Chapter 1
The Applications of Water as Reagents in Organic Synthesis

Zhengkai Chen and Hongjun Ren

Zhejiang Sci-Tech University, Department of Chemistry, Hangzhou, 310018, PR China

1.1 Introduction

Water due to their low cost, easy availability, nontoxic and nonflammable properties has been considered one of the most ideal and promising solvents in organic synthesis from the green and sustainable point of view. Furthermore, with regard to enormous enzyme-catalyzed biosynthesis in nature, water serves as a favorable medium for the versatile synthesis of a variety of complicated molecules and compounds. Over the past decades, considerable efforts had been devoted into the organic reactions by using water as solvent from economy and environment perspectives [1]. Even more, the proposed concept of "in-water" and "on-water" further stimulated the booming development of the utilization of water as solvent for organic synthesis [1e, 2]. Therefore, in recent years, more and more general organic reactions were successfully exploited to perform in water instead of organic solvents to achieve sustainable and environmental benefits.

From a different perspective, the water itself could also be applied as a useful reagent to participate in the reaction through incorporating a hydrogen or oxygen atom or hydroxyl group into the target product. Generally, water is indispensable for various hydrolysis reactions. As a hydrogen source, water is used to quench numerous susceptible reaction systems by providing active hydrogen. Meanwhile, as a versatile nucleophile, the hydroxyl group could be readily introduced into the specific reaction sites by the employment of water as hydroxyl precursor. The hydroxyl group could also be readily oxidized to carbonyl group during the reaction. It is worth mentioning that, in some cases, the presence of water could obviously improve the efficiency of the reaction, albeit the exact reason is elusive for some special reactions.

This chapter is divided into the following four parts for further discussion: (i) incorporation of hydrogen atom from water; (ii) incorporation of oxygen atom from water; (iii) incorporation of hydroxyl group from water; and (iv) traceless promotion of the reactions by water.

1.2 Incorporation of Hydrogen Atom from the Water

Aggarwal and coworkers demonstrated a versatile strategy through lithiation/borylation/protodeboronation of a homoallyl carbamate for the highly enantioselective synthesis of (+)-sertraline and (+)-indatraline, which served as potent inhibitors (Scheme 1.1) [3]. It was observed that the presence of the alkene could hamper the lithiation/borylation process, so the modifications of the reaction conditions were necessary by the use of 12-crown-4, TMSCl, H2O or a solvent switch to achieve 1,2-metalate rearrangement in order to ensure high yields and enantioselectivity. As for the protodeboronation step of tertiary boronic ester, the amount of water played a crucial role in the reaction. In 2010, the same group had disclosed a simple approach for the protodeboronation of tertiary boronic esters employing CsF-H2O or TBAF·3H2O with complete stereoselectivity to access to diverse enantioenriched tertiary alkanes [4].

Scheme 1.1 Enantioselective synthesis of (+)-sertraline and (+)-indatraline.

A catalyst-free sulfonylation of activated alkenes with sulfonyl hydrazides in water for highly efficient construction of monosubstituted ethyl sulfones was demonstrated by Wang and coworkers (Scheme 1.2) [5]. Remarkably, the reaction proceeded through without any catalyst, additive, ligand, or organic solvent, with the release of N2 as single by-product. The results of control experiments indicated that an anion pathway was involved in the reaction and the a-hydrogen atom of ß-sulfone esters originated from water.

Scheme 1.2 Catalyst-free sulfonylation of activated alkenes in water.

The sulfinyl anion I was first formed assisted by water with the release of one molecule of N2, which could transform into sulfur-centered anion II through resonance process in the presence of water. The sulfur-centered anion readily added to the activated alkene to give the oxygen-centered anion III, followed by another resonance interaction leading to the carbon-centered anion IV. Finally, the proton transfer of intermediate IV from hydronium ions to deliver the desired ß-sulfone ester product.

A silver(I)-catalyzed chemo- and regioselective hydroazidation of ethynyl carbinols for the construction of 2-azidoallyl alcohols was developed by Bi and coworkers (Scheme 1.3) [6]. In this transformation, trimethylsilyl azide (TMS-N3) was chosen as the optimal azide source and the pendent hydroxyl group directed the chemo- and regioselectivity of hydroazidation by stabilizing the vinyl azide products. Catalyzed by 10 mol% Ag2CO3, a wide range of secondary and tertiary ethynyl carbinols bearing different substituents could be transformed into the corresponding products in good to excellent yields.

