Synthesis of Unprecedented Benzofused [1,2,4]-Triazoloquinazolines via Benzyne Diels–Alder Reaction with 7-Vinyl-[1,2,4]triazolo[1,5-c]pyrimidines as Dienes

Abstract

The benzyne Diels–Alder reaction with 7-vinyl-[1,2,4]triazolo[1,5-c]pyrimidines as a kind of unusual acyclic dienes has been investigated. The transformation proceeded smoothly in the presence of CsF to afford the unprecedented partially hydrogenated benzo[f][1,2,4]triazolo[1,5-c]quinazolines in good yields. Treatment of benzo[f][1,2,4]triazolo[1,5-c]quinazolines with DDQ provided the respective dehydroaromatization products.

Since the introductive proposal of benzyne species by Roberts,[1] arynes have evoked considerable interests, and this is attributed in large measure to their intrinsically high reactivity created from the ring strain and electrophilicity from the formal triple bond.[2] Nowadays, the aryne chemistry has elicited remarkable success for the convergent construction of complex structures and application in the generation of key synthetic intermediates.[3]

Even at very low temperatures, benzynes are notoriously reactive, but can be trapped by various reactions. Their reactivity profiles can be divided into three categories: (1) the nucleophilic additions, (2) the transition-metal-catalyzed reactions, and (3) the pericyclic reactions. In particular, since Wittig’s first report,[4] the Diels–Alder (DA)-type reaction with aryne as the dienophile has fascinated the synthetic community for decades. The usefulness of the aryne DA reaction arises from its versatility that diverse carbocyclic structures can be built up.[2a] [3] A wide range of dienes including simple benzene derivatives or other benzenoid aromatic compounds are known to participate well in the transformations.[5] However, as illustrated in Scheme [1], whereas cyclic dienes are frequently employed,[6] acyclic dienes have not enjoyed widespread use.[7] [8] In fact, the latter case has been viewed as an uncommon occurrence in aryne DA methodology.[3] Therefore, aryne–acyclic diene cycloadditions have been recognized as one of the most important topics in recent years.[7]

On the other hand, compounds carrying a [1,2,4]triazolo[1,5-c]pyrimidine nucleus have found an assortment of applications as bioactive heterocycles.[9] [10] Towards the increasing demand in these pharmaceutically intriguing polyheterocycles, various strategies have been developed.[11–14]

In spite of considerable advances, utility of benzyne in the assembly of benzo-annulated triazoloquinazolines remains undiscovered. In light of this and our recent interest in the synthesis of novel triazolopyrimidines,[15] herein, we wish to report a convergent synthesis of unprecedented benzo[f][1,2,4]triazolo[1,5-c]quinazolines by the direct DA reaction of 7-vinyl-substituted [1,2,4]triazolo[1,5-c]pyrimidines as the acyclic dienes with benzynes.

The imperative acyclic diene materials 4 have been readily prepared by the Kumada coupling of 7-chloro-substituted [1,2,4]triazolo[1,5-c]pyrimidines 3 with vinylmagnesium bromide.[16] Compounds 3 were in turn synthesized according to our established method[15b] as outlined in Scheme [2], which features the hypervalent iodine (IBD)-mediated oxidative cyclization of aldehyde pyrimidinylhydrazones 1 and consecutive Dimroth isomerization via 2.[17] [18] The detailed syntheses of all of the starting materials are provided in the Supporting Information.[19]

To examine the reactivity of the vinyl-substituted 4 as a kind of possible diene, we first explored the reaction of 4a (R¹ = Me, R² = Ph) with benzyne. Arynes must be generated in situ because of their extraordinary reactivity. Many methods of generating benzyne from a variety of precursors exist, in addition to benzoic acids by ortho C–H activation with Pd(II),[20] and the recent de novo generation of benzynes.[21]

