Chapter 4 Divergent synthesis of Amino alcohols
4.2 Introduction
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Because of its ubiquitous presence and its function as an essential synthetic building block, excellent chiral ligand, its preparation is crucial. As a result, various methods for the preparation of amino alcohols have been invented and developed.
The common methods of preparing amino alcohol rely on the aminohydroxylation of olefins, small ring-opening reactions by the nucleophiles such as epoxide or aziridine by the counter nucleophiles.1–8 (Scheme-4.2).
Scheme 4.2 Conventional methods of vicinal amino alcohol synthesis
Compared to conventional polar chemistry, radical chemistry used to prepare amino alcohol was milder and more efficient. The radical reaction for the preparation of α, β amino alcohols in the presence of borane and zinc reagent was reported by Tomioka etal9 (Scheme 4.3). Their method uses the nucleophilic radical addition to imines through acyloxymethyl radicals produced from the corresponding iodomethyl esters through dimethylzinc or triethyl borane reagent. The resulting acyloxy amine is hydrolyzed to produce the amino alcohol. This tin-free method worked under very mild conditions. Still, it necessitates longer reaction times, pre-formation of aldimines, the use of halogenated derivatives, and the extra step of hydrolysis of the acyloxy group resulted in the formation of the amino alcohol which requires an additional step.
88 Scheme 4.3
The direct method of vicinal amino-alcohol preparation by the radical reaction is described by the Porta and co-worker9 (Scheme 4.4) They have developed the one-pot multi-component coupling of amine, aldehyde, and alcohol to synthesize 1,2, amino alcohols, employing the TiCl3 catalyst and TBHP as an oxidant. Alkoxy methyl radical was generated by the reaction of TiCl3 with the TBHP, thereby inducing the decomposition of the TBHP, and forms the alkoxy radical then reacts with the methanol and gets protonated and forms t-butanol. Meanwhile, methanol converts into hydroxymethyl radical. The addition of the hydroxymethyl radical to the in situ derived imine results in the formation of 1, 2 amino alcohols. Even though their process uses inexpensive and readily available starting materials and provides access to the vicinal amino alcohol in a single step, harsh oxidizing reagents, and the use of a sub-stoichiometric metal reagent are needed for the synthesis of 1,2 amino alcohols.
H R1
O
R2 HN
R3 R2
N OH
Ti(III) t-BuOOH
R1 CH3OH
R3
Scheme 4.4
The general radical reactions for the synthesis of 1,2 amino alcohols require toxic reagents, metal catalysts, and harsher reaction conditions. Therefore, the development of more environmentally friendly and milder reactions is necessary.
Photoredox catalysis has changed the paradigm of radical reaction in organic synthesis. Its mild and successful radical generation through single electron transfer processes, as well as its widespread use, have piqued the interest of the entire synthetic world.
The Knowles group published a diastereoselective and stereoselective photoinduced proton-coupled electron transfer (PCET) protocol based on chiral phosphoric acid for reductive coupling of ketones
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with hydrazones to produce 1,2-amino alcohol derivatives (Scheme 4.5). Their protocol, however, was restricted to the intramolecular coupling of the tethered ketones and hydrazone10.
Scheme 4.6
Because of their stability and ubiquity, alkyl carboxylic acids are favored among radical precursors. For the synthesis of vicinal amino alcohols, amine-derived radicals and their successive addition to the aldehyde is an attractive approach. The amino acid was used as a precursor for amino radicals by Hu et al11. This amino acid, after the decarboxylation, renders the amino radical, which then engages with the aldehyde to form the vicinal amino alcohol products.
Scheme 4.7
Later, Nagib and colleagues published the synthesis of photoinduced radical-mediated 1,2 amino alcohols with primary alcohol groups using imidate-based chaperones (Scheme 4.8). These imidate- based chaperones act as a traceless activator, facilitating C-H functionalization via 1-5 hydrogen atom transfer and incorporating the amine group. Subsequent oxidation and hydrolysis of this intermediate furnish the amino alcohol having primary alcohol group. Though no photocatalyst is used in this strategy, an environmentally harmful iodine reagent is required for this reaction.
Directed β C-H Amination of Alcohols via Radical Relay Chaperones
Scheme 4.8
Amino hydroxylation of olefins is an attractive strategy to prepare the vicinal amino alcohols.
