Blaise reaction of ethyl 3-bromodifluoromethyl-3-benzyloxyacrylate with nitriles: A convenient synthesis of α-difluorovinyl-substituted β-enaminoesters and β-ketoesters

Article abstract of DOI:10.1055/s-2006-926436

The Blaise reaction between the zinc dienolate of ethyl 3-bromodifluoromethyl-3-benzyloxyacrylate and a variety of nitriles gave a series of α-difluorovinyl substituted β-enaminoesters in good yield, which readily underwent hydrolysis to the corresponding

Full text of DOI:10.1055/s-2006-926436

1470
PAPER
Blaise Reaction of Ethyl 3-Bromodifluoromethyl-3-benzyloxyacrylate
with Nitriles: A Convenient Synthesis of a-Difluorovinyl-Substituted
b-Enaminoesters and b-Ketoesters
Synthesis of
a
-Difluorov
e
inyl-Substitute
d
b
m
-Enaminoesters and
i
b
-Keto
n
esters Peng,1 Jingwei Zhao, Shizheng Zhu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: zhusz@mail.sioc.ac.cn
Received 2 November 2005; revised 12 December 2005
chemical science.7 In previous studies, the application of
Abstract: The Blaise reaction between the zinc dienolate of ethyl
ethyl 3-bromodifluoromethyl-3-benzyloxyacrylate (1) as
a fluorine-containing building-block for conveniently in-
3-bromodifluoromethyl-3-benzyloxyacrylate and a variety of ni-
triles gave a series of a-difluorovinyl substituted b-enaminoesters in
good yield, which readily underwent hydrolysis to the correspond-
troducing CF2 into newly formed hydroxyl esters or ami-
ing b-ketoesters. Direct coupling of this zinc dienolate with acyl no esters was exploited.8 During this research it was noted
chloride also furnished the same a-difluorovinyl substituted b-ke-
toester, though in low yield, while the tetrakis(dimethylamino)eth-
ylene (TDAE) mediated reaction provided g-CF2 carbon and
oxygen acylated products.
that the nucleophilic addition reaction of 1, in the presence
of zinc and acetonitrile, unexpectedly gave the Blaise re-
action product, though in low yield. The zinc reagent of 1,
a zinc dienolate species in solution, has two possible
modes of addition to acetonitrile, either with its a-carbon
or g-CF2 carbon. In fact, 1 condensed with acetonitrile
solely through its a-carbon to give the corresponding b-
enaminoester 3a, in which, fascinatingly, a 2,2-difluoro-
1-benzyloxy-1-vinyl group was attached at the a-position.
This compound was quite stable, could be purified by sil-
ica gel column chromatography and was fully character-
ized.
Key words: zinc dienolate, nitrile, Blaise reaction, b-enamino-
esters, b-ketoester
The addition of zinc ester enolates to nitriles, named the
Blaise reaction after its discoverer,2 is a very useful meth-
odology for the synthesis of b-enaminoesters3 and b-
ketoesters. Several modifications have dramatically im-
proved the reaction3–5 and overcome the inherent draw-
backs of low yield, narrow substrate scope, requirement of
excess a-bromoester, and competing self-condensation.
This straightforward transformation can easily introduce
functionalities into the resultant product, and has been
successfully used to synthesize b-aminoesters and hetero-
cycles from multifunctionalized b-enaminoesters or b-ke-
toesters.6 The Blaise reaction of zinc ester dienolates
which, to the best of our knowledge, has never been inves-
tigated, extends the scope of this reaction through its du-
alistic reactivity affording either the a- or g-carbon-
coupling-mode product with nitriles.
This reaction was further investigated. When an equimo-
lar mixture of 1 and acetonitrile was refluxed for three
hours in THF in the presence of zinc, the condensation
product 3a was isolated in moderate yield, with the only
side-product being the zinc-reduced compound 4
(Scheme 1). After thorough examination, we found that
slow addition of 1 into a refluxing mixture of zinc and ex-
cess acetonitrile in THF minimized the reduction of 1 and
gave the highest yield of the corresponding enaminoester
3 (Scheme 1). Results obtained with a range of nitriles un-
der these optimum conditions are assembled in Table 1. It
is worth noting that, due to hydrogen bonding between the
amino group and the ethoxy carbonyl group, the two pro-
tons on the amino group are greatly differentiated and ap-
pear with 1H NMR shifts of 5.12 and 9.00 ppm.
