Limitations of the Wittig-Horner-type annulation of fluorobutenolide moiety to 3-hydroxyquinoline-2,4(2H,3H)-diones. Novel modifications of the Perkow reaction including fluorinated acyloxy leaving groups

Article abstract of DOI:10.1016/j.tet.2007.07.058

3-(Fluoroacyloxy)quinoline-2,4(1H,3H)-diones react with triethyl phosphite to afford either the product of the Perkow reaction or the corresponding 4-ethoxyquinolin-2(1H)-one. In both reactions, the fluorocarboxylate anion acts as the leaving group. For t

Full text of DOI:10.1016/j.tet.2007.07.058

Tetrahedron 63 (2007) 10549–10561
Limitations of the Wittig–Horner-type annulation of fluoro-
butenolide moiety to 3-hydroxyquinoline-2,4(2H,3H)-
diones. Novel modifications of the Perkow reaction
including fluorinated acyloxy leaving groups
b
b
c
c
Karel Pomeisl,a, Jaroslav Kvıcala, Oldrich Paleta, Antonın Klasek, Stanislav Kafka,
*
ˇ
ꢀꢁ
ꢀ
ꢀ
ꢁ
d
d
e
ꢀꢁ
Vladislav Kubelka, Jaroslav Havlıcek and Jan Cejka
aInstitute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
Flemingovo naꢀm. 2, 166 10 Prague, Czech Republic
bDepartment of Organic Chemistry, Prague Institute of Chemical Technology, Technickaꢀ 5, 166 28 Prague 6, Czech Republic
cEnviromental Department of Chemistry and Environmental Technology, Tomaꢀꢁs Bat’a University,
Naꢀm. TGM 275, 762 72 Zlꢀın, Czech Republic
dZentiva, U Kabelovny 130, 102 37 Prague 10, Czech Republic
eDepartment of Solid State Chemistry, Prague Institute of Chemical Technology, Technickaꢀ 5, 166 28 Prague 6, Czech Republic
Received 26 January 2007; revised 29 June 2007; accepted 19 July 2007
Available online 26 July 2007
Dedicated to Professor Miloslav Ferles on the occasion of his 85th birthday
Abstract—3-(Fluoroacyloxy)quinoline-2,4(1H,3H)-diones react with triethyl phosphite to afford either the product of the Perkow reaction or
the corresponding 4-ethoxyquinolin-2(1H)-one. In both reactions, the fluorocarboxylate anion acts as the leaving group. For the corresponding
3-(fluoroiodoacetoxy) derivative this observation precludes the application of the intramolecular Wittig–Horner synthesis to modify quino-
line-2,4(1H,3H)-diones by the annulation of a fluorinated but-2-enolide moiety.
Ó 2007 Elsevier Ltd. All rights reserved.
O
O
1. Introduction
O
OH
Substituted quinoline-2,4(1H,3H)-diones (A) as metabolites
of some Pseudomonas species exhibited interesting bioac-
tivity1 initiating the search for novel classes of non-steroidal
anti-inflammatory agents based on the lead structure A.2 As
a g-lactone moiety attached to an aromatic cycle system
showed strong anti-inflammatory activity,3 some substituted
3-hydroxyquinoline-2,4(1H,3H)-diones were modified by
the annulation of the but-2-enolide cycle (type B).4 The
annulation was carried out by the Wittig strategy at C-4-
carbonyl group using (ethoxycarbonylmethylene)-triphenyl-
phosphorane or more conveniently at C-3-hydroxyl group
via 3-(bromoacetoxy)derivative and the subsequent 3-(2-
triphenylphosphonioacetoxy)derivative.4
R2
O
R2
N
N
O
R1
R1
A
B
A further modification of the properties of the compounds B
can be carried out by the introduction of halogen atoms and
groups in the butenolide moiety. Fluoro substituents, such as
F, CF3 or OCF3 are powerful modifiers of chemical and bi-
ological properties of organic compounds.5 A combination
of fluorine substituents with but-2-en-4-olide cycle could
thus afford compounds with new and interesting bioactivity.6
Wittig–Horner-type reactions have been applied to the syn-
theses of monofluorinated butenolide compounds using flu-
orohalogenoacetates as the building blocks affording the
desired products in good yields.7 The reactions proceeded
with complete stereoselectivity resulting in configurations
suitable for the subsequent cyclization.7a,b
Keywords:Wittig–Hornersynthesis;Lithium2-(diethoxyphosphoryl)-2-fluo-
roacetate; 3-Halogenoacyloxyquinoline-2,4(1H,3H)-diones; Fluorofura-
none; But-2-enolide, Perkow reaction; 19F NMR reaction profile;
Cytostatic activity; Chronic myeloid leukemia; Breast carcinoma.
* Corresponding author. Tel.: +420 220 183 475; fax: +420 220 183 560;
e-mail: pomeisl@uochb.cas.cz
However, when 1-benzyl-3-butyl-3-(fluoroiodoacetoxy)qui-
noline-2,4(1H,3H)-dione (9a) was reacted with triethyl
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.058

10550
K. Pomeisl et al. / Tetrahedron 63 (2007) 10549–10561
phosphite the unexpected product 17a (Scheme 3) was ob-
tained instead of the assumed Wittig–Horner intermediate
10a (Scheme 2). The formation of the product 17a corre-
sponds to a novel modification of the Perkow reaction.8 As
is known from the literature, the Wittig–Horner synthesis9
cannot be applied when a carbonyl group is present in the
a-position relative to the carbon–halogen bond, because
enol phosphites are formed instead of phosphonates accord-
ing to the general equation of the Perkow reaction (1).10a
On the other hand, the intermolecular synthesis involving
ethyl (triphenylphosphoranylidene)acetate4a afforded the
non-cyclizable (E)-4-(ethoxycarbonyl)methylene derivative
5 (yield 68%) and only negligible amount (ca. 0.5%) of
the desired 4a (Scheme 1).
In contrast, the analogous reaction of 1a with the Wittig–
Horner reagent, alkyl (diethoxyphosphoryl)fluoroacetate,
proceeded with only low conversion of starting material to
form desired products with cyclizable configuration (vide
infra).7b,12
P(OR)2
CH
Perkow
reaction
X
O
C
O
C
R1
A
CH
R1
A
ð1Þ
In the synthesis of the desired 5-fluorofuro[2,3-c]quinoline-
2,4-(3aH,5H)-diones 8a,b (Scheme 2), the Wittig–Horner
intramolecular strategy involving 2-fluoro-2-iodoacetate 9a
was also unsuccessful, because the (diethoxyphosphoryl)-
fluoroacetate 10a was not formed. Instead, an unexpected
product corresponding to a novel modification of the Perkow
reaction was obtained (vide infra). In the intermolecular
strategy, the reaction of the acetates 6a,b with lithium salt
of ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate7b,12 af-
forded directly the final products 8a,b (Scheme 2), as the
Wittig–Horner products (E)-7a,b cyclized rapidly, but the
yields of 8a,b were surprisingly very low (ca. 2 and 16%,
respectively).
+
+
P(OR)3
X
R
Halogenated ketones, diketones, aldehydes, esters, amides,
acyl halides,10a,b polycyclic compounds,10c,d a-halogenoni-
troalkanes,10a and 1,3-dichloro-1,1,3,3-tetrafluoroacetone10e
react in this manner. The leaving groups in halogeno com-
pounds are halogen anions. In one case, the Perkow reaction
with an acetoxy leaving group has been reported in the
chemistry of D-fructose.11
In this paper, we report our findings on the limitations of a
Wittig–Horner-typefluorobutenolideannulationto3-hydroxy-
quinoline-2,4(2H,3H)-diones and approach our observations
of novel modifications of the Perkow reaction, in which
halogenated acyloxy anions are the new leaving groups.
O
O
OH
OAc
R2
O
a
R2
O
N
R1
N
R1
2. Results and discussion
6a-b
1a-b
b
Firstly, we attempted the annulation of the but-2-en-4-olide
cycle to 1-benzyl-3-butyl-3-hydroxy-quinoline-2,4(2H,3H)-
dione (1a). The recently reported procedures4 used the in-
tramolecular Wittig-type synthesis (Scheme 1): The reaction
of 1a with bromoacetyl bromide afforded bromoacetyl de-
rivative 2a, which was transformed to phosphonium salt
3a by reaction with triphenylphosphane. Compound 3a
was difficult to purify for analyses, because it was spontane-
ously converted to 4a at room temperature. However, the
subsequent treatment of 3a with 0.5 M NaOH results in
the complete closure to obtain the target furo[2,3-c]quino-
line-2,4(3aH,5H)-dione 4a.
O
C
O
O
F
F
OEt
OAc
R2
O
R2
N
R1
O
N
R1
8a-b
7a-b
derivatives a, R1 = CH2Ph, R2 = Bu
derivatives b, R1 = Me, R2 = Ph
CHF
(EtO)2P
O
CHFI
O
O
Intramolecular strategy
O
C
C
O
EtOOC
O
N
O
O
O
OH
d
O
R2
O
OH
R2
O
c
Bu
O
CH2Ph
d
Bu
R2
O
1a
+
N
O
N
N
N
CH2Ph
R1
R1
R1
10a
9a
4a
5
1a
Scheme 2. Reagents and conditions: (a) AcCl, Py, CH2Cl2, ꢀ20 ꢁC to rt, 73–
82%; (b) (EtO)2P(O)CHFC(O)OEt, n-BuLi, THF, ꢀ78 ꢁC; (c) IFHC-
C(O)Cl, Py, CH2Cl2, 48%; (d) P(OEt3), toluene, D.
a
c
Intermolecular
strategy
+
CH2PPh3
O
O
CH2Br
O
O
-
Br
To obtain further information about the reaction course, the
reaction mixture leading potentially to 8a,b was monitored
O
O
b
R2
O
R2
O
19
by F NMR within the interval of ꢀ70 to 25–35 ꢁC (Figs.
N
N
R1
R1
1–3). As shown in Figure 1, fluorophosphonate 11 was com-
pletely converted to its lithium salt 12 (19F NMR signal
ꢀ229.1 ppm) by n-butyllithium at ꢀ70 ꢁC, while at higher
temperatures the portion of the unreacted 11 increased
with increasing temperature.
2a
3a
1a, 2a, 3a, 4a, 5, R1 = CH2Ph , R2 = Bu
Scheme 1. Reagentsandconditions:(a)BrCH2C(O)Br, 65%;(b)PPh3, C6H6,
D, 61%; (c) aq 0.5 M NaOH, CHCl3, 52%; (d) Ph3P]CHC(O)OEt, D, 68%.

