Annulation
Annulation is a transformation in organic chemistry involving the fusion of a new ring to a molecule via the formation of two new bonds.[1] Although some sources distinguish "annelation" for fusing rings to existing cyclic systems and "annulation" for ring formation from acyclic precursors, this differentiation is not universally applied.[1]
These reactions are fundamental in synthetic organic chemistry, enabling the efficient construction of complex polycyclic frameworks that are prevalent in natural products, pharmaceuticals, and materials.[2] Annulation strategies often proceed through sequential bond-forming steps, such as cycloadditions, condensations, or radical processes, and have evolved to include catalytic and asymmetric variants for enhanced selectivity and sustainability.[3] Their versatility allows for the synthesis of carbocycles, heterocycles, and fused aromatic systems, making them indispensable tools in total synthesis.[4]
Among the most notable annulation reactions is the Robinson annulation, pioneered in 1935, which unites a ketone with an α,β-unsaturated ketone via Michael addition followed by intramolecular aldol condensation to afford cyclohexenone derivatives.[5] This method has been pivotal in steroid and alkaloid syntheses. Other prominent types include benzannulation for aromatic ring fusion, as developed by Danheiser in 1984,[6] and radical-mediated annulations that enable stereoselective carbocycle formation. Recent advances, such as decarbonylative and electrochemical annulations, along with transition metal-catalyzed alkyne annulations reported as of 2025, further expand their scope by minimizing waste and enabling access to diverse heterocycles.[2][7]
Fundamentals
Definition and Scope
Annulation is a fundamental transformation in organic chemistry that constructs a new ring fused to an existing molecular framework by forming two new bonds between molecular fragments. This ring-forming process typically integrates mechanisms such as cycloaddition, condensation, or cyclization, resulting in polycyclic structures that are central to the synthesis of complex natural products and pharmaceuticals. The International Union of Pure and Applied Chemistry (IUPAC) formally defines annulation as "a transformation involving fusion of a new ring to a molecule via two new bonds," distinguishing it from broader ring-closure processes.[1][8]
The term "annulation" originates from the Latin annulus, meaning "ring," highlighting its focus on ring construction, and entered common usage among organic chemists in the early 20th century, with no official IUPAC definition until the 1994 glossary of physical organic chemistry terms. Early adoption is evident in reactions like the Robinson annulation, developed in 1935, which exemplifies the strategy for building fused cyclohexenone rings.[9][10][8]
Annulation reactions span intramolecular processes, where a single precursor cyclizes to append a ring to itself, and intermolecular variants, where two distinct molecules combine to form the fused system. Their scope includes the efficient assembly of 5- to 7-membered rings onto acyclic or cyclic substrates, primarily through carbon-carbon or carbon-heteroatom bond formation, enabling diverse applications in synthetic methodology. Unlike general cyclization, which generates an isolated ring from acyclic precursors, annulation uniquely emphasizes fusion to a pre-existing scaffold, enhancing molecular rigidity and functionality. A generalized depiction of annulation illustrates this as the union of fragments A and B to produce a fused ring system, often under specific catalytic or thermal conditions.[8][10]
Historical Development
The concept of annulation in organic chemistry, referring to the formation of a new ring fused to an existing cyclic structure, emerged prominently in the 1930s and 1940s during intensive efforts in steroid synthesis, where constructing fused polycyclic frameworks was essential for mimicking natural hormones and related compounds. Derived from the Latin "annulus" meaning ring, the term encapsulated these ring-building strategies amid post-Depression advancements in alkaloid and terpenoid chemistry.[8]
A pivotal milestone came in 1935 with the development of the Robinson annulation by British chemist Robert Robinson and collaborator William S. Rapson, who demonstrated its utility in synthesizing fused six-membered rings, such as octalone derivatives, through sequential carbon-carbon bond formations initially explored in tropinone-related systems. This base-catalyzed process became a cornerstone for decalones and steroid scaffolds, enabling efficient access to bicyclic enones critical for natural product analogs. Robinson's contributions, building on his earlier work in alkaloid synthesis, highlighted annulation's potential for stereocontrolled polycycle assembly.[11]
