Regioselective γ-alkylation of tert-butyl 2,4-dioxopiperidine-1- carboxylate

Article abstract of DOI:10.1055/s-2007-990792

A method for the regioselective γ-alkylation of N-Boc protected piperidine-2,4-dione is reported. The use of a wide variety of electrophiles demonstrates the robustness of the procedure. The reaction offers facile access to synthetically useful derivatives. A mechanistic hypothesis is given, explaining the essential role played by the lithium counter-ion. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990792

PAPER
3185
Regioselective g-Alkylation of tert-Butyl 2,4-Dioxopiperidine-1-carboxylate
Synthesis of
ga
o
l
e
ridine
o
s
Orsini,* Alessandro Maccario, Nicoletta Colombo
Department of Chemistry, B.U. Oncology, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI), Italy
Fax +39(0331)581347; E-mail: paolo.orsini@nervianoms.com
Received 19 February 2007; revised 18 July 2007
the literature regarding applications to ring-systems such
as lactones and lactams.
Abstract: A method for the regioselective g-alkylation of N-Boc
protected piperidine-2,4-dione is reported. The use of a wide variety
of electrophiles demonstrates the robustness of the procedure. The
reaction offers facile access to synthetically useful derivatives. A
mechanistic hypothesis is given, explaining the essential role played
by the lithium counter-ion.
While trying to obtain 5-substituted 2,4-dioxopiperidines
(2), we found that it is possible to directly introduce an
alkyl moiety in position 5 by reacting tert-butyl 2,4-di-
oxopiperidine-1-carboxylate (1) with different alkyl ha-
lides (Scheme 1) under basic conditions.
Key words: g-alkylation, regioselectivity, carbanions, b-keto-
amides, piperidine-2,4-dione
Preparation of the starting material 1 was accomplished
on multigram scale, in two steps, in 65% overall yield
(Scheme 2). Commercially available N-Boc-b-alanine
was activated with N-ethyl-N-(3-dimethylaminopro-
pyl)carbodiimide (EDC), condensed with 2,2-dimethyl-
1,3-dioxane-4,6-dione (Meldrum’s acid), and finally cy-
clized to give the Boc-protected piperidine-2,4-dione (1).
1,3-Dicarbonyl derivatives, bearing both electrophilic and
nucleophilic centers, constitute very important and widely
used synthetic tools in organic synthesis1,2 since they can
be versatile intermediates for the selective construction of
more complex structures.
Given the easy access to piperidindione 1, alkylation of
the corresponding dianion-enolate was explored. Unfortu-
nately, the aforementioned Weiler procedure, involving
NaH/BuLi or LDA in THF and n-PrBr as a test electro-
phile, proved unsatisfactory in terms of yield (<40%) and
a considerable amount of starting material was recovered
after work-up. We thus decided to seek new conditions
and were pleased to find that selective g-alkylation of 1
could be accomplished by using n-PrBr/LiHMDS in THF
at –20 °C. The desired 5-propyl derivative 2b was ob-
tained after Boc removal (HCl/THF), in 70% overall
yield. Interestingly, improved yields could be obtained by
adding the base to a previously cooled solution containing
both the piperidindione and the alkylating agent. Reaction
temperature and reaction time seemed to be critical pa-
In the course of a program aimed at finding a new, low-
molecular-weight kinase inhibitor,3,4 we had to devise an
efficient synthesis of 5-substituted 2,4-dioxopiperidines
(2) as precursors for new heterocycles. We needed to pre-
pare a series of such compounds and were particularly in-
terested in 5-alkyl derivatives.
Although a large variety of b-ketoesters have been in-
volved in g-alkylation reactions, quite surprisingly, utili-
zation of cyclic compounds such as b-ketolactones or b-
ketolactams has not stimulated much interest so far. In
fact, whereas direct g-alkylation of b-ketoesters with alkyl
halides via the corresponding dianions is a well-known
procedure, being mainly referred as Weiler alkylation,5,6
to the best of our knowledge, no reports have appeared in
O
O
O
O
O
H+
2
R-X, base
THF
N
O
NH
3
N1
O
6
O
O
O
4
5
R
R
2
1
Scheme 1
O
O
O
O
O
O
EDC, DMAP
Boc
EtOAc
N
Boc
Boc
N
O
Meldrum's acid
N
OH
∆
H
H
O
1
Scheme 2
SYNTHESIS 2007, No. 20, pp 3185–3190
x
x.
x
x
.
