Hydrogen-bonded chains of rings in 3-tert-butyl-1-phenyl-7-(4-trifluoro- methyl-benz-yl)-4,5,6,7-tetra-hydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1′- cyclo-hexane-2′,6′-dione and 3-tert-butyl-7-(4-methoxy-benz-yl)-1- phenyl-4,5,6,7-tetra-hydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1′-cyclo- hexane-2′,6′-dione

Article abstract of DOI:10.1107/S0108270108038808

In each of 3-tert-butyl-1-phenyl-7-(4-trifluoro-methyl-benz-yl)-4,5,6,7- tetra-hydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1′-cyclo-hexane-2′, 6′-dione, C₂₉H₃₀F₃N₃O ₂, (I), and 3-tert-butyl-7-(4-methoxy-benz-yl)-1-phenyl-4,5,6,7- tetra-hydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1′-cyclo-hexane-2′, 6′-dione, C₂₉H₃₃N₃O₃, (II), the reduced pyridine ring adopts a half-chair conformation. The mol-ecules of compound (I) are linked by two C - H...O hydrogen bonds to form a C(5)C(5)[R ¹ 2(8)] chain of rings, while in compound (II), two C - H...O hydrogen bonds link the mol-ecules into a C(6)C(7)[R ² 2(11)] chain of rings, which is further reinforced by a C - H...π hydrogen bond. The significance of this study lies in its observation of significant differences in hydrogen-bonded structures consequent upon very minor changes in remote substituents.

Full text of DOI:10.1107/S0108270108038808

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
novel heterocycles, we now report the molecular and supra-
molecular structures of the two title N7-benzyl derivatives
(Figs. 1 and 2). Compounds (I) and (II) are related to the
analogues (III) (Cruz et al., 2008) and (IV) (Trilleras et al.,
2008) reported earlier, but they differ from these earlier
examples in carrying no methyl substituents on the spiro-
cyclohexane ring. Compounds (I) and (II) were synthesized
using a straightforward modification of the synthetic method
employed earlier (Cruz et al., 2008; Trilleras et al., 2008), using
cyclohexane-1,3-dione in place of the 5,5-dimethylcyclohex-
ane-1,3-dione used previously.
ISSN 0108-2701
Hydrogen-bonded chains of rings in
3-tert-butyl-1-phenyl-7-(4-trifluoro-
methylbenzyl)-4,5,6,7-tetrahydro-
1H-pyrazolo[3,4-b]pyridine-5-spiro-
10-cyclohexane-20,60-dione and 3-tert-
butyl-7-(4-methoxybenzyl)-1-phenyl-
4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]-
pyridine-5-spiro-10-cyclohexane-20,60-
dione
Jorge Trilleras,a Silvia Cruz,b Justo Cobo,c John N. Lowd
and Christopher Glidewelle*
a
´
´
´
Grupo de Investigacion de Compuestos Heterocıclicos, Departamento de Quımica,
b
´
Universidad de Valle, AA 25360 Cali, Colombia, Departamento de Quımica,
Universidad de Narino, Ciudad Universitaria, Torobajo, AA 1175 Pasto, Colombia,
˜
c
´
´
´
´
Departamento de Quımica Inorganica y Organica, Universidad de Jaen, 23071
Jaen, Spain, dDepartment of Chemistry, University of Aberdeen, Meston Walk, Old
´
Aberdeen AB24 3UE, Scotland, and eSchool of Chemistry, University of St Andrews,
Fife KY16 9ST, Scotland
Correspondence e-mail: cg@st-andrews.ac.uk
Received 19 November 2008
Accepted 19 November 2008
Online 27 November 2008
In each of 3-tert-butyl-1-phenyl-7-(4-trifluoromethylbenzyl)-
4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-10-cyclo-
hexane-20,60-dione, C29H30F3N3O2, (I), and 3-tert-butyl-7-
(4-methoxybenzyl)-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo-
[3,4-b]pyridine-5-spiro-10-cyclohexane-20,60-dione, C29H33-
N3O3, (II), the reduced pyridine ring adopts a half-chair
conformation. The molecules of compound (I) are linked by
two C—Hꢀ ꢀ ꢀO hydrogen bonds to form a C(5)C(5)[R21(8)]
chain of rings, while in compound (II), two C—Hꢀ ꢀ ꢀO
hydrogen bonds link the molecules into a C(6)C(7)[R22(11)]
chain of rings, which is further reinforced by a C—Hꢀ ꢀ ꢀꢀ
hydrogen bond. The significance of this study lies in its
observation of significant differences in hydrogen-bonded
structures consequent upon very minor changes in remote
substituents.
Despite their different molecular constitutions, different
space groups and different patterns of supramolecular
aggregation, described below, the conformations of
compounds (I) and (II) are fairly similar (Table 1). The
reduced pyridine rings both adopt half-chair conformations,
for which the idealized ring-puckering angles (Cremer &
Pople, 1975), assuming equal bond distances throughout the
rings, are ꢁ = 50.8ꢁ and ’ = (60n + 30)ꢁ, where n represents an
integer. Similarly, the orientation of the three peripheral
substituents relative to the heterocyclic core of the molecule is
very similar in compounds (I) and (II), as shown by the
relevant torsion angles. The overall molecular conformations,
together with the pyramidal coordination at N7, mean that the
molecules have no internal symmetry, and hence that they are
chiral. However, the centrosymmetric space group in each
case accommodates a racemic mixture of the two enantiomers.
The molecules of compound (I) are linked into a chain of
rings by two independent C—Hꢀ ꢀ ꢀO hydrogen bonds
(Table 2). Atoms C6 and C53 in the molecule at (x, y, z) both
act as hydrogen-bond donors to carbonyl atom O55 in the
Comment
In continuation of our structural study of N7-benzyl-substi-
tuted pyrazolo[3,4-b]pyridine-5-spiro-10-cyclohexane-20,60-di-
ones (Cruz et al., 2008; Trilleras et al., 2008), itself part of a
programme exploring the use of multicomponent condensa-
tion reactions, especially those induced by microwave irra-
diation under solvent-free conditions, for the synthesis of
Acta Cryst. (2008). C64, o671–o674
doi:10.1107/S0108270108038808
# 2008 International Union of Crystallography o671

