Structural study involving 9-(pyrid-2-yl)indolizine-1-one and related derivatives of dipyridyl methanol

Article abstract of DOI:10.1016/j.molstruc.2019.05.037

For the first time, the synthesis of 9-(pyrid-2-yl)indolizine-1-one from dipyridylpropargyl alcohol together with its molecular structure is reported. As the racemate was used for crystallization, the asymmetric unit contains both enantiomers. The molecular conformation of the pyridyl indolizinone scaffold of the title compound is similar to the one found for the respective chlorophenyl substituted derivative. Furthermore, we report here on the synthesis and X-ray structures of two alkylated dipyridyl methanols, which have been recovered in connection with the synthesis of the indolizinone. Both prochiral alcohols show conformational chirality in the solid state. In both compounds, intramolecular O–H … N_pyridine hydrogen bonds stabilizing their molecular conformation are typical. As a common packing motif, we found a O–H?N bonding system featuring the graph set descriptor R₂ ²(10). With reference to the structural relationship that can be found between pharmaceutically interesting agents and title compounds, the presented molecules are promising models for future drug design.

Full text of DOI:10.1016/j.molstruc.2019.05.037

Journal of Molecular Structure 1193 (2019) 215e222
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Structural study involving 9-(pyrid-2-yl)indolizine-1-one and related
derivatives of dipyridyl methanol
,
, **
Felix Katzsch a, Tobias Gruber b *, Anke Schwarzer a, Edwin Weber a
a Institut für Organische Chemie, TU Bergakademie Freiberg, Leipziger Straße 29, 09596, Freiberg/Sachsen, Germany
b School of Pharmacy, University of Lincoln, Joseph Banks Laboratories, Green Lane, Lincoln, Lincolnshire, LN6 7DL, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
For the first time, the synthesis of 9-(pyrid-2-yl)indolizine-1-one from dipyridylpropargyl alcohol
together with its molecular structure is reported. As the racemate was used for crystallization, the
asymmetric unit contains both enantiomers. The molecular conformation of the pyridyl indolizinone
scaffold of the title compound is similar to the one found for the respective chlorophenyl substituted
derivative. Furthermore, we report here on the synthesis and X-ray structures of two alkylated dipyridyl
methanols, which have been recovered in connection with the synthesis of the indolizinone. Both pro-
chiral alcohols show conformational chirality in the solid state. In both compounds, intramolecular OeH
… Npyridine hydrogen bonds stabilizing their molecular conformation are typical. As a common packing
motif, we found a OeH/N bonding system featuring the graph set descriptor R22ð10Þ. With reference to
the structural relationship that can be found between pharmaceutically interesting agents and title
compounds, the presented molecules are promising models for future drug design.
Received 22 January 2019
Received in revised form
8 May 2019
Accepted 12 May 2019
Available online 16 May 2019
Keywords:
Heterocycles
Indolizine
X-ray crystallography
Supramolecular interactions
Conformational chirality
© 2019 Elsevier B.V. All rights reserved.
1. Introduction
Furthermore, we report on two alkylated dipyridyl methanols (2
and 3) occurring during the reaction. Their structural behaviour
Indolizine (pyrrolo[1,2-a]pyridine) is an aromatic heterocycle,
which is isomeric to indole and a scaffold of well-known drugs like
butoprozine as well as an important building block for emerging
pharmaceutical products [1,2]. The saturated ring system, i.e.
indolizidine, occurs in a number of prominent alkaloids such as
castanospermine and swainsonine [3]. The introduction of a keto
function at carbon atom C1 leads to indolizine-1-ones with some
derivatives of them being studied for their potential as anticancer
agents [4] or as antioxidants [5]. A number of indolizinone syn-
theses are known, e.g. the thermally induced cycloisomerization of
tertiary propargylic alcohols [6], the copper catalysed cyclo-
isomerization of 2-pyridyl substituted propargylic acetates [7] and
a palladium catalysed domino process from tertiary propargylic
alcohols [8]. To the best of our knowledge, so far only one molecular
structure of an indolizine-1-one has been described [9]. Here we
present the synthesis of 9-(pyrid-2-yl)indolizine-1-one (1) from di-
2-pyridylmethanone together with its molecular structure.
will be analysed and compared with those of similar compounds
(4e9) reported.
