A convenient synthetic access to δ-amino-γ,γ-difluoro-β-ketoesters

Article abstract of DOI:10.1055/s-2002-33905

The zinc-cuprous chloride promoted Reformatsky-imine addition reaction of 4-bromo-4,4-difluoroacetoacetate with aldimines derived from aromatic aldehydes and with ketimines derived from aryl alkyl ketone provided an efficient and practical access to δ-amino-γ,γ-difluoro-β-ketoesters. The scope and limitation of this procedure are also discussed.

Full text of DOI:10.1055/s-2002-33905

PAPER
1813
A Convenient Synthetic Access to -Amino- , -difluoro- -ketoesters
S
ynthesis of -A
m
a
ino-
,
-dif
n
luoro- -ketoe
l
sters i Wang, Shizheng Zhu*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai, 200032, China
Fax +86(21)64166128; E-mail: zhusz@pub.sioc.ac.cn
Received 30 April 2002; revised 10 June 2002
the synthesis of biologically active molecules, such as
pyrrolidines and alkaloids.7
Abstract: The zinc-cuprous chloride promoted Reformatsky-imine
addition reaction of 4-bromo-4,4-difluoroacetoacetate with ald-
imines derived from aromatic aldehydes and with ketimines derived
from aryl alkyl ketone provided an efficient and practical access to
-amino- , -difluoro- -ketoesters. The scope and limitation of this
procedure are also discussed.
Although preparation of difluorinated amines from imines
is advantageous, literature reports of the Reformatsky re-
actions of halodifluoroacetate with aldimines and chiral
1,3-oxazolidines often give difluorinated -lactams,8
whereas only a few examples for the direct synthesis of di-
fluorinated amines have been presented.9 However, we
found that the Reformatsky-imine addition reaction of 1
with a series of aldimines derived from aromatic alde-
hydes and with ketimines derived from aryl alkyl ketone,
provided difluorinated amines as the sole product and no
lactam was detected in this reaction.
Key words: difluorinated amines, imines, zinc, cuprous chloride,
4-bromo-4,4-difluoroacetoacetate
Replacement of hydrogen with fluorine frequently con-
fers bioactivity to organic molecules.1 In particular, diflu-
orinated amines are important building blocks for
pharmaceutical research. Especially, difluoroketone con-
taining peptides have been often used as enzyme inhibi-
tors since they can form stable hydrates or hemiketals
which are thought to inhibit proteolytic enzyme by mim-
icking the tetrahedral transition state of the amide bond
cleavage.2 In spite of its prominent role in organic synthe-
sis and medicinal fields, only few examples for the prepa-
First, the effect of solvent, temperature and the ratio of cu-
prous chloride on the efficiency and yield were briefly in-
vestigated with the reaction of 4-bromo-4,4-
difluoroacetoacetate (1) with N-benzylideneaniline (2a),
the results are summarized in Table 1. When 1 was treated
with 2a in the presence of zinc dust and cuprous chloride
for two hours at room temperature, the expected 3a was
produced in 80% yield along with 20% of reduction prod-
uct HCF2COCH2CO2Et detected by 19F NMR.10 Temper-
ature was found to be critical. Raising the reaction
temperature to refluxing THF, the yield was lowered since
more reduction product HCF2COCH2CO2Et was detected
by 19F NMR (entry 4, Table 1). We found that the property
of solvent effected the yield greatly and THF was the op-
timal solvent. It was also found that addition of 4Å molec-
ular sieves to the reaction system could improve the yield
(entry 6, Table 1).11 However, increasing the ratio of CuCl
could not improve the yield.
ration of
-amino- , -difluoroketones have been
reported. McCarthy reported that treatment of 1,1-di-
fluoro-2-trimethylsiloxy-2-phenylethylene with benzyl or
methyl N-methoxycarbonyl-2-chloroglycinate and alumi-
num chloride provided the , -difluoroketones in low
yields.3 Taguchi found that N-protonated N-acyliminium
salts could react with 1,1-difluorovinyl methylethers to
give difluorinated ketones in the presence of 4Å molecu-
lar sieves.4 Another report was that generating -oxo- , -
difluorinated amino acids by a [3,3]-rearrangement of
protected glycinate esters of readily available difluoroal-
lylic alcohols followed by release of the masked carbonyl
group.5 We have previously examined the zinc-cuprous
chloride promoted reactions of 4-bromo-4,4-difluoroace-
toacetate (1) with aldehydes and ketones to provide a se-
ries of difluorinated ketoesters in moderate to good
yields.6 As part of our further research studies, herein we
describe a straightforward and convenient method for the
preparation of -amino- , -difluoro- -ketoesters 4 from
the Reformatsky-imine addition of 1 with imines. The re-
sulting -amino- , -difluoro- -ketoesters 4 would cer-
tainly find wide applications in selective introduction of
difluoromethylene moieties to biologically active mole-
cules since -amino- -ketoesters have been reported as
useful building blocks in pseudopeptide chemistry and in
Having established the optimal reaction conditions (entry
6, Table 1), we screened the reactions of 4-bromo-4,4-di-
fluoroacetoacetate (1) with a range of aromatic aldimines
and found that the reaction proceeded successfully with
mild to good yields. Even sterically bulky 2f could react
with 1 to give the anticipated addition product 3f in 60%
isolated yield (Scheme 1, entry 6, Table 2). Both electron-
withdrawing and electron-donating substituents on the R1
were tolerated in the reaction (entries 1 3, Table 2). Ad-
ditionally, aldimine with R2, a phenyl bearing an electron-
withdrawing group afforded low yield possibly due to the
weak reactivity of the corresponding imine (entry 4,
Table 2). Heteroaromatic aldimine 2g and N-alkyl aldi-
mine 2h could also afford the addition products in slightly
lower yields (entries 7 and 8, Table 2) as compared to al-
dimines derived from aromatic aldehydes and aromatic
amines (entries 1 6, Table 2).
