New Tricyclic Aryl Quinazoline Derivatives by Suzuki‐Miyaura Cross‐Coupling

Burkhon Elmuradov; Rasul Okmanov; Bakhromjon Juraev; Gerald Dräger; Prof Dr Holger Butenschön

doi:10.1002/open.202400197

. 2024 Sep 27;13(12):e202400197. doi: 10.1002/open.202400197

New Tricyclic Aryl Quinazoline Derivatives by Suzuki‐Miyaura Cross‐Coupling

Burkhon Elmuradov ^1,^2,^✉, Rasul Okmanov ², Bakhromjon Juraev ², Gerald Dräger ¹, Holger Butenschön ^1,^✉

PMCID: PMC11625927 PMID: 39329258

Abstract

A number of new deoxyvasicinone (2,3‐dihydropyrrolo[2,1‐b]quinazolin‐9(1H)‐one) and mackinazolinone (6,7,8,9‐tetrahydro‐11H‐pyrido[2,1‐b]quinazolin‐11‐one) derivatives with aryl substituents at C7/C8 and at C5 are reported. These compounds are rare representatives of their kind and were prepared in high yields by Suzuki‐Miyaura cross‐coupling reactions between 7‐bromo‐2,3‐dihydro[2,1‐b]quinazoline‐9‐(1H)‐one, 5,7‐dibromo‐2,3‐dihydro[2,1‐b]quinazoline‐9‐(1H)‐one or 8‐bromomackinazolinone and respective arylboronic acids with palladium acetate as the catalyst. The products were characterized spectroscopically and, in addition, by X‐ray crystal structure analyses in six cases.

Keywords: Cross-Coupling, Palladium Catalysis, Suzuki-Miyaura Reaction, Quinazoline

New quinazoline derivatives are prepared in high yields by single or double Suzuki‐Miyaura cross‐coupling of the rare respective brominated precursors. Six of the products are crystallographically characterized, and results of some DFT calculations of the new products are reported.

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Introduction

Deoxyvasicinone (2,3‐dihydropyrrolo[2,1‐b]quinazolin‐9(1H)‐one, 1) ^[1] and mackinazolinone (6,7,8,9‐tetrahydro‐11H‐pyrido[2,1‐b]quinazolin‐11‐one, 2) ^[2] are tricyclic quinazoline alkaloids with significant anti‐inflammatory, anti‐microbial, anti‐depressant and anti‐oxidant activities,[ ³ , ⁴ , ⁵ , ⁶ , ⁷ ] which also deserve interest as ligands in the context of the treatment of Alzheimer's disease. ^[8] Therefore a number of derivatives have been prepared with a variety of substitution patterns.[ ⁹ , ¹⁰ ] Interestingly, there are less than 80 derivatives of 1 known, which bear an aryl substituent at C‐7 (Scheme 1). ^[11]

Scheme 1 — Deoxyvasicinone (1), mackinazolinone (2), and bromo derivatives 3–5.

Remarkably, reports of the bromo derivatives 3,[ ¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² ] 4,[ ¹⁷ , ²³ ] and 5[ ²¹ , ²⁴ ] are comparatively rare. However, they offer the attractive possibility to obtain a variety of new derivatives by using palladium‐catalyzed coupling reactions such as the Suzuki‐Miyaura cross‐coupling.[ ²⁵ , ²⁶ , ²⁷ , ²⁸ ] In the context of our ongoing research[ ¹⁰ , ¹⁶ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ ] we investigated this possibility and report here the syntheses and characterization of a number of new tricyclic quinazoline derivatives starting from 3–5. 3–5 were obtained by condensation of 5‐bromoanthranilic acid or 3,5‐dibromoanthranilic acid with respective lactams according to the published procedures (see Experimental Section).[ ¹⁷ , ¹⁹ , ³⁴ ]

Results and Discussion

Biaryl derivatives have a remarkable importance in a variety of fields such as natural products synthesis, medicinal chemistry or materials science.[ ³⁵ , ³⁶ , ³⁷ , ³⁸ ] While stoichiometric reactions targeting at axially chiral derivatives[ ³⁹ , ⁴⁰ ] and dehydrogenative couplings such as the Scholl reaction ^[41] are still important, over the last decades catalytic reactions allowing for the coupling of two aryl building blocks have been developed,[ ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ ] the most common ones being Suzuki‐Miyaura,[ ⁴⁶ , ⁴⁷ , ⁴⁸ ] Negishi, and Stille coupling reactions. ^[27] Among these the Suzuki‐Miyaura coupling often gives highest yields and, in addition, has the advantage of using the least toxic, often commercially available and most easily to handle reagents.

New deoxyvasicinone derivatives 6–11 (Scheme 2) were prepared in high yields by palladium‐catalyzed Suzuki‐Miyaura coupling of 3 (Table 1) with the respective boronic acids. Use of Pd(OAc)₂ gave 10–15 % higher yields than reactions performed with [Pd(PPh₃)₄] as the catalyst. Smaller catalyst amounts resulted in reduced product yields.

Table 1.

Suzuki‐Miyaura coupling reactions of 7‐bromo‐2,3‐dihydropyrrolo[2,1‐b]quinazoline‐9‐(1H)‐one (3).

Entry	Product	Conditions	Yield (%)
1	6	Pd(OAc)₂ (4.2 mol %), PhB(OH)₂ (2.2 equiv.), Na₂CO₃ (2.0 equiv.), acetone/water (1 : 1), 40–45 °C, 3 h.	92
3	7	Pd(OAc)₂ (4.2 mol %), 4‐NCC₆H₄B(OH)₂ (1.1 equiv.), Na₂CO₃ (2.5 equiv.), acetone/water (2 : 1), 40–45 °C, 3 h.	96
4	8	Pd(OAc)₂ (4.2 mol %), 8‐quinolinyl B(OH)₂, (1.2 equiv.), Na₂CO₃ (2.5 equiv.), acetone/water (2 : 1), 40–45 °C, 5 h.	83
5	9	Pd(OAc)₂ (4.2 mol %), (3,4,5‐trimethoxyphenyl) B(OH)₂ (1.2 equiv.), Na₂CO₃ (2.5 equiv.), acetone/water (2 : 1), 40–45 °C, 0.5 h.	97
6	10	Pd(OAc)₂ (4.2 mol %), benzothiophene‐3‐B(OH)₂ (2.2 equiv.), Na₂CO₃ (2.0 equiv.), acetone/water (2 : 1), 40–45 °C, 3 h.	89
7	11	Pd(OAc)₂ (4.2 mol %), dibenzothiophene‐4‐B(OH)₂ (1.2 equiv.), Na₂CO₃ (2.5 equiv.), acetone/water (2 : 1), 40–45 °C, 7 h.	91

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6–11 were characterized on the basis of their consistent spectroscopic data (¹H NMR, ¹³C{¹H} NMR, IR, MS). In addition, compounds 9 and 10 were subjected to X‐ray crystal structure analyses (Figures 1, 2).

Structure of 9 in the crystal. ^[49] Ellipsoids at 50 % probability level. Hydrogen atoms omitted for clarity. For selected bond lengths, bond angles and torsional angles see Table 3.

Structure of 10 in the crystal. ^[49] Ellipsoids at 50 % probability level. For selected bond lengths, bond angles and torsional angles see Table 3.

Most of the reactions give the π extended reaction products in very high yields. However, use of 2,4,6‐trifluorophenyl boronic acid under the usual conditions did not result in product formation, presumably because of the electron withdrawing effect of the fluoro substituents in ortho and para positions.

5,7‐Dibromo derivative 5 offers the possibility of a double cross‐coupling reaction. This was tested and gave disubstituted derivatives 12–16 in 74–98 % yield (Table 2, Scheme 3). Remarkably, the reaction with 8‐quinolineboronic acid remained incomplete and gave mono‐substituted derivative 16 in 68 % yield clearly indicating that the Suzuki‐Miyaura coupling at C7 is significantly faster than that at C5 with the additional option of attaching different substituents at C5 and C7. This may be a result of the proximity of the nitrogen atom N4, which bears a lone electron pair possibly interacting with the catalyst metal. 5,7‐Diarylated 2,3‐dihydro[2,1‐b]quinazoline‐9‐(1H)‐one derivatives are very rare, a SciFinder® substructure search gave only five loosely related compounds mentioned in a Chinese patent in the context of electroluminescence applications. ^[50]

Table 2.

Suzuki‐Miyaura coupling of 5,7‐dibromo‐2,3‐dihydro[2,1‐b]quinazoline‐9‐(1H)‐one (5). Conditions: Pd(OAc)₂ (8.4 mol %), ArB(OH)₂ (2.4 equiv.), Na₂CO₃ (2.5 mmol), acetone/water (1 : 1), 40–45 °C, 5 h.

Entry	Product	Yield (%)
1	12	84
3	13	97
4	14	98
5	15	75
6	16	68

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Scheme 3 — Arylated deoxyvasicinone derivatives 12–16.

Coupling products 12–16 were characterized spectroscopically, and crystals suitable for X‐ray structure analyses were obtained from 13 and 14 (Figures 3 and 4).

Structure of 13 in the crystal. ^[49] Ellipsoids at 50 % probability level. Hydrogen atoms omitted for clarity. For selected bond lengths, bond angles and torsional angles see Table 3.

Structure of 14 in the crystal. ^[49] Ellipsoids at 50 % probability level. Hydrogen atoms omitted for clarity. For selected bond lengths, bond angles and torsional angles see Table 3.

Selected geometrical data of coupling products 9, 10, 13, and 14 are listed in Table 3. Within the systematic error the data in Table 3 indicate same geometries for the basic tricyclic quinazoline systems in 9, 10, 13, and 14. Slight deviations can be observed at the substituted positions. Differences are observed for the torsional angles indicating the degree of non‐coplanarity of up to 48.3° of the π systems of the basic system and that of the substituents, particularly reflecting the steric bulk of the substituents in 10 and 13.

Table 3.

Selected bond lengths, bond angles, and torsion angles of deoxyvasicinone derivatives 9, 10, 13, and 14 as determined by X‐ray crystal structure analyses. ^[49] For atom numbering schemes see Figures 1, 2, 3, 4.