2. Experimental
2.1. Synthesis
2.1.1. General
The melting points were measured on a microscope heating
stage PHMK Rapido (VEB Dresden Analytik) and are uncorrected. 1H
and 13C NMR spectra were obtained from a Bruker Avance 500 at
500.1 (1H) and 125.8 (13C) using TMS as internal standard. Chemical
shifts for proton and carbon resonances are given in ppm (d). Signal
multiplicity is characterized by s (singlet), d (doublet), dd (double
doublet) and t (triplet). Mass spectra were recorded on a Hewlett
Packard 5890 Series II/MS 5971 A. Elemental analyses have been
performed on a Heraeus CHN-Rapid Analyzer. The reagents and
solvents were used as purchased from the chemical suppliers
except otherwise stated.
Di(pyrid-2-yl) ketone was synthesized from 2-bromopyridine
(via halogen lithium exchange reaction using n-BuLi) and ethyl
chloroformiate following a literature procedure [10].
* Corresponding author.
** Corresponding author.
E-mail addresses: tgruber@lincoln.ac.uk (T. Gruber), edwin.weber@chemie.tu-
freiberg.de (E. Weber).
https://doi.org/10.1016/j.molstruc.2019.05.037
0022-2860/© 2019 Elsevier B.V. All rights reserved.

216
F. Katzsch et al. / Journal of Molecular Structure 1193 (2019) 215e222
2.1.2. 1,1-Di(pyrid-2-yl)prop-2-yne-1-ol (2)
Evaporation of the solvent and column chromatography (SiO2,
eluent Et2O/n-hexane, 1:4, v/v) resulted in a yellow oil, which has
been identified as compound 3. Yield 0.30 g (11%), Rf ¼ 0.56 (EtOAc/
To a stirred solution of di(pyrid-2-yl) ketone (5.00 g, 27.1 mmol)
in 150 ml THF (dried over molecular sieves), a solution of ethy-
nylmagnesium bromide (81.4 ml, 40.7 mmol, 0.5 M in THF) was
slowly added via syringe at ꢀ78 ꢁC and under argon. The mixture
was stirred for 1.5 h at ꢀ78 ꢁC and subsequently for 11 h at room
temperature. After quenching with aqueous ammonium chloride
solution, the mixture was extracted with diethyl ether (3 ꢂ 150 ml).
The combined organic phases were washed with brine (200 ml)
and dried over sodium sulfate. Evaporation of the solvent and
column chromatography (SiO2/EtOAc) yielded the product (3.50 g,
61%) as a brownish-yellow solid. M.p. 116 ꢁC. Rf ¼ 0.72 (EtOAc). 1H
n-hexane, 1:4, v/v). 1H NMR: (CDCl3)
d
¼ 0.83 (t, 3H, CH3,
3JHH ¼ 7.20 Hz); 1.19 (m, 2H, CH2eCH2eCH2eCH3); 1.28 (m, 2H,
CH2eCH2eCH2eCH3); 2.37 (m, 2H, CH2eCH2eCH2eCH3); 6.50 (s,
3
1H, OH); 7.11 (m, 2H, PyH5); 7.62 (td, 2H, PyH4, JHH ¼ 7.80 Hz,
4JHH ¼ 1.80 Hz); 7.84 (d, 2H, PyH3, 3JHH ¼ 8.10 Hz); 8.50 (d, 2H, PyH6,
3JHH ¼ 4.8 Hz). 13C NMR: (CDCl3)
d
¼ 14.1 (CH3); 23.0, 25.8, 41.6
(CH2); 78.2 (CeOH); 121.0 (PyC5); 121.9 (PyC3); 136.7 (PyC4); 147.5
(PyC6); 163.7 (PyC2). IR: (KBr)
n
¼ 3354; 3054; 3004; 2954; 2926;
2867; 2860; 1633; 1611; 1586; 1562; 1465; 1430; 1393; 1299; 1246;
1209; 1171; 1081; 1049; 981; 940; 896; 853; 790; 768; 750; 672;
653; 631; 612; 547; 497; 462. MS: Calc. for C15H18N2O: 242.14 g/
mol. Found: 243 g/mol [MþH]_þ (GC/MS: 60 ꢁC, 3 min, 20 ꢁC/min,
M ¼ 350) Rt ¼ 10.97 min, m/z ¼ 243, 185 (100), 164, 130, 106, 78, 51.
