Parallel synthesis of 2-substituted 6-(5-Oxo-1-phenylpyrrolidin-3-yl) pyrimidine-5-carboxamides

Article abstract of DOI:10.3390/molecules17055363

A library of 24 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamides 10{1,2; 1-12} was prepared by a parallel solution-phase approach. The synthesis comprises a five-step transformation of itaconic acid (11) into 1-methyl and 1-phenyl substituted 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxylic acids 17{1,2} followed by parallel amidation of 17{1,2} with a series of 12 aliphatic amines 18{1-12} to afford the corresponding carboxamides 10 in good overall yields and in 80-100% purity.

Full text of DOI:10.3390/molecules17055363

Molecules 2012, 17, 5363-5384; doi:10.3390/molecules17055363
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Parallel Synthesis of 2-Substituted 6-(5-Oxo-1-phenylpyrrolidin-
3-yl)pyrimidine-5-carboxamides
Bojana Črček 1, Jernej Baškovč 1, Uroš Grošelj 1, Drago Kočar 1, Georg Dahmann 2,
Branko Stanovnik 1 and Jurij Svete 1,*
1
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5,
P.O. Box 537, 1000 Ljubljana, Slovenia
2
Boehringer Ingelheim Pharma GmbH & Co. KG, Medicinal Chemistry, 88397 Biberach, Germany
* Author to whom correspondence should be addressed; E-Mail: jurij.svete@fkkt.uni-lj.si;
Tel.: +386-1-2419-254; Fax: +386-1-2419-360.
Received: 20 March 2012; in revised form: 24 April 2012 / Accepted: 26 April 2012 /
Published: 8 May 2012
Abstract: A library of 24 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamides
10{1,2; 1–12} was prepared by a parallel solution-phase approach. The synthesis
comprises a five-step transformation of itaconic acid (11) into 1-methyl and 1-phenyl
substituted 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxylic acids 17{1,2}
followed by parallel amidation of 17{1,2} with a series of 12 aliphatic amines 18{1–12} to
afford the corresponding carboxamides 10 in good overall yields and in 80–100% purity.
Keywords: parallel synthesis; pyrimidines; 2-(heteroaryl)ethylamines
1. Introduction
2-[(Hetero)aryl]ethylamines, such as dopamine, histamine, tryptamine, serotonin, and melatonin are
representative chemical messengers playing a crucial role in biological processes [1]. Therefore, the
preparation of libraries of their novel synthetic analogues is of particular interest and represents an
important target in medicinal [2–5], synthetic organic, and combinatorial chemistry [6–10].
In the last two decades, alkyl 2-substituted 3-(dimethylamino)prop-2-enoates and related
enaminones have proven to be easily available and versatile reagents for the preparation of various
functionalized heterocycles [11–15]. Recently, a part of our research in this field has been focused on
the synthesis of aminoethyl functionalized heterocycles. In this context, we first reported the synthesis

Molecules 2012, 17
5364
of non-racemic 1-heteroaryl-2-phenylethylamines 1–3 from α-amino acid derived enaminoketones [16].
Further, the syntheses of the pyrazole analogues of histamine were developed: 2-aminoethyl
substituted 1H-pyrazole derivatives 4–6 as the open-chain analogues [17–20] and 6,7-dihydro-1H-
pyrazolo[4,3-c]pyridin-4(5H)-one derivatives 7 [21], 5-(2-aminophenyl)pyrazole derivatives 8 [22],
and 5-(5-oxo-1-phenylpyrrolidin-3-yl)-1H-pyrazole-4-carboxamides 9 [23] as the conformationally
constrained analogues of histamine. In continuation, we have focused our attention on 2-substituted 6-
(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamides 10 (Figure 1).
Figure 1. Aminoethyl substituted heterocycles 1–10.
Herein, we report a parallel solution-phase synthesis of a library of 24 6-(5-oxo-1-phenylpyrrolidin-
3-yl)pyrimidine-5-carboxamides 10{1,2; 1–12} as novel 2-heteroarylethylamine derivatives.
2. Results and Discussion
2.1. Synthesis of Title Compounds 10
First, the starting compound 12 was prepared from commercially available itaconic acid (11) and
aniline following the literature procedure [24]. Transformation of 12 into the enaminone 14 as the first
key intermediate was performed following the literature protocol [23]: Masamune-Claisen
condensation of 12 with 1,1'-carbonyldiimidazole (CDI) as activating agent in anhydrous acetonitrile
at room temperature gave the β-keto ester 13, which when treated with N,N-dimethylformamide
dimethylacetal (DMFDMA) in refluxing toluene gave the enaminone intermediate 14. Subsequent
cyclisation of 14 with acetamidine 15{1} and benzamidine 15{2} afforded methyl 4-(5-oxo-1-
phenylpyrrolidin-3-yl)pyrimidine-5-carboxylates 16{1} and 16{2} in 50% and 65% yield,
respectively. Finally, hydrolysis of 16{1} and 16{2} with 1 M aqueous NaOH in a mixture of

Molecules 2012, 17
5365
methanol and THF at room temperature furnished the corresponding carboxylic acids 17{1} and 17{2}
in 86% and 92% yield, respectively (Scheme 1).
Scheme 1. Synthesis of 4-(5-Oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxylic Acids 17{1,2}.
With the desired carboxylic acids 17{1,2} as the key-intermediates in our hands, a parallel
solution-phase synthesis of 2-substituted 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamides
10 was studied. We supposed that the reaction conditions for the parallel amidation step as well as the
workup protocol should be similar to those employed in the synthesis of closely related pyrazole
analogues 9 [23]. Accordingly, bis(pentafluorophenyl) carbonate BPC was chosen as the reagent for
activation of the carboxylic acids 17 and acetonitrile as the solvent. Preliminary amidations of 17{1,2}
with benzylamine (18{3}) as the model primary amine proceeded smoothly to furnish the desired
N-benzylcarboxamides 17{1; 3} and 17{2; 3}, which precipitated from the reaction mixtures and were
isolated by filtration. Somewhat surprisingly, analogous amidations of 17{1,2} with diethylamine
(18{8}) did not proceed to completion unless excess diethylamine (18{8}) was employed. The
corresponding carboxamides 17{1; 8} and 17{2; 8} did not precipitate from the reaction mixtures and
were isolated by evaporation of the reaction mixtures followed by purification by dry flash column
chromatography (DFCC) [25,26] over aluminium oxide [27]. Consequently, the following procedure
for parallel amidation was applied: the acids 17{1,2} were activated with triethylamine and
bis(pentafluorophenyl) carbonate (BPC) in acetonitrile at room temperature to give the intermediate
pentafluorophenyl esters 19{1,2}, which were subsequently treated with 1 equiv. of primary amines
18{1–7} or with 10 equiv. of secondary amines 18{8–12} at room temperature for 12 h. Nine products
that precipitated from the reaction mixtures were isolated by filtration to afford carboxamides
10{1; 3,4} and 10{2; 1–7} in 28–100% yields and in 84–100% purity (Workup A). The rest of the
products, which did not precipitate from the reaction mixtures, were isolated by evaporation of the

Molecules 2012, 17
5366
reaction mixtures followed by purification of the residues by DFCC over aluminium oxide, and
evaporation of the eluates to give compounds 10{1; 1,2,5–12} and 10{2; 8–12} in 40–100% yields and
in 80–100% purity (Workup B). In this manner, all 24 carboxamides 10{1,2; 1–12} were successfully
obtained in 18–100% yields and in 80–100% purity. Out of 24 library members, 17 were ≥95% pure
and 7 were ≥80% pure (Scheme 2, Table 1).
Scheme 2. Parallel synthesis of 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamides 10.
Table 1. Selected experimental data for compounds 10{1,2; 1–12}.
Compd.
10{1; 1}
10{1; 2}
10{1; 3}
10{1; 4}
10{1; 5}
10{1; 6}
10{1; 7}
10{1; 8}
10{1; 9}
10{1; 10}
R1
R2R3NH 18
1-pentylamine 18{1}
cyclohexylamine 18{2}
benzylamine 18{3}
2-methoxyethylamine 18{4}
3-amino-1-propanol 18{5}
3-dimethylamino-1-propylamine 18{6}
2-picolylamine 18{7}
diethylamine 18{8}
Workup [a] Yield (%) Purity (%)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
B
B
A
A
B
B
B
B
B
B
85
69
77
28
94
40
76
100
79
100
80 [b]
100 [b]
100 [b,c]
100 [b,c]
81 [b]
94 [b]
100 [b]
100 [b]
100 [b]
100 [b]
pyrrolidine 18{9}
piperidine 18{10}

Molecules 2012, 17
5367
Table 1. Cont.
Compd.
10{1; 11}
10{1; 12}
10{2; 1}
10{2; 2}
10{2; 3}
10{2; 4}
10{2; 5}
10{2; 6}
10{2; 7}
10{2; 8}
10{2; 9}
10{2; 10}
10{2; 11}
10{2; 12}
R1
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R2R3NH 18
morpholine 18{11}
4-methylpiperazine 18{12}
1-pentylamine 18{1}
cyclohexylamine 18{2}
benzylamine 18{3}
2-methoxyethylamine 18{4}
3-amino-1-propanol 18{5}
3-dimethylamino-1-propylamine 18{6}
2-picolylamine 18{7}
diethylamine 18{8}
Workup [a] Yield (%) Purity (%)
B
B
A
A
A
A
A
A
A
B
B
B
B
B
99
100 [b]
100 [b]
100 [b,c]
86 [b,c]
100 [b,c]
100 [b,c]
84 [b,c]
100 [b]
87 [b,c]
88 [b,c]
100 [b]
100 [b]
100 [b]
100 [b]
100
100
100
77
65
98
71
89
68
pyrrolidine 18{9}
piperidine 18{10}
morpholine 18{11}
4-methylpiperazine 18{12}
100
100
95
100
[a] Workup A: filtration of the reaction mixture; Workup B: evaporation of the reaction mixture,
followed by DFCC purification. [b] Determined by LC-MS, 1H-NMR, and 13C-NMR. [c] Confirmed
by elemental analysis. The found values for C, H, and N were within ±0.4% range with respect to
the theoretical values.
2.2. Structure Determination
The structures and purities of novel compounds 10{1,2; 1–12}, 16{1,2}, and 17{1,2} were
1
13
determined by spectroscopic methods (IR, H-NMR and C-NMR, MS, HRMS), by LC-MS, and by
elemental analyses for C, H, and N. Spectral and analytical data for novel compounds 10{1,2; 1–12},
16{1,2}, and 17{1,2} were in agreement with the proposed structures. Correlation of NMR data for
compounds 10{1,2; 1–12}, 16{1,2}, and 17{1,2} revealed very good agreement of chemical shifts and
coupling constants for the core nuclei (Table 2).
Since the products 10{1,2; 1–12} were isolated as racemic mixtures [28], we also tried to find
suitable conditions for separation of the enantiomers of compounds 10 by HPLC using analytical chiral
stationary phase column Chiralcel® OD-H (0.46 cm × 25 cm) and n-hexane/isopropanol as mobile
phase. To our pleasant surprise, all 24 racemic compounds were resolved under these conditions. Most
probably, the results obtained on analytical column should be applicable in (semi)preparative
separation of enantiomers of 10{1,2; 1−12}, while these separation conditions could also serve as a
important information for separation of analogous racemic compounds (Table 3).
Finally, some physicochemical properties of compounds 10{1,2; 1–12} were calculated to estimate
their drug-likeness. The compounds have molecular weight (MW) between 160 and 500, number of
atoms between 20 and 70, CLogP between –0.4 and 5.6, number of hydrogen bond donors (HBD) ≤ 5,
number of hydrogen bond acceptors (HBA) ≤ 10, and polar surface area (PSA) bellow 140 Ǻ2 [29,30].
These calculated physicochemical properties compliant with Lipinski’s rule of five indicate promising
drug-likeness of the synthesized compounds 10{1,2; 1–12} (Table 4).

