Letter pubs.acs.org/OrgLett
Catalytic Conjugate Addition of Electron-Rich Heteroarenes to β,βDisubstituted Enones Tanner L. Metz, Joshua Evans, and Levi M. Stanley* Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States S Supporting Information *
ABSTRACT: Catalytic conjugate additions of heteroarenes to β,βdisubstituted enones are reported. Additions of a range of heteroarene nucleophiles, including furans, indoles, a pyrrole, and a thiophene, to a variety of β,β-disubstituted enones occur to form the corresponding ketone products containing heteroarylated, all-carbon quaternary centers in up to 90% yield. These reactions occur under mild reaction conditions in the presence of low loadings of bismuth triflate.
C
Scheme 1. Current Challenges in Conjugate Additions of Heteroarenes to β,β-Disubstituted, Cyclic Enones
onjugate additions of aryl and heteroaryl nucleophiles to β,β-disubstituted enones enable rapid generation of arylated and heteroarylated quanternary carbon centers. Transition-metal-catalyzed conjugate additions of aryl nucleophiles to β,β-disubstituted enones are established methods to generate benzylic and bis-benzylic all-carbon quaternary centers.1 However, transition-metal-catalyzed conjugate additions of heteroaryl nucleophiles to β,β-disubstituted enones to construct related heteroarylated all-carbon quaternary centers remain challenging. For example, the conjugate addition of 2furylboronic acid to 3-methyl-2-cyclohexenone in the presence of a previously reported palladium(II) catalyst does not occur,2 likely due to protodeboronation of the heteroarylboronic acid.3 The use of Lewis or Bronsted acid catalysts to promote the direct attack of heteroarenes provides an alternative method to construct heteroarylated quaternary centers that circumvents this pathway for deactivation of the heteroaryl nucleophile. Catalytic additions of indoles and furans to β,β-disubstituted enones form heteroarylated quaternary carbon centers; however, these transformations are currently limited in terms of scope and reaction efficiency. The majority of these reactions involve additions of indole or 2-methylfuran to 4-methyl-3penten-2-one,4 and additions to cyclic β,β-disubstituted enones remain challenging (Scheme 1). Lewis acid catalyzed conjugate additions of difuranyl cyanocuprate and 2-methylfuran to 3methyl-2-cyclohexenone occur to form the corresponding cyclic ketone products in modest yields in the presence of a high loading of catalyst (Scheme 1a).5 Conjugate additions of indole to β,β-disubstituted cyclic enones occur in low-to-modest yields when the reactions are conducted at high pressures in the presence of a Lewis acid catalyst or an organocatalyst (Scheme 1b).4e,6 Catalytic conjugate additions of thiophenes to β,β-disubstituted enones have not been reported. The most efficient approach to direct conjugate addition of heteroaryl nucleophiles to β,β-disubstituted enones involves diastereoselective addition of indoles and a pyrrole to progesterone in the presence of a Ru(III) catalyst.7 Despite these advances, current catalysts of these © 2017 American Chemical Society
transformations require high reaction pressures and high catalyst loadings, do not encompass a range of heteroaryl nucleophiles, or are limited to acyclic β,β-disubstituted enones. Herein, we report studies to identify a catalyst system that operates at ambient pressure with low catalyst loadings and encompasses a range of heteroaryl nucleophiles and β,βdisubstituted enones to enable the formation of ketone products containing heteroarylated quaternary centers. We began our studies by evaluating the model conjugate addition of 3-methyl-2-cylohexenone 1a and 2,3-dimethylfuran 2a to generate 3-(4,5-dimethylfuran)-3-methylcyclohexan-1one 3a (Table 1). We initially evaluated RuCl3·xH2O as a catalyst based on the high activity of this catalyst in conjugate Received: May 9, 2017 Published: June 26, 2017 3442
DOI: 10.1021/acs.orglett.7b01402 Org. Lett. 2017, 19, 3442−3445
Letter
Organic Letters Table 1. Identification of Reaction Conditionsa
Scheme 2. Catalytic Conjugate Addition of Heteroarenes to 1aa
entry
catalyst
ratio 1a:2a
yield (%)b
1 2 3 4 5c 6d 7e 8 9 10f 11e,g
RuCl3·xH2O Sc(OTf)3 Bi(OTf)3 TfOH Bi(OTf)3 Bi(OTf)3 Bi(OTf)3 Bi(OTf)3 Bi(OTf)3 Bi(OTf)3 Bi(OTf)3
1:2 1:2 1:2 1:2 1:2 1:2 1:2 2:1 3:1 3:1 3:1
60 74 76 67 0 22 76 89 98 98 98
a
Conditions: 1a (0.25 mmol), 2a (0.50 mmol), catalyst (0.013 mmol), MeCN/MeOH (10:1, 0.5 mL), 1 h. bDetermined by 1H NMR spectroscopy using dibromomethane as an internal standard. cReaction run in the presence of 15 mol % 2,6-di-tert-butylpyridine. dReaction run with MeCN (0.5 mL) as solvent. eReaction run for 2 h. fReaction run in the presence of 2.5 mol % Bi(OTf)3. gReaction run in the presence of 1 mol % Bi(OTf)3.