Bond length [pm], bond angle [°] or torsion angle [°]	9	10	13	14
C1‐C2	152.9(4)	151.5(3)	153.9(3)	153.2(5)
C1‐N9a	146.7(3)	147.6(3)	147.3(3)	147.7(4)
C2‐C3	151.9(4)	150.8(4)	152.4(4)	154.1(5)
C3‐C3a	150.0(4)	150.4(3)	151.0(3)	150.1(5)
C3a‐N4	128.9(3)	128.4(3)	129.6(3)	129.4(3)
C3a‐N9a	137.7(3)	137.8(2)	137.3(3)	137.5(4)
N4‐C4a	139.8(3)	139.4(2)	140.6(3)	139.5(3)
C4a‐C5	139.5(4)	140.2(2)	141.9(3)	143.7(3)
C5‐C6	137.6(3)	136.9(3)	139.6(3)	139.1(3)
C6‐C7	140.3(3)	141.2(3)	141.3(3)	140.4(3)
C7‐C8	138.2(3)	138.1(2)	138.8(3)	138.9(3)
C7‐C11	149.0(3)	148.4(3)	150.2(3)	149.0(3)
C8‐C8a	140.0(3)	139.8(2)	140.7(3)	139.9(4)
C8a‐C9	146.1(4)	146.4(2)	146.8(3)	146.9(4)
C9‐N9a	137.7(3)	137.9(2)	138.6(3)	138.4(4)
C9‐O10	122.7(3)	122.6(2)	122.7(3)	122.5(3)
C1‐N9a‐C9	123.0(2)	123.9(1)	123.1(2)	123.5(2)
C3‐C3a‐N4	126.0(2)	126.9(2)	125.0(2)	126.1(3)
N4‐C4a‐C5	118.9(2)	119.1(1)	119.8(2)	119.5(2)
C6‐C7‐C11‐C12	−37.0(3)	47.8(3)	−11.2(3)	−20.5(4)
C6‐C7‐C11‐C12′	142.9(2)		168.8(2)	157.3(2)
C6‐C7‐C11‐C17a		−134.6(2)
C6‐C5‐C19‐C20			48.4(3)
C6‐C5‐C19‐C20′			−130.4(2)
C6‐C5‐C17‐C18				38.4(3)
C6‐C5‐C17‐C18′				−137.3(2)

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Starting from bromomackinazolinone 4 with one methylene group more than 7‐bromo‐2,3‐dihydropyrrolo[2,1‐b]quinazoline‐9‐(1H)‐one (3) new arylated derivatives 17–21 were prepared by Suzuki‐Miyaura coupling reactions in 90 % and 95 % yield, respectively (Scheme 4). Remarkably, according to a SciFinder® search, there are so far only eight arylated mackinazolinione derivatives known including a patent in the context of electroluminescent properties. ^[51]

Scheme 4 — Mackinazolinone derivatives 17–21.

In addition to their spectroscopic characterization, 18 and 19 were subjected to crystal structure analyses (Figures 5 and 6). Selected geometrical data of 18, and 19 are listed in Table 4.

Structure of 18 in the crystal. ^[49] Ellipsoids at 50 % probability level. Hydrogen atoms omitted for clarity. For selected bond lengths, bond angles and torsional angles see Table 4.

Structure of 19 in the crystal. ^[49] Ellipsoids at 50 % probability level. Hydrogen atoms omitted for clarity. For selected bond lengths, bond angles and torsional angles see Table 4.

Table 4.

Selected bond lengths, bond angles, and torsion angles of mackinazolinone derivatives 18 and 19. For atom numbering schemes see Figures 5–6.

Bond length [pm], bond angle [°] or torsion angle [°]	18	19
C1‐C2	150.8(7)	151.9(3)
C1‐N10a	148.3(2)	148.0(2)
C2‐C3	151.1(7)	147.3(4)
C3‐C4	150.1(5)	149.9(3)
C4‐C4a	151.1(3)	150.4(3)
C4a‐N5	130.0(2)	129.3(2)
C4a‐N10a	137.5(2)	137.4(2)
N5‐C5a	138.7(2)	138.2(2)
C5a‐C6	140.1(2)	139.7(3)
C5a‐C9a	140.1(2)	138.7(2)
C6‐C7	137.7(2)	136.5(3)
C7‐C8	140.7(2)	140.5(3)
C8‐C9	138.8(2)	138.4(2)
C8‐C12	148.4(2)	148.7(2)
C9‐C9a	140.0(2)	139.6(2)
C9a‐C10	145.5(2)	145.6(2)
C10‐N10a	140.5(2)	140.1(2)
C10‐O11	121.8(2)	122.0(2)
C1‐N10a‐C10	114.8(1)	114.5(2)
C4‐C4a‐N5	116.9(1)	117.2(2)
C7‐C8‐C12‐C13	40.5(2)	13.7(3)
C7‐C8‐C12‐C13′	−138.9(1)	−167.4(2)

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In 18 the methylene groups of the molecule are disordered over two positions (C2, C3). Refinement of the structure yielded 0.628 (12) : 0.372 (12) occupancy ratio of the disordered atoms (i. e. two conformers). The disorder of the methylene groups was previously observed in the quinazoline derivative crystals of 2‐bromo‐6,8,9,11‐tetrahydro‐7H‐pyrido[2,1‐b]quinazolin‐11‐ol and 6,8,9,11‐tetrahydro‐7H‐pyrido[2,1‐b]quinazolin‐11‐ol. ^[52] The piperidine ring with two sp ²‐hybridized atoms of C4a and N10a adopts half‐chair conformation.

Some DFT calculations of 1 and 6–11 have been performed. ^[53] Calculated HOMO and LUMO energies are listed in Table 5, which also contains the energies of the HOMO‐LUMO gaps and the torsional angles between the aryl substituents and the quinazoline system based on the structure analyses and on the calculations. As a representative examples, the HOMOs of 7 and 14 are shown in Figures 7 and 8.

Table 5.

Calculated HOMO and LUMO energies in eV and torsional angles. ^[53] Groups A‐C refer to 7‐monosubstituted (A), 5,7‐disubstituted deoxyvasicinone (B), and 8‐monosubstituted mackinazolinone (C) derivatives.

Group	Compound	HOMO [eV]	LUMO [eV]	Δ [eV]	Torsion^[a]
A	1	−8.33	0.48	8.81	–
	6	−7.98	0.38	8.36	C7 : 40.8°
	7	−8.34	−0.34	8.00	C7 : 39.9°
	8	−7.84	−0.10	7.74	C7 : 51.0°
	9	−7.86	0.40	8.26	C7 : 37.0°/39.6°
	10	−7.77	0.39	8.16	C7 : 47.8°/51.3°
	11	−7.81	0.28	8.09	C7 : 57.1°
B	12	−7.87	0.28	8.15	C5 : 50.4° C7 : 40.3°
	13	−7.67	0.29	7.96	C5 : 48.4°/50.1° C7 : 11.2°/40.0°
	14	−8.19	−0.28	7.91	C5 : 38.4°/47.6° C7 : 20.5°/39.2°
	15^b	−7.43	0.56	7.99	C5 : 67.5° C7 : 51.5°
	16	−7.94	−0.22	7.72	C7 : 49.3°
C	17	−7.94	0.39	8.33	C8 : 41.1°
	18	−8.29	−0.32	7.97	C8 : 40.5°/40.3°
	19	−7.73	0.42	8.15	C8 : 13.7°/40.8°
	20	−7.71	0.38	8.09	C8 : 48.2°
	21	−7.78	0.28	8.06	C8 : 55.9°

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[a] The numbers give the torsional angle between the connected π systems at the indicated carbon atom. Torsional angle signs omitted for clarity. Italics: by X‐ray structure analysis; non‐italics: by DFT calculation (ωB97X−D, 6–311+G**). [b] Calculation with 6–311+G** failed, data calculated with 6–31G*.

The data show that the calculated torsions of the substituents at C7 in 9 and 10 are reasonably in agreement with those of the structure analyses. For 13 and 14 this is the case only for the substituents at C5, while the calculated torsions at C7 significantly deviate from those measured. While there is an excellent agreement between the measured and the calculated torsion for 18, this is not the case for the methoxy substituted derivative 19. A possible reason for the observed deviations may be the fact that the calculations were done for the gas phase, while the measurements show the compounds in the crystalline state more prone to intermolecular interactions.

As representative examples Figures 7, 8, 9 show the HOMOs of 7, 14, and 18. These derivatives are those with the lowest HOMO in the respective group as a result of the electron withdrawing cyano substituents. All three HOMOs show a nodal plane between the substituent and the quinazoline π systems. For 18 HOMO‐6 is the highest π orbital with a significant overlap between the aryl substituent and the quinazoline π system as shown in Figure 10.

HOMO‐6 of 18 as calculated by DFT. ^[53]

Within group A (7‐monosubstituted deoxyvasicinones) 4‐cyanophenyl derivative 7 with an electron withdrawing substituent has the lowest HOMO and also the lowest LUMO. Compound 10 with an electron rich benzo[b]thiophen‐3‐yl substituent has the highest HOMO and a similar LUMO as the electron rich 9. The reliability of the calculations for 9 and 10 is high as indicated by the close matches for the torsional angles between the calculated and the measured values (vide supra). Within group B (5,7‐disubstituted deoxyvasicinones) the di(4‐cyanophenyl) substituted derivative 14 has the lowest HOMO and also the lowest LUMO with a HOMO‐LUMO gap of only 7.91 eV. The highly electron rich derivative 13 has the highest HOMO and also the highest LUMO in this group. Among the 2‐substituted mackinazolinone derivatives (group C) 4‐cyanophenyl derivative 18 has the lowest HOMO and also the lowest LUMO with excellent match of the calculated and measured torsional angle (vide supra). Electron rich derivatives 19 and 20 show the highest HOMOs. Over all, the (4‐phenyl) substituted derivatives 7, 14, and 18 consistently show the lowest HOMOs in their respective groups.

Conclusions

In conclusion, we report the syntheses of a number of new deoxyvasicinone and mackinazolinone derivatives. The deoxyvasicinone derivatives bear aryl substituents at C7 and at C5, while mackinazolinone derivatives are substituted at C2. The systems with substituents at C5 or C2 are rare, so that the number of compounds of these types has significantly been increased. The compounds have been prepared in high yields by Suzuki‐Miyaura cross‐coupling reactions with palladium acetate as the catalyst and the respective boronic acids. Six of the compounds have been characterized by X‐ray crystal structure analyses showing very similar geometries for the tricyclic base systems of the derivatives. DFT calculations have been performed showing very good matches with the structural measurements of the torsional angles between the connected π systems for some cases. For all three groups of compounds the 4‐cyanophenyl substituted derivatives show the lowest HOMO energies.

Experimental Section

General. Starting materials were either commercially acquired or were prepared according to published procedures.[ ¹⁷ , ¹⁹ , ³⁴ ] ¹H and ¹³C{¹H} NMR spectra were obtained with Bruker AVS 400 (¹H: 400 MHz, ¹³C: 100.6 MHz) and AVS 500 (¹H: 500 MHz, ¹³C: 125.7 MHz) and with Varian Unity400 plus and Jeol JNM‐ECZ 600 R instruments. Chemical shifts δ refer to δ _TMS=0 ppm (¹H NMR) or to residual solvent signals (¹³C{¹H} NMR). Primary, secondary, tertiary and quaternary carbon atom signals were identified as such by the APT or DEPT spectra. IR spectra were obtained with Perkin‐Elmer instruments FT‐IR 580 and 1170 using the ATR technique. Signal characteristics are abbreviated as s (strong), m (medium), w (weak), and br (broad). Mass spectra were obtained with a Micromass LCT instrument with lockspray source and direct injection and with a Q−TOF premier LC–MS/MS instrument with an Ionsabre‐APCI‐source (25 μA, 350 °C). In all cases acetonitrile was used as the solvent. Crystal structure analyses were obtained with CCD Xcalibur diffractometer (Oxford Diffraction) or Bruker SMART X2S instruments and were deposited with the CCDC. Analytical TLC was performed with Merck 60F‐254 silica gel thin layer plates. Column chromatography was performed with J. T. Baker silica gel (60 μm) as the stationary phase using the flash chromatography method. ^[54] Melting points were measured with an instrument Electrothermal IA9000. All operations were performed in an argon atmosphere.

