Convenient preparation of 2-phenylethyl 3,3-difluoro-2-methylpropionate

Article abstract of DOI:10.1135/cccc20021479

The slow inverse addition of an LDA solution at -78 °C to an ester of 2-(trifluoromethyl)acrylic acid enabled efficient dehydrofluorination. Hydrogenation of the resulting difluoromethylacrylate furnished the target ester of 3,3-difluoro-2-methylpropionic

Full text of DOI:10.1135/cccc20021479

Preparation of 2-Phenylethyl 3,3-Difluoro-2-methylpropionate
1479
CONVENIENT PREPARATION OF 2-PHENYLETHYL
3,3-DIFLUORO-2-METHYLPROPIONATE
a,
b1
b2
Takashi YAMAZAKI *, Tatsuro ICHIGE and Tomoya KITAZUME
a
Department of Applied Chemistry, Tokyo University of Agriculture and Technology,
2-24-16 Nakamachi, Koganei 184-8588, Japan; e-mail: tyamazak@cc.tuat.ac.jp
Department of Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku,
b
1
2
Yokohama 226-8501, Japan; e-mail: tichige@bio.titech.ac.jp, tkitazum@bio.titech.ac.jp
Received May 2, 2002
Accepted Septem ber 16, 2002
Dedicated to the memory of Professor Miloš Hudlický.
Th e slow in verse addition of an LDA solution at –78 °C to an ester of 2-(trifluoro-
m eth yl)acrylic acid en abled efficien t deh ydrofluorin ation . Hydrogen ation of th e resultin g
difluorom eth ylacrylate furn ish ed th e target ester of 3,3-difluoro-2-m eth ylpropion ic acid in
good overall yield.
Keyw ord s: Fluorin e; Hydrogen ation s; Deh ydrofluorin ation ; α,β-Un saturated esters; Fluori-
n ated com poun ds; Ab initio calculation s.
Fluorin e-con tain in g m aterials h ave attracted sign ifican t atten tion of syn -
th etic organ ic ch em ists due to th eir un ique ph ysical properties wh ich can -
n ot be usually attain ed by th e presen ce of an y oth er atom s. However, th eir
application in various fields h as been som etim es h am pered by lim ited
m eth ods available for th e syn th esis of specific fluorin e-con tain in g struc-
tures.
2-Ph en yleth yl 3,3-difluoro-2-m eth ylpropion ate (5), recen tly required for
our purpose1, was actually th e case, an d th ere h ave been on ly a few preced-
in g in stan ces for obtain in g th is target com poun d. On e of th e m ost straigh t-
forward path ways would be th e alkylation of appropriate en olates with
CHClF2 2, but severe global restriction h as been im posed on th e em ploy-
m en t of th is CFC respon sible for ozon e depletion . On th e oth er h an d, our
previous experien ce3 with con ven ien t ultrason ic-assisted h ydrogen ation led
us to th e idea th at tran sform ation of 3,3-difluoroacrylates could be regar-
ded as an altern ative solution for obtain in g th e desired α-difluorom eth yl-
ated esters.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)
doi:10.1135/cccc20021479

1480
Yamazaki, Ichige, Kitazume:
In Sch em e 1 are collected th e th ree represen tative m eth ods wh ich afford
3,3-difluoroacrylates or -m eth acrylates. Equation (1) was reported by th e
Norm an t’s group two decades ago4 on sec-BuLi-prom oted lith iation of
1,1-difluoroeth en e an d trappin g of th e in term ediate with CO2. Brom odi-
fluorom eth ylated m alon ate5, readily prepared in 76% yield by th e reaction
of CBr2F2 an d sodium salt of dieth yl m eth ylm alon ate6, was successfully
decarboxylated un der h eatin g to furn ish difluorin ated m eth acrylate (Eq. (2)).
Recen t publication by Bottegh i an d h is coworkers7 deals with deh ydro-
fluorin ation of trifluorin ated isobutyrate (Eq. (3)) as well as Wittig difluoro-
m eth ylen ation of pyruvate (Eq. (4)) with reason ably good ch em ical yields
in both in stan ces.