Remarkably, 2-(trimethylsilyl)phenyl triflates have been used as versatile aryne precursors via other routes than metal–halogen exchange since the first discovery of mild fluoride ion induced formation of benzyne from 2-(trimethylsilyl)phenyl trifluoromethanesulfonate.[22] Several important modifications have been reported on the preparation of the coveted benzyne precursor.[23] Thus, the present study commenced with the treatment of the vinyl-tethered compound 4a and the benzyne generated in situ by the fluoride-induced 1,2-elimination of o-(trimethylsilyl)phenyl triflate (5a). We envisioned that the generated benzyne is intercepted by DA reaction with 4a (Scheme [3]). It should be noted that compounds 4 belong to the type of acyclic dienes. This is of highly interests to utilize a carbon–carbon double bond, which is involved in aromaticity of 4, as the 4π component in DA reactions.

To test the hypothesis and find optimal conditions, the reaction was performed in the presence of different fluoride sources (Table [1]). At the outset, KF was employed with or without 18-crown-6 in acetonitrile at 90 °C, however, only a trace amount of the desired product 7a was detected after 72 hours until all diene starting material 4a was consumed (Table [1], entries 1 and 2). Similar results were obtained when the fluoride source was changed to tetra-n-butylammonium fluoride (TBAF) and performing the reaction in the less polar solvent or 1,4-dioxane or toluene (Table [1], entries 3–5). Further study showed that lower temperatures also failed to give 7a (Table [1], entries 6 and 7). To our delight, a good yield (65%) of the expected 7,8-dihydrobenzo[f][1,2,4]triazolo[1,5-c]quinazoline (7a) was achieved when four equivalents of CsF were used under the comparable initial reaction conditions (Table [1], entry 8). Apparently, 7a is formed by aromatization of the initial tetracyclic product 6a (Scheme [3,]R¹ = Me, R² = Ph). Increasing the loading of 5a and fluoride source (CsF) afforded higher yields (Table [1], entry 8 vs. 9 or 10).

A variety of solvents have also been screened. The yield could be slightly improved to 76% when 1,4-dioxane was performed (Table [1], entry 11) at 110 °C. Intriguingly, THF, a solvent with lower boiling point that has commonly been used as solvent for benzyne reactions,[3] seems to be deleterious and the desired product was obtained in only 39% isolated yield (Table [1], entry 12). Finally, the reaction in toluene also failed to provide the expected product (Table [1], entry 13).

The optimized reaction conditions (3.0 equiv of triflate 5a, 6.0 equiv of CsF, dioxane at 110 °C) were then applied to a variety of substrates 4 carrying diverse aryl groups in the triazole ring (R²) with or without methyl substitution on the pyrimidine ring (R¹) as diene to establish the generality of this unique DA reaction. The results are summarized in Table [2].[24] Gratifyingly, substrates with the methyl substitution on the pyrimidine ring and diverse aryl groups R² on the triazole ring were all compatible to the reaction conditions, providing good yields of the respective partially hydrogenated benzo[f][1,2,4]triazolo[1,5-c]quinazolines 7b–k.

As shown in Table [2], while the reactions for the C(5)-methyl-substituted substrates 4b–k, irrespective of the nature of the C(2)-aryl substituents, proceeded uniformly well to furnish the desired cycloadducts (Table [2], entries 1–11), a limitation was observed when a substrate with no methyl substitution on the pyrimidine ring was used. Thus, only trace amount of the expected products of 5-unsubstituted 4l could be isolated from the reaction mixture (Table [2], entry 12). In addition, substituent at the C-2 position with an aliphatic group was also found to be unsuitable diene in the cycloaddition. Thus, the C(2)-ethyl-substituted 4m was unsuccessful in the desired transformation (Table [2], entry 13). Nevertheless, within these constrains, the scope of the present DA reactions with vinyl-substituted heterocycles 4 as the acyclic diene under these conditions is satisfactory.

