Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of Dihydroquinolinones Barry M. Trost,* Anugula Nagaraju, Feijun Wang, Zhijun Zuo, Jiayi Xu, and Kami L. Hull Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
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S Supporting Information *
ABSTRACT: A palladium-catalyzed decarboxylative asymmetric allylic alkylation (Pd-DAAA) of benzo-fused and nonbenzo-fused δ-valerolactams is disclosed. This methodology gives access to chiral lactams bearing C3-quaternary stereocenters, which are central to many natural products and biologically active compounds. The reaction proceeds via palladium-catalyzed ionization of an allyl ester, followed by carbon dioxide extrusion and recombination of the electrophilic Pd-π-allyl complex with the in situ generated lactam enolate. This final step converts racemic allylic ester starting materials into enantiomerically enriched substituted lactams with high yield and enantiomeric excess.
N
itrogen-containing heterocycles are ubiquitous in natural products, pharmaceuticals,1,2 and drug molecules.3 Among such compounds, 4-monosubstituted and 3,4-disubstituted dihydroquinoline-2(1H)-ones are particularly important structural motifs and appear in many natural products and biologically relevant compounds (Figure 1).
Scheme 1. Approaches To Access Chiral 3,3-Substituted Dihydroquinolinones
Figure 1. Biologically active compounds containing 3,4-dihydroquinolin-2-ones.
approach lies in the ease of accessibility of the racemic allyl ester, bearing 3-substituted dihydroquinolinone substrates from commercially available dihydroquinolinones in high yield and straightforward procedure (Scheme 2). Under asymmetric palladium catalysis, the racemic allyl esters would give rise to 3,3-disubstituted dihydroquinolinone products with high enantioselectivity. We began our endeavor by identifying an efficient approach to access the racemic dihydroquinolinone materials. As illustrated in Scheme 2, allyl imidazolates were selected as acylating agents to synthesize the desired substituted dihydroquinolinones. In the alkylation step, one might be concerned about an enolate Claisen rearrangement competing with the desired alkylation event.
The importance of this structural motif has stimulated activities within the synthetic community to evolve methodologies that could give access to tetrahydroquinolone compounds.4−8 Nonetheless, the synthesis of chiral 3-substituted and 3,3-disubstituted dihydroquinolin-2(1H)-ones is far less developed,9 despite the frequent appearance of such motifs in pinolinone,10 scandine,11 and a norepinephrine reuptake inhibitor10b(Figure 1). Scheme 1 illustrates some of the existing synthetic methods for accessing 3-substituted dihydroquinolinones as illustrated by Cai and co-workers shown in Scheme 1a9c and Pan and co-workers as shown in Scheme 1b.9d,e We envisioned a possible alternative strategy using palladium-catalyzed allylic alkylation to access this motif with high efficiency (Scheme 1c). The effectiveness of our © XXXX American Chemical Society
Received: January 28, 2019
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DOI: 10.1021/acs.orglett.9b00358 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Synthesis of Dihydroquinolin-2-one DAAA Substrates
Figure 2. Chiral diamine ligands.
Table 1. Optimization of Reaction Conditions for Pd-DAAA on Benzo-Fused Lactamsa
entry
ligand
solvent
temp (°C)
yieldb (%)
ee (%)
1 2 3 4 5 6
L1 L2 L3 L4 L4 L4
dioxane dioxane dioxane dioxane toluene dioxane
23 23 23 23 23 60
43 10 47 76 68 80
27 3 10 98 97 97
a
The reactions were run by using 0.1 mmol of 1a, 2.5 mol % of Pd2dba3·CHCl3, and 7.5 mol % of L4 in 1 mL solvents. bIsolated yields.