Molecules 2012, 17
5368
Table 2. Selected NMR data for compounds 10{1,2; 1–12}.
δ (ppm)
3JH–H (Hz)
4-H 2'-Ha 2'-Hb 3'-H 4'-Ha 4'-Hb
Compd.
2'a-2'b 2'a-3' 2'b-3' 3'-4'a 3'-4'b 4'a-4'b
16{1}
16{2}
17{1}
17{2}
9.11 4.15
9.28 4.16
9.05 4.00
9.25 4.06
4.24 4.70 2.96
4.36 4.78 3.04
3.17
3.29
9.6
9.7
9.8
9.9
9.3
9.1
9.5
9.4
9.6
9.6
9.5
8.5
9.5
[a]
[a]
[a]
9.1
9.6
9.6
9.4
9.6
9.7
9.6
[a]
9.7
[a]
[a]
[a]
6.4
5.4
5.4
4.1
6.5
6.5
6.8
7.1
6.8
6.7
7.1
8.5
8.4
[a]
[a]
[a]
5.2
4.8
5.8
5.8
5.6
5.8
6.1
[a]
6.8
[a]
[a]
[a]
8.4
8.1
8.5
7.9
7.3
8.7
8.9
8.6
8.9
8.4
8.9
8.5
7.6
[a]
[a]
[a]
8.6
[a]
8.8
8.8
8.9
8.1
8.3
[a]
8.2
[a]
[a]
[a]
9.1
8.9
[a]
4.9
8.8
8.8
9.0
8.9
9.0
9.1
9.0
8.8
9.0
[a]
[a]
[a]
6.5
8.8
8.8
8.6
8.7
8.9
8.9
8.9
8.9
[a]
8.3
[a]
7.3
6.2
[a]
8.6
7.3
7.5
7.7
7.9
7.7
7.8
8.0
[a]
8.7
[a]
[a]
[a]
8.7
6.5
6.7
6.8
6.5
6.7
7.1
[a]
7.8
[a]
7.0
[a]
16.9
16.9
[a]
4.23 4.56
2.92 [a]
4.35 4.73 2.96
4.23 4.28 2.90
4.22 4.27 2.91
4.18 4.28 2.83
4.21 4.28 2.90
4.22 4.31 2.92
4.25 4.43 2.92
4.22 4.34 2.93
4.20 3.84 2.88
4.21 3.96 2.90
3.03
3.15
3.15
3.10
3.16
3.12
3.18
3.19
[b]
3.17
3.19
3.18
3.19
3.23
3.23
3.26
3.27
3.21
3.29
3.29
[a]
16.7
17.0
16.9
16.9
16.8
16.9
16.9
16.9
16.7
16.9
[a]
10{1; 1} 8.62 4.14
10{1; 2} 8.60 4.16
10{1; 3} 8.63 4.09
10{1; 4} 8.65 4.15
10{1; 5} 8.65 4.16
10{1; 6} 8.61 4.14
10{1; 7} 8.78 4.16
10{1; 8} 8.49 4.13
10{1; 9} 8.56 4.17
10{1;10} 8.47
4.19 [a]
4.19 [a]
4.17 [a]
3.90 2.90
3.91 2.90
3.89 2.90
10{1; 11 8.48
10{1;12} 8.47
[a]
[a]
10{2; 1} 8.77 4.14
10{2; 2} 8.75 4.15
10{2; 3} 8.81 4.14
10{2; 4} 8.82 4.17
10{2; 5} 8.80 4.17
10{2; 6} 8.77 4.20
10{2; 7} 8.96 4.19
10{2; 8} 8.65 4.22
10{2; 9} 8.72 4.24
10{2;10} 8.63 4.24
10{2;11} 8.64 4.23
10{2;12} 8.64 4.25
4.31 4.35 2.95
~4.3 [a] 2.95
16.9
16.9
16.9
16.8
16.9
16.9
16.9
16.9
16.9
[a]
4.31 4.39 2.96
4.32 4.37 2.98
4.31 4.38 2.98
4.28 4.51 3.00
4.32 4.44 3.00
4.24 3.92 2.95
4.27 4.06 2.97
4.24 3.98 2.96
4.25 3.99 2.97
4.25 3.98 2.98
3.28
3.27
3.27
3.29
16.3
[a]
[a] Multiplet or broad singlet; [b] Overlapped by other signals.
Table 3. Analytical data for separation of enantiomers of racemic compounds 10{1,2; 1–12}.
Rt (min)
Compound n-hexane:i-PrOH
Enantiomer A
4.084
Enantiomer B
5.078
10{1; 1}
10{1; 2}
10{1; 3}
10{1; 4}
10{1; 5}
10{1; 6}
10{1; 7}
10{1; 8}
10{1; 9}
10{1; 10}
50:50
50:50
50:50
50:50
50:50
50:50
50:50
50:50
50:50
50:50
9.987
8.208
5.321
3.828
5.083
7.577
5.728
6.960
16.650
12.734
7.031
4.542
5.477
8.352
6.380
9.471
7.185
5.798

Molecules 2012, 17
5369
Table 3. Cont.
Rt (min)
Enantiomer A Enantiomer B
Compound n-hexane:i-PrOH
10{1; 11}
50:50
50:50
50:50
50:50
50:50
50:50
80:20
50:50
50:50
50:50
50:50
50:50
80:20
50:50
8.509
7.206
4.409
4.537
11.292
6.462
14.864
6.160
10.778
5.293
9.284
7.102
14.864
14.429
9.619
7.928
5.515
5.840
29.227
7.522
18.975
19.660
12.764
24.904
10.960
8.212
10{1; 12}
10{2; 1}
10{2; 2}
10{2; 3}
10{2; 4}
10{2; 5}
10{2; 6}
10{2; 7}
10{2; 8}
10{2; 9}
10{2; 10}
10{2; 11}
10{2; 12}
18.975
19.625
Table 4. Calculated physicochemical properties of compounds 10{1,2; 1–12} [a].
Compound MW (g·mol–1) No. of atoms CLogP No. of HBD No. of HBA PSA (Ǻ2)
10{1; 1}
10{1; 2}
10{1; 3}
10{1; 4}
10{1; 5}
10{1; 6}
10{1; 7}
10{1; 8}
10{1; 9}
10{1; 10}
10{1; 11}
10{1; 12}
10{2; 1}
10{2; 2}
10{2; 3}
10{2; 4}
10{2; 5}
10{2; 6}
10{2; 7}
10{2; 8}
10{2; 9}
10{2; 10}
10{2; 11}
10{2; 12}
366
378
386
354
354
381
387
352
350
364
366
379
428
440
448
416
416
443
449
414
412
426
428
441
53
54
51
48
48
55
50
50
48
51
49
53
60
61
58
55
55
62
57
57
55
58
56
60
2.82
2.73
2.67
0.90
0.46
1.39
1.17
1.63
1.20
1.76
0.73
1.29
4.42
4.33
4.27
2.50
2.06
2.99
2.77
3.22
2.80
3.36
2.33
2.89
1
1
1
1
2
1
1
0
0
0
0
0
1
1
1
1
2
1
1
0
0
0
0
0
6
6
6
7
7
7
7
6
6
6
7
7
6
6
6
7
7
7
7
6
6
6
7
7
74
74
74
83
94
77
86
65
65
65
75
69
74
74
74
83
94
77
86
65
65
65
75
69
[a] Calculated with ChemBioDraw Ultra v11.0.

Molecules 2012, 17
5370
3. Experimental
3.1. General Methods
Melting points were determined on a Stanford Research Systems MPA100 OptiMelt automated
melting point system (Sunnyvale, CA, USA). The NMR spectra were obtained on a Bruker Avance III
UltraShield 500 plus (Karlsruhe, Germany) at 500 MHz for 1H and 126 MHz for the 13C nucleus, using
DMSO-d6 and CDCl3 with TMS as the internal standard, as solvents. Mass spectra were recorded on a
Agilent 6224 Accurate Mass TOF LC/MS spectrometer (Santa Clara, CA, USA), IR spectra on a
Perkin-Elmer Spectrum BX FTIR spectrophotometer (Waltham, MA, USA). Microanalyses were
performed on a Perkin-Elmer CHN Analyzer 2400 II (Waltham, MA, USA). Drying of the compounds
10 and 17 was performed in a Büchi drying oven (Flawil, Switzerland). Dry flash column
chromatography (DFCC) was performed on Aluminium Oxide Fluka for Chromatography, cat. #
06310, type 506 C weakly acidic, 0.05–0.15 mm, pH 6.0 ± 0.5 (Buchs, Switzerland).
For LC-MS/MS experiments, liquid chromatograph Perkin Elmer Series 200 from Perkin Elmer
(Shelton, CT, USA) with UV detector and 3200 QTRAP LC/MS/MS System equipped with ESI and
APCI ion sources from Applied Biosystems/MDS Sciex (Foster City, CA, USA) were used. HPLC
column was Gemini, dimensions 150 mm × 4.6 mm, 3 m particles from Phenomenex (Torrance, CA,
USA). Mobile phase was a gradient of acetonitrile (A) and deionised water (B): 0 min-10% A,
25 min-100% A, 3 min equilibration time with initial mobile phase (10% A) was allowed for column
equilibration. Mobile phase flow was 1 mL/min. Injection volume was 20 L. Signal was recorded
using UV detector at 254 nm and mass spectra were recorded using positive (ESI+) and negative
(ESI−) ionization mode simultaneously. Mass range was from 70 to 500 amu. Electrospray ion source
(ESI) conditions were as follows: cone voltage 5500 V (ESI+) and −4500 V (ESI−), respectively, ion
source temperature 4,000 °C, curtain gas N2 pressure was set to 10 psi, nebulizer gas N2 pressure was
set to 20 psi and turbo gas (air) pressure was set to 40 psi. Declustering potential 30 V and entrance
potential 10 V was used, respectively.
Itaconic acid (11), 1,1'-carbonyldiimidazole, N,N-dimethylformamide dimethylacetal (DMFDMA),
acetamidine hydrochloride 15{1}, benzamidine 15{2}, bis(pentafluorophenyl) carbonate (BPC), and
amines 18{1–12} are commercially available (Sigma-Aldrich). 5-Oxo-1-phenylpyrrolidin-3-carboxylic
acid (12) [24] and methyl 3-oxo-3-(5-oxo-1-phenylpyrrolidin-3-yl)propanoate (13) [23] were prepared
according to the literature procedures.
Parallel stirring and filtrations were carried out on Mettler-Toledo Bohdan MiniBlock™ Compact
Shaking and Washing Station and Vacuum Collection Base (2 × 12 positions, Vortex stirring,
400 r.p.m. in all cases). Parallel evaporations were carried out on Büchi Syncore® Polyvap parallel
evaporator (24 positions, Vortex stirring, 400 r.p.m. in all cases). Parallel drying was carried out on
Hettlab IR-Dancer Infra-Red Vortex-Evaporator (42 positions, Vortex stirring, 400 r.p.m. in all cases).
3.2. Synthesis of Methyl 3-(Dimethylamino)-2-(5-oxo-1-phenylpyrrolidine-3-carbonyl)acrylate (14)
This compound was prepared according to a slightly modified literature procedure [23]. A mixture
of β-keto ester 13 [23] (5.2 g, 20 mmol), anhydrous toluene (20 mL), and DMFDMA (2.8 g, 3 mL,

