Catalytic Intermolecular Coupling of Rhodacyclopentanones with

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Catalytic Intermolecular Coupling of Rhodacyclopentanones with Alcohols Enabled by Dual Directing Strategy Ya-Lin Zhang,† Rui-Ting Guo,† Jia-Hao He, and Xiao-Chen Wang* State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China

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S Supporting Information *

ABSTRACT: A catalytic carbonylative ring-opening and functionalization reaction of poorly activated cyclopropanes has been developed. The key achievement of this work is the accomplishment of an unprecedented effective intermolecular trapping of the rhodacyclopentanone intermediate, which is derived from rhodiummediated carbonylative insertion of poorly activated cyclopropanes, by an external reactant. The success of this development hinges upon the use of a dual directing strategy.

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Scheme 1. Carbonylative C−C Activation Reactions of Poorly Activated Cyclopropanes

ransition-metal-catalyzed carbon−carbon (C−C) bond activation reactions have been demonstrated to be a highly useful tool in constructing diversely functionalized organic structures.1 Among existing examples, cyclopropanes are the most frequently studied substrates because of the enhanced reactivity by ring strain.1,2 Activated cyclopropanes, including alkylidenecyclopropanes3 and vinylcyclopropanes,4 have been extensively studied. Recently, by using directing groups, studies on less activated or nonactivated cyclopropanes, such as cyclopropylketones,5 -imines,6 -carboxamides,7 and -amines,8 as well as alkylcyclopropanes9 have made significant progress. In particular, a series of directing-group-assisted carbonylative C−C activation reactions of poorly activated cyclopropanes have been developed (Scheme 1a).7c,8,9 These reactions occur via three key steps: first, directed oxidative addition of a C−C bond to a metal catalyst generates a metallacyclobutane intermediate; second, migratory insertion of carbon monoxide (CO) forms a metallacyclopentanone intermediate; third, trapping of the intermediate by an alkene, an alkyne, or a nucleophile gives the final product. Using this strategy, Narasaka demonstrated rhodium-catalyzed (3 + 1 + 2) cycloaddition reactions between alkyne-tethered cyclopropanes and CO;9a Bower significantly advanced the field by developing several transformations via (3 + 1 + 2) cycloaddition or fragmentation of metallacyclopentanone intermediates.7c,8,9b Notably, all these works utilize substrates that have the trapping functional group covalently tethered to cyclopropanes so that trapping of metallacyclopentanones has occurred in an intramolecular fashion. In contrast, intermolecular reactions with an external trapping reagent remained unexplored. It could be expected that the establishment of intermolecular reactions will significantly improve the diversity and synthetic utility of these powerful transformations. We reasoned that the lack of intermolecular reactions might be due to relatively weak association of the metallacyclopentanone intermediate with external reactants; metal© XXXX American Chemical Society

lacyclopentanones, if not trapped efficiently, could easily undergo decompositions.8a,10,11 To overcome this limitation, we hypothesized that the installation of a directing group to an external trapping reagent might improve its association with metal, thus perhaps leading to the accomplishment of an intermolecular reaction. Specifically, we hoped that a trapping Received: April 24, 2019

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DOI: 10.1021/acs.orglett.9b01420 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

effective (entries 11−15), perhaps due to the decreased strength of coordination with these directing groups. With the optimal reaction conditions in hand, we first tested a number of α-hydroxy carbonyl compounds for reactions with cyclopropylamine 1a (Scheme 2). Analogs of 2-hydroxyaceto-

reagent would bind to metallacyclopentanones in a bidentate fashion, and then, an unsaturated functional group or a nucleophilic unit in the reagent would react with metallacyclopentanones (Scheme 1b). Herein, we report that by using 1,2-diols and α-hydroxy ketones as the bidentate trapping reagents, rhodacyclopentanones underwent a ring-opened coupling reaction with the hydroxy group to afford γaminobutyric acids (GABAs) as the final product. Notably, GABA serves as inhibitory neurotransmitter in the central nervous system (CNS) of mammals, and GABA analogs have been used for treatment of a range of CNS disorders.12 We began our study with the reaction of cyclopropylamines with 2-hydroxyacetophenone (2a) in the presence of carbon monoxide (Table 1). We chose 2a for investigation because

