropionic acid (3a;
2.2 g, 10 mmol) was dissolved in a 25% aqueous solution
of ammonia (20 mL) placed in a pressure-resistant vessel,
which was hermetically closed. After heating to 60 8C for
5 h, sodium borohydride (1.1 g, 30 mmol) was added to the
mixture through which a gentle current of nitrogen was
bubbled for 30 min at 25 8C. At 0 8C, the mixture was
acidified with 37% hydrochloric acid (5.0 mL) before being
poured into a column filled with an ion exchange resin
(Dowex 50W-X8, acid form, 50–100 mesh, 110 mL) and
which was eluted consecutively with 50% aqueous
isopropanol (0.50 L) and neat water (0.50 L). These eluents
were combined and evaporated. The residue was suspended
in a 2.0 M aqueous solution of sodium hydroxide (50 mL)
and washed with diethyl ether (3£25 mL). The aqueous
phase was acidified with 5.0 M hydrochloric acid which was
beforehand saturated with sodium chloride. Extraction with
diethyl ether (3£25 mL) and evaporation of the dried
organic phases left a residue behind, the crystallization of
which provided the 3,3-difluoro-2-hydroxy-3-phenylpro-
pionic acid 11a as described below (Section 6.13). Finally
the ion exchange column was eluted with a 1.0 M aqueous
solution of ammonia. Evaporation of the solvents afforded
the aminoacid 4a; colorless needles crystallized as the
chlorhydrate from hydrogen chloride-containing ethanol;
mp 176–177 8C (decomp.; Ref. 8: mp 178–179 8C); yield:
1.34 g (67%). 1H NMR (CD3OD): d 7.6 (5H, m), 4.95 (1H,
dd, J¼20.7, 5.4 Hz). 13C NMR (CD3OD): d 165.8 (s), 133.6
(t, J¼24 Hz), 132.4 (s), 129.8 (s), 126.9 (t, J¼6 Hz), 120.1
(t, J¼250 Hz), 59.6 (t, J¼29 Hz). 19F NMR (CD3OD): d
290.4 (1F, dd, J¼250.3, 4.8 Hz), 2109.3 (1F, dd, J¼250.3,
21.1 Hz). MS: 202 (4%, Mþþ1), 156 (4%), 137 (24%), 127
(100%), 109 (24%), 91 (4%). Anal. Calcd for C9H10ClF2-
NO2 (237.64) C 45.49, H 4.24; found C 45.81, H 4.10%.
6.11.1. 3,3-Difluoro-2-oxo-3-phenylpropionic acid (3a)
hydrate. Ethyl 3,3-difluoro-2-oxo-3-phenylpropionate
(10a; 4.92 g, 20 mmol) and sodium hydrogen carbonate
(5.0 g, 60 mmol) in 50% aqueous isopropanol (40 mL) were
heated to 50 8C for 24 h. The solvents were evaporated. The
residue was taken up in water (10 mL), washed with diethyl
ether and acidified with 1.0 M hydrochloric acid (50 mL),
which had beforehand been saturated with sodium chloride.
The product was extracted with diethyl ether (3£50 mL)
and, after drying and evaporation of the solvent, crystallized
from a mixture of ethyl acetate and hexanes; colorless
needles; mp 116–118 8C (Ref. 47: mp 90–91 8C); yield:
1
4.09 g (94%). H NMR*: d 7.62 (2H, dm, J¼7.8 Hz), 7.5
(3H, m). 13C NMR*: d 170.1 (s), 133.4 (t, J¼25 Hz), 129.9
(s), 127.4 (s), 127.3 (t, J¼7 Hz), 119.3 (t, J¼252 Hz), 93.1
(t, J¼34 Hz). 19F NMR*: d 2107.9 (2F, s). MS: 199 (2%,
Mþ), 127 (100%), 109 (5%), 91 (2%).