It has been found that the difluorovinyl moiety forms the
crucial structural element of a number of mechanism-
based fluoroolefin-derived enzyme inhibitors, which have
been receiving increasing attention in medicinal and agro-
H
H
N
O
OBn
OBn
1) Zn, THF, reflux
2) NH4Cl
R
F
OEt
OBn
Br
F
CO2Et
+
RCN
F
CO2Et
F
F
F
1
2
3
4
Scheme 1 Condensation of 1 with nitriles 2 and the reduced side product (boxed)
SYNTHESIS 2006, No. 9, pp 1470–1474
x
x
.
x
x
.2
0
0
6
Advanced online publication: 07.04.2006
DOI: 10.1055/s-2006-926436; Art ID: F18905SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of a-Difluorovinyl-Substituted b-Enaminoesters and b-Ketoesters
1471
Table 1 Blaise Reaction of Ethyl 3-Bromodifluoromethyl-3-ben-
zyloxyacrylate (1) with Nitriles 2
inoester 3f, only the defluorination product 6f could be
obtained in 46% yield (Table 2, Entry 7). The reaction of
3g proved to be very complex and no meaningful product
could be isolated (Table 2, Entry 8).
Entry
Nitrile (2)
Reflux time Product (%)a
(h)
1
2
3
4
5
6
7
8
2a R = CH3
2
3a (72)
3b (69)
3c (62)
3d (85)
3e (81)
3f (89)
3g (31)
Table 2 Hydrolysis of b-Enaminoesters 3
NH2
O
OH
O
2b R = CH3CH2
2c R = PhCH2
3
2 N HCl
R
F
OEt
OBn
R
F
OEt
OBn
3
solvent
r.t.
2d R = Ph
3
F
F
3
5
2e R = 3-MeC6H4
2f R = 2,4-Cl2C6H3
2g R = trans-CH3CH=CH
2h R = (CH3)2CH
4
Entry
b-Enaminoester 3
Solvent Time
Product
(%)a
4.5
4
1
2
3
4
5
6
7
8
3a R = CH3
AcOEt 17 h
5a (72)
5b (82)
5c (85)
5d (28)
5d (53)b
5e (52)b
–
b
4
–
3b R = CH3CH2
3c R = PhCH2
3d R = Ph
EtOH
EtOH
AcOEt
EtOH
EtOH
EtOH
3 d
3 d
a Isolated yield.
b No b-enaminoester product detected.
1 d
This reaction worked generally well with both aryl and
alkyl nitriles, though the yield employing the former was
higher than that with the latter. This difference in yield is
probably due, to some extent, to the ability of the relative-
ly acidic a-protons of the alkyl nitriles to quench the zinc
dienolate reactive species. The a-branched alkyl nitrile 2h
failed to condense with 1, presumably due to its unfavor-
able steric hindrance (Table 1, Entry 8), with only the re-
duced product being detected. The aforementioned results
are consistent with those reported by Cason et al.9 The re-
action of 1 with the a,b-unsaturated nitrile 2g was compli-
cated by a competing Michael addition of the zinc reagent
to this nitrile, and resulted in a relatively low yield of the
corresponding enaminoester 3g.
3d R = Ph
60 h
3 d
3e R = 3-MeC6H4
3f R = 2,4-diClC6H3
3 d
3g R = trans-CH3CH=CH EtOH
3 d
–
a Isolated yield.
b The defluorination product 6 was also isolated.
Since the above two-stage procedure afforded the corre-
sponding aryl-substituted b-ketoesters 5d–e in only mod-
erate yield, we tried to develop an alternative method for
the synthesis of this kind of b-ketoester. The cross-cou-
pling of this zinc regent with acid chlorides is known to be
a versatile method of preparing ketones.11 Unfortunately,
treatment of the zinc dienolate of 1 with benzoyl chloride
7 furnished the difluorovinyl-substituted b-ketoester 5d
only in low yield (28%) (Scheme 3). Addition of copper
or palladium catalyst to this reaction failed to improve the
yield. The reduced product 4 was predominantly formed
instead of the coupling product, and this is ascribed to the
high tendency of the zinc dienolate towards protonation.