Scheme 2. Scope of α-Hydroxy Carbonyl Compoundsa

Table 1. Study of Reaction Conditionsa

entry

variation from the standard conditions

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

none without P(C6F5)3 P[3,5-(CF3)2C6H3]3 as ligand PPh3 as ligand P(OiPr)3 as ligand [Rh(cod)2]OTf as catalyst [Rh(cod)Cl]2 as catalyst DMF as solvent mesitylene as solvent 120 °C DG = tosyl DG = Cbz DG = Piv DG = Boc DG = benzoyl

88 (80c) 62 60 30 75 59 69 23 67 69 trace 44 20 36 52

a Unless otherwise specified, all reactions were performed with 0.1 mmol of 1a and 0.2 mmol of 2a−2v in 0.5 mL of DCB; isolated yields are reported. b5 mol % [Rh(CO)2Cl]2, 20 mol % P(C6F5)3. c96 h. d 3.75 mol % [Rh(CO)2Cl]2, no phosphine.

a Unless otherwise specified, all reactions were performed with 0.1 mmol of 1a and 0.2 mmol of 2a in 0.5 mL of DCB. bIsolated yields. c The yield of the reaction when performed at 1.0 mmol scale (1a).

phenone were investigated. 2-Naphthyl (2b), benzodioxole (2c), 2-furyl (2d), and 2-thienyl (2e) as the aryl substituents as well as secondary alcohols, such as benzoin (2f) and αhydroxytetralone (2g), and tertiary alcohols, such as 2,2dimethyl-2-hydroxyacetophenone (2h) and 1-benzoylcyclohexanol (2i), were all compatible. Among them, substrate 2e gave a low yield (38%) probably because of the competitive bidentate coordination of the sulfur atom and the carbonyl group to the catalyst. And, the compatibility of tertiary alcohols (2h and 2i) suggests that the reaction is relatively robust toward steric hindrance. Cyclic ketones with an α-hydroxy group (2j, 2k, and 2l) were also reactive, regardless of the ring size. Sterically encumbered 2-hydroxycamphor (2m) was tolerated, giving the corresponding product in 61% yield. Furthermore, α-hydroxy esters were reactive; reactions of methyl mandelate (2n), diethyl tartrate (2o), butyl lactate (2p), pantolactone (2q), and D-glucurono-6,3-lactone acetonide (2r) gave the desired products in 62−81% yields. Moreover, enols adjacent to a carbonyl group were suitable for this reaction; the compatible substrates included 2-hydroxy-2cyclohexenones (2s and 2t) and 2-hydroxy-2-cyclopentenones (2u and 2v). 1,2-Diols were also found to be suitable for this coupling reaction (Scheme 3). The reaction temperature of 120 °C with no addition of any phosphine ligands provided the highest yields. In the obtained products, the uncoupled hydroxy groups were retained without undergoing β-hydride elimi-

the bidentate coordination of the carbonyl group and the hydroxy group to metal would generate a relatively stable fivemembered metallacycle, which surely strengthens the binding of this reactant to the metal center. Moreover, besides functioning as a chelating arm, the hydroxy group is a reactive nucleophile for the desired cross-coupling reaction. After optimization, we were pleased to discover that using [Rh(CO)2Cl]2 (3.75 mol %) as catalyst, P(C6F5)3 (15 mol %) as ligand, N,N-dimethylurea as the directing group (in substrate 1a), and 1,2-dichlorobenezene (DCB) as solvent under 1 atm of CO was able to generate the carbonylative C− C activation/cross-coupling product 3a in 88% isolated yield (entry 1). Ligand P(C6F5)3 was beneficial but not essential for reactivity because the reaction did proceed to give 3a in 62% yield when no phosphine ligand was used (entry 2). Use of P[3,5-(CF3)2C6H3]3, PPh3, or P(OiPr)3 in place of P(C6F5)3 decreased the yields (entries 3−5). [Rh(cod)2]OTf and [Rh(cod)Cl]2 were less active than [Rh(CO)2Cl]2 (entries 6 and 7). Switching the solvent to DMF or mesitylene or running the reaction at 120 °C also decreased the yields (entries 8−10). The reaction is quite sensitive to the variation of directing groups; tosyl, Cbz, Piv, Boc, and benzoyl were less B