General Procedure (GP): 7‐Bromo‐2,3‐dihydropyrrolo[2,1‐b]quinazoline‐9‐(1H)‐one (3), 5,7‐dibromo‐2,3‐dihydro[2,1‐b]quinazoline‐9‐(1H)‐one (5) or 2‐bromo‐6,7,8,9‐tetrahydro‐11H‐pyrido[2,1‐b]quinazolin‐11‐one (4), arylboronic acid, sodium carbonate and palladium (II) acetate in acetone/water are stirred at 40–45 °C. After cooling the reaction mixture to 20–25 °C aqueous sodium hydroxide (1 M) is added, and the mixture is extracted with chloroform (2×15 mL) and then washed with water (2×5 mL). The organic layer is separated and dried over anhydrous sodium sulfate. After solvent removal at reduced pressure the product is purified by column chromatography or crystallized from benzene.

7‐Bromo‐2,3‐dihydropyrrolo[2,1‐ b ]quinazolin‐9(1H)‐one (7‐bromodeoxyvasicinone, 3):[ ¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² ] At 0–2 °C phosphorus oxychloride (13 mL, 21.8 g, 142.0 mmol) is added dropwise with stirring over 1 h to anthranilic acid (4.32 g, 20.0 mmol) and γ‐butyrolactam (2.72 g, 32 mmol). After heating the reaction mixture at reflux for 2 h it is cooled to 25 °C, and ice (200 g) is added. Then aqueous ammonia (25 %) is added up to pH 10–11. The yellow precipitate is filtered off and dried. After recrystallization from methanol 7‐bromo‐2,3‐dihydropyrrolo[2,1‐b]quinazolin‐9(1H)‐one (3, 4.35 g, 16.4 mmol, 82 %) is obtained as yellow crystals (m. p. 159–160 °C).

¹H NMR (400 MHz, CDCl₃): δ=8.40 (1H, d, J=2.4 Hz, NCCHCHCCH), 7.80 (1 H, dd, J=2.4, 8.8 Hz, NCCHCH), 7.52 (1H, d, J=8.8 Hz, NCCH), 4.22 (2H, t, J=8.0 Hz, NCH₂), 3.18 (2H, t, J=7.6 Hz, NCH₂CH₂CH ₂), 2.31 (2 H, m, NCH₂CH ₂) ppm. ¹³C{¹H} NMR (100.6 MHz, CDCl₃): δ=159.9 (CO), 159.8 (OCCCH), 148.0 (OCC), 137.3 (NCCH), 129.0 (NCCH₂), 128.7 (OCCCHCCH), 122.0 (NCCH), 119.7 (CBr), 46.7 (NCH₂), 32.6 (NCH₂CH₂ CH₂), 19.5 (NCH₂ CH₂) ppm.

2‐Bromo‐6,7,8,9‐tetrahydro‐11H ‐pyrido[2,1‐ b ]quinazolin‐11‐one (2‐bromomackinazolinone, 4):[ ¹⁷ , ²³ ] At 0–2 °C phosphorus oxychloride (26 mL, 43.55 g, 280.0 mmol) is added dropwise with stirring over 1 h to 5‐bromoanthranilic acid (8.0 g, 40.0 mmol) and δ‐valerolactam (6.34 g, 64.0 mmol). After heating the reaction mixture at reflux for 2 h it is cooled to 25 °C, and ice (200 g) is added. Then aqueous ammonia (25 %) is added up to pH 10–11. The yellow precipitate is filtered off and dried. After recrystallization from methanol 2‐bromo‐6,7,8,9‐tetrahydro‐11H‐pyrido[2,1‐b]quinazolin‐11‐one (4, 8.6 g, 33.2 mmol, 83 %) is obtained as yellow crystals (m. p. 163–164 °C).

¹H NMR (600 MHz, CDCl₃): δ=8.35 (1 H, d, J=2.3 Hz, OCCCH), 7.75 (1 H, dd, J=2.4, 8.7 Hz, NCCHCH), 7.45 (1 H, d, J=8.7 Hz, NCCH), 4.04 (2 H, t, J=6.2 Hz, NCH₂), 2.98 (2 H, t, J=6.7 Hz, NCCH₂), 2.02–1.98, 1.95–1.91 (2×2 H, 2 m, NCH₂CH ₂, NCH₂CH₂CH ₂) ppm. ¹³C{¹H} NMR (150 MHz, CDCl₃): δ=161.1 (CO), 155.6 (OCCCH), 146.2 (OCC), 137.5 (NCCH), 129.3 (NCN), 128.4 (OCCCHCCH), 121.8 (NCCH), 119.6 (CBr), 42.7 (NCH₂CH₂ CH₂), 32.0 (NCH₂ CH₂), 22.1 (NCH₂CH₂CH₂ CH₂), 19.3 (NCH₂) ppm.

5,7‐Dibromo‐2,3‐dihydropyrrolo[2,1‐ b ]quinazolin‐9(1H)‐one (5,7‐dibromodeoxyvasicinone, 5):[ ²¹ , ²⁴ ] At 0–2 °C phosphorus oxychloride (23.8 mL, 39.86 g, 260.0 mmol) is added dropwise with stirring over 1 h to 3,5‐dibromoanthranilic acid (10.0 g, 34.0 mmol) and γ‐butyrolactam (4.44 g, 52.0 mmol). After heating the reaction mixture at reflux for 2 h it is cooled to 25 °C, and ice (200 g) is added. Then aqueous ammonia (25 %) is added up to pH 10–11. The yellow precipitate is filtered off and dried. After recrystallization from methanol 5,7‐dibromo‐2,3‐dihydropyrrolo[2,1‐b]quinazolin‐9(1H)‐one (5, 9.8 g, 28.6 mmol, 84 %) is obtained as yellow crystals (m. p. 243–244 °C).

¹H NMR (600 MHz, CDCl₃): δ=8.35 (1 H, m, NCCCHCCH), 8.09 (1 H, m, NCCCH), 4.19 (2 H, t, J=7.1 Hz, NCH₂), 3.24 (2 H, t, J=8.0 Hz, NCH₂CH₂CH ₂), 2.30 (2 H, m, NCH₂CH ₂) ppm. ¹³C{¹H} NMR (150 MHz, CDCl₃): δ=161.2 (CO), 159.3 (OCCCH), 146.0 (OCC), 140.4 (NCCH), 128.8 (NCCH₂), 123.0 (NCCBr), 122.8 (NCCH), 119.5 (OCCCHCBr), 47.0 (NCH₂), 33.0 (NCH₂CH₂ CH₂), 19.6 (NCH₂ CH₂) ppm.

7‐Phenyl‐2,3‐dihydropyrrolo[2,1‐ b ]quinazolin‐9(1H)‐one (6): GP; 7‐bromo‐2,3‐dihydropyrrolo[2,1‐b]quinazoline‐9‐(1H)‐one (3, 132.5 mg, 0.5 mmol), phenylboronic acid (137 mg, 1.1 mmol), sodium carbonate (106.0 mg, 1.0 mmol) and palladium (II) acetate (9.43 mg, 0.042 mmol) in acetone / water (1 : 1, 6 mL), aqueous sodium hydroxide (1 M, 2 mL), 7‐phenyl‐2,3‐dihydropyrrolo[2,1‐b]quinazolin‐9(1H)‐one (6, 120 mg, 0.46 mmol, 92 %), colorless solid (m. p. 170–171 °C).

R _f=0.21 (ethyl acetate). ¹H NMR (400 MHz, CDCl₃): δ=8.51 (1 H, d, J=2.0 Hz, NCCHCHCCH), 7.98 (1 H, dd, J=2.4, 8.0 Hz, NCCHCH), 7.70 (3 H, t, J=8.0 Hz, m‐CH_Ph, NCCH), 7.47 (2 H, d, J=8.0 Hz, o‐CH_Ph), 7.38 (1 H, t, J=8.0 Hz, p‐CH_Ph), 4.23 (2 H, t, J=8.0 Hz, NCH₂), 3.20 (2 H, t, J=8.0 Hz, NCH₂CH₂CH ₂), 2.30 (2 H, m, NCH₂CH ₂) ppm. ¹³C{¹H} NMR (100.6 MHz, CDCl₃): δ=161.1 (CO), 159.6 (OCCCH), 148.3 (OCC), 139.8 (OCCCHC), 139.3 (NCCH), 133.2 (NCCH₂), 129.1 (OCCCHCCH), 127.9 (OCCCHCC), 127.4 (NCCH), 127.3 (o‐CH), 124.4 (m‐CH), 120.9 (p‐CH), 46.7 (NCH₂), 32.7 (NCH₂CH₂ CH₂), 19.7 (NCH₂ CH₂) ppm. IR (ATR): ν=1661 (C=O), 1609 (C=N), 1474 (C−N) cm⁻¹. EI−MS: m/z (%)=262 ([M]⁺, 100), 261 ([M−H]⁺, 37), 219 ([M−H−(CH₂)₃]⁺, 6.2). HRMS: Calcd. for C₁₇H₁₅N₂O ([M+H]⁺) 263.1184; found 263.1184. Calcd. for C₁₇H₁₄N₂O 262.1106; found: 262.1109.

4‐(9‐Oxo‐1,2,3,9‐tetrahydropyrrolo[2,1‐ b ]quinazolin‐7‐yl)benzonitrile (7): GP; 7‐bromo‐2,3‐dihydropyrrolo[2,1‐b]quinazoline‐9‐(1H)‐one (3, 132.5 mg, 0.5 mmol), 4‐cyanophenylboronic acid (80.8 mg, 0.55 mmol), sodium carbonate (132.5 mg, 1.25 mmol), palladium (II) acetate (9.43 mg, 0.042 mmol), acetone/water (2 : 1, 6 mL), aqueous sodium hydroxide (1 M, 2 mL), purification by column chromatography (20×1 cm, SiO₂, ethyl acetate), 4‐(9‐oxo‐1,2,3,9‐tetrahydropyrrolo[2,1‐b]quinazolin‐7‐yl)benzonitrile (7, 138 mg, 0.48 mmol, 96 %), colorless crystals, m. p. 240–241 °C.

