Tandem retro-Michael addition-Claisen rearrangement-intramolecular cyclization: One-pot synthesis of densely functionalized ethyl dihydropyrimidine-4-carboxylates from simple building blocks

Article abstract of DOI:10.1055/s-2008-1032088

Pyrolysis of suitably functionalized oxadiazoline diesters in refluxing xylenes provided ethyl 1,2-disubstituted 5-hydroxy-6-oxo-1,6-dihydropyrimidine- 4-carboxylates in moderate to good yields. Under thermal conditions, the oxadiazoline esters undergo a sequence of complex molecular reorganizations, namely retro-Michael addition, Claisen rearrangement, and cyclization, to produce the desired pyrimidinones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032088

LETTER
547
Tandem Retro-Michael Addition–Claisen Rearrangement–Intramolecular
Cyclization: One-Pot Synthesis of Densely Functionalized Ethyl Dihydropyri-
midine-4-carboxylates from Simple Building Blocks
One-Pot Synthes
.
D
ensely
N
Functionalize
d
Et
a
hyl
D
ihydr
r
opyrimid
a
ine-4-carb
soxylates imhulu Naidu*
Discovery Chemistry, Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492, USA
Fax +1(203)6776574; E-mail: b.narasimhulunaidu@bms.com
Received 19 November 2007
During the course of our drug discovery efforts, we sought
Abstract: Pyrolysis of suitably functionalized oxadiazoline di-
esters in refluxing xylenes provided ethyl 1,2-disubstituted 5-hy-
droxy-6-oxo-1,6-dihydropyrimidine-4-carboxylates in moderate to
good yields. Under thermal conditions, the oxadiazoline esters un-
access to several pyrimidinone carboxylic acid esters 2. In
the literature, these compounds have typically been pre-
pared from 1 by a three-step sequence involving protec-
dergo a sequence of complex molecular reorganizations, namely tion–alkylation–deprotection,
as
summarized
in
Scheme 1.2,3a Frequently, the alkylation step was
nonchemoselective and produces, in addition to desired
N-alkylated pyrimidinone 4, the unwanted O-alkylated
pyrimidine 5 often as a major product. Although this pro-
cedure is reliable, it requires several steps and suffers
from poor chemoselectivity and low overall yield. Conse-
retro-Michael addition, Claisen rearrangement, and cyclization, to
produce the desired pyrimidinones.
Key words: retro-Michael addition, Claisen rearrangement, in-
tramolecular cyclization, 1,6-dihydropyrimidine-4-carboxylates
Pyrimidines and pyrimidinones are a very important class quently, we sought to develop a short and versatile syn-
of diazine heterocycles and are constituents of many bio- thetic approach to pyrimidinone carboxylic acid esters 2.
logically active compounds.1 5-Hydroxy-6-oxo-1,6-dihy- In this paper, we describe a one-pot synthetic protocol for
dropyrimidine-4-carboxylic acid esters 1 and 2 (Figure 1) the preparation of 2 from readily accessible oxadiazolines
are a newly emerging group of densely functionalized 6.
pyrimidine derivatives. Recently, these compounds have
received increased attention because of their ability to co-
We envisaged that under the pyrolytic conditions, oxadi-
azoline 6 would undergo ring opening via a retro-Michael
reaction to afford 7 (Scheme 2), a transient intermediate
that could undergo a thermal Claisen rearrangement to
ordinate metal ions, a property that confers promising bi-
ological properties.2,3
provide the keto diester 8. Intramolecular cyclization of 8
O
OH
5
would furnish the desired pyrimidinone 2. Although, the
Claisen rearrangement followed by cyclization of unsub-
stituted amidoxime 7, in which R1 = H is known,4 we
were concerned about the fate of this transformation when
the hydrogen atom is replaced by a sterically more de-
4
O
EtO
1: R1 = H
2: R1 = alkyl
6
3 N
N
1
R1
2
R2
Figure 1 Ethyl-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxy- manding alkyl group.5
lates
O
OPG
N
O
R3O
"– PG"
2
4
N
R1
O
OPG
R2
+
O
R3O
base
R1
"+ PG"
1
N
NH
X
3
O
OPG
OR1
R2
R3O
N
N
5
R2
Scheme 1 Current approach to N-alkylpyrimidinones 2
SYNLETT 2008, No. 4, pp 0547–0550
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.02.2008
DOI: 10.1055/s-2008-1032088; Art ID: S08907ST
© Georg Thieme Verlag Stuttgart · New York

548
B. N. Naidu
LETTER
OH
R2
Table 1 Ethyl 1,2-Disubstituted 5-Hydroxy-6-oxo-1,6-dihydropyr-
imidine-4-carboxylates
EtO2C
CO2Et
O1
EtO2C
O
N
xylenes
reflux
3
R1
R2
Ph
Time
(h)
Yield
(%)a
N
N
Entry
1
Product
N
R2
R1
2
R1
2a
Me
20
58
6a–p
2a–p
2
3
2b
2c
Me
Me
15
53
EtO2C
CO2Et
O
EtO2C
CO2Et
O
EtO2C
O
F
F
F
HN
R2
HN
R2
N
CO2Et
NH
N
N
R2
12
57
R1
R1
R1
7
8a
8b
F
Scheme 2 Proposed mechanism
F
4
5
6
2d
2e
2f
Me
Me
Me
3
1.5
6
69
60
47
CO2Et
OH
N
R1
EtOH–H2O
HN
R2CN
R1
NH
+
HCl
+
F
Na2CO3
HO
R2
CO2Et
CO2Et
F
F
EtO2C
N
HN
R2
CO2Et
CO2Et
O
N
R1
r.t.
