Reaction of ethyl 5-acetyl-3,4-dihydropyridine-1(2H)-carboxylate with 1,3- N, N-bis-nucleophiles: A facile access to novel pyrimidine derivatives

Article abstract of DOI:10.1055/s-0030-1259970

Reaction of ethyl 5-acetyl-3,4-dihydropyridine-1(2H)-carboxylate with diverse 1,3-N,N-bis-nucleophiles results in the regioselective formation of the correspondingly substituted pyrimidines in good yields.

Full text of DOI:10.1055/s-0030-1259970

PAPER
1465
Reaction of Ethyl 5-Acetyl-3,4-dihydropyridine-1(2H)-carboxylate with
1,3-N,N-Bis-nucleophiles: A Facile Access to Novel Pyrimidine Derivatives
A
Facile
A
ccess to
a
Novel
P
yr
z
imidine De
r
ivatives r B. Maximov,a,b Pavel K. Mykhailiuk,*a,b Andrei I. Kisel,b Zoia V. Voitenko,b Andrey A. Tolmacheva,b
a
Enamine Ltd., Alexandra Matrosova Street 23, 01103 Kiev, Ukraine
Department of Chemistry, Kiev National Taras Shevchenko University, Volodymyrska Street 64, 01033 Kiev, Ukraine
Fax +380(44)2351273; E-mail: pavel.mykhailiuk@gmail.com
b
Received 27 January 2011; revised 9 February 2011
over, performing the reaction at 60 °C in methanol al-
lowed isolation of the corresponding intermediate 8 from
the reaction mixture. As expected, heating imine 8 at
150 °C in anhydrous ethylene glycol afforded pyrimidine
7, again as the sole isomer (Scheme 2).
Abstract: Reaction of ethyl 5-acetyl-3,4-dihydropyridine-1(2H)-
carboxylate with diverse 1,3-N,N-bis-nucleophiles results in the re-
gioselective formation of the correspondingly substituted pyrim-
idines in good yields.
Key words: pyrimidines, amidines, amino heterocycles, tetrahy-
dropyridine
NH2
HN
6
In 1970, Quin and Pinion showed that b-enamino ketone
1 reacts with phenylhydrazine to form a mixture of two
isomeric pyrazoles 2/3 (Scheme 1).1 Recently, we found
that the N-ethoxycarbonyl-substituted compound 4, in
contrast to 1, regioselectively reacts with various hydra-
zines to form only one isomer of the corresponding pyra-
zoles, e.g. 5 (Scheme 1).2 Herein, we report our studies on
the reaction of compound 4 with 1,3-N,N-bis-nucleo-
philes to regioselectively form novel pyrimidine deriva-
tives.3
N
N
N
N
O
(CH2OH)2
heat
NH
EtO2C
N
NH
EtO2C
not observed
N
N
N
CO2Et
84%
4
7
6
MeOH
heat
96%
(CH2OH)2
heat
85%
N
N
HN
EtO2C
N
8
Ph
PhNHNH2
heat
O
N
N
+
Scheme 2 Synthesis of pyrimidine 7
N
N
N
H
Ph
NH2
NH2
1
2
3
Having at hand a successful result, we next tested a set of
various 1,3-N,N-bis-nucleophiles 9–20 (Figure 1).
PhNHNH2
heat
Ph
NH2
NH2
N
N
NH2
NH2
O
N
N
HN
HN
CN
N
Ph
NH
NH
CO2Et
not observed
HN
HN
N
N
CO2Et
CO2Et
N
N
4
5
6
9
10
11
Scheme 1 Synthesis of the mixture of pyrazoles 2/3 according to the
literature method1 and regioselective synthesis of pyrazole 5, also ac-
cording to the literature2
NH2
NH2
NH2
NH2
N
HN
N
HN
N
HN
HN
N
3-Aminopyrazole (6) was used as a simple model of a het-
erocyclic 1,3-N,N-bis-nucleophile. Heating a mixture of
N-ethoxycarbonyl-protected compound 44 and 3-amino-
pyrazole (6) in anhydrous ethylene glycol at 150 °C for
six hours resulted in the formation of pyrimidine 7 as a
single isomer in a good yield of 84% (Scheme 2). More-
CONH2
14
N
12
13
15
NH2
NH2
NH2
NH2
NH2
Ph
HN
HN
NH2
⋅HCl
19
HN
N
HN
N
HN
N
N
N
⋅HCl
⋅HBr
18
SYNTHESIS 2011, No. 9, pp 1465–1471
x
x
.
x
x
.2
0
1
1
16
17
20
Advanced online publication: 24.03.2011
DOI: 10.1055/s-0030-1259970; Art ID: Z15811SS
Figure 1 1,3-N,N-Bis-nucleophiles 6, 9–20
© Georg Thieme Verlag Stuttgart · New York

1466
N. B. Maximov et al.
PAPER
Indeed, all products were obtained as single regioisomers only 25% yield, probably due to the highly electron-
21–32 in 25–82% yield (Table 1). It is worth noting that withdrawing nature of the tetrazole moiety.
aminotetrazole 17 gave the corresponding product 29 in
Table 1 Structures of Pyrimidines 7, 21–32 Arising from the Reaction of b-Enamino Ketone 4 with 1,3-N,N-Bis-nucleophiles 6, 9–20, and
the Corresponding Amines 33–45
NH2
HN
R
O
concd HCl
HN
CO2Et
N
H2N
N
(CH2OH)2
N
N
N
R
R
CO2Et
7, 21–32
33–45
4
1,3-N,N-Bis-nucleophile Protected pyrimidine
Yield (%) Aminea
Yield (%)
95
H2N
N
N
HN
N
6
9
7
84
72
71
60
33
34
35
36
CO2Et
N
N
N
N
HN
CO2Et
N
H2N
21
22
23
91
99
96
N
N
N
N
HN
CO2Et
N
N
H2N
N
N
10
11
CN
N
CO2H
N
⋅HCl
N
N
H2N
HN
CO2Et
N
N
N
N
HN
CO2Et
H2N
N
N
12
13
24
25
82
66
37
38
92
89
N
N
N
N
N
N
HN
CO2Et
H2N
N
N
N
N
N
N
N
N
N
N
HN
CO2Et
H2N
14
15
26
27
63
54
39
40
99
83
N
N
⋅HCl
CONH2
CO2H
HN
CO2Et
H2N
N
N
N
N
N
N
Synthesis 2011, No. 9, 1465–1471 © Thieme Stuttgart · New York

PAPER
A Facile Access to Novel Pyrimidine Derivatives
1467
Table 1 Structures of Pyrimidines 7, 21–32 Arising from the Reaction of b-Enamino Ketone 4 with 1,3-N,N-Bis-nucleophiles 6, 9–20, and
the Corresponding Amines 33–45 (continued)
NH2
HN
R
O
concd HCl
HN
CO2Et
N
H2N
N
(CH2OH)2
N
N
N
R
R
CO2Et
7, 21–32
33–45
4
1,3-N,N-Bis-nucleophile Protected pyrimidine
Yield (%) Aminea
Yield (%)
94
HN
H2N
H2N
H2N
N
N
16
17
28
29
56
25
41
42
CO2Et
N
N
N
N
N
N
N
N
N
HN
CO2Et
N
N
99
95
N
⋅HCl
N
N
N
N
HN
CO2Et
N
N
18
30
46
43
N
N
⋅HCl
19
20
31
32
66
52
44
45
84
96
HN
CO2Et
N
N
H2N
H2N
N
N
N
NH2
N
NH2
HN
CO2Et
N
N
Ph
Ph
a Compounds 35, 39, 42 and 43 were isolated as the hydrochloride salts.
