Categories: C-C Bond Formation > Arenes, Alkynes >

Alkynylation

Name Reactions

Versatile Cross Coupling Methods:

Hiyama Coupling
(R-X + R'-SiR''₃)

Hiyama-Denmark Coupling
(R-X + R-SiMe₂OH)

Kumada Coupling
(R-X + R'-MgX)

Negishi Coupling
(R-X + R'-ZnX)

Stille Coupling
(R-X + R'-SnR''₃)

Suzuki Coupling
(R-X + R'-BY₃)

Recent Literature

Rapid Homogeneous-Phase Sonogashira Coupling Reactions Using Controlled Microwave Heating
M. Erdélyi, A. Gogoll, J. Org. Chem., 2001, 66, 4165-4169.

Substoichiometric amounts of ZnCl₂ promote a room temperature, Pd/P(t-Bu)₃-catalyzed cross-coupling of aryl bromides with alkynes. A Pd(I) dimer is a particularly active precatalyst for this reaction. The reaction is general for a broad range of aryl bromides.
A. D. Finke, E. C. Elleby, M. J. Boyd, H. Weissman, J. S. Moore, J. Org. Chem., 2009, 74, 8897-8900.

N¹-(2,6-Dimethylphenyl)-N²-(pyridin-2-ylmethyl)oxalamide (DMPPO) is an effective ligand for copper-catalyzed coupling reactions 1-alkynes with (hetero)aryl bromides at 100 °C and with iodides at 80 °C. Both (hetero)aryl and alkyl substituted 1-alkynes worked well leading to the formation of internal alkynes in great diversity using low catalyst loadings.
Y. Chen, S. Li, L. Xu, D. Ma, J. Org. Chem., 2023, 88, 3330-3334.

Sustainable HandaPhos-ppm Palladium Technology for Copper-Free Sonogashira Couplings in Water under Mild Conditions
S. Handa, J. D. Smith, Y. Zhang, B. S. Takale, F. Gallou, B. H. Lipshutz, Org. Lett., 2018, 20, 542-545.

An efficient ligand-, copper-, and amine-free palladium-catalyzed Sonogashira reaction of aryl iodides and bromides with terminal alkynes at room temperature has been developed. The key reagent is tetrabutylammonium acetate as the base. This method tolerates a broad range of functional groups.
S. Urgaonkar, J. G. Verkade, J. Org. Chem., 2004, 69, 5752-5755.

t-Bu₂(p-NMe₂C₆H₄)P is an efficient ligand for palladium catalysts in Heck alkynylation of various aryl halides with a range of aryl- and alkyl-acetylenes in excellent yields, under relatively low Pd loadings. Preliminary mechanistic studies on the negative copper effect and substrate effect of aryl acetylenes help to better understand the cross-coupling pathway of Heck alkynylation.
X. Pu, H. Li, T. J. Colacot, J. Org. Chem., 2013, 78, 568-581.

A highly efficient and practical protocol for the coupling of terminal alkynes with aryl iodides is catalyzed by the inexpensive and environmentally benign combination of Fe/Cu. The versatility, generality, low cost, and environmental friendliness, in combination with exceptionally high reaction rates, render this method particularly attractive for industrial applications.
H. Huang, H. Jiang, K. Chen, H. Liu, J. Org. Chem., 2008, 73, 9061-9064.

An inexpensive catalytic system using a readily available copper/ligand combination for the Sonogashira-type cross-coupling of aryl iodides and phenyl- and hexyl-acetylene affords disubstituted alkynes in good yields.
F. Monnier, F. Turtaut, L. Duroure, M. Taillefer, Org. Lett., 2008, 10, 3203-3206.

A Cu₂O-catalyzed cross-coupling reaction of alkynes with aryl iodides tolerates a broad range of functional groups and enables even the conversion of sterically demanding substrates with only 5-10 mol% of the catalyst.
W.-T. Tsai, Y.-Y. Lin, Y.-A. Chen, C.-F. Lee, Synlett, 2014, 25, 443-447.