(i) sec-BuLi, -115 oC
(ii) CO2, -105 oC
F2C CHCO2H
(Eq. (1))
(Eq. (2))
F2C CH2
61% yield
KBr, 170 oC
H3C CO2Et
59% yield
BrF2C CO2Et
(i) TMSOTf
(ii) neat, 100 oC
F
F
CO2Et
CH3
H3C
H3C
CO2Et
CF3
(Eq. (3))
(Eq. (4))
85% yield
PPh3, Zn, CBr2F2
80 oC
CO2Et
85% yield
O
SCHEME 1
In th e course of th e above literature search , th e absen ce of on e of th e
m ost direct path ways, th e elim in ation of HF from α-trifluorom eth ylated
carbon yl com poun ds, m ade us quite curious8. Con siderin g th at recen t ex-
ploitation 9 allowed th eir facile form ation via Et3B-m ediated reaction of
keten e silyl acetals with ozon e-n on destructive CF3I, success in th is
deh ydrofluorin ation process would open a n ew route to variously substi-
tuted α-difluorom eth ylated carbon yl com poun ds. Based on th is con cept,
we report h ere th e con ven ien t preparation of 3,3-difluoro-2-m eth yl-
propion ate from th e correspon din g 3,3,3-trifluorin ated an alog by th e HF
elim in ation -h ydrogen ation procedure.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Preparation of 2-Phenylethyl 3,3-Difluoro-2-methylpropionate
1481
RESULTS AND DISCUSSION
We h ave selected th e com m ercially available α,β-un saturated acid 1 as th e
startin g m aterial an d con verted it first to th e 2-ph en yleth yl ester 2 for facile
h an dlin g an d UV detection (Sch em e 2). Hydrogen ation of 2 was realized in
a quite sm ooth m an n er by th e action of a catalytic am oun t (0.5 m ole %) of
10% Pd/C un der atm osph eric pressure of h ydrogen . Th is easy con version
m igh t be attributed to th e appreciably low LUMO en ergy level of ester 2
due to direct attach m en t of th e stron gly electron -with drawin g CF3 an d car-
bon yl groups10 to th e C=C system .
CO2H
CO2R
CO2R
CF3
(i), (ii)
(iii)
CF3
CF3
1
2
3
CO2R
CF2
CO2R
CHF2
(iv)
(iii)
4
5
R = CH2CH2Ph
(i) phthaloyl dichloride; (ii) ROH, pyridine; (iii) 10% Pd/Cl, H2; (iv) base
SCHEME 2
Th is saturated CF3 ester 3 in h an d, we started to study th e action of
stron g but weakly n ucleoph ilic bases as LDA or LHMDS (Table I). As ex-
pected, addition of ester 3 to solution s con tain in g th ese bases at 0 °C
seem ed to abstract th e activated α-proton to th e carbon yl group, but on ly
TABLE I
Brief exam in ation of th e deproton ation con dition s
19F NMR yield, %
Tem perature,
Base
Equivalen t
Meth oda
°C
4
3
LDA
(1.05)
(1.05)
(1.05)
(2.00)
(1.05)
(1.30)
(1.50)
A
A
A
A
B
B
B
0
11
0
39
40
26
0
LHMDS
LDA
0
–78
–78
–78
–78
–78
25
2
LDA
LDA
65
79
86b
15
1
LDA
LDA
0
a
A: 3 was added to a solution of a base, B: a base solution was added to a solution of 3.
bIsolated yield.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1482
Yamazaki, Ichige, Kitazume:
com plex m ixture was form ed. Lowerin g th e tem perature sligh tly in creased
th e yield of ester 4, but th is was apparen tly far from th e required level. Th is
protocol allowed 3 to con tact an excess am oun t of th e base especially at th e
11
early stage of th e reaction , an d h igh ly electroph ilic n ature of ester 4
could be con sidered to be th e m ajor reason for its un favorable decom posi-
tion . For verifyin g th is h ypoth esis, we ch an ged th e con dition s an d a THF
solution of LDA was slowly in troduced to a cooled solution of 3. Th is alter-
ation clearly affected th e reaction an d sign ifican tly im proved th e yield to
65%. Th e judicious adjustm en t of th e equivalen t of th e base fin ally at-
tain ed th e isolated yield as h igh as 86%. Hydrogen ation of difluorin ated
m eth acrylate 4 th us obtain ed was th e last step. A larger am oun t (13 m ole
%) of Pd/C was required an d th is process was foun d to proceed at h igh er
rate un der positive pressure of h ydrogen rath er th an un der previous ultra-
son ic treatm en t. Followin g th is procedure, our target m aterial 5 was even -
tually obtain ed in 48% overall yield in five steps. Reduction of a Pd/C
am oun t to 0.5 m ole % as in th e case of th e tran sform ation of ester 2 to 3
did n ot lead to th e com plete con version , an d approxim ately 30% of ester 4
rem ain ed in tact even after 40 h stirrin g.
