research communications
Unusual formation of (E)-11-(aminomethylene)-8,9,10,11-tetrahydropyrido[2′,3′:4,5]pyrimido[1,2-a]azepin-5(7H)-one and its crystal structure
aS.Yunusov Institute of the Chemistry of Plant Substances Academy of Sciences of, Uzbekistan Mirzo Ulugbek Str., 77, Tashkent 100170, Uzbekistan
*Correspondence e-mail: kk_turgunov@rambler.ru
Selective C-formylation of 8,9,10,11-tetrahydropyrido[2′,3′:4,5]pyrimido[1,2-a]-azepin-5(7H)-one has been studied for the first time. It was revealed that formylation proceeds by the formation of an intermediate salt, which due to the re-amination process on treatment with aqueous ammonia transformed into the corresponding (E)-11-(aminomethylene)-8,9,10,11-tetrahydropyrido[2′,3′:4,5]-pyrimido[1,2-a]azepin-5(7H)-one, C13H14N4O, as an E-isomer. Formylation was carried out by Vilsmeier–Haack reagent and the structure of the synthesized compound was confirmed by X-ray structural analysis, spectroscopic and LC–MS methods. In the molecule, the seven-membered pentamethylene ring adopts a twist-boat conformation.
Keywords: fused pyrimidines; formylation; Vilsmeier–Haack reagent; X-ray structure analysis; crystal structure.
CCDC reference: 1530092
1. Chemical context
Pyrimidine-containing ) and among synthetic compounds (Joshi et al., 2016; Roopan & Sompalle, 2016). These compounds are of theoretical and practical interest, having plural reactivity and with many prospective biologically active compounds among the synthesized derivatives.
are widely distributed in nature (Lagoja, 2005In previous reports we have described several syntheses, viz. the reaction of 2,3-trimethylenepyrido[2,3-d]pyrimidin-4-one with aromatic (Khodjaniyazov, 2015a,b; Khodjaniyazov & Ashurov, 2016), selective reduction with sodium borohydride (Khodjaniyazov et al., 2016b), and the formation of (E)-9-(N,N-dimethylaminomethylidene)-8,9-dihydropyrido[2,3-d]pyrrolo[1,2-a]pyrimidin-5(7H)-one (Khodjaniyazov et al., 2016a). In this current report we present the results of reaction of 8,9,10,11-tetrahydropyrido[2′,3′:4,5]pyrimido[1,2-a]azepin-5(7H)-one (1) with the Vilsmeier–Haack reagent, decomposition by water and subsequent treatment with aqueous ammonia. We carried out the interaction of 1 with a formylating agent and, at the end of the reaction, the unusual final product (E)-11-(aminomethylene)-8,9,10,11-tetrahydropyrido[2′,3′:4,5]pyrimido-[1,2-a]azepin-5(7H)-one (3) was isolated after treatment (re-amination) of 11-dimethylaminomethylidene derivative (2) with aqueous ammonia. The reaction proceeds as shown in Fig. 1. The reaction product was different from that obtained in the case of formylation of 2,3-trimethylenepyrido[2,3-d]pyrimidin-4-one [pyrido[2,3-d]pyrrolo[1,2-a]pyrimidin-5(7H)-one; Khodjaniyazov et al., 2016a]. This fact was explained by re-amination of the initially formed dimethylaminomethylidene derivative 2 under action of aqueous ammonia to give (E)-11-(aminomethylene)-8,9,10,11-tetrahydropyrido[2′,3′:4,5]pyrimido[1,2-a]azepin-5(7H)-one (3) as the final product
.2. Structural commentary
The title compound crystallizes in the centrosymmetric monoclinic P21/c (No. 14) The contains one crystallographically independent molecule. A displacement ellipsoid plot showing the atom-numbering scheme is presented in Fig. 2. In the molecule, the seven-membered pentamethylene ring exhibits a twist-boat conformation and has an approximate twofold symmetry with a C2 axis passing through atom C12 and midpoint of the C2—C9 bond. The amino group is E-oriented and of the N atom in this group lies between sp3 and sp2. The C—N bond makes an angle of 155° with the bisector of the H—N—H angle. The equivalent angle in methylamine with a pyramidal sp3-hybridized N atom is ∼123° (Klingebiel et al., 2002) and it is nearly 180° in formamide with a planar sp2-hybridized N atom (Gajda & Katrusiak, 2011). The pyrimidine ring is twisted slightly, which may be because of the influence of the twisted seven-membered azepane ring. The N1—C8A—N4A—C4 torsion angle of is 8.7 (4)°.