In the 1940s, Soviet chemist Ivan Nazarov advanced annulation for five-membered rings with his discovery of the Nazarov cyclization, an acid-promoted electrocyclization of divinyl ketones to cyclopentenones, providing a complementary tool for unsaturated carbocycles in terpenoid frameworks. The 1970s marked a shift toward catalytic methods with the Pauson-Khand reaction, reported in 1973 by Peter L. Pauson and Ihsan U. Khand, which utilized cobalt-mediated [2+2+1] cycloadditions of alkynes, alkenes, and carbon monoxide to forge cyclopentenones, broadening annulation beyond purely organic mediators.[12][13]
This evolution from base- and acid-catalyzed condensations to transition-metal involvement in the 1970s and 1980s onward expanded annulation's versatility, facilitating diverse ring fusions and influencing post-World War II natural product synthesis by enabling scalable routes to complex polycycles like those in steroids and alkaloids. These innovations not only accelerated total syntheses but also inspired extensions, such as benzannulation for aromatic systems.[14]
Classical Annulation Reactions
Robinson Annulation
The Robinson annulation is a classic method in organic synthesis for constructing fused six-membered carbocyclic rings through a tandem process involving a Michael addition followed by an intramolecular aldol condensation.[15] This reaction typically employs a ketone as the Michael donor and an α,β-unsaturated ketone, such as methyl vinyl ketone (MVK), as the acceptor, under basic conditions to generate a 1,5-diketone intermediate that cyclizes to an α,β-unsaturated ketone.[16] Developed in the 1930s, it played a pivotal role in early steroid chemistry by enabling the efficient assembly of polycyclic frameworks.[15]
The mechanism proceeds in two main stages. First, the enolate derived from the ketone adds conjugately to the β-position of the α,β-unsaturated ketone in a Michael addition, yielding a 1,5-diketone.[16] Second, under the reaction conditions, the enolate from one carbonyl group of the diketone performs an intramolecular aldol addition to the other carbonyl, followed by dehydration to afford the cyclohexenone product.[17] This sequence forms two new carbon-carbon bonds and is particularly effective for creating fused ring systems.[15]
A representative example is the base-catalyzed reaction of cyclohexanone with MVK, which produces the bicyclic enone known as Δ^{9,10}-octalin-1-one (or "Great Octalone"):
O O
/ \ / \
// \\ + // \\
/ \ / \
O C=CH2 base fused ring system with α,β-unsaturated ketone
(cyclohexanone) (MVK) (e.g., NaOEt)
O O
/ \ / \
// \\ + // \\
/ \ / \
O C=CH2 base fused ring system with α,β-unsaturated ketone
(cyclohexanone) (MVK) (e.g., NaOEt)
This transformation occurs in one pot, typically in ethanol or toluene with sodium ethoxide as the base.[17][15]
The reaction excels at forming six-membered rings but has limitations, including regioselectivity challenges with unsymmetrical ketones, where competing enolate formation can lead to mixtures of products. It is most reliable with cyclic ketones and MVK derivatives, but less suited for five- or seven-membered ring formation.[16]
Variations include the use of preformed enolates or silyl enol ethers to enhance regioselectivity and control the site of Michael addition. In steroid synthesis, modifications such as incorporating angular methyl groups via substituted donors (e.g., 2-methylcyclohexanone) allow construction of key intermediates like those in the Wieland-Miescher ketone, facilitating total syntheses of complex natural products.[15][17]
Nazarov Cyclization
The Nazarov cyclization is an acid-catalyzed electrocyclization reaction that constructs cyclopentenone rings through the 4π conrotatory ring closure of 1,4-dien-3-ones, also known as divinyl ketones. First reported by Ivan Nazarov in 1941 during studies on allyl vinyl ketone derivatives,[18] the process involves protonation or Lewis acid coordination to activate the substrate, leading to the formation of a pentadienyl cation intermediate that undergoes pericyclic closure. This annulation method is particularly valued in organic synthesis for its ability to generate five-membered carbocycles with defined stereochemistry, distinguishing it from stepwise annulation processes like the Robinson annulation by its pericyclic nature.
