Synthesis and molecular structure of novel 4-aryloctahydropyrido-[1,2-c]pyrimidine derivatives

Article abstract of DOI:10.1002/jhet.5570390424

A series of new 4-aryloctahydropyrido[1,2-c]pyrimidine-1,3-diones 6a,b,d-h and j were synthesized by intramolecular cyclization of α-aryl-α(1-ethoxycarbonyl-2-piperidyl)-acetamide derivatives 5a,b,d-h and j. The structures of compounds were determined by ¹H and ¹³C nmr spectroscopy. Nmr and X-ray diffraction data indicate that the configuration at the C4, C4a stereocenters constitute RR and SS pair.

Full text of DOI:10.1002/jhet.5570390424

Jul-Aug 2002
Synthesis and Molecular Structure of Novel 4-Aryloctahydropyrido-
773
[1,2-c]pyrimidine Derivatives
*
Franciszek Herold [a], Jerzy Kleps [a], Romana Anulewicz-Ostrowska [b]
and Beata Szcz˛esna [a]
[a] Department of Drug Technology, Faculty of Pharmacy, The Medical University of Warsaw,
Banacha 1, 02 097 Warsaw, Poland
[b] Department of Crystallography, Faculty of Chemistry, Warsaw University, Pasteura 1, 02 093 Warsaw, Poland
Received December 28, 2001
A series of new 4-aryloctahydropyrido[1,2-c]pyrimidine-1,3-diones 6a,b,d-h and j were synthesized by
intramolecular cyclization of α-aryl-α-(1-ethoxycarbonyl-2-piperidyl)-acetamide derivatives 5a,b,d-h and
1
13
j. The structures of compounds were determined by H and C nmr spectroscopy. Nmr and X-ray diffrac-
tion data indicate that the configuration at the C4, C4a stereocenters constitute RR and SS pair.
J. Heterocyclic Chem., 39, 773 (2002).
In continuation of our research on the synthesis of con-
mixture of threo and erythro forms (20/80) [28,29]. In the
case of new compound 4b the composition of its diastere-
omers (also: threo and erythro 20/80) was established by
gas chromatography analysis. The crystallization of the iso-
meric mixture of hydrochlorides 4a,b,d-h and j usually
provided pure forms erythro, therefore mainly the erythro
isomers were used for acylation. After acylation of com-
pounds 4a,b,d-h and j, their derivatives 5a,b,d-h and j
were obtained. The products 6a,b,d-h and j were finally
formed in the intramolecular cyclisation reaction (in the
presence of sodium ethoxide) of 5a,b,d-h and j.
densed heterocyclic compounds we focused our interest on
the derivatives of octahydropyrido[1,2-c]pyrimidine [1,2].
Several methods of synthesis of such a heterocyclic ring
system are described in the literature [3-18]. Numerous
papers have been devoted to the synthesis and determina-
tion of pharmacological activity of these compounds. The
differences in activity were related to the nature and posi-
tion of substituents on the ring system [7,13-15]. In the
present paper, the synthesis of a series of new derivatives
of 4-aryl-octahydropyrido[1,2-c]pyrimidine (Scheme 1) is
reported. The obtained compounds will be further applied
as starting materials in the synthesis of new ligands of the
Scheme 1
5HT receptor. Due to the increased lipophilicity, the
1A
presence of imide group in their structure, and the ele-
ments providing a possibility of interaction with the
5HT receptor, higher affinity for this receptor can be
1A
expected for octahydropyridopyrimidine series [19,20].
Results and Discussion.
Chemical Synthesis.
The derivatives of the octahydropyrido[1,2-c]pyrimidine
6a,b,d-h and j were obtained according to the synthetic
pathway given in Scheme 1. The respective nitriles 2a-m,
used as substrates, were synthesised by a new method. The
-
reaction of C-arylation of the stabilised anion (Ar-CH-CN)
was carried out in the presence of 2-bromopyridine in apro-
tic polar solvent (with the addition of potassium hydrox-
ide). This method in nitrile synthesis has some advantages:
i) it avoids the use of expensive reagents for condensation
(such as sodium amide, sodium hydride, potassium-tert-
butoxide) and, therefore, strictly anhydrous conditions are
not necessary, ii) the reaction temperature can be kept at 50
°C, which no need to use boiling benzene or toluene. The
yields of the products were comparable with those
described in [21-28]. As the next step in the synthesis, the
nitriles 2a-m were hydrolysed using a mixture of sulfuric
and acetic acids, to obtain the amides 3a-m in good yields.
The catalytic reduction of the amides 3a,b,d-h and j was
performed in the presence of catalysts Pt/C(10%) or PtO .
2
This reaction afforded the compounds 4a,b,d-h and j as a

774
F. Herold, J. Kleps, R. Anulewicz-Ostrowska and B. Szcz˛esna
Vol. 39
It is worth mentioning that dominanting forms erythro of
increase in intensity of the C-2-H resonance (for isomer
a
compounds 4a,b,d-h and j and 5a,b,d-h and j (the
absolute configuration R,S), which were used for cyclisa-
tion, underwent epimerisation since the compounds
6a,b,d-h and j exhibited absolute configuration R,R.
The physicochemical data for compounds 5a,b,d-h and j
and 6a,b,d-h and j are given in Table 1.
erythro) at 3.81ppm.
The H nmr data, which characterize the compounds
5a,b,d-h and j are collected in Table 2. The chemical shift
of the amino group, δ is in the range of 5.7-6.7 ppm and
the signals (even those of the ethyl group) are broader than
0.5-1 Hz, typically found in the H spectra. The half width
1
NH
1
Table 1
Physical, Analytical and IR Spectroscopic Data of Compounds 5a, b, d-h, j and 6a, b, d-h, j
No.
