Synthesis and Crystallographic Characterisation of Pyridyl- and Indoleninyl-Substituted Pyrimido[1,2-b]Indazoles

Abstract

Pyridyl- and indoleninyl-substituted pyrimido[1,2-b]indazole were synthesised in good to high yields from the condensation reaction of 1,3-dialdehydes with 3-aminoindazoles. The structural features of the compounds were determined by NMR (¹H, ¹³C and ¹⁹F), FT-IR and HR-MS. The spectroscopic assignments were confirmed by X-ray crystallography for two derivatives, i.e., 9-Bromo-3-(pyridin-4-yl)pyrimido[1,2-b]indazole (1b) and 10-Methoxy-3-(pyridin-4-yl)pyrimido[1,2-b]indazole (1c), which further provides support for significant delocalisation of π-electron density over the entire fused ring system. The molecular packing was assessed by conventional methods together with Hirshfeld surface analyses. In 1b, the molecular packing features pyrimidyl-N–H···N(pyrimidyl), π(pyrazolyl)···π(pyrimidyl) and Br···N interactions within a two-dimensional array. In 1c, pyrimidyl-C–H···N(pyrazolyl) and pyridyl-C–H···O(methoxy) interactions feature within a three-dimensional architecture.

1. Introduction

Nitrogen-fused tricyclic frameworks are frequently found in a diverse range of naturally occurring products and synthetic drugs [1,2]. The nitrogen-rich structural core plays an important role in numerous biological activities such as anti-cancer [3], anti-inflammatory [4], monoamine oxidase (MOA) [5], PDE10A inhibitors [6], anti-anxiety [7], anti-malarial [8], anti-microbial [9] and are effective against the hepatitis C virus (HCV) infection [1]. Interestingly, some derivatives have been clinically used for the treatment of various ailment diseases [10]. The incorporation of the extended π-conjugation substituents alters the chromophore of the core which displays interesting photophysical and fluorescent properties in solution [11]. Despite the achievements in numerous fields, less effort has focused upon the preparation of pyrimido[1,2-b]indazole derivatives due to the low availability of appropriate starting materials, poor synthetic options and lack of functional group tolerance [1,12]. Hence, an efficient synthetic methodology to functionalise and extend the range of nitrogen-fused tricyclic frameworks is highly desirable.

A literature survey revealed that several research groups have reported a facile synthetic approach to synthesise the pyrimido[1,2-b]indazole core in recent years. Most strategies involve the condensation of 3-aminoindazoles with carbonyl groups to deliver a diverse range of pyrimido[1,2-b]indazole analogues [11,13,14,15,16,17,18,19,20,21,22]. Among those strategies, Gao et al. [2] reported the core can be achieved from the three-component reaction of 3-aminoindazoles, aromatic aldehydes and triethylamine in the presence of ammonium iodide (Scheme 1a). However, the method only decorated the core with a broad range of phenyl moieties at the C4-position. Furthermore, a straightforward and low-cost technique to synthesise the core was described by Abarbi et al. [5] through a condensation of 3-aminoindazoles with 2-bromomalonaldehyde in the presence of catalytic acetic acid to afford the products in high yields (Scheme 1b). The synthetic approach was further utilised by Ramle et al. [23] to furnish the C-3 position of the core with a wide scope of indolenine substituents. Recently, Cao et al. [12] reported an efficient protocol to decorate the C2-position of the core with a variety of electronic substituents from the reaction between 3-aminoindazoles and ynals in the presence of ammonium thiocyanate under blue light-emitting diode (LED) irradiation (Scheme 1c). It is noted that the regioselective synthesis of pyrimido[1,2-b]indazole is due to the actions of both the reactants and the conditions used in the synthetic media, which involves a specific synthetic mechanism for the formation of the products.

As part of continuing interest in this area, this article describes the preparation of two new series of pyrimido[1,2-b]indazoles containing pyridine and indolenine moieties via a simple and direct approach. The structural identity was physically characterised by various spectroscopic methods and complemented by X-ray crystallography on two derivatives. The outcomes of these investigations are reported herein.

2. Materials and Methods

2.1. Chemicals and Instrumentation

All chemicals and solvents were purchased from Fischer Scientific, Merck Millipore, and Sigma Aldrich, Malaysia. ¹H and ¹³C NMR spectra were recorded on a JEOL ECX 400 MHz (JEOL Ltd., Tokyo, Japan), Bruker DMX 400 MHz (BRUKER Corporation, Massachusetts, USA) and Bruker DMX 600 MHz (BRUKER Corporation, Massachusetts, USA) instruments; the ¹⁹F NMR spectra of 1d and 4d (Supplementary Materials) were measured on JEOL ECX 400 MHz and BRUKER DMX 400 MHz instruments, respectively. The chemical shifts (δ) and coupling constant (J) values are expressed in terms of ppm and Hz units, respectively. FT-IR spectra were collected on an ATR-FT-IR Perkin Elmer Spectrum 400 IR spectrophotometer (PerkinElmer Inc, Waltham, USA). An Agilent 6530 Accurate-Mass Q-TOF LC/MS instrument (Agilent Technologies Inc, Santa Clara, CA, USA) was used to obtain the LCMS spectra. Melting points were recorded on a Mel-Temp II (American Laboratory Trading, San Diego, CA, USA).

