Two intermediates in the synthesis of decahydroisoquinolines with NMDA and AMPA receptor antagonist activity

Article abstract of DOI:10.1107/S0108270101009702

In 6-methyl-N-(4-nitrobenzoyl)-5,6-dihydropyridin-2(1H)-one, C₁₃H₁₂N₂O₄, (I), the piperidone ring is in a distorted half-chair conformation. In 8-methoxy-3-methyl-N-(4-nitrobenzoyl)-1,2,3,4,5,6,7,8 -octahydroisoquinoline-1,6-dione, C₁₈H₂₀N₂O₆, (II), the heterocyclic ring is in a slightly distorted half-boat conformation, while the other six-membered ring is in a distorted chair conformation. Compound (II) presents a strong intramolecular C - H···O hydrogen bond. In both (I) and (II), the molecules interact through C - H···O interactions.

Full text of DOI:10.1107/S0108270101009702

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
mate, the excitatory amino acid antagonist activities of a series
of decahydroisoquinoline-3-carboxylic acids were explored. It
was found that compound (III) possesses both NMDA and
AMPA receptor antagonist activity (Simmons et al., 1998;
O'Neill et al., 1998).
ISSN 0108-2701
A new route to the synthesis of (III) was proposed, based
on an intermolecular Diels±Alder cycloaddition reaction of a
6-substituted dihydropyridone with an appropriate diene. This
key reaction would need a group at position 6 (to the nitro-
gen) in an axial position, so before the cycloaddition reaction
was attempted, a crystal structure determination of (I) was
undertaken. After con®rmation that the methyl group (at
position 6, labelled C5 in the ®gure) occupied an axial posi-
tion, a thermally induced Diels±Alder reaction was performed
using the highly reactive Danishefsky's diene, (IV). As the
Diels±Alder reaction could lead to several different products
and as the relative stereochemistry of this product is of great
importance for subsequent reaction steps, the crystal structure
of (II) was determined.
Two intermediates in the synthesis of
decahydroisoquinolines with NMDA
and AMPA receptor antagonist activity
J. Zukerman-Schpector,a,b* Mauricio Vega,b I. Caracelli,b
Luiz C. Diasc and Anna M. A. P. Fernandesc
a
Â
Instituto de Quõmica, Universidade de Sao Paulo, Sao Paulo, SP, Brazil,
Ä
Ä
b
Â
Ã
Laboratorio de Cristalografia, Estereodinamica e Modelagem Molecular,
Â
Departamento Quõmica, Universidade Federal de Sao Carlos, Caixa Postal 676,
Ä
c
Â
13565-905 Sao Carlos, SP, Brazil, and Instituto de Quõmica, UNICAMP, Caixa
Ä
Postal 6154, 13083-970 Campinas, SP, Brazil
Correspondence e-mail: julio@power.ufscar.br
The molecular structure of (I) is shown in Fig. 1. As stated,
the methyl group at C5 is in an axial position, as required for
the continuation of the reaction path. The piperidone ring is in
a half-chair conformation distorted towards a half-boat, as
indicated by the Cremer & Pople (1975) puckering parameters
shown in Table 3. The lone pair of the piperidone N atom is
involved in conjugation with the carbonyl groups. This is
indicated by the slight lengthening of the C O double bond
Received 30 May 2001
Accepted 12 June 2001
In
6-methyl-N-(4-nitrobenzoyl)-5,6-dihydropyridin-2(1H)-
one, C13H12N2O4, (I), the piperidone ring is in a distorted
half-chair conformation. In 8-methoxy-3-methyl-N-(4-nitro-
benzoyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline-1,6-dione, C18-
H20N2O6, (II), the heterocyclic ring is in a slightly distorted
half-boat conformation, while the other six-membered ring is
in a distorted chair conformation. Compound (II) presents a
strong intramolecular CÐHÁ Á ÁO hydrogen bond. In both (I)
and (II), the molecules interact through CÐHÁ Á ÁO interac-
tions.
Ê
[1.214 (3) A] and the concomitant shortening of the two NÐ
2
Csp single bonds [1.395 (3) and 1.399 (3) A]. Accordingly, the
Ê
state of hybridization of the N atom is sp2, as shown by the
sum (358.2ꢀ) of the angles around it and the small deviation
Ê
[ 0.050 (2) A] of the atom from the N1/C2/C4/C13 plane.
