Letter Cite This: Org. Lett. 2018, 20, 7141−7144
pubs.acs.org/OrgLett
Palladium(0)-Catalyzed Intramolecular Cascade Cyclization of Methylenecyclopropanes Wei Fang,† Yin Wei,‡ and Min Shi*,†,‡,§
Org. Lett. 2018.20:7141-7144. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 11/16/18. For personal use only.
†
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China ‡ State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, University of Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China § State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China S Supporting Information *
ABSTRACT: A Pd(0)-catalyzed cascade cyclization of methylenecyclopropanes (MCPs) involving an intramolecular Heck-type reaction and β-H eliminations has been disclosed in this paper. The reaction proceeds smoothly through an unprecedented ring-opening pattern of MCPs via a cyclopropene intermediate and a vinylpalladium carbene species seemingly, furnishing spirocyclic compounds containing fluorene and 1,2-dihydronaphthalene moieties in moderate to good yields.
M
Scheme 1. Transition-Metal-Catalyzed Ring-Opening Patterns of MCPs
ethylenecyclopropanes (MCPs), containing the smallest carbocycle with an exo-methylene moiety,1 are useful building blocks in the field of organic synthesis due to their high ring strain and high reactivity.2 MCPs can undergo various ring-opening reactions because of a thermodynamic driving force derived from the release of the cyclopropyl ring strain (40 kcal/mol)3 and the kinetic opportunity originating from the π-character of the ring bonds of the cyclopropane to initiate the unleashing of the strain.4 In recent decades, transition-metal-catalyzed ring-opening reaction of MCPs has drawn much attention from organic chemists.5 Previously, the reaction modes of MCPs under transition metal catalysis could be classified into four patterns.6 When MCP I is treated with transition metal catalyst M, the reaction proceeds through two different types of reaction processes; the insertion of M into the distal C−C bond affords metallacyclobutane species II, and the insertion of M into the proximal C−C bond gives another metallacyclobutane species III, which are able to undergo various cycloaddition reactions with other species (Scheme 1, reaction 1).7 Moreover, when the exo-methylene moiety of MCP I reacts with an organic transition metal complex, two different types of addition processes offer the corresponding two adducts, such as cyclopropylmethyl metal species IV and cyclopropyl metal species V, respectively. After subsequently going through β-C elimination, the ring-opening reaction of cyclopropane takes place to give the corresponding products (Scheme 1, reaction 2).5b,8 However, a novel ring-opening pattern of MCPs is also conceivable. The addition of an organic transition metal complex to the exo-methylene moiety of MCP I affords adduct VI, which subsequently undergoes βH elimination to give the corresponding cyclopropene intermediate VII. The cyclopropene VII can isomerize to another cyclopropene VIII via the addition of in situ generated HMLn species and the β-H elimination. The oxidative addition © 2018 American Chemical Society
of M with the proximal C−C bond of cyclopropene VIII can produce metallacyclobutene species IX (Scheme 1, reaction 3). To realize this working hypothesis, we designed and prepared new MCPs 1 containing a bromine atom at the ortho-position and used them as substrates upon treatment with the Pd catalyst. We found that this novel cyclopropane ring-opening process could indeed take place to give the corresponding spirocyclic compounds 2 through a possible vinylpalladium carbene intermediate (Scheme 1, this work). Herein, we wish to report this finding. At the outset, we optimized the reaction conditions using substrate 1a as a model, and the screening results are shown in Table 1. First, we examined various palladium catalysts such as Pd2(dba)3, Pd(OAc)2, Pd(TFA)2, PdBr2, PdCl2, Pd(PPh3)4, Received: September 26, 2018 Published: November 2, 2018 7141
DOI: 10.1021/acs.orglett.8b03084 Org. Lett. 2018, 20, 7141−7144
Letter
Organic Letters Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
base
temp (°C)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Pd2(dba)3 Pd(OAc)2 Pd(TFA)2 PdBr2 PdCl2 Pd(PPh3)4 [Pd(allyl)Cl]2 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3
Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 K2CO3 Na2CO3 K3PO4 Na3PO4 CsOAc 2,6-lutidine Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3
120 120 120 120 120 120 120 110 100 90 80 90 90 90 90 90 90 90 90 90 90 90
Pd2(dba)3 as a catalyst and Cs2CO3 as a base and carrying out the reaction in toluene at 90 °C. With the best reaction conditions established, we next investigated the generality of this reaction with respect to various substituted substrates 1 (Scheme 2). Regardless of
solvent
yield (%)b
toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene dioxane PhCl DCE PhOMe DMF
66 − − − − − − 70 72 75 68 7 − 35 − 45 − 38 64 26 70 −
Scheme 2. Substrate Scope of 1a,b,c
a
Reaction conditions: 1a (0.1 mmol), catalyst (10.0 mol %), base (0.2 mmol), solvent (1.0 mL). bYields are determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. a
Reactions were carried out using 1 (0.5 mmol), Pd2(dba)3 (10.0 mol %) and Cs2CO3 (1.0 mmol) in toluene (4.0 mL) at 90 °C within 4 h, isolated yields. bReaction time was 10 h. cThe ratio of 2na:2nb was 5:1.
