Xiaoxun Li

Rhodium- and platinum-catalyzed [4+3] cycloaddition with concomitant indole annulation: synthesis of cyclohepta[b]indoles.

Seven-membered rings fused with an indole, cyclohepta[b]-indoles, are present in many bioactive natural products such as silicine,[1] ervitsine,[2] and actinophyllic acid (Figure 1).[3] They are also important structural motifs in numerous pharmaceuticals with various pharmacological properties such as inhibition of deacetylase SIRT1,[4] inhibition of adipocyte fatty-acid-binding protein (A-FABP),[5] and anti-tubercular activity.[6] Most previous efforts have focused on building the seven-membered ring and the indole separately by cyclization reactions.[4,5,7] Recently, an elegant three-component [4+3] cycloaddition was reported by Wu and co-workers for the synthesis of cyclohepta[b]indoles from indoles, aldehydes, and dienes.[8] It represents the first example of a [4+3] cycloaddition involving an indole as the 2π component. We herein report an efficient and versatile process that allows the simultaneous construction of both the indole and seven-membered ring through a [4+3] cycloaddition with concomitant indole annulation.[9] Figure 1 Representative cyclohepta[b]indoles. Vinyl metal carbenes derived from vinyl diazo compounds can undergo formal [4+3] cycloadditions with dienes through a cyclopropanation/Cope rearrangement sequence (Scheme 1).[10,11] Similarly, vinyl Fisher carbenes[12] or vinyl gold carbenes derived from propargylic esters[13] can also react with dienes to form various seven-membered rings. It was recently reported that vinyl metal carbenes could be conveniently generated from propargylic ethers tethered with a nucleophile for a [3+2] cycloaddition[14] and a synthesis of furans.[15] We envisioned that the vinyl metal carbene 2, derived from 1, would undergo a formal [4+3] cycloaddition[16] with diene 3 to afford the cyclohepta[b]indole 4 by either a cyclopropanation/Cope rearrangement sequence involving the divinyl-cyclopropane 5, or an unusual [4+4] cycloaddition to form the eight-membered metallacycle 6 with subsequent reductive elimination. Both indole and seven-membered rings may be constructed very efficiently in this tandem process from simple building blocks. Scheme 1 [4+3] Cycloaddition of vinyl carbenes and dienes. The transformation from the propargylic ether 1 to the product 4 requires a metal catalyst which has enough π acidity[17] to induce cyclization of 1, thus forming a carbene intermediate, and the ability to promote cycloadditions. The catalyst [{Rh(CO)2Cl}2] can facilitate 1,3-acyloxy migration of propargylic esters, a process that is typically catalyzed by π-acidic metals,[17] and effects cycloadditions as well.[18,19] When a mixture of the propargylic ether 1a and diene 3a was treated with this catalyst at 80°C, no reaction occurred (Table 1, entry 1). We have previously found that electron-deficient phosphine or phosphite ligands often increase the acidity of rhodium catalysts and promote 1,2-acyloxy[20] or 1,3-acyloxy[19] migration of propargylic esters. Indeed, a mixture of the [4+3] cycloaddition product 4a and simple indole 7 was observed when 1a was treated with [{Rh(CO)2Cl}2] in the presence of such ligands (entries 2–4). The amount of 7 could be minimized by employing a greater excess of 3a (entry 4). A 67% yield of the isolated tricyclic product 4a could be obtained in the presence of a rhodium(I) metal complex and an electron-deficient phosphite ligand. Table 1 Optimization for the reaction between 1a and 3a.[a] We also examined PtCl2, PtCl2/alkene, and PtCl2/PPh3, all of which have been used in the generation of vinyl platinum carbenes from propargylic ethers.[14,15] A low yield of 4a or no product, however, was observed using these catalysts (Table 1, entries 5–8). We suspect that the coordination of the bidentate diene 3a to PtCl2 may reduce the acidity of the metal. Electron-deficient phosphite or phosphine ligands were then added to further enhance the reactivity of the PtCl2 catalyst (entries 9–11). Indeed, the yield of 4a was increased significantly. The tris(pentafluorophenyl)phosphine ligand provided the highest yield of the isolated product 4a (entry 11). A lower catalyst loading led to lower conversion, and other metal catalysts did not afford the desired product (entries 12–14). With the two catalysts in hand (Table 1, entries 4 and 11), we studied the scope of this tandem indole annulation/[4+3] cycloaddition with different propargylic ethers (Table 2, entries 1–7). The ketone 8a was isolated in 82% yield after in situ hydrolysis of the silyl enol ether 4a (entry 1). A benzyl ether could also be tolerated (entry 2), and other leaving groups (e.g. X=OH, OPiv, or Cl) led to a complex mixture. Electron-withdrawing or electron-donating groups on the benzene ring change the nucleophilicity of the aniline nitrogen atom, however the efficiency of the indole annulation/[4+3] cycloaddition did not change with either type of substituent (entries 3 and 4). A lower yield was observed for the substrate 1e having a free alcohol (entry 5), and a formyl group did not interfere with the tandem reaction (entry 6). The secondary propargylic ether 1g also participated in the tandem reaction and yielded 4g (entry 7). Table 2 Scope of propargylic ethers and acyclic dienes.