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Article

Four-Component Synthesis of 9H-Pyrimido[4,5-b]indoles Using Ammonium Iodide as the Nitrogen Source

by
Yufeng Chen
1,
Ruitong Yang
1,
Fuhong Xiao
1,*,
Tong Li
1,
Guojiang Mao
2 and
Guo-Jun Deng
1,*
1
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, Hunan Province Key Laboratory of Green Organic Synthesis and Application, College of Chemistry, Xiangtan University, Xiangtan 411105, China
2
School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
*
Authors to whom correspondence should be addressed.
Catalysts 2023, 13(3), 623; https://doi.org/10.3390/catal13030623
Submission received: 20 February 2023 / Revised: 17 March 2023 / Accepted: 18 March 2023 / Published: 20 March 2023
(This article belongs to the Special Issue Catalytic Annulation Reactions)
Browse Figures
Versions Notes

Abstract

:
A four-component synthesis of 2-phenyl-9H-pyrimido[4,5-b]indoles was developed using indole-3-carboxaldehydes, aromatic aldehyde and ammonium iodide as the raw materials under transition-metal-free conditions. The pyrimidine ring was formed in one pot through [4 + 2] annulation reaction. Four C–N bonds were formed in one pot promoted by iodine and iodide additives. This work is highlighted by using two ammonium iodides as the sole nitrogen source.

1. Introduction

As an important part of nitrogen-containing heterocycles, pyrimidines are widespread in natural products and pharmaceuticals [1,2,3]. Among them, the 9H-pyrimido[4,5-b]indole motif has important application in many fields, such as anti-inflammatory, antimicrobial, antimalarial agents and cytotoxic inhibitors [4,5,6]. Furthermore, the core structure of 9H-pyrimido[4,5-b]indoles was found in many biologically active molecules, such as HSCex vivo expansion agent, pyruvate dehydrogenase kinases (PDHKs) inhibitors, epidermal growth factor receptor (EGFr) tyrosine kinase inhibitors, and endogenous hormones (Figure 1) [7,8,9,10,11]. Therefore, significant research effort has been focused on the synthesis of 9H-pyrimido[4,5-b]indole derivatives. According to the reported methods, the synthesis of 9H-pyrimido[4,5-b]indoles usually started with highly functionalized materials [12,13,14,15]. For example, 4-azido-5-phenylpyrimidine, 1,3,5-triazines, benzamidine, guanidine nitrate and o-nitrobiphenyl were successfully used as the starting materials for the synthesis of target products [16,17,18,19]. Furthermore, most reactions often use stoichiometric amount of strong acids or bases which do not meet the requirement of green chemistry. For example, Shkurko and co-workers developed a multi-step synthesis of 2-phenyl-9H-pyrimido[4,5-b]indole from indolin-2-one using sodium ethylate prepared from sodium as the base [20]. Therefore, efficient and green synthetic methods for constructing 9H-pyrimido[4,5-b]indole derivatives in one pot are highly desirable.
In the last decades, the multi-component reactions (MCRs) have played an increasingly dominant role in the organic synthesis of wide and diverse compounds which provides atom economy, and featured productivity and easy execution [21,22,23,24,25,26,27,28,29]. MCRs usually start with simple and commercially available materials as the reaction substrates thus providing a shortcut for the synthesis of functional molecules. Meanwhile, ammonium salts are ideal nitrogen sources for the synthesis of nitrogen-containing heterocycles due to their low cost and ease of handling [30,31,32,33,34,35,36]. In 2009, Konakahara and coworkers developed a ZnCl2-catalyzed three-component coupling reaction for the synthesis of 4,5-disubstituted pyrimidines from ammonium acetate, enamines and triethyl orthoformate (Scheme 1a) [37]. In recent years, our group also developed several MCRs for the synthesis of nitrogen-containing heterocycles using ammonium salts as the nitrogen source [38,39,40]. For example, in 2018, we reported a four-component procedure for the synthesis of quinazoline using anilines, aromatic aldehydes and ammonium iodide as starting materials (Scheme 1b) [41]. In 2020, we developed a base-promoted aerobic oxidation approach for the synthesis of benzimidazo[1,2-a]-1,3,5-triazines involving 2-aminobenzimidazoles, aromatic aldehydes and ammonium iodide [42]. However, in most cases, ammonium salts only provided a single nitrogen atom source in these multi-component reactions. When two nitrogen atom rings were formed, another organic nitrogen source such as amines is usually required. In 2019, Chen’s group demonstrated a three-component reaction of ammonium acetate, chalcone and phenyl-methanol using copper (II) as the catalyst providing tri-substituted pyrimidines in moderate yields (Scheme 1c) [43]. In this process, both nitrogen atoms in the pyrimidine ring come from the ammonium acetate. However, for the synthesis of N-heterocycles containing multiple nitrogen atoms which are easy to form a stable complex with the transition metals but encounter difficulties in removing the toxic transition metals, it is particularly important to perform the reaction without the aid of transition-metal catalysts. In the pursuit of research on heterocycle construction using ammonium salts as the nitrogen source under transition-metal-free conditions, herein we describe a general four-component reaction for the synthesis of 2-phenyl-9H-pyrimido[4,5-b]indole from indole-3-carboxaldehydes, aromatic aldehydes and ammonium salt (Scheme 1d). In this reaction, both nitrogen atoms in the pyrimidine ring come from ammonium salt and four C–N bonds were formed in one pot in the absence of a transition metal catalyst.

