Seven 3-methyl-idene-1H-indol-2(3H)-ones related to the multiple-receptor tyrosine kinase inhibitor sunitinib

Article abstract of DOI:10.1107/S0108270109054134

The solid-state structures of a series of seven substituted 3-methyl-idene-1H-indol-2(3H)-one derivatives have been determined by single-crystal X-ray diffraction and are compared in detail. Six of the structures {(3Z)-3-(1H-pyrrol-2-ylmethyl-idene)-1H-in

Full text of DOI:10.1107/S0108270109054134

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
or affinity of ligands binding to enzymes or receptors (Patrick,
2009; King, 2002). Sunitinib, (1), is a conformationally
restricted clinically approved MRTKI (multi-receptor tyrosine
kinase inhibitor) anticancer drug, combining a 1H-indol-
ISSN 0108-2701
2
2
(3H)-one (oxindole) core with a Z-substituted 3-(1H-pyrrol-
-ylmethylidene) side chain (Fig. 1; Atkins et al., 2006). The
Seven 3-methylidene-1H-indol-2(3H)-
ones related to the multiple-receptor
tyrosine kinase inhibitor sunitinib
pyrrole NH group in (1) forms an intramolecular hydrogen
bond with the oxindole carbonyl group, evidenced in solution,
1
by H NMR spectroscopy, and in the cocrystal structure of (1)
bound to an RTK (receptor tyrosine kinase) (Mohammadi
et al., 1997). Compound (2a), a lead molecule in the design of
(1), exhibits biological activity towards kinases [IC50 =
0.39 mM, PDGF (platelet-derived growth factor)], whereas
the 1-methylpyrrole analogue (E)-(3b) exhibits drastically
reduced biological activity (IC50 > 100 mM) towards PDGF
(Sun et al., 1998; Boiadjiev & Lightner, 2003).
Given the strong correlation between stereochemistry and
kinase inhibitory action within this series of molecules, we
have undertaken a structural study of oxindole analogues in
the solid phase to complement the extensive prior studies
undertaken in solution (Sun et al., 1998). Our investigation of
compounds (2)–(4) by Raman and FT–IR spectroscopy
a
a
a
John Spencer, Babur Z. Chowdhry, Samiyah Hamid,
a
b
b
Andrew P. Mendham, Louise Male, *‡ Simon J. Coles
b
and Michael B. Hursthouse
a
School of Science, University of Greenwich at Medway, Central Avenue, Chatham,
b
Kent ME4 4TB, England, and EPSRC National Crystallography Service, School of
Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, England
Correspondence e-mail: l.male@bham.ac.uk
Received 9 July 2009
Accepted 15 December 2009
Online 15 January 2010
(
(
Spencer et al., 2010), supported by theoretical calculations
Kausar et al., 2009; Bell et al., 2007), has been facilitated by
The solid-state structures of a series of seven substituted
3-methylidene-1H-indol-2(3H)-one derivatives have been
determined by single-crystal X-ray diffraction and are
compared in detail. Six of the structures {(3Z)-3-(1H-pyrrol-
structure determinations from single-crystal X-ray diffraction
analysis, reported here. The molecules selected for this study
can be subdivided into several categories:
i) heterocycle-substituted analogues (2), found to exist
exclusively as the Z isomer in solution;
ii) heterocycle-substituted analogues (3), found to exist
exclusively as the E isomer in solution;
iii) simple symmetrically substituted analogues (4) and (5),
obtained in order to provide a fingerprint region for the FT–
IR and Raman studies, especially (4a), given that the parent
methylidene compound (4d) is reported to be unstable in
solution (Rossiter, 2002).
Analogues (2)–(4) were synthesized by a standard Knoe-
venagel condensation of oxindole with a variety of aldehydes
2-ylmethylidene)-1H-indol-2(3H)-one, C H N O, (2a); (3Z)-
13 10 2
(
3
-(2-thienylmethylidene)-1H-indol-2(3H)-one, C H NOS,
1
3
9
(2b); (3E)-3-(2-furylmethylidene)-1H-indol-2(3H)-one mono-
(
hydrate, C H NO ꢀH O, (3a); 3-(1-methylethylidene)-1H-
1
3
9
2
2
indol-2(3H)-one, C H NO, (4a); 3-cyclohexylidene-1H-
1
1
11
(
0
indol-2(3H)-one, C H NO, (4c); and spiro[1,3-dioxane-2,3 -
4
1
15
0
indolin]-2 -one, C H NO , (5)} display, as expected, inter-
1
1
11
3
molecular hydrogen bonding (N—Hꢀ ꢀ ꢀO C) between the
H-indol-2(3H)-one units. However, methyl 3-(1-methylethyl-
idene)-2-oxo-2,3-dihydro-1H-indole-1-carboxylate, C H N-
1
13
13
O , (4b), a carbamate analogue of (4a) lacking an N—H
3
bond, displays no intermolecular hydrogen bonding. The
structure of (4a) contains three molecules in the asymmetric
unit, while (4b) and (4c) both contain two independent
molecules.