2.2. Synthetic Procedure for the Preparation of 1a–d

A mixture of 2-(4-pyridinyl)malonaldehyde (0.5 mmol, 1 equiv.) and 3-aminoindazoles (0.5 mmol, 1 equiv.) in EtOH/AcOH (v/v = 4:1, 5 mL) was heated at 78 °C for 4 h. Upon completion, the reaction was cooled to room temperature. The solid was filtered, washed with diethyl ether (50 mL) and dried at 60 °C for several hours to afford the pure product.

3-(Pyridin-4-yl)pyrimido[1,2-b]indazole (1a): Yellow solid. Yield: 55%. mp: 246–248 °C. ¹H NMR (400 MHz, DMSO-d₆): δ = 10.00 (d, 1H, J = 2.0 Hz, CHN), 9.24 (d, 1H, J = 1.6 Hz, CHN), 8.77 (d, 2H, J = 6.4 Hz, Ar-H), 8.31 (d, 1H, J = 8.0 Hz, Ar-H), 8.05 (d, 2H, J = 8.0 Hz, Ar-H), 7.87 (d, 1H, J = 8.8 Hz, Ar-H), 7.70 (t, 1H, J = 5.2 Hz, Ar-H), 7.38 (t, 1H, J = 7.6 Hz, Ar-H). ¹³C NMR (150 MHz, DMSO-d₆): δ = 151.29, 150.44, 145.02, 142.46, 140.96, 132.69, 130.05, 122.53, 121.59, 121.11, 120.49, 116.09, 112.51. FT-IR (ATR): ν 3036 (C-H), 1637, 1602, (C=N pyridine), 1591, 1551 (C=C), 1223 (C-N) cm⁻¹. HRMS (ESI): m/z [M+H]⁺ calcd. for C₁₅H₁₁N₄: 247.0978; found: 247.0850.

9-Bromo-3-(pyridin-4-yl)pyrimido[1,2-b]indazole (1b): Yellow solid. Yield: 60%. mp: 254–256 °C. ¹H NMR (600 MHz, DMSO-d₆): δ = 10.02 (d, 1H, J = 2.4 Hz, CHN), 9.29 (d, 1H, J = 1.8 Hz, CHN), 8.78 (dd, 2H, J = 6.0, 3.0 Hz, Ar-H), 8.49 (d, 1H, J = 1.8 Hz, Ar-H), 8.05 (dd, 2H, J = 6.0, 3.0 Hz, Ar-H), 7.87 (d, 1H, J = 9.6 Hz, Ar-H), 7.78 (dd, 1H, J = 9.0, 1.8 Hz, Ar-H). ¹³C NMR (150 MHz, DMSO-d₆): δ = 150.95, 150.08, 146.42, 142.22, 141.23, 133.59, 133.49, 123.67, 123.03, 122.15, 118.94, 114.32, 113.67. FT-IR (ATR): ν 3054 (C-H), 1633, 1591 (C=N pyridine), 1554 (C=C), 1166 (C-N) cm⁻¹. HRMS (ESI): m/z [M+H]⁺ calcd. for C₁₅H₁₀N₄Br: 326.9089; found: 326.9909. X-ray quality crystals were grown from a toluene solution after five days.

10-Methoxy-3-(pyridin-4-yl)pyrimido[1,2-b]indazole (1c): Yellow solid. Yield: 59%. mp: 230–232 °C. ¹H NMR (400 MHz, DMSO-d₆): δ = 9.95 (d, 1H, J = 2.4 Hz, CHN), 9.22 (d, 1H, J = 2.4 Hz, CHN), 8.77 (dd, 2H, J = 6.4, 2.8 Hz, Ar-H), 8.03 (dd, 2H, J = 6.0, 2.8 Hz, Ar-H), 7.61 (t, 1H, J = 8.4 Hz, Ar-H), 7.39 (d, 1H, J = 8.8 Hz, Ar-H), 6.74 (d, 1H, J = 7.6 Hz, Ar-H), 4.04 (s, 3H, OCH₃). ¹³C NMR (150 MHz, DMSO-d₆): δ = 155.79, 153.34, 150.93, 145.67, 142.52, 141.47, 132.78, 131.60, 122.22, 121.99, 108.53, 104.60, 100.06, 56.04. FT-IR (ATR): ν 3045 (C-H), 1637, 1593 (C=N), 1567, 1506 (C=C), 1102 (C-N) cm⁻¹. HRMS (ESI): m/z [M+H]⁺ calcd. for C₁₆H₁₃N₄O: 277.1084; found: 277.0942. X-ray quality crystals were grown from a toluene solution after five days.