Molecules 2012, 17
5371
20 mmol) was stirred at 60 °C for 3 h. Volatile components were evaporated in vacuo to give the crude
14 as a yellow oil in quantitative yield.
3.3. Synthesis of Methyl 2-Methyl-6-(5-Oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxylate (16{1})
Cold (0 °C) solution of t-BuOK (2.3 g, 20 mmol) in anhydrous methanol (20 mL) was added to a
cold (0 °C) solution of acetamidine hydrochloride (15{1}, 1.9 g, 20 mmol) in methanol (20 mL) and
the mixture was stirred at 0 °C for 5 min. The suspension was filtered with suction through a fritted
funnel and the precipitated KCl was washed with anhydrous methanol (2 × 10 mL) to afford a solution
of the free acetamidine 15{1} (20 mmol) in methanol. This was added to a solution of the crude
enaminone 13 (20 mmol) in methanol (100 mL) and the mixture was stirred at room temperature for
18 h. The precipitate was collected by filtration, and washed with methanol (2 × 10 mL) to give 16{1}.
1
Yield: 3.2 g (50%) of white solid; m.p. 131–133 °C. H-NMR (500 MHz, DMSO-d6): δ 2.77 (3H, s,
2-CH3); 2.96 (1H, dd, J = 9.1, 16.9 Hz, 4'-Ha); 3.17 (1H, dd, J = 7.3, 16.9 Hz, 4'-Hb); 3.97 (3H, s,
OCH3); 4.15 (1H, dd, J = 6.4, 9.6 Hz, 2'-Ha); 4.24 (1H, dd, J = 8.4, 9.5 Hz, 2'-Hb); 4.70 (1H, quintet,
J = 8.3 Hz, 3'-H); 7.14 (1H, br t, J = 7.4 Hz, p-Ph); 7.37 (2H, br t, J = 8.0 Hz, o-Ph); 7.63 (2H, br d,
13
J = 7.9 Hz, m-Ph); 9.06 (1H, s, 4-H). C-NMR (126 MHz, CDCl3): δ 26.5, 35.5, 38.0, 52.9, 53.3,
120.1, 120.3, 124.8, 129.0, 139.3, 159.5, 165.2, 170.1, 171.2, 172.7. LC-MS: Rt = 13.217 min,
m/z = 312 (MH+), area% = 80. m/z (HRMS) Found: 312.1345 (MH+). C17H18N3O3 requires:
m/z = 312.1343. (Found: C, 65.22; H, 5.46; N, 13.16. C17H17N3O3 requires: C, 65.58; H, 5.50; N,
13.50.); νmax (KBr) 3420, 1718, 1693, 1598, 1572, 1545, 1480, 1397, 1306, 1268, 1097, 818, 764,
693 cm−1.
3.4. Synthesis of Methyl 6-(5-Oxo-1-phenylpyrrolidin-3-yl)-2-phenylpyrimidine-5-carboxylate (16{2})
Benzamidine 15{2} (2.4 g, 20 mmol) was added to a solution of the crude enaminone 14 (20 mmol)
in anhydrous methanol (100 mL) and the mixture was stirred at room temperature for 72 h. The
precipitate was collected by filtration, and washed with methanol (2 × 30 mL) to give 16{2}. Yield:
1
4.9 g (65%) of white solid; m.p. 146–147 °C. H-NMR (500 MHz, CDCl3): δ 3.04 (1H, dd, J = 8.9,
16.9 Hz, 4'-Ha); 3.29 (1H, dd, J = 6.2, 16.9 Hz, 4'-Hb); 4.00 (3H, s, OCH3); 4.16 (1H, dd, J = 5.4, 9.7
Hz, 2'-Ha); 4.36 (1H, dd, J = 8.1, 9.6 Hz, 2'-Hb); 4.78 (1H, tt, J = 5.9, 8.4 Hz, 3'-H); 7.16 (1H, t,
J = 7.4 Hz, p-Ph); 7.38 (2H, br t, J = 8.0 Hz, o-Ph); 7.47–7.55 (3H, m, 3H of Ph); 7.64 (2H, br d,
J = 7.7 Hz, m-Ph); 8.50–8.52 (2H, m, m-Ph); 9.28 (1H, s, 4-H). 13C-NMR (126 MHz, CDCl3): δ 35.9,
38.0, 52.9, 53.6, 120.2, 120.3, 124.8, 128.9, 129.0, 129.2, 132.2, 136.3, 139.3, 160.1, 165.1, 166.2,
170.5, 173.0. LC-MS: Rt = 19.692 min, m/z = 374 (MH+), area% = 100. m/z (ESI) = 374 (MH+). m/z
(HRMS) Found: 374.1499 (MH+). C22H20N3O3 requires: m/z = 374.1499. (Found: C, 69.61; H, 5.44;
N, 11.07. C22H19N3O3·⅓H2O requires: C 69.59; H 5.23; N 11.07.); νmax (KBr) 3484, 1717, 1676, 1569,
1478, 1406, 1311, 1281, 1196, 1108, 836, 766, 692 cm−1.
3.5. Synthesis of 2-Methyl-6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxylic Acid (17{1})
A mixture of the ester 16 (13 mmol), 1 M aqueous NaOH (30 mL), methanol (30 mL), and THF
(30 mL) was stirred at room temperature for 5 h. Methanol and THF were removed by evaporation

Molecules 2012, 17
5372
in vacuo (35 °C, 100 mbar), the aqueous residue was acidified with concentrated hydrochloric acid to
pH ~1, and the product was extracted with dichloromethane (4 × 200 mL). The combined organic
phases were dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated in vacuo to give
17{1}. Yield: 3.33 g (86%) of a pale yellow solid; m.p. 70–82 °C. 1H-NMR (500 MHz, DMSO-d6): δ
2.66 (3H, s, 2-CH3); 2.88–2.96 (2H, m, 4'-CH2); 4.00 (1H, dd, J = 5.4, 9.8 Hz, 2'-Ha); 4.23 (1H, dd,
J = 8.5, 9.7 Hz, 2'-Hb); 4.56 (1H, dq, J = 5.6, 8.0 Hz, 3'-H); 7.13 (1H, br t, J = 7.4 Hz, p-Ph); 7.37 (2H,
br t, J = 8.0 Hz, o-Ph); 7.65 (2H, br d, J = 7.8 Hz, m-Ph); 9.05 (1H, s, 4-H); 13.78 (1H, s, COOH).
13C (126 MHz, DMSO-d6): δ 26.0, 34.4, 37.4, 52.6, 119.6, 121.0, 124.0, 128.7, 139.3, 159.1, 166.0,
169.6, 170.0, 172.3. LC-MS: Rt = 13.7 min, m/z = 296 (M–H+), area% = 100. m/z (ESI) = 296
(M–H+). m/z (HRMS) Found: 298.1189 (MH+). C16H16N3O3 requires: m/z = 298.1186. (Found: C
64.51; H 5.16; N 13.95. C16H15N3O3 requires: C 64.64; H 5.09; N 14.13.); νmax (KBr) 3418, 1700,
1676, 1597, 1542, 1500, 1400, 1265, 762, 692 cm−1.
3.6. Synthesis of 6-(5-Oxo-1-phenylpyrrolidin-3-yl)-2-phenylpyrimidine-5-carboxylic Acid (17{2})
A mixture of the ester 16 (13 mmol), 1 M aqueous NaOH (30 mL), methanol (30 mL), and THF
(30 mL) was stirred at room temperature for 5 h. Methanol and THF were removed by evaporation
in vacuo (35 °C, 100 mbar) and the aqueous residue was acidified with concentrated hydrochloric acid
to pH ~1. The precipitate was collected by filtration to give 17{2}. Yield: 4.34 g (92%) of a pale
1
yellow solid; m.p. 251–253 °C. H-NMR (500 MHz, DMSO-d6): δ 2.96 (1H, dd, J = 4.9, 16.7 Hz,
4'-Ha); 3.03 (1H, dd, J = 8.6, 16.7 Hz, 4'-Hb); 4.06 (1H, dd, J = 4.1, 9.9 Hz, 2'-Ha); 4.35 (1H, dd,
J = 7.9, 9.9 Hz, 2'-Hb); 4.73 (1H, br septet, J = 4.2 Hz, 3'-H); 7.13 (1H, br t, J = 7.4 Hz, p-Ph); 7.37
(2H, br t, J = 8.0 Hz, o-Ph); 7.52 (2H, br t, J = 8.0 Hz, o-Ph); 7.57 (1H, br t, J = 7.3 Hz, p-Ph); 7.69
(2H, br d, J = 7.8 Hz, m-Ph); 8.43 (2H, br d, J = 7.2 Hz, m-Ph); 9.25 (1H, s, 4-H); 13.84 (1H, s,
COOH). 13C (126 MHz, DMSO-d6): δ 35.0, 37.7, 52.8, 119.5, 121.2, 123.9, 128.4, 128.7, 128.8, 131.9,
136.2, 139.5, 159.8, 164.3, 165.9, 170.8, 172.6. LC-MS: Rt = 18.192 min, m/z = 358 (M–H+),
area% = 100. m/z (ESI) = 358 (M–H+). m/z (HRMS) Found: 360.1346 (MH+). C21H18N3O3 requires:
m/z = 360.1343. (Found: C 69.38; H 4.65; N 11.38. C21H17N3O3·¼H2O requires: C 69.37; H 4.84;
N 11.56.); νmax (KBr) 3420, 2364, 1708, 1654, 1567, 1500, 1424, 1312, 1257, 1183, 756, 697 cm−1.
3.7. Parallel Synthesis of 2-Substituted 6-(5-Oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamides
10{1,2; 1–12}
Two MiniBlocksTM were equipped with 12 fritted vessels each and mounted on a compact stirring
and washing station. The reaction vessels were charged with carboxylic acids 17{1} (12 × 149 mg,
12 × 0.5 mmol) and 17{2} (12 × 180 mg, 12 × 0.5 mmol), anhydrous acetonitrile (24 × 5 mL), BPC
(24 × 236 mg, 24 × 0.6 mmol), and triethylamine (24 × 0.14 mL, 24 × 1 mmol) and the mixtures were
stirred at room temperature for 30 min. Then, the amines 18{1–7} (2 × 12 × 0.5 mmol) and amines
18{8–12} (2 × 4 × 5 mmol) were added and stirring at room temperature was continued for 12 h. The
reaction mixtures were filtered to afford 10{1; 3,4} and 10{2; 1–7} (Workup A). The filtrates
containing the products 10{1; 1,2,5–12} and 10{2; 8–12} were evaporated in vacuo (40 °C/2 mbar)
and the residues (resins) were dissolved in dichloromethane (15 × 2.5 mL) and purified sequentially by
DFCC over aluminium oxide (5 g, d = 15 mm) by gradient elution with a) EtOAc (30 mL) and b)