[a] We next investigated the scope of acyclic dienes that could be used in this process (Table 2, entries 8–10). The more functionalized 2,3-disubstituted diene 3b afforded 4ab in high yield (entry 8, Table 2). The monosubstituted diene 3c produced 8ac in 59% yield in the presence of a rhodium catalyst (entry 9), and lower yields were obtained when various platinum catalysts were employed in this case. The same trend was also observed for 3d (entry 10). When platinum catalysts were employed, the yield of 4ad was 20–30% lower than that obtained from using the rhodium catalyst, and a diastereomeric mixture of 4gd was isolated when 3d was reacted with the propargylic ether 1g (entry 11). A complex mixture was observed when substrate 1a was treated with 2-methyl-1,3-butadiene in the presence of either the platinum or rhodium catalyst, thus suggesting that the siloxy substituent is critical for the reactivity of acyclic dienes. We were pleased to find that the furan 9a participated in the tandem reaction and afforded the tetracyclic product 10a in 71% yield (Table 3, entry 1). The arylation product 11a was isolated in 14% yield. For the 3,4-disubstituted furan 9b, a single product, 10b, was observed (entry 2). The yields for the ester-substituted furans 9c and 9d were slightly lower (entries 3 and 4), and two tetracyclic isomers were obtained for the nonsymmetric furans 9d and 9e (entries 4 and 5). The 2,3-dimethylfuran 9 f only afforded one tetracyclic isomer (10 f; entry 6), however, the arylation product 11 f was also obtained in this case. When pyrrole was employed, only the arylation product was observed.[21] To our surprise, the tetracyclic product 10g could be prepared in 63% yield from the simple cyclopentadiene (9g; entry 7). Cyclohexadiene (9h) also participated in the tandem reaction and afforded the free indole 10h after removing the Boc-protecting group (entry 8). It is worth mentioning that the substitution pattern of the products and the scope of dienes are complementary to that of the [4+3] cycloaddition for the synthesis of cyclohepta[b]indoles reported by Wu and co-workers[8] Table 3 Scope of cyclic dienes for the tandem reaction with the propargylic ether 1a.[a] Possible mechanisms for the tandem indole annulation/[4+3] cycloaddition are shown in Scheme 2. The metal carbene 14 can be generated by 5-endo-cyclization and elimination of methanol.[14,15] Several potential pathways can be proposed for the cycloaddition. In path a, cyclopropanation of diene 3a may afford the divinylcyclopropanes 15 or 16, which undergo Cope rearrangement to produce the products 4a or 4a′, respectively. In path b, nucleophilic attack of the silyl enol ether onto the vinyl carbene may produce the ionic intermediate 17. The metallacycle 18 can be formed through path b1 directly or from a six-membered metallacycle by path b2 followed by a 1,3-shift. Reductive elimination of 18 can then afford the product 4a. Alternatively, cyclization through path b3 may produce product 4a directly. In path c1, a concerted [4+4] cycloaddition between the carbene 14 and diene 3a may also lead to metallacycle 18. A [4+3] cycloaddition with a concomitant elimination of the metal through path c2 is also possible and may yield product 4a directly. Scheme 2 Proposed mechanisms for the [4+3] cycloaddition accompanied by an indole annulation. Based on the regioselectivity reported previously,[10,11] cyclopropanation of diene 3a should occur on the electron-rich silyl enol ether selectively and afford the cyclopropane 16, which would produce the isomeric product 4a′. Since only isomer 4a was observed, [4+3] cycloadditions through paths b or c are more likely for the dienes 3 and 9. This reactivity represents a new class of [4+3] cycloadditions in which the 2π component is an indole derivative.[8] Treatment of the product 4ab with HF/pyridine provided 19, which could be easily functionalized [Eq. (1)]. Saegusa oxidation[22] of the same silyl enol ether yielded enone 20. In summary, a novel indole annulation/[4+3] cycloaddition sequence was developed for the synthesis of various substituted cyclohepta[b]indoles. Both acyclic and cyclic dienes participated in this tandem reaction, and high regioselectivity was observed for the [4+3] cycloaddition in most cases. Application of this method to the synthesis of natural products and pharmaceutical agents is underway and will be reported in due course.