O
SO2Me
N
R2
R1
6a–p
F
Scheme 3 Synthesis of oxadiazolines
OMe
7
8
2g
Me
2
56
The required 1,2,4-oxadiazoline diesters 6 were prepared
using appropriate nitrile, N-alkylhydroxylamine and di-
ethyl acetylenedicarboxylate (DEAD) according to the lit-
erature procedure (Scheme 3).6 The pyrolytic reaction
was examined in several solvents and we quickly found
that the reaction does not take place in refluxing toluene.
However, we were gratified that the transformation oc-
curred as anticipated in refluxing xylenes and, moreover,
the reaction proceeds more rapidly at higher temperatures.
For example, the conversion of oxadiazolines into pyri-
midinones was two- to threefold faster at 180 °C in 1,3,5-
trimethylbenzene than in boiling xylenes (bp 140–145
°C). However, in xylenes the reactions were generally
N
Me
MeO2S
OMe
2h
2i
Me
Me
3
2
43
62
OMe
9
OMe
10
2j
Me
Bn
Bn
5
20
24
24
24
24
15
51
cleaner and provided better yields of the desired products. 11
2k
2l
Me
41
The thermal rearrangement of oxadiazoline diesters 6
with a variety of N2-substituents, including methyl, ben-
zyl, isopropyl, and cyclohexyl, and C3-substituents, in-
cluding aryls and alkyls, were investigated and the results
are summarized in Table 1. This conversion proceeded
uneventfully with diverse C3-aryl groups, providing the
desired pyrimidinones in good yields (entries 1–9). Both
electron-donating and electron-withdrawing substituents
on the C3-aryl ring are well tolerated.
12
13
14
15
16
i-Pr Me
i-Pr Bn
7
2m
2n
2o
2p
traceb
traceb
38
Cy
Me
Me
Bn
i-Pr
c-C5H9
35
a Isolated yields.
b Observed by LCMS.
Interestingly, oxadiazolines with an unsubstituted C3-
phenyl and C3-phenyl incorporating meta and para sub-
stitution took significantly longer to rearrange to products
(entries 1–3) than oxadiazolines incorporating ortho sub-
stitution (entries 4–9). This difference in rate may, in part,
arise from the presence of the ortho substituent, which
Synlett 2008, No. 4, 547–550 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of Densely Functionalized Ethyl Dihydropyrimidine-4-carboxylates
549
solid (1.4 g, 60% yield).
will restrict rotation and orient the phenyl moiety orthog-
onally to the plane of the amidine C–N bond. This ar-
rangement may minimize steric interactions in the
transition state for the Claisen rearrangement and/or in-
tramolecular cyclization steps that, in turn, results in the
faster reaction rate.
Method B: A solution of 6j (9.77 g, 29.22 mmol) in xylenes
(100 mL) was heated at reflux for 5 h and cooled. Then, the
reaction mixture was diluted with EtOAc (100 mL) and
extracted with 0.5 M Na2CO3 (3 × 30 mL). The combined
aqueous layers were acidified with concd HCl and extracted
with CH2Cl2 (4 × 50 mL). The combined CH2Cl2 layers were
dried (Na2SO4), filtered, and concentrated to give a brown
solid which was triturated with Et2O and filtered to afford 2j
as a light-brown powder (4.32 g, 51%).