and [Pd(allyl)Cl]2 using 2.0 equiv of Cs2CO3 as a base for the reaction at 120 °C in toluene (Table 1, entries 1−7). We found that Pd2(dba)3 was an exclusively effective catalyst for the reaction, affording the desired product 2a in 66% yield within 4 h. Next, using 0.1 equiv of Pd2(dba)3 as a catalyst and 2.0 equiv of Cs2CO3 as a base, the reaction temperature was screened at 110, 100, 90, and 80 °C, respectively in toluene within 4 h, revealing that the reaction should be carried out at 90 °C, giving 2a in 75% yield (Table 1, entries 8−11). The base effect was then examined using K2CO3, Na2CO3, K3PO4, Na3PO4, CsOAc, and 2,6-lutidine in this transformation under the standard conditions. We found that the desired product 2a was given in lower yields when K2CO3, K3PO4 and CsOAc were used as bases and none of the desired product 2a was delivered when Na2CO3, Na3PO4, and 2,6-lutidine were used as bases (Table 1, entries 12−17). The examination of solvent effects with dioxane, chlorobenzene (PhCl), 1,2-dichloroethane (DCE), anisole (PhOMe), and N,N-dimethylformamide (DMF) revealed that 2a was produced in 38%, 64%, 26%, and 70% yields in dioxane, PhCl, DCE, and PhOMe, respectively, and no desired product 2a was formed in DMF (Table 1, entries 18−22). In addition, the use of ligands impaired the reaction without formation of the desired product 2a (see Table S1 in the Supporting Information (SI) for the details). It should be noted that the substituted phenanthrene 3 was separated in less than 10% yield as a byproduct (see Scheme 4), and prolonging the reaction time over 4.0 h did not further improve the yield of 2a. Therefore, we identified that the best conditions for the production of 2a include utilizing
whether electron-withdrawing or -donating groups were introduced on the aromatic R1 group at the para-position, the desired products 2b−2k could be formed in moderate to good yields. The substrates bearing an electron-donating R1 group delivered the corresponding products 2b, 2c, 2d, 2e, 2i, and 2j in 75%, 68%, 75%, 74%, 54%, and 78% yields, respectively. The structure of 2j was assigned by X-ray diffraction (see SI for the details). The substrates with electron-withdrawing R1 groups afforded the corresponding products 2f, 2g, 2h, and 2k in 80%, 73%, 66%, and 62% yields, respectively. When the substituent R1 was introduced at the meta-position of the benzene ring, the desired products 21 and 2k could be obtained in 60% and 42% yields. A 2-naphthyl moiety was also tolerated, giving the corresponding products 2na and 2nb in 48% total yield as a regioisomeric mixture in a 5:1 ratio. However, for a 1-naphthyl moiety containing substrate 1o, none of the desired product 2o was formed. When the R1 substituent was introduced at the ortho-position of the benzene ring, the desired products 2p and 2q could not be afforded, perhaps due to the steric effect. With Cl and NTsBoc substituents being introduced on the aromatic R2 group, the desired products 2r and 2s were furnished in 84% and 68% yields, respectively. When NHTs were introduced on the aromatic R2 group, a complex mixture was given rather 7142
DOI: 10.1021/acs.orglett.8b03084 Org. Lett. 2018, 20, 7141−7144
Letter
Organic Letters than the corresponding product 2t. Substrate 1u containing a D-δ-tocopherol moiety could also provide the desired product 2u in 52% yield. Introducing a MeO group on the aromatic R3 group also gave the desired product 2v in 86% yield. However, heteroaromatic group containing substrate 1w only afforded a trace amount of the desired product under the standard conditions. To identify the hydrogen transfer in this transformation, we conducted the deuterium labeling experiment with the addition of 5.0 equiv of D2O into the reaction mixture (Scheme 3, reaction 1). The obtained product 2a did not
Scheme 4. Proposed Reaction Mechanism
Scheme 3. Deuterium Labeling Experiments
electrophilic attack of the aromatic ring to the palladium carbene G offers intermediate H, which goes through a 1,3migration of η3-allylpalladium to generate intermediate J. The intramolecular 1,4-H migration and protodepalladation13 give the final product 2a. To further illustrate the synthetic utility of this transformation, we carried out this reaction on a 0.780 g scale of 1a under the standard conditions, affording 2a in 59% yield (0.33 g) (Scheme 5). Furthermore, the epoxidation of 2a with meta-
