Microwave-Assisted aza-Friedel-Crafts Arylation of N-Acyliminium Ions: Expedient Access to 4-Aryl 3,4-Dihydroquinazolinones.

A one-pot microwave-assisted aza-Friedel-Crafts arylation of N-acyliminium ions, generated in situ from o-formyl carbamates and different amines, is reported. This metal-free protocol provides rapid access to diverse 4-aryl 3,4-dihydroquinazolinones in excellent yield without any aqueous workup. A solvent-directed process for the selective aza-Friedel-Crafts arylation of electron-rich aryl/heteroaryl/butenyl-tethered N-acyliminium ions is also described.

Introduction

N-Acyliminium ions[1−5] are versatile electrophiles that provide direct access to α-substituted amino derivatives via the intra- or intermolecular addition of various nucleophiles. In particular, in situ-generated N-acyliminium ions have been widely exploited in the synthesis of bioactive nitrogen-containing heterocycles, especially in the preparation of alkaloid natural products.[1,2,6,7] Accordingly, the development of rapid, convenient, and high-yielding protocols for the selective intra- or intermolecular nucleophilic addition to cyclic N-acyliminium ions remains a field of considerable interest.[8−11] The C4-substituted quinazolinone framework is known to exhibit a wide range of biological properties. For example, SM-15811 is a potent Na+/Ca2+ exchanger inhibitor,[12−14] proquazone is an anti-inflammatory drug,[15,16] and 4-disubstituted 3,4-dihydroquinazolinones are T-type channel selective calcium blockers with in vivo central nervous system efficacy in epilepsy and tremor models[17,18] (Figure ). Finally, the 3,4-dihydroquinazolinones DPC 961 and DPC 083 and related analogs are potent human immunodeficiency virus non-nucleoside reverse transcriptase inhibitors.[19,20]

Figure 1

Structures of pharmaceutically important 4-aryl quinazolinones.

The known methods for the synthesis of 4-aryl substituted 3,4-dihydroquinazolinones include a two-step condensation of aldehyde, urea, and carboxylic acid,[21] and a three-step synthesis from o-amino acetophenones[12−14,17,18] and the organocatalytic asymmetric synthesis of trifluoromethyl 3,4-dihydroquinazolinones based on the aza-Friedel–Crafts reaction of indoles with cyclic N-acylketimines using a chiral phosphoric acid catalyst.[22] Xie and co-workers reported the enantioselective aza-Friedel–Crafts reaction of naphthols/phenols with cyclic N-acylketimines using a chiral quinine-squaramide catalyst.[23] Despite these elegant approaches, the existing methods require either lengthy reaction sequences or isolation of cyclic N-acylketimines, which limits their utility in the generation of diverse 3,4-dihydroquinazolinone libraries.

During the preparation of this manuscript, Chandrasekharam and co-workers reported a water-mediated multicomponent synthesis of 4-aryl substituted 3,4-dihydroquinazolinones under conventional heating.[24] However, it is important to highlight that the use of water as a reaction medium demanded long reaction times, and, in many cases, chromatographic purification was required, both of which detract from its appeal as a green protocol. Moreover, the scope of this method is restricted to indole and mono-functional amine nucleophiles, limiting its utility in library generation. In this context, an environmentally benign and expedient method for the rapid synthesis of 4-aryl 3,4-dihydroquinazolinone libraries is highly desirable.

As part of our ongoing research program, we recently reported a highly efficient solvent-directed diversity-oriented synthesis of skeletally diverse 3,4-dihydroquinazolinones scaffold libraries based on N-acyliminium ion chemistry under environmentally benign reaction conditions.[25−29] Our recent findings demonstrated that the intramolecular cyclization of aryl/heteroaryl tethered nucleophiles with N-acyliminium ions[27] leads to the formation of 3,4-dihydroquinazolinone-embedded polyheterocycles (Scheme ). With the aim of developing an expedient approach to 4-aryl/heteroaryl 3,4-dihydroquinazolinones, we were encouraged to investigate the intermolecular functionalization of N-acyliminium ions (I) with indoles and arenes to produce 4-aryl 3,4-dihydroquinazolinone scaffold libraries based on a cascade imine/cyclization/aza-Friedel–Crafts reaction sequence. Herein, we present one-pot microwave-assisted metal-free sequential N-acyliminium ion/aza-Friedel–Crafts arylation that provides rapid access to 4-aryl/heteroaryl 3,4-dihydroquinazolinones from readily available precursors (Scheme ).

Scheme 1

Proposed Reaction Sequence for the aza-Friedel–Crafts Arylation of N-Acyliminium Ions

Results and Discussion

We started our investigation by optimization of the reaction conditions for the aza-Friedel–Crafts arylation of the N-acyliminium ion generated in situ from o-formyl carbamate 1a and NH4OAc 2a (Scheme ). We were pleased to observe that the reaction proceeded in either AcOH or EtOH/AcOH as the solvent. The reaction between o-formyl carbamate 1a and NH4OAc 2a (2 equiv) in AcOH under microwave heating at 130 °C for 10 min provided N-acyliminium ion intermediate Ia (confirmed by liquid chromatography/mass spectrometry (LC/MS)), which upon subsequent treatment with indole 3a (1.3 equiv) and an additional 20 min of heating at 130 °C produced 4-indolyl 3,4-dihydroquinazolinone 4a in excellent yield (95%). Similarly, the two-step reaction sequence in EtOH/AcOH (9:1) afforded dihydroquinazolinone 4a in a slightly reduced yield (91%) under optimal protic solvent/Brønsted acid combinations (Scheme ).

Scheme 2

Optimization Studies for the aza-Friedel–Crafts Arylation of an N-Acyliminium Ion

With the optimized reaction conditions in hand, we first explored the scope of the aza-Friedel–Crafts arylation of different cyclic N-acyliminium ions generated in situ from o-formyl carbamates 1b–1h and NH4OAc 2a with indole 3a in AcOH (Scheme ). N-Acyliminium ions 1b–1h derived from aldehydes 1b–1h containing electron-donating/withdrawing and halogen substituents reacted smoothly with indole to afford the corresponding 4-indolyl 3,4-dihydroquinazolinones 4b–4f in good to excellent yields (86–92%). The introduction of an o-substituent and N-1-benzyl substituent was also well-tolerated, giving 3,4-dihydroquinazolinones 4g and 4h in good yield. Next, the scope of the indole nucleophile was explored and indole derivatives containing electron-donating/withdrawing, and halogen substituents furnished the corresponding 4-indolyl 3,4-dihydroquinazolinones 4i, 4j, and 4n in good to excellent yield (83–92%). Sterically hindered o-substituted indoles reacted smoothly, producing 3,4-dihydroquinazolinones 4k–4m in good to excellent yield. The protocol also worked well with N-methylindole and 7-azaindole to afford 3,4-dihydroquinazolinones 4o and 4p in 84 and 90% yield, respectively (Scheme ).