To get unambiguous structural proof, a single crystal was developed for 7f and subjected to X-ray diffraction analysis. The result ascertained the spectral determination.[25]

To account for the role of C(5)-methyl facilitation, we also performed a preliminary DFT calculation on the reaction of 4a as well as 4l with benzyne. In view of the low LUMO character of benzyne, the enhancement in nucleo­philicity of ‘diene’ 4 would entail favorable HOMO_diene–LUMO_benzyne interactions, and hence a decrease of the activation energy for the cycloaddition. It is indicated that methyl substitution (4a) brings the electrophilicity power from ω = 1.91 eV in 4l to 1.77 eV in 4a, and increases the nucleophilic power from N = 2.82 eV in 4l to 2.93 eV in 4a. Thus, methyl in 4 makes them less electrophilic and hence more nucleophilic in global terms, benefiting the electrophilic–nucleophilic interaction in these benzyne (ω = 1.95 eV) DA reactions.[26] [27]

To further investigate the substrate scope, various 7-vinyl-substituted [1,2,4]triazolo[1,5-c]pyrimidines 4 with a phenyl group residing at C(5) were reacted with benzyne. The reaction was performed by employing the optimal conditions shown above, but with acetonitrile as the solvent in place of the dioxane for the sake of better performance in terms of conversion and yields. The reaction progress was detected by TLC analysis to ensure a full conversion. Thus, the reaction time required was modulated for individual substrate. As exhibited in Table [3], introducing a phenyl group instead of methyl group into the 4-position of the bicyclic diene 4, the reaction performed equally well for all the tested substrates, furnishing the anticipated benzo[f][1,2,4]triazolo[1,5-c]quinazolines 7n–u in good to excellent yields.[28] Significant lower yield was obtained in the reaction of 4p (Table [3], entry 3) even though it gave the fastest reaction. Nevertheless, it is not possible to establish correlation between the yield and the electron-donating or electron-withdrawing effect at the phenyl group fixed at the C(2) position of the triazole moiety. From the above data, both alkyl and aryl substitution at C(5) of 4 benefits these benzyne DA reactions.

Inspired by the above success, we next examined the reaction with substituted benzyne precursors 5b and 5c. As exhibited in Table [3], reactions of the unsymmetrical benzyne generated from the 4-methyl-substituted triflate 5b with 4o or 4u worked well, and the desired products were formed as an inseparable mixture of regioisomers 7v,w/7v′,w′ (Figure [1]) in an approximate 1:1 ratio (based on ¹H NMR spectroscopy; Table [3], entries 9 and 10). When the symmetrical benzyne precursor 5c was employed, the reaction with 4o or 4t proceeded smoothly to provide good yields of the expected products 7x and 7y, respectively (Table [3], entries 11 and 12).

Finally, the DDQ-mediated oxidative aromatization of products 7 was attempted. As exemplified by the C(5)-methyl-substituted 7b and C(5)-phenyl-substituted 7n, the dehydroaromatization proceeded well in the presence of DDQ in methylene under refluxing conditions, leading to the formation of the expected aromatized tetracyclic heterocycles 8a as well 8b in moderate to high yields (Scheme [4]).[29]

The proposed mechanism of the above cycloaddition reaction is depicted in Scheme [5]. The vinyl-substituted bicyclic compounds 4 acting as arynophile dienes react with the in situ generated benzyne to afford the [4+2] cycloadduct 6. Subsequently, intermediates 6 undergo a fluoride ion activated isomerization to yield the isolated products 7.

In summary, we present herein a novel, robust, convergent Diels–Alder protocol of benzynes with 7-vinyl-substituted [1,2,4]triazolo[1,5-c]pyrimidines. These reactions feature a vinyl-substituted triazolopyrimidine as an unconventional acyclic 1,3-diene component, allowing easy access to biologically interesting polynuclear heterocyclyes of benzo[f][1,2,4]triazolo[1,5-c]quinazolines, which are difficult to access by other methods. To our knowledge this represents an unusual use of pyrimidine core with a pendant vinyl group as diene to participate in benzyne Diels–Alder reactions. Further work to include a broader substrate scope is currently under way in our group. We envisage that this method will be highly amenable to the synthesis of more complex heterocyles.

Acknowledgment

This study was financially supported by the National Science Foundation of China (No. 21372045). Wang is grateful to Hangzhou Government for Qian-Jiang scholar assistance.

