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New efficient synthesis of polysubstituted 3,4-dihydroquinazolines and 4H-3,1-benzothiazines through a Passerini/Staudinger/aza-Wittig/addition/nucleophilic substitution sequence

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Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Hubei International Scientific and Technological Cooperation Base of Pesticide and Green Synthesis, Central China Normal University, Wuhan, 430079, P. R. China
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Associate Editor: D. Spring
Beilstein J. Org. Chem. 2022, 18, 286–292. https://doi.org/10.3762/bjoc.18.32
Received 05 Jan 2022, Accepted 24 Feb 2022, Published 04 Mar 2022
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Abstract

A new efficient synthesis of polysubstituted 3,4-dihydroquinazolines and 4H-3,1-benzothiazines via sequential Passerini/Staudinger/aza-Wittig/addition/nucleophilic substitution reaction has been developed. The three-component Passerini reactions of 2-azidobenzaldehydes 1, benzoic acid (2), and isocyanides 3 produced the azide intermediates 4, which were treated sequentially with triphenylphosphine, isocyanates (or CS2), and secondary amines to give polysubstituted 3,4-dihydroquinazolines 8 and 4H-3,1-benzothiazines 11 in good overall yields through consecutive Passerini/Staudinger/aza-Wittig/addition/nucleophilic substitution reactions.

Keywords: aza-Wittig reaction; 3,4-dihydroquinazoline; 4H-3,1-benzothiazine; nucleophilic substitution; Passerini reaction; Staudinger reaction

Introduction

The chemistry of 3,4-dihydroquinazolines and 4H-3,1-benzothiazines is of constant interest owing to the occurrence of these ring systems in various biologically important compounds (Figure 1). A number of 3,4-dihydroquinazolines were found to show remarkable anticancer [1], antiviral [2], antidepressant [3], antifungal [4], selective somatostatin 2 (ss2) agonistical [5], β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) inhibitive [6], and cholinesterase enzyme inhibitive activities [7]. The 3,4-dihydroquinazoline skeleton also exists in some natural products such as vasicine and vasicoline [8]. Some 4H-3,1-benzothiazine derivatives have also received attention due to their good biological activities, including anticancer [9], neuroprotective [10], antiproliferative and antifungal activities [11]. Due to the significant bioactive properties of the 3,4-dihydroquinazoline and 4H-3,1-benzothiazine moieties, many preparation procedures have appeared in the literature for the synthesis of their derivatives [12-22]. For example (Scheme 1), a one-pot Tf2O-mediated assembly of amides, amines, and ketones provided 3,4-dihydroquinazolines in good yields via successive triflic anhydride-mediated amide dehydration, ketimine addition, and Pictet–Spengler-like cyclization processes [12]. Some 4-substituted 3,4-dihydroquinazolines were prepared by copper-catalyzed oxidative cross coupling of hydroxy intermediates with various nucleophiles [13]. Other 3,4-dihydroquinazolines were also obtained efficiently by intramolecular aza-Wittig reactions [14]. Some 4H-3,1-benzothiazines were prepared by intramolecular thia-Michael addition with broad reaction scopes [19]. The rearrangement of 2-isothiocyano triarylmethanes in the presence of AlCl3 were also used for the synthesis 2,4-diaryl-4H-3,1-benzothiazines through aromatic ring transfer [20]. A facile protocol towards the synthesis of 4H-3,1-benzothiazines was established by using a P(NMe2)3-mediated C–N/C–S bond formation reaction of 2-aminobenzyl alcohol with isothiocyanates under aerobic conditions [21]. Despite of the above achievements, the development of new efficient methods for the synthesis of polysubstituted 3,4-dihydroquinazolines and 4H-3,1-benzothiazines under mild reaction conditions is still of high demand in the discovery of biologically active compounds.

[1860-5397-18-32-1]

Figure 1: Some bioactive 3,4-dihydroquinazolines and 4H-3,1-benzothiazines.

[1860-5397-18-32-i1]

Scheme 1: Representative preperation of 3,4-dihydroquinazolines and 4H-3,1-benzothiazines.