2. Results

In order to explore the optimized reaction conditions, our study was initiated by using indole-3-carboxaldehyde (1a), benzaldehyde (2a) and ammonium iodide as model substrates and 20 mol% of iodine as the catalyst under oxygen atmosphere (Table 1). To begin with, potassium iodide was used as an additive to the reaction, affording the target product 3aa in 45% yield (entry 1). Then, various iodide-containing additives were screened to find the appropriate promotor, among which NaIO4 is the best candidate reagent to provide the product 3aa in 76% yield (entries 2–5). Moderate yields were obtained when reactions were carried out in PhCl, toluene, mesitylene and PhCF3 (entries 6–9). DMF, CH3CN, NMP and pyridine as the reaction media completely quenched the reaction (entries 10–13). Furthermore, oxidants screening among others showed that DMSO was superior to others such as H2O2, tert-butyl hydroperoxide (TBHP), di-tert-butyl peroxide (DTBP), K2S2O8, and Na2S2O8 (entries 14–18). Diminished yield was obtained when the reaction was performed without I2 (entry 19). Lower yield was obtained when the reaction was carried out in air atmosphere (entry 20). Finally, no desired product was detected when using NH4Cl instead of NH4I as nitrogen source for this kind of transformation (entry 21). We believed that iodine, periodate and oxygen were used as the oxidant. The iodine anion could be oxidized to iodine, which could further promote the oxidative aromatization process.
With the optimal conditions established, the substrate scope of indole-3-carboxaldehydes was explored (Scheme 2). As depicted, various substitutes of indole-3-carboxaldehyde could participate in current reaction regardless of the electronic nature of substituents incorporated on the C4, C5, C6, C7 positions. The model reaction provided product 3aa in 73% isolated yield. N-methylindole-3-carbaldehyde could also be used as the substrate to give product 3ba in 66% isolated yield. To our surprise, 4-chloro-1H-indole-3-carbaldehyde was the best effective substrate that the corresponding product 3ca was obtained in 96% yield, whereas 4-bromo substituent indole-3-carbaldehyde afforded 3da in 71% yield. Moreover, when fluoro, chloro and methyl substituents were located at C5, C6 and C7 positions, the counterparts were obtained in moderate to good yields (3ea, 3fa, 3ga, 3ia, 3la and 3ma). Similarly, bromo substituent at C5 and C6 positions led to lower isolated yields (3ha and 3ja). It was regrettable that 6-methoxy-1H-indole-3-carbaldehyde only provided product 3ka in 23% yield. Further study revealed that 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde was also a viable substrate for this kind of reaction, leading to the corresponding product 3na in 59% yield. Unfortunately, sulfur containing heterocyclic aldehyde such as benzo[b]thiophene-3-carbaldehyde was ineffective for this type of cyclization process.
Additional experiments revealed that the current protocol for 2-aryl-9H-pyrimido[4,5-b]indole synthesis was very effective and efficient, and various aromatic aldehydes derived from 2a could also react well with indole-3-carboxaldehyde 1a (Scheme 3). Electron-donating and electron-withdrawing groups decorated on the aryl ring were well tolerated, regardless of the position. A series of para-substituted benzaldehydes smoothly reacted with indole-3-carboxaldehyde 1a to give the desired products in moderate to good yields (3ab–3al). It should be noted that other substrates with electron-withdrawing groups at the 4-position on the phenyl ring such as trifluoromethyl, trifluoromethoxy and cyano performed well in the reaction, affording target products 3ai–3ak in good yields. Halogen substituents located at the para, meta and ortho positions were able to smoothly involve the reaction (3af–3ah, 3ap–3ar, 3at and 3au). The steric effect of the reaction is unintelligible. For example, when chloro substituent was located at the para, meta and ortho positions, the corresponding products 3ag, 3aq and 3au were obtained in 71%, 56% and 43% yields, respectively. However, the use of meta-methoxybenzaldehyde could afford product 3an in 91% yield. Benzaldehyde with two functional groups could also react with 1a and ammonium iodide, affording tricyclic N-heterocyclic products 3aw and 3ax in 47% and 64% yields, respectively. Moreover, the tolerance of chloro and bromo groups has offered a convenient handle for further transition-metal catalyzed cross-coupling reactions. Analogously, 2-naphthaldehyde was suitable for this cyclization reaction, providing product 3av in 70% yield. Although picolinaldehyde was not appropriate substrate, thiophene-2-carbaldehyde and thiophene-3-carbaldehyde were also well tolerated under this reaction condition. No desired products were observed when alkyl- or cycloalkyl aldehydes reacted with 1a.
Based on the above research and some related literatures [44,45], a plausible reaction pathway is depicted in Scheme 4. Nucleophilic addition of indole-3-carboxaldehyde with ammonium iodide generates animine intermediate A. Meanwhile, the nucleophilic addition of benzaldehyde with another ammonium iodide affords an imine intermediate B. The [4+2] annulations reaction of A and B formed an intermediate C. Oxidative dehydrogenation of the intermediate C in the presence of iodine/DMSO affords the final product 2-phenyl-9H-pyrimido[4,5-b]indole 3aa.

3. Discussion

In summary, we have developed a four-component strategy which can provide an efficient approach to various substituted pyrimido[4,5-b]indoles from commercially available indole-3-carboxaldehyde, aromatic aldehydes and ammonium iodide under simple reaction conditions. The C–H bond on the C2 position of indole was directly functionalized and used for a further cyclization process under metal-free conditions. Ammonium iodide was involved in this reaction and was used as two nitrogen sources for the pyrimidine ring construction. The reaction showed good functional group tolerance and wide substrate scope. This four-component mixture could be selectively assembled into the target products in one pot without the use of transition-metal catalyst.

4. Materials and Methods

4.1. General Information

All reactions were carried out under an atmosphere of oxygen unless otherwise noted. Column chromatography was performed using silica gel (200–300 mesh) or neutral alumina. 1H NMR and 13C NMR spectra were recorded on Bruker-AV (400 and 100 MHz, respectively, Hangzhou, China) instrument internally referenced to tetramethylsilane (TMS) and using chloroform-d (CDCl3) and dimethyl sulphoxide-d6 (DMSO-d6) as solvent. The obtained spectra can be found in Supplementary Materials. Mass spectra were measured on Agilent 5975 GC-MS instrument (EI) from Agilent Technologies Co., Ltd. (Beijing, China). High-resolution mass spectra (ESI) were obtained with the Thermo Scientific LTQ Orbitrap XL mass spectrometer from Thermo Fisher Scientific (Shanghai, China). Melting points were measured with a YUHUA X-5 melting point instrument from Gongyi Yuhua Instrument Co., Ltd. (Gongyi, China) and were uncorrected. The structures of known compounds were further corroborated by comparing their 1H NMR, 13C NMR data and MS data with those of literature. All reagents were obtained from commercial suppliers and used without further purification unless otherwise noted.

