Letter pubs.acs.org/OrgLett
A Cascade Dehydrogenative Cross-Coupling/Annulation Reaction of Benzamides with β‑Keto Esters for the Synthesis of Isoquinolinone Derivatives Guo-Dong Xu† and Zhi-Zhen Huang*,† †
Department of Chemistry, Zhejiang University, Hangzhou 310028, P. R. China S Supporting Information *
ABSTRACT: A novel cascade DCC/annulation reaction of N-alkoxybenzamides with β-keto esters has been developed for the synthesis of isoquinolinone derivatives under palladium catalysis. A plausible mechanism involving α-C(sp2)−H activation and a Pd(II)/Pd(IV) catalytic cycle is also proposed.
S
Liu and co-workers disclosed that in the presence of Cu(OAc)2, N-quinolinyl benzamides and cyanoacetates can perform a DCC reaction followed by cyclization to afford N-quinolinyl 3aminoisoquinolinone derivatives in good yields (eq 2, Scheme 1).4 However, the transformation requires an equivalent of copper salt and a bidentate directing group. To the best of our knowledge, the DCC reaction of benzamides with β-keto esters remains unknown. Thus, we envisioned that if we were to use a transition-metal catalyst to activate α-C(sp2)−H bonds with the assistance of a common and monodentate directing group, such as a carbonyl group, a DCC reaction of benzamides with β-keto esters and a successive annulation reaction may occur to produce isoquinolinone derivatives. A lot of isoquinolinone derivatives have important biological activities, and the isoquinolinone moiety widely exists in natural products and pharmacologically relevant therapeutic agents.5 Therefore, we carried out the investigation on a transition-metal-catalyzed cascade DCC/annulation reaction of N-alkoxybenzamides with β-keto esters for the synthesis of isoquinolinone derivatives. Initially, N-methoxybenzamide (1a) and ethyl acetoacetate (2a) were chosen as model substrates to explore and optimize the cascade DCC/annulation reaction. When Pd(OAc)2 (5 mol %) and K2S2O8 (2.0 equiv) were employed as a transition-metal catalyst and an oxidant respectively, the cascade reaction of benzamide 1a (0.2 mmol) and acetoacetate 2a (0.4 mmol) in AcOH (2.5 mL) was able to occur at 80 °C to furnish the desired isoquinolinone derivative 3aa, albeit in a low yield (entry 1, Table 1). Then other transition-metal catalysts were also examined (entries 2−4, Table 1; also see the Supporting Information (SI)). It was found that when Pd(OOCCF3)2 was employed, the yield of 3aa increased to 56% (entry 4, Table 1). Among the various oxidants, K2S2O8 proved to be best in the yield of 3aa, although TBHP also resulted in a yield of 50% (entries 4−8, Table 1). In the absence of Pd(OOCCF3)2 or K2S2O8, no 3aa was obtained (see the SI). Among the solvents screened, HOAc resulted in the best yield of 3aa (entries 4 and
ince dehydrogenative cross-coupling (DCC) reactions feature the use of only C−H bonds to form C−C bonds (thus avoiding prefunctionalization of substrates) and are stepefficient, they are considered as a new generation of C−C bond formations.1 As we know, a cascade reaction combines two or more bond-forming reactions into one process and does not isolate intermediates. Both DCC reactions and cascade reactions are step-efficient and atom-economical, which reduce resource consumption and environmental impact. Active methylene compounds, such as acetoacetates, malonates, and acetylacetones, have excellent reactivities and are very important and useful reagents in organic synthesis. Along with the many investigations of their DCC reactions with C(sp3)−H partners, such as benzylic and allylic C(sp3)−H bonds, some of the literature revealed their DCC reactions with C(sp2)−H bonds.2−4 In 2015, Yu and co-workers developed a Cu(II)-catalyzed oxidative coupling of N-oxazolyl benzamides with malonates followed by intramolecular oxidative N−C bond formation, furnishing N-oxazolyl isoindolinone derivatives with a remaining N-oxazolyl group (eq 1, Scheme 1).3 In 2014, Scheme 1. Cascade DCC/Annulation Reactions of αC(sp2)−H Bonds in Aromatic Compounds and α-C(sp3)−H Bonds in Active Methylene Compounds
Received: September 22, 2017 Published: November 20, 2017 © 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b02978 Org. Lett. 2017, 19, 6265−6267
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Organic Letters
Scheme 2. Cascade DCC/Annulation Reaction of NAlkoxybenzamides 1a−n with Acetoacetates 2a−g To Give Isoquinolinone Derivatives 3a,b
Table 1. Optimization of the Cascade DCC/Annulation Reaction of N-Alkoxybenzamide 1a with Acetoacetate 2aa
entry
[M]
oxidant
solvent
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13c 14c,d
Pd(OAc)2 [Cp*RhCl2]2 PdCl2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2
K2S2O8 K2S2O8 K2S2O8 K2S2O8 DTBP TBHP DDQ Ag2O K2S2O8 K2S2O8 K2S2O8 K2S2O8 K2S2O8 K2S2O8
AcOH AcOH AcOH AcOH AcOH AcOH AcOH AcOH THF DCE toluene DMF AcOH AcOH
43 0 trace 56 0 50 0 0 42 19 8 0 76 84
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [M] (5 mol %), oxidant (2.0 equiv), solvent (2.5 mL), 80 °C, 12 h. bIsolated yields. c 24 h. d60 °C.