6.11.2. 3,3-Difluoro-3-(4-fluorophenyl)-2-oxopropionic
acid (3b) hydrate. Analogously from ethyl 3,3-difluoro-3-
(4-fluorophenyl)-2-oxopropionate (10b; 5.3 g, 20 mmol);
colorless needles; mp 135–137 8C; yield: 4.52 g (96%). 1H
NMR*: d 7.68 (2H, dd, J¼9.0, 5.4 Hz), 7.21 (2H, t,
J¼9.0 Hz), 6.23 (2H, broad s). 13C NMR*: d 170.7 (s),
164.7 (d, J¼247 Hz), 130.7 (q, J¼7 Hz), 130.1 (t,
J¼26 Hz), 119.9 (t, J¼252 Hz), 115.3 (d, J¼22 Hz), 94.0
(t, J¼34 Hz). 19F NMR*: d 2107.4 (2F, s), 2111.9 (1F,
symm. m). MS: 218 (1%, Mþ), 199 (2%), 145 (100%), 125
(20%), 95 (31%). Anal. Calcd for C9H7F3O4 (236.14) C
45.78, H 2.99; found C 45.82, H 3.20%.
6.11.3. 3-(4-Chlorophenyl)-3,3-difluoro-2-oxopropionic
acid (3c) hydrate. Analogously from ethyl 3-(4-chloro-
6.12.2. 2-Amino-3,3-difluoro-3-(4-fluorophenyl)pro-
pionic acid (4b). Analogously from 3,3-difluoro-3-(4-
fluorophenyl)-2-oxopropionic acid (3b; 2.4 g, 10 mmol);
colorless needles; mp 174–176 8C (decomp.); yield: 0.46 g
(21%). 1H NMR (CD3OD): d 7.67 (2H, dd, J¼8.6, 5.1 Hz),
7.27 (3H, t, J¼8.6 Hz), 5.01 (1H, dd, J¼21.6, 5.0 Hz). 13C
NMR (CD3OD): d 165.9 (d, J¼250 Hz), 165.7 (s), 129.9 (t,
J¼25 Hz), 129.6 (q, J¼7 Hz), 119.9 (t, J¼250 Hz), 116.9
(d, J¼23 Hz), 59.5 (t, J¼29 Hz). 19F NMR (CD3OD): d
289.1 (1F, d, J¼250.8 Hz), 2108.4 (1F, dd, J¼250.8,
21.6 Hz), 2109.3 (1F, symm. m). MS (c.i.): 237 (8%,
MþþNH4), 220 (100%, Mþþ1), 176 (14%), 156 (41%),
145 (49%), 127 (17%), 95 (6%). Anal. Calcd for C9H10-
ClF2NO2 (237.64) C 42.29, H 3.55; found C 42.82, H
4.16%.
phenyl)-3,3-difluoro-2-oxopropionate
(10c;
5.6 g,
20 mmol); colorless needles; mp 156–158 8C (hydrate);
mp 167–169 8C (without hydrate water); yield: 4.40 g
1
(87%). H NMR*: d 7.63 (2H, d, J¼8.4 Hz), 7.48 (2H, d,
J¼8.4 Hz), 6.22 (2H, s). 13C NMR*: d 170.5 (s), 136.5 (s),
132.9 (t, J¼26 Hz), 130.0 (t, J¼6 Hz), 128.5 (s), 119.8 (t,
J¼252 Hz), 93.8 (t, J¼33 Hz). 19F NMR*: d 2108.2 (2F, s).
MS: 234 (1%, Mþ), 189 (1%), 161 (100%), 143 (3%), 125
(9%), 111 (6%). Anal. Calcd for C9H7ClF2O4 (252.60) C
42.80, H 2.79; found C 42.92, H 2.73%.