4.2. General Procedure for the Synthesis of 2-Phenyl-9H-pyrimido[4,5-b]indole Derivatives

It was added to an oven-dried reaction vessel with a stir bar including indole-3-carboxaldehyde (0.2 mmol), benzaldehyde (0.4 mmol) and ammonium iodide (0.6 mmol), NaIO4 (0.2 mmol), DMSO (0.4 mmol), I2 (0.04 mmol), and 1,2-dichlorobenzene (0.6 mL). The reaction vessel was purged with oxygen for three times and then stirred at 150 °C for 16 h. After cooling to room temperature, the volatiles were removed under reduced pressure. The residue was purified by column chromatography on neutral alumina to give the desired product 3aa in 73% yield.
Characterization of products are below:
2-Phenyl-9H-pyrimido[4,5-b]indole (3aa, CAS: 1904604-60-9)
Yellow solid (37.3 mg, yield 76%, petroleum ether/ethyl acetate = 15:1), m.p. 295–297 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.53 (s, 1H), 8.51 (d, J = 6.1 Hz, 2H), 8.24 (d, J = 7.8 Hz, 1H), 7.60–7.48 (m, 5H), 7.33 (t, J = 7.3 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 160.1, 156.5, 149.4, 139.5, 138.7, 130.7, 129.1, 128.2, 128.0, 122.1, 121.5, 119.5, 112.8, 112.3.
9-Methyl-2-phenyl-9H-pyrimido[4,5-b]indole (3ba):
Yellow solid (34.2 mg, yield 66%, petroleum ether/ethyl acetate = 15:1), m.p. 190–192 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.56 (d, J = 5.9 Hz, 2H), 8.22 (d, J = 7.8 Hz, 1H), 7.71–7.48 (m, 5H), 7.36 (t, J = 7.5 Hz, 1H), 3.93 (s, 3H). 13C NMR (101 MHz, DMSO) δ 160.0, 155.6, 149.1, 140.6, 138.5, 130.8, 129.0, 128.3, 128.0, 122.0, 121.8, 119.0, 112.5, 110.7, 27.9. HRMS (ESI): m/z calcd. for C17H14N3 [M + H]+ 260.1182, found 260.1185.
5-Chloro-2-phenyl-9H-pyrimido[4,5-b]indole (3ca):
Yellow solid (53.7 mg, yield 96%, petroleum ether/ethyl acetate = 15:1), m.p. 320–322 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 9.57 (s, 1H), 8.50 (d, J = 7.1 Hz, 2H), 7.56–7.46 (m, 5H), 7.36 (d, J = 6.4 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 160.6, 156.5, 150.3, 140.6, 138.3, 131.0, 129.1, 129.0, 128.4, 128.3, 121.6, 117.5, 111.8, 111.3. HRMS (ESI): m/z calcd. for C16H11ClN3 [M + H]+ 280.0636, found 280.0632.
5-Bromo-2-phenyl-9H-pyrimido[4,5-b]indole (3da):
Yellow solid (55.0 mg, yield 71%, petroleum ether/ethyl acetate = 15:1), m.p. 274–276 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 9.74 (s, 1H), 8.55–8.47 (m, 2H), 7.63–7.43 (m, 6H). 13C NMR (101 MHz, DMSO) δ 160.7, 156.5, 149.9, 140.6, 138.3, 131.0, 129.2, 129.1, 128.4, 124.8, 119.3, 116.6, 112.5, 111.7. HRMS (ESI): m/z calcd. for C16H11BrN3 [M + H]+ 324.0131, found 324.0160.
6-Methyl-2-phenyl-9H-pyrimido[4,5-b]indole (3ea):
Yellow solid (36.8 mg, yield 71%, petroleum ether/ethyl acetate = 15:1), m.p. 359–361 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 9.47 (s, 1H), 8.51 (d, J = 6.4 Hz, 2H), 8.02 (s, 1H), 7.58–7.43 (m, 4H), 7.38–7.31 (m, 1H), 2.47 (s, 3H). 13C NMR (101 MHz, DMSO) δ 160.0, 156.6, 149.2, 138.8, 137.6, 130.6, 130.4, 129.3, 129.0, 128.2, 121.8, 119.6, 112.7, 112.0, 21.5. HRMS (ESI): m/z calcd. for C17H14N3 [M + H]+ 260.1182, found 260.1181.
6-Fluoro-2-phenyl-9H-pyrimido[4,5-b]indole (3fa):
Yellow solid (30.0 mg, yield 57%, petroleum ether/ethyl acetate = 15:1), m.p. 317–319 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.54 (s, 1H), 8.51 (d, J = 7.1 Hz, 2H), 8.10 (d, J = 8.1 Hz, 1H), 7.60–7.50 (m, 4H), 7.38 (t, J = 8.0 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 160.6, 158.0 (d, J = 235.0 Hz), 157.1, 150.3, 138.6, 135.9, 130.8, 129.1, 128.3, 120.2 (d, J = 10.5 Hz), 115.8 (d, J = 25.6 Hz), 113.5 (d, J = 9.2 Hz), 112.7 (d, J = 4.5 Hz), 108.0 (d, J = 24.9 Hz). 19F NMR (376 MHz, DMSO) δ −121.9. HRMS (ESI): m/z calcd. for C16H11FN3 [M + H]+ 264.0932, found 264.0929.
6-Chloro-2-phenyl-9H-pyrimido[4,5-b]indole (3ga):
Yellow solid (45.7 mg, yield 82%, petroleum ether/ethyl acetate = 15:1), m.p. 290–292 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 9.58 (s, 1H), 8.51 (d, J = 7.9 Hz, 2H), 8.38 (s, 1H), 7.61–7.49 (m, 5H). 13C NMR (101 MHz, DMSO) δ 160.8, 156.9, 150.4, 138.5, 138.0, 130.9, 129.1, 128.3, 127.9, 125.8, 121.8, 120.9, 113.9, 112.2. HRMS (ESI): m/z calcd. for C16H11ClN3 [M + H]+ 280.0636, found 280.0632.
6-Bromo-2-phenyl-9H-pyrimido[4,5-b]indole (3ha):
Yellow solid (25.9 mg, yield 40%, petroleum ether/ethyl acetate = 15:1), m.p. 292–294 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 9.59 (s, 1H), 8.55–8.48 (m, 3H), 7.67 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 6.9 Hz, 4H). 13C NMR (101 MHz, DMSO) δ 160.8, 156.7, 150.5, 138.5, 138.2, 130.9, 130.5, 129.1, 128.3, 124.8, 121.5, 114.3, 113.6, 112.0. HRMS (ESI): m/z calcd. for C16H11BrN3 [M + H]+ 324.0131, found 324.0155.
