Structural Characterization of Two Polymorphs of 1-(4-Methylpyridin-2-yl)thiourea and Two Derived 2-Aminothiazoles

Article abstract of DOI:10.1007/s10870-020-00863-0

Abstract: Two polymorphic forms of 1-(4-methylpyridin-2-yl)thiourea (1) and the crystal and molecular structures of the 2-aminothiazoles N-(4-methylpyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (2) and N-(4-methylpyridin-2-yl)-4-(pyrazin-2-yl)thiazol-2-amine (3), derived from 1 and the respective α-bromoketone via the Hantzsch reaction, are described. Both polymorphic forms 1α (space group P2₁/c, Z = 4) and 1β (space group P2₁/n, Z = 8) crystallize in the monoclinic system but exhibit distinctly different intermolecular hydrogen bonding patterns. Compound 2 (orthorhombic, space group Pca2₁, Z = 8) forms polymeric N–H?N hydrogen-bonded zigzag tapes in the polar crystal structure, with a significant twisting between the thiazole and pyridine rings. In contrast, the crystal structure of 3 (monoclinic, space group P2₁/c, Z = 4) features nearly planar centrosymmetric N–H?N hydrogen-bonded dimers, which are laterally joined through long C–H?N contacts, affording a π?π stacked layered structure. Graphic Abstract: Two polymorphs of 1-(4-methylpyridin-2-yl)thiourea and the crystal and molecular structures of two 2-aminothiazoles, derived from 1-(4-methylpyridin-2-yl)thiourea and α-bromoketones via Hantzsch reaction, are reported.[Figure not available: see fulltext.]

Full text of DOI:10.1007/s10870-020-00863-0

Journal of Chemical Crystallography
https://doi.org/10.1007/s10870-020-00863-0
ORIGINAL PAPER
Structural Characterization of Two Polymorphs
of 1‑(4‑Methylpyridin‑2‑yl)thiourea and Two Derived 2‑Aminothiazoles
Denise Böck1 · Andreas Beuchel · Richard Goddard · Peter Imming1 · Rüdiger W. Seidel1
1
2
Received: 11 June 2020 / Accepted: 12 September 2020
©
The Author(s) 2020
Abstract
Two polymorphic forms of 1-(4-methylpyridin-2-yl)thiourea (1) and the crystal and molecular structures of the 2-ami-
nothiazoles N-(4-methylpyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (2) and N-(4-methylpyridin-2-yl)-4-(pyrazin-2-yl)
thiazol-2-amine (3), derived from 1 and the respective α-bromoketone via the Hantzsch reaction, are described. Both poly-
morphic forms 1α (space group P2 /c, Z=4) and 1β (space group P2 /n, Z=8) crystallize in the monoclinic system but
1
1
exhibit distinctly diꢀerent intermolecular hydrogen bonding patterns. Compound 2 (orthorhombic, space group Pca2 , Z=8)
1
forms polymeric N–H⋯N hydrogen-bonded zigzag tapes in the polar crystal structure, with a signiꢁcant twisting between
the thiazole and pyridine rings. In contrast, the crystal structure of 3 (monoclinic, space group P2 /c, Z=4) features nearly
1
planar centrosymmetric N–H⋯N hydrogen-bonded dimers, which are laterally joined through long C–H⋯N contacts, aꢀord-
ing a π⋯π stacked layered structure.
Graphic Abstract
Two polymorphs of 1-(4-methylpyridin-2-yl)thiourea and the crystal and molecular structures of two 2-aminothiazoles,
derived from 1-(4-methylpyridin-2-yl)thiourea and α-bromoketones via Hantzsch reaction, are reported.
Keywords 1-(4-Methylpyridin-2-yl)thiourea · 2-Aminothiazoles · Hantzsch reaction · Hydrogen bonding · Polymorphism ·
Crystal structure
*
Rüdiger W. Seidel
ruediger.seidel@pharmazie.uni-halle.de
Extended author information available on the last page of the article
Vol.:(0
1
123456789)
3

Journal of Chemical Crystallography
Introduction
conformational preferences in the solid-state. The extent of
the conjugated system and the steric accessibility of the sul-
fur atom and 5-position is expected to have an inꢂuence on
the stability, particularly with regard to oxidation.