Scheme 3

Scope of aza-Friedel–Crafts Arylation of N-Acyliminium Ions with Indoles

Isolated yield. All reactions were performed with 1 equiv o-formyl carbamate (1b–1h), 2 equiv NH4OAc (2a) in 1 mL AcOH, 130 °C, MW, 10 min, and then 1.3 equiv indole (3a–3i) 130 °C, MW, 20–30 min.

Next, to further expand the scope and applicability of microwave-assisted aza-Friedel–Crafts arylation of N-acyliminium ions, we investigated the effect of varying the arene and amine components (Scheme ). Our protocol tolerated a wide range of amine nucleophiles, affording the corresponding 3,4-dihydroquinazolinone in up to 95% yield. Primary alkyl amines such as benzylamine 2a and 2-thiophenemethylamine 2b worked well to afford N-3-functionalized 3,4-dihydroquinazolinones 6a, 6b in excellent yields (>94%). A one-step three-component reaction between aldehyde 1a, benzylamine 2b, and indole 3a afforded 6a in reduced yield (85%) confirming that the two-step sequential approach is preferable. N-Acyliminium ions also reacted smoothly with 1,3-dimethoxybenzene 5a to produce 4-aryl 3,4-dihydroquinazolinones 6c–6e in moderate to good yields. It is important to highlight that the branched amine N-methyl 4-amino piperidine 2d was efficiently transformed into 6e, an analog of SM-15811 in satisfactory yield. Finally, m-cresol 5b underwent chemoselective C-functionalization to produce 6f in 52% yield (Scheme ).

Scheme 4

Scope of aza-Friedel–Crafts Arylation of N-Acyliminium Ions with Arenes,

Isolated yield. Unless otherwise stated, reactions were performed with 1 equiv o-formyl carbamate (1b–1h), 2 equiv NH4OAc (2a) and 1.3 equiv amine (2b–2d) in 1 mL AcOH, 130 °C, MW, 10 min, and then 1.3 equiv Nu (3a/5a/5b) 130 °C, MW, 20–30 min.

One-step reaction in AcOH, MW, 130 °C, 20 min.

Next, we sought to expand the scope of the selective cascade arylation reaction using challenging amine nucleophiles bearing pendant electron-rich aryl/alkenyl moieties (2e–2j, Scheme ). Gratifyingly, electron-rich aryl/heteroaryl/butenyl-tethered N-acyliminium ions were generated in situ from o-formyl carbamate and amines 2e–2h in EtOH/AcOH (9:1) and reacted smoothly with indole 3a to afford N-3-aryl/heteroaryl/butenyl-tethered 4-aryl 3,4-dihydroquinazolinones 7a–7d in excellent yield (Scheme ). However, with indole tethered N-acyliminium ions, intramolecular aza-Friedel–Crafts cyclization was more favored under the optimized reaction conditions. The N-acyliminium ion derived from 4-aminomethyl indole 2i gave 7e in 36% yield along with the polycyclic product 7e′, whereas the tryptamine derivative gave only traces of 7f (Scheme ). It is important to highlight that by changing the solvent composition the reaction can be paused at the N-acyliminium ion stage, followed by selective functionalization at the C-4 position with an external indole nucleophile, despite the presence of a pendant electron-rich aryl, thiophene, indole, or alkene nucleophile. Thus, the two-step protocol using a minimum of acetic acid can effectively suppress competing intramolecular aza-Friedel–Crafts[27] and aza-Prins cyclization[28] reactions, allowing the selective C-4 functionalization by an indole nucleophile.

Scheme 5

Solvent-Directed Selective 4-Arylation of Aryl/Alkenyl Tethered N-Acyliminium Ions,

Isolated yield. All reactions were performed with 1 equiv o-formyl carbamate (1a), 1.3 equiv amine (2e–2j) in 1 mL EtOH/AcOH (9:1), 130 °C, MW, 10 min, and then 1.5 equiv Nu (3a) 130 °C, MW, 20 min.

Product not isolated.

Conclusions

In conclusion, we have developed a highly efficient, metal-free microwave-assisted aza-Friedel–Crafts arylation of N-acyliminium ions. The solvent-directed selective aza-Friedel–Crafts arylation of challenging aryl/heteroaryl/butenyl-tethered N-acyliminium ions was achieved to produce 4-aryl 3,4-dihydroquinazolinones. This protocol offers a rapid and direct approach to generate polyfunctionalized 4-aryl 3,4-dihydroquinazolinone libraries in excellent yields under environmentally benign reaction conditions and in a short reaction time. Moreover, the protocols utilize readily available and stable o-formyl carbamate precursors and are compatible with a broad scope of amine and aryl/heteroaryl nucleophiles. Further investigations to expand the scope of this approach and explore the biological activity of these compounds are underway in our laboratory.

Experimental Section

All reagents and solvents were obtained from commercial suppliers and used without further purification. The yields stated refer to homogenous and spectroscopically pure isolated material. Thin layer chromatography (TLC, 0.25 mm E. Merck silica plates, 60F-254) was used to assess reaction progress and the plates were visualized with 254 nm UV light. Silica gel chromatography was performed using E. Merck silica gel (60 Å pore size, particle size 40–63 nm). 1H NMR spectra were recorded at 400 MHz and 13C NMR spectra at 100 MHz. The chemical shifts for 1H NMR and 13C NMR were referenced to tetramethylsilane via residual solvent signals (1H, CDCl3 at 7.26 ppm; 13C, CDCl3 at 77.16 ppm; 1H, DMSO-d6 at 2.45 ppm; 13C, DMSO-d6 at 39.43 ppm; 1H, CD3OD at 3.31 ppm; and 13C, CD3OD at 49.0 ppm). Microwave reactions were performed in an Initiator single mode reactor producing controlled irradiation at 2450 MHz and the temperature was monitored using the built-in online IR sensor. LC/MS was performed on an instrument equipped with a CP-Sil 8 CB capillary column (50 × 3.0 mm2, particle size 2.6 μm, pore size 100 Å) operating at an ionization potential of 70 eV using a CH3CN/H2O gradient (0.05% HCOOH). High-resolution mass values were determined using a 7-T hybrid ion trap and a time of flight detector and an electrospray ionization source. All reactions were performed in sealed Pyrex microwave-transparent process vials designed for 0.5–2 mL reaction volumes, unless otherwise stated.

