Synthesis of 1,2-Dihydroquinazolines via Rearrangement of

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Cite This: J. Org. Chem. 2018, 83, 8750−8758

Synthesis of 1,2-Dihydroquinazolines via Rearrangement of Indazolium Salts Qian Chen,*,†,‡ Zhuqing Mao,‡ Kunqi Gao,‡ Fang Guo,‡ Li Sheng,*,‡ and Zhonglin Chen*,§ †

School of Chemical Engineering, Southwest Forestry University, Kunming 650224, China School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150080, China § State Key Laboratory of Urban Water Resource and Environment, School of Environment, Harbin Institute of Technology, Harbin 150090, China Downloaded via UNIV OF SOUTH DAKOTA on August 3, 2018 at 09:58:27 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

‡

S Supporting Information *

ABSTRACT: A convenient synthesis of 1,2-dihydroquinazolines via rearrangement of indazolium salts was described. A mechanistic study using isotope labeling experiment revealed that the rearrangement passes through cleavage of N−N bond/ ring opening after basic deprotonation of 2-benzyl in indazolium salts to yield intermediate E, which proceeds in an intramolecular N-nucleophilic addition to form the observed product. Computational analyses imply that the pathway of the rearrangement is determined by the energy barriers of the ring-closing process and the stability of the product.

T

decades ago by Bertrand and co-workers; this study ushered a dramatic surge in the research on isolable carbene.11 NHCs have become one of the most significant developments in both organometallic chemistry and organocatalysis.12 NHCs have been widely utilized as alternatives to phosphine ligands for transition metal-catalytic reactions because of their strong σdonating ability and high stability toward oxygen and moisture.13,14 The steric hindrance and electronic properties of NHCs can also be readily fine-tuned through the variation in the backbone of N-heterocycles and/or N-substituents.15 NHCs with a carbene center adjacent to only one heteroatom have shown some different features from that of NHCs adjacent to two heteroatoms, such as imidazole, imidazoline and benzimidazoline.16,17 Indazolin-3-ylidenes are the representative examples of this class of NHCs, and their coordination chemistry and utility as ligands were investigated.18 We also described the use of indazolium salts as efficient carbene precursors for palladium-catalyzed Suzuki coupling of aryl bromides with arylboronic acids.19 As a rational extension, we attempted to use indazolium salts for the palladium-catalytic Heck reaction between ester acrylate with aryl bromide. Unexpectedly, we were unable to obtain the Heck reaction product and a trace of new compound was isolated. After analysis of the spectrum of the new compound, we inferred that the new compound possibly came from the rearrangement of indazolium salts. Molecular rearrangement has gained consid-

he quinazoline skeleton is a common structural motif in the N-containing heterocycles compounds with an extensive spectrum of bioactivities.1 Recent research results of the quinazoline analogues have shown their potential applications in antibacterial,2 anticancer,3 antiviral,4 antiinflammatory activities,5 antimalarial activities,6 and calcium channel antagonists.7 Dihydroquinazoline derivatives are known to act as selective inhibitors of the trypanothione reductase (TryR).8 Considerable efforts have been made toward the synthesis of these quinazoline and dihydroquinazoline derivatives because of the above-mentioned application possibilities.7b−d,8,9 For example, Movassaghi reported the synthesis of quinazoline derivatives by using benzamides and alkylnitriles in the presence of Tf2O and a base additive.9a Buchwald described an efficient approach for preparing quinazolines through a Pd-catalyzed Narylation of amidines followed by addition of aldehydes.9g Mancheño’s group disclosed a straightforward iron catalyzed oxidative tandem procedure for the synthesis of dihydroquinazolines from N-alkylanilines using TEMPO oxoammonium salt as an oxidant.9d Dihydroquinazolines skeleton can be constructed from 2-aminobenzophenone and aldehydes under microwave irradiation.9b Although these reported methods are efficient, the mild and rapid approaches for the synthesis of dihydroquinazolines from readily available starting materials would still be desired. Carbenes containing a divalent carbon atom have been regarded as highly reactive species in organic transformations.10 The preparation of the first isolable carbene bearing adjacent phosphorus and silicon substituents was only achieved three © 2018 American Chemical Society

Received: April 25, 2018 Published: July 17, 2018 8750

DOI: 10.1021/acs.joc.8b01044 J. Org. Chem. 2018, 83, 8750−8758

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The Journal of Organic Chemistry