Synthesis 2002, No. 13, Print: 20 09 2002.
Art Id.1437-210X,E;2002,0,13,1813,1818,ftx,en;F03402SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1814
Y. Wang, S. Zhu
PAPER
Table 1 Reformatsky-imine Addition Reaction Conditions
Unfortunately, the reaction of aldimines derived from , -
unsaturated aldehyde and alkyl aldehyde with 1 were
problematic. The reaction of 2i with 1 resulted in an uni-
dentified mixture indicated by 19F NMR and TLC. On the
other hand, only reduction product HCF2COCH2CO2Et
was detected by 19F NMR in the reaction of 2j with 1. The
use of different catalysts, such as TMSCl, BF3 Et2O,
TiCl4, longer reaction time (up to 2 days), and elevated re-
action temperature (toluene, reflux) did not afford the de-
sired product with a reasonable yield. The results may be
due to the enolization of the aldimine 2i and the weak re-
activity of , -unsaturated aldimine 2j.
Entrya Addition
(equiv)
Solvent
T/°C
Time/h
Yieldb,c
1
2
3
4
5
6
0.3 CuCl
0.3 CuCl
0.3 CuCl
0.3 CuCl
0.6 CuCl
0.3 CuCl
THF
0
0
0
r.t.
r.t.
r.t.
2
24
24
2
80
CH2Cl2
Et2O
THF
40d
60d
65
reflux
THF
0
0
r.t.
r.t.
2
80
THF
2
85e
It was worthwhile to note that this imine-condensation re-
action could also be extended to ketimines derived from
aryl alkyl ketone. Under the similar reaction conditions as
mentioned above (entry 6, Table 1), 1 could react with N-
(1-phenyl-ethylidene)-aniline 4a giving the correspond-
ing addition product 5a in 40% yield. Conducting this re-
action in refluxing toluene could improve the yield to
50%. Similarly, the reaction of 1 with benzyl-(1-phenyl-
ethylidene)-amine (4b) in refluxing toluene could also
proceed successfully to afford 5b in 38% isolated yield
(Scheme 2).
a The reaction was conducted on a scale of 1mmol 1 with 1.1 mmol
benzylideneaniline 2a and 3 mmol Zn dust in 3 mL solvent.
b Yield determined by 19F NMR vs CF3C6H5.
c In all cases, 20 40 mol% of HCF2COCH2CO2Et was detected by 19
NMR.
F
d About 30 mol% of 1 could still be detected by 19 F NMR after the
corresponding reaction time.
e 1 g of 4 Å molecular sieves was added.
R2
R2
R2
HN
O
R2
O
O
HN
R1
O
O
HN
R1
OH
O
HO
OH
Zn (3 equiv.)
CuCl (0.3 equiv.)
N
Br
R1
OEt
+
OEt
OEt
OEt
F
F
F
MS
4Å
THF
F
R1
F
F
F
F
3-hydrated
3-enol
0 °C to r.t.
3-keto
2
1
Scheme 1
Table 2 Reaction Results of 4-Bromo-4,4-difluoroacetoacetate (1) with Aldimines
Aldimines
Product
Entry
2
R1
R2
Time (h)
Yield (%)a,b
K:E:Hc
1
2
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
Ph
2.5
3
3a (70)
3b (63)
3c (75)
3d (60)
3e (68)
3f (60)
3g (45)
3h (40)
41.9:48.8:9.3
45.6:51.7:2.7
41.1:54.9:4.0
37.1:56.9:6.0
43.0:50.0:7.0
43.9:50.8:5.3
44.9:49.4:5.7
54.9:31.9:13.2
4-MeOC6H4
4-ClC6H4
Ph
Ph
3
Ph
2
4
2-ClC6H4
4
5
4-ClC6H4
2-naphthyl
2-furyl
Ph
4-MeOC6H4
2
6
Ph
Ph
Bn
Ph
Ph
2.5
6
7
8
6
9
(CH3)2CH
PhCH=CH
24
24
_
d
10
2j
_
d
a Isolated yields of pure compounds based on 1.
b 10 40 mol% HCF2COCH2CO2Et was detected by 19F NMR.
c The ratio of keto ester, enol ester and hydrate determined by 19F NMR.
d No addition product was detected.
Synthesis 2002, No. 13, 1813–1818 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of -Amino- , -difluoro- -ketoesters
1815
R3
R3
O
O
Zn (3 equiv.)
CuCl (0.3 equiv.)