DOI: 10.1021/acs.orglett.9b01420 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Scope of 1,2-Diolsa

Scheme 4. Scope of Cyclopropanesa

a

Unless otherwise specified, all reactions were performed with 0.1 mmol of 1a and 0.2 mmol of 4a−4l in 0.5 mL of DCB; isolated yields are reported. b5 mol % [Rh(CO)2Cl]2, 130 °C, 96 h.

nation. Unsymmetrical diols (4a−4d) gave poor regioselectivities. Among them, 1,2,6-hexanetriol (4c) preferentially reacted at the 1,2-diol site rather than at the isolated hydroxy group, highlighting the importance of bidentate coordination for reactivity. The reaction of cis-1,2-cyclopentanediol (4e) gave a 63% yield while trans-1,2-cyclopentanediol (4f) was unreactive owing to the ring strain that disfavored the bidentate coordination. In comparison, because of the decreased ring strain, the trans isomers of 1,2-cyclohexanediol (4h) and 1,2cyclooctanediol (4j) were as reactive or even more reactive than their cis isomers (4g and 4i). The reaction of exo,exo-2,3norbornanediol (4k) gave a 75% yield. Moreover, although weakly nucleophilic catechol (4l) was unreactive with 1a, the desired transformation occurred with 63% yield when the directing group on the cyclopropylamine was changed to a benzoyl group. Diverse cyclopropanes were then investigated for the reaction with 2-hydroxyacetophenone (2a) (Scheme 4). Despite the challenge with regiocontrol, the reactions of 1,2disubstituted cyclopropanes 1b−1e proceeded in a highly selective manner under the modified reaction conditions. The bond cleavage preferentially occurred at the more congested C−C bond (bond B) with cis-1,2-disubstituted cyclopropane 1b, while it occurred at the less hindered C−C bond (bond A) with trans-1,2-disubstituted cyclopropanes 1c−1e; this regioselectivity is consistent with that observed in the intramolecular trapping reactions of 1,2-disubstituted cyclopropanes.8b,e gem-Dimethyl-substituted cyclopropylamine 1f underwent ring opening exclusively at the less hindered C−C bond. However, the reaction of trans-2-phenyl-substituted cyclopropylamine 1g was unselective (regiomeric ratio = 1:1). Sterically encumbered 1,2,3-trisubstituted cyclopropane 1h was tolerated, giving the desired product in 42% yield. We next explored a series of symmetrical cyclopropanes. The reaction of α-methylcyclopropylamine 1i gave the corresponding product in 43% yield. When the nitrogen protecting group was changed to n-butyl (1j) and benzyl (1k), the reactions proceeded with high yields; when it was changed to an alkyl substituent with a terminal ester (1l), the yield dropped to 53%. With substrate 1m, which has two potentially reactive cyclopropane rings, the C−C bond cleavage preferentially occurred at the ring directly connected to nitrogen, indicating a

a

All reactions were performed with 0.1 mmol of 1b−1s and 0.2 mmol of 2a in 0.5 mL of DCB; isolated yields are reported. b10 mol % [Rh(cod)2]OTf, 20 mol % P(4-FC6H4)3, PhCN (2 mL) as solvent. c1 equiv of PhCO2H was used as an additive. d10 mol % [Rh(cod)2]OTf, no phosphine, PhCN (2 mL) as solvent. e5 mol % [Rh(CO)2Cl]2, 20 mol % P(C6F5)3. f5 mol % of [Rh(CO)2Cl]2, no phosphine.

