Danheiser benzannulation

Last updated August 13, 2024

The Danheiser benzannulation is a chemical reaction used in organic chemistry to generate highly substituted phenols in a single step. It is named after Rick L. Danheiser who developed the reaction.

Annulation

An annulation is defined as a transformation of one or more acyclic precursors resulting in the fusion of a new ring via two newly generated bonds.^[1] These strategies can be used to create aromatic systems from acyclic precursors in a single step, with many substituents already in place.^[2] A common synthetic annulation reaction is the Robinson annulation. It is a useful reactions for forming six-membered rings and generating polycyclic compounds. It is the combination of the Michael Addition and the Aldol Condensation reaction.^[3]

Reaction development

Polysubstituted benzenes were originally synthesized by substitution reactions on aromatic precursors. However, these reactions can have low regioselectivity and are prone to over substitution. Directed ortho metalation requires precursors that are often unstable to metallating reagents. Both these synthetic routes pose issues in total synthesis. In 1984 a new synthetic strategy was developed by Rick Danheiser to address these shortcomings.^[4]

Reaction

The Danheiser benzannulation is a regiocontrolled phenol annulation. This annulation provides an efficient route to form an aromatic ring in one step.^[5] It is a thermal combination of a substituted cyclobutenones with heterosubstituted acetylenes to produce highly substituted aromatic compounds, specifically phenols or resorcinols (Scheme 1).^[6] This benzannulation reaction creates previously unaccessed aromatic substitution patterns. A variety of substituted aromatic rings can be prepared using this method including: phenols, naphthalenes, benzofurans, benzothiophenes, indoles, and carbazoles.^[2]

The modified Danheiser benzannulation allows the synthesis of polycyclic aromatic and heteroaromatic systems. This also includes naphthalenes, benzofurans and indoles.^[7] This second generation aromatic annulation is achieved by irradiation of a solution of acetylene and a vinyl or aryl α-diazo ketone in dichloroethane.^[2] This reaction utilizes the photochemical Wolff rearrangement of a diazoketone to generate an aryl or vinylketene.^[2] These ketene intermediates cannot be isolated due to their high reactivity to form diketenes. These rearrangements are performed in the presence of unsaturated compounds which undergo [2+2] cycloadditions with the in situ generated ketenes.^[8] When ketenes are formed in the presence of alkynes they proceed through pericyclic reactions to generate a substituted aromatic ring (Scheme 2). Avoiding the use of the high energy cyclobutenone starting materials provides access to a wider variety of substituted aromatic compounds.^[2]

This reaction is quite complementary to the Wulff–Dötz reaction.^[2] This is a [2+1] cycloaddition of a carbene to an alkyne or alkene (more specifically in the Dӧtz reaction a carbene coordinated to a metal carbonyl group) to produce substituted aromatic phenols.^[9]

Mechanism

The reaction proceeds via a cascade of four subsequent pericyclic reactions (Scheme 3). Heating a cyclobutenone above 80 °C initiates a four-electron electrocyclic cleavage generating a vinyl ketene which reacts with an acetylene in a regiospecific [2+2] cycloaddition (Scheme 4). Reversible electrocyclic cleavage of the 2-vinylcyclobutenone yields a dienylketene. The dienylketene then undergoes a six-electron electrocyclization to give a hexadienone intermediate which rapidly tautomerizes to yield a highly substituted phenol or naphthol structures.^[5]

In the case of the modified benzannulation reaction (Scheme 5); irradiation of the diazoketones induces the Wolff rearrangement yielding the vinyl ketene intermediate which reacts with the acetylene in a [2+2] cycloaddition then a four-electron cleavage of the resulting 4-substituted cyclobutenone produces a dienylketene which then undergoes a six-electron electrocyclization to give the 2,4-cyclohexanedione which tautomerizes to the final aromatic product.^[2]

Reaction conditions

A typical Danheiser benzannulation reaction is run with a 0.4-2.0 M solution of the cyclobutenone in toluene heated at 80-160 °C with a slight excess of the cyclobutenone. Upon addition of the alkyne a [2+2] cycloaddition occurs. The crude annulation product is treated with 10% potassium hydroxide in methanol to saponify the ester side product formed from the reaction of the phenolic product with excess vinylketene (Scheme 6).^[5]