The 2-aminothiazole moiety is a synthetically ꢂexible and
pharmacologically promising scaꢀold in medicinal chem-
istry, and a number of drugs containing a 2-aminothiazole-
Synthesis of 2-amino-4-substituted thiazoles can be
accomplished via diꢀerent routes [8]. Hantzsch synthesis
from α-haloketones and thiourea derivatives in polar sol-
vents is a general method [9, 10]. From 1-(4-methylpyri-
din-2-yl)thiourea (1) and the respective α-bromoketone, we
synthesized the two 2-aminothiazoles N-(4-methylpyridin-
2-yl)-4-(pyridin-2-yl)thiazol-2-amine (2) and N-(4-methyl-
pyridin-2-yl)-4-(pyrazin-2-yl)thiazol-2-amine (3) through
Hantzsch synthesis (Scheme 1). Compound 2 is contained
in the Stasis Box (Medicines for Malaria Venture, MMV,
Geneva, Switzerland) as MMV006357 and was identiꢁed
as an antimycobacterial [4, 11] agent and potential drug
candidate for eumycetoma [12]. Although coordination
compounds bearing 2 as ligand were reported more than
40 years ago [13], to the best of our knowledge and based on
a WebCSD search in June 2020 [14], small molecule crystal
structures of 2, its pyrazine derivative 3 and the starting thio-
urea derivative 1 have not been reported so far. Likewise, a
search of the Protein Data Bank [15] yielded no structures
containing 2 or 3 as ligands. Herein, we describe the struc-
tures of two polymorphs of 1, henceforth named 1α and 1β,
and the crystal and molecular structures of 2-aminothiazoles
4
-subsituted moiety, e.g. cefdinir (antibiotic), mirabegron (β
3
adrenergic agonist) or the tyrosine kinase inhibitor dasatinib,
are on the market. In recent years, anticancer, antiepileptic,
neuroprotective, antidiabetic, antihypertensive, anti-inꢂam-
mamory, antiviral, antibiotic and antileishmanial properties
of 2-aminothiazoles were investigated [1].
N,4-Diaryl substituted 2-aminothiazoles were prepared
based on one of the ten scaꢀolds with antileishmanial prop-
erties from a screening of 200,000 compounds [2]. Other
microorganisms that are inhibited by this class of com-
pounds include plasmodia [3] and mycobacteria [4]. For
mycobacteria, the Tuberculosis Antimicrobial Acquisition
and Coordinating Facility discovered an aminothiazole
cluster of active compounds that formed the basis of an
extensive structure–activity relationship (SAR) study [5].
Makam and Kannan showed that several substituted 2-ami-
nothiazole derivatives exhibited antimycobacterial activity
against Mycobacterium tuberculosis, H Rv, with minimum
3
7
inhibitory concentration (MIC) values of 6.25–12.50 μM
and proposed that these may be targeting the KasA protein
in turn disturbing the cell wall biosynthesis by obstructing
mycolic acid synthesis [6]. Another study explored struc-
ture–activity relationships for 2-aminothiazoles as potassium
channel blockers [7], an undesirable pharmacological eꢀect
in most cases, which needs to be prevented by modiꢁcation
of the substitution pattern on the 2-aminothiazole moiety.
While N-alkyl and N-aryl 2-aminothiazoles are distinguished
by therapeutically very desirable acitivities, they are also
known to be cytotoxic [5]. This is most likely due to the
unsubstituted 5-position, which unspeciꢁcally engages in
redox reactions in biochemical pathways. In the course of
our ongoing investigations towards reduced toxicity of this
compound class, we structurally characterized 2-aminothia-
zoles by X-ray crystallography to gain information on the
2
and 3, as determined by X-ray crystallography.
Experimental Section
General
Starting materials were purchased and used as received.
Solvents were of analytical grade. The syntheses of 1-ben-
zoyl-3-(4-methylpyridin-2-yl)thiourea [16] and 2-bromo-1-
(pyridin-2-yl)ethanone hydrobromide [17] can be found in
the literature.