K. Pomeisl et al. / Tetrahedron 63 (2007) 10549–10561
10551
Figure 1. 19F NMR temperature profile (ꢀ70 ꢁC to >rt) of the equilibrium of fluorophosphonate 11 and its lithium salt 12 (w89% content in the mixture).
A temperature profile of the reaction mixture of lithium
phosphonate 12 and 6a (Scheme 2) is depicted in Figure 2.
The 19F NMR signal of 8a (ꢀ144.1 ppm) did not occur at
temperatures below ꢀ10 ꢁC and only patterns of 8a could
be observed in the reaction mixture. At higher temperatures,
phosphonate salt 12 was decomposed (ꢀ201.2 ppm, 13) and
therefore the product 8a was formed only in a small yield.
mixture after 2 h 45 min reaction: phosphonate was com-
pletely decomposed and the product 8b was present in
a low concentration. These results are in contrast with the
relatively easy reactions employing the Wittig reagents in
the preparation of 4a (Scheme 1).
We have mentioned above (Scheme 2) that 2-fluoro-2-iodo-
acetyl derivative9a, which was formed by the treatment of 1a
with fluoroiodoacetyl chloride, afforded an unexpected
product in the reaction with triethyl phosphite. This com-
pound is enol phosphate 17a as depicted in Scheme 3. Its
A similar temperature profile was observed for the reaction
of lithium phosphonate 12 and quinolinedione 6b (Scheme
2, Fig. 3). The last scan corresponds the state of the reaction
Figure 2. 19F NMR temperature profile (ꢀ70 ꢁC to >rt) of the reaction of lithium fluorophosphonate 12 with 3-acetoxyquionoline-2,4-dione 6a to afford the
target 8a (w2% content in the mixture).

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K. Pomeisl et al. / Tetrahedron 63 (2007) 10549–10561
Figure 3. 19F NMR temperature profile (+10 to >+35 ꢁC) of the reaction of fluorophosphonate 12 with 3-acetoxyquionoline-2,4-dione 6b to afford the target 8b
(w16% content in the mixture).
R3
formation has corresponded a new modification of the
R3
O
O
O
O
O
Perkow reaction involving 2-fluoro-2-iodoacetate anion
(CHFICOOꢀ) as the leaving group. Departure of acetate
ion in the Perkow reaction has been observed only once be-
fore in the reaction of pentaacetylated D-fructose with tri-
methyl phosphite.11 This rather unusual transformation
may be attributed to the structural nature of the sugar skele-
ton and its multiple acetoxy groups. Surprisingly, we have
found that the 3-acetoxyquinoline-2,4(1H,3H)-diones 6a,b
bearing acetoxy group did not react (Table 1, entries 2 and
3). Thus, we assumed that acyloxy groups having a higher
electronegativity than the acetyloxy group could act as leav-
ing groups in the new modification of the Perkow reaction.
O
H
O
O
a
a
R2
O
R2
O
Ph
O
N
N
R1
N
R1
CH3
1a-d
9a,14a-15a;16a,c-d
15b,16b
c
b
c
EtO
EtO
O
O
P
O
O
OEt
Br
R2
O
O
Bu
O
Ph
O
N
N
N
R1
CH2Ph
CH3
We prepared a series of 3-(halogenoacyloxy)quinoline-
2,4(1H,3H)-diones, viz. 14a–c, 15a,b, and 16a–d to study
their ability to act as the leaving groups. The results of the
study are summarized in Scheme 3 and Table 1 (entries 5–
13). According to Scheme 3, the reactions of 2a, 14a–c,
15a,b, and 16a–d afforded three kinds of products: the prod-
ucts of the Perkow reaction (17a–d), 1-methyl-4-ethoxyqui-
nolin-2(1H)-one (18) and the compound 19 possessing an
annulated furanone moiety. In the first two reactions, the halo-
carboxylate anion was eliminated. The role of halocarboxy-
lates as leaving groups in the Perkow reaction is previously
undescribed feature. In both the reactions shown in the
Scheme 3, the elimination of the acyloxy moiety results in
energetically favored extension in conjugation of the p-
system of the heterocyclic cycle. In the reactions of the
halogenoacyl derivatives, the carbonyl groups in the acyl
R3–CO or at C-4 of the heterocyclic cycle are attacked by
the phosphorus atom of triethyl phosphite (Scheme 4).
Also in the reaction of the fluoroiodoacetyl derivative 9a, tri-
ethyl phosphite attacks C-4 of the heterocyclic cycle to form
18
2a
17a-d
c
EtO
O
EtO
P
O
O
1a, 17a, R1 = CH2Ph, R2 = Bu
1b, 17b, R1 = Me, R2 = Ph
1c, 17c, R1 = Ph, R2 = Me
1d, 17d, R1 = Me, R2 = CH2Ph
9a, R1 = CH2Ph, R2 = Bu, R3 = CHFI
14a, R1 = CH2Ph, R2 = Bu, R3 = CF3
14b, R1 = Me, R2 = Ph, R3 = CF3
14c, R1 = Ph, R2 = Me, R3 = CF3
Bu
O
N
CH2Ph
19
15a, R1 = CH2Ph, R2 = Bu, R3 = CClF2-CClF
15b, R1 = Me, R2 = Ph, R3 = CClF2-CClF
16a, R1 = CH2Ph, R2 = Bu, R3 = C3F7O-CF(CF)CF2O-CF(CF)
3
3
16b, R1 = Me, R2 = Ph, R3 = C3F7O-CF(CF)CF2O-CF(CF)
3
3
16c, R1 = Ph, R2 = Me, R3 = C3F7O-CF(CF)CF2O-CF(CF)
3
3
16d, R1 = Me, R2 = CH2Ph, R3 = C3F7O-CF(CF3)CF2O-CF(CF3)
Scheme 3. Reagents and conditions: (a) R3–C(O)X, Py, CH2Cl2; (b)
BrCH2C(O)Cl, Py, C6H6, 65%; (c) P(OEt), toluene, D, 11–68%(see Table 1).

K. Pomeisl et al. / Tetrahedron 63 (2007) 10549–10561
10553
Table 1. Reaction of halogenoacyl-substituted quinoline-2,4(1H,3H)-diones with triethyl phosphite
Entry
Starting compound
R2
Product
Yielda (%)
No.
R1
Leaving group R3-COO(ꢀ)
No.
1
2
3
4
5
6
7
8
2a
6a
6b
9a
14a
14b
14c
15a
15b
16a
16b
16c
16d
Bn
Bn
Me
Bn
Bn
Me
Ph
Bn
Me
Bn
Me
Ph
Bu
Bu
Ph
Bu
Bu
Ph
Me
Bu
Ph
Bu
Ph
Me
Bn
CH2Br
CH3
CH3
CHFI
CF3
CF3
CF3
CClF2–CClF
CClF2–CClF
C3F7O–CF(CF3)–CF2O–CF(CF3)
C3F7O–CF(CF3)–CF2O–CF(CF3)
C3F7O–CF(CF3)–CF2O–CF(CF3)
C3F7O–CF(CF3)–CF2O–CF(CF3)
19b
—
52
—
—
68
36
36
31
—
27
18
11
21
54
—
17a
17a
17b
17c
—
18
17a
18
9
10
11
12
13
17c
17d
Me
a
Isolated unoptimized yields.
The structure of 19 was determined by NMR and X-ray analysis (see Supplementary data).
b
A
B
C
better access to the less
access to the more
acces to the C-4 carbonyl group
Arbuzov reaction
D
shielded C-4 carbonyl group
reactive C-3 carbonyl group
directed with trifluoroacetate
as a powerful leaving group
EtO
EtO
O
Rf
EtO P
O
CH2Br
O
CF3
O
N
EtO
O
Rf
EtO
P
O
N
O
EtO
O
O
N
OEt
OEt
O
O
P
O
OEt
O
O
N
O
O
CH3
CH2Ph
CH3
16d
CH3
14b
2a
16b
2 (EtO)3P
toluene,reflux
EtO
OEt
(EtO)3P
EtO
leaving group disconnection
from benzylic-type carbon
O
EtO
P
EtO
P
O
P
EtO
O
O
+
R
H
(-)
f
O
O
CF3
O
OEt
O
OEt
O
O
O
CH
O
O
+
O
Ph
(-)
P
N
O
O
R
N
O
f
CH3
O
N
O
20
CH3
22
CH2Ph
24
N
CH3
O
Wittig-Horner intermediate
Claisen-type condensation
23
O
O
EtO
EtO
EtO
P
P
EtO
O
O
R
O
f
Ph
EtO
Et
O
EtO
P
O
O
O
Ph
O
N
CH3
O
H
Ph
HO
O
N
O
17b
N
CH3
21
Bu
CH3
N
O
18
CH2Ph
25
O
O
EtO
EtO
P
Rf = C3F7-O-CF(CF3)-CF2-O-CF(CF3)
O
EtO
Ph
EtO
P
O
O
N
CH3
O
17d
Bu
O
N
CH2Ph
19
Scheme 4. The proposed mechanisms of the modified Perkow reaction and Claisen-type condensation.