incorporate the deuterium atom at all, suggesting that the newly generated hydrogen atom at the methylene site in product 2 was not derived from the proton source in the reaction system. Then, the deuterated D-1a (99% D content) was prepared and used as a substrate under the standard conditions. We found that a deuterium atom was entirely transferred to the methylene site in product 2a from the benzene-d5 ring of D-1a along with a H/D KIE of 0.9 for this reaction, indicating that the C−H activation was not the ratedetermining step in this reaction (Scheme 3, reactions 2 and 3; also see SI for the details). We also carried out a crossover experiment with a 1:1 mixture of D-1a and 1j to probe the intramolecular deuterium transferring process and found that product 2j had no deuterium incorporation from D-1a (Scheme 3, reaction 4), indicating that the protodemetalation step (J to 2a, Scheme 4) did not proceed through an intermolecular manner. On the basis of the previous reports and the control experiments mentioned above, a plausible reaction mechanism has been outlined in Scheme 4. Initiatively, substrate 1a is converted to the RPdBr species A through the oxidative insertion of Pd(0) into the C−Br bond of 1a, which undergoes the carbopalladation to generate the cyclopropylpalladium intermediate B and cyclopropylcarbinylpalladium intermediate B′. The β-H elimination from intermediate B gives the cyclopropene intermediate C. Alternatively, the β-C elimination from intermediate B′ generates intermediate C′, which ultimately produces ethenylphenanthrene 3 via β-H elimination. The hydropalladation of cyclopropene intermediate C with the in situ generated HPdBr species affords the cyclopropylpalladium intermediate D,9 which gives cyclopropene intermediate E through β-H elimination. The 13C NMR measurement of the reaction mixture after 1 h indicated a peak at δ 112.8 ppm, which matches the reported 13C NMR chemical shift of cyclopropenes (δ 98.8−117.6 ppm) (see SI on p S6).10 Next, the oxidative insertion of Pd(0) into the proximal bond of cyclopropene intermediate E delivers a palladacyclobutene intermediate F,11 which undergoes a rearrangement to furnish the palladium carbene G.12 An
Scheme 5. Gram-Scale Synthesis and the Further Transformation of 2a
chloroperbenzoic acid (m-CPBA) in dichloromethane provided the corresponding product 4 in 52% yield, derived from the ring opening of the in situ generated epoxide with metachlorobenzoic acid (Scheme 5). The structure of 4 has been assigned by X-ray diffraction (see SI for the details). In summary, we have disclosed a novel and efficient cascade cyclization of MCPs 1 involving an intramolecular Heck-type reaction and β-H eliminations to furnish spirocyclic compounds containing fluorene and 1,2-dihydronaphthalene moieties in moderate to good yields in the presence of a Pd(0) catalyst. An unprecedented ring-opening pattern of MCP via a cyclopropene intermediate and a vinylpalladium carbene species has also been disclosed upon mechanistic investigations. Furthermore, the reaction proceeds smoothly under mild conditions regardless of whether an electronwithdrawing or -donating substituent is incorporated, suggesting that the electronic effect hardly affects the reaction outcome. Further investigations on the mechanistic details and applications of this method for the synthesis of spirocyclic 7143
DOI: 10.1021/acs.orglett.8b03084 Org. Lett. 2018, 20, 7141−7144
Letter
Organic Letters
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compounds containing other functional moieties are underway in our laboratory.
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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.8b03084. Experimental procedure; characterization data for all compounds; X-ray crystal data for 2j and 4 (PDF) Accession Codes
CCDC 1825664 and 1866396 contain 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
Min Shi: 0000-0003-0016-5211 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for the financial support from the National Basic Research Program of China ((973)-2015CB856603), the Strategic Priority Research Program of the Chinese Academy of Sciences, Grant Nos. XDB20000000 and sioczz201808, the National Natural Science Foundation of China (20472096, 21372241, 21572052, 20672127, 21421091, 21372250, 21121062, 21302203, 20732008, 21772037, and 21772226), and the Fundamental Research Funds for the Central Universities (222201717003).
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DOI: 10.1021/acs.orglett.8b03084 Org. Lett. 2018, 20, 7141−7144