3-(Pyridin-4-yl)-8-(trifluoromethyl)pyrimido[1,2-b]indazole (1d): Yellow solid. Yield: 60%. mp: 215–216 °C. ¹H NMR (600 MHz, DMSO-d₆): δ = 10.08 (d, 1H, J = 1.8 Hz, CHN), 9.33 (d, 1H, J = 1.8 Hz, CHN), 8.78 (dd, 2H, J = 6.0, 3.0 Hz, Ar-H), 8.51 (d, 1H, J = 8.4 Hz, Ar-H), 8.28 (s, 1H, Ar-H), 8.05 (dd, 2H, J = 6.0, 3.0 Hz, Ar-H), 7.56 (dd, 1H, J = 8.4, 1.2 Hz, Ar-H). ¹³C NMR (150 MHz, DMSO-d₆): δ = 172.47, 150.95, 150.09, 146.98, 142.91, 141.04, 133.77, 130.62 (q, J = 30.6 Hz), 127.56 (q, J = 271.2 Hz), 124.18, 123.03, 122.18, 116.69 (q, J = 3.3 Hz), 114.75 (q, J = 4.4 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆): δ = −60.57. FT-IR (ATR): ν 3060 (C-H), 1648, 1595 (C=N), 1505 (C=C), 1122 (C-N) cm⁻¹. HRMS (ESI): m/z [M+H]⁺ calcd. for C₁₆H₁₀N₄F₃: 315.0856; found: 315.0701.

2.3. Synthetic Procedure for the Preparation of 3

To a solution of 1 (1.0 mmol, 1 equiv.) in MeOH/water (v/v = 1:1, 10 mL) was added 0.5 M NaOH (8 mL, 4 equiv.). The mixture of stirred vigorously at room temperature for 12 h (monitored by TLC). After completion of the reaction, the mixture was diluted with ethyl acetate (10 mL) and water (10 mL). The aqueous phase was collected and acidified to pH 4 by adding 0.1 M HCl. The resulting product was filtered, washed with water (50 mL) and dried at 60 °C to give the pure product.

2-(1,3-Dioxopropan-2-ylidene)-3,3-dimethylindoline-5-carboxylic acid (3): Yellow solid. Yield: 68%. mp: 279–278 °C. ¹H NMR (400 MHz, DMSO-d₆): δ = 13.11 (br, 1H, NH), 9.81 (s, 2H, CHO), 8.01 (d, 1H, J = 0.8 Hz, Ar-H), 7.89 (dd, 1H, J = 8.4, 1.6 Hz, Ar-H), 7.63 (d, 1H, J = 8.0 Hz, Ar-H), 1.65 (s, 6H, CH₃). ¹³C NMR (100 MHz, DMSO-d₆): δ = 191.44, 188.76, 178.57, 167.53, 144.53, 140.94, 130.69, 127.88, 123.67, 114.15, 110.13, 50.76, 24.29. FT-IR (ATR): ν 3191, 3060, 2874, 2340, 1706 (C=O aldehyde), 1654 (C=O acid), 1609 (C=C) cm⁻¹. HRMS (ESI): m/z [M−H]⁻ calcd. for C₁₄H₁₂NO₄: 258.0772; found: 258.0771.

2.4. General Procedure for the Preparation of 4a–d

A mixture of 3 (0.15 mmol, 1 equiv.) and 3-aminoindazoles (0.15 mmol, 1.0 equiv.) in EtOH/AcOH (v/v = 4:1, 5 mL) was heated at 78 °C for 4 h. After cooling to room temperature, the solid was filtered, washed with EtOH (25 mL) and dried at 60 °C for several hours to afford the pure product.

3,3-Dimethyl-2-(pyrimido[1,2-b]indazol-3-yl)-3H-indole-5-carboxylic acid (4a): Yellow solid. Yield: 85%. mp: >300 °C. ¹H NMR (400 MHz, DMSO-d₆): δ = 10.00 (d, 1H, J = 2.0 Hz, CHN), 9.53 (d, 1H, J = 2.0 Hz, CHN), 8.31 (d, 1H, J = 8.4 Hz, Ar-H), 8.18 (s, 1H, Ar-H), 8.05 (dd, 1H, J = 8.0, 1.6 Hz, Ar-H), 7.89 (d, 1H, J = 8.8 Hz, Ar-H), 7.82 (m, 1H, Ar-H), 7.72 (m, 1H, Ar-H), 7.39 (m, 1H, Ar-H), 1.70 (s, 6H, CH₃). ¹³C NMR (100 MHz, DMSO-d₆): δ = 182.18 (C=N indole), 167.83 (C=O), 156.32, 152.26, 148.35, 146.21, 143.10, 134.83, 130.97, 130.48, 129.34, 123.25, 122.10, 121.21, 121.11, 118.06, 116.76, 113.27, 54.30, 23.90. FT-IR (ATR): ν 1695 (C=O), 1638 (C=N), 1501 (C=C), 1238 (C-N) cm⁻¹. HRMS (ESI): m/z [M−H]⁻ calcd. for C₂₁H₁₅N₄O₂: 355.1201; found: 355.1210.