HN
O
O
N
Br
+
Ph
OEt
Ph
Me
OEt
Me
F
MS
4Å
F
F
F
toluene refluxing
1
4a-b
5a-b
4a R3 = Ph
4b R3 = Bn
5a 50%
5b 38%
Scheme 2
Due to the strong electron-withdrawing ability of with imines. This procedure proved to be quite general,
difluoromethylene, the adjacent carbonyl is known to working well for non-enolizable imines derived from aro-
have a marked proclivity for becoming hydrated.12 In our matic aldehydes and aryl alkyl ketones.10 The resulting -
research work, the addition products 3a h were all isolat- amino- , -difluoro- -ketoesters with a series of syntheti-
ed as a mixture of keto ester, enol ester and minor hydrat- cally useful functional groups, such as amine, carbonyl,
ed forms. The existing ratio of the three forms of 3a h ester, and active methylene, are anticipated to undergo
deduced from 19F NMR are summarized in Table 2. How- some further transformations to difluorinated molecules.
ever, 5a b were isolated only as keto ester and enol ester Further work is in progress.
forms, but no hydrated form was detected after the same
1
work-up procedure. The H NMR, 19F NMR and 13C
1H NMR, 13C NMR and 19F NMR spectra were recorded on Varian-
NMR spectral datas of all the compounds in the work
were in accordance with the proposed structures. Distinc-
tive 19F NMR spectra were observed for 3a h and 5a b,
fully consistent with the presence of a CF2 group next to a
chiral carbon atom. The 19F NMR spectrum (CDCl3) of
each of these compounds 3a h showed three signals, cor-
responding to the keto ester, enol ester, and minor hydrat-
ed (3-gem-diol) forms of 3a h, and each group was a
typical AB pattern further split by hydrogen present on the
adjacent atom. One of low intensity at high field (hydrated
form), and the other two of much greater intensity always
shifted 1 4 ppm to lower field (keto ester and enol ester
forms). Unambiguous assignment of the minor high-field
peak to the hydrated ketones was deduced from the corre-
sponding 13C NMR (CDCl3) spectra.13 There were no trip-
let peaks in the diagnostic region (about 90 ppm)
consistent with a quarternary gem-diol carbon atom with
carbon fluorine coupling (about 20 30Hz).12b In con-
trast, there was the presence of keto carbonyl group (about
194 ppm, dd or t) and 3-C of the enol form (about 165
360L or Bruker AM-300 instruments with Me4Si and CFCl3 (with
upfield negative) as internal and external standards, respectively.
NMR spectra were recorded in deuterated CHCl3 unless otherwise
stated. IR spectra were obtained with a Nicolet AV-360 spectropho-
tometer using KBr disks of the compounds. Low mass spectrum
was obtained with HP 5989a instrument. Elemental analyses were
performed by this Institute. Mps were measured in Temp-Melt ap-
paratus. All reactions as well as column chromatography were mon-
itored routinely with TLC or 19F NMR spectroscopy. Anhyd THF
was dried and freshly distilled from sodium wire. Anhyd toluene
was distilled from P2O5, and then dried over sodium wire. All other
reagents were purified before use according to the standard meth-
ods. Petroleum ether (PE) used had a bp range 60–90 °C.
Reformatsky-type Imine Addition Reactions of 1 with Ald-
imines; Typical Procedure
A soln of benzylideneaniline [(2a), 0.199 g, 1.1 mmol] and 1 (0.245
g, 1 mmol) in THF (1 mL) was added dropwise to a heterogeneous
soln of acid-washed zinc dust (0.196 g, 3.0 mmol) and CuCl (0.030
g, 0.3 mmol) in THF (2 mL), which had been stirred at r.t. for 0.5 h.
After the addition was completed, the reaction mixture was warmed
to r.t. and stirred for another 2 h. Then sat. NH4Cl (5 mL) was added.
Excess zinc was removed by suction filtration and washed with
EtOAc (10 mL). The organic layer was separated. The aq layer was
extracted with EtOAc (10 mL 3), the organic layers were com-
bined and washed with H2O, brine, then dried over Na2SO4. After
evaporation of the solvents, the residue was chromatographed on
silica gel eluting with PE EtOAc, 3:1 to give 3a (0.243 g) in 85%
yield as a mixture of keto ester, enol ester and corresponding hy-
drate.
1
166 ppm, dd or t). The H NMR spectra of the mixtures
also showed a AB pattern for the C(2)-hydrogen of hy-
drated form at about = 2.80 ppm with hydrogen-hydro-
gen coupling (2JH H = 12 22 Hz).
A
complete
dehydration of the substrates could be obtained after the
mixture was simply treated with 4Å molecular sieves in
CDCl3 for one to two hours,12a and 19F NMR and 1H NMR
spectra indicated the disappearance of signals of hydrated
form. On the contrary, treatment of the chloroform solu-
tion of 3 with acids, such as concentrated hydrochloric ac-
id, trifluoroacetic acid, could increase the ratio of
hydrated form.
Ethyl 4,4-Difluoro-3-oxo-5-phenyl-5-phenylamino-pentanoate
(3a)
Slightly yellowish solid, mp 74–75 °C.
IR (neat): 3383, 1765, 1707, 1663, 1372–1118 cm–1.
1H NMR (CDCl3) = 12.20 (s, OH of enol form), 6.63–7.45 (m, 10
H), 5.48 (s, 2-H of enol form), 5.08–5.20 (m, 1 H, 5-H), 4.50 (s, 1
H, N-H), 4.22 (q, 2 H, J = 7.1 Hz), 3.59 (s, 2-H of keto form), 2.92
and 2.82 (AB system, 2JH-H = 12.0 Hz, 2-H of hydrate form), 1.30
(t, 3 H, J = 7.1 Hz).
