Spiroannulation Reaction Research Articles

Synthesis of spirosuccinimides via annulative cyclization between N-aryl indazolols and maleimides under rhodium(III) catalysis.

The rhodium(III)-catalyzed spiroannulation reaction between N-aryl indazol-3-ols and maleimides is described herein. The developed method is showcased by the construction of spirosuccinimides using bioactive molecule-linked and chemical probe-linked maleimides. Combined mechanistic investigations including the determination of an isolable rhodacycle complex aided the elucidation of a plausible reaction mechanism.

Ruthenium(II)-Catalyzed Regioselective [3 + 2] Spiroannulation of 2H-Imidazoles with 2-Alkynoates.

The C═N double bond of 2H-imidazole has been employed as a C-electrophile for the ruthenium(II)-catalyzed [3 + 2] spiroannulation reaction of 4-phenyl-2H-imidazoles and 2-alkynoates to synthesize spiroimidazole-4,1'-indenes. This strategy features high regioselectivity, broad functional group tolerance, and use of ruthenium as a catalyst, providing a new method to synthesize spirocycles with potential applications in pharmaceuticals.

Cp*Co(III)-Catalyzed Dearomative [3 + 2] Spiroannulation of 2-Alkenylphenols with Ynamides via C-H Activation.

An oxidative [3 + 2] C-H spiroannulation reaction of 2-alkenylphenols with ynamides has been developed toward the synthesis of spiro[4,5]decane derivatives. This dearomative reaction employs earth-abundant cobalt as the metal catalyst and occurs under rather mild reaction conditions (room temperature). The use of ynamides confers unique reactivity and exclusive regioselectivity. The products bearing an all-carbon quaternary stereogenic center were constructed in generally good yields with good functional group tolerance being observed. Experimental mechanistic studies were conducted, and a possible reaction mechanism is proposed.

Rhodium-Catalyzed Selective Oxidative (Spiro)annulation of 2-Arylindoles by Using Benzoquinone as a C2 or C1 Synthon

Rhodium-catalyzed substrate-tunable oxidative annulation and spiroannulation reactions of 2-arylindoles with benzoquinone leading to 9H-dibenzo[a,c]carbazol-3-ols and new spirocyclic products are reported. Intriguingly, with 2-aryl-substituted indoles, benzoquinone could act as a C2 synthon to afford dibenzo[a,c]carbazoles. On the contrary, when 2-aryl-3-substituted indoles were used, benzoquinone switched to act as a C1 synthon to furnish spirocyclic compounds. In addition, further transformations of the obtained products demonstrate the synthetic utility of the present protocol.

Recent Advances in Prins Spirocyclization

The classical Prins cyclization has been one of the most intensively studied reactions during the last two decades, and it has found many applications in key steps of natural product syntheses, especially for products containing tetrahydropyran motifs and related structures in their core skeletons. The application of this reaction to the synthesis of spirocylic networks has made substantial progress recently. Spiro motifs are found in many natural products with promising biorelevance and are increasingly being incorporated in drug candidates. Further, various spirocyclic chiral ligands have shown promising efficiency in asymmetric synthesis. Here a compilation of recent spiroannulation reactions by Prins cyclization is presented, focusing on the scope and versatility of this method.

Organocatalytic Enantioselective Vinylogous Michael-Aldol Cascade for the Synthesis of Spirocyclic Compounds.

Enantioselective synthesis of pyrazolone-fused spirocyclohexenols by the secondary amine-catalyzed cascade reaction of α,β-unsaturated aldehydes with α-arylidene pyrazolinones is reported. This formal [3 + 3] organocascade reaction proceeds through a vinylogous Michael-aldol sequence to furnish the spiroheterocycles with three stereocenters including an all-carbon quaternary center in good yields and selectivities. The catalytic generation of α,β-unsaturated iminium ions from enals and tandem dienolate/enolate formation from pyrazolinones are the key for the success of this spiroannulation reaction.

PPh3-Catalyzed [3 + 2] Spiroannulation of 1C,3N-Bisnucleophiles Derived from Secondary β-Ketoamides with δ-Acetoxy Allenoate: A Route to Functionalized Spiro N-Heterocyclic Derivatives.

A [3 + 2] annulation of α-substituted secondary β-ketoamides with δ-acetoxy-modified allenoate has been developed in the presence of phosphine catalyst. In this spiroannulation reaction, β-ketoamides were used as the bis-nucleophilic partner while the γ,δ-carbon of 5-acetoxypenta-2,3-dienoate participated as a C2 synthon, affording the desired functionalized five-membered N-heterocyclic derivatives in moderate to excellent yields and diastereoselectivities under mild conditions. Preliminary attempts on the asymmetric variant of this reaction have been also examined, giving the corresponding products with moderate ee values.

