Gold(I)-Catalyzed 1,3-Carbofunctionalizations of Anthranils with Vinyl

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Gold(I)-Catalyzed 1,3-Carbofunctionalizations of Anthranils with Vinyl Propargyl Esters To Yield 1,3-Dihydrobenzo[c]‑isoxazoles Manisha Skaria, Pankaj Sharma, and Rai-Shung Liu* Frontier Research Center for Matter Science and Technology and Department of Chemistry, National Tsing-Hua University, Hsinchu, Taiwan, Republic of China

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ABSTRACT: This work describes gold-catalyzed 1,3-carbofunctionalizations of anthranils with vinyl propargyl esters to form 1,3-dihydrobenzo[c]-isoxazoles. Excellent diastereoselectivity has been achieved to yield products containing three stereogenic carbons. These new catalytic reactions are operable with anthranils and vinyl propargyl esters over a wide scope, further manifesting the synthetic utility.

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reactions,3a−d,6 we report gold-catalyzed 1,3-carbofunctionalizations of anthranils with 3-vinyl propargyl esters7,8 to afford 1,3-dihydrobenzo[c]-isoxazoles. Herein, vinyl propargyl esters 1 serve as the sources of cyclic enolates and acyl cations to enable a 1,3-functionalization of anthranils. Particularly notable is the stereoselective formation of 1,3-dihydrobenzo[c]isoxazoles 3 as one diastereomeric product, in which three stereogenic centers are generated on two rings. We postulate that compound 3 arises from a stepwise formation of an eightmembered intermediate In-2, followed by a ring cleavage of the oxonium moiety; this process presumably controls the stereochemistry of the products. Furthermore, this work highlights the synthetic utility of vinyl propargyl ester as a potential 1,5-dipole in a stepwise annulation (see eq 3).9 We tested the reaction of vinyl propargyl ester 1a with anthranil 2a (1.2 equiv) using PPh3AuCl/AgOTf (10 mol %) in DCE (25 °C, 3 h; see Table 1, entry 1). To our delight, a new compound 3a was isolated in 58% as only one diastereomer according to the NMR spectra. We tested other gold catalysts LAuCl/AgOTf (L = P(t-Bu)2(o-biphenyl) and IPr) that turned out to be very inefficient, giving desired 3a in yields of 0−10% (Table 1, entries 2 and 3). Notably, the use of P(OPh)3AuCl/AgOTf greatly improved the yield of compound 3a up to 74% (Table 1, entry 4). Different silver salts for P(OPh)3AuCl/AgX (X = NTf2 and SbF6) afforded compound 3a in yields of 42% and 30%, respectively (Table 1, entries 5 and 6). P(OPh)3AuCl/AgOTf in other solvents gave 3a in the following yields (Table 1, entries 7−9): DCM (63%), toluene (28%), THF (5%). The reaction in toluene was operated at 110 °C to ensure a complete dissolution of anthranil 2a. AgOTf alone was catalytically inactive in DCE (Table 1, entry 10). The stereochemistry of compound 3a is inferred from X-ray diffractions of its relatives 4c and 5a (Figure 1), further clarifying the molecular structure. With this optimized condition, we assess the scope and generality of various propargyl esters 1; the results are

ne notable achievement in gold catalysis is to develop new functionalizations of alkynes to access useful heterocycles and carbocycles.1−3 Interest in the gold-catalyzed N,O-functionalizations of alkynes with isoxazoles2 and anthranils3 is rapidly growing, because of the facile generation of α-imino gold carbenes In-1 (eq 1). These α-imino carbenes

are chemically versatile to undergo various intramolecular cyclizations to yield pyrrole, indole, and other azacyclic compounds.1−3 Anthranils are conceivably more reactive than isoxazoles in this N−O cleavage process; the former typically produce functionalized benzenes whereas isoxazoles yield nonaromatic products instead. The generation of α-imino gold carbenes inevitably leads to cleavage of a N−O bond; this process is not a viable route to access cyclic nitroxy compounds, which commonly exist in many bioactive or naturally occurring molecules.4 We sought new alkyne functionalizations via a noncarbene route to access nitroxy-containing heterocycles. To demonstrate the 4-π donor ability of anthranils,5 we reported6 two distinct [3 + 3]-nitroxy annulations between anthranils and 2alkenyl-1-alkynylbenzenes in which the chemoselectivity was controlled by the alkynyl substituents (R = alkynyl versus H; see eq 2). From our continued interest in novel anthranil © XXXX American Chemical Society

Received: March 12, 2019

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DOI: 10.1021/acs.orglett.9b00880 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

entry

catalyst

solvent

time (h)

yieldb (%)