Non-heterocyclic 1,3-N,N-bis-nucleophiles 19 and 20 Finally, the protected pyrimidines 7, 21–32 were easily
were used as the hydrochlorides. Notably, the cyclization converted into the corresponding amines 33–45 by heat-
was successfully performed without the addition of any ing in concentrated hydrochloric acid (Table 1). Indeed,
base. Moreover, when the reaction was performed in the under these reaction conditions, hydrolysis of the nitrile
presence of triethylamine, the corresponding products 31, group in compound 22 and the amide group in compound
32 were isolated in only 5–10% yield, probably due to the 26 also occurred, so that amino acids 35 and 39, respec-
instability of the free amidines 19 and 20 at high temper- tively, were isolated.
ature.
In summary, we have shown that the reaction of ethyl 5-
The structures of compounds 25 and 28 were additionally acetyl-3,4-dihydropyridine-1(2H)-carboxylate (4) with
confirmed by NOESY experiments (Figure 2).
1,3-N,N-bis-nucleophiles occurs in a regioselective man-
ner to provide novel pyrimidine derivatives in good
yields.
HN
CO2Et
N
HN
CO2Et
N
Solvents were purified according to standard procedures. Com-
pound 4 was prepared according to the literature method.3 All other
materials were purchased from Enamine Ltd. Melting points were
measured using a Thiele tube. Analytical TLC was perfomed using
H
N
H
N
N
N
N
H
H
25
28
1
Polychrom SI F254 plates. H and 13C NMR spectra were recorded
on a Bruker Avance 500 spectrometer (at 499.9 MHz and 124.9
MHz, respectively). Chemical shifts are reported in ppm downfield
from TMS as an internal standard. Mass spectra were recorded on
an Agilent 1100 LC/MSD SL instrument using chemical ionization
(CI).
NOESY correlation
Figure 2 The key correlations in the NOESY spectra of compounds
25 and 28
Synthesis 2011, No. 9, 1465–1471 © Thieme Stuttgart · New York

1468
N. B. Maximov et al.
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Pyrimidines 7, 21–32; General Procedure
1 H, C6H4), 7.11 (t, 3J = 6.5 Hz, 1 H, C6H4), 5.54 (br s, 1 H, NH),
4.04 (q, 3J = 6.5 Hz, 2 H, OCH2), 3.14 (m, 3J = 6 Hz, 2 H, CH2NH),
2.44 (s, 3 H, CH3), 2.38 (t, 3J = 7 Hz, 2 H, CCH2), 1.66 (m, 3J = 7
Hz, 2 H, CH2), 1.15 (t, 3J = 6.5 Hz, 3 H, CH3CH2).
13C NMR (125 MHz, CDCl3): d = 156.95 (s, tert-C, MeC), 155.66
(s, CO), 150.75 (s, tert-C, NCN), 141.57 (s, tert-C, C6H4), 131.05
(s, CH), 129.27 (s, CH, C6H4), 124.67 (s, tert-C, C6H4), 120.51 (s,
tert-C, CCH2), 120.15 (s, CH, C6H4), 115.59 (s, CH, C6H4), 112.62
(s, CH, C6H4), 60.74 (s, OCH2), 40.16 (s, CH2NH), 29.00 (s, CCH2),
27.28 (s, CH2), 22.28 (s, CH3), 14.68 (s, CH3CH2).
A 25-mL reaction vessel equipped with a condenser was charged
with a soln of the 1,3-N,N-bis-nucleophile (10.0 mmol) and com-
pound 4 (2.07 g, 10.5 mmol) in anhyd ethylene glycol (10–15 mL).
The solution was stirred under inert atmosphere at 80 °C for 3 h and
at 150–160 °C for 6 h. Then, the volatiles were evaporated under re-
duced pressure. The gummy residue was dissolved in CHCl3 (50
mL), then washed with 5% aq HCl (2 × 20 mL) and sat. aq NaHCO3
(2 × 30 mL), and dried (MgSO4). The solvent was removed under
reduced pressure to give the corresponding pure pyrimidine deriva-
tive 7, 21–32.
MS: m/z = 313.2 [M + 1]+.
Ethyl 3-(5-Methylpyrazolo[1,5-a]pyrimidin-6-yl)propylcar-
bamate (7)
Yield: 2.31 g (84% from 4), 2.23 g (85% from 8); yellow solid; mp
56–58 °C.
Ethyl 3-(2-Methylpyrido[2¢,3¢:3,4]pyrazolo[1,5-a]pyrimidin-3-
yl)propylcarbamate (24)
Yield: 2.70 g (82%); yellow caramel.
1H NMR (500 MHz, CDCl3): d = 8.75 (s, 1 H, CH), 8.11 (d, 3J = 4.5
Hz, 1 H, py), 8.31 (d, 3J = 8 Hz, 1 H, py), 6.98 (dd, 3J = 7.7, 3.4 Hz,
1 H, py), 5.59 (br s, 1 H, NH), 4.00 (q, 3J = 6.5 Hz, 2 H, OCH2), 3.15
(m, 3J = 6 Hz, 2 H, CH2NH), 2.57 (s, 3 H, CH3), 2.44 (t, 3J = 7 Hz,
2 H, CCH2), 1.54 (m, 3J = 7 Hz, 2 H, CH2), 1.02 (t, 3J = 6.5 Hz, 3 H,
CH3CH2).