NMR: (CDCl3)
d
¼ 2.75 (s, 1H, C^CeH); 6.81 (s, 1H, OH); 7.21 (m,
2H, PyH5); 7.70 (td, 2H, PyH3, 3JHH ¼ 7.60 Hz, 4JHH ¼ 1.75 Hz); 7.86 (d,
3
3
2H, PyH4, JHH ¼ 7.95 Hz); 8.55 (d, 2H, PyH6, JHH ¼ 4.75 Hz). 13C
NMR: (CDCl3)
d
¼ 73.4 (C^CeH); 73.5 (CeOH); 85.7 (C^CeH);
121.1 (PyC5); 122.9 (PyC3); 137.2 (PyC4); 147.9 (PyC6); 160.2 (PyC2).
IR: (KBr)
¼ 3386; 3294; 3180; 3050; 2999; 2357; 2107; 1587;
n
2.2. X-ray structure determination
1572; 1464; 1432; 1369; 1334; 1302; 1287; 1252; 1204; 1154; 1116;
1078; 1052; 1017; 998; 957; 922; 894; 793; 767; 742; 666; 634;
615; 568; 546; 492; 460. MS: Calc. for C13H10N2O: 210.08 g/mol.
Found: 211 g/mol [MþH]_þ (GC/MS: 60 ꢁC, 3 min, 20ꢁ/min,
M ¼ 350); Rt ¼ 10.26; m/z ¼ 211, 182, 132, 106, 78 (100), 51.
Elementary analysis: Calc. C: 74.27% H: 4.79% N: 13.33%. Found: C:
74.66% H: 4.75% N: 13.39%.
Crystals suitable for single crystal X-ray diffraction have been
grown by slow evaporation of their solutions in EtOAc/n-hexane
(1:1) (1), toluene (2) and from EtOAc/n-hexane/acetone (1:1:1) (3),
respectively. Suitable single crystal for X-ray diffraction experi-
ments were selected under a microscope and mounted on a glass
fibre. Intensity data collection was performed on a Bruker Kappa
CCD X8 Apex II equipped with a low-temperature device with Mo-
2.1.3. 9-(Pyrid-2-yl)indolizine-1-one (1)
Ka
radiation (
l
¼ 0.71073 Å) using
u and 4 scans. Software for data
To a degassed solution of 1,4-diiodobenzene (0.79 g, 2.4 mmol)
and 2 (1.00 g, 4.8 mmol) in triethylamine (20 ml, dried over KOH) a
catalyst mixture composed of Pd(PPh3)2Cl2 (3.5 mg, 0.005 mmol),
CuI (1.9 mg, 0.010 mmol) and PPh3 (3.9 mg, 0.015 mmol) was added.
The reaction mixture was heated to reflux for 7 h, then cooled to
room temperature, diluted with Et2O and washed with aqueous
ammonium chloride solution. After drying over sodium sulfate, the
solvent was evaporated. Column chromatography (SiO2, eluent
EtOAc/n-hexane 1:1, v/v) resulted in a yellow solid, which was
identified as indolizine 1. Yield 0.49 g (49%). M.p. 114 ꢁC. Rf ¼ 0.15
collection and cell refinement was SMART and that for data
reduction SAINT [11]. Reflections were corrected for background,
Lorentzian and polarisation effects. Preliminary structure models
were derived by direct methods and the structures were refined by
full-matrix least-squares calculations based on F2 for all reflections
using SHELXL [12]. With the exception of the hydroxyl hydrogen
atoms in 2 and 3 all other hydrogen atoms were included in the
models in calculated positions and were refined as constrained to
bonding atoms. The hydroxyl hydrogen atoms in 2 and 3 were
located in a difference Fourier map and freely refined.
CCDC 1873757e1873759 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: þ44 1223 336033).