2-(9-Bromopyrimido[1,2-b]indazol-3-yl)-3,3-dimethyl-3H-indole-5-carboxylic acid (4b): Yellow solid. Yield: 70%. mp: >300 °C. ¹H NMR (400 MHz, DMSO-d₆): δ = 9.97 (d, 1H, J = 1.6 Hz, CHN), 9.53 (d, 1H, J = 2.0 Hz, CHN), 8.45 (d, 1H, J = 2.0 Hz, Ar-H), 8.14 (s, 1H, Ar-H), 8.01 (dd, 1H, J = 6.4, 2.0 Hz, Ar-H), 7.85 (d, 1H, J = 9.2 Hz, Ar-H), 7.79 (m, 2H, Ar-H), 1.65 (s, 6H, CH₃). The ¹³C NMR spectrum could not be measured due to the low solubility. FT-IR (ATR): ν 1675 (C=O), 1636, 1608, (C=N), 1519 (C=C), 1258 (C-N) cm⁻¹. HRMS (ESI): m/z [M−H]⁻ calcd. for C₂₁H₁₄N₄O₂Br: 433.0300; found: 433.0304.

2-(10-Methoxypyrimido[1,2-b]indazol-3-yl)-3,3-dimethyl-3H-indole-5-carboxylic acid (4c): Yellow solid. Yield: 77%. mp: >300 °C. ¹H NMR (400 MHz, DMSO-d₆): δ = 9.95 (d, 1H, J = 2.0 Hz, CHN), 9.54 (d, 1H, J = 2.0 Hz, CHN), 8.18 (d, 1H, J = 1.6 Hz, Ar-H), 8.05 (d, 1H, J = 7.6, 1.2 Hz, Ar-H), 7.83 (d, 1H, J = 8.4 Hz, Ar-H), 7.63 (t, 1H, J = 8.4 Hz, Ar-H), 7.41 (d, 1H, J = 8.0 Hz, Ar-H), 6.76 (d, 1H, J = 7.6 Hz, Ar-H), 4.05 (s, 3H, OCH₃), 1.69 (s, 6H, CH₃). ¹³C NMR (100 MHz, DMSO-d₆): δ = 182.15 (C=N indole), 167.85 (C=O), 156.33, 155.77, 153.80, 148.32, 146.46, 142.72, 134.43, 132.09, 130.46, 129.33, 123.22, 121.16, 117.35, 108.62, 105.04, 100.29, 56.07, 54.26, 23.91. FT-IR (ATR): ν 1700 (C=O), 1640, 1615 (C=N), 1500 (C=C), 1228 (C-N) cm⁻¹. HRMS (ESI): m/z [M−H]⁻ calcd. for C₂₂H₁₇N₄O₂: 385.1306; found: 385.1306.

3,3-Dimethyl-2-(8-(trifluoromethyl)pyrimido[1,2-b]indazol-3-yl)-3H-indole-5-carboxylic acid (4d): Yellow solid. Yield: 64%. mp: >300 °C. ¹H NMR (400 MHz, DMSO-d₆): δ = 10.11 (d, 1H, J = 2.0 Hz, CHN), 9.65 (d, 1H, J = 2.0 Hz, CHN), 8.56 (d, 1H, J = 8.8 Hz, Ar-H), 8.35 (s, 1H, Ar-H), 8.20 (d, 1H, J = 1.6 Hz, Ar-H), 8.07 (dd, 1H, J = 8.0, 1.2 Hz, Ar-H), 7.86 (d, 1H, J = 7.6 Hz, Ar-H), 7.61 (d, 1H, J = 8.8 Hz, Ar-H), 1.71 (s, 6H, CH₃). ¹³C NMR (100 MHz, DMSO-d₆): δ = 181.85 (C=N indole), 167.80 (C=O), 156.17, 150.49, 148.36, 147.59, 143.13, 135.28, 130.98 (q, J = 31.5 Hz), 130.45, 129.52, 126.19 (q, J = 270.7 Hz), 123.26, 123.21, 121.33, 119.18, 117.11, 114.99 (q, J = 4.7 Hz), 114.86, 54.37, 23.75. ¹⁹F NMR (376 MHz, DMSO-d₆): δ = −60.75. FT-IR (ATR): ν 1699 (C=O), 1652, 1598 (C=N), 1496 (C=C), 1211 (C-N) cm⁻¹. HRMS (ESI): m/z [M−H]⁻ calcd. for C₂₂H₁₄N₄O₂F₃: 423.1069; found: 423.1069.

2.5. X-ray Crystallography

X-ray intensity data for yellow crystals of 1b and 1c were measured at T = 100 K on a Rigaku/Oxford Diffraction XtaLAB Synergy (Dualflex, AtlasS2) diffractometer (Rigaku Oxford Diffraction, Oxford, UK) fitted with CuKα radiation (λ = 1.54178 Å) so that θ_max = 67.7° (corresponding to 100% data completeness). Data reduction, including absorption correction, was accomplished with CrysAlisPro (Oxfordshire, England) [24]. The structures were solved by direct methods [25] and refined (anisotropic displacement parameters and C-bound H atoms in the riding model approximation) on F² [26] A weighting scheme of the form w = 1/[σ²(F_o²) + (aP)² + bP] where P = (F_o² + 2F_c²)/3) was introduced towards the end of each refinement. The absolute structure of 1c was determined based on differences in Friedel pairs included in the data set. The molecular structure diagrams were generated with ORTEP for Windows [27] with 70% displacement ellipsoids, and the packing diagrams were drawn with DIAMOND [28]. Additional data analysis was made with PLATON [29]. Crystal data and refinement details are given in

Table 1. Crystallographic data and refinement details for 1b and 1c.