As illustrated in Scheme 3, a wide range of dihydroquinolinones with various substituents at the 3-position of the dihydroquinolinone core were subjected to the optimized reaction conditions. With tert-butyloxycarbonyl (Boc)-protected dihydroquinolinones (1a−1f), alkyl, propargyl, vinyl, nitrile, and ester substituents were well tolerated, and the desired allylated products 2a−2f were obtained in high yield and enantioselectivity. Of note, a vinyl chloride is tolerated under the palladiumcatalyzed allylation conditions, and 2d was isolated in 91% yield and 91% ee. Similarly, favorable results were obtained when benzoyl-protected dihydroquinolinones 1j−1k were utilized as substrates, affording allylated products 2j−2k with high enantioselectivity. Reaction of racemic 1a on 1.0 mmol scale under the conditions described in Scheme 3 at room temperature led to product 2a in 71% yield and 97% ee. Extension of the above reaction conditions to simple δvalerolactams was also explored (Scheme 4). N-Benzoyl piperidones with various substituents at the 3-position were effective, and the allylated products 4a−4e were isolated in good yield and high enantioselectivity. The results for these δvalerolactams are comparable to the results for dihydrobenzoquinolinone in Scheme 3. In the case of δ-valerolactams, utilization of substituted allyl motifs is particularly notable (4c and 4e). We further explored the use of a 2-substituted allyl fragment in the allylation of dihydroquinolinone 1l, and the allylated product 2l was obtained in moderate yield and with perfect enantioselectivity (eq 1). Utilization of 1-substituted allyl groups in the case of δ-valerolactams 3f and 3g was also demonstrated (eqs 2 and 3).
Fortunately, such a competition was not observed in this case, and a wide range of functionalized allylating agents were successfully employed (Scheme 2, 1a−1l). With these racemic substrates in hand, we set out to identify conditions that could affect the decarboxylative asymmetric allylic alkylation sequence. Although the Stoltz group12 described the use of the Pfaltz ligands for the DAAA of cyclic amides, they only applied this methodology to simple lactams. We planned to use the 2-diphenylphosphinobenzoate chiral ligands L1−L4 (Figure 2)in our studies because the DPPBA ligands have generally shown broader scope in terms of both the electrophile and nucleophile. We began the optimization of the reaction using 1a as the model substrate (Table 1). In dioxane, low to moderate yield and poor enantioselectivity were observed with ligands L1, L2, and L3. Fortunately, utilizing ligand L4 resulted in a drastic improvement in the yield and the enantioselectivity of the reaction (Table 1, entry 4). Switching to a less polar solvent (i.e., toluene) gave a lower yield and similar enantioselectivity (Table 1, entry 5). Performing the reaction in 1,4-dioxane at 60 °C instead of room temperature led to 80% yield of the allylated product with 97% ee (Table 1, entry 6). Thus, the highlighted conditions in entries 4 and 6 in Table 1 were selected as the optimal conditions to explore the generality of this transformation. B
DOI: 10.1021/acs.orglett.9b00358 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 3. Scope of the Decarboxylative Asymmetric Allylic Alkylation of Benzo-Fused δ-Valerolactamsa,b
Scheme 4. Scope of the Decarboxylative Asymmetric Allylic Alkylation of Simple δ-Valerolactamsa
a Reaction conditions: lactam 3 (0.1 mmol), Pd2dba3·CHCl3 (2.5 mol %), (R,R)-L4 (5.5 mol %), and 1 mL of dioxane.
a
Reactions were carried out on 0.1 mmol scale using 2.5 mol % of Pd2dba3·CHCl3 and 7.5 mol % of L4 in dioxane (0.1 M) for 12 h. b Isolated yields. c0.05 mmol of 1 was treated with 2.5 mol % of Pd2dba3·CHCl3 and 7.5 mol % of L4 in 0.5 mL of dioxane.