R
Yield (%)
Mp
( C)
Molecular
Formula
Analysis (%)
Calcd./Found
H
IR
-1
(potassium bromide, cm )
o
C
N
5a
5b
5d
5e
5f
H
2-Me
4-Me
2-F
68.0
107.8-111.8
96.2
172.3-172.5
72.0
201-202
65.0
172-173
33.0
194.3-194.5
46.0
160-161
89.2
155.6-155.8
81.0
205-206
68.8
260-261
94.3
185-186
74.0
253-254
80.0
275-277
98.0
199.9-202
59.0
245-246
75.7
198-199
75.7
273-274
C
C
C
H
N O
66.19 / 66.11
7.64 / 7.70
7.95 / 7.95
7.95 / 7.98
6.86 / 6.64
6.86 / 7.01
6.86 / 6.80
7.55 / 7.59
7.55 / 7.50
6.60 / 6.55
7.02 / 7.09
7.02 / 7.09
5.76 / 5.60
5.76 / 5.80
5.76 / 5.60
6.61 / 6.61
6.61 / 6.54
9.64 / 9.60
3372, 3170
1684, 1665
3395, 3186
1689, 1669
3369, 3159
1693, 1666
3374, 3194
1691, 1665
3385, 3192
1692, 1669
3396, 3197
1687, 1664
3367, 3186
1687, 1665
3396, 3184
1692, 1658
3170, 1714,
1676
3218, 1708,
1692
3190, 1713,
1681
3178, 1714,
1676
3180, 1715,
1681
16 22
2
3
3
3
H
N O
67.08 / 66.95
67.08 / 67.02
62.32 / 62.27
62.32 / 62.30
62.32 / 62.28
63.73 / 63.66
63.73 / 63.49
68.83 / 68.79
69.75 / 69.75
69.75 / 69.70
64.11 / 64.12
64.11 / 64.18
64.11 / 64.15
65.68 / 65.49
65.68 / 65.60
9.20 / 9.18
9.20 / 9.14
17 24
2
H
N O
2
17 24
C
C
C
H
FN O
9.08 / 9.00
16 21
2
3
3
3
3-F
H
FN O
9.08 / 9.04
16 21
2
5g
5h
5j
4-F
H
FN O
9.08 / 9.10
16 21
2
2-MeO
4-MeO
H
C
H
N O
2 4
8.74 / 8.59
17 24
C
C
C
C
H
N O
8.74 / 8.67
17 24
2
4
2
2
2
6a
6b
6d
6e
6f
H
N O
11.46 /11.32
10.84 / 10.81
10.84 / 10.80
10.68 / 10.65
10.68 / 10.61
10.68 / 10.72
10.21 / 10.14
10.21 / 10.21
14 16
2
2-Me
4-Me
2-F
H
N O
15 18
2
H
N O
15 18
2
C
C
C
H
FN O
14 15
2
2
2
2
3-F
H
FN O
14 15
2
6g
6h
6j
4-F
H
FN O
3187, 1714,
1681
3185, 1721,
1666
3192, 1704,
1687
14 15
2
2-MeO
4-MeO
C
H
N O
2 3
15 18
C
H
N O
2 3
15 18
1
13
H and C NMR Studies.
of the NH signal varies from 7.8 to 62.6 Hz, probably due
to fast proton exchange (within intramolecular hydrogen
bond and/or between tautomeric forms). C nmr data for
1
In the H nmr spectra of 4b the signals of the two
13
diastereomers erythro and threo were observed, best
resolved in the spectrum of hydrochloride. Chemical shifts
of the diagnostic protons for the two isomers were as fol-
lows: 4b erythro: 4.13 (d, 1H, CHCO), 3.81 (m, 1H, C-2-
H ), 3.32 (m, 1H, C-6-H ), 2.99 (m, 1H, C-6-H ), 2.45 (s,
3H, CH ). 4b threo: 4.13 (d, 1H, CHCO), 3.73 (m, 1H,
5a,b,d-h and j are given in Table 3.
1
13
The H and C nmr data of compounds 6a,b,d-h and j
are summarised in Tables 4, 5 and 6. The assignment of
proton and carbon resonances was made on the basis of 2D
a
e
a
1
1
1
13
H- H COSY (see Figure 1a) and H- C HECTOR
3
(Figure 1b) correlations and comparison with literature
C-2-H ), 3.50 (m, 1H, C-6-H ), 3.03 (m, 1H, C-6-H ), 2.40
(s, 3H, CH ).
e
e
a
1
data [30-33]. Most H signals, which appear as multiplets,
3
were attributed to the equatorial and axial methylene pro-
tons of the saturated ring. The largest separation of signals
The above assignments were confirmed by the
Overhauser effect observed in H nmr spectrum of 4b: the
1
irradiation of the CH-CO signal at 4.13 ppm gave an
can be observed for H8 and H8 (δ - δ =1.72 ppm),
e a e a

Jul-Aug 2002
Molecular Structure of Novel 4-Aryloctahydropyrido[1,2-c]pyrimidine Derivatives
775

776
F. Herold, J. Kleps, R. Anulewicz-Ostrowska and B. Szcz˛esna
Vol. 39
1
1
Figure 1. a) The COSY H/ H spectrum of 6b.
