Larock indole synthesis

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Larock indole synthesis
Named afterRichard C. Larock
Reaction type Ring forming reaction
Identifiers
RSC ontology ID RXNO:0000396

The Larock indole synthesis is a heteroannulation reaction that uses palladium as a catalyst to synthesize indoles from an ortho-iodoaniline and a disubstituted alkyne. [1] It is also known as Larock heteroannulation. The reaction is extremely versatile and can be used to produce varying types of indoles. Larock indole synthesis was first proposed by Richard C. Larock in 1991 at Iowa State University. [2]

Annulation

In organic chemistry annulation is a chemical reaction in which a new ring is constructed on a molecule.

Palladium Chemical element with atomic number 46

Palladium is a chemical element with symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1803 by William Hyde Wollaston. He named it after the asteroid Pallas, which was itself named after the epithet of the Greek goddess Athena, acquired by her when she slew Pallas. Palladium, platinum, rhodium, ruthenium, iridium and osmium form a group of elements referred to as the platinum group metals (PGMs). These have similar chemical properties, but palladium has the lowest melting point and is the least dense of them.

Indole chemical compound

Indole is an aromatic heterocyclic organic compound with formula C8H7N. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indole is widely distributed in the natural environment and can be produced by a variety of bacteria. As an intercellular signal molecule, indole regulates various aspects of bacterial physiology, including spore formation, plasmid stability, resistance to drugs, biofilm formation, and virulence. The amino acid tryptophan is an indole derivative and the precursor of the neurotransmitter serotonin.

Contents

The Larock indole synthesis Larock Indole Synthesis Scheme.png
The Larock indole synthesis

Overall reaction

The reaction usually occurs with an o-iodianiline or its derivatives, 2–5 equivalents of an alkyne, palladium(II) (PdII), an excess of sodium or potassium carbonate base, PPh3, and 1 equivalent of LiCl or n-Bu4NCl. N-methyl, N-acetyl, and N-tosyl derivatives of ortho-iodoanilines have been shown to be the most successful anilines that can be used to produce good to excellent yields. [3]

Reagents and optimal conditions

Chlorides

Either LiCl or n-Bu4N are used depending on the reaction conditions, but LiCl appears to be the more effective base in Larock indole annulation. [3] The stoichiometry of LiCl is also considerably important, as more than 1 equivalent of LiCl will slow the rate of reaction and lower the overall yield. [1]

Bases

Bases other than sodium or potassium carbonate have been used to produce a good overall yield of the annulation reaction. [3] For example, KOAc can be used with 1 equivalent of LiCl. However, the reaction using KOAc must be used at 120 °C to reach completion of the reaction at a reasonable time. In contrast K2CO3 can be used at 100 °C.

Alkynes

The Larock indole synthesis is a flexible reaction partly due to the variety of substituted alkynes that can be used in the annulation reaction. In particular, alkynes with substituents including alkyls, aryls, alkenyls, hydroxyls, and silyls have been successfully used. [3] However, bulkier tertiary alkyl or trimethylsilyl groups have been shown to provide a higher yield. [1] The annulation reaction will also proceed more efficiently when 2–5 equivalents of an alkyne is used. Less than two equivalents appear to create suboptimal conditions for the reaction.

PPh3 as a catalyst

5% mol of PPh3 was initially used in the reaction as a catalyst. [1] However, later experiments have shown that PPh3 does not significantly improve the overall yield and is not necessary. [3]

Reaction mechanism

The Larock indole synthesis proceeds via the following intermediate steps: [3]

  1. Pd(OAc)2 is reduced to Pd(0).
  2. A coordination of the chloride occurs to form a chloride-ligated zerovalent palladium.
  3. The o-iodoaniline undergoes oxidative addition to Pd(II).
  4. The alkyne coordinates to the Pd(II) by ligand exchange.
  5. A migratory insertion causes the alkyne to undergo regioselective syn-insertion into arylpalladium bond. Regioselectivity is determined during this step.
  6. The nitrogen displaces the halide in the resulting vinylic palladium intermediate to form the six-membered palladium-containing heteroatom.
  7. The Pd(II) center undergoes a reductive elimination to form the indole and regenerate Pd(0) which can then be recycled into the catalytic indole process.
Larock indole synthesis mechanism. Mechanism of the Larock Indole Synthesis.jpg
Larock indole synthesis mechanism.

The carbopalladation step is regioselective when unsymmetrical alkynes are used. [1] [3] Although it was previously believed that the alkyne is inserted with the less sterically-hindering R-group adjacent to the arylpalladium, Larock et al. observed that the larger more sterically-hindering R-group is inserted next to the arylpalladium. [1] They suggest that the driving force of the alkyne insertion may be the steric hindrance present in the developing carbon-carbon bond and the orientation of the alkyne prior to syn-insertion of the alkyne into the aryl palladium bond. [3] Alkyne insertion occurs so that the large substituent on the alkyne avoids steric strain from the short developing carbon-carbon bond by interacting with the longer carbon-palladium bond.