The tetrakis(dimethylamino)ethylene (TDAE) mediated
condensation of fluorocarbon iodides with acyl chloride
was reported to lead readily to the corresponding ketone.12
Because the fluorine-containing nucleophilic species,
formed in situ under the promotion of TDAE, was trapped
immediately by the electrophile, the reduction product of
the fluorocarbon iodides was minimized. It was interest-
ing to find that when TDAE was used in the direct cou-
The enaminoester 3 readily underwent hydrolysis to the
corresponding a-difluorovinyl substituted b-ketoester 5
under acidic conditions at room temperature. The enami-
noesters 3a–c, with R as alkyl group, gave b-ketoesters
5a–c in good yield, while the aryl- substituted enami-
noesters 3d–e gave inferior yield of b-ketoesters 5d–e
(Table 2) with defluorination products 6 (Scheme 2) iso-
lated in 20–30% yield. It is proposed that, for compounds
3d–e, stabilization by the aryl group of the enamino moi-
ety might result in a much slower rate of hydrolysis and,
for these compounds, hydrolysis of the benzyl vinyl ether
subunit leading to the tricarbonyl intermediate I may be-
come significant. This proposed intermediate is not stable
under acidic conditions and undergoes further hydrolysis
to give the new b-ketoester 6 through the loss of difluoro-
acetic acid (Scheme 2).10 Indeed, in the reaction of enam-
NH2
O
OH
O
O
OH
O
H+
2 N HCl
HCF2CO2H
+
Ar
OEt
OBn
Ar
HF2C
OEt
Ar
OEt
H2O
F
F
3
I
6
Scheme 2 Proposed formation of the defluorination product 6.
Synthesis 2006, No. 9, 1470–1474 © Thieme Stuttgart · New York

1472
W. Peng et al.
PAPER
OH
F
O
1) Zn, THF
Ph
F
OEt
OBn
1
2) PhCOCl (7)
5d (28%)
O
F
TDAE, THF
–10 °C to r.t.
O
OBn
O
Ph
1
+
Ph
Cl
F
CO2Et
+
Ph
OBn OEt
O
F
F
7
8 (Z/E)
9
Scheme 3 Direct coupling of 1 with benzoyl chloride
Ethyl 3-Amino-2-(1-benzyloxy-2,2-difluoro-1-vinyl)-2-
butenoate (3a)
pling of 1 with benzoyl chloride 7, the reaction afforded a
stereoisomeric mixture of oxygen-acylated product 8
(Z/E) and g-CF2-carbon-acylated product 9 with a ratio of
1:1:2 in a combined yield of around 60% (Scheme 3), in-
stead of the a-carbon-acylation product 5.
IR (KBr): 3426, 3314, 3032, 2981, 2933, 1756, 1664, 1614, 1522,
1454, 1370, 1260, 1138, 1106, 1031, 927, 793, 740, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.22 (t, J = 7.0 Hz, 3 H), 1.89 (s,
3 H), 4.12 (q, J = 7.0 Hz, 2 H), 4.69 (s, 2 H), 5.02 (br s, 1 H), 7.24–
7.35 (m, 5 H), 8.87 (br s, 1 H).
19F NMR (282 MHz, CDCl3): d = –102.5 (d, J = 64.6 Hz, 1 F),
–111.4 (d, J = 64.6 Hz, 1 F).
MS (EI, 70 eV): m/z (%) = 252 (1) [M+ – OEt], 207 (4), 206 (40),
178 (33), 156 (7), 130 (23), 128 (11), 110 (5), 92 (9), 91 (100), 65
(15), 42 (21).
In summary, we have demonstrated that the zinc dienolate
of ethyl 3-bromodifluoromethyl-3-benzyloxyacrylate 1
condensed with a variety of nitriles 2. The Reformatsky
reaction-like mode of addition provided a series of new a-
difluorovinyl-substituted b-enaminoesters 3 in good
yield, which readily hydrolyzed to the corresponding b-
ketoesters 5. This is the first investigation of the conden-
sation of a metal dienolate with nitriles. Our attempts at
direct coupling of this zinc dienolate with benzoyl chlo-
ride furnished the b-ketoester 5 in low yield, while
TDAE-mediated reaction of 1 with the same electrophile
provided both the oxygen-acylated product 8 and CF2-car-
bon-acylated product 9.