we opted to use toluene as solvent. Lower yields were observed when the reaction temperature was lowered (entries 7−8). Investigations into the effects of bases suggested that Cs2CO3, K2CO3, Na2CO3 and K3PO4 are suitable bases for the present rearrangement reaction (entries 9−11). However, Et3N proved to be less effective (entry 12). We also attempted to determine the possibility of asymmetric version using (+)-cinchonine as base. However, racemic target compound was obtained in reasonable yield (entry 13). With the identified optimal reaction conditions (Table 1, entry 9), we first evaluated the different functionalities of Nsubstituted benzyl in indazolium salts. Scheme 2 shows that the different substituents and substitution patterns of the Nsubstituted benzyl of indazolium salts were all tolerated. Methyl substituted 1b−1d were successfully transferred into the corresponding 2b−2d in good to high yields (70−95%). A bulkier substrate with mesityl group also provided the desired product 2e in good yield. Indazolium salts containing strong electron-donating substituted aryl group were good substrates for the present rearrangement, affording the desired product in high yields (2f−2g). Substrates bearing electron-withdrawing substituted aryl groups, including chloro-, fluoro- and nitrogroups were tested for the present rearrangement, and the desired rearrangement products were afforded in moderate to good yields (2h−2m). Results indicate that electronic property and steric hindrance on the N-substituted benzyl had a slight effect on the observed rearrangement. Further investigations showed that the present rearrangement has a broad substrate scope (Scheme 2). Indazolium salts with 1methyl and 1-ethyl groups were good substrates for the present rearrangement, forming the desired product in good to high yields (2n−2p). Furthermore, substrates, the core aryl groups of which have electron-donating and electron-withdrawing substituted groups, including methoxy, benzyloxy, and bromo groups, were examined for the present rearrangement, and the corresponding rearrangement products were obtained in moderate to high yields (2q−2z). Indazolium salt, whose 2benzyl group replaced by a cinnamyl group, was a good substrate for the present rearrangement, producing 3a in high yield. Next, we investigated the mechanism of the present rearrangement. Initially, we supposed that the rearrangement should be followed a mechanism as shown in Scheme 3.23 Thus, deprotonation of 1a by base gave ylide A or carbene A′, which proceeds cleavage of N−N bond/ring opening to afford an intermediate keteneimine B. 1,3-H shift or 1,5′-H shift of the keteneimine B produces intermediate C or D, respectively.24 6πElectrocyclization of the intermediate C gave the observed product 2a. However, another possible rearrangement product 4 derived from intermediate D through 1,5′-H shift could not be detected, which ruled out the possibility of 1,5′-H shift. If it is true, the rearrangement of deuterated 1-benzyl or 2-benzyl should give two different products. Thus, the rearrangement of isotope labeling 1-benzyl and 2benzyl 1a were carried out at the same condition as that of 1a (Scheme 4). Interestingly, the rearrangement of 1a-1-benzyl D2 gave the expected 2a-1-benzyl D2 containing total D, while 1a-2benzyl D2 gave 2a-2-benzyl D containing 58−64% D and the desired 2a-2,4-di-D was not observed. This result implies that the present rearrangement did not proceed 1,3-H shift of the keteneimine B. On the basis of the above results, we propose the second mechanism of the rearrangements, as shown in Scheme 5. Given the intramolecular N-nucleophilic addition of intermediate E or

erable attention in organic synthesis, because it represents a new pathway based on the reorganization of the bonds of easily available reactants.20 Several examples of organic synthesis based on N−N bond cleavage have been reported,21 and have also been considered to be fairly helpful in understanding the mechanisms of nitrogen fixation and searching the possibility of developing new transformations that can utilize molecular nitrogen and/or other compounds containing N−N bond.22 However, reports on the molecular rearrangement based on N− N bond cleavage have been scarce. Rearrangement of NHCs of pyrazoles and indazols were observed, which can be used as an approach for the synthesis of 4-aminoquinolines, acridines, and the relative compounds (Scheme 1a).23 Interestingly, the Scheme 1. Rearrangement of Indazoliums

present rearrangement demonstrated a different mechanism from previous reports and produced 1,2-dihydroquinazolines (Scheme 1b). Herein, we report the rearrangement of the indazolium salts bearing various N-substituents and their mechanism by experiment and density functional theory (DFT) calculation. On the basis of the primary discovery, indazolium bromide 1a was examined as the model compound to optimize the rearrangement condition (Table 1). The initial screening of solvents indicated that toluene, dioxane and DMSO are suitable for the study, whereas DMF and THF yielded moderate results (entries 1−5). The present rearrangement is tolerant to H2O (entry 6). Considering the convenience of being free of workup, Table 1. Optimization of the Rearrangement Reaction Conditionsa

entry

solvent

base

T (°C)

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13

toluene dioxane THF DMF DMSO toluene/H2O toluene toluene toluene toluene toluene toluene toluene

Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 K2CO3 Na2CO3 K3PO4 Et3N (+)-cinchonine

70 70 70 70 70 70 50 rt 70 70 70 70 70

82 76 67 65 75 60 70 40 84 83 67 21 50

a

Reaction condition: indazolium halides (0.2 mmol), base (0.3 mmol), solvent (2 mL) at 70 °C for 12 h. bIsolated yield. 8751


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The Journal of Organic Chemistry Scheme 2. Scope for the Rearrangement Reactiona,b

Reaction: indazolium haildes (0.2 mmol), base (0.3 mmol), solvent (2 mL) at 70 °C for 12 h. bIsolated yield.

a

Scheme 3. Proposed Rearrangement Mechanism I

Scheme 4. Isotope Labeling Experiment of the Rearrangement

6π-electrocyclization of the intermediate C to obtain the desired product 2a, we speculated that formation of intermediate G through deprotonation of 2-benzyl in 1a with bases and

subsequent cleavage of N−N bond/ring opening yielded intermediate E or its nonpolar resonance structure C (Scheme 5, top). In principle, formation of intermediate H through 8752


Note


°C, respectively, which can be regarded that the acidity of H1 equals to the acidity of H2. Therefore, the charge difference of N1 and N2 has no effect on the activity of H atoms. However, because of its more negative charge, N1 can attack C2 more easily than when N2 attacks C1. The results are in line with the observed regioselectivity outcomes. Furthermore, the results are in accordance with the following energy analyses. The calculated energy profiles of the main reaction (MR) (Scheme 5, top) and side reaction (SR) pathways (Scheme 5, bottom) are depicted in Figure 2. In our calculation, the reaction

Scheme 5. Proposed Mechanism for the Rearrangement II

deprotonation of 1-benzyl in 1a with bases and similar cleavage of N−N bond/ring opening process could yield intermediate F or its nonpolar resonance structure D, proceeding in a similar rout to form the product 4 (Scheme 5, bottom). However, the conceivable rearrangement product 4 was not observed. We estimated that the observed regioisomeric product resulted from the difference in the stability of transition state and/or intermediates of both E and F. The observed facts can be readily explained following the new mechanism of these rearrangements. We ascribe the lower deuterated ratio of 2a-2benzyl D (58−64%) to the exchange of proton with deuterium under alkalic conditions.25 We carried out quantum chemical calculations for the reaction pathway to gain further understanding of the mechanism of the present rearrangements (see SI for computational details).26 The equilibrium geometries of indazolium are presented in Figure 1. As shown in Figure 1, the DFT-calculated Mulliken charge (Q) of N1 atom differs significantly from that of the N2 atom. The N1 possesses a negative charge of 0.389, which is 0.156 greater than the 0.233 value for N2. Meanwhile, H1 and H2 possess almost the same positive charge of around 0.248. The calculated pKa values of H1 and H2 are 0.15 and 0.14 at 70