6.11.4. 3,3-Difluoro-2-oxo-3-(4-methoxyphenyl)propio-
nic acid (3d) hydrate. Analogously from ethyl 3,3-
difluoro-2-oxo-3-(4-methoxyphenyl)propionate
5.5 g, 20 mmol); colorless needles; mp 122–124 8C; yield:
(10d;
6.12.3. 2-Amino-3-(4-chlorophenyl)-3,3-difluoropro-
pionic acid (4c). Analogously from 3-(4-chlorophenyl)-
3,3-difluoro-2-oxopropionic acid (3c; 2.5 g, 10 mmol);
colorless needles; mp 186–188 8C (decomp.); yield:
0.76 g (32%). 1H NMR (CD3OD): d 7.61 (2H, d,
J¼8.3 Hz), 7.56 (2H, d, J¼8.3 Hz), 5.03 (1H, dd, J¼22.0,
4.8 Hz). 13C NMR (CD3OD): d 165.6 (s), 138.7 (s), 132.4 (t,
J¼25 Hz), 130.1 (s), 128.8 (t, J¼6 Hz), 119.8 (t,
J¼250 Hz), 59.3 (t, J¼28 Hz). 19F NMR (CD3OD): d
1
4.52 g (91%). H NMR*: d 7.54 (2H, d, J¼9.0 Hz), 6.97
(2H, d, J¼9.0 Hz), 6.09 (2H, broad s), 3.83 (3H, s). 13C
NMR*: d 170.9 (s), 162.0 (s), 129.8 (t, J¼6 Hz), 126.2 (t,
J¼26 Hz), 120.3 (t, J¼252 Hz), 113.7 (s), 94.1 (t,
J¼34 Hz), 55.6 (s). 19F NMR*: d 2106.9 (2F, s). MS:
230 (12%, Mþ), 211 (10%), 186 (7%), 157 (100%), 139
(43%). Anal. Calcd for C10H10F2O5 (248.19) C 48.40, H
4.06; found C 48.60, H 4.16%.

7740
M. Schlosser et al. / Tetrahedron 60 (2004) 7731–7742
289.7 (1F, d, J¼252.0 Hz), 2109.3 (1F, dd, J¼252.0,
22.0 Hz). MS (c.i.): 253 (6%, MþþNH4), 238 (6%, Mþþ1),
183 (79%), 166 (100%). Anal. Calcd for C9H9Cl2F2NO2
(272.08) C 39.73, H 3.33; found C 40.10, H 3.06%.
6.13.4. 3,3-Difluoro-2-hydroxy-3-(4-methoxyphenyl)pro-
pionic acid (11d). Colorless needles; mp 104–105 8C;
1
yield: 0.74 g (32%). H NMR*: d 7.50 (2H, d, J¼8.9 Hz),
7.00 (2H, d, J¼8.9 Hz), 4,65 (1H, dd, J¼13.7, 7.7 Hz), 3.83
(3H, s). 13C NMR*: d 170.4 (s), 162.0 (s), 128.4 (t, J¼6 Hz),
127.2 (t, J¼26 Hz), 120.9 (t, J¼249 Hz), 114.3 (s), 74.3 (t,
J¼33 Hz), 55.7 (s). 19F NMR*: d 299.1 (1F, dd, J¼250.9,
7.7 Hz), 2104.8 (1F, dd, J¼250.9, 13.7 Hz). MS: 232 (9%,
Mþ), 213 (9%), 168 (14%), 157 (100%), 139 (22%), 114
(14%). Anal. Calcd for C10H10F2O4 (232.19) C 51.73, H
4.34; found C 52.08, H 4.30%.
6.12.4. 2-Amino-3,3-difluoro-3-(4-methoxyphenyl)pro-
pionic acid (4d). Analogously from 3,3-difluoro-2-oxo-3-
(4-methoxyphenyl)propionic acid (3d; 2.5 g, 10 mmol);
colorless platelets; mp 168–170 8C (decomp.); yield:
1.11 g (48%). 1H NMR (CD3OD): d 7.52 (2H, d, J¼
8.9 Hz), 7.05 (2H, d, J¼8.9 Hz), 4.89 (1H, dd, J¼20.5,
5.5 Hz), 3.85 (3H, s). 13C NMR (CD3OD): d 167.6 (s), 164.5
(s), 130.0 (t, J¼6 Hz), 127.0 (t, J¼25 Hz), 121.8 (t, J¼
249 Hz), 116.6 (s), 61.2 (t, J¼30 Hz), 57.5 (s). 19F NMR
(CD3OD): d 288.8 (1F, dd, J¼248.8, 5.1 Hz), 2107.4 (1F,
dd, J¼248.8, 20.5 Hz). MS (c.i.): 249 (22%, MþþNH4),
232 (100%, Mþþ1), 188 (20%), 168 (86%), 157 (53%), 114
(10%). Anal. Calcd for C10H12ClF2NO3 (267.66) C 44.87, H
4.52; found C 44.61, H 4.74%.
