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Synthesis 2022; 54(04): 1115-1124
DOI: 10.1055/a-1667-3977
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Copper-Catalyzed Oxidative Cyclization of 2-Aminobenzamide Derivatives: Efficient Syntheses of Quinazolinones and Indazolones

Karthick Govindan
a   Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, ROC
,
Tamilselvan Duraisamy
a   Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, ROC
,
Alageswaran Jayaram
a   Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, ROC
,
Gopal Chandru Senadi
b   Department of Chemistry, Faculty of Engineering and Technology SRM Institute of Science and Technology, Kattankulathur, Tamilnadu – 603203, India
,
Wei-Yu Lin  ∗
a   Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, ROC
c   Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan, ROC
d   Drug Development and Value Creation Research Centre, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, ROC
› Author Affiliations

The authors gratefully acknowledge funding from the Ministry of Science and Technology, Taiwan (MOST 109-2113-M-037-013) and Kaohsiung Medical University Research Foundation (KMU-M109004).
› Further Information
 
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Abstract

A simple copper-catalyzed assembly to formulate quinazolinone and indazolone derivatives in a single protocol manner is reported. These transformations are based on the fact that DMF can serve as a reaction solvent and one carbon synthon for the construction of heterocyclic rings. Moreover, this protocol features base-free and Brønsted acid free environmentally benign conditions with broad synthetic scope. A good scalability is demonstrated.


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Key words

copper - catalysis - C1 synthon - DMF - oxidative process - quinazolinone - indazolone

Over the past few decades, a plethora of new synthetic methods, catalysts, and reagents have been significantly developed to aid in the construction of an array of heterocycles and chemical structures. The development of new reagents with the potential for higher reactivity or efficiency has become one of the pivotal areas of chemical research. Recently, carbon synthon chemistry has emerged as a versatile synthetic strategy for introducing one or more extra carbon in modern chemical transformations.[1] To lengthen the carbon chain and to introduce suitable functionalities are the core value, with an increasing interest dedicated to C1 chemistry. Thus, the direct introduction of one extra carbon from cheap and readily available materials under mild conditions to provide cost-effective, practical, and valuable methods are achieved and have remarkable progress from fundamental studies to industrial applications.

So far, numerous reagents and solvents have been developed in recent years as one-carbon (C1) sources for the construction of CH3, CH2, CH, CHO, and CN units for the synthesis of organic compounds. A significant attention has been paid for DMF,[2] DMSO,[3] and MeOH[4] as C1 sources owing to its cost-effectiveness, high abundance, and less toxicity in nature. On the other hand, quinazolinone[5] and indazolone[6] derivatives are heteroaromatic compounds usually found in pharmaceuticals and natural products. Most notably, Febrifugine,[7] Halofuginone,[8] and 1,2-disubstituted 5-nitrodiazolin-3-ones (VA5-131 and VATR-5)[9] with the unique bioactive core exhibit a wide range of biological and pharmaceutical properties such as antimalarial, anticancer, and antichagasic activities (Figure [1]).

Zoom Image
Figure 1 Selected examples of biologically important compounds containing quinazolinone and indazolone structures

Since quinazolinones are so important, several well-established methods have been developed. The most widely used method is the reaction of antharanilamide derivatives with various methine sources such as triethylamine,[10] trialkyl orthoformate,[11] dicumyl peroxide,[12] oxalic acid,[13] methanol,[14] aldehydes,[15] ethylene glycol,[16] DMA,[17] CO2,[18] and CO[19] using Pd-Ag, Pd, or Ir as catalyst. Recently, the copper-catalyzed reactions of o-aminobenzamides with biomass-derived furan-2-carbaldehydes,[20] and renewable resources derived from MeOH[21] as well as carbohydrates[22] as C1 synthon to generate quinazolinone have been reported.

N,N-Dimethylformamide (DMF) is considered to be a versatile synthon to generate different functionalities to incorporate such as C,[23] CH,[24] CH3,[25] CHO,[26] CN,[27] CO,[27a] NH2,[28] and NMe2 [29] units into value added products due to affordable, cheap, readily available, low toxic and high in abundance.[2] [30] These results show the importance of DMF in the organic synthesis as an effective polar solvent and as a versatile reagent. Recently, we reported the synthesis of 3-formylindoles and 3-acyl-4-aminoquinolines by copper-catalyzed oxidative annulation using DMF as a formyl[31] and dual synthon[32] to afford methine and N′,N-dimethyl functionality, respectively (Scheme [1a, b]). These results inspired us to envision a copper-catalyzed synthesis of bicyclic N-heterocycles using readily available DMF. In this work, we propose an efficient strategy to synthesize quinazolinones and indazolones by the reaction of o-aminobenzamide derivatives using copper-catalyzed reaction under atmospheric oxygen for 24 hours at 130 °C in the presence of DMF as a C1 synthon or solvent (Scheme [1c]). Indeed, this is one of the most efficient and straightforward methods for constructing quinazolinone and indazolone via copper-catalyzed oxidative DMF reaction.

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Scheme 1Strategies for the syntheses of quinazolinones and indazolones

We focused on finding a Cu-catalyzed reaction of 2-amino-N-phenylbenzamide (1a) with DMF, using our previously described conditions to construct quinazolinone derivatives as shown in Table [1]. When the reaction was carried out with 1a using 20 mol% CuCl2 under oxygen atmosphere in 130 °C, the reaction was completed in 65% NMR yield. This result encouraged us to screen various copper(I) and (II) salts. Interestingly, the reaction worked with all the copper catalysts to afford the desired compound 2a in moderate reaction yields (Table [1], entries 2–6).