For the second generation reaction starting with the diazoketone, the reaction is performed by irradiation of a 0.7 M solution of the ketone with 1.0-1.2 equivalents of acetylene. A low-pressure mercury-vapor lamp at 254 nm in a photochemical reactor is used for 5–8 hours until all the diazoketone has been consumed as determined by TLC analysis. Dichloromethane, chloroform, and 1,2-dichloroethane, are all appropriate solvents for the annulation reaction.^[2]

Reagent Preparations

Cyclobutenone was originally synthesized from the 3-bromocyclobutanone and 3-chlorocyclobutanone precursors which were prepared from an allene and a ketene via two independent routes. Scheme 7 shows the preparation from cyclobutenone from an allene.^[10]

Activated alkyoxyacetylenes can be synthesized in a single-pot preparation of triisopropylsilyloxyacetylenes from esters. The silyloxyacetylenes are useful substitutes for alkoxyacetylenes in [2 + 2] cycloaddition reactions with ketenes and vinylketenes affording cyclobutenones (Scheme 8).^[6]

Diazoketones can be synthesized in one-step from readily available ketones or carboxylic acid precursors by the addition of diazomethane to acyl chlorides. A diazo group transfer method can be used to produce α,β-unsaturated ketones.^[2] The traditional method of the deformylative diazo transfer approach has been improved upon by substituting the trifluoroacetylation of generated lithium enolates for the Claisen formylation step. The key step in this procedure is activation of the ketone starting material to the corresponding α-trifluoroacetyl derivative using trifluoroethyltrifluoroacetate (TFEA) (Scheme 9).^[11]

Alkynes or ketenophiles can be synthesized by various methods. Trialkylsilyloxyalkynes have proven to be excellent ketenophiles. These alkynes react in the annulation reaction to form resorcinol monosilyl ethers which can be de-protected under mild reaction conditions. Base-promoted dehydrohalogenation of (Z)-2-halovinyl ethers to form alkoxyacetylenes is one of the most well established routes of alkyne synthesis (Scheme 10).^[12]

The synthesized alkynes are then heated in benzene or toluene in presence of excess cyclobutenone initiating the benzannulation reaction. Treatment with n-Bu₄NF in tetrahydrofuran removes the siloxy groups to form the desired diols.^[12]

Scope

Alkynyl ethers and siloxyacetylenes have proven to be the ideal pair for aromatic annulations. The reactions can be run with both activated heterosubstituted alkynes and un-activated acetlyenes.^[2] Alkynyl thioethers and ynamines have been used as reactants in the annulation reaction.^[5]

Conjugated enynes have also been used for benzannulation reactions catalyzed by cobalt. This type of benzannulation involves a [4+2] cycloaddition followed by a 1,3-hydrogen shift. In dichloromethane, the symmetrical benzannulation products are yielded but in tetrahydrofuran (THF), unsymmetrical benzannulation products were obtained with good regioselectivity. These reactions utilize 1,3-bis(diphenylphosphino)propane (dppp) substituted cobalt catalyst in the presence of powdered zinc and zinc iodide for a solvent dependent benzannulation reaction (Scheme 11). In dichloromethane the ratio of A:B is 78:22 with an overall combined yield of 90% and in THF the ratio has switched to 7:93 (A:B) with a combined yield of 85%.^[13]

Palladium-catalyzed benzannulations have been developed using allylic compounds and alkynes. This palladium catalyzed reaction has been performed in both inter- and intramolecular forms. The cationic palladium complex [(η³-C₃H₅)Pd(CH₃CN)₂](BF₄) reacts with an excess of 4-octyne when heated to 80 °C in the presence of triphenylphosphine forming the aromatic compound 1-methyl-2,3,4,5-tetrapropylbenzene (Scheme 12). It was determined that the presence of exactly one equivalent of palladium catalyst (from which the allyl group adds into the final aromatic structure) is crucial for the catalyzed benzannulation to occur in good yield.^[14]

This catalyzed reaction was also optimized for allyl substrates with catalytic [Pd₂(dba)₃]CHCl₃ and triphenylphosphine (dba =dibenzylideneacetone) (Scheme 13).^[14]

Applications in Total Synthesis

Mycophenolic acid is a Penicillium metabolite that was originally prepared via a key benzannulation step. An alkyne and a cyclobutenone were reacted to form a substituted phenol in a single step in a 73% yield (Scheme 14). Mycophenolic acid was prepared in nine steps in an overall yield of 17-19%.^[15]

