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One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline

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1School of Pharmacy, Changzhou University, 1 Gehu Road, Changzhou 213164, China
2School of Chemistry and Life Sciences, Suzhou University of Science and Technology, 99 Xuefu Road, Suzhou 215009, China
3Department of Chemistry and Center for Green Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd, Boston, MA 02125, USA
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  2. ‡ Equal contributors
This article is part of the thematic issue "Multicomponent reactions IV".
Associate Editor: T. J. J. Müller
Beilstein J. Org. Chem. 2024, 20, 912–920. https://doi.org/10.3762/bjoc.20.81
Received 17 Jan 2024, Accepted 11 Apr 2024, Published 23 Apr 2024
A non-peer-reviewed version of this article has been posted as a preprint https://doi.org/10.3762/bxiv.2024.2.v1
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Abstract

A new method for the synthesis of heterocyclic systems containing tetrazole and tetrahydroisoquinoline is developed via the performance of one-pot Ugi-azide and Heck cyclization reactions. The integration of the multicomponent and post-condensation reactions in one-pot maximizes the pot-, atom-, and step-economy (PASE).

Keywords: Heck reaction; one-pot; tetrahydroisoquinoline; tetrazolo-pyrazino[2,1-a]isoquinolin-6(5H)-ones; tetrazole; Ugi-azide reaction

Introduction

Tetrazole is a privileged heterocycle existing in a range of biological and medicinally interesting compounds [1,2] with antifungal [3,4], antibacterial [5], anticancer [6,7], antiparasitic [8], and antihypertensive properties [9] including FDA approved drugs such as valsartan and cefmetazole [10,11] (Figure 1). The tetrazole ring can also be found in functional materials for photography, imaging, and military applications [12-17]. The hydroisoquinoline core, such as 1,2,3,4-tetrahydroisoquinoline and pyrazino[2,1-a]isoquinolinone, is also a privileged heterocycle which can be found in natural products and synthetic compounds with antitumor, anti-HIV, antibiotic, antifungal, antivirus, and anti-inflammatory activities [18-21]. The antischistosomal drug praziquantel (PZQ), a tetrahydroisoquinoline derivative, is a commercialized drug for the treatment of schistosomiasis [22-25]. The combination of the privileged heterocycles tetrazole and tetrahydroisoquinoline in one molecule generates new molecules which could have biological activities.

[1860-5397-20-81-1]

Figure 1: Representative bioactive tetrazole- and tetrahydroisoquinoline-containing compounds.

A standard Ugi four-component reaction (Ugi-4CR) of an aldehyde, amine, isocyanide, and a carboxylic acid produces highly diverse peptidic structures A with up to four points of substitution (Scheme 1) [26,27]. By replacing the carboxylic acid with a nucleophilic azide reagent XN3 (generally TMSN3), the Ugi-azide four-component reaction (UA-4CR) of an aldehyde, amine, isocyanide, and azide gives 1,5-disubstituted 1H-tetrazoles (1,5-DS-1H-Ts) B. The performance of post-condensation reactions of UA-4CR adducts has resulted in various 1,5-DS-1H-Ts containing heterocyclic compounds [28-32], such as bis-heterocyclic lactam-tetrazoles [33,34], 2-tetrazolylmethyl-2,3,4,9-tetrahydro-1H-β-carbolines [35], ketopiperazinetetrazoles [36], imidazotetrazolodiazepinones [37], tetracyclic tetrazolylpyridoimidazoquinolines [38], bis-heterocyclic 1,5-disubstituted tetrazoleindolizines [39] and (E)-12-tetrazolyl-5H-quinazolino[3,2-a]quinazolines [40]. Among them, the Hulme group reported a UA-4CR/post-condensation sequence to give fused imidazotetrazolodiazepinones (Scheme 2A) [37]. The Gámez-Montaño group introduced a one-pot synthesis of Ugi-azide/N-acylation/Diels–Alder/dehydration reactions for isoindolin-1-one and 1,5-DS-T in a linked manner (Scheme 2B) [41]. The Ding group developed sequential Ugi-azide/Ag-catalyzed oxidative cycloisomerization reactions for the synthesis of 2-tetrazolyl-substituted 3-acylpyrroles (Scheme 2C) [42]. The Ding group also reported sequential Ugi-azide/Staudinger/aza-Wittig/addition/Ag-catalyzed cyclization reactions for obtaining 12-tetrazolyl-substituted (E)-5H-quinazolino[3,2-a]quinazolines (Scheme 2D) [40].