7-Fluoro-2-phenyl-9H-pyrimido[4,5-b]indole (3ia):
Yellow solid (37.9 mg, yield 72%, petroleum ether/ethyl acetate = 15:1), m.p. 286–288 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.52 (s, 1H), 8.50 (d, J = 6.4 Hz, 2H), 8.27 (dd, J = 8.6, 5.5 Hz, 1H), 7.59–7.48 (m, 3H), 7.34 (d, J = 7.3 Hz, 1H), 7.19 (t, J = 9.2 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 162.4 (d, J = 242.0 Hz), 159.9, 157.2, 149.3, 140.4 (d, J = 12.5 Hz), 138.5, 130.7, 129.1, 128.2, 123.8 (d, J = 10.6 Hz), 116.2, 112.5, 109.6 (d, J = 24.2 Hz), 99.1 (d, J = 26.7 Hz). HRMS (ESI): m/z calcd. for C16H11FN3 [M + H]+ 264.0932, found 264.0930.
7-Bromo-2-phenyl-9H-pyrimido[4,5-b]indole (3ja):
Yellow solid (27.6 mg, yield 43%, petroleum ether/ethyl acetate = 15:1), m.p. 291–293 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 9.57 (s, 1H), 8.50 (d, J = 8.1 Hz, 2H), 8.21 (d, J = 8.3 Hz, 1H), 7.72 (s, 1H), 7.57–7.46 (m, 4H). 13C NMR (101 MHz, DMSO) δ 160.6, 156.8, 150.0, 140.4, 138.5, 130.9, 129.1, 128.3, 124.4, 123.9, 120.7, 118.7, 115.0, 112.3. HRMS (ESI): m/z calcd. for C16H11BrN3 [M + H]+ 324.0131, found 324.0160.
7-Methoxy-2-phenyl-9H-pyrimido[4,5-b]indole (3ka):
Yellow solid (12.4 mg, yield 23%, petroleum ether/ethyl acetate = 10:1), m.p. 244–246 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.39 (s, 1H), 8.49 (d, J = 6.5 Hz, 2H), 8.10 (d, J = 8.6 Hz, 1H), 7.57–7.46 (m, 3H), 7.05–6.90 (m, 1H), 3.87 (s, 3H). 13C NMR (101 MHz, DMSO) δ 160.2, 158.9, 156.8, 147.9, 141.1, 138.8, 130.4, 129.0, 128.0, 123.0, 113.1, 112.8, 110.5, 95.9, 55.9. HRMS (ESI): m/z calcd. for C17H14N3O [M + H]+ 276.1131, found 276.1137.
8-Chloro-2-phenyl-9H-pyrimido[4,5-b]indole (3la):
Yellow solid (42.9 mg, yield 77%, petroleum ether/ethyl acetate = 15:1), m.p. 247–249 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 9.57 (s, 1H), 8.51 (d, J = 7.1 Hz, 2H), 8.20 (d, J = 7.7 Hz, 1H), 7.61–7.50 (m, 4H), 7.31 (t, J = 7.8 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 160.9, 156.9, 150.4, 138.5, 136.7, 130.9, 129.1, 128.3, 127.4, 122.5, 121.6, 120.8, 116.8, 112.9. HRMS (ESI): m/z calcd. for C16H11ClN3 [M + H]+ 280.0636, found 280.0632.
8-Methyl-2-phenyl-9H-pyrimido[4,5-b]indole (3ma):
Yellow solid (36.8 mg, yield 71%, petroleum ether/ethyl acetate = 15:1), m.p. 189–191 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 9.49 (s, 1H), 8.52 (d, J = 7.4 Hz, 2H), 8.02 (d, J = 7.7 Hz, 1H), 7.53 (q, J = 9.8, 8.5 Hz, 3H), 7.30 (d, J = 7.3 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 2.56 (s, 3H). 13C NMR (101 MHz, DMSO) δ 160.0, 156.7, 149.4, 138.8, 138.8, 130.6, 129.1, 128.6, 128.2, 121.9, 121.6, 119.3, 119.2, 113.2, 17.5. HRMS (ESI): m/z calcd. for C17H14N3 [M + H]+ 260.1182, found 260.1181.
2-Phenyl-9H-pyrido[3’,2’:4,5]pyrrolo[2,3-d]pyrimidine (3na):
Yellow solid (29.0 mg, yield 59%, petroleum ether/ethyl acetate = 10:1), 1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 9.57 (s, 1H), 8.63 (d, J = 7.7 Hz, 1H), 8.57–8.48 (m, 3H), 7.59–7.50 (m, 3H), 7.39 (dd, J = 7.8, 4.9 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 160.8, 156.3, 152.0, 150.6, 148.3, 138.4, 131.0, 130.6, 129.1, 128.3, 117.9, 112.8, 111.3. HRMS (ESI): m/z calcd. for C15H11N4 [M + H]+ 247.0978, found 247.0972.
2-(p-Tolyl)-9H-pyrimido[4,5-b]indole (3ab):
Yellow solid (39.4 mg, yield 76%, petroleum ether/ethyl acetate = 15:1), m.p. 277–279 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 9.49 (s, 1H), 8.40 (d, J = 7.9 Hz, 2H), 8.22 (d, J = 7.8 Hz, 1H), 7.61–7.45 (m, 2H), 7.36–7.27 (m, 3H), 2.38 (s, 3H). 13C NMR (101 MHz, DMSO) δ 160.3, 156.6, 149.4, 140.3, 139.4, 136.1, 129.7, 128.2, 127.9, 122.0, 121.4, 119.6, 112.6, 112.3, 21.5. HRMS (ESI): m/z calcd. for C17H14N3 [M + H]+ 260.1182, found 260.1181.
2-(4-(tert-Butyl)phenyl)-9H-pyrimido[4,5-b]indole (3ac):
Yellow solid (47.6 mg, yield 79%, petroleum ether/ethyl acetate = 15:1), m.p. 171–173 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 9.50 (s, 1H), 8.43 (d, J = 8.5 Hz, 2H), 8.22 (d, J = 7.6 Hz, 1H), 7.58–7.49 (m, 4H), 7.36–7.28 (m, 1H), 1.33 (s, 9H). 13C NMR (101 MHz, DMSO) δ 160.2, 156.6, 153.4, 149.3, 139.4, 136.0, 128.1, 128.0, 125.9, 122.0, 121.4, 119.5, 112.6, 112.3, 35.0, 31.5. HRMS (ESI): m/z calcd. for C20H20N3 [M + H]+ 302.1652, found 302.1635.