organic compounds
Figure 3
A stereoview of part of the crystal structure of compound (I), showing the
formation of a C(5)C(5)[R12(8)] chain of rings along [010]. For the sake of
clarity, the H atoms bonded to C atoms not involved in the motifs shown
have been omitted.
Figure 1
The molecular structure of compound (I), showing the atom-labelling
scheme. Displacement ellipsoids are drawn at the 30% probability level.
Figure 4
A stereoview of part of the crystal structure of compound (II), showing
the formation of a complex chain of rings along [010]. For the sake of
clarity, the H atoms bonded to C atoms not involved in the motifs shown
have been omitted.
involved (Table 2), and the chain of rings is thus more complex
than that observed in the structure of compound (I). Two of
the hydrogen bonds are of the C—Hꢀ ꢀ ꢀO type, utilizing both
of the carbonyl O atoms as acceptors, in contrast to the
hydrogen bonding in compound (I); these interactions link
1
molecules related by the 21 screw axis along (12, y, ) into a
4
C(6)C(7)[R22(11)] chain of rings. The third hydrogen bond is of
the C—Hꢀ ꢀ ꢀꢀ type, and this reinforces the chain generated by
the C—Hꢀ ꢀ ꢀO hydrogen bonds. As in compound (I), two
inversion-related chains pass through each unit cell, but there
are no direction-specific interactions between adjacent chains.
Thus, the overall molecular shapes for compounds (I) and
(II) are rather similar, while their molecular constitutions vary
only in the identity of the 4-substituent in the pendent benzyl
ring; nonetheless, the intermolecular hydrogen bonding in
compounds (I) and (II) is significantly different. It is thus
interesting to note not only that these substituents, viz. CF3 in
(I) and OCH3 in (II), play no direct role in the hydrogen
bonding, but also that they are located well away from the
atoms which do participate in hydrogen-bond formation, most
of which in fact are components of the spirocyclohexane ring.
It is also of interest to compare briefly the crystal structures
of compounds (I) and (II) with those of the analogous 40,40-
Figure 2
The molecular structure of compound (II), showing the atom-labelling
scheme. Displacement ellipsoids are drawn at the 30% probability level.
molecule at (12 ꢂ x, ꢂ + y, ꢂ z); in this manner, molecules
1
3
2
2
3
4
related by the 21 screw axis along (14, y, ) are linked into a
C(5)C(5)[R12(8)] (Bernstein et al., 1995) chain of rings running
parallel to the [010] direction (Fig. 3). Two chains of this type,
related to one another by inversion, pass through each unit
cell, but there are no direction-specific interactions between
adjacent chains.
In the structure of compound (II), the molecules are again
linked into a chain of rings, but now three hydrogen bonds are
ꢃ
o672 Cruz et al. C29H30F3N3O2 and C29H33N3O3
Acta Cryst. (2008). C64, o671–o674

