One Pot Synthesis of 2-Arylquinazoline and Tetracyclic-Isoindolo[1,2-a]quinazoline Derivatives via Cyanation Followed by the Rearrangement of o-Substituted 2-Halo-N-Arylbenzamides
Ι.D.1. Introduction
The synthesis of N-heterocycles via transition metal mediated cross-coupling reactions had become an area of interest. This may be due to the fact that traditional synthetic methods are often laborious and the desired products are produced in relatively lower yields. The synthesis of these N-heterocycles via copper catalyzed and copper mediated C-C and C-N bond coupling reactions are very popular. Copper catalysts are inexpensive, less toxic and the use of air sensitive and expensive ligands that are used on palladium and other metal complex-based methodologies can be avoided. Further, applications of such copper mediated handy protocols on 2-haloarylbenzamide derivatives with structural changes at the amidic position leads to the formation of multicyclic fused rings via multibond formation. Structural motifs such as dibenzoxazepinones, indoloquinolines and tetracyclic fused N-heterocyclic compounds can be easily synthesized using these methodologies, compared to traditional multistep synthesis.1
Figure Ι.D.1.1. Biologically active quinazoline derivatives
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2-arylquinazolines are an important class of structural motifs that possess remarkable pharmacological properties with anticonvulsant, antibacterial, antiviral, antitubercular, antiplasmodial, anticancer and topoisomerase I inhibitory activities (Figure Ι.D.1.1).2 Besides tetracyclic isoindolo[1,2-a]quinazoline derivatives are ubiquitous structural motifs and possess excellent biological activities (Figure Ι.D.1.2). A structural analogue such as Batracylin has potent activity against colon carcinomas, cisplatin and doxorubicin resistant tumors. A Luotonin derivative was also reported to be effective against leukemia cells. Recent reports indicate that tryptanthrin can be used effectively as a chemotherapeutic agent in the treatment of sleeping disorders.3
Figure Ι.D.1.2. Biologically active tetracyclic isoindolo[1,2-a]quinazoline derivatives
Ι.D.2. Review of literature Ι.D.2.1. 2-phenylquinazolin
Numerous approaches are available for the synthesis of 2-arylquinazoline derivatives.4 However, the synthesis of 2-arylquinazoline derivatives is a cumbersome task, since it involves either the use of starting materials such as 2-(aminomethyl)aniline, benzimidamide, 2-(bromomethyl)aniline, 2-(aminomethyl)aniline, benzimidamide, which are not readily available, dangerous peroxides or hazardous reagents (Scheme Ι.D.2.1).5 Wang and co-workers in their publications in 2001 demonstrated the synthesis of substituted quinazoline using copper oxide nano particles and iodine using TBHP as oxygen source in heating. The corresponding quinazoline derivatives was furnished good yields.6
Scheme Ι.D.2.1
In another report, Han and co-workers had reported aerobic oxidative synthesis of 2-substitutes phenylquinazoline. The reaction was conducted in catalytic amount of CuCl
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and DABCO as ligand in oxygen balloon pressure to afford 2-substituted phenylquinazoline derivatives (Scheme Ι.D.2.2).7
Scheme Ι.D.2.2
Excellent method have been reported by Wang and co-workers for the synthesis of multi-substituted quinazoline derivatives (Scheme Ι.D.2.3).8 Iodine-catalyzed oxidative amination of C(sp3)-H bonds adjacent to nitrogen or oxygen atoms have developed by the reaction of 2-carbonyl anilines, ammonia, solvents such as ethers, amides and alcohols with TBHP was used as oxygen source for the conversion.
Scheme Ι.D.2.3
Thus, We wish to report herein on the solvent-dependent one pot synthesis of multi-substituted 2-arylquinazoline and tetracyclic isoindolo[1,2-a]quinazoline derivatives via cyanation followed by rearrangement of the resulting o-substituted 2-halo-N-arylbenzamide.