10554
K. Pomeisl et al. / Tetrahedron 63 (2007) 10549–10561
Perkow product instead of corresponding product of Arbuzov
reaction as is usual for the alkyl fluoroiodoacetates.7b
formation of the intermediate 24 to 25 can be understood
as a Claisen-type condensation.15
As the acetoxy derivatives 6a or 6b did not react at all (Table
1, entries 2 and 3) it can be inferred that the new reactions
(Scheme 1) require the presence of a stronger electron-
withdrawing acyl group. Halogenated acyloxy groups pos-
sess a more reactive carbonyl group and as such are better
leaving groups. Perhaps the increase in reactivity of the
C-4-carbonyl group is also due to halogenated acyloxy
group. In any case, the two carbonyl groups are preferential
reaction sites for the attack by the phosphorus atom of
triethyl phosphite in compounds 9a and 14–16 (Scheme 4).
The obtained enol phosphates 17a–d as products of the Per-
kow reaction displayedasignificantcytostaticactivityincells
K-562 (chronic myeloid leukemia) and MCF7 (breast carci-
noma) compared with olomoucine as the most frequently ex-
amined cyclin-dependent kinase (CDK) inhibitor together
with roscovitine16 (Table 2, entries 1–4). The results also in-
dicate that compounds 17a–c exhibit a comparable or even
a better cytostatic activity (inhibition of the cell growth
invitro) toward leukemic K-562 cells compared with roscovi-
tine, while the bioactivity of these compounds toward breast
carcinoma MCF7 is less sensitive. The most promising anti-
proliferative potency is exerted by compound 17a. On the
other hand, the bioactivity of phosphonate 19 decreased by
annulationoftherigidbut-2-enolidemoiety(Table2, entry5).
The directing factors of the phosphite attack to form the enol
phosphates 17a–d, the usual products of the Perkow reac-
tion, or the unusual Perkow product 18 may be formulated
as follows: as the Perkow reaction leading to the Perkow
products 17a–d was observed for all the compounds that
possess an aliphatic (butyl, methyl) or benzyl substituent
at C-3 (9a, 14a–c, and 16a,c,d). The nucleophilic attack
then occurs at the cycle C-4 carbonyl group. (Scheme 4;
see pathway A). The proposed mechanism for compound
16d via intermediates 20 and 21 featuring the fluorinated
acyloxy leaving group corresponds to proposed mecha-
nisms10a,d,13 of the Perkow reaction. In contrast, the product 18
is most likely the result of an attack of the acyl-carbonyl
moiety in the derivatives 15b and 16b (Scheme 4; see path-
way B). Both compounds possess a rigid phenyl substituent
at C-3. In the case of 15b or 16b, the triethyl phosphite nucleo-
phile attacks the more reactive carbonyl carbon in the ester
group, which is probably less shielded or its reactivity in-
creased by a different electronic effect of phenyl substituent
in contrast to, e.g., butyl or benzyl.14 However, if this idea is
correct, 14b should be rather transformed to 18 than 17b via
intermediate 22 (Scheme 4, see pathway C). We have no ex-
planation for the unexpected outcome but note that trifluoro-
acetate is a particularly good substituted acetate leaving
group. This may exert a powerful effect on the outcome of
the Perkow reaction.
Table 2. Bioactivity of enol phosphates 17 and 19
Entry
Product
R1
IC50/mmol Lꢀ1
K-562a MCF7b
No.
R2
1
2
3
4
17a
17b
17c
17d
19
Bn
Me
Ph
Me
Bn
Bu
Ph
Me
Bn
Bu
9.6
68.5
32.4
100.3
18.1
134.5
45.4
92.3
>167
5
>167
Olomoucine
Roscovitine
150
45
134
12
a
Chronic myeloid leukemia.
Breast carcinoma.
b
3. Conclusions
The reactions reported in this paper show that the applica-
tion of the Horner–Wadworth–Emmons strategy for the
annulation of the a-fluorobut-2-enolide cycle to hetero-
(poly)cyclic systems may completely fail from two reasons:
first, due to the low reactivity of lithium (diethoxyphos-
phoryl)-fluoroacetate reagent toward 3-acetyloxyquinoline-
2,4(1H,3H)-dione substrates as verified by 19F NMR study;
second, trialkyl phosphite attacks preferentially highly
reactive carbonyl groups in 3-(fluoroiodoacetoxy)quino-
line-2,4(1H,3H)-diones to afford the product of the Perkow
reaction. We have found that analogously reacted a number
of 3-(fluoroacyloxy)quinoline-2,4(1H,3H)-diones. Thus, we
developed the method for preparation of a new class of
bioactive quinoline-2-one enol phosphates from easily avail-
able quinoline-2,4(1H,3H)-dione building blocks.
An analogous mechanism to the formation of product 18 via
23 featuring fluoride anion as a leaving group was proposed
(reported) previously for the reaction of perfluorinated ali-
phatic ketones with trialkyl phosphites.10e The products
17a–d and 18 were obtained in isolated yields of 18–68%
and 11–27% (Table 1), owing in part to the difficulties
with their separation. In fact, the reactions reached almost
complete conversions of the starting acyloxy compounds
9–16 after 2–26 h, and the isolated products 17a–d or 18
were the major or exclusive compounds in the reaction mix-
tures according to TLC analyses. From this point of view, the
presented reactions included only unoptimized yields.
4. Experimental
An unexpected product 19 possessing an annulated furanone
moiety (Scheme 3) was obtained in the reaction of bromo-
acetyl derivative 2a with triethyl phosphite in boiling toluene.
Its formation could be explained by a lower reactivity of the
carbonyl groups in the acyl R3–CO and at C-4 of the hetero-
cyclic cycle, which are not attacked by the phosphorus atom
of triethyl phosphite. The hypothetical intermediates 24,25
and the proposed mechanism for formation of product 19
are depicted in Scheme 4 (see pathway D). The trans-
4.1. General comments
Melting points were determined on a Kofler block and are un-
corrected. NMR spectra were measured on a Bruker WP 80
SY (FT, 19F at 75.4 MHz), Bruker 400 AM (FT, 19F at
376.5 MHz, 31P at 202.5 MHz) and Gemini 300 (1H at
300.1 MHz, 13C at 75.5 MHz using 1H decoupling) in
CDCl3 and tetrahydrofuran-d8, respectively. Chemical
shifts are reported relative to tetramethylsilane,

K. Pomeisl et al. / Tetrahedron 63 (2007) 10549–10561
10555
fluorotrichloromethane, and phosphorous acid as internal
4.4. 1-Benzyl-3-butyl-2,4-dioxo-1,2,3,4,-tetrahydroqui-
nolin-3-yl bromoacetate (2a)
standards. IR spectra were recorded on a FTIR Spec. Nicolet
740 in CHCl3. Mass spectra were scanned on a Autospec
Ultima (Micromass) using GC (HP 6890, ionization with
electron impact at 70 eV) and ZAB-EQ (VG Analytical)
spectrometers using FAB (ionization with xenon, accelerat-
ing voltage 8 kV, glycerol matrix). Preparative TLC was
carried out on 45ꢂ18ꢂ0.4 cm loose layer on silica gel con-
taining UV indicator (system S1).
To a solution of 1a (1.62 g, 5.0 mmol) in benzene (15 mL)
was added a solution of pyridine (830 mg, 10.5 mmol) in
benzene (5 mL) and a solution of 2-bromoacetyl bromide
(2.12 g, 10.5 mmol) in benzene (5 mL). The resulting mix-
ture was stirred at room temperature for 14 h. After complete
conversion of 1a (TLC, 20% benzene/EtOAc), the precipi-
tate was filtered off and the filtrate was evaporated to dryness
in vacuo. Purification of the crude product by crystallization
with xylene/methanol gave 2a (1.45 g, 65%) as white nee-
dles, mp 142–145 ꢁC. Found: C, 59.22; H, 4.95; N, 3.12.
C22H22O4NBr requires: C, 59.47; H, 4.99; N, 3.15%. Rf
(20% EtOAc/benzene) 0.67; nmax (CHCl3) 1711, 1673,
1601 cmꢀ1; dH (300.1 MHz, CDCl3) 0.86 (3H, t, J 7.1 Hz),
1.29 (2H, m, J 7.3 Hz), 1.36–1.52 (2H, m), 2.07 (2H, ddd,
J 14.0, 9.3, 6.9 Hz), 4.05 (2H, s), 5.26 (1H, d, J 16.5 Hz),
5.33 (1H, d, J 16.5 Hz), 7.04 (1H, d, J 8.2 Hz), 7.14 (1H, t,
J 7.5 Hz), 7.21–7.40 (6H, m), 7.49 (1H, dt, J 8.0, 1.7 Hz),
8.00 (1H, dd, J 8.0, 1.4 Hz); dC (75.5 MHz, CDCl3) 14.3,
23.0, 25.2, 36.8, 25.4, 47.0, 87.5, 116.9, 124.3, 127.1,
128.3, 129.4, 129.8, 137.2, 121.1, 136.2, 142.6, 167.3,
169.7, 190.8.
Chemicals used were as follows: quinoline-2,4-diones
ꢀꢁ
ꢀ
1a–d were obtained from Tomas Bat’a University (Zlın,
Czech Republic). Ethyl 2-(diethoxyphosphoryl)-2-
fluoroacetate was prepared by several reactions from
trifluorochloroethylene.7b,17–19
2,5-Bis(trifluoromethyl)-
2,4,4,5,7,7,8,8,9,9,9-undecafluoro-3,6-dioxanonanoyl fluo-
ride was synthesized as described in Ref. 20 and
distilled at 115–117 ꢁC. 2,3,3-Trifluoro-2,3-dichloropropa-
noyl chloride was prepared as described in Ref. 21 and
distilled at 86–88 ꢁC. Standard chemicals were purchased
from Sigma–Aldich (Czech Republic). Pyridine, tetrahy-
drofuran, and methylene chloride were dried and purified
according to standard procedures. 2-Fluoro-2-iodoacetyl
chloride was prepared by the hydrolysis of ethyl 2-fluo-
ro-2-iodoacetate followed by the treatment of correspond-
ing 2-fluoro-2-iodoacetatic acid with thionyl chloride.22
The products were isolated in low preparative yields prob-
ably due to losses caused by difficulties in purification.
From this point of view, the reactions report only unopti-
mized yields (vide infra).
4.5. {2-[(1-Benzyl-3-butyl-2,4-dioxo-1,2,3,4-tetrahydro-
quinolin-3-yl)oxycarbonyl]methyl}(triphenyl)phospho-
nium bromide (3a)
A suspension of 2a (1.32 g, 2.97 mmol) and triphenylphos-
phane (857 mg, 3.27 mmol) was refluxed in benzene
(10 mL) for 3 h. After 15 min, the suspension became clear
and after 20 min a precipitate was formed. After cooling, the
precipitate of the product was filtered off and the filtrate was
refluxed for 3 h. Another portion of the crude product con-
tained a variable quantity of butenolide 4a (according to
TLC, 20% benzene/EtOAc), which was then filtered off to
give 3a (1.29 g, 61%) as a white amorphous solid. Found:
C, 67.80; H, 5.41; N, 1.77. C40H37O4NBrP requires: C,
67.99; H, 5.28; N, 1.98%. Rf (20% EtOAc/benzene) 0.00;
nmax (CHCl3) 3438, 2959, 2929, 1739, 1706, 1673, 1601,
1470, 1436, 1111, 756, 691 cmꢀ1; dH (300.1 MHz, CDCl3)
0.80 (3H, t, J 6.6 Hz), 1.11–1.29 (4H, m), 1.79–1.96 (2H,
m), 5.05 (1H, d, J 16.5 Hz), 5.26 (1H, d, J 16.5 Hz), 5.33
(1H, dd, J 30.2, 14.3 Hz), 5.47 (1H, dd, J 31.3, 16.5 Hz),
6.94–7.97 (24H, m); dC (75.5 MHz, CDCl3) 14.2, 23.0,
25.2, 36.7, 32.4 (d, J 56.1 Hz), 46.8, 87.4, 116.6, 117.5,
118.7, 116.8, 124.4, 127.1, 128.3, 129.4, 129.7, 137.2,
131.0, 131.2, 136.0, 120.9, 129.1, 142.2, 164.4, 170.0, 189.8.
4.2. Synthesis of 2-fluoro-2-iodoacetic acid
A flask (500 mL) was charged with ethyl 2-fluoro-2-iodoace-
tate (60 g, 0.26 mol) and phenolphthalein (0.4 mL). A solu-
tion of 5% aq sodium hydroxide (11.4 g, 0.28 mol) was
added dropwise to the reaction mixture at room temperature
until a colorless residue was obtained. The mixturewas acidi-
fied with concentrated HCl to pH 2. The resulting homoge-
nous solution was extracted with ether (2ꢂ50 mL). The
organic layer was dried over anhydrous magnesium sulfate.
The solvent was evaporated in vacuo. The residue was crys-
tallized from methylene chloride/light petroleum to give 2-
fluoro-2-iodocetic acid (8.6 g, 16%) as white needles, mp
76–79 ꢁC. Found: C, 12.17; H, 1.13; F, 9.40. C2H2O2FI re-
quires: C, 11.78; H, 0.99; F, 9.32%. nmax (CCl4) 3517, 3120,
3040, 2898, 2743, 2636, 2549, 2477, 1793, 1743, 1245, 1154,
1083, 917 cmꢀ1; dH (300.1 MHz, CDCl3) 7.20 (1H, d, J
51.1 Hz), 11.13 (1H, s); dC (75.5 MHz, CDCl3) 55.9 (J
264 Hz), 173.2 (J 25 Hz); dF (75.4 MHz, CDCl3) ꢀ162.1
(d, J 50.7 Hz).
4.6. 5-Benzyl-3a-butyl-furo[2,3-c]quinoline-
2,4(3aH,5H)-dione (4a)
4.3. 2-Fluoro-2-iodoacetic chloride
A solution of 3a (1.25 g, 1.77 mmol) in chloroform (20 mL)
was shaken with 0.5 M sodium hydroxide (7.1 mL,
3.53 mmol) in a separatory funnel for 5 min. The mixture
was then set aside for 20 min. The aqueous layer was sepa-
rated and extracted with chloroform (2ꢂ10 mL). The com-
bined organic layers were washed with water (5 mL) and
dried with anhydrous sodium sulfate. The solvent was then
evaporated to dryness in vacuo. Purification of the crude
product by crystallization with benzene/hexane gave 4a
(322 mg, 52%) as white needles, mp 172–174 ꢁC. Found:
A mixture of 2-fluoro-2-iodoacetic acid (8.4 g, 41 mmol)
and thionyl chloride (17 g, 0.20 mol) in methylene chloride
(9 mL) was heated to reflux for 25 h. After removal of
thionyl chloride and methylene chloride at 78 ꢁC under
low pressure (99 mmHg), purification of the crude product
by distillation gave 2-fluoro-2-iodoacetic chloride (3.1 g,
34%) as a deep red liquid, bp 69–70 ꢁC/95 mmHg; dH
(300.1 MHz, CDCl3) 7.26 (1H, d,
J 51.7 Hz); dF
(75.4 MHz, CDCl3) ꢀ149.2 (d, J 51.8 Hz).

