Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Pd-Catalyzed Three-Component Domino Reaction of Vinyl Benzoxazinanones for Regioselective and Stereoselective Synthesis of Allylic Sulfone-Containing Amino Acid Derivatives Jiping Hao,†,‡,§ Yi Xu,†,‡ Zhongliang Xu,†,‡ Zhiqiang Zhang,∥ and Weibo Yang*,†,‡,∥
Org. Lett. Downloaded from pubs.acs.org by UNIV OF RHODE ISLAND on 12/04/18. For personal use only.
†
Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai 201203, China ‡ University of Chinese Academy of Sciences, Beijing, China § Nano Science and Technology Institute, University of Science and Technology of China, Suzhou, Jiangsu 215123, China ∥ University of Science and Technology Liaoning, Anshan 114051, China S Supporting Information *
ABSTRACT: A Pd-catalyzed, highly regioselective and stereoselective three-component domino allylic substitution/N−H carbene insertion reaction under mild conditions is described. This reaction demonstrates a wide substrate scope and satisfactory functional group tolerance, providing a broad range of allylic sulfone-containing amino acid derivatives. Moreover, DBU mediates highly diastereoselective cross-dehydrogenative coupling annulation of allylic sulfones without using peroxides or any metal oxidants. This developed protocol affords 7-membered ring heterocyclic compounds incorporating both sulfonecontaining amino acid esters and one quaternary carbon center. Mechanistic studies indicate that an unusual umpolung of glycine occurred in this annulation.
S
tedious multistep synthesis. From the viewpoint of step economy and environmentally friendly synthesis, an attractive and streamlined strategy would be a one-pot, multicomponent domino reaction. Recently, vinyl benzoxazinones have attracted considerable attention in organic synthesis, with the π-allylpalladium species formed via a decarboxylation process.6 After Tunge’s pioneering work,7 significant contributions have been made in this field from Xiao,8 Glorius,9 Jorgensen,10 Lu,8a and others.11 Notably, most of the reported systems are based on the reactivity of C,N-1,4 synthons, which could participate in Pdcatalyzed [4+n] cycloadditions to access a variety of different N-heterocyclic compounds. In comparison with Pd-catalyzed [4+n] cycloadditions of vinyl benzoxazinones, Pd-catalyzed allylic substitution reactions have rarely been explored. In 2017, Lu and Xiao reported an elegant Pd-catalyzed branchand enantioselective allylic amination between N-Ts protected vinyl benzoxazinones and amines.12 However, to the best of our knowledge, to date, Pd-catalyzed three-component domino linear-allylic substitution of vinyl benzoxazinones has never been described (Scheme 1). In continuation of our current research on controllable transformations of π-allylpalladium intermediates,13 we envisioned a Pd-catalyzed, one pot, three-component domino
ulfur-containing amino acid derivatives are important, pharmaceutically relevant compounds, because of their wide spectrum of biological activities, such as being antithrombotic agents,1 enzyme inhibitors,2 and antibacterial agents.3 (Figure 1). As a result, the development of highly efficient synthetic methods to access these compounds has been intensively pursued by the synthetic community.
Figure 1. Selected sulfur-containning amino acid units in drugs.
In this context, ring opening of aziridinium ions by nucleophilic sulfur reagents4 and trapping of sulfonium ylides with imines5 have become two useful and practical strategies. Although these strategies have been frequently used for the synthesis of sulfur-containing amino acid analogies, methods allowing rapid access to sulfone-containing amino acid derivatives are especially underdeveloped. With regard to the latter target construction, a thiolation/oxidation sequence synthesis route may be a reasonable method. However, it suffers from the requirement of odorous thiols, together with © XXXX American Chemical Society
Received: October 28, 2018
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DOI: 10.1021/acs.orglett.8b03440 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
(a) Direct cyclization of 1a to form 1,2-dihydroquinoline derivatives might be a competitive side reaction.7b (b) Controlling branch or linear allylic sulfonation of vinyl benzoxazinones could also present a dilemma. Keeping these challenges and our hypothesis in mind, we initiated our study of Pd-catalyzed, three-component, domino allylic substitution reaction by choosing vinyl benzoxazinones (1a), diazo esters (2a), and sodium sulfinates (3a) as the model substrates (Table 1).