2-(4-Methoxyphenyl)-9H-pyrimido[4,5-b]indole (3ad):
White solid (40.7 mg, yield 74%, petroleum ether/ethyl acetate = 10:1), m.p. 256–258 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.47 (s, 1H), 8.45 (d, J = 8.9 Hz, 2H), 8.21 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.54–7.46 (m, 1H), 7.35–7.26 (m, 1H), 7.08 (d, J = 8.9 Hz, 2H), 3.84 (s, 3H). 13C NMR (101 MHz, DMSO) δ 161.5, 160.2, 156.6, 149.4, 139.3, 131.3, 129.8, 127.8, 121.8, 121.4, 119.6, 114.4, 112.3, 112.2, 55.8. HRMS (ESI): m/z calcd. for C17H14N3O [M + H]+ 276.1131, found 276.1133.
2-(4-Ethoxyphenyl)-9H-pyrimido[4,5-b]indole (3ae):
Yellow solid (49.1 mg, yield 85%, petroleum ether/ethyl acetate = 10:1), m.p. 244–246 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.46 (s, 1H), 8.44 (d, J = 8.9 Hz, 2H), 8.20 (d, J = 7.8 Hz, 1H), 7.58–7.47 (m, 2H), 7.34–7.26 (m, 1H), 7.05 (d, J = 8.9 Hz, 2H), 4.09 (q, J = 6.9 Hz, 2H), 1.35 (t, J= 6.9 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 160.8, 160.2, 156.6, 149.4, 139.3, 131.1, 129.8, 127.8, 121.8, 121.4, 119.6, 114.8, 112.2, 112.2, 63.7, 15.1. HRMS (ESI): m/z calcd. for C18H16N3O [M + H]+ 290.1288, found 290.1289.
2-(4-Fluorophenyl)-9H-pyrimido[4,5-b]indole (3af):
Yellow solid (38.9 mg, yield 74%, petroleum ether/ethyl acetate = 15:1), m.p. 247–249 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 9.51 (s, 1H), 8.58–8.50 (m, 2H), 8.23 (d, J = 7.8 Hz, 1H), 7.60–7.48 (m, 2H), 7.40–7.28 (m, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.1 (d, J = 247.4 Hz), 159.2, 156.5, 149.4, 139.4, 135.2 (d, J = 2.9 Hz), 130.5 (d, J = 8.6 Hz), 128.1, 122.1, 121.5, 119.5, 116.0 (d, J = 21.6 Hz), 112.7, 112.3. 19F NMR (376 MHz, DMSO) δ −111.5. HRMS (ESI): m/z calcd. for C16H11FN3 [M + H]+ 264.0932, found 264.0929.
2-(4-Chlorophenyl)-9H-pyrimido[4,5-b]indole (3ag):
Yellow solid (39.7 mg, yield 71%, petroleum ether/ethyl acetate = 15:1), m.p. 288–290 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 9.53 (s, 1H), 8.50 (d, J= 8.6 Hz, 2H), 8.24 (d, J = 7.8 Hz, 1H), 7.63–7.51 (m, 4H), 7.36–7.31 (m, 1H). 13C NMR (101 MHz, DMSO) δ 159.1, 156.4, 149.4, 139.5, 137.6, 135.5, 129.9, 129.2, 128.2, 122.1, 121.6, 119.4, 113.0, 112.4. HRMS (ESI): m/z calcd. for C16H11ClN3 [M + H]+ 280.0636, found 280.0632.
2-(4-Bromophenyl)-9H-pyrimido[4,5-b]indole (3ah):
Yellow solid (42.8 mg, yield 66%, petroleum ether/ethyl acetate = 15:1), m.p. 284–286 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 9.52 (s, 1H), 8.43 (d, J = 8.6 Hz, 2H), 8.24 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 8.6 Hz, 2H), 7.61–7.50 (m, 2H), 7.38–7.29 (m, 1H). 13C NMR (101 MHz, DMSO) δ 159.2, 156.4, 149.4, 139.5, 137.9, 132.1, 130.2, 128.2, 124.4, 122.2, 121.6, 119.4, 113.0, 112.4. HRMS (ESI): m/z calcd. for C16H11BrN3 [M + H]+ 324.0131, found 324.0160.
2-(4-(Trifluoromethyl)phenyl)-9H-pyrimido[4,5-b]indole (3ai):
Yellow solid (48.3 mg, yield 78%, petroleum ether/ethyl acetate = 10:1), m.p. 290–292 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.58 (s, 1H), 8.69 (d, J = 8.1 Hz, 2H), 8.27 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.63–7.51 (m, 2H), 7.39–7.31 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 158.6, 156.4, 149.5, 142.5, 139.7, 130.5 (q, J = 31.6 Hz), 128.8, 126.0 (q, J = 4.0 Hz), 124.8 (q, J = 272.1 Hz), 122.3, 121.7, 119.3, 113.4, 112.4. 19F NMR (376 MHz, DMSO) δ −61.1. HRMS (ESI): m/z calcd. for C17H11F3N3 [M + H]+ 314.0900, found 314.0930.
2-(4-(Trifluoromethyl)phenyl)-9H-pyrimido[4,5-b]indole (3aj):
Yellow solid (37.6 mg, yield 60%, petroleum ether/ethyl acetate = 10:1), m.p. 285–287 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.52 (s, 1H), 8.59 (d, J = 8.9 Hz, 2H), 8.24 (d, J= 7.8 Hz, 1H), 7.59–7.48 (m, 4H), 7.37–7.29 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 158.8, 156.4, 150.3, 149.4, 139.5, 137.8, 130.2, 128.2, 122.2, 121.6, 121.4, 120.6 (q, J = 256.8 Hz), 119.4, 113.0, 112.4.19F NMR (376 MHz, CDCl3) δ −51.9. HRMS (ESI): m/z calcd. for C17H11F3N3O [M + H]+ 330.0849, found 330.0876.
4-(9H-Pyrimido[4,5-b]indol-2-yl)benzonitrile (3ak):
Yellow solid (27.0 mg, yield 50%, petroleum ether/ethyl acetate = 10:1), m.p. 298–300 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.56 (s, 1H), 8.62 (d, J = 8.2 Hz, 2H), 8.25 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.62–7.51 (m, 2H), 7.38–7.30 (m, 1H). 13C NMR (101 MHz, DMSO) δ 158.2, 156.3, 149.4, 142.8, 139.7, 133.1, 128.7, 128.5, 122.3, 121.7, 119.3, 119.3, 113.5, 112.8, 112.4. HRMS (ESI): m/z calcd. for C17H11N4 [M + H]+ 271.0978, found 271.0976.
