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Synlett 2025; 36(11): 1535-1539
DOI: 10.1055/s-0043-1773540
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Synthesis of Indolo[1,2-a]quinoxalines and 2-Arylquinazolinones by Oxidative Aromatization from Aromatic Aldehydes or Benzyl Alcohols

Jinlong Zhang  ∗
,
Zening Huang
,
Kaicheng Zuo
,
Chengyang Zhang
,
Gaoxi Jiang∗

Financial support from the Natural Science Foundation of Jiangsu Province (BK20191197) and Suzhou University of Science and Technology is gratefully acknowledged.
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Abstract

We report a simple protocol for the synthesis of heterocyclic indoloquinoxalines and 2-naphthylquinazolinones by an oxidative aromatization from aromatic aldehydes or benzyl alcohols. For aromatic aldehydes, a diphenyl hydrogen phosphate/Cu(OTf)2/t-BuOOH system delivered the products in high yields (73–93%). From benzyl alcohols, a Fe(NO3)3·9H2O/(2,2,6,6-tetramethylpiperidin-1-yl)oxyl/air system was effective, and the products were obtained in moderate to high yields (51–75%). The indolo[1,2-a]quinoxaline compounds displayed fluorescence emission bands at 501–533 nm. Moreover, intramolecular hydrogen bonding was vital for the free rotation of the aryl–aryl bond in ortho-hydroxyindolo[1,2-a]quinoxalines.


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Key words

Brønsted acid catalysis - Pictet–Spengler reaction - aromatization - axial chirality - quinoxalines

As privileged nitrogen-containing heterocycles, quinazolines and quinazolinones constitute fundamental scaffolds prevalent in bioactive natural products and therapeutic agents.[1] For example, compounds A [1c] and B [1d] have been demonstrated to have anti-HIV and antiproliferative activities, respectively, whereas luotonin A[2] has been isolated from a plant used in Chinese medicine for the treatment of rheumatism and inflammation (Figure [1]).

Zoom Image
Figure 1 Representative bioactive indoloquinoxalines and quinazolinones

Conventionally, these heterocyclic cores are synthesized through a Lewis acid-[3] [4] [5] or Brønsted acid-catalyzed[6] Pictet–Spengler reaction[7]/oxidative aromatization employing functionalized aniline derivatives such as 2-(1H-indol-1-yl)anilines or 2-aminobenzamides with carbonyl compounds under an aerobic atmosphere[8] or I2-mediated oxidative conditions.[9] Notably, recent synthetic advances have focused on substituting aldehydes with benzylic alcohols as carbonyl surrogates in oxidative coupling systems.[10] In 2012, the Watson group reported a Ru-catalyzed oxidative synthesis of quinazolines from benzyl alcohols.[11] Subsequently, catalysts based on the transition metals Ni, Cu, and Ir have been used in this transformation for the construction of various quinazolines and quinazolinones.[11] [12] However, bulky substrates such as naphthaldehyde and 1-naphthylmethanol have rarely been used to prepare extended π-conjugated quinoxaline or quinazolinone scaffolds.[13]

Here, we report a simple and practical protocol for the synthesis of indoloquinoxalines and 2-naphthylquinazolinones by oxidative aromatization from aromatic aldehydes or benzylic alcohols. The aldehyde-based route employs a tandem diphenyl hydrogen phosphate-catalyzed Pictet–Spengler cyclization/copper-mediated oxidative aromatization with t-BuOOH as the terminal oxidant, delivering the target compounds in high yields (73–93%). For the alcohol substrates, a Fe(NO3)3·9H2O/(2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO)/air system was demonstrated to be effective, giving the required products in moderate to high yields (51–75%).