13C NMR (125 MHz, CDCl3): d = 159.62 (s, tert-C, MeC), 157.15
(s, CO), 153.32 (s, tert-C, NCN), 140.61 (s, tert-C, py), 132.26 (s,
CH, py), 130.29 (s, CH), 120.51 (s, tert-C, CCH2), 117.77 (s, CH,
py), 116.85 (s, CH, py), 105.45 (s, tert-C, py), 60.39 (s, OCH2),
40.38 (s, CH2NH), 30.56 (s, CCH2), 27.34 (s, CH2), 22.27 (s, CH3),
14.57 (s, CH3CH2).
1H NMR (500 MHz, CDCl3): d = 8.35 (s, 1 H, CH), 7.83 (s, 1 H,
NCHCH), 6.34 (s, 1 H, NCHCH), 5.75 (br s, 1 H, NH), 3.95 (q,
3J = 6.5 Hz, 2 H, OCH2), 3.11 (m, 3J = 6 Hz, 2 H, CH2NH), 2.45 (t,
3J = 6.5 Hz, 2 H, CCH2), 2.38 (s, 3 H, CH3), 1.68 (m, 3J = 7 Hz, 2
H, CH2), 1.01 (t, 3J = 6.5 Hz, 3 H, CH3CH2).
13C NMR (125 MHz, CDCl3): d = 159.12 (s, tert-C, MeC), 157.07
(s, CO), 146.73 (s, tert-C, NCN), 144.00 (s, NCHCH), 132.28 (s,
CH), 120.67 (s, tert-C, CCH2), 95.08 (s, NCHCH), 60.68 (s, OCH2),
40.05 (s, CH2NH), 29.15 (s, CCH2), 26.84 (s, CH2), 22.45 (s, CH3),
14.52 (s, CH3CH2).
MS: m/z = 263.3 [M + 1]+.
MS: m/z = 314.4 [M + 1]+.
Ethyl 3-(2,5-Dimethylpyrazolo[1,5-a]pyrimidin-6-yl)propylcar-
bamate (21)
Ethyl 3-(7-Methylimidazo[1,2-a]pyrimidin-6-yl)propylcarbam-
ate (25)
Yield: 1.81 g (66%); brown caramel.
Yield: 2.01 g (72%); pale brown oil.
1H NMR (500 MHz, CDCl3): d = 8.24 (s, 1 H, CH), 6.18 (s, 1 H,
3
NCMeCH), 5.48 (br s, 1 H, NH), 4.02 (q, J = 6 Hz, 2 H, OCH2),
1H NMR (500 MHz, CDCl3): d = 8.24 (s, 1 H, CH), 7.51 (s, 1 H,
NCHCHNC), 7.36 (s, 1 H, NCHCHNC), 5.74 (br s, 1 H, NH), 4.03
(q, 3J = 6 Hz, 2 H, OCH2), 3.19 (m, 3J = 6 Hz, 2 H, CH2NH), 2.57
(t, 3J = 6 Hz, 2 H, CCH2), 2.46 (s, 3 H, CH3), 1.75 (m, 3J = 6 Hz, 2
H, CH2), 1.15 (t, 3J = 6 Hz, 3 H, CH3CH2).
13C NMR (125 MHz, CDCl3): d = 160.10 (s, tert-C, MeC), 157.07
(s, CO), 147.75 (s, tert-C, NCN), 136.90 (s, NCHCHNC), 133.71 (s,
CH), 121.37 (s, tert-C, CCH2), 110.10 (s, NCHCHNC), 60.66 (s,
OCH2), 39.94 (s, CH2NH), 29.28 (s, CCH2), 26.74 (s, CH2), 22.68
(s, CH3), 14.61 (s, CH3CH2).
3.16 (m, 2 H, CH2NH), 2.51 (t, 3J = 7.5 Hz, 2 H, CCH2), 2.41 (s, 3
H, CH3), 2.35 (s, 3 H, CH3), 1.72 (m, 3J = 7.5 Hz, 2 H, CH2), 1.13
(t, 3J = 6 Hz, 3 H, CH3CH2).
13C NMR (125 MHz, CDCl3): d = 158.57 (s, tert-C, MeC), 156.96
(s, CO), 154.28 (s, NCMeCH), 147.66 (s, tert-C, NCN), 131.78 (s,
CH), 119.53 (s, tert-C, CCH2), 94.38 (s, NCMeCH), 60.72 (s,
OCH2), 40.12 (s, CH2NH), 29.42 (s, CCH2), 26.91 (s, CH2), 22.49
(s, CH3), 14.57 (s, CH3CH2), 14.38 (s, CH3).
MS: m/z = 277.3 [M + 1]+.
MS: m/z = 263.0 [M + 1]+.
Ethyl 3-(3-Cyano-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)pro-
pylcarbamate (22)
Ethyl 3-[2-(Aminocarbonyl)-7-methylimidazo[1,2-a]pyrimidin-
6-yl]propylcarbamate (26)
Yield: 2.02 g (63%); red crystalline; mp 96–98 °C.
Yield: 2.10 g (71%); pale brown solid; mp 84–86 °C.
1H NMR (500 MHz, DMSO-d6): d = 8.46 (s, 1 H, CH), 7.50 (s, 1 H,
NCHCCN), 5.92 (br s, 1 H, NH), 3.97 (q, 3J = 6.5 Hz, 2 H, OCH2),
3.09 (m, 3J = 6 Hz, 2 H, CH2NH), 2.66 (t, 3J = 6.5 Hz, 2 H, CCH2),
2.55 (s, 3 H, CH3), 1.72 (m, 3J = 7 Hz, 2 H, CH2), 1.12 (t, 3J = 6.5
Hz, 3 H, CH3CH2).
13C NMR (125 MHz, DMSO-d6): d = 163.94 (s, tert-C, MeC),
156.77 (s, CO), 150.53 (s, tert-C, NCN), 140.54 (s, NCHCCN),
134.13 (s, CH), 122.64 (s, tert-C, CCH2), 116.19 (s, CN), 95.08 (s,
NCHCCN), 59.83 (s, OCH2), 41.85 (s, CH2NH), 27.31 (s, CCH2),
25.08 (s, CH2), 21.74 (s, CH3), 15.06 (s, CH3CH2).