In the presence of bis(dibenzylideneacetone)palladium(0) and cesium carbonate, a variety of alkynyl halides underwent a ligand-free Suzuki-Miyaura cross-coupling reaction with organoboronic acids at room temperature under aerobic conditions to afford the corresponding unsymmetrical diarylalkynes in good yields.
J.-S. Tang, M. Tian, W.-B. Sheng, C.-C. Guo, Synthesis, 2012, 44, 541-546.

Pd(PhCN)₂Cl₂/P(t-Bu)₃ serves as an efficient and a versatile catalyst for Sonogashira reactions of aryl bromides, accomplishing a wide range of couplings at room-temperature. This study provides further evidence of the usefulness of bulky, electron-rich phosphines in palladium-catalyzed coupling reactions.
T. Hundertmark, A. F. Littke, S. L. Buchwald, G. C. Fu, Org. Lett., 2000, 2, 1729-1731.

General protocols for the palladium-catalyzed coupling of aryl chlorides and alkynes and aryl tosylates and alkynes were developed. Addition of a copper cocatalyst can inhibit product formation. In the case of highly active catalysts, screening for new catalyst systems need to be carried out both in the presence and absence of copper.
D. Gelman, S. L. Buchwald, Angew. Chem. Int. Ed., 2003, 42, 5993-5996.

A Suzuki-Miyaura coupling reaction between alkynylboronic ester "ate-complexes" and arylbromides or vinylbromides provides the desired products in good yields. Alkynylboronic ester "ate-complexes" are generated in situ from acetylenic derivatives, n-butyllithium, and triisopropylborate.
A.-S. Castanet, F. Colobert, T. Schlama, Org. Lett., 2000, 2, 3559-3561.

NIS mediates a transition-metal-free arylation of terminal alkynes with a tetracoordinate boron intermediate. The reaction offers high efficiency, wide substrate range, and good functional group tolerance.
M. Ye, M. Hou, Y. Wang, X. Ma, K. Yang, Q. Song, Org. Lett., 2023, 25, 1787-1792.

A palladium-catalyzed cross-coupling reaction of alkyl-, vinyl-, alkynyl-, and arylindium compounds with vinyl and aryl triflates or iodides proceeds in excellent yields and high chemoselectivity without any excess of the organometallic. Remarkably, indium organometallics transfer efficiently all organic groups attached to the metal.
I. Pérez, J. P. Sestelo, L. A. Sarandeses, Org. Lett., 1999, 1, 1267-1269.

The palladium-catalyzed cross-coupling reaction of potassium alkynyltrifluoroborates with aryl halides or triflates proceeds readily with moderate to excellent yields. The potassium alkynyltrifluoroborates are air- and moisture-stable crystalline solids that can be stored indefinitely, which will provide an advantage in applications to combinatorial chemistry.
G. A. Molander, B. W. Katona, F. Machrouhi, J. Org. Chem., 2002, 67, 8416-8423.

A highly active, air- and moisture-stable and easily recoverable magnetic-nanoparticle-supported palladium catalyst enables the Suzuki cross-coupling reaction of alkynyl bromides with organoboron derivatives in very good yields in ethanol. The supported palladium catalyst can be recovered and reused up to 16 times without significant loss of catalytic activity.
X. Zhang, P. Li, Y. Ji, L. Zhang, L. Wang, Synthesis, 2011, 2975-2983.

The use of TMPLi base in a pentane/THF mixture at 25°C or use of a metal alkoxide base in dioxane at elevated temperature enable base-mediated, transition-metal-free alkynylations of aryl chlorides that proceed via benzyne intermediates. Fluoro, trifluoromethyl, silyl, cyano, and alcohol functionalities are compatible with the reaction conditions.
T. Truong, O. Daugulis, Org. Lett., 2011, 13, 4172-4175.