Asymmetric Construction of Spiro[thiopyranoindole-benzoisothiazole] Scaffold via a Formal [3 + 3] Spiroannulation.

An enantioselective formal thio[3 + 3] spiroannulation reaction of indoline-2-thiones to 1-azadienes has been developed by the use of a quinine-derived bifunctional tertiary amine-thiourea catalyst, which furnished a series of optically active spiro[thiopyranoindole-benzoisothiazole] heterocycles with a spiro quaternary C-N/C-S stereogenic centers in high yields with good to excellent diastereo- and enantioselectivities.

ChemInform Abstract: Ru(II)‐Catalyzed Oxidative Spiroannulation of 2‐Arylphenols with Alkynes via a C—H Activation/Dearomatization Strategy.

An intermolecular spiroannulation reaction of appropriately substituted 2-arylphenols with internal alkynes has been developed by using a Ru(II) catalyst and an oxidant. This transformation was realized by a phenol-directed C–H activation, migratory insertion of the alkyne, and subsequent dearomatization of the phenolic ring, providing a broad range of highly functionalized spirocyclic compounds in moderate yields with high regioselectivity.

ChemInform Abstract: Palladium(II)‐Catalyzed Oxidative Dearomatization of Free Naphthols with Two Alkyne Units.

AbstractThe novel [2+2+1] spiroannulation reaction of naphthols with alkynes succeeds using symmetrical diaryl and dialkyl alkynes.Mixed aryl‐alkyl alkynes provide three regioisomeric products one of which is formed with moderate to good excess (not shown).

Ru(II)-catalyzed oxidative spiroannulation of 2-arylphenols with alkynes via a C-H activation/dearomatization strategy.

An intermolecular spiroannulation reaction of appropriately substituted 2-arylphenols with internal alkynes has been developed by using a Ru(II) catalyst and an oxidant. This transformation was realized by a phenol-directed C-H activation, migratory insertion of the alkyne, and subsequent dearomatization of the phenolic ring, providing a broad range of highly functionalized spirocyclic compounds in moderate yields with high regioselectivity.

Palladium(II)-catalyzed oxidative dearomatization of free naphthols with two alkyne units.

Readily available 2-naphthols undergo [2 + 2 + 1] spiroannulation reactions with alkynes in the presence of a Pd(II) catalyst and an oxidant. This process relies on C-H functionalization and naphthyl ring dearomatization at the 1-position of 2-naphthols to provide a variety of spirocyclic compounds. Using alkyl-aryl alkynes as the coupling partners led to regioisomeric mixtures in favor of the head-to-tail isomer bearing a quaternary carbon stereocenter.

Synthesis of a Spirocyclic Seco Structure of the Principal Vetiver Odorant Khusimone

AbstractThe three‐dimensional structure of tricyclic compounds with a zero‐bridge to one bridgehead atom is determined by the underlying spirocyclic framework. (–)‐Khusimone (1), the principal odorant of vetiver oil (content up to 2 %), is such a tricyclic norsesquiterpene, and dissection of the 7,8‐bond between the methylene and the gem‐dimethyl unit of 1 results in a spirocycle extending over an almost identical molecular volume and shape. Given that the “vetiver rule” postulates that one α‐branched carbonyl osmophore in a certain spatial distance to a bulky moiety is responsible for the odor of vetiver, a 7,8‐seco structure of 1 could prove or disprove these structural requirements. Therefore, (4R*,5R*)‐7‐isopropyl‐4‐vinylspiro[4.4]nonan‐1‐one [(4R*,5R*)‐2] was synthesized in a 10‐step synthetic sequence commencing with Steglich esterification of allyl alcohol (15) and isovaleric acid (14). Ireland–Claisen rearrangement of the formed allyl isovalerate (16) with subsequent lithium aluminum hydride reduction of resulting γ,δ‐unsaturated acid 18, Appel bromination of corresponding alcohol 19, and ozonolysis provided 4‐bromo‐3‐isopropylbutanal (23) in 19 % overall yield as a building block for the projected spiroannulation reactions. Although attempts on cyclopentanone (7) failed, cyclopent‐2‐en‐1‐one, via its TMS‐trapped lithium 3‐vinylcyclopent‐1‐enolate 12, turned out to be a successful starting material. Evans' variant of the Mukaiyama aldol reaction with 1‐trimethylsiloxy‐3‐vinylcyclopent‐1‐ene (12) in the presence of BF3·OEt2, followed by palladium‐catalyzed conjugate tin hydride reduction of resulting enone 28 provided 2‐(4′‐bromo‐3′‐isopropylbutyl)‐3‐vinylcyclopentanone (29) in 50 % overall yield as the anlation precursor. LDA‐mediated 5‐exo‐tet cyclization of 29 concluded the synthesis of the racemic 7,8‐seco‐/6‐epi‐7,8‐secokhusimone mixture (4R*,5R*)‐2, which possessed a floral, rosy, green, geranium‐like odor with a threshold of 42.0 ng L–1 air, which is 10 times less intense than that of (–)‐khusimone (1). Most importantly, seco structure (4R*,5R*)‐2 did not display any woody nor any vetiver character, which proves the postulated vetiver rule wrong.