2
0
0
7
Advanced online publication: 21.09.2007
DOI: 10.1055/s-2007-990792; Art ID: T03507SS
© Georg Thieme Verlag Stuttgart · New York

3186
P. Orsini et al.
PAPER
Table 1 Synthesis of g-Alkylated 2,4-Dioxopiperidine
O
O
3–5 equiv R-X
2.5 equiv LiHMDS
O
R
O
O
R
HCl, THF
N
O
N
O
NH
0.15 M in THF
–20 °C
O
O
O
1.5 h
1
2a–p
Entry
RX
Product
2a
Yield
84
1
2
3
Br
I
2a
88
2a
n.r.a
O
O
S
O
4
5
2a
2a
n.r.a
n.r.a
O
O
S
O
O
CF3
O
S
O
6
7
2b
2b
2c
2c
2d
75
Br
Cl
n.r.a
72
8
O
O
Br
9
n.r.a
40
Cl
10
Br
11
2e
<10
Br
12
13
14
15
2f
2g
2h
2i
55
n.r.a
49
I
Br
Br
O
84
Br
16
17
2l
87
76
O
Br
2m
O
Br
18
19
2n
2o
70
85
Cl
Br
Br
20
2p
98
Br
a No reaction.
Synthesis 2007, No. 20, 3185–3190 © Thieme Stuttgart · New York

PAPER
Synthesis of g-Alkylated 2,4-Dioxopiperidines
3187
M
N
O
O
O
O
O
O
M+B–
N
O
O
N
O
M
O
O
O
1
A
M+B–
M
N
O
O
O
B
M
O
Scheme 3
rameters. Alkylation at –78 °C proceeded sluggishly, were obtained using NaHMDS and no reaction at all was
while raising the temperature to 0 °C or to room tempera- seen with KHMDS.
ture, led to the formation of a number of side-products. It
was also found that g,g-dialkylated products are obtained
This trend can be rationalized by invoking a six-mem-
bered ring (Scheme 3) in which the carbonyl of the Boc
after prolonged reaction times. In terms of experimental
protecting group and the counter-ion play an essential
conditions, the best compromise was reached by main-
role.
taining the temperature at around –20 °C and conducting
We suggest that addition of the first equivalent of base
the reaction for 1–1.5 hours in the presence of 3–5 equiv-
alents of alkylating agent. Under such conditions, spectral
analysis of the crude reaction mixture failed to give any
evidence of O-alkylated products.
(M+B–) generates the mono-enolate A (Scheme 3). In-
deed, HPLC-MS analysis of the reaction mixture
quenched with tert-butyldimethyltrifluoromethoxysilane,
after addition of one equivalent of base, showed the pres-
ence of two O-silyl derivatives, presumably the two pos-
sible silyl derivatives of enolate A. After addition of the
second equivalent of base, the equilibrium moves towards
the reactive intermediate B, which is more stable and thus
more easily formed when M = Li. Differences in reactivi-
Having succeeded in developing a practical synthesis of
5-propyl-2,4-dioxopiperidine (2b), we then focused our
attention on the general applicability of the g-alkylation of
tert-butyl 2,4-dioxopiperidine-1-carboxylate (1; Table 1)
using the optimized procedure.
First, we studied the effect of the electrophile on alkyla- ty in the series Li>Na>K can be rationalized taking into
tion yields. Among several leaving groups, only iodo and account the size of the cation, the degree of salt dissocia-
bromo gave good results, while reactions with the corre- tion and the chelating effect of the lithium cation.7
sponding chloride, tosylate, triflate and mesylate were un-
In order to study the importance of having both the carbo-
successful (entries 1–5). Interestingly, the great difference
nyl of the Boc-protecting group and the lithium counter-
in reactivity between bromo and chloro derivatives (en-
ion, we performed two further experiments: 1) the alkyla-
tion on the N-ethyl-substituted 2,4-dioxopiperidone 3 and
2) the use of additive LiBr as font of lithium ions in the re-
tries 6–9), allows the chlorinated products, with a further
point of reactivity, to be obtained directly without the use
of protecting groups (entry 18). It appears evident that
action mixture.
these reactions are severely affected by steric hindrance
Preparation of N-ethyl-2,4-dioxopiperidine (3) was ac-
on the electrophilic partner (entries 10–14), unless the re-
complished in four steps (Scheme 4) by using slight mod-
agents are highly activated for nucleophilic substitutions
ifications of a synthesis already reported in the literature.8
(entries 19–20). Protected functional groups seem to be
well tolerated (entries 15–17). It is noteworthy that this
procedure has been successfully scaled up and applied to
75 grams of starting material.
