Synthesis of N-heterocycles containing 1,5-disubstituted-1H-tetrazole via post-Ugi-azide reaction

Ugi-azide four-component reaction (UA-4CR) as development on Ugi four-component reaction (U-4CR) is the condensation reaction involving an aldehyde, an amine, an isocyanide, and an azide source. Nowadays, UA-4CR has been employed for the efficient and facile production of 1,5-disubstituted-1H-tetrazoles (1,5-DS-1H-Ts). Interestingly, the combination of 1,5-DS-1H-Ts with suitable post-transformations in a tandem manner results in the construction of various classes of heterocyclic compounds bearing 1,5-DS-1H-T moiety. This review aims to provide the application of diverse post-Ugi-azide reaction in the preparation of different N-heterocyclic compounds bearing 1,5-DS-1H-T such as substituted and fused 1,5-DS-1H-Ts.


Introduction
In 1885, tetrazole was synthesized and characterized by the Swedish chemist, Bladin at the University of Upsala through the reaction of the anhydrous hydrazoic acid with hydrogen cyanide under pressure [1]. Since then and due to their wide range of biological activities, the synthesis of tetrazoles has attracted the attention of synthetic organic chemists, resulting in the significant development in their biology and chemistry [2]. The extensive studies on the chemistry of tetrazoles have led to the disclosure of their various use in other fields, including photographic industry, coordination chemistry, and being used as explosives, and agriculture [3]. Tetrazoles also constitute the core structure of numerous non-natural compounds which display significant biological activity [4]. Several prescribed drugs have tetrazole moiety in their structures, for example, Valsartan [5], Candesartan [6,7], and Losartan [8,9] as angiotensin II receptor antagonists.
IMCRs have gained significant attention during the past two decades and have emerged as efficient and powerful tools for the syntheses of several synthetic intermediates, bioactive agents, highly complex natural products and diverse drug-like compounds [17][18][19][20][21]. Undoubtedly, one of the most important and well-established IMCRs is Ugi four-component reaction (U-4CR) which was discovered in 1959 by an Estonian-born German chemist, Ivar Karl Ugi and reported in Angewandte Chemie for the rapid and facile construction of an N-substituted acyl aminoamide via condensation of an amine, an isocyanide, an aldehyde, and a carboxylic acid. Nowadays, this reaction is known as Ugi four-component reaction (U-4CR) [22]. A development on U-4CR involves a slight modification, in which an azide source such as azidotrimethylsilane (TMSN 3 ) or hydrazoic acid (HN 3 ) is employed instead of carboxylic acid as one of the required components in classical U-4CR. In 1961, the first Ugi-azide four-component reaction (UA-4CR) was reported by Ugi [23]. Since then, UA-4CR has been used for the facile and efficient construction of 1,5-DS-1H-Ts [24][25][26][27]. Interestingly, 1,5-DS-1H-Ts also can be prepared using various imines through Ugi-azide three-component reaction (UA-3CR) [28].
Remarkably, the UA-R can be combined with suitable post-transformations, particularly cyclization, in a cascade manner to produce various classes of heterocyclic compounds bearing 1,5-DS-1H-T moiety as scaffolds which cannot be easily synthesized by other reactions in two steps [29][30][31][32][33].
In continuation of that work, Gunawan's group used the above protocol to prepare the highly unique δ-lactam tetrazoles 4. Ugi 1,5-DS-1H-Ts 3 which were generated from the tethered keto-acid 5-oxohexanoic acid, isocyanides, primary amines, and TMSN 3 in MeOH at room temperature undergo intramolecular amide formation in the presence of 1,1′-carbonyldiimidazole (CDI) as the coupling reagent to give the expected products 4 (Scheme 2) [50].
γ-Oxo esters having geminal CH 2 CHO and CO 2 Et fragments at saturated cycle were selected as the source of aldehydes and mixed with amines, isocyanides, and TMSN 3 in EtOH at room temperature in 8-12 h (TLC control) to furnish the Ugi 1,5-DS-1H-Ts 5. The subjection of the latter to the intramolecular amide bond formation under acidic condition afforded the target compounds, 5-tetrazole substituted spirocyclic γ-lactams 6 in 50-72% (Scheme 3) [51].