Regioselectivity of the alkyne insertion in Larock indole synthesis Showing that Larock Indole Synthesis is regioselective.jpg
Regioselectivity of the alkyne insertion in Larock indole synthesis

Modifications and variations

o-bromoanilines or o-chloroanilines do not undergo Larock indole synthesis. However, researchers from Boehringer-Ingelheim were able to successfully use both o-bromoanilines and o-chloroanilines to form indoles by using N-methyl-2-pyrrolidone (NMP) as the solvent with 1,1'bis(di-tert-butylphosphino)ferrocene as the palladium ligand. [4] O-bromoanilines and o-chloroanilines are more readily available and cost-effective over using o-iodianiline in Larock indole synthesis. [2]

Heterannulation of an indole using o-chloroaniline Heterannulation using o-chloroaniline derivative.jpg
Heterannulation of an indole using o-chloroaniline

Monguchi et al. also derived 2- and 2,3-substituted indoles without using LiCl. [5] The optimized Indole reaction uses 10% Pd/C (3.0 mol%) with 1.1 equivalent of NaOAc, and NMP at 110–130 °C. Monguchi et al. state that their optimized condition of the Larock indole synthesis without LiCl is a more mild, environmentally benign, and efficient strategy for producing indoles.

Applications

Indoles are one of the most prevalent heterocyclic structures found in biological processes, so the production of indole derivatives are important in a diversity of fields.

Nishikawa et al. derived iso-tryptophan by using Larock indole synthesis with pre-synthesized α-C-glucosylpropargyl glycine and o-iodo-tosylanilide. [6] This reaction produced the product which had the reverse regioselectivity of normal Larock indole synthesis. The larger substituent was placed adjacent to the forming carbon-carbon bond, rather than the carbon-palladium bond. The explanation for the reverse regioselectivity which produced the iso-tryptophan is unknown.

Larock indole synthesis of iso-tryptophan using a-C-glycosylamino acid Larock Indole Synthesis of alpha-C-Glycosylamino Acid to Iso-Tryptophan.jpg
Larock indole synthesis of iso-tryptophan using α-C-glycosylamino acid

Optically active tryptophan which adheres to the regioselectivity of the Larock indole synthesis can also be synthesized using o-iodoaniline with propargyl substituted bislactim ethyl ether. Propargyl substituted bislactim ethyl ether is generated by using Schöllkopf chiral auxiliary bis lactam ether with n-BuLi, THF, and 3-halo-1-9trimethylsily1)-1-propyne and extracting the trans-isomer of the propargyl-substituted bislactim. [7]

Chirally active tryptophan by Larock indole synthesis A reaction using Larock Indole Synthesis to produce chirally active tryptophan.jpg
Chirally active tryptophan by Larock indole synthesis

Other relevant applications include the synthesis of 5-HT1D receptor agonist MK-0462, an anti-migraine drug. [8]

Related Research Articles

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Wilkinsons catalyst chemical compound

Wilkinson's catalyst, is the common name for chloridotris(triphenylphosphane)rhodium(I), a coordination complex of rhodium with the formula [RhCl(PPh3)3] (Ph = phenyl). It is a red-brown colored solid that is soluble in hydrocarbon solvents such as benzene, and more so in tetrahydrofuran or chlorinated solvents such as dichloromethane. The compound is widely used as a catalyst for hydrogenation of alkenes. It is named after chemist and Nobel Laureate, Sir Geoffrey Wilkinson, who first popularized its use.

An alkyne trimerisation reaction is a 2+2+2 cyclization reaction in which three molecules of alkyne react to form an arene. The reaction requires metal catalysts. The process is of historic interest as well as being applicable to organic synthesis. Many variations have been developed including cyclization of mixtures of alkynes and alkenes as well as alkynes and nitriles.

Organopalladium chemistry is a branch of organometallic chemistry that deals with organic palladium compounds and their reactions. Palladium is often used as a catalyst in the reduction of alkenes and alkynes with hydrogen. This process involves the formation of a palladium-carbon covalent bond. Palladium is also prominent in carbon-carbon coupling reactions, as demonstrated in tandem reactions.

Palladium(II) chloride chemical compound

Palladium(II) chloride, also known as palladium dichloride and palladous chloride, are the chemical compounds with the formula PdCl2. PdCl2 is a common starting material in palladium chemistry – palladium-based catalysts are of particular value in organic synthesis. It is prepared by the reaction of chlorine with palladium metal at high temperatures.