Synthesis of Highly Functionalized Cyclohexenone Rings: Rhodium-Catalyzed 1,3-Acyloxy Migration and Subsequent [5+1] Cycloaddition

The Diels–Alder cycloaddition represents the most powerful technology for the preparation of substituted cyclohexenes and has proven to be extremely valuable in organic synthesis.[1] However, efficient syntheses of cyclohexenes having diverse substitutions, stereochemistry, and functionalities are still challenging and continue to stimulate the development of novel cycloaddition reactions.[2] We report herein a stereoselective synthesis of highly functionalized cyclohexenones from substituted cyclopropanes through a rhodium-catalyzed 1,3-acyloxy migration and subsequent [5+1] cycloaddition. Given the well-documented strategies for the preparation of optically pure cyclopropanes,[3] this promises to be a versatile method for the synthesis of complex cyclohexenones from cyclopropanes.[4]

Rhodium-catalyzed intra- and intermolecular [5 + 2] cycloaddition of 3-acyloxy-1,4-enyne and alkyne with concomitant 1,2-acyloxy migration.

A new type of rhodium-catalyzed [5 + 2] cycloaddition was developed for the synthesis of seven-membered rings with diverse functionalities. The ring formation was accompanied by a 1,2-acyloxy migration event. The five- and two-carbon components of the cycloaddition are 3-acyloxy-1,4-enynes (ACEs) and alkynes, respectively. Cationic rhodium(I) catalysts worked most efficiently for the intramolecular cycloaddition, while only neutral rhodium(I) complexes could facilitate the intermolecular reaction. In both cases, electron-poor phosphite or phosphine ligands often improved the efficiency of the cycloadditions. The scope of ACEs and alkynes was investigated in both the intra- and intermolecular reactions. The resulting seven-membered-ring products have three double bonds that could be selectively functionalized.

Rhodium-catalyzed tandem annulation and (5 + 1) cycloaddition: 3-hydroxy-1,4-enyne as the 5-carbon component.

A Rh-catalyzed tandem annulation and (5 + 1) cycloaddition was realized. 3-Hydroxy-1,4-enyne served as the new 5-carbon component for the (5 + 1) cycloaddition. Substituted carbazoles, dibenzofurans, and tricyclic compounds containing a cyclohexadienone moiety could be prepared efficiently. The identification of a byproduct suggests that metal carbene and ketene intermediates may be involved in the (5 + 1) cycloaddition.