Figure 2. Energy profile of minimum energy path for indazolium rearrangement.

mechanism involves ring-opening and ring-closing processes. In the ring-opening process, MR and SR, exhibit almost same energy barriers, which are 7.3 and 6.1 kcal mol−1, respectively. The SR intermediate F is much more stable than the MR intermediate E. However, in the ring-closing process, the energy barriers of MR and SR are 3.7 and 11.4 kcal mol−1, respectively, and the MR product 2a is more stable by 15.9 kcal mol−1 than that of SR product 4. As a result, the MR product 2a is the proposed product. The results, which are in agreement with the observed regioselectivity, suggest that the reaction route of the present rearrangement is determined by the energy barriers of the ring-closing step and the stability of the rearrangement product. We also estimated the synergic reaction pathways, i.e. the reaction with the simultaneous breaking of old bonds (N1− N2 bond) and formation of new bonds (N1−C2 bond) through a three-member ring transition state (TS) (Scheme 6).27 In this Scheme 6. Proposed Synergic Reaction Pathway

calculation, the angle of N1−N2−C2 was fixed at a reasonable angle (from 70° to 150° by step size 5°), and other structural parameters were optimized. The energy curve formed by each minimized energy shows that the concerted reaction had to overcome a huge energy barrier of more than 40 kcal mol−1. Therefore, this reaction path is highly unlikely to occur.

Figure 1. Equilibrium geometries of indazolium. Part Mulliken charges and part bond length (Å) are signed. H: white, C: yellow, N: blue. 8753


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50.3, 21.2. HRMS-ESI (m/z) Calcd for C22H21N2 [M + H]+ 313.1699, found 313.1693. 1-(4-Methylbenzyl)-2-p-tolyl-1,2-dihydroquinazoline (2c). Silica gel column chromatography (hexane/AcOEt = 4/1) gave 2c as a white solid (48 mg, 73%), mp 144−145 °C; 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.30−7.08 (m, 10H), 6.61 (dd, J = 7.6 and 7.2 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 6.21 (s, 1H), 4.51 (d, J = 16.4 Hz, 1H), 4.11 (d, J = 16.4 Hz, 1H), 2.32 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 157.1, 145.3, 138.4, 138.1, 136.9, 133.8, 133.7, 129.4, 129.37, 129.3, 128.6, 126.8, 126.3, 116.9, 110.8, 78.6, 50.3, 21.2, 21.1. HRMS-ESI (m/z) Calcd for C23H23N2 [M + H]+ 327.1856, found 327.1847. 1-(2-Methylbenzyl)-2-phenyl-1,2-dihydroquinazoline (2d). Silica gel column chromatography (hexane/AcOEt = 3/1) gave 2d as a white solid (44 mg, 70%), mp 153−155 °C; 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.39−7.23 (m, 11H), 6.64 (dd, J = 7.6 and 7.6 Hz, 1H), 6.46 (d, J = 8.0 Hz, 1H), 6.18 (s, 1H), 4.54 (d, J = 16.8 Hz, 1H), 4.05 (d, J = 16.4 Hz, 1H), 2.23 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 157.3, 145.4, 141.3, 136.0, 134.0, 133.9, 130.5, 128.8, 128.7, 128.4, 127.3, 127.0, 126.3, 126.2, 116.9, 116.6, 110.5, 78.2, 48.6, 19.1. HRMS-ESI (m/z) Calcd for C22H21N2 [M + H]+ 313.1699, found 313.1682. 2-Phenyl-1-(2,4,6-trimethylbenzyl)-1,2-dihydroquinazoline (2e). Silica gel column chromatography (hexane/AcOEt = 5/1) gave 2e as a white solid (50 mg, 74%), mp 150−152 °C; 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.35 (dd, J = 7.6 and 7.2 Hz, 1H), 7.25−7.07 (m, 5H), 7.08 (d, J = 7.2 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.82 (s, 2H), 6.69 (dd, J = 7.6 and 7.2 Hz, 1H), 5.79 (s, 1H), 4.55 (d, J = 13.2 Hz, 1H), 4.24 (d, J = 13.2 Hz, 1H), 2.27 (s, 3H), 2.04 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 156.6, 146.2, 141.5, 138.3, 137.4, 133.8, 129.4, 128.6, 128.4, 128.0, 126.0, 117.9, 116.6, 110.5, 73.4, 45.2, 21.0, 19.7. Calcd for C24H25N2 [M + H]+ 341.2012, found 341.2020. 1-(4-Methoxybenzyl)-2-phenyl-1,2-dihydroquinazoline (2f). Silica gel column chromatography (hexane/AcOEt = 4/1) gave 2f as a white solid (50 mg, 76%), mp 135−136 °C; 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.38−7.28 (m, 5H), 7.22−7.16 (m, 3H), 7.09 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 6.63 (dd, J = 7.6 and 7.2 Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 6.23 (s, 1H), 4.51 (d, J = 16.4 Hz, 1H), 4.09 (d, J = 16.4 Hz, 1H), 3.78 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 158.9, 157.3, 145.3, 141.3, 133.8, 128.7, 128.6, 128.3, 128.1, 126.4, 117.0, 116.6, 114.1, 110.9, 78.6, 55.3, 50.2. HRMS-ESI (m/z) Calcd for C22H21N2O [M + H]+ 329.1648, found 329.1652. 1-(4-Methoxybenzyl)-2-p-tolyl-1,2-dihydroquinazoline (2g). Silica gel column chromatography (hexane/AcOEt = 4/1) gave 2g as a white solid (48 mg, 70%), mp 137−139 °C; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.26−7.09 (m, 9H), 6.83 (d, J = 7.2 Hz, 2H), 6.64 (dd, J = 7.2 and 7.2 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 6.20 (s, 1H), 4.52 (d, J = 16.4 Hz, 1H), 4.10 (d, J = 16.4 Hz, 1H), 3.78 (s, 3H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 158.9, 157.2, 145.4, 138.2, 134.0, 129.4, 128.7, 128.6, 128.2, 126.3, 116.9, 116.6, 114.1, 110.9, 78.1, 55.3, 50.1, 21.2. HRMS-ESI (m/z) Calcd for C23H23N2O [M + H]+ 343.1805, found 343.1795. 1-Benzyl-2-(3-chlorophenyl)-1,2-dihydroquinazoline (2h). Silica gel column chromatography (hexane/AcOEt = 2/1) gave 2h as a white solid (50 mg, 75%), mp 136−138 °C; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.37−7.11 (m, 10H), 7.11 (d, J = 7.6 Hz, 1H), 6.66 (dd, J = 7.2 and 7.6 Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.23 (s, 1H), 4.59 (d, J = 16.8 Hz, 1H), 4.17 (d, J = 16.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 157.7, 144.9, 143.3, 136.5, 134.6, 134.1, 133.0, 128.83, 128.79, 128.5, 127.4, 126.9, 126.7, 124.6, 117.1, 111.0, 78.2, 51.0. HRMS-ESI (m/z) Calcd for C21H18ClN2 [M + H]+ 333.1153, found 333.1159. 1-(4-Chlorobenzyl)-2-phenyl-1,2-dihydroquinazoline (2i). Silica gel column chromatography (hexane/AcOEt = 2/1) gave 2i as a white solid (33 mg, 50%), mp 159−161 °C; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.37−7.16 (m, 10H), 7.11 (d, J = 7.6 Hz, 1H), 6.66 (dd, J = 7.6 and 6.8 Hz, 1H), 6.44 (d, J = 8.0 Hz, 1H), 6.22 (s, 1H), 4.49 (d, J = 16.8 Hz, 1H), 4.15 (d, J = 16.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 157.3, 145.0, 141.1, 135.4, 133.9, 133.0, 128.9, 128.8, 128.7, 128.5, 128.2, 126.4, 117.1, 117.0, 110.8, 79.1, 50.3. HRMS-ESI (m/z) Calcd for C21H18ClN2 [M + H]+ 333.1153, found 333.1127. 2-(4-Chlorophenyl)-1-(2,4,6-trimethylbenzyl)-1,2-dihydroquinazoline (2j). Silica gel column chromatography (hexane/AcOEt = 3/1)