Comment
Conformational restriction is a useful tactic employed in
medicinal chemistry, which often leads to an improvement in
the biological properties of a molecule by reducing entropy
and contributing to enhanced binding to a receptor or enzyme.
This extends to the presence of a conformational blocker, such
as an ortho-substituent in biphenyl derivatives, which hinders
free rotation, or a strong hydrogen bond to ‘lock’ two groups
together into a favourable binding orientation. A strategically
placed double bond (E or Z isomer) in the molecule also falls
within this category, since it can drastically affect the activity
‡ Current address: School of Chemistry, University of Birmingham,
Edgbaston, Birmingham B15 2TT, England.
Figure 1
Examples of oxindoles tested for anticancer activity.
Acta Cryst. (2010). C66, o71–o78
doi:10.1107/S0108270109054134
# 2010 International Union of Crystallography o71

organic compounds
or ketones under both thermal (oil bath; Sun et al., 1998, 2003;
Maskell et al., 2007) and microwave conditions (Villemin &
Martin, 1998; Zhang & Go, 2009) (see Experimental and
supplementary information for details of synthetic optimiza-
tion studies and extraction and purification procedures).
Compound (4b) was synthesized from (4a) by reaction with
dimethyl carbonate (Trost et al., 2007). Compound (5) was
purchased from Maybridge Chemicals. Crystals of (2a), (2b),
(3a), (4a)–(4c) and (5), of suitable quality for analysis by
single-crystal X-ray diffraction, were grown from dichloro-
methane/hexane. The molecular structures are shown in Figs.
Figure 3
2
–8, while selected bond lengths and angles are given in
The molecular structure of (2b), showing the atom-numbering scheme.
Displacement ellipsoids are drawn at the 50% probability level and H
atoms are shown as small spheres of arbitrary radii. The dashed line
indicates the intramolecular hydrogen bond.
Table 1. The structure of (5) determined at room temperature
has been published previously (De & Kitagawa, 1991). The
geometry of the structure reported here, determined at 120 K,
corresponds very closely with that of the previously reported
structure.
Figure 4
The molecular structure of (3a), showing the atom-numbering scheme.
Displacement ellipsoids are drawn at the 50% probability level and H
atoms are shown as small spheres of arbitrary radii. Dashed lines indicate
hydrogen bonds.
closely with oxindole fragments found in a search of the
Cambridge Structural Database (CSD, Version 5.30 with
November 2008 and February 2009 updates; Allen, 2002).
However, the only structure in which atom N1 is substituted,
In the following discussion, atom Xy refers also to X100+y
0
and X200+y in structures where Z is greater than 1 [(4a)–
(4c)].
The geometry of the oxindole portion of the molecules is
generally very similar for all seven structures, and compares
(4b), displays significantly longer N1—C1 and N1—C4
distances, a shorter O1—C1 distance and a smaller C1—N1—
C4 angle compared with the other six structures (Table 1).
3
Also, the only structure in which atom C2 is sp hybridized,
(5), displays significantly longer C1—C2 and C2—C3 bond
lengths compared with the other six structures.
2
By comparing the six structures in which atom C2 is sp
hybridized, we have observed differences in the heterocycle-
substituted analogues (2a), (2b) and (3a), where atom C10 is
2
sp hybridized, compared with structures (4a), (4b) and (4c),
3
where atom C10 is sp hybridized. It is interesting to note that,
while structures (2a), (2b) and (3a) are all in the orthorhombic
crystal system and have just one molecule in the asymmetric
0
unit (Z = 1), the remaining structures all occupy lower-
0
0
Figure 2
symmetry crystal systems and have Z > 1 [Z = 3 for (4a), and
0
The molecular structure of (2a), showing the atom-numbering scheme.
Displacement ellipsoids are drawn at the 50% probability level and H
atoms are shown as small spheres of arbitrary radii. The dashed line
indicates the intramolecular hydrogen bond.
Z = 2 for (4b) and (4c)]. The heterocycle-substituted oxind-
oles determined by Boiadjiev & Lightner (2003), namely (3Z)-
[(4,5-dimethylpyrrol-2-yl)methylidenyl]indolin-2-one and (3E)-
ꢁ
o72 Spencer et al.
C
13
10 2
H N O and six related compounds
Acta Cryst. (2010). C66, o71–o78

organic compounds
Figure 5
Figure 6
The independent molecules of (4a), showing the atom-numbering
scheme. Displacement ellipsoids are drawn at the 50% probability level
and H atoms are shown as small spheres of arbitrary radii. Dashed lines
indicate hydrogen bonds.