6.14. 3,3-Difluorophenylalanine derivatives
6.14.1. Ethyl 2-amino-3,3-difluoro-3-phenylpropionate
hydrochloride. A solution of 2-amino-3,3-difluoro-3-
phenylpropionic acid (4a; 1.0 g, 5.0 mmol) and concen-
trated sulfuric acid (1.0 mL) in ethanol (10 mL) was heated
under reflux for 24 h. The mixture was concentrated by
evaporation and, after addition of a 2.0 M solution of
sodium hydroxide (20 mL), was extracted with diethyl ether
(3£25 mL). The combined organic layers were dried and
evaporated. The residue was crystallized from ethanol
saturated with hydrogen chloride; colorless needles; mp
158–160 8C; yield: 0.73 g (55%). 1H NMR (CD3OD): d 7.6
(5H, m), 5.08 (1H, dd, J¼21.2, 5.0 Hz), 4.09 (2H, q, J¼
7.1 Hz), 0.99 (3H, t, J¼7.1 Hz). 13C NMR (CD3OD): d
164.8 (s), 133.4 (t, J¼24 Hz), 132.7 (s), 130.0 (s), 126.8 (t,
J¼6 Hz), 119.9 (t, J¼250 Hz), 64.3 (s), 59.6 (t, J¼28 Hz),
13.9 (s). 19F NMR (CD3OD): d 290.6 (1F, dd, J¼248.4,
4.6 Hz), 2110.2 (1F, dd, J¼248.4, 21.2 Hz). MS: 230 (7%,
Mþþ1), 210 (4%), 189 (6%), 156 (5%), 127 (15%), 102
(100%). Anal. Calcd for C11H14ClF2NO2 (265.69) C 49.79,
H 5.31; found C 49.57, H 5.36%.
6.13. 3-Aryl-3,3-difluoro-2-hydroxypropionic acids
The 3-aryl-3,3-difluoro-2-hydroxypropionic acids 11
were the first components to be eluted from the ion
exchange column as described in the preceding section.
They were purified by crystallization from diethyl ether and
hexanes.
6.13.1. 3,3-Difluoro-2-hydroxy-3-phenylpropionic acid
(11a). Colorless needles; mp 100–102 8C; yield: 0.59 g
1
(29%). H NMR*: d 7.5 (5H, m), 5.17 (1H, broad s), 4.64
(1H, dd, J¼13.7, 6.6 Hz). 13C NMR*: d 170.3 (s), 135.1 (t,
J¼25 Hz), 131.1 (s), 129.0 (s), 126.9 (t, J¼6 Hz), 120.7 (t,
J¼249 Hz), 74.2 (t, J¼32 Hz). 19F NMR*: d 2102.7 (1F,
dd, J¼253.6, 6.4 Hz), 2108.7 (1F, dd, J¼253.6, 13.6 Hz).
MS: 202 (1%, Mþ), 138 (4%), 127 (100%), 109 (17%), 91
(3%). Anal. Calcd for C9H8F2O3 (202.16) C 53.57, H 3.99;
found C 53.27, H 4.04%.