Molecules 2012, 17
5373
EtOAc–EtOH (5:1, 50 mL). The combined eluates were evaporated in vacuo (60 °C/1 mbar) to afford
compounds 10{1; 1,2,5–12} and 10{2; 8–12} (Workup B). The following compounds were prepared
in this manner.
3.7.1. 2-Methyl-6-(5-oxo-1-phenylpyrrolidin-3-yl)-N-pentylpyrimidine-5-carboxamide (10{1; 1})
Prepared from 17{1} and 1-pentylamine (18{1}), workup B. Yield: 204 mg (85%) of yellow-brown
resin. 1H-NMR (500 MHz, CDCl3): δ 0.92 (3H, dd, J = 4.7, 9.0 Hz, CH3 of C5H11), 1.35–1.40 (4H, m,
2CH2 of C5H11), 1.64 (2H, quintet, J = 7.3 Hz, CH2 of C5H11), 2.74 (3H, s, 2-CH3), 2.90 (1H, dd,
J = 8.8, 17.0 Hz, 4'-Ha), 3.15 (1H, dd, J = 7.3, 17.0 Hz, 4'-Hb), 3.45 (2H, br q, J = 7.3 Hz, CH2NH),
4.14 (1H, dd, J = 6.5, 9.3 Hz, 2'-Ha), 4.23 (1H, t, J = 8.8 Hz, 2'-Hb), 4.28 (1H, br q, J = 8.2 Hz, 3'-H),
6.24 (1H, s, NH), 7.15 (1H, br t, J = 7.4 Hz, p-Ph), 7.36 (2H, br t, J = 7.9 Hz, m-Ph), 7.59 (2H, br d,
J = 7.6 Hz, o-Ph), 8.62 (1H, s, 4-H). 13C-NMR (126 MHz, CDCl3): δ 14.2, 22.5, 26.3, 29.3, 29.4, 35.7,
38.3, 40.6, 53.9, 120.6, 125.1, 126.5, 129.1, 139.1, 154.7, 165.9, 168.3, 169.8, 172.9. LC-MS:
Rt = 14.733 min, m/z = 367 (MH+), area% = 80. m/z (ESI) = 365 (M−H+). m/z (HRMS) Found: 365.1987
([M−H]−). C21H25N4O2 requires: m/z = 365.1983. νmax (KBr) 3460, 2356, 1651, 1516, 1501, 985, 760,
694 cm−1.
3.7.2. N-Cyclohexyl-2-methyl-6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamide (10{1; 2})
Prepared from 17{1} and (cyclohexylamine 18{2}), workup B. Yield: 228 mg (69%) of
yellow-brown resin. 1H-NMR (500 MHz, CDCl3): δ 1.16–1.32 (4H, m, 4H of C6H11), 1.43 (2H, br tq,
J = 3.5, 12.1 Hz, 2H of C6H11), 1.68 (1H, br td, J = 3.5, 12.8 Hz, 2H of C6H11), 1.75–1.81 (2H, m, 2H
of C6H11), 2.05 (2H, br dd, J = 2.2, 12.3 Hz, 2H of C6H11), 2.74 (3H, s, 2-CH3), 2.91 (1H, dd, J = 8.8,
16.9 Hz, 4'-Ha ), 3.15 (1H, dd, J = 7.5, 16.9 Hz, 4'-Hb), 3.95 (1H, ttd, J = 3.9, 7.8, 14.5 Hz, 1H of
C6H11), 4.16 (1H, dd, J = 6.5, 9.1 Hz, 2'-Ha), 4.22 (1H, t, J = 8.7 Hz, 2'-Hb), 4.27 (1H, quintet,
J = 8.0 Hz, 3'-H), 6.04 (1H, J = 6.8 Hz, NH), 7.16 (1H, br t, J = 7.8 Hz, p-Ph), 7.36 (2H, br t,
J = 8.0 Hz, m-Ph), 7.59 (2H, br d, J = 7.7 Hz, o-Ph), 8.60 (1H, s, 4-H). 13C-NMR (126 MHz, CDCl3): δ
25.0, 25.6, 26.2, 33.2, 35.7, 38.3, 49.6, 53.9, 120.6, 125.1, 126.7, 129.1, 139.1, 154.6, 165.1, 168.2,
169.7, 173.0. LC-MS: Rt = 14.483 min, m/z = 379 (MH+), area% = 100. m/z (ESI) = 379 (MH+). m/z
(HRMS) Found: 379.2131 (MH+). C22H27N4O2 requires: m/z = 379.2129. νmax (KBr) 3418, 2934, 1634,
1516, 1501, 1400, 1281, 1150, 1007, 839, 762, 694 cm−1.
3.7.3. N-Benzyl-2-methyl-6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamide (10{1; 3})
Prepared from 17{1} and benzylamine (18{3}), workup A. Yield: 150 mg (77%) of white solid;
m.p. 153–155 °C. 1H-NMR (500 MHz, CDCl3): δ 2.72 (3H, s, 2-CH3), 2.83 (1H, dd, J = 9.0, 16.9 Hz,
1H, 4'-Ha), 3.10 (1H, dd, J = 7.7, 16.9 Hz, 4'-Hb), 4.09 (1H, dd, J = 6.8, 9.5 Hz, 2'-Ha), 4.18 (1H, t,
J = 8.9 Hz, 2'-Hb), 4.28 (1H, quintet, J = 7.9 Hz, 3'-H), 4.59 and 4.63 (2H, 2dd, 1:1, J = 5.5, 14.5 Hz,
CH2Ph), 6.72 (1H, t, J = 5.3 Hz, NH), 7.14 (1H, br t, J = 7.4 Hz, p-Ph), 7.31–7.38 (7H, m, m-Ph, Ph'),
7.55 (2H, br d, J = 7.4 Hz, o-Ph), 8.63 (1H, s, 4-H). 13C-NMR (126 MHz, CDCl3): δ 26.4, 35.6, 38.3,
44.6, 53.9, 120.5, 125.0, 126.2, 128.2, 128.3, 129.1, 129.2, 137.6, 139.2, 155.0, 165.9, 168.3, 170.0,
172.9. LC-MS: Rt = 13.808 min, m/z = 387 (MH+), area% = 100. m/z (ESI) = 385 (M–H+).

Molecules 2012, 17
5374
m/z (HRMS) Found: 385.1669 ([M−H]−). C23H21N4O2 requires: m/z = 385.167. (Found: C 71.30; H
5.83; N 14.44. C23H22N4O2 requires: C 71.48; H 5.74; N 14.50); νmax (KBr) 3422, 3269, 1706, 1634,
1560, 1498, 1446, 1396, 1308, 1279, 1218, 824, 756, 691 cm−1.
3.7.4. N-(2-Methoxyethyl)-2-methyl-6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamide
(10{1; 4})
Prepared from 17{1} and 2-methoxyethylamine (18{4}), workup A. Yield: 48 mg (28%) of white
1
solid; m.p. 101–103 °C. H-NMR (500 MHz, CDCl3): δ 2.74 (3H, s, 2-CH3), 2.90 (1H, dd, J = 8.9,
16.8 Hz, 1H, 4'-Ha), 3.16 (1H, dd, J = 7.9, 16.8 Hz, 4'-Hb), 3.39 (3H, s, OCH3), 3.57–3.59 and
3.63–3.66 (4H, 2m, 1:1, CH2CH2), 4.15 (1H, dd, J = 7.1, 9.4 Hz, 2'-Ha), 4.21 (1H, t, J = 8.6 Hz,
2'-Hb), 4.28 (1H, quintet, J = 8.1 Hz, 3'-H), 6.25 (1H, s, NH), 7.15 (1H, br t, J = 7.4 Hz, p-Ph), 7.36
(2H, br t, J = 8.0 Hz, m-Ph), 7.61 (2H, br d, J = 8.5 Hz, o-Ph), 8.65 (1H, s, 4-H). 13C-NMR (126 MHz,
CDCl3): δ 26.3, 35.7, 38.3, 40.1, 53.8, 59.1, 70.9, 120.4, 120.4, 124.9, 126.2, 129.0, 129.0, 139.2, 155.0,
166.0, 168.1, 169.9, 172.8. LC-MS: Rt = 10.167 min, m/z = 355 (MH+), area% = 100. m/z (ESI) = 355
(MH+). m/z (HRMS) Found: 389.1387 ([M+Cl]−). C19H22ClN4O3 requires: m/z = 389.1386. (Found: C
64.17; H 6.22; N 15.67. C19H22N4O3 requires: C 64.39; H 6.26; N 15.81); νmax (KBr) 3422, 3269, 1706,
1634, 1560, 1498, 1446, 1396, 1308, 1279, 1218, 824, 756, 691 cm−1.
3.7.5. N-(3-Hydroxypropyl)-2-methyl-6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamide
(10{1; 5})
Prepared from 17{1} and 3-amino-1-propanol (18{5}), workup B. Yield: 205 mg (94%) of
yellow-brown resin. 1H-NMR (500 MHz, CDCl3): δ 1.85 (2H, quintet, J = 6.3 Hz, CH2CH2CH2), 2.73
(3H, s, 2-CH3), 2.92 (1H, dd, J = 9.0, 16.9 Hz, 4'-Ha), 3.12 (1H, dd, J = 7.7, 16.9 Hz, 4'-Hb), 3.62 (2H,
ddd, J = 2.2, 5.6, 11.5 Hz, CH2NH), 3.81 (2H, t, J = 5.5 Hz, CH2OH), 4.16 (1H, dd, J = 6.8, 9.6 Hz,
2'-Ha), 4.22 (1H, t, J = 8.9 Hz, 2'-Hb), 4.31 (1H, quintet, J = 7.9 Hz, 3'-H), 6.40 (1H, br s, NH), 7.16
(1H, br t, J = 7.5 Hz, p-Ph), 7.19 (1H, br t, J = 5.0 Hz, OH), 7.36 (2H, br t, J = 8.0 Hz, m-Ph), 7.58
13
(2H, d, J = 7.8 Hz, o-Ph), 8.65 (1H, s, 4-H). C-NMR (126 MHz, CDCl3): δ 26.2, 31.4, 35.6, 38.4,
38,7, 54.0, 61.2, 120.7, 125.2, 126.3, 129.1, 139.0, 155.0, 166.4, 168.3, 169.8, 173.1. LC-MS:
Rt = 9.183 min, m/z = 355 (MH+), area% = 81. m/z (ESI) = 353 ([M−H]−). m/z (HRMS) Found:
353.1623 ([M−H]−). C19H21N4O3 requires: m/z = 353.1619. νmax (KBr) 3444, 2370, 1645, 1517, 1501,
1309, 984, 838, 761, 691 cm−1.
3.7.6. N-(3-Dimethylaminopropyl)-2-methyl-6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamide
(10{1; 6})
Prepared from 17{1} and 3-(dimethylamino)propylamine (18{6}), workup B. Yield: 115 mg (40%)
1
of yellow resin. H-NMR (500 MHz, CDCl3): δ 1.79 (2H, br quintet, J = 5.8 Hz, CH2CH2CH2), 2.28
(6H, s, NMe2), 2.54 (2H, t, J = 5.7 Hz, CH2NMe2), 2.74 (3H, s, 2-CH3), 2.92 (1H, dd, J = 9.1, 16.9 Hz,
4'-Ha), 3.18 (1H, dd, J = 7.8, 16.9 Hz, 4'-Hb), 3.56 (2H, tq, J = 6.0, 7.0 Hz, CH2NH), 4.14 (1H, dd,
J = 6.7, 9.6 Hz, 2'-Ha), 4.25 (1H, dd, J = 8.4, 9.6 Hz, 2'-Hb), 4.43 (1H, quintet, J = 8.2 Hz, 3'-H), 7.15
(1H, br t, J = 7.4 Hz, p-Ph), 7.36 (2H, br t, J = 8.0 Hz, m-Ph), 7.62 (2H, br d, J = 7.7 Hz, o-Ph), 8.61