The Passerini reaction is an isocyanide-based multicomponent reaction, which has been used in preparing various α-acyloxy adducts starting from aldehydes, a carboxylic acid, and a isonitrile as the three components [23]. The sequences of Passerini reactions, followed by post-condensation reactions, constitute useful synthetic methods in the preparation of structurally diverse heterocyclic compounds [24-29]. The aza-Wittig reaction has also been utilized widely in preparation of various heterocycles under mild neutral conditions [30-32]. Recently we have reported the synthesis of 3H-2-benzoxepin-1-ones, 4H-3,1-benzoxazines and oxazoles by combination of a Passerini with an intramolecular aza-Wittig reaction [33-35]. Continuing our interest in the synthesis of N-heterocycles via the aza-Wittig reaction and multicomponent reactions [36-38], we wish to report herein a facile synthesis of polysubstituted 3,4-dihydroquinazolines and 4H-3,1-benzothiazines via sequential Passerini/Staudinger/aza-Wittig/addition/nucleophilic substitution reactions. Compared with the synthetic method to 4H-3,1-benzothiazines in Scheme 1f, we provide another new sequential synthetic route to 4H-3,1-benzothiazines, especially for N,N-disubstituted 2-amino-4H-3,1-benzothiazines.

Results and Discussion

We initially selected 2-azidobenzaldehyde (1a), benzoic acid (2a) and tert-butyl isocyanide (3a) as the reactants (Scheme 2). When a mixture of 1a, 2a, and 3a in CH2Cl2 was stirred at room temperature for 48 h, the three-component Passerini reaction was carried out smoothly and the azide 4a (R = Ph) was finally obtained in 87% yield. Compound 4a was then allowed to react with triphenylphosphine in CH2Cl2 at room temperature for 2 h to produce the iminophosphorane 5a by Staudinger reaction. Aza-Wittig reaction of 5a with phenyl isocyanate generated carbodiimide 6a, which was then treated with diethylamine to form the guanidine intermediate 7a. In the presence of K2CO3 in CH3CN at refluxing temperature, the 3,4-dihydroquinazoline 8a was finally obtained in 84% yield (Table 1, entry 1, the overall yield is 73%) by intramolecular nucleophilic substitution. The reaction conditions for the transformation of guanidine intermediate 7a into 3,4-dihydroquinazoline 8a was then optimized (Table 1). As K2CO3 in different solvents (DMF, CH2Cl2 and toluene) were used, 0–72% yields of the product 8a were obtained (Table 1, entries 2–4). Utilizing a stronger base (NaOH and EtONa) resulted in a dark solution and no product was received (entries 5 and 6) owning to side reactions under the stronger base conditions. No product 8a was obtained when NEt3 in CH3CN was used (Table 1, entry 7) probably due to the weaker basic conditions. The effect of different R groups on the reaction yield was also investigated. With R = methyl, no product 8a was obtained in the presence of K2CO3/CH3CN probably due to the lower reactivity of the -OAc leaving group. In case when R was a 4-NO2C6H4 group, 86% yield of the product 8a was obtained, however, in this case the Passerini product 4a (R = 4-NO2C6H4) was obtained only in 62% yield and the overall yield of product 8a was 53%. Therefore, the reaction conditions of entry 1 in Table 1 were optimal for the above transformation.

[1860-5397-18-32-i2]

Scheme 2: Preparation of 3,4-dihydroquinazoline 8a.

Table 1: Optimization of the reaction conditions for the preparation of compound 8a.

entry R Conditions Yield (%)
1 Ph K2CO3/CH3CN 84
2 Ph K2CO3/DMF 72
3 Ph K2CO3/CH2Cl2 0
4 Ph K2CO3/toluene 41
5 Ph NaOH/CH3CN 0
6 Ph NaOEt/EtOH 0
7 Ph NEt3/CH3CN 0
8 Me K2CO3/CH3CN 0
9 4-NO2C6H4 K2CO3/CH3CN 86

The optimal reaction conditions were then utilized for the sequential reactions of different 2-azidobenzaldehydes 1, benzoic acid (2a), isocyanides 3, isocyanates and secondary amines. Most of the reactions took place smoothly to give the corresponding 3,4-dihydroquinazolines 8 in good yields (Scheme 3 and Table 2). Various isocyanates and secondary amines can be used in the above one-pot cyclization to prepare 3,4-dihydroquinazolines 8. As indicated in Table 2, when aromatic isocyanates (Table 2, compounds 8a–l, R3 = Ph, 4-ClC6H4, 3-MeC6H4, 4-MeC6H4 and 4-CF3OC6H4) were used, good yields (69–86%) of the products were obtained, whereas moderate yields (54–57%) were obtained when the more steric secondary amines were utilized (Table 2, compound 8m and 8n, NR4R5 = N(Cy)2, N(iPr)2). In cases when aliphatic isocyanates (compounds 8o–q, R3 = n-Bu, cyclohexyl and PhCH2) were used, 65–74% yields of the products were obtained. Even as the steric tert-butyl isocyanate was applied, the 3,4-dihydroquinazoline 8r was obtained in 42% yield, but when diphenylamine was used, no product was obtained (compounds 8s, NR4R5 = NPh2).