• References and Notes

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• 19 General Procedure for Kumada Coupling of 3a–u with Vinylmagnesium Bromide A flask charged with substrate 3 (1.0 mmol) and Pd(PPh₃)₂Cl₂ (35 mg, 0.05 mmol) was flushed with nitrogen. Anhydrous THF (10 mL) was added by syringe, and then vinylmagnesium bromide in THF (0.7 M in THF, 1.9 mL, 1.3 mmol) was added slowly by syringe over a period of about 30 min. The whole was further refluxed until the reaction was considered complete as determined by TLC analysis. The reaction solvent was removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel to provide the corresponding 7-vinyl-[1,2,4]triazolo[1,5-c]pyrimidines 4. Spectral Data of 4a White powder; yield 77%; mp 187–188 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.28 (d, J = 4.0 Hz, 2 H, ArH), 7.48 (s, 3 H, ArH), 7.35 (s, 1 H, ArH), 6.75 (dd, J = 10.4, 16.8 Hz, 1 H, CH), 6.45 (d, J = 16.8 Hz, 1 H, CH₂), 5.59 (d, J = 10.4 Hz, 1 H, CH₂), 3.01 (s, 3 H, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 165.3, 153.7, 150.8, 150.1, 134.5, 130.7, 130.3, 128.8, 127.7, 121.2, 106.0, 20.0. IR (KBr): ν_max = 3061, 3016, 1626, 1543, 1459, 1428, 1321, 1287, 1216, 925, 714, 690 cm^–1. ESI-HRMS: m/z calcd for C₁₄H₁₂N₄ [M + H]⁺: 237.1140; found: 237.1143.
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• 24 General Procedure for the Benzyne DA Cycloaddition of 7-Vinyl-[1,2,4]triazolo[1,5-c]pyrimidines 4a–k (Table 2) To the flask charged with a heterocyclic diene 4 (0.5 mmol), CsF (0.46 g, 3.0 mmol,) and o-(trimethylsilyl)phenyl triflate (5a, 0.45 g, 1.5 mmol) was carefully added degassed dry 1,4-dioxane (12 mL). The mixture was heated under reflux until complete consumption of the starting material (TLC monitoring – the time required was as indicated in Table 2). Concentration of the reaction mixture in vacuum followed by flash column chromatography over SiO₂ (hexane–EtOAc = 1:5) afforded 7a–k. Spectral Data of 7a (Table 2, Entry 1) Yellow powder; yield 76%; mp 164–165 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.09 (d, J = 8.0 Hz, 1 H, ArH), 8.42 (d, J = 6.8 Hz, 2 H, ArH), 7.53–7.43 (m, 4 H, ArH), 7.35–7.28 (m, 2 H, ArH), 3.13–3.05 (m, 7 H, 2 CH₂, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 165.2, 152.2, 151.1, 148.3, 136.0, 130.6, 130.5, 129.7, 128.8, 128.6, 128.1, 127.9, 127.8, 127.2, 115.6, 30.5, 28.2, 20.1. IR (KBr): ν_max = 3061, 2944, 1614, 1599, 1576, 1533, 1484, 1457, 1433, 1333, 1278, 1246, 713, 687 cm^–1. ESI-HRMS: m/z calcd for C₂₀H₁₆N₄ [M + H]⁺: 313.1453; found: 313.1449.
• 25 CCDC-1036102 contains the supplementary crystallographic data for this compound. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif. See also the Supporting Information.
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• 27 See also Supporting Information for computation details.