Preparation of o-Formyl Carbamates

The required known compounds 1a–1h were prepared from the corresponding amino alcohols following the literature procedure.[25,26]

General Procedure A

One-Pot, Two-Step Preparation of 4-Aryl 3,4-Dihydroquinazolinones (4a–4p and 6a–6f) Exemplified by 4a

A 0.5–2 mL Pyrex process vial was charged with aldehyde 1a (40 mg, 224 μmol), NH4OAc 2a (34 mg, 448 μmol), and acetic acid (1 mL). The vial was sealed and subjected to microwave irradiation at 130 °C for 10 min, after which indole (3a, 34 mg, 290 μmol) was added. The vial was re-sealed and heated by microwave at 130 °C for 20 min, and thereafter the reaction mixture was concentrated in vacuo. Silica gel chromatography (2–5% MeOH in dichloromethane (DCM) or 30–85% EtOAc in n-pentane) provided the title compound as a white solid (56 mg, 95%).

General Procedure B

One-Pot, Two-Step Preparation of 4-Aryl 3,4-Dihydroquinazolinones (7a–7e) Exemplified by 7b

A 0.5–2 mL Pyrex process vial was charged with aldehyde 1a (40 mg, 224 μmol), amine 2f (53 mg, 290 μmol), and ethanol/acetic acid (9:1, 1 mL). The vial was sealed and subjected to microwave irradiation at 130 °C for 10 min, after which indole (3a, 39 mg, 334 μmol) was added. The vial was re-sealed and heated by microwave at 130 °C for 20 min, and thereafter the reaction mixture was concentrated in vacuo. Silica gel chromatography (2–5% MeOH in DCM or 55–70% EtOAc in n-pentane) provided the title compound as a white solid (85 mg, 90%).

4-(1H-Indol-3-yl)-3,4-dihydroquinazolin-2(1H)-one (4a)[24]

Prepared following the general procedure (A), starting from aldehyde 1a (40 mg, 224 μmol), amine 2a (34 mg, 448 μmol), and nucleophile 3a (34 mg, 290 μmol). Yield: 56 mg (95%); white solid. 1H NMR (DMSO-d6, 400 MHz): δ 10.99–10.90 (m, 1H), 9.27–9.22 (m, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.18–7.14 (m, 2H), 7.11–7.02 (m, 2H), 6.96–6.87 (m, 2H), 6.86–6.81 (m, 1H), 6.79–6.73 (m, 1H), 5.80 (d, J = 2.2 Hz, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 154.1, 137.6, 137.1, 127.9, 127.0, 125.3, 123.5, 122.2, 121.6, 121.2, 119.6, 119.0, 118.7, 114.0, 112.0, 50.9. High resolution mass spectrometry HRMS (electrospray ionization, ESI): calcd for C18H17N4O [M + MeCN + H]+ 305.1402; found 305.1418. TLC (SiO2): Rf = 0.06 (60% EtOAc in n-pentane).

4-(5-Methoxy-2-methyl-1H-indol-3-yl)-3,4-dihydroquinazolin-2(1H)-one (4b)

Prepared following the general procedure (A), starting from aldehyde 1b (40 mg, 191 μmol), amine 2a (29 mg, 376 μmol), and nucleophile 3a (29 mg, 248 μmol). Yield: 52 mg (92%); white solid. 1H NMR (DMSO-d6, 400 MHz): δ 10.98 (d, J = 2.5 Hz, 1H), 9.12 (d, J = 1.9 Hz, 1H), 7.66–7.48 (m, 1H), 7.37 (m, 1H), 7.18 (d, J = 2.5 Hz, 1H), 7.11 (m 1H), 7.07 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 6.94 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H), 6.73 (dd, J = 8.7, 2.7 Hz, 1H), 6.56 (d, J = 2.7 Hz, 1H), 5.79 (d, J = 2.3 Hz, 1H), 3.58 (s, 3H). 13C NMR (DMSO-d6, 100 MHz): δ 153.9, 153.7, 136.7, 130.8, 124.9, 123.0, 122.9, 121.2, 119.2, 118.6, 118.2, 114.4, 112.9, 112.2, 111.6, 55.2, 50.6. HRMS (ESI): calcd for C19H19N4O2 [M + MeCN + H]+ 335.1508; found 335.1517. TLC (SiO2): Rf = 0.13 (5% MeOH in DCM).

6-Bromo-4-(1H-indol-3-yl)-3,4-dihydroquinazolin-2(1H)-one (4c)

Prepared following the general procedure (A), starting from aldehyde 1c (40 mg, 155 μmol), amine 2a (24 mg, 311 μmol), and nucleophile 3a (47 mg, 292 μmol). Yield: 48 mg (91%); white solid. 1H NMR (DMSO-d6, 400 MHz): δ 11.19–10.92 (m, 1H), 9.56–9.44 (m, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.35–7.31 (m, 1H), 7.28 (dd, J = 8.5, 2.3 Hz, 1H), 7.25 (d, J = 2.5 Hz, 1H), 7.13–7.05 (m, 2H), 7.00–6.93 (m, 1H), 6.81 (d, J = 8.5 Hz, 1H), 5.92–5.82 (m, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 153.3, 136.7, 136.6, 130.3, 129.0, 124.7, 124.3, 123.3, 121.3, 119.0, 118.8, 117.7, 115.7, 112.0, 111.8, 50.1. HRMS (ESI): calcd for C18H16BrN4O [M + MeCN + H]+ 383.0507; found m/z 383.0516. TLC (SiO2): Rf = 0.15 (5% MeOH in DCM).