CONCLUSIONS In summary, we disclosed the rearrangement of indazolium salts bearing various N-substituents under mild conditions, producing 1,2-dihydroquinazolines. Research on the mechanism through isotope labeling experiment and DFT calculation imply that the present rearrangement passes through a cleavage of N−N bond/ring opening after deprotonation of 2-benzyl in 1a with base to yield intermediate E. The reaction then proceeds as an intramolecular N-nucleophilic addition to yield the observed product 2a. The reaction pathway of the present rearrangement was determined by the energy barriers of the ring-closing process and the stability of the product. The rearrangement products with a broad range of substituted benzyl or alkyl were obtained in good to high yields. Further transformation potential and possible bioactive tests are currently underway.

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EXPERIMENTAL SECTION

General Methods. 1H and 13C NMR data was acquired on a Bruker AV-400 MHz spectrometer. HRMS were obtained from Agilent 6520 Q-TOF LC−MS. Commercial reagents were purchased and used without further purification. THF and toluene were distilled over benzophenone ketyl under nitrogen. DMF was distilled over CaH2 under nitrogen. Dioxane was distilled over LiAlH4 under nitrogen. Indazolium halides were prepared according to our provious procedure.19 General Procedure for Ring-Enlargemeng Rearrangement of Indazolium Salts. A reaction tube was charged with indazolium salt (0.20 mmol), potassium carbonate (0.30 mmol). To the reaction tube was added toluene (2.0 mL). The mixture was stirred at 70 °C for several hours. The mixture was cooled to room temperature and directly purified through silica gel column chromatography to give the product. 1-Benzyl-2-phenyl-1,2-dihydroquinazoline (2a). Silica gel column chromatography (hexane/AcOEt = 3/1) gave 2a as a white solid (50 mg, 84%), mp 140−142 °C; 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.39−7.23 (m, 10H), 7.17 (dd, J = 7.4 and 8.4 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.63 (dd, J = 7.6 and 8.0 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 6.27 (s, 1H), 4.55 (d, J = 8.8 Hz, 1H), 4.17 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 157.5, 145.3, 141.3, 136.8, 133.9, 128.74, 128.67, 128.4, 127.3, 126.9, 126.4, 116.9, 116.7, 110.8, 78.9, 50.7. HRMS-ESI (m/z) Calcd for C21H19N2 [M + H]+ 299.1543, found 299.1523. 2a-1-Benzyl D2. Silica gel column chromatography (hexane/AcOEt = 3/1) gave 2a-1-benzyl D2 as a white solid (15 mg, 88%), mp 127−129 °C; 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.39−7.23 (m, 10H), 7.17 (dd, J = 7.4 and 8.4 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.63 (dd, J = 7.6 and 8.0 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 6.26 (s, 0.37H). 13C NMR (100 MHz, CDCl3) δ 157.3, 145.3, 141.3, 136.7, 133.9, 128.73, 128.67, 128.4, 127.3, 126.9, 126.4, 116.9, 116.7, 110.8, 78.9. HRMS-ESI (m/z) Calcd for C21H17D2N2 [M + H]+ 301.1668, found 301.1666. 2a-2-Benzyl D. Silica gel column chromatography (hexane/AcOEt = 3/1) gave 2a-2-benzyl D as a white solid (15 mg, 86%), mp 134−135 °C; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.39−7.23 (m, 10H), 7.17 (dd, J = 7.4 and 8.4 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.63 (dd, J = 7.6 and 8.0 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 6.27 (s, 0.37H), 4.55 (d, J = 8.8 Hz, 1H), 4.17 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 157.5, 145.3, 141.3, 136.8, 133.9, 128.74, 128.67, 128.4, 127.3, 126.9, 126.4, 116.9, 116.7, 110.8, 78.9, 50.7. HRMS-ESI (m/z) Calcd for C21H18DN2 [M + H]+ 300.1606, found 300.1578. 1-Benzyl-2-p-tolyl-1,2-dihydroquinazoline (2b). Silica gel column chromatography (hexane/AcOEt = 4/1) gave 2b as a white solid (59 mg, 95%), mp 149−151 °C; 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.30−7.08 (m, 11H), 6.63 (dd, J = 7.6 and 7.2 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 6.21 (s, 1H), 4.54 (d, J = 16.4 Hz, 1H), 4.16 (d, J = 16.4 Hz, 1H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 157.2, 145.3, 138.4, 138.1, 136.9, 133.8, 129.4, 128.7, 126.8, 126.3, 116.9, 110.8, 78.6, 8754