1H NMR (500 MHz, CDCl3): d = 8.95 (d, 2 H, CONH2), 8.22 (s, 1
H, CH), 8.10 (s, 1 H, NCHCN), 5.42 (br s, 1 H, NH), 4.03 (q, 3J = 6
Hz, 2 H, OCH2), 3.21 (m, 3J = 6 Hz, 2 H, CH2NH), 2.55 (t, 3J = 6
Hz, 2 H, CCH2), 2.44 (s, 3 H, CH3), 1.74 (m, 3J = 6 Hz, 2 H, CH2),
1.09 (t, 3J = 6 Hz, 3 H, CH3CH2).
13C NMR (125 MHz, CDCl3): d = 164.15 (s, CONH2), 161.51 (s,
tert-C, MeC), 157.63 (s, CO), 145.74 (s, tert-C, NCN), 136.43 (s,
CH), 133.62 (s, NCHCN), 122.40 (s, tert-C, CCONH2), 121.28 (s,
tert-C, CCH2), 60.43 (s, OCH2), 39.54 (s, CH2NH), 29.21 (s,
CCH2), 26.35 (s, CH2), 22.42 (s, CH3), 14.62 (s, CH3CH2).
MS: m/z = 288.4 [M + 1]+.
MS: m/z = 306.4 [M + 1]+.
Ethyl 3-(2-Methylpyrimido[1,2-b]indazol-3-yl)propylcarbam-
ate (23)
Ethyl 3-(2-Methylpyrimido[1,2-a]benzimidazol-3-yl)propylcar-
bamate (27)
Yield: 1.71 g (54%); pale brown caramel.
Yield: 1.96 g (60%); pale brown oil.
1H NMR (500 MHz, CDCl3): d = 8.46 (s, 1 H, CH), 8.11 (d, 3J = 6.5
Hz, 1 H, C6H4), 7.62 (t, 3J = 6.5 Hz, 1 H, C6H4), 7.44 (t, 3J = 6.5 Hz,
Synthesis 2011, No. 9, 1465–1471 © Thieme Stuttgart · New York

PAPER
A Facile Access to Novel Pyrimidine Derivatives
1469
3
1H NMR (500 MHz, CDCl3): d = 8.32 (s, 1 H, CH), 7.98 (d, 3J = 6.5
Hz, 1 H, C6H4), 7.79 (t, 3J = 6.5 Hz, 1 H, C6H4), 7.45 (t, 3J = 6.5 Hz,
1 H, C6H4), 7.35 (t, 3J = 6.5 Hz, 1 H, C6H4), 5.65 (br s, 1 H, NH),
4.01 (q, 3J = 6.5 Hz, 2 H, OCH2), 3.16 (m, 3J = 6 Hz, 2 H, CH2NH),
2.45 (s, 3 H, CH3), 2.40 (t, 3J = 7 Hz, 2 H, CCH2), 1.69 (m, 3J = 7
Hz, 2 H, CH2), 1.22 (t, 3J = 6.5 Hz, 3 H, CH3CH2).
2 H, CH2NH), 2.35 (t, J = 6 Hz, 2 H, CCH2), 2.14 (s, 3 H, CH3),
1.77 (m, 3J = 6 Hz, 2 H, CH2), 1.14 (t, 3J = 6 Hz, 3 H, CH3CH2).
13C NMR (125 MHz, DMSO-d6): d = 174.40 (s, tert-C, CNH2),
158.31 (s, tert-C, MeC), 156.75 (s, CO), 145.58 (s, CH), 108.79 (s,
tert-C, CCH2), 60.65 (s, OCH2), 40.97 (s, CH2NH), 29.68 (s,
CCH2), 26.56 (s, CH2), 22.41 (s, CH3), 14.80 (s, CH3CH2).
13C NMR (125 MHz, CDCl3): d = 157.52 (s, tert-C, MeC), 156.61
(s, CO), 152.45 (s, tert-C, NCN), 142.78 (s, tert-C, C6H4), 132.01
(s, CH), 127.65 (s, CH, C6H4), 125.61 (s, tert-C, C6H4), 122.22 (s,
tert-C, CCH2), 121.46 (s, CH, C6H4), 119.19 (s, CH, C6H4), 112.59
(s, CH, C6H4), 60.78 (s, OCH2), 40.03 (s, CH2NH), 29.04 (s, CCH2),
26.26 (s, CH2), 22.14 (s, CH3), 14.77 (s, CH3CH2).
MS: m/z = 239.3 [M + 1]+.
Ethyl 3-(4-Methyl-2-phenylpyrimidin-5-yl)propylcarbamate
(32)
Yield: 1.63 g (52%); red oil.
1H NMR (500 MHz, CDCl3): d = 8.60 (s, 1 H, CH), 7.67 (d, 3J = 7.5
Hz, 2 H, Ph), 7.40 (t, 3J = 7.5 Hz, 2 H, Ph), 7.21 (t, 3J = 7.5 Hz, 1 H,
Ph), 5.45 (br s, 1 H, NH), 4.02 (q, 3J = 6 Hz, 2 H, OCH2), 3.33 (m,
MS: m/z = 313.4 [M + 1]+.
Ethyl 3-(7-Methyl[1,2,4]triazolo[4,3-a]pyrimidin-6-yl)propyl-
carbamate (28)
Yield: 1.55 g (56%); brown caramel.
3
2 H, CH2NH), 2.31 (t, J = 6 Hz, 2 H, CCH2), 2.12 (s, 3 H, CH3),
1.72 (m, 3J = 6 Hz, 2 H, CH2), 1.24 (t, 3J = 6 Hz, 3 H, CH3CH2).
13C NMR (125 MHz, CDCl3): d = 161.12 (s, tert-C, CPh), 157.05
(s, tert-C, MeC), 156.75 (s, CO), 140.16 (s, tert-C, Ph), 130.54 (s,
CH), 129.32 (s, 2 C, Ph), 125.32 (s, Ph), 121.54 (s, tert-C, CCH2),
118.37 (s, 2 C, Ph), 60.55 (s, OCH2), 40.84 (s, CH2NH), 29.23 (s,
CCH2), 25.59 (s, CH2), 21.48 (s, CH3), 14.85 (s, CH3CH2).