6-Fluoro-4-(1H-indol-3-yl)-3,4-dihydroquinazolin-2(1H)-one (4d)

Prepared following the general procedure (A), starting from aldehyde 1d (40 mg, 203 μmol), amine 2a (31 mg, 402 μmol), and nucleophile 4a (31 mg, 265 μmol). Yield: 50 mg (88%); white solid. 1H NMR (DMSO-d6, 400 MHz): δ 11.01 (s, 1H), 9.31 (s, 1H), 7.65–7.48 (m, 1H), 7.48–7.31 (m, 1H), 7.24 (s, 1H), 7.22–7.19 (m, 1H), 7.13–7.04 (m, 1H), 7.01–6.92 (m, 2H), 6.91–6.82 (m, 1H), 6.82–6.75 (m, 1H), 5.84 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 156.4 (d, 1JCF = 236.1 Hz), 153.2, 136.3, 133.3 (d, 4JCF = 1.9 Hz), 124.3, 123.1 (d, 3JCF = 7.0 Hz), 122.8, 120.8, 118.7, 118.3, 117.1, 114.4 (d, 3JCF = 7.7 Hz), 113.9 (d, 2JCF = 22.7 Hz), 112.50 (d, 2JCF = 23.6 Hz), 111.3, 49.9. HRMS (ESI): calcd for C16H13FN4O [M + H]+ 282.1043; found 282.1054. TLC (SiO2): Rf = 0.16 (5% MeOH in DCM).

7-Chloro-4-(1H-indol-3-yl)-3,4-dihydroquinazolin-2(1H)-one (4e)

Prepared following the general procedure (A), starting from aldehyde 1e (40 mg, 187 μmol), amine 2a (29 mg, 376 μmol), and nucleophile 3a (29 mg, 248 μmol). Yield: 49 mg (88%); white solid. 1H NMR (CD3OD, 400 MHz): δ 7.41 (m, 1H), 7.35 (m, 1H), 7.19 (s, 1H), 7.09 (ddd, J = 8.2, 7.0, 1.1 Hz, 1H), 6.94 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.82 (dd, J = 8.3, 0.9 Hz, 1H), 6.76 (dd, J = 8.3, 2.0 Hz, 1H), 5.92 (s, 1H). 13C NMR (CD3OD, 100 MHz): δ 153.8, 139.4, 137.4, 132.3, 128.9, 125.4, 123.9, 121.8, 121.4, 121.1, 119.7, 119.3, 118.2, 113.6, 112.3, 50.7. HRMS (ESI): calcd for C18H16ClN4O [M + MeCN + H]+ 339.1013; found 339.1029. TLC (SiO2): Rf = 0.09 (5% MeOH in DCM).

4-(1H-Indol-3-yl)-7-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (4f)

Prepared following the general procedure (A), starting from aldehyde 1f (40 mg, 162 μmol), amine 2a (25 mg, 324 μmol), and nucleophile 3a (25 mg, 213 μmol). Yield: 46 mg (86%); white solid. 1H NMR (DMSO-d6, 400 MHz): δ 11.17–10.91 (m, 1H), 9.85–9.48 (m, 1H), 7.54–7.48 (m, 1H), 7.45–7.41 (m, 1H), 7.41–7.36 (m, 1H), 7.28–7.22 (m, 1H), 7.20–7.14 (m, 2H), 7.14–7.05 (m, 2H), 6.99–6.93 (m, 1H), 5.94 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 152.7, 137.5, 136.3, 127.9 (q, 2JCF = 31.8 Hz), 127.2, 125.7 (q, 4JCF = 1.2 Hz), 123.6 (q, 1JCF = 272.1 Hz), 124.3, 123.0, 120.9, 118.6, 118.4, 116.9, 115.95 (q, 3JCF = 4.5 Hz), 111.3, 109.5 (q, 3JCF = 4.2 Hz), 49.9. HRMS (ESI): calcd for C19H16F3N4O [M + MeCN + H]+ 373.1276; found 373.1281. TLC (SiO2): Rf = 0.15 (5% MeOH in DCM).

4-(1H-Indol-3-yl)-8-methoxy-3,4-dihydroquinazolin-2(1H)-one (4g)

Prepared following the general procedure (A), starting from aldehyde 1g (40 mg, 191 μmol), amine 2a (29 mg, 376 μmol), and nucleophile 3a (29 mg, 248 μmol). Yield: 45 mg (80%); white solid. 1H NMR (CDCl3/CD3OD, 400 MHz): δ 7.31–7.24 (m, 1H), 7.23–7.16 (m, 1H), 7.03 (s, 1H), 6.97–6.90 (m, 1H), 6.82–6.76 (m, 1H), 6.68–6.64 (m, 2H), 6.46–6.37 (m, 1H), 5.82 (s, 1H), 3.76 (s, 3H). 13C NMR (CDCl3/CD3OD, 100 MHz): δ 156.2, 146.5, 138.3, 126.1, 126.0, 124.2, 123.1, 122.9, 122.5, 120.0, 119.7, 117.8, 56.3, 52.5. HRMS (ESI): calcd for C19H19N4O2 [M + MeCN + H]+ 335.1508; found 335.1524. TLC (SiO2): Rf = 0.16 (5% MeOH in DCM).

1-Benzyl-4-(1H-indol-3-yl)-3,4-dihydroquinazolin-2(1H)-one (4h)

Prepared following the general procedure (A), starting from aldehyde 1h (40 mg, 149 μmol), amine 2a (23 mg, 298 μmol), and nucleophile 3a (23 mg, 196 μmol). Yield: 45 mg (86%); white solid. 1H NMR (CDCl3, 400 MHz): δ 8.34 (s, 1H), 7.66–7.49 (m, 1H), 7.42–7.29 (m, 6H), 7.25–7.17 (m, 1H), 7.15–7.05 (m, 3H), 6.98–6.90 (m, 1H), 6.88–6.81 (m, 2H), 6.00 (s, 1H), 5.55 (s, 1H), 5.29 (d, J = 16.6 Hz, 1H), 5.21 (d, J = 16.6 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ 155.5, 137.8, 137.6, 137.0, 128.8, 128.3, 127.1, 126.9, 126.6, 125.4, 124.0, 123.4, 122.7, 122.4, 120.2, 119.7, 117.0, 114.3, 111.7, 51.0, 46.2. HRMS (ESI): calcd for C23H20N3O [M + MeCN + H]+ 354.1606; found 354.1606. TLC (SiO2): Rf = 0.13 (5% MeOH in DCM).