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K. Pomeisl et al. / Tetrahedron 63 (2007) 10549–10561
C, 76.63; H, 6.35; N, 3.86. C22H21O3N requires: C, 76.36; H,
6.09; N, 4.03%. Rf (20% EtOAc/benzene) 0.56; nmax
(CHCl3) 3437, 3101, 2954, 2927, 1745, 1700, 1640, 1467,
1209, 775 cmꢀ1; dH (300.1 MHz, CDCl3) 0.81 (3H, t, J
7.1 Hz), 1.16–1.41 (4H, m), 1.68–1.82 (1H, m), 2.14–2.29
(1H, m), 4.86, 5.51 (2H, 2ꢂd, J 16.2, 15.9 Hz), 6.10 (1H,
s), 7.05 (1H, d, J 8.2 Hz), 7.12–7.45 (7H, m), 7.56 (1H, d,
J 7.4 Hz); dC (75.5 MHz, CDCl3) 14.3, 22.8, 25.2, 38.1,
47.3, 87.5, 117.2, 113.0, 124.8, 127.1, 127.9, 128.4, 129.8,
133.8, 118.0, 136.6, 139.5, 163.4, 168.1, 171.7.
2932, 2876, 1744, 1712, 1679, 1602, 1469, 1374, 1247,
700 cmꢀ1; dH (300.1 MHz, CDCl3) 0.86 (3H, t, J 7.1 Hz),
1.18–1.52 (4H, m), 1.91–2.17 (2H, ddd, J 19.8, 8.3,
7.2 Hz), 2.25 (3H, s), 5.22 (1H, d, J 16.5 Hz), 5.38 (1H, d,
J 15.9 Hz), 7.03 (1H, d, J 8.8 Hz), 7.13 (1H, t, J 7.5 Hz),
7.20–7.38 (5H, m), 7.47 (1H, t, J 7.7 Hz), 8.01 (1H, d, J
7.7 Hz); dC (75.5 MHz, CDCl3) 14.3, 20.9, 23.1, 25.3,
36.7, 46.9, 84.6, 116.8, 124.1, 127.0, 128.2, 129.3, 129.7,
136.9, 121.2, 136.4, 142.6, 170.5, 171.2, 191.7.
4.8.2. 1-Methyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-
quinolin-3-yl acetate (6b). Yield, 157 mg (82%) as white
needles (benzene/methanol), mp 149–152 ꢁC. Found: C,
69.63; H, 4.94; N, 4.23. C18H15O4N requires: C, 69.81; H,
4.89; N, 4.63%. Rf (20% EtOAc/benzene) 0.72; nmax
(CHCl3) 3025, 1742, 1715, 1679, 1605, 1474, 1359, 1247,
685 cmꢀ1; dH (300.1 MHz, CDCl3) 2.30 (3H, s), 3.57 (3H,
s), 7.18 (1H, t, J 7.4 Hz), 7.20 (1H, d, J 8.8 Hz), 7.28–7.49
(5H, s), 7.64 (1H, t, J 8.0 Hz), 7.99 (1H, d, J 7.7 Hz); dC
(75.5 MHz, CDCl3) 21.0, 30.8, 85.6, 116.0, 121.3, 124.3,
127.4, 129.6, 129.8, 130.6, 133.2, 137.3, 143.4, 169.0,
171.4, 190.0.
4.7. Reaction of 1-benzyl-3-butyl-3-hydroxy-1,2,3,4-tet-
rahydroquinolin-2,4-dione (1a) with ethyl 2-(triphenyl-
phosphoranylidene)acetate (products 4a and 5)
A mixture of 1a (1.62 g, 5.0 mmol) and ethyl 2-(triphenyl-
phosphoranylidene)acetate (1.91 g, 5.5 mmol) in xylene
(15 mL) was heated to reflux for 4 h. After cooling, the mix-
ture was purified by chromatography on silica gel (benzene
and 95% benzene/EtOAc). Compound 5 was then crystal-
lized from benzene.
4.7.1. 5-Benzyl-3a-butyl-furo[2,3-c]quinoline-2,4(3aH,5H)-
dione (4a). Yield, 9 mg (0.5%) of white amorphous solid.
NMR data were identical to above-mentioned compound
(see Section 4.6).
4.9. The stability study of lithium salt of ethyl 2-(dieth-
oxyphosphoryl)-2-fluoroacetate (12) using 19F NMR at
temperature gradient
4.7.2. Ethyl (E)-[1-benzyl-3-butyl-3-hydroxy-2-oxo-2,3-
dihydroquinoline-4(1H)-ylidene]acetate (5). Yield, 1.23 g
(68%) of white needles, mp 72–74 ꢁC. Found: C, 73.26; H,
6.92; N, 3.56. C24H27O4N requires: C, 72.95; H, 6.91; N,
3.72%. Rf (20% EtOAc/benzene) 0.82; nmax (CHCl3) 3363,
2978, 2953, 2868, 1714, 1669, 1628, 1600, 1466, 1179 cm;ꢀ1
dH (300.1 MHz, CDCl3) 0.80 (3H, t, J 7.1 Hz), 1.10–1.44 (4H,
m), 1.24(3H,t,J7.1 Hz),1.63(2H,t, J8.2 Hz), 4.08(1H,brs),
4.17 (2H, q, J 7.1 Hz), 4.78 (1H, d, J 15.9 Hz), 5.52 (1H, d, J
16.5 Hz), 6.52 (1H, s), 6.93 (1H, d, J 8.2 Hz), 7.08 (1H, t, J
7.7 Hz), 7.16–7.41 (6H, m), 7.66 (1H, d, J 7.7 Hz); dC
(75.5 MHz, CDCl3) 14.3, 14.6, 23.1, 25.7, 38.8, 48.6, 61.1,
77.0, 116.4, 124.2, 126.9, 128.3, 129.7, 131.0, 131.5, 123.0,
137.0, 138.5, 167.1, 173.8.
A flask (25 mL) was charged with ethyl 2-(diethoxyphos-
poryl)-2-fluoroacetate (150 mg, 0.62 mmol) in dry tetrahy-
drofuran (3 mL) and cooled under argon to ꢀ78 ꢁC. A
solution of n-butyllithium in hexane (2.5 M, 0.71 mmol)
was added dropwise to the flask with stirring. A NMR tube
was charged with dry tetrahydrofuran-d8 (200 mL) and
cooled under argon to ꢀ78 ꢁC. After 20 min of stirring,
a sample of resulting reaction mixture including a lithium-
fluorophosphonate salt was rapidly withdrawn by a pre-
cooled syringe (300 mL), added to a cooled NMR tube and
the 19F NMR spectrum was taken while cooling. The reac-
tion temperature was stepwise increased from ꢀ70 to +35 ꢁC
and the NMR analysis was carried out. dF (75.4 MHz,
CDCl3) ꢀ229.1 (1F, br s at ꢀ70 ꢁC). The content of the com-
pounds in the reaction mixture was determined by 19F NMR
and are as follows [time (min)/temperature (ꢁC)/13 (rel %)/
12 (rel %)]: 20/ꢀ70/0/100; 31/ꢀ35/0/100; 42/ꢀ15/7/93; 67/
5/10/90; 85/25/11/89; 100/35/11/89.
4.8. Synthesis of quinoline-2,4-diones 6a,b: general
procedure
To a mixture of 1a,b (0.62 mmol) and pyridine (68.5 mg,
0.87 mmol) in methylene chloride (3 mL) was added drop-
wise at 0 ꢁC acetyl chloride (2.81 mmol). After warming
to room temperature, the mixture was stirred for 14 h and
then diluted with methylene chloride (20 mL) and shaken
with 0.1 N HCl (5 mL). The water layer was extracted
with chloroform (2ꢂ10 mL), the combined extracts were
washed with sodium hydrogen carbonate solution (2 mL)
and water (2 mL) and dried over magnesium sulfate. Meth-
ylene chloride was then removed in vacuo and the products
6a,b were crystallized (the solvent is indicated for each
compound).
4.10. Wittig–Horner reaction of quinoline-2,4-diones
6a,b with lithium salt of ethyl 2-(diethoxyphosphoryl)-2-
fluoroacetic acid (12) using 19F NMR at temperature
gradient: general procedure
A NMR tube was charged with ethyl 2-(diethoxyphos-
phoryl)-2-fluoroacetate (25 mg, 105 mmol) in dry tetrahy-
drofuran (300 mL) and tetrahydrofuran-d8 (200 mL) and
cooled under nitrogen to ꢀ78 ꢁC. A solution of n-butyl-
lithium in hexane (2.5 M, 172 mmol) was added dropwise
to the flask with stirring. After 20 min of stirring, the 19F
NMR spectrum was taken while cooling. The quinoline-
2,4-dione 1a or 1b (100 mmol) was dissolved in tetra-
hydrofuran and the resulting solution was added to the
cooling mixture. The reaction temperature was stepwise
increased from ꢀ70 to +35 ꢁC and the NMR analysis was
carried out.
4.8.1. 1-Benzyl-3-butyl-2,4-dioxo-1,2,3,4-tetrahydroqui-
nolin-3-yl acetate (6a). Yield, 160 mg (73%) as white nee-
dles (methanol), mp 122–125 ꢁC. Found: C, 72.74; H, 6.65;
N, 3.51. C21H23O4N requires: C, 72.51; H, 6.36; N, 3.83%.
Rf (20% EtOAc/benzene) 0.80; nmax (CHCl3) 3027, 2962,

