Crystal Structure of Ethyl 2,4-Dimethyl-1-phenyl-6-thioxo-1,6-dihydropyrimidine-5-carboxylate: The Product from the Reaction of Ethyl 3-Aminocrotonate, Phenylisothiocyanate and Acetic Anhydride

Article abstract of DOI:10.1007/s10870-018-0714-6

Abstract: The crystal structure of ethyl 2,4-dimethyl-1-phenyl-6-thioxo-1,6-dihydropyrimidine-5-carboxylate (7) has been determined (monoclinic, P2₁/n, a 12.5543(9); b 7.6345(4); c 16.1568(14) ?, β 107.210(9)°) revealing a thioamide functional group instead of the thiazine ethyl (Z)-2,4-dimethyl-6-(phenylimino)-6H-1,3-thiazine-5-carboxylate (5) proposed previously. This has required the revision of the published structure for this multicomponent reaction which now has identified (7), not (5), as the product, supported by NMR and IR analysis. Graphical Abstract: The crystal structure of the major product from the reaction of ethyl 3-aminocrotonate, phenylisothiocyanate and acetic anhydride is ethyl 2,4-dimethyl-1-phenyl-6-thioxo-1,6-dihydropyrimidine-5-carboxylate (shown), not the previously identified ethyl (Z)-2,4-dimethyl-6-(phenylimino)-6H-1,3-thiazine-5-carboxylate. [Figure not available: see fulltext.].