Molecules 2012, 17
5375
13
(1H, s, NH), 8.78 (1H, br s, 4-H). C-NMR (126 MHz, CDCl3): δ 24.6, 26.2, 35.8, 37.6, 38.5, 43.7,
53.9, 56.0, 120.5, 125.0, 126.0, 129.0, 139.2, 155.3, 166.5, 168.2, 169.7, 173.0. LC-MS:
Rt = 1.867 min, m/z = 382 (MH+), area% = 94. m/z (ESI) = 353 (MH+). m/z (HRMS) Found: 382.2242
(MH+). C21H28N5O2 requires: m/z = 382.2238. νmax (KBr) 3444, 2356, 1651, 1503, 1312, 1163, 1008,
985, 838, 762, 693 cm−1.
3.7.7. 2-Methyl-6-(5-oxo-1-phenylpyrrolidin-3-yl)-N-((pyridin-2-yl)methyl)pyrimidine-5-carboxamide
(10{1; 7})
Prepared from 17{1} and 2-picolylamine (18{7}), workup B. Yield: 214 mg (76%) of yellow-brown
resin. 1H-NMR (500 MHz, CDCl3): δ 2.76 (3H, s, 2-CH3), 2.93 (1H, dd, J = 9.0, 16.9 Hz, 4'-Ha), 3.19
(1H, dd, J = 8.0, 16.9 Hz, 4'-Hb), 4.16 (1H, dd, J = 7.1, 9.5 Hz, 2'-Ha), 4.22 (1H, t, J = 8.9 Hz, 2'-Hb),
4.34 (1H, quintet, J = 8.9 Hz, 3'-H), 4.74 and 4.78 (2H, 2dd, 1:1, J = 4.8, 16.5 Hz, CH2NH), 7.15 (1H,
br t, J = 7.4 Hz, p-Ph), 7.28 (1H, dd, J = 5.3, 7.2 Hz, 5''-H), 7.36 (3H, br t, J = 8.0 Hz, m-Ph, NH),
7.58–7.64 (3H, m, o-Ph, 3''-H), 7.75 (1H, dt, J = 1.7, 7.7 Hz, 4''-H), 8.53 (1H, br d, J = 4.6 Hz, 6''-H),
13
8.78 (1H, s, 4-H). C-NMR (126 MHz, CDCl3): δ 26.3, 35.7, 38.4, 44.7, 53.9, 120.5, 122.8, 123.2,
125.0, 126.3, 129.1, 137.7, 139.2, 149.1, 155.0, 155.2, 165.9, 168.3, 170.0, 173.0. LC-MS:
Rt = 11.775 min, m/z = 388 (MH+), area% = 100. m/z (ESI) = 388 (MH+). m/z (HRMS) Found:
388.1769 (MH+). C22H22N5O2 requires: m/z = 388.1768. νmax (KBr) 3452, 1654, 1515, 1500, 1405,
1311, 986, 760, 696 cm−1.
3.7.8. N,N-(Diethyl)-2-methyl-6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamide (10{1; 8})
Prepared from 17{1} and diethylamine (18{8}), workup B. Yield: 219 mg (100%) of yellow resin.
1H-NMR (500 MHz, CDCl3): δ 1.14 and 1.29 (6H, 2t, 1:1, J = 7.1 Hz, 2CH2CH3), 2.75 (3H, s, 2-CH3),
2.86 (1H, dd, J = 8.8, 16.7 Hz, 4'-Ha), 3.15–3.27 (3H, m, 4'-Hb, CH2CH3), 3.53–3.67 (2H, m,
CH2CH3), 3.83 (1H, quintet, J = 8.6 Hz, 3'-H), 4.12 (1H, br t, J = 8.5 Hz, 2'-Ha), 4.20 (1H, br t,
J = 8.6 Hz, 2'-Hb), 7.17 (1H, br t, J = 7.4 Hz, p-Ph), 7.37 (2H, br t, J = 8.0 Hz, m-Ph), 7.60 (2H, br d,
J = 7.8 Hz, o-Ph), 8.49 (1H, s, 4-H). 13C-NMR (126 MHz, CDCl3): δ 13.1, 14.5, 26.1, 36.1, 39.9, 43.7,
120.5, 125.2, 127.3, 129.1, 139.0, 153.7, 166.2, 166.6, 168.9, 172.5. LC-MS: Rt = 13.242 min,
m/z = 353 (MH+), area% = 100. m/z (ESI) = 353 (MH+). m/z (HRMS) Found: 353.1973 (MH+).
C20H25N4O2 requires: m/z = 353.1972. νmax (KBr) 3413, 2346, 1637, 1516, 1500, 1430, 1310, 995, 761,
691 cm−1.
3.7.9. 2-Methyl-6-(5-oxo-1-phenylpyrrolidin-3-yl)-N-(pyrrolidin-1-yl)pyrimidine-5-carboxamide
(10{1; 9})
Prepared from 17{1} and pyrrolidine (18{9}), workup B. Yield: 205 mg (79%) of yellow resin.
1H-NMR (500 MHz, CDCl3): δ 1.90–2.08 (4H, m, 4H of pyrrolidine), 2.75 (3H, s, 2-CH3), 2.88 (1H,
dd, J = 9.0, 16.8 Hz, 4'-Ha), 3.17 (1H, dd, J = 8.7, 16.8 Hz, 4'-Hb), 3.23–3.29 (1H, m, 1H of
pyrrolidine), 3.30–3.37 (1H, m, 1H of pyrrolidine), 3.68 (2H, br t, J = 6.9 Hz, 2H of pyrrolidine), 3.97
(1H, quintet, J = 8.4 Hz, 3'-H), 4.15 (1H, br t, J = 8.9 Hz, 2'-Ha), 4.21 (1H, dd, J = 7.6, 9.5 Hz, 2'-Hb),
7.17 (1H, br t, J = 7.4 Hz, p-Ph), 7.37 (2H, br t, J = 8.0 Hz, m-Ph), 7.60 (2H, d, J = 7.4 Hz, o-Ph), 8.56

Molecules 2012, 17
5376
13
(1H, s, 4-H). C-NMR (126 MHz, CDCl3): δ 24.6, 26.1, 26.4, 36.2, 38.3, 46.3, 49.5, 53.8, 120.6,
125.2, 127.5, 129.1, 138.9, 154.4, 165.4, 166.5, 169.1, 172.7. LC-MS: Rt = 12.258 min, m/z = 351
(MH+), area% = 100. m/z (ESI) = 351 (MH+). m/z (HRMS) Found: 351.1815 (MH+). C20H23N4O2
requires: m/z = 351.1816. νmax (KBr) 3422, 2362, 1638, 1516, 1426, 997, 764, 670 cm−1.
3.7.10. 2-Methyl-6-(5-oxo-1-phenylpyrrolidin-3-yl)-N-(piperidin-1-yl)pyrimidine-5-carboxamide
(10{1; 10})
Prepared from 17{1} and piperidine (18{10}), workup B. Yield: 201 mg (100%) of yellow resin.
1H-NMR (500 MHz, CDCl3): δ 1.54 (2H, br s, 2H of piperidine), 1.72 (4H, br s, 4H of piperidine),
2.76 (3H, s, 2-CH3), 2.81–2.99 (1H, m, 4'-Ha), 3.13–3.25 (1H, m, 4'-Hb), 3.29 (2H, br s, 2H of
piperidine), 3.77 (2H, br s, 2H of piperidine), 3.90 (1H, quintet, J = 8.5 Hz, 3'-H), 4.19 (2H, br s,
2'-CH2), 7.17 (1H, br t, J = 7.4 Hz, p-Ph), 7.38 (2H, br t, J = 8.0 Hz, m-Ph), 7.60 (2H, br d, J = 7.7 Hz,
13
o-Ph), 8.47 (1H, s, 4-H). C-NMR (126 MHz, CDCl3): δ 24.4, 25.8, 26.1, 27.0, 36.2, 43.3, 48.9,
120.6, 125.2, 126.8, 129.1, 139.0, 154.2, 165.5, 166.4, 169.0, 172.6. LC-MS: Rt = 12.55 min,
m/z = 365 (MH+), area% = 100. m/z (ESI) = 365 (MH+). m/z (HRMS) Found: 365.197 (MH+).
C21H25N4O2 requires: m/z = 365.1972. νmax (KBr) 3438, 2325, 1630, 1515, 1500, 1431, 1288, 1000,
760, 692 cm−1.
3.7.11. 2-Methyl-6-(5-oxo-1-phenylpyrrolidin-3-yl)-N-(morpholin-4-yl)pyrimidine-5-carboxamide
(10{1; 11})
Prepared from 17{1} and morpholine (18{11}), workup B. Yield: 228 mg (99%) of yellow resin.
1H-NMR (500 MHz, CDCl3): δ 2.76 (3H, s, 2-CH3), 2.86–2.95 (1H, m, 4'-Ha), 3.11–3.23 (1H, m,
4'-Hb), 3.32–3.43 (2H, m, 2H of morpholine), 3.60–3.71 (2H, m, 2H of morpholine), 3.79–3.88 (4H,
m, 4H of morpholine), 3.91 (1H, quintet, J = 8.4 Hz, 3'-H), 4.12–4.25 (2H, m, 2'-CH2), 7.17 (1H, br t,
J = 7.4 Hz, o-Ph), 7.38 (2H, br t, J = 8.0 Hz, m-Ph), 7.60 (2H, br d, J = 7.7 Hz, o-Ph), 8.48 (1H, s,
13
4-H). C-NMR (126 MHz, CDCl3): δ 26.2, 36.2, 42.7, 45.8, 48.1, 67.0, 120.6, 125.2, 125.8, 129.1,
138.9, 154.5, 165.9, 166.9, 169.5, 172.4. LC-MS: Rt = 10.342 min, m/z = 367 (MH+), area% = 100.
m/z (ESI) = 367 (MH+). m/z (HRMS) Found: 367.1766 (MH+). C20H23N4O3 requires: m/z = 367.1765.
νmax (KBr) 3454, 2326, 1633, 1516, 1501, 1428, 1284, 1117, 984, 840, 762, 696 cm−1.
3.7.12. 2-Methyl-6-(5-oxo-1-phenylpyrrolidin-3-yl)-N-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamide
(10{1; 12})
Prepared from 17{1} and 4-methylpiperazine (18{12}), workup B. Yield: 203 mg (100%) of yellow
resin. 1H-NMR (500 MHz, CDCl3): δ 2.38 (3H, s, 4''-CH3), 2.39 (1H, br s, 1H of piperazine), 2.46 (1H,
br s, 1H of piperazine), 2.53–2.65 (2H, m, 2H of piperazine), 2.76 (3H, s, 2-CH3), 2.82–2.98 (1H, m,
4'-Ha), 3.12–3.25 (1H, m, 4'-Hb), 3.40 (2H, m, 2H of piperazine), 3.78–3.87 (1H, m, 1H of
piperazine), 3.89 (1H, quintet, J = 8.4 Hz, 3'-H), 3.90–3.97 (1H, m, 1H of piperazine), 4.17 (2H, m,
2'-CH2), 7.17 (1H, br t, J = 7.4 Hz, p-Ph), 7.38 (2H, br t, J = 8.0 Hz, m-Ph), 7.60 (2H, br d, J = 7.7 Hz,
o-Ph), 8.47 (1H, s, 4-H). 13C-NMR (126 MHz, CDCl3): δ 26.2, 31.1, 36.2, 41.8, 45.7, 45.9, 47.3, 54.7,
55.3, 120.5, 125.2, 126.1, 129.1, 139.0, 154.5, 165.7, 166.7, 169.4, 172.4. LC-MS: Rt = 9.683 min,