Ι.D.2.1. Tetracyclic isoindolo[1,2-a]quinazoline
Very few methods are available for the synthesis of isoindolo[1,2-a]quinazoline. Pal and co-workers have presented the synthesis of isoindolo[1,2-a]quinazoline derivatives by a green and efficient domino reaction.9 The multicomponent reaction was carried out by using isatoic anhydride, various aniline derivatives, 2-formylbenzoic acid and 5% (w/w) Montmorillonite K10 resine in ethanol. The authors also found 6,6a-dihydroisoindolo-[2,1-a]quinazoline-5,11-diones as novel inhibitors of TNF-a in vitro analysis.
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Scheme Ι.D.2.1.1
In another report, Martínez-Viturro et al. have developed the stepwise synthesis of antitumoural agent batracylin and isoindolo[1,2-b]quinazolin-12(10H)-one derivatives (Scheme Ι.D.2.2).10 The preparation of tetracyclic isoindolo[1,2-a]quinazoline derivatives was achieved by step wise process. First, the benzyl alcohol required for the Mitsunobu reaction was obtained from 2-acyl aniline by sodium borohydride reduction. Next, the substituted benzyl alcohol underwent Mitsunobu reaction followed by spontaneous cyclodehydration to form and isoindolo[1,2-b]quinazolin-12(10H)-one derivatives.
Scheme Ι.D.2.2 Ι.D.3. Results and Discussion:
Our group previously reported on numerous protocols for the synthesis of medicinally active N-heterocycles.11 In a continuation of this interest, we noted the recently published articles on copper catalyzed reactions of ethyl cyanoacetate and ethyl 2-(2-bromobenzamido)benzoate for the synthesis of isoquinolino[2,3-a]quinazolinones by Fu and co-workers 12a and Pal and co-workers12b.Based on these reports, we hypothesized, the reaction of 1a with CuCN would first undergo cyanation followed by cyclization in the presence of an amidic N-H, which would lead to the formation of the tetracyclic compound 2a (Scheme Ι.D.3.1). Further, the hydroxyl group can be easily functionalized using various protocols. To investigate this hypothesis, we treated 1a in the presence of CuCN in DMSO and K2CO3 as a base at 100oC. The reaction resulted in multiple spots on TLC after 2h, however, when the reaction was continued for a period of up to 16h, a new compound was observed with a higher Rf than the starting material (entry 1). The compound was isolated and purified by column chromatography. Further characterization by 1H NMR, 13C NMR, LRMS, HRMS, single crystal X-ray diffraction revealed that the
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compound was 2-phenylquinazoline (3a, Figure Ι.D.3.1) and not compound 2a (Scheme Ι.D.3.1).
Figure Ι.D.3.1. X-Ray Crystal structure of 3a (ORTEP diagram)
Scheme Ι.D.3.1. Synthesis of tetracyclic compound 2a from 1a
Interestingly, the combination of such a strained five membered ring and a strong base leads to base catalyzed cleavage of the C-N bond in compound 2a. Moreover, further decarboxylation resulted in the formation of compound 3a (Scheme Ι.D.3.1). To our knowledge, such types of cleavages have not been reported in the literature. This motivated us to study this reaction further. To optimize the reaction conditions, we increased the reaction temperature from 100oC to 120oC and then to 135oC. An elevation in the temperature resulted in an increase in yield to 24% and 74%, respectively (entries 2-3). However, a further increase in temperature failed to result in any improvement in yield (entry 4). Next, various inorganic bases such as Na2CO3, NaHCO3, K3PO4, Cs2CO3
we examined for the reaction (entries 5-8) but these resulted in, either a lower yield of the desired product or no product being formed. Further, the use of organic bases also resulted in lower yields of compound 3a (entries 9-11). Based on this information, it was concluded that K2CO3 was the preferred base for use in this transformation. Different solvents were then examined. However, we found that the product was formed in DMF and DMA but afforded a lower yield of 3a (entries 12-13).
75 Table Ι.D.3.1. Optimization of reaction condition
a Reactions were performed on 0.5 mmol of 1a, CuCN (1 equiv) and Base (2.5 equiv). b Yields refer to isolated and purified compounds.