Scheme 1 Synthesis of aminothiazoles 2 and 3 from 1 and the respective α-bromoketone
1
3

Journal of Chemical Crystallography
Physical Methods
(2.18 g, 4.4 mol) as reagent and used in situ without puri-
1
ꢁ
cation. Yield (based on 1): 75 mg (0.28 mmol, 7%). H
1
13
H and C NMR spectra were recorded at room temper-
NMR (500 MHz, DMSO-d6): δ = 11.46 (s, 1H), 9.14 (d,
J = 1.5 Hz, 1H), 8.64 (dd, J = 2.5, 1,5 Hz, 1H), 8.55 (d,
J=2.5 Hz, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.75 (s, 1H), 6.89
ature on a Varian INOVA 500 NMR spectrometer. The
residual solvent signals of DMSO-d6 (δ = 2.50 ppm,
1
H
1
3
δ
=39.51 ppm) were used to reference the spectra (s=sin-
(bs, 1H), 6.79 (dd, J=5.2 Hz, 1H), 2.28 (s, 3H) ppm;
C
13C
glet, bs = broad singlet, d=doublet, dd=double doublet).
The high-resolution mass spectrum was measured on a
Bruker Daltonics Apex III FT-ICR mass spectrometer.
NMR (126 MHz, DMSO-d6): δ=160.5, 151.8, 148.7, 147.7,
146.2, 146.0, 144.4, 143.3, 141.4, 117.7, 111.7, 110.7,
+
20.7 ppm. HRMS(ESI): calcd. for C H N S [M + H]
1
3
11
5
2
70.0813, found 270.0806. Crystals for X-ray diꢀraction
Synthesis and Crystallization
were taken from the mother liquor.
1‑(4‑Methylpyridin‑2‑yl)thiourea (1)
Crystal Structure Determination
Compound 1 was synthesized by adapting a literature pro-
tocol [18]. 7.4 mL of 1 N aqueous NaOH were added to a
stirred suspension of 1-benzoyl-3-(4-methylpyridin-2-yl)thi-
ourea (2.00 g, 7.37 mmol) in 15 mL of methanol. The mix-
ture was then heated to reꢂux for 1 h. After cooling to room
temperature, a white solid formed, which was separated by
The X-ray intensity data for 1α and 3 were measured on a
Bruker AXS Apex II diꢀractometer, equipped respectively
with an Incoatec IµS microfocus X-ray source and a FR591
rotating anode radiation source. The diꢀraction data for 2
were collected on an Enraf–Nonius KappaCCD diꢀrac-
tometer with a FR591 rotating anode. The SAINT software
was used to perform data reductions [22]. The intensity
measurements for 1β were carried out on the P11 beam-
line at the PETRA III light source (DESY, Hamburg) at an
X-ray energy of 22.0 keV. The primary beam intensity was
monitored continuously and stored during the experiment.
The P11 X-ray optics consisted of a liquid nitrogen-cooled
Si(111) and Si(113) double-crystal monochromator and one
vertical and two horizontal deꢂecting X-ray mirrors. The
ꢁ
ltration, washed with deionized water and dried over P O
2 5
in a vacuum desiccator to yield 1.00 g of 1 (5.98 mmol,
8
1%). Physical properties were in agreement with those
reported in the literature [19]. Crystals of 1α suitable for
X-ray diꢀraction were obtained by recrystallization from
methanol, and those of 1β were grown from a solution in
CDCl by slow evaporation of the solvent.
3
1
2
N‑(4‑Methylpyridin‑2‑yl)‑4‑(pyridin‑2‑yl)thiazol‑2‑amine (2)
source brilliance at the crystal was 1.7 × 10 photons per
second. The data were collected using a 200 μm beam on
a PILATUS 6 M-0109 detector (Dectris Ltd, Baden, Swit-
zerland) [23] at a distance of 163.4 mm from the crystal.
The 20-bit dynamic range of the PILATUS 6 M detector
allowed for collection of weak high-order and stronger low-
order reꢂections at the same time in one run. The crystal
was rotated by 360° in steps of 0.5° with an exposure of
0.250 s per frame with a ꢁlter transmission of 0.1 using the
P11 Crystallography Control graphical user interface at the
P11 beamline [24]. The data were processed with the XDS
program package [25]. Absorption corrections were carried
out with SADABS [26].