R _f=0.16 (ethyl acetate). ¹H NMR (400 MHz, CDCl₃): δ=8.50 (1 H, d, J=2.3 Hz, OCCCH), 7.96 (1 H, dd, J=2.3, 8.5 Hz, NCCHCH), 7.73–7.80 (5 H, m, NCCH, 4 C_PhH), 4.24 (2H, t, J=7.2 Hz, NCH₂), 3.21 (2 H, t, J=8.0 Hz, NCH₂CH₂CH ₂), 2.32 (2H, m, NCH₂CH ₂) ppm. ¹³C{¹H} NMR (100.6 MHz, CDCl₃): δ=160.9 (C≡N), 160.4 (CO), 149.4 (OCCCH), 144.2 (OCC), 137.0 (OCCCHC), 132.9 (OCCCHCCCHCH, OCCCHCCCHCHC), 128.0 (OCCCHCCCH), 127.9 (OCCCHCCCH), 125.0 (NCN), 121.1 (NCCHCH), 118.9 (NCCH), 111.5 (NCCH), 46.8 (NCH₂), 32.8 (NCH₂CH₂ CH₂), 19.7 (NCH₂ CH₂). IR (ATR): ν=2970 (CH₂), 2221 (CN), 1670 (C=O), 1600 (C=N), 1508 (C=C), 1462 (C−N) cm⁻¹. MS (TOF, ES+): m/z (%)=288 ([M+H]⁺, 100), 261 ([M−CN]⁺, 2), 183 ([M−HCN−C₆H₅]⁺, 1.8), 142 ([M−C₆H₅−CN−(CH₂)₃]⁺, 3.1). HRMS: Calcd. for C₁₈H₁₄N₃O ([M+H]⁺) 288.1137; found 288.1371.

7‐(Quinolin‐8‐yl)‐2,3‐dihydropyrrolo[2,1‐ b ]quinazolin‐9(1H)‐one (8): GP; 7‐bromo‐2,3‐dihydropyrrolo[2,1‐b]quinazoline‐9‐(1H)‐one (3, 132.5 mg, 0.5 mmol), 8‐quinolinylboronic acid (103.8 mg, 0.6 mmol), sodium carbonate (132.5 mg, 1.25 mmol), palladium (II) acetate (9.43 mg, 0.042 mmol), acetone/water (2 : 1, 6 mL), stirring at 40–45 °C for 5 h, aqueous sodium hydroxide (1 M, 2 mL), purification by column chromatography (20×1 cm, SiO₂, ethyl acetate/methanol 25 : 1), 7‐(quinolin‐8‐yl)‐2,3‐dihydropyrrolo[2,1‐b]quinazolin‐9(1H)‐one (8, 130 mg, 0.42 mmol, 83 %), light purple crystals, m. p. 215–216 °C.

R _f=0.21 (ethyl acetate/methanol 15 : 1). ¹H NMR (400 MHz, CDCl₃): δ=8.97 (1 H, dd, J=1.8, 4.2 Hz, NCCCHCHCHCCH), 8.58 (1 H, dd, J=0.5, 2.1 Hz, OCCCH), 8.22 (1 H, dd, J=1.8, 8.3 Hz, NCHCH), 8.17 (1 H, dd, J=2.1, 8.4 Hz, NCCHCH), 7.87 (1 H, dd, J=1.5, 8.2 Hz, NCCCHCHCH), 7.83 (1 H, dd, J=1.5, 7.2 Hz, NCHCHCHC), 7.76 (1 H, d, J=8.4 Hz, NCCH), 7.63 (1 H, dd, J=7.2, 8.1 Hz, NCCCHCH), 7.44 (1 H, dd, J=4.2, 8.3 Hz, NCH), 4.24 (2 H, t, J=7.2 Hz, NCH₂), 3.22 (2H, t, J=7.9 Hz, NCH₂CH₂CH ₂), 2.30–2.37 (2 H, m, NCH₂CH ₂) ppm. ¹³C{¹H} NMR (100.6 MHz, CDCl₃): δ=161.3 (CO), 159.5 (OCCCHC), 150.5 (OCC), 148.6 (OCCCH), 146.0 (NCCH), 139.6 (NCCH), 138.0 (NCN), 137.3 (NCCHCH), 136.5 (OCCCHCC), 130.7 (OCCCHCCC), 128.9 (OCCCHCCCC), 128.2 (OCCCHCCNCH), 128.0 (OCCCHCCNCHCHCH), 126.5 (OCCCHCCNCHCH), 126.4 (OCCCHCCCH), 121.3 (OCCCHCCCHCHCH), 120.5 (OCCCHCCCHCHCH), 46.7 (NCH₂), 32.7 (NCH₂CH₂ CH₂), 19.7 (NCH₂ CH₂CH₂) ppm. IR (ATR): ν=1678 (C=O), 1610 (C=N), 1546 (C=C), 1483 (C−N) cm⁻¹. EI−MS: m/z (%)=313 ([M]⁺, 22), 312 ([M−H]⁺, 100). HRMS: Calcd. for C₂₀H₁₄N₃O 312.1137; found: 312.1137. ESI HRMS (LCT): Calcd. for C₂₀H₁₅N₃ONa ([M+Na]⁺) 336.1113; found: 336.1107.

7‐(3,4,5‐Trimethoxyphenyl)‐2,3‐dihydropyrrolo[2,1‐ b ]quinazolin‐9(1H)‐one (9): GP; 7‐bromo‐2,3‐dihydropyrrolo[2,1‐b]quinazoline‐9‐(1H)‐one (3, 132.5 mg, 0.5 mmol), 3,4,5‐trimethoxyphenylboronic acid (127.2 mg, 0.6 mmol), sodium carbonate (132.5 mg, 1.25 mmol), palladium (II) acetate (9.43 mg, 0.042 mmol), acetone/water (2 : 1, 6 mL), stirring at 40–45 °C for 5 h, aqueous sodium hydroxide (1 M, 2 mL), purification by column chromatography (20×1 cm, SiO₂, ethyl acetate / petroleum ether 7 : 1), 7‐(3,4,5‐trimethoxyphenyl)‐2,3‐dihydropyrrolo[2,1‐b]quinazolin‐9(1H)‐one (9, 171.3 mg, 0.47 mmol, 97 %), yellow crystals, m. p. 169–170 °C.

R _f=0.13 (ethyl acetate/petroleum ether 7 : 1). ¹H NMR (400 MHz, CDCl₃): δ=8.47 (1 H, d, J=1.9 Hz, OCCCH), 7.96 (1 H, dd, J=2.2, 8.5 Hz, NCCHCH), 7.72 (1 H, d, J=8.5 Hz, NCCH), 6.88 (2 H, s, o‐CH), 4.25 (2 H, t, J=7.2 Hz, NCH₂), 3.97 (6H, s, m‐COCH₃), 3.92 (3H, s, p‐COCH₃), 3.22 (2H, t, J=7.8 Hz, NCH₂CH₂CH ₂), 2.29–2.37 (2H, m, NCH₂CH ₂) ppm. ¹³C{¹H} NMR (100.6 MHz, CDCl₃): δ=161.1 (CO), 159.4 (OCCCHC), 153.6 (OCC), 148.3 (NCCHCH), 139.2 (NCCH), 135.6 (NCCH), 133.1 (NCN), 127.3 (o‐CH), 124.1 (m‐COCH₃), 120.7 (p‐COCH₃), 104.4 (OCCCHCC), 60.9 (p‐COCH₃), 58.3 (m‐COCH₃), 46.6 (NCH₂), 32.5 (NCH₂CH₂ CH₂), 19.5 (NCH₂ CH₂CH₂) ppm. IR (ATR): ν=1672 (C=O), 1620 (C=N), 1481 (C−N) cm⁻¹. EI‐MS: m/z (%)=352 ([M]⁺, 96), 337 ([M−CH₃]⁺, 100), 309 (8.4), 279 (5.3), 223 (9.5), 176 (4.2), 139 (3.1), 111 (6.3). HRMS: Calcd. for C₂₀H₂₀N₂O₄ 352.1423; found 352.1422.

Crystal structure analysis: ^[49] CCDC 2344447. Single crystals suitable for X‐ray crystallographic analysis were obtained by crystallization from ethyl acetate at −15 °C. C₂₀H₂₀N₂O₄, yellow prism, M _r=352.38 g . mol⁻¹, crystal system monoclinic, space group P 1 21/c 1, a=13.9978(18), b=7.4552(9), c=17.018(2) Å, α=90°, β=103.547(4)°, γ=90°. V=1726.5(4) Å³, Z=4, d _calc=1.356 g cm⁻³, μ=0.094 mm⁻¹, crystal size 0.62×0.26×0.20 mm³, F(000)=744, Bruker SMART X2S diffractometer, graphite crystal monochromator, T=200 K, Mo−K_α radiation (λ=0.71073 Å), 2.46≤θ≤27.59°, index ranges −18≤h≤18, −9≤k≤9, −20≤l≤22, reflections collected/unique 3980/2568, numerical absorption correction, structure solution and refinement with SHELXL‐2018/3, ^[55] parameters/restrains 238/0, R ₁=0.0647 [l>2 s(l)], wR ₂=0.1638 (all data), S=1.022, final maximum/minimum difference electron density 0.268/–0.248 eÅ⁻³.

7‐(Benzo[b]thiophen‐3‐yl)‐2,3‐dihydropyrrolo[2,1‐ b ]quinazolin‐9(1 H)‐one (10): GP; 7‐bromo‐2,3‐dihydropyrrolo[2,1‐b]quinazoline‐9‐(1H)‐one (3, 132.5 mg, 0.5 mmol), benzothiophene‐3‐boronic acid (106.8 mg, 0.6 mmol), sodium carbonate (132.5 mg, 1.25 mmol), palladium (II) acetate (9.43 mg, 0.042 mmol) in acetone/water (2 : 1, 6 mL), stirring at 40–45 °C for 3 h, then for 8 h a 25 °C, aqueous sodium hydroxide (1 M, 2 mL), purification by column chromatography (20×1 cm, SiO₂, ethyl acetate / petroleum ether 8 : 1), 7‐(benzo [b] thiophen‐3‐yl)‐2,3‐dihydropyrrolo[2,1‐b]quinazolin‐9(1H)‐one (10, 142 mg, 0.45 mmol, 89 %), colorless crystals, m. p. 340 °C.

R _f=0.18 (ethyl acetate/petroleum ether 8 : 1). ¹H NMR (400 MHz, CDCl₃): δ=8.53 (1 H, d, J=2.0 Hz, OCCCH), 7.95–8.00 (3 H, m, NCCHCH, H‐6, SCCH, SCCHCHCH), 7.78 (1 H, d, J=8.4 Hz, NCCH), 7.54 (1 H, s, SCH), 7.42–7.46 (2H, m, SCCHCH, SCCHCHCHCH), 4.27 (2 H, t, J=8.1 Hz, NCH₂), 3.24 (2 H, t, J=7.8 Hz, NCH₂CH₂CH ₂), 2.30–2.38 (2 H, m, NCH₂CH ₂) ppm.¹³C{¹H} NMR (100.6 MHz, CDCl₃): δ=161.0 (CO), 159.6 (NCCHCHC), 148.5 (NCCHCHCC), 140.7 (OCCCH), 137.6 (SCH), 136.7 (OCC), 134.6 (NCC), 134.1 (NCCH), 127.3 (NCCHCH), 125.9 (NCCH₂), 124.6 (SCCH, SCCCH), 124.4 (SCCHCHCHCH), 123.0 (SCCH), 122.7 (SCCHCH), 120.8 (SCCHCHCH), 46.6 (NCH₂), 32.6 (NCH₂CH₂ CH₂), 19.6 (NCH₂ CH₂) ppm. IR (ATR): ν=1675 (C=O), 1618 (C=N), 1474 (C−N) cm⁻¹. HRMS: Calcd. for C₁₉H₁₄N₂NaO ([M+Na]⁺) 341.0725; found: 341.0725.