organic compounds
Table 2
Hydrogen bonds and short intermolecular contacts (A, ) for compounds
(I) and (II).
dimethyl compounds (III) (Cruz et al., 2008) and (IV) (Tril-
leras et al., 2008). Firstly, both (III) and (IV) crystallize in the
triclinic system, where (III) forms an ethanol hemisolvate,
while compounds (I) and (II) both form monoclinic crystals.
Secondly, the heterocyclic molecules in compounds (III) and
(IV) are both linked by a combination of one C—Hꢀ ꢀ ꢀO
hydrogen bond and one C—Hꢀ ꢀ ꢀꢀ hydrogen bond. However,
the resulting structures differ not only from those of
compounds (I) and (II) but also from each other. In (III), the
hydrogen bonds generate a chain of edge-fused centrosym-
metric rings, while in (IV) a centrosymmetric dimer is formed.
Thus, the presence or absence of two peripheral methyl groups
has a marked influence, albeit indirect, on the range of
hydrogen bonds displayed and thence on the overall supra-
molecular structures.
ꢁ
˚
Cg1 represents the centroid of the N1/N2/C3/C3a/C7a ring.
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
(I)
C6—H6Aꢀ ꢀ ꢀO55i
0.99
0.99
0.99
0.99
0.99
2.42
2.54
2.57
2.54
2.82
3.309 (3)
3.448 (4)
3.236 (3)
3.275 (3)
3.384 (2)
149
153
124
131
117
C53—H53Bꢀ ꢀ ꢀO55i
C52—H52Aꢀ ꢀ ꢀO55ii
C77—H77Aꢀ ꢀ ꢀO51iii
C52—H52Bꢀ ꢀ ꢀCg1ii
(II)
Symmetry codes: (i) 21 ꢂ x, ꢂ þ y, 23 ꢂ z; (ii) 1 ꢂ x, ꢂ 12 + y, 21 ꢂ z; (iii) 1 ꢂ x, 21 + y, 12 ꢂ z.
1
2
Data collection
Bruker–Nonius KappaCCD
diffractometer
Absorption correction: multi-scan
(SADABS; Sheldrick, 2003)
Tmin = 0.975, Tmax = 0.982
31891 measured reflections
5621 independent reflections
3742 reflections with I > 2ꢅ(I)
Rint = 0.055
Experimental
Microwave-induced syntheses were carried out using a focused
microwave reactor (CEM Discover TM). A mixture of the appro-
priately substituted N-benzylaminopyrazole (2 mmol), cyclohexane-
1,3-dione (2 mmol) and an excess of paraformaldehyde (80–100 mg)
was exposed to microwave radiation at 473 K with a maximum power
of 300 W for 25 min. The reaction mixtures were dissolved in hot
ethanol. After cooling, the solid products were collected by filtration
and washed with ethanol and then with hexane (2 ꢄ 5 ml) to afford
the pure products. Colourless crystals suitable for single-crystal X-ray
diffraction were grown from solutions in ethanol. For (I), yield 75%,
m.p. 488–490 K; HRMS found 509.2295, C29H30F3N3O2 requires
509.2290. For (II), yield 75%, m.p. 466–468 K; HRMS found 471.2524,
C29H33N3O3 requires 471.2522.
Refinement
R[F2 > 2ꢅ(F2)] = 0.061
wR(F2) = 0.151
S = 1.07
337 parameters
H-atom parameteꢂrs3 constrained
˚
Áꢆmax = 0.43 e A
ꢂ3
˚
5621 reflections
Áꢆmin = ꢂ0.38 e A
Compound (II)
Crystal data
3
˚
V = 2426.1 (4) A
Z = 4
C29H33N3O3
Mr = 471.58
Monoclinic, P21=c
˚
a = 9.1904 (10) A
b = 11.9402 (14) A
˚
c = 22.2888 (16) A
ꢂ = 97.287 (9)ꢁ
Mo Kꢃ radiation
ꢄ = 0.08 mmꢂ1
T = 120 (2) K
0.39 ꢄ 0.38 ꢄ 0.16 mm
˚
Compound (I)
Crystal data
3
˚
C29H30F3N3O2
Mr = 509.56
Monoclinic, P21=n
a = 11.9298 (18) A
˚
b = 10.5678 (10) A
V = 2456.2 (5) A
Z = 4
Data collection
Bruker–Nonius KappaCCD
diffractometer
Absorption correction: multi-scan
(SADABS; Sheldrick, 2003)
Tmin = 0.977, Tmax = 0.987
37788 measured reflections
5566 independent reflections
3161 reflections with I > 2ꢅ(I)
Rint = 0.084
Mo Kꢃ radiation
ꢄ = 0.10 mmꢂ1
T = 120 (2) K
0.33 ꢄ 0.32 ꢄ 0.18 mm
˚
˚
c = 19.614 (2) A
ꢂ = 96.627 (10)ꢁ
Refinement
R[F2 > 2ꢅ(F2)] = 0.054
wR(F2) = 0.143
S = 1.04
320 parameters
H-atom parameteꢂrs3 constrained
Table 1
Selected geometric parameters (A, ) for compounds (I) and (II).
ꢁ
˚
˚
Áꢆmax = 0.26 e A
ꢂ3
˚
5566 reflections
Áꢆmin = ꢂ0.32 e A
Ring-puckering parameters are specified for the atom sequence N7—C6—
C5—C4—C3a—C7a.
(I)
(II)
For compounds (I) and (II), the space groups P21/n and P21/c,
respectively, were uniquely assigned from the systematic absences.
All H atoms were located in difference maps and then treated as
riding atoms in geometrically idealized positions, with C—H
Ring-puckering parameters
Q
ꢁ
0.480 (2)
51.5 (2)
96.6 (4)
0.477 (2)
49.5 (2)
93.6 (3)
’
˚
distances of 0.95 (aromatic), 0.98 (CH3) or 0.99 A (CH2) and
Uiso(H) = kUeq(carrier), where k = 1.5 for the methyl and 1.2 for all
other H atoms. The conformationally chiral reference molecules for
the two compounds were chosen to have the same hand.
Torsion angles
N2—C3—C31—C32
N2—C3—C31—C33
N2—C3—C31—C34
N2—N1—C11—C12
C6—N7—C77—C71
N7—C77—C71—C72
C73—C74—O74—C741
ꢂ119.6 (3)
0.2 (3)
121.0 (3)
ꢂ148.4 (2)
66.9 (3)
ꢂ111.2 (2)
8.6 (3)
128.7 (2)
ꢂ151.52 (19)
62.6 (2)
For both compounds, data collection: COLLECT (Nonius, 1999);
cell refinement: DIRAX/LSQ (Duisenberg et al., 2000); data reduc-
tion: EVALCCD (Duisenberg et al., 2003); program(s) used to solve
structure: SIR2004 (Burla et al., 2005); program(s) used to refine
ꢂ157.1 (2)
ꢂ155.42 (19)
14.1 (3)
ꢃ
Acta Cryst. (2008). C64, o671–o674
Cruz et al. C29H30F3N3O2 and C29H33N3O3 o673