4-(5-Methyl-1H-indol-3-yl)-3,4-dihydroquinazolin-2(1H)-one (4i)

Prepared following the general procedure (A), starting from aldehyde 1a (40 mg, 224 μmol), amine 2a (34 mg, 441 μmol), and nucleophile 3b (38 mg, 290 μmol). Yield: 57 mg (92%); yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ 10.87 (s, 1H), 9.29 (s, 1H), 7.36–7.33 (m, 1H), 7.31–7.26 (m, 1H), 7.20–7.17 (m, 1H), 7.16–7.10 (m, 2H), 7.01–6.87 (m, 3H), 6.84–6.78 (m, 1H), 6.10–5.68 (m, 1H), 2.35 (s, 3H). 13C NMR (DMSO-d6, 100 MHz): δ 153.8, 137.2, 135.1, 127.5, 126.9, 126.5, 125.2, 123.2, 122.8, 121.9, 120.8, 118.8, 117.5, 113.6, 111.3, 50.5, 21.4. HRMS (ESI): calcd for C19H19N4O [M + MeCN + H]+ 319.1559; found m/z 319.1575. TLC (SiO2): Rf = 0.16 (5% MeOH in DCM).

4-(5-Bromo-1H-indol-3-yl)-3,4-dihydroquinazolin-2(1H)-one (4j)

Prepared following the general procedure (A), starting from aldehyde 1a (40 mg, 224 μmol), amine 2a (34 mg, 441 μmol), and nucleophile 3c (57 mg, 291 μmol). Yield: 70 mg (91%); white solid. 1H NMR (DMSO-d6, 400 MHz): δ 11.17 (br s, 1H), 9.29 (br s, 1H), 7.67 (d, J = 1.9 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.21–7.14 (m, 2H), 7.11–7.08 (m, 1H), 6.93 (d, J = 7.5 Hz, 1H), 6.85 (dd, J = 8.0, 1.2 Hz, 1H), 6.79 (ddd, J = 7.5, 7.5, 1.2 Hz, 1H), 5.80 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 153.7, 137.2, 135.4, 127.7, 126.7, 126.5, 124.8, 123.7, 121.5, 121.4, 121.0, 118.1, 113.7, 111.4, 50.1. HRMS (ESI): calcd for C18H16BrN4O [M + MeCN + H]+ 383.0507; found 383.0502. TLC (SiO2): Rf = 0.16 (5% MeOH in DCM).

4-(2-Methyl-1H-indol-3-yl)-3,4-dihydroquinazolin-2(1H)-one (4k)

Prepared following the general procedure (A), starting from aldehyde 1a (40 mg, 224 μmol), amine 2a (34 mg, 441 μmol), and nucleophile 3d (38 mg, 290 μmol). Yield: 58 mg (93%); white solid. 1H NMR (DMSO-d6, 400 MHz): δ 10.93 (s, 1H), 9.28 (s, 1H), 7.34–7.26 (m, 1H), 7.26–7.20 (m, 1H), 7.11 (m, 1H), 7.01–6.96 (m, 1H), 6.89–6.81 (m, 2H), 6.77–6.72 (m, 2H), 5.95 (s, 1H), 2.46 (s, 3H). 13C NMR (DMSO-d6, 100 MHz): δ 153.7, 137.7, 135.8, 133.2, 127.9, 127.0, 126.7, 121.9, 121.2, 120.5, 118.8, 113.9, 113.7, 110.9, 49.9, 11.8. HRMS (ESI): calcd for C19H19N4O [M + MeCN + H]+ 319.1551; found 319.1559. TLC (SiO2): Rf = 0.16 (5% MeOH in DCM).

4-(2-Phenyl-1H-indol-3-yl)-3,4-dihydroquinazolin-2(1H)-one (4l)

Prepared following the general procedure (A), starting from aldehyde 1a (40 mg, 224 μmol), amine 2a (34 mg, 441 μmol), and nucleophile 3e (56 mg, 290 μmol). Yield: 69 mg (91%); yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ 11.43 (s, 1H), 9.35 (d, J = 1.9 Hz, 1H), 7.81–7.73 (m, 2H), 7.63–7.55 (m, 2H), 7.54–7.47 (m, 1H), 7.45–7.41 (m, 1H), 7.37–7.32 (m, 1H), 7.29–7.24 (m, 1H), 7.17–7.05 (m, 2H), 6.98–6.91 (m, 1H), 6.89 (dd, J = 8.0, 1.1 Hz, 1H), 6.70 (m, 1H), 6.61–6.54 (m, 1H), 5.99 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 153.8, 137.6, 136.8, 136.8, 132.6, 129.3, 129.2, 128.5, 128.1, 126.7, 126.5, 122.0, 121.6, 121.3, 120.3, 119.3, 114.0, 113.5, 111.8, 50.5. HRMS (ESI): calcd for C24H21N4O [M + MeCN + H]+ 381.1715; found 381.1730. TLC (SiO2): Rf = 0.20 (5% MeOH in DCM).

4-(5-Methoxy-1H-indol-3-yl)-3,4-dihydroquinazolin-2(1H)-one (4m)

Prepared following the general procedure (A) starting from aldehyde 1a (40 mg, 224 μmol), amine 2a (34 mg, 441 μmol), and nucleophile 3f (47 mg, 292 μmol). Yield: 52 mg (76%); pink solid. 1H NMR (DMSO-d6, 400 MHz): δ 10.76 (s, 1H), 9.34 (d, J = 1.9 Hz, 1H), 7.17 (d, J = 8.7 Hz, 1H), 7.15–7.09 (m, 1H), 7.01–6.96 (m, 1H), 6.90–6.85 (m, 1H), 6.81–6.74 (m, 3H), 6.65 (dd, J = 8.7, 2.5 Hz, 1H), 5.90 (d, J = 1.7 Hz, 1H), 3.64 (s, 3H), 2.43 (s, 3H). 13C NMR (DMSO-d6, 100 MHz): δ 153.8, 153.2, 137.8, 133.8, 130.8, 127.9, 127.2, 127.1, 121.8, 121.3, 114.0, 113.8, 111.4, 109.5, 101.7, 55.5, 49.9, 11.9. HRMS (ESI): calcd for C20H21N4O2 [M + MeCN + H]+ 349.1665; found 349.1669. TLC (SiO2): Rf = 0.16 (5% MeOH in DCM).