Comment
Glutamate is the major excitatory neurotransmitter in the
brain and can act on three major types of ligand-gated ion
channels that are de®ned by the activity of the subtype-
Figure 1
The molecular structure of (I) showing the atomic labelling and 50%
probability displacement ellipsoids.
selective agonists NMDA (N-methyl-d-aspartate), kainate and
AMPA (ꢀ-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid) (Ornstein et al., 1994). In a search for new therapeutic
agents which are potent and selective antagonists of gluta-
Figure 2
The molecular structure of (II) showing the atomic labelling and 50%
probability displacement ellipsoids.
ꢁ
Acta Cryst. (2001). C57, 1089±1091
# 2001 International Union of Crystallography
Printed in Great Britain ± all rights reserved 1089

organic compounds
Table 1
Selected geometric parameters (A, ) for (I).
The molecular diagram of (II) is shown in Fig. 2, and shows
that the two rings have a cis fused stereochemistry with an
H1ÐC1ÐC6ÐH6 torsion angle of 41ꢀ. The heterocyclic ring
is in a slightly distorted (towards a chair) half-boat confor-
mation, whereas the other six-membered ring is in a distorted
chair (towards a half-chair) conformation, as indicated by the
Cremer & Pople (1975) puckering parameters given in Table 6.
The existence of a CÐHÁ Á Áꢁ interaction between C12ÐH12B
and the C14±C19 phenyl ring is noted. According to Ciunik et
al. (1998), this kind of interaction should be characterized by
three parameters. In the present structure, these are the
ꢀ
Ê
N1ÐC7
N1ÐC1
N1ÐC5
1.395 (3)
1.399 (3)
1.481 (3)
N2ÐO2
N2ÐO4
N2ÐC11
1.210 (4)
1.226 (3)
1.482 (4)
C7ÐN1ÐC1
C7ÐN1ÐC5
C1ÐN1ÐC5
121.7 (2)
117.6 (2)
119.0 (2)
O2ÐN2ÐO4
O2ÐN2ÐC11
O4ÐN2ÐC11
123.6 (3)
118.5 (3)
118.0 (3)
Table 2
Hydrogen-bonding geometry (A, ) for (I).
ꢀ
Ê
H12BÁ Á ÁCgi (Cg is the centroid of the C14±C19 ring) distance
i
ꢀ
Ê
of 2.69 A, the C12ÐH12BÁ Á ÁCg angle of 158 and the angle
between the HÁ Á ÁCg vector and the plane of the aromatic ring,
which in this case is 88ꢀ [symmetry code: (i) 12 + x, 1 y, z].
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
C2ÐH2Á Á ÁO2i
0.93
0.93
0.93
0.96
0.93
2.69
2.78
2.66
2.82
2.55
3.619 (4)
3.446 (5)
3.276 (3)
3.710 (5)
3.451 (4)
174
130
124
154
163
C3ÐH3Á Á ÁO4ii
C12ÐH12Á Á ÁO1iii
C6ÐH6AÁ Á ÁO4iii
C9ÐH9Á Á ÁO3iv
ꢀ
Ê
These values are in the expected ranges of 2.7±3.4 A, 140±160
and 80±100ꢀ, respectively, as described by Ciunik et al. (1998).
This compound also exhibits three intramolecular hydrogen
bonds (Table 5); in fact, C11ÐH11AÁ Á ÁO4 and C15Ð
H15Á Á ÁO3 are responsible for the particular arrangement of
the phenyl ring. In order to study the in¯uence of these
hydrogen bonds on molecular conformation, a series of
Potential Energy Surfaces (PES) calculations were performed
[MOPAC7.01: Stewart (1990) and Csern (2000); GAMESS98:
Schmidt et al. (1993)]. The geometry optimization calculations,
using AM1 and 6±31G*, showed a change in the conformation
involving the three CÐHÁ Á ÁO interactions; the H15Á Á ÁO3
Symmetry codes: (i) 2 x; 12 ‡ y; 23 z; (ii) 23 x; 1 y; 12 ‡ z; (iii) 2 x; y
;
z; (iv)
1
2
3
2
1
x; 12 ‡ y; 32 z.
Table 3
Cremer & Pople (1975) puckering parameters (A, ) for (I).
ꢀ
Ê
Ring
q2
q3
'
2
ꢂ2
Q
N1ÐC1ÐC2ÐC3ÐC4ÐC5 0.27 (2)
0.32 (2) 38 (5) 139 (3) 0.42 (2)
followed by addition of phenylselenyl bromide. This last
intermediate was converted into (I) using standard oxidation
and elimination conditions. Heating of (I) with an excess of
Danishefsky's diene (IV) at re¯ux in xylene in the presence of
BHT, followed by treatment of the intermediate adduct with
KF in THF, gave (II).