2-([1,1′-Biphenyl]-4-yl)-9H-pyrimido[4,5-b]indole (3al):
Yellow solid (36.6 mg, yield 57%, petroleum ether/ethyl acetate = 15:1), m.p. 298–300 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 9.55 (s, 1H), 8.60 (d, J = 8.4 Hz, 2H), 8.25 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 7.2 Hz, 2H), 7.60–7.47 (m, 4H), 7.41 (t, J = 7.4 Hz, 1H), 7.34 (t, J = 7.1 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 159.9, 156.5, 149.5, 142.1, 140.0, 139.5, 137.8, 129.5, 128.8, 128.3, 128.1, 127.3, 127.2, 122.1, 121.5, 119.5, 112.8, 112.3. HRMS (ESI): m/z calcd. for C22H16N3 [M + H]+ 322.1339, found 322.1325.
2-(m-Tolyl)-9H-pyrimido[4,5-b]indole (3am):
Yellow solid (39.4 mg, yield 76%, petroleum ether/ethyl acetate = 15:1), m.p. 247–249 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.51 (s, 1H), 8.34 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 7.60–7.48 (m, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.36–7.28 (m, 2H), 2.42 (s, 3H). 13C NMR (101 MHz, DMSO) δ 160.3, 156.5, 149.3, 139.4, 138.6, 138.1, 131.3, 129.0, 128.8, 128.0, 125.5, 122.0, 121.5, 119.5, 112.8, 112.3, 21.6. HRMS (ESI): m/z calcd. for C17H14N3 [M + H]+ 260.1182, found 260.1185.
2-(3-Methoxyphenyl)-9H-pyrimido[4,5-b]indole (3an):
Yellow solid (50.0 mg, yield 91%, petroleum ether/ethyl acetate = 10:1), m.p. 265–267 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.51 (s, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.06 (s, 1H), 7.60–7.49 (m, 2H), 7.45 (t, J = 7.9 Hz, 1H), 7.33 (t, J = 7.3 Hz, 1H), 7.13–7.04 (m, 1H), 3.87 (s, 3H). 13C NMR (101 MHz, DMSO) δ 160.0, 159.9, 156.5, 149.3, 140.2, 139.5, 130.1, 128.1, 122.1, 121.5, 120.7, 119.5, 116.7, 113.0, 112.9, 112.3, 55.6. HRMS (ESI): m/z calcd. for C17H14N3O [M + H]+ 276.1131, found 276.1137.
2-(3-(Trifluoromethoxy)phenyl)-9H-pyrimido[4,5-b]indole (3ao):
Yellow solid (46.7 mg, yield 71%, petroleum ether/ethyl acetate = 10:1), m.p. 280–282 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.56 (s, 1H), 8.53 (d, J = 7.8 Hz, 1H), 8.39 (s, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.61–7.48 (m, 3H), 7.35 (t, J = 7.2 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 158.4, 156.4, 149.5, 149.3, 141.1, 139.6, 131.3, 128.4, 127.1, 123.1, 122.2, 121.6, 120.7 (q, J = 256.4 Hz), 119.9, 119.4, 113.4, 112.4. 19F NMR (376 MHz, DMSO) δ −56.6. HRMS (ESI): m/z calcd. for C17H11F3N3O [M + H]+ 330.0849, found 330.0844.
2-(3-Fluorophenyl)-9H-pyrimido[4,5-b]indole (3ap):
Yellow solid (36.3 mg, yield 69%, petroleum ether/ethyl acetate = 15:1), m.p. 210–212 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 9.54 (s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.22–8.15 (m, 1H), 7.64–7.49 (m, 3H), 7.39–7.29 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 163.01 (d, J = 242.5 Hz),158.77 (d, J = 3.3 Hz), 156.32, 149.39, 141.32 (d, J = 7.8 Hz), 139.64, 131.15 (d, J = 8.3 Hz), 128.25, 124.20 (d, J = 2.6 Hz), 122.18, 121.56, 119.36, 117.41 (d, J = 21.1 Hz), 114.47 (d, J = 23.1 Hz), 113.20, 112.47. HRMS (ESI): m/z calcd. for C16H11FN3 [M + H]+ 264.0932, found 264.0930.
2-(3-Chlorophenyl)-9H-pyrimido[4,5-b]indole (3aq):
Yellow solid (31.3 mg, yield 56%, petroleum ether/ethyl acetate = 15:1), m.p. 201–203 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.55 (s, 1H), 8.48 (s, 1H), 8.47–8.42 (m, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.63–7.50 (m, 4H), 7.38–7.30 (m, 1H). 13C NMR (101 MHz, DMSO) δ 158.6, 156.4, 149.4, 140.8, 139.6, 134.0, 131.1, 130.4, 128.3, 127.8, 126.7, 122.2, 121.6, 119.4, 113.3, 112.4. HRMS (ESI): m/z calcd. for C16H11ClN3 [M + H]+ 280.0636, found 280.0632.
2-(3-Bromophenyl)-9H-pyrimido[4,5-b]indole (3ar):
Yellow solid (38.9 mg, yield 60%, petroleum ether/ethyl acetate = 15:1), m.p. 213–215 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 9.54 (s, 1H), 8.63 (s, 1H), 8.49 (d, J = 7.8 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.58–7.47 (m, 2H), 7.33 (t, J = 7.5 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 158.4, 156.3, 149.4, 141.0, 139.6, 133.2, 131.4, 130.7, 128.3, 127.1, 122.5, 122.2, 121.6, 119.4, 113.2, 112.5. HRMS (ESI): m/z calcd. for C16H11BrN3 [M + H]+ 324.0131, found 324.0160.
2-(o-Tolyl)-9H-pyrimido[4,5-b]indole (3as):