Methyl 3-(2-oxo-1,2,3,4-Tetrahydroquinazolin-4-yl)-1H-indole-4-carboxylate (4n)

Prepared following the general procedure (A), starting from aldehyde 1a (40 mg, 224 μmol), amine 2a (34 mg, 441 μmol), and nucleophile 3g (51 mg, 291 μmol). Yield: 60 mg (83%); white solid. 1H NMR (DMSO-d6, 400 MHz): δ 11.46 (s, 1H), 9.28 (s, 1H), 7.75–7.66 (m, 2H), 7.27–7.20 (m, 1H), 7.19–7.14 (m, 1H), 7.03–6.97 (m, 1H), 6.93–6.88 (m, 1H), 6.87–6.83 (m, 1H), 6.84–6.73 (m, 2H), 6.27 (d, J = 2.5 Hz, 1H), 3.93 (s, 3H). 13C NMR (DMSO-d6, 100 MHz): δ 168.7, 154.1, 137.8, 137.6, 127.6, 126.9, 126.4, 123.1, 122.8, 122.6, 122.3, 121.1, 120.3, 118.8, 117.0, 113.8, 52.2, 49.8. HRMS (ESI): calcd for C18H16N3O3 [M + H]+ 322.1192; found 322.1202. TLC (SiO2): Rf = 0.17 (5% MeOH in DCM).

4-(1-Methyl-1H-indol-3-yl)-3,4-dihydroquinazolin-2(1H)-one (4o)[24]

Prepared following the general procedure (A), starting from aldehyde 1a (40 mg, 224 μmol), amine 2a (34 mg, 441 μmol), and nucleophile 3h (38 mg, 290 μmol). Yield: 52 mg (84%); white solid. 1H NMR (DMSO-d6, 400 MHz): δ 9.27 (d, J = 1.9 Hz, 1H), 7.56 (m, 1H), 7.40 (m, 1H), 7.21 (t, J = 2.2 Hz, 1H), 7.15 (s, 1H), 7.17–7.07 (m, 1H), 7.13–7.06 (m, 1H), 6.99 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 7.00–6.93 (m, 1H), 6.86 (dd, J = 8.0, 1.2 Hz, 1H), 6.78 (m, 1H), 5.82 (d, J = 2.2 Hz, 1H), 3.74 (s, 3H). 13C NMR (DMSO-d6, 100 MHz): δ 153.7, 137.1, 127.6, 127.2, 126.5, 125.3, 121.7, 121.3, 120.8, 119.4, 118.8, 117.6, 113.7, 109.8, 50.2, 32.3. HRMS (ESI): calcd for C19H19N4O [M + MeCN + H]+ 319.1559; found m/z 319.1567. TLC (SiO2): Rf = 0.08 (60% EtOAc in n-pentane).

4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroquinazolin-2(1H)-one (4p)

Prepared following the general procedure (A), starting from aldehyde 1a (40 mg, 224 μmol), amine 2a (34 mg, 441 μmol), and nucleophile 3i (34 mg, 288 μmol). Yield: 53 mg (90%); white solid. 1H NMR (DMSO-d6, 400 MHz): δ 11.53 (s, 1H), 9.31 (s, 1H), 8.19 (d, J = 4.6 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.33–7.26 (m, 2H), 7.17–7.08 (m, 1H), 7.05–6.95 (m, 2H), 6.91–6.84 (m, 1H), 6.83–6.78 (m, 1H), 6.07–5.61 (m, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 153.7, 148.9, 142.7, 137.1, 127.7, 127.3, 126.6, 123.3, 121.3, 121.0, 117.2, 117.2, 115.2, 113.7, 50.5. HRMS (ESI): calcd for C15H13N4O [M + H]+ 265.1089; found 265.1076. TLC (SiO2): Rf = 0.09 (5% MeOH in DCM).

3-Benzyl-4-(1H-indol-3-yl)-3,4-dihydroquinazolin-2(1H)-one (6a)[24]

Prepared following the general procedure (A), starting from aldehyde 1a (40 mg, 224 μmol), amine 2b (36 mg, 336 μmol), and nucleophile 3a (34 mg, 290 μmol). Yield: 75 mg (95%); yellow solid. 1H NMR (CDCl3/CD3OD, 400 MHz): δ 11.14 (d, J = 2.5 Hz, 1H), 9.70 (s, 1H), 7.53–7.48 (m, 1H), 7.47–7.45 (m, 1H), 7.44–7.35 (m, 3H), 7.34–7.27 (m, 3H), 7.15–7.07 (m, 2H), 7.04–6.94 (m, 2H), 6.92 (dd, J = 8.0, 1.1 Hz, 1H), 6.78 (m, 1H), 5.75 (s, 1H), 5.17 (d, J = 15.5 Hz, 1H), 3.77 (d, J = 15.4 Hz, 1H). 13C NMR (CDCl3/CD3OD, 100 MHz): δ 155.8, 138.5, 138.3, 136.6, 129.5, 128.9, 128.7, 128.3, 128.1, 126.1, 124.7, 123.0, 122.8, 122.5, 120.3, 119.9, 117.0, 114.7, 112.6, 56.5, 47.8. HRMS (ESI): calcd for C23H20N3O [M + H]+ 354.1606; found 354.1613. TLC (SiO2): Rf = 0.20 (40% EtOAc in n-pentane).

4-(1H-Indol-3-yl)-3-(thiophen-2-ylmethyl)-3,4-dihydroquinazolin-2(1H)-one (6b)

Prepared following the general procedure (A), starting from aldehyde 1a (40 mg, 224 μmol), amine 2c (33 mg, 292 μmol), and nucleophile 3a (34 mg, 290 μmol). Yield: 76 mg (94%); white solid. 1H NMR (CDCl3/CD3OD, 400 MHz): δ 7.44 (m, 1H), 7.38 (m, 1H), 7.35 (s, 1H), 7.31 (dd, J = 4.8, 1.6 Hz, 1H), 7.14–7.07 (m, 2H), 6.99–6.95 (m, 2H), 6.95–6.91 (m, 1H), 6.91–6.86 (m, 2H), 6.79 (m, 1H), 5.86 (s, 1H), 5.29 (dd, J = 15.5, 0.9 Hz, 1H), 4.07 (d, J = 15.5 Hz, 1H). 13C NMR (CDCl3/CD3OD, 100 MHz): δ 156.1, 141.8, 139.4, 137.3, 129.8, 129.1, 128.7, 128.4, 127.2, 127.1, 126.0, 123.9, 123.8, 123.3, 121.3, 120.9, 117.5, 115.6, 113.6, 57.1, 43.7. HRMS (ESI): calcd for C21H18N3OS [M + H]+ 360.1171; found 360.1168. TLC (SiO2): Rf = 0.16 (5% MeOH in DCM).