Compound	1b	1c
Formula	C15H9BrN4	C16H12N4O
Molecular weight	325.17	276.30
Crystal size/mm3	0.03 × 0.04 × 0.34	0.03 × 0.07 × 0.31
Colour	yellow	yellow
Crystal system	triclinic	orthorhombic
Space group	P$\overline{1}$	P212121
a/Å	4.44212(11)	5.35980(8)
b/Å	12.0067(2)	9.27255(15)
c/Å	12.4922(3)	24.9428(4)
a/°	112.154(2)	90
β/°	90.006(2)	90
γ/°	93.8346(19)	90
V/Å3	615.47(3)	1239.63(3)
Z	2	4
Dc/g cm−3	1.755	1.480
μ/mm−1	4.499	0.788
Measured data	15400	9411
θ range/°	3.8–67.7	3.5–67.7
Unique data	2531
Observed data (I ≥ 2.0σ(I))	2420	2476
No. parameters	181	192
R, obs. data; all data	0.027; 0.028	0.028; 0.029
a; b in weighting scheme	0.041; 0.400	0.044; 0.250
Rw, obs. data; all data	0.069; 0.070	0.074; 0.075
Range of residual electron density peaks/eÅ−3	−0.77–0.43	−0.19–0.212

2.6. Computational Details

The Hirshfeld surface analysis was performed using CrystalExplorer17 (Perth, Australia) [30] based on the methods reported in the literature [31], of which the d_norm-map was obtained by calculating the normalised distances from the contact points on the surface to the nearest nucleus inside (d_i) or outside (d_e) the surface upon the adjustment of all X-H bond length to the neutron-derived values [32]. The qualitative energy frameworks were computed for a cluster of 2 × 2 × 3 unit cells with the energy cut-off being set to 8 kJ/mol, using the dispersion corrected CE-B3LYP/DGDZVP model executed through the Tonto quantum modelling package [33] integrated in CrystalExplorer17 [30].

The strength of intermolecular interactions between the molecules was modelled using NCIPLOT (Paris, France) [34] by plotting the reduced density gradient as a function of density across the molecules. The computed density derivatives were mapped as isosurfaces which correspond to any favourable or unfavourable interactions as determined by the sign of the second density Hessian eigenvalue times the density [35]. The VMD Molecular Graphics Viewer (Champaign, USA) [36] was used to visualise the non-covalent interaction indices.

3. Result and Discussion

3.1. Synthesis and Characterisation

As shown in Scheme 2, the condensation reaction of 2-(4-pyridyl)malondialdehyde with 3-aminoindazoles in the presence of acetic acid in refluxing ethanol afforded the corresponding 1a–d in 55–60% yields. The reaction is more favourable in the presence of a substituent in the 3-aminoindazole substrate, which gives 1b–d in higher yields compared to that for 1a.

The proposed synthetic mechanism for the formation of 1 is illustrated in Scheme 3, and is based on the assumed condensation reaction. Intermediate I is achieved via the mono-condensation reaction between the aldehyde and amino groups. Then, the carbonyl group is protonated to produce intermediate II. The nucleophilic attack from the nitrogen atom of the pyrazole to the carbocation centre generates a six-membered ring of intermediate III. Next, the deprotonation of the pyrazole ring gives intermediate IV. The protonation of a hydroxyl group produces intermediate V. Finally, the hydration followed by a deprotonation reaction affords the final product 1.

The ¹H NMR spectra of 1a–d show that the two distinctive pyrimidine olefinic protons appear as doublets (J = 1.6–2.4 Hz) in the range δ 9.21–10.08 ppm, which is consistent with previous findings [23]. The carbon signal of the CF₃ group for 1d manifests as a quartet (J = 271.2 Hz) at δ 127.56 ppm. The fluorine signal due to the CF₃ group of 1d is observed at δ −60.57 ppm. In the FT-IR spectra, the typical sp² C-H stretching modes of 1a-d are characterised in the range 3036–3060 cm⁻¹, while the peaks between 1102 to 1223 cm⁻¹ are attributed to the C–N of the pyrimidine ring.

Subsequently, the synthetic scope of 1,3-dialdehyde substrate was further explored. As illustrated in Scheme 4, precursor 2 was synthesised according to the previous method [37]. The ester hydrolysis reaction of 2 produced 3 in 68% yield. Further, an equimolar condensation reaction of 3 with 3-aminoindazoles generated 4a–d in 64–85% yields. It was found that the presence of the electronic substituents on the indazole rings slightly reduces the reaction reactivity which resulted in lower yields of 4b–d as compared to that of 4a. The synthetic mechanism for the formation of 4a–d is presented in the literature [23].