1 2 3 4 5 6 7 8 9 10

PPh3AuCl/AgOTf LAuCl/AgOTfc IPrAuCl/AgOTfd P(OPh)3AuCl/AgOTf P(OPh)3AuCl/AgNTf2 P(OPh)3AuCl/AgSbF6 P(OPh)3AuCl/AgOTf P(OPh)3AuCl/AgOTf P(OPh)3AuCl/AgOTf AgOTf

DCE DCE DCE DCE DCE DCE DCM toluene THF DCE

3 3 2 3 3 3 3 10 10 2

58 10 nde 74 42 30 63 28 5 nde

bearing varied alkynyl and alkenyl substituents (R = Et, Ph, and CH2Ph; R2 = Me); their corresponding products 3h−3j were obtained in satisfactory yields (68%−92%). For propargyl ester 1k bearing Ar = 3-thienyl, compound 3k was obtained in 52% yield (Scheme 1, entry 10). When a pivalate was used in the reaction, its ester derivative 1l afforded a cyclic nitroxy compound 3l with dr = 19:1 (Scheme 1, entry 11). We examined also the reactions of various anthranils 2 to show the generality of reactions. For anthranils 2b−2f bearing various 5-substituted R1 groups (R1 = Cl, Br, Me, OMe, and OCO2Et), their reactions with vinyl propargyl ester (1a) delivered the 1,3-addition products 4a−4e in 56%−84% yields (see Scheme 2, entries 1−5) with the electron-withdrawing R1 Scheme 2. Scope of Various Benzisoxazolesa,b

a

1a = 1.8 M. bProduct yields are reported after separation from a silica column. c L = P(t-Bu) 2 (o-biphenyl). d IPr = 1,3-bis(diisopropylphenyl)-imidazol-2-ylidene. DCE = 1,2-dichloroethane. e Not detected.

summarized in Scheme 1; resulting products 3b−3l were produced with excellent diastereoselectivity with dr >19:1. For Scheme 1. Reaction Scope with Various Propargyl Estersa,b

a

1a = 0.16 M, 2a (1.2 equiv). bProduct yields are reported after separation from a silica column.

group being more productive. In the case of benzisoxazoles 2g and 2h with R2 = Cl and Br, the corresponding products 4f and 4g were obtained in yields of 70% and 75% (Scheme 2, entries 6 and 7). We tested also the reactions with anthranils 2i and 2j bearing R2 = Me and 2-thienyl, affording the desired compounds 4h and 4i in yields of 60% and 86% (Scheme 2, entries 8 and 9). X-ray diffraction (XRD) of compound 4c (Figure 1) was performed to reconfirm the stereochemistry of resulting products 3 and 4. Equation 4 depicts the transformation of functional groups of a cyclic nitroxy molecule 3a.Treatment of this nitroxy a

1a = 0.16 M, 2a = (1.2 equiv). bProduct yields are reported after separation from a silica column.

various para-phenyl substituents of propargyl esters 1b−1d (X = Me, F, Cl), compounds 3b−3d were obtained in high yields (75%−82%; see Scheme 1, entries 1−3). These reactions were applicable also to alkyl-substituted alkynes 1e and 1f (R2 = Me and cyclopropyl), affording the desired products 3e and 3f in moderate yields (42%−58%; see Scheme 1, entries 4 and 5); notably, a quaternary carbon was successfully generated within the molecules. Such new reactions are compatible with species 1g bearing a distinct alkenyl substituent (R = Et); its resulting product 3g was obtained in 55% yield (Scheme 1, entry 6). These catalytic reactions were amenable also to propargyl esters 1h−1j

species with Mo(CO)610 (1.2 equiv) in MeCN/water led to a N−O cleavage to deliver compound 5a in 56% yield; XRD of this compound revealed the same stereochemistry as that for compound 4c (Figure 1). Reduction of species 3a with NaBH4 in MeOH afforded an alcohol derivative 6a with dr = 4.5:1; the structure of the major diastereomer 5b was verified by 1H NOE effect. We performed control experiments to elucidate the reaction mechanism. We first isolated a cyclopentenone 6a from a B