Identification and optimization of novel pyrimido-isoxazolidine and oxazine as selective hydride donors

Two novel carbon skeletons (3S,3a′R)-6′-(methylthio)-5′,7a′-dihydro-1′H-spiro[indoline-3,3′-isoxazolo[3,4-d]pyrimidine]-2,4′(3a′H)-dione (11a) and 3-(methylthio)-4a,5,7,11c-tetrahydropyrimido[4′,5′:3,4][1,2]oxazino[6,5-b]indol-1(2H)-one (12a) are characterized as hydride donors. The generation of these hydride sources during the spiroannulation reaction between isatin (4) and pyrimidine (5) through the free radical mechanism, was confirmed by (i) the increase in the stoichiometric yields of 11 and 12 when the same reaction was carried out in the presence of free radical initiators (e.g., mCPBA) and (ii) the formation of oxazepine (14) when AIBN was used as free radical initiator. The PKIE [KH/KD] values 4.5 and 4.9 obtained when deuterated 11a (d) was used in the presence of TFA and TFA-d, respectively, suggest the hydride transfer step to be the rate determining step. These hydrides donors selectively reduce aldehyde in the presence of other reducible groups.

Reductive Spiroannulation of Nitriles with Secondary Electrophiles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Reductive Spiroannulation of Nitriles with Secondary Electrophiles

The scope of reductive decyanation and spiroannulation reactions has been expanded to include secondary electrophiles for potentially useful transformations. Secondary phosphates and chlorides, as well as terminal epoxides, cyclize in a stereospecific fashion. Both endo and exo modes of cyclization were observed with terminal epoxides.

ChemInform Abstract: Regiocontrolled Construction of Functionalized Spiro[4.4]nonanones Through Mercury(II) Salt‐Assisted and Acid‐Induced Spiroannulation Reactions.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Regiocontrolled Construction of Functionalized Spiro[4.4]Nonanones Through Mercury(II) Salt-Assisted and Acid-Induced Spiroannulation Reactions

The mercuric(II)-assisted spiroannulation reactions of the enol silyl ethers derived from α-(4-pentynyl)-cyclopentanones 8a and 11 gave functionalized spiro[4.4]nonanones, exo-3 and exo-4 respectively, in moderate yields. On the other hand, the treatment of 8a and 8b with methanesulfonic acid provided endo-3 in high yield.

Cyclization and Reductive Cleavage of Monospirodienone Calix[4]arene Derivatives. Trihydroxy-p-tert-butylcalix[4]arene Revisited

The monospirodienone derivative of 5,11,17,23-tetra-tert-butyl-25,26, 27,28-tetrahydroxycalix[4]arene (2) undergoes in the presence of an am- monium tribromide salt a spiroannulation reaction at the α-position to the carbonyl. Reaction of (2) with an equimolar amount of LDA followed by treatment with a phosphorylating agent yielded a monosubstituted spirodienone. Reductive cleavage of the latter (K/NH 3 ) afforded 5,11, 17,23-tetra-tert-butyl-25,26,27-trihydroxycalixrene (10). The structure of (10) was corroborated indirectly by X-ray crystallography of its bromo dispiro derivative (11). It is concluded that the compound obtai- ned by cleavage of the bis(diethyl phosphate) ester derivative (13), and previously described by us as (10), is 5,11,17,23-tetra-tert-butyl- 25,27-dihydroxy-26-aminocalix[4]arene (12). The latter readily forms a tosylate salt in CDCl 3 solution. Considering this reassignement, the inversion barriers of several OH-depleted aminocalixarenes and their salts are reexamined

A new access to homoerythrina alkaloids

A new spiroannulation reaction based on a «one-pot», tandem alkylation-Michael addition sequence of 2-tetralone has been developed. The combination of this process with an intramolecular Schmidt rearrangement of an azido ketone allows an efficient access to the Homoerythrina skeleton