Anal. Calcd for C15H17F2NO3: C, 60.60; H, 5.76; N, 4.71. Found: C,
60.59; H, 5.83; N, 4.54.
Ethyl 3-Amino-2-(1-benzyloxy-2,2-difluoro-1-vinyl)-2-pen-
tenoate (3b)
IR (KBr): 3430, 3312, 3031, 2981, 2939, 1756, 1663, 1611, 1519,
1455, 1370, 1260, 1138, 1106, 1066, 1033, 959, 900, 799, 739, 698
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.11 (t, J = 7.7 Hz, 3 H), 1.21 (t,
J = 7.2 Hz, 3 H), 2.27 (br s, 2 H), 4.12 (q, J = 7.2 Hz, 2 H), 4.70 (s,
2 H), 5.14 (br s, 1 H), 7.24–7.36 (m, 5 H), 8.99 (br s, 1 H).
19F NMR (282 MHz, CDCl3): d = –101.5 (d, J = 62.6 Hz, 1 F),
–110.1 (d, J = 62.6 Hz, 1 F).
NMR spectra were recorded on a Varian-360L, a Varian VXR400S
or a Bruker AM-300 spectrometer with TMS as internal standards,
CFCl3 as external standards and CDCl3 as solvent, unless otherwise
stated. For 19F NMR spectra, up-field shifts are quoted as negative.
Mass spectra were recorded on a HP 5989a spectrometer; accurate
mass measurements were performed on a Finnigan MAT instru-
ment. IR spectra were obtained with a Perkin–Elmer 983G spectro-
photometer on KBr disks and elemental analyses were performed
in-house. TLC was performed on silica gel plates and column chro-
matography over silica gel (purchased from Qingdao Ocean Chem-
icals). The preparation of 1 was performed as described
previously.13 All other reagents were obtained from commercial
sources and used as such. Solvents were purified by conventional
methods prior to use (THF–Na wire, DMF–CaH2).
13C NMR (75.4 MHz, CDCl3): d = 169.3 (dd, 4JC–F = 3.0, 1.8 Hz),
168.2 (dd, 4JC–F = 3.8, 1.1 Hz), 154.1 (dd, 1JC–F = 290.4, 274.5 Hz),
2
3
137.7, 112.9 (dd, JC–F = 41.5, 19.6 Hz), 83.9 (t, JC–F = 3.7 Hz),
70.6 (t, 4JC–F = 2.4 Hz), 59.2, 26.8, 14.3, 11.8.
MS (EI, 70 eV): m/z (%) = 312 (7) [M + H+], 295 (2), 266 (24), 246
(2), 220 (62), 204 (10), 192 (29), 170 (8), 144 (31), 124 (4), 96 (3),
92 (9), 91 (100), 65 (11), 56 (16), 41 (3).
HRMS (EI): m/z [M+] calcd for C16H19F2NO3: 311.133; found:
311.131.
Blaise Reaction of Acrylate 1 with Nitriles 2; General Procedure
To a refluxing mixture of activated zinc powder (100 mg, 1.5 mmol)
and nitrile 2 (5 mmol) in THF (4 mL) under N2 was added acrylate
1 (335 mg, 1 mmol) dropwise over 30 minutes. The mixture was re-
fluxed for 2 h then quenched with sat. aq NH4Cl (5 mL) and extract-
ed with EtOAc (3 × 10 mL). The combined organic extracts were
washed with brine (30 mL), dried (Na2SO4) and evaporated to dry-
ness. The residue was purified by column chromatography (n-hex-
ane–EtOAc, either 5:1 or 3:1) to give the a-difluorovinyl substituted
b-enamino esters 3 as slightly yellow oils.
Ethyl 4-Phenyl-3-amino-2-(1-benzyloxy-2,2-difluoro-1-vinyl)-
2-butenoate (3c)
IR (KBr): 3467, 3306, 3031, 2980, 1755, 1662, 1606, 1514, 1497,
1454, 1367, 1256, 1135, 1099, 1031, 929, 791, 739, 699, 457 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.22 (t, J = 7.2 Hz, 3 H), 3.64 (d,
J = 13.2 Hz, 2 H), 4.15 (q, J = 7.2 Hz, 2 H), 4.75 (s, 2 H), 4.87 (br
s, 1 H), 7.13–7.38 (m, 10 H), 9.03 (br s, 1 H).