Yellow solid (28.5 mg, yield 55%, petroleum ether/ethyl acetate = 15:1), m.p. 235–237 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.73 (s, 1H), 8.36 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.71–7.61 (m, 2H), 7.52–7.37 (m, 4H), 2.53 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 156.2, 140.2, 137.5, 131.7, 131.0, 130.7, 129.5, 126.5, 122.9, 122.8, 119.4, 113.1, 112.4, 20.8. HRMS (ESI): m/z calcd. for C17H14N3 [M + H]+ 260.1182, found 260.1181.
2-(2-Fluorophenyl)-9H-pyrimido[4,5-b]indole (3at):
Yellow solid (30.0 mg, yield 57%, petroleum ether/ethyl acetate = 15:1), m.p. 271–273 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 9.57 (s, 1H), 8.27 (d, J = 7.8 Hz, 1H), 8.11 (t, J = 7.9 Hz, 1H), 7.61–7.49 (m, 3H), 7.40–7.31 (m, 3H). 13C NMR (101 MHz, DMSO-d6) δ 162.1, 159.6, 158.7 (d, J = 4.3 Hz), 149.3, 139.4, 132.5 (d, J = 2.1 Hz), 131.9 (d, J = 8.5 Hz), 128.3, 127.7 (d, J = 9.7 Hz), 124.8 (d, J = 3.7 Hz), 122.3, 121.5, 119.2, 117.2 (d, J = 22.3 Hz), 112.6, 112.4. 19F NMR (376 MHz, DMSO) δ −114.4. HRMS (ESI): m/z calcd. for C16H11FN3 [M + H]+ 264.0932, found 264.0929.
2-(2-Chlorophenyl)-9H-pyrimido[4,5-b]indole (3au):
Yellow solid (30.0 mg, yield 43%, petroleum ether/ethyl acetate = 15:1), m.p. 261–263 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.57 (s, 1H), 8.28 (d, J = 7.5 Hz, 1H), 7.82–7.76 (m, 1H), 7.63–7.45 (m, 5H), 7.37 (t, J = 6.1 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 161.0, 155.9, 149.1, 139.4, 139.2, 132.4, 132.1, 130.7, 130.6, 128.3, 127.5, 122.3, 121.6, 119.2, 112.6, 112.4. HRMS (ESI): m/z calcd. for C16H11ClN3 [M + H]+ 280.0636, found 280.0632.
2-(Naphthalen-2-yl)-9H-pyrimido[4,5-b]indole (3av):
Yellow solid (41.2 mg, yield 70%, petroleum ether/ethyl acetate = 15:1), m.p. 304–306 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.56 (s, 1H), 9.06 (s, 1H), 8.63 (d, J = 8.6 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.12–8.07 (m, 1H), 8.05 (d, J = 8.7 Hz, 1H), 8.00–7.94 (m, 1H), 7.62–7.51 (m, 4H), 7.33 (t, J = 6.9 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 160.1, 156.6, 149.4, 139.5, 136.1, 134.4, 133.4, 129.4, 128.5, 128.1, 128.1, 127.6, 127.0, 125.5, 122.1, 121.6, 119.5, 112.9, 112.4. HRMS (ESI): m/z calcd. for C20H14N3 [M + H]+ 296.1182, found 296.1170.
2-(2,4-Dichlorophenyl)-9H-pyrimido[4,5-b]indole (3aw):
Yellow solid (29.5 mg, yield 47%, petroleum ether/ethyl acetate = 15:1), m.p. 212–214 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.58 (s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.63–7.55 (m, 3H), 7.37 (t, J = 6.4 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 160.0, 155.8, 149.1, 139.5, 138.0, 134.5, 133.8, 133.2, 130.1, 128.5, 127.8, 122.4, 121.7, 119.1, 112.8, 112.4. HRMS (ESI): m/z calcd. for C16H10Cl2N3 [M + H]+ 314.0246, found 314.0273.
2-(3,4-Dimethylphenyl)-9H-pyrimido[4,5-b]indole (3ax):
Yellow solid (35.0 mg, yield 64%, petroleum ether/ethyl acetate = 15:1), m.p. 299–301 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 9.49 (s, 1H), 8.30 (s, 1H), 8.22 (d, J = 7.9 Hz, 2H), 7.58–7.47 (m, 2H), 7.35–7.25 (m, 2H), 2.34 (s, 3H), 2.30 (s, 3H). 13C NMR (101 MHz, DMSO) δ 160.4, 156.6, 149.3, 139.4, 139.1, 136.7, 136.4, 130.2, 129.3, 127.9, 125.8, 121.9, 121.4, 119.6, 112.5, 112.3, 20.1, 19.9. HRMS (ESI): m/z calcd. for C18H16N3 [M + H]+ 274.1339, found 274.1338.
2-(Thiophen-3-yl)-9H-pyrimido[4,5-b]indole (3ay):
Yellow solid (22.6 mg, yield 45%, petroleum ether/ethyl acetate = 15:1), m.p. 283–285 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 9.46 (s, 1H), 8.39 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 5.0 Hz, 1H), 7.70–7.63 (m, 1H), 7.58–7.47 (m, 2H), 7.32 (t, J = 6.4 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 157.8, 156.4, 149.5, 142.7, 139.3, 127.9, 127.7, 127.7, 127.4, 121.9, 121.5, 119.6, 112.4, 112.3. HRMS (ESI): m/z calcd. for C14H10N3S [M + H]+ 252.0590, found 252.0588.
2-(Thiophen-2-yl)-9H-pyrimido[4,5-b]indole (3az):
Yellow solid (13.6 mg, yield 27%, petroleum ether/ethyl acetate = 15:1), m.p. 272–274 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 9.42 (s, 1H), 8.21 (d, J = 7.8 Hz, 1H), 8.02–7.96 (m, 1H), 7.73 (d, J = 4.1 Hz, 1H), 7.57–7.47 (m, 2H), 7.36–7.28 (m, 1H), 7.25–7.18 (m, 1H). 13C NMR (101 MHz, DMSO) δ 157.2, 156.2, 149.4, 144.7, 139.3, 130.3, 128.9, 128.4, 128.0, 121.9, 121.6, 119.6, 112.5, 112.3. HRMS (ESI): m/z calcd. for C14H10N3S [M + H]+ 252.0590, found 252.0588.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal13030623/s1, 1H NMR, 13C NMR and 19F NMR spectra of products 3aa–3az.

