Letter Cite This: Org. Lett. 2017, 19, 5665-5668
pubs.acs.org/OrgLett
Transformable Sulfoximine Assisted One-Pot Double Annulation of Vinylic C−H Bonds with Unactivated Alkynes Majji Shankar, Tirumaleswararao Guntreddi, E. Ramesh, and Akhila K. Sahoo* School of Chemistry, University of Hyderabad, Hyderabad 500046, India S Supporting Information *
ABSTRACT: The methylphenyl sulfoximine (MPS) directing group (DG) successfully promotes the one-pot double annulation of acrylic acids with alkynes under Ru catalysis, which is unprecedented. Diverse arrays of pyrido-fused-isoquinolinone skeletons are fabricated from acrylamides, creating two C−C and two C−N bonds in a single operation. The unsymmetrical annulation with two distinct alkynes is presented. The recovery of methylphenyl sulfoxide, a precursor of MPS, validates the synthetic adaptability of transformable-DG (TfDG) in C−H activation.
C
omplexity driven synthetic manipulations hold unequivocal significance in chemistry.1 In this context, transitionmetal (TM)-catalyzed and directing group (DG) aided oxidative annulations of ubiquitous C−H bonds with olefins/ alkynes have proven to be unparalleled, as they can be used for the efficient construction of complex carbo(hetero)cycles from readily accessible precursors.2 Importantly, the DG in such reactions is vital, as it dictates the regioselective activation of C−H bonds and participates in the annulation process.3 Notably, DG-enabled arene C−H motifs have been used in diverse annulations.3,4 In contrast, studies regarding nonaromatic acrylic acid derivatives have been less explored, despite their utility, perhaps because acrylic acid derivatives are prone to polymerization under oxidative conditions, susceptible to conjugate additions, and the cyclometalation species are unstable.5 In addition, the β-substitution of acrylate sterically inhibits the effective cyclometalation (Figure 1A).6 Despite these challenges, the TM-catalyzed monoannulation,7 βalkenylation,8 and β-alkynylation9 of DG-bearing-acrylamides provides pyridone motifs and highly substituted olefins (Figure 1B). At this juncture, we speculate that the amide NH moiety of pyridone, formed through the monoannulation of the acrylamide and alkyne, would be capable of undergoing further annulation with the proximal arene moiety in the presence of an alkyne under one-catalytic conditions (Figure 1B), generating a polyfused-heteroarene skeleton in a single operation.10 To our knowledge, a direct double annulation strategy of acrylamide (vinylic-C−H bonds) with unactivated alkynes has not been explored, despite its broad synthetic potential. As π-conjugated polycyclic heteroaryl frameworks are widely present in natural products, pharmaceuticals, agrochemicals, and optoelectronic materials,11 we developed a step and atomefficient strategy for the construction of complex pyrido-fused isoquinolinone skeletons based on the one-pot double © 2017 American Chemical Society
Figure 1. Annulation of acrylamides and 2H-chromenes.