Table 1 Optimization of Reaction Conditionsa

Entry

Catalyst

Oxidant

Yield (%)b

 1

CuCl2

–

65

 2

Cu(OAc)2

–

70 (66)c

 3

Cu(TFA)2·xH2O

–

55

 4

Cu(OAc)2·H2O

–

32

 5

CuI

–

44

 6

CuBr

–

51

 7

Cu(OAc)2

DMSO

42

 8

Cu(OAc)2

TBHP

46

 9

Cu(OAc)2

DTBP

66

10

Cu(OAc)2

open air

56

11

Cu(OAc)2

–

36d

12

CuCl

DMSO

75 (73)c

13

CuCl

–

62 (45)e

14

CuCl

–

N.R.f

15

CuCl

DMSO/open air

60

16

CuCl

DMSO/N2

10

17

ZnBr2

–

 8

18

NiBr2

–

15

19

CuCl

DMSO

34c,g

20

CuCl

DMSO

59c,h

21

CuCl

DMSO

N.R.i

22

CuCl

DMSO

60c,j

a Reaction conditions: 1a (0.2 mmol) was reacted with catalyst in DMF (2 mL) at 130 °C for 24 h under O2.

b NMR yield using 1,3,5-trimethoxybenzene as internal standard. N.R.: No reaction.

c Isolated yield.

d DMSO was used as solvent instead of DMF.

e DMA was used as solvent instead of DMF.

f N,N-Diethylformamide was used as solvent instead of DMF.

g Reaction carried out at 130 °C for 12 h under O2.

h Reaction carried out at 130 °C for 48 h under O2.

i Reaction carried out at 80 °C for 24 h under O2.

j Reaction carried out at 150 °C for 24 h under O2.

In addition, the reaction was performed with and without external oxidant like, DMSO, TBHP, DTBP, and open air, however, the yield of the product was reduced (Table [1], entries 7–10). Further, the desired product yield was suppressed when the reaction was performed with DMSO as solvent instead of DMF (entry 11). To our surprise, the reaction gladly worked well when performing with CuCl (entry 12). In order to search for a more efficient and effective synthon system, we examined the reaction with DMA. The result showed that DMF was more efficacious than DMA (entry 13). No product 2a was obtained when N,N-diethylformamide was used as solvent (entry 14). Eventually, the reaction was performed in open air and under N2 atmosphere, but the reaction yield dropped thereby suggesting the reaction atmosphere may facilitate for effective cyclization (entries 15, 16). Notably, the outcome of C1 synthon from DMF and cyclization was highly efficient and more suitable only for copper salts; ZnBr2, and NiBr2 were not effective (entries 17, 18). Moreover, shortening or prolonging the reaction time and increasing or decreasing the reaction temperature did not improve the yield (entries 19–22). Based on the above results, the optimal reaction conditions were set up as described in entry 12 of Table [1] for further investigations.

With the optimal reaction parameters in hand, various substrate scope of this copper-catalyzed reaction of quinazolinone derivatives were explored (Scheme [2]). Most of the reaction proceeded smoothly with functionalities such as p-MeC6H4 (1b), m-MeC6H4 (1c), 2,5-(MeO)2C6H3 (1d), p-MeOC6H4 (1e), p-FC6H4 (1f), p-BrC6H4 (1g), p-ClC6H4 (1h) on R1 group to obtain the desired compounds 2b–h in 53–72% yields. The functional group containing heteroaryl substrates such as pyridine and 5-methylpyridine moiety on R1 group were well tolerated in the copper-catalyzed reactions, affording the products 2i–j in 35–65% yields.

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Scheme 2Substrate scope of quinazolinones. Reagents and conditions: The reactions were performed with 1a–w (0.3 mmol) in DMF (3 mL) at 130 °C for 24 h under O2. Isolated yields are shown. For 2b and 2m, the yield in parentheses is based on recovered starting material.

To illustrate the applicability of the reaction conditions, R1 group containing aminostilbene 1k was tested and the reaction underwent smooth conversion to furnish 2k in 50% yield. Changing from an aryl to benzyl group, 1l produced the corresponding 2l in 60% yield. To further demonstrate the utility of our method, we subjected two bioactive alkaloid precursors to the copper-catalyzed reaction to afford 2m and 2n in 30–68% yield, which are the important precursors for rutecarpine, evodiamine, and echinozolinone.[33] More interestingly, when the R1 group was changed to heterobenzyl groups 1o,p they provided the corresponding products 2o and 2p in 46–50% yields. To expedite the synthetic aid of this strategy and to expand the substrate of this reaction, R1 group containing an aliphatic functionality like Bu (1q), C12H25 (1r), i-Pr (1s), cyclohexyl (1t), Et (1u), allyl (1v), and 1-methoxypropan-2-yl (1w) were scrutinized. Interestingly, the desired products 2q–w were formed in 50–61% yields. Relying on the previous research[34] copper-catalyzed reaction using N-phenyl-2-(phenylamino)benzamide provided 1,2-diphenyl-1H-indazolone. Intriguingly, this development was unsuccessful for the N-alkylindazolone derivatives. Given the more importance of N–N bond forming reactions in copper-catalyzed oxidative cyclization, we further took advantage of our strategy to construct N-alkylindazolone derivatives. Surprisingly, when N-methyl-2-(phenylamino)benzamide (3a) was subjected to identical conditions, the expected quinazolinone was not observed, only the indazolone 4a was isolated in 70% yield (Scheme [3]).