(EtOAc/n-hexane, 1:1, v/v). 1H NMR: (CDCl3)
d
¼ 5.11 (d, 1H, IndH2,
3JHH ¼ 3.70 Hz); 5.40 (m, 1H, IndH6); 6.10 (dd, 1H, IndH7,
3
JHH ¼ 9.20 Hz, 5.55 Hz); 6.34 (d, 1H, IndH8, JHH ¼ 9.25 Hz); 6.59 (d,
3
1H, IndH5, JHH ¼ 6.95 Hz); 7.17 (ddd, 1H, PyH5, JHH ¼ 7.50 Hz,
3
4.80 Hz, 1.00 Hz); 7.45 (d, 1H, PyH3, JHH ¼ 8.00 Hz); 7.67 (td, 1H,
3
PyH4, JHH ¼ 7.80 Hz, 1.85 Hz); 8.11 (d, 1H, IndH3, JHH ¼ 3.75 Hz);
8.56 (m, 1H, PyH6). 13C NMR: (CDCl3)
108.8 (IndC2); 120.6 (PyC5); 121.2 (PyC3); 122.8 (IndC5); 123.9
(IndC8); 128.5 (IndC7); 137.0 (PyC4); 149.4 (IndC3); 157.9 (PyC6);
d
¼ 72.2 (IndC9); 98.4 (IndC6);
3. Results and discussion
3.1. Preparation of compounds
162.2 (PyC2); 201.1 (C]O). IR: (KBr)
n
¼ 3098; 3063; 3003; 1663;
1632; 1581; 1565; 1515; 1464; 1429; 1391; 1353; 1312; 1258; 1207;
1188; 1173; 1150; 1112; 1090; 1068; 1055; 1014; 995; 948; 932;
888; 843; 812; 789; 777; 748; 720; 707; 644; 625; 599; 542; 511;
485; 441. MS: Calc. for C28H22N4O2: 210.08 g/mol. Found: 211 g/mol
[MþH]_þ (GC/MS: 80 ꢁC, 3 min, 20 ꢁC/min, M ¼ 350) Rt ¼ 10.20 min,
m/z ¼ 211, 182, 169, 155, 132, 106, 78. Elementary analysis: Calc. C:
74.27% H: 4.79% N: 13.33%. Found: C: 74.28% H: 4.71% N: 12.78%.
Title compounds 1 and 2 have been synthesized during our
studies on alkyne-linked heteroaromatic systems [13]. Starting
point for the preparation of 1 has been a Grignard type reaction [14]
with ethynylmagnesium bromide and di(pyrid-2-yl) ketone, which
delivered the corresponding dipyridyl alcohol 2 in good yields
(Scheme 1). In the second step, we planned to couple 2 with 1,4-
diiodobenzene in a Sonogashira-Hagihara cross-coupling reaction
[15]. Instead of the anticipated wheel-and-axle type host com-
pound [16] featuring a linear molecule with di(pyrid-2-yl methanol
at both ends, indolizinone 1 has formed in good yields during a
metal-induced cycloisomerization [17].
Title compound 3 has been recovered during the attempted
synthesis of 1,4-bis[di(pyrid-2-yl)hydroxymethyl]benzene [18] via
the lithiation of dibromobenzene in diethylether [19]. Obviously,
the employed n-BuLi has not been active enough to react with the
substrate. Hence, the excess of the lithium reagent leads to the
reaction of the n-butyl group with the di(pyrid-2-yl)ketone to form
3 in a low yield of 11%..
2.1.4. 1,1- Di(pyrid-2-yl)pentane-1-ol (3)
To a suspension of 1,4-dibromobenzene (1.42 g, 6.0 mmol) in
Et2O (20 ml, dried over molecular sieves) was added n-BuLi (7.5 ml,
12.0 mmol, 1.6 M in n-hexane) at 70 ꢁC and under argon. The
mixture was stirred for 30 min at ꢀ30 ꢁC and then a solution of
di(pyrid-2-yl) ketone (2.20 g, 12.0 mmol) in Et2O/THF (3:1, v/v,
40 ml) was added dropwise. After having stirred for 2 h at room
temperature, the mixture was quenched with an aqueous solution
of ammonium chloride (50 ml). The organic phase was separated,
washed with aqueous NaCl solution (50 ml) and dried (Na2SO4).

F. Katzsch et al. / Journal of Molecular Structure 1193 (2019) 215e222
217
right), the second molecule gives the (R) configuration at C6B
(Fig. 1a, left). The overlay of both molecules including the inversion
of 1B is depicted in Fig. 1b and shows the similarity of both mole-
cules. The bond lengths of the heterobicyclic backbone are com-
parable to one another and with those of the respective
chlorophenyl derivative (4) [9].
O
MgBr
THF
HO
N
Pd(PPh3)2Cl2
CuI, PPh3, Et3N
N
O
N
N
N
49 %
61 %
N
2
1
The molecules of 1 are linked via weak CeH/N [d(C/N)
3.248(5), 3.299(5) Å] and CeH/O contacts [d(C/O) 3.278(4)-
3.398(5) Å] to form sheets coplanar to the crystallographic ab plane.