a
Conditions: 1a (0.75 mmol), 2 (0.25 mmol), Bi(OTf)3 (0.0063 mmol), MeCN/MeOH (10:1, 0.5 mL), 1 h. bReaction run with 1a (1.25 mmol) for 3 h.
methylfuran to 1a occurs to form product 3b in 90% yield. Additions were not limited to furan derivatives, and the reactions of 2-methoxythiophene 2c and 2-methylpyrrole 2d to 1a formed ketone products 3c and 3d in 70% yield. The conjugate addition of indole 2e to 3-methyl-2-cyclohexenone 1a generated the corresponding ketone product 3e in 63% yield. The modest yield of 3e led us to further investigate reaction conditions, and we found that the reaction of 2e with 5 equiv of 1a formed 3e in 84% yield when the reaction was run for 3 h. Additions of benzofuran and benzothiophene to 1a did not occur, while additions of unsubstituted pyrrole and furan formed the products of double addition exclusively. The lower yields observed for conjugate additions of more nucleophilic 2-methylpyrrole 2d and indole 2e compared to additions of less nucleophilic 2,3-dimethylfuran 2a and 2methylfuran 2b were unexpected.9 We conducted a series of competition experiments between 2-methylfuran, indole, and 2methylpyrrole to gain insight into these results (Scheme 3). The competition between 2-methylfuran and indole formed ketone 3e, the product of indole addition, exclusively. The observed relative rates of addition of 2-methylfuran and indole are consistent with nucleophilicity parameters determined for these heterocycles.9 In addition, the competition between 2methylfuran and 2-methylpyrrole formed ketone 3d, the product of 2-methylpyrrole addition, exclusively. Competition reactions between indole (3.0 equiv) and 2-methylpyrrole (3.0 equiv) did not occur to form products of conjugate addition. This result suggests that pyrrole and/or indole nucleophiles can inhibit the acid catalyst (see Supporting Information for additional information) and offers a plausible explanation for the lower reaction efficiency observed for the conjugate addition reactions of pyrrole and indole nucleophiles. However, a competition between indole (1.5 equiv) and 2-methylpyrrole (1.5 equiv) formed ketone 3d exclusively, again consistent with nucleophilicity parameters for these heterocycles. With practical reaction conditions identified for addition of indole to 1a, we next evaluated conjugate additions of a variety of substituted indoles. These results are summarized in Table 2.
additions of indoles to progesterone. However, the model reaction catalyzed by RuCl3·xH2O formed 3a in modest yield (60%, entry 1). Increased yields of 3a (74−76%) were observed when the model reaction was run in the presence of Sc(OTf)3 and Bi(OTf)3 (entries 2−3). Based on a previously reported work, we hypothesized that Bi(OTf)3 could be a source of triflic acid, and ketone 3a is formed in 67% yield when the reaction is conducted in the presence of triflic acid (entry 4).8 Next, we sought to determine whether this transformation is catalyzed by the Lewis acidic Bi(OTf)3or triflic acid generated in situ. When the model reaction was run in the presence of catalytic amounts of Bi(OTf)3 and 2,6-di-tert-butylpyridine, ketone 3a was not formed (entry 5). These results suggest that triflic acid catalyzes the model reaction, but we chose to proceed with further studies using Bi(OTf)3 as a convenient source of triflic acid. When the model reaction was run in the absence of methanol, a decrease in reaction efficiency was observed (entries 6). We hypothesize methanol serves as a proton shuttle that enhances the efficiency of the model conjugate addition reaction. Longer reaction times did not lead to an increase in the yield of 3a (entry 7), likely to due to product inhibition of the acid catalyst when higher concentrations of 3a relative to 1a are present in solution. When the model reaction is run in the presence of excess enone 1a, increased yields of 3a (89−98%) were observed (entries 8−9). The loading of the Bi(OTf)3 can be lowered to 2.5 mol % without impacting the yield of 3a when the model reaction is conducted with a 3:1 ratio of 1a:2a, but a decrease in reaction efficiency is observed at a 1 mol % catalyst loading (entries 10−11). We chose to proceed with studies to evaluate the conjugate additions of various heteroarenes nucleophiles to 3-methyl-2cyclohexenone 1a under the reaction conditions shown in entry 10 of Table 1. These results are summarized in Scheme 2. As noted above, the addition of 2,3-dimethylfuran 2a to 1a generated 3a in high yield (88%). The addition of 23443
DOI: 10.1021/acs.orglett.7b01402 Org. Lett. 2017, 19, 3442−3445
Letter
Organic Letters
phene 2c, and indole 2e to a variety of 3-substituted enones (Scheme 4). The reactions of 3-ethyl-2-cyclohexenone 1b, 3-
Scheme 3. Competition Experiments between 2Methylfuran, Indole, and 2-Methylpyrrolea
Scheme 4. Scope of β,β-Disubstituted Enonesa
a Yields determined by 1H NMR spectroscopy using dibromomethane as an internal standard.