Compound 2 was synthesized following a modiꢁed litera-
ture procedure [20]. Compound 1 (83 mg, 0.50 mmol) and
2
0
-bromo-1-(pyridin-2-yl)ethanone hydrobromide (140 mg,
.50 mmol) were dissolved in 5 mL of ethanol and trieth-
ylamine (0.1 mL) was added. The reaction mixture was
reꢂuxed for 2 h. Subsequently, the solvent was removed
using a rotary evaporator. The residue was taken up in 10 mL
of a saturated K CO solution and extracted three times with
2
3
ethyl acetate. The combined organic layers were washed
with brine and dried over MgSO . The solvent was removed
4
under reduced pressure and the crude product recrystallized
from methanol. Yield: 54 mg (0.20 mmol, 40%). Spectro-
scopic properties were in agreement with those reported
in the literature [2, 20]. Crystals for X-ray diꢀraction were
taken from the mother liquor.
The crystal structures were solved with SHELXT-2018/1
[27] and reꢁned with SHELXL-2018/3 [28]. The structure
of 1β was reꢁned using aspherical atomic scattering factors
[29] and corrected for dispersion according to Kissel and
Pratt [30]. Asphericity parameters were generated by the
APEX3 software (IDEAL) [31]. Anisotropic displacement
parameters were introduced for all non-hydrogen atoms. For
1α, 2 and 3, carbon-bound hydrogen atoms were placed at
N‑(4‑Methylpyridin‑2‑yl)‑4‑(pyrazin‑2‑yl)thiazol‑2‑amine (3)
Compound 3 was prepared in analogy to 2 from 1 and
2
-bromo-1-(pyrazin-2-yl) ethanone hydrobromide [21]
geometrically calculated positions with C
–H=0.95 Å
aromatic
(
note that the compound was not named hydrobromide by
these authors), which was synthesized from acetylpyrazine
0.50 g, 4.00 mmol) using 2-pyrrolidinone hydrotribromide
and C
–H=0.98 Å and reꢁned with the appropriate rid-
methyl
ing model. Methyl groups were allowed to rotate to match
the underlying electron density maxima. Hydrogen atoms
(
1
3

Journal of Chemical Crystallography
attached to nitrogen were localized in diꢀerence electron
density maps and, for 1α, 2 and 3, reꢁned with the N–H
bond lengths restrained to a target value of 0.88(2) Å.
U (H)=1.2 U (C, N) (1.5 for methyl groups) was applied
parent 1-(pyridine-2-yl)thiourea (CSD refcode: HIRPAA)
[35]. Both 1α and 1β have in common a six-membered
ring intramolecular N–H⋯N hydrogen bond between the
primary amino group on the thiourea moiety and the pyri-
dine nitrogen atom, which is in accord with Etter’s second
hydrogen bond rule for organic compounds, namely that six-
membered ring intramolecular hydrogen bonds form in pref-
erence to intermolecular hydrogen bonds [36]. The graph-
set assignment for this hydrogen bond motif is S(6). This
requires a synperiplanar conformation between the pyridine
nitrogen atom and the thiocarbonyl carbon atom C1, and
likewise between the pivot carbon atom C2 of the pyridine
ring and the primary amino group. The same intramolecular
hydrogen bond and molecular conformation was found in
HIRPAA. Like in HIRPAA, the molecule is virtually pla-
nar in 1α (r.m.s. deviation 0.0234 Å for the non-hydrogen
atoms). In contrast, the two unique molecules in 1β deviate
markedly from planarity by a tilt of the thiourea group from
the plane of the pyridine ring, as revealed by the respective
angles between the mean planes of the two groups [molecule
1: 14.16(5)°; molecule 2: 18.08(5)°] and the torsion angles
listed in Table 2.
iso
eq
for all hydrogen atoms. Packing indices were calculated with
PLATON [32]. Structure pictures were generated with Dia-
mond [33] and Mercury [34]. Crystal data and reꢁnement
details for 1α, 1β, 2 and 3 are listed in Table 1.
