Preparation of β-fluoro-β-ketoesters from α-ketoesters and their conversion to (Z)-β-fluoro-α-aminoacrylate derivatives

Full text of DOI:10.1021/jo9806761

J . Org. Chem. 1998, 63, 6409-6413
6409
didehydroamino acids possess interesting biological ac-
tivities and are important constituents of antibiotic and
phytotoxic peptides,7 fluorinated analogues might display
altered biological activities. â-Fluorinated didehydroam-
ino acid derivatives are also interesting as precursors to
the biologically important â-fluoro R-amino acids1c,8 and
as substrates for cross-coupling reactions.7 We wish to
report an improved synthesis of 3-fluoro-2-ketoesters
from R-ketoesters and describe their condensation reac-
tions with methyl carbamate and acetamide as a means
of accessing â-fluorinated didehydroamino esters.
P r ep a r a tion of â-F lu or o-r-k etoester s fr om
r-Ketoester s a n d Th eir Con ver sion to
(Z)-â-F lu or o-r-a m in oa cr yla te Der iva tives
J ohn F. Okonya, M. Catherine J ohnson, and
Robert V. Hoffman*
Department of Chemistry and Biochemistry, New Mexico
State University, Las Cruces, New Mexico 88003-8001
Received April 13, 1998
In tr od u ction
Resu lts a n d Discu ssion
The presence of fluorine in biologically active com-
pounds can impart a profound influence on their biologi-
cal activity. This influence has led to the development
of several potent agricultural and therapeutic agents.1
As a consequence, organofluorine chemistry has seen a
flurry of research activity recently. A continuing em-
phasis in this field has been placed on the development
and evaluation of new fluorinating reagents,2 enantiose-
lective synthesis of R-fluorocarbonyl compounds,2,3 and
the synthesis of biologically active fluorinated com-
pounds.2,4 R-Fluorinated carbonyl compounds have pre-
viously been synthesized and studied as potential enzyme
inhibitors.1c,5 In this context, monofluorinated R-ke-
toesters have received a fair share of attention as pep-
tidomimetic serine and cysteine protease inhibitors,5c as
mechanistic probes for proteolysis,1c and as intermediates
for the synthesis of â-fluoro R-amino esters.1c
Our interest in chemistry of 1,2,3-trifunctionalized
compounds, which can efficiently be transformed into
other 1,2,3-trifunctionalized products by independent,
orthogonal functional group manipulation,6 suggested
that 3-fluoro-2-ketoesters could be very useful intermedi-
ates. For example, condensation reactions of 3-fluoro-2-
ketoesters with carbamates and acetamide might provide
â-fluorinated analogues of didehydroamino esters. Since
Several methods have been developed for the prepara-
tion of R -fluorinated carbonyl compounds.1c,5a,b,9 Of
these, several have previously been applied to the syn-
thesis of 3-fluoro-2-ketoesters and acids. These include
the ring opening of glycidic esters with HF-pyridine
followed by J ones, Dess-Martin, or Swern oxidation;5c,10
treatment of aminomalonates with chlorofluorocarbene
followed by acid hydrolysis and decarboxylation to pro-
vide fluoropyruvic acid;11 Claisen condensation of ethyl
fluoroacetic acid and diethyl oxalate followed by hydroly-
sis and decarboxylation;12 and fluorination of enolizable
pyruvates with molecular fluorine.13 With the advent of
electrophilic NF fluorinating reagents, efficient and
selective R-fluorination of carbonyl compounds can now
be achieved.2,3,9,14 One particular reagent, 1-(chloro-
methyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetraflu-
oroborate) (4, also commonly referred to as Selectfluor)
has proven to be extremely useful as a mild and site-
selective electrophilic fluorinating agent.4,14 Taking ad-
vantage of the convenience and mild reactivity of Select-
fluor, we have developed an effective method for the
synthesis of 3-fluoro-2-ketoesters 3 from R-ketoesters 1
(Scheme 1).
R-Ketoesters 1a -f were transformed to the corre-
sponding silyl enol ethers 2a -f in quantitative yields by
treatment with Et3N and TMSCl in THF at room
temperature.6e,15 These were not purified but merely
(1) (a) Banks, R. E.; Smart, B. E.; Tatlow, J . C., Eds. Organofluorine
Chemistry: Principles and Commercial Applications; Plenum Press:
New York, 1994. (b) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M., Eds.
Organofluorine Compounds in Medicinal Chemistry and Biomedical
Applications; Elsevier Science Publishers: Amsterdam, 1993. (c) Welch,
J . T.; Eswarakrishnan, S. Fluorine in Bioorganic Chemistry; J ohn
Wiley and Sons: New York, 1991. (d) Hudlicky, M.; Pavlath, A. E.,
Eds. Chemistry of Organic Fluorine Compounds II; ACS Monograph
187; American Chemical Society: Washington, DC, 1985. (e) Banks,
R. E., Ed. Fluorine in Agriculture; Fluorine Technology Limited: Sale,
Cheshire, U. K., 1995. (f) Ojima, I.; McCarthy, J . R.; Welch, J . T., Eds.
Biomedical Frontiers of Fluorine Chemistry; ACS Symposium Series
639; American Chemical Society: Washington, D.C., 1996.
(2) Davis, F. A.; Kasu, P. V. N.; Sundrababu, G.; Qi, H. J . Org. Chem.
1997, 62, 7546-7547.