The reaction was also carried out in DMSO[34] and a sharp decrease of the conversion(<20 %) was observed, indicating the importance of the O2 pressure of 1 atm and DMF in this reaction. The generality of the reaction was considered in order to advance the scope by testing with R1 substituents containing 4-MeC6H4 (3b) and 4-MeOC6H4 (3c), both were well tolerated and afforded 4b,c in 83–90% yield. R1 containing electron-withdrawing substituents also gave access to 4d,e in 60–70% moderate yields. By contrast, heterocycle substrate 3f and n-butyl substrate 3g led to lower yields of the desired products 4f,g. N-Benzyl substrate 3h afforded the corresponding product 4h in 71% yield.

Zoom Image
Scheme 3Substrate scope of indazolones. Reagents and conditions: The reactions were performed with 3a–h (0.3 mmol) in DMF (3 mL) at 130 °C for 24 h under O2. Isolated yields are shown.

To elucidate the possible reaction mechanism for the syntheses of quinazolinone and indazolone, several preliminary experiments were carried out (Scheme [4]). At first, radical scavengers such as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 2,6-bis(1,1-dimethylethyl)-4-methylphenol (BHT) were tested with 1a and 3a; they did not affect the formation of 2a but they dramatically suppressed the formation of 4a. Moreover, the addition of 1 equivalent of DMSO slightly increased the yield of 2a and 4a, which indicates that the oxidation process may be facile with the external oxidizing agent (Table [1], entry 13 and Scheme [4], eq. iii). On the other hand, when the reactions were carried out under air, the reaction yield of 2a was slightly decreased, and only trace amount of 4a was observed (Table [1] entry 15 and Scheme [4], eq. iv). This result suggests that the formation of 4a via a single electron transfer process in free NH might be influenced under oxygen atmospheric pressure and the presence of copper salt in DMF than open air. Instead of DMF and DMSO any other solvents such as ethylene glycol or nitromethane was inefficient for this oxidative process (Scheme [4], eqs. v and vi). These results indicate that the formation of quinazolinone 2 and indazolone 4 may involve non-radical and radical pathway, respectively.

Zoom Image
Scheme 4Control reactions

Based on these findings and previous reports,[32] [34] [35] a plausible mechanism is proposed as presented in Scheme [5]. DMF is first converted into the iminium ion A in the presence of O2 and Cu(I),[32] and a nucleophilic addition reaction of iminium ion A with 1a generates B followed by elimination of dimethylamine. Subsequent aza-endo-trig cyclization results in the formation of D, which is then oxidized to yield the quinazolinone 2a product under the Cu(I)/O2 condition (Scheme [5] i). In contrast, the mechanism of the indazolone synthesis may involve the generation of radical cation intermediate I by the single electron transfer (SET) in the presence of Cu(I)/O2 and two mechanistic pathways 1 and 2 leading to the formation of 4a are proposed. In the first pathway 1, tautomerization of I to II is followed by intramolecular cyclization to generate the radical intermediate III and further SET oxidation to yield the final product (Scheme [5] ii, pathway 1). On the other hand, radical oxidation of I with copper forms IV. In this Cu(II) intermediate, a second radical type oxidation occurs with the elimination of H2 to form Cu(III) intermediate V, followed by reductive elimination to afford the product 4a (Scheme [5] ii, pathway 2).

Zoom Image
Scheme 5Proposed mechanisms toward 2a and 4a

Gratifyingly, to demonstrate the scalability of this catalytic protocol, gram-scale reactions were conducted under the optimized conditions using 1.44 g of 1a (6.8 mmol) and 1.59 g of 3b (7.0 mmol) to isolate 1.03 g of quinazolinone 2a in 68% yield and 1.33 g of N-methylindazolone 4b in 80% yield, respectively (Scheme [6]). Thus, this procedure could be used as a robust method for synthesizing quinazolinone and indazolone on the gram scale under the copper catalysis reaction.

In conclusion, we have developed a simple copper-catalyzed cyclization method in DMF to synthesize quinazolinone and indazolone selectively under mild conditions. DMF can serve as one carbon synthon and reaction solvent for the construction of aromatic heterocyclic moieties. The syntheses of quinazolinone and indazolone may involve oxidation process via nonradical and radical pathways. The reaction features base-free and Brønsted acid free, environmentally benign, broad substrate, and scalability.

Zoom Image
Scheme 6Gram-scale syntheses of 2a and 4b under the standard conditions

All chemicals were purchased from commercial providers (Sigma Aldrich, Alfa Aesar, TCI, and matrix scientific) and used directly without further purification, unless otherwise noted. Well cleaned and oven-dried glassware were used for the experiments. Reactions were monitored by TLC on pre-coated silica gel 60 F254 from Merck. Column chromatography was carried out using the silica gel 230–400 mesh (purchased from Merck) with a mixture of EtOAc/hexane or hexane as the eluent. 1H NMR spectra were recorded at 400 MHz, 13C NMR spectra were recorded at 100 MHz on a Varian mercury spectrometer using CDCl3 or DMSO-d 6 as solvent. The spectra were recorded and presented in chemical shifts (ppm) with TMS as internal standard. Multiplicities are denoted by standard abbreviations. Coupling constants (J) are reported in hertz (Hz). All compounds were characterized by ESI mass on Thermo Finnigan (TRACEGCPOLARISQ) and HRMS (ESI+ mode) on JMS-700 spectrometer. Melting points were determined using Fargo instruments.

All starting materials 1a–w were synthesized on a 3 mmol scale, according to literature procedure and obtained in 25–83% yields, unless otherwise noted. The 1H NMR spectra of starting materials 1a–j, 1l–q, 1s–v matched with previous literature. The rest of the new starting materials 1k, 1r, 1w were characterized and the data are presented in the Supporting Information.

