Coupling reactions of α-Bromocarboxylate with Non-aromatic N-heterocycles

Article abstract of DOI:10.3390/molecules14083019

The conditions for the C-N bond forming reaction (C-N coupling reaction) between α-bromocarboxylate and nitrogen-containing non-aromatic heterocyclic rings under heterogeneous copper(I) oxide catalysis are investigated in this paper. All the generated com

Full text of DOI:10.3390/molecules14083019

Molecules 2009, 14, 3019-3029; doi:10.3390/molecules14083019
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Coupling Reactions of α-Bromocarboxylate with Non-Aromatic
N-Heterocycles ‡
Katerina Brychtova 1, Barbora Slaba 1,2, Lukas Placek 1,2, Josef Jampilek 1,2,*, Ivan Raich 3 and
Jozef Csollei 1
1
Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical
Sciences, Palackeho 1-3, 612 42 Brno, Czech Republic; E-mails: brychtovak@vfu.cz (K.B.),
csolleij@vfu.cz (J.C.)
2
Zentiva k.s., U kabelovny 130, 102 37 Prague 10, Czech Republic;
E-mails: barbora.slaba@zentiva.cz (B.S.), lukas.placek@zentiva.cz (L.P.)
3
Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology,
Institute of Chemical Technology, Technicka 5, 166 28 Prague 6, Czech Republic;
E-mail: ivan.raich@vscht.cz (I.R.)
‡
Preliminary results connected with the topic of the article were presented at The Twelfth Electronic
Conference on Synthetic Organic Chemistry (ECSOC-12, http://www.usc.es/congresos/ecsoc/12/
ECSOC12.htm), November 1-30, 2008, paper C0005).
* Author to whom correspondence should be addressed; E-mail: josef.jampilek@zentiva.cz;
Tel.: +420267243695; Fax: +420272701331
Received: 20 July 2009; in revised form: 30 July 2009 / Accepted: 12 August 2009 /
Published: 13 August 2009
Abstract: The conditions for the C-N bond forming reaction (C-N coupling reaction)
between α-bromocarboxylate and nitrogen-containing non-aromatic heterocyclic rings
under heterogeneous copper(I) oxide catalysis are investigated in this paper. All the
generated compounds were fully characterized by IR, NMR and MS spectroscopy. Ab
initio/DFT calculations of partial charges on nitrogen atoms in all the discussed
heterocycles and on C(2) of carboxylate under applied conditions were predicted. These in
silico results correlate relatively with the experimental observations.

Molecules 2009, 14
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Keywords: C-N nucleophilic coupling; N-heterocycles; ω-lactams; copper catalyst; ab
initio/DFT calculations
1. Introduction
Transdermal penetration enhancers (also called sorption promoters or accelerants) are special
pharmaceutical excipients that interact with skin components to increase the penetration of drugs from
topical dosage forms to blood circulation [1-3]. Numerous compounds (with different chemical
structures) have been evaluated as penetration enhancers and a number of potential sites and modes of
action were identified [1,3]. Some of the important penetration enhancers, as classified by Sinha and
Kaur [4], are terpenes and terpenoids, pyrrolidinones, fatty acids and esters, sulfoxides, alcohols and
glycerides and miscellaneous enhancers including phospholipids, cyclodextrin complexes, amino acid
derivatives, lipid synthesis inhibitors, clofibric acid, dodecyl-N,N-dimethylamino acetate and enzymes.
As part of a project directed at the synthesis of new potential transdermal penetration enhancers
based on the structure of 6-aminohexanoic acid derivatives [1,3], the problem of C-N coupling
reactions of ethyl-2-bromo-6-(2,5-dioxopyrrolidin-1-yl)hexanoate (2) and several nitrogen-containing
saturated rings, including mainly basic heterocycles, ω-lactams and a cyclic imide, was solved.
Nitrogen-containing heterocycles are very important targets in the organic chemistry. They are
abundant in natural products and in pharmaceutical agents. A number of various compounds
containing C-N bond have important biological, pharmaceutical, or material properties [5-7].