Initially, 2-methoxy-1-naphthaldehyde (1a) and 2-(3-methyl-1H-indol-1-yl)aniline (2a) were selected as model substrates to optimize the reaction conditions [Table [1]; for more details, see the Supporting Information (SI), Table S1]. The diphenyl hydrogen phosphate (5.0 mol%) catalyzed Pictet­–Spengler reaction was performed in toluene at 80 °C. This was followed by an oxidative aromatization to deliver the corresponding product 3a. A series of oxidants [MnO2, PhI(OAc)2, PhI(OCOCF3)2, 3-chloroperoxybenzoic acid (CPBA), KMnO4, PCC] were used to oxidize the precursor, but only DDQ gave the desired product in an acceptable 61% yield (Table [1], entries 1–8). Fortunately, the addition of a catalytic amount of a Cu salt promoted the oxidation reaction with t-BuOOH as the oxidant, giving a higher 73% yield of 3a (entry 9). Finally, to obtain the indoloquinoxaline 3a, Cu(OTf)2 (5.0 mol%) and t-BuOOH (3.0 equiv) was shown to be the best oxidation system in toluene as a solvent at room temperature, following a first step involving the diphenyl hydrogen phosphate (5.0 mol%)-catalyzed Pictet–Spengler reaction between the aldehyde and 2a.

Table 1 Optimization of the Reaction Conditions for Aldehyde 1a a

Entry

Catalyst

Oxidant

Yield (%)

1

–

MnO2

–

2

–

PhI(OAc)2

–

3

–

PhI(OCOCF3)2

–

4

–

CPBA

–

5

–

KMnO4

trace

6

–

PCC

–

7

–

t-BuOOH

–

8

–

DDQc

61

9

Cu(OTf)2

t-BuOOH

73

a Reaction conditions: 1a (0.15 mmol), 2a (0.1 mmol), (PhO)2P(O)OH (5.0 mol%), toluene (1.0 mL), 80 °C, 4 h; then Cu(OTf)2 (5.0 mol%), oxidant (3.0 equiv), r.t., 1 h.

b Yield of the isolated product.

c DDQ (0.1 mmol, 1.0 equiv).

We then focused on the optimization of the reaction conditions employing 1-naphthylmethanol (1a′) as the starting material (Table [2]). Various oxidants were screened under both acidic and basic reaction conditions (For details of the catalyst and solvent screening, see the SI, Table S2). Under the same acidic reaction conditions in the presence of 50 mol% of (PhO)2P(O)OH as those used for aldehyde 1a, none of the desired product 3a was detected when using various oxidants [K2S2O8, di-tert-butyl peroxide (DTBP), t-BuOOH, H2O2, O2] (Table [2], entries 1–6). Fortunately, t-BuOOH as a terminal oxidant delivered the corresponding product 3a in 15% yield % under basic reaction conditions using 0.5 equivalents of KOH as an additive (entry 7). Finally, Fe(NO3)3·9H2O (10 mol%) and TEMPO (10 mol%) with KOH (0.5 equiv) was demonstrated to be the best catalytic system under an aerobic atmosphere at 100 °C (entry 11). When the reaction was scaled up from 0.1 mmol to 0.2 mmol for 2a, it afforded a similar yield of 3a (51%; entry 12).

Table 2 Optimization of the Reaction Conditions for the Benzylic Alcohol 1a′ a

Entry

Oxidant

Additive

Yieldb (%)

 1

K2S2O8

(PhO)2P(O)OH

–

 2

DTBP

(PhO)2P(O)OH

–

 3

t-BuOOH

(PhO)2P(O)OH

–

 4

H2O2

(PhO)2P(O)OH

–

 5

O2

(PhO)2P(O)OH

–

 6

air

(PhO)2P(O)OH

–

 7

t-BuOOH

KOH

15

 8

H2O2

KOH

13

 9

O2

KOH

29

10

air

KOH

25

11c

air

KOH

55

12d

air

KOH

51

a Reaction conditions: 1a′ (0.2 mmol), 2a (0. 1 mmol), Fe(NO3)3·9H2O (10 mol%), TEMPO (10 mol%), oxidant (2.0 equiv), additive (0.5 equiv), toluene (1.0 mL), 60 °C, 16 h.

b Yield of the isolated products.

c At 100 °C.

d Scaled up to 2a (0.2 mmol).