3. Supramolecular features
In the crystal, hydrogen bonds with 16 ring and three chain motifs are generated by N—H⋯N and N—H⋯O contacts (Table 1). The amino group is located close to the nitrogen atoms N1 and N8 of an inversion-related molecule, forming hydrogen bonds with R12(4) and R22(12) graph-set motifs (Fig. 3). This amino group also forms a hydrogen bond with the C=O oxygen atom of a molecule translated along the a axis, which links the molecules into R44(16) rings. Hydrogen-bonded chains are formed along [100] by alternating R22(12) and R44(16) rings (Fig. 4). These chains are stabilized by intermolecular π-π-stacking interactions observed between the pyridine and pyrimidine rings [centroid–centroid distance = 3.669 (2) Å; 1 − x, 1 − y, 1 − z].
4. Database survey
A search of the Cambridge Structural Database (Version 5.38, last update November 2016; Groom et al., 2016) for the 4-azaquinazoline moiety gave eight hits. Only one of these is a related structure, a tricyclic 4-azaquinazolin-4-one with a substituent on the third ring (VAMBET; Khodjaniyazov & Ashurov, 2016).
5. Synthesis and crystallization
Materials and methods. The results of electro spray ionization (ESI–MS) were recorded using a 6420 TripleQuadLC/MC (Agilent Technologies, US) LC–MS spectrometer. The measurements were carried out in positive-ion mode. 1H NMR spectra were recorded in CD3OD on a Varian 400-MR spectrometer operating accordingly at 400 MHz. Hexamethyldisiloxcane (HMDSO) was used as internal standard and the of 1H was recorded in ppm. Melting points were measured on a Boetius and MEL–TEMP apparatus manufactured by Branstead international (USA) and are uncorrected. IR spectra were recorded on an IR Fourier System 2000 (Perkin–Elmer) as KBr pellets.
The reaction process was monitored by TLC on Silufol UV-254 plates using a CHCl3/CH3OH (12:1) solvent system and the developed plates were visualized under a UV lamp. Solvents were purified by standard procedures. Organic solutions were dried over anhydrous Na2SO4 or with dried CaCl2.
Synthesis of (E)-11-(aminomethylene)-8,9,10,11-tetrahydropyrido[2′,3′:4,5]-pyrimido[1,2-a]azepin-5(7H)-one (3). A round-bottom flask with freshly distilled DMF (3 ml, 39 mmol) was cooled by an ice–water bath and POCl3 (1 ml, 10.7 mmol) was added dropwise. The mixture was stirred (30 min), then 8,9,10,11-tetrahydropyrido[2′,3′:4,5]pyrimido[1,2-a]azepin-5(7H)-one (1) (0.51 g, 2.4 mmol) was added into the reaction mixture. The reaction mixture was heated in a water bath for 1.5 h at 343 K and left for another day. Water (4 ml) was poured into the flask. TLC monitoring showed that the initial compound had fully transformed. The reaction mixture was treated by aqueous ammonia solution up to pH 9. The obtained solution was extracted by chloroform (30 mL) three times. The chloroform part was dried over Na2SO4 and the solvent was removed. Yield 0.34 g (60%), m.p. 458–460 K, Rf 0.63. Single crystals of 3 were grown from acetone solution by slow evaporation of the solvent at room temperature.
UV spectrum (ethanol, λmax, nm) neutral medium: 279.58, 348.97; acidic medium (HCl): 280.24, 362.37, 420.80; neutralization (HCl+NaOH): 279.12, 318.11, 362.29; basic medium (NaOH): 275.83, 347.71. IR spectrum (KBr, ν, cm−1): 3382 (NH2), 3325, 3203, 3064, 2924, 2869, 2824, 1642, 1613 (NH), 1591, 1562, 1523, 1470, 1433, 1389, 1353, 1319, 1267, 1249, 1227, 1184, 1126, 1107, 1077, 1045, 976, 934, 864, 825, 783, 735, 688, 663, 601, 548, 420. LC–MS (+ESI): 243 [M+H]+, 216.1, 201.1, 174, 160.9, 148.0, 121.0, 93.0, 79.0, 55.1, 39.1. 1H NMR spectrum [400 MHz, CD3OD, δ, ppm, J (Hz]): 1.77 (2H, m, γ-CH2), 1.92 (2H, m, δ-CH2), 2.385 (2H, m, β-CH2), 4.195 (2H, t, J = 6.1, ∊-CH2), 7.454 (1H, br s, =CH), 7.28 (1H, dd, J = 4.6, 7.9, H-6), 8.45 (1H, dd, J = 7.9, 2.1, H-5), 8.735 (1H, dd, J = 4.6, 2.1, H-7).