Oxadiazolines incorporating a variety of C3-alkyl substit-
uents are converted into pyrimidinones in low to moderate
yields (entries 10, 11, 15, and 16). However, substrates
with bulky N2-substituents, such as isopropyl and cyclo-
hexyl groups, failed to furnish the desired products in ac-
ceptable yield (entries 12–14). This may be due to the
bulky N2-substituents making this nitrogen less accessi-
ble for nucleophilic attack. Conversely, oxadiazolines
with bulky C3-alkyl groups readily participate in this
transformation, providing the desired products in moder-
ate yields, as captured by entries 15 and 16.
(8) Analytical Data for New Compounds
Compound 2a: 1H NMR (500 MHz, CDCl3): d = 10.76 (1 H,
s), 7.49–7.46 (5 H, m), 4.48 (2 H, q, J = 7.0 Hz), 3.45 (3 H,
s), 1.41 (3 H, t, J = 7.0 Hz). HRMS: m/z calcd for
C14H15N2O4 [M + H]: 275.1032; found: 275.1042. Anal.
Calcd for C14H14N2O4: C, 61.30; H, 5.14; N, 10.21. Found:
C, 61.31; H, 5.10; N, 10.21.
Compound 2b: 1H NMR (500 MHz, CDCl3): d = 10.63 (1 H,
s), 7.39–7.23 (3 H, m), 4.49 (2 H, q, J = 7.0 Hz), 3.47 (3 H,
s), 1.42 (3 H, t, J = 7.0 Hz). HRMS : m/z calcd for
C14H13F2N2O4 [M + H]: 311.0844; found: 311.0832. Anal.
Calcd for C14H14N2O4: C, 54.19; H, 3.89; N, 9.03. Found: C,
54.21; H, 3.85; N, 8.85.
In summary, we have described a simple and convenient
route to the synthesis of ethyl dihydropyrimidine-4-car-
boxylates from readily available 2,4-oxadiazoline diesters
6. This methodology works well with a variety of sub-
strates and furnishes densely functionalized pyrimidino-
nes in moderate to good yields. One of the important
advantages of this protocol is that, in most cases, the prod-
ucts are obtained without resort to chromatographic puri-
fication either by crystallization or by simple acid–base
extraction from the crude reaction mixture.7,8
Compound 2c: 1H NMR (500 MHz, CDCl3): d = 10.85 (1 H,
s),), 7.06–7.01 (2 H, m), 6.98–6.94 (1 H, m), 4.50 (2 H, q,
J = 7.0 Hz), 3.47 (3 H, s), 1.42 (3 H, t, J = 7.0 Hz). HRMS:
m/z calcd for C14H13F2N2O4 [M + H]: 311.0843; found:
311.0836. Anal. Calcd for C14H14N2O4: C, 54.19; H, 3.89; N,
9.03. Found: C, 54.15; H, 3.79; N, 9.15.
Compound 2d: 1H NMR (500 MHz, CDCl3): d = 10.81 (1 H,
s), 7.51–7.46 (1 H, m), 7.04 (2 H, td, J = 8.2, 1.8 Hz), 6.95–
6.91 (1 H, m), 4.49 (2 H, q, J = 7.0 Hz), 3.42 (3 H, s), 1.41
(3 H, t, J = 7.0 Hz). HRMS: m/z calcd for C14H13F2N2O4
[M + H]: 311.0843; found: 311.0828. Anal. Calcd for
C14H14N2O4: C, 54.19; H, 3.89; N, 9.03. Found: C, 54.21; H,
3.65; N, 8.94.
Acknowledgment
We thank Drs. Nicholas A. Meanwell and Michael A. Walker for
their support of this work.
Compound 2e: 1H NMR (500 MHz, CDCl3): d = 10.96 (1 H,
s), 7.50–7.45 (1 H, m), 7.04 (2 H, t, J = 7.3 Hz), 4.51 (2 H,
q, J = 7.0 Hz), 3.41 (3 H, s), 1.41 (3 H, t, J = 7.0 Hz). HRMS:
m/z calcd for C14H13F2N2O4 [M + H]: 311.0843; found:
311.0837. Anal. Calcd for C14H14N2O4: C, 54.19; H, 3.89; N,
9.03. Found: C, 54.10; H, 3.77; N, 9.00.
References and Notes
(1) For reviews, see: (a) Brown, J. D. The Pyrimidine, In The
Chemistry of Heterocyclic Compounds, Vol. 16;
Compound 2f: 1H NMR (500 MHz, CDCl3): d = 10.57 (1 H,
s), 7.90 (1 H, dd, J = 7.93, 2.44 Hz), 7.49–7.42 (2 H, m),
4.54–4.47 (1 H, m), 4.41–4.34 (1 H, m), 3.31 (3 H, s), 3.30
(3 H, s), 1.35 (3 H, t, J = 7.02 Hz). ESI-HRMS: m/z calcd for
C15H16FN2O6S [M + H]: 371.0713; found: 371.0724.