The synthesis of 3a–h is also provided in the Supporting Information.


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Quinazolinone Derivatives; General Procedure

A 15 mL pressure tube was charged with 1 (0.3 mmol), DMF (0.1 M), DMSO (1.0 equiv), and CuCl (20 mol%). The reaction mixture was allowed to stir at 130 °C under O2 for about 24 h and allowed to reach rt and then diluted with H2O (5 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined EtOAc layers were washed with brine (5 mL), dried (MgSO4) and concentrated under reduced pressure. The obtained crude product was purified by column chromatography by eluting with EtOAc/hexane (1:9) to afford the desired pure quinazolinone 2.


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Indazolone Derivatives; General Procedure

A 15 mL pressure tube was charged with 3 (0.3 mmol), DMF (0.1 M), DMSO (1.0 equiv), and CuCl (20 mol%). The reaction mixture was allowed to stir at 130 °C under O2 for about 24 h and allowed to reach rt and then diluted with H2O (5 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined EtOAc layers were washed with brine (5 mL), dried (MgSO4) and concentrated under reduced pressure. The obtained crude product was purified by column chromatography by eluting with EtOAc/hexane (1:9) to afford the desired pure indazolone derivative 4.


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3-Phenylquinazolin-4(3H)-one (2a)[36]

White solid; yield: 49 mg (73%); mp 146–148 °C.

1H NMR (400 MHz, CDCl3): δ = 8.37 (d, J = 8.0 Hz, 1 H),8.13 (s,1 H), 7.83–7.75 (m, 2 H), 7.57–7.53 (m, 3 H), 7.51–7.47 (m, 1 H), 7.44–7.41 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 160.71, 147.86, 146.05, 137.47, 134.53, 129.61, 129.07, 127.61, 127.56, 127.14, 126.97, 122.37.


#

3-(p-Tolyl)quinazolin-4(3H)-one (2b)[36]

White solid; yield: 39 mg (55%); mp 149–151 °C.

1H NMR (400 MHz, CDCl3): δ = 8.37 (dd, J = 8.0, 1.2 Hz, 1 H), 8.12 (s, 1 H), 7.82–7.75 (m, 2 H), 7.56–7.52 (m, 1 H), 7.36–7.26 (m, 4 H), 2.44 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 160.87, 147.89, 146.29, 139.22, 134.90, 134.48, 130.22, 127.55, 127.52, 127.16, 126.71, 122.39.


#

3-(m-Tolyl)quinazolin-4(3H)-one (2c)[36]

White solid; yield: 47 mg (67%); mp 145–148 °C.

1H NMR (400 MHz, CDCl3): δ = 8.36 (d, J = 8.0 Hz, 1 H), 8.10 (s, 1 H), 7.81–7.74 (m, 2 H), 7.56–7.51 (m, 1 H), 7.42 (t, J = 8.0 Hz, 1 H), 7.30–7.19 (m, 3 H), 2.43 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 160.82, 147.92, 146.17, 139.81, 137.42, 134.51, 129.91, 129.45, 127.63, 127.57, 127.16, 123.97, 122.41, 21.32.


#

3-(2,4-Dimethoxyphenyl)quinazolin-4(3H)-one (2d)

White solid; yield: 45 mg (53%); mp 177–180 °C.

1H NMR (400 MHz, CDCl3): δ = 8.34 (d, J = 8.0 Hz, 1 H), 7.94 (s, 1 H), 7.76 (m, 2 H), 7.50 (td, J = 8.0, 1.2 Hz, 1 H), 7.25–7.22 (m, 1 H), 6.60–6.58 (m, 2 H), 3.85 (s, 3 H), 3.77 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 161.64, 160.96, 155.63, 148.07, 147.64, 134.27, 129.56, 127.43, 127.18, 127.14, 122.67, 119.07, 104.76, 99.70, 55.80, 55.64.


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3-(4-Methoxyphenyl)quinazolin-4(3H)-one (2e)[36]

White solid; yield: 50 mg (66%); mp 190–193 °C.

1H NMR (400 MHz, CDCl3): δ = 8.37 (dd, J = 8.0, 1.2 Hz, 1 H), 8.11 (s, 1 H), 7.82–7.75 (m, 2 H), 7.57–7.53 (m, 1 H), 7.36–7.32 (m, 2 H), 7.07–7.03 (m, 2 H), 3.87 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 161.06, 159.94, 147.93, 146.43, 134.49, 130.19, 128.14, 127.56, 127.17, 122.40, 114.80, 55.60.


#

3-(4-Fluorophenyl)quinazolin-4(3H)-one (2f)[36]

White solid; yield: 43 mg (60%); mp 201–203 °C.

1H NMR (400 MHz, CDCl3): δ = 8.35 (dd, J = 8.0, 1.6 Hz, 1 H), 8.08 (s, 1 H), 7.82–7.75 (m, 2 H), 7.57–7.53 (m, 1 H), 7.43–7.38 (m, 2 H), 7.26–7.20 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 163.86, 161.38, 160.79, 147.84, 145.82, 134.69, 133.37, 128.90 (d, J C,F = 8.4 Hz), 127.72 (d, J C,F = 12.0 Hz), 127.16, 122.26, 116.68 (t, J C,F = 23.0 Hz).


#

3-(4-Bromophenyl)quinazolin-4(3H)-one (2g)[36]

White solid; yield: 52 mg (58%); mp 208–211 °C.