Michael addition of ethyl acrylate with ethylamine, fol-
lowed by coupling with ethyl malonyl chloride and subse-
quent Dieckmann condensation in the presence of sodium
ethoxide, gave intermediate 4. Subsequent hydrolysis and
decarboxylation afforded the desired substrate 3. All at-
tempts to alkylate the ethyl derivative 3 using the opti-
mized protocol, in the presence of bromopropane, failed.
This observation underlines the importance of having a
moiety such as a carbonyl group that is able to coordinate
the counter-ion and stabilize the six-membered-ring inter-
mediate.
Having a procedure with which to directly introduce g-
substituents on the piperidin-2,4-dione skeleton in hand,
we turned out our attention to fine-tuning the effect of the
base. We were particularly interested in exploring the dif-
ferential reactivity of lithium, sodium and potassium salts
of hexamethyldisilazide (HMDS). Quite surprisingly,
only LiHMDS gave good results, while very low yields
Synthesis 2007, No. 20, 3185–3190 © Thieme Stuttgart · New York

3188
P. Orsini et al.
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O
O
COOEt
Et3N
52% (2 steps)
Cl
NaOEt
THF
NH2
EtOOC
EtOOC
COOEt
COOEt
N
N
∆
H
THF
4
O
O
EtOOC
O
HCl 5%
N
N
∆
O
55% (2 steps)
3
Scheme 4
Table 2 Effect of LiBr Additive
O
O
O
O
O
O
n-PrBr, THF, –20 °C
HCl, THF
N
O
N
NH
base
additive
O
O
O
2b
1
Entry
Base
Additive
Product
2b
Yield (%)
75
1
2
3
4
5
LiHMDS
NaHMDS
NaHMDS
KHMDS
KHMDS
–
–
2b
<10
65
LiBr
–
2b
2b
n.r.a
45
LiBr
2b
a No reaction.
a Finnigan LCQ ion trap. Exact mass data ESI(+) were obtained on
a Waters Q-TOF Ultima instrument, directly connected with micro
HPLC 1100 Agilent as previously described.9 Flash column chro-
matographic separations were carried out on 40/60 mm silica gel
(Carlo Erba). Thin-layer chromatography was performed on What-
man silica gel 60 plates coated with a 250 mm layer containing flu-
orescent indicator. Components were visualized by iodine vapor.
All experiments dealing with moisture-sensitive compounds were
conducted under dry nitrogen. Starting materials, unless otherwise
specified, were commercially available (Aldrich, Fluka), of the best
grade and were used without further purification.
We then focused our attention on the possibility of using
LiBr as a source of lithium ions. As reported in Table 2,
by adding LiBr in the alkylation procedure involving the
use of NaHMDS or KHMDS, conversion of N-Boc-2,4-
dioxopiperidine (1) into its g-alkylated derivatives was
accomplished in moderate to good yields (entries 3 and 5),
thus supporting the suggestion that the lithium counter-
ion is involved in the reaction mechanism.
In conclusion, we have developed a facile and efficient
protocol for the regioselective g-alkylation of tert-butyl
2,4-dioxopiperidine-1-carboxylate to form useful inter-
mediates in the synthesis of nitrogen heterocycles.3,4
Benefits of this method arise from the use of easily avail-
able starting materials and practical experimental condi-
tions that allow easy scale-up of this procedure.
tert-Butyl 2,4-Dioxopiperidine-1-carboxylate (1)
Boc-b-alanine (25 g, 132 mmol), Meldrum’s acid (1.1 equiv, 145
mmol, 20.9 g) and DMAP (1.5 equiv, 198 mmol, 24.2 g) were dis-
solved in anhydrous CH2Cl2 (700 mL) at 0 °C under a nitrogen at-
mosphere. EDC hydrochloride (1.2 equiv, 158 mmol, 30.4 g) was
added and the resulting solution was allowed to reach r.t. and stirred
overnight. The reaction mixture was washed with aq KHSO4 (5%,
4 × 500 mL) and the organic layer was taken and dried (Na2SO4),
filtered and evaporated under vacuum. The crude intermediate was
dissolved in EtOAc (600 mL) and refluxed for 4 h. The solvent was
reduced to 150 mL under vacuum and the resulting solution was al-
lowed to crystallize at 4 °C overnight. The solid was filtered off and
washed with cooled EtOAc to afford the product 1.