6.14.2. Ethyl 2-acetamido-3,3-difluoro-3-phenylpropio-
nate (12a). Ethyl 2-amino-3,3-difluoro-3-phenylpropionate
hydrochloride (see preceding paragraph; 0.73 g, 2.8 mmol),
acetic anhydride (5.0 mL) and pyridine (5.0 mL) were
combined and stored at 25 8C for 24 h. The mixture was
absorbed on silica gel (5 mL) and eluted with diethyl ether
from a column filled with more silica (0.10 L); colorless
needles (from diethyl ether and hexanes); mp 92–93 8C;
6.13.2. 3,3-Difluoro-3-(4-fluorophenyl)-2-hydroxypro-
pionic acid (11b). Colorless needles; mp 109–110 8C;
1
yield: 1.49 g (68%). H NMR*: d 7.65 (2H, dd, J¼9.0,
5.3 Hz), 7.24 (2H, t, J¼9.0 Hz), 4.72 (1H, dd, J¼14.0 Hz,
7.8). 13C NMR*: d 170.2 (s), 164.6 (d, J¼248 Hz), 131.1 (t,
J¼26 Hz), 129.4 (q, J¼26 Hz), 120.4 (t, J¼249 Hz), 115.9
(d, J¼22 Hz), 74.1 (t, J¼32 Hz). 19F NMR*: d 299.7 (1F,
dd, J¼252.5, 7.4 Hz), 2105.5 (1F, dd, J¼252.5, 14.0 Hz),
2111.3 (1F, symm. m). MS: 220 (1%, Mþþ1), 201 (1%),
156 (2%), 145 (100%), 127 (14%), 95 (7%). Anal. Calcd for
C9H7F3O3 (220.15) C 49.10, H 3.21; found C 49.32, H
2.85%.
1
yield: 0.24 g (32%). H NMR: d 7.5 (5H, m), 6.44 (1H, d,
J¼9.3 Hz), 5.36 (1H, ddd, J¼13.6, 12.5, 9.5 Hz), 4.10 (2H,
q, J¼7.2 Hz), 2.01 (3H, s), 1.10 (3H, t, J¼7.2 Hz). 13C
NMR: d 169.7 (s), 167.0 (s), 133.7 (t, J¼25 Hz), 130.6 (s),
128.4 (s), 125.5 (t, J¼6 Hz), 119.5 (t, J¼251 Hz), 62.2 (s),
57.4 (t, J¼30 Hz), 23.0 (s), 13.7 (s). 19F NMR: d 2101.2
(1F, dd, J¼247.4, 12.4 Hz), 2105.2 (1F, dd, J¼247.4,
13.7 Hz). MS: 271 (11%, Mþ), 231 (3%), 198 (6%),
156 (18%), 127 (76%), 102 (100%). Anal. Calcd for
C13H15F2NO3 (271.26) C 57.56, H 5.57; found C 56.83, H
5.42%.
6.13.3. 3-(4-Chlorophenyl)-3,3-difluoro-2-hydroxypro-
pionic acid (11c). Colorless needles; mp 128–129 8C;
1
yield: 1.51 g (64%). H NMR*: d 7.60 (2H, d, J¼8.5 Hz),
7.52 (2H, d, J¼8.5 Hz), 4.71 (1H, dd, J¼14.0, 7.9 Hz). 13C
NMR*: d 170.1 (s), 136.7 (s), 134.0 (t, J¼26 Hz), 128.9 (s),
128.8 (t, J¼6 Hz), 120.4 (t, J¼249 Hz), 74.0 (t, J¼32 Hz).
19F NMR*: d 2100.5 (1F, dd, J¼252.8, 7.8 Hz), 2106.4
(1F, dd, J¼252.8, 14.0 Hz). MS (c.i.): 254 (11%, Mþþ
NH4), 236 (6%, Mþ), 216 (1%), 161 (100%), 143 (11%),
111 (10%). Anal. Calcd for C9H7ClF2O3 (236.60) C 45.69,
H 2.98; found C 45.78, H 3.03%.