In this paper, we have described an efficient and straight-
forward method for the preparation of -amino- , -diflu-
oro- -ketoesters based on the Reformatsky-imine
addition reactions of 4-bromo-4,4-difluoroacetoacetate
Synthesis 2002, No. 13, 1813–1818 ISSN 0039-7881 © Thieme Stuttgart · New York

1816
Y. Wang, S. Zhu
PAPER
19F NMR (CDCl3) = –107.5 (dd, 2JF–F = 264.0, 3JH–F = 7.9 Hz) and
HRMS: m/z calcd for C17H12ClNF2O2 (M+ – EtOH), 336.05978;
found, 336.05652.
2
–120.0 (dd, JF–F = 264.0 ,3JH–F = 19.5 Hz) keto form, –110.3 (dd,
2
2JF–F = 259.0 ,3JH–F = 9.1 Hz) and –119.0 (dd, JF–F = 259.0,
3JH–F = 15.0 Hz) enol form, –111.8 (d, 2JF–F = 260.0 Hz) and –128.3
Ethyl 4,4-Difluoro-5-(4-chlorophenyl)-3-oxo-5-(4-methoxyphe-
nyl)amino-pentanoate (3e)
(dd, 2JF–F = 260.0,3JH–F = 24.5 Hz) hydrate form.
Slightly yellowish oil.
IR (neat): 3372, 1722, 1660, 1235–1098 cm–1.
MS (EI): m/z (%) = 347 (M+, 5), 227 (M+ – EtOH, 14), 182 [Ph(Ph-
NH)CH+, 100].
HRMS: m/z calcd for C19H19NF2O3, 347.13330; found, 347.13283.
1H NMR (CDCl3): = 12.09 (s, O–H of enol form), 7.19–7.30 (m,
4 H), 6.62–6.69 (m, 2 H), 6.45–6.51 (m, 2 H), 5.40 (s, 2-H of enol
form), 5.10 and 5.19 (O–H of hydrate form), 4.86–4.96 (m, 1 H,
5-H), 4.06–4.18 (m, 3 H, OCH2CH3 and N–H), 3.63 (s, 3 H,
OCH3), 3.59 (s, 2-H of keto form), 2.78 and 2.82 (AB system,
2JH–H = 15.8,2-H of hydrate form), 1.16 and 1.23 (t, 3 H, J = 7.2
Hz).
Ethyl 4,4-Difluoro-5-(4-methoxyphenyl)-3-oxo-5-phenylamino-
pentanoate (3b)
Slightly yellowish oil.
IR (neat): 3377, 1753, 1729, 1665, 1367–1180 cm–1.
1H NMR (CDCl3): = 12.11 (s, O-H of enol form), 6.62–7.37 (m, 9
H), 5.46 (s, 2-H of enol form), 5.00–5.10 (m, 1 H, 5-H), 4.46 (d, 1
H, J = 8.9 Hz, N–H), 4.16 and 4.22 (q, 2 H, J = 7.1 Hz), 3.77 (s, 3
H), 3.57 (s, 2-H of keto form), 1.23 and 1.29 (t, 3 H, J = 7.1 Hz).
13C NMR (CDCl3): spectral data for the -keto ester form;
2
= 13.0 (s, OCH2CH3), 55.6 (s, OCH3), 60.4 (dd, JC–F = 27.0,
3
22.9,5-C), 61.9 (s, OCH2CH3), 91.9 (t, JC–F = 5.5,2-C), 116.6 (t,
2
1JC–F = 249.1 Hz, 4-CF2), 171.8 (s, 1-C), 194.0 (dd, JC–F = 35.7,
2
19F NMR (CDCl3): = –108.5 (dd, JF–F = 261.0,3JH–F = 7.9 Hz)
27.2, 3-C=O).
2
3
and –119.9 (dd, JF–F = 261.0, JH–F = 18.9 Hz) keto form, –110.8
(dd, 2JF–F = 259.0, 3JH–F = 9.6 Hz) and –118.8 (dd, 2JF–F = 259.0 Hz,
3JH–F = 16.5 Hz) enol form, –111.8 (d, 2JF–F = 259.0 Hz) and –128.3
(dd, 2JF–F = 259.0, 3JH–F = 24.9 Hz) hydrate form.
13C NMR (CDCl3): spectral data for the enol ester form; = 13.9
(s, OCH2CH3), 55.5 (s, OCH3), 61.2 (s, OCH2CH3), 115.2 (t,
1JC–F = 234.0, 4-CF2), 165.4 (s, 1-C), 165.5 (dd, 2JC–F = 32.3, 27.3,
3-C=O).
MS (EI): m/z (%) = 377 (M+, 4), 331 (M+ – EtOH, 11), 285 (M+ –
2
3
19F NMR (CDCl3): = –105.8 (dd, JF–F = 265.0, JH–F = 6.1 Hz)
PhNH, 9), 212 (M+ – CF2COCH2CO2Et, 100).
2
3
and –121.9 (dd, JF–F = 265.0, JH–F = 20.7 Hz) keto form,–109.9
2
3
2
Anal. Calcd for C20H21NF2O4: C, 63.66; H, 5.57; N, 3.71. Found: C,
63.55; H, 5.75; N, 3.43.
(dd, JF–F = 260.0, JH–F = 8.0 Hz) and –119.5 (dd, JF–F = 260.0,
3JH–F = 16.7 Hz) enol form,–111.7 (d, 2JF–F = 259.4 Hz) and –129.0
(dd, 2JF–F = 259.4, 3JH–F = 26.0 Hz) hydrate form.