Conventional methods of amino hydroxylation require precarious osmium reagent (Scheme 4.7). The
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development of newer methods to replace the use of osmium for amino hydroxylation is important. The Akita research group demonstrated regiospecific olefin aminohydroxylation to produce vicinal amino alcohols by using the aminopyridinium salt as a precursor of the amidyl radical in the photoredox reaction12. This gentle procedure unquestionably prepares the regioselective amino alcohols with a secondary alcohol group.
Scheme 4.7
In synthetic organic chemistry, the β -amino ether functionality is also a common motif. The synthesis of these structural units, on the other hand, is often challenging and sometimes necessitates several steps, functional group manipulations, organometallic reagents, and harsh reaction conditions. Preparation of β amino ethers is mainly using amino alcohol. Approaches that easily give access to the β amino ethers and β amino alcohols are alluring and step economical.
In the organic synthesis, it is often necessary to protect the alcohol functionality, which often calls for additional functional group manipulation steps followed by the following steps' deprotection. These extra steps make reaction less step economical. Hence there is a need to devise a strategy that could synthesis β amino ether and β amino alcohol in a protection group free manner. Such a strategy described by the Opats and co-workers (Scheme 4.8). This protocol describes the alkoxy radical generation from ethers and the next addition to the in situ generated imine from the aldehyde and amine13. Resultant amino ether after subsequent hydrolysis step gives the vicinal amino alcohols. But this strategy relies on the use of the metal catalyst and high energy light source. Recently, Dilman research reported the visible-light-induced C-H activation by generating the radical and successive addition to the imine14 (Scheme 4.9). This C-H activation strategy and hydrogen atom transfer results in the formation of the alkoxy radical from the alcohols and ether to form the β- amino ether. The β- amino alcohol is produced because of further hydrolysis of this product.
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Scheme 4.8
Scheme 4.9
The conventional radical and photoinduced radical reactions are used to synthesize β-amino ether and β-amino alcohol described above. Most of these reactions necessitate the use of metal catalysts, halogenated or hypervalent halogen reagents, and harsh oxidation conditions; however, metal-free, and mild reaction conditions are required to synthesize amino alcohols without protecting groups.
Macmilan and co-workers reported the synthesis of β amino ether by the radical coupling between the benzylic ethers and imine (Scheme 4.10). Their strategy relies on the activation of C- H bonds of the benzylic ether to generate the benzylic ether radical by employing the thiol catalyst i.e Schiff base15. This generated benzylic ether radical then couples with the imidyl radical in the next catalytic step to furnish the β amino ether product. Impressively enough, C-H bond activation is a novel strategy for amino-ether synthesis but requires the special activating group to limit this reaction.
Scheme 4.10
The use of milder and ready and inexpensive reagents for the radical reaction is important in the step and atom economy as well as an environmental concern. Silicon reagents are excellent radical progenitors, and their implication can be seen from the many novels, mild bond-forming reactions.
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Gloriuos research group employed the α -silyl amine as an α aminyl radical precursor and coupled with the aldehyde by using Chromium catalyst in the photocatalytic settings16 (Scheme 4.11).
Chromium catalyst is crucial in this reaction because it is believed to activate both the aldehyde and silyl amine by sigma bond metathesis. This silyl amine reagent for amino alcohol synthesis is an excellent technique, but it involves the use of a metal reagent for substrate activation.
Scheme 4.11
The significance of 1,2 amino alcohol and 1,2 amino ether can be seen in their use in synthesis as well as their important function in pharmaceuticals due to their biological activity. It is important to develop new synthetic methods for the synthesis of β-amino ethers and β-amino alcohols that are moderate, metal-free, greener, and more environmentally friendly. Despite this, all of the reactions of amino- alcohol synthesis mentioned here are of 1,2 amino-alcohol with a secondary alcoholic group. The primary alcoholic group in the 1,2 amino alcohol moiety allows for direct synthesis of amino acids through oxidation.
Organo-silicon reagents have been discovered to be an ideal substitute for widely used toxic radical reagents such as Tin. The mild and non-toxic nature of silicon reagents, as well as the smooth generation of radicals, led us to develop and use silicon reagents in photocatalyzed reactions. This thesis has already identified the developed organo-silicon reagents and their photocatalytic reactions. We discovered the amino alcohol synthesis while studying the use of silicon reagents in different reactions.
For the Giese reaction, we previously used alkoxymethyl silane reagents.So, we hypothesized that this alkoxymethyl silane could react with the imine, resulting in the formation of β amino alcohol products.
The key highlight of our reaction is the formation of an amino alcohol product with a primary alcoholic group that, when oxidized, results in the synthetically essential amino acid.
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