The independent molecules of (4b), showing the atom-numbering
scheme. Displacement ellipsoids are drawn at the 50% probability level
and H atoms are shown as small spheres of arbitrary radii.
[(1-methylpyrrol-2-yl)methylidenyl]indolin-2-one, also have
Z = 1. However, a search of the CSD revealed that this trend
0
is not observed in all substituted oxindoles and we must thus
0
conclude that the fact that (4a)–(4c) have Z > 1 is based on a
number of different factors.
In addition to the more obvious geometric differences
between the heterocycle-substituted analogues and structures
(4a), (4b) and (4c), it is found that the average C1—C2 bond
distance in (4a) and (4c) [1.509 (2) A] is significantly longer
˚
˚
than that in (2a), (2b) and (3a) [1.488 (2) A], while in (4b) (in
which atom N1 is substituted) it is only slightly longer at
˚
1.490 (8) A. In the heterocycle-substituted oxindoles deter-
mined by Boiadjiev & Lightner (2003), the average of the
˚
equivalent of the C1—C2 bond distance is 1.474 (3) A, shorter
than in any of the seven structures reported here. In turn, the
average of the equivalent distance to N1—C1 reported by
˚
Boiadjiev & Lightner is somewhat longer [1.372 (3) A] than
˚
the average for (2a), (2b), (3a), (4a), (4c) and (5) [1.359 (5) A].
It is postulated that these differences arise from the differing
temperatures at which the single-crystal X-ray data sets were
collected, 298 K for the Boiadjiev & Lightner structures and
Figure 7
The independent molecules of (4c), showing the atom-numbering
scheme. Displacement ellipsoids are drawn at the 50% probability level
and H atoms are shown as small spheres of arbitrary radii.
120 K for those reported here.
The solid-state structures agree with the results from solu-
tion NMR studies (see supplementary information) in that
the equivalent angles in the Z and E isomers reported by
ꢂ
structures (2a) and (2b) exist as Z isomers [average C1—C2—
ꢂ
Boiadjiev & Lightner (2003), 128.3 (3) and 117.5 (5) ,
respectively. The formation of the Z isomers in (2a) and (2b)
can be attributed to intramolecular N—Hꢀ ꢀ ꢀO [in 2a)] and
C9 bond angle = 128.6 (2) ], while (3a) exists as the E isomer
ꢂ
[C1—C2—C9 = 118.9 (2) ]. These angles compare well with
ꢁ
Acta Cryst. (2010). C66, o71–o78
Spencer et al.
13
C H
10 2
N O and six related compounds o73

organic compounds
Figure 8
The molecular structure of (5), showing the atom-numbering scheme.
Displacement ellipsoids are drawn at the 50% probability level and H
atoms are shown as small spheres of arbitrary radii.
Oꢀ ꢀ ꢀS (R e´ thor e´ et al., 2007) [in (2b)] interactions, while in (3a)
the lack of a suitable group to form an intramolecular inter-
action with atom O1, combined with the formation of a weak
C—Hꢀ ꢀ ꢀO contact (C8—H8ꢀ ꢀ ꢀO2), makes the adoption of the
E isomer more favourable (Table 3).
The oxindole portion of all seven structures is highly planar,
while the entire molecule does not generally deviate far from
planarity for (2a), (2b), (3a), (4a) and (4b), and this seems to
be related to the formation of intramolecular interactions
between groups in the oxindole and substituent portions of the
molecules (Tables 1 and 3, and Table S3 in the supplementary
information). By contrast, the E isomer reported by Boiadjiev
Figure 9
A view of the hydrogen-bonded dimer and hydrogen bonding (thin lines)
involving the solvent water molecule in the structure of (3a). [Symmetry
1
1
codes: (i) 1 ꢃ x, ꢃ1 ꢃ y, ꢃz; (ii) ꢃ x, + y, z.]
2
2
&
Lightner (2003) has no suitable groups with which to form
intramolecular interactions and the molecule is much more
twisted than in the structures reported here, with the angle
between the planes through the oxindole and substituent
ꢂ
portions being approximately 30 (cf. Table S3). In (4c), the
formation of weak intramolecular C—Hꢀ ꢀ ꢀO interactions
involving atoms C14 and C114 (Table 3) corresponds with an
average C1—C2—C9—C10 torsion angle which is relatively
ꢂ
close to 180 (Table 1). It seems that the formation of even
weak C—Hꢀ ꢀ ꢀO interactions has a significant effect on the
conformation of these molecules in the solid state.