Ethyl 4,4-Difluoro-5-(4-chlorolphenyl)-3-oxo-5-phenylamino-
pentanoate (3c)
Slightly yellowish oil.
IR (neat): 3383, 1754, 1729, 1666, 1368–1130 cm–1.
1H NMR (CDCl3): = 12.19 (s, O-H of enol form), 6.60–7.41 (m, 9
H), 5.48 (s, 2-H of enol form), 5.10–5.19 (m, 1 H, 5-H), 4.45–4.55
(m, 1 H, N–H), 4.18 and 4.24 (q, 2 H, J = 7.1 Hz), 3.65 (s, 2-H of
keto form), 1.24 and 1.30 (t, 3 H, J = 7.1 Hz).
MS (EI): m/z (%) = 411(M+, 16), 409 (M+– N2, 16), 366 (M+– EtO,
16), 344 (M+ – 1 – Cl – OCH3, 1), 246 (M+– CF2COCH2CO2Et,
100).
HRMS: m/z calcd for C20H20ClNF2O4. 411.10490; found,
411.10576.
Spectral data for the dehydrated form:
1H NMR (CDCl3): = 12.09 (s, 0.51 H, O–H of enol form), 7.23–
7.31 (m, 4 H), 6.61–6.65 (m, 2 H), 6.46–6.51 (m, 2 H), 5.40 (s, 0.51
H, 2-H of enol form), 4.88–4.96 (m, 1 H, 5-H), 4.04 and 4.20 (m, 3
H, OCH2CH3 and N-H), 3.63 (s, 3 H, OCH3), 3.60 (s, 2-H of keto
form, 0.96 H), 1.17 and 1.24 (t, 3 H, J = 7.2 Hz).
2
19F NMR (CDCl3): = –106.2 (dd, JF–F = 240.0,3JH–F = 6.9 Hz)
2
and –120.8 (dd, JF–F = 240.0,3JH–F = 19.9 Hz) keto form, –110.3
2
2
(dd, JF–F = 260.0,3JH–F = 9.0 Hz) and –118.9 (dd, JF–F = 260.0,
3JH–F = 16.5 Hz) enol form, –111.4 (d, 2JF–F = 260.2 Hz) and –128.5
(dd, 2JF–F = 260.2,3JH–F = 24.7 Hz) hydrate form.
2
3
19F NMR (CDCl3): = –106.3 (dd, JF–F = 265.0, JH–F = 7.3 Hz)
2
3
and –122.3 (dd, JF–F = 265.0, JH–F = 20.0 Hz) keto form, –110.4
(dd, JF–F = 259.4, JH–F = 11.0 Hz) and –119.9 (dd, JF–F = 259.4,
MS (EI): m/z (%) = 381 (M+, 7), 336 (M+ – EtOH, 10), 289 (M+ –
2
3
2
PhNH, 1), 216 (M+ – CF2COCH2CO2Et, 100).
3JH–F = 16.9 Hz) enol form.
Anal. Calcd for C19H18ClNF2O3: C, 59.76; H, 4.72; N, 3.67. Found:
C, 60.00; H, 4.95; N, 3.40%.
Ethyl 4,4-Difluoro-5-naphthyl-3-oxo-5-phenylamino-pentan-
oate (3f)
White solid, mp 91–93 °C.
IR (neat): 3383, 1755, 1371–1144 cm–1.
Ethyl 4,4-Difluoro-5-phenyl-3-oxo-5-(2-chlorophenyl)amino-
pentanoate (3d)
Slightly yellowish oil.
1H NMR (CDCl3): = 12.19 (s, O–H of enol form), 7.82–7.94 (m,
4 H), 7.46–7.55 (m, 3 H), 7.09–7.15 (m, 2 H), 6.66–6.71 (m, 3 H),
5.48 (s, 2-H of enol form), 5.26–5.35 (m, 1 H, 5-H), 4.64 (br, 1 H,
N–H), 4.14 and 4.21 (q, 2 H, J = 7.2 Hz), 3.40 (s, 2-H of keto form),
1.20 and 1.26 (t, 3 H, J = 7.2 Hz).
IR (neat): 3410, 1734, 1664, 1322–1095 cm–1.
1H NMR (CDCl3): = 12.18 (s, O-H of enol form), 7.35–7.47 (m, 5
H), 7.25–7.29 (m, 1 H), 7.03–7.05 (m, 1 H), 6.57–6.68 (m, 2 H),
5.51 (s, 2-H of enol form), 5.14–5.25 (m, 2 H), 4.14–4.24 (m, 2 H),
3.60 (s, 2-H of keto form), 1.24 and 1.31 (t, 3 H, J = 7.1 Hz).
13C NMR (CDCl3): spectral data for the -keto ester form; = 14.0
2
19F NMR (CDCl3): = –108.0 (dd, JF–F = 264.0,3JH–F = 6.3 Hz)
2
(s, OCH2CH3), 60.1 (dd, JC–F = 25.2, 23.9,5-C), 61.9 (s,
2
and –120.0 (dd, JF–F = 264.0,3JH–F = 17.1 Hz) keto form, –110.2
OCH2CH3), 92.0 (t, 3JC–F = 5.4 Hz, 2-C), 119.3 (t, JC F = 259.7 Hz,
4-CF2), 171.8 (s, 1-CO2Et), 194.5 (t, 2JC–F = 34.0, 3-C=O).