Thereby, two different systems of cyclic hydrogen bonding are
found featuring the graph set descriptors R22ð10Þ and R23ð9Þ [26]
O
n-BuLi,
THF/Et2O
HO
N
N
N
N
11 %
(Fig. 2). Neighbouring strands of molecules are stabilized by
p…p
3
interactions [27] involving pyridine rings with a centre-to-centre
distance of 3.801(2) Å along the crystallographic a-axis. In addi-
Scheme 1. Synthesis of the title compounds 1e3.
tion, the same pyridine unit interacts in CeH,,,p interaction [28]
of 2.98 Å. These molecular strands of 1A along the crystallographic
c-axis are further stabilized by CeH,,,O interactions [29] ([d(C/O)
3.606(6) Å] at O1A. Therefore, the oxygen atom O1A shows an
inversed trifurcated hydrogen bond with the CeH groups of C8A-
H8A, C11A-H11A and C12BeH12B (Table 2).
3.2. X-ray single crystal analysis
Crystals suitable for single crystal X-ray diffraction have been
grown by slow evaporation of their solutions in EtOAc/n-hexane
(1:1) (1), toluene (2) and EtOAc/n-hexane/acetone (1:1:1) (3),
respectively. Details of the data collection and refinement calcula-
tions can be found in Table 1. Non-covalent interactions are sum-
marized in Table 2 and conformational parameters are displayed in
Table 3. For comparison reasons, we discuss in this paper also the
molecular structures of related compounds (4e9) (Scheme 2).
Indolizinone 1 crystallised in the orthorhombic space group
Pna21 containing two enantiomeric molecules in the asymmetric
part of the unit cell (Fig. 1a). While the first molecule labelled with
A shows (S) configuration at the asymmetric C6A atom (Fig. 1a,
The comparison of the packing behaviour of 1 and 4 shows a
significant influence of the additional chlorine substituted phenyl
ring. Additional
p…p interactions are observed between this aro-
matic moiety and an adjacent equivalent. Furthermore, the phenyl
ring interacts in CeH/O interactions, and therefore prevents the
formation of the cyclic hydrogen bond motifs observed in 1. How-
ever, the molecular conformations of the pyridyl indolizinone
scaffold in 1 and 4 are quite similar (Fig. 3), which may be signifi-
cant for future applications of this class of compounds in biology
[30].
Compound 2 crystallizes as colourless block-shaped crystals
Fig. 1. a) Molecular structure of 1 at 50% probability level. b) Least-square overlays of the independent molecules of 1 without (left) and with inversion (right). The r.m.s. deviations
are 0.0101 Å (left) and 0.0094 Å (right) for an overlay of the following atoms: N1, C1eC5. All hydrogen atoms are omitted for clarity.

218
F. Katzsch et al. / Journal of Molecular Structure 1193 (2019) 215e222
Fig. 2. Intermolecular interaction in the packing of 1. Cyclic H bonding motifs, R22ð10Þ
(O1B, C11B, C10B, N1B) and R32ð9Þ (O1B, C12A, O1A, C12B, C11B) are highlighted. The
following CeH/O/N interactions (H/O/N distance) are shown:
CarylH … Npyridin
(a ¼ 2.51 Å), CarylH…O]C (b ¼ 2.39 Å), CarylH…O (c ¼ 2.45 Å), CarylH…Npyridin
(d ¼ 2.45 Å), CarylH…O]C (e ¼ 2.34 Å), CarylH…O (f ¼ 2.44 Å).
showing the monoclinic space group P21/c with two molecules in
the asymmetric part of the unit cell (Fig. 4). The crystals form
pseudo-merohedral twins giving them
a higher symmetry
compared to the crystal system. Therefore, the crystal structure was
refined after twin integration using PLATON [31]. Due to the
different orientation of the pyridine moieties with respect to their
nitrogen atom, the molecules show a chiral conformation in the
solid state. Apart from the anti orientation of the pyridine rings
[32], the two molecules differ slightly in the dihedral angle of the
aromatic units (75.1 and 75.4ꢁ), which is about 10ꢁ lower than
found for the corresponding benzene [20] (5) or thiophene [22] (6)
derivatives (Table 3). Furthermore, the so-called pitch angles can be
used to describe the propeller-like nature of the molecular struc-
ture. In detail, this means the angle between the plane of an aro-
matic unit and the plane defined by Caryl-Cbridge-Caryl [33]. In 2,
these angles are rather different within the one molecule but
similar to one another (2-A: 68.7/84.9ꢁ; 2-B: 65.12/87.0ꢁ). The
molecular conformation is stabilized by intramolecular OeH/N
hydrogen bonds involving the hydroxyl group and the pyridine
nitrogen atom [d(O/N) 2.698(2); 2.714(2) Å] (Fig. 4).