1H NMR (400 MHz, CDCl3): δ = 8.36 (dd, J = 8.0, 1.2 Hz, 1 H), 8.08 (s, 1 H), 7.84–7.76 (m, 2 H), 7.70–7.67 (m, 2 H), 7.58–7.54 (m, 1 H), 7.34–7.30 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 160.55, 147.79, 145.47, 136. 43, 134.76, 132.86, 128.62, 127.85, 127.70, 123.19, 122.23.


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3-(4-Chlorophenyl)quinazolin-4(3H)-one (2h)[37]

White solid; yield: 55 mg (72%); mp 180–183 °C.

1H NMR (400 MHz, CDCl3): δ = 8.36 (dd, J = 8.0, 1.6 Hz, 1 H), 8.09 (s, 1 H), 7.83–7.76 (m, 2 H), 7.58–7.51 (m, 3 H), 7.40–7.36 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 160.61, 147.79, 145.54, 135.90, 135.17, 134.74, 129.86, 128.33, 127.82, 127.68, 127.18, 122.22.


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3-(Pyridin-4-yl)quinazolin-4(3H)-one (2i)[38]

White solid; yield: 23 mg (35%); mp 152–155 °C.

1H NMR (400 MHz, CDCl3): δ = 8.84 (dd, J = 4.0, 1.2 Hz, 2 H), 8.38 (dd, J = 8.0, 1.2 Hz, 1 H), 8.11 (s, 1 H), 7.86–7.78 (m, 2 H), 7.61–7.57 (m, 1 H), 7.47–7.45 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 159.98, 151.45, 149.94, 147.52, 144.42, 135.09, 128.15, 127.82, 127.31, 121.26.


#

3-(5-Methylpyridin-2-yl)quinazolin-4(3H)-one (2j)[22]

White solid; yield: 46 mg (65%); mp 181–184 °C.

1H NMR (400 MHz, CDCl3): δ = 8.50 (d, J = 8.0 Hz, 1 H), 8.37 (d, J = 8.0 Hz, 1 H), 8.16 (s, 1 H), 7.84–7.74 (m, 3 H), 7.56 (td, J = 8.0, 2.0 Hz, 1 H), 7.57–7.54 (m, 1 H), 2.28 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 159.88, 149.54, 148.02, 147.38, 145.44, 140.18, 134.70, 131.72, 127.71, 127.62, 127.11, 124.83, 122.22, 17.51.


#

(E)-3-(4-Styrylphenyl)quinazolin-4(3H)-one (2k)

White solid; yield: 49 mg (50%); mp 208–211 °C.

1H NMR (400 MHz, CDCl3): δ = 8.40 (dd, J = 8.0, 1.2 Hz, 1 H), 8.15 (s, 1 H), 7.84–7.77 (m, 2 H), 7.68 (d, J = 12.0 Hz, 2 H), 7.58–7.54 (m, 3 H), 7.43–7.37 (m, 4 H), 7.31–7.28 (m, 1 H), 7.17 (d, J = 2.4 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 160.77, 147.84, 145.97, 138.32, 136.79, 136.37, 134.59, 130.53, 128.75, 128.10, 127.67, 127.59, 127.47, 127.18, 126.69, 122.36.

HRMS (ESI+): m/z [M + H]+ calcd for [C22H16N2O]+: 325.1341; found: 325.1330.


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3-Benzylquinazolin-4(3H)-one (2l)[36]

White solid; yield: 43 mg (60%); mp 135–138 °C.

1H NMR (400 MHz, CDCl3): δ = 8.34 (dd, J = 8.0, 1.6 Hz, 1 H), 8.11 (s, 1 H), 7.78–7.70 (m, 2 H), 7.51 (td, J = 8.0, 1.2 Hz, 1 H), 7.36–7.29 (m, 5 H), 5.21 (s, 2 H).

13C NMR (100 MHz, CDCl3): δ = 161.08, 148.01, 146.32, 135.70, 134.31, 129.02, 128.31, 127.99, 127.51, 127.38, 126.89, 122.19, 49.60.


#

3-[2-(1H-Indol-3-yl)ethyl)]quinazolin-4(3H)-one (2m)[22]

White solid; yield: 26 mg (30%); mp 161–164 °C.

1H NMR (400 MHz, CDCl3): δ = 8.36 (dd, J = 8.0, 1.6 Hz, 1 H), 8.05 (s, 1 H), 7.76–7.72 (m, 1 H), 7.65 (t, J = 8.0 Hz, 2 H), 7.52 (td, J = 8.0, 1.6 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.22 (td, J = 8.0, 1.2 Hz, 1 H), 7.15–7.11 (m, 1 H), 6.88 (d, J = 4.0 Hz, 1 H), 4.30 (t, J = 8.0 Hz, 2 H), 3.27 (t, J = 8.0 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 161.11, 148.18, 146.71, 136.46, 134.11, 127.37, 127.01, 126.83, 126.65, 122.72, 122.41, 122.13, 119.79, 118.38, 111.48, 111.38, 47.53, 24.94.


#

3-(2-Hydroxyethyl)quinazolin-4(3H)-one (2n)[39]

White solid; yield: 39 mg (68%); mp 153–156 °C.

1H NMR (400 MHz, CDCl3): δ = 8.12 (dd, J = 8.0, 1.6 Hz, 1 H), 8.05 (s, 1 H), 7.68 (td, J = 8.0, 1.6 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 7.42–7.38 (m, 1 H), 6.84 (s, 1 H), 4.12 (t, J = 4.0 Hz, 2 H), 3.99 (t, J = 4.0 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 161.39, 147.67, 147.39, 134.31, 127.24, 127.02, 126.46, 121.70, 60.42, 49.65.


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3-(Furan-2-ylmethyl)quinazolin-4(3H)-one (2o)[40]

White solid; yield: 31 mg (46%); mp 136–139 °C.

