A decade review of triphosgene and its applications in organic reactions

doi:10.1016/j.tet.2020.131553

Tetrahedron

Volume 76, Issue 47, 20 November 2020, 131553

https://doi.org/10.1016/j.tet.2020.131553 Get rights and content

Highlights

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A versatile reagent in organic synthesis and convenient substitute for phosgene gas.
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Enabling the preparation of a vast scope of value-added compounds.
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Applicable in solution- and solid-phase syntheses, as well as flow chemistry.

Abstract

This review article highlights selected advances in triphosgene-enabled organic synthetic reactions that were reported in the decade of 2010–2019. Triphosgene is a versatile reagent in organic synthesis. It serves as a convenient substitute for the toxic phosgene gas. Despite its first known preparation in the late 19th century, the upward surge in the development of organic reactions using triphosgene interestingly began only three decades ago. Despite the relatively short history, triphosgene has been proven to be very useful in facilitating the preparation of a vast scope of value-added compounds, such as organohalides, acid chlorides, isocyanates, carbonyl addition adducts, heterocycles, among others. Furthermore, applications of triphosgene in complex molecules synthesis, polymer synthesis, and other techniques, such as flow chemistry and solid phase synthesis, have also emerged in the literature.

Graphical abstract

Introduction

This review article describes recent advancement in organic synthetic reactions that utilize triphosgene as the key reagent. It is comprised of brief summaries on selected chemistries that were published in the literature between the decade of 2010–2019. This review is intended to provide updates to existing surveys published by Eckert [1], Sennyey [2], Imagawa [3], Bracher [4], Su [5], Ghorbani-Chogaramani [6], and Cotarca [7], as well as to further supplement the Encyclopedia of Reagents for Organic Synthesis entries initially reported by Mobashery, followed by Banerjee on the first update and Kartika on the second update [8]. The contents in this review are arranged primarily based on groups of reactions that are enabled by triphosgene. Each topic is then expanded further to include the various structural motifs that are produced and isolated from these reactions.

Section snippets

Triphosgene

Triphosgene, also known as bis(trichloromethyl) carbonate or BTC, is a convenient substitute for the extremely toxic phosgene gas (Fig. 1). It exists as a stable crystalline solid with a melting point of 80 °C, but it decomposes at temperature above 200 °C. The first preparation of triphosgene was reported by Councler in 1880 [9], in which its synthesis was accomplished through liquid-phase photochlorination of dimethyl carbonate. The physical and chemical properties of triphosgene were

Synthesis of organohalides

There has been a growing number of reports that demonstrate the use of triphosgene to synthesize organohalides. In the past 10 years, a significant advancement was particularly realized in the development of reaction protocols that facilitated Halogenation of a much broader scope of substrates and functional groups, such as aliphatic alcohols and diols, epoxides, ketones, arenes, etc.

Functional group interconversions

The versatility of triphosgene was showcased in the interconversion of several functional groups, such as amines and alcohols, to other valuable synthetic intermediates.

Preparation of carbonyl chlorides

A series of carbonyl chloride compounds could be effectively synthesized through the use of triphosgene. Despite their high reactivity, these electrophiles, particularly those discussed below, could be isolated for further use.

Activation of carboxylic acids

Carboxylic acids could be readily activated by triphosgene to form reactive intermediates, such acid chlorides, acid anhydrides, or even N-succinimidyl esters. In the examples below, these activated carboxylic acid species could be directly subjected to in situ nucleophilic acyl substitution reactions.

Addition of carbonyl groups

Triphosgene is a unique electrophile. It is a source of a carbonyl group that can link two heteroatoms through double nucleophilic acyl substitution. This carbonyl connectivity could be forged intramolecularly, therefore providing opportunities for the assembly of structurally diverse carbonyl heterocycles. As discussed below, other noteworthy advancements in the past decade included the strategic application of triphosgene to deduce relative stereochemistry of functional groups, such as

Electrophilic heterocyclization reactions

While triphosgene readily serves as an electrophilic carbonyl donor for various heterocyclization reactions, this versatile reagent can be employed to generate useful electrophilic promoters, such as the Vilsmeier reagent from DMF and chlorotriphenylphosphonium ion from triphenylphosphine oxide. As shown below, these reactive species can be strategically exploited for the preparation of various N-heterocyclic motifs.

Application to polymer synthesis

In recent years, the synthetic utility of triphosgene in polymerization reactions, in which it serves as a monomeric linchpin, has been exemplified. As depicted in Scheme 43, Jeon reported interfacial polymerization of bisphenol A and eugenol in the presence of triphosgene, triethylamine, and a phase-transfer catayst tetrabutylammonium chloride to produce eugenol polycarbonate polymer 187 [105]. Kim demonstrated a complementary reaction by employing 4,4′-bis(4-hydroxyphenyl)-valeric acid (BHPV)

Flow chemistry

Adaption of triphosgene-promoted reactions in flow synthesis has been documented in the past decade. This advancement has garnered attention due to several key advantages. For instance, reactive intermediates generated upon substrate activation by triphosgene can be captured to furnish the target products in a single continuous operation. The smaller reaction volume and residence time that accompany flow synthesis can potentially minimize risk of unwanted side reactions, such as epimerization

Solid phase synthesis

The compatibility of triphosgene in the solid phase synthesis methodology has been displayed in the preparation of oligoamides and oligopeptides. In general, triphosgene was used as a reagent to activate the carboxylic acid residues, thereby enabling amide bond coupling with the resin-bound amines. As discussed below, the successful utility of this emerging technology in the past decade has been realized in several elegant total syntheses of complex natural products.