K. Pomeisl et al. / Tetrahedron 63 (2007) 10549–10561
10557
4.10.1. 5-Benzyl-3a-butyl-1-fluorofuro[2,3-c]quinoline-
2,4(3aH,5H)-dione (8a). The conversion of 1a to butenolide
8a was approximatelyw2% at 25–35 ꢁC. After 188 min, the
mixture contained only the decomposed Wittig–Horner re-
agent. Butenolide 8a was characterized in the mixture by
19F NMR. dF (75.4 MHz, CDCl3) ꢀ144.1 (s); m/z (EI) 365
(25%, M+). HRMS (EI): M+, found 365.1419; C22H20FNO3
requires 365.1421. The content of the compounds in the re-
action mixture was determined by 19F NMR and are as fol-
lows [time (min)/temperature (ꢁC)/8a (rel %)/12 (rel %)]:
24/ꢀ70 to 50/0/100; 70/ꢀ50/0/68; 108/ꢀ30/0/49; 143/10/
0/44; 188/35/w2/36.
4.12.1. 1-Benzyl-3-butyl-2,4-dioxo-1,2,3,4-tetrahydro-
quinolin-3-yl 2,2,2-trifluoroacetate (14a). The reaction of
1a (100 mg, 0.70 mmol) with pyridine (112 mg, 1.42 mmol)
and trifluoroacetic anhydride (300 mg, 1.42 mmol) afforded
after evaporation of solvents a residue containing the crude
unstable compound 14a in quantitative yield (according to
TLC, 20% EtOAc/benzene). The product was used in the
Perkow reaction (see Section 4.13.4) without further purifi-
cation. Rf (20% EtOAc/benzene) 0.74; dF (376.5 MHz,
CDCl3) ꢀ75.07 (s); m/z (EI) 419 (4, M+), 305 (13), 234
(4), 214 (5), 180 (4), 91 (100), 65 (9%).
4.12.2. 1-Methyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-
quinolin-3-yl 2,2,2-trifluoroacetate (14b). The reaction of
1b (100 mg, 0.37 mmol) with pyridine (112 mg, 1.42 mmol)
and trifluoroacetic anhydride (300 mg, 1.42 mmol) afforded
after evaporation of solvents a residue containing the crude
unstable product 14b in quantitative yield (according to
TLC, 20% EtOAc/benzene). The product was used in the
Perkow reaction (see Section 4.13.5) without further purifi-
cation. Rf (20% EtOAc/benzene) 0.75; dF (376.5 MHz,
CDCl3) ꢀ75.17 (s); m/z (FAB) 364 (60%, MH+).
4.10.2. 1-Fluoro-5-methyl-3a-phenyl-furo[2,3-c]quino-
line-2,4(3aH,5H)-dione (8b). The conversion of 1b to bute-
nolide 8b was approximately 16% at +35 ꢁC. After 166 min,
the reaction contained only the decomposed Wittig–Horner
reagent. Butenolide 6b was characterized in the mixture
by 19F NMR. dF (75.4 MHz, CDCl3) ꢀ148.1 (s); m/z (EI)
309 (11%, M+); HRMS (EI): M+, found 309.0820;
C18H12FNO3 requires 309.0801. The content of the com-
pounds in the reaction mixture were determined by 19F
NMR and were as follows [time (min)/temperature (ꢁC)/8b
(rel %)/12 (rel %)]: 300/ꢀ70 to 10/0/100; 314/10/0/100;
331/35/0.4/95; 366/35/16/43; 496/35/16/0.
4.12.3. 3-Methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydro-
quinolin-3-yl 2,2,2-trifluoroacetate (14c). The reaction of
1c (100 mg, 0.37 mmol) with pyridine (112 mg, 1.42 mmol)
and trifluoroacetic anhydride (300 mg, 1.42 mmol) afforded
after evaporation of solvents a residue containing the crude
unstable product 14c in quantitative yield (according to
TLC, 20% EtOAc/benzene). The product was used in the
Perkow reaction (see Section 4.13.6) without further purifi-
cation. Rf (20% EtOAc/benzene) 0.79; dF (376.5 MHz,
CDCl3) ꢀ75.10 (s); m/z (FAB) 364 (22%, MH+).
4.11. 1-Benzyl-3-butyl-2,4-dioxo-1,2,3,4-tetrahydro-
quinolin-3-yl 2-fluoro-2-iodoacetate (9a)
To a mixtureof 1a(300 mg, 0.93 mmol) and pyridine (92 mg,
1.12 mmol) in methylene chloride (5 mL) was added
dropwise at ꢀ20 ꢁC fluoroiodoacetyl chloride (329 mg,
1.48 mmol). After warming to room temperature, the mixture
was stirred for 14 h. Methylene chloride was then removed in
vacuo. Purification of the crude product by chromatography
on neutral aluminum oxide (20% EtOAc/benzene) gave 9a
(227 mg, 48%) as a white amorphous solid. Found: C,
51.52; H, 4.22; N, 24.78. C22H21FINO4 requires: C, 51.88;
H, 4.16; N, 24.92%. Rf (20% EtOAc/benzene) 0.82; dH
(300.1 MHz, CDCl3) 0.86 (3H, t, J 7.1 Hz), 1.29 (2H, m, J
7.3 Hz), 1.42 (2H, pent, J 7.8 Hz), 1.97–2.23 (2H, m), 5.32
(1H, d, J 16.5 Hz), 5.36 (1H, d, J 16.5 Hz), 7.06 (1H, dd, J
8.2, 2.2 Hz), 7.16 (1H, dt, J 7.7, 2.2 Hz), 7.20–7.40 (5H, m),
7.37 (1H, d, J 51.1 Hz), 7.51 (1H, m), 8.0 (1H, dd, J 7.7,
1.7 Hz); dC (75.5 MHz, CDCl3) 14.3, 23.0, 25.3, 36.9, 47.1,
56.4 (J 263.4 Hz), 86.4, 116.9, 124.5, 127.1, 128.4, 129.5,
129.8, 137.3, 121.0, 136.1, 142.6, 165.9 (J 28.3 Hz), 169.0,
190.6; dF (376.5 MHz, CDCl3) ꢀ162.50 (d, J 50.7 Hz); m/z
(EI) 306 (52; M+ꢀCHFICOO), 277 (11), 266 (15), 234 (5),
208 (7), 146 (5), 103 (2), 91 (100), 77 (5), 67 (16%).
4.12.4. 1-Benzyl-3-butyl-2,4-dioxo-1,2,3,4-tetrahydro-
quinolin-3-yl 2,3,3-trifluoro-2,3-dichloropropanoate
(15a). The reaction of 1a (100 mg, 0.31 mmol) with pyridine
(293 mg, 3.60 mmol) and 2,3,3-trifluoro-2,3-dichloropropa-
noyl chloride (782 mg, 3.63 mmol) afforded ester 15a
(123 mg, 79%) as a slightly yellow oil. Found: C, 55.29;
H, 4.31; N, 2.88. C23H20Cl2F3NO4 requires: C, 55.00; H,
4.01; N, 2.79%. Rf (20% EtOAc/benzene) 0.91; dH
(300.1 MHz, CDCl3) 0.87 (3H, t, J 7.1 Hz), 1.31 (2H, m, J
7.1 Hz), 1.44 (2H, m), 2.04–2.27 (2H, m), 5.31 (1H, s),
7.08 (1H, d, J 8.2 Hz), 7.17 (1H, t, J 7.7 Hz), 7.22–7.36
(5H, m), 7.52 (1H, t, J 7.9 Hz), 8.00 (1H, d, J 7.7 Hz); dC
(75.5 MHz, CDCl3) 14.3, 22.0, 24.6, 36.7, 47.1, 86.4,
98.7–103.0 (m), 116.9, 119.8–128.4 (m), 121.0, 124.3,
127.1, 128.2, 129.4, 129.8, 137.1, 121.0, 136.2, 142.6,
165.5 (J 28.1 Hz), 170.0, 191.6. dF (376.5 MHz, CDCl3)
2ꢂdiastereoisomers, ds1 (50% rel), ds2 (50% rel): ꢀ64.3,
ꢀ66.6 (2F, ds1, 2ꢂdd, J 171.2, 6.6, 12.7 Hz), ꢀ64.3,
ꢀ66.6 (2F, ds2, 2ꢂdd, J 171.2, 6.6, 12.7 Hz), ꢀ72.8 (2F,
ds1+ds2, t, J 9.3 Hz); m/z (EI) 501 (2, M+), 305 (15), 262
(7), 214 (8), 146 (7), 91 (100), 57 (10%); HRMS (EI): M+,
found 501.0735; C23H20Cl2F3NO4 requires 501.0721.
4.12. Synthesis of quinoline-2,4-diones 14a–16d: general
procedure
To a mixture of 1a–d and pyridine in methylene chloride
(5 mL) was added dropwise at 0 ꢁC acyl agent (see Sections
4.12.1–4.12.9). After warming to room temperature, the
mixture was stirred for 14 h. Methylene chloride was then
removed (rotary evaporator) and the crude product was puri-
fied by flash chromatography on neutral aluminum oxide
(20% EtOAc/benzene, see Sections 4.12.4–4.12.9) or used
in the Perkow reaction without further purification (see
Sections 4.12.1–4.12.3).
4.12.5. 1-Methyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-
quinolin-3-yl 2,3,3-trifluoro-2,3-dichloropropanoate
(15b). The reaction of 1b (100 mg, 0.37 mmol) with pyri-
dine (293 mg, 3.60 mmol) and 2,3,3-trifluoro-2,3-dichloro-
propanoyl chloride (775 mg, 3.60 mmol) afforded the
crude ester 15b (162 mg, 98%) as a slightly yellow oil.