annulation of MPS-enabled acrylamides with a wide range of alkynes (Figure 1C). These unprecedented double annulations reliably occur in the presence of a cost-effective, air-stable Ru catalyst. The MPS-DG is transformable, as validated by the isolation of methyl phenyl sulfoxide, the sole precursor of MPS.12 In addition, the double annulations of 2H-chromene Received: September 9, 2017 Published: October 6, 2017 5665
DOI: 10.1021/acs.orglett.7b02824 Org. Lett. 2017, 19, 5665−5668
Letter
Organic Letters
functionalization’s (Table 1).3,7 To our surprise, none of the acrylamides provided the product 3aa above 60% yield [Ia-NH2 (52%), oxidiazable IIa-NHOMe (59%), IIIa-NHTs (trace), and IVa-NHPh (0%)]. In contrast, the MPS enabled acrylamide 1a delivered 82% of 3aa, which is remarkable.13 The optimized catalytic conditions in entry 10, Table 1 [[RuCl2(p-cymene)]2 (10 mol %), AgSbF6 (40 mol %), and Cu(OAc)2·H2O (1.5 equiv) in 1,4-dioxane at 120 °C] were scrutinized to authenticate the synthetic power of the double annulation of MPS-DG-enabled acrylamides with unactivated alkynes (Schemes 1 and 2). At first, diannulation of 1a (0.5
derivatives and the challenging unsymmetrical annulations of acrylamides with two distinct alkynes are presented for the first time (Figure 1C). As envisaged in Figure 1C, the double annulation between N-(methacryloyl)-MPS (1a; 0.3 mmol) and 1,2-diphenylacetylene (2a; 0.9 mmol) was at first commenced in the presence Ru(II)-catalyst, additives, and solvents (Table 1). To our Table 1. Optimization of Reaction Conditionsa
Scheme 1. Double Annulation of 1a with 1,2-Diarylacetylene (2) entry
additive (20 mol %)
acetate source (1.0 equiv)
solvent
yield of 3aab (%)
1 2 3 4 5 6 7 8 9 10c 11c,d 12c,e
AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgBF4 KPF6 AgSbF6 AgSbF6 AgSbF6
Mn(OAc)2 Zn(OAc)2·2H2O NaOAc KOAc Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O
ClCH2CH2Cl ClCH2CH2Cl ClCH2CH2Cl ClCH2CH2Cl ClCH2CH2Cl ClCH2CH2Cl 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane
10 16 21 19 23 39 51 43 23 82 70 71
a
Conditions: Ru-cat (5.0 mol %), additive (20 mol %), acetate source (1.0 equiv), solvent. bIsolated yield. cRu-cat (10 mol %), Ag (40 mol %), Cu(OAc)2·H2O (1.5 equiv) was employed. dCu(OAc)2·H2O (1.0 equiv) instead of 1.5 equiv was used. e2a (0.66 mmol; 2.2 equiv) was used.
delight, the diannulation product 3aa (10%; structure was unambiguously confirmed by the detailed analytical studies) was produced under the catalytic conditions [[RuCl2(pcymene)]2 (5.0 mol %) and AgSbF6 (20 mol %) in 1,2dichloroethane (ClCH2CH2Cl; DCE) at 120 °C for 24 h] (entry 1). Interestingly, use of acetate bases (1.0 equiv) [Mn(OAc)2, Zn(OAc)2, NaOAc, and KOAc] improved the formation of 3aa (10−23%; entries 2−5). Pleasingly, Cu(OAc)2·H2O was found to be superior, affording 3aa (39%); the yield of 3aa was enhanced to 51% when the annulation conducted in 1,4-dioxane (entries 6 and 7). Disappointingly, other silver salts AgBF4 and KPF6 did not perform any better (entries 8 and 9). Gratifyingly, the use of Ru catalyst (10 mol %) along with Cu(OAc)2·H2O (1.5 equiv) yielded 82% of 3aa (entry 10). While 3aa (70%) was formed when Cu(OAc)2·H2O (1.0 equiv) was employed (entry 11), the role of oxidant is thus essential.4b The productivity was affected when 2a (2.2 equiv) was subjected in this annulation (entry 12), perhaps because the higher concentration of 2a in the reaction inhibits selfpolymerization of 1a. Obviously, the easy isolation of unreacted 2a fulfills the atom-efficient and sustainable double-annulation protocol developed herein. We next probed examining double annulation of acrylamides Ia−IVa that are successfully employed to various C−H