Results and Discussion
Polymorphic Forms of 1
Two monoclinic crystal forms of 1 were encountered. 1α
with one molecule in the asymmetric unit (Z′ = 1) formed
upon recrystallization from methanol, and 1β with two
crystallographically unique molecules (Z′ = 2) crystal-
lized from a solution of the compound in CDCl . Figure 1
3
shows displacement ellipsoid plots of both structures,
and Table 2 compares selected bond lengths and torsion
angles. The bond lengths are comparable with those in the
Table 1 Crystal data and reꢁnement details for 1α, 1β, 2 and 3
1
α
1β
2
3
Empirical formula
Mr
T (K)
C H N S
167.23
100(2)
C H N S
C H N S
268.34
100(2)
0.71073
C H N S
269.33
100(2)
1.54178
7
9
3
7
9
3
14 12
4
13 11
5
167.23
100(2)
0.6199
λ (Å)
0.71073
Crystal system
Space group
a (Å)
b (Å)
c (Å)
Monoclinic
Monoclinic
Orthorhombic
Monoclinic
P2 /c (No. 14)
P2 /n (No. 14)
Pca2 (No. 29)
P2 /c (No. 14)
1
1
1
1
6.9526(13)
14.473(3)
8.1672(15)
102.395(4)
802.7(3)
4, 1
200.7
1.384
0.337
352
8.2312(16)
16.095(3)
12.240(3)
97.10(3)
1609.2(6)
8, 2
201.2
1.381
0.230
704
7.3353(7)
26.7342(16)
13.1949(9)
90
2587.6(3)
8, 2
323.5
1.378
0.241
1120
7.3009(2)
15.5664(4)
10.8403(3)
96.320(1)
1224.50(6)
4, 1
306.1
1.461
2.290
560
β (°)
V (Å )
3
Z, Z′
V/molecule (Å )
ρcalc (g cm
μ (mm
F(000)
3
−
3
)
−
1
)
Crystal size (mm)
θ range (°)
Reꢂections collected / unique
Rint
0.168×0.106×0.021
2.815–30.982
20,352 / 2538
0.0642
0.156×0.103×0.091
1.832–26.193
30,415 / 4753
0.0226
0.170×0.120×0.110
2.880–33.098
59,604 / 9807
0.0542
0.223×0.196×0.120
4.992–73.002
42,832 / 2360
0.0427
Observed reꢂections [I>2σ(I)]
Goodness-of-ꢁt on F2
Parameters/restraints
R1 [I>2σ(I)]
2109
1.195
110/3
0.0420
0.1078
0.601, − 0.480
4542
1.060
256/0
0.0248
0.0702
0.583, − 0.316
8482
1.081
359/3
0.0425
0.1014
0.367, − 0.293
2122
1.215
176/1
0.0410
0.1129
0.278, − 0.405
wR (all data)
2
Δρmax, Δρmin (eÅ−3
)
1
3

Journal of Chemical Crystallography
Fig. 1 a Hydrogen-bonded
association of two symmetry-
related molecules in 1α and
b of the two crystallographi-
cally distinct molecules in 1β.
Symmetry code: (a) x, 0.5 − y,
0
.5+z. Displacement ellipsoids
are drawn at the 50% prob-
ability level. Hydrogen atoms
are shown as small spheres of
arbitrary radii. Dashed lines
represent hydrogen bonds
Table 2 Selected bond lengths (Å) and torsion angles (°) for 1α and
shows the symmetric combination formed solely by the
primary amino groups (type II). Type I is also observed
for the structure of HIRPAA. Table 3 lists geometric
parameters of the hydrogen bonds in 1α and 1β, which
are as expected [35]. In 1α, this hydrogen bond arrange-
ment results in polymeric tapes extending through glide
symmetry in the [001] direction (Fig. 2). In contrast, the
secondary amino groups in 1β are directed towards sulfur
atoms of adjacent hydrogen-bonded dimers in the crystal
structure with N⋯S distances of ca. 3.4 Å and signiꢁ-
cantly smaller H⋯S–C angles than in 1α. The symmet-
ric dimer in 1β exhibits local inversion symmetry in the
crystal structure. Frustration between competing intermo-
lecular interactions, such as hydrogen bonds, and close
packing has been put forward as a possible explanation
for the Z’ > 1 phenomenon [38]. The crystal structures of
both 1α and 1β belong to the same space group type (No.