3-Benzyl-4-(2,4-dimethoxyphenyl)-3,4-dihydroquinazolin-2(1H)-one (6c)

Prepared following the general procedure (A) but with 30 min of heating in the second step, starting from aldehyde 1a (40 mg, 224 μmol), amine 2b (36 mg, 336 μmol), and nucleophile 5a (40 mg, 289 μmol). Yield: 72 mg (86%); yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.96 (s, 1H), 7.51 (m, 5H), 7.45–7.40 (m, 1H), 7.30 (m, 1H), 7.22–7.15 (m, 1H), 7.08–6.93 (m, 2H), 6.77–6.57 (m, 2H), 6.05 (s, 1H), 5.62 (d, J = 15.1 Hz, 1H), 4.01 (s, 6H), 3.93 (d, J = 15.1 Hz, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 160.1, 157.0, 153.4, 137.8, 136.4, 128.4, 127.9, 127.7, 127.4, 127.1, 125.9, 122.9, 121.6, 121.1, 113.6, 105.7, 98.6, 55.6, 55.2, 54.6, 46.8. HRMS (ESI): calcd for C23H23N2O3 [M + H]+ 375.1709; found 375.1711. TLC (SiO2): Rf = 0.26 (40% EtOAc in n-pentane).

4-(2,4-Dimethoxyphenyl)-3,4-dihydroquinazolin-2(1H)-one (6d)

Prepared following the general procedure (A) but with 30 min of heating in the second step, starting from aldehyde 1a (40 mg, 224 μmol), amine 2a (34 mg, 441 μmol), and nucleophile 5a (40 mg, 289 μmol). Yield: 35 mg (55%); white solid. 1H NMR (DMSO-d6, 400 MHz,): δ 9.21 (s, 1H), 7.17–7.07 (m, 1H), 7.05–6.95 (m, 3H), 6.86–6.79 (m, 2H), 6.64–6.59 (m, 1H), 6.54–6.48 (m, 1H), 5.80 (d, J = 2.4 Hz, 1H), 3.86 (s, 3H), 3.76 (s, 3H). 13C NMR (DMSO-d6, 400 MHz,): δ 159.4, 156.2, 153.6, 136.7, 127.3, 127.2, 125.8, 124.9, 121.2, 120.6, 113.3, 104.6, 98.1, 55.2, 54.8, 50.2. HRMS (ESI): calcd for C18H20N3O3 [M + MeCN + H]+ 326.1505; found 326.1508. TLC (SiO2): Rf = 0.21 (5% MeOH in DCM).

4-(2,4-Dimethoxyphenyl)-3-(1-methylpiperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (6e)

Prepared following the general procedure (A) but with 30 min of heating the second step, starting from aldehyde 1a (40 mg, 224 μmol), amine 2d (33 mg, 289 μmol), and nucleophile 5a (68 mg, 492 μmol). Yield: 43 mg (50%); white solid. 1H NMR (CDCl3, 400 MHz): δ 7.47 (s, 1H), 7.24–7.20 (m, 2H), 7.08–6.96 (m, 1H), 6.86–6.76 (m, 1H), 6.65–6.58 (m, 1H), 6.40–6.31 (m, 1H), 6.29 (dd, J = 8.5, 2.4 Hz, 1H), 5.95 (s, 1H), 4.41–4.14 (m, 1H), 3.84 (s, 3H), 3.67 (s, 3H), 2.95 (d, J = 10.7 Hz, 1H), 2.79 (d, J = 11.7 Hz, 1H), 2.24 (s, 3H), 2.21–1.97 (m, 4H), 1.59 (d, J = 12.1 Hz, 1H), 1.45 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ 160.0, 155.3, 154.9, 135.0, 127.5, 127.0, 125.3, 125.0, 123.2, 121.8, 113.3, 104.4, 98.2, 55.2, 55.0, 54.9, 54.8, 52.2, 51.4, 45.2, 29.4, 28.7, 21.8. HRMS (ESI): calcd for C22H28N3O3 [M + H]+ 382.2131; found 382.2132. TLC (SiO2): Rf = 0.23 (10% MeOH in DCM).

4-(4-Hydroxy-2-methylphenyl)-3,4-dihydroquinazolin-2(1H)-one (6f)

Prepared following the general procedure (A) but with 30 min in heating the second step, starting from aldehyde 1a (40 mg, 224 μmol), amine 2a (33 mg, μmol), and nucleophile 5b (31 mg, 289 μmol). Yield: 30 mg (52%); white solid. 1H NMR (DMSO-d6, 400 MHz): δ 9.62 (s, 1H), 9.15 (s, 1H), 7.07 (t, J = 7.9 Hz, 2H), 6.95 (s, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.81–6.74 (m, 2H), 6.63 (s, 1H), 6.55 (d, J = 7.8 Hz, 1H), 5.79 (d, J = 2.3 Hz, 1H), 2.17 (s, 3H). 13C NMR (DMSO-d6, 100 MHz): δ 154.0, 153.4, 137.5, 137.0, 128.5, 127.5, 126.9, 126.3, 121.9, 120.9, 119.9, 115.9, 113.6, 50.7, 20.7. HRMS (ESI): calcd for C15H15N2O2 [M + H]+ 255.1143; found 255.1134. TLC (SiO2): Rf = 0.22 (5% MeOH in DCM).

4-(1H-Indol-3-yl)-3-(3-methoxyphenethyl)-3,4-dihydroquinazolin-2(1H)-one (7a)

Prepared following the general procedure (B), starting from aldehyde 1a (40 mg, 224 μmol), amine 2e (43 mg, 290 μmol), and nucleophile 3a (39 mg, 334 μmol). Yield: 82 mg (92%); off-white solid. 1H NMR (CDCl3, 400 MHz): δ 8.33–8.20 (m, 1H), 7.99 (s, 1H), 7.56 (m, 1H), 7.34 (m, 1H), 7.20–7.13 (m, 3H), 7.13–7.04 (m, 2H), 6.91–6.86 (m, 1H), 6.79 (ddd, J = 14.3, 7.7, 1.1 Hz, 2H), 6.74 (dd, J = 7.9, 2.1 Hz, 2H), 6.67–6.63 (m, 1H), 5.59 (s, 1H), 4.01 (ddd, J = 14.0, 9.0, 5.0 Hz, 1H), 3.66 (s, 3H), 3.22 (ddd, J = 13.8, 8.7, 7.1 Hz, 1H), 2.95 (ddd, J = 13.2, 9.0, 7.1 Hz, 1H), 2.71 (ddd, J = 13.4, 8.6, 5.0 Hz, 1H). δ 13C NMR (CDCl3, 100 MHz): δ 159.7, 154.1, 141.3, 136.7, 135.7, 129.6, 128.2, 126.8, 125.4, 122.8, 122.6, 122.1, 121.6, 121.3, 120.3, 119.4, 117.5, 114.3, 113.8, 112.2, 111.6, 56.9, 55.2, 47.3, 34.6. HRMS (ESI): calcd for [M + H]+ 398.1869; found 398.1873. TLC (SiO2): Rf = 0.13 (50% EtOAc in n-pentane).