(3) (a) Hoffman R. V.; Tao, J . Tetrahedron Lett., in press. (b) Enders,
D.; Potthoff, M.; Raabe, G.; Runsink, J . Angew. Chem., Int. Ed. Engl.
1997, 36, 2362-2364.
(4) Burkhart, M. D.; Zhang, Z.; Hung, S.-H.; Wong, C.-H. J . Am.
Chem. Soc. 1997, 119, 11743-11746.
(5) (a) Parisi, M. F.; Gattuso, G.; Noti, A.; Raymo, F. M.; Abeles, R.
H. J . Org. Chem. 1995, 60, 5174-5179. (b) Garret, G. S.; Emje, T. J .;
Lee, S. C.; Dyehouse, K.; McIver, J . M. J . Org. Chem. 1991, 56, 4823-
4826. (c) Parisi, M. F.; Abeles, R. H. Biochemistry 1992, 31, 9429-
9435.
(6) (a) Hoffman, R. V.; Kim, H.-O.; Wilson, A. L. J . Org. Chem. 1990,
55, 2820-2822. (b) Hoffman, R. V.; Wilson, A. L.; Kim, H.-O. J . Org.
Chem. 1990, 55, 1267-1270. (c) Hoffman, R. V.; Huizenga, D. J . J .
Org. Chem. 1991, 56, 6435-6439. (d) Hoffman, R. V.; Kim, H.-O. J .
Org. Chem. 1991, 56, 6759-6764. (e) Hoffman, R. V.; J ohnson, M. C.;
Okonya, J . F. J . Org. Chem. 1997, 62, 2458-2465. (f) Hoffman, R. V.;
J ohnson, M. C.; Okonya, J . F. Tetrahedron Lett. 1998, 39, 1283.
(7) Burk, M. J .; Allen, J . G.; Kiesman, W. F.; Stoffan, K. M.
Tetrahedron Lett. 1997, 38, 1309-1312 and references therein.
(8) (a) Shi, G.; Cao, Z.; Zhang, X. J . Org. Chem. 1995, 60, 6608-
6611. (b) Charvillon, F. B.; Amourox, R. Tetrahedron Lett. 1996, 37,
5103-5106. (c) Tsushima, T.; Kawada, K. Tetrahedron Lett. 1996, 37,
5103-5106.
(9) (a) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96,
1737-1755. (b) Tozer, M. J .; Herpin, T. F.Tetrahedron 1996, 52, 8619-
8683.
(10) (a) Guedj, R.; Ayi, A. I.; Remli, M. Ann. Chim. Fr. 1984, 9, 691-
694. (b) Ourari, A.; Condom, R.; Guedj, R. Can. J . Chem. 1982, 60,
2707-2710.
(11) Tsushima, T.; Kawada, K. Tetrahedron Lett. 1985, 26, 2445-
2448.
(12) (a) Blank, I.; Mager, J .; Bergmann, E. D. J . Chem. Soc. 1955,
2190-2193. (b) Nair, P. V.; Busch, H. J . Org. Chem. 1958, 23, 137-
139.
(13) (a) Tsushima, T.; Kawada, K.; Nishikawa, J .; Sato, T.; Tori, K.;
Tsuji, T.; Misaki, S. J . Org. Chem. 1984, 49, 1163-1169. (b) Tsushima,
T.; Nishikawa, J .; Sato, T.; Tanida, H.; Tori, K.; Tsuji, T.; Misaki,
S.; Suefuji, M. Tetrahedron Lett. 1980, 21, 3593-3594. (c) Tsushima,
T.; Kawada, K.; Tsuji, T.; Misaki, S. J . Org. Chem. 1982, 47, 1107-
1110.
(14) (a) Lal, G. S. J . Org. Chem. 1993, 58, 2791-2796. (b) Stavber,
S.; Zupan, M. Tetrahedron Lett. 1996, 37, 3591-3594. (c) Hoffman R.
V.; Saenz, J . E. Tetrahedron Lett. 1997, 38, 587-590.
(15) Creary, X.; Inocencio, P. A.; Underiner, T. L.; Kostromin, R. J .
Org. Chem. 1985, 50, 1932-1938.
S0022-3263(98)00676-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/15/1998

6410 J . Org. Chem., Vol. 63, No. 18, 1998
Notes
Sch em e 1
F igu r e 1. Chemical shifts for (E)- and (Z)-6a and their
nonfluorinated analogs (E)- and (Z)-7.
isolated and then fluorinated with Selectfluor in CH3CN
at room temperature for a period of 3.5-6 h. The
resulting 3-fluoro-2-ketoesters 3a -f were obtained in
generally high yields (Scheme 1). The isolated yields
(after purification by column chromatography and bulb-
to-bulb distillation) shown in Scheme 1 are a reflection
of the high volatility of most of the fluorides 3, particu-
larly 3e. The use of silyl enol ethers as fluorination
substrates was necessary because the amount of enoliza-
tion in R-ketoesters is insufficient for direct reaction with
Selectfluor and because Selectfluor is ineffective at
fluorinating highly reactive ketone enolates.14a
was obtained as a mixture of Z- and E-diastereoisomers
in the ratio of 5:2, respectively, as determined by 1H NMR
With a simple and practical synthesis of monofluoro-
R-ketoesters 3 in hand, their reactions could be examined
easily. In an attempt to prepare â-fluorinated didehydro-
amino acids, a relatively unknown class of compounds,8c,16
the condensation reaction of 3-fluoro-2-ketoesters 3 with
methyl carbamate and acetamide was investigated.