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We next examined the use of refluxing 1,4-dioxane as the solvent for 12h. Interestingly, a highly polar compound was produced, as evidence by its TLC properties. The compound was isolated and purified. 1H NMR, 13C NMR, LRMS, HRMS data revealed that the compound formed was a tetracyclic isoindole fused quinazoline (2a) and was produced in 79 % yield (entry 14). Further screening of the reaction using other solvents such as acetonitrile and ethanol failed to improve product yield (entries 15, 16). Fine tuning of organic and inorganic bases also failed to improve reaction yield (entries 17-22).
Finally, based on the optimization study, the reaction of 1a with 1 equivalent of CuCN using K2CO3 as a base in 1,4-dioxane at 101oC were the optimal conditions for the preparation of tetracyclic isoindole fused quinazoline (2a) and the reaction with K2CO3 as a base and DMSO as a solvent at 135oC were the optimized conditions for the preparation of 2-phenyl quinazoline (3a).
After optimizing the reaction conditions, the scope of the reaction was studied, first with unsubstituted cyclic compounds A and cyclic compounds B with aldehyde, ketone and cyanide groups at the ortho position. The reaction of CuCN with a model substrate 1a containing an aldehyde at the ortho position afforded the 2-phenylquinazoline derivative (3a) in 74% yield (entry 1, table Ι.D.3.2). However, the reaction of CuCN with 1b and 1c bearing ketone and cyanide groups at the ortho position yielded 4-methyl-2-phenylquinazoline 3b and 2-phenylquinazolin-4-amine 3c in 77% and 57% yields, respectively, with longer reaction time. The longer reaction time for compound 3b and 3c may be due to less electrophilic nature of the ketone and the nitrile functional groups.
Next, electron donating amides were examined. The reaction afforded the corresponding quinazoline derivatives in moderate to good yields but a longer reaction time was needed in most cases (entries 4 to 9). Surprisingly, the reaction with N-(2-cyanophenyl)-2-iodo-4,5-dimethoxybenzamide (1h) reached completion within 9h, producing a product yield of 74% (entry 8). Further, a similar trend was observed, when electron withdrawing amide-containing substrates were used in the reaction. Nitro substituted amides formed the corresponding 2-arylquinazoline derivatives in good yields, but a longer reaction time was needed (entries 10-12). However, the use of electron withdrawing amides afforded better product yields than electron donating amides. The reaction also proceeded when amides bearing bromo and bulkier naphthyl groups were used, resulting in the formation of the corresponding products 3m and 3n in good yield.
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Table Ι.D.3.2. Synthesis of 2-Arylquinazoline from 1a and different 2-halo benzamides
Continue………..
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a Reactions were performed on 0.5 mmol of 1, CuCN (1 equiv) and K2CO3 (2.5 equiv) at 135oC. b Yields refer to isolated and purified compounds.
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As an expansion of this study, we further explored the scope of the protocol with amidic linkages using chalcone derivatives as depicted in scheme Ι.D.3.2. The reaction of CuCN with the unsubstituted chalcone amide (1o) resulted in the formation of the corresponding 2-aryl-4-styrylquinazoline (3o) in 76% yield. In the case of an electron donating substituent on the chalcone, the yield of the respective compound 3p was reduced to 67%
and a longer reaction time was needed. However, an electron withdrawing substituent on the chalcone (1q) resulted in a slightly increased product yield and a reduced reaction time for the synthesis of 4-(4-chlorostyryl)-2-phenylquinazoline (3q).
