Allylic

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Tandem Pd-Catalyzed Intermolecular Allylic Alkylation/Allylic Dearomatization Reaction of Benzoylmethyl pyridines, Pyrazines, and Quinolines Hui-Jun Zhang,† Ze-Peng Yang,‡ Qing Gu,‡ and Shu-Li You*,†,‡

Org. Lett. Downloaded from pubs.acs.org by UNIV AUTONOMA DE COAHUILA on 04/19/19. For personal use only.

†

School of Chemistry and Molecular Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China ‡ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China S Supporting Information *

ABSTRACT: An efficient synthesis of nitrogen-containing heterocycles via Pd-catalyzed tandem allylic alkylation and dearomatization reactions was reported. In this reaction design, heteroarenes such as pyridines, pyrazines, and quinolines serve as bis-nucleophiles by installing a benzoyl group at the C2 benzylic position. With but-2-ene-1,4-diyl dimethyl dicarbonate as the bis-electrophile, the tandem Pd-catalyzed intermolecular allylic alkylation/allylic dearomatization reaction of benzoylmethylsubstituted heteroarenes has been developed. 2,3-Dihydroindolizine, 6,7-dihydropyrrolo[1,2-a]pyrazine, and 1,2dihydropyrrolo[1,2-a]quinolin derivatives were obtained in moderate to good yields.

T

Scheme 1. Allylic Dearomatization Reaction of Pyridine

he palladium-catalyzed allylic substitution reaction is a powerful method for constructing carbon−carbon or carbon−heteroatom bonds.1 With this strategy, allylic dearomatization reactions of a wide range of aromatic compounds have been achieved to provide various dearomatized polycyclic- or spiro-compounds in a concise manner in the past years.2 On the other hand, the nitrogen-containing heterocycles existed widely in natural products and biologically active compounds.3 In this regard, the dearomatization reaction of N-heteroarenes has proven to be a straightforward access to these nitrogen-containing heterocyclic scaffolds.4 Of particular note, pyridines, pyrazines, and quinolines are readily available and inexpensive. Recently, we reported an Ircatalyzed intramolecular asymmetric allylic dearomatization of these heteroarenes, providing dearomatized heterocycliccompounds in good yields and enantioselectivity (Scheme 1a).5,6 However, the synthesis of the required substrates for an intramolecular reaction usually requires multiple steps, which limits the practical application of these methods. The tandem reaction that comprises at least two consecutive steps is becoming an increasingly important way to access a relatively complex skeleton, especially heterocyclic-compounds, which significantly reduces synthetic steps.7 Therefore, we decided to design a tandem allylic alkylation and dearomatization reaction by the application of a bisnucleophile and a bis-electrophile as substrates (Scheme 1b). © XXXX American Chemical Society

2-(Benzoylmethyl)heteroarene and but-2-ene-1,4-diyl dimethyl were employed successfully as a bis-nucleophile and biselectrophile, respectively. Herein, we report the results on the Received: March 26, 2019

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DOI: 10.1021/acs.orglett.9b01060 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

With the optimized reaction conditions in hand, we examined the generality of this reaction (Scheme 2). The cis-

Pd-catalyzed allylic substitution/allylic dearomatization tandem reaction of pyridines, pyrazines, and quinolines. At the outset, 2-(benzoylmethyl)pyridine (1a) and (E)-but2-ene-1,4-diyl dimethyl dicarbonate (2a) were used as the model substrates. With the utilization of 5 mol % Pd(PPh3)4 as the catalyst, to our delight, the designed tandem reaction proceeded smoothly in the absence of base at room temperature, providing the desired product 3a in 65% NMR yield (Table 1, entry 1). For an enhancement of the reaction

Scheme 2. Substrate Scope for the Pd-Catalyzed Allylic Substitution/Allylic Dearomatization Tandem Reactiona

Table 1. Optimization of the Reaction Conditionsa

entry

base

solvent

time (h)

3ab (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

none Cs2CO3 K2CO3 Li2CO3 K3PO4 Et3N DBU LDA n BuLi NaH Et3N Et3N Et3N Et3N Et3N Et3N

THF THF THF THF THF THF THF THF THF THF toluene Et2O CH3CN 1,4-dioxane CH2Cl2 hexane

11 5 2 4 6.5 1.5 24 1 1 7 2.5 2.5 2.5 24 24 24

65 74 73 79 76 79 (74c) 16 71 72 60 60 60 70 24 38 13

a Reaction conditions: 1a (0.4 mmol), 2a (0.48 mmol), 5 mol % Pd(PPh3)4, base (0.48 mmol) in solvent (4 mL) at 25 °C. bYields were determined by 1H NMR of the crude reaction mixture using dibromomethane as an internal standard. cIsolated yield.

