Oxyanion-accelerated C2-C6 cyclization of benzannulated enyne-allenes

The cyclization of oxyanion-substituted, benzannulated enyne-allenes was found to proceed rapidly and efficiently at room temperature, producing substituted indanones and fluorenones through a C2-C6 cyclization pathway. These reactions bear close resemblance to thermal C2-C6 cyclizations of enyne-allenes previously reported by Schmittel and others, though the oxyanion-substituted cases cyclize far more rapidly, and stand in noteworthy contrast to the C2-C7 (Myers) cyclization of (Z)-1,2,4-heptatrien-6-yne, the parent enyne-allene. The rate of reaction was found to be sensitive to the size of the alkyne and allene substituents, though the electronic effects of substitution are not known. The acceleration imparted by the oxyanion substituent is consistent with the electronic stabilization of a proposed diradicaloid transition state for the C2-C6 cyclization, but the available evidence does not permit the distinction between concerted and stepwise mechanisms. Studies are ongoing to further elucidate the mechanism and expand the scope of these transformations.     

Radical-anionic cyclizations of enediynes: remarkable effects of benzannelation and remote substituents on cyclorearomatization reactions

The reasons for large changes in the energetics of C1-C5 and C1-C6 (Bergman) cyclizations of enediynes upon one-electron reduction were studied by DFT and Coupled Cluster computations. Although both of these radical-anionic cyclizations are significantly accelerated relative to their thermal counterparts, the acceleration is especially large for benzannelated enediynes, whose reductive cyclizations are predicted to proceed readily under ambient conditions. Unlike their thermal analogues, the radical-anionic reactions can be efficiently controlled by remote substitution, and the effect of substituent electronegativity is opposite of the effect on the thermal cycloaromatization reactions. For both radical-anionic cyclizations, large effects of benzannelation and increased sensitivity to the properties of remote substituents result from crossing of out-of-plane and in-plane MOs in the vicinity of transition states. This crossing leads to restoration of the aromaticity decreased upon one-electron reduction of benzannelated enediynes. Increased interactions between nonbonding orbitals as well as formation of new aromatic rings (five membered for the C1-C5 cyclization and six membered for C1-C6 cyclizations) are the other sources of increased exothermicity for both radical-anionic cyclizations. The tradeoff between reduction potentials and cyclization efficiency as well as the possibilities of switching of enediyne cyclization modes (exo or C1-C5 vs endo or C1-C6)) under kinetic or thermodynamic control conditions are also outlined.     

Thermal C2-C6 cyclization of enyne-allenes. Experimental evidence for a stepwise mechanism and for an unusual thermal silyl shift

Enyne-allenes 4a-c bearing various cyclopropyl systems as radical clock reporter groups at the allene terminus have been synthesized and subjected to thermal C2-C6 cyclization. The ratio of ene versus formal Diels-Alder products could be rationalized on the basis of steric effects. Only the thermolysis of 4c, equipped with the fast diphenylcyclopropylcarbinyl radical clock, afforded a 1,3-butadienyl benzofulvene clearly formed via cyclopropyl ring opening. This finding provides unambiguous evidence for a stepwise mechanism of the C2-C6 cyclization making it possible to suggest a lifetime for the intermediate diradical of >1x10(-10) s (at 170 degrees C). An interesting corollary was the isolation of an unexpected silyl shift product in the thermolysis of all three enyne-allenes that allows explanation of the loss of the TIPS group in some of the Diels-Alder products. For a full understanding of the mechanism, silyl and hydrogen shift processes were interrogated using DFT.     

Ring size and substituent effects in oxyanion-promoted cyclizations of enyne-allenes: observation of a Myers-Saito cycloaromatization at cryogenic temperature

A series of acetoxy-substituted enyne-allenes, fused to cyclopentene and cyclohexene ring systems, were synthesized and treated with methyllithium to generate the corresponding enolates. It was found that whereas the cyclohexannulated examples underwent either C2-C7 (Myers-Saito) cycloaromatization or C2-C6 (Schmittel) cyclization depending on their terminal subsituents, the cyclopentannulated examples either failed to cyclize altogether or underwent C2-C7 cyclization. Both of these results lie in contrast to the behavior of their benzannulated analogues, which underwent exclusive C2-C6 cyclization independent of substituents. These findings are rationalized on the basis of both ring strain effects and the steric encumbrance of the terminal alkynyl and allenyl subsituents.     