Scheme 1. Strategies in Building Sulfone-Containing Amino Acids
Table 1. Catalyst Screening and Optimization of the Reaction Conditionsa
allylic substitution reaction of vinyl benzoxazinones with easily available diazo esters14 and sodium sulfinates. The underlying principle is shown in Scheme 2. Oxidative addition of vinyl
entry
catalyst
solvent
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Pd2(dba)3·CHCl3 Pd2(dba)3 Pd(PPh3)4 Pd(OAc)2 Pd(COD)Cl2 PdCl2[P(Cy)3]2 Pd(acac)2 [Pd(allyl)Cl]2 Cu(OAc)2 [Cp*RhCl2]2 [Pd(allyl)Cl]2 [Pd(allyl)Cl]2 [Pd(allyl)Cl]2 [Pd(allyl)Cl]2
DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF MeCN 1,4-dioxane THF toluene
trace trace 0 trace trace 0 29 65 0 0 0 trace trace 42
a
Reaction conditions: 1a (0.05 mmol, 1.0 equiv), 2a (0.1 mmol, 2.0 equiv) and catalyst (5 mol %), stirred at DMF (0.5 mL) for 10 min, then 3a (0.1 mmol, 2.0 equiv) was added. The mixture was stirred at 60 °C for 12 h. bYields of isolated products.
Scheme 2. Schematic Describing Our Design Principles
We first investigated the effects of different catalysts, and we were surprised to discover that Pd(0) catalysts such as Pd2(dba)3·CHCl3, Pd2(dba)3, and Pd(PPh3)4, which were highly effective in Pd-catalyzed cycloaddition of vinyl benzoxazinones, showed no effectiveness. When we utilized Pd(acac)2 as a catalyst, the allylic sulfone-containing amino acid ester 4aaa with exclusively linear distribution was obtained in 29% isolated yield. Switching the catalyst to [Pd(allyl)Cl]2, the yield of desired product 4aaa was significantly improved to 65%. This reason could be rationalized as being due to the similar π-allylpalladium species between catalyst [Pd(allyl)Cl]2 and intermediate I, which likely enhances the interaction and accelerates the ligand exchange. Notably, no formation of 4aaa was observed under Rh16 or Cu catalysis. In addition, the solvent effect was further explored, and it was found that DMF was the best choice for this transformation. With the optimized conditions in hand, the scope of vinyl benzoxazinones was first examined, and a range of N-free protected vinyl benzoxazinones containing both electrondonating and electron-withdrawing substituents on the benzene ring could be well-tolerated to produce the domino products in moderate to good isolated yields with excellent regioselectivity and sole formation of the E-isomer. Similarly, vinyl benzoxazinones with ortho- and meta-substituents on the
benzoxazinones 1a to a Pd(0) species and subsequent decarboxylation gives intermediate I. Intermediate I then could react with sodium sulfonate 2a to form intermediate II, followed by reductive elimination to afford aa and regenerate the Pd(0) species. Subsequently, the Pd(0) species would induce decomposition of diazo ester 3a to produce Pd carbene intermediate III,15 which is expected to undergo N−H carbene insertion and eventually provide the product 4aaa. To realize this Pd-catalyzed, three-component, domino allylic substitution reaction, two challenges must be addressed: B
DOI: 10.1021/acs.orglett.8b03440 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
strates also proceeded smoothly in this reaction, leading to similar isolated yields of products. With the domino allylic substitution/N−H carbene insertion products in hand, we became interested in the exploration of selective annulation of these compounds. When compound 4aaa was treated with the Lewis base DBU, an unusual 7membered ring N-heterocyclic compound 5aaa was obtained in 46% yield with high diastereoselectivity (diastereomeric ratio (dr) of 96:4). A safe assignment of the structure 5aaa was unambiguously validated by single-crystal X-ray analysis, which indicated that allylic sulfone-containing amino acid ester and one quaternary carbon center as privileged structures were coexistent. In addition, this annulation reaction worked well for other substrates bearing different substituents, in all cases, and the diastereoselectivity of the products was excellent (Scheme 4).