Structures (2a), (2b), (3a), (4a), (4c) and (5) are also
affected by the formation of intermolecular hydrogen bonds
involving the oxindole N—H and C O units, which leads to
the formation of molecular dimers in every case (Fig. 9–11,
Figs. S1–S4 in the supplementary information, and Table 2).
The hydrogen-bonding motif leading to the formation of the
2
molecular dimers can be described as an R (8) ring (Etter et
2
Figure 10
A view of the two hydrogen-bonded dimers (thin lines) formed in the
structure of (4a). [Symmetry codes: (i) 1 ꢃ x, ꢃy, 1 ꢃ z; (ii) ꢃ1 + x, y, z.]
al., 1990). Analysis of Fig. 11 shows that, while the dimers
formed in (3a), (4a) and (4c) are fairly planar [not taking into
account the conformation of the cyclohexyl rings in (4c)], the
molecules forming the dimers in (2a), (2b) and (5) are quite
staggered with respect to one another. This is borne out by
analysis of the N—Hꢀ ꢀ ꢀO hydrogen-bond angles (Table 2).
ecule is involved in hydrogen bonding both to the oxindole
C O group and to other water molecules (Fig. 9 and Table 2).
The molecular dimers in this structure are connected with one
another via ꢀ–ꢀ stacking interactions (Hunter & Sanders,
˚
1990), the parallel dimer planes being separated by 3.3 A,
While the average for the interactions in (2a), (2b) and (5) is
ꢂ
163 (3) , the average for those in (3a), (4a) and (4c) is
significantly larger at 172 (3) .
ꢂ
Structure (3a) is the only one of the seven to incorporate a
molecule of solvent in the crystal structure. This water mol-
while atom O1 and the N1/C1–C4 ring form a lone-pair–ꢀ
interaction (Mooibroek et al., 2008) (O1ꢀ ꢀ ꢀring centroid =
ꢁ
o74 Spencer et al.
C
13
10 2
H N O and six related compounds
Acta Cryst. (2010). C66, o71–o78

organic compounds
˚
distances ranging from 3.1 A in (4c) to approximately 3.6 A in
˚
(2b) (Figs. S5–S10 in the supplementary information).
In conclusion, the X-ray single-crystal structure determi-
nations described here have brought to light a number of
interesting properties in oxindoles in the solid phase, including
0
high Z values and inter- and intramolecular hydrogen
bonding. This offers the potential for synthesizing oxindoles
with extended molecular architectures and biological proper-
ties (Spencer et al., 2009) and will be of continuing invaluable
assistance to theoretical calculations (Kausar et al., 2009).
Experimental
The starting materials for the syntheses of the title compounds were
purchased from commercial sources (Sigma–Aldrich, Fisher,
Fluorochem and Frontier Scientific) and were used without further
purification. All reactions were carried out in air, and commercial
grade solvents and materials were used except where specified.
Elemental analyses were performed on a CE Instruments Eager 300
apparatus. Crystals of each of compounds (2a)–(5) of sufficient
quality for X-ray diffraction analysis were obtained by the diffusion
Figure 11
Side views of the hydrogen-bonded dimers (thin lines) formed in the
structures of (2a), (2b), (3a), (4a), (4c) and (5).
2 2
of hexane into a CH Cl solution.
Synthetic and purification procedure for (2a). 1,3-Dihydro-2H-
indol-2-one (oxindole) (0.319 g, 2.40 mmol) and 1H-pyrrole-2-
carbaldehyde (0.190 g, 2.00 mmol) were added to EtOH (5 ml) with
2
–3 drops of piperidine as a catalyst. The reaction mixture was
refluxed until complete according to thin-layer chromatographic
TLC) monitoring, which equates to approximately 3 h. The reaction
(
mixture was cooled to room temperature and, on further cooling with
ice, afforded a precipitate. The crude product was obtained by
filtration and washed with cold EtOH. Product (2a) was purified by
column chromatography on silica with chloroform–methanol (90:10
v/v) as eluant. Crystals of (2a) were obtained as a yellow solid (yield
0
.420 g, 84%; m.p. 483–486 K). Analysis found: C 73.0, H 4.9,
N 13.6%; C13 Cl requires: C 73.1, H 4.7, N 13.1%.
Oꢀ0.05CH
While the empirical formula was found to contain a very small
amount of CH Cl by elemental analysis and NMR, no dichloro-
H
10
N
2
2
2
2
2
methane was found in the crystal structure.
Synthetic and purification procedure for (2b). Oxindole (0.133 g,
.00 mmol) and thiophene-2-carbaldehyde (0.159 g, 1.20 mmol) were
1
reacted, and purification was achieved as for (2a), except that
hexane–ethyl acetate (50:50 v/v) was used as eluant during chroma-
tographic purification. Crystals of (2b) were obtained as a yellow
solid (yield 0.178 g, 79%; m.p. 463–466 K). Analysis found: C 68.9, H
9
4.2, N 6.2%; C13H NOS requires: C 68.7, H 4.0, N 6.2%.