Theoretical investigation of the photochemical C2-C6 cyclisation of enyne-heteroallenes

Herein we discuss computations that explain experimental results regarding a highly efficient triplet analogue of the C(2)-C(6) cyclisation of enyne-heteroallenes recently discovered by Schmittel and co-workers.1 To shed some light on the reasons for the differences found between enyne-carbodiimides, enyne-ketenimines and enyne-allenes, we have computed the reaction profiles of the C(2)-C(6) and of the C(2)-C(7) cyclisations for various model compounds, assuming that the reactions take place on the lowest-lying triplet surfaces. Our results nicely explain the differences and the unexpected high efficiency found for the enyne-carbodiimides. The differences between enyne-carbodiimides and enyne-ketenimines prove to be due to differences in the shapes of the corresponding triplet surfaces. In contrast to the enyne-carbodiimides, for which our calculations predict that a direct cyclisation to the biradical intermediates should occur after the vertical excitation, the enyne-ketenimines relax into a local minimum on the triplet surface. As a consequence, further reaction channels are opened. Our computations indicate that enyne-allene compounds do not react because the necessary excitation energy lies outside the range of the employed triplet photosensitizer. Finally, the close agreement between our results and the experimental findings indicates that the underlying reasons for the differences in the photochemical behaviour of enyne-carbodiimides, enyne-ketenimines and enyne-allenes are related to differences in the electronic structures of the parent systems, while substituent effects are less important.     

Photochemical C2-C6 cyclization of enyne-allenes: detection of a fulvene triplet diradical in the laser flash photolysis

A series of enyne-allenes, with and without benzannulation at the ene moiety and equipped with aromatic and carbonyl groups as internal triplet sensitizer units at the allene terminus, was synthesized. Both sets, the cyclohexenyne-allenes and benzenyne-allenes, underwent thermal C(2)-C(6) cyclization exclusively to formal ene products. In contrast, the photochemical C(2)-C(6) cyclization of enyne-allenes provided formal Diels-Alder and/or ene products, with higher yields for the benzannulated systems. A raise of the temperature in the photochemical cyclization of enyne-allene 1b' led to increasing amounts of the ene product in relation to that of the formal Diels-Alder product. Laser flash photolysis at 266 and 355 nm as well as triplet quenching studies for 1b,b' indicated that the C(2)-C(6) cyclization proceeds via the triplet manifold. On the basis of a density functional theory (DFT) study, a short-lived transient (tau = 30 ns) was assigned as a triplet allene, while a long-lived transient (tau = 33 micros) insensitive to oxygen was assigned as fulvene triplet diradical. An elucidation of the reaction mechanism using extensive DFT computations allowed rationalization of the experimental product ratio and its temperature dependence.     

Thermal C1-C5 diradical cyclization of enediynes

Computational studies at the BLYP/6-31G(d) level (supplemented by BCCD(T)/cc-pVDZ calculations) suggest that in aryl-substituted 1,2-diethynylbenzenes, steric effects disfavor the thermal C1-C6 diradical cyclization reaction (Bergman) and electronic effects favor the regiovariant C1-C5 cyclization to the extent that the C1-C5 process should become an important reaction pathway in the thermolyses of such compounds. Experimentally, thermolyses of 1,2-bis(2,4,6-trichlorophenylethynyl)benzene, a particularly favorable case, yields only products derived from C1-C5 cyclization [specifically, 1-(2,4,6-trichlorobenzylidene)-2-(2,4,6-trichlorophenyl)-1H-indene and its hydrogenation product 3-(2,4,6-trichlorobenzyl)-2-(2,4,6-trichlorophenyl)-1H-indene], and even for the parent hydrocarbon 1,2-bis(phenylethynyl)benzene, the formation of C1-C5 cyclization products is competitive with the major Bergman reaction. Although some C1-C5 cyclization products are probably formed by transfer hydrogenation from 1,4-cyclohexadiene (commonly included in such reactions), thermolyses in the absence of 1,4-CHD as well as deuterium labeling studies confirm the existence of direct C1-C5 diradical cyclizations for diaryl-substituted enediynes.     