1H NMR spectra were recorded on a Varian INOVA 400 spectrom-
eter, equipped with a pulse field gradient accessory (PFG) and a 5
1
mm H{15N-31P} z-axis-PFG indirect detection probe. 13C NMR
data were obtained by heteronuclear correlation spectra (H–C) re-
corded on a Varian Unity INOVA 500 spectrometer, equipped with
triple resonance 1H{13C, 15N} indirect detection Cold-Probe. Chem-
ical shifts were referenced with respect to the residual solvent sig-
nals (DMSO-d6: 2.50 ppm for 1H and 39.5 ppm for 13C). Tautomeric
keto-enolic equilibrium, which is highly solvent-dependent, is al-
ways present in 1 and 2a–p derivatives; reported NMR data refer to
the major isomer. Electrospray (ESI) mass spectra were obtained on
Yield: 86.3 mmol (65.4%).
1H NMR (400 MHz, DMSO-d6): d = 1.44 (s, 9 H), 2.43 (t, J = 6.6
Hz, 2 H), 3.70 (t, J = 6.6 Hz, 2 H), 4.94 (s, 1 H), 11.12 (br s, 1 H).
Synthesis 2007, No. 20, 3185–3190 © Thieme Stuttgart · New York

PAPER
Synthesis of g-Alkylated 2,4-Dioxopiperidines
3189
13C NMR (125 MHz, DMSO-d6): d = 27.5, 27.6, 41.6, 96.0, 152.5,
5-Isobutylpiperidine-2,4-dione (2f)
165.6, 172.7.
1H NMR (400 MHz, DMSO-d6): d = 0.86 (d, J = 6.5 Hz, 3 H), 0.89
(d, J = 6.5 Hz, 3 H), 1.16 (m, 1 H), 1.53 (m, 1 H), 1.58–1.66 (m,
1 H), 2.49 (m, 1 H), 3.05–3.13 (m, 1 H), 3.21–3.38 (m, 2 H), 3.34
(m, 1 H), 8.03 (br s, 1 H).
MS (ESI): m/z (%) = 214 (100) [MH+].
HRMS (ESI): m/z [M + H]+ calcd for C10H15NO4: 214.1074; found:
214.1071.
13C NMR (125 MHz, DMSO-d6): d = 21.6, 22.5, 24.7, 35.8, 41.1,
47.9, 44.6, 168.1, 206.5.
MS (ESI): m/z (%) = 171 (100) [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C9H15NO2: 170.1175; found:
Regioselective g-Alkylation; Typical Procedure
LiHMDS (1 M in THF, 7.5 mL) was added dropwise to a stirred so-
lution of tert-butyl 2,4-dioxopiperidine-1-carboxylate (1; 0.64 g, 3
mmol) and n-propyl bromide (1.47 g, 12 mmol) in anhydrous THF
(25 mL) at –20 °C under nitrogen. The mixture was stirred for 1.5 h
at –20 °C, diluted with CH2Cl2 (300 mL) and washed with KHSO4
(5%, 300 mL). The organic phase was dried (Na2SO4), filtered and
concentrated in vacuo. The crude residue was dissolved in THF (60
mL) and HCl (4 M in dioxane, 6 mL) was added. The reaction mix-
ture was stirred at r.t. for 16 h then the solvent was evaporated and
the crude material was purified by column chromatography
(CH2Cl2–EtOH, 100:2) to give the desired product 2b (0.35 g, 75%
yield).
170.1178.
5-Isoproylpiperidine-2,4-dione (2g)
1H NMR (400 MHz, DMSO-d6): d = 0.85 (d, J = 6.9 Hz, 3 H), 0.94
(d, J = 6.9 Hz, 3 H), 2.07–2.17 (m, 1 H), 2.25–2.33 (m, 1 H), 3.09–
3.41 (m, 4 H), 8.03 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 18.2, 19.7, 25.6, 37.2, 49.1,
51.8, 167.9, 205.6.
MS (ESI): m/z (%) = 156 (100) [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C8H13NO2: 156.1019; found:
156.1017.