Scheme Ι.D.3.2. Synthesis of 2-arylquinazoline from 2-halo-N-phenyl benzamide
Further, we used the optimum reaction conditions to check the scope of tetracyclic isoindole fused quinazoline, as depicted in table 3. First, the reaction was screened when the ring B contained aldehyde, ketone and cyanide groups at the ortho position. The reaction of N-(2-formylphenyl)-2-iodobenzamide (1a) with CuCN in 1,4-dioxane afforded the hydroxy substituted tetracyclic isoindole fused quinazoline derivative in 79%
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Table Ι.D.3.3. Synthesis of tetracyclic isoindolo[1,2-a]quinazoline
a Reactions were performed on 0.5 mmol of 1, CuCN (1 equiv) and K2CO3 (2.0 equiv) at 101oC.b Yields refer to isolated and purified compounds.CInseparable mixtures of products
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(entry 1). Whereas, when a ketone group was located at the ortho position, the corresponding tetracyclic derivative (2b) was obtained in good yield. The lower yield of compound 2c was observed, when the reaction was carried out with the ortho-cyano substituted N (2-phenyl)-2-iodobenzamide as a substrate (entry 3). Further, when ring A contained an electron donating dioxymethylene group, a produced moderate yield the desired product (2r) and a slightly longer reaction time was needed (entry 4). However, electron withdrawing bromo substituents on ring A and ring B afforded moderate yields of compounds 2m and 2s. Further, the protocol failed to form compound 2k, when the strong electron withdrawing nitro substituted 1k was used as a substrate.
A plausible mechanism for the formation both 2 and 3 is depicted in Scheme Ι.D.3.3. The reaction is initiated by the formation of intermediate I through cyanation in the presence a base and CuCN, which may undergo intramolecular cyclization via the nucleophilic addition of the amidic nitrogen to the cyanide functionality to generate the imine intermediate II. This intermediate further undergoes an intramolecular cyclization via the nucleophilic addition of the imine nitrogen to the aldehyde functionality to produce the tetracyclic compound 2. The tetracyclic compound 2 then undergoes decarboxylation in the presence of the base to form compound 3.
Scheme Ι.D.3.3. Plausible mechanism for the synthesis of compound 2 and 3
To support our proposed mechanism, we carried out, two control experiments. In the first experiment, we carried out the reaction of 1b with CuCN and potassium carbonate in 1,4-dioxane as the solvent to obtain 2b. After the complete conversion of 1b to the tetracyclic compound 2b, which was confirmed by TLC, DMSO was then added and the reaction
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mixture heated at 110oC. The reaction produced 3b in 51% yield after 16h of reaction (Scheme Ι.D.3.4).
Scheme Ι.D.3.4. Control experiment 1
In the second controlled experiment, we treated the tetracyclic compound 2b with potassium carbonate in the absence copper in DMSO as the solvent at 135oC. Under these conditions, we observed the conversion of 2b into the corresponding 2-arylquinazoline derivative in 50 % yield (Scheme Ι.D.3.5). The findings from the control experiments indicate that the formation of 2-arylquinazoline derivative from the thermal decomposition of tetracyclic compound is facilitated by the base.
Scheme Ι.D.3.5. Control experiment 2 Ι.D.4. Conclusions
In conclusion, we report on the synthesis of a series of substituted 2-arylquinozaline derivatives and tetracyclic isoindolo[1,2-a]quinazoline derivatives in moderate to good yield in a one pot process simply by changing solvent and temperature. A novel base catalyzed cleavage of tetracyclic isoindolo[1,2-a]quinazoline was observed during the synthesis of the 2-arylquinazoline. Further, the synthesis of 2-arylquinazolin-4-amine and 2-phenyl-4-styrylquinazoline were achieved very efficiently compared to currently used methods. The synthesis of good yields of tetracyclic isoindolo[1,2-a]quinazoline derivatives was achieved using 1,4-dioxane as the solvent.
Ι.D.5. Experimental Section Ι.D.5.1. General
All chemicals were purchased from various sources and were used directly without further purification. Analytical thin-layer chromatography was performed using silica gel
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60F glass plates and silica gel 60 (230–400 mesh) was used in flash chromatographic separations. NMR spectra were recorded in DMSO-d6 with DMSO and CDCl3 with CHCl3 as the internal standards for 1H NMR (400 MHz) and 13C NMR (100 MHz).
Coupling constants were expressed in Hertz. HRMS spectra were recorded using MALDI, ESI- or ESI+ mode. Melting points were recorded using an electro thermal capillary melting point apparatus and are uncorrected.