Table 2. Scope of Indole Nucleophilesa
a
Conditions: 1a (0.75 mmol), 2 (0.25 mmol), Bi(OTf)3 (0.0063 mmol), MeCN/MeOH (0.5 mL), 1 h. bReaction run at 1.0 mmol (2a) scale. cReaction run with 1a, 1e, or 1f (1.25 mmol) for 3 h. entry
2
R1
R2
3
yield (%)b
1 2 3 4 5 6 7 8 9 10
2e 2f 2g 2h 2i 2j 2k 2l 2m 2n
H H H H Me H H H H H
H 5-MeO 5-Br 5-CN H 2-Me 4-Me 5-Me 6-Me 7-Me
3e 3f 3g 3h 3i 3j 3k 3l 3m 3n
84 58 54 46 70 0 0 58 76 76
benzyl-2-cyclohexenone 1c, and 3,5,5-trimethyl-2-cyclohexenone 1d with 2,3-dimethylfuran 2a occurred to form the ketone products 3o−3q in 53−69% yield. Additions of 2a to 3substituted cyclo-2-hexenones with larger substituents at the 3position did not occur. Additions of 2,3-dimethylfuran 2a, 2-methoxythiophene 2c, and indole 2e to 3-methyl-2-cyclopentenone 1e and 3-methyl2-cycloheptenone 1f occurred to form ketone products 3r−3w in 37−79% yield. Additions of heteroarenes 2a, 2c, and 2e are not limited to β,β-disubstituted cyclic enones, and reactions of these heteroarenes with 4-methyl3−3penten-2-one 1g occurred to form the conjugate addition products 3x−3z in 66−79% yield. In conclusion, we have developed a series of conjugate additions of heteroarenes to β,β-disubstituted enones that form ketones containing heteroarylated, all-carbon quaternary centers. These addition reactions occur in the presence of catalytic Bi(OTf)3 and improve the efficiency and expand the scope of heteroarene additions to β,β-disubstituted enones. Additions of furan, thiophene, pyrrole, and indole nucleophiles to a variety of cyclic and acyclic β,β-disubstituted enones occur to form the ketone products bearing the heteroarylated, allcarbon quaternary centers in up to 90% yield. Studies are ongoing in our laboratory to develop an enantioselective variant of this method and to expand these conjugate addition reactions to encompass additional classes of heteroarene nucleophiles.
a
Conditions: 1a (1.25 mmol), 2a (0.25 mmol), Bi(OTf)3 (0.0063 mmol), MeCN/MeOH (10:1, 0.5 mL), 3 h. bIsolated yields after purification by flash column chromatography.
As noted above, the addition of indole 2e to 3-methyl-2cyclohexenone 1a occurred to form 3e in 84% yield (entry 1). Reactions of indoles containing electron-donating and -withdrawing substituents at the 5-position with 1a occurred to form ketone products 3f−3h,l in moderate yields (46−58%). The addition of N-methylindole 2i to enone 1a formed product 3i in 67% yield (entry 5). Reactions of 2-methyl and 4methylindole did not occur likely due to the increased steric bulk adjacent to the C3 position of indole (entries 6−7). However, additions of 5-methyl-, 6-methyl-, and 7-methylindole to 1a formed 3l−n in 58−77% yield (entries 8−10). To further expand the scope of these reactions, we evaluated conjugate additions of 2,3-dimethylfuran 2a, 2-methoxythio3444
DOI: 10.1021/acs.orglett.7b01402 Org. Lett. 2017, 19, 3442−3445
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Organic Letters
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(8) (a) Kwie, F. H. A.; Baudoin-Dehoux, C.; Blonski, C.; Lherbet, C. Synth. Commun. 2010, 40, 1082. (b) Ollevier, T.; Nadeau, E. Org. Biomol. Chem. 2007, 5, 3126. (c) Dumeunier, D.; Markò, I. E. Tetrahedron Lett. 2004, 45, 825. (9) (a) Nigst, A. T.; Westermaier, M.; Ofial, A. R.; Mayr, H. Eur. J. Org. Chem. 2008, 2008, 2369. (b) Lakhdar, S.; Westermaier, M.; Terrier, F.; Goumont, R.; Boubaker, T.; Ofial, A. R.; Mayr, H. J. Org. Chem. 2006, 71, 9088. (c) Herrlich, M.; Mayr, H. Org. Lett. 2001, 3, 1633.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01402. Experimental procedures, characterization data, and copies of NMR spectra for new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Levi M. Stanley: 0000-0001-8804-1146 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Research Corporation for Science Advancement, Iowa State University, and the Iowa State University Center for Catalysis for supporting this work.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b01402 Org. Lett. 2017, 19, 3442−3445