With the optimized conditions in hand, we reacted several different aldehydes with 2-(3-methyl-1H-indol-1-yl)aniline (2a) (Scheme [1]). 2-Methoxybenzaldehyde and 2,3,4-trimethoxybenzaldehyde gave the corresponding products 3b and 3c in yields of 84 and 81%, respectively, under reaction conditions A, and yields of 63 and 56% under reaction conditions B. 1-Naphthaldehyde gave product 3d in yields of 84 and 59% under conditions A and B respectively. When an axially chiral binaphthalene-based dicarbaldehyde was employed as the aldehyde substrate, the corresponding product 3e was obtained in 52% yield under conditions A.

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Scheme 1 Synthesis of indolo[1,2-a]quinoxalines under reaction conditions A and B. Reaction conditions A: 1 (0.15 mmol), 2 (0.1 mmol), (PhO)2P(O)OH (5.0 mol%), toluene (1.0 mL), 80 °C, 4 h, then Cu(OTf)2 (5.0 mol%), t-BuOOH (3.0 equiv), r.t., 1 h. B: 1′ (0.2 mmol), 2 (0.1 mmol), Fe(NO3)3·9H2O (10 mol%), TEMPO (10 mol%), KOH (0.5 equiv), toluene (1.0 mL), 100 °C, under air, 16 h. The yields of the isolated products are given. a The reaction was scaled up to 5.0 mmol (Conditions A). b Reaction scale: 1.0 mmol (Conditions B).

The synthetic utility of this process was highlighted by a 5.0 mmol-scale synthesis of 3a in 68% yield under conditions A. However, a decreased yield of 32% for 3a was obtained from a 1.0 mmol-scale synthesis under conditions B. Additionally, a diastereomeric ratio of 13.9:2.6:2.6:1 was detected for the four diastereomers (R,R,R)-3e, (R,R,S)-3e, (R,S,R)-3e, and (R,S,S)-3e, respectively, by virtue of the different activation energies between the transition states TS-1 and TS-2.[7] The large steric repulsion between the naphthyl moiety and the methyl group in the indolylaniline section in transition state TS-2 was detrimental in energy to the formation of the S-configuration in (R,S,S)-3e. Consequently, (R,R,R)-3e was obtained as the major product through the energetically favorable TS-1. The same ratio of (R,R,S)-3e and (R,S,R)-3e resulted from a similar reaction pathway involving TS-1 and TS-2. Simple demethylation of 3e by BBr3 in dichloromethane (DCM) gave compound (R)-3f in 92% yield. Interestingly, the rotational stability of the compound 3f decreased dramatically because of the free rotation of the aryl–aryl bond accelerated by the intramolecular hydrogen bond between the basic nitrogen and the acidic proton.

The photophysical properties and emissions of compounds 3a–f were measured in DCM solvent at ambient temperature under illumination from a 365 UV lamp (Table [3]). The decay lifetimes (measured by using a transient spectrometer) were a few tenths of nanoseconds, indicating a typical fluorescence feature rather than a phosphorescence decay process. All the compounds displayed emission bands at λ = 501–533 nm.

Table 3 Photophysical Properties of the Indolo[1,2-a]quinoxalinesa

Entry

Compound

λem a (nm)

τb (ns)

1

3a

501

3.91

2

3b

508

4.06

3

3c

508

4.24

4

3d

508

2.17

5

3e

533

1.28

7

(R)-3f

531

1.30

a Measured in DCM at rt under illumination from a 365 UV lamp.

b Decay lifetime of the emitter as a neat film

We next investigated the reaction scope by employing various 2-aminobenzamides (Figure [2]). Under reaction conditions A, products 3g–k were obtained exclusively in high yields (87–93%). Pleasingly, the reactions of 2,6-substituted benzaldehydes and 2-aminobenzamides proceeded smoothly giving products 3m–r in excellent yields (79–92%). In comparison, lower yields (56–75%) of products 3g–r were obtained under reaction conditions B.