Note

The Journal of Organic Chemistry gave 2j as a white solid (59 mg, 79%), mp 159−161 °C; 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.35 (dd, J = 7.6 and 7.2 Hz, 1H), 7.25− 7.07 (m, 5H), 7.08 (d, J = 7.2 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.82 (s, 2H), 6.69 (dd, J = 7.6 and 7.2 Hz, 1H), 5.76 (s, 1H), 4.55 (d, J = 13.2 Hz, 1H), 4.25 (d, J = 13.2 Hz, 1H), 2.27 (s, 3H), 2.06 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 156.6, 146.2, 141.5, 138.3, 137.4, 133.8, 129.4, 128.6, 128.4, 128.0, 126.0, 117.9, 116.6, 110.5, 73.4, 45.2, 21.0, 19.7. Calcd for C24H24ClN2 [M + H]+ 375.1623, found 375.1637. 1-(3-Fluorobenzyl)-2-phenyl-1,2-dihydroquinazoline (2k). Silica gel column chromatography (hexane/AcOEt = 2/1) gave 2k as a white solid (40 mg, 63%), mp 149−151 °C; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.36−7.29 (m, 5H), 7.20−7.16 (m, 2H), 7.12 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.96−6.90 (m, 2H), 6.66 (dd, J = 6.8 and 7.6 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 6.24 (s, 1H), 4.51 (d, J = 16.8 Hz, 1H), 4.18 (d, J = 17.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 157.3, 145.0, 141.1, 139.8 (d, J = 6.7 Hz), 133.9, 130.2 (d, J = 8.0 Hz), 128.8, 128.7, 128.5, 126.4, 122.3 (d, J = 2.8 Hz), 117.1, 117.0, 114.2 (d, J = 21.2 Hz), 113.7 (d, J = 21.9 Hz), 110.8, 79.1, 50.5. 19F NMR (CDCl3) δ −110.8, −112.6. Calcd for C21H18FN2 [M + H]+ 317.1449, found 317.1447. 1-Benzyl-2-(3-fluorophenyl)-1,2-dihydroquinazoline (2l). Silica gel column chromatography (hexane/AcOEt = 3/1) gave 2l as a white solid (43 mg, 68%), mp 147−179 °C; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.38−7.09 (m, 11H), 6.66−6.61 (m, 1H), 6.55−6.49 (m, 1H), 6.24 (s, 1H), 4.55 (d, J = 16.8 Hz, 1H), 4.17 (d, J = 17.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 157.5 (d, J = 39.2 Hz), 145.1 (d, J = 21.9 Hz), 141.3, 136.7 (d, J = 23.4 Hz), 134.0 (d, J = 18.7 Hz), 130.2(d, J = 8.0 Hz), 128.8, 128.72, 128.66, 128.4, 127.4 (d, J = 12.8 Hz), 126.9 (d, J = 3.2 Hz), 126.4, 122.0 (d, J = 2.9 Hz), 117.0 (d, J = 18.4 Hz), 116.7, 115.2 (d, J = 21.2 Hz), 113.4 (d, J = 21.7 Hz), 110.9 (d, J = 25.2 Hz), 78.9, 50.9 (d, J = 25.0 Hz). 19F NMR(CDCl3) δ −111.0, −112.2. Calcd for C21H18FN2 [M + H]+ 317.1449, found 317.1454. 1-(4-Nitrobenzyl)-2-phenyl-1,2-dihydroquinazoline (2m). Silica gel column chromatography (hexane/AcOEt = 2/1) gave 2m as a white solid (30 mg, 44%), mp 153−155 °C; 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 8.18 (d, J = 7.6 Hz, 4H), 7.55 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 7.26−7.20 (m, 2H), 7.19 (d, J = 7.6 Hz, 1H), 6.77 (dd, J = 7.2 and 6.8 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 6.34 (s, 1H), 4.70 (d, J = 17.2 Hz, 1H), 4.32 (d, J = 17.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 158.3, 153.0.0, 144.2, 134.5, 129.2, 127.5, 127.3, 124.20, 124.18, 121.0, 118.6, 111.4, 78.4, 51.2. HRMS-ESI (m/z) Calcd for C21H18N3O2 [M + H]+: 344.1394, found 344.1391. 1-Methyl-2-phenyl-1,2-dihydroquinazoline (2n). Silica gel column chromatography (hexane/AcOEt = 4/1) gave 2n as a white solid (29 mg, 65%), mp 140−142 °C; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.38−7.28 (m, 6H), 7.05 (d, J = 7.6 Hz, 1H), 6.61 (dd, J = 7.6 and 6.8 Hz, 2H), 6.51 (d, J = 6.8 Hz, 1H), 6.15 (s, 1H), 2.76 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 157.1, 145.9, 140.7, 134.1, 128.7, 128.42, 128.36, 126.2, 116.5, 109.8, 80.2,34.4. Calcd for C15H15N2 [M + H]+ 223.1230, found 223.1260. 2-(3-Fluorophenyl)-1-methyl-1,2-dihydroquinazoline (2o). Silica gel column chromatography (hexane/AcOEt = 2/1) gave 2o as a white solid (40 mg, 83%), mp 145−147 °C; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.32−7.28 (m, 2H), 7.14 (d, J = 7.6 Hz, 1H), 7.10−7.04 (m, 2H),6.98 (dd, J = 8.0 and 8.4 Hz, 1H), 6.67 (dd, J = 7.2 and 7.2 Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 6.14 (s, 1H), 2.78 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 163.5 (d, J = 163.8 Hz), 157.4, 145.6, 143.4 (d, J = 3.7 Hz), 134.2, 130.3 (d, J = 5.5 Hz), 128.5, 121.8, 116.8, 116.4, 115.2 (d, J = 13.9 Hz), 113.2 (d, J = 14.5 Hz), 110.0, 79.7, 34.5. Calcd for C15H14FN2 [M + H]+ 241.1136, found 241.1133. 1-Ethyl-2-phenyl-1,2-dihydroquinazoline (2p). Silica gel column chromatography (hexane/AcOEt = 4/1) gave 2p as a white solid (38 mg, 80%), mp 142−144 °C; 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.33−7.24 (m, 4H), 7.07 (d, J = 7.6 Hz, 1H), 6.65 (dd, J = 7.2 and 7.2 Hz, 2H), 6.20 (s, 1H), 3.32 (q, J = 7.2 Hz, 1H), 3.14 (q, J = 7.2 Hz, 1H), 1.08 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 156.9, 144.9, 142.6, 133.8, 128.8, 128.6, 128.2, 126.3, 116.6, 116.0, 110.0, 78.8,42.5, 12.1. Calcd for C16H17N2 [M + H]+ 237.1386, found 237.1183.