[1860-5397-20-81-i1]

Scheme 1: The Ugi and Ugi-azide reactions.

[1860-5397-20-81-i2]

Scheme 2: Ugi-azide and post-condensation reactions for the synthesis of various heterocyclic scaffolds.

There are numbers of Ugi and subsequential Heck (or reductive Heck) reactions that have been developed for the synthesis of poly-heterocyclic compounds [43-51]. Reported in this paper is a one-pot Ugi-azide reaction followed by an intramolecular Heck reaction for the synthesis of tetrazolyl-1,2,3,4-tetrahydroisoquinoline scaffolds 6 and 8 (Scheme 3). The first step is the Ugi-azide reaction of a 2-bromobenzoaldehyde 1, allylamine hydrochloride (2), azidotrimethylsilane (TMSN3, 3), and an isocyanide 4 affording tetrazoles 5. If ethyl isocyanoacetate is used as the isocyanide source, the Ugi-azide reaction gives rise to ring-fused tetrazolo[1,5-a]pyrazin-6(5H)-one adducts 5. The subsequent Pd-catalyzed intramolecular Heck reaction of compounds 5 or 7 then affords 1,2,3,4-tetrohydroisoquinolines 6 and 8, respectively.

[1860-5397-20-81-i3]

Scheme 3: One-pot synthesis of tetrazolyl-1,2,3,4-tetrahydroisoquinoline.

Results and Discussion

Following the reported procedures [41], the Ugi-azide reaction of 2-bromobenzaldehyde (1a, 1 mmol), allylamine hydrochloride (2, 1 mmol), trimethylsilyl azide (3, 1 mmol) and tert-butyl isocyanide (4a, 1 mmol) in MeOH at 40 °C for 24 h afforded 1,5-DS-1H-T 5a in 92% yield after chromatography purification. Our effort was then focused on the optimization of the intramolecular Heck reaction of 5a for making 1,2,3,4-tetrahydroisoquinoline 6a. A systematic evaluation of different catalysts and ligands, solvents, bases, as well as reaction temperatures and times was conducted (Table 1). The Heck reaction of 5a was first examined by using 10 mol % Pd(OAc)2, 20 mol % PPh3, 2 equiv of Et3N in CH3CN or DMF at 105 °C for 24 h under N2 atmosphere. However, the reactions failed under these conditions (Table 1, entries 1 and 2). When K2CO3 was used as a base to replace Et3N, the reactions in either CH3CN or DMF for 3 h both gave cyclized product 6a in 70% yield (Table 1, entries 3 and 4). An increase of the reaction time to 12 h did not improve the yield (Table 1, entry 5). The reaction was further evaluated in the absence of ligand which afforded the product in 35% yield (Table 1, entry 6). Screening of ligands, e.g., PCy3 and P(o-tol)3 reduced the yield of the desired product 6a (Table 1, entries 7 and 8). Lowering the amount of Pd(OAc)2 or changing the reaction temperatures resulted low yields of 6a (Table 1, entries 9–11). Similar results were observed from the reactions using other bases, such as K3PO4, NaOAc, and Cs2CO3 (Table 1, entries 12–14). Investigating other Pd catalysts, suche as PdCl2 and Pd(dba)2 also gave low yields (Table 1, entries 15 and 16). Since CH3CN is a more favorable solvent than DMF in green chemistry consideration [52,53], the optimal reaction conditions for the Heck reaction were to use 1 mmol of 5a with 10 mol % Pd(OAc)2 and 20 mol % PPh3, 2 equiv of K2CO3 in 3 mL CH3CN at 105 °C for 3 h under N2 atmosphere which afforded product 6a in 70% yield (Table 1, entry 3).