Compound 2g: 1H NMR (500 MHz, CDCl3): d = 10.65 (1 H,
s), 7.57–7.52 (1 H, m), 7.28 (1 H, d, J = 7.9 Hz), 7.22 (1 H,
t, J = 8.9 Hz), 4.55–4.49 (1 H, m), 4.40–4.33 (1 H, m), 3.46
(3 H, s), 3.30 (3 H, s), 2.90 (3 H, s), 1.37 (3 H, t, J = 7.0 Hz).
ESI-HRMS: m/z calcd for C16H19FN3O6S [M + H]:
400.0979; found: 400.0979.
Weissberger, A., Ed.; Wiley-Interscience: New York, 1962.
(b) Hurst, D. T. An Introduction to the Chemistry and
Biochemistry of Pyrimidines, Purines and Pteridines;
Wiley: Chichester, 1980.
(2) Sunderland, C. J.; Botta, M.; Aime, S.; Raymond, K. N.
Inorg. Chem. 2001, 40, 6746.
(3) (a) Summa, V.; Petrocchi, A.; Matassa, V. G.; Taliani, M.;
Laufer, R.; Francesco, R. D.; Altamura, S.; Pace, P. J. Med.
Chem. 2004, 47, 5336. (b) Stansfield, I.; Avolio, S.;
Colarusso, S.; Gennari, N.; Narjes, F.; Picini, B.; Ponzi, S.;
Harper, S. Bioorg. Med. Chem. Lett. 2004, 14, 5085.
(4) Culbertson, T. P. J. Heterocycl. Chem. 1979, 16, 1423.
(5) For related work, see: (a) Colarusso, S.; Attenni, B.; Avolio,
S.; Malancona, S.; Harper, S.; Altamura, S.; Koch, U.;
Narjes, F. ARKIVOC 2006, (vii), 479. (b) Kinzel, O. D.;
Monteagudo, E.; Muraglia, E.; Orvieto, F.; Pescatore, G.;
Rico Ferreira, M.; Rowley, M.; Summa, V. Tetrahedron
Lett. 2007, 48, 6552. (c) Ferrara, M.; Crescenzi, B.; Donghi,
M.; Muraglia, E.; Nizi, E.; Pesci, S.; Summa, V.; Gardelli, C.
Tetrahedron Lett. 2007, 48, 8379.
Compound 2h: 1H NMR (500 MHz, CDCl3): d = 10.76 (1 H,
s), 7.45 (1 H, td, J = 7.3, 1.53 Hz), 7.34 (1 H, d, J = 7.3 Hz),
7.06 (1 H, t, J = 7.3 Hz), 6.94 (1 H, d, J = 8.6 Hz), 4.55–4.41
(2 H, m), 3.79 (3 H, s), 3.34 (3 H, s), 1.40 (3 H, t, J = 7.0 Hz).
HRMS: m/z calcd for C15H15N2O5 [M + H]: 303.0981;
found: 303.0980.
Compound 2i: 1H NMR (500 MHz, CDCl3): d = 10.83 (1 H,
s), 7.35 (1 H, t, J = 8.5 Hz), 6.59 (2 H, d, J = 8.5 Hz), 4.50 (2
H, q, J = 7.0 Hz), 3.75 (6 H, s), 3.28 (3 H, s), 1.39 (3 H, t,
J = 7.0 Hz). HRMS: m/z calcd for C16H19N2O6 [M + H]:
335.1243; found: 335.1240.
(6) Naidu, B. N.; Sorenson, M. E. Org. Lett. 2005, 7, 1391.