The ¹H NMR spectra of 4a–d reveal that the two olefinic pyrimidine protons resonate between δ 9.47–10.04 ppm as doublets (J = 1.6–2.0 Hz). A singlet signal between δ 1.64–1.66 ppm is assigned to the six methyl protons. Furthermore, the ¹³C NMR spectra indicate that the most deshielded signals between δ 181.85–182.18 ppm correspond to the C=N(indole) [37], whereas the signals at around δ 167.80 ppm are assigned to the C=O group. The carbon chemical shift of the CF₃ for 4d appears as a quartet (J = 270.7 Hz) at δ 126.19 ppm. In ¹⁹F NMR spectrum of 4d, the CF₃ signal appeared at δ −60.75 ppm indicating no significant fluorine signal shift is observed when replacing pyridyl with indoleninyl at the C-3 position of the ring. The FT-IR spectra show that the strong intensity bands between ν 1675–1700 cm⁻¹ which are ascribed to the stretching mode of the C=O. Moreover, the vibration bands between 1211–1258 cm⁻¹ are assigned to the C-N of the pyrimidine ring.

3.2. Crystal and Molecular Structures

Crystals of two representative examples of series 1, i.e., 1b and 1c, were obtained and their structures established by X-ray crystallography. The molecular structures are shown in Figure 1.

The 13 atoms comprising the pyrimido[1,2-b]indazole core of 1b are strictly co-planar exhibiting a r.m.s. deviation of 0.009 Å with the maximum deviation from the plane being 0.011(2) Å for the C4 atom. Appended to the fused ring system is a 4-pyridyl ring which is twisted out of the plane of the core, as manifested in dihedral angle between the planes of 21.55(8)°. As anticipated, within the five-membered ring, considerable delocalisation of the π-electron density is evident, especially, by the relative shortening of the N1–N3 [1.364(2) Å] and lengthening of the C1–C6 [1.404(3) Å] bonds.

While the molecular structure of 1c presents similar features to those just described, the r.m.s. deviation for the fused ring system of 0.042 Å is significantly greater than noted for 1b and is reflected in a dihedral angle of 4.29(8)° between the outer six-membered rings of the pyrimido[1,2-b]indazole core, data indicative of a small kink in the molecule. The 4-pyridyl residue forms a dihedral angle of 17.77(6)° with the fused ring system. Despite the aforementioned conformational differences between 1b and 1c, the delocalisation of π-electron density is similar. Thus, the N1–N3 [1.3537(18) Å] and C1–C6 [1.406(2) Å] bond lengths follow the same trends established above for 1b.

The similarity in molecular structures notwithstanding, the molecular packing of 1b and 1c present quite distinct features. The unit-cell contents for 1b are illustrated in Figure 2 with the geometric parameters describing the identified intermolecular contacts included in

Table 2. Geometric parameters characterising the specified intermolecular contacts for 1b and 1c.

A	H	B	H···B	A···B	A–H···B	Symmetry Operation
1b
C2	H2	N2	2.46	3.298(3)	146	2 + x, y, 1 + z
C8	Br1	N4	1.895(2)	3.0613(19)	171.72(7)	2 + x, y, 1 + z
Cg(N1,N3,C1,C5,C6)	Cg(N1,N2,C1–C4)	3.4764(11)	0.07(10)	1 + x, y, z
C4		C12		3.074(3)		1 + x, y, z
1c
C14	H14	O1	2.44	3.161(2)	133	1 − x, ½ + y, 1½ − z
C4	H4	N3	2.51	3.435(2)	163	½ + x, 1½ − y, 2 − z

. A prominent mode of association between molecules are pyrimidyl-N–H···N(pyrimidyl) interactions leading to six-membered {···NCH}₂ synthons. These aggregates stack along the a-axis direction and feature π(pyrazolyl)···π(pyrimidyl) contacts between them. An important consequence of these links and the twist between the fused-ring system and the 4-pyridyl group (see above) is that the C4 and C12 atoms of the respective residues are brought into close proximity, these atoms being separated by 3.074(3) Å. Columns are linked into supramolecular layers by type 1 [38,39], Br···N halogen bonding interactions. The layers stack along the b-axis without directional interactions between them.

The unit-cell contents for 1c are illustrated in Figure 3 and the intermolecular contacts listed in Table 2. Here, molecules stack along the a-axis, being connected by pyrimidyl-C–H···N(pyrazolyl) interactions involving three different molecules in addition to pyridyl-C–H···O(methoxy) interactions within a three-dimensional architecture.

3.3. Computational Chemistry

The X-ray structures of 1b and 1c were subjected to Hirshfeld surface analysis to better understand the nature of interactions present in these crystals; see

Table 3. List of contact distance between the corresponding red spots as identified on the d_norm-surfaces for 1b and 1c.

