Synthesis of 2-chloro-3-oxoesters by reaction of the dianion of ethyl 2-chloroacetoacetate with electrophiles

Article abstract of DOI:10.1007/s00706-012-0897-z

2-Chloro-3-oxoalkanoates and related molecules were prepared by regioselective reaction of the dianion of ethyl 2-chloroacetoacetate with alkyl halides and other electrophiles. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-012-0897-z

Monatsh Chem
DOI 10.1007/s00706-012-0897-z
ORIGINAL PAPER
Synthesis of 2-chloro-3-oxoesters by reaction of the dianion
of ethyl 2-chloroacetoacetate with electrophiles
•
Verena Specowius Thomas Rahn Muhammad Adeel Stefanie Reim
•
•
•
•
Holger Feist Ashot S. Saghyan Peter Langer
•
Received: 8 June 2012 / Accepted: 4 December 2012
Ó Springer-Verlag Wien 2013
Abstract 2-Chloro-3-oxoalkanoates and related mole-
cules were prepared by regioselective reaction of the
dianion of ethyl 2-chloroacetoacetate with alkyl halides
and other electrophiles.
(examples of pharmacologically active chlorinated natural
products and drugs include griseofulvin [1–7] and dihydro-
nidulin [8]). In fact, in many cases, they show better
pharmacological activities than their chloride-free derivatives
(for an example from our laboratory, see [9, 10]). Chloroa-
renes and chlorohetarenes are building blocks in transition
metal catalyzed cross-coupling reactions [11]. As difficulties
(such as low regioselectivity or multiple chlorination) are
often encountered during the direct chlorination of arenes,
hetarenes, and open-chain molecules, chloride-containing
building blocks play an important role in condensation and
cyclization reactions. For example, Manzanares and
coworkers reported the synthesis of a 4-chlorophenol by the
[4 ? 2] cycloaddition of a chlorinated thiophene to dimethyl
acetylenedicarboxylate [12]. We have also previously repor-
ted cyclocondensation reactions of 2- and 4-chloro-1-ethoxy-
1,3-bis(silyloxy)-1,3-butadiene, which are derived from ethyl
2-chloroacetoacetate and ethyl 4-chloroacetoacetate, respec-
tively[13, 14]. Despitethefactthatchlorinated1,3-dicarbonyl
compounds play an important role as building blocks, no
general strategy for their preparation has been reported.
Herein, we describe the synthesis of various 2-chloro-3-
oxoalkanoates and related chlorinated molecules by what
are—to the best of our knowledge—the first reactions of the
dianion of ethyl 2-chloroacetoacetate with alkyl halides and
other electrophiles.
Keywords Dianions ꢀ Condensation ꢀ
Organochlorine compounds ꢀ Ketones ꢀ Esters ꢀ
Regioselectivity
Introduction
Chlorinated arenes and hetarenes occur in a number of natural
products and are lead structures in medicinal chemistry
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-012-0897-z) contains supplementary
material, which is available to authorized users.
V. Specowius ꢀ T. Rahn ꢀ M. Adeel ꢀ S. Reim ꢀ H. Feist ꢀ
P. Langer (&)
¨
Institut fu¨r Chemie, Universitat Rostock, Albert Einstein Str. 3a,
18059 Rostock, Germany
e-mail: peter.langer@uni-rostock.de
P. Langer
Leibniz-Institut fu¨r Katalyse an der Universitat Rostock e.V.,
¨
Albert Einstein Str. 29a, 18059 Rostock, Germany
T. Rahn ꢀ M. Adeel
Department of Chemistry, Gomal University Dera Ismael Khan,
Khyber-Pakhtunkhwa, Dera Ismael Khan, Pakistan
Results and discussion
A. S. Saghyan
Scientific and Production Center ‘‘Armbiotechnology’’
of NAS RA, Gyurjyan str. 14, 0056 Yerevan, Armenia
Treatment of commercially available ethyl 2-chloroace-
toacetate (1) with LDA (2.3 equiv.) and the subsequent
addition of alkyl halides 2a–2g afforded the 2-chloro-3-
oxoalkanoates 3a–3g in yields of 57–85 % (Scheme 1;
Table 1).