• 28 General Procedure for the Benzyne DA Cycloaddition of 7-Vinyl-[1,2,4]triazolo[1,5-c]pyrimidines 4n–u To the flask charged with 4 (1.0 mmol), CsF (0.91 g, 6.0 mmol), and o-(trimethylsilyl)phenyl triflate 5 (2.0 mmol) was carefully added degassed anhydrous MeCN (10 mL). The mixture was heated under reflux until complete consumption of the starting material (TLC monitoring). Concentration of the reaction mixture in vacuum followed by flash column chromatography over SiO₂ (hexane–EtOAc, 10:1) afforded 7n–y (Table 2). Spectral Data of 7n (Table 3, Entry 1) White solid; yield 56%; mp 155–156 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.19 (d, J = 7.8 Hz, 1 H), 8.80–8.71 (m, 2 H), 8.51–8.41 (m, 2 H), 7.64–7.60 (m, 3 H), 7.56–7.50 (m, 3 H), 7.47 (dd, J = 7.1, 0.8 Hz, 1 H), 7.38–7.33 (m, 1 H), 7.31 (d, J = 7.4 Hz, 1 H), 3.24 (t, J = 7.5 Hz, 2 H), 3.12 (t, J = 7.5 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 165.2, 152.5, 152.4, 146.5, 136.3, 131.7, 131.6, 130.6, 130.4, 129.8, 128.8, 128.7, 128.4, 128.0, 127.8, 127.2, 115.9, 30.7, 28.3. ESI-HRMS: m/z calcd for C₂₅H₁₈N₄ [M + H]⁺: 375.1610; found: 375.1605.
• 29 Procedure for the DDQ-Mediated Dehydrogenation of 7b and 7n 7,8-Dihydrobenzo[f][1,2,4]triazolo[1,5-c]quinazoline 7b or 7n (0.3 mmol) and DDQ (136 mg, 0.6 mmol) were dissolved in CH₂Cl₂ (10 mL). The mixture was heated under reflux until complete consumption of the starting material (TLC monitoring). After filtration and removal of the solvent, the residue was purified by the flash column chromatography on SiO₂ with hexane–EtOAc (10:1) as eluent to afford, respectively, the dehydrogenated benzo[f][1,2,4]triazolo[1,5-c]quinazolines 8a and 8b. Spectral Data of 8a White solid; yield 90%; mp 177–178 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.17 (d, J = 8.5 Hz, 1 H), 8.31–8.14 (m, 2 H), 8.06–7.98 (m, 2 H), 7.93–7.83 (m, 1 H), 7.79–7.68 (m, 1 H), 7.66–7.55 (m, 1 H), 7.52–7.42 (m, 2 H), 3.20 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 150.9, 148.1, 144.8, 143.29, 133.7, 133.1, 132.4, 132.1, 131.1, 131.0, 129.8, 129.7, 128.5, 128.3, 127.9, 127.5, 126.9, 126.1, 113.1, 20.2. ESI-HRMS: m/z calcd for C₂₀H₁₃ClN₄ [M + H]⁺: 345.0907; found: 345.0886. Spectral Data of 8b White solid; yield 60%; mp 192–193 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.32 (d, J = 8.4 Hz, 1 H), 8.82–8.70 (m, 2 H), 8.60–8.45 (m, 2 H), 8.19 (d, J = 8.9 Hz, 1 H), 8.11 (d, J = 8.9 Hz, 1 H), 8.03 (d, J = 7.9 Hz, 1 H), 7.96–7.86 (m, 1 H), 7.80–7.71 (m, 1 H), 7.69–7.63 (m, 3 H), 7.61–7.51 (m, 3 H).¹³C NMR (100 MHz, CDCl₃): δ = 156.1, 153.0, 146.7, 143.6, 133.2, 132.5, 132.1, 131.7, 130.8, 130.7, 128.9, 128.6, 128.5, 128.3, 128.1, 127.7, 126.8, 113.2, 107.0, 103.5, 101.9. ESI-HRMS: m/z calcd for C₂₅H₁₆N₄ [M + H]⁺: 373.1453; found: 373.1440.