It should be noted that efforts to employ allyl fragments like those in eqs 2 and 3 were unsuccessful when Pfaltz-type ligands were utilized. The absolute stereochemistry of the products obtainedthrough this methodology was assigned using chemical manipulation of product 2a to access known compound 6 with established stereochemistry (Scheme 5).13 Comparison of the optical rotation of 6 with the reported data was then utilized to establish the absolute configuration of the stereocenter in this compound. The absolute stereochemistry of 4a was previously established12 and is consistent with our findings for 2a; therefore, all other products were assigned by analogy. This reaction presumably proceeds via a typical DAAA mechanism, as described previously (Scheme 6).14 The major alteration is the differential behavior of the anthracene-derived ligand, which showed an enabling effect on these reactions. Structurally, ligand L4 has the largest dihedral angle among the DPPBA ligands, and the larger P−Pd−P bite angle may be instrumental in allowing this reaction to proceed. The catalytic cycle is initiated by interaction of the active palladium catalyst (Pd0Ln) with the racemic substrate 1 to form a palladium π-allyl
complex, along with the carboxylate anion. Decarboxylation of the carboxylate anion would then easily occur to generate the stabilized enolate. Nucleophilic attack of this enolate on the electrophilic palladium π-allyl complex would result in αallylation of the enolate, along with regeneration of the palladium active catalyst (Pd0Ln) for the following catalytic cycles. The success of these new classes of prochiral nucleophiles further demonstrates the effectiveness of the chiral palladium DPPBA complexes for asymmetric allylic alkylation reactions. In summary, we have developed a palladium-catalyzed decarboxylative asymmetric allylic alkylation (Pd-DAAA) of dihydroquinolinones, wherein quaternary stereocenters can be accessed with high selectivity. Furthermore, this methodology C
DOI: 10.1021/acs.orglett.9b00358 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Notes
Scheme 5. Application to the Synthesis of a Norepinephrien Reuptake Inhibitor and Assignment of Absolute Stereochemistry
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge the Science and Engineering Research Board, India and Indo−U.S. Science and Technology Forum, India for financial support (fellowship Indo-US PDF-78/2017 to A.N.). We thank Hadi Gholami for help in preparing the final manuscript.
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(1) (a) Alkaloids; Cordell, G. A., Ed.; Academic Press, 2010; Vol. 69. (b) Joule, J. A.; Mills, K. Heterocyclic Chemsitry, 5th ed.; Wiley, 2010. (2) (a) Amat, M.; Lozano, O.; Escolano, C.; Molins, E.; Bosch, J. J. Org. Chem. 2007, 72, 4431. (b) Magnus, P.; Rainey, T. Tetrahedron 2001, 57, 8647. (3) For selected examples, see: (a) Ito, C.; Itoigawa, M.; Otsuka, T.; Tokuda, H.; Nishino, H.; Furukawa, H. J. Nat. Prod. 2000, 63, 1344. (b) Uchida, R.; Imasato, R.; Shiomi, K.; Tomoda, H.; Omura, S. Org. Lett. 2005, 7, 5701. (c) Patel, M.; McHugh, R. J.; Cordova, B. C.; Klabe, R. M.; Bacheler, L. T.; Erickson-Viitanen, S.; Rodgers, J. D. Bioorg. Med. Chem. Lett. 2001, 11, 1943. (d) Chen, M.; Shao, C.-L.; Meng, H.; She, Z.-G.; Wang, C.-Y. J. Nat. Prod. 2014, 77, 2720. (4)For selectedreferences, see: (a) Turner,K. L.;Baker, T.M.; Islam, S.; Procter, D. J.; Stefaniak, M. Org. Lett. 2006, 8, 329. (b) Felpin, F.-X.; Coste, J.; Zakri, C.; Fouquet, E. Chem. - Eur. J. 2009, 15, 7238. (c) Zhou, W.; Zhang, L.; Jiao, N. Tetrahedron 2009, 65, 1982. (d) Dantas de Araujo, A.; Christensen, C.; Buchardt, J.; Kent, S. B. H.; Alewood, P. F. Chem. Eur. J. 2011, 17, 13983. (e) Zhang, L.; Sonaglia, L.; Stacey, J.; Lautens, M. Org. Lett. 2013, 15, 2128. (f) Mai, W.