Treatment of 3-fluoro-2-ketoester 3a with excess methyl
carbamate (3 equiv) and catalytic p-TSA in refluxing
toluene provided the bis-carbamate adduct 5a as the
major product in 62% isolated yield (eq 1). A small
amount of the â-fluorinated didehydroamino ester 6a
(11% isolated yield) was produced as well.
of the crude product. The two diastereoisomers (Z)-6a
and (E)-6a were separable by column chromatography
(silica gel, EtOAc/hexanes, 1:4). The configuration of the
isomers (Z)-6a and (E)-6a were assigned based on the
following observations:
i. The same trends in melting points and chemical
shifts were seen in fluorinated derivatives 6 as for the
Z- and E-isomers of the nonfluorinated analogues 7
(Figure 1).18 The benzylic protons, the urethane N-H
proton, and the methylene protons of the ester ethoxy
group in (E)-7, which is an oil, all lie at lower field than
that of the corresponding protons in (Z)-7 which is a solid
with mp 72-73 °C. Of the isomers of 6a , one is an oil
with the chemical shifts of the benzylic protons, the
urethane N-H proton, and the methylene group of the
ester ethoxy group downfield from the corresponding
protons in the other isomer, which is a solid with mp 83
°C. Thus the oil is assigned as (Z)-6a , and the solid is
assigned as (E)-6a .
ii. This assignment is corroborated by the vicinal
fluorine-carbon coupling constants between the ester
carbonyl carbon and the vinylic fluorine atom. In the
3
F-coupled 13C NMR spectrum, isomer (Z)-6a had J C,F
)
The product distribution seen here contrasted with
that seen in the condensation reaction of nonfluorinated
analogues in which the bis-carbamate adduct and the
didehydroamino ester were obtained in the ratio of 4:6,
respectively.17 The difference in the product distribution
is a result of the enhanced electrophilicity of the central
carbon in the fluorinated 1,2,3-trisubstituted intermedi-
ates.
3
12.2 Hz while (E)-6a had J C,F ≈ 0 (slight broadening).
In the corresponding nonfluorinated didehydroamino acid
derivatives such as 7, it has been shown that the vicinal
coupling constant between the ester carbonyl carbon and
3
the vinyl hydrogen is J C,H ) 10 Hz for the E-isomer and
3J C,H )5.5 Hz for the Z-isomer. Thus the same trend in
coupling constants is seen for the fluorinated analogues
as for the protio compounds.18b
Using 1.0-1.5 equiv of methyl carbamate, the conden-
sation reaction provided only the â-fluorinated didehy-
droamino ester 6a in 47% yield (eq 2). Fluoro ester 6a
(iii) Although the chemical shifts of the benzylic
protons and the carbamate methoxy group protons are
very close in the spectrum of the E-isomer making the
use of NOE measurements to distinguish the two isomers
problematic, the data support the assignment shown
(Figure 2).
(16) (a) Wanner, M. J .; Hageman, J . J . M.; Koomen, G.-J .; Pandit,
U. K. J . Med. Chem. 1980, 23, 85-87. (b) Uneyama, K.; Kato, T.
Tetrahedron Lett. 1998, 39, 587-590. (c) Uneyama, K.; Yan, F.;
Hirama, S.; Karagiri, T. Tetrahedron Lett. 1996, 37, 2045-2048.
(17) Mellilo, D. G.; Larsen, R. D.; Mathre, D. J .; Shukis, W. F.; Wood,
A. W.; Colleluori, J . R. J . Org. Chem. 1987, 52, 5143-5150.
Addition of silver ion to the condensation reaction of
3a and methyl carbamate was used to test whether Ag+

Notes
J . Org. Chem., Vol. 63, No. 18, 1998 6411
is not. Since the same compounds can be produced more
efficiently from â-(nosyloxy)-R-ketoesters,6f this reaction
was not pursued further.
F igu r e 2. NOE measurements of (Z)- and (E)-6a .
could enhance the leaving ability of F and thereby
produce the corresponding oxazolones as observed for the
related â-nosyloxy-R-ketoesters.6f Interestingly, the con-
densation of 3a and methyl carbamate in the presence
of AgOTf provided only the Z-isomer of 3-fluoro-2-
Attempts to reduce 3-fluoro-2-aminoacrylate derivative
6a using NaCNBH316 or by catalytic hydrogenation with
Et-DuPHOS-Rh(I) as catalyst in order to produce â-fluoro-
R-amino esters have thus far been unsuccessful. Cata-
lytic hydrogenation of 6a over 10% Pd-C (catalyst:
substrate ratio of 1:4 by mass), H2 pressure of 50 psi, and
reaction time of 24 h led to only 5% conversion to product.
Under forcing conditions with a catalyst:substrate ratio
of 3:1 by mass, hydrogenation of 6a over 10% Pd-C at
H2 pressure of 50 psi and reaction time of 24 h provided
a 1:1 mixture of what appeared to be the corresponding
â-fluoro R-amino ester 10 and R-amino ester 11 (eq 5);
however, these compounds were not separated nor pur-
sued further.
1
aminoacrylate derivative 6a (as determined by H NMR
of the crude product).