Synthetic and purification procedure for (3a). Oxindole (0.133 g,
.00 mmol) and 2-furaldehyde (0.115 g, 1.20 mmol) were reacted, and
1
Figure 12
The packing of the hydrogen-bonded dimers (thin lines) in (3a). Only
those H atoms involved in hydrogen bonding are shown.
purification was achieved as for (2a), except that hexane–ethyl
acetate (50:50 v/v) was used as eluant for chromatographic purifica-
tion. Crystals of (3a) were obtained as a yellow solid [yield 0.166 g,
7
9%; m.p. 443–446 K (literature value 451 K; Villemin & Martin,
998)]. Analysis found: C 67.9, H 4.7, N 6.8%; C13
ꢀH
ꢂ
1
requires: C 68.1, H 4.8, N 6.1%.
H
11NO
3
2
O
˚
3
.2 A and C1—O1ꢀ ꢀ ꢀring centroid = 92 ). This stacking of
dimers leads to the formation of columns along the (010)
direction which are connected to one another in the (100)
direction via hydrogen bonding with the water molecules
Synthetic and purification procedure for (4a). Oxindole (0.133 g,
.00 mmol) and acetone (7.90 g, 136 mmol) were reacted, and puri-
1
fication was achieved as for (2a), except that chloroform–ethyl
acetate (50:50 v/v) was used as eluant. Crystals of (4a) were obtained
as an orange solid (yield 0.158 g, 92%; m.p. 459–461 K). Analysis
found: C 76.2, H 6.5, N 8.3%; C H NO requires: C 76.3, H 6.4, N
(
Fig. 12).
The delocalized bonding and planar nature of these mol-
ecules mean that the other six structures also exhibit varying
11
11
degrees of ꢀ–ꢀ stacking interactions, with interplanar
8.1%.
ꢁ
Acta Cryst. (2010). C66, o71–o78
Spencer et al.
13
C H
10 2
N O and six related compounds o75

organic compounds
Synthetic and purification procedure for (4b). Compound (4b) was
made according to a published method (Trost et al., 2007) [m.p. 341–
Refinement
2
2
R[F > 2ꢄ(F )] = 0.054
wR(F ) = 0.125
145 parameters
H-atom parameters constrained
2
3
42 K (literature value 341–343 K)]. Analysis found: C 76.4, H 5.7, N
.9%; C13 requires: C 76.2, H 5.7, N 6.0%.
˚
ꢃ3
Áꢅmax = 0.34 e A
5
H
13NO
3
S = 1.09
2463 reflections
Áꢅmin = ꢃ0.42 e A˚
ꢃ3
Synthetic and purification procedure for (4c). Oxindole (0.319 g,
.40 mmol) and cyclohexanone (0.196 g, 2.00 mmol) were reacted,
2
and purification was achieved as for (2a), except that chloroform–
ethyl acetate (50:50 v/v) was used as eluant. Crystals of (4c) were
obtained as a brown solid [yield 0.450 g, 88%; m.p. 458–460 K
Compound (3a)
Crystal data
˚
V = 2154.3 (2) A
3
[
literature value 464 K (Villemin & Martin, 1998)]. Analysis found: C
C
13
H
9
NO
2
ꢀH
2
O
7
5.8, H 6.9, N 6.3%; C14
.3%. While the empirical formula was found to contain a very small
Cl by elemental analysis and NMR, no dichloro-
H
15NOꢀ0.1CH
2
Cl
2
requires: C 76.3, H 6.9, N
M
r
= 229.23
Orthorhombic, Pbcn
Z = 8
Mo Kꢁ radiation
6
˚
a = 19.2250 (7) A
ꢃ1
ꢂ = 0.10 mm
T = 120 K
amount of CH
2
2
˚
b = 5.0503 (3) A
methane was found in the crystal structure.
˚
c = 22.1886 (14) A
0.30 ꢄ 0.06 ꢄ 0.04 mm
Synthetic and purification procedure for (5). Compound (5) was
purchased from Maybridge Chemicals.
Data collection
Microwave-mediated syntheses of analogues (2)–(4) (Spencer,
007, 2008). Oxindole (1 mmol), the aldehyde or ketone (1.5
Bruker–Nonius Roper CCD camera
on ꢃ-goniostat diffractometer
Absorption correction: multi-scan
13065 measured reflections
1881 independent reflections
1355 reflections with I > 2ꢄ(I)
2
equivalents), ethanol (5 ml) and piperidine (2 drops) were placed in a
sealable microwave tube and heated to 423 K for 30 min using
continuous cooling (Pmax) in a CEM Discover unit. After cooling the
reaction mixture, the crude product was subjected to the same work-
up as for the thermal-mediated route.