A. S. Saghyan
Department of Chemistry, Yerevan State University,
Alex Manoogian 1, 0025 Yerevan, Armenia
123

V. Specowius et al.
Scheme 1
Scheme 2
R X
2a-2g
Br
O
O
O
O
Cl
Br
O
O
O
R
OEt
O
OEt
OEt
OEt
i
Cl
Cl
3a-3g
i
Cl
1
4 (65%)
1
X = Br, I
R = Alkyl
i: LDA (2.5 equiv.), THF, 1 (1 equiv.), 1,4-dibromobut-2-ene (1.2 equiv.), -
→
78 20 °C
Scheme 2
i: 1) LDA (2.5 equiv.), THF, 0 °C, 1 h; 2) 2a-2g (1.2 equiv.), -78 → 20 °C,
12 h.
Scheme 1
Scheme 3
O
O
O
O
O
Table 1 Synthesis of 3a–3g
ClCO2Et
EtO
OEt
OEt
R
Yield of 3/ %a
Cl
5 (27%)
i
Cl
3a
3b
3c
3d
3e
3f
3g
a
Me
57
68
85
70
60
59
64
1
Et
i: LDA (2.2 equiv.), THF, ethyl chloroformate (1.1 equiv.), -78 → 20 °C
Scheme 3
n-Pr
n-Bu
n-Pent
PhCH2
n-Hept
Scheme 4
O
O
O
OH O
O
Ar
H
OEt
Ar
OEt
Isolated yields
i
Cl
Cl
1
6a-6d
Treatment of the dianion of 1 with (E)-1,4-dibromobut-2-
i: 1) LDA (2.2 equiv.), THF, -78 → 20 °C; 2) NH4Cl, H2O
Scheme 4
ene gave the Z-configured 5-vinyl-2-alkylidenetetrahy-
drofuran 4 (Scheme 2). The fo0rmation of the products can be
explained by a domino SN/SN cyclization (for related reac-
tions of nonchlorinated 1,3-dicarbonyl dianions, see [15–17]).
Treatment of the dianion of 1 with ethyl chloroformate
afforded the novel 1,3,5-tricarbonyl compound 5, albeit in
low yield (Scheme 3). The compound exclusively resides
in the keto tautomeric form. The yield could not be opti-
mized under various conditions.
Table 2 Synthesis of 6a–6d
R
Yield of 6 %a
6a
6b
6c
6d
a
4-(O2N)C6H4
15
30
43
12
C6H5
The reaction of the dianion of 1 with various benzalde-
hydes gave the 2-chloro-5-hydroxy-3-oxoesters 6a–6d in
low to moderate yields (Scheme 4; Table 2). The relative
configurations could not be determined unambiguously. The
yields of products 6a and 6d derived from an electron-poor
and electron-rich benzaldehyde, respectively, were lower
than those of products 6b and 6c derived from the parent
benzaldehyde and 4-fluorobenzaldehyde, respectively.
These relatively low yields, which could not be optimized
under various conditions, can be accounted for by the
decomposition of the product during the reaction or losses
during the chromatography. However, no side products
could be isolated. The synthesis of 3-oxotetrahydrofurans by
the base-mediated attack of the alcohol oxygen on the
chloride group was not possible under various conditions.
4-FC6H4
4-(MeO)C6H4
Isolated yields; products were isolated as a mixture of diastereo-
mers (dr = 9:1)
diethyl 2-chloro-3-oxo-pentane-1,5-dioate, and 2-chloro-5-
hydroxy-3-oxoesters by regioselective reaction of the
dianion of ethyl 2-chloroacetoacetate with alkyl halides, 1,4-
dibromobut-2-ene, ethyl chloroformate, and benzaldehydes.