19F NMR (282 MHz, CDCl3): d = –101.0 (d, J = 61.5 Hz, 1 F),
–109.6 (d, J = 61.5 Hz, 1 F).
13C NMR (75.4 MHz, CDCl3): d = 169.3 (dd, 4JC–F = 3.1, 1.7 Hz),
164.8 (t, 4JC–F = 1.5 Hz), 138.0, 135.4, 113.3 (dd, 2JC–F = 40.6, 18.8
Hz), 85.4 (t, 3JC–F = 3.4 Hz), 71.0, 59.5, 39.2, 14.5.
Synthesis 2006, No. 9, 1470–1474 © Thieme Stuttgart · New York

PAPER
Synthesis of a-Difluorovinyl-Substituted b-Enaminoesters and b-Ketoesters
1473
MS (EI, 70 eV): m/z (%) = 374 (1) [M + H+], 328 (3), 282 (59), 254
(50), 232 (3), 218 (2), 206 (11), 186 (36), 158 (5), 130 (8), 118 (9),
115 (6), 92 (9), 91 (100), 77 (4), 65 (14), 41 (4).
HRMS (EI): m/z [M+ – OEt] calcd for C19H16F2NO2: 328.115;
found: 328.113.
Ethyl 3-Amino-2-(1-benzyloxy-2,2-difluoro-1-vinyl)-2,4-hexa-
dienoate (3g)
IR (KBr): 3446, 3313, 2980, 1755, 1665, 1650, 1597, 1505, 1455,
1367, 1252, 1136, 1032, 962, 915, 739, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.23 (t, J = 7.2Hz, 3 H), 1.81 (d,
J = 5.7 Hz, 3 H), 4.14 (q, J = 7.2 Hz, 2 H), 4.70 (s, 2 H), 6.17–6.21
(m, 2 H), 7.26–7.33 (m, 5 H).
19F NMR (282 MHz, CDCl3): d = –101.3 (d, J = 62.9 Hz, 1 F),
–110.6 (d, J = 62.9 Hz, 1 F).
MS (EI, 70 eV): m/z (%) = 323 (1) [M+], 294 (1), 278 (1), 248 (1),
232 (21), 204 (14), 186 (2), 182 (11), 173 (2), 156 (10), 136 (7), 118
(2), 92 (8), 91 (100), 68 (12), 65 (7).
Ethyl 4,4-Difluoro-3-benzyloxy-2-(aminophenylmethene)-3-
butenoate (3d)
IR (KBr): 3463, 3418, 3306, 3032, 2980, 1754, 1663, 1598, 1575,
1523, 1488, 1444, 1366, 1263, 1141, 1024, 965, 774, 739, 699, 541
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.24 (t, J = 7.1 Hz, 3 H), 4.18 (q,
J = 7.1 Hz, 2 H), 4.71 (s, 2 H), 5.12 (br s, 1 H), 7.24–7.44 (m, 10 H),
9.00 (br s, 1 H).
19F NMR (282 MHz, CDCl3): d = –100.9 (d, J = 65.4 Hz, 1 F),
–109.4 (d, J = 65.4 Hz, 1 F).
Anal. Calcd for C17H19F2NO3: C, 63.15; H, 5.92; N, 4.33. Found: C,
63.43; H, 6.05; N, 4.28.
Hydrolysis of Enaminoesters 3; General Procedure
MS (EI, 70 eV): m/z (%) = 314 (1) [M+ – OEt], 269 (6), 268 (40),
240 (28), 222 (5), 218 (7), 192 (14), 190 (8), 145 (2), 129 (6), 117
(3), 104 (41), 92 (11), 91 (100), 77 (9), 65 (16), 43 (21).
To a solution of enaminoester 3 (1 mmol) in either EtOH or EtOAc
(25 mL) was added HCl (2 N, 8 mL). The mixture was stirred at r.t.
for the time specified in Table 2 until TLC analysis showed com-
plete conversion of the enaminoester, then H2O (10 mL) was added
and the mixture was extracted with EtOAc (3 × 20 mL). The com-
bined organic extracts were washed with brine (30 mL), dried
(Na2SO4) and evaporated to dryness. The residue was purified by
column chromatography (n-hexane–EtOAc, 40:1) to give the a-di-
fluorovinyl substituted b-ketoesters 5 as colorless oils.