Ê
distance changes from 2.49 to 2.58 A, while the other two
distances, H5BÁ Á ÁO3 and H11CÁ Á ÁO4, shorten to 2.47 and
Ê
2.49 A, respectively. The PES obtained after rotation of the
C4ÐN1ÐC13ÐC14 torsion angle showed that there were two
minima, one corresponding to the global minimum (162.77ꢀ),
which is close to the crystallographic conformation
[144.0 (2)ꢀ], and the other at 77.32ꢀ. This last conformation is
around 7 kcal higher (1 kcal = 4.184 kJ) than the other and
results in the loss of the C15ÐH15Á Á ÁO3 hydrogen bond. We
can postulate that, in this case, the molecular conformation is
driven more by the intramolecular interactions.
In both compounds, the molecules interact through a series
of CÐHÁ Á ÁO interactions, as shown in Tables 2 and 5.
Whether all these interactions are true hydrogen bonds is
dif®cult to assert because, as pointed out by Cotton et al.
(1997), `the ®eld is getting muddier and muddier as the de®-
nition of a hydrogen bond is relaxed'. In any case, the Tables
include those contacts with an HÁ Á ÁO distance less than the
sum of the van der Waals radii (Pauling, 1960) plus 10% and a
CÐHÁ Á ÁO angle greater than 100ꢀ.
Compound (I)
Crystal data
C13H12N2O4
Mr = 260.25
Mo Kꢀ radiation
Cell parameters from 25
re¯ections
Orthorhombic, P212121
Ê
a = 7.3677 (9) A
Ê
ꢂ = 10.0±18.4ꢀ
1
b = 10.054 (1) A
Ê
ꢃ = 0.11 mm
T = 293 K
Irregular, colourless
0.20 Â 0.10 Â 0.05 mm
c = 16.834 (2) A
3
Ê
V = 1247.0 (2) A
Z = 4
Dx = 1.386 Mg m
3
Data collection
Enraf±Nonius CAD-4±MACH3
diffractometer
!/2ꢂ scans
2382 measured re¯ections
2098 independent re¯ections
995 re¯ections with F2 > 2ꢄF2
Rint = 0.018
ꢂmax = 30.0ꢀ
h = 1 ! 10
k = 14 ! 0
l = 0 ! 23
3 standard re¯ections
frequency: 30 min
intensity decay: 1.1%
Experimental
Addition of methyl magnesium bromide to commercially
available glutarimide, followed by treatment of the inter-
mediate aminal with NaBH3CN/HCl, afforded the corre-
sponding lactam. The lactam was then N-protected using
n-BuLi in tetrahydrofuran (THF) followed by addition of
p-nitrobenzoyl chloride to afford the corresponding imide
which, in turn, was deprotonated with LiHMDS in THF,
Re®nement
Re®nement on F2
R[F2 > 2ꢄ(F2)] = 0.037
wR(F2) = 0.103
S = 0.98
2098 re¯ections
w = 1/[ꢄ2(Fo2) + (0.0692P)2
+ 0.0290P]
where P = (Fo2 + 2Fc2)/3
(Á/ꢄ)max < 0.001
3
Ê
Áꢅmax = 0.17 e A
3
Ê
0.18 e A
173 parameters
H-atom parameters constrained
Áꢅmin
=
ꢁ
1090 J. Zukerman-Schpector et al.
C13H12N2O4 and C18H20N2O6
Acta Cryst. (2001). C57, 1089±1091

organic compounds
Table 4
Selected geometric parameters (A, ) for (II).
Table 6
Cremer & Pople (1975) puckering parameters (A, ) for (II).
ꢀ
ꢀ
Ê
Ê
N1ÐC2
N1ÐC13
N1ÐC4
1.388 (3)
1.414 (3)
1.490 (3)
N2ÐO2N
N2ÐO1N
N2ÐC17
1.180 (4)
1.216 (4)
1.464 (4)
Ring
q2
q3
'
ꢂ2
Q
2
C1ÐC6ÐC7ÐC8ÐC9ÐC10 0.11 (2) 0.47 (2) 95 (11) 13 (3) 0.49 (2)
N1ÐC2ÐC1ÐC6ÐC5ÐC4 0.297 (3) 0.380 (3) 122.4 (5) 38.2 (3) 0.482 (3)
C2ÐN1ÐC13
C2ÐN1ÐC4
C13ÐN1ÐC4
120.7 (2)
122.3 (2)
116.3 (2)
O2NÐN2ÐO1N
O2NÐN2ÐC17
O1NÐN2ÐC17
122.5 (3)
119.2 (3)
118.3 (3)
1.2 (for the other H atoms) times the value of the equivalent isotropic
displacement parameter of the attached atom.