Experimental
1H NMR spectra were taken in CDCl3 at 250 and
300 MHz, respectively. 13C NMR spectra were taken in
CDCl3 at 62.5 and 75 MHz, respectively. Chemical shifts
are reported in parts per million, using the solvent as the
internal standard (chloroform, 7.26 and 77.0 ppm, respec-
tively). Infrared spectra were recorded on a FT-IR
spectrometer. Mass spectrometric data (MS) were obtained
Conclusions
In conclusion, we have reported the synthesis of 2-chloro-3-
oxoalkanoates, a chlorinated 2-alkylidenetetrahydrofuran,
123

Synthesis of 2-chloro-3-oxoesters
CH2, OCH2CH3), 1.56–1.66 (m, 2H, CH2), 2.65–2.71 (m, 2H,
CH2), 4.27 (q, 3J = 7.2 Hz, 2H, OCH2CH3), 4.76 (s, 1H, CH)
ppm; 13C NMR (CDCl3, 75 MHz): d = 13.8 (CH3), 13.9
(OCH2CH3), 22.3 (CH2), 23.1 (CH2), 31.0 (CH2), 38.8 (CH2),
60.9 (CH), 63.0 (OCH2CH3), 165.1 (COOEt), 199.0 (C = O)
by electron ionization (EI, 70 eV), chemical ionization (CI,
isobutane), or electrospray ionization (ESI). Analytical
thin-layer chromatography was performed on 0.20 mm 60
˚
A silica gel plates. Column chromatography was performed
˚
on 60 A silica gel (60–200 mesh). All cyclization reactions
ꢀ
ppm; IR (ATR): m = 2,968 (w), 2,933 (w), 2,872 (w), 1,726
were carried out in Schlenk tubes under an argon atmo-
sphere using dried solvents.
(s), 1,643 (w), 1,606 (w), 1,466 (m), 1,402 (w), 1,377 (w),
1,369 (w), 1,299 (w), 1,247 (s), 1,176 (w), 1,095 (w), 1,061
(w), 1,021 (s) cm-1; MS (EI, 70 eV): m/z (%) = 222 ([M]?,
[37Cl], 1), 220 ([M]?, [35Cl], 2), 99 (100), 71 (46), 55 (11), 43
(48), 41 (13), 29 (15); HRMS (EI): calcd. for C10H17ClO3
([M]?, [35Cl]) 220.08607, found 220.085675.
Typical procedure for the synthesis of ethyl 2-chloro-3-
oxoalkanoates 3a–3g and the synthesis of 4 and 5
To a solution of 3.5 cm3 diisopropylamine (25.0 mmol) in
25 cm3 THF were added 9.8 cm3 n-butyllithium
(25.0 mmol) at 0 °C. After stirring for 30 min, 1.4 cm3
1 (10.0 mmol) were added and the solution was stirred
for 1 h. The solution was cooled to -78 °C and 0.75 cm3
iodoalkane 2a (12.0 mmol) were added by syringe. The
mixture was allowed to slowly warm to 20 °C over the
course of 14 h. To the mixture were added 100 cm3
hydrochloric acid (10 %), and the resulting mixture was
extracted with diethyl ether (3 9 100 cm3). The combined
organic layers were dried (Na2SO4), filtered, and the filtrate
was concentrated in vacuo. The residue was purified by
chromatography (silica gel, n-heptane/EtOAc = 10:1).
Ethyl 2-chloro-3-oxononanoate (3e)
Starting with 3.5 cm3 diisopropylamine (25.0 mmol) in
25.0 cm3 tetrahydrofuran, 9.8 cm3 butyllithium (25.0 mmol),
1.4 cm3 1 (10.0 mmol), and 1.57 cm3 2e (12.0 mmol), 3e
(1,417 mg, 60 %) was isolated as a yellow oil (keto/
enol = 10:8). The spectroscopic data are identical to those
reported previously [21].
Ethyl 2-chloro-3-oxo-5-phenylpentanoate (3f)
Starting with 3.5 cm3 diisopropylamine (25.0 mmol) in
25.0 cm3 tetrahydrofuran, 9.8 cm3 butyllithium (25.0 mmol),
1.4 cm3 1 (10.0 mmol), and 2053 mg 2f (1.44 cm3,
12.0 mmol), 3f was isolated as a brownish oil (1503 mg,
59 %). 1HNMRdataareidenticaltothosereportedpreviously
[22, 23].