Herein the utility of copper(I) oxide as a heterogeneous catalyst in the process of C-N bond forming
reactions is reported. Several reviews describing recent progress of copper-mediated coupling
reactions for C-N bond formation have been published [8-10] and nucleophilic substitutions using
copper(I) catalysts were described in other papers where copper(I) oxide [11,12], sulfide [13,14],
iodide [15,16] or other copper(I) derivatives were used [17]. Contrary to the above referred articles
dealing mostly with copper-mediated arylation of aromatic or aliphatic amines, coupling of the
aliphatic compounds is discussed in this paper.
2. Results and Discussion
The starting material ethyl-2-bromo-6-(2,5-dioxopyrrolidin-1-yl)hexanoate (2) was prepared by
multistep synthesis from 6-aminohexanoic acid. This amino acid was condensed with succinic
anhydride to obtain succinimide intermediate 1, which was then transformed by means of one-pot
synthesis under the optimized Schwenk and Papa procedure conditions [18,19] to α-bromocarboxylate
2. The synthesis route is shown in Scheme 1. This synthesis was reported recently in [20], dealing with
the problems associated with the generation of α-bromocarboxyl compounds and their reaction with
pyrrolidin-2-one under different conditions and describing various synthetic by-products.
During the process of preparation of adducts with cyclic amines (compounds 3a-3c) the coupling
reaction of pyrrolidine, piperidine and morpholine with compound 2 was successful under
conventional conditions (Method A) and provided very satisfactory yields (Table 1). The key interest
was to prepare derivatives with ω-lactam substitution at the α position of the carboxylate, but the

Molecules 2009, 14
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coupling reaction of compound 2 and the ω-lactam ring either did not occur under any conventional
conditions (e.g. Method A) or undesirable products were obtained [20]. To overcome these difficulties,
special conditions were used in Method B, in particular, a specific heterogeneous copper catalyst –
powdered copper(I) oxide.
Scheme 1. Synthesis of ethyl-2-bromo-6-(2,5-dioxopyrrolidin-1-yl)hexanoate (2).
1. SOCl2
2. Br2
O
O
Br
O
acetone
OH
3. EtOH
O
OH
N
N
+
O
H2N
ONE-POT
O
O
O
1
2
O
O
O
When piperidin-4-one was used as a positional isomer of the 6-membered ω-lactam ring for
nucleophilic coupling under the conditions of Method A (compound 3g), a yield comparable to that
obtained with Method B was achieved. In the coupling reaction of pyrrolidin-2,5-dione and compound
2 Method A for the did not give any of compound 3h, therefore Method B was used. It yielded 66% of
3h. Attempts were made to prepare compounds 3d-3f, 3h under the conditions of Method B, but
without copper heterogeneous catalyst. In all cases no product was obtained. Compounds 3a-3c were
additionally prepared under conditions of Method B. The yields and the used methods are summarized
in Table 1.
These results were supported by ab initio/DFT calculations [21-24] of partial charges. All the
calculated data are shown in Table 1. Ab initio/DFT calculations of partial charges on C(2) of the
carboxylate in Method A (in toluene) is –0.01 and in Method B (in DMF) is –0.30. It means, that C(2)
of the carboxylate possesses relatively negative charges under the conditions of both methods and it
can be assumed that a nucleophilic substitution is not the preferred reaction, i.e. the C(2) position is not
activated for nucleophilic attack.
According to Table 1, it may be concluded that the calculated negative partial charge on the
nitrogen atom of nucleophile in the range from –0.48 to –0.55 (ω-lactams and cyclic imide) is not
sufficient for successful nucleophilic substitution. When the nucleophile possesses the computed value
of charge –0.73, the coupling reaction is possible. This was conformed by very similar yields of
compound 3g generated using both Methods A and B. Taking into account the above mentioned facts,
it can be assumed that the reaction mechanism could be a combination of SN1 and SN2 in Method A, or
radical-ionic substitution using heterogeneous copper catalyst in Method B [13,14].
The interdependence between experimental yields of Method B and ab initio/DFT calculation data
for δN salt is illustrated in Figure 1. The deviation of this dependence is R2=0.92. The dependence
deviation between experimental (yields of Method A) and calculation (δN base) values for compounds
3a-3c and 3g is R2=0.67, but only for 3a-3c the dependence deviation is 0.97. Piperidin-4-one (starting
material for 3g) as a position isomer of piperidin-2-one (starting material for 3e) is a specific
compound; it does not possess physico-chemical properties of 6-membered ω-lactam or cyclic
6-membered amine and therefore should not be included to this dependence. According to these
deviations (R2=0.92, R2=0.97) it can be concluded that experimental and predicted data relatively
correlate.