14), which is available for densest packing of molecules
of arbitrary shape. The packing index is 69.6% for 1α and
70.4% for 1β, revealing a dense crystal packing in both
forms [39]. It is worth noting that in spite of the diꢀerent
hydrogen bonding patterns, the calculated crystallographic
density is almost the same for 1α and 1β (Table 1).
1
β
1α
1β
Molecule 1
Molecule 2
C1–S1
C1–N2
C1–N3
C2–N2
N1–C2–N2–C1
N3–C1–N2–C2
1.7011(17)
1.355(2)
1.322(2)
1.403(2)
2.5(3)
1.7038(7)
1.3634(9)
1.3206(9)
1.4045(8)
17.0(1)
1.7047(7)
1.3644(8)
1.3228(9)
1.4069(8)
− 19.48(10)
15.49(10)
− 2.8(3)
− 9.36(11)
1
α and 1β exhibit distinctly diꢀerent intermolecular
hydrogen bonding patterns. Two self-complementary
N–H⋯S hydrogen bonding sites on each molecule, pro-
vided by the sulfur atom as hydrogen bond acceptor and
each of the primary and secondary amino groups as hydro-
gen bond donor sites, can lead to three possible combi-
2
nations with R (8) motifs (Scheme 2) [37]. As shown in
2
Fig. 1, 1α exhibits the asymmetric combination involving
primary and secondary amino groups (type I), whereas 1β
1
3

Journal of Chemical Crystallography
2
Scheme 2 Possible N–H⋯S hydrogen bond associations of 1 (the black circle represents 4-methylpyridin-2-yl) with R (8) motifs. 1α exhibits
2
type I and 1β shows type II. Type III is not seen here
Table 3 Hydrogen bond parameters (Å, °) for 1α and 1β
d(D–H) d(H⋯A) d(D⋯A)
lengths, bond angles and torsion angles are given in Table 4.
In both molecules the thiazole sulfur atom S1 and the pivot
carbon atom C10 of the pyridine ring as well as the pivot
carbon atom of the thiazole ring C2 and the picoline nitrogen
atom N1 are in a synperiplanar arrangement. The intramo-
lecular N1⋯S1 distance is ca. 2.8 Å in both molecules and
the C5–S1⋯N1 angles are 161.5 and 160.1° in molecule 1
and 2, respectively. From the structural point of view, this
can be interpreted as chalcogen bonds between the pico-
line nitrogen lone pairs and the σ hole at the sulfur atoms
opposite to the C5–S1 σ bonds [40, 41]. Interestingly, all
<(DHA)
1
αa
N2–H2⋯S1a
N3–H3A⋯N1
N3–H3B⋯S1b
0.880(15) 2.462(16) 3.3324(15) 170(2)
0.873(16) 1.961(19) 2.670(2) 137(2)
0.872(15) 2.485(16) 3.3553(16) 175(2)
b
1
β
N31–H31A⋯N11 0.889(12) 1.990(11) 2.6844(10) 134.0(10)
N31–H31B⋯S12 0.922(12) 2.443(12) 3.3425(10) 165.1(10)
N32–H32A⋯N12 0.897(12) 1.994(11) 2.6970(9) 134.2(10)
N32–H32B⋯S11 0.913(11) 2.507(11) 3.3977(9) 165.0(9)
1
5 crystal structures of 2-aminothiazoles with N-bonded
a
heteroaromatic substituents containing a nitrogen atom in
the 2-position in the Cambridge Structural Database (June
Symmetry codes: (a) x, − y+1/2, z − 1/2; (b) x, − y+1/2, z+1/2
The second integer indicates unique molecule 1 or 2 (cf. Fig. 1)
b
2
020) [42] exhibit planar conformations with intramolecu-
lar N⋯S distances of 2.70(4) Å (mean) in spite of diꢀerent
crystal environments, including structures of dasatinib and
nine of its solvates [43, 44], as well as thiazovivin, a small
molecule tool for stem cell research [45]. In contrast, 41
crystal structures of 2-aminothiazoles with variously sub-
stituted N-phenyl groups contain molecules in which the
two moieties are randomly orientated to one another. The
absence of any classical or weak hydrogen bonds towards
the picoline nitrogen N1 corroborates this view. The dihe-
dral angles between the mean planes through the thiazole
rings and those through the pyridine rings attached to C4 is
2
2.96(8)° for molecule 1 and 37.53(6)° for molecule 2. Both
molecules are thus signiꢁcantly non-planar in this region.