Crystal structure analysis: ^[49] CCDC 2344448. Single crystals suitable for X‐ray crystallographic analysis were obtained by crystallization from toluene at 5 °C. C₁₉H₁₄N₂OS, colorless needle, M _r=318.38 g . mol⁻¹, crystal system orthorhombic, space group P b c a, a=17.041(3), b=7.0846(10), c=25.021(4) Å, α=90°, β=90°, γ=90°, V=3020.8(8) Å³, Z=8, d _calc=1.400 g cm⁻³, μ=0.220 mm⁻¹, crystal size 0.97×0.28×0.25 mm³, F(000)=1328, Bruker SMART X2S diffractometer, graphite crystal monochromator, T=300(2) K, Mo−K_α radiation (λ=0.71073 Å), 2.39≤θ≤28.66°, index ranges −22≤h≤22, −9≤k≤9, −33≤l≤33, reflections collected/unique 3868/2944, multi‐scan absorption correction, structure solution and refinement with SHELXL‐2018/3, ^[55] parameters/restrains 208/0, R ₁=0.0532 [l>2 s(l)], wR ₂=0.1457 (all data), S=1.020, final maximum/minimum difference electron density 0.351/–0.485 eÅ⁻³.

7‐(Dibenzo[b,d] thiophen‐4‐yl)‐2,3‐dihydropyrrolo[2,1‐ b ]quinazolin‐9(1H )‐one (11): GP; 7‐bromo‐2,3‐dihydropyrrolo[2,1‐b]quinazoline‐9‐(1H)‐one (3, 132.5 mg, 0.5 mmol), dibenzothiophene‐4‐boronic acid (137 mg, 0.60 mmol), sodium carbonate (132.5 mg, 1.25 mmol), palladium (II) acetate (9.43 mg, 0.042 mmol) in acetone/water (2 : 1, 6 mL), stirring at 40–45 °C for 7 h, aqueous sodium hydroxide (1 M, 2 mL), purification by column chromatography (20×1 cm, SiO₂, ethyl acetate/petroleum ether 4 : 1), 7‐(dibenzo[b,d]thiophen‐4‐yl)‐2,3‐dihydropyrrolo[2,1‐b]quinazolin‐9(1H)‐one (11, 168 mg, 0.46 mmol, 91 %), yellow crystals, m. p. 180–182 °C.

R _f=0.2 (ethyl acetate/petroleum ether 4 : 1). ¹H NMR (400 MHz, CDCl₃): δ=8.67 (1 H, d, J=2.1 Hz, OCCCH), 8.20–8.23 (2 H, m, C_aromH), 8.14 (1 H, dd, J=2.2, 8.4 Hz, NCCHCH), 7.84–7.87 (1 H, m, C_aromH), 7.80 (1 H, d, J=8.4, NCCH), 7.57–7.59 (2H, m, C_aromH), 7.46–7.49 (2H, m, C_aromH), 4.25 (2H, t, J=7.2 Hz, NCH₂), 3.23 (2H, t, J=7.8 Hz, NCH₂CH₂CH ₂), 2.34 (2 H, m, NCH₂CH ₂) ppm. ¹³C{¹H} NMR (100.6 MHz, CDCl₃): δ=161.1 (CO), 160.0 (NCCHCHC), 148.9 NCCHCHCC), 139.6 (OCCCH), 138.8 (NCCHCHCCS), 138.7 (NCCHCHCCSC), 136.6 (NCCH), 135.8 (NCCH), 135.8 (NCCHCH), 134.3 (NCN), 127.5 (SCCH), 127.3 (SCCH), 127.1 (SCCCH), 126.2 (SCCCCH), 125.4 (NCCHCHCCCHCH), 124.6 (SCCHCH), 122.8 (SCCCH), 121.9 (SCCHCHCH), 121.0 (NCCHCHCC), 120.9 NCCHCHCCCH), 46.7 (NCH₂), 32.8 (NCH₂CH₂ CH₂), 19.7 (NCH₂ CH₂) ppm. IR (ATR): ν=2968 (CH₂), 1661 (C=O), 1612 (C=N), 1496 (C=C), 1423 (C−N) cm⁻¹. EI−MS: m/z (%)=368 ([M]⁺, 4), 264 (86), 150 (14), 131 (100). HRMS: Calcd. for C₂₃H₁₆N₂OS 368.0983; found 368.0982.

5,7‐Diphenyl‐2,3‐dihydropyrrolo[2,1‐ b ]quinazolin‐9(1H)‐one (12): GP; 5,7‐dibromo‐2,3‐dihydropyrrolo[2,1‐b]quinazoline‐9‐(1H)‐one (5, 172 mg, 0.5 mmol), phenylboronic acid (146.3 mg, 1.2 mmol), sodium carbonate (265 mg, 2.5 mmol), palladium (II) acetate (18.86 mg, 0.084 mmol) in acetone/water (1 : 1, 12 mL), stirring at 40–45 °C for 4 h, aqueous sodium hydroxide (1 M, 2 mL), purification by column chromatography (20×1 cm, SiO₂, ethyl acetate/petroleum ether 1 : 1), 5,7‐diphenyl‐2,3‐dihydropyrrolo[2,1‐b]quinazolin‐9(1H)‐one (12, 142 mg, 0.42 mmol, 84 %), colorless crystals, m. p. 207–208 °C.

R _f=0.27 (ethyl acetate/petroleum ether 1 : 1). ¹H NMR (400 MHz, CDCl₃): δ=8.56 (1 H, d, J=2.4 Hz, OCCCHCCH), 8.02 (1 H, d, J=2.4 Hz, OCCCHCCH), 7.67–7.75 (4 H, dt, J=1.2, 8.8 Hz, 2×2 o‐CH), 7.50 (4 H, t, J=7.2 Hz, 2×2 m‐CH), 7.46–7.48 (2H, td, J=1.2, 7.6 Hz, 2 p‐CH), 4.24 (2 H, t, J=7.2 Hz, NCH₂), 3.14 (2H, t, J=8.0 Hz, NCH₂CH₂CH ₂), 2.23–2.31 (2H, m, NCH₂ CH ₂) ppm. ¹³C{¹H} NMR (100.6 MHz, CDCl₃): δ=161.5 (CO), 158.7 (OCCCH), 146.0 (OCC), 139.8 (OCCC), 139.5 (OCCCHC), 138.9 (OCCCHCCHC), 138.7 (NCN), 134.3 (OCCCHCCH), 130.7 (ipso‐C), 129.1 (ipso‐C), 128.1 (o‐CH), 127.9 (o‐CH), 127.6 (m‐CH), 127.3 (m‐CH), 123.8 (p‐CH), 121.7 (p‐CH), 46.6 (NCH₂), 32.9 (NCH₂CH₂ CH₂), 19.8 (NCH₂ CH₂) ppm. IR (ATR): ν=1670 (C=O), 1604 (C=N), 1494 (C=C), 1477 (C−N) cm⁻¹. EI‐MS: m/z (%)=338 ([M]⁺, 37), 337 ([M−H]⁺, 100). HRMS: Calcd. for C₂₃H₁₇N₂O 337.1341; found 337.1340. ESI HRMS (LCT): Calcd. for C₂₃H₁₉N₂O ([M+H]⁺) 339.1497; found: 339.1497.

5,7‐Bis (3,4,5‐trimethoxyphenyl)‐2,3‐dihydropyrrolo[2,1‐ b ]quinazolin‐9(1H)‐one (13): GP; 5,7‐dibromo‐2,3‐dihydropyrrolo[2,1‐b]quinazoline‐9‐(1H)‐one (5, 103 mg, 0.3 mmol), (3,4,5‐trimethoxyphenyl) boronic acid (148.3 mg, 0.70 mmol), sodium carbonate (79.5 mg, 0.75 mmol), palladium (II) acetate (7.2 mg, 0.03 mmol) in acetone/water (1 : 1, 10 mL), stirring at 40–45 °C for 8 h, aqueous sodium hydroxide (1 M, 2 mL), purification by column chromatography (20×1 cm, SiO₂, ethyl acetate/petroleum ether 6 : 1), 5,7‐bis (3,4,5‐trimethoxyphenyl)‐2,3‐dihydropyrrolo[2,1‐b]quinazolin‐9(1H)‐one (13, 151 mg, 0.29 mmol, 97 %), colorless crystals, m. p. 257–258 °C.

R _f=0.20 (ethyl acetate/petroleum ether 6 : 1). ¹H NMR (400 MHz, CDCl₃): δ=8.48 (1 H, d, J=2.3 Hz, OCCH), 7.95 (1 H, d, J=2.3 Hz, OCCCHCCH), 6.90 (4 H, 2 s, 4 o‐CH), 4.25 (2 H, t, J=7.1 Hz, NCH₂), 3.95 (6 H, s, m‐OCH₃), 3.93 (3 H, s, p‐OCH₃), 3.91 (6 H, s, m‐OCH₃), 3.91 (3 H, s, p‐OCH₃), 3.17 (2 H, t, J=7.8 Hz, NCH₂CH₂CH ₂), 2.29 (2 H, m, NCH₂CH ₂) ppm. ¹³C{¹H} NMR (100.6 MHz, CDCl₃): δ=161.4 (CO), 158.9 (OCC), 153.8 (ipso‐C), 153.0 (ipso‐C), 145.8 (NCCCH), 139.4 (OCCCHC), 139.0 (OCCCH), 138.3 (NCCCH), 137.8 (NCCCH), 135.7 (p‐C), 134.2 (o‐CH), 134.0 (o‐CH), 123.7 (2 C, m‐C), 121.6 (2 C, m‐C), 108.1 (p‐C), 104.7 (NCN), 61.1 (6 C, m‐OCH₃), 61.0 (3 C, p‐OCH₃), 56.5 (6 C, m‐OCH₃), 56.4 (3 C, p‐OCH₃), 46.7 (NCH₂), 32.9 (NCH₂CH₂ CH₂), 19.8 (NCH₂ CH₂CH₂) ppm. IR (ATR): ν =2987, 2939 (CH₂), 1670 (C=O), 1629 (C=N), 1508 (C=C), 1455 (C−N). EI‐MS: m/z (%)=518 ([M]⁺, 100), 519 ([M+H]⁺, 33), 332 ([M−6OMe]⁺, 51), 259 ([M−C₆H(OMe)₃]⁺, 20), 187 (23), 144 (quinazoline, 28). HRMS calcd. for C₂₉H₃₀N₂O₇ 518.2053; found: 518.2066.