Table 1: Conditions for one-pot Ugi-azide and Heck reactions.a

[Graphic 1]
Entry Catalyst Ligand Solvent Base Temp (°C) Time (h) Yield (%)b
1 Pd(OAc)2 PPh3 MeCN Et3N 105 24 –
2 Pd(OAc)2 PPh3 DMF Et3N 105 24 –
3 Pd(OAc)2 PPh3 MeCN K2CO3 105 3 70
4 Pd(OAc)2 PPh3 DMF K2CO3 105 3 70
5 Pd(OAc)2 PPh3 MeCN K2CO3 105 12 65
6 Pd(OAc)2 – MeCN K2CO3 105 6 35
7 Pd(OAc)2 PCy3 MeCN K2CO3 105 6 46
8 Pd(OAc)2 P(o-tol)3 MeCN K2CO3 105 6 56
9c Pd(OAc)2 PPh3 MeCN K2CO3 105 3 58
10 Pd(OAc)2 PPh3 MeCN K2CO3 70 8 60
11 Pd(OAc)2 PPh3 MeCN K2CO3 120 3 62
12 Pd(OAc)2 PPh3 MeCN K3PO4 105 3 39
13 Pd(OAc)2 PPh3 MeCN NaOAc 105 3 62
14 Pd(OAc)2 PPh3 MeCN Cs2CO3 105 3 56
15 PdCl2 PPh3 MeCN K2CO3 105 5 53
16 Pd(dba)2 PPh3 MeCN K2CO3 105 6 61
17d Pd(OAc)2 PPh3 MeCN K2CO3 105 3 60

aReaction conditions: Ugi-azide step, 2-bromobenzaldehyde (1a, 1 mmol), allylamine hydrochloride (2, 1 mmol), trimethylsilyl azide (3, 1 mmol) and tert-butyl isocyanide (4a, 1 mmol), Et3N (1.2 mmol) in 5 mL MeOH, 40 °C for 24 h. Heck reaction step, catalyst (10 mol %), ligand (20 mol %), solvent (3 mL), base (2 equiv), nitrogen atmosphere. bIsolated yield. cPd(OAc)2 5 mol %, PPh3 10 mol %. dReaction was carried out in one-pot, starting compound is 1a (1 mmol), first Ugi-azide reaction followed by the Heck reaction.

The combination of an initial multicomponent reaction with post-condensation reactions in one-pot is a good strategy to develop high pot, atom and step economy (PASE) syntheses [54-58]. We then made the effort to integrate the Ugi and Heck reactions in one-pot for making tetrazolyl-1,2,3,4-tetrahydroisoquinolines 6. Thus, a mixture of 2-bromobenzaldehyde (1a, 1 mmol), allylamine hydrochloride (2, 1 mmol), trimethylsilyl azide (3, 1 mmol), and tert-butyl isocyanide (4a, 1 mmol) was stirred in MeOH at 40 °C for 24 h, and after the reaction was completed, the solvent was evaporated under vacuum to give crude Ugi adduct 5a which was used for the intramolecular Heck reaction without further purification. Thus, to the solution of crude 5a dissolved in MeCN (3 mL) were added 10 mol % of Pd(OAc)2, 20 mol % of PPh3, and 2 equiv of K2CO3 and the mixture stirred for 3 h at 105 °C under N2 atmosphere to give the desired product 6a in 60% isolated yield (entry 17 in Table 1).

With the optimized one-pot reactions in hands, we next evaluated the substrate scope by synthesizing 11 derivatives (Scheme 4) using nine benzaldehydes 1, two isonitriles or ethyl isocyanoacetate 4, allylamine hydrochloride (2), and trimethylsilyl azide (3) for the initial Ugi-azide reaction. Among them, products 6a and 6b from the reaction of isonitriles were synthesized in moderate yields (58–60%). For the Ugi reaction involving isocyanoacetate, lactamination occurred spontaneously to provide the ring-fused tetrazolo[1,5-a]pyrazin-6(5H)-one adducts 5 which after intramolecular Heck reaction gave functionalized tetracyclic tetrazolo-pyrazino[2,1-a]isoquinolin-6(5H)-ones 6c–k in 73–79% yields. The presence of electron-donating or electron-withdrawing groups on the aromatic ring did not show significant effects on the Heck reaction.

