Formal (4+1) Cycloaddition of Methylenecyclopropanes with 7-Aryl-1,3,5-cycloheptatrienes by Triple Gold(I) Catalysis**

7-Aryl-1,3,5-cycloheptatrienes react intermolecularly with methylenecyclopropanes in a triple gold(I)-catalyzed reaction to form cyclopentenes. The same formal (4+1) cycloaddition occurs with cyclobutenes. Other precursors of gold(I) carbenes can also be used as the C1 component of the cycloaddition.

Carbenes have been widely used as one-carbon synthon in organic synthesis, particularly in the context of cyclopropanation reactions. [1] However, only a few (4+1) cycloadditions [2] have been reported mainly with Fischer alkoxy-(alkenyl)carbene complexes [3] and dialkoxycarbenes. [2,4] To the best of our knowledge, there is no report on the (4+1) cycloaddition of aryl carbenes with 1,3-dienes, probably because of the known propensity of carbenes to give cyclopropanation products with 1,3-dienes. [5] We postulated that due to their high strain and unique electronic properties, cyclobutenes [6] could be used as synthetic equivalents of 1,3dienes for the development of a formal (4+1) cycloaddition with metal carbenes.
We have recently found that 7-substituted 1,3,5-cycloheptatrienes 1 undergo gold(I)-catalyzed retro-Buchner reaction to form carbenes 2 (Scheme 1). [7] Herein, we report a novel and potentially general formal (4+1) cycloaddition by reaction of 1 with methylenecyclopropanes 3 [8] or cyclobutenes 4 to form cyclopentenes 5. In this transformation, methylenecyclopropanes 3 undergo an isomerization to form cyclobutenes 4 similar to that catalyzed by platinum or palladium. [9] Therefore, in the reaction between 1 and 3, gold(I) plays a triple catalytic role, isomerizing 3 into 4 and, in parallel, generating gold(I) carbenes 2 from 1, which cyclopropanate the cyclobutenes. Finally, gold(I) cleaves the internal C À C bond of the resulting bicyclo[2.1.0]pentanes to form the cyclopentenes. This reaction can be viewed as an insertion of one carbon into a double bond, a process that has only been achieved in rare cases with dihalocarbenes. [10,11] Methylenecyclopropanes (MCPs) 3 can be readily prepared in one step by the Wittig olefination of carbonyl compounds with commercially available 3-bromo-triphenylphosphonium bromide. We first examined the reaction of phenylmethylenecyclopropane (3 a) with 7-naphthyl-cyclohepta-1,3,5-triene (1 a) in the presence of gold(I) complexes (Table 1). Using cationic [(JohnPhos)Au(MeCN)]SbF 6 (A) in 1,2-dichloroethane at 120 8C, disubstituted cyclopentene 5 a was isolated in 76 % yield (Table 1, entry 1). Other phosphine or N-heterocyclic carbene gold(I) complexes B-E gave lower yields (entries 2-5), whereas complexes F and G failed to promote this transformation, presumably due to their instability at the temperature required for the retro-Buchner reaction. The reaction also failed with silver(I), copper(II), and platinum(II) catalysts (entries 8-10).
7-Aryl-cyclohepta-1,3,5-trienes containing groups with different electronic and steric effects at the ortho, meta, or para positions reacted with MCPs 3 a-h to yield the (4+1) cycloadducts 5 b-m ( Table 2). The (4+1) cycloaddition proceeds satisfactorily with MCP bearing arenes with fluoro-, chloro-, and bromo-substituents. However, the reaction with o-bromophenylmethylenecyclopropane (3 f) led to cycloadduct 5 k in lower yield. The structure of 5 k was confirmed by X-ray diffraction ( Figure 1). [12] To demonstrate the synthetic utility of this method, cyclopentene 5 l was prepared on a 500 mg scale using only 1 mol % gold catalyst A in 51 % yield after purification by column chromatography. Alkylmethylenecyclopropanes also reacted to give (4+1) cycloaddition products, although in this case the reactions led to mixtures of regioisomers 5 n/n'-5 p/p'.
Substrate 3 l reacted intramolecularly using catalyst E to form 2,3-dihydro-1H-cyclopenta[l]phenanthrene (5 q') by iso- merization of the initially formed adduct 5 q (Scheme 2). In addition, polyarene fragments can be obtained by photochemical cyclization. Thus, compound 5 f can be transformed into a cyclopenta derivative of benzo [g]chrysene (6) by a one pot photo-induced isomerization/oxidative Mallory cyclization. [13] Tetrasubstituted MCP 3 m reacted with 1 a to give only the product of cyclopropanation 7 (Scheme 3 and Figure 1), whose structure was confirmed by X-ray diffraction (Figure 1). [12] Given that 3 m does not undergo ring-expansion, the isolation of spiro derivative 7 strongly suggests that the cyclopropanation of MCP is not the initial step in the formal (4+1) cycloaddition and that cyclobutenes are likely intermediates in this transformation.
To confirm the hypothesis that cyclobutenes are intermediates in the (4+1) reaction of MCP, we performed the reaction of 1 a with cyclobutene 4 a, which was isolated from the reaction mixture of 1 a and 3 g. Under identical conditions, cycloadduct 5 l was isolated in 77 % yield. Trisubstituted cyclobutenes [14] also took part in the (4+1) cycloaddition reaction to afford cyclopentenes 5 r-z (Table 3).
Cyclobutenes also react with intermediate gold(I) carbenes generated by 1,2-acyloxy migration of propargylic acetates [15] under mild conditions with catalyst E to give two separable isomers 5 aa-ac and 5'aa-ac in good overall yields (Scheme 4). By performing the reaction at room temperature at only 60 % conversion, bicyclo[2.1.0]pentane 10 a [16] could be isolated and then transformed cleanly into 5 aa at 40 8C in the presence of gold(I) catalyst. The gold(I) carbene generated from phenyl diazomethane [17][18][19][20] reacted similarly at room temperature with cyclobutene 4 c to form the desired formal (4+1) product 5 ad, along with 10 b. [21] This bicyclo-[2.1.0]pentane was converted quantitatively into cyclopentene 5 ad by warming at 60 8C in the presence of gold complex A.