Table 3
13
C NMR Spectral Data of Compounds 5a,b,d-h and j [a]
5a
5b
5d
5e
5f
5g
5h
5j
C-2
C-3
52.9
27.4
51.6
27.2
52.6
27.3
52.3
27.3
52.8
27.2
52.9
27.2
51.6
27.5
52.7
25.4
C-4
25.4
25.3
25.4
25.3
25.3
25.3
25.4
25.7
C-5
19.3
19.4
19.4
19.4
19.4
19.4
19.5
18.8
C-6
39.4
39.8
39.4
39.4
39.6
39.4
39.4
39.9
N-1-CO
C-H
155.5
51.2
155.4
47.2
155.5
50.9
155.3
42.3
155.4
51.1
155.4
50.5
155.4
41.8
156.5
52.3
CONH
174.4
61.1
14.5
174.4
61.1
14.5
174.4
61.0
14.5
173.5
61.1
14.5
173.3
61.2
14.4
173.9
61.1
14.5
174.5
61.0
14.7
174.5
61.8
14.7
2
O-CH CH
2
3
3
O-CH CH
2
C-1'
C-2'
C-3'
C-4'
C-5'
C-6'
R
136.6
128.2
128.5
127.6
128.5
128.2
-
135.9
134.7
130.7
130.4
127.0
127.4
137.3
128.3
129.0
133.5
129.0
128.3
123.4[b]
160.7[b]
115.0[b]
128.9
124.1
128.3
138.9[b]
115.4[b]
162.7[b]
114.7[b]
129.8[b]
124.3
132.2[b]
130.0[b]
115.2[b]
162.3[b]
115.2[b]
130.0[b]
124.8
156.6
110.4
128.4
120.9
129.3
129.6
129.1
114.5
159.2
114.5
129.1
CH
CH
OCH
OCH
3
3
-
-
-
3
3
19.9
21.0
55.6 [b]
55.3 [b]
13
[a] C Chemical shifts of the ipso carbon atoms of the phenyl rings are given in bold numbers [δ, ppm], in deuteriochloroform compounds 5a,b,d-h and j,
n
13 19
1
2
2
1
tetramethylsilane as the Internal Standard. Coupling Constants J( C- F) (Hz) for compounds: 5e J =243.6, J =14.1 and J =21.1; 5f J =246.0,
2’
1’
3’
3’
2
2
3
3
1
2
3
4
1
1
13 17
J =21.5, J =19.7, J =8.2 and J =7.3; 5g J =245.8, J =21.0, J =7.8 and J =3.3; 5h J=1.4 and 5j J=1.3 ( C- O); [b] appear as doublet.
2’
4’
5’
1’
4’
3’,5’
2’,6’
1’

Jul-Aug 2002
Molecular Structure of Novel 4-Aryloctahydropyrido[1,2-c]pyrimidine Derivatives
777
1
1
Figure 1. b) The HECTOR H/ H spectrum of 6b.
whereas smaller separation of signals is observed for H5
The aryl substituent at C4 cannot be coplanar with the
e,a
(0.34 ppm), H6 (0.49 ppm) and H7 (0.24 ppm), as
pyrido[1,2-c]pyrimidine system for steric reasons and the
e,a
e,a
illustrated in Figure 1a,b for 6b (2'-Me). The analysis of
twisting reduces the electronic influence of substituents to
'
the splittings of signals of H4a, H4, H8 , H8 , H7 yielded
the aromatic ring on the vicinal carbons C4, C4a and C1
.
a
e
a
a collection of coupling constants (Table 5). The problem
of determination of stereochemistry around the chiral car-
bon C4 was of special interest. The coupling constants J
Nevertheless, an increased shielding of C4 (δ48.9-50.2
ppm) for 2'-substituted compounds is observed, as com-
pared with 51.6-58.4 for other derivatives; a smaller effect
can be noticed for C4a (Table 6). An increased shielding of
3
(H4/H4a) for 6a,b,d-h and j are within the range 8.0-10.5
Hz, and are slightly higher (9.5-10.5 Hz) for the deriva-
tives with 2'-R. According to Karplus and Conroy [30,31]
3
C4 and C4a as well as higher values of the JH-H coupling
constants (mentioned above) result from a larger twist
angle of the aromatic ring. A more hindered substituent at
the ortho position makes the rotation around the C4-C1'
bond particularly difficult to perform.
3
the largest values of JH /H , of ca. 12-13.5 Hz, can be
a
a
expected for planar trans arrangement (dihedral angle H4-
3
C4-C4a-H4a, θ=180°). The J H4a/H4 are smaller and
indicate that the values of θ equal to 155-180° (included in
Table 5) are probable. Such location of H4a and H4 hydro-
gens enabled an equatorial position of the aromatic ring,
which is usually energetically more favoured.
X-ray Diffraction.
The crystal structure of 6e was determined by X-ray dif-
fraction, the compound with the ortho substituent (2'-F)

778
F. Herold, J. Kleps, R. Anulewicz-Ostrowska and B. Szcz˛esna
Vol. 39
Table
4
1
H NMR Chemical Shifts [ δ, ppm, deuteriochloroform] of Compounds 6a,b,d-h and j [a]
Compound
No
R
N-2
1H
C-4
1H 1H[b]
C-4a
C-5
1H
C-5,C-6
2H
C-6
1H
C-7
1H