5-Ethylpiperidine-2,4-dione (2a)
1H NMR (400 MHz, DMSO-d6): d = 0.89 (t, J = 7.4 Hz, 3 H), 1.29–
1.41 (m, 1 H), 1.63–1.73 (m, 1 H), 2.33–2.43 (m, 1 H), 3.10–3.17
(m, 1 H), 3.18 (d, J = 18.4 Hz, 1 H), 3.29 (d, J = 18.4 Hz, 1 H),
3.37–3.43 (m, 1 H), 8.05 (s, 1 H).
5-(3-Methylbutyl)piperidine-2,4-dione (2h)
1H NMR (400 MHz, DMSO-d6): d = 0.85 (d, J = 6.5 Hz, 3 H), 0.86
(d, J = 6.5 Hz, 3 H), 1.09–1.33 (m, 3 H), 1.44–1.55 (m, 1 H), 1.59–
1.69 (m, 1 H), 2.35–2.44 (m, 1 H), 3.07–3.14 (m, 1 H), 3.14–3.30
(m, 2 H), 3.33–3.41 (m, 1 H), 8.02 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 10.7, 19.8, 40.2, 47.7, 48.4,
168.2, 206.5.
MS (ESI): m/z (%) = 142 (100) [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C7H11NO2: 142.0862; found:
13C NMR (125 MHz, DMSO-d6): d = 22.1, 24.6, 27.4, 35.1, 40.6,
46.5, 48.2, 168.2, 206.9.
MS (ESI): m/z (%) = 184 (100) [M + H+].
142.0860.
HRMS (ESI): m/z [M + H+] calcd for C10H17NO2: 184.1332; found:
184.1333.
5-Propylpiperidine-2,4-dione (2b)
1H NMR (400 MHz, DMSO-d6): d = 0.87 (t, J = 7.4 Hz, 3 H), 1.22–
1.37 (m, 3 H), 1.56–1.65 (m, 1 H), 2.40–2.48 (m, 1 H), 3.11 (ddd,
J = 12.89, 9.18, 2.32 Hz, 1 H), 3.14–3.30 (m, 2 H), 3.37 (ddd,
J = 12.93, 5.67, 4.69 Hz, 1 H), 8.02 (s, 1 H).
5-(2-Benzyloxyethyl)piperidine-2,4-dione (2i)
1H NMR (400 MHz, DMSO-d6): d = 1.53–1.64 (m, 1 H), 1.93–2.03
(m, 1 H), 2.54–2.63 (m, 1 H), 3.13–3.18 (m, 1 H), 3.14–3.20 (m,
1 H), 3.26–3.31 (m, 1 H), 3.42 (ddd, J = 12.9, 5.7, 4.9 Hz, 1 H),
3.50 (t, J = 6.4 Hz, 2 H), 4.45 (s, 2 H), 7.23–7.41 (m, 5 H), 8.06 (br
s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 13.6, 18.9, 28.8, 40.3, 45.9,
48.1, 168.3, 206.7.
MS (ESI): m/z (%) = 156 (100) [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C8H13NO2: 156.1019; found:
13C NMR (125 MHz, DMSO-d6): d = 26.7, 40.6, 44.0, 48.1, 67.0,
71.7, 127.5, 128.4, 138.2, 168.2, 206.5.
MS (ESI): m/z (%) = 248 (100) [M + H+].
156.1017.
5-(2-Methoxyethyl)piperidine-2,4-dione (2c)
1H NMR (400 MHz, DMSO-d6): d = 1.47–1.59 (m, 1 H), 1.87–1.98
(m, 1 H), 2.50–2.58 (m, 1 H), 3.22 (s, 3 H), 3.13–3.46 (m, 6 H),
8.05 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 26.6, 40.1, 43.8, 48.1, 57.5,
69.0, 168.0, 206.1.
MS (ESI): m/z (%) = 172 (100) [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C8H13NO3: 172.0968; found:
HRMS (ESI): m/z [M + H+] calcd for C14H17NO3: 248.1281; found:
248.1285.
5-(2-Benzyloxypropyl)piperidine-2,4-dione (2l)
1H NMR (400 MHz, DMSO-d6): d = 1.30–1.41 (m, 1 H), 1.54–1.63
(m, 2 H), 1.68–1.79 (m, 1 H), 2.43–2.50 (m, 1 H), 3.10–3.40 (m,
4 H), 3.43 (t, J = 6.3 Hz, 2 H), 4.45 (s, 2 H), 7.26–7.39 (m, 5 H),
8.04 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 23.6, 26.6, 40.8, 42.3, 48.5,
71.8, 127.5, 128.0, 138.7, 168.2, 206.7.