This stereocontrol was found to be general for a series
3-fluoro-2-ketoesters 3a -d ,f (eq 3) which gave only the
Z-isomers of 6a -d ,f after refluxing with methyl carbam-
ate in toluene in the presence of p-TSA and AgOTf for a
period of 16-24 h. The 3-fluoro-2-aminoacrylate deriva-
tives 6 were obtained in fair to good yields, in part,
because the products were difficult to purify by column
chromatography. The stereocontrol wrought by Ag(I) in
this reaction was intriguing. Performing the reaction in
two steps, i.e., initial reflux (24 h) of 3-fluoro-2-ketoester
3a , methyl carbamate, and p-TSA in toluene followed by
addition of AgOTf and refluxing of the reaction mixture
for a further 24 h, provided the same 5:2 mixture of (Z)-
6a and (E)-6a as was obtained in the complete absence
of AgOTf. Clearly, AgOTf does not isomerize the E-
isomer of 6a to the Z-isomer. It is thus clear that the
stereocontrol exerted by silver ion occurs before the
dehydration of adduct 8 to the final product. One
explanation for this stereocontrol is that chelation of
silver ion with the fluorine atom and the carbamate
nitrogen produces a conformational bias which favors the
formation of the Z-isomer on dehydration.
Thus â-fluoro didehydroamino acids are remarkably
resistant to hydrogenation. While dehydroamino esters
and â-(silyloxy)-R,â-unsaturated esters are readily hy-
drogenated with a variety of chiral and achiral cata-
lysts,19 derivatives containing both an R-substituent and
a â-substituent each with lone pairs of electrons are
apparently poor substrates for catalytic hydrogenation.7,20
In summary, we have developed an efficient two-step
synthesis of 3-fluoro-2-ketoesters 3 from R-ketoesters 1
using Selectfluor as fluorinating reagent. 3-Fluoro-2-
ketoesters 3 were shown to condense with methyl car-
bamate in the presence of p-TSA, with or without AgOTf,
to provide â-fluorinated didehydroamino esters 6. The
efficiency of this approach is somewhat better than
results obtained by previously reported methods.8a Ste-
reocontrol using AgOTf can direct the stereoselectivity
of the condensation reaction leading to exclusive forma-
tion of the Z-isomer of 3-fluoro-2-aminoacrylate deriva-
tives 6. In contrast to carbamates, reaction of acetamides
with â-fluoro R-ketoesters and p-TSA provided oxazoles
9 instead of fluorinated didehydroamino esters.
Exp er im en ta l Section
In contrast to the good results obtained with methyl
carbamate, benzyl carbamate was found to be a poor
partner for the condensation reaction with 3-fluoro-2-
ketoester 3a , giving the corresponding [(benzyloxycar-
bonyl)amino]acrylate in low yield (22%).
Acetamide showed different reactivity with 3-fluoro-
2-ketoesters 3. When 3-fluoro-2-ketoesters 3a ,b, aceta-
mide, and p-TSA were refluxed in toluene for a period of
16-24 h, cyclocondensation to the oxazoles 9a ,b occurred,
rather than formation of the expected 3-fluoro-2-(acetyl-
amino)acrylate derivatives (eq 4). Apparently the nu-
cleophilicity of an amide carbonyl group is sufficient to
displace fluoride whereas the carbamate carbonyl group
Descriptions of instruments, general procedures, and chro-
matographic procedures have been described previously.6e
(18) Nitz, T. J .; Holt, E. M.; Rubin, B.; Stammer, C. H. J . Org. Chem.
1981, 46, 2667-2671. (b) Prokof′ev, E. P.; Karpeiskaya, E. I. Tetra-
hedron Lett. 1979, 737.
(19) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345 and
references therein.
(20) Enamides with â-oxygen substituents such as i are also very
resistant to hydrogenation.

6412 J . Org. Chem., Vol. 63, No. 18, 1998
Notes
Gen er a l P r oced u r e for t h e P r ep a r a t ion of Silyl E n ol
Eth er s 2.6e A solution of the R-ketoester (1, 29.1 mmol) and
chlorotrimethylsilane (3.73 g, 4.36 mL, 34.3 mmol) in anhydrous
THF (30 mL) was stirred at room temperature as triethylamine
(4.18 g, 5.76 mL, 41.3 mmol) was added dropwise. After 3.5 h
at room temperature, the mixture was diluted with pentanes
(≈50 mL) and filtered. The filtrate was washed with cold water
(2 × 50 mL) and with cold brine (1 × 50 mL). The organic layer
was dried (MgSO4) and evaporated under reduced pressure to
provide the crude silyl enol ether 2 as a clear yellow liquid in
quantitative yield. This material was used in the next step
without further purification:
purification by vacuum distillation (Kugelrohr, rt-40 °C/0.06
mmHg); 1H NMR δ 1.39 (t, J ) 7.3 Hz, 3H), 1.65 (dd, J H,F
)
23.6 Hz, J ) 7.1 Hz, 3H), 4.37 (q, J ) 7.2 Hz, 2H), 5.45 (dq, J H,F
) 48.3 Hz, J ) 7.0 Hz, 1H); 13C NMR δ 13.9, 17.1 (d, J C,F ) 21.3
Hz), 62.9, 89.7 (d, J C,F ) 180.5 Hz), 160.6, 191.3 (d, J C,F ) 23.0
Hz); IR (neat, including hydrate) 3484, 1735 br, 1054 cm-1
.
Meth yl 4-Ca r bom eth oxy-3-flu or o-2-oxobu ta n oa te (3f).