-P.; Wang, J.-T.; Yang, L.-R.; Yuan, J.-W.; Xiao, Y.-M.; Mao, P.; Qu, L.-B. Org. Lett. 2014, 16, 204. (g) Li, B.; Park, Y.; Chang, S. J. Am. Chem. Soc. 2014, 136, 1125. (5) (a) Dong, C.; Alper, H. Tetrahedron: Asymmetry 2004, 15, 35. (b) Li, W.; Liu, X.; Hao, X.; Cai, Y.; Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2012, 51, 8644. (6) (a) Bach, T.; Grosch, B.; Strassner, T.; Herdtweck, E. J. Org. Chem. 2003, 68, 1107. (b) Müller, C.; Bauer, A.; Maturi, M. M.; Cuquerella, M. C.; Miranda, M. A.; Bach, T. J. Am. Chem. Soc. 2011, 133, 16689. (7) (a) Neel, M.; Gouin, J.; Voituriez, A.; Marinetti, A. Synthesis 2011, 2011, 2003. (b) Xia, A.-B.; Zhang, X.-L.; Wang, T.; Du, X.-H.; Xu, D.-Q.; Xu, Z.-Y. New J. Chem. 2015, 39, 5088. (8) (a) Dressel, M.; Bach, T. Org. Lett. 2006, 8, 3145. (b) Harmata, M.; Hong, X. Org. Lett. 2007,9, 2701. (c) Bakowski, A.;Dressel, M.; Bauer,A.; Bach, T. Org. Biomol. Chem. 2011, 9, 3516. (d) Zou, Y.; Zhan, Z.; Li, D.; Tang, M.; Cacho, R. A.; Watanabe, K.; Tang, Y. J. Am. Chem. Soc. 2015, 137, 4980. (9) (a) Szollosi, G.; Bartok, M. ARKIVOC 2012, 16. (b) Lee, A.; Younai, A.; Price, C. K.; Izquierdo, J.; Mishra, R. K.; Scheidt, K. A. J. Am. Chem. Soc. 2014, 136, 10589. (c) He, N.; Huo, Y.; Liu, J.; Huang, Y.; Zhang, S.; Cai, Q. Org. Lett. 2015, 17, 374. (d) Mukhopadhyay, S.; Nath, U.; Pan, S. C. Adv. Synth. Catal. 2017, 359, 3911. (e) Mukhopadhyay, S.; Pan, S. C. Org. Biomol. Chem. 2018, 16, 5407. (f) Kitagawa, O.; Kurihara, D.; Tanabe, H.; Shibuya, T.; Taguchi, T. Tetrahedron Lett. 2008, 49, 471. (g) Takahashi, M.; Tanabe, H.; Nakamura, T.; Kuribara, D.; Yamazaki, T.; Kitagawa, O. Tetrahedron 2010, 66, 288. (10) (a) Mayr, F.; Wiegand, C.; Bach, T. Chem. Commun. 2014, 50, 3353. (b) Beadle, C. D.; Boot, J.; Camp, N. P.; Dezutter, N.; Findlay, J.; Hayhurst, L.; Masters, J. J.; Penariol, R.; Walter, M. W. Bioorg. Med. Chem. Lett. 2005, 15, 4432. (11) (a) Denmark, S. E.; Cottell, J. J. Adv. Synth. Catal. 2006, 348, 2397. (b) Goldberg, A. F. G.; Stoltz, B. M. Org. Lett. 2011, 13, 4474. (c) Hayashi, Y.; Inagaki, F.; Mukai, C. Org. Lett. 2011, 13, 1778. (12) Behenna, D. C.; Liu, Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nat. Chem. 2012, 4, 130. (13) Takahashi, M.; Tanabe, H.; Nakamura, T.; Kuribara, D.; Yamazaki, T.; Kitagawa, O. Tetrahedron 2010, 66, 288.
Scheme 6. Mechanism for Pd-DAAA
was extended to non-benzenoid δ-valerolactams with comparable efficiency. Of particular note is the ability to convert the dihydroquinolinone products into norepinephrine reuptake inhibitors simply and enantioselectively by a straightforward strategy. The reaction presumably proceeds through a palladiumcatalyzed ionization of the racemic allyl esters, leading to the formation of palladium π-allyl complexes and carboxylates. Decarboxylation and recombination of the electrophilic π-allyl complex with the lactam enolate would allow the product formation. This study revealed the enabling effect of anthracenyl ligand L4 for achieving the desired reactivity and enantioselectivity.
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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.9b00358. Experimental details and NMR, HPLC, and ESI-HRMS data (PDF)
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REFERENCES
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Barry M. Trost: 0000-0001-7369-9121 Kami L. Hull: 0000-0003-3102-2686 D
DOI: 10.1021/acs.orglett.9b00358 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters (14) For selected reviews, see: (a) Weaver, J. D.; Recio, A., III; Grenning, A. J.; Tunge, J. A. Chem. Rev. 2011, 111, 1846. (b) Trost, B. M.; Schultz, J. E. Synthesis 2019, 51, 1 and references therein .
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DOI: 10.1021/acs.orglett.9b00358 Org. Lett. XXXX, XXX, XXX−XXX
