Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Complex Hydroindoles by an Intramolecular Nitrile-Intercepted Allylic Alkylation Cascade Reaction Peter Vertesaljai, Ion Ghiviriga, and Alexander J. Grenning* Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, Florida 32611, United States S Supporting Information *
ABSTRACT: Bisnucleophilic reagents derived from malononitrile, ketones, benzaldehydes, and nitromethane can react with bisallylic electrophiles via a nitrile-intercepted allylic alkylation cascade reaction to yield complex hydroindole architectures. Also noteworthy is that the only stoichiometric byproducts from the preparation and reaction of the bisnucleophile and biselectrophile are water, acetic acid, and bicarbonate, making it a potentially “green” platform for multistep complex molecule synthesis. These scaffolds can be converted into hydrooxindoles by a unique olefin isomerization followed by Witkop−Winterfeldt-like oxidation.
C
Scheme 1. Initial Proposal: Cascade Allylic Alkylation To Access Terpenoid Scaffolds
omplex hydroindoles (e.g., perhydroindoles/octahydroindoles, and hexahydroindoles) are common in nature and drug molecules (Figure 1).1 The diversity of structure results in innumerous bioactivities and creative synthetic solutions for many specific targets.2
Figure 1. Representative hydroindole-containing natural and unnatural products.
Our research program aims to discover tunable routes to complex natural product architectures.3 Key requirements for tunable/modular synthesis include abundance of starting materials, efficiency (yield and step count), and simplicity of synthetic operations.4 Strategies that can adhere to these key requirements may streamline natural-product-inspired drug discovery. With this in mind, we were attracted to building blocks 1, molecules prepared by operationally simple and eco-friendly condensation reactions5 and a catalytic asymmetric Michael addition (Scheme 1A).6 At the outset, we envisaged that these substrates could serve as platforms for tunable terpenoid synthesis (Scheme 1B,C). Specifically, cascade bisallylic alkylation of 1 with buten-1,4-diol derivative 2a or related reagents would yield arylated 6,7 ring systems by Pd-catalyzed deconjugative α-alkylation7 to form [I-a] followed by nitronate alkylation8 to afford 3. © XXXX American Chemical Society
To test the proposal, 1a was prepared racemically by aminecatalyzed Michael addition.6,9 Interestingly, the reaction of 1a with 1,4-diol derivative 2a gave hydroindole 4a as a separable mixture of three diastereomers. Under a variety of conditions, this was the exclusive product (Table 1). The optimal protocol discovered for hydroindole synthesis was 1:2.5 1a:2a, 5 mol % Pd(PPh3)4, and Cs2CO3 as a base in dichloromethane at room temperature for 24 h. We also found that many other solvents worked modestly to reasonably well (entries 1−3). The reaction could be accelerated at a higher temperature, though the Received: February 12, 2018
A
DOI: 10.1021/acs.orglett.8b00499 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of the Nitrile-Intercepted Cascade Allylic Alkylation Reaction
entry
Pd(0) (10 mol %)
base (1.1 equiv)
equiv of 2a
solvent
time (h)
temp. (°C)
yield (%)
1 2 3 4 5 6 7 8 9
Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd/BINAP Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4
Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 K2CO3 K3PO4
1.1 1.1 1.1 1.1 1.1 1.1 2.5 2.5 2.5
THF DMF Tol CH2Cl2 THF THF CH2Cl2 CH2Cl2 CH2Cl2
24 24 24 24 12 24 24 24 24
rt rt rt rt 50 rt rt rt rt
31 43 39 48 27 19 67 56 55
yield in this experiment was modest (entry 5). Monodentate ligands on the Pd metal center appear to be more effective than bidentate ligands, as suggested by the result examining racBINAP/Pd2dba3 (entry 6). Also, other mild inorganic bases promoted the hydroindole synthesis as well (entries 8 and 9). Unfortunately, all optimization attempts resulted in diastereomeric mixtures. As a final point, 6/7 bicycloalkanes (the initial targets; Scheme 1) were never observed in our optimization studies. Hydroindole 4a is presumed to be prepared from 1a and 2a by a Pd-catalyzed deconjugative α-allylation to form [I-a′], an intramolecular nitrile−nitronate coupling reaction (“Pinnerlike” transformation) to form [I-b], and then an intramolecular allylic alkylation reaction between the resultant enamine and Pd−π-allyl electrophile (Scheme 2). In one mechanistic
Scheme 3. Scope of Hydroindole Synthesis
Scheme 2. Reaction Sequence Yielding Hydroindole 4a
a
Diastereomeric ratios were determined after purification. bDiastereomers were separable and individually characterized. See the Supporting Information. cIsolated as a mixture of two diastereomers. See the Supporting Information. dA diastereomer was isolated pure. Two diastereomers were inseparable by silica gel chromatography. e Two diastereomers were isolated pure. Two diastereomers were inseparable by silica gel chromatography.
