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<title>Chan–Lam coupling</title>

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<span id="openzim-page-title" class="mw-page-title-main"><span class="mw-page-title-main">Chan–Lam coupling</span></span>

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<th style="width: 30%; background: #ACE1AF; text-align: center;" colspan="2">Chan-Lam coupling

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<td>Named after

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<td>Dominic Chan <br> Patrick Lam

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<td>Reaction type

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<td><a href="Coupling_reaction" title="Coupling reaction">Coupling reaction</a>

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<th style="width: 30%; background: #ACE1AF; text-align: center;" colspan="2">Identifiers

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<td>Organic Chemistry Portal

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<td><span class="reflink nourlexpansion"><a rel="nofollow" class="external text" href="https://www.organic-chemistry.org/namedreactions/chan-lam-coupling.shtm">chan-lam-coupling</a></span>

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<td><a href="Royal_Society_of_Chemistry" title="Royal Society of Chemistry">RSC</a> ontology ID

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<p>The <b>Chan–Lam coupling</b> reaction, also known as the <b>Chan–Evans–Lam coupling</b>, is a <a href="Cross-coupling_reaction" title="Cross-coupling reaction">cross-coupling reaction</a> between an aryl <a href="Boronic_acid" title="Boronic acid">boronic acid</a> and an <a href="Alcohol_(chemistry)" title="Alcohol (chemistry)">alcohol</a> or an <a href="Amine" title="Amine">amine</a> to form the corresponding secondary aryl amines or <a href="Aryl_ether" class="mw-redirect" title="Aryl ether">aryl ethers</a>, respectively.<sup id="cite_ref-1" class="reference"><a href="#cite_note-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup> The Chan–Lam coupling is catalyzed by <a href="Copper" title="Copper">copper</a> complexes. It can be conducted open to air at room temperature. The more popular <a href="Buchwald%E2%80%93Hartwig_coupling" class="mw-redirect" title="Buchwald–Hartwig coupling">Buchwald–Hartwig coupling</a> relies on the use of <a href="Palladium" title="Palladium">palladium</a>.

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<div class="mw-heading mw-heading2"><h2 id="History">History</h2></div>

<p>Dominic Chan, <a href="David_A._Evans" title="David A. Evans">David Evans</a>, and Patrick Lam published their work nearly simultaneously.<sup id="cite_ref-2" class="reference"><a href="#cite_note-2"><span class="cite-bracket">[</span>2<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-3" class="reference"><a href="#cite_note-3"><span class="cite-bracket">[</span>3<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-4" class="reference"><a href="#cite_note-4"><span class="cite-bracket">[</span>4<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-5" class="reference"><a href="#cite_note-5"><span class="cite-bracket">[</span>5<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-6" class="reference"><a href="#cite_note-6"><span class="cite-bracket">[</span>6<span class="cite-bracket">]</span></a></sup> The mechanism however remained uncertain for many years. Later developments by others extended the scope to include using <a href="Carboxylic_acid" title="Carboxylic acid">carboxylic acids</a>, giving aryl-ester products.<sup id="cite_ref-7" class="reference"><a href="#cite_note-7"><span class="cite-bracket">[</span>7<span class="cite-bracket">]</span></a></sup>

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<div class="mw-heading mw-heading2"><h2 id="Mechanism">Mechanism</h2></div>

<p>Analysis of the mechanism is complicated by the lability of copper reagents and the multicomponent nature of the reaction.<sup id="cite_ref-JACS_8-0" class="reference"><a href="#cite_note-JACS-8"><span class="cite-bracket">[</span>8<span class="cite-bracket">]</span></a></sup> The reaction proceeds via the formation of copper-aryl complexes. A copper(III)-aryl-alkoxide or copper(III)-aryl-amide intermediate undergoes <a href="Reductive_elimination" title="Reductive elimination">Reductive elimination</a> to give the aryl ether or aryl amine, respectively:

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<div class="mw-heading mw-heading2"><h2 id="Example">Example</h2></div>

<p>An example of the Chan–Lam coupling to synthesize biologically active compounds is shown below:

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<p>Compound 1, a pyrrole, is coupled with aryl boronic acid, 2, to afford product 3, which is then carried forward to the target 4. The <a href="Nitrile_group" class="mw-redirect" title="Nitrile group">nitrile group</a> of 2 does not poison the catalyst. <a href="Pyridine" title="Pyridine">Pyridine</a> is the ligand used for the reaction. Although the reaction requires three days, it was carried out at room temperature in ambient air and resulted in a 93% yield.