Crystal structure analysis: ^[49] CCDC 2344450. Single crystals suitable for X‐ray crystallographic analysis were obtained by crystallization from ethyl acetate at 5 °C. C₂₉H₃₀N₂O₇, colorless plate, M_r=518.55 g . mol⁻¹, crystal system monoclinic, space group P 1 21/n 1, a=7.821(3), b=12.927 (5), c=25.543(9) Å, α=90°, β=94.384 (13)°, γ=90°. V=2574.9(15) Å³, Z=4, d_calc=1.338 g cm⁻³, μ=0.096 mm⁻¹, crystal size 0.78×0.35×0.19 mm³, F(000)=1096.0, Bruker SMART X2S diffractometer, graphite crystal monochromator, T=300(2) K, Mo−K_α radiation (λ=0.71073 Å), 2.67≤θ≤27.56°, index ranges −10≤h≤9, −16≤k≤16, −33≤l≤31, reflections collected/unique 5760/3644, multi‐scan absorption correction, structure solution and refinement with SHELXL‐2018/3, ^[55] parameters/restrains 349/0, R₁=0.0629 [l>2 s(l)], wR₂=0.1699 (all data), S=1.023, final maximum/minimum difference electron density 0.270/−0.262 eÅ⁻³.

4,4′‐(9‐oxo‐1,2,3,9‐tetrahydropyrrolo[2,1‐b]quinazoline‐5,7‐diyl)dibenzonitrile (14): GP; 5,7‐dibromo‐2,3‐dihydropyrrolo[2,1‐b]quinazoline‐9‐(1H)‐one (5, 103 mg, 0.3 mmol), 4‐cyanophenylboronic acid (103 mg, 0.70 mmol), sodium carbonate (79.5 mg, 0.75 mmol), palladium (II) acetate (7.2 mg, 0.03 mmol) in acetone/water (1 : 1, 10 mL), stirring at 40–45 °C for 8 h, aqueous sodium hydroxide (1 M, 2 mL), purification by column chromatography (20×1 cm, SiO₂, ethyl acetate/petroleum ether 4 : 1), 4,4′‐(9‐oxo‐1,2,3,9‐tetrahydropyrrolo[2,1‐b]quinazoline‐5,7‐diyl) dibenzonitrile (14, 114.5 mg, 0.29 mmol, 98 %), colorless crystals, m. p. 261–262 °C.

R _f=0.53 (ethyl acetate/petroleum ether 4 : 1). ¹H NMR (400 MHz, CDCl₃): δ=8.60 (1 H, d, J=2.3 Hz, OCCCH), 7.95 (1 H, d, J=2.3 Hz, OCCCHCCH), 7.81–7.83 (2 H, m, 2 o‐CH), 7.77 (6 H, m, 2 o‐CH, 4 m‐CH), 4.25 (2 H, t, J=7.2 Hz, NCH₂), 3.15 (2 H, t, J=7.8, NCH₂CH₂CH ₂), 2.31 (2H, m, NCH₂CH₂) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ=160.9 (CO), 160.3 (OCC), 146.7 (OCCCHC), 143.7 (NCCCCH), 143.1 (NCCCH), 138.0 (COCCH), 136.7 (NCN), 133.7 (OCCCHCCH), 133.0 (NCCCH), 131.9 (NCCCH), 131.3 (2 C, 2 ipso‐C), 127.9 (2 C, 2 NCC), 125.5 (NCCCHCHC), 122.0 (NCCCHCHC), 119.1 (NCCCH), 118.8 (NCCCH), 111.8 (NCCCHCH), 111.6 (NCCCHCH), 46.8 (NCH₂), 32.9 (NCH₂CH₂ CH₂), 19.7 (NCH₂ CH₂ CH₂) ppm. IR (ATR): ν=2954 (CH₂), 2226 (CN), 1676 (C=O), 1602 (C=N), 1504 (C=C), 1462 (C−N) cm⁻¹. EI‐MS: m/z (%)=388 ([M]⁺, 3.3), 366 (89), 362 ([M−CN]⁺, 24), 351 (100), 286 ([M−C₆H₄CN]⁺, 3.2), 260 ([M−C₆H₄−2CN]⁺, 3.5), 184 ([M−2 C₆H₄CN]⁺, 5.4). HRMS calcd. for C₂₅H₁₆N₄O 388.1324; found 388.1330.

Crystal structure analysis: ^[49] CCDC 2345691. Single crystals suitable for X‐ray crystallographic analysis were obtained by crystallization from ethyl acetate at 25 °C. C₂₅H₁₆N₄O, colorless plates, M_r=388.42 g . mol⁻¹, crystal system monoclinic, space group P 2₁/c, a=10.9030(5), b=7.4973(4), c=46.124(3) Å, α=90°, β=95.000(5)°, γ=90°, V=3755.5(3) Å³, Z=8, Z′=2, d_calc=1.374 g cm⁻³, μ=0.693 mm⁻¹, crystal size 0.24×0.23×0.06 mm³, F(000)=1616, CryoLoop (20 micron, 0.2–0.3 mm, Hampton Research) XtaLAB AFC12 (RINC): Kappa single diffractometer, mirror monochromator, T=100.00(10) K, Cu−K_α radiation (λ=1.54184 Å), 1.923°≤θ≤82.122°, index ranges −13≤h≤13, −9≤k≤9, −56≤l≤58, reflections llllcollected/unique 37418/7983, multi‐scan absorption correction, structure solution with ShelXT 2018/2 ^[55] with Intrinsic Phasing solution method and by using Olex2 ^[56] as the graphical interface, refinement with ShelXL 2019/3, ^[55] parameters/restraints 542/0, R₁=0.0673 [l>2 s(l)], wR₂=0.2004 (all data), S=1.137, final maximum/minimum difference electron density 0.415/−0.374 eÅ⁻³.

5,7‐Bis(dibenzo[b,d]thiophen‐4‐yl)‐2,3‐dihydropyrrolo[2,1‐b]quinazolin‐9(1H)‐one (15): GP; 5,7‐dibromo‐2,3‐dihydropyrrolo[2,1‐b]quinazoline‐9‐(1H)‐one (5, 103 mg, 0.3 mmol), dibenzothiophene‐4‐boronic acid (160 mg, 0.70 mmol), sodium carbonate (79.5 mg, 0.75 mmol), palladium (II) acetate (7.2 mg, 0.03 mmol) in acetone/water (1 : 1, 10 mL), stirring at 40–45 °C for 20 h, aqueous sodium hydroxide (1 M, 2 mL), purification by column chromatography (20×1 cm, SiO₂, ethyl acetate/petroleum ether 3 : 1), 5,7‐bis (dibenzo[b,d]thiophen‐4‐yl)‐2,3‐dihydropyrrolo[2,1‐b]quinazolin‐9(1H)‐one (15, 124 mg, 0.23 mmol, 75 %), yellow crystals, m. p. 195–196 °C.

R _f=0.68 (ethyl acetate/petroleum ether 3 : 1). ¹H NMR (400 MHz, CDCl₃): δ=8.85 (1 H, d, J=2.2 Hz, OCCCH), 8.35 (1 H, d, J=2.2 Hz, OCCCHCCH), 8.18–8.24 (4 H, m, dibenzothiophenyl), 7.78–7.87 (2 H, m, dibenzothiophenyl), 7.58–7.68 (4 H, m, dibenzothiophenyl), 7.45–7.49 (4 H, m, dibenzothiophenyl), 4.25 (2 H, t, J=7.2 Hz, NCH₂), 3.07 (2 H, t, J=7.8 Hz, NCH₂CH₂CH ₂), 2.25 (2 H, m, NCH₂CH ₂) ppm. ¹³C{¹H} NMR (100.6 MHz, CDCl₃): δ=161.3 (OC), 159.5 (OCC), 146.7 (OCCCHC), 140.6 (NCC), 139.9 (OCCCH), 139.6 (OCCCHCCHC), 138.7 (CCCHCCH), 138.4 (NCN), 138.3 (SCC), 136.6 (SCC), 136.0 (SCC), 135.9 (SCCH), 135.8 (SCCH), 135.5 (SCCHCH), 135.3 (SCCHCH), 134.1 (SCCHCHCH), 129.1 (SCCHCHCH), 127.4 (SCCHCHCHCH), 127.0 (SCCHCHCHCH), 126.8 (SCCHCHCHCHC), 126.3 (SCCHCHCHCHC), 125.4 (SCCHCHCHCHCC), 124.6 (2 C, SCCHCHCHCHCC), 124.4 (SCCHCHCHCHCCC), 122.8 (SCCHCHCHCHCCC), 122.7 (SCCHCHCHCHCCCH), 121.9 (SCCHCHCHCHCCCH), 121.87 (SCCHCHCHCHCCCHCH), 121.82 (SCCHCHCHCHCCCHCH), 121.1 (SCCHCHCHCHCCCHCHCH), 121.0 (SCCHCHCHCHCCCHCHCH), 46.7 (NCH₂), 32.8 (NCH₂CH₂ CH₂), 19.7 (NCH₂ CH₂) ppm.

IR (ATR): ν=3059 (CH₂), 1670 (C=O), 1604 (C=N), 1465 (C=C), 1415 (C−N) cm⁻¹. EI−MS: m/z (%)=367 ([M‐dibenzothiophenyl]⁺, 10.5), 366 ([M‐dibenzothiophene]⁺, 89.5), 351 ([M‐dibenzothiophenyl−O]⁺, 100), 183 ([dibenzothiophenyl]⁺, 6.8). MS (TOF ES+): m/z (%)=551 ([M+H]⁺, 100), 552 ([M+2H]⁺, 37.4), 526 (26.4), 512 (8.8). HRMS: Calcd. for C₃₅H₂₃N₂OS₂ ([M+H]⁺) 551.1252; found 551.1236.

5‐Bromo‐7‐(quinolin‐8‐yl)‐2,3‐dihydropyrrolo[2,1‐b]quinazolin‐9(1H)‐one (16): GP; 5,7‐dibromo‐2,3‐dihydropyrrolo[2,1‐b]quinazoline‐9‐(1H)‐one (5, 103 mg, 0.3 mmol), 8‐quinolineboronic acid (121 mg, 0.70 mmol), sodium carbonate (79.5 mg, 0.75 mmol), palladium (II) acetate (7.2 mg, 0.03 mmol) in acetone/water (1 : 1, 10 mL), stirring at 40–45 °C for 23 h, aqueous sodium hydroxide (1 M, 2 mL), purification by column chromatography (20×1 cm, SiO₂, ethyl acetate/petroleum ether 5 : 1), 5‐bromo‐7‐(quinolin‐8‐yl)‐2,3‐dihydropyrrolo[2,1‐b]quinazolin‐9(1H)‐one (16, 80 mg, 0.20 mmol, 68 %), yellow crystals, m. p. 359–360 °C.