172.0971.
MS (ESI): m/z (%) = 262 (100) [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C15H19NO3: 262.1438; found:
5-Cyclopropylmethylpiperidine-2,4-dione (2d)
1H NMR (400 MHz, DMSO-d6): d = 0.03–0.9 (m, 2 H), 0.34–0.48
(m, 2 H), 0.66–0.76 (m, 1 H), 1.17–1.26 (m, 1 H), 1.53–1.61 (m,
1 H), 2.50–2.56 (m, 1 H), 3.13–3.31 (m, 3 H), 3.45–3.53 (m, 1 H),
8.06 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 4.5, 7.8, 31.3, 47.0, 47.7,
168.0, 206.3.
262.1444.
5-(2-Phenoxypropyl)piperidine-2,4-dione (2m)
1H NMR (400 MHz, DMSO-d6): d = 1.39–1.50 (m, 1 H), 1.70–1.88
(m, 3 H), 2.50–2.60 (m, 1 H), 3.12–3.24 (m, 2 H), 3.29–3.48 (m,
2 H), 3.97 (t, J = 6.2 Hz, 2 H), 6.90–6.96 (m, 3 H), 7.29 (m, 2 H),
8.07 (s, 1 H).
MS (ESI): m/z (%) = 168 (100) [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C9H13NO2: 168.1019; found:
168.1017.
Synthesis 2007, No. 20, 3185–3190 © Thieme Stuttgart · New York

3190
P. Orsini et al.
PAPER
13C NMR (125 MHz, DMSO-d6): d = 23.3, 25.7, 40.7, 46.1, 48.1,
66.7, 114.2, 120.3, 129.5, 158.6, 168.2, 206.6.
13C NMR (125 MHz, DMSO-d6): d = 12.3, 13.6, 13.8, 31.9, 32.6,
39.2, 40.5, 41.0, 42.5, 42.7, 60.2, 165.5, 167.8, 171.2.
MS (ESI): m/z (%) = 248 (100) [M + H+].
MS (ESI): m/z (%) = 260 (100) [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C14H17NO3: 248.1281; found:
HRMS (ESI): m/z [M + H+] calcd for C12H21NO5: 260.1492; found:
248.1274.
260.1494.
5-(3-Chloropropyl)piperidine-2,4-dione (2n)
1-Ethylpiperidine-2,4-dione (3)
1H NMR (400 MHz, DMSO-d6): d = 1.36–1.44 (m, 1 H), 1.73–1.84
(m, 3 H), 2.50–2.60 (m, 1 H), 3.09–3.17 (m, 1 H), 3.17–3.32 (m,
2 H), 3.36–3.43 (m, 1 H), 3.65 (t, J = 6.3 Hz, 2 H), 8.05 (s, 1 H).
A solution of EtONa (1.32 g, 19 mmol) and N-(2-ethoxycarbonyl-
ethyl)-N-ethylmalonic acid ethyl ester (4; 4.5 g, 17 mmol) in anhyd-
rous THF (100 mL) was refluxed for 16 h under a nitrogen
atmosphere. After addition of Et2O (60 mL), the resulting precipi-
tate was filtered and the crude intermediate was dissolved in HCl
(5%, 300 mL) and refluxed for 1 h. The solvent was removed under
vacuum, and the residue was purified by column chromatography
(CH2Cl2–acetone, 10:1) to give the desired product 3 (1.32 g, 55%
yield).
13C NMR (125 MHz, DMSO-d6): d = 23.6, 28.8, 40.4, 44.9, 45.6,
48.1, 168.1, 206.3.
MS (ESI): m/z (%) = 190 (100) [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C8H12ClNO2: 190.0629;
found: 190.0625.
1H NMR (400 MHz, DMSO-d6): d = 1.06 (t, J = 7.2 Hz, 3 H), 2.51–
2.58 (m, 2 H), 3.30 (s, 2 H), 3.40 (q, J = 7.2 Hz, 2 H), 3.56 (t,
J = 6.1 Hz, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 12.0, 37.7, 40.4, 41.3, 49.5,
165.6, 205.5.