10558
K. Pomeisl et al. / Tetrahedron 63 (2007) 10549–10561
Found: C, 51.33; H, 2.98; N, 3.38. C19H12Cl2F3NO4 re-
quires: C, 51.14; H, 2.71; N, 3.14%. Rf (20% EtOAc/benz-
ene) 0.88; dH (300.1 MHz, CDCl3) 3.57 (3H, d, J 4.4 Hz),
7.19 (2H, m), 7.40 (5H, m), 7.63 (1H, t, J 7.7 Hz), 7.98
(1H, d, J 6.6 Hz); dC (75.5 MHz, CDCl3) 30.8, 84.0, 98.7–
103.0 (m), 115.8, 119.7–128.8 (m), 121.3, 124.4, 127.4,
129.7, 129.8, 130.6, 133.2, 134.0–140.5 (m), 143.2, 164.5
(J 28.5 Hz), 171.4, 191.3; dF (376.5 MHz, CDCl3) 2ꢂ
diastereoisomers, ds1 (34% rel), ds2 (66% rel): ꢀ64.2, ꢀ66.6
(2F, 2ꢂdd, ds1, J 171.3, 9.2, 11.5 Hz), ꢀ64.3, ꢀ66.6
(2F, 2ꢂdd, ds2, J 171.3, 7.1, 11.3 Hz), ꢀ72.8 (2F,
ds1+ds2, t, J 9.6 Hz); m/z (EI) 445 (7, M+), 266 (78), 250
(10), 222 (13), 151 (5), 105 (100), 77 (43), 51 (10%);
HRMS (EI): M+, found 445.0089; C19H12Cl2F3NO4 requires
445.0095.
171.4, 193.0; dF (376.5 MHz, CDCl3) 2ꢂdiastereoisomers,
ds1 (50% rel), ds2 (50% rel): ꢀ79.7 (2F, ds1+ds2, m, J
150.6 Hz), ꢀ80.4 (6F, ds1+ds2, m), ꢀ81.9 (6F, ds1+ds2,
m), ꢀ82.4 (6F, ds1+ds2, m, J 15.4 Hz), ꢀ82.9 (2F, ds1,
2ꢂd, J 150.6 Hz), ꢀ83.6 (2F ds2, 2ꢂd, J 150.6 Hz),
ꢀ130.0 (6F, ds1+ds2, 2ꢂs), ꢀ132.7 (1F, ds1, dd, J 20.3 Hz),
132.9 (1F, ds2, m), ꢀ145.1 (1F, ds1, t, J 21.8 Hz), ꢀ145.5
(1F, ds2, dd, J 21.1 Hz); m/z (EI) 250 (31, M+ꢀC3F7CF-
(CF3)CF2OCF(CF3)COO), 266 (100), 222 (23), 194 (3),
169 (28, C3F+7), 152 (4), 125 (4), 105 (85, PhCO+), 77
(28), 69 (32, CF3+), 51 (7%, CHF2+); HRMS (EI): ds1
M+ꢀC3F7CF(CF3)CF2OCF(CF3)COO, found 250.0855;
C16H12NO2 requires 250.0870; ds2 M+ꢀC3F7CF(CF3)-
CF2OCF(CF3)COO, found 250.0862; C16H12NO2 requires
250.0870.
4.12.6. 1-Benzyl-3-butyl-2,4-dioxo-1,2,3,4-tetrahydro-
quinolin-3-yl 2,5-bis(trifluoromethyl)-2,4,4,5,7,7,8,8,
9,9,9-undecafluoro-3,6-dioxanonanoate (16a). The reac-
tion of 1a (100 mg, 0.31 mmol) with pyridine (21.5 mg;
0.27 mmol) and 2,5-bis(trifluoromethyl)-2,4,4,5,7,7,8,8,
9,9,9-undecafluoro-3,6-dioxanonanoyl fluoride (164 mg,
0.33 mmol) afforded 16a (245 mg,w100%) as a slightly yel-
low oil. Found: C, 43.23; H, 2.38; N, 1.68. C29H20F17NO6
requires: C, 43.46; H, 2.51; N, 1.75%. Rf (20% EtOAc/benz-
ene) 0.93; dH (300.1 MHz, CDCl3) 0.87 (3H, t, J 7.1 Hz),
1.29 (2H, m), 1.43 (2H, m), 2.14 (2H, m), 5.30 (2H, s),
7.07 (1H, m), 7.17 (1H, t, J 7.7 Hz), 7.22–7.38 (5H, m),
7.52 (1H, t, J 8.2), 7.98 (1H, m); dC (75.5 MHz, CDCl3)
14.1, 22.4, 24.9, 40.9, 46.9, 82.9, 99.6–124.7 (m), 123.9,
126.3, 126.7, 127.7, 128.1, 128.3, 129.0, 134.0, 136.1,
141.9, 142.5, 144.4, 162.5 (J 28.1 Hz), 172.8, 193.1; dF
(376.5 MHz, CDCl3) 2ꢂdiastereoisomers, ds1 (50% rel),
ds2 (50% rel): ꢀ79.7 (4F, ds1+ds2, m), ꢀ80.4 (6F, ds1+ds2,
m), ꢀ81.8 (6F, ds1+ds2, m), ꢀ82.4 (6F, ds1+ds2, m), ꢀ83.4
(4F, ds1+ds2, m), ꢀ130.0 (4F, ds1+ds2, s), ꢀ132.9 (1F, ds1,
dd, J 20.3 Hz), ꢀ133.1 (1F, ds2, m), ꢀ145.1 (1F, ds1, t, J
20.9 Hz), ꢀ145.5 (1F, ds2, m); m/z (EI) ds1 306 (19,
M+ꢀC3F7CF(CF3)CF2OCF(CF3)CO2), 262 (8, CF3CFO+-
CF2COCF3), 234 (5, CF3CF2O+CF2CF3), 214 (4), 180 (3),
169 (13, C3F+7), 119 (3), 91 (100), 69 (16, CF3+), 41 (5); ds2
306 (29, M+ꢀC3F7CF(CF3)CF2OCF(CF3)COO), 262 (11,
CF3CFO+CF2C(O)CF3), 234 (6, CF3CF2O+CF2CF3), 214
(8), 180 (3), 169 (15, C3F+7), 146 (6), 119 (4), 91 (100), 69
(15, CF+3), 41 (5); HRMS (EI): ds1 M+ꢀC3F7CF(CF3)-
CF2OCF(CF3)COO, found 306.1472; C20H20NO2 requires
306.1490; ds2 M+ꢀC3F7CF(CF3)CF2OCF(CF3)COO, found
306.1480; C20H20NO2 requires 306.1490.
4.12.8. 3-Methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydro-
quinolin-3-yl 2,5-bis(trifluoromethyl)-2,4,4,5,7,7,8,8,
9,9,9-undecafluoro-3,6-dioxanonanoate (16c). The reac-
tion of 1c (100 mg, 0.37 mmol) with pyridine (108 mg,
1.41 mmol) and 2,5-bis(trifluoromethyl)-2,4,4,5,7,7,8,8,
9,9,9-undecafluoro-3,6-dioxanonanoyl fluoride (661 mg,
1.33 mmol) afforded 16c (268 mg, 96%) as a slightly yellow
oil. Found: C, 40.42; H, 1.51; N, 1.77. C25H12F17NO6 re-
quires: C, 40.29; H, 1.62; N, 1.88%. Rf (20% EtOAc/benz-
ene) 0.88; dH (300.1 MHz, CDCl3) 1.92 (3H, s), 6.51
(3H, d, J 8.5 Hz), 7.20 (1H, t, J 7.6 Hz), 7.26 (2H, m),
7.46 (1H, t, J 8.5 Hz), 7.56 (3H, m), 8.04 (1H, ddd, J 7.6,
3.5, 1.4 Hz); dC (75.5 MHz, CDCl3) 16.8, 83.1, 100.0–
124.8 (m), 116.4, 120.7, 123.9, 124.2, 129.4, 129.5, 130.6,
130.8, 136.5, 139.9, 163.0 (J 28.2 Hz), 172.4, 193.2; dF
(376.5 MHz, CDCl3) 2ꢂdiastereoisomers, ds1 (50% rel),
ds2 (50% rel) ꢀ79.7 (4F, ds1+ds2, m, J 150.6 Hz);
ꢀ80.4 (6F, ds1+ds2, m), ꢀ81.9 (6F, ds1+ds2, m), ꢀ82.4
(6F, ds1+ds2, m, J 15.4 Hz), ꢀ82.9 (2F, ds1, 2ꢂd, J
150.6 Hz), ꢀ83.6 (2F, ds2, 2ꢂd, J 150.6 Hz), ꢀ130.0 (4F,
ds1+ds2, 2ꢂs), ꢀ133.9 (1F, ds1, dd, J 19.9 Hz), 132.9 (1F,
ds2, m), ꢀ145.5 (1F, ds1, q, J 19.9 Hz), ꢀ145.8 (2F,
ds1+ds2, q, J 21.7 Hz); m/z (FAB) 746 (3, MH+); HRMS
(FAB): MH+, found 746.0038; C25H13F17NO6 requires
746.0047.
4.12.9. 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
quinolin-3-yl 2,5-bis(trifluoromethyl)-2,4,4,5,7,7,8,8,
9,9,9-undecafluoro-3,6-dioxanonanoate (16d). The reac-
tion of 1d (104 mg, 0.37 mmol) with pyridine (108 mg,
1.41 mmol) and 2,5-bis(trifluoromethyl)-2,4,4,5,7,7,8,8,9,
9,9-undecafluoro-3,6-dioxanonanoyl fluoride (759 mg,
1.52 mmol) afforded 16d (237 mg, 84%) as a slightly yellow
oil. Found: C, 41.22; H, 1.92; N, 1.98. C26H14F17NO6 re-
quires C, 41.12; H, 1.86; N, 1.84%. Rf (20% EtOAc/benz-
ene) 0.90; dH (300.1 MHz, CDCl3) 3.33 (2H, d, J 6.7 Hz),
3.40 (3H, s), 6.90 (3H, m), 7.12 (4H, m), 7.53 (1H, t, J
8.2 Hz), 7.89 (1H, t, J 7.3 Hz); dF (376.5 MHz, CDCl3)
2ꢂdiastereoisomers, ds1 (50% rel), ds2 (50% rel): ꢀ79.7
(4F, ds1+ds2, m, J 150.6 Hz), ꢀ80.4 (6F, ds1+ds2, m),
ꢀ81.9 (6F, ds1+ds2, m), ꢀ82.4 (6F, ds1+ds2, m, J 15.4 Hz),
ꢀ82.9 (2F, ds1, 2ꢂd, J 150.6 Hz), ꢀ83.6 (2F, ds2, 2ꢂd, J
150.6 Hz), ꢀ130.0 (4F, ds1+ds2, 2ꢂs), ꢀ132.7 (1F, ds1,
dd, J 20.3 Hz), 132.9 (1F, ds2, m), ꢀ145.1 (1F, t, ds1, J
21.8 Hz), ꢀ145.5 (1F, ds2, dd, J 21.1 Hz); m/z (FAB) 760
(3%, MH+); HRMS (FAB): MH+, found 760.0622;
C26H15F17NO6 requires 760.0630.
4.12.7. 1-Methyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-
quinolin-3-yl 2,5-bis(trifluoromethyl)-2,4,4,5,7,7,8,8,
9,9,9-undecafluoro-3,6-dioxanonanoate (16b). The re-
action of 1b (100 mg, 0.37 mmol) with pyridine (29.3 mg,
0.37 mmol) and 2,5-bis(trifluoromethyl)-2,4,4,5,7,7,8,8,
9,9,9-undecafluoro-3,6-dioxanonanoyl fluoride (224 mg,
0.45 mmol) afforded 16b (278 mg,w100%) as a slightly yel-
low oil. Found: C, 40.51; H, 1.40; N, 1.62. C25H12F17NO6
requires: C, 40.29; H, 1.62; N, 1.88%. Rf (17% EtOAc/benz-
ene) 0.93; dH (300.1 MHz, CDCl3) 3.57 (3H, d, J 4.4 Hz),
7.19 (2H, m), 7.40 (5H, m), 7.63 (1H, t, J 7.7 Hz), 7.97
(1H, t, J 7.7 Hz); dC (75.5 MHz, CDCl3) 30.8, 83.5, 115.5,
100.0–125.1 (m), 124.4, 126.0, 126.9, 128.8, 129.4, 129.7,
136.7, 138.2, 142.7, 143.0, 144.5, 163.0 (J 28.3 Hz),