In situ conversion of terminal alkynes into alkynylzinc derivatives enables an efficient Pd-catalyzed cross coupling with aryl electrophiles. One procedure is particularly valuable in cases where electron-deficient alkynes are used, whereas the other is operationally simple and very satisfactory in less demanding cases.
L. Anastasia, E.-i. Negishi, Org. Lett., 2001, 3, 3111-3113.

Cross coupling of ortho-substituted aryl Grignard reagents with alkynyl Grignard reagents can be performed without adding any transition metal in the presence of 2,2,6,6-tetramethylpiperidine-N-oxyl radical (TEMPO) as an environmentally benign organic oxidant. Importantly, functional groups such as esters, amides, and cyanides are tolerated.
M. S. Maji, S. Murarka, A. Studer, Org. Lett., 2010, 12, 3878-3881.

Triarylsulfonium, alkyl- and fluoroalkyl(diaryl)sulfonium, and aryl(dialkyl)sulfonium triflates are successfully used as cross-coupling participants in the Sonogashira reaction. Terminal alkynes reacted mildly with arylsulfonium salts at room temperature under Pd- and Cu-cocatalysis to give the corresponding arylalkynes in very good yield.
Z.-Y. Tian, S.M. Wang, S.-J. Jia, H.-X. Song, C.-P. Zhang, Org. Lett., 2017, 19, 5454-5457.

Palladium catalyzes a coupling reaction of diaryliodonium compounds with enynes and electron-deficient alkynes to give aryl alkynes in good yields.
U. Radhakrishnan, P. J. Stang, Org. Lett., 2001, 3, 859-860.

A palladium-catalyzed C-C cross-coupling reaction of gem-dibromoalkenes and halobenzenes provides terminal alkynes in one pot through a tandem elimination-hydrodebromination process. This convenient reaction proceeded under copper-free Sonogashira coupling reaction conditions in good to excellent yields.
Y. Ji, N. Zhong, Z. Kang, G. Yan, M. Zhao, Synlett, 2018, 29, 209-214.

A palladium-catalyzed domino coupling reaction of 1,1-dibromo-1-alkenes with triarylbismuth nucleophiles furnishes disubstituted alkynes directly. The couplings are very fast, affording high yields of alkynes in a short reaction time.
M. L. N. Rao, D. N. Jadhav, P. Dasgupta, Org. Lett., 2010, 12, 2048-2051.

A triethylamine-catalyzed metalation of terminal alkynes with trimethylaluminum (a readily available, inexpensive, and nontoxic metalating agent) gives alkynyldimethylaluminum reagents. These compounds react efficiently with various aromatic and heterocyclic halides in the presence of a palladium catalyst offering a simple entry to numerous internal alkynes.
B. Wang, M. Bonin, L. Micouin, Org. Lett., 2004, 6, 3481-3484.

Cross-Coupling of Alkynylsilanols with Aryl Halides Promoted by Potassium Trimethylsilanolate
S. E. Denmark, S. A. Tymonko, J. Org. Chem., 2003, 68, 9151-9154.

A CsF-mediated in situ TMS-alkyne desilylation followed by Sonogashira coupling enables the synthesis of various alkynyl benzenes and heteroarenes in good yields. This methodology offers excellent functional group tolerance and simple purification, which allows large-scale applications, and avoids the challenging use of volatile free alkynes.
J. S. Capani Jr., J. E. Cochran, J. Liang, J. Org. Chem., 2019, 84, 9378-9384.

Unsymmetrical diarylalkynes are accessible by a one-pot procedure from two different aryl halides and (trimethylsilyl)acetylene. A Pd/Cu-catalyzed Sonogashira coupling of an aryl halide with (trimethylsilyl)acetylene is followed by desilylation of the formed aryl(trimethylsilyl)acetylene with aqueous potassium hydroxide and a second Sonogashira coupling with an aryl iodide.
R. Severin, J. Reimer, S. Doye, J. Org. Chem., 2010, 75, 3518-3521.