five-membered cyclic transition state is favored over a sixmembered cyclic transition state for C−C activation. Additionally, several fused and spiro bicyclic cyclopropylamines 1n−1q were also reactive. Interestingly, with 1n and 1q, the cis configuration of the bicyclic scaffold was preserved in the obtained products, but with 1o, a trans product was predominantly obtained. We reasoned that the inversion might have occurred after product formation via a thermodynamically controlled keto/enol tautermerization that preferentially placed both bulky substituents at equatorial positions in the chair conformation of the cyclohexane. Remarkably, cyclopropanes that are even less polarized and less activated than cyclopropylamines are feasible for this transformation. Although cyclopropanemethylamine 1r was poorly reactive (20% yield), cyclopropaneacetamide 1s was able to give the coupling product 6s (CCDC 1895332) in 56% yield. C

DOI: 10.1021/acs.orglett.9b01420 Org. Lett. XXXX, XXX, XXX−XXX

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pentanone intermediate by a bidentate hydroxy nucleophile gives the ring-opened cross-coupling product. The success relies on the use of a dual directing strategy: one directing group on cyclopropanes for facilitating the C−C bond activation and another on the trapping reagent for chelation with metallacyclopentanones. Further studies aiming at extending the intermolecular trapping reaction to other nucleophiles and unsaturated hydrocarbons using the dual directing strategy are underway in our laboratory.

To further demonstrate the utility of this method, we tried to apply the reaction to several bioactive or drug molecules (Scheme 5a). Remarkably, despite the potential influence of Scheme 5. Examples of Applications

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01420. Experimental details, compound characterization data, and spectra (PDF) Accession Codes

coexisting functional groups, the reactions of Formestane,13 16α-Hydroxyestrone,14 Hydroxy Lactam,15 and Guaifenesin16 with cyclopropylamine 1a proceeded selectively at the site of bidentate coordination (for detailed reaction conditions, see the Supporting Information). Moreover, the coupling product 3a could be easily transformed into an oxazole by a cascade process of amination and cyclization (Scheme 5b). Therefore, our method is applicable for late-stage functionalization and for constructing new heterocycles. We then performed several control experiments. First, we ran the standard reaction of 1a with 2a in the presence of CD3OD (3 equiv); in the obtained product, deuterium was found at the α-carbon of the ketone group and at the carbon directly connected to the directing group (Scheme 6a). In

CCDC 1895332 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xiao-Chen Wang: 0000-0001-5863-0804 Author Contributions †

Y.-L.Z. and R.-T.G. contributed equally.

Scheme 6. Control Experiments

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (21602114, 21871147), the Natural Science Foundation of Tianjin Municipality (16JCYBJC42500), and the Fundamental Research Funds for Central Universities. This paper is dedicated to the 100th birthday of Nankai University.

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comparison, no deuterium incorporation was detected when the undeuterated product was subjected to the same reaction conditions (Scheme 6b). These results indicate that the rhodium catalyst is indeed cleaved by protodemetalation, and enolization of the ketone occurs during the reaction. Furthermore, 1-hexanol, isopropyl alcohol, and tert-butanol as well as a monomethylated 1,2-diol were found to be unreactive with 1a (Scheme 6c). Therefore, the compatiblitiy of bidentate primary, secondary, and tertiary alcohols in Schemes 2 and 3, together with the regioselectivity in the reaction of substrate 4c and the reactivity difference between 4e and 4f, demonstrates that the bidentate coordination is essential for the observed reactivity. In summary, we have developed a new synthetic method that exploits the Rh-catalyzed carbonylative C−C activation of poorly activated cyclopropanes. Trapping of the rhodacyclo-

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DOI: 10.1021/acs.orglett.9b01420 Org. Lett. XXXX, XXX, XXX−XXX