2
2
(dd, JF–F = 260.4,3JH–F = 8.3 Hz) and –119.4 (dd, JF–F = 260.4,
3JH–F = 16.2 Hz) enol form, –111.7 (d, 2JF–F = 260.9 Hz) and –125.7
(dd, 2JF–F = 260.9,3JH–F = 22.0 Hz) hydrate form.
13C NMR (CDCl3): spectral data for the enol ester form; = 13.9 (s,
OCH2CH3), 61.1 (s, OCH2CH3), 116.9 (t, JC–F = 251.7, 4-CF2),
165.4 (s, 1-CO2Et), 165.9 (t, 2JC–F = 27.2, 3-C=O).
MS (EI): m/z (%) = 381 (M+, 4), 336 (M+– EtO, 9), 216 (M+–
CF2COCH2CO2Et, 100).
2
3
19F NMR (CDCl3): = –107.2 (dd, JF–F = 263.5, JH–F = 7.8 Hz)
2
3
and –119.3 (dd, JF–F = 263.5, JH–F = 19.2 Hz) keto form, –110.3
Synthesis 2002, No. 13, 1813–1818 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of -Amino- , -difluoro- -ketoesters
1817
2
3
2
2
3
(dd, JF–F = 259.4, JH–F = 9.2 Hz) and –117.2 (dd, JF–F = 259.4,
3JH–F = 16.2 Hz) keto form, –111.4 (d, 2JF–F = 259.7 Hz) and –127.8
(dd, 2JF–F = 259.7, 3JH–F = 2 4.8 Hz) hydrate form.
19F NMR (CDCl3): = –106.6 (dd, JF–F = 256.6, JH–F = 20.0
2
Hz) and –124.2 (d, JF–F = 256.6 Hz) keto form,–110.64 (d,
2JF–F = 257.5 Hz) and –119.3 (dd, JF–F = 257.5, JH–F = 16.4
2
3
2
Hz) enol form, –112.3 (d, JF–F = 260.1 Hz) and –129.8 (dd,
MS (EI): m/z (%) = 397 (M+, 6.41), 352 (M+ – OEt, 1.22), 232 (M+
– CF2COCH2CO2Et, 100.00).
2JF–F = 260.1,3JH–F = 27.1 Hz) hydrate form.
HRMS: m/z calcd for C20H21NF2O3, 316.12193; found, 316.11842.
Spectral data for the dehydrated form:
Anal. Calcd for C23H21ClNF2O3: C, 69.52; H, 5.29; N, 3.53. Found:
C, 69.45; H, 5.16; N, 3.34.
1H NMR (CDCl3): = 11.95 (s, 0.30 H, O–H of enol form), 7.14–
7.39 (m, 10 H), 5.37 (s, 0.30 H, 2-H of enol form), 4.13–4.22 (m, 3
H, OCH2CH3 and H-5), 3.64 (s, 1.40 H, 2-H of keto form), 3.45–
3.71 (m, 2 H), 1.96 (br, 1 H, N-H), 1.23 and 1.25 (t, 3 H, J = 7.2 Hz).
Ethyl 4,4-Difluoro-5-(2-furyl)-3-oxo-5-phenylamino-pentan-
oate (3g)
Slightly yellowish oil.
IR (neat): 3383, 1755, 1371–1144 cm–1.
1H NMR (CDCl3): = 12.10 (s, O–H of enol form), 7.40–7.42 (m,
1 H), 7.15–7.25 (m, 2 H), 6.71–6.85 (m, 3 H), 6.33–6.37 (m, 2 H),
5.55 (s, 2-H of enol form), 5.20–5.32 (m, 1 H), 4.14–4.30 (m, 2 H),
3.77 (s, 0.96 H, 2-H of keto form), 2.89 and 2.94 (AB system,
2JH–H = 22.5, H-2 of hydrate form) 1.23 and 1.30 (t, 3 H, J = 7.1
Hz).
2
3
19F NMR (CDCl3): = –107.0 (dd, JF–F = 257.5, JH–F = 5.4 Hz)
2
3
and = –124.2 (dd, JF–F = 257.5, JH–F = 24.3 Hz) keto form,
2
3
–111.0 (dd, JF–F = 259.4, JH–F = 11.8 Hz) and –119.4 (dd,
2JF–F = 259.4, 3JH–F = 17.8 Hz) enol form,
Ethyl 4,4-Difluoro-5-phenyl-3-oxo-5-phenylamino-hexanoate
(5a)
The same procedure as above in refluxing toluene for 4 h. Slightly
yellowish oil.
IR (neat): 3406, 1750, 1727, 1662, 1379–1120 cm–1.
13C NMR (CDCl3): spectral data for the -keto ester form; = 14.1
2
(s, OCH2CH3), 54.7 (dd, JC–F = 21.1, 17.3, 5-C), 61.9 (s,
OCH2CH3), 91.9 (t, 3JC–F = 3.9, 2-C), 117.8 (t, 1JC–F = 241.8 Hz, 4-
CF2), 171.9 (s, 1-CO2Et), 194.1 (dd, 2JC–F = 25.7, 20.1, 3-C=O).