Our in itial syn th etic plan of com poun d 5 is sh own in Sch em e 3. As was
also poin ted out by Bottegh i an d h is coworkers7, tran sform ation of sodium
salt 6 to acid 7 followin g th e Fuch ikam i’s protocol12 did n ot give an y clean
product. Moreover, esterification of th is crude m ixture con tain in g difluo-
rin ated m eth acrylic acid 7 led to th e form ation of m eth acrylate 4 alon g
13
with th e un expected ch lorin ated ester 8 in a ratio of ca 7 : 3 in less th an
30% total yield from ester 6 as was con firm ed by 19F NMR spectroscopy.
CO2R
CHF2
CO2Na
CF3
R = CH2CH2Ph
5
6
(i)
(iv)
CO2R
CClF2
CO2R
CF2
CO2H
CF2
(ii), (iii)
+
8
4
7
7 :3
(i) LiAlH4; (ii) phthaloyl dichloride; (iii) ROH, pyridine; (iv) Bu3SnH
SCHEME 3
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Preparation of 2-Phenylethyl 3,3-Difluoro-2-methylpropionate
1483
Wh ile ester 8, probably obtain ed by th e HCl addition to 4 from th e in situ
gen erated pyridin ium h ydroch loride, was alm ost quan titatively tran s-
form ed in to 5 by th e action of Bu3Sn H, difficult separation of ch lorin ated
ester 8 from m eth acrylate 4 as well as th e low efficien cy of tran sform ation
of acid 7 to ester 5 m ade us to aban don th is in itial plan an d select th e
above procedure.
As dem on strated above, we h ave succeeded in th e syn th esis of 2-difluoro-
m eth ylated ester 5 from th e correspon din g trifluorom eth ylated precursor 3
in good overall yields usin g com m on an d facile tech n iques. We believe th at
th is m eth od is applicable to a wide ran ge of esters as on e of th e prom isin g
routes to syn th esize such target com poun ds by way of α-trifluorom eth yl-
ation .
EXPERIMENTAL
Un less oth erwise n oted, m aterials were obtain ed from com m ercial suppliers an d were used
with out furth er purification . An h ydrous eth er, THF an d CH2Cl2 were purch ased an d were
used with out furth er purification .
1H an d 13C NMR spectra were recorded with a Varian Gem in i-200 (200 MHz) or a Varian
VXR-500 (500 MHz) in CDCl3 un less oth erwise n oted an d ch em ical sh ifts (δ) were reported
in ppm down field from in tern al stan dard, tetram eth ylsilan e. 19F NMR spectra were recorded
with a Varian VXR-500 (470 MHz) in CDCl3 un less oth erwise n oted an d ch em ical sh ifts (δ)
were reported in ppm down field from in tern al stan dard, h exafluoroben zen e (C6F6). NMR
data were tabulated in th e followin g order: m ultiplicity (s, sin glet; d, doublet; t, trip-
let; q, quartet; m , m ultiplet), n um ber of n uclei, couplin g con stan ts J (in Hz). In frared spectra
were obtain ed on a JASCO FT/IR-5000 spectrom eter as th in film s on NaCl plates, an d were
reported usin g waven um bers ν (in cm –1). Colum n ch rom atograph y was perform ed with
silica gel (BW-200) by usin g m ixtures of h exan es an d eth yl acetate (v/v).
2-Ph en yleth yl 2-(Trifluorom eth yl)acrylate (2)
Th e roun d-bottom flask con tain in g 2-(trifluorom eth yl)acrylic acid (1; 54.6 g, 390 m m ol) an d
ph th aloyl dich loride (84.3 m l, 580 m m ol) was con n ected to th e Claisen distillation h ead,
an d th e m ixture was h eated to 150 °C with collectin g th e resultin g acid ch loride. Th e tem -
perature was raised fin ally to 190 °C to furn ish 86.5 g (545 m m ol) of th e desired acid ch lo-
ride in 94% yield.
To a CH2Cl2 (200 m l) solution con tain in g th is acid ch loride (54.4 g, 343 m m ol) an d
2-ph en yleth an ol (52.1 m l, 411 m m ol) was slowly added pyridin e (37.8 m l, 446 m m ol) at
–20 °C for 2 h an d th e m ixture was furth er stirred at th at tem perature for 2 h . Th e usual
work-up an d ch rom atograph ic purification afforded 77.1 g (316 m m ol) of th e target ester 2
in 92% yield as a colorless oil. RF 0.43 (AcOEt–h exan e 1 : 10). 1H NMR: 7.35–7.25 (5 H, m );
4
4
3
6.68 (1 H, q, JHF = 1.7); 6.42 (1 H, q, JHF = 1.1); 4.46 (2 H, t, JHH = 7.1); 3.02 (2 H, t,
3JHH = 6.9). 13C NMR: 160.96, 137.23, 132.68 (q, JCF = 5.0); 131.17 (q, JCF = 32.1); 128.79,
128.40, 126.57, 121.23 (q, JCF = 272.5); 66.12, 34.69. 19F NMR: 96.06 (s). IR (n eat): 3 030,
3
2
1
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1484
Yamazaki, Ichige, Kitazume:
2 361, 1 736, 1 456, 1 398, 1 352, 1 247, 1 146, 1 097, 989, 810, 748, 696. For C12H11F3O2
(244.2) calculated: 59.02% C, 4.54% H; foun d: 58.75% C, 4.49% H.