[1860-5397-18-32-i3]

Scheme 3: Preparation of 3,4-dihydroquinazolines 8.

Table 2: Yields of 3,4-dihydroquinazolines 8.

  R1 R2 R3 NR4R5 Yielda (%)
8a H t-Bu Ph NEt2 84
8b H t-Bu 4-ClC6H4 NEt2 80
8c H t-Bu 3-MeC6H4 NEt2 76
8d H t-Bu 4-MeC6H4 NEt2 79
8e H t-Bu Ph morpholin-4-yl 72
8f H t-Bu 4-MeC6H4 NPr2 85
8g H t-Bu 4-MeC6H4 NBu2 69
8h H Cyb 4-MeC6H4 NEt2 71
8i H Cyb Ph NEt2 86
8j H Cyb 4-ClC6H4 NEt2 78
8k H Cyb 4-CF3OC6H4 NEt2 80
8l H t-Bu 4-MeC6H4 morpholin-4-yl 70
8m H t-Bu 4-MeC6H4 NCy2b 57
8n 4-Cl Cyb 4-CH3OC6H4 N(iPr)2 54
8o 4-Cl n-Bu n-Bu N(Ph)Me 65
8p 5-Me t-Bu Cyb N(CH2Ph)Me 74
8q 4-Cl Cyb PhCH2 N(CH2Ph)2 67
8r 5-Me Cyb t-Bu NEt2 42
8s H n-Bu Ph NPh2 0

aIsolated yields based on the azides 4. bCyclohexyl.

The aza-Wittig reaction of iminophosphoranes 5 with an excess of CS2 took place smoothly at 40 °C to produce isothiocyanates 9, which were allowed to react with secondary amines to generate thiourea intermediates 10. In the presence of K2CO3 in CH3CN at refluxing temperature, thioureas 10 were also successfully transformed into 4H-3,1-benzothiazines 11 via intramolecular nucleophilic substitution (Scheme 4). The results were listed in Table 3. Various secondary amines can be used in this one-pot cyclization to prepare 4H-3,1-benzothiazines 11. As indicated in Table 3, when dialkylamines including cyclic dialkylamines (Table 3, compounds 11a–k, NR4R5 = NEt2, NPr2, N(CH2Ph)Me, N(CH2Ph)2, piperidin-1-yl, morpholin-4-yl and pyrrolidin-1-yl) were used, good yields (72–84%) of the products were obtained, whereas mederate yield (48–54%) was obtained when the more steric dialkylamines were utilized (Table 3, compounds 11l and 11m, NR4R5 = N(Cy)2, N(iPr)2). In cases when phenylmethylamine (compounds 11n and 11o, NR4R5 = N(Ph)Me) was used, 51–56% yields of the products were obtained, but when diphenylamine was used, no product was obtained (compound 11p, NR4R5 = NPh2).

[1860-5397-18-32-i4]

Scheme 4: Preparation of 4H-3,1-benzothiazines 11.

Table 3: Yields of 4H-3,1-benzothiazines 11.

  R1 R2 NR4R5 Yielda (%)
11a H t-Bu NEt2 82
11b H t-Bu piperidin-1-yl 83
11c H t-Bu morpholin-4-yl 84
11d H n-Bu morpholin-4-yl 78
11e H Cyb pyrrolidin-1-yl 77
11f H Cyb N(CH2Ph)Me 79
11g 5-Me Cyb NEt2 72
11h 5-Me n-Bu piperidin-1-yl 81
11i 5-Me Cyb N(CH2Ph)2 78
11j 5-Me t-Bu NPr2 75
11k 4-Cl Cyb NEt2 83
11l 4-Cl t-Bu NCy2b 54
11m 5-Me Cyb N(iPr)2 48
11n H Cyb N(Ph)Me 56
11o 5-Me Cyb N(Ph)Me 51
11p H n-Bu NPh2 0

aIsolated yields based on the azides 4. bCyclohexyl.

Conclusion

In conclusion, we have developed a new Passerini/Staudinger/aza-Wittig/addition/nucleophilic substitution sequence for the synthesis of polysubstituted 3,4-dihydroquinazolines and 4H-3,1-benzothiazines. By this method, 3,4-dihydroquinazolines and 4H-3,1-benzothiazines were prepared in good overall yields with the advantages of mild one-pot operation conditions and easily accessible starting materials containing various common substituents.

Supporting Information

Supporting Information File 1: Experimental section and copies of NMR spectra.
Format: PDF Size: 6.4 MB Download

Funding

We gratefully acknowledge financial support of this work by the National Natural Science Foundation of China (No. 21572075) and the 111 Project B17019.

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