Ethyl 2-chloro-3-oxopentanoate (3a)
Starting with 3.5 cm3 diisopropylamine (25.0 mmol) in
25.0 cm3 tetrahydrofuran, 9.8 cm3 butyllithium (25.0 mmol),
1.4 cm3 1 (10.0 mmol), and 0.75 cm3 2a (12.0 mmol), 3a
(1,025 mg, 57 %) was isolated as a yellow oil. The spectro-
scopic data are identical to those reported previously [18].
Ethyl 2-chloro-3-oxoundecanoate (3g, C13H23ClO3)
Starting with 3.5 cm3 diisopropylamine (25.0 mmol) in
25.0 cm3 tetrahydrofuran, 9.8 cm3 butyllithium (25.0 mmol),
1.4 cm3 1 (10.0 mmol), and 2,727 mg 2g (1.98 cm3,
12.0 mmol), 3g was isolated as a red oil (1,690 mg, 64 %).
1H NMR (CDCl3, 250 MHz): d = 0.86 (t, 3J = 6.8 Hz, 3H,
CH3), 1.26–1.38 (m, 13H, OCH2CH3, CH2), 1.58–1.64 (m,
2H, CH2), 2.64–2.74 (m, 2H, CH2), 4.28 (q, 3J = 7.1 Hz, 2H,
OCH2CH3), 4.76 (s, 1H, CH) ppm; 13C NMR (CDCl3,
62.5 MHz): d = 13.9 (CH3), 14.0 (OCH2CH3), 22.6 (CH2),
23.5 (CH2), 28.9 (CH2), 29.0 (CH2), 29.2 (CH2), 31.7 (CH2),
38.9 (CH2), 60.9 (CH), 63.1 (OCH2CH3), 165.1 (COOEt),
Ethyl 2-chloro-3-oxohexanoate (3b)
Starting with 3.5 cm3 diisopropylamine (25.0 mmol) in
25.0 cm3 tetrahydrofuran, 9.8 cm3 n-butyllithium(25.0mmol),
1.4 cm3 1 (10.0 mmol), and 1.17 cm3 2b (12.0 mmol), 3b
(1,116 mg, 68 %) was isolated as a yellow oil. The spectro-
scopic data are identical to those reported previously [18].
Ethyl 2-chloro-3-oxoheptanoate (3c)
Starting with 3.5 cm3 diisopropylamine (25.0 mmol) in
25.0 cm3 tetrahydrofuran, 9.8 cm3 butyllithium (25.0 mmol),
1.4 cm3 1 (10.0 mmol), and 1.17 cm3 2c (12.0 mmol), 3c
(1,753 mg, 85 %) was isolated as a colorless oil. The
spectroscopic data are identical to those reported previously
[19].
ꢀ
199.1 (C = O) ppm; IR (ATR): m = 2,925 (s), 2,855 (s),
1,726 (s), 1,642 (w), 1,605 (m), 1,465 (m), 1,402 (w), 1,377
(w), 1,300 (w), 1,248 (s), 1,176 (w), 1,095 (m), 1,064 (m),
1,022 (s) cm-1; MS (EI, 70 eV): m/z (%) = 264 ([M]?,
[37Cl], 1), 262 ([M]?, [35Cl], 1), 142 (10), 141 (100), 129 (11),
81 (12), 71 (54), 69 (13), 57 (59), 55 (25), 43 (34), 41 (29), 29
(23); HRMS (EI): calcd. for C13H23ClO3 ([M]?,
[35Cl]) 262.13302, found 262.132970.