2-Ph en yleth yl 3,3,3-Trifluoro-2-m eth ylpropion ate (3)
Un saturated ester 2 (29.8 g, 122 m m ol) in MeOH (100 m l) was h ydrogen ated with 10% Pd/C
(0.647 g, 0.61 m m ol) un der atm osph eric pressure of h ydrogen at room tem perature over
12 h . Rem oval of th e catalyst by filtration an d ch rom atograph ic purification yielded th e cor-
respon din g saturated ester 3 (27.6 g, 112 m m ol) in 92% yield as a colorless oil. RF 0.49
(AcOEt–h exan e 1 : 10). 1H NMR: 7.33–7.20 (5 H, m ); 4.42–4.35 (2 H, m ); 3.18 (1 H, qq,
3
3
3
3JHF = 8.3, JHH = 7.3); 2.97 (2 H, t, JHH = 7.1); 1.36 (3 H, d, JHH = 7.3). 13C NMR: 167.59
3
1
(q, JCF = 2.9); 137.18, 128.72, 128.34, 126.50, 124.88 (q, JCF = 279.3); 65.84, 44.32 (q,
2JCF = 28.4); 34.62, 10.60 (q, JCF = 2.7). 19F NMR: 91.76 (d, JFH = 7.6). IR (n eat): 2 959,
3
3
2 364, 1 748, 1 603, 1 461, 1 335, 1 268, 1 204, 1 124, 1 079, 1 008, 748, 699. For
C
12H13F3O2 (246.2) calculated: 58.54% C, 5.32% H; foun d: 58.18% C, 5.00% H.
2-Ph en yleth yl 3,3-Difluoro-2-m eth ylacrylate (4)
To a THF solution (150 m l) con tain in g ester 3 (25.6 g, 104 m m ol) was slowly added LDA at
–78 °C, prepared from diisopropylam in e (21.8 g, 156 m m ol) an d BuLi (97.5 m l, 156 m m ol;
1.6 m ol/l in h exan es) in 100 m l of THF at 0 °C , an d th e m ixture was stirred at th e sam e
tem perature for 1 h . Th e usual work-up an d ch rom atograph ic purification afforded 20.4 g
(89.4 m m ol) of th e desired term in ally difluorin ated α,β-un saturated ester 4 in 86% yield as a
colorless oil. RF 0.50 (AcOEt–h exan e 1 : 10). 1H NMR: 7.33–7.23 (5 H, m ); 4.38 (2 H, t,
3
4
3
3JHH = 7.1); 2.98 (2 H, t, JHH = 6.8); 1.78 (3 H, t, JHF = 3.2). 13C NMR: 164.23 (dd, JCF
=
=
1
2
7.7, 5.4); 158.91 (dd, JCF = 307.8, 293.7); 137.33, 128.48, 127.99, 126.11, 83.92 (dd, JCF
24.1, 7.7); 65.32, 34.75, 9.18 (d, JCF = 1.7). 19F NMR: 92.52 (1 F, q, JFH = 3.1); 88.41 (1 F, q,
4JFH = 3.1). IR (n eat): 3 030, 2 959, 2 364, 2 343, 1 750, 1 722, 1 498, 1 395, 1 332, 1 159,
1 128, 764, 750, 700. For C12H12F2O2 (226.2) calculated: 63.71% C, 5.35% H; foun d:
63.88% C, 5.70 H.