Synthesis and thermal cyclization of an enediyne-sulfonamide

The synthesis of an enediyne sulfonamide by alkylidene carbene rearrangement is reported. The compound cyclizes thermally to give the Bergman product, which was prepared independently for comparison. Like other σ-acceptor substituents at the enediyne alkyne termini, such as fluoride, oxonium or ammonium groups, the sulfonamide moiety enhances the reactivity for thermal Bergman cyclization as shown by the cyclization kinetic of the title compound.     

The importance of the ene reaction for the C(2)-C(6) cyclization of enyne-allenes

The present study establishes the ene reaction as a competing reaction mechanism to the diradical mechanism for the thermal C(2)-C(6) cyclization of enyne-allenes which possess bulky substituents at the alkyne terminus. Both reaction routes are found to possess nearly equal free energies of activation. As shown by our computations, primary H/D isotope effects could be used for a definite decision about the mechanism. Concerning the regioselectivity of the cyclization reactions of enyne-allenes our study resolves a long-standing deviation between theoretical results and experimental findings.     

Coupling of Fischer carbene complexes with conjugated enediynes featuring radical traps: Novel structure and reactivity features of chromium complexed arene diradical species

The reaction of Fischer carbene complexes with conjugated enediynes that feature a pendant alkene group has been examined. The reaction proceeds through carbene–alkyne coupling to generate an enyne–ketene intermediate. This intermediate then undergoes Moore cyclization to generate a chromium complexed arene diradical, which then undergoes cyclization with the pendant alkene group. The radical cyclization prefers the 6-endo mode unless radical-stabilizing groups are present to favor the 5-exo mode. The intermediate diradical species were evaluated computationally in both the singlet and triplet configurations. Arene triplet diradicals feature minimal spin density at oxygen and delocalization to chromium. The 6-endo cyclization product was kinetically and thermodynamically favored.     

Deciphering the mechanistic dichotomy in the cyclization of 1-(2-ethynylphenyl)-3,3-dialkyltriazenes: competition between pericyclic and pseudocoarctate pathways

The mechanistic aspects of the cyclization of (2-ethynylphenyl)triazenes under both thermal and copper-mediated conditions are reported. For cyclization to an isoindazole, a carbene mechanistic pathway is proposed. The carbene intermediate can react with oxygen, dimerize to give an alkene, or be trapped either intermolecularly (using 2,3-dimethyl-2-butene to generate a cyclopropane) or intramolecularly (using a biphenyl moiety at the terminus of the acetylene to form a fluorene). Density-functional theory (DFT) calculations support a pseudocoarctate pathway for this type of cyclization. Thermal cyclization to give a cinnoline from (2-ethynylphenyl)triazenes is proposed to occur through a pericyclic pathway. DFT calculations predict a zwitterionic dehydrocinnolinium intermediate that is supported by deuterium trapping studies as well as cyclizations performed using a 2,2,6,6-tetramethylpiperidine moiety at the 3-position of the triazene.     