C-7 C-8
1H[c] 1H[d] 1H[e]
C-8 C-4-Ph-R [ƒ]
(bs)
(d)
(m)
(m,e)
(m,a)
(m,e)
(m,e)
(m,a) (m,e) (m,a)
6a
6b
6d
6e
6f
H
7.73
7.81
7.95
7.62
8.04
3.56
3.49 1.65-1.70 1.33-1.40 1.82-1.91 1.73-180
1.53 4.43
2.75 7.31-7.40 (m, 3H, C-3'-H, C-4'-H,
C-5'-H), 7.20-7.24 (m, 2H, C-2'-H,
C-6'-H), J = 6.5 Hz
o
2-CH
3.85
3.52
3.81
3.56
3.49 1.67-1.74 1.28-1.42 1.81-1.88 1.74-1.81 1.52 4.43
3.46 1.64-1.72 1.29-1.42 1.80-1.88 1.72-1.79 1.52 4.43
2.73 7.18-7.25 (m, 3H, C-3'-H, C-4'-H,
C-5'-H), 7.11 (d, 1H, C-6'-H),
3
2.36 (s, 3H, CH ), J = 7.0 Hz
3
o
4- CH
2-F
2.74 7.17 (pd, 2H, C-3'-H, C-5'-H),
7.40 (pd, 2H, C-2'-H, C-6'-H),
3
2.34 (s, 3H, CH ), J = 8.0 Hz
3
o
3.50 1.64-1.70 1.23-1.39
1.76-1.88
1.51 4.40
2.73 7.34 (m, 1H, C-4'-H),
7.17 (m, 2H, C-5'-H, C-6'-H),
7.12 (m, 1H, C-3'-H),
2.76 7.34 (m, 1H, C-5'-H),
3-F
3.49 1.63-1.70 1.31-1.44 1.84-1.91 1.74-1.80 1.53 4.43
7.00-7.06 (m, 2H, C-4'-H, C-6'-H),
6.95 (m, 1H, C-2'-H),
J = 9.5 Hz, J = 2.0 Hz
o
m
6g
6h
4-F
7.74
8.32
3.55
3.71
3.46 1.62-1.69 1.31-1.42 1.84-1.90 1.75-1.81 1.53 4.43
2.75 7.20 (m, 2H, C-2'-H, C-6'-H),
7.07 (m, 2H, C-3'-H, C-5'-H)
2.69 7.30 (m, 1H, C-4'-H),
7.10 (dd,1H, C-6'-H),
2-OCH
3.51 1.64-1.71 1.20-1.35
3.49 1.42-1.50 1.14-1.26
1.72-1.82
1.60-1.72
1.48 4.41
1.32 4.17
3
6.92 (m, 2H, C-3'-H, C-5'-H),
3.80 (s, 3H, OCH )
3
J = 7.5 Hz, J = 1.5 Hz
o
m
6j
4- OCH 10.38[g] 3.64
2.65 7.16 (pd, 2H, C-2'-H, C-6'-H),
6.90 (pd, 2H, C-3'-H, C-5'-H),
3
3.74 (s, 3H, OCH ), J = 8.5 Hz
3
o
[a] Coupling constants and calculated dihedral angles are given in Table 5. Abbreviatious used: bs= broad singlet, d= doublet, m= multipled, pd= pseudo-
dublet, e= equatorial, a= axial [b] Multipled (7 lines) from d t d pattern. [c] Multiplet (12 lines) from t t t t coupling pattern. [d] Multiplet (10 lines) from
q q coupling pattern. [e] Multiplet (6 lines) from d d d coupling pattern. [f] Coupling constants for aromatic protons were discribed as ortho, meta (J );
o,m
[g] Spectra in dimethyl-d –sulfoxide.
6
Figure 2. Ortep view of compound 6e with 50% probability thermal
elipsoides.
was chosen. Of special interest was the configuration at the
stereocenters (C4 and C4a) and the twisting of the aromatic
ring at C4 with respect to the pyridopyrimidine skeleton.
Figure 3. Hydrogen bonded dimer of 6e.

Jul-Aug 2002
Molecular Structure of Novel 4-Aryloctahydropyrido[1,2-c]pyrimidine Derivatives
779
Table 5
Coupling Constants [Hz] and Calculated Dihedral Angles [deg] of compounds 6a, b, d –h and j [a]
Compound
No
C-4-H
C-4a-H
C-7-H
(a)
C-8-H
(e)
C-8-H
(a)
C-4a-H C-5-H C-4-H C-5-H C-7-H C-8-H C-6-H C-8-H C-6-H C-8-H C-7-H C-7-H C-6-H C-8-H C-7-H C-7-H
(a)
(e)
(e)
(a)
(a)
(e)
(e)
(a)
(a)
(e)
(a)
(e)
(a)
(e)
3
3
3
3
2
3
3
3
3
2
3
3
4
2
3
3
Coupling Constant
Dihedral Angles
J
J
J
J
J
J
J
J
J
J
J
J
J
J
J
J
6a
6b
6d
6e
6f
8.5
155
9.0
160
8.0
150
10.5
180
8.5
150
8.5
155
10.5
180
9.0
10.8
180
11.5
180
10.5
180
9.0
180
10.8
180
11.0
180
10.5
180
11.0
180
8.5
155
9.5
160
8.0
150
10.5
180
8.2
150
9.3
160
10.5
180
8.5
2.5
55
3.0
50
3.5
40
2.5
55
3.0
50
3.0
50
3.0
50
3.0
50
12.0
12.5
12.5
13.0
13.0
12.5
13.0
12.5
12.0 12.0
180 180
12.5 12.5
180 180
12.5 12.5
180 180
13.0 13.0
180 180
13.0 13.0
180 180
12.5 12.5
180 180
13.0 13.0
180 180
12.5 12.5
3.5
40
4.0
40
4.0
40
4.5
40
4.0
40
3.5
40
3.5
40
4.0
40
3.5
45
4.0
40
4.0
40
4.5
40
4.0
40
3.5
45
3.5
45
4.0
40
13.5
13.0
13.0
13.5
13.5
13.5
13.5
-
4.5
40
4.5
40
4.5
40
4.5
40
4.5
40
4.5
40
4.5
40
-
2.0
55
2.0
55
2.0
55
2.5
55
2.0
55
2.0
55
2.0
55
-
2.0
2.0
2.0
2.5
2.0
2.0
2.0
-
13.0
13.3
13.3
13.5
13.0
13.0
13.0
13.0
13.0 3.0
180 50
13.3 3.0
180 50
13.3 3.5
180 45
13.5 3.5
180 45
13.0 3.5
180 45
13.0 3.0
180 50
13.0 3.0
180 50
13.0 3.0
180 50
6g
6h
6j
160
155
180
180
[a] Abbreviations used : a = axial, e = equatorial.