Scheme 1.3 Silver(I)-catalyzed hydroazidation of ethynyl carbinols.

The observation data of control experiments implied that the residual water in the DMSO played the critical role in the reaction. The initial step of the plausible pathway involved the generation of silver acetylide intermediate I. Meanwhile, the hydrazoic acid (HN3) was in situ formed by silver-catalyzed hydrolysis of TMS-N3, which added to the intermediate I to lead to vinyl silver intermediate II. Under the promotion of a trace amount of H2O in the DMSO solvent, the protonation of intermediate II released the final product. As a class of functionalized synthetic intermediates, 2-azidoallyl alcohols could be readily transformed into NH aziridines under the mild reaction conditions.

1.2.1 1,2,3-Triazoles

Inspired by the previous work of silver(I)-catalyzed hydroazidation of ethynyl carbinols, Bi and coworkers extended their study to the general hydroazidation of unactivated alkynes (Scheme 1.4a) [7]. The key point of the progress lay in the necessity of a trace amount of water in DMSO with regard to hydroazidation of ethynyl carbinols. Therefore, it was speculated that a stoichiometric amount of H2O could enhance the reactivity of the reaction and the relevant experiments confirmed the hypothesis. The condition screening of the amount of H2O demonstrated 2.0 equiv. of H2O was appropriate for high efficiency. Furthermore, it was essential to control the reaction time to circumvent the further conversion of vinyl azides to nitriles. The protocol featured readily accessible starting materials, mild reaction conditions, broad substrate scope, and good scalability.

Scheme 1.4 Silver-catalyzed hydroazidation of alkynes and the application to access to 1,5-fused 1,2,3-triazoles.

The significance of the aforementioned synthetic method was embodied in the application for the assembly of several valuable heterocyclic frameworks. In 2015, the strategy of hydroazidation of unactivated alkynes was combined with alkyne-azide 1,3-dipolar cycloaddition reaction to access to a variety of piperidine-fused 1,2,3-triazoles by Bi and coworkers (Scheme 1.4b) [8]. Under silver-catalyzed conditions, the treatment of diyne with TMS-N3 in the presence of H2O gave rise to pharmaceutically relevant 1,5-fused 1,2,3-triazoles in excellent yields. The reaction was assumed to undergo the tandem hydroazidation/alkyne-azide 1,3-dipolar cycloaddition sequence, which presented a concise method for the synthesis of structurally complicated fused heterocyclic compounds in one pot.

Taylor and coworkers developed a variant of Staudinger reaction on a-azido esters with trialkyl phosphines for the formation of 2H-1,2,3-triazol-4-ols (Scheme 1.5) [9]. In this reaction, phosphazides were generated from the reaction of trialkyl phosphines with a-azido esters in THF/H2O, which underwent intramolecular cyclization to afford the desired products. Upon using PPh3, the major product was the reduced amine from the classic Staudinger pathway [10]. As shown in Scheme 1.5, phosphazide I could cyclize to deliver intermediate II, which occurred hydrolysis to give intermediate III. The final product was formed by the protonation of intermediate III and the following isomerization. Notably, phosphazide I could lose nitrogen and release iminophosphorane V, followed by the hydrolysis of intermediate V to produce a-amino ester.

Scheme 1.5 Formation of 2H-1,2,3-triazol-4-ols from a-azido esters.

In 2014, an efficient modification toward Staudinger reaction for the facile reduction of azides had been realized by Ito, Abe, and coworkers (Scheme 1.6) [11]. As for traditional Staudinger reaction, the formed iminophosphorane intermediate could undergo additional hydrolysis process for long reaction times to convert into the primary amines. In the current transformation, the triphenylphosphinecarboxamide (TPPc) derivatives were designed depending on the fact that the specific substituent was introduced at the ortho position of the phenyl ring of triphenylphosphine (TPP), which could promote the hydrolysis process through neighboring group participation effect. Under the improved conditions, the reaction could be completed in 10 min to 2 h to produce the primary amines in high...