A new, one-pot two-step methodology comprising UA-4CR and RNCX (X = O, S) cyclization for the rapid assembly of the novel and biologically appealing 1,5-substituted tetrazole-hydantoins and thiohydantoins 8 was described by Medda and Hulme in 2012. The reaction was initiated with the mixing of ethyl glyoxalate and amines in DCE followed Scheme 1 Synthesis of pyrrolidinone tetrazoles 2 by subjection to MWI to pre-form the resulting Schiff base. Subsequent addition of solvent TFE isocyanides and TMSN 3 with stirring at room temperature for 12 h yielded the condensation products 7 in good isolated yields. Treatment of Ugi-azide products 7 with an excess of isocyanate or isothiocyanate enabled rapid assembly of the 1,5-substituted tetrazole-hydantoins and thiohydantoins 8 in moderate to good yields, respectively (Scheme 4) [52].
Synthesis of a series of interesting isoindolin-1-ones 10 bearing a 1-substituted tetrazol-5-yl moiety in position 3 was accomplished and reported using post-Ugi-azide cyclization. The smooth UA-4CR between methyl ortho-formylbenzoates, amines, isocyanides, and TMSN 3 in MeOH for 2 days at room temperature constructed easily the desired Ugi products 9, which were cyclized by a straightforward and rapid fashion in the presence of sodium ethoxide in ethanol to give the tetrazolylisoindolinones 10. The final products were precipitated from the mother liquors in a pure form without the need for tedious workup procedures (Scheme 5) [53].
El Kaïm et al. described the application of orthonitrobenzaldehyde in the UA-4CR and its post-cyclization. The Ugi 1,5-DS-1H-Ts 18, afforded from U-4CR involving ortho-nitrobenzaldehyde, amines, isocyanides, and TMSN 3 , were directly heated with triethylphosphite (P(OEt) 3 ) as a reducing agent in DMF as the solvent at 140 °C for 10 h resulted in the formation a novel N-N bond, giving the expected tetrazolyl indazole 19 without the need of purification (Scheme 9) [30].

Synthesis of fused 1,5-DS-1H-Ts
For the first time in 1998, post-UA-4CR was employed as a highly convergent one-pot two-step following protocol by Bienaymé and Bouzid for the construction of stable fused tetrazoles 37. In the first step, Ugi-azide intermediate adducts 36 were prepared through the reaction between alkyl-β-(N,N-dimethylamino)-α-isocyanoacrylate, aldehydes, primary amines, and TMSN 3 in MeOH at 25 °C. In the next step, cyclization of Ugi-azide intermediate adducts 36 under diluted acidic conditions afforded the desired rigid hydrophobic tetrazoles 37. The use of TMSN 3 as a convenient source for HN 3 in MeOH has led to an increase in the versatility of this method (Scheme 18) [64].
In 2000, Nixey et al. disclosed a unique application of the TMSN 3 -modified UA-4CR for the solution phase synthesis of the fused ketopiperazine-tetrazole class of molecule. UA-4CR of substituted methylisocyanoacetates with an aldehyde, primary amine, and TMSN 3 in MeOH at ambient temperature in 24 h followed by refluxing generated the expected heterocycles 38, fused tetrazole-ketopiperazines, containing three potential diversity points in good yields (Scheme 19) [65].
The tricyclic tetrazolo[1,5-a]quinoxaline 41 were constructed via one-pot reaction. 2-Fluorophenylisocyanide as a new isocyanide source was used in the UA-4CR involving aldehydes, amines, and TMSN 3 in MeOH at room temperature to provide the corresponding 1,5-DS-1H-Ts 40. Next, the latter were subjected to nucleophilic aromatic substitution (S N Ar) in the presence of Cs 2 CO 3 as the base in DMF as the solvent to give the desired fused 4,5-dihydrotetrazolo[1,5-a]quinoxalines 41 (Scheme 21) [67].
Recently, Patil et al. described a one-pot, short straightforward, and versatile synthesis of N-unsubstituted tetrazolopiperidines 42. The first step of this synthesis consists of the UA-4CR using aqueous ammonia as ammonia source and as a base in this multicomponent synthesis to enable a post-cyclization reaction. Experimentally, the four components, aqueous ammonia, α-amino acid methyl ester derived isocyanides, ketones (aldehydes), and TMSN 3 , selected and mixed together in MeOH/H 2 O at room temperature to obtain the best yields of Ugi adducts which then were cyclized upon treatment with NH 4 OH leading to the final tetrazolopyrazinones 42 in good to high yields (Scheme 22) [68].