Table 6
13
C NMR Spectral Data of Compounds 6a,b,d-h and j [a]
6a
6b
6d
6e
6f
6g
6h
6j
C-1
C-3
C-4
C-4a
C-5
C-6
C-7
C-8
152.5
169.5
53.8
58.4
32.0
23.7
24.3
44.7
152.7
169.6
50.2
58.2
31.9
23.7
24.3
44.4
152.7
169.8
53.4
58.4
32.0
23.7
24.3
44.6
152.9
168.4
48.9
56.4
31.8
23.3
24.2
44.1
152.6
169.0
53.4[b]
58.1
32.0
23.7
24.2
44.7
152.5
169.3
53.1
58.2
31.9
23.6
24.2
44.6
153.5
169.8
50.2
56.1
32.0
23.5
34.4
44.0
153.1
170.3
51.6
57.0
31.0
23.0
24.0
43.6
C-1’
C-2’
C-3’
C-4’
C-5’
C-6’
135.5
129.1
128.7
128.2
128.7
129.1
134.1
136.8
131.1
128.0
126.7
128.3
132.5
128.6
129.7
137.9
129.7
128.6
122.2[b]
160.9[b]
116.0[b]
130.1[b]
124.6[b]
131.1[b]
137.7[b]
115.9[b]
163.0[b]
115.2[b]
130.6[b]
124.5[b]
131.1[b]
130.4[b]
116.1[b]
162.5[b]
116.1[b]
130.4[b]
123.9
157.0
111.6
129.5
120.9
131.2
128.6
129.9
113.8
158.4
113.8
129.9
R
-
20.2
21.1
-
-
55.6 [b]
55.0 [b]
13
[a] C Chemical shifts of the ipso carbon atoms of the phenyl rings are given in bold numbers [δ, ppm], in deuteriochloroform; compounds 6a,b,d-
n
13
19
h and compound 6j in dimethyl-d -sufoxide, tetramethylsilane as the Internal Standard. Coupling Constants J ( C – F) (Hz) for compounds 6e
6
1
4
2
2
3
3
4
1
2
2
3
3
4
J
J
= 247.2 , J = 22.0, J = 14.2 ,
J
= 8.3,
J
= 4.0 and
J
= 3.6; 6f J =247.2, J =22.4, J =21.1, J =8.7, J =7.8, J =3.2 and
= 8.3 and J = 3.3; 6h J=1.2 and 6j J =1.4 Hz ( C- O); [b] appear as doublet.
2’
3’
1’
2
4’
3
6’
5’
3’
2’
4’
17
5’
1’
6’
1
4
1
1
13
=1.8; 6g J = 247.2 , J
= 22.0,
J
C-4
4’
3’,5’
2’,6’
1’
The space group is centrosymmetric P2(1)c, therefore the
configuration of the chiral molecule was determined as RR
(SS) since the RR and SS pairs are present in the crystal unit.
The compound forms cyclic dimers linked by C1=O...H-N
hydrogen bonds (O...N distance of 2.81 Å) and the analysis
of crystal packing does not show any strong intermolecular
contact. An ORTEP view of the molecule 6e (2'-F) is
shown in Figure 2 and the hydrogen bonded dimer is illus-
trated in Figure 3. The 2'-fluorophenyl substituent at C4 is
twisted with respect to the pyrido[1,2-c]pyrimidine system

780
F. Herold, J. Kleps, R. Anulewicz-Ostrowska and B. Szcz˛esna
Vol. 39
1
plus 500 MHz spectrometers (200 MHz for H, 50 MHz for
Table 7
Selected Bond Lengths [ Å ] and Angles [deg] for Compound 6e
13
1
13
C, and 500 MHz for H, 125 MHz for C, respectively).
Two-dimensional NMR H- H COSY and H- C HETCOR
experiments were performed on a Bruker DRX 500 MHz spec-
1
1
1
13
C1-O10
C1-N9
1.210 (4)
1.323 (4)
1.357 (4)
1.337 (4)
1.190 (3)
1.486 (4)
1.482 (4)
1.503 (4)
1.450 (4)
1.479 (4)
1.496 (5)
1.480 (5)
1.461 (5)
1.447 (4)
1.339 (4)
123.2 (3)
118.9 (3)
N9-C1-N2
C3-N2-C1
O11-C3-N2
O11-C3-C4
N2-C3-C4
C1'-C4-C3
C1'-C4-C4a
C3-C4-C4a
N9-C4a-C5
N9-C4a-C4
C5-C4a-C4
C4a-C5-C6
C7-C6-C5
C8-C7-C6
N9-C8-C7
C1-N9-C8
C1-N9-C4a
C8-N9-C4a
117.9 (3)
127.6 (3)
121.3 (3)
123.8 (3)
114.8 (3)
110.9 (3)
112.0 (2)
113.2 (3)
110.2 (3)
111.1 (2)
110.7 (3)
113.5 (3)
109.5 (3)
111.9 (3)
112.6 (3)
116.3 (3)
120.8 (3)
116.5 (3)
1
13
trometer. The H- C GHMQC correlations were run on a
Varian UNITY plus 500 MHz spectrometer. For the two dimen-
sional experiments the pulse sequences, acquisition and pro-
cessing parameters were taken from standard Bruker and Varian
software library.
The single crystal of 6e (2'-F) suitable for X-ray analysis was
grown from ethanol by slow evaporation. The data were collected
on a KM 4 KUMA-diffractometer, with graphite monochromated
Mo Kα radiation. The θ-2θ scan technique and a variable scan
speed range from 1.2 to 18.0 °/minute were applied. Intensity
data were corrected for Lorenz and polarization effects [34]. The
structure was solved by direct method with SHELXS86 program
[35] and refined by the full-matrix least-squares method with
C1-N2
N2-C3
C3-O11
C3-C4
C4-C1'
C4-C4a
C4a-N9
C4a-C5
C5-C6
C6-C7
C7-C8
C8-N9
C2'-F1
2
O10-C1-N9
O10-C1-N2
SHELXL93 [36] on F . All non-hydrogen atoms were refined
anisotropically. The isotropic thermal parameters of hydrogen
atoms were set at 1.2 times U of the bonded atom. Only for
eq
hydrogen atoms involved in hydrogen bonding the positional and
thermal parameters were refined. Crystal data together with the
data collection and structure refinement details are listed in Table
8. All geometric and thermal parameters are as supplementary
material (deposited at Cambridge Crystallographic Data Center
No 178742).