6-Methoxy-1-methyl-2-phenyl-1,2-dihydroquinazoline (2q). Silica gel column chromatography (hexane/AcOEt = 4/1) gave 2q as a white solid (33 mg, 66%), mp 175−177 °C; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.34−7.26 (m, 5H), 6.91(dd, J = 8.8 and 8.8 Hz, 1H), 6.69 (s, 1H), 6.48 (d, J = 8.8 Hz, 1H), 6.55 (s, 1H), 3.76 (s, 3H), 2.74 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 157.0, 151.2, 140.7, 141.4, 128.6, 128.3, 126.3, 120.4, 117.3, 112.9, 111.3, 80.1, 55.9, 34.7. Calcd for C16H17N2O [M + H]+ 253.1335, found 253.1360. 2-(4-Chlorophenyl)-6-methoxy-1-methyl-1,2-dihydroquinazoline (2r). Silica gel column chromatography (hexane/AcOEt = 3/1) gave 2r as a white solid (41 mg, 71%), mp 172−174 °C; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.34−7.26 (br, 4H), 6.93(dd, J = 8.8 and 8.8 Hz, 1H), 6.70 (s, 1H), 6.49 (d, J = 8.8 Hz, 1H), 6.02 (s, 1H), 3.77 (s, 3H), 2.74 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 157.3, 151.4, 138.9, 134.0, 130.5, 128.8, 127.8, 120.6, 112.9, 111.6, 79.4, 55.9, 34.7. Calcd for C16H16ClN2O [M + H]+ 287.0946, found 287.0954. 6-(Benzyloxy)-1-methyl-2-phenyl-1,2-dihydroquinazoline (2s). Silica gel column chromatography (hexane/AcOEt = 4/1) gave 2s as a white solid (39 mg, 60%), mp 142−144 °C; 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.44−7.28 (m, 10H), 6.98(dd, J = 8.8 and 2.8 Hz, 1H), 6.81 (d, J = 3.2 Hz, 1H), 6.47 (d, J = 8.8 Hz, 1H), 6.05 (s, 1H), 5.00 (s, 2 H), 2.74 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 156.9, 150.4, 140.5, 137.2, 128.7, 128.62, 128.59, 128.3, 128.0, 127.5, 126.3, 121.6, 117.3, 114.4, 111.2, 80.1, 71.0, 34.6. Calcd for C22H21N2O [M + H]+ 329.1648, found 329.1659. 1-Benzyl-6-(benzyloxy)-2-(4-chlorophenyl)-1,2-dihydroquinazoline (2t). Silica gel column chromatography (hexane/AcOEt = 2/1) gave 2t as a white solid (70 mg, 80%), mp 148−150 °C; 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.46−7.27 (m, 14H), 6.93(dd, J = 8.8 and 2.8 Hz, 1H), 6.81 (d, J = 3.2 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 6.19 (s, 1H), 5.01 (s, 2 H), 4.55 (d, J = 16.4 Hz, 1H), 4.20 (d, J = 16.4 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 157.4, 150.8, 139.7, 139.5, 137.0, 134.0, 128.8, 128.6, 128.1, 128.0, 127.5, 127.4, 127.0, 121.5, 118.0, 114.1, 113.1, 77.8, 70.8, 51.9. Calcd for C28H24ClN2O [M + H]+ 439.1572, found 439.1615. 6-Bromo-1-methyl-2-phenyl-1,2-dihydroquinazoline (2u). Silica gel column chromatography (hexane/AcOEt = 3/1) gave 2u as a white solid (52 mg, 86%), mp 158−160 °C; 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.36−7.31 (m, 6H), 7.17(s, 1H), 6.39 (d, J = 8.4 Hz, 1H), 6.14 (s, 1H), 2.74 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 155.7, 144.8, 140.2, 136.4, 130.6, 128.8, 128.6, 126.1, 117.8, 111.7, 108.0, 80.3, 34.5. Calcd for C15H14BrN2 [M + H]+ 301.0335, found 301.0315. 1-Benzyl-6-bromo-2-phenyl-1,2-dihydroquinazoline (2v). Silica gel column chromatography (hexane/AcOEt = 2/1) gave 2v as a white solid (49 mg, 65%), mp 152−154 °C; 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.36−7.20 (m, 12H), 6.38 (d, J = 8.8 Hz, 1H), 6.27 (s, 1H), 4.50 (d, J = 16.8 Hz, 1H), 4.18 (d, J = 16.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 155.7, 144.1, 139.2, 136.3, 136.2,130.9, 128.8, 128.6, 127.5, 126.8, 126.3, 118.3, 112.8, 108.3, 79.1, 50.9. Calcd for C21H18BrN2 [M + H]+ 377.0648, 379.0633 Found: 377.0679, 379.0654. 1-Benzyl-6-bromo-2-p-tolyl-1,2-dihydroquinazoline (2w). Silica gel column chromatography (hexane/AcOEt = 2/1) gave 2w as a white solid (41 mg, 52%), mp 140−142 °C; 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.30−7.11 (m, 10H), 6.36 (d, J = 8.8 Hz, 1H), 6.23 (s, 1H), 4.48 (d, J = 16.8 Hz, 1H), 4.17 (d, J = 16.4 Hz, 1H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 144.1, 142.3, 139.9, 138.5, 136.2, 133.8, 130.9, 129.5, 128.8, 127.5, 126.8, 126.2, 122.1, 112.8, 78.8, 50.7, 29.7. Calcd for C22H20BrN2 [M + H]+ 391.0804, found 391.0824. 6-Bromo-1-(2-methylbenzyl)-2-phenyl-1,2-dihydroquinazoline (2x). Silica gel column chromatography (hexane/AcOEt = 2/1) gave 2x as a white solid (63 mg, 81%), mp 169−171 °C; 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.35−7.11 (m, 11H), 6.34 (d, J = 8.8 Hz, 1H), 6.19 (s, 1H), 4.49 (d, J = 16.8 Hz, 1H), 4.05 (d, J = 16.8 Hz, 1H), 2.25 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 155.9, 144.2, 140.8, 136.4, 136.0, 133.3, 131.0, 130.7, 128.9, 128.6, 127.5, 126.9, 126.3, 118.2, 112.5, 108.2, 78.3, 48.7, 19.1. Calcd for C22H20BrN2 [M + H]+ 391.0804, found 391.0803. 8755