The mechanism begins with the activation of the carbonyl oxygen by a protic or Lewis acid, such as H₂SO₄ or BF₃·OEt₂, generating a resonance-stabilized pentadienyl cation. This cation then participates in a thermal 4π electrocyclization, proceeding in a conrotatory fashion as dictated by the Woodward-Hoffmann rules for suprafacial closure under thermal conditions, forming a cyclic allyl cation (oxyallyl cation) with two new stereocenters. Subsequent deprotonation from the alpha position to the original carbonyl restores aromaticity in the enone system and yields the cyclopentenone product, often accompanied by tautomerization if necessary. The stereospecificity of the conrotatory ring closure ensures predictable relative configurations in substituted cases, though proton loss can lead to cis-trans isomerization in the product enone.
A representative example is the sulfuric acid-catalyzed cyclization of 1-(prop-1-en-2-yl)prop-2-en-1-one, CH₂=CH–C(O)–CH=C(CH₃)₂, to 3-methylcyclopent-2-en-1-one, demonstrating the transformation of a cross-conjugated dienone into a functionalized five-membered ring.
The reaction's scope is primarily limited to the formation of five-membered rings from 1,4-dien-3-ones, with substrates bearing electron-donating or stabilizing groups on the vinyl moieties enhancing cation stability and improving efficiency. Limitations include sensitivity to steric hindrance or electron-withdrawing substituents that destabilize the pentadienyl cation, often resulting in side reactions like polymerization or elimination, and typical yields ranging from 40% to 90% depending on conditions and substitution patterns.
Variations of the Nazarov cyclization, known as interrupted Nazarov processes, involve trapping the intermediate allyl cation with nucleophiles before deprotonation, enabling further annulation or functionalization for access to polycyclic systems.[19] These modifications expand the utility by incorporating heteroatoms or additional rings, with examples including siloxy or alkene trapping to form bicyclic enol ethers or fused cyclopentenones.
Aromatic Annulations
Benzannulation
Benzannulation is a specific type of annulation reaction that constructs a six-membered aromatic ring fused to an existing cyclic or acyclic structure, typically involving the formation and subsequent aromatization of a non-aromatic precursor such as a cyclohexadiene intermediate.[20] This process is particularly valuable in organic synthesis for building polycyclic aromatic hydrocarbons (PAHs) and fused aromatic systems, where the final aromatization step imparts stability and planarity to the molecule.[21]
Classical methods for benzannulation rely on stepwise carbon-carbon bond formations followed by dehydrogenative aromatization. A prominent example is the Haworth reaction, developed in the 1930s, which employs intramolecular Friedel-Crafts acylation on tetralone derivatives to initiate ring closure. In this approach, 1-tetralone undergoes acylation at the α-position with acetyl chloride in the presence of AlCl₃ to yield 2-acetyl-1-tetralone.