R _f=0.68 (ethyl acetate/petroleum ether 3 : 1). ¹H NMR (500 MHz, CDCl₃): δ=8.96 (1 H, dd, J=1.2, 2.7 Hz, C_quinH), 8.57 (1 H, d, J=1.4 Hz, OCCCH), 8.47 (1 H, d, J=1.3, OCCCHCCH), 8.23 (1 H, dd, J=1.2, 5.5 Hz, C_quinH), 7.89 (1 H, dd, J=0.9, 5.4 Hz, C_quinH), 7.82 (1 H, dd, J=1.0, 4.8, C_quinH), 7.64 (1 H, t, J=4.8 Hz, C_quinH), 7.46 (1 H, dd, J=2.7, 5.5, C_quinH), 4.24 (2 H, t, J=4.8, NCH₂), 3.31 (2 H, t, J=5.2 Hz, NCH₂CH ₂), 2.33 (2 H, m, NCH₂CH ₂CH₂) ppm. ¹³C{¹H} NMR (125 MHz, CDCl₃): δ=160.7 (OC), 160.5 (OCC), 150.7 (OCCCHCCHC), 146.3 (NCCCH), 145.8 (OCCCH), 140.6 (CBr), 138.6 (BrCCH), 138.2 (NCN), 136.5 (BrCCHCC), 130.7 (BrCCHCCCH), 128.9 (BrCCHCCCN), 128.7 (NCHCHCHC), 127.7 (NCHCHCHC), 126.5 (NCCCHCH), 121.9 (NCHCHCHC), 121.5 (NCHCHCHC), 121.2 (NCHCHCHCCH), 46.9 (NCH₂), 33.1 (NCH₂CH₂ CH₂), 19.8 (NCH₂ CH₂) ppm. IR (ATR): ν=2987 (CH₂), 1668 (C=O), 1600 (C=N), 1471 (C=C), 1406 (C−N), 748 (C−Br) cm⁻¹. EI‐MS: m/z (%)=392 ([M−H]⁺, 50), 391 ([M]⁺, 93), 390 ([M−H]⁺, 100), 312 ([M−⁷⁹Br]⁺, 82.8), 310 ([M−⁸¹Br]⁺, 9.0), 155 (11.3). HRMS calcd. for C₂₀H₁₄BrN₃O 391.0320; found 391.0337.

2‐Phenyl‐6,7,8,9‐tetrahydro‐11H ‐pyrido[2,1‐ b ]quinazolin‐11‐one (17): GP; 2‐bromo‐6,7,8,9‐tetrahydro‐11H‐pyrido[2,1‐b]quinazolin‐11‐one (4, 139.5 mg, 0.5 mmol), phenylboronic acid (67 mg, 0.56 mmol), sodium carbonate (132.5 mg, 1.25 mmol) and palladium (II) acetate (9.43 mg, 0.042 mmol) in acetone/water (1 : 1, 6 mL) were stirred at 40–45 °C for 3 h. Column chromatography (20×1 cm, SiO₂, ethyl acetate/petroleum ether 10 : 1) gave 2‐phenyl‐6,7,8,9‐tetrahydro‐11H‐pyrido[2,1‐b]quinazolin‐11‐one (17, 124 mg, 0.45 mmol, 90 %), colorless crystals (m. p. 143–144 °C).

R _f=0.62 (benzene/methanol 5 : 1). ¹H NMR (400 MHz, CDCl₃): δ=8.49 (1 H, d, J=2.4 Hz, OCCCH), 7.98 (1 H, dd, J=2.4, 8.0 Hz, NCCHCH), 7.66–7.71 (3 H, m, m‐CH, p‐CH), 7.44–7.49 (2 H, m, o‐CH), 7.37 (1 H, d, J=8.0 Hz, NCCH), 4.10 (2H, t, J=6.1 Hz, NCH₂), 3.01 (2 H, t, J=6.7 Hz, NCCH₂), 1.95–2.05 (4 H, m, NCH₂CH ₂, NCH₂CH₂CH ₂) ppm. ¹³C{¹H} NMR (100.6 MHz, CDCl₃): δ=162.4 (CO), 155.0 (OCCCH), 146.8 (OCC), 139.9 (OCCCHC), 139.1 (NCCH), 133.3 (NCN), 129.1 (OCCCHCCH), 127.8 (OCCCHCC), 127.3 (NCCH), 127.1 (o‐CH), 124.6 (m‐CH), 120.8 (p‐CH), 42.5 (NCH₂CH₂ CH₂), 32.1 (NCH₂ CH₂), 22.3 (NCH₂CH₂CH₂ CH₂), 19.5 (NCH₂) ppm. IR (ATR): ν=1654 (C=O), 1600 (C=N), 1473 (C−N) cm⁻¹. EI−MS: m/z (%)=276 ([M]⁺, 100), 275 ([M−H]⁺, 15), 261 ([M−H−CH₂]⁺, 4.4), 220 ([M−H−(CH₂)₃−CH₃]⁺, 2.5), 199 ([M−C₆H₅]⁺, 2.3), 185 ([M−C₆H₅−CH₂]⁺, 2.4). HRMS: Calcd. for C₁₈H₁₆N₂O 276.1263; found: 276.1264.

4‐(11‐Oxo‐6,8,9,11‐tetrahydro‐7H ‐pyrido[2,1‐b]quinazolin‐2‐yl) benzonitrile (18): GP; 2‐bromo‐6,7,8,9‐tetrahydro‐11H‐pyrido[2,1‐b]quinazolin‐11‐one (4, 139.5 mg, 0.5 mmol), (4‐cyanophenyl) boronic acid (81.0 mg, 0.55 mmol), sodium carbonate (132.5 mg, 1.25 mmol) and palladium (II) acetate (9.43 mg, 0.042 mmol) in acetone / water (2 : 1, 6 mL) were stirred at 40–45 °C for 3 h. Column chromatography (20×1 cm, SiO₂, ethyl acetate) gave 4‐(11‐oxo‐6,8,9,11‐tetrahydro‐7H‐pyrido[2,1‐b]quinazolin‐2‐yl) benzonitrile (18, 138.5 mg, 0.46 mmol, 92 %), colorless crystals (m. p. 194–195 °C).

R _f=0.36 (ethyl acetate¹H NMR (400 MHz, CDCl₃): δ=8.49 (1 H, d, J=2.2 Hz, OCCCH), 7.95 (1 H, dd, J=2.3, 8.5 Hz, NCCHCH), 7.68–7.79 (5 H, m, NCCH, o‐CH, m‐CH), 4.11 (2 H, t, J=6.2 Hz, NCH₂), 3.03 (2 H, t, J=6.7 Hz, NCCH₂), 1.95–2.07 (4 H, m, NCH₂CH ₂, NCH₂CH₂CH ₂) ppm. ¹³C{¹H} NMR (100.6 MHz, CDCl₃): δ=162.2 (CN), 155.9 (CO), 147.7 (NCH₂), 144.3 (OCC), 136.8 (OCCCHC), 132.92 (m‐CH), 127.8 (o‐CH), 127.6 (OCCCHCC), 125.3 (NCN), 121.0 (NCCHCH), 118.9 (NCCH), 111.4 (NCCH), 42.7 (NCH₂), 32.2 (NCH₂CH₂CH₂ CH₂), 22.2 (NCH₂ CH₂), 19.4 (NCH₂CH₂ CH₂) ppm. IR (ATR): ν=2220 (CN), 1661 (C=O), 1583 (C=N), 1492 (C−N) cm⁻¹. MS (TOF ES+): m/z (%)=303 ([M+2H]⁺, 16.5), 302 ([M+H]⁺, 100), 287 ([M−CH₂]⁺, 1.3), 261 ([M−C₃H₄ (cyclopropene)]⁺, 1.3), 145 (4‐oxo‐3,4‐dihydroquinazolin‐1‐ium, 4.9). HRMS: Calcd. for C₁₉H₁₅N₃O 302.1293; found 302.1465.

Crystal structure analysis: ^[49] CCDC 1994934. Single crystals suitable for X‐ray crystallographic analysis were obtained by crystallization from ethyl acetate at 25 °C. C₁₉H₁₅N₃O, colorless prism, M_r=301.34 g . mol⁻¹, crystal system monoclinic, space group C2/c, a=16.456(3), b=6.814(1), c=27.286(6) Å, α=90°, β=99.65(3)°, γ=90°. V=3016.5(11) Å³, Z=8, d_calc=1.327 g cm⁻³, m=0.674 mm⁻¹, crystal size 0.48×0.44×0.31 mm³, F(000)=1264, CCD Xcalibur diffractometer, graphite monochromator, T=291(2) K, Mo−K_α radiation (λ=0.71073 Å), 3.29≤θ≤75.78°, index ranges −20≤h≤10, −8≤k≤8, −34≤l≤32, reflections collected/unique 6013/3064, multi‐scan absorption correction, structure solution and refinement with SHELXL, ^[57] parameters/restrains 227/0, R₁=0.0505 [l>2 s(l)], wR₂=0.1398 (all data all data R₁=0.0610, wR₂=0.1536), S=1.031, final maximum/minimum difference electron density 0.184/−0.262 eÅ⁻³.

2‐(3,4,5‐Trimethoxyphenyl)‐6,7,8,9‐tetrahydro‐11H ‐pyrido[2,1‐ b ]quinazolin‐11‐one (19): GP; 2‐bromo‐6,7,8,9‐tetrahydro‐11H‐pyrido[2,1‐b]quinazolin‐11‐one (4, 139.5 mg, 0.5 mmol), (3,4,5‐trimethoxyphenyl)boronic acid (127.2 mg, 0.6 mmol), sodium carbonate (132.5 mg, 1.25 mmol) and palladium (II) acetate (9.43 mg, 0.042 mmol) in acetone/water (2 : 1, 6 mL) were stirred at 40–45 °C for 3 h. Column chromatography (20×1 cm, SiO₂, ethyl acetate / petroleum ether 6 : 1) gave 2‐(3,4,5‐trimethoxyphenyl)‐6,7,8,9‐tetrahydro‐11H‐pyrido[2,1‐b]quinazolin‐11‐one (19, 180 mg, 0.49 mmol, 98 %), yellow crystals (m. p. 160–161 °C).