(
T
SADABS; Sheldrick, 2007)
min = 0.970, Tmax = 0.996
Rint = 0.085
Refinement
2
2
R[F > 2ꢄ(F )] = 0.052
wR(F ) = 0.118
H atoms treated by a mixture of
independent and constrained
refinement
2
S = 1.06
1881 reflections
160 parameters
3 restraints
˚
ꢃ3
Áꢅmax = 0.24 e A
Compound (2a)
Áꢅmin = ꢃ0.25 e A˚
ꢃ3
Crystal data
˚
V = 2079.25 (17) A
3
C
13
10
H N
2
O
M
r
= 210.23
Orthorhombic, Pbca
Z = 8
Mo Kꢁ radiation
ꢂ = 0.09 mm
T = 120 K
Compound (4a)
˚
a = 14.6031 (6) A
ꢃ1
˚
b = 6.2725 (3) A
Crystal data
˚
c = 22.6997 (12) A
ꢂ
0.28 ꢄ 0.10 ꢄ 0.01 mm
C H NO
11
ꢇ = 96.617 (2)
V = 1311.45 (7) A
11
˚
3
M
r
= 173.21
Data collection
Triclinic, P1
a = 9.7504 (3) A
b = 10.2281 (3) A
Z = 6
Mo Kꢁ radiation
ꢂ = 0.09 mm
T = 120 K
˚
Bruker–Nonius Roper CCD camera
on ꢃ-goniostat diffractometer
Absorption correction: multi-scan
15759 measured reflections
1828 independent reflections
1412 reflections with I > 2ꢄ(I)
ꢃ1
˚
˚
c = 14.0530 (5) A
ꢂ
ꢁ
= 95.766 (2)
0.30 ꢄ 0.08 ꢄ 0.04 mm
(
T
SADABS; Sheldrick, 2007)
min = 0.976, Tmax = 0.999
R
int = 0.085
ꢂ
ꢆ = 107.842 (2)
Data collection
Refinement
2
Bruker–Nonius APEXII CCD
camera on ꢃ-goniostat
diffractometer
21390 measured reflections
5972 independent reflections
4122 reflections with I > 2ꢄ(I)
2
R[F > 2ꢄ(F )] = 0.053
wR(F ) = 0.110
145 parameters
H-atom parameters constrained
2
˚
ꢃ3
S = 1.05
1828 reflections
Áꢅmax = 0.18 e A
Absorption correction: multi-scan
Rint = 0.059
Áꢅmin = ꢃ0.22 e A˚
ꢃ3
(
T
SADABS; Sheldrick, 2007)
min = 0.975, Tmax = 0.997
Compound (2b)
Refinement
2
2
R[F > 2ꢄ(F )] = 0.079
wR(F ) = 0.168
358 parameters
H-atom parameters constrained
Crystal data
2
3
Áꢅmax = 0.36 e A˚
ꢃ3
˚
V = 2157.32 (19) A
S = 1.08
5972 reflections
C
13
9
H NOS
Áꢅmin = ꢃ0.31 e A˚
ꢃ3
M
r
= 227.27
Orthorhombic, Pbcn
Z = 8
Mo Kꢁ radiation
˚
ꢃ1
a = 11.9297 (5) A
b = 10.8294 (6) A
˚
c = 16.6986 (9) A
ꢂ = 0.27 mm
T = 120 K
˚
Compound (4b)
0.16 ꢄ 0.08 ꢄ 0.04 mm
Crystal data
Data collection
3
˚
V = 2237.73 (8) A
C
13
H13NO
3
Bruker–Nonius APEXII CCD
camera on ꢃ-goniostat
diffractometer
18202 measured reflections
2463 independent reflections
2024 reflections with I > 2ꢄ(I)
M
r
= 231.24
Monoclinic, P2
Z = 8
Mo Kꢁ radiation
ꢂ = 0.10 mm
T = 120 K
=n
1
˚
ꢃ1
a = 10.6939 (2) A
b = 17.2595 (4) A
˚
c = 12.7714 (3) A
˚
Absorption correction: multi-scan
R
int = 0.052
(
T
SADABS; Sheldrick, 2007)
min = 0.958, Tmax = 0.989
0.36 ꢄ 0.30 ꢄ 0.18 mm
ꢂ
ꢆ = 108.3220 (10)
ꢁ
o76 Spencer et al.
C
13
10 2
H N O and six related compounds
Acta Cryst. (2010). C66, o71–o78

organic compounds
Table 1
Selected bond lengths (A), angles ( ) and torsion angles ( ) from structures (2a), (2b), (3a), (4a)–(4c) and (5).