Reactions of Aromatic S‐ and O‐Enynes with Two Methyl Substituents on the Olefinic Unit Assisted by a Ruthenium Complex: Tandem Cyclization and Product Selectivity

Ruthenium‐assisted cyclizations of two enynes, HC≡CCH(OH)(C₆H₄)X? CH₂CH?CMe₂ (X=S ( 1a ), O ( 1b )), each of which contains two terminal methyl substituents on the olefinic parts, are explored. The reaction of 1a in CH₂Cl₂ gives the vinylidene complex 2a from the first cyclization and two side products, 3a and the carbene complex 4a with a benzothiophene ligand. The same reaction in the presence of HBF₄ affords 4a exclusively. Air oxidation of 4a in the presence of Et₃N readily gives an aldehyde product. In MeOH, tandem cyclizations of 1a generate a mixture of the benzothiochromene compound 10a and the carbene complex 7a also with a benzothiochromene ligand. First, cyclization of 1b likewise proceeds in CH₂Cl₂ to give 2b . Tandem cyclization of 1b in MeOH yields comparable products 10b and 7b with benzochromene moieties, yet with no other side product. The reaction of [Ru]Cl with HC≡CCH(OH)(C₆H₄)S? CH₂CH?CH₂ ( 1c ), which contains no methyl substituent in the olefinic part, in MeOH gives the carbene complex 15c with an unsubstituted thiochromene by means of a C? S bond formation. Structures of 3a and 15c are confirmed by X‐ray diffraction analysis. The presence of methyl groups of enynes 1a and 1b promotes sequential cyclization reactions that involve C? C bond formation through carbocationic species.     

Syntheses and reactivity of naphthalenyl-substituted arenediynes

A series of naphthalenyl-substituted arenediynes were prepared to examine photochemical reactivity. For naphthalen-1-ylethynyl arenediyne, 350 nm photolysis resulted in a tandem [2 + 2] photocycloaddition to afford cyclobutene adducts. For naphthalen-2-ylethynyl derivatives, electron-donating methoxy substituents were found to facilitate C(1)-C(6) Bergman cyclization at 300 nm. Theoretical calculations provided further insight into thermal and photochemical reactivity.     

Synthesis of plagiochiline N from santonin.

This article reports the transformation of O-acetylisophotosantonin, obtained by photochemical rearrangement of santonin, into plagiochiline N, an ent-2,3-secoaromadendrane isolated from Plagiochila ovalifolia. The synthesis was carried out in a sequence involving as the key steps (a) the substitution of the lactone moiety by a gem-dimethylcyclopropane ring through a synthetic intermediate having a C(6)-C(7) double bond and (b) the ozonolysis of the C(2)-C(3) bond followed by cyclization to the dihydropyran ring characteristic of plagiochiline N. Spectroscopic data of the synthetic product fully coincided with the reported data for the natural product.     

Thermische Cyclisierung von α-Alkinonen zu 2-Cyclopentenonen

Thermal Cyclization of α-Alkynones to 2-Cyclopentenones Gas phase thermolysis at 600–740° of substituted 1-pentyn-3-ones (α-alkynones), which are easily prepared by acylation of trimethylsilyl acetylenes, leads to substituted 2-cyclopentenones. The intramolecular formation of a new C, C-bond between an acetylenic and a non-activated carbon atom is accompanied by a [1,2]-migration of one of the substituents at the triple bond. This novel ‘-alkynone cyclization’ reaction may be explained by postulating an alkylidene carbene intermediate which inserts into a C,H-bond five carbon atoms away at the non-acetylenic part of the ketone. Several examples demonstrate that the α-alkynone cyclization offers a simple tool for the preparation of certain monocyclic, bicyclic and spiro compounds containing a 2-cyclopentenone moiety.     

Zum Mechanismus der α-Alkinon-Cyclisierung: Synthese und Thermolyse von 1-(1-Methylcyclopentyl)[3-13C]prop-2-inon