Table 8
Crystal Data and Structure Refinement of 6e
Molecular formula
Molecular weight
Temperature
C H FN O
14 15 2 2
262.28
293 (2) K
0.71073 Å
Monoclinic
The flash column chromatography was carried out on Merck
Kieselgel 60 (230 – 400 mesh). TLC was performed on the plates
Wavelength
Crystal System
Space Group
DC-Platten Kieselgel 60 F
of Merck, using a mobile phase
254
P2 / n
1
CHCl , MeOH and Et O (7:2:1) and visualized using a UV lamp
3
2
Unit Cell Dimensions
a = 5.8680 (10) Å
b =18.083 (4) Å
c =11.364 (2) Å
or dyed with benzene solution of p-chloranil.
Melting points were determined on an Electrothermal 9100
instrument without corrections.
0
β =101.82 (3)
Gas chromatography was performed on a Hewlett-Packard
5972A apparatus (HP-5MS column, 30m x 0.25mm, carrier gas
helium). The analysis was carried out at 70 °C during the first 5
minutes with the increase of temperature 5 °C per minute up to
300 °C.
Microanalytical data were obtained on a Perkin Elmer
Analyser CHN 2400 in the Department of Chemistry, Technical
University of Warsaw.
3
Volume, Z
1180.3 (4) Å , 4
3
Density (Calculated)
Absorption Coefficient
F (000)
Crystal Size
Θ Range for Data Collection
Index Ranges
Reflections Collected
Independent Reflections
Refinement Method
Data / Restraints / Parameters
Goodness-of-Fit on F
Final R Indices [ I > 2 δ (I ) ]
R Indices (All Data)
1.476 Mg ⁄ m
- 1
0.111 mm
552
0.3 x 0.25 x 0.22 mm
0
2.15 to 24.99
0 ≤ h ≤ 6, 0 ≤ k ≤ 19, -12 ≤ 1 ≤ 12
2094
1909 (R
= 0.0160)
Full-Matrix Least-Squares on F
1905 / 0 / 188
i n t
The starting materials, substituted phenyl acetonitriles 1a-m
were purchased from Aldrich.
2
2
1.050
α-(o-Tolyl)- α-(2-pyridyl)acetonitrile (2b).
R1= 0.0501, wR2 = 0.1288
R1= 0.0967, wR2 = 0.1775
0.000 (3)
2-Methylbenzoacetonitrile (1b) 26.2 g (0.2 mole) was added
dropwise for 0.5 hour, while stirring, to a solution of 56 g (1
mole) potassium hydroxide in 100 ml of dimethylsulphoxide.
The stirring was continued for the next 0.5 hour. To the mixture
obtained above 47.4 g (0.3 mole) of 2-bromopyridine was added
dropwise. After 14 hours of stirring at 50 °C the cooled reaction
mixture was poured into 500 ml of ice water. The reaction prod-
uct was extracted twice with 100 ml portions of chloroform. The
organic phase was washed twice with 100 ml of water, dried over
anhydrous magnesium sulfate and evaporated. The residue
obtained upon solvent evaporation was distilled at 165-170 °C at
0.1 mm to give 2b 39 g (62 %); ir (potassium bromide pellets):
Extinction Coefficient
Largest Diff. Peak and Hole
- 3
0.328 and – 0.375e Å
and the torsion angle C4-C4a-C1'-C2' is 71°. Table 7 lists
selected bond lengths and angles for 6e, the structure
refinement details are given in Table 8.
EXPERIMENTAL
-1
1
cm : 2230 (CN); H nmr (200 MHz, deuteriochloroform): δ,
ppm 8.61 (m, 1H, pyridine H-6), 7.68 (m, 1H, pyridine H-4), 7.46
(m, 1H, pyridine H-3), 7.26 (m, 5H, pyridine H-5 and Ph-H), 5.48
The ir spectra (potassium bromide pellets) were recorded on
either a Perkin-Elmer FT-IR spectrometer Spectrum 1000, PE
AutoIMAGE System or a Bio-Rad FTS-135 spectrometer. The
nmr spectra were recorded on a Varian Gemini 200 or a Unity
(s, 1H, CH-CN), 2.32 (s, 3H, CH ); coupling constants, Hz: J
=
3
5-6

Jul-Aug 2002
Molecular Structure of Novel 4-Aryloctahydropyrido[1,2-c]pyrimidine Derivatives
781
13
'
4.9, J = 2.4, J = 7.7, J = 2.0; C nmr (50 MHz, deuterio-
(500 MHz, deuteriochloroform): δ, ppm 7.50 (d, 1H C–6 –H,
4-6
3-4
3-6
chloroform): δ, pyridine carbons 155.1 C-2, 122.0 C-3, 137.4
C-4, 128.6 C-5, 149.9 C-6, benzene ring carbons: 132.8 C-1,
136.2 C-2, 131.2 C-3, 128.7 C-4, 123.1 C-5, 126.9 C-6 and 119.1
J =7.5), 7.18 (m, 3H, C–3'–H, C–4'–H, C–5'–H), 6.53 and 5.65
(bs, 2H, 2 x NH), 3.69 (d, 1H, CHCO, J=7.5), 3.16 (m, 1H, C-2-
0
3
3
3
H, 7 lines d t d coupling pattern,
J
=10.8,
J
=7.8,
2-3a
2–CH
3
C≡N, 42.8 CH, 19.6 CH
J
J
=2.5), 2.97 (m, 1H, C–6–H , 10 lines q q coupling pattern,
3.
2–3e
e
2
3
3
3
Anal. Calcd. For C
H N : C, 80.74; H, 5.81; N, 13.45.