Summary

This review article gleans various organic synthetic reactions that are enabled by the use of triphosgene in the decade of 2010–2019. Triphosgene has been effectively employed as a convenient surrogate to the highly toxic phosgene gas. Owing to its perceived safety and ease of handling, a surge of new chemistries based on this reagent, including its applications in the syntheses of complex molecular architectures, has been reported. Equally significant, the utility of triphosgene in emerging

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

Generous financial supports from the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R01GM127649 and Louisiana State University are gratefully acknowledged. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Moshood Ganiu was born in Lagos, Nigeria. He obtained his B.S in Chemistry from Lagos State University in 2012 under the tutelage of Dr. M.S. Owolabi. Moshood joined the Department of Chemistry at LSU in the Fall of 2016 and is currently a 5th year Ph.D. candidate in the Kartika Lab. His projects encompass synthetic reactions development enabled by triphosgene.

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Triphosgene, with chemical name bis(trichloromethyl) carbonate (BTC), also known as solid phosgene, is an excellent organic synthetic compound, which can not only replace phosgene, diphosgene, sulfoxide chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride and other traditional acylation reagents to react with many nucleophiles (such as alcohol, aldehyde, amine, amide, carboxylic acid, phenol, hydroxylamine, etc.) [1].
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Binod Nepal was born in Dhading district in Nepal. He completed undergraduate studies from the Amrit Campus in 2011 and the Master’s Degree in Organic Chemistry from the Central Department of Chemistry, Tribhuvan University in 2015 under the supervision of Prof. Susan Joshi. Binod then began his graduate studies at LSU in Fall 2016. He is currently a 5th year graduate student under the guidance of Prof. Rendy Kartika. Binod is working on synthetic reactions based on oxyallyl and amidoallyl cations.

Joshua P. Van Houten is a 5th year graduate student from Louisiana. Upon receiving his B.S. in Chemistry from Southwestern University in 2016, Joshua then continued with his graduate studies at LSU in Prof. Rendy Kartika’s laboratory. Presently, he is working on a one-pot synthetic reaction to access complex δ-valerolactones.

Rendy Kartika is an Associate Professor in the Department of Chemistry at Louisiana State University (LSU). Rendy was born in Malang, Indonesia and immigrated to the US in 1998. He earned his B.S. in Chemistry from California State Polytechnic University, Pomona in 2003 and his Ph.D. in Organic Chemistry from the University of Notre Dame in 2008 under the direction of Prof. Richard Taylor. After a postdoctoral training with Prof. David Spiegel at Yale University, Rendy began his independent academic career as an Assistant Professor at LSU in 2011 and rose to the rank of Associate Professor with tenure in 2017. Research in the Kartika lab centers in the development of organic synthetic reactions to assemble complex molecules of biological, pharmaceutical, and industrial importance.

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A decade review of triphosgene and its applications in organic reactions

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Triphosgene

Synthesis of organohalides

Functional group interconversions

Preparation of carbonyl chlorides

Activation of carboxylic acids

Addition of carbonyl groups

Electrophilic heterocyclization reactions

Application to polymer synthesis

Flow chemistry

Solid phase synthesis

Summary

Declaration of competing interest

Acknowledgments

Org. Process Res. Dev.

Eur. J. Org Chem.

J. Org. Chem.

Chin. Chem. Lett.

J. Org. Chem.

Org. Chem. Front.

Tetrahedron Lett.

Tetrahedron

Tetrahedron

Biomacromolecules

Chin. Chem. Lett.

J. Org. Chem.

Org. Lett.

Org. Biomol. Chem.

Synth. Commun.

Tetrahedron

J. Heterocycl. Chem.

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron

Bioorg. Chem.

Tetrahedron

J. Heterocycl. Chem.

Tetrahedron

Org. Lett.

J. Heterocycl. Chem.

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Bioorg. Med. Chem.

Org. Lett.

Tetrahedron Lett.

J. Org. Chem.

Chin. Chem. Lett.

Chin. Chem. Lett.

Angew Chem. Int. Ed. Engl.

Spec. Chem.

J. Syn. Org. Chem. Jpn.

J. Prakt. Chem. Chem. Ztg.

Org. Prep. Proced. Int.

Curr. Org. Chem.

Synthesis-Stuttgart

Encyclopedia of Reagents for Organic Synthesis

Ber. Dtsch. Chem. Ges.

J. Prakt. Chem.

J. Prakt. Chem.

J. Prakt. Chem.

Acta Chem. Scand.

J. Prakt. Chem.

J. Prakt. Chem.

Chem. Soc. Rev.