Author Contributions

Conceptualization, Y.C., F.X. and G.-J.D.; Methodology, Y.C.; data curation, Y.C., R.Y. and T.L.; validation, Y.C., R.Y., F.X., T.L. and G.-J.D.; investigation, Y.C.; writing—original draft preparation, Y.C.; writing—review and editing, Y.C., F.X. and G.-J.D.; supervision, F.X. and G.-J.D.; funding acquisition, G.M. and G.-J.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (22271244, 21871226), the Undergraduate Investigated Study and Innovated Experiment Plan from Ministry of Education of China and Hunan Province, and the Open Research Fund of School of Chemistry and Chemical Engineering, Henan Normal University (2022C02).

Data Availability Statement

The authors declare that the raw data supporting the findings and conclusions of this research are available from the corresponding author upon request.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 13 00623 g001 550
Figure 1. Representative biologically active 9H-pyrimido[4,5-b]indoles ((a) [7], (b) [9], (c) [8], (d) [11]).
Figure 1. Representative biologically active 9H-pyrimido[4,5-b]indoles ((a) [7], (b) [9], (c) [8], (d) [11]).
Catalysts 13 00623 g001
Catalysts 13 00623 sch001 550
Scheme 1. N-heterocycles synthesis through ammonium salts ((a) [37], (b) [41], (c) [43], (d) this work).
Scheme 1. N-heterocycles synthesis through ammonium salts ((a) [37], (b) [41], (c) [43], (d) this work).
Catalysts 13 00623 sch001
Catalysts 13 00623 sch002 550
Scheme 2. Scope of indole-3-carboxaldehydes.
Scheme 2. Scope of indole-3-carboxaldehydes.
Catalysts 13 00623 sch002
Catalysts 13 00623 sch003 550
Scheme 3. Scope of aromatic aldehydes.
Scheme 3. Scope of aromatic aldehydes.
Catalysts 13 00623 sch003
Catalysts 13 00623 sch004 550
Scheme 4. Plausible reaction pathway.
Scheme 4. Plausible reaction pathway.
Catalysts 13 00623 sch004
Table
Table 1. Optimization of the reaction conditions 1.
Table 1. Optimization of the reaction conditions 1.
Catalysts 13 00623 i001
EntryAdditiveOxidantSolventYield (%) 2
1KIDMSOo-DCB45
2KIO3DMSOo-DCB68
3NaIO4DMSOo-DCB76
4I2O5DMSOo-DCBtrace
5NISDMSOo-DCBtrace
6NaIO4DMSOPhCl65
7NaIO4DMSOtoluene53
8NaIO4DMSOmesitylene 40
9NaIO4DMSOPhCF339
10NaIO4DMSODMFtrace
11NaIO4DMSOCH3CNtrace
12NaIO4DMSONMPtrace
13NaIO4DMSOPyridinetrace
14NaIO4H2O2o-DCB38
15NaIO4TBHPo-DCB35
16NaIO4DTBPo-DCB30
17NaIO4K2S2O8o-DCBtrace
18NaIO4Na2S2O8o-DCB15
19 3NaIO4DMSOo-DCB58
20 4NaIO4DMSOo-DCB63
21 5NaIO4DMSOo-DCB0
1 Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), NH4I (0.6 mmol), I2 (0.04 mmol), additive (0.2 mmol), oxidant (0.4 mmol), solvent (0.6 mL), 150 °C, 16 h, oxygen. 2 GC yield based on 1a. 3 Without I2. 4 Under air. 5 With NH4Cl (0.6 mmol) instead of NH4I.
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MDPI and ACS Style

Chen, Y.; Yang, R.; Xiao, F.; Li, T.; Mao, G.; Deng, G.-J. Four-Component Synthesis of 9H-Pyrimido[4,5-b]indoles Using Ammonium Iodide as the Nitrogen Source. Catalysts 2023, 13, 623. https://doi.org/10.3390/catal13030623

AMA Style

Chen Y, Yang R, Xiao F, Li T, Mao G, Deng G-J. Four-Component Synthesis of 9H-Pyrimido[4,5-b]indoles Using Ammonium Iodide as the Nitrogen Source. Catalysts. 2023; 13(3):623. https://doi.org/10.3390/catal13030623

Chicago/Turabian Style

Chen, Yufeng, Ruitong Yang, Fuhong Xiao, Tong Li, Guojiang Mao, and Guo-Jun Deng. 2023. "Four-Component Synthesis of 9H-Pyrimido[4,5-b]indoles Using Ammonium Iodide as the Nitrogen Source" Catalysts 13, no. 3: 623. https://doi.org/10.3390/catal13030623

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