Full text of DOI:10.1007/s10870-018-0714-6

Journal of Chemical Crystallography
https://doi.org/10.1007/s10870-018-0714-6
ORIGINAL PAPER
Crystal Structure of Ethyl 2,4-Dimethyl-1-phenyl-6-thioxo-1,6-
dihydropyrimidine-5-carboxylate: The Product from the Reaction
of Ethyl 3-Aminocrotonate, Phenylisothiocyanate and Acetic
Anhydride
Peter J. Cossar1 · Cecilia C. Russell1 · Siobhann N. McCluskey1 · Dylan Pope1 · Paul V. Bernhardt2 · Adam McCluskey1
Received: 23 August 2017 / Accepted: 18 May 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
The crystal structure of ethyl 2,4-dimethyl-1-phenyl-6-thioxo-1,6-dihydropyrimidine-5-carboxylate (7) has been determined
(monoclinic, P21/n, a 12.5543(9); b 7.6345(4); c 16.1568(14) Å, β 107.210(9)°) revealing a thioamide functional group
instead of the thiazine ethyl (Z)-2,4-dimethyl-6-(phenylimino)-6H-1,3-thiazine-5-carboxylate (5) proposed previously. This
has required the revision of the published structure for this multicomponent reaction which now has identified (7), not (5),
as the product, supported by NMR and IR analysis.
Graphical Abstract
The crystal structure of the major product from the reaction of ethyl 3-aminocrotonate, phenylisothiocyanate and acetic
anhydride is ethyl 2,4-dimethyl-1-phenyl-6-thioxo-1,6-dihydropyrimidine-5-carboxylate (shown), not the previously identi-
fied ethyl (Z)-2,4-dimethyl-6-(phenylimino)-6H-1,3-thiazine-5-carboxylate.
Keywords Multicomponent reaction · Thiazine · Dihydropyrimidine · Structure revision
Introduction
Electronic supplementary material The online version of this
The ability to rapidly probe the subtle nuances of chemical
article (https://doi.org/10.1007/s10870-018-0714-6) contains
space through the decoration of simple and complex chemi-
cal scaffolds is critical to the development of lead com-
pounds and new therapeutic agents. Medicinal chemistry
relies on a robust toolkit of chemical modification broadly
applicable across a diverse array of chemotypes [1, 2]. These
robust, reliable synthetic tools enable rapid development
of structure activity relationship data, the installation of
favourable physicochemical properties and the bioisosteric
supplementary material, which is available to authorized users.
* Adam McCluskey
adam.mccluskey@newcastle.edu.au
1
Chemistry, School of Environmental and Life Sciences,
University of Newcastle, Callaghan, NSW 2308, Australia
2
School of Chemistry and Molecular Biosciences, University
of Queensland, Brisbane, QLD 4072, Australia
Vol.:(0123456789)
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Journal of Chemical Crystallography
replacement of toxicophores that may stymie drug develop-
ment endeavours.
HPLC grade bulk. Reaction progress was monitored by
TLC, on aluminium plates coated with silica gel and fluo-
rescent indicator (Merck 60 F254). Flash chromatography
was conducted on Merck silica gel 60 (230–400 mesh).
1H and 13C spectra were recorded on a Brüker Avance
III 400 MHz (or 600 MHz) spectrometer, where 1H-NMR
and 13C-NMR were acquired at 400 and 101 MHz (or 600
and 150 MHz), respectively. Spectra were recorded using
deuterated chloroform (CDCl3) and chemical shifts are
relative to TMS as internal standard. Mass spectroscopic
analysis was conducted using an Agilent 6100 series
single quadrupole LCMS using a mobile phase of 1:1
acetonitrile:H2O with 0.1% formic acid. Melting points
were recorded using a Büchi melting point M-565 appa-
ratus and are uncorrected.
Multicomponent reactions (MCRs) are key ‘medicinal
chemistry toolkit’ reactions permitting rapid assembly of
three or more components in a one-pot sequence to produce
a final product [3–5]. MCRs present the medicinal chem-
ist with additional benefits beyond rapid compound access
and diversity, they are typically highly atom-economic pro-
ducing less waste and require fewer resources, less time,
energy and human effort. In many cases, simpler purifica-
tion processes and high convergence are also evident [6, 7].
Isocyanide-based MCRs are one of the most important and
widely used of all the MCRs, and have been extensively used
in the development of biologically active compounds [8–10].
Isothiocyanate based MCRs have facilitated rapid access to
thiazoles, thiadiazoles, triazoles, benzimidazoles, dithiolane,
spiro-fused oxazolines, (dihydroisoquinolin-1-yl)phospho-
nates and related systems [11–20]. Our original interest in
isothiocyanate based MCRs was sparked by a report by Vasu
and their development of quinazolin-2-yl-tetrasubstituted
thiophenes [21]. We reasoned that we could intercept the
postulated thiolate anion (4) with electrophiles and reported
the synthesis of 1,3-thiazine-6-phenylimino-5-carboxylates
(5) (Scheme 1) [22].
Synthesis
A mixture of ethyl 3-aminocrotonate (1) (0.3 mL,
2.373 mmol) and phenylisothiocyanate (2) (0.283 mL,
2.373 mmol) was stirred, under solvent free conditions,
at room temperature overnight under a nitrogen atmos-
phere. To the stirred mixture was added acetic anhydride
(0.26 mL, 2.61 mmol) and acetonitrile (5 mL). The reac-
tion mixture was stirred for 24 h at room temperature and
the crude material was subjected to silica gel chromatogra-
phy (1:4 ethyl acetate/petroleum ether) to afford 7 (0.41 g,
65%) as a bright yellow solid (mp 145.3–146.5 °C).
IR (cm−1): 2984 (CH), 1728 (COO), 1231 (CO).
1H NMR (400 MHz, CDCl3) δ 7.65–7.43 (m, 3H),
7.25–7.09 (m, 2H), 4.42 (q, J = 7.1 Hz, 2H), 2.31 (s, 3H),
2.22 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H).
In our original submission we reported on the successful
synthesis of a range of aromatic substituted variants of 5,
as well as modifications of the anhydride moiety to intro-
duce ethyl, phenyl and trifluoromethyl substituents. These
structural assignments were supported by NMR, MS and
IR analysis. However, recent slow crystallisation of product
from the MCR detailed in Scheme 1 from 10% ethyl ace-
tate–hexanes and subsequent X-ray crystallographic analysis
revealed that the primary product was not the reported ethyl
(Z)-2,4-dimethyl-6-(phenylimino)-6H-1,3-thiazine-5-car-
boxylate (5) [22].
13C NMR (400 MHz, CDCl3) δ 183.0, 166.1, 159.2,
153.9, 140.6, 132.3, 130.5 (C 2), 129.7, 127.1 (C2), 62.0,
25.1, 21.9, 14.0.
LRMS (ESI+) m/z 288, 288 [M]+ 40%.
Experimental
HRMS (ES+), calculated for C15H16N2O2S 288.0932.
RP-HPLC Alltima™ C18 5 µm 150 mm × 4.6 mm,
10–100% B in 15 min, Rt = 5.19 min, 100%.
Materials
Slow evaporation from 10% ethyl acetate–hexanes
afforded crystals suitable for X-ray crystallographic
analysis.
All starting materials were purchased from Aldrich Chem-
ical Co. and Lancaster Synthesis. Solvents were of AR or
Scheme 1 Synthesis of
ethyl (Z)-2,4-dimethyl-
6-(phenylimino)-6H-1,3-thia-
zine-5-carboxylate (5) [22]
1 3