Note

The Journal of Organic Chemistry 6-Bromo-1-(4-chlorobenzyl)-2-phenyl-1,2-dihydroquinazoline (2y). Silica gel column chromatography (hexane/AcOEt = 2/1) gave 2y as a white solid (59 mg, 72%), mp 163−164 °C; 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.35−7.14 (m, 11H), 6.32 (d, J = 8.8 Hz, 1H), 6.23 (s, 1H), 4.45 (d, J = 16.4 Hz, 1H), 4.16 (d, J = 16.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 155.9, 143.8, 140.6, 136.3, 134.8, 133.2, 131.0, 129.0, 128.9, 128.7, 128.1, 126.3, 118.4, 112.8, 108.7, 79.2, 50.5. HRMS-ESI (m/z) Calcd for C21H17BrClN2 [M + H]+ 411.0258, 413.0243, found 411.0304, 413.0277. 1-Benzyl-6-bromo-2-(4-bromophenyl)-1,2-dihydroquinazoline (2z). Silica gel column chromatography (hexane/AcOEt = 2/1) gave 2z as a white solid (80 mg, 88%), mp 163−164 °C; 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.33−7.21 (m, 10H), 6.41 (d, J = 8.8 Hz, 1H), 6.21 (s, 1H), 4.51 (d, J = 16.8 Hz, 1H), 4.15 (d, J = 16.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 156.2, 143.8, 139.7, 136.5, 136.0, 131.9, 131.0, 128.9, 128.1, 127.6, 126.8, 122.6, 118.3, 113.1, 108.7, 78.3, 51.1. Calcd for C21H17Br2N2 [M + H]+ 454.9753, found 454.9730. (E)-1-Benzyl-2-styryl-1,2-dihydroquinazoline (3a). Silica gel column chromatography (hexane/AcOEt = 3/1) gave 3a as a white solid (46 mg, 71%), mp 160−162 °C; 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.35−7.14 (m, 10H), 6.68 (dd, J = 6.8 and 7.2 Hz, 1H), 6.56 (d, J = 15.6 Hz, 1H), 6.33 (d, J = 8.4 Hz, 1H), 6.32 (dd, J = 15.6 and 7.6 Hz, 1H), 5.66 (d, J = 7.6 Hz, 1H), 4.57 (d, J = 16.0 Hz, 1H), 4.34 (d, J = 16.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 158.4, 145.0, 137.1, 136.2, 133.6, 131.8, 128.8, 128.6, 128.5, 128.0, 127.4, 126.8, 125.5, 117.8, 117.1, 111.7, 77.4, 50.7. HRMS-ESI (m/z) Calcd for C23H21N2 [M + H]+ 325.1699, found 325.1724.