By the same procedure 1,3-dicarbomethoxy-1-(trimethylsilyloxy)-
propene (2f, 3.70 g, 15.0 mmol) was treated with Selectfluor (4,
5.32 g, 15.0 mmol). Monofluorinated R-ketoester 3f was obtained
as a clear yellow oil (1.45 g, 50%) following purification by bulb-
to-bulb distillation (150 °C, 0.10 mmHg). An analytical sample
of 3f was obtained upon further purification by flash chroma-
tography (EtOAc/CH2Cl2, 1:9): 1H NMR (0.4 ketoester and 0.6
hydrate) δ 2.84-3.27 (m, 2H, CH2-ketoester and hydrate), 3.74
(s, 1.2H, OCH3-ketoester), 3.75 (s, 1.8H, OCH3-hydrate), 3.90
(s, 1.8H, OCH3-hydrate), 3.94 (s, 1.2H, OCH3-ketoester), 4.60
(br s, 1H, OH-hydrate), 4.72 (br s, 1H, OH-hydrate), 5.17 (ddd,
J H,F ) 45.7 Hz, J ) 7.5 and 5.0 Hz, 0.6H, CHF-hydrate), 5.70
(ddd, J H,F ) 46.3 Hz, J ) 6.0 and 4.4 Hz, 0.4H, CHF-ketoester);
13C NMR (0.4 ketoester and 0.6 hydrate) δ 34.0 (d, J C,F ) 23.5
Hz, hydrate), 36.8 (d, J C,F ) 22.8 Hz, ketoester), 52.3, 52.6, 53.3,
53.8, 89.0 (d, J C,F ) 185.9 Hz, hydrate), 89.5 (d, J C,F ) 176.7
Hz, ketoester), 92.7 (d, J C,F ) 26.6 Hz), 160.4 (d, J C,F ) 1.6 Hz,
ketoester), 169.3, 170.7, 171.3 (d, J C,F ) 6.1 Hz, hydrate), 188.1
(d, J C,F ) 22.0 Hz, ketoester); IR (neat, ketoester + hydrate)
Eth yl 3-F lu or o-2-oxo-4-p h en ylbu ta n oa te (3a ). To a solu-
tion of 1-carbethoxy-1-(trimethylsilyloxy)-3-phenylpropene (2a ,
2.78 g, 10.0 mmol) in 25 mL of anhydrous acetonitrile under N2
was added 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane
bis(tetrafluoroborate) (Selectfluor, 4, 3.54 g, 10.0 mmol). The
mixture was stirred for 5 h at room temperature and monitored
by TLC (EtOAc/hexanes, 1:4). After the starting material was
gone, EtOAc (100 mL) was added to the reaction mixture, and
the solution was washed with saturated brine (2 × 60 mL). The
aqueous layer was extracted with EtOAc and the combined
organic layers were dried (MgSO4) and evaporated. The residue
was purified by column chromatography (hexanes: EtOAc, 4:1
to 2:1) to give the monofluorinated R-ketoester 3a as a clear
yellow oil (1.86 g, 83%). An analytical sample was prepared by
vacuum distillation (Kugelrohr, 145 °C/0.06 mmHg): 1H NMR
δ 1.36 (t, J ) 7.1 Hz, 3H), 3.12-3.37 (m, 2H), 4.33 (q, J ) 7.1
Hz, 2H), 5.61 (ddd, J H,F ) 48.3 Hz, J ) 8.2 and 4.0 Hz, 1H),
7.23-7.24 (m, 5H); 13C NMR δ 13.9, 37.7 (d, J C,F ) 20.5 Hz),
62.9, 93.2 (d, J C,F ) 185.8 Hz), 127.4, 128.6 (d, J C,F ) 7.6 Hz),
129.3, 134.5 (d, J C,F ) 1.5 Hz), 160.3, 190.2 (d, J C,F ) 23.5 Hz);
3467, 2960, 1746 (br) cm-1
0.6H2O: C, 41.43; H, 5.07. Found: C, 41.37; H, 4.84.
.
Anal. Calcd for C12H13O3F‚
Eth yl 2,2-Bis[(m eth oxycar bon yl)am in o]-3-flu or o-4-ph en -
ylbu ta n oa te (5a ). A mixture of ethyl 3-fluoro-2-oxo-4-phen-
ylbutanoate (3a , 0.670 g, 3.00 mmol), methyl carbamate (1.13
g, 15.0 mmol), and p-toluenesulfonic acid monohydrate (0.060
g, 0.30 mmol) in 60 mL of toluene was refluxed overnight. The
reaction mixture was cooled to room temperature, EtOAc (60
mL) was added, and the mixture was washed with water (2 ×
60 mL) and brine (60 mL), dried (MgSO4), and concentrated in
vacuo to provide a yellow solid. The crude product was chro-
matographed on a silica gel column eluting with CH2Cl2/EtOAc
(9:1) to provide the bis-carbamate adduct 5a as a white crystal-
line solid upon recrystallization from EtOAc/hexanes (0.667 g,
62%): mp 142-145 °C; 1H NMR δ 1.34 (t, J ) 7.1 Hz, 3H), 2.72-
3.50 (m, 2H), 3.64 (s, 3H), 3.66 (s, 3H), 4.35 (q, J ) 7.1 Hz, 2H),
5.44 (ddd, J H,F ) 47.3 Hz, J H,H ) 9.4 and 2.7 Hz, 1H), 6.40 (br
s, 1H), 6.49 (br s, 1H), 7.25 (m, 5H); 13C NMR δ 14.0, 36.2 (d,
J C,F ) 21.2 Hz), 52.3, 52.4, 63.4, 71.8 (d, J C,F ) 22.7 Hz), 92.4
(d, J C,F ) 188.9 Hz), 126.9, 128.6, 129.2, 136.2, 154.9, 155.3,
IR (neat) 1756, 1732, 1051 cm-1
. Anal. Calcd for C12H13O3F:
C, 64.28; H, 5.84. Found: C, 64.09; H, 5.81.