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<div class="mw-heading mw-heading2"><h2 id="Further_reading">Further reading</h2></div>

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</style><cite id="CITEREFKodepelly_Sanjeeva_RaoTian-Shung_Wu2012" class="citation journal cs1">Kodepelly Sanjeeva Rao; Tian-Shung Wu (2012). "Chan-Lam coupling reactions: synthesis of heterocycles". <i>Tetrahedron</i>. <b>68</b> (38): <span class="nowrap">7735–</span>7754. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1016%2Fj.tet.2012.06.015">10.1016/j.tet.2012.06.015</a>.</cite></li></ul>

<div class="mw-heading mw-heading2"><h2 id="References">References</h2></div>

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<li id="cite_note-1"><span class="mw-cite-backlink"><b><a href="#cite_ref-1">^</a></b></span> <span class="reference-text"><cite id="CITEREFJennifer_X._Qiao,_Patrick_Y.S._Lam2011" class="citation book cs1">Jennifer X. Qiao, Patrick Y.S. Lam (2011). "Recent Advances in Chan–Lam Coupling Reaction: Copper-Promoted C–Heteroatom Bond Cross-Coupling Reactions with Boronic Acids and Derivatives". In Dennis G. Hall (ed.). <i>Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials</i>. Wiley-VCH. pp. <span class="nowrap">315–</span>361. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1002%2F9783527639328.ch6">10.1002/9783527639328.ch6</a>. <a href="ISBN_(identifier)" class="mw-redirect" title="ISBN (identifier)">ISBN</a> <bdi>9783527639328</bdi>.</cite></span>

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<li id="cite_note-2"><span class="mw-cite-backlink"><b><a href="#cite_ref-2">^</a></b></span> <span class="reference-text"><cite id="CITEREFChan,_DominicMonaco,_KevinWang,_R.Winter,_Michael1998" class="citation journal cs1">Chan, Dominic; Monaco, Kevin; Wang, R.; Winter, Michael (1998). "New N- and O-Arylations with Phenylboronic acids and Cupric Acetate". <i>Tetrahedron Lett</i>. <b>39</b> (19): <span class="nowrap">2933–</span>2936. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1016%2Fs0040-4039%2898%2900503-6">10.1016/s0040-4039(98)00503-6</a>.</cite></span>

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<li id="cite_note-3"><span class="mw-cite-backlink"><b><a href="#cite_ref-3">^</a></b></span> <span class="reference-text"><cite id="CITEREFEvans,_DavidKatz,_J.West,_T.1998" class="citation journal cs1">Evans, David; Katz, J.; West, T. (1998). "Synthesis of Diaryl Ethers through the Copper-Promoted Arylation of Phenols with Arylboronic Acids. An Expedient Synthesis of Thyroxine". <i>Tetrahedron Lett</i>. <b>39</b> (19): <span class="nowrap">2937–</span>2942. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1016%2Fs0040-4039%2898%2900502-4">10.1016/s0040-4039(98)00502-4</a>.</cite></span>

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<li id="cite_note-4"><span class="mw-cite-backlink"><b><a href="#cite_ref-4">^</a></b></span> <span class="reference-text"><cite id="CITEREFLam,_PatrickClark,_CharlesSaubern,_SimonAdams,_Jessica1998" class="citation journal cs1">Lam, Patrick; Clark, Charles; Saubern, Simon; Adams, Jessica; Winters, Michael; Chan, Dominic; Combs, Andrew (1998). "New Aryl/Heteroaryl C-N Bond Cross-coupling Reactions via Arylboronic Acid/Cupric Acetate Arylation". <i>Tetrahedron Lett</i>. <b>39</b> (19): <span class="nowrap">2941–</span>2944. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1016%2Fs0040-4039%2898%2900504-8">10.1016/s0040-4039(98)00504-8</a>.</cite></span>