Molecules 2009, 14
Table 1. The C-N coupling reactions of compound 2 with nitrogen-containing heterocycles
3022
and calculated partial charges on nitrogen atoms (δN) of the free bases in toluene or the
sodium salts in dry DMF.
O
O
O
O
Method A, B
N
O
N
O
O
Br
O
R
2
3a-h
Comp.
3a
R
Conditionsa Yield (%)
δN base δN salt
Method A
Method B
Method A
94
80
77
N
–0.77
–0.73
–1.10
–1.17
N
3b
3c
Method B
Method A
Method B
95
80
85
N
O
–0.73
–1.13
Method A
Method B
Method A
0
67
0
N
3d
3e
–0.50
–0.55
–0.94
–1.01
O
N
O
Method B
Method A
Method B
72
0
N
N
O
3f
–0.53
–0.76
–0.98
–1.13
68
Method A
Method B
Method A
Method B
81
83
0
3g
O
O
N
3h
–0.48
–0.90
66
O
aReaction conditions: Method A: toluene, reflux, 5h; Method B: NaH, DMF, Cu2O, reflux, 9h.

Molecules 2009, 14
Figure 1. Correlation between experimental (Method B) and calculated data (δN salt).
3023
-0.85
-0.90
-0.95
-1.00
-1.05
-1.10
-1.15
-1.20
65
70
75
80
85
90
95
100
3h
3d
3f
3e
R2 = 0.92
3a
3c
3g
3b
Yield [%] - Method B
All eight compounds 3a-3h prepared in this article are intermediates from which alkyl-6-(2,5-
dioxopyrrolidin-1-yl)-2-(substituted)hexanoates with C6–C12 linear alkyl ester chains will be prepared.
The preliminary results were presented recently [25]. The intermediates 3a-3h do not meet the
requirements/recommendations for effective transdermal penetration enhancers [1,3,4], in particularly
they possess low hydrophobicity in comparison with substitution of ethyl esters by C6–C12 linear
alkyl chains.
3. Conclusions
A series of eight substituted ethyl-6-(2,5-dioxopyrrolidin-1-yl)hexanoate derivatives and two
intermediates were prepared from 6-aminohexanoic acid. Ten newly prepared compounds were
1
characterized by H-, 13C-NMR spectra and IR spectra. Reaction conditions for the coupling of
ethyl-2-bromo-6-(2,5-dioxopyrrolidin-1-yl)hexanoate (2) with nitrogen-containing heterocycles were
described and a radical-ionic mechanism for the substitution, catalyzed by heterogeneous copper
catalyst, was proposed. According to the above discussed facts, it could be concluded that the coupling
of compound 2 and heterocycles α-substituted with keto moiety gave products only in presence of
copper heterogeneous catalyst. Ab initio/DFT calculations of partial charges on nitrogen atoms in all
the discussed heterocycles and on C(2) of carboxylate under the applied conditions were predicted.
These in silico results correlated relatively with the experimental observations.
4. Experimental
4.1. General
All reagents were purchased from Sigma-Aldrich (Schnelldorf, Germany) or Merck (Darmstadt,
Germany). Kieselgel 60, 0.040-0.063 mm (Merck) was used for column chromatography. TLC

Molecules 2009, 14
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experiments were performed on alumina-backed silica gel 40 F254 plates (Merck). The plates were
illuminated under UV (254 nm) and evaluated in iodine vapour. The melting points were determined
on a Boetius PHMK apparatus (Nagema, Germany) and are uncorrected. All 1H- and 13C-NMR spectra
were recorded on a Bruker Avance-500 FT-NMR spectrometer (500 MHz for 1H and 125 MHz for 13C,
Bruker Comp., Karlsruhe, Germany). Chemical shifts are reported in ppm (δ) to internal Si(CH3)4,
when diffused easily exchangeable signals are omitted. Infrared (IR) spectra were recorded on a Smart
MIRacle™ ATR ZnSe for Nicolet™ 6700 FT-IR Spectrometer (Nicolet - Thermo Scientific, U.S.A.).