Eth yl 3-F lu or o-2-oxoocta n oa te (3b). By the same proce-
dure 1-carbethoxy-1-(trimethylsilyloxy)-1-heptene (2b, 3.75 g,
14.5 mmol) was treated with Selectfluor (4, 5.14 g, 14.5 mmol).
Monofluorinated R-ketoester 3b was obtained as a clear yellow
oil (2.77 g, 90%) following purification by vacuum distillation
1
(Kugelrohr, 85 °C/0.06 mmHg); H NMR δ 0.90 (t, J ) 6.0 Hz,
3H), 1.30-1.50 (m, 7H), 1.52 (t, J ) 7.0 Hz, 2H), 1.75-2.05 (m,
2H), 4.37 (q, J ) 7.1 Hz, 2H), 5.41 (ddd, J H,F ) 48.9 Hz, J ) 8.1
and 4.0 Hz, 1H); 13C NMR δ 13.74, 13.78, 22.2, 24.07, 24.09,
31.1 (d, J C,F ) 20.5 Hz), 62.7, 93.1 (d, J C,F ) 182.8 Hz), 160.6,
191.3 (d, J C,F ) 23.5 Hz); IR (neat) 1756, 1732, 1057 cm-1. Anal.
Calcd for C10H17O3F‚1/2H2O: C, 56.32; H, 8.51. Found: C, 56.38;
H, 8.56.
167.1; IR (KBr) 3415, 3317, 3100-2900, 1756, 1734, 1692 cm-1
;
Eth yl 3-F lu or o-5-m eth yl-2-oxoh exa n oa te (3c). By the
same procedure 1-carbethoxy-4-methyl-1-(trimethylsilyloxy)-1-
pentene (2c, 2.44 g, 10.0 mmol) was treated with Selectfluor (4,
3.54 g, 10.0 mmol). Monofluorinated R-ketoester 3c was ob-
tained as a clear yellow oil (1.70 g, 89%) following purification
by vacuum distillation (Kugelrohr, 75 °C/0.06 mmHg); 1H NMR
δ 0.99 (d, J ) 7.3 Hz, 3H), 1.19 (d, J ) 7.1 Hz, 3H), 1.40 (t, J )
7.1 Hz, 3H), 1.60-1.90 (m, 3H), 4.36 (q, J ) 7.1 Hz, 2H), 5.45
(ddd, J H,F ) 49.7 Hz, J ) 9.2 and 2.5 Hz, 1H); 13C NMR δ 13.9,
MS (ES+) 378.9 (M + Na)+. Fluoroaminoacrylate 6a was also
isolated as a yellow oil (0.090 g, 11%): Spectral characterization
identical with that given below.
(Z)-Eth yl 2-[(Meth oxyca r bon yl)a m in o]-3-flu or o-4-p h en -
yl-2-bu ten oa te (6a ). To ethyl 3-fluoro-2-oxo-4-phenylbutanoate
(3a , 0.66 g, 3.0 mmol) in toluene (60 mL) were added methyl
carbamate (0.22 g, 3.0 mmol), AgOTf (0.78 g, 3.0 mmol), and
p-toluenesulfonic acid monohydrate (0.06 g, 0.30 mmol). The
mixture was refluxed overnight then cooled to room temperature,
EtOAc (60 mL) was added, and the mixture was washed with
water (2 × 60 mL) and brine (60 mL), dried (MgSO4), and
concentrated in vacuo to provide a yellow solid. The crude
product was chromatographed on a silica gel column eluting with
CH2Cl2/EtOAc (97:3) to provide fluoroaminoacrylate (Z)-6a as
a yellow oil (0.41 g, 50%): 1H NMR δ 1.32 (t, J ) 7.1 Hz, 3H),
3.72 (s, 3H), 4.10 (d, J H,F ) 26.8 Hz, 2H), 4.30 (q, J ) 7.1 Hz,
2H), 5.96 (br s, 1H), 7.31 (m, 5H); 13C NMR δ 14.1, 35.7 (d, J C,F
) 22.0 Hz), 52.8, 61.7, 111.9 (d, J C,F ) 15.9 Hz), 127.1, 128.7,
21.4, 23.0, 24.7, 39.7 (d, J C,F ) 20.5 Hz), 62.8, 92.1 (d, J C,F
182.1 Hz), 160.6, 191.4 (d, J C,F ) 23.5 Hz); IR (neat) 1756, 1732,
1057 cm-1
Anal. Calcd for C9H15O3F: C, 56.83; H, 7.95.
)
.
Found: C, 56.64; H, 8.16.