Journal of Chemical Crystallography
X‑Ray Crystallography
Results and Discussion
Crystallographic data (MoKα, 2θmax = 50°) were collected
on an Oxford Diffraction Gemini S Ultra CCD diffrac-
tometer at 190 K. Data reduction and empirical absorp-
tion corrections were carried out with the CrysAlis Pro
program (Oxford Diffraction vers. 171.38.43). The struc-
ture was solved by direct methods with SHELXS86 and
refined with SHELXL97 [23]. All non-H atoms were
refined anisotropically and H-atoms were constrained at
their estimated positions using a riding model. The ther-
mal ellipsoid diagram was generated with ORTEP3 [24].
All crystallographic calculations were carried out within
the WinGX graphical user interface [25]. The crystal and
instrumental parameters used in the unit-cell determina-
tion and data collection are summarized in Table 1.
We were interested in the possible development of the
1,3-thiazine scaffold as a novel pseudo-aromatic moiety in
a number of the medicinal chemistry programs underway
in our laboratory [26–28]. We anticipated that obtaining
crystals would enable determination of the ring deviation
from planarity and provide insights that would allow fur-
ther substituted analogues to be developed and also highlight
potential selective modifications that could be installed at a
later date.
In a typical experiment, the solvent free reaction of 3-ami-
nocrotonate (1) with phenyl thioisocyanate (2) afforded, ini-
tially the two component adduct (6), which on treatment
with acetic anhydride afforded a single major product, origi-
nally assigned, based on NMR analysis as the 1,3-thiazine
(5) (Scheme 2).
Table 1 Crystal data and refinement details for (7)
(7)
Formula
C15H16N2O2S
288.36
190(2)
0.71073
Monoclinic
P 21/n
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
Unit cell dimensions
a (Å)
12.5543(9)
b (Å)
c (Å)
7.6345(4)
16.1568(14)
107.210(9)
1479.23(18)
Scheme 2 Reagents and conditions (i) rt, solvent free, N2, overnight;
(ii) acetic anhydride, CH3CN, rt, 24 h
β (°)
Volume (Å3)
Z
4
Density (calculated) (g cm−3
)
1.295
0.221
608
Absorption coefficient (mm−1
F(000)
)
Crystal size (mm)
0.5×0.2×0.2
3.62–25.00
6029
2601
1864
0.0350
θ range for data collection (°)
Reflections collected
Independent reflections
Observed reflections
Rint
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I>2σ(I)]
R indices [all data]
CCDC deposition no.
2601/0/184
1.087
R1=0.0489, wR2=0.1001
R1=0.0782, wR2=0.1198
1570117
Fig. 1 ORTEP 3D view of 7 (30% ellipsoids shown). Selected
bond lengths (Å) C(1)–N(2) 1.396(3); C(1)–C(2) 1.419(3); C(1)–
S(1) 1.659(2); C(2)–C(3) 1.366(3); C(3)–N(1) 1.369(3); C(4)–N(1)
1.297(3); C(4)–N(2) 1.384(3); C(5)–N(2) 1.448(3)
1 3