=12.0, J
= 4.0, J
=2.0, J
= 2.0 ), 2.56 (
14 12 2
6e-6a
6e-5a
6e-5e
6e-NH
2
3
Found: C, 80.80; H, 5.79; N, 13.50.
m, 1H, C–6–H , 6 lines d d d coupling pattern, J
= 12.0, J
a
J
6a-6e
3
The synthesis of the nitriles 2a and c-m was performed using
the method described above for compound 2b. Compounds
2c,g,k and m were oils and were isolated, as indicated above, by
vacuum distillation (for compound 2c at 150-152 °C at 1 mm, in
the reference no data) [28]. Nitriles 2a,d,e,f,h,i,j and l in ice
water formed solids. Crude solids were purified by crystalliza-
tion. Melting and boiling points were in agreement with literature
data, the overall yields were equal to or higher than those
described in the literature: 2a (60,4 %) [21]; 2d (60,8 %) [22]; 2e
(72,1 %) [22], 2f (49,6 %) [22], 2g (65,3 %) [23], 2h (66.5 %)
[24], 2i (46,2 %) [25], 2j (54.2 %) [26], 2k (63,5 %) [27], 2l (
46,7 %) [28 ] and 2m (40.3 %) [27].
=12.0,
=2.5), 2.39 (s, 3H, CH ), 1.55 (m, 1H,
6a-5a
6a-5e 3
C–5–H ), 1.42 (m, 1H, C–4–H , 12 lines t t t t coupling pattern,
e
e
2
3
3
3
3
J
=12.5, J
= 12.5, J
=12.5, J
= 4.0, J
4e-4a
4e-5e
4e-3e
4e-5a 4e-3a
= 4.0), 1.84 (m, 3H, NH piperidine, C–3–H , C–3–H ), 1.40 (m,
e
a
2
3
1H, C–5–H , 12 lines t t t t coupling pattern, J
= 12.5, J
= 4.0), 1.22 (m,
a
5a-5e
5a-
3
3
3
= 12.5, J
= 12.5, J
= 4.0, J
4a
5a-6a
5a-4e
5a-6e
13
1H, C–4–H ); C nmr (125 MHz, deuteriochloroform): δ,
a
piperidine carbons 58.8 C–2, 47.2 C–6, 30.7 C–3, 26.1 C–5, 24.7
C–4, benzene ring carbons: 137.3 C–1', 135.1 C–2', 130.9 C–3',
127.6 C– 4', 127.3 C–6', 126.6 C–5' and 174.8 C=O, 53.7 CH,
20.3 CH .
3
Anal. Calcd. For C H N O: C, 72.31; H, 8.61; N, 12.05.
14 20
2
Found: C, 72.36; H, 8.71; N, 11.84.
α-Aryl-α-(2-pyridyl)acetamides 3 a-m.
Approximately 0.5 mg of 4b hydrochloride, obtained before
recrystallization, was derivatized with trifluoroacetic anhydride
(0.25 ml in screw-cap vial, 100 °C, 0.5 hour) and subjected to gas
chromatograph analysis: 80/20 erythro-threo; retention time:
33.9 and 34.4 minutes, respectively.
General Procedure.
The appropriate nitrile 2 a-m (0.01 mole) was added portion-
wise, while stirring, to a solution composed of 60 ml acetic acid
and 20 ml sulfuric acid. The mixture obtained above was stirred
at 100 °C for 1 hour. After cooling to 5 °C the mixture was care-
fully made alkaline with ammonia to pH 9. The reaction product
was extracted with chloroform (3 x 40 ml), dried over anhydrous
magnesium sulfate and evaporated. The residue was crystallized
from the appropriate solvent, yielding analytically pure com-
pounds 3a-m. Melting points and yields were in agreement with
literature data for 3a [21], 3b [1], 3i and m [5], 3j [29] and 3l
[28]. Melting points and yields for 3c (97-98 °C; 64.5 %), 3d
(109-110 °C; 78.4 %), 2e (126-127 °C; 80.3 %), 3f ( 95.2-95.6 °C
; 76.4 %), 3g (103- 104 °C; 68.2 %), 3h (127-128 °C; 74.8 %)
and 3k (152-153 °C; 79.4 %) [28]. In reference [28] only the
preparation mode was given, not the values of mp and yields.
The amides 4a,d,e,f,g,h and j were synthesized using the same
procedure, only the trifluoroacetic acid was not added during the
synthesis. After the evaporation of acetic acid, the residue was
transformed into the base, which made the method much simpler.
The melting point of the pure base 4a was 158-159 °C (74.6%),
and for the mixture of erythro-threo 172-173 °C was found in
[21]; for compounds 4j the melting point was 175.5-176 °C
(81.3%), whereas for the salt it amounts to 222-223 °C [29]. For
the other amides, such as 4d (185-186 °C, 62.5 %), 4e (163-164
°C, 71.2 %), 4f (257.7-257.9 °C, 61.7 %) [b], 4g (195-196 °C,
60.5 %) and 4h (140-142 °C, 70.9 %), the method of synthesis
was described, but without the analytical data, mp and yields of
the compounds obtained [28 ] [a].
1
(Erythro and threo) α-(2-Tolyl)- α-(2-piperidyl)acetamide (4b).
[a] Abbreviations used in H nmr text: e = equatorial, a =
axial.
To a solution of 10 g (0.044 mole) of (3b) in 120 ml of acetic acid
and 3 ml trifluoroacetic acid 1.3 g of 10 % Pt/C was added. The cat-
alytic reduction was carried out under 10 atmospheres of hydrogen
pressure at 35 °C for 30 hours. The catalyst was removed by filtra-
tion and the filtrate was evaporated to dryness (in vacuo). The oil
was dissolved in methanol and then an excess of a solution of
methanol saturated with hydrogen chloride was added. A white
solid was obtained. The solid was stirred in 100 ml dichloromethane
for 4 hours at room temperature and filtered off, yielding 11 g (93
%) 4b, mp 221.2-221.4 °C, as a mixture of diastereomers erythro
and threo. The precipitate was recrystallized from methanol, obtain-
ing pure erythro form 4b, mp 239.2-239.6 °C.