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<li id="cite_note-5"><span class="mw-cite-backlink"><b><a href="#cite_ref-5">^</a></b></span> <span class="reference-text"><cite id="CITEREFLam,_PatrickBonne,_DamienVincent,_GuillaumeClark,_Charles2003" class="citation journal cs1">Lam, Patrick; Bonne, Damien; Vincent, Guillaume; Clark, Charles (2003). "Copper-promoted/catalyzed C-N and C-O Bond Cross-coupling with Vinylboronic Acid and Its Utilities". <i>Tetrahedron Lett</i>. <b>44</b>: <span class="nowrap">4927–</span>4931. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1016%2Fs0040-4039%2803%2901037-2">10.1016/s0040-4039(03)01037-2</a>.</cite></span>

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<li id="cite_note-6"><span class="mw-cite-backlink"><b><a href="#cite_ref-6">^</a></b></span> <span class="reference-text"><cite id="CITEREFChan,_DominicMonaco,_KevinLi,_RenhuaBonne,_Damien2003" class="citation journal cs1">Chan, Dominic; Monaco, Kevin; Li, Renhua; Bonne, Damien; Clark, Charles; Lam, Patrick (2003). "Copper Promoted C-N and C-O Bond Cross-coupling with Phenyl and Pyridylboronates". <i>Tetrahedron Lett</i>. <b>44</b>: <span class="nowrap">3863–</span>3865. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1016%2Fs0040-4039%2803%2900739-1">10.1016/s0040-4039(03)00739-1</a>.</cite></span>

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<li id="cite_note-7"><span class="mw-cite-backlink"><b><a href="#cite_ref-7">^</a></b></span> <span class="reference-text"><cite id="CITEREFZhangZhangZhangCheng2010" class="citation journal cs1">Zhang, Lingli; Zhang, Guoying; Zhang, Manli; Cheng, Jiang (2010). "Cu(OTf)<sub>2</sub>-Mediated Chan–Lam Reaction of Carboxylic Acids to Access Phenolic Esters". <i>J. Org. Chem</i>. <b>75</b> (21): <span class="nowrap">7472–</span>7474. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1021%2Fjo101558s">10.1021/jo101558s</a>. <a href="PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/20942492">20942492</a>.</cite></span>

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<cite id="CITEREFVantourout,_J._C.Miras,_H._N.Isidro-Llobet,_A.Sproules,_S.2017" class="citation journal cs1">Vantourout, J. C.; Miras, H. N.; Isidro-Llobet, A.; Sproules, S.; Watson, A. J. B. (2017). <a rel="nofollow" class="external text" href="http://eprints.gla.ac.uk/139910/1/139910.pdf">"Spectroscopic Studies of the Chan–Lam Amination: A Mechanism-Inspired Solution to Boronic Ester Reactivity"</a> <span class="cs1-format">(PDF)</span>. <i>Journal of the American Chemical Society</i>. <b>139</b> (13): <span class="nowrap">4769–</span>4779. <a href="Bibcode_(identifier)" class="mw-redirect" title="Bibcode (identifier)">Bibcode</a>:<a rel="nofollow" class="external text" href="https://ui.adsabs.harvard.edu/abs/2017JAChS.139.4769V">2017JAChS.139.4769V</a>. <a href="Doi_(identifier)" class="mw-redirect" title="Doi (identifier)">doi</a>:<a rel="nofollow" class="external text" href="https://doi.org/10.1021%2Fjacs.6b12800">10.1021/jacs.6b12800</a>. <a href="PMID_(identifier)" class="mw-redirect" title="PMID (identifier)">PMID</a> <a rel="nofollow" class="external text" href="https://pubmed.ncbi.nlm.nih.gov/28266843">28266843</a>.</cite></span>

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