The spectra were obtained by accumulation of 256 scans with 2 cm-1 resolution in the 4,000-600 cm-1
region. Mass spectra were measured using the LTQ Orbitrap Hybrid Mass Spectrometer (Thermo
Electron Corporation, U.S.A.) with direct injection into APCI source (400 °C) in the positive mode.
4.2. Synthesis
6-(2,5-Dioxopyrrolidin-1-yl)hexanoic acid (1): A solution of succinic anhydride (45.0 g, 450.0 mmol)
in acetone (230 mL) was added dropwise to a suspension of 6-aminohexanoic acid (34.4 g,
262.0 mmol) in acetone (140 mL). The reaction mixture was stirred at room temperature for 24 hours
after which it was filtered and the pure white crystalline product was washed with acetone. Yield 82%.
Mp 100–102 °C; IR (cm-1) 3315, 2929, 1688, 1560, 1414, 1250, 1183; 1H-NMR (DMSO-d6), δ: 12.05
(s, 1H, OH), 3.02 (t, 2H, J=7.0 Hz, NCH2), 2.90 (s, 4H, OCCH2CH2CO), 2.41 (t, 2H, J=6.0 Hz,
OOCCH2), 2.32–2.15 (m, 4H, CH2), 1.52–1.24 (m, 2H, CH2); 13C NMR (DMSO-d6), δ: 174.25,
173.66, 38.27, 33.52, 28.72, 28.62, 25.83, 24.11; HR-MS: for C10H16O4N [M+H]+ calculated 214.2378
m/z, found 214.2377 m/z.
Ethyl-2-bromo-6-(2,5-dioxopyrrolidin-1-yl)hexanoate (2): To the organic acid 1 (45.8 g, 214.8 mmol),
held at 30 °C, SOCl2 (29.4 g, 247.0 mmol, 17.9 mL) was slowly added dropwise and the mixture was
stirred at 60–80 °C until the gas evolution essentially stopped. Br2 (36.1 g, 225.5 mmol, 11.6 mL) was
added dropwise at 80 °C at approximately the same rate as Br2 was consumed. Stirring was continued
for several hours until the evolution of HBr nearly stopped. Absolute EtOH (27 mL) was added slowly
to the crude acid chloride at 20–30 °C. After stirring overnight, the mixture was evaporated until dry in
a vacuum and the residue was dissolved in Et2O (50 mL). The solution was washed with diluted
NaHSO3 and water, the organic layer was dried over anhydrous MgSO4, filtered and the organic
solvent was removed under rotary evaporation. The crude product was purified by flash
chromatography on silica gel, eluting with EtOAc/petroleum ether. Yield 81%, colourless oil; RF 0.37
1
(EtOAc/petroleum ether 1:1); IR (cm-1) 2939, 1730, 1692, 1436, 1399, 1143, 818; H-NMR (CDCl3),
δ: 4.16 (q, 2H, J=7.0 Hz, OCH2), 4.11 (t, 1H, J=7.3 Hz, BrCH), 3.44 (t, 2H, J=7.2 Hz, NCH2), 2.64 (s,
4H, OCCH2CH2CO), 1.99 (q, 2H, J=7.3 Hz, CHCH2), 1.54 (qi, 2H, J=7.0 Hz, CH2), 1.43–1.15 (m, 2H,
13
CH2), 1.23 (t, 3H, J=7.1 Hz, CH3); C-NMR (CDCl3), δ: 176.94, 169.43, 61.84, 45.63, 38.23, 34.17,
28.08, 26.77, 24.43, 13.82. HR-MS: for C12H19O4NBr [M+H]+ calculated 320.0492 m/z, found
320.0491 m/z.
Compounds 3a-h. General procedures: Method A: The appropriate nitrogen compound (13.4 mmol)
was dissolved in toluene (25 mL) and compound 2 (6.7 mmol) was added. The mixture was refluxed

Molecules 2009, 14
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under argon for 5 hours. The solvent was evaporated and the rest was suspended in Et2O, solid was
filtered off, washed with Et2O and the filtrate was concentrated under reduced pressure. Purification by
flash chromatography on silica gel, eluting with EtOAc/petroleum ether + 1% TEA or CH2Cl2/MeOH.