Ι.D.5.2. General procedure for synthesis of substituted 2-halo-N-arylbenzamide 1(a-s): In a stir-bar-equipped flame-dried 50 mL round-bottom flask containing 2-halobenzoic acid (A) (4 mmol) was added SOCl2 (2 mL) carefully followed by one drop of DMF. The reaction mixture was then stirred at 80oC for 3h. The reaction mixture was then evaporated under reduced pressure at 40-45oC temperature to remove excess of SOCl2. The resultant acid chloride was diluted in DCM (15 mL) and then added drop wise to ice cold solution of substituted aniline (B) (6 mmol), pyridine (3 mL) in DCM (10 mL). The reaction mixture was then allowed to warm to room temperature and stirred overnight.
After completion of the reaction as determined by TLC analysis, the reaction mixture was evaporated under reduced pressure and the poured on crushed ice (50 gm). The resultant solid was washed with excess of ice cold water to afford pure compound 1(a-s).
Ι.D.5.3. General Experimental for the Synthesis of 2-arylquinazoline (3a-3q): In an oven-dried, 10 mL round-bottom flask equipped with magnetic stirrer was added 1a (0.5 mmol), CuCN (1.0 equiv), K2CO3 (2.5 equiv) in DMSO (2 mL). The reaction mixture was then stirred at 135oC under a nitrogen atmosphere. After completion of the reaction, as determined by TLC, the reaction mixture was allowed to cool to room temperature. The crude reaction mixture was then purified by column chromatography without workup using Hexane-Ethyl acetate as the eluent to yield compound 3a.
Ι.D.5.4. General Experimental for the Synthesis of isoindole fused quinazoline derivatives (2a-2c, 2m, 2r and 2s): In an oven-dried, 10 mL round-bottom flask
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equipped with magnetic stirrer was added 1a (0.5 mmol), CuCN (1.0 equiv), K2CO3 (2.5 equiv) in 1.4-dioxane (2 mL). The reaction mixture was then stirred at 101oC under a nitrogen atmosphere. After completion of the reaction, as determined by TLC, the reaction mixture was allowed to cool to room temperature. The crude reaction mixture was then purified by column chromatography without workup using dichloromethane-methanol as the eluent to yield compound 2a.
Ι.D.5.4. Spectral Data of compounds 168.3, 141.7, 140.8, 140.7, 136.5, 136.3, 131.9, 128.6, 128.4, 123.8, 122.3, 120.4, 92.9;
LRMS (EI) (m/z) (relative intensity): 352 (100) [M+H]+, 324 (33); HRMS (MALDI)
85 125.0, 121.8, 118.9, 116.4, 114.6, 102.9, 80.5, 55.9; LRMS (EI) (m/z) (relative intensity):
378 (100) [M]+, 352 (59); HRMS calcd for C15H11IN2O2 [M]+: 378.9865, Found 378.9870.
86 139.7, 134.9, 133.8, 133.3, 126.3, 126.1, 118.6, 116.7, 108.7, 108.2, 102.3, 83.0; LRMS (EI) (m/z) (relative intensity): 393 (100) [M+H]+, 362 (45); HRMS calcd for C15H9IN2O3 128.6, 128.5, 116.8, 115.2, 103.5, 92.8, 56.8, 56.5; LRMS (EI) (m/z) (relative intensity):
411 (100) [M]+, 285 (36); HRMS calcd for C16H14INO4 [M]+: 410.9968, Found 410.9962. (100 MHz, CDCl3) δ 195.6, 166.3, 148.2, 143.4, 142.0, 140.2, 136.7, 136.4, 125.8, 124.5, 123.0, 122.4, 120.6, 101.2; LRMS (EI) (m/z) (relative intensity): 396 (100) [M]+, 368 (67); HRMS calcd for C14H9IN2O4 [M]+: 395.9607, Found 395.9610.