Ethyl 2-chloro-3-oxooctanoate (3d)
Starting with 3.5 cm3 diisopropylamine (25.0 mmol) in
25.0 cm3 tetrahydrofuran, 9.8 cm3 butyllithium (25.0 mmol),
1.4 cm3 1 (10.0 mmol), and 1.37 cm3 2d (12.0 mmol), 3d
(1,528 mg, 70 %) was isolated as a yellow oil. The prepara-
tion of this compound was reported previously [20], but
Ethyl (Z)-2-chloro-2-(5-vinyldihydrofuran-2(3H)-
ylidene)acetate (4, C10H13ClO3)
Starting with LDA (62.5 mmol), 3.51 cm3 1 (25 mmol),
and 6.41 g trans-1,2-dibromobut-2-ene (30 mmol) at
-78 °C, 4 was isolated as a light yellow oil (3.50 g,
1
spectroscopic data were not provided. H NMR (CDCl3,
300 MHz): d = 0.85–0.91 (m, 3H, CH3), 1.27–1.36 (m, 7H,
123

V. Specowius et al.
65 %). 1H NMR (250 MHz, CDCl3): d = 1.21 (t, 3H,
J = 7.5 Hz, CH3), 1.77–1.92 (m, 1H, CH2), 2.18–2.32 (m,
1H, CH2), 2.92–3.06 (m, 1H, CH2), 3.12–3.25 (m, 1H,
CH2), 4.34 (q, 2 H, J = 7.5 Hz, OCH2), 4.84 (q, 1H,
J = 7.5 Hz, CH), 5.13–5.29 (m, 2 H, C = CH2), 5.72–5.85
(m, 1H, CH) ppm; 13C NMR (75 MHz, CDCl3): d = 14.1
(CH3), 30.1, 31.6 (CH2), 60.8 (CH2), 85.2 (CH), 95.4 (C),
117.9 (CH2), 135.0 (CH), 164.15 (C), 169.4 (C = O) ppm;
6a was isolated as a yellow oil (0.17 g, 15 %, dr = 90:10).
1H NMR (300 MHz, CDCl3, only signals of the main
diastereomer are listed): d = 1.32 (t, 3J = 7.2 Hz, 3H,
CH3), 2.96–3.26 (m, 2H, CH2), 4.30 (q, J = 7.2 Hz, 2H,
3
CH2), 4.86 (d, J = 5.5 Hz, 1H, CHOH), 5.31–5.37 (br,
1H, CHOH), 7.57 (d, 3J = 8.9 Hz, 2H, Ar), 8.21 (d,
3J = 8.7 Hz, 2H, Ar) ppm; 13C NMR (75 MHz, CDCl3):
d = 13.9 (CH3), 47.6 (CH2), 60.8 (CHOH), 63.6 (CH2),
68.9 (CHCl), 123.9, 126.6 (CHAr), 147.5, 149.5 (CAr),
3
ꢀ
IR (ATR): m = 3,087 (w), 2,982 (w), 2,905 (w), 1,744 (w),
ꢀ
1,695 (s), 1,614 (s), 1,367 (m), 1,275 (s), 1,225 (s), 1,059
(s), 936 (s) cm-1; GC–MS (EI, 70 eV): m/z (%) = 218
([M]?, [37Cl], 16), 216 ([M]?, [35Cl], 49), 171 (31), 149
(35), 135 (69), 121 (100), 103 (34); HRMS (EI): calcd. for
C10H13ClO3 ([M]?, [35Cl]) 216.05477, found 216.054810.
164.7, 198.1, 198.5 (CO) ppm; IR (ATR): m = 2,984 (w),
2,942 (w), 2,908 (w), 1,726 (m, br), 1,606 (w), 1,518 (s),
1,345 (s), 1,300 (m, br), 1,250 (m, br), 1,179 (m), 1,064 (m,
br), 1,014 (m), 910 (m), 854 (s), 730 (s) cm-1; HRMS
(ESI): calcd. for C13H14ClNaO6 ([M ? Na]?, [35Cl])
338.04019, found 338.04032.
Diethyl 2-chloro-3-oxopentanedioate (5)
Starting with LDA (22 mmol), 1.64 g 1 (0.91 cm3,
10 mmol), and 1.19 g ethyl chloroformate (1.05 cm3,
11 mmol) at -78 °C, 5 was obtained as a yellow oil
(639 mg, 27 %). This compound was reported previously
[24, 25], but spectroscopic data were not provided.