The crystal packing of 2 is dominated by strong OeH/N in-
teractions [d(O/N) ¼ 2.8973(18); 2.8985(19) Å] involving the sec-
ond nitrogen atom and featuring a cyclic motif of hydrogen bonds
with the graph set descriptor R22ð10Þ (Fig. 5). The resulting dimers
are connected via CeH/N interactions [d(C/N) ¼ 3.292(2),
3.302(3) Å] between the terminal alkyne hydrogens and the pyri-
dine nitrogen atoms to form supramolecular zigzag chains along
the crystallographic a-axis. Additional weak CeH/O contacts
[d(C/O) ¼ 3.022(2), 3.094(2) Å] stabilise the chains. Stacking in-
teractions of the aromatic units connect adjacent chains via dimer
formation along the crystallographic a-axis. The centre-to-centre
Fig. 3. Least-square overlays of the independent molecules of 1A and 4 with inversion
(right). The r.m.s. deviation is 0.0144 Å for an overlay of the following atoms: N1,
C1eC5. All hydrogen atoms are omitted for clarity.
proton. In 2, CalkyneH…N contacts occurs, while in 5e7 the alkyne
proton interacts with a
alkyne group, in 6e7 an adjacent aryl ring.
p
system. In 5, this
p
system is an adjacent
stacking in-
p
…p
teractions of the aryl units are only observed in the heterocyclic
derivatives 2 and 7.
distances are 3.92 and 3.91 Å. Both molecules form CeH …
p
contacts of 2.91 and 3.00 Å between the other pyridine unit and the
aromatic bonded hydrogen atoms to form molecular zigzag chains
along the a-axis to complete the molecular packing.
The comparison of the crystal packing of 2 with the corre-
sponding compounds known in literature (5e7), shows a signifi-
cant difference in the interaction of the OH group. While in 2 the
OH group contacts in a typical OeH/N interaction to the pyridine
Compound 3 was found to crystallise as colourless needles in
the triclinic space group P1 with one molecule in the asymmetric
part of the unit cell. The dihedral angle for the two pyridine rings is
73.3ꢁ, the pitch angles are 64.9 and 86.3ꢁ, respectively, and there-
fore similar to the conformation of dipyridyl alcohol 2. Again, the
molecules of 3 show conformational chirality in the solid state due
to the anti orientation of the heteroaromatic units. Due to the
inversion centre between adjacent molecules, the crystal is achiral.
The OH group and one of the pyridine nitrogens form an intra-
molecular OeH/N hydrogen bond [d(O/N) ¼ 2.5833(12) Å]
(Fig. 6), which is a typical feature for this family of compounds
nitrogen atom, in 5e7, the OH group interacts in OeH…
p contacts
with an aryl moiety presenting the system. However, in all cases,
p
the OH group is not engaged in OeH/O contacts. An additional
difference between 2 and 5e7, is the interaction of the alkyne

F. Katzsch et al. / Journal of Molecular Structure 1193 (2019) 215e222
219
Fig. 4. a) Molecular structure of 2 at 50% probability level. The following intramolecular OeH/N interactions (H/N distance) are shown: OH…Npyridin (a ¼ 2.70 Å), OH…Npyridin
(b ¼ 2.71 Å), b) Least-square overlays of the independent molecules of 2 with inversion and an r.m.s. deviation of 0.0103 Å for an overlay of the following atoms: O1, C11eC13. All
hydrogen atoms are omitted for clarity.
Fig. 6. Molecular structure of 3 at 50% probability level. The intramolecular OeH/N
interaction is shown as broken line (H/N distance, OH … Npyridin ¼ 2.58 Å).
interactions form an intermolecular strand connecting adjacent
OeH/N dimers.
The comparison of 3 with the methyl 8 [23,24] and ethyl 9 [25]
substituted derivatives shows significant differences of the inter-
molecular interactions. While the methyl derivative 8 forms a
tetramer via OeH/O interactions, the crystal packing of the ethyl
substituted compound is dominated by CeH…p interactions.
Fig. 5. Intermolecular interaction in the packing of 2. Representation of the H bonding
motif descriptor R22ð10Þ and the zigzag chain. The following C/OeH/N interactions
(H/O/N distance) are shown: OH … Npyridin (c ¼ 2.20 Å), OH … Npyridin (d ¼ 2.26 Å),
C
alkyneH … Npyridin (e ¼ 2.36 Å), CalkyneH … Npyridin (f ¼ 2.34 Å).