In the synthesis of highly substituted indoles performed by Danheiser, the key step was a benzannulation reaction using cyclobutenone and ynamides to produce highly substituted aniline derivatives. In this case, the ortho position can be functionalized with various substituents. Following the benzannulation reaction with various heterocyclization reactions can provide access to substituted indoles (Scheme 15).^[16]

Danheiser also used the benzannulation with ynamides for the synthesis of polycyclic benzofused nitrogen heterocycles followed by ring-closing metathesis (Scheme 16) for the total synthesis of (+)-FR900482, an anticancer agent.^[17]

Kowalski used the benzannulation reaction with siloxyacetylenes for the first time, reacting them with cyclobutenones to synthesize a substituted phenol for the total synthesis of Δ-6-tetrahydrocannabinol (Scheme 17).^[6]

Scheme 17: Synthesis of D-6-tetrahydrocannabinol via a Benzannulatio Shceme17.png — Scheme 17: Synthesis of Δ-6-tetrahydrocannabinol via a Benzannulatio

The benzannulation reaction was used by Smith in the total synthesis of cylindrocyclophanes specifically (−)-Cylindrocyclophane F. He utilized the reaction of a siloxyalkyne and a cyclobutenone to construct the dihydroxyl aromatic intermediate for an olefin metathesis reaction to access the target (Scheme 18).^[18]

An outstanding application of Danheiser benzannulation in 6-step synthesis of dictyodendrins was demonstrated by Zhang and Ready. They obtained the cyclobutenone substrate using a hetero-[2+2] cycloaddition between aryl ynol ethers (aryl ketene precursors),^[19] and the following benzannulation enabled the rapid construction of the carbazole cole of dictyodendrins F, H and I. ^[20] The successful usage of Danheiser benzannulation allows Zhang and Ready to achieve the so-far shortest synthesis of dictyodendrin natural products.^[21]

Related Research Articles

<span class="mw-page-title-main">Alkyne</span> Hydrocarbon compound containing one or more C≡C bonds

In organic chemistry, an alkyne is an unsaturated hydrocarbon containing at least one carbon—carbon triple bond. The simplest acyclic alkynes with only one triple bond and no other functional groups form a homologous series with the general chemical formula C_nH_2n−2. Alkynes are traditionally known as acetylenes, although the name acetylene also refers specifically to C₂H₂, known formally as ethyne using IUPAC nomenclature. Like other hydrocarbons, alkynes are generally hydrophobic.

The following outline is provided as an overview of and topical guide to organic chemistry:

The Sonogashira reaction is a cross-coupling reaction used in organic synthesis to form carbon–carbon bonds. It employs a palladium catalyst as well as copper co-catalyst to form a carbon–carbon bond between a terminal alkyne and an aryl or vinyl halide.

The 1,3-dipolar cycloaddition is a chemical reaction between a 1,3-dipole and a dipolarophile to form a five-membered ring. The earliest 1,3-dipolar cycloadditions were described in the late 19th century to the early 20th century, following the discovery of 1,3-dipoles. Mechanistic investigation and synthetic application were established in the 1960s, primarily through the work of Rolf Huisgen. Hence, the reaction is sometimes referred to as the Huisgen cycloaddition. 1,3-dipolar cycloaddition is an important route to the regio- and stereoselective synthesis of five-membered heterocycles and their ring-opened acyclic derivatives. The dipolarophile is typically an alkene or alkyne, but can be other pi systems. When the dipolarophile is an alkyne, aromatic rings are generally produced.

In organic chemistry, arynes and benzynes are a class of highly reactive chemical species derived from an aromatic ring by removal of two substituents. Arynes are examples of didehydroarenes, although 1,3- and 1,4-didehydroarenes are also known. Arynes are examples of alkynes under high strain.

An alkyne trimerisation is a [2+2+2] cycloaddition reaction in which three alkyne units react to form a benzene ring. The reaction requires a metal catalyst. The process is of historic interest as well as being applicable to organic synthesis. Being a cycloaddition reaction, it has high atom economy. Many variations have been developed, including cyclisation of mixtures of alkynes and alkenes as well as alkynes and nitriles.

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. 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.