1H NMR (500 MHz, CDCl3): d = 8.65 (s, 1 H, NCHN), 8.13 (s, 1 H,
CH), 5.15 (br s, 1 H, NH), 3.95 (q, 3J = 6 Hz, 2 H, OCH2), 3.21 (m,
3J = 6 Hz, 2 H, CH2NH), 2.56 (t, 3J = 6 Hz, 2 H, CCH2), 2.42 (s, 3
3
3
H, CH3), 1.74 (m, J = 6 Hz, 2 H, CH2), 1.26 (t, J = 6 Hz, 3 H,
CH3CH2).
MS: m/z = 300.4 [M + 1]+.
13C NMR (125 MHz, CDCl3): d = 161.29 (s, tert-C, MeC), 157.34
(s, CO), 149.86 (s, tert-C, NCN), 138.59 (s, NCHN), 135.31 (s,
CH), 122.08 (s, tert-C, CCH2), 60.62 (s, OCH2), 39.66 (s, CH2NH),
29.23 (s, CCH2), 26.54 (s, CH2), 21.88 (s, CH3), 14.37 (s, CH3CH2).
Ethyl 5-[(1Z)-1-(1H-Pyrazol-5-ylimino)ethyl]-3,4-dihydropyri-
dine-1(2H)-carboxylate (8)
A 50-mL reaction vessel equipped with a condenser was charged
with a soln of 3-aminopyrazole (6; 0.83 g, 10 mmol) and compound
4 (1.97 g, 10 mmol) in MeOH (30 mL). The solution was heated at
reflux for 4 h. Thereafter, the solvent was evaporated under reduced
pressure. The residue was washed with H2O (30 mL) and hexane
(25 mL), and dried under reduced pressure to give pure imine 8;
yield: 2.52 g (96%); mp 81–83 °C.
MS: m/z = 264.4 [M + 1]+.
Ethyl 3-(5-Methyltetrazolo[1,5-a]pyrimidin-6-yl)propylcar-
bamate (29)
Yield: 0.69 g (25%); brown caramel.
1H NMR (500 MHz, DMSO-d6): d = 7.83 (s, 1 H, CH), 5.69 (br s, 1
H, NH), 4.05 (q, 3J = 6.5 Hz, 2 H, OCH2), 3.07 (m, 3J = 6 Hz, 2 H,
1H NMR (500 MHz, CDCl3): d = 7.85 (s, 1 H, CH), 7.62 (d, 3J = 2
3
3
CH2NH), 2.35 (t, J = 7 Hz, 2 H, CCH2), 2.20 (s, 3 H, CH3), 1.48
Hz, 1 H, NCHCH), 5.75 (br s, 1 H, NH), 5.70 (d, J = 2 Hz, 1 H,
(m, 3J = 7 Hz, 2 H, CH2), 1.19 (t, 3J = 6.5 Hz, 3 H, CH3CH2).
NCHCH), 4.08 (q, 3J = 7 Hz, 2 H, OCH2), 3.40 (t, 3J = 6 Hz, 2 H,
NCH2), 2.08 (m, 5 H, CH2C + CH3), 1.60 (m, 3J = 6 Hz, 2 H, CH2),
1.14 (t, 3J = 7 Hz, 3 H, CH3CH2).
13C NMR (125 MHz, DMSO-d6): d = 167.27 (s, tert-C, MeC),
166.14 (s, CO), 162.05 (s, NCN), 157.58 (s, CH), 121.22 (s, tert-C,
CCH2), 59.35 (s, OCH2), 41.74 (s, CH2NH), 30.15 (s, CCH2), 25.92
(s, CH2), 21.20 (s, CH3), 14.87 (s, CH3CH2).
13C NMR (125 MHz, CDCl3): d = 159.39 (s, CO), 151.11 (s, tert-C,
CN), 137.46 (s, tert-C, NCN), 131.37 (s, CHCHN), 123.33 (s, CH),
119.00 (s, tert-C), 91.92 (s, CHCHN), 62.97 (s, OCH2), 42.37 (s,
CH2N), 24.33 (s, CCH2), 20.19 (s, CH2), 19.54 (s, CH3), 14.19 (s,
CH3CH2).
MS: m/z = 265.2 [M + 1]+.
Ethyl 3-(2-Methylpyrimido[2,1-a]isoindol-3-yl)propylcarbam-
ate (30)
MS: m/z = 263.4 [M + 1]+.
Yield: 1.50 g (46%); pale brown oil.
Amines 33–45; General Procedure
1H NMR (500 MHz, DMSO-d6): d = 8.56 (s, 1 H, CH), 7.63 (s, 1 H,
A one-necked 50-mL round-bottomed flask equipped with a reflux
condenser was charged with an ethyl carbamate 7, 21–32 (10 mmol)
and concd HCl (25 mL). The solution was heated at reflux for 16 h.
Thereafter, the volatiles were evaporated under reduced pressure.
The residue was suspended in 10% NaOH soln (20 mL) and extract-
ed with CHCl3 (3 × 25 mL). The organic layer was washed with
H2O (40 mL) and dried (MgSO4). The solvent was removed under
reduced pressure to give the corresponding (aminopropyl)pyrimi-
dine derivative 33–45 (except for 35, 39, 42, 43).
NCH), 7.34 (m, 2 H, C6H4), 7.24 (m, 2 H, C6H4), 5.44 (br s, 1 H,
3
3
NH), 3.93 (q, J = 6.5 Hz, 2 H, OCH2), 3.00 (m, J = 6 Hz, 2 H,
3
CH2NH), 2.40 (s, 3 H, CH3), 2.23 (t, J = 7 Hz, 2 H, CCH2), 1.67
(m, 3J = 7 Hz, 2 H, CH2), 1.12 (t, 3J = 6.5 Hz, 3 H, CH3CH2).
13C NMR (125 MHz, DMSO-d6): d = 166.45 (s, tert-C, MeC),
161.20 (s, tert-C, NCN), 157.34 (s, CO), 144.51 (s, NCH), 133.01
(s, CH), 131.73 (s, CH, C6H4), 128.09 (s, CH, C6H4), 124.17 [s, 2 C
(CH + tert-C), C6H4], 123.15 [s, 2 C (CH + tert-C), C6H4], 121.53
(s, tert-C, CCH2), 59.35 (s, OCH2), 45.46 (s, CH2NH), 31.21 (s,
CCH2), 25.80 (s, CH2), 20.40 (s, CH3), 15.19 (s, CH3CH2).