• References and Notes

• 1 Roberts JD, Simmons HE, Carlsmith LA, Vaughan CW. J. Am. Chem. Soc. 1953; 75: 3290
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For selected reviews on aryne chemistry, see:
• 2a Pérez D, Peña D, Guitián E. Eur. J. Org. Chem. 2013; 5981
• 2b Dubrovskiy AV, Markina NA, Larock RC. Org. Biomol. Chem. 2013; 11: 191
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• 2c Bhunia A, Yetra SR, Biju AT. Chem. Soc. Rev. 2012; 41: 3140
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• 2d Gampe CM, Carreira EM. Angew. Chem. Int. Ed. 2012; 51: 3766 ; Angew. Chem. 2012, 124, 3829
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• 4 Wittig G, Dürr H. Justus Liebigs Ann. Chem. 1964; 672: 55
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• 5 For an early example of DA reaction between α-pyrone and aryne, see: Perez D, Guitian E, Castedo L. J. Org. Chem. 1992; 57: 5911
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For selected reports, see:
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• 19 General Procedure for Kumada Coupling of 3a–u with Vinylmagnesium Bromide A flask charged with substrate 3 (1.0 mmol) and Pd(PPh₃)₂Cl₂ (35 mg, 0.05 mmol) was flushed with nitrogen. Anhydrous THF (10 mL) was added by syringe, and then vinylmagnesium bromide in THF (0.7 M in THF, 1.9 mL, 1.3 mmol) was added slowly by syringe over a period of about 30 min. The whole was further refluxed until the reaction was considered complete as determined by TLC analysis. The reaction solvent was removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel to provide the corresponding 7-vinyl-[1,2,4]triazolo[1,5-c]pyrimidines 4. Spectral Data of 4a White powder; yield 77%; mp 187–188 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.28 (d, J = 4.0 Hz, 2 H, ArH), 7.48 (s, 3 H, ArH), 7.35 (s, 1 H, ArH), 6.75 (dd, J = 10.4, 16.8 Hz, 1 H, CH), 6.45 (d, J = 16.8 Hz, 1 H, CH₂), 5.59 (d, J = 10.4 Hz, 1 H, CH₂), 3.01 (s, 3 H, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 165.3, 153.7, 150.8, 150.1, 134.5, 130.7, 130.3, 128.8, 127.7, 121.2, 106.0, 20.0. IR (KBr): ν_max = 3061, 3016, 1626, 1543, 1459, 1428, 1321, 1287, 1216, 925, 714, 690 cm^–1. ESI-HRMS: m/z calcd for C₁₄H₁₂N₄ [M + H]⁺: 237.1140; found: 237.1143.
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• 24 General Procedure for the Benzyne DA Cycloaddition of 7-Vinyl-[1,2,4]triazolo[1,5-c]pyrimidines 4a–k (Table 2) To the flask charged with a heterocyclic diene 4 (0.5 mmol), CsF (0.46 g, 3.0 mmol,) and o-(trimethylsilyl)phenyl triflate (5a, 0.45 g, 1.5 mmol) was carefully added degassed dry 1,4-dioxane (12 mL). The mixture was heated under reflux until complete consumption of the starting material (TLC monitoring – the time required was as indicated in Table 2). Concentration of the reaction mixture in vacuum followed by flash column chromatography over SiO₂ (hexane–EtOAc = 1:5) afforded 7a–k. Spectral Data of 7a (Table 2, Entry 1) Yellow powder; yield 76%; mp 164–165 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.09 (d, J = 8.0 Hz, 1 H, ArH), 8.42 (d, J = 6.8 Hz, 2 H, ArH), 7.53–7.43 (m, 4 H, ArH), 7.35–7.28 (m, 2 H, ArH), 3.13–3.05 (m, 7 H, 2 CH₂, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 165.2, 152.2, 151.1, 148.3, 136.0, 130.6, 130.5, 129.7, 128.8, 128.6, 128.1, 127.9, 127.8, 127.2, 115.6, 30.5, 28.2, 20.1. IR (KBr): ν_max = 3061, 2944, 1614, 1599, 1576, 1533, 1484, 1457, 1433, 1333, 1278, 1246, 713, 687 cm^–1. ESI-HRMS: m/z calcd for C₂₀H₁₆N₄ [M + H]⁺: 313.1453; found: 313.1449.