K. Pomeisl et al. / Tetrahedron 63 (2007) 10549–10561
10559
4.13. Reactions of quinoline-2,4-diones 6a,b, 9a, and
14a–16d with triethyl phosphite: general procedure
lin-4-yl)diethyl phosphate (17b). A mixture of 14b (see
Section 4.12.2) and triethyl phosphite (562 mg, 3.38 mmol)
in toluene (5 mL) was heated to reflux for 9 h. After removal
of the solvents, the residue was purified by chromatography
on neutral aluminum oxide (17–50% EtOAc/benzene). The
obtained product 17b (55 mg, 36%) was crystallized for an-
alytical purposes from acetone/hexane to give white needles
(32 mg, 28%), mp 97–99 ꢁC. Found: C, 62.05; H, 5.83; N,
3.53. C20H22O5NP requires: C, 62.04; H, 5.73; N, 3.73%.
Rf (50% EtOAc/benzene) 0.25; nmax (CDCl3) 3011, 1639,
1597, 1464, 1042, 970, 901 cmꢀ1; dH (300.1 MHz, CDCl3)
1.14 (3H, dt, J 7.1, 1.1 Hz), 3.64, 3.80 (4H, 2ꢂm), 3.76
(3H, s), 7.29–7.51 (7H, m), 7.63 (1H, dt, J 7.2, 1.1 Hz),
8.11 (1H, dd, J 8.0, 1.4 Hz); dC (75.5 MHz, CDCl3) 15.9
(J 7 Hz), 30.0, 64.4 (J 6 Hz), 113.9, 117.1, 122.2, 123.4,
124.8, 127.9, 130.9, 131.3, 132.4, 139.2, 151.4 (J 7 Hz),
162.6; dP (202.5 MHz, CDCl3) ꢀ5.72 (pent, J 14.1 Hz);
m/z (EI) 387 (100, M+), 358 (16), 330 (14), 312 (6), 260
(34), 250 (68), 205 (37), 178 (9), 165 (18), 134 (24), 104
(16), 81 (48), 77 (32), 51 (9%).
A mixture of 6a,b, 9a, and 14a–16d and triethyl phosphite in
toluene was vigorously refluxed until the reaction was com-
pleted. After removal of solvents, the residue was purified in
the below-mentioned systems (vide infra) and the obtained
products 17a,b and 18 were crystallized from acetone/
hexane.
4.13.1. Reaction of 1-benzyl-3-butyl-2,4-dioxo-1,2,3,4-
tetrahydroquinolin-3-yl acetate (6a) with triethyl phos-
phite. A mixture of 6a (65 mg, 0.16 mmol) and triethyl
phosphite (278 mg, 1.60 mmol) in toluene (2 mL) was vig-
orously heated to reflux for 16 h; no product was formed
(according to TLC, 20% EtOAc/benzene).
4.13.2. Reaction of 1-methyl-2,4-dioxo-3-phenyl-1,2,3,4-
tetrahydroquinolin-3-yl acetate (6b) with triethyl phos-
phite. A mixture of 6b (100 mg, 0.32 mmol) in toluene
(2 mL) and triethyl phosphite (278 mg, 1.60 mmol) was vig-
orously heated to reflux for 10 h; no product was formed
(according to TLC, 20% EtOAc/benzene).
4.13.6. Reaction of quinoline-2,4-dione 14c with triethyl
phosphite: (3-methyl-2-oxo-1-phenyl-1,2-dihydroquino-
lin-4-yl)diethyl phosphate (17c). A mixture of 14c (see
Section 4.12.3) and triethyl phosphite (562 mg, 3.38 mmol)
in toluene (5 mL) was heated to reflux for 2 h. After removal
of the solvents, the residue was purified by chromatography
on neutral aluminum oxide (20–50% EtOAc/benzene) to
give 17c (45 mg, 31%). NMR spectra were identical to
below-mentioned compound (see Section 4.13.11).
4.13.3. Reaction of quinoline-2,4-dione 9a with triethyl
phosphite: (1-benzyl-3-butyl-2-oxo-1,2-dihydroquinolin-
4-yl)diethyl phosphate (17a). A mixture of 9a (168 mg,
0.34 mmol) and triethyl phosphite (562 mg, 3.38 mmol) in
toluene (5 mL) was vigorously heated to reflux for 7 h. After
removal of the solvents, the residue was purified by chroma-
tography on neutral aluminum oxide (20% EtOAc/benzene).
The obtained product 17a (102 mg, 68%) was crystallized
from acetone/hexane for analytical purposes to give white
needles (61 mg, 41%), mp 94–97 ꢁC. Found: C, 65.00; H,
6.82; N, 3.06. C24H30O5NP requires: C, 65.00; H, 6.81; N,
3.16%. Rf (20% EtOAc/benzene) 0.31; nmax (CDCl3) 3010,
2961, 1643, 1600, 1461, 1050, 1031, 967, 902 cmꢀ1; dH
(300.1 MHz, CDCl3) 0.96 (3H, t, J 7.1 Hz), 1.36 (6H, dt, J
7.1, 1.1 Hz), 1.45 (2H, m, J 7.4 Hz), 1.62 (2H, pent, J
7.7 Hz), 2.85 (2H, t, J 8.0 Hz), 4,26 (4H, m), 5.55 (2H, br
s), 7.16–7.34 (7H, m), 7.41 (1H, ddd, J 7.1, 1.7 Hz), 8.00
(1H, dd, J 8, 1.4 Hz); dC (75.5 MHz, CDCl3) 13.9, 16.1 (J
7 Hz), 23.0, 25.5, 30.1, 46.4, 65.0 (J 6 Hz), 114.6, 117.3,
122.0, 123.9 (J 5 Hz), 124.1, 126.5, 127.2, 128.7, 130.3,
136.3, 137.9, 151.3 (J 9 Hz), 163.3; dP (202.5 MHz,
CDCl3) ꢀ5.19 (pent, J 15.1 Hz); m/z (EI) 443 (3, M+), 414
(1), 401 (7), 289 (8), 282 (4), 254 (9), 198 (13), 91 (100),
77 (3), 65 (8), 43 (2%).
4.13.7. Reaction of quinoline-2,4-dione 15a with triethyl
phosphite. A mixture of 15a (100 mg, 0.20 mmol) and tri-
ethyl phosphite (562 mg, 3.38 mmol) in toluene (3 mL)
was heated to reflux for 38 h; no product was formed
(according to TLC, 20% EtOAc/benzene).
4.13.8. Reaction of quinoline-2,4-dione 15b with triethyl
phosphite: 4-ethoxy-1-methyl-3-phenylquinolin-2(1H)-
one (18). A mixture of 15b (162 mg, 0.37 mmol) and triethyl
phosphite (1.91 g, 11.56 mmol) in toluene (4 mL) was
heated to reflux for 14 h. After removal of the solvents, the
residue was purified by chromatography on neutral alumi-
num oxide (20% EtOAc/benzene). The obtained product
18 (28 mg, 27%) was crystallized for analytical purposes
from acetone/hexane to give white needles (10 mg, 10%),
mp 98–101 ꢁC. Found: C, 77.19; H, 6.20; N, 5.01.
C18H17O2N requires: C, 77.40; H, 6.13; N, 5.30%. Rf
(17% EtOAc/benzene) 0.27; nmax (CDCl3) 3010, 1624,
1592, 1463, 699 cmꢀ1; dH (300.1 MHz, CDCl3) 1.16 (3H,
t, J 7.1 Hz), 3.64 (2H, q, J 7.1 Hz), 3.75 (3H, s), 7.24–7.55
(7H, m), 7.60 (1H, m, J 7.2, 1.7 Hz), 8.03 (1H, dd, J 8.0,
1.4 Hz); dC (75.5 MHz, CDCl3) 15.4, 29.8, 69.2, 113.8,
121.8, 124.2, 127.6, 127.9, 130.6, 130.7, 119.7, 118.7, 133.7,
139.3, 159.6, 163.3; m/z (EI) 279 (97, M+), 264 (28), 250
(100), 234 (40), 222 (21), 208 (9), 194 (12), 178 (8), 165
(16), 152 (15), 134 (39), 104 (16), 91 (13), 77 (37), 63 (13%).
4.13.4. Reaction of quinoline-2,4-dione 14a with triethyl
phosphite: (1-benzyl-3-butyl-2-oxo-1,2-dihydroquinolin-
4-yl)diethyl phosphate (17a). A mixture of 14a (see Section
4.12.1) and triethyl phosphite (562 mg, 3.38 mmol) in tolu-
ene (6 mL) was heated to reflux for 3 days. After the removal
of the solvents, the residue was purified by chromatography
on neutral aluminum (20% EtOAc/benzene). The obtained
product 17a (43 mg, 36%) was crystallized for analytical
purposes with acetone/hexane to give (31 mg, 26%) of white
crystals. NMR spectra were identical to above-mentioned
compound (see Section 4.13.3).
4.13.9. Reaction of quinoline-2,4-dione 16a with triethyl
phosphite: (1-benzyl-3-butyl-2-oxo-1,2-dihydroquinolin-
4-yl)diethyl phosphate (17a). A mixture of 16a (247 mg,
0.31 mmol) and triethyl phosphite (1.91 g, 11.56 mmol) in
toluene (4 mL) was heated to reflux for 14 h. After removal
4.13.5. Reaction of quinoline-2,4-dione 14b with triethyl
phosphite: (1-methyl-2-oxo-3-phenyl-1,2-dihydroquino-