1H NMR (250 MHz, CDCl3): d = 1.20–1.34 (m, 6H,
CH3), 3.50–3.80 (m, 2H, CH2), 4.12–4.29 (m, 4H,
OCH2), 4.98 (s, 1H, CH) ppm; 13C NMR (75 MHz,
CDCl3): d = 13.6 (2C, CH3), 45.1 (CH2), 60.4 (CH),
61.6 (OCH2), 63.0 (OCH2), 164.1, 165.7, 191.4 (C = O)
Ethyl 2-chloro-5-hydroxy-3-oxo-5-phenylpentanoate
(6b, C13H15ClO4)
Starting with LDA (10.0 mmol) in 10 cm3 THF, 0.55 cm3
1 (4.0 mmol), and 0.49 cm3 benzaldehyde (4.8 mmol), 6b
was isolated as a yellow oil (0.32 g, 30 %, dr = 90:10). 1H
NMR (300 MHz, CDCl3, only signals of the main diaste-
3
reomer are listed): d = 1.29 (t, J = 7.1 Hz, 3H, CH3),
2.88–3.25 (m, 2H, CH2), 4.26 (q, J = 7.2 Hz, 2H, CH2),
3
3
4.65 (s, 1H, CHCl), 4.83 (d, J = 10.4 Hz, 1H, CHOH),
5.17–5.21 (br, 1H, CHOH), 7.24–7.36 (m, 5H, Ph) ppm;
13C NMR (75 MHz, CDCl3): d = 13.9 (CH3), 47.9 (CH2),
61.2 (CHOH), 65.3 (CH2), 70.0 (CHCl), 125.6, 127.0,
128.7 (CHAr), 142.3 (CAr), 164.8, 198.2, 198.6 (CO) ppm;
ꢀ
ppm; IR (ATR): m = 2,984 (m), 2,940 (w), 2,875 (w), 1,727
(s), 1,651 (w), 1,446 (w), 1,369 (m), 1,245 (s), 1,019
(s) cm-1; MS (ESI-TOF/MS) (ESI?): C9H13ClNaO5
([M ? Na]?) 259.03463, (ESI-): C9H12ClO5 ([M-H]-)
235.03787.
ꢀ
IR (ATR): m = 3,064 (w), 3,032 (w), 2,983 (w), 2,940 (w),
1,726 (m, br), 1,605 (w), 1,495 (w), 1,453 (w), 1,369 (w),
1,300 (m), 1,249 (m), 1,179 (m), 1,021 (s), 916 (w), 885
(w), 845 (w), 808 (w), 736 (s), 699 (s) cm-1; HRMS (ESI):
calcd. for C13H15ClNaO4 ([M ? Na]?, [35Cl]) 293.05511,
found 293.05469.
General procedure for the condensation
of benzaldehydes with the dianion of ethyl 2-chloro-3-
oxobutanoate
Ethyl 2-chloro-5-(4-fluorophenyl)-5-hydroxy-3-
oxopentanoate (6c, C13H14ClFO4)
To a solution of diisopropylamine (2.5 equiv.) in THF
(2.5 cm3/mmol) was added n-butyllithium (2.5 equiv.) at
0 °C. After stirring for 30 min, 1 (1.0 equiv.) was added
and the solution was stirred for 1 h. The solution was
cooled to -78 °C and the benzaldehyde (1.2 equiv.) was
added by syringe. The mixture was allowed to slowly warm
to 20 °C for 6 h. To the mixture were added 10 cm3 of an
aqueous solution of ammonium chloride (1.0 M), and the
mixture was extracted with diethyl ether (3 9 10 cm3).
The combined organic layers were dried (Na2SO4), filtered,
and the filtrate was concentrated in vacuo. The residue was
purified by chromatography (silica gel, n-heptane/
EtOAc = 10:1).