Zoom Image
Figure 2 Synthesis of 2-arylquinazolinones. Reaction conditions A: 1 (0.15 mmol), 2 (0.1 mmol), (PhO)2P(O)OH (5.0 mol%), toluene (1.0 mL), 80 °C, 4 h, then Cu(OTf)2 (5.0 mol%), t-BuOOH (3.0 equiv), r.t., 1 h. Reaction conditions B: 1′ (0.2 mmol), 2 (0. 1 mmol), Fe(NO3)3·9H2O (10 mol%), TEMPO (10 mol%), KOH (0.5 equiv), toluene (1.0 mL), 100 °C, under air, 16 h. The yields of the isolated products are given.

In conclusion, we have developed a protocol for the synthesis of indoloquinoxalines and quinazolinones by an oxidative aromatization from aldehydes or benzyl alcohols.[14] The aldehyde-based route involves a Pictet–Spengler cyclization and a copper-mediated oxidative aromatization, giving high yields (73–93%). For benzyl alcohols, a Fe(NO3)3·9H2O/TEMPO/air system was demonstrated to be effective, giving moderate to high yields (51–75%). The obvious difference in the rotational stabilities of indolo[1,2-a]quinoxalines with ortho-hydroxy and methoxy groups might be used in the asymmetric construction of axial chirality by ortho-hydroxy functionalization: this is the subject of an ongoing study in our laboratory.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0043-1773540.
  • Supporting Information

Corresponding Authors

Jinlong Zhang
School of Materials Science and Engineering, Institute of Materials Science and Devices, Suzhou University of Science and Technology
Suzhou, 215009
P. R. of China   

Gaoxi Jiang
School of Materials Science and Engineering, Institute of Materials Science and Devices, Suzhou University of Science and Technology
Suzhou, 215009
P. R. of China   

Publication History

Received: 26 February 2025

Accepted after revision: 21 March 2025

Article published online:
22 April 2025

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Zoom Image
Figure 1 Representative bioactive indoloquinoxalines and quinazolinones
Zoom Image
Scheme 1 Synthesis of indolo[1,2-a]quinoxalines under reaction conditions A and B. Reaction conditions A: 1 (0.15 mmol), 2 (0.1 mmol), (PhO)2P(O)OH (5.0 mol%), toluene (1.0 mL), 80 °C, 4 h, then Cu(OTf)2 (5.0 mol%), t-BuOOH (3.0 equiv), r.t., 1 h. B: 1′ (0.2 mmol), 2 (0.1 mmol), Fe(NO3)3·9H2O (10 mol%), TEMPO (10 mol%), KOH (0.5 equiv), toluene (1.0 mL), 100 °C, under air, 16 h. The yields of the isolated products are given. a The reaction was scaled up to 5.0 mmol (Conditions A). b Reaction scale: 1.0 mmol (Conditions B).
Zoom Image
Figure 2 Synthesis of 2-arylquinazolinones. Reaction conditions A: 1 (0.15 mmol), 2 (0.1 mmol), (PhO)2P(O)OH (5.0 mol%), toluene (1.0 mL), 80 °C, 4 h, then Cu(OTf)2 (5.0 mol%), t-BuOOH (3.0 equiv), r.t., 1 h. Reaction conditions B: 1′ (0.2 mmol), 2 (0. 1 mmol), Fe(NO3)3·9H2O (10 mol%), TEMPO (10 mol%), KOH (0.5 equiv), toluene (1.0 mL), 100 °C, under air, 16 h. The yields of the isolated products are given.