Contact	Distance (Å)	∑vdw(X···Y)	Symmetry Operation
1b
Br1···N4	3.06	3.40	2 + x, y, 1 + z
N2···H2	2.36	2.64	−1 − x, −y, −z
N3···H4	2.56	2.64	−x, 1 − y, −z
C4···C12	3.07	3.40	1 + x, y, z
C12···H10	2.65	2.79	−x, 1 − y, −z
C13···H10	2.67	2.79	−x, 1 − y, −z
1c
O1···H14	2.35	2.61	1 − x, −½ + y, 3/2 − z
N4···H2	2.61	2.64	2 − x, ½ + y, 3/2 − z
N3···H4	2.39	2.64	−½ + x, 1½ − y, 2 − z
C13···H10	2.78	2.79	1½ + x, 1½ − y, 2 − z
C1···C8	3.40	3.40	1 + x, y, z
N2···H16c	2.58	2.79	1 + x, y, z

for geometric data. As shown in Figure 4, the analysis reveals a number of red spots on the d_norm-surfaces indicating the presence of close contacts with distances shorter than the sum of the respective van der Waals radii (∑vdw); the intensity of the spots is directly proportional to the contact distance between the interacting atoms [32]. Owing to the sharing of a common structural framework, 1b and 1c exhibit some red spots featuring the same interacting atoms but leading to different contacts as demonstrated by N3···H4 and C13···H10. Among the distinctive contacts in 1b are Br1···N4 (∑d_i + d_e = 3.06 Å vs. ∑vdw = 3.40 Å), C4···C12 (∑d_i + d_e = 3.07 Å vs. ∑vdw = 3.40 Å) and N2···H2 (∑d_i + d_e = 2.36 Å vs. ∑vdw = 2.64 Å). In 1c, these include O1···H14 (∑d_i + d_e = 2.35 Å vs. ∑vdw = 2.61 Å).

Among those close contacts, only N2···H2 and Cg2(C4)···Cg3(C12) of 1b, as well as N3···H4, O1···H14 and Cg1(C1)···Cg4(C8) of 1c, are in line with the PLATON analysis [29], based on geometric criteria, while the rest are identified in the analysis of the calculated Hirshfeld surfaces. Of particular interest is the interaction between Br1 and N4, for which the contact arises from the complementarity between electron-deficient region at the σ-hole [40,41] of Br1 and negatively charge pyridyl-N4 lone-pair of electrons, thereby leading to the charge-induced attraction between the atoms as evident from the electrostatic surface mapping on the Hirshfeld surfaces, Figure 5a. Shape complementarity studies were also conducted for the stacking of the pyrimido[1,2-b]indazole fused rings in each of 1b and 1c by mapping the curvedness property on the Hirshfeld surface. The mapping reveals that although C4···C12 of 1b and C1···C8 of 1c are the only contacts within the aromatic rings having distances shorter than the ∑vdw, the overall fused rings in the respective structure are well stacked as shown in Figure 5b,c which could maximise the configuration entropy and lead to effective entropy-induced attraction for optimum aggregation within the molecules [42].

The fingerprint plot analysis was performed to quantify the corresponding close contacts identified through the Hirshfeld surface analysis. The resulting overall fingerprint plots, Figure 6, reveal two essential qualitative observations about the packing in the crystals. Firstly, the analysis affirms the contrast between the packing in 1b and 1c as evident from the vastly different paw-like and shield-like profiles, respectively. Secondly, the profile of 1b is slightly more diffuse in the tail region indicating relatively low packing efficiency as compared to the 1c counterpart [43], an observation that tallies with the calculated Kitaigorodskii packing index of 73.3% for the former in contrast to 74.8% for the latter [29]. As expected, a comparison of the major common decomposed fingerprint plots delineated into H···H, H···N/N···H, H···C/C···H and C···C contacts shows that the distribution of the corresponding contacts between 1b and 1c is different in each case, with the percentage contributions also being distinct, i.e., 31.8, 15.8, 12.0 and 11.5% for 1b compared to 35.1, 23.2, 22.6 and 7.3% for 1c. With the exception of H···H contact for 1b, the remaining major contacts display a tip in their respective profile with d_i + d_e corresponding to the shortest d_norm-distance listed in Table 3.

The crystals of 1b and 1c also display some additional contacts owing to the presence of the Br and O atoms, respectively. Due to the polarisation effect, the Br atom in 1b tends to participate more in interactions as compared to the O atom in 1c with the overall contact distribution involving Br being 19.1% which can be delineated into H···Br/Br···H (12.7%), N···Br/Br···N (4.2%), C···Br/Br···C (2.0%) and Br···Br (0.2%). In comparison, O only participates in about 6.5% of the overall contacts which are delineated into H···O/O···H (5.0%), O···C/C···O (0.8%) and O···N/N···O (0.7%) contacts. Among these contacts, only N···Br/Br···N and H···O/O···H have d_i + d_e contact distances less than the respective ∑vdw (cf. Table 1) as revealed through the respective fang-like profiles evident in Figure 7.

The enrichment ratios [44] were calculated to establish the propensity for the formation of specific intermolecular interactions in 1b and 1c. The calculations show that H···H, H···N/N···H, H···Br/Br···H, C···C, N···C/C···N and N···Br/Br···N contacts of 1b as well as H···H, H···N/N···H, C···C and H···O/O···H of 1c have a ratio equal to or greater than unity indicating these contacts are favoured in the molecular packing [44], Figure 8. While the calculated ratios are not exactly in line with the trends of d_i + d_e distances, in particular for H···H, H···Br/Br···H and N···C/C···N in 1b, these contacts have been established to play an essential role in the molecular packing.