˚
ꢂ
ꢂ
(2a)
(2b)
(3a)
(4a)†
(4b)†
(4c)†
(5)
N1—C1
N1—C4
O1—C1
C1—C2
C2—C3
C3—C4
C2—C9/C2—O2‡
C9—C10/C2—O3‡
1.358 (3)
1.396 (3)
1.250 (2)
1.486 (3)
1.467 (3)
1.401 (3)
1.360 (3)
1.424 (3)
1.366 (3)
1.405 (3)
1.240 (3)
1.488 (3)
1.463 (3)
1.401 (3)
1.352 (3)
1.432 (3)
1.352 (3)
1.406 (3)
1.246 (3)
1.489 (3)
1.477 (3)
1.408 (3)
1.353 (3)
1.414 (3)
1.360 (3)
1.393 (3)
1.2337 (15)
1.510 (2)
1.4730 (10)
1.406 (2)
1.352 (2)
1.503 (4)
1.4335 (7)
1.426 (3)
1.2114 (14)
1.490 (8)
1.464 (3)
1.4070 (14)
1.3560 (14)
1.5045 (7)
1.3605 (7)
1.398 (2)
1.2350 (14)
1.5075 (7)
1.485 (2)
1.4075 (7)
1.3535 (7)
1.510 (6)
1.3519 (16)
1.4082 (16)
1.2298 (15)
1.5670 (16)
1.5053 (16)
1.3935 (17)
1.4093 (15)
1.4096 (14)
C1—N1—C4
C1—C2—C9/C1—C2—O2‡
C2—C9—C10/C2—O2—C9‡
111.60 (17)
128.77 (19)
131.5 (2)
111.20 (19)
128.5 (2)
134.1 (2)
111.0 (2)
118.9 (2)
133.2 (2)
111.90 (17)
124.9 (4)
122.03 (15)
109.7 (3)
123.1 (3)
121.325 (7)
111.8 (3)
124.3 (4)
123.2 (2)
111.91 (10)
111.85 (9)
113.62 (9)
C1—C2—C9—C10/C1—C2—O2—C9‡
C2—C9—C10—X/C2—O2—C9—C10§
ꢃ2.6 (4)
ꢃ2.6 (4)
ꢃ3.3 (4)
176.8 (2)
ꢃ0.4 (4)
ꢃ177 (3)
179.57 (7)
170.4 (19)
ꢃ72.13 (12)
ꢃ54.98 (13)
0.3 (4)
†
The reported values are averages of the parameters from the different crystallographically independent molecules in the asymmetric unit. ‡ For structure (5), the second parameter
is reported, while for the remaining six structures the first parameter is given. § In (2a), X = N2, in (2b) X = S1 and in (3a) X = O2, and the second parameter is reported for structure
5).
(
Table 2
Intermolecular hydrogen-bonding interactions (A, ) in (2a), (2b), (3a),
4a), (4c) and (5).
Data collection
˚
ꢂ
Bruker–Nonius APEXII CCD
camera on ꢃ-goniostat
diffractometer
18503 measured reflections
4997 independent reflections
3778 reflections with I > 2ꢄ(I)
(
Structure Interaction
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
Absorption correction: multi-scan
Rint = 0.059
(
T
SADABS; Sheldrick, 2007)
min = 0.935, Tmax = 0.995
i
(
(
(
2a)
2b)
3a)
N1—H1ꢀ ꢀ ꢀO1
N1—H1ꢀ ꢀ ꢀO1
N1—H1ꢀ ꢀ ꢀO1
0.88
0.88
0.88
1.99
1.99
1.95
2.841 (2) 162
2.835 (2) 160
2.828 (3) 174
ii
iii
iv
O101—H1Wꢀ ꢀ ꢀO101
O101—H2Wꢀ ꢀ ꢀO1
0.87 (2) 1.90 (2) 2.763 (2) 172 (3)
0.86 (2) 2.00 (2) 2.852 (2) 173 (3)
Refinement
2
v
2
(4a)
N1—H1ꢀ ꢀ ꢀO1
0.88
0.88
0.88
0.88
0.88
0.88
1.98
1.96
1.98
1.97
1.98
1.98
2.859 (3) 174
2.837 (3) 176
2.848 (3) 170
2.846 (2) 171
2.850 (2) 169
2.844 (1) 165
R[F > 2ꢄ(F )] = 0.066
wR(F ) = 0.135
289 parameters
H-atom parameters constrained
N101—H101ꢀ ꢀ ꢀO201
N201—H201ꢀ ꢀ ꢀO101
2
˚
ꢃ3
Áꢅmax = 0.33 e A
S = 1.07
4997 reflections
vi
(4c)
N1—H1ꢀ ꢀ ꢀO1
Áꢅmin = ꢃ0.24 e A˚
ꢃ3
v
N101—H101ꢀ ꢀ ꢀO101
v
(5)
N1—H1ꢀ ꢀ ꢀO1
Symmetry codes: (i) ꢃx þ 1; ꢃy; ꢃz þ 1; (ii) ꢃx þ 1; ꢃy þ 1; ꢃz þ 1; (iii) ꢃx þ 1,
1
1
2
ꢃy ꢃ 1; ꢃz; (iv) ꢃx þ 2 ; y þ ; z; (v) ꢃx þ 2; ꢃy; ꢃz þ 1; (vi) ꢃx þ 3; ꢃy þ 1; ꢃz.