1H NMR (400 MHz, CDCl3): δ = 8.31 (dd, J = 8.0, 0.8 Hz, 1 H), 8.17 (s, 1 H), 7.77–7.69 (m, 2 H), 7.52–7.48 (m, 1 H), 7.38–7.37 (m, 1 H), 6.47 (d, J = 4.0 Hz, 1 H), 6.35–6.34 (m, 1 H), 5.18 (s, 2 H).

13C NMR (100 MHz, CDCl3): δ = 160.69, 148.41, 147.99, 145.99, 143.17, 134.32, 127.52, 127.34, 126.82, 122.14, 110.77, 109.96, 42.09.


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3-(Thiophen-2-ylmethyl)quinazolin-4(3H)-one (2p)[38]

White solid; yield: 36 mg (50%); mp 120–123 °C.

1H NMR (400 MHz, CDCl3): δ = 8.33 (dd, J = 8.0, 1.2 Hz, 1 H), 8.13 (s, 1 H), 7.77–7.68 (m, 2 H), 7.52–7.48 (m, 1 H), 7.27–7.26 (m, 1 H), 7.15 (d, J = 4.0 Hz, 1 H), 6.97 (m, 1 H), 5.34 (s, 2 H).

13C NMR (100 MHz, CDCl3): δ = 161.36, 150.67, 138.25, 135.21, 129.03, 128.54, 126.45, 125.84, 123.02, 113.54, 39.34, 30.76.


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3-Butylquinazolin-4(3H)-one (2q)[39]

White solid; yield: 34 mg (56%); mp 70–73 °C.

1H NMR (400 MHz, CDCl3): δ = 8.31 (dd, J = 8.0, 1.2 Hz, 1 H), 8.02 (s, 1 H), 7.77–7.69 (m, 2 H), 7.52–7.48 (m, 1 H), 4.0 (t, J = 8.0 Hz, 2 H), 1.82–1.74 (m, 2 H), 1.46–1.37 (m, 2 H), 0.97 (t, J = 8.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 160.06, 148.10, 146.56, 134.10, 127.20, 127.69, 122.18, 46.79, 31.41, 19.87, 13.61.


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3-Dodecylquinazolin-4(3H)-one (2r)

White solid; yield: 45 mg (52%); mp 64–67 °C.

1H NMR (400 MHz, CDCl3): δ = 8.32 (dd, J = 8.0, 1.2 Hz, 1 H), 8.02 (s, 1 H), 7.77–7.69 (m, 2 H), 7.50 (td, J = 8.0, 1.2 Hz, 1 H), 4.00 (t, J = 8.0 Hz, 2 H), 1.80 (m, 2 H), 1.32–1.25 (m, 18 H), 0.87 (t, J = 8.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 161.05, 148.15, 146.58, 134.09, 127.40, 127.18, 126.69, 122.21, 47.09, 31.88, 29.56, 29.51, 29.43, 29.38, 29.30, 29.17, 26.67, 22.65, 14.09.

HRMS (ESI+): m/z [M + H]+ calcd for [C19H28N2O]+: 301.2280; found: 301.2271.


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3-Isopropylquinazolin-4(3H)-one (2s)[41]

White solid; yield: 34 mg (61%); mp 87–90 °C.

1H NMR (400 MHz, CDCl3): δ = 8.30 (d, J = 8.0 Hz, 1 H), 8.11 (s, 1 H), 7.75–7.68 (m, 2 H), 7.48 (td, J = 8.0, 1.2 Hz, 1 H), 5.19 (m, 1 H), 1.48 (d, J = 8.0 Hz, 6 H).

13C NMR (100 MHz, CDCl3): δ = 160.69, 147.56, 143.56, 134.11, 127.27, 127.15, 126.88, 121.96, 46.03, 21.99.


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3-Cyclohexylquinazolin-4(3H)-one (2t)[36]

White solid; yield: 34 mg (50%); mp 120–123 °C.

1H NMR (400 MHz, CDCl3): δ = 8.32 (dd, J = 8.0, 0.8 Hz, 1 H), 8.13 (s, 1 H), 7.77–7.69 (m, 2 H), 7.52–7.47 (m, 1 H), 4.82 (tt, J = 12.0, 3.6 Hz, 1 H), 2.03–1.93 (m, 4 H), 1.81–1.78 (m, 1 H), 1.65 (qd, J = 12.0, 3.2 Hz, 2 H), 1.58–1.51 (m, 2 H), 1.27–1.21 (m, 1 H).

13C NMR (100 MHz, CDCl3): δ = 160.70, 147.47, 143.91, 134.10, 127.22, 127.10, 126.97, 121.95, 53.40, 32.61, 25.90, 25.28.


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3-Ethylquinazolin-4(3H)-one (2u)[42]

White solid; yield: 32 mg (61%); mp 82–85 °C.

1H NMR (400 MHz, CDCl3): δ = 8.32 (dd, J = 8.0, 1.6 Hz, 1 H), 8.05 (s, 1 H), 7.77–7.66 (m, 2 H), 7.52–7.48 (m, 1 H), 4.07 (q, J = 8.0 Hz, 2 H), 1.43 (m, 3 H).

13C NMR (100 MHz, CDCl3): δ = 160.92, 148.15, 146.25, 134.11, 127.38, 127.22, 126.65, 122.15, 42.09, 14.86.


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3-Allylquinazolin-4(3H)-one (2v)[43]

White solid; yield: 32 mg (58%); mp 70–73 °C.