(7) Representative Procedures
Compound 2j: 1H NMR (500 MHz, CDCl3): d = 10.64 (1 H,
s), 7.33–7.14 (5 H, m), 4.53 (2 H, q, J = 7.0 Hz), 4.17 (2 H,
s), 3.41 (3 H, s), 1.46 (3 H, t, J = 7.0 Hz). 13C NMR (125
Method A: A solution of 6e (2.68 g, 7.52 mmol) in xylenes
(50 mL) was heated at reflux for 1.5 h and cooled to r.t. The
precipitate was filtered and dried to give 2e as an off-white
Synlett 2008, No. 4, 547–550 © Thieme Stuttgart · New York

550
B. N. Naidu
LETTER
[M + H]: 357.1262; found: 357.1273. Anal. Calcd for
MHz, CDCl3): d = 169.5, 158.9, 149.8, 149.0, 134.7, 129.2,
128.2, 127.5, 124.7, 63.1, 42.3, 32.0, 14.3. HRMS: calcd for
C15H17N2O4 [M + H]: 289.1188; found: 289.1186. Anal.
Calcd for C15H16N2O4: C, 62.49; H, 5.59; N, 9.71. Found: C,
62.44; H, 5.79; N, 9.60.
C16H18N2O5F2: C, 53.93; H, 5.09; N, 7.86. Found: C, 53.82;
H, 4.90; N, 8.13.
Compound 6c: yield 72%. 1H NMR (500 MHz, CDCl3): d =
7.29–7.25 (2 H, m), 6.99–6.95 (1 H, m), 4.35–4.12 (4 H, m),
3.40 (1 H, d, JAB = 16.5 Hz), 3.18 (3 H, s), 3.04 (1 H, d,
Compound 2k: 1H NMR (500 MHz, CDCl3): d = 10.88 (1 H,
s), 7.31–7.24 (3 H, m), 7.14 (2 H, d, J = 7.3 Hz), 5.29 (2 H,
s), 4.47 (2 H, q, J = 7.0 Hz), 2.43 (3 H, s), 1.41 (3 H, t, J = 7.0
Hz). 13C NMR (125 MHz, CDCl3): d = 169.1, 158.7, 149.5,
148.9, 134.6, 129.1, 128.2, 126.8, 124.7, 63.2, 48.2, 31.7,
22.6, 14.2. HRMS: m/z calcd for C15H17N2O4 [M + H]:
289.1188. Found: 289.1176.
JAB = 16.5 Hz), 1.32 (3 H, t, J = 7.0 Hz), 1.25 (3 H, t, J = 7.0
Hz). HRMS: m/z calcd for C16H19N2O5F2 [M + H]:
357.1262; found: 357.1262. Anal. Calcd for C16H18N2O5F2:
C, 53.93; H, 5.09; N, 7.86. Found: C, 53.90; H, 4.84; N, 7.81.
Compound 6d: yield 60%. 1H NMR (500 MHz, CDCl3): d =
7.73 (1 H, dd, J = 14.5, 8.1 Hz), 6.96 (1 H, td, J = 8.5, 2.4
Hz), 6.91 (1 H, td, J = 8.2, 2.5 Hz), 4.36–4.10 (4 H, m), 3.40
(1 H, d, JAB = 16.5 Hz), 3.11 (3 H, s), 3.07 (1 H, d, JAB = 16.5
Hz), 1.32 (3 H, t, J = 7.0 Hz), 1.25 (3 H, t, J = 7.0 Hz).
HRMS: m/z calcd for C16H19N2O5F2 [M + H]: 357.1262;
found: 357.1253. Anal. Calcd for C16H18N2O5F2: C, 53.93;
H, 5.09; N, 7.86. Found: C, 53.91; H, 5.01; N, 7.75.
Compound 6f: yield 64%. 1H NMR (500 MHz, CDCl3): d =
7.89 (1 H, dd, J = 8.1, 2.6 Hz), 7.62 (1 H, dd, J = 8.4, 5.04
Hz), 7.40 (1 H, td, J = 8.2, 2.4 Hz), 4.35–4.26 (2 H, m),
4.19–4.13 (2 H, m), 3.40 (3 H, s), 3.38 (1 H, d, JAB = 16.2
Hz), 3.15 (1 H, d, JAB = 16.2 Hz), 3.02 (3 H, s), 1.36–1.30 (3
H, m), 1.27–1.23 (3 H, m). HRMS: m/z calcd for
Compound 2l: 1H NMR (500 MHz, CDCl3): d = 8.89 (1 H,
br s), 4.60–4.49 (1 H, m), 4.47 (2 H, q, J = 7.0 Hz), 2.57 (3
H, s), 1.63 (6 H, d, J = 6.7 Hz), 1.42 (3 H, t, J = 7.0 Hz). 13
NMR (125 MHz, CDCl3): d = 168.6, 158.7, 149.4, 149.0,
123.5, 77.7, 63.1, 22.9, 19.1, 14.1. HRMS: m/z calcd for
C11H17N2O4 [M + H]: 241.1188; found: 241.1191.