9−12, Table 1). When the reaction time was extended from 12 to 24 h, the yield of 3aa increased to 76% (entry 13, Table 1). It was also found that decreasing the temperature to 60 °C was beneficial to the reaction (entry 14, Table 1; also see the SI). Thus, it can be concluded that the optimized reaction should be performed under the catalysis of Pd(OOCCF3)2 (5 mol %) in the presence of K2S2O8 (2.0 equiv) at 60 °C in AcOH (2.5 mL) for 24 h. With the optimized conditions in hand, the scopes of benzamides 1 and β-keto esters 2 in the cascade reaction were examined (Scheme 2). We found that various N-methoxybenzamides 1a−k were able to undergo the cascade DCC/ annulation reaction smoothly with acetoacetate 2a to give the desired isoquinolinone derivatives 3aa−ka in moderate to good yields. The cascade reaction seems to be insensitive to the electronic effects of substituents on the benzene rings in Nmethoxybenzamides 1a−h. N-Methoxybenzamides bearing electron-donating groups (1b−e) resulted in similar yields of isoquinolinone derivatives (3ba−ea) as for those bearing electron-withdrawing groups (1f−h). When o-methyl-substituted N-methoxybenzamide 1k was employed, the yield of 3ka decreased remarkably to 60%, probably because of the decrease in the number of α-C(sp2)−H bonds. N-Benzyloxybenzamides 1l−n were also able to perform the cascade reaction smoothly to give the corresponding products 3la−na in satisfactory yields. Besides 2a, methyl, isopropyl, and benzyl acetoacetate (2b−d) underwent the cascade reaction expediently as well, furnishing the desired isoquinolinone derivatives 3ab−ad in 70−83% yields. Moreover, other β-keto acetates besides acetoacetate 2a, i.e., propionylacetate 2e, butyrylacetate 2f, and cyclopropanecarbonylacetate 2g, also performed the cascade reaction expediently to give 4-ethyl-, 4-n-propyl-, and 4-cyclopropyl-substituted isoquinolinone derivatives 3ae−ag, respectively. It is noteworthy that naphthamide 1o was also able to perform the cascade reaction to give 3oa in 46% yield (eq 1, Scheme 3). Benzoylacetate (2h) and 4-chloroacetoacetate 2i
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Pd(OOCCF) (5 mol %), K2S2O8 (0.4 mmol), AcOH (2.5 mL), 60 °C, 24 h. bIsolated yields are shown.
Scheme 3. Naphthamide 1o and Other β-Keto Esters 2h−i in the Cascade DCC/Annulation Reaction
also performed the cascade reaction, but the yields of the corresponding isoquinolinone derivatives 3ah and 3ai were lower (eqs 2 and 3, Scheme 3). To gain insight into the mechanistic pathway of the cascade reaction, a kinetic isotopic experiment was carried out under the standard conditions. Two parallel reactions of benzamide 6266
DOI: 10.1021/acs.orglett.7b02978 Org. Lett. 2017, 19, 6265−6267
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Organic Letters
such as nitro, fluoro, chloro, bromo, and methoxy groups, affording a range of isoquinolinone derivatives 3 in 50−87% yield. A plausible mechanism involving Pd(II) for α-C(sp2)−H activation and Pd(IV) for C−C bond formation is also proposed. The new cascade reaction has the advantages of mild reaction conditions, satisfactory yields, high efficiency, and environmental friendliness, making its possible application in the synthesis of related natural products and pharmaceuticals.