Anal. Calcd for C20H19F2NO3: C, 66.84; H, 5.33; N, 3.90. Found: C,
66.77; H, 5.43; N, 4.20.
Ethyl 4,4-Difluoro-3-benzyloxy-2-[amino(3-methylphen-
yl)methene]-3-butenoate (3e)
IR (KBr): 3462, 3419, 3305, 2981, 2931, 1755, 1663, 1599, 1583,
1519, 1482, 1455, 1367, 1266, 1215, 1133, 1102, 1028, 1001, 965,
913, 792, 736, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.23 (t, J = 7.1 Hz, 3 H), 2.33 (s,
3 H), 4.18 (q, J = 7.1 Hz, 2 H), 4.70 (s, 2 H), 5.08 (br s, 1 H), 7.20–
7.34 (m, 9 H), 8.99 (br s, 1 H).
19F NMR (282 MHz, CDCl3): d = –101.5 (d, J = 64.6 Hz, 1 F),
–110.1 (d, J = 64.6 Hz, 1 F).
Ethyl 3-Hydroxy-2-(1-benzyloxy-2,2-difluoro-1-vinyl)-2-
butenoate (5a)
IR (KBr): 2984, 2937, 1755, 1644, 1608, 1455, 1404, 1381, 1338,
1271, 1235, 1133, 1063, 1014, 941, 878, 740, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.29 (t, J = 7.1 Hz, 3 H), 1.97 (s,
3 H), 4.25 (q, J = 7.1 Hz, 2 H), 4.72 (s, 2 H), 7.27–7.37 (m, 5 H),
13.40 (s, 1 H).
MS (EI, 70 eV): m/z (%) = 328 (1) [M+ – OEt], 282 (50), 254 (34),
236 (11), 232 (14), 214 (1), 206 (15), 204 (7), 186 (5), 159 (2), 143
(7), 130 (4), 118 (40), 103 (2), 92 (8), 91 (100), 77 (4), 65 (15), 51
(2), 41 (1).
19F NMR (282 MHz, CDCl3): d = –100.0 (d, J = 62.0 Hz, 1 F),
–109.0 (d, J = 62.0 Hz, 1 F).
MS (EI, 70 eV): m/z (%) = 207 (15) [M+ – Bn], 190 (1), 179 (5), 157
(2), 129 (1), 111 (1), 92 (11), 91 (100), 65 (11), 43 (22).
Anal. Calcd for C21H21F2NO3: C, 67.55; H, 5.67; N, 3.75. Found: C,
67.46; H, 5.79; N, 3.57.
Anal. Calcd for C15H16F2O4: C, 60.40; H, 5.41. Found: C, 60.36; H,
5.50.
Ethyl 4,4-Difluoro-3-benzyloxy-2-[amino(2,4-dichlorophen-
yl)methene]-3-butenoate (3f)
IR (KBr): 3459, 3412, 3304, 2981, 2934, 1755, 1666, 1602, 1556,
1527, 1474, 1370, 1267, 1246, 1144, 1102, 1053, 1026, 966, 824,
796, 738, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.23 (t, J = 7.2 Hz, 3 H), 4.18 (q,
J = 7.2 Hz, 2 H), 4.68 (s, 2 H), 5.19 (br s, 1 H), 7.16–7.43 (m, 3 H),
8.96 (br s, 1 H).
19F NMR (282 MHz, CDCl3): d = –100.6 (br s, 1 F), –108.4 (br s,
1 F).
13C NMR (75.4 MHz, CDCl3): d = 169.1 (dd, 4JC–F = 2.9, 1.5 Hz),
160.6 (dd, 4JC–F = 4.2, 1.9 Hz), 154.2 (dd, 1JC–F = 291.1, 277.2 Hz),
112.8 (dd, 2JC–F = 41.0, 20.2 Hz), 87.9 (t, 3JC–F = 3.8 Hz), 65.5, 59.8,
14.2.
Ethyl 3-Hydroxy-2-(1-benzyloxy-2,2-difluoro-1-vinyl)-2-pen-
tenoate (5b)
IR (KBr): 3034, 2983, 2942, 2881, 1756, 1644, 1603, 1466, 1455,
1403, 1374, 1345, 1274, 1230, 1133, 1093, 1039, 739, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.05 (t, J = 7.2 Hz, 3 H), 1.18 (t,
J = 7.2 Hz, 3 H), 2.24 (q, J = 7.2 Hz, 2 H), 4.15 (q, J = 7.2 Hz, 2 H),
4.62 (s, 2 H), 7.21–7.28 (m, 5 H), 13.41 (s, 1 H).