Eth yl 3-F lu or o-4-m eth yl-2-oxop en ta n oa te (3d ). By the
same procedure 1-carbethoxy-3-methyl-1-(trimethylsilyloxy)-1-
butene (2d , 1.70 g, 7.40 mmol) was treated with Selectfluor (4,
2.62 g, 7.40 mmol). Monofluorinated R-ketoester 3d was ob-
tained as a clear yellow oil (0.900 g, 69%) following purification
by vacuum distillation (Kugelrohr, 45 °C/0.06 mmHg); 1H NMR
δ 0.97 (d, J ) 7.0 Hz, 3H), 1.11 (d, J ) 7.0 Hz, 3H), 1.38 (t, J )
7.1 Hz, 3H), 2.20-2.45 (m, 1H), 4.36 (q, J ) 7.1 Hz, 2H), 5.21
(dd, J H,F ) 48.5 Hz, J ) 3.8 Hz, 1H); 13C NMR δ 13.9, 15.8, 30.3
(d, J C,F ) 20.5 Hz), 62.7, 96.8 (d, J C,F ) 185.8 Hz), 161.0, 191.6
(d, J C,F ) 24.3 Hz); IR (neat) 1756, 1732, 1060 cm-1. Anal. Calcd
for C9H15O3F: C, 54.54; H, 7.44. Found: C, 54.77; H, 7.30.
Eth yl 3-F lu or o-2-oxobu ta n oa te (3e). By the same proce-
dure 1-carbethoxy-1-(trimethylsilyloxy)propene (2e, 90% purity,
2.02 g, 10.0 mmol) was treated with Selectfluor (4, 3.54 g, 10.0
mmol). Monofluorinated R-ketoester 3e was obtained as a
volatile clear yellow oil (0.66 g, 90% purity, 31% yield) following
128.8, 134.9, 154.5, 163.9 (d, J C,F ) 12.2 Hz), 164.0 (d, J C,F
270.8 Hz); IR (neat) 3322, 3100-2850, 1723 (br), 1650 cm-1
Anal. Calcd for 14H16NO4F: C, 59.78; H, 5.73; N, 4.98.
Found: C, 59.68; H, 5.58; N, 4.83.
)
.
C
Performing this reaction in the absence of AgOTf provided a
mixture of the E- and Z-isomers of 3a in the ratio of 5:2,
respectively, with a combined yield of 47%. The two isomers
were separated by column chromatography (EtOAc/hexanes, 1:4)
to give (Z)-6a as a yellow oil and (E)-6a : White needle-shaped
crystals, mp 84-85 °C; 1H NMR δ 1.28 (t, J ) 7.1 Hz, 3H), 3.73
(s, 3H), 3.79 (d, J H,F ) 18.3 Hz, 2H), 4.24 (q, J ) 7.1 Hz, 2H),
5.86 (d, J ) 3.4 Hz, 1H), 7.28 (m, 5H); 13C NMR δ 14.1, 36.3 (d,

Notes
J . Org. Chem., Vol. 63, No. 18, 1998 6413
J C,F ) 23.5 Hz), 52.9, 61.5, 111.0 (d, J C,F ) 29.6 Hz), 127.3, 128.7,
128.9, 134.0, 156.0, 163.3 (br, J C,F ) 0 Hz), 168.4 (d, J C,F ) 280.7
Hz)
Hz, 1H), 3.72 (s, 3H), 4.26 (q, J ) 7.2 Hz, 2H), 5.86 (br s, 1H);
13C NMR δ 14.0, 18.7, 28.4 (d, J C,F ) 21.3 Hz), 52.6, 61.3, 109.8
(d, J C,F ) 17.5 Hz), 154.6, 164.0 (d, J C,F ) 12.2 Hz), 169.9 (d,
J C,F ) 275.3 Hz); IR (neat) 3320, 2978-2850, 1723 (br), 1650
cm-1. Anal. Calcd for C10H16NO4F: C, 51.50; H, 6.9, N, 6.01.
Found: C, 51.49; H, 6.81; N, 6.07.
Eth yl 2-[(Meth oxyca r bon yl)a m in o]-3-flu or o-2-octen oa te
(6b). By the same procedure ethyl 3-fluoro-2-oxooctanoate (3b,
0.31 g, 1.5 mmol) in toluene (30 mL) was condensed with methyl
carbamate (0.11 g, 1.5 mmol) in the presence of AgOTf (0.39 g,
1.5 mmol) and p-toluenesulfonic acid monohydrate (0.030 g, 0.15
mmol). The crude product was chromatographed on a silica gel
column eluting with CH2Cl2/EtOAc (97:3) to provide fluoroami-
noacrylate 6b as a yellow oil (0.30 g, 70%): 1H NMR δ 0.90 (t,
J ) 7.0 Hz, 3H), 1.30 (t, J ) 7.1 Hz, 3H), 1.33 (m, 4H), 1.65 (m,
2H), 2.75 (dt, J H,F ) 26.4 Hz, J H,H ) 7.5 Hz, 2H), 3.73 (s, 3H),
4.26 (q, J ) 7.1 Hz, 2H), 5.90 (br s, 1H); 13C NMR δ 13.9, 14.1,
22.3, 25.9, 29.7 (d, J C,F ) 22.0 Hz), 31.1, 52.7, 61.4, 111.1 (d,
2-Meth yl-4-car beth oxy-5-ben zyloxazole (9a). By the same
procedure ethyl 3-fluoro-2-oxo-4-phenylbutanoate (3a , 0.33 g, 1.5
mmol) in toluene (30 mL) was condensed with acetamide (0.09
g, 1.5 mmol) in the presence of p-toluenesulfonic acid monohy-
drate (0.030 g, 0.15 mmol). The crude product was chromato-
graphed on a silica gel column eluting with CH2Cl2/EtOAc (9:1)
to provide oxazole 9a as a clear yellow oil (0.18 g, 49%): 1H NMR
δ 1.40 (t, J ) 7.2 Hz, 3H), 2.42 (s, 3H), 4.34 (s, 2H), 4.40 (q, J )
7.2 Hz, 2H), 7.29 (m, 5H); 13C NMR δ 13.7, 14.3, 31.9, 60.9, 126.9,
128.6, 128.7, 136.3, 157.4, 160.1, 162.2; IR (neat) 3100-2850,
1750, 1708, 1616 cm-1. Anal. Calcd for C14H15NO3•0.4H2O: C,
66.6; H, 6.31; N, 5.55. Found: C, 66.85; H, 6.10; N, 5.72.