For compounds 35, 39, 42, 43, the soln of the amine hydrochloride
in concd HCl was washed with CH2Cl2 (3 × 5 mL). The aqueous
phase was concentrated under reduced pressure to provide the pure
product 35, 39, 42, 43 as the hydrochloride salt.
MS: m/z = 312.4 [M + 1]+.
Ethyl 3-(2-Amino-4-methylpyrimidin-5-yl)propylcarbamate
(31)
3-(5-Methylpyrazolo[1,5-a]pyrimidin-6-yl)propan-1-amine
(33)
Yield: 1.80 g (95%); yellow oil.
Yield: 1.65 g (66%); yellow oil.
1H NMR (500 MHz, CDCl3): d = 7.67 (s, 1 H, CH), 5.51 (br s, 2 H,
NH2), 5.15 (br s, 1 H, NH), 4.05 (q, 3J = 6 Hz, 2 H, OCH2), 3.28 (m,
Synthesis 2011, No. 9, 1465–1471 © Thieme Stuttgart · New York

1470
N. B. Maximov et al.
PAPER
1H NMR (500 MHz, CDCl3): d = 8.41 (s, 1 H, CH), 7.73 (s, 1 H,
NCHCH), 6.39 (s, 1 H, NCHCH), 3.42 (m, 3J = 6 Hz, 2 H,
CH2NH2), 2.41 (t, 3J = 6.5 Hz, 2 H, CCH2), 2.34 (br s, 2 H, NH2),
2.25 (s, 3 H, CH3), 1.70 (m, 3J = 7 Hz, 2 H, CH2).
CH, py), 106.53 (s, tert-C, py), 39.99 (s, CH2NH2), 28.35 (s, CCH2),
26.56 (s, CH2), 22.22 (s, CH3).
MS: m/z = 242.3 [M + 1]+.
13C NMR (125 MHz, CDCl3): d = 159.20 (s, tert-C, MeC), 145.82
(s, NCHCH), 145.37 (s, tert-C, NCN), 135.11 (s, CH), 120.52 (s,
tert-C, CCH2), 95.14 (s, NCHCH), 39.43 (s, CH2NH2), 27.65 (s,
CCH2), 25.66 (s, CH2), 21.41 (s, CH3).
3-(7-Methylimidazo[1,2-a]pyrimidin-6-yl)propan-1-amine (38)
Yield: 1.69 g (89%); brown oil.
1H NMR (500 MHz, CDCl3): d = 8.36 (s, 1 H, CH), 7.59 (s, 1 H,
3
NCHCHNC), 7.44 (s, 1 H, NCHCHNC), 3.39 (m, J = 6 Hz, 2 H,
MS: m/z = 191.2 [M + 1]+.
CH2NH2), 2.48 (t, 3J = 6 Hz, 2 H, CCH2), 2.36 (s, 3 H, CH3), 2.14
(br s, 2 H, NH2), 1.78 (m, 3J = 6 Hz, 2 H, CH2).
3-(2,5-Dimethylpyrazolo[1,5-a]pyrimidin-6-yl)propan-1-amine
(34)
Yield: 1.86 g (91%); pale brown oil.
13C NMR (125 MHz, CDCl3): d = 159.02 (s, tert-C, MeC), 147.65
(s, tert-C, NCN), 136.95 (s, NCHCHNC), 133.56 (s, CH), 120.42 (s,
tert-C, CCH2), 111.23 (s, NCHCHNC), 39.67 (s, CH2NH2), 27.89
(s, CCH2), 26.71 (s, CH2), 22.39 (s, CH3).
1H NMR (500 MHz, CDCl3): d = 8.35 (s, 1 H, CH), 6.22 (s, 1 H,
3
NCMeCH), 3.36 (m, 2 H, CH2NH2), 2.41 (t, J = 7.5 Hz, 2 H,
MS: m/z = 191.3 [M + 1]+.
CCH2), 2.33 (s, 3 H, CH3), 2.24 (s, 3 H, CH3), 2.11 (br s, 2 H, NH2),
1.75 (m, 3J = 7.5 Hz, 2 H, CH2).
6-(3-Aminopropyl)-7-methylimidazo[1,2-a]pyrimidine-2-car-
boxylic Acid Hydrochloride (39)
Yield: 2.68 g (99%); red crystalline; mp 178–180 °C (dec).
13C NMR (125 MHz, CDCl3): d = 157.61 (s, tert-C, MeC), 152.32
(s, NCMeCH), 145.64 (s, tert-C, NCN), 130.88 (s, CH), 119.46 (s,
tert-C, CCH2), 95.21 (s, NCMeCH), 39.67 (s, CH2NH2), 28.44 (s,
CCH2), 25.89 (s, CH2), 22.42 (s, CH3), 14.45 (s, CH3).
1H NMR (500 MHz, DMSO-d6): d = 11.28 (br s, 1 H, COOH), 8.42
+
(s, 1 H, CH), 8.28 (s, 1 H, NCHCN), 8.02 (br s, 3 H, NH3 ), 3.44 (m,
MS: m/z = 205.3 [M + 1]+.
3J = 6 Hz, 2 H, CH2NH3 ), 2.61 (t, 3J = 6 Hz, 2 H, CCH2), 2.42 (s, 3
+
H, CH3), 1.80 (m, 3J = 6 Hz, 2 H, CH2).
6-(3-Aminopropyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-car-
boxylic Acid Hydrochloride (35)
Yield: 2.67 g (99%); white crystalline; mp 187–189 °C (dec).
13C NMR (125 MHz, DMSO-d6): d = 173.07 (s, COOH), 161.54 (s,
tert-C, MeC), 145.62 (s, tert-C, NCN), 135.83 (s, CH), 132.97 (s,
NCHCN), 122.87 (s, tert-C, CCOOH), 121.21 (s, tert-C, CCH2),
44.46 (s, CH2NH3 ), 28.42 (s, CCH2), 26.33 (s, CH2), 22.12 (s,
CH3).
1H NMR (500 MHz, DMSO-d6): d = 11.20 (br s, 1 H, COOH), 8.49
+
+
(s, 1 H, CH), 8.32 (br s, 3 H, NH3 ), 7.59 (s, 1 H, NCHCCN), 3.35
+
(m, 3J = 6 Hz, 2 H, CH2NH3 ), 2.56 (t, 3J = 6.5 Hz, 2 H, CCH2), 2.46
MS: m/z = 271.7 [M + 1]+.