Starting with LDA (10.0 mmol) in 10 cm3 THF, 0.55 cm3
1
(4.0 mmol), and 0.51 cm3 4-fluorobenzaldehyde
(4.8 mmol), 6c was isolated as a yellow oil (0.50 g,
43 %, dr = 90:10). 1H NMR (300 MHz, CDCl3, only
signals of the main diastereomer are listed): d = 1.31 (t,
3J = 7.1 Hz, 3H, CH3), 2.87–3.24 (m, 2H, CH2), 4.29 (q,
3J = 7.2 Hz, 2H, CH2), 4.83 (d, 3J = 7.5 Hz, 1H, CHOH),
5.18–5.22 (br, 1H, CHOH), 7.02–7.07 (m, 2H, Ar),
7.32–7.37 (m, 2H, Ar) ppm; 13C NMR (75 MHz, CDCl3):
d = 13.9 (CH3), 47.9 (CH2), 61.1, 61.4 (CHOH), 63.4
2
(CH2), 69.3 (CHCl), 115.5 (d, J = 21.6 Hz, CHAr), 127.4
(d, 4J = 8.4 Hz, CHAr), 138.0 (CAr), 162.4 (d,
1J = 245.9 Hz, CFAr), 164.7 (d, 5J = 5.7 Hz, CO),
198.3, 198.7 (CO) ppm; 19F NMR (282 MHz, CDCl3):
Ethyl 2-chloro-5-hydroxy-5-(4-nitrophenyl)-3-
oxopentanoate (6a, C13H14ClO6)
Starting with LDA (10.0 mmol) in 10 cm3 THF, 0.55 cm3
1 (4.0 mmol), and 0.73 g 4-nitrobenzaldehyde (4.8 mmol),
ꢀ
d = -113.85 (CFAr) ppm; IR (ATR): m = 2,985 (w), 2941
(w), 2,908 (w), 1,727 (m), 1,605 (m), 1,510 (m), 1,467 (w),
123

Synthesis of 2-chloro-3-oxoesters
5. Rosefort C, Fauth E, Zankl H (2004) Mutagenesis 19:277
6. Kinobe RT, Dercho RA, Vlahakis JZ, Brien JF, Szarek WA,
Nakatsu KJ (2006) Pharmacol Exp Ther 319:277
7. Albaugh D, Albert G, Bradford P, Cotter V, Froyd JJ (1998) J
Antibiot 51:317
1,446 (w), 1,369 (w), 1,222 (s), 1,159 (m), 1,097 (m), 1,015
(m), 910 (m), 835 (s), 732 (m) cm-1; HRMS (ESI): calcd.
for C13H14ClFNaO4 ([M ? Na]?, [35Cl]) 311.04569, found
311.04554.
8. Finlay-Jones PF, Sala T, Sargent MV (1981) J Chem Soc Perkin
Trans 1 874
9. Albrecht U, Lalk M, Langer P (2005) Bioorg Med Chem 13:1531
Ethyl 2-chloro-5-hydroxy-5-(4-methoxyphenyl)-3-
oxopentanoate (6d, C14H15ClO4)
Starting with LDA (10.0 mmol) in 10 cm3 THF, 0.55 cm3
¨
10. Nguyen VD, Wolf C, Mader U, Lalk M, Langer P, Lindequist U,
Hecker M, Antelmann H (2007) Proteomics 7:1391
11. de Meijere A, Diederich F (eds) (2004) Metal-catalyzed cross-
coupling reactions. Wiley, Weinheim
12. Corral C, Lissavetzky J, Manzanares I (1997) Synthesis 29
13. Wolf V, Adeel M, Reim S, Villinger A, Fischer C, Langer P
(2009) Eur J Org Chem 5854
1
(4.0 mmol), and 0.58 cm3 4-methoxybenzaldehyde
(4.80 mmol), 6d was isolated as a yellow oil (0.15 g,
12 %, dr = 90:10). 1H NMR (300 MHz, CDCl3, only
signals of the main diastereomer are listed): d = 1.31
3
(t, J = 7.1 Hz, 3H, CH3), 2.88–3.26 (m, 2H, CH2), 3.81
(s, 3H, OCH3), 4.28 (q, 3J = 7.2 Hz, 2H, CH2), 4.84
14. Reim S, Hussain I, Adeel M, Yawer MA, Villinger A, Langer P