4. Conclusions
The first synthesis and molecular structure of 9-(pyrid-2-yl)
indolizine-1-one (1) have been described. The asymmetric unit
containing both enantiomers as the racemate was used for crys-
tallization. The molecular conformation of the pyridyl indolizinone
scaffold in 1 is similar to the respective chlorophenyl derivative (4).
Furthermore, the synthesis and X-ray structures of two alky-
lated dipyridyl methanols (2 and 3), which have been recovered in
connection with the synthesis of 1 are reported. Both prochiral
alcohols show conformational chirality in the solid state. Compared
to the other 1,1-(hetero)aryl methanol compounds, title com-
pounds 2 and 3 have lower Caryl-Cbridge-Caryl angles (except for 8),
lower dihedral angles and higher pitch angles. This may be
[34,35].
Adjacent molecules of 3 occur as dimers connected by inter-
molecular OeH/N [d(O/N) ¼ 3.1280(12) Å] and CeH/O contacts
[d(C/O) ¼ 3.1257(13) Å]. Furthermore, CeH/O interactions
[d(C/O) ¼ 3.3413(13) Å] form molecular chains along the crystal-
lographic a-axis and, therefore, connect adjacent dimers. Within
the strands, cyclic motifs of hydrogen bonds can be described by the
graph set descriptors R42ð10Þ and R22ð10Þ (Fig. 7) with the latter also
found in some of the related dipyridyl alcohols [34].
With the smallest distance of 4.6 Å, stacking interactions of the
pyridyl moieties are not observed. In contrast, two CeH…
p

220
F. Katzsch et al. / Journal of Molecular Structure 1193 (2019) 215e222
Table 1
Crystal data and selected details of the data collection and refinement calculations of compounds 1e3.
1
2
3
empirical formula
formula weight
crystal system
space group
C13H10N2O
210.23
Orthorhombic
Pna21
C13H10N2O
210.23
monoclinic
P21/c
C15H18N2O
242.31
triclinic
P1
a/Å
b/Å
c/Å
27.1509(14)
6.5076(3)
11.7866(6)
90
90
90
7.7965(4)
22.2818(9)
11.8063(5)
90
90.244(2)
90
8.0672(2)
9.1089(3)
9.6553(3)
76.809(1)
74.010(1)
85.657(1)
663.99(3)
2
ꢁ
ꢁ
a
/
b
/
ꢁ
g
/
V/Å3
2082.54(18)
8
2050.97(16)
8
Z
Data collection
T/K
100(2)
0.087
100(2)
0.089
100(2)
0.077
m
/mm-1
)
No. of collected reflections
No. of unique reflections
Rint
16508
4082
0.0407
16676
3979
0.0431
12978
2457
0.0265
data/restraints/parameters
R1 values (I > 2s(I))
4082/1/289
0.0548
0.1288
0.0665
0.1375
1.058
0.457 and ꢀ0.223
3979/0/298
0.0377
0.0915
0.0485
0.0990
1.014
0.208 and ꢀ0.213
2457/0/165
0.0336
0.0809
0.0377
0.0845
1.034
0.239 and ꢀ0.190
wR(F2) values (I > 2
R1 values (all data)
s
(I))
wR(F2) values (all data)
Goodness of fit on F2
Largest diff. peak and hole/eÅ-3
Table 2
Selected distances and angles of hydrogen bond type interactions.
