Some Practical Methods for the Application of 5-Metallo-1-benzyl-1H-tetrazoles in Synthesis

Abstract

Nucleophilic reagents such as 5-lithiotetrazoles are synthetically powerful tools for the installation of tetrazole functional groups, but they are of limited utility due to the instability of tetrazole-derived carbanions. Herein, we report practical methods for the generation and use of new 5-metallo-1-benzyl-1H-tetrazoles (M = K, MgX, ZnX) derived from either 1-benzyl-1H-tetrazole or 1-benzyl-5-bromo-1H-tetrazole. By varying the metal counterion, the tetrazole carbanion stability was improved. Potassium-and magnesium-derived reagents underwent additions to carbonyl compounds at -30 and -20°C, respectively. The isolated yields (41-85%) from these and other reactions were comparable to those reported for 5-lithiotetrazoles at much lower temperatures (-78 to -98 °C).The tetrazole functional group, by virtue of its ability to act as a carboxylic acid isostere, has been incorporated into a number of drug-candidate structures. 1 Our research group recently became interested in methods for the formation of tetrazoles 2 with the generic structure 1, where R 1 and R 2 are generally aryl groups. Initial routes to 1 called for reacting an elaborated nitrile 2 with an azide species via [3+2] cycloaddition (Scheme 1). 3 Due to safety concerns and problems of efficiency on larger reaction scales, we sought alternatives to this strategy. 4 Scheme 1 Typical tetrazole synthesis via [3+2] cycloadditionOther common approaches to the synthesis of 5-substituted tetrazoles include multicomponent coupling reactions and the transformation of carboxylic acid derivatives into tetrazoles via imidoyl azides. 5 Ultimately, we were attracted to the idea of preparing 1 from an advanced tetrazolylcarbinol intermediate 3, which could be further traced back to a tetrazole carbanion synthon 4 and a ketone 5 (Scheme 2). 6 This approach offered the advantage of allowing the tetrazole moiety to be installed at a late stage in a complex setting while avoiding the use of azide reagents 7 .Scheme 2 Retrosynthetic analysis of drug candidate 1 A number of tetrazole synthetic equivalents (Figure 1) are capable of participating in C-C bond-forming reactions. 8 These reagents operate through reactive 5-metallotetrazole intermediates that are formed either by metal insertion into the C5-X bond or by selective deprotonation at the C5 position. Figure 1 Tetrazole synthetic equivalents with developed methodologyThe greatest limitation to the application of 5-metallotetrazoles in synthesis to date has been their susceptibility to spontaneous decomposition (Scheme 3). 9 The tetrazole ring can undergo [3+2] cycloreversion with loss of N 2 . This process is irreversible, and the metallocyanamide byproduct 12 that it generates can interfere with desired reactivity. Very low reaction temperatures (≤-78°C) do effectively suppress metallotetrazole decomposition, but such conditions can be impractical on large scales. In an effort to extend the range and practicality of transformations available for direct tetrazole installation, we explored the properties of some avai...

The Dibenzosuberenone Scaffold as a Privileged Substructure: From Synthesis to Application

“…The Wiedemann group reported some practical methods for the application of 5-metallo-1benzyl-1H-tetrazoles in synthesis and found that that potassio-and magnesiotetrazoles prepared in situ participate in carbonyl addition to 5-dibenzosuberenone (1) to yield the addition products, such as tertiary alcohol 146 ( Figure 13). 99 The Kobayashi group reported the synthesis of 5-benzothiophen-2-yl-5H-benzo[a,d]cyclohepten-5-ols 147 as substrates for the formation of a novel cage-like tetracyclic compound 148 via intramolecular [2+2]-photocyclization ( Figure 13); 100 compounds 147b and 148 were characterized by X-ray diffraction. 3-Lithioquinuclidin-2ene was generated as a novel nucleophilic intermediate for the synthesis of muscarinic agonists and antagonists, which were trapped with aldehydes and ketones (5 examples).…”

MCM-41-SO3H: as an efficient reusable Nano-ordered heterogeneous catalyst for the synthesis of divers 1- & 5-substituted 1H-tetrazoles

“…Furthermore, one of the most important methods for synthesis of tetrazoles is the reaction of substituted amines with triethyl orthoformate and sodium azide [21][22][23][24][25][26][27].…”

Synthesis and Characterization of Sodium 5‐Chlorotetrazolate Dihydrate by Chlorination of 1H‐Tetrazole

“…Tetrazoles are a special class of five‐membered heterocyclic compounds with many C–N, N–N, and N=N bonds that possess excellent thermal stability, high density and enthalpy of formation, good chemical reactivity, which have attracted great interest as pharmaceuticals,1–3 photographic materials,4 polydentate linker,5,6 and energy materials 7. The halogenating reaction of tetrazoles is of utmost importance for increasing the activity and halogen compounds are promising chemical intermediates for synthesizing many excellent materials that are used in medicines, agricultural agents, and even energy materials 8,9…”

“…To date, the traditional methods for introducing halogen elements have included the following: (1) the [3+2] dipolar cycloaddition of dichloroisocyanide compounds with sodium azide10–12 (Scheme ); (2) Sandmeyer reaction of amino tetrazole derivatives with sodium nitrite and cuprous halides13 (Scheme ); (3) direct halogenation of tetrazole derivatives by elemental halogen, NBS or NCS8,9,14 (Scheme ); (4) halogenating reaction of nitro compounds15,16 (Scheme ). However, the four approaches suffer from drawbacks such as high toxicity, high raw materials cost, a complex reaction procedure, harsh reaction conditions, and the formation of sensitive intermediates and by‐products that are difficult to separate.…”