Schwartzs reagent chemical compound

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Organocopper compound Organometallic compound with C-Cu bonds

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Bis(triphenylphosphine)palladium chloride chemical compound

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Palladium-catalyzed coupling reactions

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Metal phosphine complex

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Early transition metal pincer complexes

A pincer ligand is a class of chelating ligand which occupies three coordination sites of a transition metal or other coordinatively unsaturated species. The ligand often occupies a meridional orientation on the metal centre due to its planarity. This invokes a planar geometry at the metal centre for three of the coordination sites.

Vinyl iodide functional group

In organic chemistry, a vinyl iodide functional group is any alkene with an iodide substituent directly bonded to one of the alkene carbons (sp2). Vinyl iodides are versatile molecules that serve as important building blocks and precursors in organic synthesis. They are commonly used in carbon-carbon forming reactions in transition-metal catalyzed cross-coupling reactions, such as Heck reaction, Sonogashira coupling, and Suzuki coupling. Synthesis of well-defined geometry or complexity vinyl iodide is important in stereoselective synthesis of natural products and drugs.

The Danheiser Benzannulation is a chemical reaction used in organic chemistry to generate highly substituted phenols in a single step. It is named after its inventor, Dr. Rick Danheiser.

Activation of cyclopropanes by transition metals

In organometallic chemistry, the activation of cyclopropanes by transition metals is a research theme with implications for organic synthesis and homogeneous catalysis. Being highly strained, cyclopropanes are prone to oxidative addition to transition metal complexes. The resulting metallacycles are susceptible to a variety of reactions. These reactions are rare examples of C-C bond activation. The rarity of C-C activation processes has been attributed to Steric effects that protect C-C bonds. Furthermore, the directionality of C-C bonds as compared to C-H bonds makes orbital interaction with transition metals less favorable. Thermodynamically, C-C bond activation is more favored than C-H bond activation as the strength of a typical C-C bond is around 90 kcal per mole while the strength of a typical unactivated C-H bond is around 104 kcal per mole.

References

  1. 1 2 3 4 5 6 Larock, R. C.; Yum, E. K. (1991). "Synthesis of indoles via palladium-catalyzed heteroannulation of internal alkynes". Journal of the American Chemical Society. 113 (17): 6689. doi:10.1021/ja00017a059.
  2. 1 2 Li, J.J. (2011) "Larock Indole Synthesis" in Name Reactions in Heterocyclic Chemistry II, John Wiley & Sons, ISBN   978-0-470-08508-0, pp. 143–166.
  3. 1 2 3 4 5 6 7 8 9 10 Larock, R. C.; Yum, E. K.; Refvik, M. D. (1998). "Synthesis of 2,3-Disubstituted Indoles via Palladium-Catalyzed Annulation of Internal Alkynes". The Journal of Organic Chemistry. 63 (22): 7652. doi:10.1021/jo9803277.
  4. 1 2 Li, G., Liu, J., Lu, B., Roschangar, F., Senanayake, C.H., Shen, M. (2005) "By reacting with substituted acetylenes in the presence of a phosphine ligand and a base (K2CO3); used to make drugs" U.S. Patent 20,050,209,465
  5. ↑ Monguchi, Y.; Mori, S.; Aoyagi, S.; Tsutsui, A.; Maegawa, T.; Sajiki, H. (2010). "Palladium on carbon-catalyzed synthesis of 2- and 2,3-substituted indoles under heterogeneous conditions". Organic & Biomolecular Chemistry. 8 (14): 3338. doi:10.1039/c004939e.
  6. 1 2 Nishikawa, T.; Wada, K.; Isobe, M. (2002). "Synthesis of Novel .ALPHA.-C-Glycosylamino Acids and Reverse Regioselectivity in Larock's Heteroannulation for the Synthesis of the Indole Nucleus". Bioscience, Biotechnology, and Biochemistry. 66 (10): 2273. doi:10.1271/bbb.66.2273.
  7. 1 2 Ma, C.; Liu, X.; Yu, S.; Zhao, S.; Cook, J. M. (1999). "Concise synthesis of optically active ring-A substituted tryptophans". Tetrahedron Letters. 40 (4): 657. doi:10.1016/S0040-4039(98)02497-6.
  8. ↑ Chen, C.-Y, Lieberman, D.R., Larsen, R.D., Reamer, R.A., Verhoeven, T.R., Reider, P.J., Cottrell, I.F., Houghton, P.G. (1994). "Synthesis of the 5-HT1D agonist MK-0462 via a Pd-catalyzed coupling reaction". Tetrahedron Lett. 35: 6981–6984. doi:10.1016/0040-4039(94)88204-5.
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