(s, 3 H, CH3), 1.88 (m, 3J = 7 Hz, 2 H, CH2).
13C NMR (125 MHz, DMSO-d6): d = 171.11 (s, COOH), 164.12 (s,
tert-C, MeC), 149.32 (s, tert-C, NCN), 141.61 (s, NCHCCN),
132.02 (s, CH), 122.68 (s, tert-C, CCH2), 95.44 (s, NCHCCN),
44.89 (s, CH2NH3 ), 27.39 (s, CCH2), 25.13 (s, CH2), 21.72 (s,
CH3).
3-(2-Methylpyrimido[1,2-a]benzimidazol-3-yl)propan-1-amine
(40)
Yield: 1.99 g (83%); pale brown, gummy substance.
1H NMR (500 MHz, CDCl3): d = 8.42 (s, 1 H, CH), 7.96 (d, 3J = 6.5
Hz, 1 H, C6H4), 7.73 (t, 3J = 6.5 Hz, 1 H, C6H4), 7.40 (t, 3J = 6.5 Hz,
1 H, C6H4), 7.29 (t, 3J = 6.5 Hz, 1 H, C6H4), 3.35 (m, 3J = 6 Hz, 2 H,
CH2NH2), 2.43 (s, 3 H, CH3), 2.33 (t, 3J = 7 Hz, 2 H, CCH2), 2.25
(br s, 2 H, NH2), 1.71 (m, 3J = 7 Hz, 2 H, CH2).
+
MS: m/z = 271.7 [M + 1]+.
3-(2-Methylpyrimido[1,2-b]indazol-3-yl)propan-1-amine (36)
Yield: 2.31 g (96%); pale brown oil.
13C NMR (125 MHz, CDCl3): d = 157.12 (s, tert-C, MeC), 151.66
(s, tert-C, NCN), 141.29 (s, tert-C, C6H4), 131.68 (s, CH), 127.68
(s, CH, C6H4), 125.66 (s, tert-C, C6H4), 122.34 (s, tert-C, CCH2),
121.33 (s, CH, C6H4), 119.25 (s, CH, C6H4), 112.51 (s, CH, C6H4),
39.83 (s, CH2NH2), 28.24 (s, CCH2), 26.39 (s, CH2), 22.17 (s, CH3).
1H NMR (500 MHz, CDCl3): d = 8.41 (s, 1 H, CH), 8.13 (d, 3J = 6.5
Hz, 1 H, C6H4), 7.66 (t, 3J = 6.5 Hz, 1 H, C6H4), 7.45 (t, 3J = 6.5 Hz,
1 H, C6H4), 7.16 (t, 3J = 6.5 Hz, 1 H, C6H4), 3.34 (m, 3J = 6 Hz, 2 H,
CH2NH2), 2.49 (s, 3 H, CH3), 2.41 (t, 3J = 7 Hz, 2 H, CCH2), 2.24
(br s, 2 H, NH2), 1.77 (m, 3J = 7 Hz, 2 H, CH2).
13C NMR (125 MHz, CDCl3): d = 156.01 (s, tert-C, MeC), 151.21
(s, tert-C, NCN), 141.45 (s, tert-C, C6H4), 132.03 (s, CH), 128.68
(s, CH, C6H4), 124.54 (s, tert-C, C6H4), 120.56 (s, tert-C, CCH2),
120.32 (s, CH, C6H4), 115.68 (s, CH, C6H4), 112.31 (s, CH, C6H4),
39.52 (s, CH2NH2), 27.85 (s, CCH2), 26.84 (s, CH2), 22.21 (s, CH3).
MS: m/z = 241.2 [M + 1]+.
3-(7-Methyl[1,2,4]triazolo[4,3-a]pyrimidin-6-yl)propan-1-
amine (41)
Yield: 1.79 g (94%); pale brown oil.
1H NMR (500 MHz, CDCl3): d = 8.67 (s, 1 H, NCHN), 8.17 (s, 1 H,
MS: m/z = 241.4 [M + 1]+.
CH), 3.36 (m, J = 6 Hz, 2 H, CH2NH2), 2.52 (t, J = 6 Hz, 2 H,
CCH2), 2.43 (s, 3 H, CH3), 2.15 (br s, 2 H, NH2), 1.78 (m, 3J = 6 Hz,
2 H, CH2).
3
3
3-(2-Methylpyrido[2¢,3¢:3,4]pyrazolo[1,5-a]pyrimidin-3-yl)pro-
pan-1-amine (37)
Yield: 2.22 g (92%); pale yellow, gummy substance.
13C NMR (125 MHz, CDCl3): d = 161.33 (s, tert-C, MeC), 149.80
(s, tert-C, NCN), 138.62 (s, NCHN), 134.85 (s, CH), 122.12 (s, tert-
C, CCH2), 41.06 (s, CH2NH2), 28.41 (s, CCH2), 25.22 (s, CH2),
21.64 (s, CH3).
1H NMR (500 MHz, CDCl3): d = 8.71 (s, 1 H, CH), 8.32 (d, 3J = 4.5
Hz, 1 H, py), 8.20 (d, 3J = 8 Hz, 1 H, py), 6.88 (dd, 3J = 7.7, 3.4 Hz,
1 H, py), 3.31 (m, 3J = 6 Hz, 2 H, CH2NH2), 2.49 (s, 3 H, CH3), 2.39
(t, 3J = 7 Hz, 2 H, CCH2), 2.10 (br s, 2 H, NH2), 1.59 (m, 3J = 7 Hz,
2 H, CH2).
13C NMR (125 MHz, CDCl3): d = 158.54 (s, tert-C, MeC), 152.39
(s, tert-C, NCN), 141.16 (s, tert-C, py), 131.92 (s, CH), 131.78 (s,
CH, py), 121.54 (s, tert-C, CCH2), 117.70 (s, CH, py), 116.82 (s,
MS: m/z = 192.3 [M + 1]+.
3-(5-Methyltetrazolo[1,5-a]pyrimidin-6-yl)propan-1-amine
Hydrochloride (42)
Yield: 2.26 g (99%); brown crystalline; mp 204–206 °C (dec).