Molecules 2012, 17
5377
m/z = 380 (MH+), area% = 100. m/z (ESI) = 380 (MH+). m/z (HRMS) Found: 380.2085 (MH+).
C21H26N5O2 requires: m/z = 380.2081. νmax (KBr) 3448, 2365, 1636, 1500, 1292, 1154, 986, 764,
694 cm−1.
3.7.13. 6-(5-Oxo-1-phenylpyrrolidin-3-yl)-N-pentyl-1-phenylpyrimidine-5-carboxamide (10{2; 1})
Prepared from 17{2} and 1-pentylamine (18{1}), workup A. Yield: 214 mg (100%) of white solid;
1
m.p. 122–126 °C. H-NMR (500 MHz, CDCl3): δ 0.93 (3H, t, J = 7.0 Hz, CH3 of C5H11), 1.36–1.41
(4H, m, 2CH2 of C5H11), 1.62–1.68 (2H, m, CH2 of C5H11), 2.95 (1H, dd, J = 8.7, 16.9 Hz, 4'-Ha), 3.23
(1H, dd, J = 6.5, 16.9 Hz, 4'-Hb), 3.46 (2H, q, J = 6.3 Hz, CH2 of C5H11), 4.14 (1H, dd, J = 5.2, 9.1 Hz,
2'-Ha), 4.31 (1H, t, J = 8.6 Hz, 3'-H), 4.32–4.37 (1H, m, 2'-Hb), 6.39 (1H, s, NH), 7.14 (1H, br t,
J = 7.4 Hz, p-Ph), 7.35 (2H, br t, J = 8.0 Hz, m-Ph), 7.44–7.52 (3H, m, m,p-Ph), 7.59 (2H, br d,
J = 7.8 Hz, o-Ph), 8.44 (2H, br d, J = 7.0 Hz, o-Ph), 8.77 (1H, s, 4-H). 13C-NMR (126 MHz, CDCl3):
δ 14.2, 22.5, 29.3, 29.4, 35.9, 38.3, 40.5, 54.1, 120.5, 125.0, 126.6, 128.8, 128.9, 129.0, 131.8, 136.6,
139.2, 155.4, 165.3, 165.9, 168.5, 173.1. LC-MS: Rt = 20.192 min, m/z = 429 (MH+), area% = 100.
m/z (ESI) = 429 (MH+). m/z (HRMS) Found: 429.2289 (MH+). C26H29N4O2 requires: m/z = 429.2285.
(Found: C 72.10; H 6.44; N 12.90. C26H28N4O2 requires (428.5): C 72.87; H 6.59; N 13.07.); νmax (KBr)
3436, 2340, 1677, 1656, 1537, 1435, 1409, 1308, 755, 693 cm−1.
3.7.14. N-Cyclohexyl-6-(5-oxo-1-phenylpyrrolidin-3-yl)-2-phenylpyrimidine-5-carboxamide (10{2; 2})
Prepared from 17{2} and cyclohexylamine (18{2}), workup A. Yield: 225 mg (100%) of white
1
solid; m.p. 196–199 °C. H-NMR (500 MHz, CDCl3): δ 1.21–1.32 (3H, m, 3H of C6H11), 1.40–1.48
(2H, m, 2H of C6H11), 1.65–1.71 (1H, m, 1H of C6H11), 1.76–1.82 (2H, m, 2H of C6H11), 2.03–2.10
(2H, m, 2H of C6H11), 2.95 (1H, dd, J = 8.8, 16.9 Hz, 4'-Ha), 3.23 (1H, dd, J = 6.5, 16.9 Hz, 4'-Hb),
3.96 (1H, tdd, J = 4.0, 8.0, 11.5 Hz, 1H of C6H11), 4.15 (1H, q, J = 4.8 Hz, 2'-Ha), 4.27–4–35 (2H, m,
2'-Hb, 3'-H), 6.22 (1H, d, J = 7.3 Hz, NH), 7.13 (1H, br t, J = 7.4 Hz, p-Ph), 7.35 (2H, br t, J = 8.0 Hz,
m-Ph), 7.43–7.52 (3H, m, p,m-Ph), 7.59 (2H, br d, J = 7.8 Hz, o-Ph), 8.44 (2H, br d, J = 7.0 Hz, o-Ph),
13
8.75 (1H, s, 4-H). C-NMR (126 MHz, CDCl3): δ 25.1, 25.6, 33.2, 35.9, 38.2, 49.6, 54.0, 120.4,
124.9, 126.8, 128.8, 128.9, 129.0, 131.8, 136.6, 139.2, 155.4, 165.1, 165.2, 168.4, 173.0. LC-MS:
Rt = 20.275 min, m/z = 441 (MH+), area% = 86. m/z (ESI) = 441 (MH+). m/z (HRMS) Found:
441.2287 (MH+). C27H29N4O2 requires: m/z = 441.2285. (Found: C 73.66; H 6.13; N 12.53.
C27H28N4O2 (440.5) requires: C 73.61; H 6.41; N 12.72.); νmax (KBr) 3411, 2342, 1691, 1633, 1567,
1431, 1400, 1316, 1229, 756, 717, 693 cm–1.
3.7.15. N-Benzyl-6-(5-oxo-1-phenylpyrrolidin-3-yl)-2-phenylpyrimidine-5-carboxamide (10{2; 3})
Prepared from 17{2} and benzylamine (18{3}), workup A. Yield: 173 mg (77%) of white solid;
m.p. 169–171 °C. 1H-NMR (500 MHz, CDCl3): δ 2.96 (1H, dd, J = 8.8, 16.9 Hz, 4'-Ha), 3.26 (1H, dd,
J = 6.7, 16.9 Hz, 4'-Hb), 4.14 (1H, dd, J = 5.8, 9.6 Hz, 2'-Ha), 4.31 (1H, t, J = 8.8 Hz, 2'-Hb), 4.39
(1H, ddd, J = 6.4, 8.3, 12.5 Hz, 3'-H), 4.64 and 4.68 (2H, 2dd, J = 5.7, 14.6 Hz, CH2Ph'), 6.48 (1H, t,
J = 5.4 Hz, NH), 7.15 (1H, br t, J = 7.4 Hz, p-Ph), 7.32–7.41 (7H, m, m-Ph, Ph'), 7.45–7.52 (3H, m,
m,p-Ph), 7.60 (2H, br d, J = 7.9 Hz, o-Ph), 8.46 (2H, br d, J = 7.0 Hz, o-Ph), 8.81 (1H, s, 4-H).

Molecules 2012, 17
5378
13C-NMR (126 MHz, CDCl3): δ 35.9, 38.2, 44.6, 54.1, 120.4, 124.9, 126.2, 128.2, 128.3, 128.9, 129.0,
129.1, 129.3, 131.9, 136.5, 137.5, 139.3, 155.4, 165.5, 165.8, 168.8, 173.0. LC-MS: Rt = 19.4 min,
m/z = 449 (MH+), area% = 100. m/z (ESI) = 449 (MH+). m/z (HRMS) Found: 449.198 (MH+).
C28H25N4O2 requires: m/z = 449.1972. (Found: C 74.63; H 5.43; N 12.38. C28H24N4O2 (448.5)
requires: C 74.98; H 5.39; N 12.49.); νmax (KBr) 3418, 1679, 1662, 1570, 1498, 1434, 1305, 760,
692 cm−1.
3.7.16. N-(2-Methoxyethyl)-6-(5-oxo-1-phenylpyrrolidin-3-yl)-2-phenylpyrimidine-5-carboxamide
(10{2; 4})
Prepared from 17{2} and 2-methoxyethylamine (18{4}), workup A. Yield: 138 mg (65%) of white
1
solid; m.p. 164–168 °C. H-NMR (500 MHz, CDCl3): δ 2.98 (1H, dd, J = 8.6, 16.8 Hz, 4'-Ha), 3.27
(1H, dd, J = 6.8, 16.9 Hz, 4'-Hb), 3.40 (3H, s, OCH3), 3.60 (2H, t, J = 4.9 Hz, CH2OMe), 3.66–3.69
(2H, t, J = 5.0 Hz, CH2NH), 4.17 (1H, dd, J = 5.8, 9.4 Hz, 2'-Ha), 4.32 (1H, t, J = 8.8 Hz, 2'-Hb),
4.34–4.40 (1H, m, 3'-H), 6.60 (1H, s, NH), 7.14 (1H, br t, J = 7.4 Hz, p-Ph), 7.36 (2H, br t, J = 8.0 Hz,
m-Ph), 7.45–7.53 (3H, m, p,m-Ph), 7.62 (2H, br d, J = 7.7 Hz, o-Ph), 8.46 (2H, dd, J = 1.4, 8.1 Hz,
13
o-Ph), 8.82 (1H, s, 4-H). C-NMR (126 MHz, CDCl3): δ 35.9, 38.3, 40.1, 54.0, 59.1, 70.9, 120.4,
124.9, 126.4, 128.8, 128.9, 129.1, 131.9, 136.6, 139.3, 155.6, 165.4, 166.0, 168.5, 173.0. LC-MS:
Rt = 15.017 min, m/z = 417 (MH+), area% = 100. m/z (ESI) = 417 (MH+). m/z (HRMS) Found: 415.1779
([M–H]–). C24H23N4O3 requires: m/z = 415.1776. (Found: C 68.03; H 5.43; N 13.11.
C24H24N4O3·⅖H2O (423.7) requires: C 68.04; H 5.90; N 13.23.); νmax (KBr) 3466, 2934, 1682, 1663,
1568, 1432, 1306, 1122, 761, 693 cm−1.
3.7.17. N-(3-Hydroxypropyl)-6-(5-oxo-1-phenylpyrrolidin-3-yl)-2-phenylpyrimidine-5-carboxamide
(10{2; 5})
Prepared from 17{2} and 3-amino-1-propanol (18{5}), workup A. Yield: 206 mg (98%) of white
1
solid; 145–146 °C. H-NMR (500 MHz, CDCl3): δ 1.86 (2H, quintet, J = 5.7 Hz, CH2CH2CH2), 2.98
(1H, dd, J = 8.7, 16.9 Hz, 4'-Ha), 3.21 (1H, dd, J = 6.5, 16.9 Hz, 4'-Hb), 3.65 (2H, br q, J = 6.1 Hz,
CH2NH), 3.82 (2H, t, J = 5.5 Hz, CH2OH), 4.17 (1H, dd, J = 5.6, 9.6 Hz, 2'-Ha), 4.31 (1H, t, J = 8.9 Hz,
2'Hb), 4.38 (1H, ddd, J = 6.4, 8.3, 12.2 Hz, 3'-H), 7.12 (1H, br s, NH); 7.14 (1H, br t, J = 7.4 Hz,
p-Ph), 7.35 (2H, br t, J = 8.0 Hz, m-Ph), 7.44–7.52 (3H, m, m,p-Ph), 7.60 (2H, br d, J = 7.7 Hz, o-Ph),
8.44 (2H, dd, J = 1.5, 8.5 Hz, o-Ph), 8.80 (1H, s, 4-H), OH exchanged. 13C-NMR (126 MHz, CDCl3): δ
31.5, 35.9, 38.4, 38.7, 54.1, 61.3, 120.6, 125.1, 126.3, 128.8, 128.9, 129.1, 131.9, 136.5, 139.2, 155.7,
165.3, 166.4, 168.6, 173.2. LC-MS: Rt = 13.117 min, m/z = 417 (MH+), area% = 84. m/z (ESI) = 417
(MH+). m/z (HRMS) Found: 417.192 (MH+). C24H25N4O3 requires: m/z = 417.1921. (Found: C 68.23;
H 5.60; N 13.21. C24H24N4O3·⅓H2O (422.5) requires: C 68.24; H 5.89; N 13.27.); νmax (KBr) 3458,
2343, 1682, 1646, 1568, 1432, 1402, 1306, 1071, 762, 694 cm−1.