Atoms
symmetry
distances/Å
angle/ꢁ
contact/figure
D$$$A
H$$$A
D-H$$$A
1
C8A-H8A$$$O1A
C9A-H9A$$$O1B
C10A-H10A$$$N1A
C11A-H11A$$$O1A
C12A-H12A$$$O1B
C10BeH10B/N1B
C11BeH11B/O1B
C12BeH12B/O1A
1-x,-y,-1/2 þ z
½þx, ½-y, z
3.606(6)
3.521(5)
3.299(5)
3.323(4)
3.398(5)
3.248(5)
3.278(4)
3.381(4)
3.604(4)
2.67
2.61
2.51
2.39
2.45
2.45
2.34
2.44
2.98
166.6
160.6
140.7
169.0
175.5
141.4
171.2
170.3
125
x, 1 þ y, z
a/Fig. 2
b/Fig. 2
c/Fig. 2
d/Fig. 2
e/Fig. 2
f/Fig. 2
x, 1 þ y, z
1/2-x, 1/2 þ y, 1/2 þ z
x, 1 þ y, z
x, 1 þ y, z
1/2-x, 1/2 þ y, ꢀ1/2 þ z
-x, 1-y, ꢀ1/2 þ z
C7A-H7A$$$p
(Cg2)a
2
O1A-H1A$$$N1A
O1BeH1B/N1B
O1A-H1A$$$N1B
O1BeH1B/N1A
C5A-H5A$$$O1B
C5BeH5B/O1A
C13A-H13A$$$N2B
C13BeH13B/N2A
C4A-H4A$$$Cg3
C4BeH4B$$$Cg1
3
x, y, z
x, y, z
1-x, 1-y, 1-z
1-x, 1-y, 1-z
1-x, 1-y, 1-z
1-x, 1-y, 1-z
-x, 1/2 þ y, 3/2-z
1-x, ꢀ1/2 þ y, 3/2-z
x, 1/2-y, ꢀ1/2 þ z
ꢀ1þx, 1/2-y, 1/2 þ z
2.698(2)
2.714(2)
2.8973(18)
2.8985(19)
3.094(2)
3.022(2)
3.302(3)
3.292(2)
3.729(2)
3.848(2)
2.19(2)
2.24(2)
2.20(2)
2.26(2)
2.60
2.46
2.36
2.34
2.91
115.1(18)
117.1(18)
134(2)
135(2)
112.9
117.5
172.1
175.2
144
a/Fig. 3
b/Fig. 3
c/Fig. 4
d/Fig. 4
e/Fig. 4
f/Fig. 4
3.00
150
O1eH1A$$$N1
O1eH1A$$$N1
C4eH4/O1
C5eH5/O1
C8eH8$$$Cg4
C14eH14B$$$Cg4
x, y, z
2.5833(12)
3.1280(12)
3.3413(13)
3.1257(13)
1.986(16)
2.579(16)
2.45
125.5(14)
126.6
156.0
1-x, -y, 1-z
ꢀ1þx, y, z
1-x, -y, 1-z
1-x, 1-y, 1-z
1-x, -y, -z
a/Fig. 6
b/Fig. 6
c/Fig. 6
2.48
125.0
3.8979(14)
3.00
152
a
Cg is defined as the centre of gravity; 1: Cg2: N1A, C1A-C5A; 2: Cg1/3: N1A/B, C1A/BeC5A/B. Cg4 N1, C1eC5.
connected with an intramolecular OeH … Npyridine hydrogen bond
stabilizing their molecular conformation. As a common packing
motif for 2 and 3, we found a OeH/N bonding system featuring the
graph set descriptor R22ð10Þ.
Surprisingly, the crystal packing of 2 is significantly different
compared with other 1,1-(hetero)arylalkynols (5e7). While in 2, the
OH group interacts in a typical OeH/N interaction with the pyri-
dine nitrogen atom, in 5e7, the OH group interacts in OeH…
p

F. Katzsch et al. / Journal of Molecular Structure 1193 (2019) 215e222
221
Table 3
Selected conformational parameters for the molecular structures of 2, 3 and 5e9.
a
b
ꢁ
ꢁ
compound
C
aryl-Cbridge-Caryl angle/ꢁ
Dihedral angle
f/
Pitch angle j/
2-A
2-B
3
5 [20]
6 [22]
7 [21]
8 [24]
9 [25]
108.49(14)
108.46(14)
108.11(8)
110.3
110.4
114.1
75.10(6)
75.38(6)
73.339(39)
85.8
84.9
89.9
68.71(12)/84.92(9)
65.12(12)/86.99(1)
64.886(61)/86.308(60)
54.4/70.3
35.4/79.5
54.9/54.8
107.8
111.0
86.4
85.1
64.5/73.9
59.0/66.7
a
Dihedral angle between the planes of the aromatic units.
Angle between the plane of each aromatic unit and the plane defined by Caryl-Cbridge-Caryl
b
.
HO
N
O
5
N
Fig. 7. Packing arrangement of 3 formed by R22ð10Þ (OeH/N hydrogen bonding) and
R42ð10Þ (inversely bifurcate H bridge involving O1, H4 and H5) motifs along the crys-
tallographic a-axis. Cyclic H bonding motifs are highlighted. Non-relevant H atoms are
omitted for clarity. The following O/CeH/O/N interactions (H/O/N distance) are
shown: OH … Npyridin (a ¼ 2.58 Å), CarylH … O (b ¼ 2.45 Å), CarylH … O (c ¼ 2.48 Å).
HO
Cl
Acknowledgment
4
We acknowledge the financial support by the 0Deutsche For-
schungsgemeinschaft (DFG Priority Program 1362 Porous Metal-
Organic Frameworks').
6
8
HO
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