Journal of Chemical Crystallography
Structural characterisation of the MCR product was origi-
nally carried out using NMR, MS and IR analysis. These
data were consistent with the proposed structure of ethyl (Z)-
2,4-dimethyl-6-(phenylimino)-6H-1,3-thiazine-5-carboxy-
late (5), and the related analogues [22]. However the X-ray
structure of the major product has revealed that the actual
product is the corresponding isomeric thioamide analogue,
ethyl 2,4-dimethyl-1-phenyl-6-thioxo-1,6-dihydropyrimi-
dine-5-carboxylate (7) (Scheme 2).
ethyl ester moiety adjacent to the thioamide C=S at C2, and
the N1-dihydropyrimidine nitrogen flanked by two methyl
groups (C11 and C12). The bond angles and bond lengths
within the dihydropyrimidine ring are within the expected
ranges for such species [29]. The phenyl and ethyl carboxy-
late groups are orthogonal to the heterocyclic ring due to the
presence of the adjacent methyl groups and S-atom.
In the absence of any classical H-bond donors there
are some weak, non-classical C–H···O contacts from the
phenyl ring (C9–H···O2 2.59 Å) and the methylene group
(C15–H···O1 2.56 Å) to the carboxyl group O-atoms. These
are illustrated in the packing diagram (Fig. 2).
The structure of 7 is shown in Fig. 1, which indicates the
presence of the thioamide moiety (C1–S1 1.659(2) Å). The
core is a 1,6-substituted dihydropyrimidine ring with the
Re-examination of the reaction mechanism based on
this data supports not the presence of a thiolate anion as
in Vasu’s report [21], but in this case the nitrogen anion
to sulfur anion resonance step favours the nitrogen anion
8 which is intercepted by the addition of acetic anhydride.
Ensuing acetate loss, and H-abstraction affords the ene-
amine 9 which effects an intramolecular condensation with
N-acyl carbonyl moiety. Loss of water and acetate removal
of the proton yields ethyl 2,4-dimethyl-1-phenyl-6-thi-
oxo-1,6-dihydropyrimidine-5-carboxylate (Fig. 3). This
mechanism differs only in the interception of the nitrogen
anion rather than sulfur anion by acetic anhydride, but
this re-working is necessitated by the structure confirmed
herein by X-ray crystallography. This data is consistent
with our previous observations of the benzoic anhydride
treatment of phenyl isothiocyanate and 3-aminocrotonate
with isolation of the two component adduct and subse-
quent N-acylation [22].
Fig. 2 Packing diagram of the structure of 7 (generated with Mer-
cury, http://www.ccdc.cam.ac.uk/mercury/) showing weak non-classi-
cal H-bonds between symmetry related molecules
Fig. 3 Revised mechanism
for the 3-component MCR
reaction of 3-aminocrotonate,
phenyl isothiocyanate (2)
and acetic anhydride to give
ethyl 2,4-dimethyl-1-phenyl-
6-thioxo-1,6-dihydropy-
rimidine-5-carboxylate (7),
not ethyl (Z)-2,4-dimethyl-
6-(phenylimino)-6H-1,3-thia-
zine-5-carboxylate (5)
1 3

Journal of Chemical Crystallography
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In summary, the structure of the major products from
the MCR reaction of 3-aminocrotonate (1) with sub-
stituted phenyl thioisocyanates and acetic anhydride
have been revised from 1,3-thiazine-5-carboxylates to
6-thioxo-1,6-dihydropyrimidines.
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Acknowledgements The authors acknowledge the financial support
of the Australian Research Council, the Australian Cancer Research
and Ramaciotti Foundations.
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