3
4
2-Ph en yleth yl 3,3-Difluoro-2-m eth ylpropion ate (5)
To a MeOH (10 m l) solution of ester 4 (0.68 g, 3.0 m m ol) was added 0.41 g (0. 39 m m ol) of
10% Pd/C an d th e m ixture was stirred un der h ydrogen at 490 kPa pressure for 3 h . Rem oval
of th e catalyst by filtration an d ch rom atograph ic purification yielded saturated ester 5
(0.48 g, 2.1 m m ol) in 70% yield as a colorless oil. RF 0.48 (AcOEt–h exan e 1 : 10). 1H NMR:
2
3
3
7.38–7.20 (5 H, m ); 5.98 (1 H, td, JHF = 55.0, JHH = 4.7); 4.37 (2 H, t, JHH = 6.9); 2.96 (2 H,
t, JHH = 6.9); 2.95–2.80 (1 H, m ); 1.25 (3 H, d, JHH = 7.4). 13C NMR: 165.52 (t, JCF = 7.2);
3
3
3
1
2
132.70, 124.17, 123.85, 121.99, 111.22 (t, JC1F = 241.9); 61.02, 39.63 (t, JCF = 22.9); 30.39,
5.12 (t, JCF = 5.2). 19F NMR: 42.26 (1 F, ddd, JFF = 282.7, JFH = 56.0, JFH = 8.6); 35.17 (1 F,
3
2
3
1
2
3
ddd, JFF = 283.5, JFH = 56.0, JFH = 17.2). IR (n eat): 2 959, 2 361, 1 740, 1 461, 1 396,
1 323, 1 258, 1 192, 1 155, 1 075, 993, 749, 700. For C12H14F2O2 (228.2) calculated:
63.15% C, 6.18% H; foun d: 63.26% C, 6.02% H.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Preparation of 2-Phenylethyl 3,3-Difluoro-2-methylpropionate
1485
REFERENCES AND NOTES
1. Yamazaki T., Ichige T., Takei S., Kawashita S., Kitazume T., Kubota T.: Org. Lett. 2001, 3,
2915.
2. For example, a) Gerus I. I., Kolomeitsev A. A., Kolycheva M. I., Kukhar V. P.: J. Fluorine
Chem. 2000, 105, 31; b) Seki M., Suzuki M., Matsumoto K.: Biosci., Biotechnol., Biochem.
1993, 57, 1024; c) Tsushima T., Kawada K., Ishihara S., Uchida N., Shiratori O., Higaki J.,
Hirata M.: Tetrahedron 1988, 44, 5375; d) Nishide K., Kobori T., Tsunemoto D., Kondo K.:
Heterocycles 1987, 26, 633.
3. Kitazume T., Ohnogi T., Miyauchi H., Yamazaki T., Watanabe S.: J. Org. Chem. 1989, 54,
5630.
4. Gillet J. P., Sauvetre R., Normant J. F.: Synthesis 1982, 297.
5. Bumgardner C. L., Burgess J. P., Everett T. S., Purrington S. T.: J. Fluorine Chem. 1992, 56,
189.
6. Everett T. S., Purrington S. T., Bumgardner C. L.: J. Org. Chem. 1984, 49, 3702.
7. Botteghi C., Paganelli S., Sbrogiò F., Zarantonello C.: Tetrahedron Lett. 1999, 40, 8435.
8. There is only one dehydrofluorination example utilizing lithium 2,2,6,6-tetra-
methylpiperidide (LTMP) in the [3,3] sigmatropic rearrangement of 2-(allyloxy)-
3,3-difluoroacrylate. Shi G.-Q., Cao Z.-Y., Cai W.-L.: Tetrahedron 1995, 51, 5011. In the
case of the elimination of HF from α-perfluoroalkylated esters, see, Cantacuzčne D.,
Wakselman C., Dorme R.: J. Chem. Soc., Perkin Trans. 1 1977, 1365.
9. a) Miura K., Takeyama Y., Oshima K., Utimoto K.: Bull. Chem. Soc. Jpn. 1991, 64, 1542;
b) Iseki K., Nagai T., Kobayashi Y.: Tetrahedron Lett. 1993, 34, 2169.
10. Our semiempirical (AM1) calculation disclosed that the LUMO energy level of ethyl ester
analogue of
2 was 0.75 eV lower than the corresponding nonfluorinated ethyl
methacrylate. Yamazaki T., Hiraoka S., Kitazume T.: J. Org. Chem. 1994, 59, 5100. See
also the following article: Borisov Yu. A., Kolomiets A. F., Fokin A. V.: Russ. Chem. Bull.
1999, 48, 647.
11. Ab initio (HF/6-311 G**) calculation of acrylaldehyde and its 3,3-difluorinated analogue
indicated that the electrostatic environment around the terminal carbon at position 3
was extraordinarily different. The former possessed the negative charge of –0.257 but the
introduction of two fluorine atoms in the latter changed it to the positive charge of
0.956. If this is the case, it is quite natural to consider that C3 of the latter should be
more sensitive to nucleophilic species.
12. Fuchikami T., Shibata Y., Suzuki Y.: Tetrahedron Lett. 1986, 27, 3173.
13. For the similar example, see, Leroy J., Molines H., Wakselman C.: J. Org. Chem. 1987, 52,
290.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)