Clearly, the tilt between the pyridine ring and the thiazole
ring should be disadvantageous for π electron delocalisation,
but appears to be outweighed by the formation of strong
intermolecular N–H⋯N hydrogen bonds between the amino
group and the pyridine nitrogen atom N4 in the solid-state
Fig. 2 Part of the crystal structure of 1α, showing hydrogen-bonded
tapes of the molecules extending parallel to the crystallographic c
axis
(
Table 5). Molecule 1 and molecule 2 each form distinct
hydrogen-bonded zigzag tapes extending in the [001] direc-
tion through glide symmetry (Fig. 4), resulting in a polar c
axis. The packing index is 69.0%.
Crystal and Molecular Structures of 2 and 3
Compound 2 crystallizes with two molecules in the asym-
metric unit (Z′ = 2), as shown in Fig. 3. Selected bond
Figure 5 shows the molecular structure of 3, bearing
a pyrazinyl group at C4 of the thiazole ring instead of a
1
3

Journal of Chemical Crystallography
Fig. 3 Asymmetric unit of
2
. Displacement ellipsoids
are drawn at the 50% prob-
ability level. Hydrogen atoms
are shown as small spheres of
arbitrary radii
Table 4 Selected bond lengths, bond angles and torsion angles (Å, °)
for 2 and 3
Table 5 Hydrogen bond parameters (Å, °) for 2 and 3
d(D–H)
d(H⋯A)
d(D⋯A) < (DHA)
2
3
2a
Molecule 1
Molecule 2
N21–H2_1…N41a 0.88(2)
N22–H2_2…N42b 0.88(2)
2.01(2)
2.10(2)
2.893(3) 177(3)
2.979(3) 177(3)
C2–N3
C2–N2
C2–S1
C4–C5
C4–N3
C4–C11
C5–S1
N3–C2–S1
C5–C4–N3
C4–C5–S1
C5–S1–C2
C2–N3–C4
S1–C2–N2–C10
N1–C10–N2–C2
C5–C4–C11–N4
N3–C4–C11–C12
1.312(3)
1.363(3)
1.748(2)
1.362(3)
1.379(3)
1.473(3)
1.732(2)
114.94(17)
115.9(2)
110.21(17)
88.6(1)
110.4(2)
– 4.2(4)
– 1.6(4)
– 22.4(3)
– 23.3(3)
1.312(3)
1.370(3)
1.744(2)
1.363(3)
1.379(3)
1.478(3)
1.724(2)
115.00(17)
115.7(2)
110.39(18)
88.67(11)
110.25(19)
14.8(3)
1.309(2)
1.367(2)
1.7480(17)
1.355(2)
1.389(2)
1.469(2)
1.7212(17)
115.31(13)
115.85(15)
110.68(13)
88.48(8)
109.67(14)
7.2(2)
3b
N2–H2…N5a
C6–H6…N4b
0.878(15) 2.053(15) 2.928(2) 174.2(19)
0.95 2.98 3.906(2) 165
a
The second integer indicates unique molecule 1 or 2 (cf. Fig. 3).
Symmetry codes: (a) – x+1/2, y, z+1/2; (b) − x+3/2, y, z+1/2
b
Symmetry codes: (a) − x+1, − y, − z; (b) − x+2, − y, − z+1
the pyridine ring as well as the pivot carbon atom of the
thiazole ring C2 and the picoline nitrogen atom N1 in 3
are in a synperiplanar orientation with an intramolecular
S1⋯N1 distance of ca. 2.7 Å with a C5–S1⋯N1 angle
of 162.5°. Thus, the observed conformation appears to
be a characteristic trait of the N-(4-methylpyridin-2-yl)
thiazol-2-amine moiety and is possibly supported by an
intramolecular chalcogen bond (vide supra). In contrast
to 2, the dihedral angle between the mean plane through
the thiazole ring and that through the pyrazin ring attached
to C4 is only 7.25(6)°. The supramolecular structure of 3
in the crystal is distinctly diꢀerent from that in 2. Instead
– 4.3(3)
37.4(3)
36.7(3)
– 1.2(2)
– 5.6(3)
– 8.0(3)
2
-pyridinyl group as in 2. Selected bond lengths, bond
angles and torsion angles are listed in Table 4. Like 2, the
thiazole sulfur atom S1 and the pivot carbon atom C10 of
1
3

Journal of Chemical Crystallography
Fig. 4 Part of the crystal struc-
ture of 2, viewed approximately
along the a axis direction and
b along the c axis direction.