In the presence of Pd(OAc)₂ and Xphos, alkynyl carboxylic acids smoothly underwent a decarboxylative coupling reaction with various benzyl halides or aryl halides, providing internal alkynes in good yields. It is noteworthy that the optimal conditions are compatible with a wide range of aryl halides.
W.-W. Zhang, X.-G. Zhang, J.-H. Li, J. Org. Chem., 2010, 75, 5259-5264.

Employing propiolic acid as a difunctional alkyne, and using the consecutive reactions of a Sonogashira coupling and a decarboxylative coupling, unsymmetrically substituted diaryl alkynes were obtained in good yield.
J. Moon, M. Jeong, H. Nam, J. Ju, J. H. Moon, H. M. Jung, S. Lee, Org. Lett., 2008, 10, 945-948.

In a Pd-catalyzed decarbonylative Sonogashira cross-coupling of carboxylic acids as ubiquitous and orthogonal electrophilic cross-coupling partners, the carboxylic acid is activated in situ by the formation of a mixed anhydride. A subsequent decarbonylation provides an aryl-Pd intermediate, which is intercepted by alkynes to access the traditional Pd(0)/(II) cycle.
C. Liu, M. Szostak, Org. Lett., 2021, 23, 4726-4730.

A palladium-catalyzed cross-coupling reaction between a wide range of aryl iodides and lithium tetrakis(ethoxycarbonylethynyl)indates (0.35 equiv) enables an efficient synthesis of ethyl arylpropiolates. Lithium tetrakis(ethoxycarbonylethynyl)indates can be generated in situ from ethyl propiolate and n-butyllithium and a subsequent transmetallation with indium trichloride.
Y. Park, D. Kang, W. H. Jeon, T. Ryu, P. H. Lee, Synthesis, 2014, 46, 2305-2311.

Air- and moisture-stable [Pd(IPr)(3-CF₃-An)Cl₂] (An = aniline) catalyzes a Sonogashira cross-coupling of aryl ammonium salts. This reaction offers broad scope and excellent C-N activation selectivity in the challenging alkynylative cross-coupling of aryl ammonium salts.
P. Lei, Y. Wang, C. Zhang, X. Hu, J. Feng, Z. Ma, X. Liu, R. Szostak, M. Szostak, Org. Lett., 2022, 24, 6310-6315.

A copper-catalyzed coupling of Grignard or organozinc nucleophiles with chloroynamides, formed in situ from 1,2-dichloroenamides, provides a broad range of ynamides. The reaction is readily scaled and overcomes typical limitations in ynamide synthesis such as the use of ureas, carbamates, and bulky or aromatic amide derivatives.
S. J. Mansfield, R. C. Smith, J. R. J. Yong, O. L. Garry, E. A. Anderson, Org. Lett., 2019, 21, 2918-2922.

Various substituted phenols are ethynylated at the ortho position with silylated chloroethyne in the presence of a catalytic amount of GaCl₃ and lithium phenoxide. The lithium salt is essential for the catalysis, and addition of 2,6-di(tert-butyl)-4-methylpyridine inhibits desilylation and hydration of the products. The mechanism is discussed.
K. Kobayahi, M. Arisawa, M. Yamaguchi, J. Am. Chem. Soc., 2002, 124, 8528-8529.

(PPh₃)₂CuBH₄ catalyzes a convenient, efficient, and inexpensive palladium-free Sonogashira cross-coupling of o-iodoanilines with terminal alkynes under an air atmosphere to provide 2-ethynylaniline derivatives in very good yield. Notable features of the approach include good functional group tolerance and scalability.
X. Chen, X.-Y. Zhou, Synthesis, 2023, 55, 1213-1220.

A carbenoid Fritsch-Buttenberg-Wiechell (FBW) rearrangement of a substituted dibromoolefinic precursor is used to generate a lithium acetylide, and subsequent trapping with carbon-based electrophiles provides a wide range of di- and triynes. The lithium acetylide formed from the FBW reaction can also undergo transmetalation to provide zinc, copper, tin, or platinum acetylides.
T. Luu, Y. Morisaki, N. Cunningham, R. R. Tykwinski, J. Org. Chem., 2007, 72, 9622-9629.