Molecules 2012, 17
5379
3.7.18. N-(3-Dimethylaminopropyl)-6-(5-oxo-1-phenylpyrrolidin-3-yl)-2-phenylpyrimidine-5-carboxamide
(10{2; 6})
Prepared from 17{2} and 3-(dimethylamino)propylamine (18{6}), workup A. Yield: 158 mg (71%)
1
of white solid; 111–114 °C. H-NMR (500 MHz, CDCl3): δ 1.78–1.84 (2H, m, CH2CH2CH2), 2.29
(6H, s, NMe2), 2.54 (2H, t, J = 5.7 Hz, CH2NMe2), 3.00 (1H, dd, J = 8.9, 16.9 Hz, 4'-Ha), 3.29 (1H,
dd, J = 6.7, 16.9 Hz, 4'-Hb), 3.54–3.65 (2H, m, CH2NH), 4.17 (1H, dd, J = 5.8, 9.7 Hz, 2'-Ha), 4.36
(1H, dd, J = 8.1, 9.7 Hz, 2'-Hb), 4.51 (1H, tt, J = 6.6, 8.5 Hz, 3'-H), 7.14 (1H, br t, J = 7.4 Hz, p-Ph),
7.37 (2H, br t, J = 8.0 Hz, m-Ph), 7.46–7.53 (3H, m, p,m-Ph), 7.64 (2H, br d, J = 7.7 Hz, o-Ph), 8.48
(2H, dd, J = 1.6, 7.9 Hz, o-Ph), 8.77 (1H, s, 4-H), 8.85 (1H, br s, NH). 13C-NMR (126 MHz, CDCl3): δ
23.7, 36.2, 38.9, 40.4, 44.6, 53.7, 58.3, 120.4, 124.8, 126.4, 128.7, 128.8, 129.0, 131.2, 137.2, 139.5, 159.6,
164.1, 168.2, 171.3, 173.8. LC-MS: Rt = 9.342 min, m/z = 444 (MH+), area% = 100. m/z (ESI) = 444
(MH+). m/z (HRMS) Found: 444.2401 (MH+). C26H30N5O2 requires: m/z = 444.2394. νmax (KBr) 3446,
2946, 1689, 1631, 1570, 1431, 754, 692 cm−1.
3.7.19. 6-(5-Oxo-1-phenylpyrrolidin-3-yl)-2-phenyl-N-((pyridin-2-yl)methyl)pyrimidine-5-carboxamide
(10{2; 7})
Prepared from 17{2} and 2-picolylamine (18{7}), workup A. Yield: 204 mg (89%) of gray solid,
m.p. 160–165 °C. 1H-NMR (500 MHz, CDCl3): δ 3.00 (1H, dd, J = 8.9, 16.9 Hz, 4'-Ha), 3.29 (1H, dd,
J = 7.1, 16.9 Hz, 4'-Hb), 4.19 (1H, dd, J = 6.1, 9.6 Hz, 2'-Ha) 4.32 (1H, dd, J = 8.3, 9.6 Hz, 2'-Hb),
4.44 (1H, t, J = 7.0, 8.4 Hz, 3'-H), 4.76 and 4.80 (2H, 2dd, 1:1, J = 4.7, 17.5 Hz, CH2NH), 7.14 (1H, br
t, J = 7.4 Hz, p-Ph), 7.25 (1H, br dd, J = 5.2, 7.1 Hz, 5''-H), 7.33–7.38 (3H, m, p,m-Ph), 7.46–7.53 (3H,
m, m-Ph, NH), 7.62 (2H, br d, J = 7.7 Hz, o-Ph), 7.73 (2H, dt, J = 1.7, 7.6 Hz, 3''-H, 4''-H), 8.49 (2H,
13
dt, J = 1.5, 8.1 Hz, o-Ph), 8.54 (1H, br d, J = 4.6 Hz, 6''-H), 8.96 (1H, s, 4-H). C-NMR (126 MHz,
CDCl3): δ 35.9, 38.4, 44.7, 54.1, 120.4, 122.4, 123.0, 124.9, 126.4, 128.8, 128.9, 129.0, 131.8, 136.6,
137.3, 139.3, 149.2, 155.1, 156.0, 165.4, 165.9, 168.5, 173.0. LC-MS: Rt = 15.65 min, m/z = 450
(MH+), area% = 87. m/z (ESI) = 450 (MH+). m/z (HRMS) Found: 448.1785 ([M−H]−). C27H22N5O2
requires: m/z = 448.1779. (Found: C 70.65; H 5.00; N 15.09. C27H23N5O2∙½H2O (458.5) requires: C
70.73; H 5.28; N 15.27.); νmax (KBr) 3472, 1682, 1662, 1569, 1434, 1404, 1307, 758, 693 cm−1.
3.7.20. N,N-(Diethyl)-6-(5-oxo-1-phenylpyrrolidin-3-yl)-2-phenylpyrimidine-5-carboxamide (10{2; 8})
Prepared from 17{2} and diethylamine (18{8}), workup B. Yield: 148 mg (68%) of yellowish resin.
1H-NMR (500 MHz, CDCl3): δ 1.17 and 1.32 (6H, 2t, 1:1, J = 7.1 Hz, 2CH3CH2), 2.95 (1H, dd,
J = 8.9, 16.9 Hz, 4'-Ha), 3.24–3.34 (3H, m, 4'-Hb, CH2CH3), 3.60 and 3.66 (2H, 2 septets, J = 7.2 Hz,
CH2CH3), 3.92 (1H, quintet, J = 8.0 Hz, 3'-H), 4.22 and 4.24 (2H, 2dd, 1:1, J = 10.0, 12.5 Hz, 2'-CH2),
7.16 (1H, br t, J = 7.4 Hz, p-Ph), 7.38 (2H, br t, J = 8.0 Hz, m-Ph), 7.46–7.54 (3H, m, p,m-Ph), 7.64
13
(2H, br d, J = 7.9 Hz, o-Ph), 8.47 (2H, dd, J = 1.8, 8.0 Hz, o-Ph), 8.65 (1H, s, 4-H). C-NMR (126
MHz, CDCl3): δ 11.6, 36.2, 38.8, 42.3, 53.9, 120.3, 124.8, 126.8, 128.8, 128.9, 129.1, 131.4, 137.2,
139.5, 159.8, 164.5, 168.6, 170.7, 173.6. LC-MS: Rt = 18.008 min, m/z = 415 (MH+), area% = 88.
m/z (ESI) = 415 (MH+). m/z (HRMS) Found: 415.2121 (MH+). C25H27N4O2 requires: m/z = 415.2129.

Molecules 2012, 17
5380
(Found: C 69.44; H 6.41; N 12.62. C25H26N4O2·H2O (432.5) requires: C 69.42; H 6.53; N 12.95.); νmax
(KBr) 3410, 2364, 1665, 1638, 1616, 1500, 1393, 1366, 1312, 751, 717, 690 cm−1.
3.7.21. 6-(5-Oxo-1-phenylpyrrolidin-3-yl)-2-phenyl-N-(pyrrolidin-1-yl)pyrimidine-5-carboxamide
(10{2; 9})
Prepared from 17{2} and pyrrolidine (18{9}), workup B. Yield: 208 mg (100%) of yellow resin.
1H-NMR (500 MHz, CDCl3): δ 1.93–2.10 (4H, m, 4H of pyrrolidine), 2.97 (2H, dd, J = 8.9, 16.9 Hz,
4'-Ha), 3.28 (1H, dd, J = 7.8, 16.9 Hz, 4'-Hb), 3.29–3.36 and 3.37–3.43 (2H, 2m, 1:1, 2H of
pyrrolidine), 3.72 (2H, t, J = 7.0 Hz, 2H of pyrrolidine), 4.06 (1H, quintet, J = 8.1 Hz, 3'-H), 4.24 (1H,
dd, J = 6.8, 9.6 Hz, 2'-Ha), 4.27 (1H, dd, J = 8.2, 9.7 Hz, 2'-Hb), 7.16 (1H, br t, J = 7.4 Hz, p-Ph), 7.38
(2H, br t, J = 8.0 Hz, m-Ph), 7.45–7.53 (3H, m, m,p-Ph), 7.63 (2H, br d, J = 7.7 Hz, o-Ph), 8.47 (2H,
13
dd, J = 1.8, 8.2 Hz, o-Ph), 8.72 (1H, s, 4-H). C-NMR (126 MHz, CDCl3): δ 24.6, 26.4, 36.3, 38.3,
46.3, 49.5, 53.9, 120.4, 120.5, 125.1, 127.8, 128.7, 128.9, 129.1, 131.7, 136.7, 139.2, 155.2, 159.6,
164.8, 172.7. LC-MS: Rt = 17.075 min, m/z = 413 (MH+), area% = 100. m/z (ESI) = 413 (MH+).
m/z (HRMS) Found: 413.1975 (MH+). C25H25N4O2 requires: m/z = 413.1972. νmax (KBr) 3431, 2361,
1636, 1500, 1418, 983, 754, 704, 668 cm−1.
3.7.22. 6-(5-Oxo-1-phenylpyrrolidin-3-yl)-2-phenyl-N-(piperidin-1-yl)pyrimidine-5-carboxamide
(10{2; 10})
Prepared from 17{2} and piperidine (18{10}), workup B. Yield: 214 mg (100%) of yellow resin.
1H-NMR (500 MHz, CDCl3): δ 1.51–1.61 (2H, m, 2H of piperidine), 1.74 (4H, br s, 4H of piperidine),
2.96 (1H, br s, 4'-Ha), 3.27 (1H, br s, 4'-Hb), 3.34 (2H, br s, 2H of piperidine), 3.79 (2H, br s, 2H of
piperidine), 3.98 (1H, quintet, J = 7.9 Hz, 3'-H), 4.24 (2H, br s, 2'-CH2), 7.16 (1H, br t, J = 7.4 Hz,
p-Ph), 7.38 (2H, br t, J = 7.9 Hz, m-Ph), 7.47–7.54 (3H, m, m,p-Ph), 7.64 (2H, br d, J = 7.8 Hz, o-Ph),
13
8.47 (2H, dd, J = 1.9, 7.9 Hz, o-Ph), 8.63 (1H, s, 4-H). C-NMR (126 MHz, CDCl3): δ 22.6, 22.9,
36.0, 38.6, 44.6, 54.0, 120.4, 124.7, 127.0, 128.6, 128.7, 129.0, 131.2, 137.2, 139.4, 159.6, 164.2,
168.4, 170.9, 173.8. LC-MS: Rt = 18.608 min, m/z = 427 (MH+), area% = 100. m/z (ESI) = 427 (MH+).
m/z (HRMS) Found: 427.2135 (MH+). C26H27N4O2 requires: m/z = 427.2129. νmax (KBr) 3438, 2326,
1630, 1515, 1500, 1431, 1288, 1000, 760, 692 cm−1.
3.7.23. 6-(5-Oxo-1-phenylpyrrolidin-3-yl)-N-(morhpolin-4-yl)-2-phenylpyrimidine-5-carboxamide
(10{2; 11})
Prepared from 17{2} and morpholine (18{11}), workup B. Yield: 204 mg (95%) of yellow resin.
1H-NMR (500 MHz, CDCl3): δ 2.97 (1H, dd, J = 8.3, 16.3 Hz, 4'-Ha), 3.27 (1H, br dd, J = 7.0,
16.3 Hz, 4'-Hb), 3.38–3.49 (2H, m, 2H of morpholine), 3.63–3.72 (2H, m, 2H of morpholine),
3.80–3.92 (4H, m, 4H of morpholine), 3.99 (1H, quintet, J = 7.7 Hz, 3'-H), 4.23 and 4.25 (2H, 2br d,
1:1, 2'-CH2), 7.17 (1H, br t, J = 7.4 Hz, p-Ph), 7.38 (2H, br t, J = 8.0 Hz, m-Ph), 7.47–7.55 (3H, m,
m,p-Ph), 7.64 (2H, br d, J = 7.7 Hz, o-Ph), 8.47 (2H, dd, J = 1.5, 8.0 Hz, o-Ph), 8.64 (1H, s, 4-H).
13C-NMR (126 MHz, CDCl3): δ 35.9, 38.6, 43.3, 54.0, 64.2, 120.4, 124.8, 126.7, 128.6, 128.7, 129.0,
131.2, 137.1, 139.3, 159.7, 164.2, 168.5, 170.8, 173.8. LC-MS: Rt = 16.042 min, m/z = 429 (MH+),