19F NMR (282 MHz, CDCl3): d = –100.2 (d, J = 60.1 Hz, 1 F),
–109.1 (d, J = 60.1 Hz, 1 F).
MS (EI, 70 eV): m/z (%) = 221 (15) [M+ – Bn], 193 (6), 175 (2), 146
(1), 92 (7), 91 (100), 77 (1), 69 (1), 65 (7), 57 (13).
Anal. Calcd for C16H18F2O4: C, 61.53; H, 5.81. Found: C, 61.92; H,
5.78.
MS (EI, 70 eV): m/z (%) = 382 (1) [M+ – OEt], 338 (25), 336 (38),
310 (23), 308 (35), 288 (4), 286 (6), 262 (7), 260 (13), 197 (3), 185
(1), 174 (12), 172 (18), 92 (7), 91 (100), 65 (8).
HRMS (EI): m/z [M+] calcd for C20H1735Cl2F2NO3: 427.055; found:
427.055.
Ethyl 4-Phenyl-3-hydroxy-2-(1-benzyloxy-2,2-difluoro-1-vi-
nyl)-2-butenoate (5c)
IR (KBr): 3032, 2983, 2933, 1755, 1642, 1596, 1570, 1496, 1454,
1401, 1377, 1343, 1273, 1231, 1131, 1041, 944, 862, 739, 702 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.24 (t, J = 7.2 Hz, 3 H), 3.65 (d,
J = 6.9 Hz, 2 H), 4.20 (q, J = 7.2 Hz, 2 H), 4.67 (s, 2 H), 7.23–7.35
(m, 10 H), 13.49 (s, 1 H).
Anal. Calcd for C20H17Cl2F2NO3: C, 56.09; H, 4.00; N, 3.27. Found:
C, 56.57; H, 4.09; N, 2.99.
Synthesis 2006, No. 9, 1470–1474 © Thieme Stuttgart · New York

1474
W. Peng et al.
PAPER
19F NMR (282 MHz, CDCl3): d = –99.1 (d, J = 56.4 Hz, 1 F),
–107.7 (d, J = 56.4 Hz, 1 F).
MS (EI, 70 eV): m/z (%) = 283 (5) [M+ – Bn], 255 (2), 237 (10), 220
(1), 205 (2), 181 (1), 131 (1), 118 (2), 92 (8), 91 (100), 77 (1), 65
(12), 51 (2).
Acknowledgment
The authors thank the National Natural Science Foundation of Chi-
na (NNSFC) (No. 20472106 and 20532040) and Innovation Foun-
dation of Chinese Academy of Sciences for financial support.
Anal. Calcd for C21H20F2O4: C, 67.37; H, 5.38. Found: C, 67.40; H,
5.22.
References
(1) Current address: Department of Medicinal Chemistry and
The Center for Protein Structure and Function, The
University of Kansas, 1251 Wescoe Hall Drive, Malott Hall
4070, Lawrence, KS 66045-7562, USA.
(2) Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132, 478.
(3) Lee, A. S.-Y.; Cheng, R.-Y.; Pan, O.-G. Tetrahedron Lett.
1997, 38, 443.
Ethyl 4,4-Difluoro-3-benzyloxy-2-(hydroxyphenylmethene)-3-
butenoate (5d)
IR (KBr): 2983, 1751, 1695, 1642, 1609, 1595, 1570, 1493, 1447,
1399, 1375, 1342, 1271, 1246, 1141, 1021, 849, 774, 739, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.31 (t, J = 6.9 Hz, 3 H), 4.28 (q,
J = 6.9 Hz, 2 H), 4.77 (s, 2 H), 7.24–7.73 (m, 10 H), 13.84 (s, 1 H).
(4) Kagan, H. B.; Suen, Y.-H. Bull. Soc. Chim. Fr. 1966, 1819.
(5) (a) Hannick, S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833.
(b) Shin, H.-I.; Choi, B.-S.; Choi, S.-C. PCT Int. Appl. WO
2003033469, 2003; Chem. Abstr. 2003, 138, 337993.