• 25 CCDC-1036102 contains the supplementary crystallographic data for this compound. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif. See also the Supporting Information.
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• 27 See also Supporting Information for computation details.
• 28 General Procedure for the Benzyne DA Cycloaddition of 7-Vinyl-[1,2,4]triazolo[1,5-c]pyrimidines 4n–u To the flask charged with 4 (1.0 mmol), CsF (0.91 g, 6.0 mmol), and o-(trimethylsilyl)phenyl triflate 5 (2.0 mmol) was carefully added degassed anhydrous MeCN (10 mL). The mixture was heated under reflux until complete consumption of the starting material (TLC monitoring). Concentration of the reaction mixture in vacuum followed by flash column chromatography over SiO₂ (hexane–EtOAc, 10:1) afforded 7n–y (Table 2). Spectral Data of 7n (Table 3, Entry 1) White solid; yield 56%; mp 155–156 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.19 (d, J = 7.8 Hz, 1 H), 8.80–8.71 (m, 2 H), 8.51–8.41 (m, 2 H), 7.64–7.60 (m, 3 H), 7.56–7.50 (m, 3 H), 7.47 (dd, J = 7.1, 0.8 Hz, 1 H), 7.38–7.33 (m, 1 H), 7.31 (d, J = 7.4 Hz, 1 H), 3.24 (t, J = 7.5 Hz, 2 H), 3.12 (t, J = 7.5 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 165.2, 152.5, 152.4, 146.5, 136.3, 131.7, 131.6, 130.6, 130.4, 129.8, 128.8, 128.7, 128.4, 128.0, 127.8, 127.2, 115.9, 30.7, 28.3. ESI-HRMS: m/z calcd for C₂₅H₁₈N₄ [M + H]⁺: 375.1610; found: 375.1605.
• 29 Procedure for the DDQ-Mediated Dehydrogenation of 7b and 7n 7,8-Dihydrobenzo[f][1,2,4]triazolo[1,5-c]quinazoline 7b or 7n (0.3 mmol) and DDQ (136 mg, 0.6 mmol) were dissolved in CH₂Cl₂ (10 mL). The mixture was heated under reflux until complete consumption of the starting material (TLC monitoring). After filtration and removal of the solvent, the residue was purified by the flash column chromatography on SiO₂ with hexane–EtOAc (10:1) as eluent to afford, respectively, the dehydrogenated benzo[f][1,2,4]triazolo[1,5-c]quinazolines 8a and 8b. Spectral Data of 8a White solid; yield 90%; mp 177–178 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.17 (d, J = 8.5 Hz, 1 H), 8.31–8.14 (m, 2 H), 8.06–7.98 (m, 2 H), 7.93–7.83 (m, 1 H), 7.79–7.68 (m, 1 H), 7.66–7.55 (m, 1 H), 7.52–7.42 (m, 2 H), 3.20 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 150.9, 148.1, 144.8, 143.29, 133.7, 133.1, 132.4, 132.1, 131.1, 131.0, 129.8, 129.7, 128.5, 128.3, 127.9, 127.5, 126.9, 126.1, 113.1, 20.2. ESI-HRMS: m/z calcd for C₂₀H₁₃ClN₄ [M + H]⁺: 345.0907; found: 345.0886. Spectral Data of 8b White solid; yield 60%; mp 192–193 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.32 (d, J = 8.4 Hz, 1 H), 8.82–8.70 (m, 2 H), 8.60–8.45 (m, 2 H), 8.19 (d, J = 8.9 Hz, 1 H), 8.11 (d, J = 8.9 Hz, 1 H), 8.03 (d, J = 7.9 Hz, 1 H), 7.96–7.86 (m, 1 H), 7.80–7.71 (m, 1 H), 7.69–7.63 (m, 3 H), 7.61–7.51 (m, 3 H).¹³C NMR (100 MHz, CDCl₃): δ = 156.1, 153.0, 146.7, 143.6, 133.2, 132.5, 132.1, 131.7, 130.8, 130.7, 128.9, 128.6, 128.5, 128.3, 128.1, 127.7, 126.8, 113.2, 107.0, 103.5, 101.9. ESI-HRMS: m/z calcd for C₂₅H₁₆N₄ [M + H]⁺: 373.1453; found: 373.1440.

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