For both compounds, data collection: CAD-4 Software (Enraf±
Nonius, 1989); cell re®nement: CAD-4 Software; data reduction:
XCAD4 (Harms & Wocadlo, 1995). Program(s) used to solve struc-
ture: SHELXS86 (Sheldrick, 1985) for compound (I) and SIR92
(Altomare et al., 1993) for compound (II). For both compounds,
program(s) used to re®ne structure: SHELXL97 (Sheldrick, 1997);
molecular graphics: ZORTEP (Zsolnai, 1995); software used to
prepare material for publication: PARST95 (Nardelli, 1995),
PLATON (Spek, 1998) and WinGX (Farrugia, 1999).
Table 5
Hydrogen-bonding geometry (A, ) for (II).
ꢀ
Ê
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
C5ÐH5BÁ Á ÁO3
0.97
0.96
0.93
0.98
0.97
0.96
0.97
0.97
0.96
0.96
0.93
0.93
2.49
2.52
2.48
2.68
2.58
2.69
2.59
2.51
2.76
2.67
2.43
2.73
3.124 (3)
3.078 (3)
3.379 (3)
3.576 (3)
3.354 (4)
3.393 (4)
3.399 (4)
3.473 (3)
3.418 (5)
3.407 (4)
3.337 (3)
3.382 (3)
123
118
163
152
136
130
141
171
126
134
166
128
C11ÐH11CÁ Á ÁO4
C15ÐH15Á Á ÁO3
C4ÐH4Á Á ÁO4i
C7ÐH7BÁ Á ÁO1Nii
C11ÐH11BÁ Á ÁO2Nii
C7ÐH7AÁ Á ÁO2iii
C9ÐH9BÁ Á ÁO1iv
C11ÐH11AÁ Á ÁO1Nv
C12ÐH12CÁ Á ÁO2vi
C16ÐH16Á Á ÁO1vii
C19ÐH19Á Á ÁO4viii
This work has received partial support from FAPESP, CNPq
and CAPES. MVacknowledges FAPESP for a PhD fellowship
Â
(98/13927-3). The X-ray facility at the Instituto de Quõmica-
USP was installed with a grant from FAPESP (94/2061-4).
1
1
2
Symmetry codes: (i)
1
x; y; z; (ii) x; y 1; z; (iii)
1
x
;
y; z; (iv)
x; 12 y; 12 z; (v) x 122; 1 y; z; (vi)
x; 12 y; 12 z; (vii) ‡ x; 1 y; z; (viii)
1
2
2
2
1
x; 1 y; z.
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: DA1198). Services for accessing these data are
described at the back of the journal.
Compound (II)
Crystal data
References
3
C18H20N2O6
Mr = 360.36
Monoclinic, I2/a
Dx = 1.356 Mg m
Mo Kꢀ radiation
Cell parameters from 25
re¯ections
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Ê
a = 10.2455 (9) A
b = 12.664 (1) A
ꢂ = 10.0±17.2ꢀ
Ê
1
Ê
c = 27.446 (3) A
ꢃ = 0.10 mm
T = 293 K
ꢆ = 97.441 (9)ꢀ
V = 3531.1 (6) A
Z = 8
3
Ê
Irregular, colourless
0.25 Â 0.20 Â 0.15 mm
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Farrugia, L. J. (1999). J. Appl. Cryst. 32, 837±838.
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Enraf±Nonius CAD-4±MACH3
diffractometer
!/2ꢂ scans
7230 measured re¯ections
3574 independent re¯ections
1846 re¯ections with F2 > 2ꢄF2
Rint = 0.046
ꢂ
max = 26.3ꢀ
h = 12 ! 0
k = 15 ! 15
l = 33 ! 34
3 standard re¯ections
frequency: 30 min
intensity decay: 1.6%
Re®nement
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1363.
Re®nement on F2
R[F2 > 2ꢄ(F2)] = 0.044
wR(F2) = 0.113
S = 1.01
3574 re¯ections
w = 1/[ꢄ2(Fo2) + (0.0616P)2
+ 1.0264P]
where P = (Fo2 + 2Fc2)/3
(Á/ꢄ)max < 0.001
3
Ê
Áꢅmax = 0.20 e A
3
Ê
0.25 e A
237 parameters
H-atom parameters constrained
Áꢅmin
=
È
Sheldrick, G. M. (1985). SHELXS86. University of Gottingen, Germany.
È
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an isotropic displacement parameter of 1.5 (for methyl H atoms) or
ꢁ
Acta Cryst. (2001). C57, 1089±1091
J. Zukerman-Schpector et al. C13H12N2O4 and C18H20N2O6 1091