\ce{1-tetralone + CH3COCl ->[AlCl3] 2-acetyl-1-tetralone}
Aromatization toward fused aromatic systems is then achieved via dehydrogenation, often using selenium or palladium catalysts.[21]
Another classical strategy involves alkyne cyclizations, where ortho-alkynyl-substituted arenes or aldehydes undergo thermal or acid-promoted intramolecular cycloaddition to form cyclohexadiene adducts, followed by dehydration and aromatization. For instance, 2-(phenylethynyl)benzaldehydes can cyclize with terminal alkynes under Brønsted acid conditions to afford substituted naphthalenes after dehydration.[22] The general mechanism proceeds stepwise: initial [4+2] cycloaddition or electrocyclization yields the cyclohexadiene, which is then oxidized to the benzene ring. Dehydrogenation commonly employs oxidants like 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), which facilitates hydride abstraction under mild conditions, often in dichloromethane at room temperature.[23][24]
These methods are commonly applied in the synthesis of polycyclic aromatics, such as naphthalenes and phenanthrenes, due to their ability to efficiently fuse benzene rings onto pre-existing carbocycles. However, they are generally limited to electron-rich aromatic substrates, as the Friedel-Crafts step requires activation for electrophilic attack, and steric hindrance can impede cyclization. Yields typically range from 30% to 70%, depending on substrate substitution and purification challenges during aromatization.[21] An extension of these classical approaches is seen in the Danheiser annulation for phenol synthesis.[25]
Danheiser Annulation
The Danheiser benzannulation is a synthetic method for constructing highly substituted phenols through the formal [2+2+2] cycloaddition of lithium ynolates with (trialkylsilyl)vinylketenes, followed by electrocyclic ring opening and aromatization.[26] This approach provides regiocontrolled access to aromatic systems from simple acyclic precursors, building on general benzannulation principles by incorporating silyl-mediated stabilization in the key intermediates.[26]
The mechanism begins with the nucleophilic addition of the lithium ynoate to the central carbon of the vinylketene, forming a cyclobutenone intermediate via [2+2] cycloaddition.[26] This cyclobutenone then undergoes thermal conrotatory electrocyclic ring opening to generate a 3-(oxido)dienylketene, which cyclizes through a 6π electrocyclization to afford a cyclohexadienone.[26] Subsequent tautomerization, accompanied by a [1,3] silyl migration from carbon to oxygen, yields the final phenol product, often isolated as a silyl ether that can be deprotected if desired.[26]
A representative example involves the reaction of lithium phenylpropiolate (Ph-C≡C-CO₂Li) with (trimethylsilyl)vinylketene ((CH₃)₃Si-CH=CH-C(=O)=CH₂) in THF at -78 °C to room temperature, producing 2-phenyl-4-(trimethylsilyloxy)phenol in 62% yield after workup.[26]
This reaction demonstrates high regioselectivity, favoring 1,2,4-trisubstituted phenols due to the directed addition and cyclization pathway, and tolerates a range of functional groups including alkyl, alkenyl, and aryl substituents on the ynoate.[26] Yields typically range from 60% to 95%, though sensitive substrates may require optimization to avoid side reactions like silyl group migration.[26] Limitations include the need for low temperatures to control the initial addition and potential challenges with sterically hindered ynolates.[26]
Key advantages of the Danheiser benzannulation include its ability to assemble complex phenols in a single step from readily available acyclic starting materials, avoiding multi-step sequences common in classical aromatic syntheses.[26] It has proven particularly valuable in total synthesis, serving as a pivotal transformation for constructing resorcinol-derived motifs in resveratrol analogs and related polyphenols.[27]
Modern Annulation Strategies
Metal-catalyzed annulations represent a cornerstone of modern synthetic chemistry, leveraging transition metals such as palladium (Pd), rhodium (Rh), and cobalt (Co) to facilitate efficient ring formations through cycloaddition pathways like [2+2+2], [4+2], and enyne cyclizations. These reactions often proceed under mild conditions, offering advantages over classical base-catalyzed methods by enabling broader substrate compatibility and higher selectivity in constructing carbocycles and heterocycles. Unlike traditional approaches such as the Robinson annulation, metal catalysis allows for precise control over bond formation via organometallic intermediates, typically involving oxidative addition, migratory insertion, and reductive elimination steps.[28]
