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. 2014 Jun 4;53(51):14022–14026. doi: 10.1002/anie.201404029

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

Yahui Wang 1, Michael E Muratore 1, Zhouting Rong 1, Antonio M Echavarren 2,*
PMCID: PMC4320749  PMID: 24898850

Abstract

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.

Keywords: (4+1) cycloaddition, carbenes, cyclobutenes, gold catalysis, methylenecyclopropanes

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) cycloadditions2 have been reported mainly with Fischer alkoxy(alkenyl)carbene complexes3 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, cyclobutenes6 could be used as synthetic equivalents of 1,3-dienes 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 38 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—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

Scheme 1.

Scheme 1

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New strategy for the formal (4+1) cycloaddition.

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)]SbF6 (A) in 1,2-dichloroethane at 120 °C, 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).

Table 1.

Gold(I)-catalyzed reaction of 7-(1-naphtyl)-1,3,5-cycloheptatriene (1a) with phenylmethylenecyclopropane (3a).[a] Inline graphic

Entry Catalyst Yield [%][b]
1 A 81 (76)[c]
2 B 25
3 C 28
4 D <5
5 E 47
6 F –[d]
7 G –[d]
8 H –[d]
9 I –[d]
10 J –[d]
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[a] Reaction at 120 °C (0.2 m in 1,2-dichloroethane), 2 equiv of 3 a, catalyst (5 mol %), 2 h. [b] Yields determined by 1H NMR spectroscopy using 1,4-diacetylbenzene as internal standard. [c] Yield of isolated product. [d] Not detected. Inline graphic

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′.

Table 2.

Scope of the formal (4+1) cycloaddition between cycloheptatrienes 1 and methylenecyclopropanes 3.[a] Inline graphic

Inline graphic
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[a] Reaction at 120 °C, 0.2 m in 1,2-dichloroethane, 2 equiv of 3 a–k, catalyst A (5 mol %), 2 h. Yields are for isolated products. [b] Reaction time=3 h. 3-Alkyl-3-arylcyclopent-1-enes 5′n–p were also obtained as minor regioisomers.

Figure 1.

Figure 1

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X-ray crystal structures of 5 k and 7.

Substrate 3 l reacted intramolecularly using catalyst E to form 2,3-dihydro-1H-cyclopenta[l]phenanthrene (5 q′) by isomerization 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

Scheme 2.

Scheme 2

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Intramolecular formal (4+1) cycloaddition and its application to the preparation of a polyarene fragment.

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.

Scheme 3.

Scheme 3

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Probing the mechanism of the formal (4+1) cycloaddition.

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 cyclobutenes14 also took part in the (4+1) cycloaddition reaction to afford cyclopentenes 5 r–z (Table 3).

Table 3.

Scope of the formal (4+1) cycloaddition between cycloheptatrienes 1 and cyclobutenes 4.[a] Inline graphic

Inline graphic
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[a] Reaction at 120 °C, 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.

Cyclobutenes also react with intermediate gold(I) carbenes generated by 1,2-acyloxy migration of propargylic acetates15 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 a16 could be isolated and then transformed cleanly into 5 aa at 40 °C in the presence of gold(I) catalyst. The gold(I) carbene generated from phenyl diazomethane17–20 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 °C in the presence of gold complex A.

Scheme 4.

Scheme 4

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Formal (4+1) cycloaddition with various gold-(I) carbenes.

To shed additional light on the reaction mechanism, we performed the reaction of cycloheptatriene 1 a with MCP [D1]-3 a in the presence of catalyst A (Scheme 5). In this experiment, [D1]-5 a was obtained with the deuterium label transferred completely to C-3.

Scheme 5.

Scheme 5

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Deuterium labeling experiment to probe the mechanism.

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, η2-MCP-gold(I) complex I undergoes ring expansion to form intermediate II, which gives η2-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 RhI, ZnII, and other catalysts.23, 24 Formation of regioisomeric 3-alkyl-3-arylcyclopent-1-enes 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.

Scheme 6.

Scheme 6

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Proposed mechanism for the formal (4+1) cycloaddition.

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.

Supporting Information

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201404029.

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