R _f=0.30 (ethyl acetate). ¹H NMR (400 MHz, CDCl₃): δ=8.43 (1H, d, J=1.9 Hz, OCCCH), 7.93 (1 H, dd, J=2.2, 8.5 Hz, NCCHCH), 7.65 (1 H, d, J=8.5 Hz, NCCH), 6.86 (2 H, s, o‐CH), 4.10 (2 H, t, J=6.1 Hz, NCH₂), 3.94 (6 H, s, m‐OCH₃), 3.89 (3 H, s, p‐OCH₃), 3.02 (2 H, t, J=6.7 Hz, NCH₂CH₂CH₂CH ₂), 1.97–2.07 (4 H, m, NCH₂CH ₂, NCH₂CH₂CH ₂) ppm. ¹³C{¹H} NMR (100.6 MHz, CDCl₃): δ=162.4 (CO), 155.0 (OCCCHC), 153.7 (OCCCH), 146.7 (NCCHCH), 139.1 (OCCCH), 138.1 (NCCH), 135.8 (NCCH), 133.2 (NCN), 127.0 (o‐CH), 124.4 (m‐CO), 120.7 (p‐CO), 104.5 (NCCHCHCC), 61.1 (p‐COCH₃), 56.4 (o‐COCH₃), 42.6 (NCH₂CH₂ CH₂), 32.1 (NCH₂ CH₂), 22.2 (NCH₂CH₂CH₂ CH₂), 19.5 (NCH₂) ppm. IR (ATR): ν=1664 (C=O), 1616 (C=N), 1473 (C−N) cm⁻¹. TOF EI‐MS: m/z (%)=367 ([M+H]⁺, 8.4), 366 ([M]⁺, 100), 351 ([M−CH₃]⁺, 97), 323 (9.5), 293 (4.2), 237 (5.3), 184 (3.1). HRMS: Calcd. for C₂₁H₂₂N₂O₄ 366.1580; found: 366.1576.

Crystal structure analysis: ^[49] CCDC 2344455. Single crystals suitable for X‐ray crystallographic analysis were obtained by crystallization from ethyl acetate at 25 °C. C₂₁H₂₂N₂O₄, yellow prism, M_r=366.40 g . mol⁻¹, crystal system monoclinic, space group P 1 21/c 1, a=14.077(2), b=8.7947(14), c=15.364(2) Å, α=90°, β=108.393(5)°, γ=90°. V=1804.9(5) Å³, Z=4, d_calc=1.348 g cm⁻³, μ=0.094 mm⁻¹, crystal size 0.62×0.38×0.35 mm³, F(000)=776, Bruker SMART X2S diffractometer, graphite crystal monochromator, T=200(2) K, Mo−K_α radiation (λ=0.71073 Å), 2.71≤θ≤27.54°, index ranges −18≤h≤18, −11≤k≤11, −14≤l≤19, reflections collected/unique 4156/2746, multi‐scan absorption correction, structure solution and refinement with SHELXL, ^[57] parameters/restrains 248/0, R₁=0.0600 [l>2 s(l)], wR₂=0.1676, S=1.056, final maximum/minimum difference electron density 0.634/−0.321 eÅ⁻³.

2‐(Benzo[b]thiophen‐3‐yl)‐6,7,8,9‐tetrahydro‐11H ‐pyrido[2,1‐b]quinazolin‐11‐one (20): GP; 2‐bromo‐6,7,8,9‐tetrahydro‐11H‐pyrido[2,1‐b]quinazolin‐11‐one (4, 139.5 mg, 0.5 mmol), benzothiophenyl‐3‐boronic acid (106.8 mg, 0.6 mmol), sodium carbonate (132.5 mg, 1.25 mmol) and palladium(II) acetate (9.43 mg, 0.042 mmol) in acetone / water (2 : 1, 6 mL) were stirred at 40–45 °C fo 3 h. Column chromatography (20×1 cm, SiO₂, ethyl acetate/petroleum ether 6 : 1) gave 2‐(benzo[b]thiophen‐3‐yl)‐6,7,8,9‐tetrahydro‐11H‐pyrido[2,1‐b]quinazolin‐11‐one (20, 158 mg, 0.47 mmol, 95 %), colorless crystals (m. p. 320 °C).

R _f=0.34 (ethyl acetate/petroleum ether 6 : 1). ¹H NMR (400 MHz, CDCl₃): δ=8.49 (1 H, d, J=2.0 Hz, OCCCH), 7.91–7.97 (3 H, m, NCCHCH, SCCH, SCCHCHCH), 7.71 (1 H, d, J=8.4 Hz, NCCH), 7.51 (1 H, s, SCH), 7.39–7.42 (2 H, m, SCCHCH, SCCHCHCHCH), 4.11 (2 H, t, J=6.1 Hz, NCH₂), 3.04 (2 H, t, J=6.7 Hz, NCH₂CH₂CH₂CH ₂), 1.97–2.07 (4 H, m, NCH₂CH ₂, NCH₂CH₂CH ₂) ppm. ¹³C{¹H} NMR (100.6 MHz, CDCl₃): δ=162.3 (CO), 155.2 (OCCCHC), 146.9 (OCCCHCC), 140.9 (OCCCH), 137.7 (SCH), 136.9 (OCCCH), 134.8 (NCCH), 134.0 (NCCHCH), 127.0 (NCN), 126.3 (SCCH, SCCCH), 124.7 (SCCHCHCHCH), 124.4 (SCCH), 123.1 (SCCHCH), 122.8 (SCCHCHCH), 120.8 (NCCH), 42.6 (NCH₂CH₂ CH₂), 32.1 (NCH₂ CH₂), 22.3 (NCH₂CH₂CH₂ CH₂), 19.5 (NCH₂) ppm. IR (ATR): ν=1654 (C=O), 1618 (C=N), 1483 (C−N). EI‐MS: m/z (%)=333 ([M+H]⁺, 44), 332 ([M]⁺, 100), 317, 195, 158. HRMS: Calcd. for C₂₀H₁₆N₂OS 332.0983; found: 332.0985.

2‐(Dibenzo [b,d] thiophen‐4‐yl)‐6,7,8,9‐tetrahydro‐11H ‐pyrido[2,1‐ b ]quinazolin‐11‐one (21): GP; 2‐bromo‐6,7,8,9‐tetrahydro‐11H‐pyrido[2,1‐b]quinazolin‐11‐one (4, 139.5 mg, 0.5 mmol), dibenzothiophenyl‐4‐boronic acid (137 mg, 0.6 mmol), sodium carbonate (132.5 mg, 1.25 mmol) and palladium (II) acetate (9.43 mg, 0.042 mmol) in acetone / water (2 : 1, 6 mL) were stirred at 40–45 °C for 7 h. Column chromatography (20×1 cm, SiO₂, ethyl acetate/petroleum ether 4 : 1) gave 2‐(dibenzo[b,d]thiophen‐4‐yl)‐6,7,8,9‐tetrahydro‐11H‐pyrido[2,1‐b]quinazolin‐11‐one (21, 180 mg, 0.47 mmol, 94 %), colorless crystals (m. p. 177–179 °C).

R _f=0.13 (ethyl acetate). ¹H NMR (400 MHz, CDCl₃): δ=8.65 (1 H, d, J=2.1 Hz, OCCCH), 8.17–8.21 (2 H, m, SCCHCH, SCCHCHCH), 8.13 (1 H, dd, J=8.4, J=2.2 Hz, NCCHCH), 7.81–7.84 (1 H, m, SCCCHCH), 7.75 (1 H, d, J=8.4 Hz, NCCH), 7.55–7.60 (2 H, m, SCCHCHCHCH, SCCCHCHCH), 7.44–7.49 (2 H, m, SCCH, SCCCH), 4.11 (2 H, t, J=6.1 Hz, NCH₂), 3.04 (2 H, t, J=6.6 Hz, NCH₂CH₂CH₂CH ₂), 1.95–2.08 (4H, m, NCH₂CH ₂, NCH₂CH₂CH ₂) ppm. ¹³C{¹H} NMR (100.6 MHz, CDCl₃): δ=162.3 (CO), 155.4 (OCCCHC), 147.2 (OCCCHCC), 139.6 (OCCCH), 138.7 (SCCCCH) 138.5 (SCCH), 136.5 (OCCCH), 135.8 (NCCH), 135.8 (NCCHCH), 134.3 (NCN), 127.2 (SCCHCHCHCHC), 127.1 (SCCHCHCHCHCC), 127.0 (SCCHCHCHCHCCC), 126.3 (SCCH), 125.3 (SCCCHCH), 124.6 (SCCHCH), 122.8 (SCCHCHCH), 121.9 (SCCHCHCHCH), 121.0 (SCCCHCHCH), 120.8 (NCCH), 42.6 (NCH₂CH₂ CH₂), 32.1 (NCH₂ CH₂), 22.2 (NCH₂CH₂CH₂ CH₂), 19.5 (NCH₂) ppm. IR (ATR): ν=1672 (C=O), 1600 (C=N), 1458 (C−N) cm⁻¹. EI‐MS: m/z (%)=383 ([M+H]⁺, 12.6), 382 ([M]⁺, 100), 191 ([M]²⁺ or 4‐oxo‐3‐propyl‐1,2,3,4‐tetrahydroquinazolin‐1‐ium, 4). HRMS: Calcd. for C₂₄H₁₈N₂OS 382.1140; found: 382.1142.

Supporting Information Summary

¹H and ¹³C{¹H} NMR spectra of compounds 3–5 as well as of the synthesized new compounds are available in the Supporting Information.

Conflict of Interests

The authors declare no conflict of interest.

1. Supporting information

As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.

Supporting Information

OPEN-13-e202400197-s001.pdf^{(10.6MB, pdf)}

Acknowledgments

We gratefully acknowledge a Research Fellowship by the German Academic Exchange Service (DAAD) and a Georg Forster Research Fellowship for Experienced Researchers of the Alexander von Humboldt Foundation for B. E. (UZB 1186936GFE). Also, we thank for financial support of the Ministry of Higher Education, Science and Innovations of Uzbekistan (Grant N^o F‐FA‐2021‐408 “Study of the regularities of introduction of pharmacophore fragments into the molecule on the basis of modern cross‐coupling and heterocyclization reactions”. Open Access funding enabled and organized by Projekt DEAL.

Elmuradov B., Okmanov R., Juraev B., Dräger G., Butenschön H., ChemistryOpen 2024, 13, e202400197. 10.1002/open.202400197

Contributor Information

Burkhon Elmuradov, Email: b_elmuradov@mail.ru.

Prof. Dr. Holger Butenschön, Email: holger.butenschoen@mbox.oci.uni-hannover.de, https://www.oci.uni‐hannover.de/de/holger‐butenschoen.

Data Availability Statement

NMR spectra of compounds 3–5 as well as of new compounds are available in the Supporting Information of this article. Crystal structure analyses were deposited with the CCDC.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting Information

OPEN-13-e202400197-s001.pdf^{(10.6MB, pdf)}

Data Availability Statement

NMR spectra of compounds 3–5 as well as of new compounds are available in the Supporting Information of this article. Crystal structure analyses were deposited with the CCDC.

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PERMALINK

New Tricyclic Aryl Quinazoline Derivatives by Suzuki‐Miyaura Cross‐Coupling

Burkhon Elmuradov

Rasul Okmanov

Bakhromjon Juraev

Gerald Dräger

Prof Dr Holger Butenschön

Abstract

Introduction

Scheme 1.

Results and Discussion

Scheme 2.

Table 1.

Figure 1.

Figure 2.

Table 2.

Scheme 3.

Figure 3.

Figure 4.

Table 3.

Scheme 4.

Figure 5.

Figure 6.

Table 4.

Table 5.

Figure 7.

Figure 8.

Figure 9.

Figure 10.

Conclusions

Experimental Section

Supporting Information Summary

Conflict of Interests

1.

Supporting information

Acknowledgments

Contributor Information

Data Availability Statement

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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