DOI: 10.1021/acs.orglett.9b00880 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 3. A Postulated Mechanism

species D to rationalize the excellent diastereoselectivity. The stereoselective formation of three stereogenic centers on two separate rings is a difficult task. For initial gold-π-alkyne species A, a 1,2-acyloxy shift11 is expected to form a 4-vinyl alkenylgold intermediate B.7 We postulate that the nitrogen of anthranil 2a is a nucleophilic center, as indicated by its resonance form 2a′.5,6 An attack of anthranil 2b at the oxonium center of species B yields new intermediate C bearing an acid/base pair, thus enabling a subsequent cyclization. The stereochemistry of this eight-membered intermediate is controlled with a syn-periplanar conformation C, because of the geometric constraint. The phenyl group of species D enhances a self-ionization to form a benzylic cation E, further inducing an intramolecular cyclization to afford the observed product 3a. In summary, we report gold-catalyzed 1,3-carbofunctionalizations of anthranils with vinyl propargyl esters to afford 1,3dihydrobenzo[c]-isoxazoles; such a one-pot 1,3-addition is undocumented in anthranil chemistry.4,12 High diastereoselectivity is particularly notable because the resulting nitroxy heterocycles bear three stereogenic carbons on two different rings. Our control experiments indicate that the gold catalyst generates reactive intermediates from vinyl propargyl esters that are trapped with anthranils to yield the observed product. A crossover experiment indicates that the delivery of acyloxy and cyclopentenonyl from propargyl esters proceeds through an intramolecular process. We postulate a mechanism13 involving a stepwise (5 + 3)-annulation between anthranils and 3-vinyl alkenylgold intermediates to form 8-membered oxacyclic intermediates, followed by a ring cleavage; this oxacyclic intermediate conceivably controls the stereochemistry of products.

Figure 1. X-ray crystallographic structures of 4c and 5a.

catalytic cycloisomerization of propargyl ester 1a; this species did not react with anthranil 2a in the presence of gold catalyst, acyl chloride and acetic acid (eq 5). We then prepared

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cyclopentadienyl acetate 6b that was the precursor of cyclopentenone 6a;7 this species failed to react with anthranil 2b in the presence of gold catalyst (eq 6). We postulate that formation of compound 3a is likely formed from the trapping of anthranils with intermediates generated from vinyl propargyl esters. We performed a crossover experiment involving two vinyl propargyl esters 1a and d1-1b with oxide 2a at a limiting amount (0.2 equiv); the resulting products contained only species 3a and d1-3b in a 1.4:1 ratio (eq 7); formation of the two products occur with comparable rates. With sufficient oxide 2a (2.2 equiv), we also obtained only compounds 3a and d1-3b in a 1:1 ratio (eq 8). The lack of crossover products in eqs 7 and 8 reveals that the acyl and cyclopentenonyl groups of product 3a arise from the same propargyl ester. Based on our control experiments (eqs 5−8), we postulate a mechanism in Scheme 3, involving eight-membered oxacyclic

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00880. Experimental procedures, characterization data, and copies of 1H and 13C NMR spectra (PDF) Accession Codes

CCDC 1901753 and 1901854 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. C

DOI: 10.1021/acs.orglett.9b00880 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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(8) Zhao, J.; Yang, S.; Xie, X.; Li, X.; Liu, Y. J. Org. Chem. 2018, 83, 1287−1297. (9) For gold-catalyzed annulations or cycloadditions of alkynes, see selected reviews: (a) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180. (b) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395. (c) Abu Sohel, S.; Liu, R.-S. Chem. Soc. Rev. 2009, 38, 2269. (d) Muratore, M. E.; Homs, A.; Obradors, C.; Echavarren, A. M. Chem. - Asian J. 2014, 9, 3066. (10) Mulvihill, M. J.; Gage, J. L.; Miller, M. J. J. Org. Chem. 1998, 63, 3357−3363. (11) (a) Marion, N.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750−2752. (b) Liu, J.; Chen, M.; Zhang, L.; Liu, Y. Chem. - Eur. J. 2015, 21, 1009−1013. (c) Rao, W.; Chan, P. W. H. Chem. - Eur. J. 2014, 20, 713. (d) Rao, W.; Koh, M. J.; Li, D.; Hirao, H.; Chan, P. W. H. J. Am. Chem. Soc. 2013, 135, 7926. (12) (a) Freeman, J. P. Chem. Rev. 1983, 83, 241−261. (b) Berthet, M.; Cheviet, T.; Dujardin, G.; Parrot, I.; Martinez. Chem. Rev. 2016, 116, 15235−15283. (13) Besides our proposed mechanism, the following mechanism is also likely to occur. Initial species B undergoes an elctrocyclization to form a gold-containing allylic cation F that reacts with anthranil in a [4 + 3]-annulation to yield a seven-membered oxonium intermediate G. A further ring opening of species G yields the observed product 3a. This alternative mechanism rationalizes our crossover experiments, and the reaction stereochemistry matches well with our observation.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Manisha Skaria: 0000-0002-6729-714X Rai-Shung Liu: 0000-0002-2011-8124 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the Ministry of Science and Technology and the Ministry of Education, Taiwan, for supporting this work.

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REFERENCES

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DOI: 10.1021/acs.orglett.9b00880 Org. Lett. XXXX, XXX, XXX−XXX