A prominent example is the Pauson-Khand reaction, a Co-catalyzed [2+2+1] cycloaddition of enynes with carbon monoxide (CO) to afford cyclopentenones. Employing Co2(CO)8 as the catalyst, this transformation coordinates the alkyne to form a cobalt complex, followed by alkene insertion and CO incorporation, culminating in a π-allyl intermediate that rearranges to the product. A simple illustrative reaction is the cyclization of pent-4-en-1-yne (HC≡C-CH2-CH=CH2) with CO to yield cyclopent-2-en-1-one:
\ce{HC#C-CH2-CH=CH2 + CO ->[Co2(CO)8] cyclopent-2-en-1-one}
This process exemplifies the method's utility in five-membered ring synthesis.[29]
Another key variant is the Pd-catalyzed enyne benzannulation, which achieves [4+2] cycloaddition of conjugated enynes with diynes to construct substituted benzenes. In this reaction, Pd(0) undergoes oxidative addition into the enyne, followed by coordination and migratory insertion of the diyne, and aromatization via reductive elimination. Developed by Gevorgyan and coworkers, it demonstrates high efficiency for polysubstituted aromatics, with typical conditions using Pd(PPh3)4 in refluxing toluene.[30]
Rh-catalyzed [2+2+2] cycloadditions further expand the toolkit, particularly for alkyne trimerizations or diyne-monoyne couplings to form six-membered rings, proceeding through metallacyclic intermediates en route to reductive elimination. These methods collectively offer broad substrate tolerance, accommodating electron-rich and -poor alkenes, alkynes, and functional groups like esters and halides, with regioselectivity tunable by ligand choice (e.g., phosphines for Pd systems). Yields commonly range from 70-95% under optimized conditions, though limitations include challenges with CO handling in Pauson-Khand variants—requiring sealed vessels or promoters to mitigate toxicity and pressure issues—and sensitivity to steric hindrance in [2+2+2] processes. Recent developments include efficient alkyne annulations using earth-abundant metals for sustainable synthesis.[7] Overall, these catalytic annulations provide versatile, high-impact strategies for complex molecule assembly.[28][29][30]
Asymmetric Annulations
Asymmetric annulations integrate chiral auxiliaries or catalysts, such as BINAP derivatives in metal-catalyzed processes or chiral phosphoramidites and N-triflylphosphoramides in organocatalytic variants, to achieve enantiomeric excesses exceeding 90% in stereocontrolled ring formation. These methods enable the synthesis of enantioenriched cyclic compounds by imparting asymmetry during key bond-forming steps, often building on established metal-catalyzed frameworks to introduce stereocontrol without compromising efficiency.[31][32]
Prominent examples include the asymmetric Pauson-Khand reaction using rhodium(I) catalysts ligated with (R)-BINAP or its modified analogs, which facilitate the [2+2+1] cycloaddition of enynes and carbon monoxide to form chiral cyclopentenones with yields up to 99% and enantioselectivities up to 99% ee under mild conditions. Another key variant is the chiral Brønsted acid-catalyzed Nazarov cyclization, employing N-triflylphosphoramide catalysts to promote the electrocyclization of divinyl ketones into substituted cyclopentenones, achieving enantioselectivities up to 92% ee with low catalyst loadings (1-5 mol%) and short reaction times. These approaches highlight the versatility of chiral ligands in directing stereochemistry across diverse annulation scaffolds.[32][31]
Enantioselective induction in these reactions typically occurs through facial selection in the transition states, where the chiral catalyst differentiates between prochiral faces of reactive intermediates. For instance, in the Nazarov cyclization, the chiral Brønsted acid protonates the divinyl ketone to generate a pentadienyl cation, followed by a conrotatory electrocyclization influenced by asymmetric protonation and torquoselectivity, leading to stereocontrolled ring closure. Similarly, in rhodium-catalyzed Pauson-Khand reactions, the chiral BINAP ligand enforces selective coordination and migratory insertion, favoring one enantiotopic pathway.[31][32]
A representative scheme for the asymmetric Pauson-Khand reaction involves the rhodium(I)-BINAP-catalyzed cycloaddition:
\ce{R-CH=CH-C#C-CH2-CH2-X + CO ->[Rh(I)/(R)-BINAP][0.1 atm CO, rt] (R)-cyclopentenone (95\% ee)}
where the prochiral enyne substrate yields the enantiopure bicyclic cyclopentenone derivative.[32]
These methods find broad application in the synthesis of chiral natural products, such as alkaloids and terpenoids, where stereocontrol is paramount for biological activity, as demonstrated in total syntheses employing organocatalytic annulations for core ring construction. However, they often incur higher costs due to expensive chiral catalysts and ligands compared to achiral counterparts, though they remain essential for accessing enantioenriched targets; typical yields range from 60-90% with consistently high enantioselectivities. Limitations include substrate scope restrictions for highly functionalized systems and the need for optimized conditions to maintain stereofidelity.[33]