Metal-Catalyzed Haloalkynylation Reactions

Abstract

Metal catalysis has revolutionized synthetic chemistry, leading to entirely new, very efficient transformations, which enable access to complex functionalized molecules. One such new transformation method is the haloalkynylation reaction, in which both a halogen atom and an alkynyl unit are transferred to an unsaturated carbon-carbon bond. This minireview summarizes the development of metal-catalyzed haloalkynylation reactions since their beginning about a decade ago. So far, arynes, alkenes and alkynes have been used as unsaturated systems and the reactivities of these systems are summarized in individual chapters of the minireview. Especially, the last few years have witnessed a rapid development due to gold-catalyzed reactions. Here, we discuss how the choice of the catalytic system influences the regio- and stereoselectivity of the addition.

Keywords: C−C coupling; catalysis; haloalkynes; haloalkynylation.

Scheme 1

The haloalkynylation reaction of arynes (A), alkenes (B) and alkynes (C) can be described by means of the synthons I, II and III.

Scheme 2

Strategies for the synthesis of ortho‐alkynylaryl halides using the Sonogashira reaction.

Scheme 3

Copper‐catalyzed bromoalkynylation of benzynes. Reaction conditions: CuBr₂ (20 mol%), KF, 18‐crown‐6, dimethoxyethane (DME), 25 °C.

Scheme 4

Plausible catalytic cycle for the copper‐catalyzed bromoalkynylation of benzynes Int1.

Scheme 5

Iodoalkynylation of aromatic compounds using the three‐component reaction of a Kobayashi reagent, an alkyne, and NIS. Reaction conditions: A (IMesCuCl) (10 %), Cs₂CO₃, CsF, MeCN, 60 °C, 12 h.

Scheme 6

Proposed catalytic cycle for the three‐component reaction of a Kobayashi reagent, an alkyne, and NIS.

Scheme 7

a) Cu(I)‐mediated bromoalkynylation via benzynes generated by the hexadehydro‐Diels‐Alder (HDDA) cycloisomerization reaction. Reaction conditions: CuBr (10 %), MeCN, 80 °C, 16 h. b) Proposed catalytic cycle for the Cu(I)‐catalyzed bromoalkynylation of benzynes Int9.

Scheme 8

Haloalkynylation of norbornadiene (17) with the haloacetylenes 18.

Scheme 9

Pd‐catalyzed haloalkynylation of the norbornene scaffolds 20 depending on the solvent. Reaction conditions: 50 °C, 12 h, Pd(OAc)₂ (5‐10 mol%).[ ¹⁶ , ¹⁷ ]

Scheme 10

Proposed catalytic cycle for the Pd‐catalyzed haloalkynylation of norbornene scaffolds 20 depending on the solvent.

Scheme 11

Gold(I)‐catalyzed chloroalkynylation of 1,1‐disubstituted alkenes with chloroarylacetylenes. Reaction conditions: B ⋅ SbF₆ ⁻ ([JohnPhosAu(NCMe)]SbF₆) (5 mol%), DCM, room temperature.

Scheme 12

Gold(I)‐catalyzed bromoalkynylation of alkenes with bromophenylacetylene (10 a). Reaction conditions: B ⋅ BArF₂₄ ⁻ ([tBuXPhosAu(NCMe)]BArF₂₄) (3 mol%), DCM (1 m), 23 °C.

Scheme 13

a) Gold(I)‐catalyzed bromoalkynylation of alkenes with bromoarylacetylenes. Reaction conditions: D (SPhosAuCl) (5 mol%), NaBArF₂₄ (10 mol%) or E (2.5 mol%), NaBArF₂₄ (2.5 mol%), CHCl₃, room temperature.

Scheme 14

Enantioselective gold(I)‐catalyzed haloalkynylation of cyclopentene with haloarylacetylenes. Reaction conditions: (S)‐F (2.5 mol%), NaBArF₂₄ (2.5 mol%), CHCl₃.

Scheme 15

Investigation of the reaction mechanism of the gold(I)‐catalyzed 1,2‐haloalkynylation of alkenes with ¹³C‐labeled starting materials. As ligands for the gold(I) complexes, t‐BuXPhos and JohnPhos were used.[ ¹⁸ , ¹⁹ ]

Scheme 16

By means of B3LYP‐D3BJ(SMD) calculated catalytic cycle for the gold(I)‐catalyzed 1,2‐chloroalkynylation of isobutene (25 j) with chlorophenylacetylene (26 a). The free energies (ΔG) of the intermediates Int23‐Int25 (black numbers) and transition states (blue numbers) are given in kcal/mol and are relative to Int22. [Au]⁺=JohnPhosAu⁺.

Scheme 17

Palladium‐catalyzed 1,1‐bromoalkynylation of terminal alkenes with the silyl‐protected alkynyl bromide 38 a. Reaction conditions: toluene, 75 °C, 20 h, Pd(OAc)₂ (10 mol%).

Scheme 18

Synthesis of functionalized enynes starting from activated alkynes (a) and haloalkynes (b).

Scheme 19

a) Palladium‐catalyzed bromoalkynylation of alkynes. Reaction conditions: Pd(OAc)₂ (5 mol%), MeCN, room temperature. b) Proposed catalytic cycle for the palladium‐catalyzed bromoalkynylation of alkynes.

Scheme 20

a) Palladium‐catalyzed addition of silyl‐substituted haloalkynes to terminal alkynes. Reaction conditions: [Pd₂(dba)₃], PPh₃, decalin, 130 °C, 6 h. b) Possible reaction mechanism.

Scheme 21

a) Dimerization of haloalkynes with dual‐activation catalysts. Reaction conditions: DAC⋅PF₆ ⁻ or DAC⋅NTf₂ ⁻, MeCN, 70 °C, 14 h. b) Mechanistic proposal for the dimerization with dual‐activation catalysts.

Scheme 22

Gold(I)‐catalyzed haloalkynylation of aryl alkynes. Reaction conditions: [JohnPhosAu(NCMe)]SbF₆ (5 mol%), DCM or DCE.[ ³⁵ , ³⁶ ]

Scheme 23

Gold(I)‐catalyzed 1,2‐haloalkynylation of aryl alkynes using ¹³C‐labeled starting materials and different phosphine ligands.

Scheme 24

By means of B3LYP‐D3BJ(SMD) calculated catalytic cycle for the gold(I)‐catalyzed 1,2‐chloroalkynylation of chlorophenylacetylene (26 a). The free energies (ΔG) of the intermediates Int36‐Int39 (numbers in brackets) and transition states (numbers above the arrows) are given in kcal/mol and are relative to Int35. [Au]⁺=JohnPhosAu⁺.

Scheme 25

Au‐catalyzed bromoalkynylation of terminal alkynes and hydroalkynylation of aromatic bromoalkynes. Reaction conditions: I (SIPrAuCl) (5 mol%), NaBArF₂₄ (5 mol%) or AgOTf (5 mol%), CHCl₃, room temperature.

Scheme 26

Ruthenium‐catalyzed trans‐chloroalkynylation of alkynes. Reaction conditions: [Cp*RuCl]₄, 1,2‐dichloroethane, 80 °C.

Scheme 27

Chemoselective heterocyclization of bromoenynes 45 via a transition‐metal‐free sulfuration/cyclization process to the thiophenes 60 and 61. TBPB=tetrabutylphosphonium bromide.