The Povarov reaction is an organic reaction described as a formal cycloaddition between an aromatic imine and an alkene. The imine in this organic reaction is a condensation reaction product from an aniline type compound and a benzaldehyde type compound. The alkene must be electron rich which means that functional groups attached to the alkene must be able to donate electrons. Such alkenes are enol ethers and enamines. The reaction product in the original Povarov reaction is a quinoline. Because the reactions can be carried out with the three components premixed in one reactor it is an example of a multi-component reaction.

In organic chemistry, a cycloalkyne is the cyclic analog of an alkyne. A cycloalkyne consists of a closed ring of carbon atoms containing one or more triple bonds. Cycloalkynes have a general formula C_nH_2n−4_. Because of the linear nature of the C−C≡C−C alkyne unit, cycloalkynes can be highly strained and can only exist when the number of carbon atoms in the ring is great enough to provide the flexibility necessary to accommodate this geometry. Large alkyne-containing carbocycles may be virtually unstrained, while the smallest constituents of this class of molecules may experience so much strain that they have yet to be observed experimentally. Cyclooctyne is the smallest cycloalkyne capable of being isolated and stored as a stable compound. Despite this, smaller cycloalkynes can be produced and trapped through reactions with other organic molecules or through complexation to transition metals.

<span class="mw-page-title-main">Wolff rearrangement</span> Chemical reaction

The Wolff rearrangement is a reaction in organic chemistry in which an α-diazocarbonyl compound is converted into a ketene by loss of dinitrogen with accompanying 1,2-rearrangement. The Wolff rearrangement yields a ketene as an intermediate product, which can undergo nucleophilic attack with weakly acidic nucleophiles such as water, alcohols, and amines, to generate carboxylic acid derivatives or undergo [2+2] cycloaddition reactions to form four-membered rings. The mechanism of the Wolff rearrangement has been the subject of debate since its first use. No single mechanism sufficiently describes the reaction, and there are often competing concerted and carbene-mediated pathways; for simplicity, only the textbook, concerted mechanism is shown below. The reaction was discovered by Ludwig Wolff in 1902. The Wolff rearrangement has great synthetic utility due to the accessibility of α-diazocarbonyl compounds, variety of reactions from the ketene intermediate, and stereochemical retention of the migrating group. However, the Wolff rearrangement has limitations due to the highly reactive nature of α-diazocarbonyl compounds, which can undergo a variety of competing reactions.

The Wulff–Dötz reaction (also known as the Dötz reaction or the benzannulation reaction of the Fischer carbene complexes) is the chemical reaction of an aromatic or vinylic alkoxy pentacarbonyl chromium carbene complex with an alkyne and carbon monoxide to give a Cr(CO)₃-coordinated substituted phenol. Several reviews have been published. It is named after the German chemist Karl Heinz Dötz (b. 1943) and the American chemist William D. Wulff (b. 1949) at Michigan State University. The reaction was first discovered by Karl Dötz and was extensively developed by his group and W. Wulff's group. They subsequently share the name of the reaction.

<span class="mw-page-title-main">Annulation</span> Chemical reaction constructing a new ring on a molecule

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

The nitrone-olefin (3+2) cycloaddition reaction is the combination of a nitrone with an alkene or alkyne to generate an isoxazoline or isoxazolidine via a (3+2) cycloaddition process. This reaction is a 1,3-dipolar cycloaddition, in which the nitrone acts as the 1,3-dipole, and the alkene or alkyne as the dipolarophile.

The Buchner ring expansion is a two-step organic C-C bond forming reaction used to access 7-membered rings. The first step involves formation of a carbene from ethyl diazoacetate, which cyclopropanates an aromatic ring. The ring expansion occurs in the second step, with an electrocyclic reaction opening the cyclopropane ring to form the 7-membered ring.

Decarboxylative cross coupling reactions are chemical reactions in which a carboxylic acid is reacted with an organic halide to form a new carbon-carbon bond, concomitant with loss of CO₂. Aryl and alkyl halides participate. Metal catalyst, base, and oxidant are required.

In organic chemistry, the hexadehydro-Diels–Alder (HDDA) reaction is an organic chemical reaction between a diyne and an alkyne to form a reactive benzyne species, via a [4+2] cycloaddition reaction. This benzyne intermediate then reacts with a suitable trapping agent to form a substituted aromatic product. This reaction is a derivative of the established Diels–Alder reaction and proceeds via a similar [4+2] cycloaddition mechanism. The HDDA reaction is particularly effective for forming heavily functionalized aromatic systems and multiple ring systems in one synthetic step.