Hydrogen atoms have been
omitted for clarity. Dashed lines
represent hydrogen bonds. Red
and blue colour indicate distinct
hydrogen-bonded tapes result-
ing from unique molecules 1
and 2, respectively (cf. Fig. 3)
Fig. 5 Molecular structure of
3
in the crystal. Displacement
ellipsoids are drawn at the 50%
probability level. Hydrogen
atoms are represented by small
spheres of arbitrary radii
of the polymeric N–H⋯N hydrogen-bonded assemblies
observed in 2, the crystal structure of 3 is characterized
by centrosymmetric dimers (Fig. 6). The amino group
of each molecule forms a hydrogen bond to the pyrazine
nitrogen atom in meta position to the thiazole ring, aꢀord-
2
ing a R (16) motif. The dimers so formed are laterally
2
connected via C–H⋯N interactions involving the oppo-
site pyrazine nitrogen atom. Although the H⋯A distance
is longer than the sum of the van der Waals radii, the
<
(DHA) angle (Table 5) supports the presence of weak
cooperative C–H⋯N hydrogen bonds [46]. The N–H⋯N
hydrogen bonds and long C–H⋯N contacts generate layers
of molecules parallel to (10–1), which are π⋯π stacked
in the third dimension. The packing index for 3 of 71.4%
reveals a denser crystal packing than in 2. Since 2 and 3
diꢀer only by one heteroatom site, it is possible that the
weak cooperative C–H⋯N hydrogen bonds in 3 may have
a structure-directing inꢂuence.
Fig. 6 Part of the crystal structure of 3, viewed towards plane (10–1),
showing two adjacent N–H⋯N hydrogen-bonded dimers laterally
connected via long C–H⋯N contacts. Hydrogen bonds are shown by
dashed lines
1
3

Journal of Chemical Crystallography
Informed Consent All authors have seen the manuscript and agree to
Conclusions
its publication.
We synthesized two pharmacologically relevant N,4-diaryl
substituted 2-aminothiazoles via Hantzsch synthesis and
elucidated their structures. Structural characterization of
the starting thiourea derivative 1 revealed two crystalline
forms, which exhibit distinctly different intermolecular
N–H⋯S hydrogen bonding patterns. For 2-aminothiazoles
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
2
and 3, the encountered synperiplanar conformation of the
N-(4-methylpyridin-2-yl)thiazol-2-amine moiety suggests
the existence of supportive intramolecular N⋯S chalcogen
bonds. Replacement of a pyridyl group in 2 by a pyrazinyl
group in 3 has a signiꢁcant eꢀect on the supramolecular
structures of 2 and 3 in the solid-state. Whereas 2 forms poly-
meric N–H⋯N hydrogen-bonded tapes, 3 forms N–H⋯N
hydrogen-bonded cyclic dimers, which may further associ-
ate by additional weak intermolecular C–H⋯N hydrogen
bonds. Since the number of structurally characterized N,4-
diaryl substituted 2-aminothiazoles is hitherto limited, the
structural insight gained from this study provides impetus
for further exploration of this compound class in medicinal
chemistry.
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Aꢀliations
Denise Böck1 · Andreas Beuchel · Richard Goddard · Peter Imming1 · Rüdiger W. Seidel1
1
2
1
2
Martin-Luther-Universität Halle-Wittenberg,
Max-Planck-Institut für Kohlenforschung,
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr,
Germany
Institut für Pharmazie, Wolfgang-Langenbeck-Str. 4,
0
6120 Halle (Saale), Germany
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