(2008) Tetrahedron Lett 49:4901
3
(d, J = 9.2 Hz, 1H, CHOH), 5.14–5.18 (br, 1H, CHOH),
¨
15. Bellur E, Gorls H, Langer P (2005) Eur J Org Chem 2074
3
3
16. Langer P, Krummel T (2001) Chem Eur J 7:1720
17. Bellur E, Langer P (2005) J Org Chem 70:10017
18. Perrone MG, Santandrea E, Dell’Uomo N, Giannessi F, Milazzo
FM, Sciarroni AF, Scilimati A, Tortorella V (2005) Eur J Med
Chem 40:143
6.89 (d, J = 8.9 Hz, 2H, Ar), 7.29 (d, J = 8.7 Hz, 2H,
Ar) ppm; 13C NMR (75 MHz, CDCl3): d = 13.9 (CH3),
47.9 (CH2), 61.2 (CHOH), 63.3 (CH2), 69.7 (CHCl), 114.0,
127.0 (CHAr), 128.7, 134.5 (CAr), 159.4, 198.3, 198.7 (CO)
19. Kitamura T, Tazawa Y, Morshed MH, Kobayashi S (2012)
Synthesis 44:1159
20. Guthrie RW, Kaplan GL, Mennona FA, Tilley JW, Kierstead
RW, O’Donnell M, Crowley H, Yaremko B, Welton A (1990) J
Med Chem 33:2856
21. Uchida H, Asagarasu A, Matsui T (2012) Preparation of hetero-
cyclic carbamate and carboxylic acid hydrazide compounds as
p27Kip1 degradation inhibitors. PCT Int Appl WO 2012002527,
Chem Abstr 156:148439
ꢀ
ppm; IR (ATR): m = 2,979 (w), 2,937 (w), 2,839 (w),
1,741 (w, br), 1,593 (m), 1,511 (m), 1,463 (w), 1,443 (w),
1,424 (w), 1,398 (w), 1,375 (m), 1,341 (w, br), 1,298 (m),
1,248 (s), 1,171 (s), 1,112 (m), 1,063 (m), 1,024 (s), 980
(m, br), 826 (m) cm-1; HRMS (ESI): calcd. for
C14H16ClO4 ([M ? H]?, [35Cl]) 283.07316, found
283.07299.
22. Tsai A-I, Chuang C-P (2008) Tetrahedron 64:5098
23. Conner SE, Knobelsdorg JA, Mantlo NB, Mayhugh DR, Wang X,
Zhu G, Schkeryantz JM, Michellys P-Y (2004) Preparation of
indole derivatives as PPAR modulators of treatment of diabetes
mellitus. PCT Int Appl WO 2004092131, Chem Abstr
141:379802
24. Ban Y, Terashima M (1965) Chem Pharm Bull 13:775
25. Gardinier KM, Garmene DJ, Hembre EJ, Brunavs M, Szekeres
HJ (2008) Thiazolopyridinone derivatives as MCH receptor
antagonists and their preparation, pharmaceutical compositions
and use in the treatment of obesity. PCT Int Appl WO
2008076562, Chem Abstr 149:104678
Acknowledgments Financial support from the State of Mecklen-
burg-Vorpommern is gratefully acknowledged.
References
1. Osborne CS, Leitner I, Hofbauer B, Fielding CA, Favre B, Ryder
NS (2006) Antimicrob Agents Chemother 50:2234
2. Takano R, Sugano K, Higashida A, Hayashi Y, Machida M, Aso
Y, Yamashita S (2006) Pharm Res 23:1144
3. Xue C, Li T, Deng Z, Fu H, Lin W (2006) Pharmazie 61:1041
4. Phelps JB, Hoffman WP, Lee C, Murphy GP, Garriott ML (2004)
Mutat Res 561:153
123