1H NMR (CDCl3): = 12.50 (s, 0.33 H), 7.57–7.63 (m, 2 H), 7.36–
7.47 (m, 3 H), 7.01–7.09 (m, 2 H), 6.67–6.75 (m, 1 H), 6.36–6.42
(m, 2 H), 5.12 (s, 0.33 H, 2-H of enol form), 4.99 (s, 0.26 H, N-H),
4.68 (s, 0.74 H, N–H), 4.08–4.23 (m, 2 H), 2.81 and 2.94 (AB sys-
13C NMR (CDCl3): spectral data for the enol ester form; = 14.0
2
(s, OCH2CH3), 54.6 (dd, JC–F = 21.8,18.3, 5-C), 61.2 (s,
1
OCH2CH3), 110.5 (t, JC–F = 247.7, 4-CF2), 165.4 (s, 1-CO2Et),
2
165.6 (dd, 2JC–F = 23.6, 20.1, 3-C=O).
tem, JH–H = 17.0, 1.34 H, 2-H of keto form), 1.91 (s, 3 H), 1.29–
1.31 (m, 3 H).
2
3
19F NMR (CDCl3): = –108.0 (dd, JF–F = 263.3, JH–F = 7.8 Hz)
2
3
and –119.6 (dd, JF–F = 263.3, JH–F = 18.5 Hz) keto form,–109.9
13C NMR (CDCl3): spectral data for the -keto ester form: = 13.9
(s, OCH2CH3), 18.9 (t, 3JC–F = 3.2,6-C), 61.5 (s, OCH2CH3), 64.2 (t,
2JC–F = 24.7, 5-C), 93.3 (t, 3JC–F = 4.0, 2-C), 117.1 (t, 1JC–F = 255.0,
4-CF2), 171.8 (s, 1-CO2Et), 194.4 (dd, 2JC–F = 34.6, 28.9, 3-C=O).
2
3
2
(dd, JF–F = 259.3, JH–F = 8.6 Hz) and –119.3 (dd, JF–F = 259.3,
3JH–F = 17.1 Hz) enol form,–112.9 (d, 2JF–F = 257.2 Hz) and –127.6
(dd, 2JF–F = 257.2, 3JH–F = 24.4 Hz) hydrate form.
MS (EI): m/z (%) = 337 (M+, 4.31), 392 (M+ – OEt, 0.75), 222 (M+
13C NMR (CDCl3): spectral data for the enol ester form; = 13.8 (s,
3
– COCH2CO2Et, 0.64), 172 (M+ – CF2COCH2CO2Et, 100.00).
OCH2CH3), 18.3 (dd, JC–F = 4.5, 1.8, 6-C), 61.1 (s, OCH2CH3),
2
63.3 (dd, JC–F = 23.4, 23.0, 5-C), 165.3 (s, 1-CO2Et), 165.8 (t,
HRMS: m/z calcd for C19H18ClNF2O3, 337.11223; found,
337.11240.
2JC–F = 31.0, 3-C=O).
19F NMR (CDCl3): = –114.9 (d, 2JF–F = 234.8 Hz) and –116.1 (d,
2JF–F = 234.8 Hz) enol form,–115.1 (d, 2JF–F = 246.6 Hz) and –117.0
(d, 2JF–F = 246.6 Hz) keto form.
Ethyl 4,4-Difluoro-5-phenyl-3-oxo-5-benzylamino-pentanoate
(3h)
Slightly yellowish oil.
MS (EI): m/z (%) = 361 (M+, 5), 316 (M+– EtO, 11), 287 (M+ – 1 –
Spectral data for the mixture of keto ester, enol ester and corre-
sponding hydrate:
IR (neat): 3338, 1755, 1733, 1664, 1369–1099 cm–1.
CO2Et, 1), 269 (M+ – PhNH, 1), 196 (M+– CF2COCH2CO2Et, 100).
HRMS: m/z calcd for C20H21NF2O3, 361.15155; found, 361.15025.
Ethyl 4,4-Difluoro-5-phenyl-3-oxo-5-benzylamino-hexanoate
(5b)
The same procedure as above in refluxing toluene for 6 h. Slightly
yellowish oil.
IR (neat): 3406, 1750, 1727, 1662, 1379–1120 cm–1.
1H NMR (CDCl3): = 7.30–7.63 (m, 10 H), 5.26 (s, 0.20 H, 2-H of
enol form), 4.06–4.13 (m, 2 H), 3.61 (s, 1.60 H, 2-H of keto form),
3.43 and 3.63 (AB system, 2JH–H = 12.6, 2 H), 1.82 (s, 3 H), 1.15–
1.20 (m, 3 H).
1H NMR (CDCl3): = 12.18 (s, O–H of enol form), 7.22–7.43 (m,
10 H), 5.48 (s, 2-H of enol form), 4.63 and 4.72 (s, O–H of hydrate
form), 4.21–4.38 (m, 3 H, OCH2CH3and H-5), 3.51–3.83 (m, NCH2
and 2-H of keto form), 2.83 and 2.88 (AB system, 2JH–H = 15.9, 2-
H of hydrate form) 2.16 (s, 1 H, N–H), 1.23 and 1.29 (t, 3 H, J = 7.2
Hz).
13C NMR (CDCl3): spectral data for the -keto ester form;
= 14.0 (s, OCH2CH3), 51.0 (s, NHCH2Ph), 61.5 (s, OCH2CH3),
63.0 (dd, 2JC–F = 20.4, 16.0, 5-C), 91.5 (t, 3JC–F = 4.0, 2-C), 117.3 (t,
1JC–F = 254.4, 4-CF2), 165.7 (s, 1-C), 194.8 (dd, 2JC–F = 26.3, 20.2,
3-C=O).