6. Refinement
Crystal data, data collection and structure . H-bound N atoms were freely refined. C-bound H atoms were refined as riding with C—H = 0.93 or 0.97 Å and Uiso(H) = 1.2Ueq(C).
details are summarized in Table 2Supporting information
CCDC reference: 1530092
https://doi.org/10.1107/S2056989017013093/xu5905sup1.cif
contains datablocks I, global. DOI:Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989017013093/xu5905Isup2.hkl
Data collection: CrysAlis PRO (Oxford Diffraction, 2007); cell
CrysAlis PRO (Oxford Diffraction, 2007); data reduction: CrysAlis PRO (Oxford Diffraction, 2007); program(s) used to solve structure: SHELXS7 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014/7 (Sheldrick, 2015); molecular graphics: XP in SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXL2014/7 (Sheldrick, 2015).C13H14N4O | Dx = 1.411 Mg m−3 |
Mr = 242.28 | Melting point: 458(2) K |
Monoclinic, P21/c | Cu Kα radiation, λ = 1.54184 Å |
a = 8.7260 (7) Å | Cell parameters from 911 reflections |
b = 15.236 (3) Å | θ = 5.9–75.7° |
c = 8.6642 (7) Å | µ = 0.76 mm−1 |
β = 98.046 (8)° | T = 293 K |
V = 1140.6 (3) Å3 | Plate, colourless |
Z = 4 | 0.40 × 0.35 × 0.15 mm |
F(000) = 512 |
Oxford Diffraction Xcalibur, Ruby diffractometer | 2328 independent reflections |
Radiation source: Enhance (Cu) X-ray Source | 1478 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.059 |
Detector resolution: 10.2576 pixels mm-1 | θmax = 76.7°, θmin = 5.1° |
ω scans | h = −9→10 |
Absorption correction: multi-scan (CrysAlis Pro; Oxford Diffraction, 2007) | k = −19→18 |
Tmin = 0.965, Tmax = 1.000 | l = −10→8 |
7589 measured reflections |
Refinement on F2 | 0 restraints |
Least-squares matrix: full | Hydrogen site location: mixed |
R[F2 > 2σ(F2)] = 0.050 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.141 | w = 1/[σ2(Fo2) + (0.0554P)2 + 0.003P] where P = (Fo2 + 2Fc2)/3 |
S = 1.04 | (Δ/σ)max = 0.001 |
2328 reflections | Δρmax = 0.18 e Å−3 |
171 parameters | Δρmin = −0.20 e Å−3 |
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. |
x | y | z | Uiso*/Ueq | ||
O1 | 0.6098 (2) | 0.35990 (15) | 0.1710 (2) | 0.0621 (5) | |
N3 | 0.3638 (2) | 0.39263 (13) | 0.2102 (2) | 0.0449 (4) | |
N1 | 0.2921 (2) | 0.40925 (14) | 0.4621 (2) | 0.0472 (5) | |
N8 | 0.4731 (3) | 0.39670 (16) | 0.6821 (2) | 0.0569 (5) | |
N15 | −0.1422 (3) | 0.49351 (19) | 0.2758 (3) | 0.0606 (6) | |
C2 | 0.2547 (3) | 0.40679 (15) | 0.3099 (3) | 0.0438 (5) | |
C9 | 0.0935 (3) | 0.41797 (17) | 0.2412 (3) | 0.0478 (5) | |
C4A | 0.5549 (3) | 0.36809 (16) | 0.4323 (3) | 0.0468 (5) | |
C8A | 0.4417 (3) | 0.39271 (15) | 0.5243 (3) | 0.0459 (5) | |
C4 | 0.5167 (3) | 0.37221 (16) | 0.2626 (3) | 0.0476 (5) | |