[1860-5397-20-81-i4]

Scheme 4: One-pot synthesis of tetrazolo-pyrazino[2,1-a]isoquinolin-6(5H)-ones 6.

Products 6c–k were obtained in higher yields than products 6a,b. We believe that the secondary amine in the Ugi reaction products 5 could affect the yield of the Heck reaction. To address the issue, compounds 5 were N-alkylated to afford intermediates 7 which were used in the subsequent Heck reaction step. Thus, an alternative one-pot Ugi-azide/N-alkylation/Heck reaction procedure was developed (Scheme 5). A mixture of 2-bromobenzaldehyde (1a, 1 mmol), allylamine hydrochloride (2, 1 mmol), trimethylsilyl azide (3, 1 mmol) and benzyl isocyanide (1 mmol) in MeOH was reacted at 40 °C for 24 h. After evaporating the solvent, 3 mL CH3CN were added to the crude 1,5-DS-1H-T 5a followed by the addition of 1 equiv of benzyl bromide and 2 equiv of K2CO3 for the alkylation reaction at 80 °C for 3 h to give N-benzylated compound 7a. Finally, 10 mol % of Pd(OAc)2, 20 mol % of PPh3, 2 equiv of K2CO3 were added to the reaction mixture for the Heck reaction at 105 °C for 3 h under N2 atmosphere to afford tetrazolyl-1,2,3,4-tetrahydroisoquinoline 8a in 74% isolated yield which is higher than the one-pot Ugi/Hecke reaction to give product 6b (58%). Under the alternative one-pot reaction conditions involving an N-alkylation step, the substrate scope was explored by the preparation of 10 derivatives 8a–j (Scheme 5) using seven benzaldehydes 1, two isonitriles 4, and allylamine hydrochloride (2) with trimethylsilyl azide (3) for the Ugi-azide reaction. The N-alkylations were conducted using benzyl bromide and iodomethane, respectively. The final products 8b–j were obtained in 66–74% yields.

[1860-5397-20-81-i5]

Scheme 5: One-pot synthesis for tetrazolyl-1,2,3,4-tetrahydroisoquinolines 8.

To evaluate the scalability of the two-step one-pot reaction protocol, we performed the synthesis of tetracyclic tetrazolo-pyrazino[2,1-a]isoquinolin-6(5H)-one 6c in gram quantity from 10 mmol of 1a which led to the formation of product 6c in a satisfactory yield 77% (Scheme 6).

[1860-5397-20-81-i6]

Scheme 6: Gram-scale two-step one-pot synthesis of 6c.

The products 6 and 8 were characterized by 1H and 13C NMR, and HRMS analysis. In addition, single crystals of compound 6d and 8c were obtained for X-ray analysis to confirm the structures (Figure 2).

[1860-5397-20-81-2]

Figure 2: ORTEP diagrams of compound 6d (left) [CCDC: 2164364] and 8c (right) [CCDC: 2321622].

Conclusion

In conclusion, we have developed a one-pot synthesis with two or three steps for making tetrazolo-pyrazino[2,1-a]isoquinolin-6(5H)-ones. The initial Ugi-azide four-component reaction constructs the tetrazole motif while the subsequent intramolecular Heck reaction assembles the tetrahydroisoquinoline. The one-pot reaction avoids the intermediate purification which has favorable PASE in the synthesis of heterocyclic compounds.

Experimental

General procedure for the synthesis of Ugi-azide adduct 5a

A solution of 2-bromobenzaldehyde 1 (1 mmol, 1 equiv), allylamine hydrochloride (2, 1 mmol, 1 equiv), trimethylsilyl azide (3, 1 mmol, 1 equiv) and tert-butyl isocyanide 4a (1 mmol, 1 equiv) in MeOH (5 mL) with Et3N (1.5 mmol) was heated at 40 °C for 24 h in a sealed vial. Upon completion of the reaction, the reaction mixture was filtered and evaporated under vacuum to give crude products 5a. Further purification was conducted by flash chromatography with 1:6 petroleum ether/EtOAc to afford 5a in 92% yields. The adduct was confirmed by NMR.