Having established the close contacts through the Hirshfeld surface analysis, all pairwise interactions were subjected to interaction energy calculations to evaluate the strength of specific contacts in the respective crystals. In the absence of conventional hydrogen bonding in the crystal, the most stable interaction in 1b arises from the π···π interaction involving N1–C1–N2–C2–C3–C4 (Cg2) and N4–C13–C12–C11–C15–C14 (Cg3) with the total interaction energy for this contact, E_int, being −60.1 kJ/mol (

Table 4. Interaction energies (kJ/mol) for all close contacts present in the crystals of 1b and 1c ^a.

Close Contact	Eelectrostatic	Epolarization	Edispersion	Erepulsion	Eint	Symmetry Operation
1b
Cg2(C4)···Cg3(C12)	−39.9	−2.9	−91.4	103.3	−60.1	1 + x, y, z
C4–H4···N3 (×2) +	−34.6	−5.9	−34.7	48.1	−41.4	−x, 1 − y, −z
C10–H10···C12 (×2) +
C10–H10···C13 (×2)
C2–H2···N2 (×2)	−28.3	−5.0	−30.2	42.3	−33.8	−1 − x, −y, −z
C8–Br1···N4	−15.3	−1.7	−8.1	26.4	−8.1	2 + x, y, 1 + z
1c
Cg1(C1)···Cg4(C8) +	H14	O1	2.44	3.161(2)	133	1 − x, ½ + y, 1½ − z
C16–H16c···N2
C14–H14···O1	−19.3	−4.6	−19.5	26.1	−24.6	1 − x, ½ + y, 1½−z
C4–H4···N3	−14.7	−4.2	−19.7	22.1	−22.2	½ + x, 1½ − y, 2 − z
C2–H2···N4	−10.5	−2.2	−13.3	12.2	−16.8	2 − x, ½ + y, 1½ − z
C10–H10···C13	−3.3	−1.0	−11.4	14.4	−5.3	−1½ + x, 1½ − y, 2 − z

^a Cg1 = N1–N3–C5–C6–C1; Cg2 = N1–C1–N2–C2–C3–C4; Cg3 = N4–C13–C12–C11–C15–C14; Cg4 = C5–C6–C7–C8–C9–C10.

) mainly owing to the effective stacking between the fused rings as discussed above. This is followed by the eight-membered {···NNCH}₂ homosynthon complemented by C10–H10···C12 and C10–H10···C13 interactions with a combined E_int of −41.4 kJ/mol. The halogen bonding contact arising from C8–Br1···N4 results in the smallest E_int of −8.1 kJ/mol.

In 1c, the π···π contacts involving N1–N3–C5–C6–C1 (Cg1) and C5–C6–C7–C8–C9–C10 (Cg4) results in an almost equivalent E_int of −59.3 kJ/mol relative to 1b, although it is noted that the π···π contacts are complemented by the C16–H16c···N2 contact identified through the Hirshfeld surface analysis. Other contacts contribute to stabilisation of the packing to a lesser extent with E_int ranging from −24.6 to −5.3 kJ/mol, respectively.

The non-covalent interaction (NCI) plots were calculated to complement the energy calculations for interactions involving the fused rings as well as the halogen bonding contact between Br1 and N4. As shown in Figure 9, a large isosurface derived from the reduced density gradient [35] is seen to be extended across the entire stacked molecules in 1b while a relatively smaller isosurface is observed across the fused rings in 1c, both indicating significant attractive forces existing between the molecules. By contrast, a clearly smaller isosurface is found between the Br1 and N4 atomds indicating a weak but attractive force for the halogen bonding contact. Overall, the results from NCI plot complement the computed interaction energies for the respective close contacts.

A simulation of energy frameworks was conducted for 1b and 1c to assess the nature of the forces characterising the interactions and their influence upon the molecular packing. Overall, the packing of 1b and 1c are mainly sustained by dispersion forces attributed to π···π interactions between the fused aromatic rings supported by relatively weaker C–H···N interactions, in which the combined forces lead to a ladder-like dispersion energy framework in 1b, while a beta sheet-like framework is observed in 1c, Figure 10. The same interactions also contributed to the electrostatic forces but to a lesser extent. For 1b, peripheral electrostatic forces arising from the Br···N halogen bonding contact is observed that strengthens the electrostatic energy framework and which subsequently inherited by the total energy framework. As for 1c, the electrostatic forces are mainly contributed by π···π and C–H···O interactions that lead to a tile-like energy framework, while the total energy framework remains very much the same as the dispersion energy framework.

4. Conclusions

In conclusion, the synthesis of substituted pyrimido[1,2-b]indazoles via a straightforward condensation reaction between the 1,3-dialdehydes and 3-aminoindazoles was accomplished. This synthetic approach offers several advantages such as economic, operationally simple and showed functional groups tolerance with different substituents on both substrates. X-ray crystallography on representative examples support the spectroscopic assignments and indicate substantial π-electron density delocalisation over the fused ring system.