3-(3,4-Dimethoxyphenethyl)-4-(1H-indol-3-yl)-3,4-dihydroquinazolin-2(1H)-one (7b)

Prepared following the general procedure (B), starting from aldehyde 1a (40 mg, 224 μmol), amine 2f (53 mg, 290 μmol), and nucleophile 3a (39 mg, 334 μmol). Yield: 85 mg (90%); white solid. 1H NMR (CDCl3/CD3OD, 400 MHz): δ 7.33–7.24 (m, 2H), 7.21–7.13 (m, 1H), 7.03–6.95 (m, 1H), 6.96–6.87 (m, 2H), 6.85–6.76 (m, 1H), 6.71–6.53 (m, 4H), 6.50–6.36 (m, 2H), 5.40 (s, 1H), 3.70–3.56 (m, 4H), 3.47 (s, 3H), 3.07–2.87 (m, 1H), 2.73–2.61 (m, 1H), 2.52–2.37 (m, 1H). 13C NMR (CDCl3/CD3OD, 100 MHz): δ 154.6, 148.9, 147.6, 137.1, 135.4, 132.4, 128.2, 127.0, 125.4, 123.6, 122.5, 122.2, 121.8, 121.0, 119.8, 119.0, 116.5, 113.9, 112.3, 111.9, 111.7, 57.2, 56.0, 55.7, 47.6, 33.9. HRMS (ESI): calcd for C26H26N3O3 [M + H]+ 428.1974; found 428.1977. TLC (SiO2): Rf = 0.10 (50% EtOAc in n-pentane).

4-(1H-Indol-3-yl)-3-(2-(thiophen-2-yl)ethyl)-3,4-dihydroquinazolin-2(1H)-one (7c)

Prepared following the general procedure (B), starting from aldehyde 1a (40 mg, 224 μmol), amine 2g (37 mg, 290 μmol), and nucleophile 3a (39 mg, 334 μmol). Yield: 80 mg (96%); light yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.32–8.24 (m, 1H), 8.15 (s, 1H), 7.58 (m, 1H), 7.35 (m, 1H), 7.21–7.13 (m, 2H), 7.14–7.03 (m, 3H), 6.94–6.85 (m, 2H), 6.83–6.70 (m, 3H), 5.67 (s, 1H), 4.01 (ddd, J = 13.3, 8.4, 5.2 Hz, 1H), 3.34–3.15 (m, 2H), 3.00–2.84 (m, 1H). 13C NMR (CDCl3, 100 MHz): δ 154.1, 141.8, 136.7, 135.6, 128.2, 127.1, 126.8, 125.4, 125.3, 123.8, 122.9, 122.7, 122.2, 121.5, 120.4, 119.4, 117.5, 113.9, 111.6, 57.2, 47.5, 28.5. HRMS (ESI): calcd for C22H29N3OS [M + H]+ 374.1327; found 374.1324. TLC (SiO2): Rf = 0.15 (50% EtOAc in pentane).

3-(But-3-en-1-yl)-4-(1H-indol-3-yl)-3,4-dihydroquinazolin-2(1H)-one (7d)

Prepared following the general procedure (B), starting from aldehyde 1a (40 mg, 224 μmol), amine 2h (21 mg, 290 μmol), and nucleophile 3a (39 mg, 334 μmol). Yield: 68 mg (96%); off-white solid. 1H NMR (CDCl3, 400 MHz): δ 8.32 (s, 1H), 8.05 (s, 1H), 7.63 (dd, J = 7.9, 1.1 Hz, 1H), 7.35 (m, 1H), 7.22–7.14 (m, 2H), 7.09 (m, 2H), 7.01 (ddd, J = 7.7, 1.5, 0.7 Hz, 1H), 6.85–6.72 (m, 2H), 5.88 (s, 1H), 5.78 (m, 1H), 5.15–4.88 (m, 2H), 3.91 (ddd, J = 13.9, 8.7, 6.4 Hz, 1H), 3.04 (ddd, J = 14.2, 8.6, 5.9 Hz, 1H), 2.47–2.35 (m, 1H), 2.33–2.20 (m, 1H). 13C NMR (CDCl3, 100 MHz): δ 154.2, 136.7, 135.7, 135.6, 128.2, 126.8, 125.4, 122.7, 122.6, 122.1, 121.5, 120.3, 119.4, 117.6, 116.7, 113.9, 111.6, 56.4, 44.7, 32.2. HRMS (ESI): calcd for [M + H]+ 318.1606; found 318.1606. TLC (SiO2): Rf = 0.2 (50% EtOAc in n-pentane).

3-((1H-Indol-4-yl)methyl)-4-(1H-indol-3-yl)-3,4-dihydroquinazolin-2(1H)-one (7e)

Prepared following the general procedure (B), starting from aldehyde 1a (40 mg, 224 μmol), amine 2i (42 mg, 290 μmol), and nucleophile 3a (39 mg, 334 μmol). Yield: 32 mg (36%); off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ 11.13 (d, J = 13.2 Hz, 2H), 9.66 (s, 1H), 8.28 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.42–7.23 (m, 4H), 7.05 (m, 3H), 6.90 (m, 4H), 6.68 (m, 1H), 6.45 (s, 1H), 5.60 (s, 1H), 5.50 (d, J = 15.0 Hz, 1H), 3.83 (d, J = 15.0 Hz, 2H). 13C NMR (DMSO-d6, 100 MHz): δ 152.9, 137.1, 136.3, 136.2, 128.4, 127.8, 127.1, 126.7, 125.3, 124.7, 124.0, 121.6, 121.3, 121.2, 121.0, 119.2, 119.0, 118.5, 116.3, 113.6, 112.1, 111.0, 99.8, 54.6, 44.7. HRMS (ESI): calcd for [M + H]+ 393.1715; found 393.1729. TLC (SiO2): Rf = 0.1 (50% EtOAc in n-pentane).