Angewandte Chemie
To shed additional light on the reaction mechanism, we performed the reaction of cycloheptatriene 1 a with MCP [D 1 ]-3 a in the presence of catalyst A (Scheme 5). In this experiment, [D 1 ]-5 a was obtained with the deuterium label transferred completely to C-3.
According to all experimental data, we propose a mechanism for this formal (4+1) cycloaddition of cycloheptatrienes 1 and MCP in which gold(I) plays a triple role (Scheme 6). In the first catalytic cycle, h 2 -MCP-gold(I) complex I undergoes ring expansion to form intermediate II, which gives h 2 -cyclobutene-gold(I) complex III. Associative ligand exchange with the 7-aryl-1,3,5-cycloheptatriene, followed by retro-Buchner reaction then leads to the highly reactive gold(I) carbene 2, [7] which reacts with cyclobutene 4 to form bicyclo[2.1.0]pentane-gold(I) complex IV. Cyclopropane opening by gold(I) forms the tertiary carbocation V, which leads to complex VI by a final 1,2-H shift. The cyclopropanation of 4 by 2, followed by electrophilic cleavage probably follows a pathway similar to that occurring in the gas phase for the cyclopropanation/retro-cyclopropanation of enol ethers with gold(I) carbenes. [22] Formation of cyclopentenes from bicyclo[2.1.0]pentanes, the presumed intermediates of these reactions, has been mechanistically examined in a few cases using Rh I , Zn II , and other catalysts. [23,24] Formation of regioisomeric 3-alkyl-3-arylcyclopent-1-enes Scheme 2. Intramolecular formal (4+1) cycloaddition and its application to the preparation of a polyarene fragment. Scheme 3. Probing the mechanism of the formal (4+1) cycloaddition. [a] Reaction at 120 8C, 0.2 m in 1,2-dichloroethane, 2 equiv of 4 a-g, catalyst A (5 mol %), 3 h. Yields are for isolated adducts. [b] Cyclobutene 4 a was isolated from the reaction mixture of 1 a and 3 g.
[c] 2 Equiv of 7-(4-chlorophenyl)cyclohepta-1,3,5-triene were used. together with 5 n-p in the reaction of alkyl-substituted MCP can be explained by the competitive migration of the aryl group in intermediates V.
In summary, we have developed a synthesis of substituted cyclopentenes by a formal (4+1) cycloaddition from methylenecyclopropanes or cyclobutenes with gold(I) carbenes generated under catalytic conditions by retro-Buchner reaction of 1,3,5-cycloheptatrienes or by other methods. Further work on the application of this cycloaddition in synthesis is underway. . Keywords: (4+1) cycloaddition · carbenes · cyclobutenes · gold catalysis · methylenecyclopropanes