1H NMR (400 MHz, CDCl3): δ = 8.3 (d, J = 8.0 Hz, 1 H), 8.02 (s, 1 H), 7.76–7.69 (m, 2 H), 7.49 (t, J = 8.0 Hz, 1 H), 6.03–5.93 (m, 1 H), 5.31–5.23 (m, 2 H), 4.63 (dd, J = 8.0, 1.6 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 160.71, 148.00, 146.18, 134.24, 131.20, 127.41, 127.30, 126.75, 126.47, 118.84, 48.30.


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3-(1-Methoxypropan-2-yl)quinazolin-4(3H)-one (2w)

Brown liquid; yield: 37 mg (56%).

1H NMR (400 MHz, CDCl3): δ = 8.31 (dd, J = 8.0, 1,2 Hz, 1 H), 8.05 (s, 1 H), 7.78–7.70 (m, 2 H), 7.51 (td, J = 8.0, 1.6 Hz, 1 H), 3.59–3.47 (m, 1 H), 3.35 (s, 3 H), 2.10–2.04 (m, 2 H), 1.62 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 161.18, 148.19, 147.06, 134.16, 127.43, 127.19, 126.61, 122.18, 68.67, 58.68, 44.34, 28.56.

HRMS (ESI+): m/z [M + H]+ calcd for [C12H14N2O2]+: 219.1133; found: 219.1122.


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1-Methyl-2-phenyl-1,2-dihydro-3H-indazol-3-one (4a)[44]

White solid; yield: 47 mg (70%); mp 89–92 °C.

1H NMR (400 MHz, CDCl3): δ = 7.94 (dd, J = 8.0, 0.8 Hz, 1 H), 7.64–7.60 (m, 3 H), 7.52–7.47 (m, 2 H), 7.32–7.24 (m, 3 H), 3.16 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 162.12, 151.72, 135.07, 132.74, 129.07, 129.23, 124.46, 123.59, 122.99, 118.98, 112.39, 39.61.


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1-Methyl-2-(p-tolyl)-1,2-dihydro-3H-indazol-3-one (4b)[44]

White solid; yield: 59 mg (83%); mp 90–93 °C.

1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.0 Hz, 1 H), 7.64–7.60 (m, 1 H), 7.50–7.48 (m, 2 H), 7.32–7.28 (m, 3 H), 7.26–7.24 (m, 1 H), 3.16 (s, 3 H), 2.41 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 161.97, 151.51, 136.24, 132.52, 132.46, 129.66, 124.38, 123.77, 122.81, 119.04, 112.28, 39.39, 20.98.


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2-(4-Methoxyphenyl)-1-methyl-1,2-dihydro-3H-indazol-3-one (4c)[44]

White solid; yield: 69 mg (90%); mp 110–113 °C.

1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.0 Hz, 1 H), 7.64–7.60 (m, 1 H), 7.51–7.47 (m, 2 H), 7.30–7.24 (m, 2 H), 7.06–7.02 (m, 2 H), 3.87 (s, 3 H), 3.14 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 162.07, 158.28, 151.34, 132.46, 127.91, 125.83, 124.43, 122.82, 119.03, 114.48, 112.20, 55.52, 39.21.


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2-(4-Chlorophenyl)-1-methyl-1,2-dihydro-3H-indazol-3-one (4d)

White solid; yield: 47 mg (60%); mp 136–139 °C.

1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 8.0 Hz, 1 H), 7.66–7.62 (m, 1 H), 7.59–7.55 (m, 2 H), 7.49–7.45 (m, 2 H), 7.32–7.26 (m, 2 H), 3.15 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 162.24, 152.02, 133.81, 133.04, 131.61, 129.23, 124.55, 124.46, 123.27, 118.91, 112.55, 39.89.

HRMS (ESI+): m/z [M + H]+ calcd for [C14H11ClN2O]+: 259.0638; found: 259.0627.


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2-(4-Fluorophenyl)-1-methyl-1,2-dihydro-3H-indazol-3-one (4e)

White solid; yield: 51 mg (70%); mp 108–111 °C.

1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 8.0 Hz, 1 H), 7.62–7.58 (m, 1 H), 7.57–7.52 (m, 2 H), 7.28–7.22 (m, 2 H), 7.20–7.14 (m, 2 H), 3.12 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 162.30 (d, J C,F = 245.00 Hz), 162.41, 162.18, 159.73, 151.90, 133.01, 131.30 (d, J C,F = 3.2 Hz), 125.60 (d, J C,F = 9.0 Hz), 125.55, 124.63, 123.27, 119.00, 116.15 (d, J C,F = 23.0 Hz), 112.56, 39.71.

HRMS (ESI+): m/z [M + H]+ calcd for [C14H11FN2O]+: 243.0933; found: 243.0922.


#

1-Methyl-2-(thiophen-2-ylmethyl)-1,2-dihydro-3H-indazol-3-one (4f)

White solid; yield: 22 mg (30%); mp 209–212 °C.

1H NMR (400 MHz, CDCl3): δ = 8.24 (dd, J = 8.0, 2.0 Hz, 1 H), 7.68–7.64 (m, 1 H), 7.27–7.23 (m, 3 H), 7.20–7.16 (m, 1 H), 6.93–6.91 (m, 1 H), 5.42 (s, 2 H), 3.60 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 140.48, 138.25, 135.21, 129.03, 128.54, 126.45, 125.84, 123.02, 115.54, 113.54, 39.34, 30.76.

HRMS (ESI+): m/z [M + H]+ calcd for [C13H12N2OS]+: 245.0748; found: 245.0739.


#

2-Butyl-1-methyl-1,2-dihydro-3H-indazol-3-one (4g)

White solid; yield: 12 mg (20%); mp 84–87 °C.