Rhodium‐Catalyzed Ring Expansion of Cyclopropanes to Seven‐membered Rings by 1,5 CC Bond Migration

Selective cleavage and subsequent elaboration of carbon–carbon σ bonds into complex molecules represents a fundamental challenge in chemistry. The C–C σ bonds of cyclopropanes are activated owing to ring strain, and the ring expansion of cyclopropanes is an attractive route to other ring systems because of the well-documented stereoselective methods for cyclopropanation.[1] Indeed, ring expansion of cyclopropanes to four- or five-membered rings by 1,2 or 1,3 migration is routinely practiced in organic synthesis [Eq. (1)].[2] In contrast, ring expansion of cyclopropanes to seven-membered rings by 1,5 C–C bond migration has not been developed as a general method, in spite of the prevalence of cycloheptane skeletons in natural products and pharmaceutical agents.[3] The 1,5 migration of a cyclopropane C–C bond has been mainly studied in bicyclo-[4.1.0]heptadienes and a few other conformationally constrained bicyclic compounds under thermal conditions.[4] In fact, it was reported that simple 1,3-dienylcyclopropanes underwent 1,3 C–C bond migration to form vinylcyclopentenes in the presence of Ni or Pd catalysts.[5]

Rhodium-Catalyzed Chemo- and Regioselective Cross-Dimerization of Two Terminal Alkynes

Cross-dimerization of terminal arylacetylenes and terminal propargylic alcohols/amides has been achieved in the presence of a rhodium catalyst. This method features high chemo- and regioselectivities rendering convenient and atom economical access to functionalized enynes.

Rhodium-Catalyzed Carbonylation of 3-Acyloxy-1,4-enynes for the Synthesis of Cyclopentenones

Functionalized cyclopentenones were synthesized by a Rh-catalyzed carbonylation of 3-acyloxy-1,4-enynes, derived from alkynes and α,β-unsaturated aldehydes. The reaction involved a Saucy-Marbet 1,3-acyloxy migration of propargyl esters and a [4 + 1] cycloaddition of the resulting acyloxy substituted vinylallene with CO.

Rhodium-catalyzed 1,3-acyloxy migration and subsequent intramolecular [4+2] cycloaddition of vinylallene and unactivated alkyne

A Rh-catalyzed 1,3-acyloxy migration of propargyl ester followed by intramolecular [4+2] cycloaddition of vinylallene and unactivated alkyne was developed. This tandem reaction provides access to bicyclic compounds containing a highly functionalized isotoluene or cyclohexenone structural motif, while only aromatic compounds were observed in related transition metal-catalyzed cycloadditions.

Rhodium-Catalyzed Carbonylation of Cyclopropyl Substituted Propargyl Esters: A Tandem 1,3-Acyloxy Migration [5+1] Cycloaddition

We have developed two different types of tandem reactions for the synthesis of highly functionalized cyclohexenones from cyclopropyl substituted propargyl esters. Both reactions were initiated by rhodium-catalyzed Saucy-Marbet 1,3-acyloxy migration. The resulting cyclopropyl substituted allenes derived from acyloxy migration then underwent [5 + 1] cycloaddition with CO. The acyloxy group not only eased the access to allene intermediates but also provided a handle for further selective functionalizations.

Synthesis of Carbazoles and Carbazole-Containing Heterocycles via Rhodium-Catalyzed Tandem Carbonylative Benzannulations

Polycyclic aromatic compounds are important constituents of pharmaceuticals and other materials. We have developed a series of Rh-catalyzed tandem carbonylative benzannulations for the synthesis of tri-, tetra-, and pentacyclic heterocycles from different types of aryl propargylic alcohols. These tandem reactions provide efficient access to highly substituted carbazoles, furocarbazoles, pyrrolocarbazoles, thiophenocarbazoles, and indolocarbazoles. While tricyclic heterocycles could be derived from vinyl aryl propargylic alcohols, tetra- and pentacyclic heterocycles were synthesized from diaryl propargylic alcohols. The tandem carbonylative benzannulation is initiated by a π-acidic rhodium(I) catalyst-mediated nucleophilic addition to alkyne to generate a key metal-carbene intermediate, which is then trapped by carbon monoxide to form a ketene species for 6π electrocyclization. Overall, three bonds and two rings are formed in all of these tandem carbonylative benzannulation reactions.