87
88 MHz, DMSO-d6) δ 202.8, 166.4, 138.3, 136.3, 134.3, 134.2, 131.6, 131.1, 128.9, 128.8, 128.6, 128.0, 127.1, 125.0, 124.7, 123.9, 120.9, 118.8, 28.8; LRMS (EI) (m/z) (relative 129.5, 129.1, 128.8, 128.7, 128.2, 127.0, 124.0, 121.8, 121.1; LRMS (EI) (m/z) (relative intensity): 453 (100) [M]+, 430 (20); HRMS calcd for C22H16INO2 [M]+: 453.0226, Found 193.3, 168.1, 150.5, 148.7, 145.9, 142.1, 140.8, 140.7, 134.8, 131.7, 130.6, 129.2, 128.6, 128.4, 125.9, 124.2, 123.3, 121.6, 120.7, 108.9, 106.9, 101.9, 92.9; LRMS (EI) (m/z) (relative intensity): 497 (100) [M]+, 231 (68); HRMS calcd for C23H16INO4 [M]+: 497.0124, Found 497.0118.
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90 168.4, 160.3, 150.6, 138.5, 133.6, 130.5, 129.4, 128.7, 127.0, 125.1, 123.2, 22.2; LRMS (ESI) (m/z) (relative intensity): 220 (100) [M]+, 204 (40); HRMS calcd for C15H12N2 [M]+: 123.6, 113.3; LRMS (ESI) (m/z) (relative intensity): 222 (100) [M+H]+, 189 (20); HRMS calcd for C14H12N3 [M+H]+: 222.1031, Found 222.1023.
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Hz, 2H), 3.89 (s, 3H), 2.99 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 168.2, 161.9, 160.2, 150.6, 133.6, 131.2, 130.4, 129.6, 125.2, 122.9, 114.1, 55.6, 22.2; LRMS (MALDI) (m/z) (relative intensity): 251 (100) [M]+, 221 (65); HRMS calcd for C16H15N2O [M+H]+: DMSO-d6) δ 161.9, 160.9, 159.5, 150.3, 132.9, 130.9, 129.4, 127.3, 124.7, 123.6, 113.5, 113.0, 55.2; LRMS (MALDI) (m/z) (relative intensity): 251 (100) [M+H]+; HRMS calcd for C15H14N3O [M+H]+:252.1137, Found 252.1142. 125.2, 122.9, 122.2, 111.5, 111.1, 56.2, 56.2, 22.2; LRMS (ESI) (m/z) (relative intensity):
281 (100) [M+H]+, 220 (40); HRMS calcd for C17H17N2O2 [M+H]+: 281.1290, Found
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113.1, 107.9, 107.6,101.3; LRMS (MALDI) (m/z) (relative intensity): 266 (100) [M+H]+, 243 (30); HRMS calcd for C15H11N3O2 [M+H]+: 266.0930 Found 266.0935.
6,7-dimethoxy-2-phenylquinazoline (3i)
Yield: (67 %); white solid; m.p.: 176-178oC; FT-IR (KBr) ν/cm−1 1635, 1230, 1140; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.23 (bs, 1H), 8.55 (d, J = 8.3 Hz, 2H), 7.48-7.55 (m, 3H), 7.38 (m, 1H) 7.11 (s, 1H), 4.09 (s, 3H), 4.04 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 160.2, 157.3, 156.5, 150.6, 148.8, 138.6, 266 (100) [M]+, 265 (80); HRMS calcd for C16H14N2O2 [M]+: 266.1055, Found 266.1049.
2-(4-nitrophenyl)quinazoline (3j)
Yield: (73 %);dark yellow solid; m.p.: 218-220oC; FT-IR (KBr) ν/cm−1 3439, 3400, 1520, 1350; 1H NMR (400 MHz, CDCl3) δ(ppm) 9.52 (s, 1H), 8.82 (d, J = 8.8 Hz, 2H), 8.37 (d, J = 8.8 Hz, 2H), 8.14 (d, J = 8.4 Hz, 1H), 7.96-8.00 (m, 2H), 7.71(t, J = 7.5 Hz, 1H),; 13C NMR (100 MHz, CDCl3) δ 160.9, 159.0, 150.8, 149.4, 144.0, 134.8, 129.6, 129.1, 128.5, 127.4, 124.1, 124.0; LRMS (EI) (m/z) (relative intensity): 251 (100) [M]+, 205 (40); HRMS calcd for C14H9N3O2 [M]+: 251.0695, Found 251.0690.