(c) Narkunan, K.; Uang, B.-J. Synthesis 1998, 1713.
(6) (a) Syed, J.; Förster, S.; Effenberger, F. Tetrahedron:
Asymmetry 1998, 9, 805. (b) Erian, A. W. J. Prakt. Chem.
1999, 341, 147. (c) Deutsch, H. M.; Ye, X.; Shi, Q.; Liu, Z.;
Schweri, M. M. Eur. J. Med. Chem. 2001, 36, 303.
(d) Wang, F.-D.; Yue, J.-M. Synlett 2005, 2077.
(7) For a leading reference, see: Bey, P.; McCarthy, J. R.;
McDonald, I. A. In Selective Fluorination; Welch, J. T., Ed.;
ACS Symposium Series 456, American Chemical Society:
Washington, DC, 1991, Chap. 8, 105–133.
(8) Peng, W. M.; He, P.; Zhu, S. Z.; Li, Z. T. Tetrahedron Lett.
2004, 45, 3677.
(9) Cason, J.; Rinehart, K. L.; Thornton, S. D. J. Org. Chem.
1953, 18, 1594.
(10) Nicolaou, K. C.; Vassilikogiannakis, G.; Montagon, T.
Angew. Chem. Int. Ed. 2002, 41, 3276.
(11) (a) Dexter, C. S.; Hunter, C.; Jackson, R. F. W. J. Org.
Chem. 2000, 65, 7417. (b) Asaoka, M.; Tanaka, M.;
Houkawa, T.; Ueda, T.; Sakami, S.; Takei, H. Tetrahedron
1998, 54, 471.
19F NMR (282 MHz, CDCl3): d (enolized form, 86%) = –98.5 (d,
J = 62.0 Hz, 1 F), –107.9 (d, J = 62.0 Hz, 1 F). d (non-enolized
form, 14%) = –96.9 (d, J = 64.9 Hz, 1 F), –108.7 (d, J = 64.9 Hz,
1 F).
MS (EI, 70 eV): m/z (%) = 269 (8) [M+ – Bn], 241 (3), 223 (7), 197
(2), 163 (1), 146 (1), 127 (1), 105 (36), 92 (8), 91 (100), 77 (19), 65
(10), 51 (7).
Anal. Calcd for C20H18F2O4: C, 66.66; H, 5.03. Found: C, 66.68; H,
5.14.
Ethyl 4,4-Difluoro-3-benzyloxy-2-[hydroxy(3-methylphen-
yl)methene]-3-butenoate (5e)
IR (KBr): 3033, 2983, 2929, 1751, 1693, 1642, 1614, 1576, 1497,
1455, 1398, 1374, 1340, 1276, 1251, 1208, 1134, 1028, 925, 867,
802, 787, 737, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.23 (t, J = 7.0 Hz, 3 H), 2.84 (s,
3 H), 4.20 (q, J = 7.0 Hz, 2 H), 4.70 (s, 2 H), 7.16–7.29 (m, 9 H),
13.76 (s, 1 H).
19F NMR (282 MHz, CDCl3): d (enolized form, 85%) = –98.4 (d,
J = 61.8 Hz, 1 F), –107.9 (d, J = 61.8 Hz, 1 F); d (non-enolized
form, 15%) = –96.7 (d, J = 64.0 Hz, 1 F), –108.6 (d, J = 64.0 Hz,
1 F).
(12) (a) Petrov, V. A. Tetrahedron Lett. 2001, 42, 3267.
(b) Takechi, N.; Aït-Mohand, S.; Médebielle, M.; Dolbier,
W. R. Jr. Tetrahedron Lett. 2002, 43, 4317.
MS (EI, 70 eV): m/z (%) = 374 (1) [M+], 329 (1), 283 (20), 263 (3),
255 (6), 237 (6), 211 (1), 189 (1), 181 (1), 163 (1), 141 (4), 119 (33),
92 (11), 91 (100), 77 (1), 65 (12), 51 (1).
(13) Peng, W. M.; Zhu, S. Z. Tetrahedron 2003, 59, 4641.
Anal. Calcd for C21H20F2O4: C, 67.37; H, 5.38. Found: C, 67.73; H,
5.39.
Synthesis 2006, No. 9, 1470–1474 © Thieme Stuttgart · New York