13C NMR (CDCl3): spectral data for the -keto ester form:
3
= 14.1 (s, OCH2CH3), 19.2 (t, JC–F = 3.2, 6-C), 46.6 (s,
13C NMR (CDCl3): spectral data for the enol ester form; = 14.0
NHCH2Ph), 61.5 (s, OCH2CH3), 63.7 (t, 2JC–F = 24.7, 5-C), 92.9 (t,
3JC–F = 6.1, 2-C), 117.5 (t, 1JC–F = 262.5, 4-CF2), 171.6 (s, 1-CO2Et),
194.2 (dd, 2JC–F = 33.9, 29.1, 3-C=O).
(s, OCH2CH3), 51.0 (s, NHCH2Ph), 60.9 (s, OCH2CH3), 61.3 (dd,
1
2JC–F = 20.4, 16.0, 5-C), 113.8 (t, JC–F = 260.8, 4-CF2), 166.6 (dd,
2JC–F = 23.9, 21.1, 3-C=O).
13C NMR (CDCl3): spectral data for the enol ester form; = 14.1 (s,
3
13C NMR (CDCl3): spectral data for the hydrate form; = 95.7 [t,
OCH2CH3), 20.1 (t, JC–F = 3.4, 6-C), 60.8 (s, OCH2CH3), 64.4 (t,
2JC–F = 23.1, 3-C(OH)2].
2JC–F = 23.7, 5-C), 166.0 (s, 1-CO2Et).
2
MS (EI): m/z (%) = 362 (M+H, 1.21), 316 (M+ – OEt, 2.50), 274 (M+
19F NMR (CDCl3):–114.0 (d, JF–F = 249.0 Hz) and –117.0 (d,
– CH2CO2Et, 0.50), 196 (M+ – CF2COCH2CO2Et, 100.00).
2JF–F = 249.0 Hz) keto form,–113.8 (d, 2JF–F = 16.6 Hz) enol form.
Synthesis 2002, No. 13, 1813–1818 ISSN 0039-7881 © Thieme Stuttgart · New York

1818
Y. Wang, S. Zhu
PAPER
(4) Kodama, Y.; Okumura, M.; Yanabu, N.; Taguchi, T.
MS (EI): m/z (%) = 373 (M+ – 2, 1), 330 (M+ – EtO, 3), 226 (M+
+ H – C6H5+ – CO2Et, 11), 210 (M+ – CF2COCH2CO2Et, 100).
Tetrahedron Lett. 1996, 37, 1061.
(5) Percy, J. M.; Prime, M. E. J. Org. Chem. 1998, 63, 8049.
(6) Wang, Y. L.; Zhu, Z. S. Tetrahedron Lett. 2001, 42, 5741.
(7) (a) Davies, F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3,
3169. (b) Davies, F. A.; Chao, B.; Fang, T.; Szewczyk, J. M.
Org. Lett. 2000, 2, 1041. (c) Leflemme, N.; Dallemagne, P.;
Rault, S. Tetrahedron Lett. 2001, 42, 8997. (d) Honma, T.;
Tada, Y.; Adachi, I.; Igarashi, K. J. Heterocycl. Chem. 1989,
26, 629.
(8) (a) Taguchi, T.; Kitagawa, O.; Suda, Y.; Ohkawa, S.;
Hashimoto, A.; Iitaka, Y.; Kokayashi, Y. Tetrahedron Lett.
1988, 29, 5291. (b) Baldwin, J. E.; Lynth, G. P.; Schofield,
C. J. J. Chem. Soc., Chem. Commun. 1991, 736.
(c) Baldwin, J. E.; Lynch, G. P.; Schofield, C. J. Tetrahedron
1992, 48, 9085. (d) Angelastro, M. R.; Bey, P.; Mendi, S.;
Peet, N. Bioorg. Med. Chem. Lett. 1992, 2, 1235. (e) Uoto,
K.; Ohsuki, S.; Takenoshita, H.; Ishiyama, T.; Iimura, S.;
Hirota, Y.; Mitsui, I.; Terasawa, H.; Soga, T. Chem. Pharm.
Bull. 1997, 45, 1793. (f) Marcotte, S.; Pannecoucke, X.;
Feasson, C.; Quirion, J.-C. J. Org. Chem. 1999, 64, 8461.
(9) Katritzky, A. R.; Nichols, D. A.; Qi, M. Tetrahedron Lett.
1998, 39, 7063.
(10) (a) Burton, D. J.; Easdon, J. C. J. Fluorine Chem. 1988, 38,
125. (b) Kitagawa, O.; Taguchi, T.; Kobayashi, Y.
Tetrahedron Lett. 1988, 29, 1803.
(11) Kuroboshi, M.; Ishihara, T. Tetrahedron Lett. 1987, 28,
6481.
(12) (a) Parisi, M. F.; Gattuso, G.; Notti, A.; Raymo, F. M. J. Org.
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Resnati, G. J. Org. Chem. 1992, 57, 2726.
(13) Some of the signals in aryl and alkene region are not
assigned in 13C NMR spectra due to complexity, since the
spectrum is obtained from a mixture of keto ester enol ester
and hydrate form.
Anal. Calcd for C21H23ClNF2O3: C, 67.20; H, 6.13; N, 3.73. Found:
C, 67.59; H, 6.18; N, 3.49.
Acknowledgement
The authors thank the National Natural Science Foundation of Chi-
na (NNSFC) (No. 20072049 and No. 20032010) and the Innovation
Foundation of Chinese Academy of Sciences for financial support.
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Synthesis 2002, No. 13, 1813–1818 ISSN 0039-7881 © Thieme Stuttgart · New York