Method B: Nitrogen compound (10 mmol) was added slowly to a suspension of NaH (11 mmol, 60%
dispersion in mineral oil) in dry DMF (25 mL). The mixture was stirred for a few minutes until the
evolution of hydrogen gas stopped. Compound 2 (6.7 mmol) and Cu2O (1.7 mmol, 25 mol %) were
then added, and the mixture was refluxed under argon for 9 hours. The cooled mixture was poured
onto ice, filtered through Celite and extracted with CHCl3. The combined organic extracts were
washed with water, dried over anhydrous MgSO4, filtered and the organic solvent was removed under
rotary evaporation. Purification by flash chromatography on silica gel, eluting with EtOAc/petroleum
ether/TEA or CH2Cl2/MeOH.
Ethyl-6-(2,5-dioxopyrrolidin-1-yl)-2-(pyrrolidin-1-yl)hexanoate (3a): For the coupling of pyrrolidine
and compound 2 both Method A and Method B conditions were used. Yield: 94% (Method A), 80%
(Method B); a light yellow oil; RF 0.27 (CH2Cl2/MeOH 95:5); IR (cm-1) 2985, 2939, 2870, 1736,
1
1690, 1408, 1382, 1147; H-NMR (CDCl3), δ: 4.19 (q, J=7.2 Hz, 2H, OCH2), 3.49 (t, J=7.4 Hz, 2H,
NCH2), 3.07 (t, J=7.1 Hz, 1H, CH), 2.70 (s, 4H, OCCH2CH2CO), 2.66–2.52 (m, 4H, NCH2),
13
1.82–1.41 (m, 10H, CH2), 1.29 (t, J=7.2 Hz, 3H, CH3); C-NMR (CDCl3), δ: 177.08, 172.89, 66.41,
60.21, 50.47, 38.57, 30.93, 28.12, 27.50, 23.47, 23.25, 14.36; HR-MS: for C16H27O4N2 [M+H]+
calculated 311.1965 m/z, found 311.1966 m/z.
Ethyl-6-(2,5-dioxopyrrolidin-1-yl)-2-(piperidin-1-yl)hexanoate (3b): For the coupling of piperidine
and compound 2 the conditions of Method A and Method B were used. Yield: 77% (Method A), 95%
(Method B); a light yellow oil; RF 0.48 (CH2Cl2/MeOH 95:5); IR (cm-1) 2934, 2856, 2809, 1698,
1
1400, 1146; H-NMR (CDCl3), δ: 4.17 (q, J=7.2 Hz, 2H, OCH2), 3.50 (t, J=7.4 Hz, 2H, NCH2), 3.08
(t, J=7.4 Hz, 1H, CH), 2.70 (s, 4H, OCCH2CH2CO), 2.62–2.40 (m, 4H, NCH2), 1.83–1.36 (m, 12H,
13
CH2), 1.28 (t, J=7.2 Hz, 3H, CH3); C-NMR (CDCl3), δ: 177.09, 172.22, 67.97, 59.86, 50.69, 38.66,
28.79, 28.12, 27.42, 26.50, 24.65, 23.54, 14.51; HR-MS: for C17H29O4N2 [M+H]+ calculated 325.2122
m/z, found 325.2120 m/z.
Ethyl-6-(2,5-dioxopyrrolidin-1-yl)-2-(morpholin-4-yl)hexanoate (3c): For the coupling of morpholine
and compound 2 the conditions of Method A and Method B were used. Yield: 80% (Method A), 85%
(Method B); a yellow oil; RF 0.53 (CH2Cl2/MeOH 95:5); IR (cm-1) 2948, 2855, 1697, 1400, 1150,
1
1114; H-NMR (CDCl3), δ: 4.18 (q, J=7.1 Hz, 2H, OCH2), 3.74–3.63 (m, 4H, OCH2morph.), 3.50 (t,
J=7.4 Hz, 2H, NCH2), 3.10 (t, J=7.4 Hz, 1H, CH), 2.71 (s, 4H, OCCH2CH2CO), 2.66–2.48 (m, 4H,
NCH2morph.), 1.80–1.52 (m, 4H, CH2), 1.45–1.27 (m, 2H, CH2), 1.29 (t, J=7.1 Hz, 3H, CH3);
13C-NMR (CDCl3), δ: 177.07, 171.72, 67.54, 67.38, 60.19, 49.95, 38.57, 28.29, 28.13, 27.38, 23.32,
14.48; HR-MS: for C16H27O5N2 [M+H]+ calculated 327.1914 m/z, found 327.1915 m/z.