N-Boc protected hydrazine was employed together with α-amino acid derived isocyanides in the UA-4CR followed by cyclization under the basic condition to construct the Boc-protected 7-aminotetrazolopyrazinone products 44. The reaction was commenced with the preparation of heterocycles 43 as Ugi 1,5-DS-1H-Ts from the UA-4CR between N-Boc protected hydrazine, α-amino acid derived isocyanides, ketones (aldehydes) and TMSN 3 in the presence of Mg(OTf) 2 in MeOH at room temperature. The post-cyclization of 43 under basic condition (NaOEt) could selectively obtain Boc-protected 7-aminotetrazolopyrazinones 44 in yield of 38-87% in a one-pot fashion (Scheme 23) [69].
In 2002, Nixey et al. developed a novel solution phase procedure utilizing UA-4CR followed by UDC strategy (involving the formation of C-N bond) to produce the fused azepine-tetrazole class of molecule. Hence, they mixed N-BOC-amino aldehydes with substituted methylisocyanoacetates, secondary amines, and TMSN 3 in methanol to obtain the Ugi 1,5-DS-1H-Ts 45. Further acid treatment of the latter with 10% TFA in CH 2 Cl 2 liberated the masked internal amino nucleophile to enable partial cyclization to 7,5-fused products. Subsequent cyclization was promoted by proton scavenging in the presence of PS-diisopropylethylamine in DMF/dioxane under reflux condition leading to the desired fused azepine-tetrazoles 46 with high yield (Scheme 24) [31].
In 2010, Nayak and Batra performed the synthesis of tetrazole-fused diazepinones using a suitable isocyanide source in the UA-4CR and post-Ugi-azide cyclization. UA-4CR of substituted isonitriles as E-isomer only with primary aliphatic amines, substituted benzaldehydes/heteroaldehydes, and TMSN 3 in MeOH at an ambient temperature obtained 1,5-DS-1H-Ts 47 which were demonstrated to be appropriate substrates for constructing tetrazolo-fused diazepinones. In order to achieve the synthesis of the target compounds, the ester group in Ugi-azide products 47 was hydrolyzed either in the presence of LiOH in THF/H 2 O (for methyl or ethyl ester) or in the presence of TFA in CH 2 Cl 2 (for t-butyl ester) to produce the corresponding acids which undergo intramolecular amide coupling reaction using EDC in NMM/CH 2 Cl 2 resulted in the formation of differently substituted tetrazole-fused diazepinone 48 in good yields (Scheme 25) [7].
A novel, efficient and one-pot method for the production of heteroannulated [1,4]benzodiazepines 50 from 1,5-DS-1H-Ts 49 through a post-Ugi-azide cyclization was reported. The aforementioned tetrazole-fused diazepines represent a remarkable class of compounds which proven to act as platelet aggregation inhibitors (Scheme 26) [29].
Gunawan et al. developed an efficient, straightforward and two-step protocol comprising UA-4CR and acid-promoted cyclization for the synthesis of arrays of tetrazolo-fused benzodiazepines 57 and benzodiazepinones 58. The protocol employs ortho-N-Boc phenylisocyanides and substituted phenylglyoxal or ethyl glyoxylate in the UA-4CR to give 1,5-DS-1H-Ts 55 and 56 equipped with the desired diversity inputs which undergo simultaneous deprotection cyclization using TFA under MWI leading to the final products 57 and 58 (Scheme 29) [58].

Conclusion
In this review, we tried to highlight the synthesis of substituted and fused 1,5-DS-1H-Ts by employing various post-Ugi-azide transformations. The UA-4CR is one of the essential and useful IMCRs which was discovered by Ivar Karl Ugi in 1961. It is used as a useful, powerful, and low-cost tool to produce a library of 1,5-DS-1H-Ts in short synthetic sequences. It is a slight modification in which a source of azide is used instead of carboxylic acid. In UA-4CRs, among solvents methanol, ethanol, and dichloromethane are the most commonly used. Combination of UA-4CR with a suitable post-transformation led to the formation of a library of heterocyclic systems bearing 1,5-DS-1H-Ts, in which a lot of them could not be readily prepared through other synthetic methods.