Compound (5)
Crystal data
˚
V = 976.42 (4) A
3
C
11
H11NO
3
M
r
= 205.21
Z = 4
Mo Kꢁ radiation
ꢂ = 0.10 mm
T = 120 K
Data collection
Monoclinic, P2 =c
1
˚
ꢃ1
Bruker–Nonius Roper CCD camera
on ꢃ-goniostat diffractometer
Absorption correction: multi-scan
26778 measured reflections
5129 independent reflections
3809 reflections with I > 2ꢄ(I)
a = 9.5406 (2) A
˚
b = 8.4295 (2) A
˚
c = 12.4103 (3) A
0.50 ꢄ 0.40 ꢄ 0.36 mm
ꢂ
(
T
SADABS; Sheldrick, 2007)
min = 0.966, Tmax = 0.983
R
int = 0.052
ꢆ = 101.956 (2)
Refinement
2
2
R[F > 2ꢄ(F )] = 0.049
wR(F ) = 0.134
313 parameters
H-atom parameters constrained
Table 3
Intramolecular hydrogen-bonding and weak interactions (A, ) in (2a),
2
˚
ꢂ
˚
ꢃ3
Áꢅmax = 0.31 e A
S = 1.04
5129 reflections
(2b), (3a) and (4a)–(4c).
Áꢅmin = ꢃ0.35 e A˚
ꢃ3
Structure
Interaction
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
(
(
(
2a)
2b)
3a)
N2—H2ꢀ ꢀ ꢀO1
0.88
1.89
2.668 (2)
2.792 (2)
3.035 (3)
2.970 (3)
2.953 (3)
2.961 (3)
2.845 (2)
2.847 (2)
2.879 (2)
2.869 (2)
2.957 (3)
2.953 (3)
147
Compound (4c)
S1ꢀ ꢀ ꢀO1
C8—H8ꢀ ꢀ ꢀO2
0.95
0.98
0.98
0.98
0.95
0.95
0.98
0.98
0.99
0.99
2.29
2.18
2.19
2.16
2.27
2.28
2.27
2.32
2.16
2.15
135
137
134
137
118
118
119
115
136
137
Crystal data
(4a)
C11—H11Aꢀ ꢀ ꢀO1
C111—H11Gꢀ ꢀ ꢀO101
C211—H21Dꢀ ꢀ ꢀO201
C5—H5ꢀ ꢀ ꢀO2
ꢂ
C
14
H15NO
ꢇ = 101.201 (2)
V = 1103.32 (5) A
˚
3
M
r
= 213.27
Triclinic, P1
a = 5.3732 (1) A
(
4b)
4c)
Z = 4
Mo Kꢁ radiation
C105—H105ꢀ ꢀ ꢀO102
C11—H11Aꢀ ꢀ ꢀO1
C111—H11Dꢀ ꢀ ꢀO101
C14—H14Bꢀ ꢀ ꢀO1
C114—H11Kꢀ ꢀ ꢀO101
˚
˚
ꢃ1
b = 13.4962 (4) A
ꢂ = 0.08 mm
T = 120 K
˚
c = 15.8088 (5) A
ꢁ
(
ꢂ
= 95.3890 (10)
ꢂ
0.85 ꢄ 0.08 ꢄ 0.06 mm
ꢆ = 98.498 (2)
ꢁ
Acta Cryst. (2010). C66, o71–o78
Spencer et al.
13
C H
10 2
N O and six related compounds o77

organic compounds
Data collection
References
Bruker Nonius Roper CCD camera
on ꢃ-goniostat diffractometer
Absorption correction: multi-scan
12504 measured reflections
2227 independent reflections
1885 reflections with I > 2ꢄ(I)
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2
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˚
˚
0
.98 A for methyl H atoms and N—H = 0.88 A, with Uiso(H) =
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1
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(
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accurate microbalance. Anjum Nazira (University of Green-
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National Mass Spectrometry Service Centre, University of
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ꢁ
o78 Spencer et al.
C
13
10 2
H N O and six related compounds
Acta Cryst. (2010). C66, o71–o78