Ethyl-6-(2,5-dioxopyrrolidin-1-yl)-2-(2-oxopyrrolidin-1-yl)hexanoate (3d): For the coupling of
pyrrolidin-2-one and compound 2 the conditions of Method A and Method B were used. Yield: 0%
(Method A), 67% (Method B); a light yellow oil; RF 0.27 (EtOAc/petroleum ether 10:1 + 1% TEA);

Molecules 2009, 14
3026
1
IR (cm-1) 2927, 1767, 1687, 1401, 1284, 1187, 1153, 1027; H-NMR (CDCl3), δ: 4.66 (dd, 1H,
J1=5.0 Hz, J2=10.6 Hz, CH), 4.16 (q, 2H, J=7.1 Hz, OCH2), 3.50 (t, 2H, J=7.2 Hz, NCH2), 3.54–3.29
(m, 2H, CH2pyrr.), 2.70 (s, 4H, OCCH2CH2CO), 2.42 (t, 2H, J=8.0 Hz, CH2pyrr.), 2.17–1.95 (m, 2H,
CH2pyrr. and 1H from CH2CH), 1.78–1.56 (m, 2H, CH2 and 1H from CH2CH), 1.34–1.28 (m, 2H,
CH2), 1.26 (t, 3H, J=7.1 Hz, CH3); 13C-NMR (CDCl3), δ: 177.13, 175.78, 170.76, 61.12, 53.51, 43.53,
38.26, 30.73, 28.08, 27.03, 23.35, 18.21, 14.07; HR-MS: for C16H25O5N2 [M+H]+ calculated 325.1758
m/z, found 325.1757 m/z.
Ethyl-6-(2,5-dioxopyrrolidin-1-yl)-2-(2-oxopiperidin-1-yl)hexanoate (3e): For the coupling of
piperidin-2-one and compound 2 the conditions of Method A and Method B were used. Yield: 0%
(Method A), 72% (Method B): a light yellow oil; RF 0.27 (EtOAc/petroleum ether 10:1 + 1% TEA);
1
IR (cm-1) 2941, 2868, 1698, 1637, 1401, 1347, 1178; H-NMR (CDCl3), δ: 5.14 (dd, J=10.3, 5.3 Hz,
1H, CH), 4.24–4.06 (m, 2H, OCH2), 3.50 (t, J=7.1 Hz, 2H, NCH2), 3.29–3.17 (m, 2H, NCH2pip.), 2.70
(s, 4H, OCCH2CH2CO), 2.48–2.42 (m, 2H, OCCH2pip.), 2.01–1.53 (m, 8H, CH2), 1.37–1.23 (m, 2H,
CH2), 1.26 (t, J=7.2 Hz, 3H, CH3); 13C-NMR (CDCl3), δ: 177.13, 171.16, 170.47, 61.00, 55.72, 44.13,
38.42, 32.21, 28.13, 27.48, 27.22, 23.46, 23.12, 20.98, 14.15; HR-MS: for C17H27O5N2 [M+H]+
calculated 339.1914 m/z, found 339.1914 m/z.
Ethyl-6-(2,5-dioxopyrrolidin-1-yl)-2-(2-oxoazepan-1-yl)hexanoate (3f): For the coupling of azepan-2-
one and compound 2 the conditions of Method A and Method B were used. Yield: 0% (Method A),
68% (Method B); a light yellow oil; RF 0.27 (AcOEt/petroleum ether + 1% TEA); IR (cm-1) 2937,
1
2863, 1695, 1674, 1401, 1156; H-NMR (CDCl3), δ: 5.10 (dd, J1=9.9 Hz, J2=5.1 Hz, 1H, CH),
4.33–4.00 (m, 2H, OCH2), 3.50 (t, J=7.2 Hz, 2H, NCH2), 3.41–3.15 (m, 2H, NCH2azep.), 2.71 (s, 4H,
OCCH2CH2CO), 2.64–2.51 (m, 2H, OCCH2azep.), 2.05–1.90 (m, 2H, CH2), 1.85–1.45 (m, 8H, CH2),
13
1.39–1.27 (m, 2H, CH2), 1.26 (t, J=6.6 Hz, 3H, CH3); C-NMR (CDCl3), δ: 177.18, 176.22, 171.47,
60.97, 57.06, 46.19, 38.41, 37.28, 29.91, 28.63, 28.11, 27.29, 23.46, 23.25, 14.12; HR-MS: for
C18H29O5N2 [M+H]+ calculated 353.2071 m/z, found 353.2071 m/z.