organic compounds
structure: OSCAIL (McArdle, 2003) and SHELXL97 (Sheldrick,
2008); molecular graphics: PLATON (Spek, 2003); software used to
prepare material for publication: SHELXL97 and PRPKAPPA
(Ferguson, 1999).
References
Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem.
Int. Ed. Engl. 34, 1555–1573.
Burla, M. C., Caliandro, R., Camalli, M., Carrozzini, B., Cascarano, G. L., De
Caro, L., Giacovazzo, C., Polidori, G. & Spagna, R. (2005). J. Appl. Cryst. 38,
381–388.
Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354–1358.
Cruz, S., Trilleras, J., Cobo, J., Low, J. N. & Glidewell, C. (2008). Acta Cryst.
C64, o637–o642.
´
The authors thank ‘Servicios Tecnicos de Investigacion of
Universidad de Jaen’ and the staff for data collection. JC
´
´
´
´
thanks the Consejerıa de Innovacion, Ciencia y Empresa
Duisenberg, A. J. M., Hooft, R. W. W., Schreurs, A. M. M. & Kroon, J. (2000).
J. Appl. Cryst. 33, 893–898.
Duisenberg, A. J. M., Kroon-Batenburg, L. M. J. & Schreurs, A. M. M. (2003).
J. Appl. Cryst. 36, 220–229.
Ferguson, G. (1999). PRPKAPPA. University of Guelph, Canada.
McArdle, P. (2003). OSCAIL for Windows. Version 10. Crystallography
Centre, Chemistry Department, NUI Galway, Ireland.
Nonius (1999). COLLECT. Nonius BV, Delft, The Netherlands.
´
´
(Junta de Andalucıa, Spain) and the Universidad de Jaen for
financial support. SC and JT thank COLCIENCIAS,
UNIVALLE (Universidad del Valle, Colombia) and
UDENAR (Universidad de Narin˜o, Colombia) for financial
support.
¨
Sheldrick, G. M. (2003). SADABS. Version 2.10. University of Gottingen,
Germany.
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122.
Spek, A. L. (2003). J. Appl. Cryst. 36, 7–13.
Trilleras, J., Quiroga, J., Cobo, J., Low, J. N. & Glidewell, C. (2008). Acta Cryst.
C64, o665–o670.
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: SK3277). Services for accessing these data are
described at the back of the journal.
ꢃ
o674 Cruz et al. C29H30F3N3O2 and C29H33N3O3
Acta Cryst. (2008). C64, o671–o674