[b] Melting point for hydrochloride.
α-Aryl-α-(1-ethoxycarbonyl-2-piperidyl) acetamide 5a,b,d–h
and j.
General Procedure.
The ethyl chloroformate 0.03 mole in 10 ml of chloroform was
added dropwise, while stirring, to a mixture of 0.02 mole of appro-
priate acetamide 4a,b,d-h and j dissolved in 50 ml of chloroform
and 0.03 mole of triethylamine. The above-obtained mixture was
refluxed for 12 hours, cooled to room temperature and washed
with 30 ml of water. The organic phase was dried over anhydrous
magnesium sulfate and then the solvent was removed. The residue
was purified by flash column chromatography (with
dichloromethane-methanol, 98:2 v⁄v) to afford the product as white
solid. The purified compounds were crystallized from: 5a from
benzene-acetonitrile (3:1 v⁄v), 5b from ligroin-absolute ethanol
(4:1 v⁄v), 5d and j from ethanol, 5e from benzene and 5h from
toluene. The reaction yields, melting points, the results of elemen-
tal analysis and ir data are given in Table 1. The results obtained by
The hydrochloride 2.2 g obtained above was dissolved in water
solution and then made alkaline to pH 9.5 using 20% solution of
sodium hydroxide in an ice water bath. The base was extracted
with chloroform (2 x 30ml). The organic phase was dried over
anhydrous magnesium sulfate and evaporated. The crystalline
residue was recrystallized from ligroin. Yielding 1.9 g (92.9 %)
4b, mp 160.1- 160.3 °C of pure form erythro (mp 144.8-145.2 °C
was established for the mixture of threo/erythro); ir (potassium
1
13
-1
1
nmr are collected in Table 2 ( H nmr) and Table 3 ( C nmr).
bromide pellets): cm : 3220, 3100 (NH), 1650 (C=O); H nmr

782
F. Herold, J. Kleps, R. Anulewicz-Ostrowska and B. Szcz˛esna
Vol. 39
[13] R. J. Chorvat, K. A. Prodan, G. W. Adelstein, R. M.
Rydzewski, K. T. McLaughlin, M. H. Stamm, L. G. Frederick, H. C.
Schniepp and J. L. Stickney, J. Med. Chem.,28, 1285 (1985).
[14] L.G. Frederick, F. R. Hatley, S. J. McDonald, M. H.
Stamm and S. M. Garthwaite, J. Cardiovasc. Pharmacol., 11, 657
(1988).
[15] P. S. Dragovich, J. E. Barker, J. French, M. Imbacuan, V. J.
Kalish, Ch. R. Kissinger, D. R. Kinghton, C. T. Lewis, E. W.
Moomaw, H. E. Parge, L.A. K. Pelletier, T. J. Prins, R. E. Showalter,
J. H. Tatlock, K. D. Tucker and J. E. Villafranca, J. Med. Chem., 39,
1872 (1996).
[16] T. Uetake, M. Nishikawa and M. Tada, J. Chem. Soc,
Perkin Trans.I, 3591 (1997).
[17] S. W. Jones, Ch. F. Palmer, J. M. Paul and P. D. Tiffin,
Tetrahedron Lett. 40, 1211 (1999).
[18] B. B. Snider and Ch. Xie, Tetrahedron Lett., 39, 7021
(1998).
[19] M. L. Lopez-Rodriguez, M. L. Rosado, B. Benhamu, M. J.
Morcillo, A. M. Sanz, L. Orensanz, M. E. Beneitez, J. A. Fuentes and
J. Manzanares, J. Med. Chem., 39, 4439 (1996).
[20] M. L. Lopez-Rodriguez, M. J. Morcillo, E. Fernandez, E.
Porras, M. Murcia, A. M. Sanz and L. Orensanz, J. Med. Chem., 40,
2653 (1997).
[21] L. Panizzon, Helv. Chim. Acta 27, 1748 (1944).
[22] A. Buschauer, Arch. Pharm. (Weinheim) 322, 165 (1989).
[23] W. Schliemann, A. Büge and L. Reppel, Pharmazie 35, 69
(1980).
4-Aryloctahydropyrido[1,2-c]pyrimidine-1,3-diones 6a,b,d-h
and j.
General Procedure.
To a mixture of 30 ml of absolute ethanol and 0.02 mole of
metallic sodium, 0.01 mole of compounds 5a,b,d-h and j was
added. The cyclization was performed for 10 hours, under reflux.
The reaction mixture was poured into ice water and was acidified
with acetic acid to pH 5. The reaction product was extracted with
chloroform (3 x 50 ml). The organic phase was dried over anhy-
drous magnesium sulfate and then the solvent was removed. The
obtained residue was purified by flash column chromatography
(with dichloromethane-methanol, 97:3 v⁄v) to provide com-
pounds 6 as colorless solids. The compounds were crystallized:
6a,e and g from acetonitrile [a]; 6b,d and h from ethanol; 6f from
ethyl acetate-hexane (1:1 v⁄v) and 6j from acetic acid. The reac-
tion yields, melting points, analytical and ir data are given in
1
Table 1. The results of H nmr analysis are collected in Tables 4
13
and 5 and of C nmr in Table 6.
[a] Compound 6a was obtained by intermolecular condensa-
tion of methyl α-phenyl-α-(2-piperidyl)acetate hydrochloride
and potassium isocyanate (mp 255 °C), however no nmr spectro-
scopic data were given [ 7].
Acknowledgements.
The authors wish to thank Professor Iwona Wawer for helpful
discussions.
[24] Ch. J. Morel and W. G. Stoll, Helv. Chim. Acta 33, 516
(1950).
[25] British Patent 589, 625 (1947); Chem. Abstr. 42, 225 h
(1948).
[26] A. Karim, R. E. Ranney and S. Kraychy, J. Pharm. Sci. 61,
888 (1972).
REFERENCES AND NOTES
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