6.15. Resolution of the 3,3-difluorophenylalanine
racemate
6.15.1. N-[(S)-1-Phenylethyl]-2,2-difluoro-2-phenylethyl-
ideneamine (13a). A solution of 2,2-difluoro-2-phenyletha-
nal (2a; 9.4 g, 60 mmol) and N-[(S)-1-phenylethyl]amine
(9.2 mL, 8.7 g, 72 mmol) in toluene (20 mL) was heated
under reflux for 4 h and the water formed was collected in a

M. Schlosser et al. / Tetrahedron 60 (2004) 7731–7742
7741
Dean-Stark trap. Fractional distillation afforded the product
as a colorless oil; bp 116–118 8C/1 mm Hg; mp 14–16 8C;
n2D0 1.5318, d240 1.115; yield: 8.57 g (55%). 1H NMR: d 7.83
(1H, t, J¼5.2 Hz), 7.5 (2H, m), 7.4 (3H, m), 7.2 (5H, m),
4.51 (1H, q, J¼6.3 Hz), 1.51 (3H, d, J¼6.3 Hz). 13C NMR:
d 155.6 (t, J¼33 Hz), 143.5 (s), 134.4 (t, J¼29 Hz), 130.4
(s), 128.5 (s), 128.4 (s), 127.3 (s), 126.7 (s), 125.8 (t, J¼
6 Hz), 116.7 (t, J¼239 Hz), 69.0 (s), 24.1 (s). 19F NMR: d
2100.1 (2F, dd, J¼13.9 Hz, 5.0). MS: 260 (61%, Mþþ1),
232 (4%), 169 (3%), 127 (9%), 105 (100%). Anal. Calcd for
C16H15F2N (259.30) C 74.11, H 5.83; found C 74.09, H
6.29%.
298.4 (0.5F, dd, J¼248.3, 8.2 Hz), 299.6 (0.5F, dd, J¼
246.8, 10.1 Hz), 2101.9 (0.5F, dd, J¼246.8, 13.0 Hz),
2106.9 (0.5F, dd, J¼248.3, 16.2 Hz). MS: 305 (4%,
Mþþ1), 260 (7%), 177 (18%), 127 (5%), 120 (40%), 105
(100%), 91 (3%). Anal. Calcd for C17H18F2N2O (304.34) C
67.09, H 5.96; found C 67.04, H 5.82%.
This oil crystallized from a mixture of diethyl ether and
hexanes at 220 8C; colorless needles; mp 75–78 8C; [a]2D0¼
1
26.9 (dichloromethane; c¼0.51); yield: 1.67 g (34%). H
NMR: d 7.5 (5H, m), 7.2 (3H, m), 7.0 (2H, m), 6.26 (1H,
broad s), 5.97 (1H, broad s), 3.68 (1H, q, J¼6.6 Hz), 3.42
(1H, dd, J¼16.2, 8.6 Hz), 2.22 (1H, broad s), 1.31 (3H, d,
J¼6.6 Hz). 13C NMR: d 170.5 (s), 143.6 (s), 134.3 (t,
J¼26 Hz), 130.1 (s), 128.5 (s), 128.1 (s), 127.2 (s), 126.7
(s), 125.9 (t, J¼6 Hz), 120.6 (t, J¼249 Hz), 65.3 (t, J¼
29 Hz), 56.7 (s), 24.8 (s). 19F NMR: d 298.3 (1F, dd,
J¼248.4, 8.4 Hz), 2106.9 (1F, dd, J¼248.4, 16.3 Hz).