Molecules 2012, 17
5381
area% = 100. m/z (ESI) = 429 (MH+). m/z (HRMS) Found: 429.1921 (MH+). C25H25N4O3 requires:
m/z = 429.1921. νmax (KBr) 3449, 2366, 1669, 1607, 1500, 1368, 1313, 1125, 752, 717,689 cm−1.
3.7.24. 6-(5-Oxo-1-phenylpyrrolidin-3-yl)-N-(4-methylpiperazin-1-yl)-2-phenylpyrimidine-5-
carboxamide (10{2; 12})
Prepared from 17{2} and 4-methylpiperazine (18{12}), workup B. Yield: 225 mg (100%) of yellow
resin. 1H-NMR (500 MHz, CDCl3): δ 2.37 (3H, s, 4''-CH3), 2.36–2.42 (1H, m, 1H of piperazine), 2.46
(1H, br s, 1H of piperazine), 2.53–2.64 (2H, m, 2H of piperazine), 2.92–3.03 (1H, m, 4'-Ha), 3.24–3.34
(1H, m, 4'-Hb), 3.45 (2H, br s, 2H of piperazine), 3.85 (1H, br s, 1H of piperazine), 3.95 (1H, br s, 1H
of piperazine), 3.98 (1H, quintet, J = 7.9 Hz, 3'-H), 4.25 (2H, br s, 2'-CH2), 7.17 (1H, br t, J = 7.4 Hz,
p-Ph), 7.38 (2H, br t, J = 8.0 Hz, m-Ph), 7.46–7.54 (3H, m, m,p-Ph), 7.63 (2H, d, J = 7.8 Hz, o-Ph),
13
8.47 (2H, dd, J = 1.5, 8.0 Hz, o-Ph), 8.64 (1H, s, 4-H). C-NMR (126 MHz, CDCl3): δ 36.3, 42.0,
46.1, 47.5, 54.8, 55.5, 120.5, 125.1, 126.4, 128.7, 128.9, 129.1, 131.8, 136.6, 139.1, 155.2, 165.0,
165.8, 166.9, 172.5. LC-MS: Rt = 9.392 min, m/z = 442 (MH+), area% = 100. m/z (ESI) = 380 (MH+).
m/z (HRMS) Found: 442.2238 (MH+). C26H28N5O2 requires: m/z = 442.2238. νmax (KBr) 3456, 2340,
1637, 1500, 1421, 1298, 1168, 983, 760, 696 cm−1.
4. Conclusions
2-Substituted 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamides 10 as a novel type of
conformationally constrained 2-(heteroaryl)ethylamines are available in six-steps from itaconic acid
(11). The synthetic pathway consists of two parts: (a) a five-step preparation of pyrimidine-5-
carboxylic acids 17{1,2} as the key-intermediates and (b) combinatorial solution-phase BPC-mediated
amidation of 17{1,2} with primary and secondary amines 18{1–12} to give the title compounds
10{1,2; 1–12} in good overall yields and purity upon simple workup. The method is general and
substrate-independent. All 24 amidations proceeded smoothly and no major differences in reactivity
was observed with respect to the C(2) substituent in the pyrimidine-5-carboxylic acids 17. On the other
hand, the secondary amines 18{8–12} were less reactive in these amidations than the primary amines
18{1–7}. Consequently, a 10-fold excess of secondary amines 18{8–12} was employed in order to
assure completion of the amidation reaction. Besides, preparation of the 2-chloro analogue of 16, e.g.,
by treatment of 14 with methyl carbamimidate followed by demethylation and chlorination, would
enable functionalization at position 2 in the pyrimidine ring, either by SNAr reaction, or by cross-coupling
reaction. These results also indicate that the above synthetic method could serve as a useful tool for the
preparation of novel compound libraries for pharmaceutical and other practical applications.
Acknowledgements
The financial support from Boehringer-Ingelheim Pharma (Biberach, Germany) and from the
Slovenian Research Agency through grant P1-0179 is gratefully acknowledged. We acknowledge with
thanks the financial contributions of pharmaceutical companies Krka d.d. (Novo mesto, Slovenia) and
Lek d.d. a new Sandoz Company (Ljubljana, Slovenia), which made the purchase of Mettler-Toledo
Bohdan MiniBlock™ Compact Shaking and Washing Station and Vacuum Collection Base possible.

Molecules 2012, 17
5382
References and Notes
1. Patrick, G.L. An Introduction to Medicinal Chemistry, 4th ed.; Oxford University Press: Oxford,
UK, 2009; pp. 1–752.
2. Takahashi, T.; Miyazawa, M. N-Caffeoyl serotonin as selective COX-2 inhibitor. Bioorg. Med.
Chem. Lett. 2012, 22, 2494–2496.
3. Zefirova, O.N.; Baranova, T.Y.; Lyssenko, K.A.; Zefirov, N.A.; Zyk, N.V.; Vassiliev, P.M.;
Yakovlev, D.S.; Spasov, A.A. Synthesis and biological testing of conformationally restricted
serotonin analogues with bridgehead moieties. Mendeleev Commun. 2012, 22, 75–77.
4. Bonner, L.A.; Laban, U.; Chemel, B.R.; Juncosa, J.I.; Lill, M.A.; Watts, V.J.; Nichols, D.E.
Mapping the catehol binding site in dopamine D1 receptors: Synthesis and evaluation of two
parallel series of bicyclic dopamine analogues. ChemMedChem 2011, 6, 1024–1040.
5. Zlotos, D.P.; Attia, M.I.; Julius, J.; Sethi, S.S.; Witt-Enderby, P.A. 2-[(2,3-Dihydro-1H-indol-1-
yl)methyl]melatonin analogues: A novel class of MT2-Selective melatonin receptor antagonists.
J. Med. Chem. 2009, 52, 826–833.
6. Dolle, R.E. Solid-phase Synthesis of Heterocyclic Systems (Heterocycles Containing One
Heteroatom). In Handbook of Combinatorial Chemistry. Drugs, Catalysts, Materials; Nicolaou, K.C.,
Hanko, R., Hartwig, W., Eds.; Wiley-VCH Verlag GmbH: Weinheim, Germany, 2002; Volume 2,
pp. 643–684.
7. Pernerstorfer, J. Molecular Design and Combinatorial Compound Libraries. In Handbook of
Combinatorial Chemistry. Drugs, Catalysts, Materials; Nicolaou, K.C., Hanko, R., Hartwig, W.,
Eds.; Wiley-VCH Verlag GmbH: Weinheim, Germany, 2002; Volume 2, pp. 725–742.
8. Dolle, R.E.; le Bourdonnec, B.; Morales, G.A.; Moriarty, K.J.; Salvino, J.M. Comprehensive
survey of chemical libraries for drug discovery and chemical biology: 2007. J. Comb. Chem.
2008, 10, 753–802.
9. Dolle, R.E.; le Bourdonnec, B.; Goodman, A.J.; Morales, G.A.; Thomas, C.J.; Zhang, W.
Comprehensive survey of chemical libraries for drug discovery and chemical biology: 2008.
J. Comb. Chem. 2009, 11, 739–790.
10. Dolle, R.E.; le Bourdonnec, B.; Worm, K.; Morales, G.A.; Thomas, C.J.; Zhang, W.
Comprehensive survey of chemical libraries for drug discovery and chemical biology: 2009.
J. Comb. Chem. 2010, 12, 765–806.
11. Stanovnik, B.; Svete, J. Synthesis of heterocycles from alkyl 3-(dimethylamino)propenoates and
related enaminones. Chem. Rev. 2004, 104, 2433–2480.
12. Svete, J. Ex-chiral pool enaminones in the synthesis of functionalised heterocycles.
Monatsh. Chem. 2004, 135, 629–641.
13. Svete, J. Utilisation of chiral enaminones and azomethine imines in the synthesis of functionalised
pyrazoles. ARKIVOC 2006, vii, 35–56.
14. Bevk, D.; Svete, J.; Stanovnik, B. Enaminones and Related Compounds in the Synthesis of
Pyrazoles. In Modern Approaches to the Synthesis of O- and N-Heterocycles; Research Signpost:
Kerala, India, 2007; Volume 3, pp. 73–88.

Molecules 2012, 17
5383
15. Stanovnik, B.; Grošelj, U. Dialkyl acetone-1,3-dicarboxylates and their mono- and
bis(dimethylamino) methylidene derivatives in the synthesis of heterocyclic systems.
Adv. Heterocycl. Chem. 2010, 100, 145–174.
16. Pirc, S.; Bevk, D.; Golobič, A.; Stanovnik, B.; Svete, J. Transformation of amino acids into
nonracemic 1-(heteroaryl)ethanamines by the enamino ketone methodology. Helv. Chim. Acta
2006, 89, 30–44.
17. Kralj, D.; Grošelj, U.; Meden, A.; Dahmann, G.; Stanovnik, B.; Svete, J. A simple synthesis of
4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles. Tetrahedron 2007, 63, 11213–11222.
18. Kralj, D.; Novak, A.; Dahmann, G.; Grošelj, U.; Meden, A.; Svete, J. One-pot parallel solution-
phase synthesis of 1-substituted 4-(2-aminoethyl)-1H-pyrazol-5-ols. J. Comb. Chem. 2008, 10,
664–670.
19. Grošelj, U.; Kralj, D.; Wagger, J.; Dahmann, G.; Stanovnik, B.; Svete, J. Synthesis of
3-(2-aminoethyl)-5-hydroxy-1H-pyrazole derivatives. ARKIVOC 2012, iii, 49–65.
20. Kralj, D.; Friedrich, M.; Grošelj, U.; Kiraly-Potpara, S.; Meden, A.; Wagger, J.; Dahmann, G.;
Stanovnik, B.; Svete, J. A synthesis of 1-substituted 5-[2-(acylamino)ethyl]-1H-pyrazole-4-
carboxamides. Tetrahedron 2009, 65, 7151–7162.
21. Žerovnik, D.; Grošelj, U.; Kralj, D.; Malavašič, Č.; Bezenšek, J.; Dahmann, G.; Stare, K.; Meden, A.;
Stanovnik, B.; Svete, J. Synthesis of 1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-ones as
conformationally constrained pyrazole analogues of histamine. Synthesis 2010, 3363–3373.
22. Janjić, M.; Prebil, R.; Grošelj, U.; Kralj, D.; Malavašič, Č.; Golobič, A.; Stare, K.; Dahmann, G.;
Stanovnik, B.; Svete, J. A simple synthesis of 5-(2-aminophenyl)-1H-pyrazoles. Helv. Chim. Acta
2011, 94, 1703–1717.
23. Perdih, P.; Baškovč, J.; Dahmann, G.; Grošelj, U.; Kočar, D.; Novak, A.; Stanovnik, B.; Svete, J.
Parallel synthesis of 1-substituted 5-(5-oxopyrrolidin-3-yl)-1H-pyrazole-4-carboxamides
Synthesis 2011, 2822–2832.
24. Paytash, P.L.; Sparrow, E.; Gathe, J.C. The reaction of itaconic acid with primary amines.
J. Am. Chem. Soc. 1950, 72, 1415–1416.
25. Harwood, L.M.; Moody, C.J. ‘Dry Flash’ Column Chromatography. In Experimental Organic
Chemistry, Principles and Practice; Blackwell Science: Oxford, UK, 1989; pp. 185–188.
26. Harwood, L.M. “Dry-Column” Flash Chromatography. Aldrichimica Acta 1985, 18, 25–25.
27. Since satisfactory results were obtained with evapotative workup and DFCC, the use of
scavenging reagents such as solid supported tosyl chloride or propionyl chloride was not explored.
Besides, covalent binding of scavenging reagents to products containing hydroxy and amino
functions would probably make the isolation of products more difficult.
28. The above method is applicable for the synthesis of libraries of racemic compounds 10 for
primary testing and screening. However, for a larger scale synthesis of certain enantiomerically
pure final products 10, a modified ‘chiral pool’ synthesis of non-racemic 10 utilizing
enantiomerically pure starting compound 12 should be developed.
29. Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational
approaches to estimate solubility and permeability in drug discovery and development settings.
Adv. Drug Del. Rev. 2001, 46, 3–26.

Molecules 2012, 17
5384
30. Ghose, A.K.; Viswandhan, V.N.; Wendoloski, J.J. A knowledge-based approach in designing
combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and
quantitative characterization of known drug databases. J. Comb. Chem. 1999, 1, 55–68.
Sample Availability: Samples of the compounds 16{1,2}, 17{1,2}, and 10{1,2; 1–12} are available
from the authors.
© 2012 by the authors; licensee MDPI, 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/).