mmol) with various 1,2-diarylalkynes were surveyed (Scheme 1). Pleasingly, 3aa (81%) was isolated from 1a and 2a. The reaction between 1a and the electron-rich (Me/tBu/OMe) group bearing para-substituted 1,2-diarylacetylenes provided the desired π-extended polycyclic amides 3ab−ad in 61−78% yield. The labile halo (F/Cl/Br) bearing products 3ae−3ag were readily synthesized; X-ray studies elucidates the structure of 3ae.14 The electron-withdrawing modifiable keto moiety did not affect the reaction, yielding 65% of 3ah. The m-Me bearing diarylalkyne was not exception, providing 3ai (60%). We then investigated reviewing the reactivity of substituted acrylamides with 2a (Scheme 2). Gratifyingly, the acrylamides having substituent at α-position [electron-donating alkyl (Et, t Bu); electron-withdrawing CF3; phenyl; or aryl (p-tBu-C6H4, m-Cl-C6H4)] underwent double annulation with 2a to produce the desired products 3ba−ga in 39−89% yield. Likewise, π5666
DOI: 10.1021/acs.orglett.7b02824 Org. Lett. 2017, 19, 5665−5668
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Organic Letters
of 2′ and heating the resulting mixture at 120 °C for 12 h]. Thus, different alkynes were successively stitched with 1a via sequential double annulations under the one catalytic conditions to afford 4a (48%; insertion of 2c and 4-octyne), 4b (41%; insertion of 2b and 2c), and 4c (51%; insertion of 2c and 2d) (Scheme 3).16 To further enlarge the molecular scaffold, we envisaged investigating the double annulation of benzopyran systems, for example: 2H-chromene-3-carboxylic acid derivatives; these motifs are widely found in natural products of biological significance (Scheme 4).17 Pleasingly, the reaction between
Scheme 2. Double Annulation of MPS-Enabled Acrylamides (1) with Diphenylacetylene (2a)
Scheme 4. Double Annulation of MPS-Enabled 2HChromene 3-Carboxamides (5) with 1,2-Diarylacetylene (2)
conjugated pyrido-fused isoquinolinones 3ha−ma were reliably fabricated through the annulation of 2a with the acrylamides having a substituent at the β-position [electron-donating methyl (3ha, 76%); phenyl (3ia, 62%); p-Me-C6H4 (3ja, 55%); p-MeO-C6H4 (3ka, 61%); p-Cl-C6H4 (3la, 63%) p-BrC6H4 (3ma, 57%)].15 Finally, the most challenging α,βdisubstituted acrylamide underwent double annulation with 2a to give 3na albeit in poor yield.15 Motivated with the successful double annulation of acrylamides with alkynes (Schemes 1 and 2), the unprecedented two-fold unsymmetrical annulations of 1a with two distinct alkynes is thus envisaged (Scheme 3). Several trials of attempts finally constructed the desired pyrido-fused isoquinolinone 4 under the following synthetic operations in one pot [reaction of 1a with 2 at 70 °C for 12 h and then the addition
MPS-enabled 2H-chromene-3-carboxamide (5a) and 2a provided 6a in 63% yield. Likewise, 6b and 6c were accessed from the naphthyl-bearing and p-OMe-substituted chromenes, respectively. Other unactivated alkynes smoothly underwent double annulations with 5a affording the desired products 6d (58%), 6e (50%), 6f (82%), 6g (74%), and 6h (40%) (Scheme 4). These demonstrations witnessed the strength of multipleannulations for the construction of enlarged fused-ring systems from readily accessible carboxylic acids. To our surprise, highly regioselective diannulation product 3aj was obtained when 1a exposed to the unsymmetrical methylphenyl acetylene (2j) under the optimized conditions (eq 1).4b,18 As predicted, the reaction of 1l with 4-octyne