Reaction conditions: 1 (0.4 mmol), 2b (0.48 mmol), 5 mol % Pd(PPh3)4, and Et3N (0.48 mmol) in THF (4 mL) at 25 °C. b10 mol % Pd(PPh3)4. cDetermined by 1H NMR of the crude reaction mixture.

rate, various inorganic bases were investigated. As seen from the results summarized in Table 1, base had a great influence on the reaction outcome. The addition of Cs2CO3, K2CO3, Li2CO3, and K3PO4 could significantly accelerate the reaction (Table 1, entries 2−5), and Li2CO3 gave the best yield (Table 1, entry 4, 4 h, 79% NMR yield). Subsequently, several other organic bases were examined (Table 1, entries 6−9). Et3N was found to be the best one, providing 3a in 74% yield in 1.5 h (Table 1, entry 6). However, only 16% NMR yield was obtained with DBU as the base even after 24 h (Table 1, entry 7). NMR yields of 71% and 72% were achieved in the presence of LDA and nBuLi, respectively (Table 1, entries 8 and 9). In addition, when NaH was employed, the reaction could be completed after 7 h, albeit with 60% NMR yield (Table 1, entry 10). Next, Et3N was chosen as the optimal base, and various solvents were further investigated (Table 1, entries 11− 16). Toluene, Et2O, and CH3CN were found to be suitable solvents affording 3a in 60−70% yields (Table 1, entries 11− 13). However, 1,4-dioxane, CH2Cl2, and hexane only gave inferior outcomes (Table 1, entries 14−16, 13−38% yields). Finally, the optimized conditions were obtained as the following: 5 mol % Pd(PPh3)4, and 1.2 equiv of Et3N in THF at room temperature (Table 1, entry 6).

dicarbonate 2b was also compatible, and comparable results were obtained (73% yield, 3 h). Therefore, cis-dicarbonate 2b was employed in the following studies because of its ready availability. For the pyridine-derived substrates, both the electron-donating group such as 4-OMe (3b: 54% yield) and electron-withdrawing groups such as 4-Cl (3c: 80% yield) and 4-Br (3d: 74% yield) on the phenyl ring were well-tolerated. Substrate 1e bearing a Br at the C5 position of the pyridine ring underwent the tandem reaction smoothly to give the desired product 3e in 52% yield. As expected, pyrazine substrates 1f, 1g, and 1h also proceeded well to afford the corresponding dearomatized products (3f−3h) in 37−58% yields, respectively. Interestingly, in addition to the expected products from nucleophilic substitution by the N atom, a small amount of five-membered O-heterocycle products (3f′, 3g′, and 3h′, respectively) was observed by 1H NMR in which ketones served as O-nucleophiles.8 Interestingly, we recently found that ketones and aldehydes could act as enol Onucleophiles in the Ir-catalyzed allylic substitution reaction.9 Quinoline-type substrates were also examined. The results of substrates 1j and 1k bearing the substituent at the C4 position of the quinoline ring were unsatisfactory (3j, 60% yield; 3k,

a

B

DOI: 10.1021/acs.orglett.9b01060 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters 42% yield). However, the substituents at the C6 or C7 position of the quinoline ring were well-tolerated regardless of their electronic properties (3l−3q: 73−86% yields). Subsequently, the reaction of 2-methyl dicarbonate (2c) as an electrophile provided a mixture of two isomers. 3r and 3s were obtained in 44% and 31% yields, respectively, with a ratio of 1.4:1 (Scheme 3a). The structures of 3r and 3s were

Scheme 4. Proposed Reaction Mechanism

Scheme 3. (a) Tandem Reaction of 2-Methyl Dicarbonate 2c and (b) the Gram-Scale Reaction

determined by X-ray crystallographic analysis (for details, see the Supporting Information). The reaction of 1i with 2b in a gram-scale under the standard reaction conditions led to 3i (1.12 g, 89% yield) without any erosion in yield, showcasing the practicality of this method (Scheme 3b). On the basis of the above experimental results, two plausible reaction pathways were proposed as depicted in Scheme 4. First, the oxidative addition of dicarbonate 2b to Pd0, followed by the decarboxylation process, generates π-allylpalladium I. Reasonably, the acidic Hα on the α position of the carbonyl group is easily deprotonated by the methoxide anion to generate the carbon anion. It then attacks the intermediate I, furnishing the allylic substituted product II. Subsequently, the intramolecular allylic dearomatization reaction occurs to afford the dearomatized compound 3 through the formation of π-allyl PdII intermediate III.5,6 Alternatively, the reaction of intermediate II with Pd catalyst leads to intermediate III′, in which enolate serves as an O-nucleophile to undergo allylic substitution, leading to the formation of the five-membered Oheterocycle 3′ (path b). Therefore, path a is an overwhelming process in the case of pyridines and quinolines with 2b, while the reaction of pyrazines proceeds through both pathways. To be noted, the intermediate II was observed during the reaction process and could be isolated. In summary, we realized a tandem Pd-catalyzed intermolecular allylic alkylation/dearomatization reaction of electronpoor N-heteroarenes including pyridines, pyrazines, and quinolines. The reaction features remarkably mild conditions, readily available substrates, and facile synthesis of structurally diverse heterocycles. In addition, the trisubstituted alkene containing dicarbonate could also be employed to yield products bearing a quaternary stereocenter.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01060. Experimental procedures, compound characterization data, and X-ray data for 3r and 3s (PDF) Accession Codes

CCDC 1890277 and 1905118 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

Qing Gu: 0000-0003-4963-2271 Shu-Li You: 0000-0003-4586-8359 Notes

The authors declare no competing financial interest. C

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ACKNOWLEDGMENTS We thank the National Key R&D Program of China (2016YFA0202900) and NSFC (21821002, 21572252) for generous financial support.

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