2-Meth yl-4-car beth oxy-5-pen tyloxazole (9b). By the same
procedure ethyl 3-fluoro-2-oxo-octanoate (3b, 0.62 g, 3.0 mmol)
in toluene (60 mL) was condensed with acetamide (0.18 g, 3.0
mmol) in the presence of p-toluenesulfonic acid monohydrate
(0.060 g, 0.30 mmol). The crude product was chromatographed
on a silica gel column eluting with CH2Cl2/EtOAc (9:1) to provide
oxazole 9b as a clear yellow oil (0.24 g, 36%): 1H NMR δ 0.90
(t, J ) 6.6 Hz, 3H), 1.35 (m, 4H), 1.39 (t, J ) 7.1 Hz, 3H), 1.67
(m, 2H), 2.45 (s, 3H), 2.99 (t, J ) 7.6 Hz, 2H), 4.37 (q, J ) 7.1
Hz, 2H); 13C NMR δ 13.7, 13.8, 14.3, 22.2, 25.8, 27.4, 31.2, 60.7,
126.9, 159.3, 160.0, 162.3; IR (neat) 2960, 2933, 2872, 1750, 1713,
J C,F ) 16.7 Hz), 154.6, 164.1 (d, J C,F ) 12.2 Hz), 167.5 (d, J C,F
)
272.4 Hz); IR (neat) 3336, 3100-2850, 1723 (br), 1650 cm-1
.
Anal. Calcd for C12H20NO4F: C, 55.16; H, 7.72; N, 5.36.
Found: C, 55.39; H, 7.46; N, 5.45.
Eth yl 2-[(Meth oxyca r bon yl)a m in o]-3-flu or o-5-m eth yl-2-
h exen oa te (6c). By the same procedure ethyl 3-fluoro-5-
methyl-2-oxohexanoate (3c, 1.14 g, 6.00 mmol) in toluene (120
mL) was condensed with methyl carbamate (0.440 g, 6.00 mmol)
in the presence of AgOTf (1.56 g, 6.00 mmol) and p-toluene-
sulfonic acid monohydrate (0.120 g, 0.600 mmol). The crude
product was chromatographed on a silica gel column eluting with
CH2Cl2/EtOAc (97:3) to provide fluoroaminoacrylate 6c as a
yellow oil (0.62 g, 42%): 1H NMR δ 0.99 (d, J ) 6.6 Hz, 6H),
1.31 (t, J ) 7.2 Hz, 3H), 2.04 (m, 1H), 2.66 (dd, J H,F ) 27.2 Hz,
J H,H ) 7.2 Hz, 2H), 3.73 (s, 3H), 4.25 (q, J ) 7.2 Hz, 2H), 5.87
(br s, 1H); 13C NMR δ 14.1, 22.2, 26.7, 38.3 (d, J C,F ) 21.2 Hz),
52.7, 61.3, 111.8 (d, J C,F ) 15.9 Hz), 154.6, 164.1 (d, J C,F ) 12.2
Hz), 166.8 (d, J C,F ) 272.3 Hz); IR (neat) 3330, 2961-2850, 1724
(br), 1650 cm-1. Anal. Calcd for C11H18NO4F: C, 53.43; H, 7.34;
N, 5.66. Found: C, 53.60; H, 7.37; N, 5.41.
Eth yl 2-[(Meth oxyca r bon yl)a m in o]-3-flu or o-4-m eth yl-2-
p en ten oa te (6d ). By the same procedure ethyl 3-fluoro-4-
methyl-2-oxopentanoate (3d , 0.820 g, 4.65 mmol) in toluene (95
mL) was condensed with methyl carbamate (0.380 g, 4.65 mmol)
in the presence of AgOTf (1.19 g, 4.65 mmol) and p-toluene-
sulfonic acid monohydrate (0.0900 g, 0.465 mmol). The crude
product was chromatographed on a silica gel column eluting with
CH2Cl2/EtOAc (97:3) to provide fluoroaminoacrylate 6d as a
yellow oil (0.470 g, 43%): 1H NMR δ 1.18 (d, J ) 7.0 Hz, 6H),
1.31 (t, J ) 7.2 Hz, 3H), 3.58 (dm, J H,F ) 27.5 Hz, J H,H ) 7.0
1615 cm-1
. Anal. Calcd for C12H19NO3: C, 63.98; H, 8.5; N,
6.22. Found: C, 64.17; H, 8.62; N, 6.01.
Ack n ow led gm en t. This work was supported by a
grant from the National Science Foundation (CHE
9520431). M.C.J . was the recipient of of a Graduate
Fellowship from the Air Force Graduate Fellowship
Program.
Su p p or t in g In for m a t ion Ava ila b le: 13C spectra of 5a
and (E)-6a (2 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O9806761