General procedure for the Heck reaction; synthesis of product 6a

A mixture of Ugi-azide adduct 5a (1 mmol), Pd(OAc)2 (0.1 mmol), PPh3 (0.2 mmol), K2CO3 (2 mmol) or NaOAc (2 mmol) in MeCN (3 mL) was stirred at 105 °C for 3 h under nitrogen atmosphere. After aqueous work-up, the crude product was purified by flash chromatography with 1:4 ethyl acetate/petroleum ether to afford product 6a.

General procedure for the one-pot synthesis of tetrazole-containing 1,2,3,4-tetrahydroisoquinolines 6

A mixture of 2-bromobenzaldehyde 1 (1 mmol), allylamine hydrochloride (2, 1 mmol), trimethylsilyl azide (3, 1 mmol) and isocyanide 4 (1 mmol) in MeOH was stirred at 40 °C for 24 h. After the reaction was complete, the solvent was evaporated under vacuum to give the crude Ugi adduct 5, which was used in the Heck reaction without further purification. To a solution of the crude intermediate 5 in MeCN (3 mL) was added 10 mol % of Pd(OAc)2, 20 mol % of PPh3, 2 equiv of K2CO3 and the mixture stirred for 3 h at 105 °C under N2 atmosphere. After aqueous work-up, the crude product was purified by flash chromatography with 1:3 ethyl acetate/petroleum ether to afford products 6.

General procedure for the one-pot synthesis of tetrazolyl-1,2,3,4-tetrahydroisoquinolines 8

A mixture of 2-bromobenzaldehyde 1 (1 mmol), allylamine hydrochloride (2, 1 mmol), trimethylsilyl azide (3, 1 mmol) and isocyanide 4 (1 mmol) in MeOH was reacted at 40 °C for 24 h. After evaporating the solvent, 3 mL CH3CN were added to the crude 1,5-DS-1H-T 5 followed by the addition of 1 equiv of benzyl bromide or iodomethane and 2 equiv of K2CO3 for the alkylation reaction at 80 °C for 3 h to give N-alkylated compounds 7. Finally, 10 mol % of Pd(OAc)2, 20 mol % of PPh3, 2 equiv of K2CO3 were added to the reaction mixture for the Heck reaction at 105 °C for 3 h under N2 atmosphere. After aqueous work-up, the crude products were purified by flash chromatography with 1:4 ethyl acetate/petroleum ether to afford products 8.

Supporting Information

Supporting Information File 1: General reaction procedures, compound characterization data, and copies of NMR spectra.
Format: PDF Size: 3.3 MB Download
Supporting Information File 2: Crystallographic information file for compound 6d.
Format: CIF Size: 247.4 KB Download
Supporting Information File 3: Crystallographic information file for compound 8c.
Format: CIF Size: 432.6 KB Download

Acknowledgements

We acknowledge Shaodong Jiang’s early work on this project.

Author Contributions

Jiawei Niu: investigation; methodology. Yuhui Wang: investigation; methodology. Shenghu Yan: investigation; methodology. Yue Zhang: investigation; methodology. Xiaoming Ma: conceptualization; data curation; supervision; validation; writing – original draft. Qiang Zhang: data curation; supervision; validation. Wei Zhang: conceptualization; supervision; writing – review & editing.

Data Availability Statement

All data that supports the findings of this study is available in the published article and/or the supporting information to this article. Data generated and analyzed during this study is openly available in CCDC. The data of CCDC-2164364 can be obtained free of charge at doi: https://doi.org/10.5517/ccdc.csd.cc2bn66f; the data of CCDC- 2321622: can be obtained free of charge at doi: https://doi.org/10.5517/ccdc.csd.cc2hxv1b.

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