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Choo, D. J.; Lee, K.-T.; Lee, J. Y. In Vivo Evaluation of Oral Antitumoral Effect of 3,4-Dihydroquinazoline Derivative on Solid Tumor. Bioorg. Med. Chem. Lett. 2012, 22, 1198−1201. (4) Chien, T.-C.; Chen, C.-S.; Yu, F.-H.; Chern, J.-W. Nucleosides XI. Synthesis and Antiviral Evaluation of 5′-Alkylthio-5′-deoxy Quinazolinone Nucleoside Derivatives as S-Adenosyl-L-homocysteine Analogs. Chem. Pharm. Bull. 2004, 52, 1422−1426. (5) Al-Shamma, A.; Drake, S.; Flynn, D. L.; Mitscher, L. A.; Park, Y. H.; Rao, G. S. R.; Simpson, A.; Swayze, J. K.; Veysoglu, T.; Wu, S. T.-S. Antimicrobial Agents from Higher Plants. Antimicrobial Agents From Peganum harmala Seeds. J. Nat. Prod. 1981, 44, 745−747. (6) (a) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H. Catalytic Asymmetric Synthesis of Febrifugine and Isofebrifugine. Tetrahedron Lett. 1999, 40, 2175−2178. (b) Verhaeghe, P.; Azas, N.; Gasquet, M.; Hutter, S.; Ducros, C.; Laget, M.; Rault, S.; Rathelot, P.; Vanelle, P. Synthesis and Antiplasmodial Activity of New 4-Aryl-2-trichloromethylquinazolines. Bioorg. Med. Chem. Lett. 2008, 18, 396−401. (7) (a) Seo, H. N.; Choi, J. Y.; Choe, Y. J.; Kim, Y.; Rhim, H.; Lee, S. H.; Kim, J.; Joo, D. J.; Lee, J. Y. Discovery of Potent T-Type Calcium Channel Blocker. Bioorg. Med. Chem. Lett. 2007, 17, 5740−5743. (b) Rhim, H.; Lee, Y. S.; Park, S. J.; Chung, B. Y.; Lee, J. Y. Synthesis and Biological Activity of 3,4-Dihydroquinazolines for Selective T-Type Ca2+ Channel Blockers. Bioorg. Med. Chem. Lett. 2005, 15, 283−286. (c) Lee, Y. S.; Lee, B. H.; Park, S. J.; Kang, S. B.; Rhim, H.; Park, J.-Y.; Lee, J.-H.; Jeong, S.-W.; Lee, J. Y. 3,4-Dihydroquinazoline Derivatives as Novel Selective T-type Ca2+ Channel Blockers. Bioorg. Med. Chem. Lett. 2004, 14, 3379−3384. (d) Jeong, J. A.; Cho, H.; Jung, S. Y.; Kang, H. B.; Park, J. Y.; Kim, J.; Choo, D. J.; Lee, J. Y. 3D QSAR Studies on 3,4-Dihydroquinazolines as T-Type Calcium Channel Blocker by Comparative Molecular Similarity Indices Analysis (CoMSIA). Bioorg. Med. Chem. Lett. 2010, 20, 38−41. (8) Patterson, S.; Alphey, M. S.; Jones, D. C.; Shanks, E. J.; Street, I. P.; Frearson, J. A.; Wyatt, P. G.; Gilbert, I. H.; Fairlamb, A. H. Dihydroquinazolines as a Novel Class of Trypanosoma bruceiTrypanothione Reductase Inhibitors: Discovery, Synthesis, and Characterization of their Binding Mode by Protein Crystallography. J. Med. Chem. 2011, 54, 6514−6530. (9) For selected examples on the synthesis of dihydroquinazolines, see: (a) Movassaghi, M.; Hill, M. D. Single-Step Synthesis of Pyrimidine Derivatives. J. Am. Chem. Soc. 2006, 128, 14254−14255. (b) Sarma, R.; Prajapati, D. Microwave-promoted Efficient Synthesis of Dihydroquinazolines. Green Chem. 2011, 13, 718−722. (c) Wiedemann, S. H.; Ellman, J. A.; Bergman, R. G. Rhodium-Catalyzed Direct C−H Addition of 3,4-Dihydroquinazolines to Alkenes and Their Use in the Total Synthesis of Vasicoline. J. Org. Chem. 2006, 71, 1969−1976. (d) Rohlmann, R.; Stopka, T.; Richter, H.; Mancheño, O. G. Ironcatalyzed Oxidative Tandem Reactions with TEMPO Oxoammonium Salts: Synthesis of Dihydroquinazolines and Quinolines. J. Org. Chem. 2013, 78, 6050−6064. (e) Luo, L.; Zhao, X.; Zhang, L.; Yuan, Y.; Lü, S.; Jia, X. An Aerobic Oxidative Aza-[4 + 2] Cycloaddition Induced by Radical Cation Salt: Synthesis of Dihydroquinazoline Derivatives. Tetrahedron Lett. 2016, 57, 5830−5833. (f) Portela-Cubillo, F.; Scott, J. S.; Walton, J. C. Microwave-Promoted Syntheses of Quinazolines and Dihydroquinazolines from 2-Aminoarylalkanone O-Phenyl Oximes. J. Org. Chem. 2009, 74, 4934−4942. (g) McGowan, M. A.; McAvoy, C. Z.; Buchwald, S. L. Palladium-Catalyzed N-Monoarylation of Amidines and a One-Pot Synthesis of Quinazoline Derivatives. Org. Lett. 2012, 14, 3800−3803. (10) (a) Bourissou, D.; Guerret, O.; Gabbaï, F. P.; Bertrand, G. Stable Carbenes. Chem. Rev. 2000, 100, 39−92. (b) Herrmann, W. A. NHeterocyclic Carbenes: a New Concept in Organometallic Catalysis. Angew. Chem., Int. Ed. 2002, 41, 1290−1309. (c) César, V.; BelleminLaponnaz, S.; Gade, L. H. Chiral N-Heterocyclic Carbenes as Stereodirecting Ligands in Asymmetric Catalysis. Chem. Soc. Rev. 2004, 33, 619−636. (d) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. An Overview of N-Heterocyclic Carbenes. Nature 2014, 510, 485−496. (11) (a) Igau, A.; Grutzmacher, H.; Baceiredo, A.; Bertrand, G. Analogous α,α’-Biscarbenoid Triply Bonded Species: Synthesis of a

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01044. Copies of 1H NMR, 13C NMR, and 19F NMR spectra for all new products, and computational data (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Qian Chen: 0000-0002-9636-9157 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge financial support from SKLUWRE (No. 2017TS01). REFERENCES

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Synthesis of 1,2-Dihydroquinazolines via Rearrangement of

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