10560
K. Pomeisl et al. / Tetrahedron 63 (2007) 10549–10561
of the solvents, the residue was purified by chromatography
on neutral aluminum oxide (17–50% EtOAc/benzene) to
give 17a (26 mg, 18%) as a white solid. NMR spectra
were identical to the above-mentioned compound (see Sec-
tion 4.13.3).
for 14 h. After removal of the solvents, the residue was pu-
rified by chromatography on neutral aluminum oxide (20%
EtOAc/benzene) to give 19 (68 mg, 52%) as a yellow amor-
phous solid. Found: C, 64.49; H, 6.43; N, 2.87. C26H30O6NP
requires: C, 64.59; H, 6.25; N, 2.90%. Rf (20% EtOAc/tolu-
ene) 0.34; nmax (CHCl3) 3014, 2964, 2934, 1769, 1703,
1619, 1602, 1251, 1028, 980 cmꢀ1; dH (300.1 MHz, CDCl3)
0.81 (3H, t, J 7.1 Hz), 1.21, 1.40 (6H, 2ꢂt, J 7.1 Hz), 1.22–
1.37 (4H, m), 1.77, 2.2 (2H, 2ꢂm), 4.01, 4.34 (4H, 2ꢂm),
4.81, 5.51 (2H, 2ꢂd, J 16.5, 15.9 Hz), 7.03 (1H, d, J
8.2 Hz), 7.18–7.36 (6H, m), 7.44 (1H, dt, J 8.2, 1.1 Hz),
8.28 (1H, dd, J 7.7, 1.7 Hz); dC (75.5 MHz, CDCl3) 13.6,
16.8 (J 6 Hz), 17.0 (J 6 Hz), 22.2, 24.7, 37.6, 47.0, 63.2
(J 6 Hz), 63.8 (J 6 Hz), 87.3 (J 16 Hz), 113.3, 116.2,
117.0, 123.9, 126.3, 127.7, 129.0, 131.3, 134.2, 135.7,
139.1, 166.4, 167.0; dP (202.5 MHz, CDCl3) 5.48 (pent,
J 18.9 Hz); m/z (EI) 483 (1, M+), 399 (17), 353 (12), 336
(2), 298 (2), 263 (3), 206 (3), 143 (3), 91 (100), 65 (8),
57 (8%).
4.13.10. Reaction of quinoline-2,4-dione 16b with triethyl
phosphite: 4-ethoxy-1-methyl-3-phenylquinolin-2(1H)-
one (18). A mixture of 16b (245 mg, 0.37 mmol) and triethyl
phosphite (1.91 g, 11.56 mmol) in toluene (5 mL) was re-
fluxed for 14 h. After removal of the solvents, the residue
was purified by chromatography on neutral aluminum oxide
(17% EtOAc/benzene) to give 18 (11 mg, 11%) as a white
solid. NMR spectra were identical to the above-mentioned
compound (see Section 4.13.8).
4.13.11. Reaction of quinoline-2,4-dione 16c with triethyl
phosphite: (3-methyl-2-oxo-1-phenyl-1,2-dihydroquino-
lin-4-yl) diethyl phosphate (17c). A mixture of 16c
(235 mg, 0.32 mmol) and triethyl phosphite (1.91 g,
11.56 mmol) in toluene (10 mL) was heated to reflux for
2 h. After removal of the solvents, the residue was purified
by chromatography on neutral aluminum oxide (17–20%
EtOAc/benzene) to give 17c (25 mg, 21%) as a white amor-
phous solid, mp 94–97 ꢁC. Found: C, 61.63; H, 5.77; N,
3.45. C20H22NO5P requires: C, 62.01; H, 5.72; N, 3.62%.
Rf (20% EtOAc/benzene) 0.36; nmax (CDCl3) 3011, 1645,
1603, 1459, 1048, 1034, 1034, 972, 871, 699 cmꢀ1; dH
(300.1 MHz, CDCl3) 1.40 (3H, t, J 7.1 Hz), 2.31 (3H, d, J
2.1 Hz), 4.30 (2H, m), 6.66 (1H, d, J 8.2 Hz), 7.27 (4H,
m), 7.55 (3H, m), 7.99 (1H, d, J 7.7 Hz); dC (75.5 MHz,
CDCl3) 12.0 (J 1 Hz), 16.8 (J 7 Hz), 65.8 (J 6 Hz), 116.3,
122.9, 124.2, 129.47, 127.51, 130.6, 130.8, 117.4 (J 2 Hz),
120.7 (J 5 Hz), 138.5, 140.0, 152.3 (J 9 Hz), 164.2; dP
(202.5 MHz, CDCl3) ꢀ4.89 (pent, J 7.3 Hz); m/z (FAB)
388.0 (100%, MH+).
Acknowledgements
The research has been supported by the Ministry of Educa-
tion of the Czech Republic (projects Nos. MSM223100001,
MSM265200015, and MSM7088352101) and Czech Sci-
ence Foundation (Grant No. 203/07/0320). Elemental analy-
ses and measurements of some NMR spectra were carried out
in the Central Laboratories of the Prague Institute of Chem-
ical Technology. The authors thank to Prof. Dr. Miroslav
ꢀ
Strnad (Palacky University & Institute of Experimental
Botany AS CR, Olomouc, Czech Republic) for a biochemical
assay of synthezised quinoline-2-ones.
Supplementary data
4.13.12. Reaction of quinoline-2,4-dione 16d with triethyl
phosphite: (3-benzyl-1-methyl-2-oxo-1,2-dihydroquino-
lin-4-yl)diethyl phosphate (17d). A mixture of 16d
(230 mg, 0.30 mmol) and triethyl phosphite (1.91 g,
11.56 mmol) in toluene (10 mL) was heated to reflux for
2 h. After removal of the solvents, the residue was purified
by preparative TLC (S1, 50% EtOAc/toluene) to give 17d
(65 mg, 54%) as a white solid, mp 65–67 ꢁC. Found: C,
62.65; H, 6.00; N, 3.51. C21H24NO5P requires: C, 62.84;
H, 6.03; N, 3.49%. Rf (50% EtOAc/toluene) 0.21; nmax
(CHCl3) 3011, 1643, 1600, 1466, 1050, 1034, 965, 904,
700, 629 cmꢀ1; dH (300.1 MHz, CDCl3) 1.32 (3H, t, J
7.3 Hz), 3.69 (3H, s), 4.20 (2H, s), 4.22 (2H, m), 7.13 (1H,
t, J 7.3 Hz), 7.18–7.40 (6H, m), 7.55 (1H, t, J 7.6 Hz),
8.02 (1H, d, J 7.9 Hz); dC (75.5 MHz, CDCl3) 16.0 (J
7 Hz), 30.0, 31.0, 65.2 (J 6 Hz), 113.9, 122.1, 124.4,
126.0, 128.17, 128.69, 130.8, 116.8 (J 2 Hz), 122.4 (J
5 Hz), 138.7, 139.3 (J 2 Hz), 151.5 (J 8 Hz), 162.8 (J
1 Hz); dP (202.5 MHz, CDCl3) ꢀ6.13 (pent, J 8.3 Hz); m/z
(FAB) 402.1 (100%, MH+).
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.07.058.
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