C
Compound 2o: 1H NMR (500 MHz, CDCl3): d = 10.39 (1 H,
s), 4.44 (2 H, q, J = 7.0 Hz), 3.61 (3 H, s), 3.05 (1 H, qt,
J = 6.7 Hz), 1.43 (3 H, t, J = 7.0 Hz), 1.30 (6 H, d, J = 6.7
Hz). 13C NMR (125 MHz, CDCl3): d = 169.5, 159.1, 155.2,
148.0, 124.9, 62.4, 32.0, 30.9, 20.7, 14.1. HRMS: m/z calcd
for C11H17N2O4 [M + H]: 241.1188; found: 241.1186. Anal.
Calcd for C11H16N2O4: C, 54.99; H, 6.71; N, 11.66. Found:
C, 55.01; H, 6.82; N, 11.68.
C17H22FN2O7S: 417.1132; found: 417.1116.
Compound 6g: yield 56%. 1H NMR (500 MHz, CDCl3): d =
7.52–7.48 (1 H, m), 7.31 (1 H, d, J = 8.2 Hz), 7.18 (1 H, t,
J = 8.6 Hz), 4.35–4.25 (2 H, m), 4.18 (2 H, q, J = 7.0 Hz),
3.40 (1 H, d, JAB = 16.5 Hz), 3.21 (3 H, s), 3.09 (1 H, d,
JAB = 16.5 Hz), 3.09 (3 H, s), 3.07 (3 H, s), 1.33 (3 H, t,
J = 7.0 Hz), 1.26 (3 H, t, J = 7.0 Hz). HRMS: m/z calcd for
C18H25FN3O7S: 446.1397; found: 446.1383.
Compound 2p: 1H NMR (500 MHz, CDCl3): d = 10.36 (1 H,
s), 4.43 (2 H, q, J = 7.0 Hz), 3.60 (3 H, s), 3.13 (1 H, qt,
J = 7.9 Hz), 2.01–1.94 (4 H, m), 1.86–1.78 (2 H, m), 1.69–
1.61 (2 H, m), 1.42 (3 H, t, J = 7.0 Hz). 13C NMR (125 MHz,
CDCl3): d = 169.6, 159.2, 154.1, 148.0, 124.6, 62.5, 43.1,
31.3, 31.1, 25.7, 14.2. HRMS: m/z calcd for C13H19N2O4 [M
+ H]: 267.1345; found: 267.1337. Anal. Calcd for
Compound 6i: yield 86%. 1H NMR (500 MHz, CDCl3): d =
4.32–4.19 (2 H, m), 4.14 (2 H, q, J = 7.0 Hz), 3.72–3.67 (1
H, m), 3.23 (1 H, d, JAB = 15.9 Hz), 2.88 (1 H, d, JAB = 15.9
Hz), 1.98 (3 H, s), 1.30 (3 H, t, J = 7.0 Hz), 1.25–1.20 (9 H,
m). 13C NMR (125 MHz, CDCl3): d = 168.9, 168.4, 162.5,
102.9, 61.9, 60.9, 53.2, 42.9, 19.2, 19.0, 14.21, 14.16, 13.0.
HRMS: m/z calcd for C13H23N2O5 [M + H]: 287.1607;
found: 287.1606.
C13H18N2O4: C, 58.63; H, 6.81; N, 10.52. Found: C, 58.63;
H, 6.72; N, 10.49.
Compound 6b: yield 75%. 1H NMR (500 MHz, CDCl3): d =
7.61–7.57 (1 H, m), 7.51–7.47 (1 H, m), 7.26–7.21 (1 H, m),
4.35–4.10 (4 H, m), 3.40 (1 H, d, JAB = 16.5 Hz), 3.17 (3 H,
s), 3.02 (1 H, d, JAB = 16.5 Hz), 1.32 (3 H, t, J = 7.0 Hz), 1.24
(3 H, t, J = 7.0 Hz). HRMS: m/z calcd for C16H19N2O5F2
Synlett 2008, No. 4, 547–550 © Thieme Stuttgart · New York

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