1H NMR (400 MHz, CDCl3): δ = 8.25 (dd, J = 8.0, 1.2 Hz, 1 H), 7.70 (td, J = 8.0, 1.2 Hz, 1 H), 7.30–7.28 (m, 1 H), 7.22 (d, J = 8.0 Hz, 1 H), 4.12 (t, J = 8.0 Hz, 2 H), 3.63 (s, 3 H), 1.48–1.39 (m, 2 H), 1.31–1.26 (m, 2 H), 1.00–0.97 (m, 3 H).

13C NMR (100 MHz, CDCl3): δ = 161.74, 140.49, 134.93, 128.90, 122.84, 115.62, 113.42, 41.80, 30.65, 29.94, 20.24, 13.80.

HRMS (ESI+): m/z [M + H]+ calcd for [C12H16N2O]+: 205.1341; found: 205.1332.


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1-Benzyl-2-(4-methoxyphenyl)-1,2-dihydro-3H-indazol-3-one (4h)[45]

White solid; yield: 71 mg (71%); mp 149–152 °C.

1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 8.0 Hz, 1 H), 7.56–7.53 (m, 1 H), 7.49–7.46 (m, 2 H), 7.28–7.26 (m, 2 H), 7.22–7.14 (m, 4 H), 7.03 (d, J = 8.0 Hz, 2 H), 6.5 (d, J = 12.0 Hz, 2 H), 4.73 (s, 2 H), 3.86 (t, J = 4.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 162.33, 158.21, 149.53, 133.54, 132.14, 128.43, 128.25, 128.15, 127.85, 125.93, 124.38, 122.64, 119.52, 114.46, 112.88, 55.45, 54.30.


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Biographical Sketches

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Karthick Govindan was born in 1996 in Chennai, Tamilnadu, India. He did his B.Sc. in chemistry in 2016 from Thiruvalluvar University, followed by M.Sc. in general chemistry from Bharathidasan University in 2018. After graduation, he moved to Kaohsiung Medical University (KMU) in Taiwan as an intern under Prof. Wei-Yu Lin. Since 2020, he is continuing his Ph.D. studies under the same professor in organic synthesis, particularly, C–N, C–C, C–O bond reactions by twisted amides and other catalytic developments.

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Tamilselvan Duraisamy was born in Tamilnadu, India in 1998. He completed his Bachelor’s studies at Periyar University in 2018. In 2020, he did his Master’s studies in chemistry at Bharathidasan University, India. Since 2021 he started his Ph.D. studies at Kaohsiung Medical University, Taiwan under the guidance of Prof. Wei-Yu-Lin. His research focuses on the organic synthesis.

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Alageswaran Jayaram was born in India in 1998. He obtained his B.Sc. at Vivekananda college (India) and M.Sc. at Bharathidasan University (India). This was followed by a Master’s thesis at the same university in 2020 and he started his Ph.D. studies at Kaohsiung Medical University (Taiwan) under the guidance of Prof. Wei-Yu-Lin. His research interests lie in the organic synthesis and new reaction methodologies.

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Prof. Gopal Chandru Senadi completed his B.Sc. in Chemistry from the University of Madras and M.Sc. in applied chemistry from Anna University, Chennai, India. After serving for 4.4 years as a synthetic organic chemist in industries, he joined the research group of Prof. Jeh-Jeng Wang at Kaohsiung Medical University, Kaohsiung, Taiwan and obtained his Ph.D. degree in chemistry in 2015. Later, he continued as a postdoctoral fellow in the same group. In September 2018, he returned back to India as an Assistant Professor at SRM Institute of Science and Technology, Kattankulathur, Chengalpattu Dist., Tamil Nadu, India. His current research interest is focused on renewable synthons and photoredox catalysis for the synthesis of heterocycles and functional group transformations.

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Professor Wei-Yu Lin received his B.S. degree from Cheng-Kung University (1998) and his Ph.D. degree from National Taiwan University with Professor T.-Y. Luh (2006). He conducted his postdoctoral studies with Professor H.-R. Tseng and Prof. C. K.-F Shen at the University of California, Los Angeles before he joined Kaohsiung Medical University as an Assistant Professor (2011). Prof. Lin’s current research interests include synthetic organic chemistry, flow microreactor for organic­ synthesis, and biortho­gonal chemistry

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors gratefully acknowledge the Centre for Research Resources and Development of Kaohsiung Medical University for Mass and 400 MHz NMR analyses.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1667-3977.
  • Supporting Information

Corresponding Author

Wei-Yu Lin
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University
Kaohsiung 80708
Taiwan, ROC   

Publication History

Received: 13 July 2021

Accepted after revision: 12 October 2021

Accepted Manuscript online:
12 October 2021

Article published online:
17 November 2021

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Figure 1 Selected examples of biologically important compounds containing quinazolinone and indazolone structures
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Scheme 1Strategies for the syntheses of quinazolinones and indazolones
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Scheme 2Substrate scope of quinazolinones. Reagents and conditions: The reactions were performed with 1a–w (0.3 mmol) in DMF (3 mL) at 130 °C for 24 h under O2. Isolated yields are shown. For 2b and 2m, the yield in parentheses is based on recovered starting material.
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Scheme 3Substrate scope of indazolones. Reagents and conditions: The reactions were performed with 3a–h (0.3 mmol) in DMF (3 mL) at 130 °C for 24 h under O2. Isolated yields are shown.
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Scheme 4Control reactions
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Scheme 5Proposed mechanisms toward 2a and 4a
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Scheme 6Gram-scale syntheses of 2a and 4b under the standard conditions