Scheme 3. One-Pot Double Annulation of Acrylamide (1a) with Different Alkynes (2 and 2′)
delivered the monoannulation product 3lk; further cyclization involving the C(sp3)−H bond remained unsuccessful (eq 3).10c Finally, the gram-scale synthesis of 3aa (1.66 g) determined the strength of the catalytic system (eq 2); the recovery of methyl
a
Conditions: 1a (0.3 mmol), 2 (0.3 mmol), Ru-cat (10 mol %), AgSbF6 (40 mol %), Cu(OAc)2·H2O (0.45 mmol) in 1,4-dioxane (2.0 mL) at 70 °C for 12 h; then 2′ (0.6 mmol) was added and the mixture heated at 120 °C for 12 h. 5667
DOI: 10.1021/acs.orglett.7b02824 Org. Lett. 2017, 19, 5665−5668
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Organic Letters phenyl sulfoxide, the precursor of MPS,12 authenticates the transformable (Tf)-DG nature of the MPS moiety. The one-pot double annulation is comprised of the cyclizations of acrylamide with two alkynes.16 The complete reaction could involve the chelation of the MPS-N moiety with the cationic Ru complex,4b formation of a five membered ruthenacycle via β-C−H activation of acrylamide, alkyne insertion to the ruthenacycle, migratory insertion, and cyclization with concomitant release of methyl phenylsulfoxide generating another 5-membered ruthenacycle via the coordination of pyridone−N-Ru−proximal-o-C−H-aryl, which would eventually undergo an annulation with the alkyne to give the desired double cyclization product.16,19 The acetate source of Cu(OAc)2·H2O presumably helps the formation of active catalyst and also behaves as oxidant in the second annulation.4,19 In conclusion, we developed a novel transformable sulfoximine DG-assisted oxidative double annulation of acrylic and 2H-chromene-3-carboxylic acid derivatives with unactivated alkynes under Ru catalysis. This transformation can be used to construct four bonds (two C−C and two C−N) in a naked acrylamide in a single operation and can be used to produce a wide range of complex π-extended polycyclic amides with good functional group tolerance in good yields. The challenging unsymmetrical double annulation of acrylamides with two distinct alkynes is also demonstrated.
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(3) (a) Yadav, M. R.; Rit, R. K.; Shankar, M.; Sahoo, A. K. J. Org. Chem. 2014, 79, 6123. (b) Yadav, M. R.; Rit, R. K.; Shankar, M.; Sahoo, A. K. Asian J. Org. Chem. 2015, 4, 846. (c) Zhu, R.-Y.; Farmer, M. E.; Chen, Y.-Q.; Yu, J.-Q. Angew. Chem., Int. Ed. 2016, 55, 10578. (4) (a) Ackermann, L.; Lygin, A. V.; Hofmann, N. Angew. Chem., Int. Ed. 2011, 50, 6379. (b) Ackermann, L. Acc. Chem. Res. 2014, 47, 281. (c) Gulías, M.; Mascareñas, J. L. Angew. Chem., Int. Ed. 2016, 55, 11000. (d) Yang, Y.; Li, K.; Cheng, Y.; Wan, D.; Li, M.; You, J. Chem. Commun. 2016, 52, 2872. (e) Kumar, N. Y. P.; Rogge, T.; Yetra, S. R; Bechtholdt, A.; Clot, E.; Ackermann, L. Chem. - Eur. J. 2017, DOI: 10.1002/chem.201703680. (5) Wang, K.; Hu, F.; Zhang, Y.; Wang, J. Sci. China: Chem. 2015, 58, 1252. (6) (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 5604. (b) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (c) Besset, T.; Kuhl, N.; Patureau, F. W.; Glorius, F. Chem. - Eur. J. 2011, 17, 7167. (d) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814. (e) Shang, X.; Liu, Z.