<span class="mw-page-title-main">Ynone</span> Organic compounds of the form RC≡CC(=O)R’

In organic chemistry, an ynone is an organic compound containing a ketone functional group and a C≡C triple bond. Many ynones are α,β-ynones, where the carbonyl and alkyne groups are conjugated. Capillin is a naturally occurring example. Some ynones are not conjugated.

Rick L. Danheiser is an American organic chemist and is the Arthur C. Cope Professor of Chemistry at the Massachusetts Institute of Technology and chair of the MIT faculty. His research involves the invention of new methods for the synthesis of complex organic compounds. Danheiser is known for the Danheiser annulation and Danheiser benzannulation reactions.

<span class="mw-page-title-main">Phenol ether</span> O-alkyl derivative of phenol

In chemistry, a phenol ether (or aromatic ether) is an organic compound derived from phenol (C₆H₅OH), where the hydroxyl (-OH) group is substituted with an alkoxy (-OR) group. Usually phenol ethers are synthesized through the condensation of phenol and an organic alcohol; however, other known reactions regarding the synthesis of ethers can be applied to phenol ethers as well. Anisole (C₆H₅OCH₃) is the simplest phenol ether, and is a versatile precursor for perfumes and pharmaceuticals. Vanillin and ethylvanillin are phenol ether derivatives commonly utilized in vanilla flavorings and fragrances, while diphenyl ether is commonly used as a synthetic geranium fragrance. Phenol ethers are part of the chemical structure of a variety of medications, including quinine, an antimalarial drug, and dextromethorphan, an over-the-counter cough suppressant.

In organic chemistry, the Conia-ene reaction is an intramolecular cyclization reaction between an enolizable carbonyl such as an ester or ketone and an alkyne or alkene, giving a cyclic product with a new carbon-carbon bond. As initially reported by J. M. Conia and P. Le Perchec, the Conia-ene reaction is a heteroatom analog of the ene reaction that uses an enol as the ene component. Like other pericyclic reactions, the original Conia-ene reaction required high temperatures to proceed, limiting its wider application. However, subsequent improvements, particularly in metal catalysis, have led to significant expansion of reaction scope. Consequently, various forms of the Conia-ene reaction have been employed in the synthesis of complex molecules and natural products.