C14 | 0.0100 (3) | 0.47631 (17) | 0.3123 (3) | 0.0491 (5) | |
H14A | 0.0630 | 0.5078 | 0.3950 | 0.059* | |
C13 | 0.3195 (3) | 0.40613 (17) | 0.0415 (3) | 0.0502 (6) | |
H13A | 0.4110 | 0.4200 | −0.0056 | 0.060* | |
H13B | 0.2492 | 0.4556 | 0.0247 | 0.060* | |
C5 | 0.7016 (3) | 0.34430 (18) | 0.5046 (3) | 0.0557 (6) | |
H5A | 0.7782 | 0.3280 | 0.4457 | 0.067* | |
C12 | 0.2420 (3) | 0.32550 (18) | −0.0367 (3) | 0.0560 (6) | |
H12A | 0.1995 | 0.3400 | −0.1432 | 0.067* | |
H12B | 0.3189 | 0.2798 | −0.0403 | 0.067* | |
C6 | 0.7310 (3) | 0.34538 (19) | 0.6636 (3) | 0.0576 (6) | |
H6A | 0.8268 | 0.3281 | 0.7154 | 0.069* | |
C10 | 0.0156 (3) | 0.3637 (2) | 0.1043 (3) | 0.0607 (7) | |
H10A | −0.0772 | 0.3374 | 0.1341 | 0.073* | |
H10B | −0.0163 | 0.4030 | 0.0177 | 0.073* | |
C7 | 0.6134 (3) | 0.3731 (2) | 0.7466 (3) | 0.0603 (6) | |
H7A | 0.6354 | 0.3750 | 0.8547 | 0.072* | |
C11 | 0.1136 (3) | 0.2911 (2) | 0.0480 (3) | 0.0617 (7) | |
H11A | 0.1589 | 0.2566 | 0.1368 | 0.074* | |
H11B | 0.0474 | 0.2527 | −0.0214 | 0.074* | |
H1 | −0.201 (4) | 0.456 (2) | 0.224 (4) | 0.112 (16)* | |
H2 | −0.181 (6) | 0.527 (3) | 0.338 (5) | 0.16 (2)* |
U11 | U22 | U33 | U12 | U13 | U23 | |
O1 | 0.0464 (10) | 0.0880 (14) | 0.0538 (10) | 0.0053 (9) | 0.0141 (8) | −0.0095 (9) |
N3 | 0.0398 (10) | 0.0537 (11) | 0.0415 (10) | −0.0006 (8) | 0.0065 (8) | −0.0030 (8) |
N1 | 0.0420 (10) | 0.0574 (12) | 0.0430 (10) | 0.0022 (9) | 0.0082 (8) | −0.0032 (8) |
N8 | 0.0562 (13) | 0.0707 (14) | 0.0428 (11) | 0.0026 (10) | 0.0039 (9) | −0.0027 (9) |
N15 | 0.0465 (13) | 0.0786 (17) | 0.0566 (13) | 0.0100 (11) | 0.0072 (10) | 0.0016 (11) |
C2 | 0.0416 (12) | 0.0462 (12) | 0.0440 (12) | −0.0003 (9) | 0.0070 (9) | −0.0030 (9) |
C9 | 0.0400 (12) | 0.0593 (14) | 0.0443 (12) | 0.0014 (10) | 0.0071 (9) | −0.0003 (10) |
C4A | 0.0424 (12) | 0.0492 (13) | 0.0484 (12) | −0.0002 (10) | 0.0047 (10) | −0.0026 (9) |
C8A | 0.0430 (12) | 0.0494 (13) | 0.0450 (12) | 0.0015 (9) | 0.0049 (9) | −0.0019 (9) |
C4 | 0.0404 (12) | 0.0500 (12) | 0.0533 (13) | 0.0002 (10) | 0.0097 (10) | −0.0076 (10) |
C14 | 0.0393 (12) | 0.0630 (15) | 0.0446 (12) | 0.0021 (11) | 0.0042 (9) | 0.0033 (10) |
C13 | 0.0478 (13) | 0.0601 (15) | 0.0436 (12) | 0.0002 (11) | 0.0088 (10) | 0.0018 (10) |
C5 | 0.0450 (14) | 0.0610 (16) | 0.0611 (15) | 0.0061 (11) | 0.0074 (11) | −0.0003 (11) |
C12 | 0.0616 (16) | 0.0598 (16) | 0.0457 (13) | 0.0034 (12) | 0.0044 (11) | −0.0082 (10) |
C6 | 0.0467 (13) | 0.0625 (16) | 0.0600 (15) | 0.0042 (11) | −0.0053 (11) | 0.0051 (12) |
C10 | 0.0461 (14) | 0.0748 (18) | 0.0598 (16) | −0.0004 (13) | 0.0023 (11) | −0.0098 (13) |
C7 | 0.0628 (16) | 0.0693 (17) | 0.0455 (13) | −0.0001 (13) | −0.0036 (11) | 0.0008 (11) |