4-methyl-2-(4-nitrophenyl)quinazoline (3k)
Yield: (79 %); red solid; m.p.:174-176oC; FT-IR (KBr) ν/cm−1 3468, 1636, 1520, 1350; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.81 (d, J = 8.9 Hz, 2H), 8.35 (d, J = 8.9 Hz, 2H), 8.10-8.15 (m, 2H), 7.93 (t, J = 7.6 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 3.05 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 168.9, 158.0, 150.3, 149.2, 144.3, 134.2, 129.6, 129.5, 128.1, 125.2, 123.8, 123.4, 22.2;
LRMS (MALDI) (m/z) (relative intensity): 265 (100) [M+H]+, 220 (28); HRMS calcd for C15H11N3O2 [M]+: 265.0851, Found 265.0846.
93 (100 MHz, CDCl3) δ 162.3, 157.8, 150.1, 148.3, 144.6, 133.3, 128.8, 127.9, 126.0, 123.6, 123.5, 113.4; LRMS (MALDI) (m/z) (relative intensity): 267 (100) [M]+, 221 (45); 133.9, 131.9, 130.4, 129.5, 127.3, 125.4, 125.2, 123.3, 22.2; LRMS (ESI) (m/z) (relative intensity): 298 (98) [M]+, 300(100); HRMS (ESI) calcd for C15H11BrN2 [M]+: 298.0106,
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Yield: (67 %); yellow solid; m.p.:169-171oC; FT-IR (KBr) ν/cm−1 1643, 1230, 1150, 1140; 1H NMR (400 MHz, 152.2, 149.3, 148.6, 139.4, 138.8, 133.6, 130.9, 130.5, 129.5, 128.8, 128.7, 126.9, 124.2, 124.0, 121.8, 119.2, 108.9, 106.8, 101.7; LRMS (EI) (m/z) (relative intensity): 352 (100) [M+], 351 (60); HRMS calcd for: C23H16N2O2 [M+]: 352.1212, Found 352.1209. 161.7, 160.3, 152.3, 138.7, 138.1, 135.6, 134.8, 133.7, 130.7, 129.6, 129.4, 129.3, 128.8, 128.7, 127.1, 123.9, 121.8, 121.6; LRMS (EI) (m/z) (relative intensity): 342 (100) [M+], 341 (75); HRMS calcd for: C22H15ClN2 (M+): 342.0924, Found 342.0922.
95 127.9, 125.4, 123.5, 123.4, 121.8, 114.7, 76.9; LRMS (ESI) (m/z) (relative intensity): 251 (100) [M+H+]; HRMS (ESI) calcd for: C15H9N2O2 (M-H-): 249.0664, Found 249.0665. 123.4, 121.8, 114.5, 81.3, 33.2; LRMS (ESI) (m/z) (relative intensity): 251 (100) [M+H+], 247 (39); HRMS (ESI) calcd for: C16H13N2O2 (M+H+): 265.0977, Found 265.0977. 128.2, 128.1, 126.4, 126.1, 116.7, 108.3, 93.4; LRMS (ESI) (m/z) (relative intensity): 248 (50) [M+H+], 231(75); HRMS calcd for: C15H9N2O (M+H+): 248.0824, Found 248.0830.
5-hydroxy-5-methyl-[1,3]dioxolo[4',5':5,6]isoindolo[2,1-a]quinazolin-12(5H)-one (2r) Yield: (76 %); grey solid; m.p.: 187-189oC; FT-IR (KBr) ν/cm−1 3334, 3459; 1H NMR (400 MHz, DMSO-d6) δ(ppm)
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8.41 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.36-7.40 (m, 3H), 7.26 (t, J = 7.4 Hz, 1H), 6.41 (s, 1H), 6.27 (s, 2H), 1.57 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 164.6, 152.7, 151.5, 144.1, 130.6, 129.1, 128.2, 127.8, 127.0, 126.0, 125.0, 114.1, 103.1, 101.7, 81.3, 33.2; LRMS (ESI) (m/z) (relative intensity): 309 (100) [M+H+], 291 (82); HRMS
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