6.15.2. 3,3-Difluoro-3-phenyl-2-[(S)-1-phenylethylamino]-
propionitrile (14a). N-[(S)-1-Phenyl-ethyl]-2,2-difluoro-2-
phenylethylideneamine (13a; 7.0 mL, 7.8 g, 30 mmol),
cyanotrimethylsilane (4.0 mL, 3.0 g, 30 mmol) and zinc
diiodide (0.96 g, 3.0 mmol) were heated in a closed vessel at
50 8C for 3 days. The mixture was absorbed on silica gel
(30 mL) and eluted from a column filled with more silica
(0.30 L) using a 1:9 (v/v) mixture of diethyl ether and
hexanes; faintly yellow oil; n2D0 1.5301, d420 1.145; yield:
7.90 g (92%). 1H NMR: d 7.5 (5H, m), 7.3 (4H, m), 7.0 (1H,
m), 4.05 (0.5H, dd, J¼10.5 Hz, 8.2), 4.03 (0.5H, q, J¼
6.5 Hz), 3.94 (0.5H, q, J¼6.5 Hz), 3.72 (0.5H, dd, J¼14.7,
6.0 Hz), 1.79 (1H, broad s), 1.32 (1.5H, d, J¼6.5 Hz), 1.27
(1.5H, d, J¼6.5 Hz). 13C NMR: d 143.2 (s), 141.9 (s), 132.6
(t, J¼25 Hz), 132.5 (t, J¼25 Hz), 131.0 (s), 130.8 (s), 128.8
(s), 128.6 (s), 128.4 (s), 127.9 (s), 126.7 (s), 125.9 (t, J¼
6 Hz), 119.0 (t, J¼250 Hz), 118.5 (t, J¼250 Hz), 115.8 (s),
56.5 (s), 56.2 (s), 55.2 (t, J¼34 Hz), 55.0 (t, J¼34 Hz), 24.9
(s), 22.6 (s). 19F NMR: d 298.6 (0.5F, dd, J¼250.3 Hz, 6.0),
2101.1 (0.5F, dd, J¼248.1, 8.1 Hz), 2103.6 (0.5F, dd,
J¼248.0, 10.4 Hz), 2107.2 (0.5F, dd, J¼250.4, 14.6 Hz).
MS: 286 (1%, Mþ), 271 (5%), 159 (12%), 127 (9%), 105
(100%), 91 (1%). Anal. Calcd for C17H16F2N2 (286.32) C
71.31, H 5.63; found C 71.19, H 5.80%.
6.15.4. (R)-2-Amino-3,3-difluoro-3-phenylpropionamide
(16a). A slurry containing the crystallized 3,3-difluoro-3-
phenyl-2-[(S)-1-phenylethylamino]propionamide (see above;
15a; 4.6 g, 15 mmol) and 10% palladium on charcoal
(0.69 g) in ethanol (50 mL) was stirred at 25 8C for 2 h
under a blanket of hydrogen (1 atm.). The solvent was
evaporated and the product absorbed on silica gel (20 mL).
Elution from a column filled with more silica (0.23 L) with
diethyl ether gave a yellowish oil which crystallized from a
mixture of chloroform and hexanes; colorless prisms; mp
77–78 8C; [a]2D0¼þ17.1 (dichloromethane; c¼0.52); yield:
1
2.91 g (91%). H NMR: d 7.5 (5H, m), 6.41 (1H, broad s),
6.06 (1H, broad s), 3.97 (1H, t, J¼11.6 Hz), 1.84 (2H, broad
s). 13C NMR: d 170.6 (s), 133.8 (t, J¼26 Hz), 130.4 (s),
128.4 (s), 125.8 (t, J¼6 Hz), 120.9 (t, J¼248 Hz), 60.9 (t,
J¼29 Hz). 19F NMR: d 2102.3 (1F, dd, J¼248.0, 11.2 Hz),
2103.1 (1F, dd, J¼248.0, 11.8 Hz). MS: 201 (100%,
Mþþ1), 181 (24%), 156 (14%), 136 (13%), 127 (16%), 109
(21%). Anal. Calcd for C9H10F2N2O (200.19) C 54.00, H
5.04; found C 54.14, H 5.13%.