C11 | 0.0616 (17) | 0.0634 (17) | 0.0589 (16) | −0.0091 (13) | 0.0046 (12) | −0.0110 (12) |
O1—C4 | 1.227 (3) | C14—H14A | 0.9300 |
N3—C4 | 1.383 (3) | C13—C12 | 1.516 (4) |
N3—C2 | 1.389 (3) | C13—H13A | 0.9700 |
N3—C13 | 1.473 (3) | C13—H13B | 0.9700 |
N1—C2 | 1.314 (3) | C5—C6 | 1.365 (4) |
N1—C8A | 1.364 (3) | C5—H5A | 0.9300 |
N8—C7 | 1.323 (4) | C12—C11 | 1.516 (4) |
N8—C8A | 1.357 (3) | C12—H12A | 0.9700 |
N15—C14 | 1.347 (3) | C12—H12B | 0.9700 |
N15—H1 | 0.852 (19) | C6—C7 | 1.398 (4) |
N15—H2 | 0.849 (19) | C6—H6A | 0.9300 |
C2—C9 | 1.458 (3) | C10—C11 | 1.519 (4) |
C9—C14 | 1.352 (3) | C10—H10A | 0.9700 |
C9—C10 | 1.525 (4) | C10—H10B | 0.9700 |
C4A—C5 | 1.392 (3) | C7—H7A | 0.9300 |
C4A—C8A | 1.405 (3) | C11—H11A | 0.9700 |
C4A—C4 | 1.463 (3) | C11—H11B | 0.9700 |
C4—N3—C2 | 122.98 (19) | C12—C13—H13B | 109.3 |
C4—N3—C13 | 117.70 (18) | H13A—C13—H13B | 107.9 |
C2—N3—C13 | 119.16 (19) | C6—C5—C4A | 118.8 (2) |
C2—N1—C8A | 118.76 (19) | C6—C5—H5A | 120.6 |
C7—N8—C8A | 117.3 (2) | C4A—C5—H5A | 120.6 |
C14—N15—H1 | 120 (3) | C11—C12—C13 | 112.1 (2) |
C14—N15—H2 | 116 (4) | C11—C12—H12A | 109.2 |
H1—N15—H2 | 118 (4) | C13—C12—H12A | 109.2 |
N1—C2—N3 | 122.2 (2) | C11—C12—H12B | 109.2 |
N1—C2—C9 | 119.8 (2) | C13—C12—H12B | 109.2 |
N3—C2—C9 | 118.0 (2) | H12A—C12—H12B | 107.9 |
C14—C9—C2 | 116.2 (2) | C5—C6—C7 | 118.4 (2) |
C14—C9—C10 | 120.1 (2) | C5—C6—H6A | 120.8 |
C2—C9—C10 | 123.6 (2) | C7—C6—H6A | 120.8 |
C5—C4A—C8A | 119.3 (2) | C11—C10—C9 | 115.8 (2) |
C5—C4A—C4 | 121.9 (2) | C11—C10—H10A | 108.3 |
C8A—C4A—C4 | 118.7 (2) | C9—C10—H10A | 108.3 |
N8—C8A—N1 | 115.9 (2) | C11—C10—H10B | 108.3 |
N8—C8A—C4A | 121.6 (2) | C9—C10—H10B | 108.3 |
N1—C8A—C4A | 122.3 (2) | H10A—C10—H10B | 107.4 |
O1—C4—N3 | 121.1 (2) | N8—C7—C6 | 124.6 (2) |
O1—C4—C4A | 124.5 (2) | N8—C7—H7A | 117.7 |
N3—C4—C4A | 114.40 (19) | C6—C7—H7A | 117.7 |
N15—C14—C9 | 126.7 (2) | C12—C11—C10 | 113.0 (2) |
N15—C14—H14A | 116.6 | C12—C11—H11A | 109.0 |
C9—C14—H14A | 116.6 | C10—C11—H11A | 109.0 |
N3—C13—C12 | 111.7 (2) | C12—C11—H11B | 109.0 |
N3—C13—H13A | 109.3 | C10—C11—H11B | 109.0 |
C12—C13—H13A | 109.3 | H11A—C11—H11B | 107.8 |
N3—C13—H13B | 109.3 |
D—H···A | D—H | H···A | D···A | D—H···A |
N15—H1···O1i | 0.85 (3) | 2.21 (3) | 3.017 (3) | 159 (3) |
N15—H2···N1ii | 0.85 (5) | 2.31 (5) | 3.146 (3) | 168 (4) |
N15—H2···N8ii | 0.85 (5) | 2.79 (5) | 3.401 (4) | 131 (4) |
Symmetry codes: (i) x−1, y, z; (ii) −x, −y+1, −z+1. |
Funding information
The work was supported by fundamental grant FA-F7-T207 `Theoretical aspects of formation of the asymmetric centers in biologically active heterocyclic molecules' from the Academy of Sciences of the Republic of Uzbekistan.
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