On the Mechanism of the α-Alkynone Cyclization: Synthesis and Thermolysis of 1-(1-Methylcyclopentyl)[3-¹³C]prop-2-ynone The relative migratory aptitude of two acetylenic substituents in the α-alkynone cyclization, a thermal conversion of α-acetylenic ketones A to 2-cyclopentenones C , was investigated by isotope-labeling experiments. The α-alkynone [β-¹³C]- 1 , specifically labeled with ¹³C at the β-acetylenic C-atom C(3), was synthesized by an intramolecular Witting reaction (230–300°) of the diacylmethylidenephosphorane [¹³C]- 7. The latter resulted from acylation of methylidenetriphenylphosphorane with the acid chloride 4 to yield the acylmethylidenephosphorane 5 , which in turn was formylated with acetic [¹³C]formic anhydride ([¹³C]- 6. ) Upon thermolysis of [β-¹³C]- 1 , its label at C(β) was transferred almost exclusively to C(β) of the 2-cyclopentenone moiety in the resulting cyclization product [¹³C]- 2. We conclude that there is a distinct preference for hydrogen migration in the acetylene → alkylidene carbene isomerization (A → B) which precedes the cyclization step (B → C). No evidence was found for a fast reversibility of this isomerization (A ? B) involving both acetylenic substituents.     

Intramolecular cyclization of ruthenium vinylidene complexes with a tethering vinyl group: facile cleavage and reconstruction of the C-C double bond

Protonation of ruthenium acetylide complexes [M]-*C*CCPh2CH2CH=CH2 (2a, [M] = (eta5-C5H5)(P(OPh)3)(PPh3)Ru; 2a', [M] = (eta5-C5H5)(dppp)Ru; *C = 13C-labeled carbon atom) with HBF4 in ether produces [[M]=*C=CHCH2CPh2*CH=CH2][BF4] (4, 4') exclusively via a metathesis process of the terminal vinyl group with the *C=*C of the resulting vinylidene group. For 4 in methanol, bond reconstruction of the two labeled *C atoms readily takes place via a retro-metathesis process followed by a cyclization of the resulting vinylidene ligand giving the cyclic carbene complex 5, which is fully characterized by single-crystal X-ray diffraction analysis. The protonation of 2a in MeOH is followed by a cyclization, also giving 5. Deuterium-labeling study indicates that the C-C bond formation of this cyclization proceeds simultaneously with the formation of 4 consistent with facile cleavage and reconstruction of C=C bonds. For comparison, complex 4 in alcohol yields, besides 5, the corresponding alkoxycyclohexene 6. Formation of 6 from 4 also involves a skeletal rearrangement with reconstruction of the C=C bond. Interestingly, [[Ru']=*C=C(Me)CH2CPh2*CH=CH2][BF4] (8') originally from a complex with two connected labeled carbon atoms also undergoes reestablishment of the *C=*C bond yielding the cyclic allenyl complex 9'. 13C-labeling studies clearly reveal the reestablishment of two C=C double bonds in the transformation of both 4 to 5 and 8' to 9'. The proposed mechanism implicates a cyclobutylidene intermediate formed either via a regiospecific [2+2] cycloaddition of two double bonds in the ruthenium vinylidene 4 or via a cyclization of 4 giving a nonclassical ion intermediate followed by a 1,2-alkyl shift.     

Binuclear biscarbene complexes of furan

Carbene complexes of chromium and tungsten with a bridging furan substituent were synthesized from lithiated furan precursors and metal hexacarbonyls. The binuclear biscarbene complexes [(CO)5M{C(OEt)-C4H2O-C(OEt)}M'(CO)5](M = M'= Cr (3), W (4)) were obtained as well as the corresponding monocarbene complexes [M{C(OEt)-C(4)H3O}(CO)5](M = Cr (1), W (2)). A method of protecting the carbene moiety during the metal acylate stage was used to increase not only the yields of the binuclear Fischer biscarbene complexes 3 and 4 but to establish a method to synthesize analogous mixed heterobinuclear carbene complexes (M = W, M'= Cr (5)) in high yields. The binuclear biscarbene complexes 3 and 5 were reacted with 3-hexyne and yielded the corresponding benzannulated monocarbene complexes [M{C(OEt)-C14H17O3}(CO)5](M = Cr (6), W(7)). Complex 5 reacted regioselectively with the benzannulation reaction occurring at the chromium-carbene centre. The major products from refluxing 3 in the presence of [Pd(PPh3)4] were a monocarbene-ester complex [Cr{C(OEt)-C4H2O-C(O)OEt}(CO)5](8), the 2,5-diester of furan (9) and a carbene-carbene coupled olefin EtOC(O)-C4H2O-C(OEt)=C(OEt)-C4H2O-C(O)OEt (10). X-Ray structure analysis of 4 and 6 confirmed the molecular structures of the compounds in the solid state and aspects of electron conjugation between the transition metals and the furan substituents in the carbene ligands were investigated.     