MS (ESI): m/z (%) = 142 (100) [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C7H11NO2: 142.0862; found:
5-Cyclohex-2-enylpiperidine-2,4-dione (2o)
Isolated as a mixture of diastereoisomers (1:1).
1H NMR (400 MHz, DMSO-d6): d = 1.24–1.76 (m, 4 H), 1.91–1.98
(m, 2 H), 2.42–2.52 (m, 1 H), 2.60–2.77 (m, 1 H), 3.10–3.23 (m,
1 H), 3.23–3.32 (m, 2 H), 3.32–3.47 (m, 1 H), 5.38–5.57 (m, 1 H),
5.68–5.20 (m, 1 H), 8.03 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 21.2, 24.1, 24.1, 25.9, 32.9,
33.9, 37.6, 49.0, 49.5, 50.5, 127.8, 128.5, 168.0, 206.2.
142.0864.
MS (ESI): m/z (%) = 194 (100) [M + H+].
Acknowledgment
HRMS (ESI): m/z [M + H+] calcd for C11H15NO2: 194.1175; found:
194.1178.
We would like to thank Dr. Sergio Mantegani, (Nerviano Medical
Sciences) and Dr. Paolo Pevarello (Centro Nacional de Investiga-
ciones Oncologicas) for their fruitful discussions and suggestions.
5-Benzylpiperidine-2,4-dione (2p)
1H NMR (400 MHz, DMSO-d6): d = 2.49 (m, 1 H), 2.77–2.86 (m,
1 H), 3.06–3.14 (m, 3 H), 3.20–3.31 (m, 2 H), 7.20–7.26 (m, 3 H),
7.28–7.36 (m, 2 H), 7.99 (s, 1 H).
References
13C NMR (125 MHz, DMSO-d6): d = 32.2, 40.2, 47.8, 48.0, 126.2,
128.3, 128.8, 138.8, 168.0, 205.6.
MS (ESI): m/z (%) = 204 (100) [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C12H13NO2: 204.1019; found:
(1) Thompson, C. M.; Green, D. L. C. Tetrahedron 1991, 47,
4223.
(2) Thompson, C. M. Dianion Chemistry in Organic Synthesis;
CRC Press Inc.: Boca Raton, 1994.
(3) D’Alessio, R.; Tibolla, M.; Varasi, M.; Vanotti, E.;
Montagnoli, A.; Santocanale, C.; Martina, K.;
Menichincheri, M. WO 2005/013986, 2005.
(4) D’Alessio, R.; Tibolla, M.; Varasi, M.; Vanotti, E.;
Montagnoli, A.; Santocanale, C.; Orsini, P.; Pillan, A. WO
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204.1026.
N-(2-Ethoxycarbonylethyl)-N-ethylmalonic Acid Ethyl Ester
(4)
A solution of ethylamine (2.0 g, 44.4 mmol) and ethyl acrylate (5.8
g, 57.7 mmol) was stirred at r.t. for 16 h. The reaction mixture was
diluted with anhydrous THF (100 mL) and cooled to 0 °C. Et3N (5.8
g, 57.7 mmol) and ethyl malonyl chloride (7.7 g, 51.1 mmol) were
added and the mixture was stirred for 3 h, diluted with CH2Cl2 (300
mL) and washed with KHSO4 (5%, 400 mL). Reverse-phase col-
umn chromatographic purification (H2O–MeCN, 1:1) afforded the
desired derivative 4 (5.98 g, 52% yield) as a mixture of rotamers.
1H NMR (400 MHz, DMSO-d6): d = 1.01–1.15 (t, J = 6.9 Hz, 3 H),
1.20 (t, J = 7.1, 6 H), 2.50 (m, 1 H), 2.63 (t, J = 6.9 Hz, 1 H), 3.23–
3.32 (m, 2 H), 3.43–3.55 (m, 4 H), 4.01–4.14 (m, 4 H).
(8) Ibenmoussa, S.; Chavignon, O.; Teulade, J.; Viols, H.;
Debouzy, J.; Chapat, J.; Gueiffier, A. Heterocycl. Commun.
1998, 4, 317.
(9) Colombo, M.; Riccardi-Sirtori, F.; Rizzo, V. Rapid
Commun. Mass Spectrom. 2004, 18, 511.
Synthesis 2007, No. 20, 3185–3190 © Thieme Stuttgart · New York