Ethyl-6-(2,5-dioxopyrrolidin-1-yl)-2-(4-oxopiperidin-1-yl)hexanoate (3g): For the coupling of
piperidin-2-one and compound 2 the conditions of Method A and Method B were used. Yield: 81%
(Method A); 83% (Method B); a light orange oil; RF 0.59 (CH2Cl2/MeOH 95:5); IR (cm-1) 2941, 2865,
2822, 1697, 1401, 1344, 1159; 1H-NMR (CDCl3), δ: 4.16 (q, J=7.1 Hz, 2H, OCH2), 3.52 (t, J=7.1 Hz,
2H, NCH2), 3.31 (t, J=7.5 Hz, 1H, CH), 3.04–2.76 (m, 4H, NCH2), 2.71 (s, 4H, OCCH2CH2CO),
13
2.51–2.34 (m, 4H, CH2COCH2), 1.80–1.33 (m, 6H, CH2), 1.28 (t, J=7.1 Hz, 3H, CH3); C-NMR
(CDCl3), δ: 208.75, 177.09, 171.72, 66.51, 60.27, 48.97, 41.95, 38.51, 28.95, 28.11, 27.29, 23.50,
14.42; HR-MS: for C17H27O5N2 [M+H]+ calculated 339.1914 m/z, found 339.1915 m/z.
Ethyl-2,6-bis(2,5-dioxopyrrolidin-1-yl)hexanoate (3h): For the coupling of pyrrolidin-2,5-dione and
compound 2 the conditions of Method A and Method B were used. Yield: 0% (Method A), 66%
(Method B); a white crystalline compound; Mp 99–101 °C; RF 0.35 (EtOAc); IR (cm-1) 2980, 2940,
1
1690, 1391, 1253, 1190; H-NMR (CDCl3), δ: 4.62 (dd, J1=9.4 Hz, J2=5.8 Hz, 1H, CH), 4.19 (dq,
J1=7.1 Hz, J2=1.6 Hz, 2H, OCH2), 3.47 (t, J=7.1 Hz, 2H), 2.79 (s, 4H, OCCH2CH2CO), 2.70 (s, 4H,

Molecules 2009, 14
3027
OCCH2CH2CO), 2.18–2.05 (m, 2H, CH2), 1.64–1.46 (m, 2H, CH2), 1.30–1.22 (m, 2H, CH2), 1.24 (t,
J=7.1 Hz, 3H, CH3); 13C-NMR (CDCl3), δ: 177.26, 176.54, 168.49, 61.80, 52.59, 38.33, 28.13, 28.08,
27.34, 26.97, 23.61, 14.04; HR-MS: for C16H23O6N2 [M+H]+ calculated 339.1551 m/z, found 339.1551 m/z.
4.3. Ab initio/DFT calculations
Geometry optimizations of all compounds were performed first at HF/6-31G(d,p) ab initio level in
the gas phase and then reoptimized at B3LYP/6-31G(d,p) level in toluene or dimethylformamide. For
nitrogen bases, both the free base and anion forms were taken into account. Solvents were simulated
using the CPCM polarizable conductor calculation solvation model [21]. Charges for optimized
structures were calculated at B3LYP/6-31G(d,p) level under the same solvent conditions using the
Merz, Singh and Kollman procedure [22,23]. All ab initio/DFT calculations were performed in
Gaussian 03W [24]. All the calculated data are shown in Table 1.
Acknowledgements
This study was supported by IGA VFU 128/2008/FaF and by the Ministry of Education of the
Czech Republic MSM 6215712403 and MSM 6046137305.
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Sample Availability: Samples of the compounds are available from the authors.
© 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).