Chromene chromium carbene complexes in the syntheses of naphthopyran and naphthopyrandione units present in photochromic materials and biologically active natural products

The carbene complex 5-(2,2-dimethyl-2H-chromene)methoxylmethylene chromium pentacarbonyl will undergo a benzannulation reaction with phenylacetylene, 1-pentyne, 3-hexyne, and trimethylsilylacetylene to give 7-hydroxy-10-methoxy-3H-naphtho[2.1-b]pyrans as the primary product. These compounds are difficult to obtain pure due to their sensitivity to air. If the benzannulation reaction is performed in conjunction with protection of the phenol function at C-7, then good to excellent yields of 7-alkoxy-10-methoxy-3H-naphtho[2.1-b]pyrans are afforded. If the 7-hydroxy products are captured by triflic anhydride, then the resulting aryl triflate can be used to access 3H-naphtho[2.1-b]pyrans bearing C-7 carbon substituents. The 7-hydroxy products can be oxidized to 3H-naphtho[2,1-b]pyran-7,10-diones which are stable. The chromenyl carbene complex reacts with 1,6-bis(triisopropylsilyl)-1,3,5-hexatriyne to give a 2,3-dihydro-2,2-dimethylbenzo[de]chromene, a product type that has not been seen before in the reaction of Fischer carbene complexes with alkynes. A mechanism is proposed for this process that involves alpha,beta-hydride elimination from a chromacyclobutane intermediate. Chromenyl tungsten complexes react with alkynes to give products that result from cyclization without CO insertion.     

Multigram synthesis of the C29-C51 subunit and completion of the total synthesis of altohyrtin C (spongistatin 2)

A multigram synthesis of the C29-C51 subunit of altohyrtin C (spongistatin 2) has been accomplished. Union of this intermediate with the C1-C28 fragment and further elaboration furnished the natural product. Completion of the C29-C51 subunit began with the aldol coupling of the boron enolate derived from methyl ketone 8 and aldehyde 9. Acid-catalyzed deprotection/cyclization of the resulting diastereomeric mixture of addition products was conducted in a single operation to afford the E-ring of altohyrtin C. The diastereomer obtained through cyclization of the unwanted aldol product was subjected to an oxidation/reduction sequence to rectify the C35 stereocenter. The C45-C48 segment of the eventual triene side chain was introduced by addition of a functionalized Grignard reagent derived from (R)-glycidol to a C44 aldehyde. Palladium-mediated deoxygenation of the resulting allylic alcohol was followed by adjustment of protecting groups to provide reactivity suitable for the later stages of the synthesis. The diene functionality comprising the remainder of the C44-C51 side chain was constructed by addition of an allylzinc reagent to the unmasked C48 aldehyde and subsequent dehydration of the resulting alcohol. Completion of the synthesis of the C29-C51 subunit was achieved through conversion of the protected C29 alcohol into a primary iodide. The synthesis of the C29-C51 iodide required 44 steps with a longest linear sequence of 33 steps. From commercially available tri-O-acetyl-d-glucal, the overall yield was 6.8%, and 2 g of the iodide was prepared. The C29-C51 primary iodide was amenable to phosphonium salt formation, and the ensuing Wittig coupling with a C1-C28 intermediate provided a fully functionalized, protected seco-acid. Selective deprotection of the required silicon groups afforded an intermediate appropriate for macrolactonization, and, finally, global deprotection furnished altohyrtin C (spongistatin 2). This synthetic approach required 113 steps with a longest linear sequence of 37 steps starting from either tri-O-acetyl-d-glucal or (S)-malic acid.