1a and deuterated benzamide 1a-D5 with 2a were performed, and the value of the kinetic isotope effect (KIE) was 2.23 (Scheme 4). The KIE result suggests that the α-C(sp2)−H functionalization may be the rate-determining step in the cascade reaction (Scheme 4). Scheme 4. Kinetic Isotope Effect Study
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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.7b02978. Experimental procedures, characterization data, and 1H NMR, 13C NMR, and HRMS spectra for products (PDF)
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AUTHOR INFORMATION
Corresponding Author
2
With reference to literature precedent, a plausible mechanism for the cascade DCC/annulation reaction is proposed as follows (Scheme 5). First, under the direction of
*E-mail:
[email protected] ORCID
Zhi-Zhen Huang: 0000-0002-2225-4242
Scheme 5. Plausible Mechanism
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from the National Natural Science Foundation of China (21372195) is gratefully acknowledged. REFERENCES
(1) Some reviews of DCC reactions: (a) Li, C.-J.; Li, Z. Pure Appl. Chem. 2006, 78, 935. (b) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (c) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (d) Liu, C.; Zhang, H.; Shi, W.; Lei, A.-W. Chem. Rev. 2011, 111, 1780. (e) Girard, S. A.; Knauber, T.; Li, C.-J. Angew. Chem., Int. Ed. 2014, 53, 74. (f) Varun, B. V.; Dhineshkumar, J.; Bettadapur, K. R.; Siddaraju, Y.; Alagiri, K.; Prabhu, K. R. Tetrahedron Lett. 2017, 58, 803. (g) Lakshman, M. K.; Vuram, P. K. Chem. Sci. 2017, 8, 5845. (h) Yang, Y.-D.; Lan, J.-B.; You, S.-L. Chem. Rev. 2017, 117, 8787. (i) Batra, A.; Singh, P.; Singh, K. N. Eur. J. Org. Chem. 2017, 2017, 3739. (2) Chan, W.-W.; Zhou, Z.-Y.; Yu, W.-Y. Chem. Commun. 2013, 49, 8214. (3) Wang, H.-L.; Shang, M.; Sun, S.-Z.; Zhou, Z.-L.; Laforteza, B. N.; Dai, H.-X.; Yu, J.-Q. Org. Lett. 2015, 17, 1228. (4) Zhu, W.; Zhang, D.-Y.; Yang, N.; Liu, H. Chem. Commun. 2014, 50, 10634. (5) (a) Krane, B. D.; Shamma, M. J. Nat. Prod. 1982, 45, 377. (b) Glushkov, V. A.; Shklyaev, Y. V. Chem. Heterocycl. Compd. 2001, 37, 663. (c) Matsui, T.; Sugiura, T.; Nakai, H.; Iguchi, S.; Shigeoka, S.; Takada, H.; Odagaki, Y.; Nagao, Y.; Ushio, Y. J. Med. Chem. 1992, 35, 3307. (d) Nagarajan, M.; Morrell, A.; Fort, B. C.; Meckley, M. R.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Cushman, M. J. Med. Chem. 2004, 47, 5651. (6) (a) Semmes, J. G.; Bevans, S. L. C.; Mullins, H.; Shaughnessy, K. H. Tetrahedron Lett. 2015, 56, 3447. (b) Djakovitch, L.; Köhler, K. J. Organomet. Chem. 2000, 606, 101.
the carbonyl group, the Pd(II) catalyst activates the α-C(sp2)− H bond in benzamide 1a to form five-membered palladacycle intermediate A. Pd(II) in intermidiate A is oxidized to Pd(IV) by K2S2O8 to form palladacycle intermediate B along with sulfate anion. Then acetoacetate anion 2a′ connects onto Pd(IV) in intermediate B via ligand exchange to form Pd(IV) intermediate C.6 Reductive elimination of intermediate C leads to C−H-functionalized intermediate D and regenerates the Pd(II) catalyst. Finally, intramolecular condensation of D via dehydration affords the desired isoquinolinone derivative 3aa. In conclusion, we have developed a cascade DCC/annulation reaction of N-alkoxybenzamides 1 with β-keto esters 2 for the synthesis of isoquinolinone derivatives 3 using Pd(OOCCF3)2 as a transitional-metal catalyst and K2S2O8 as an oxidant. The cascade reaction is compatible with various functional groups, 6267
DOI: 10.1021/acs.orglett.7b02978 Org. Lett. 2017, 19, 6265−6267