Synthesis 2011, No. 9, 1465–1471 © Thieme Stuttgart · New York

PAPER
A Facile Access to Novel Pyrimidine Derivatives
1471
1H NMR (500 MHz, DMSO-d6): d = 8.44 (s, 1 H, CH), 4.22 (br s, 3
3-(4-Methyl-2-phenylpyrimidin-5-yl)propan-1-amine (45)
Yield: 2.18 g (96%); pale brown oil.
1H NMR (500 MHz, CDCl3): d = 8.62 (s, 1 H, CH), 7.65 (d, 3J = 7.5
Hz, 2 H, Ph), 7.40 (t, 3J = 7.5 Hz, 2 H, Ph), 7.25 (t, 3J = 7.5 Hz, 1 H,
Ph), 3.39 (m, 2 H, CH2NH2), 2.30 (t, 3J = 6 Hz, 2 H, CCH2), 2.24 (s,
3 H, CH3), 2.03 (br s, 2 H, NH2), 1.72 (m, 3J = 6 Hz, 2 H, CH2).
H, NH3 ), 3.41 (m, 3J = 6 Hz, 2 H, CH2NH3 ), 2.34 (t, 3J = 7 Hz, 2
H, CCH2), 2.21 (s, 3 H, CH3), 1.51 (m, 3J = 7 Hz, 2 H, CH2).
+
+
13C NMR (125 MHz, DMSO-d6): d = 167.85 (s, tert-C, MeC),
161.82 (s, NCN), 156.22 (s, CH), 121.29 (s, tert-C, CCH2), 40.76 (s,
+
CH2NH3 ), 28.11 (s, CCH2), 25.99 (s, CH2), 21.26 (s, CH3).
MS: m/z = 229.7 [M + 1]+.
13C NMR (125 MHz, CDCl3): d = 161.16 (s, tert-C, CPh), 157.12
(s, tert-C, MeC), 140.11 (s, tert-C, Ph), 133.14 (s, CH), 129.38 (s, 2
C, Ph), 125.30 (s, Ph), 121.59 (s, tert-C, CCH2), 118.30 (s, 2 C, Ph),
39.54 (s, CH2NH2), 29.11 (s, CCH2), 25.59 (s, CH2), 20.68 (s, CH3).
3-(2-Methylpyrimido[2,1-a]isoindol-3-yl)propan-1-amine Hy-
drochloride (43)
Yield: 2.61 g (95%); red crystalline; mp 202–203 °C (dec).
MS: m/z = 228.3 [M + 1]+.
1H NMR (500 MHz, DMSO-d6): d = 8.51 (s, 1 H, CH), 8.09 (br s, 3
+
H, NH3 ), 7.68 (s, 1 H, NCH), 7.33 (m, 2 H, C6H4), 7.22 (m, 2 H,
C6H4), 3.11 (m, 3J = 6 Hz, 2 H, CH2NH3 ), 2.42 (s, 3 H, CH3), 2.28
+
References
(t, 3J = 7 Hz, 2 H, CCH2), 1.69 (m, 3J = 7 Hz, 2 H, CH2).
(1) Quin, L. D.; Pinion, D. O. J. Org. Chem. 1970, 35, 3130.
(2) Maximov, N. B.; Mykhailiuk, P. K.; Golovach, S. M.;
Tverdokhlebov, A. V.; Voitenko, Z. V.; Tolmachev, A. A.
Synthesis 2010, 1781.
13C NMR (125 MHz, DMSO-d6): d = 166.24 (s, tert-C, MeC),
161.15 (s, tert-C, NCN), 144.56 (s, NCH), 133.11 (s, CH), 131.69
(s, CH, C6H4), 128.14 (s, CH, C6H4), 124.15 [s, 2 C (CH + tert-C),
C6H4], 123.13 [s, 2 C (CH + tert-C), C6H4], 121.57 (s, tert-C,
(3) Wenkert, E.; Dave, K. G.; Haglid, F.; Lewis, R. G.; Oishi, T.;
Stevens, R. V.; Terashima, M. J. Org. Chem. 1968, 33, 747.
(4) For similar recyclizations of cyclic 1,3-bis-electrophiles into
pyrimidines, see: (a) Kawase, M.; Hirabayashi, M.; Saito,
S.; Yamamoto, K. Tetrahedron Lett. 1999, 40, 2541.
(b) Zanatta, N.; Fagundes, M. B.; Ellensohn, R.; Marques,
M.; Bonacorso, H. G.; Martins, M. A. P. J. Heterocycl.
Chem. 1998, 35, 451. (c) Zanatta, N.; Cortelini, M. F. M.;
Carpes, M. J. S.; Bonacorso, H. G.; Martins, M. A. P.
J. Heterocycl. Chem. 1997, 34, 509. (d) Effenberger, F.;
Barthelmess, I. J. Heterocycl. Chem. 1995, 32, 599.
(e) Rossi, E.; Abbiati, G.; Pini, E. Synlett 1999, 1265.
(f) Sagar, R.; Kim, M.-J.; Park, S. B. Tetrahedron Lett. 2008,
49, 5080. (g) Kotljarov, A.; Irgashev, R. A.; Sosnovskikh,
V. Y.; Iaroshenko, V. O.; Sevenard, D. V. Synthesis 2009,
3233.
+
CCH2), 46.32 (s, CH2NH3 ), 31.22 (s, CCH2), 25.83 (s, CH2), 21.64
(s, CH3).
MS: m/z = 240.4 [M – HCl + 1]+.
5-(3-Aminopropyl)-4-methylpyrimidin-2-amine (44)
Yield: 1.39 g (84%); pale brown oil.
1H NMR (500 MHz, CDCl3): d = 7.45 (s, 1 H, CH), 5.25 (br s, 2 H,
NH2), 3.22 (m, 2 H, CH2NH2), 3.01 (br s, 2 H, NH2), 2.34 (t, 3J = 6
Hz, 2 H, CCH2), 2.12 (s, 3 H, CH3), 1.79 (m, 3J = 6 Hz, 2 H, CH2).
13C NMR (125 MHz, DMSO-d6): d = 174.40 (s, tert-C, CNH2),
158.31 (s, tert-C, MeC), 145.58 (s, CH), 108.79 (s, tert-C, CCH2),
40.97 (s, CH2NH2), 28.19 (s, CCH2), 23.66 (s, CH2), 20.66 (s, CH3).
MS: m/z = 167.2 [M + 1]+.
Synthesis 2011, No. 9, 1465–1471 © Thieme Stuttgart · New York