References

↑ IUPAC , Compendium of Chemical Terminology , 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) " annulation ". doi : 10.1351/goldbook.A00367
1 2 3 4 5 6 7 8 9 10 Danheiser, R L., Brisbois, R G. James, J. Kowalczyk, Miller, R. F. “An Annulation Method for the Synthesis of Highly Substituted Polycyclic Aromatic and Heteroaromatic Compounds.” J. Am. Chem. Soc. 1990, 112, 3093-3100.
↑ "Robinson Annulation." Organic-Chemistry. Organic Chemistry Portal, Web. 06 Nov. 2014.
↑ Chung, Won-jin. "Regioselective [4+2] Benzannulation: Synthesis of Polysubstituted Benzenes Archived 2014-02-07 at the Wayback Machine ." Chemistry Department. University of Illinois, 20 Nov. 2003. Web. 23 Nov. 2014.
1 2 3 4 Danheiser, R. L., Gee, S. K. “Regiocontrolled Annulation Approach to Highly Substituted Aromatic Compounds.” J. Org. Chem. 1984, 49, 1672-1674.
1 2 3 Kowaiski, C. J., Lak, S. G. “Cycloadditions Reactions of Silyloxyacetylenes with Ketenes: Synthesis of Cyclobutenones, Resorcinols, and Δ-6-Tetrahydrocannabinol.” J. Am. Chem. Soc. 1988, 110, 3693-3695.
↑ Kürti László, Barbara Czakó. Strategic Applications of Named Reactions in Organic Synthesis. Elsevier Inc.: Burlington, Massachusetts.
↑ "Wolff Rearrangement." Organic-Chemistry. Organic Chemistry Portal, Web. 09 Nov. 2014.
↑ Dӧtz, K. H. “Synthesis of Naphthol Skeleton from Pentacarbonyk [methoxy(phenyl)carbine]chromium(0) and Tolan.” Angew. Chem. Internat. Edit. 1975, 14, 644-645.
↑ Sieja, J. B. “Synthesis of Cyclobutenone.” J. Am. Chem. Soc.1971, 93, 2481-2483.
↑ Danheiser, R.L., Miller, R. F., Brisbois, R. G., Park, S. Z. “An Improved Method for the Synthesis of α-Diazoketones.” J. Org. Chem. 1990, 55, 1959-1964.
1 2 Danheiser, R.L., Nishida, A., Savariar, S., Trova, M. P. “Trialkylsiloxyalkynes: Synthesis and Aromatic Annulation Reactions. Tetrahedron Lett. 1988, 29, 4917-4920.
↑ Pünner, F., Hilt, G. “Regioselective Solvent-dependent Benzannulation of Conjugated Enynes.” Chem. Commun. 2012, 48, 3617–3619.
1 2 Tsukada, N., Sugawara, S., Nakaoka, K., Inoue, Y. “Palladium-Catalyzed Benzannulation from Alkynes and Allylic Compounds.” J. Org. Chem. 2003, 68, 5961-5966.
↑ Danheiser, R. L., Gee, S. K., Perez, J. J. “Total Synthesis of Mycophenolic Acid.” J. Am. Chem. Soc. 1986, 108, 807.
↑ Lam, T. Y., Wang, Y., Danheiser, R. L. “Benzannulation via the Reaction of Ynamides and Vinylketenes. Application to the Synthesis of Highly Substituted Indoles.” J. Org. Chem. 2013, 78, 9396−9414.
↑ Mak, X. Y., Crombie, L. A., Danheiser, R. L. “Synthesis of Polycyclic Benzofused Nitrogen Heterocycles via a Tandem Ynamide Benzannulation/Ring-Closing Metathesis Strategy. Application in a Formal Total Synthesis of (+)-FR900482.” J. Org. Chem. 2011, 76, 1852–1873.
↑ Smith, A.B., III, Adams, C. M., Kozmin, S. A., Paone, D. V. “Total Synthesis of (−)-Cylindrocyclophanes A and F Exploiting the Reversible Nature of Olefin Cross Metathesis Reaction. J. Am. Chem. Soc. 2001, 123, 5925-5937.
↑ Zhang, Wenhan; Ready, Joseph M. (2014). "The Ketene-Surrogate Coupling: Catalytic Conversion of Aryl Iodides into Aryl Ketenes through Ynol Ethers". Angewandte Chemie International Edition. 53 (34): 8980–8984. doi:10.1002/anie.201405036. ISSN 1521-3773. PMC 4134717 . PMID 24975840.
↑ Zhang, Wenhan; Ready, Joseph M. (2016-08-24). "A Concise Total Synthesis of Dictyodendrins F, H, and I Using Aryl Ynol Ethers as Key Building Blocks". Journal of the American Chemical Society. 138 (33): 10684–10692. doi:10.1021/jacs.6b06460. ISSN 0002-7863. PMC 5006189 . PMID 27471872.
↑ Zhang, Wenhan; Ready, Joseph M. (2017). "Total synthesis of the dictyodendrins as an arena to highlight emerging synthetic technologies". Natural Product Reports. 34 (8): 1010–1034. doi:10.1039/C7NP00018A. ISSN 0265-0568. PMID 28737179.

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[1] IUPAC , Compendium of Chemical Terminology , 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) " annulation ". doi : 10.1351/goldbook.A00367

[RLD_RGB_1990-2] 1 2 3 4 5 6 7 8 9 10 Danheiser, R L., Brisbois, R G. James, J. Kowalczyk, Miller, R. F. “An Annulation Method for the Synthesis of Highly Substituted Polycyclic Aromatic and Heteroaromatic Compounds.” J. Am. Chem. Soc. 1990, 112, 3093-3100.

[oc_robinson-3] "Robinson Annulation." Organic-Chemistry. Organic Chemistry Portal, Web. 06 Nov. 2014.

[4] Chung, Won-jin. "Regioselective [4+2] Benzannulation: Synthesis of Polysubstituted Benzenes Archived 2014-02-07 at the Wayback Machine ." Chemistry Department. University of Illinois, 20 Nov. 2003. Web. 23 Nov. 2014.

[RLD_SKG_1984-5] 1 2 3 4 Danheiser, R. L., Gee, S. K. “Regiocontrolled Annulation Approach to Highly Substituted Aromatic Compounds.” J. Org. Chem. 1984, 49, 1672-1674.