6.15.3. 3,3-Difluoro-3-phenyl-2-[(S)-1-phenylethylamino]-
propionamide (15a). At 0 8C, the mixture of 3,3-difluoro-3-
phenyl-2-[(S)-1-phenylethylamino]propionitrile (14a; 6.3 mL,
7.2 g, 25 mmol) in dichloromethane (25 mL) and 97%
sulfuric acid (40 mL) were stirred for 3 h. The mixture was
poured on ice (0.10 L) and a 25% solution of ammonia
(0.10 L) was cautiously added. The organic layer was
collected and the aqueous one was extracted with dichloro-
methane (3£50 mL). The combined organic layers were
evaporated and the residue was absorbed on silica gel
(30 mL). Elution with a 1:1 (v/v) mixture of diethyl ether
and hexanes provided first a small amount of unconsumed
starting material 14a (0.22 g, 3%) and then the product 15a
as a colorless oil; yield: 4.87 g (64%). 1H NMR: d 7.4 (5H,
m), 7.2 (4H, m), 7.0 (1H, m), 6.36 (0.5H, broad s), 6.27
(0.5H, broad s), 6.16 (0.5H, broad s), 5.95 (0.5H, broad s),
3.65 (0.5H, q, J¼6.7 Hz), 3.60 (0.5H, q, J¼6.8 Hz), 3.59
(0.5H, dd, J¼13.2, 10.2 Hz), 3.39 (0.5H, dd, J¼16.3,
8.4 Hz), 2.12 (1H, broad s), 1.28 (3H, d, J¼6.6 Hz), 1.25
(3H, d, J¼6.6 Hz). 13C NMR: d 170.7 (s), 170.2 (s), 144.4
(s), 143.7 (s), 134.4 (t, J¼26 Hz), 130.2 (s), 130.1 (s), 128.6
(s), 128.5 (s), 128.1 (s), 127.3 (s), 127.2 (s), 126.7 (s), 126.6
(s), 126.0 (t, J¼6 Hz), 125.9 (t, J¼6 Hz), 121.6 (t, J¼
250 Hz), 120.6 (t, J¼249 Hz), 65.3 (t, J¼29 Hz), 64.7 (t,
J¼29 Hz), 57.3 (s), 56.7 (s), 24.8 (s), 23.8 (s). 19F NMR: d
6.15.5. (R)-2-Amino-3,3-difluoro-3-phenylpropionic acid
(L-3,3-difluorophenylalanine) (R-4a) hydrochloride.
(R)-2-Amino-3,3-difluoro-3-phenylpropionamide (16a; 2.4 g,
10 mmol) and 20% aqueous sulfuric acid (10 mL) were
heated under reflux for 4 h. After addition of a 5.0 M
aqueous solution of sodium hydroxide (50 mL), the mixture
was extracted with diethyl ether (3£50 mL). In this way a
major amount of the starting material 16a (1.54 g, 65%) was
recovered. The aqueous phase was acidified with 37%
hydrochloric acid (10 mL) before being loaded in a column
filled with an ion exchange resin (Dowex 50W-X8, acid
form, 50–100 mesh, 0.11 L). The column was washed
consecutively with 50% aqueous isopropanol (0.50 L) and
water (0.50 L). The product was eluted with a 1.0 M
aqueous solution of ammonia and isolated, after evaporation
of the solvent and crystallization from ethanol saturated
with hydrogen chloride, as colorless needles; mp 176–
177 8C (decomp.); [a]2D0¼þ1.0 (HCl 1.2 N; c¼0.52) (Ref. 8:
[a]2D0¼þ14.5 (HCl 1.2 N; c¼0.15)); yield: 0.44 g (22%).
6.16. Determination of the acidity constants
The samples were dissolved in a 0.10 M aqueous solution of

7742
M. Schlosser et al. / Tetrahedron 60 (2004) 7731–7742
medicinal Targets; Soloshonok, V. A., Ed.; Wiley: Chichester,
1999; pp 613–659.
potassium chloride and the pH of the solution was adjusted
to 2.5 by addition of 0.50 M hydrochloric acid. The sample
concentrations fell in the range between 5£1024 and
2£1023 M. Using a automatic titrator equipment (model
PCA 101) and working under argon, the sample was titrated
with a 0.50 M solution of potassium hydroxide until pH 10
was attained, the change in pH being monitored with a glass
electrode.48,49 This electrode was calibrated in the pH range
of 1.8–12.2 by means of a 0.10 M aqueous solution of
potassium chloride following the instructions of the
supplier. The pKa value was calculated as a function of
the change in shape of the titration curve in comparison with
a blank titration carried out without any sample present.
The data were processed with the pKaLOGP software.48 To
check the reproducibility, all measurements were performed
three-fold.
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