-Q. Chem. Soc. Rev. 2013, 42, 3253. (7) (a) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2008, 10, 325. (b) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74, 6295. (c) Su, Y.; Zhao, M.; Han, K.; Song, G.; Li, X. Org. Lett. 2010, 12, 5462. (d) Ackermann, L.; Lygin, A. V.; Hofmann, N. Org. Lett. 2011, 13, 3278. (e) Shi, Z.; Koester, D. C.; Arapinis, M. B.; Glorius, F. J. Am. Chem. Soc. 2013, 135, 12204. (f) Yu, Y.; Huang, L.; Wu, W.; Jiang, H. Org. Lett. 2014, 16, 2146. (8) (a) Shibata, Y.; Otake, Y.; Hirano, M.; Tanaka, K. Org. Lett. 2009, 11, 689. (b) Meng, K.; Zhang, J.; Li, F.; Lin, Z.; Zhang, K.; Zhong, G. Org. Lett. 2017, 19, 2498. (9) (a) Collins, K. D.; Lied, F.; Glorius, F. Chem. Commun. 2014, 50, 4459. (b) Xie, F.; Qi, Z.; Yu, S.; Li, X. J. Am. Chem. Soc. 2014, 136, 4780. (c) Feng, C.; Feng, D.; Luo, Y.; Loh, T.-P. Org. Lett. 2014, 16, 5956. (d) Feng, C.; Feng, D.; Loh, T.-P. Chem. Commun. 2014, 50, 9865. (e) Xu, Y.-H.; Zhang, Q.-C.; He, T.; Meng, F.-F.; Loh, T.-P. Adv. Synth. Catal. 2014, 356, 1539. (10) (a) Song, G.; Chen, D.; Pan, C.-L.; Crabtree, R. H.; Li, X. J. Org. Chem. 2010, 75, 7487. (b) Mochida, S.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Chem. Lett. 2010, 39, 744. (c) Shankar, M.; Ghosh, K.; Mukherjee, K.; Rit, R. K.; Sahoo, A. K. Org. Lett. 2016, 18, 6416. (11) (a) Ahmed, E.; Briseno, A. L.; Xia, Y.; Jenekhe, S. A. J. Am. Chem. Soc. 2008, 130, 1118. (b) Mei, J.; Leung, N. L. C.; Kwok, R. T. K.; Lam, J. W. Y.; Tang, B. Z. Chem. Rev. 2015, 115, 11718. (12) (a) Siu, T.; Yudin, A. K. Org. Lett. 2002, 4, 1839. (b) Okamura, H.; Bolm, C. Org. Lett. 2004, 6, 1305. (c) Wang, J.; Frings, M.; Bolm, C. Chem. - Eur. J. 2014, 20, 966. (13) The DG-assisted Ru-mediated activation of the C−H bond occurs at room temperature, and the release of sulfoxide from the sterically encumbered metallacycle RuL-MPS moiety (Int-II; see the SI) and the direct participation of Int-IV (see the SI) presumably helps the annulation. (14) CCDC 1572523 (3ae) and 1572524 (3aj) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. (15) The isolation of unreacted monocyclization product and starting material satisfies the mass balance of the reaction. (16) See the Supporting Information. (17) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.; Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939. (18) The reaction of 2a with unsymmetrical diarylalkynes provided a mixture of annulated products, leading to a tedious and unsuccessful purification. (19) Li, B.; Feng, H.; Wang, N.; Ma, J.; Song, H.; Xu, S.; Wang, B. Chem. - Eur. J. 2012, 18, 12873.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02824. Detailed experimental procedures, NMR spectra, and Xray crystallographic data (PDF) HRMS data (PDF) X-ray data for compound 3ae (CIF) X-ray data for compound 3aj (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected],
[email protected]. ORCID
Akhila K. Sahoo: 0000-0001-5570-4759 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank SERB (EMR/2014/385) for financial support and University of Hyderabad (UoH; UPE-CAS and PURSE-FIST) for overall facility. M.S. and E.R. thank CSIR, and T.R.G. (NPDF; DST), India, for fellowships. Dr. K. Nagarjuna (UoH) is thanked for the crystallographic studies.
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REFERENCES
(1) Chen, D. Y.-K.; Youn, S. W. Chem. - Eur. J. 2012, 18, 9452. (2) Selected reviews of oxidative annulation: (a) Satoh, T.; Miura, M. Chem. - Eur. J. 2010, 16, 11212. (b) Wencel-Delord, J.; Dröge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (c) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (d) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. 5668
DOI: 10.1021/acs.orglett.7b02824 Org. Lett. 2017, 19, 5665−5668