benzene ring did not suffer from steric hindrance effects and delivered the corresponding products in satisfactory yields. Gratifyingly, the reaction was also compatible with fluorine and trifluoromethyl-substituted substrates, which are commonly encountered in target-oriented synthesis, because of their unique physical and biological properties. It was noteworthy that the bromo-substituted vinyl benzoxazinone proceeded well under standard conditions and gave the product in 58% yield. This offered the chance for further elaboration through traditional cross-coupling reactions. Changing the aromatic ring to naphthalene did not remarkably influence the reaction efficiency, and the target compound (4jaa) was isolated in 57% yield. We next turned our attention to the scope of the sulfinate salts. The reaction was applicable to a variety of sulfinate salts 2 bearing different substituents on the benzene ring, regardless of whether an electron-donating or electron-withdrawing group on the benzene ring could be tolerated. Beyond the tolerance to simple aromatic ring systems, nonaromatic substrates were also amenable to the standard conditions. For instance, when the isopropyl-, methyl-, and ethyl-substituted sulfinate salts were used as coupling partners, they exhibited good reactivity and furnished the desired products in synthetically acceptable yields (47%−57% 4afa−4aha). The reaction was further extended to a series of arylsubstituted diazo ester compounds. As shown in Scheme 3, various substituents on the benzene ring were tolerated, and the reaction was found to be minimally affected by the electronic properties and steric hindrance of the aryl substituents. Moreover, naphthalene and benzyl ester sub-
Scheme 4. DBU Mediates Annulation of Allylic Sulfonesa
Scheme 3. Substrate Scopes in Domino Reactionsa
a
Reaction conditions: 4 (0.1 mmol, 1.0 equiv), DBU (0.1 mmol, 1.0 equiv), DMF (1 mL), 60 °C, 12 h. Yields of isolated products. bThe reaction was run in 1.0 mmol. cThe diastereomeric ratio (dr) value was determined by 1H NMR analysis.
It is noteworthy that this intriguing annulation involves geometric isomerism and dehydrogenation. To elucidate the detailed mechanism, several control experiments were performed (Scheme 5). Initially, when substrate 4aaa was subjected to an argon atmosphere, the yield of 5aaa was significantly diminished. When 4aaa was conducted under an oxygen atmosphere condition, the yield of 5aaa was improved to 50%, albeit with low dr value (78:22). Treatment of imine 4aaa-1, under the standard conditions, led to the formation of 5aaa in 68% yield with excellent diastereoselectivity (98:2). Interestingly, we also performed the methyl-substituted substrate 4aaa-2 in the presence of DBU, and, as we expected, no desired product 5aaa′ was formed. All these results demonstrate that the original substrate 4aaa could undergo dehydrogenation and form intermediate imine
a
Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.2 mmol, 2.0 equiv) and catalyst (5 mol%), stirred at DMF (0.5 mL) for 10 min then 3a (0.2 mmol, 2.0 equiv) was added. The mixture was stirred at 60 °C for 12 h. bThe reaction was run in 3.0 mmol scale. C
DOI: 10.1021/acs.orglett.8b03440 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
intermediate 4aaa-1′ followed by nucleophilic addition to produce the final product. In conclusion, we have developed a novel Pd-catalyzed three-component domino reaction via sequence decarboxylation/allylic substitution/N−H carbene insertion processes, which allows expedient access to various allylic sulfonecontaining amino acid derivatives. This reaction not only features mild conditions, broad substrate scope, N-protected group free, and excellent functional group compatibility, but also avoids the requirement of odorous thiols and tedious multistep synthesis. In addition, the construction of 7membered ring N-heterocyclic compounds incorporating both sulfones-containing amino acid esters and quaternary carbon center was successfully realized by DBU-mediated annulation of allylic sulfones. Further biological activity screening of these compounds is ongoing in our laboratory.
Scheme 5. Control Experiments for Mechanism Studies
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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.8b03440. Experimental procedures and spectral data for all new compounds (PDF) Accession Codes
CCDC 1875689 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.
4aaa-1.17 Although the exact reason to explain imine formation was unclear, H2 was excluded from gas chromatography (GC) analysis. In parallel, 2,2,6,6-tetramethylpiperidine (TEMPO), as a radical scavenger, was added to capture some radical species; however, the efficiency of this transformation was not affected at all. This suggested that the DBU-mediated annulation likely does not involve a radical process. The importance of DBU was next examined in imine formation by choosing 4bb as a substrate. No reactivity or a low yield was observed in the absence of DBU, even though other oxidizing reagents were added, such as 1 atm O2, 1 equiv TBHP, or 1 equiv DDQ. These control experiments highlighted DBU playing the crucial role in imine formation. The above outcomes provide information on the plausible mechanism of the DBU-mediated annulation. As rationalized in Scheme 6, the reaction begins with release of two H atoms promoted by Lewis base DBU and provides the imine intermediate. Subsequently, geometric isomerism occurs from E-isomer to Z-isomer under basic conditions, which gives
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Weibo Yang: 0000-0003-1633-7655 Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge the 100 Talent Program of the Chinese Academy of Sciences, Chinese NSF (No. 21702217), “1000-Youth Talents Plan”, Shanghai-Youth Talent, and Shanghai-Technology Innovation Action Plan (No. 18JC1415300) for financial support of this research.
Scheme 6. Mechanism of the DBU-Mediated Annulation
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DOI: 10.1021/acs.orglett.8b03440 Org. Lett. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.orglett.8b03440 Org. Lett. XXXX, XXX, XXX−XXX