[Kowaiski,_C._J._1988-6] 1 2 3 Kowaiski, C. J., Lak, S. G. “Cycloadditions Reactions of Silyloxyacetylenes with Ketenes: Synthesis of Cyclobutenones, Resorcinols, and Δ-6-Tetrahydrocannabinol.” J. Am. Chem. Soc. 1988, 110, 3693-3695.

[7] Kürti László, Barbara Czakó. Strategic Applications of Named Reactions in Organic Synthesis. Elsevier Inc.: Burlington, Massachusetts.

[8] "Wolff Rearrangement." Organic-Chemistry. Organic Chemistry Portal, Web. 09 Nov. 2014.

[9] Dӧtz, K. H. “Synthesis of Naphthol Skeleton from Pentacarbonyk [methoxy(phenyl)carbine]chromium(0) and Tolan.” Angew. Chem. Internat. Edit. 1975, 14, 644-645.

[10] Sieja, J. B. “Synthesis of Cyclobutenone.” J. Am. Chem. Soc.1971, 93, 2481-2483.

[11] Danheiser, R.L., Miller, R. F., Brisbois, R. G., Park, S. Z. “An Improved Method for the Synthesis of α-Diazoketones.” J. Org. Chem. 1990, 55, 1959-1964.

[RLD_AN_1988-12] 1 2 Danheiser, R.L., Nishida, A., Savariar, S., Trova, M. P. “Trialkylsiloxyalkynes: Synthesis and Aromatic Annulation Reactions. Tetrahedron Lett. 1988, 29, 4917-4920.

[13] Pünner, F., Hilt, G. “Regioselective Solvent-dependent Benzannulation of Conjugated Enynes.” Chem. Commun. 2012, 48, 3617–3619.

[NT_SS_2003-14] 1 2 Tsukada, N., Sugawara, S., Nakaoka, K., Inoue, Y. “Palladium-Catalyzed Benzannulation from Alkynes and Allylic Compounds.” J. Org. Chem. 2003, 68, 5961-5966.

[15] Danheiser, R. L., Gee, S. K., Perez, J. J. “Total Synthesis of Mycophenolic Acid.” J. Am. Chem. Soc. 1986, 108, 807.

[16] Lam, T. Y., Wang, Y., Danheiser, R. L. “Benzannulation via the Reaction of Ynamides and Vinylketenes. Application to the Synthesis of Highly Substituted Indoles.” J. Org. Chem. 2013, 78, 9396−9414.

[17] Mak, X. Y., Crombie, L. A., Danheiser, R. L. “Synthesis of Polycyclic Benzofused Nitrogen Heterocycles via a Tandem Ynamide Benzannulation/Ring-Closing Metathesis Strategy. Application in a Formal Total Synthesis of (+)-FR900482.” J. Org. Chem. 2011, 76, 1852–1873.

[18] Smith, A.B., III, Adams, C. M., Kozmin, S. A., Paone, D. V. “Total Synthesis of (−)-Cylindrocyclophanes A and F Exploiting the Reversible Nature of Olefin Cross Metathesis Reaction. J. Am. Chem. Soc. 2001, 123, 5925-5937.

[19] Zhang, Wenhan; Ready, Joseph M. (2014). "The Ketene-Surrogate Coupling: Catalytic Conversion of Aryl Iodides into Aryl Ketenes through Ynol Ethers". Angewandte Chemie International Edition. 53 (34): 8980–8984. doi:10.1002/anie.201405036. ISSN 1521-3773. PMC 4134717 . PMID 24975840.

[20] Zhang, Wenhan; Ready, Joseph M. (2016-08-24). "A Concise Total Synthesis of Dictyodendrins F, H, and I Using Aryl Ynol Ethers as Key Building Blocks". Journal of the American Chemical Society. 138 (33): 10684–10692. doi:10.1021/jacs.6b06460. ISSN 0002-7863. PMC 5006189 . PMID 27471872.

[21] Zhang, Wenhan; Ready, Joseph M. (2017). "Total synthesis of the dictyodendrins as an arena to highlight emerging synthetic technologies". Natural Product Reports. 34 (8): 1010–1034. doi:10.1039/C7NP00018A. ISSN 0265-0568. PMID 28737179.

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