product, the diastereomers could be isolated independently and characterized by detailed NMR analysis.9 The stereochemistry of each diastereomer was unequivocally established by a combination of 1H−1H coupling constants, 1H−13C coupling constants, and quantitative NOEs.9,11 In regard to the scope, the reaction could be performed with substrates derived from cyclohexanones (4a−d) or cycloheptanone (4e). The cyclohexyl series also explored various substitution patterns, including a gem-dimethyl group (4b), a heterocycle (4c), and an additional stereocenter (4d). Scaffolds bearing diverse aryl/alkenyl groups could also be prepared from different benzaldehyde derivatives (4f−h), such as 2-bromophenyl (4f) and 2,5-dimethoxyphenyl (4g). The styrenyl-containing product (4h) can be traced back to cinnamaldehyde.
experiment, we found that 1a undergoes a Pinner-like transformation to afford enamine 5a under mildly basic conditions.6b The facile Pinner-like transformation is initially surprising, but the high nitrile electrophilicity of dialkylmalononitriles has been previously noted in the literature.6b,d,10 With the optimized conditions in hand, we next examined the scalability and scope of the cascade transformation (Scheme 3). Regarding the former, 2.5 g of 4a was prepared without change from the optimal protocol as a mixture of diastereomers. For this B
DOI: 10.1021/acs.orglett.8b00499 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
nature with powerful biological activities (e.g., lysergic acid/ergot natural products).12 The stereochemistry-determining events of this transformation include desymmetrization of the diastereotopic nitriles and the Pd-catalyzed allylic alkylation step, likely by a double inversion mechanism, and can potentially be rationalized by the conformations [I-c] and [I-d] shown in Scheme 4. We next examined acyclic starting materials for nitrileintercepted cascade allylic alkylation reactivity (Scheme 5). Substrate 8a derived from diethyl ketone was a competent reactant, yielding the desired product in 34% yield as a mixture of separable diastereomers. The reactants 8b and 8c underwent only deconjugative alkylation because the olefin geometry from deconjugative alkylation precluded the cascade transformation. However, by reduction first, hydroindole synthesis was reinstated, albeit in modest yield. In this case, the NaBH4 reduction step to prepare 10a was not diastereoselective because of the remoteness of the stereocenter, and the cascade transformation yielded hydroindole 11a in 17% yield as a single diastereomer (34% based on one diastereomer of 10a). An additional 9% of product was isolated as an unassigned mixture of four diastereomers. Although we were pleased that the transformation was successful, it is clear that acyclic starting materials are less efficient than their cyclic counterparts and may benefit from further optimization in the future. Having outlined the scope and limitations of the transformation, we set out to examine the reactivity of these scaffolds (Scheme 6). Under standard hydrogenation conditions, only
Through the course of the studies, several other notable experiments were performed to examine the scope (Schemes 4 and 5). Scheme 4. Reduced Substrates Yield Single Diastereomers of Hydroindoles and Hydroquinolines by Cascade Transformation
Scheme 6. Functional Group Interconversion Reactions
Scheme 5. Examination of Acyclic Substrates
the terminal alkene was reduced, yielding 12. The other alkenes and nitro group survived unscathed. Under basic conditions, we uncovered an unexpected isomerization of the terminal olefin to the enamine 13. We suspect that the isomerization involves double deprotonation; the imine−nitronate [I-e] is generated first, and then the fully conjugated dianion [I-f] is formed. Hydrolysis then yields the isomerized product 13. This is analogous to nitronate dianion chemistry, which also is interesting and underexplored.13 Finally, mCPBA-promoted Witkop− Winterfeldt-like oxidation of enamine 13 yields hydrooxindole 14 with excellent efficiency.14 Thus, hydroindole scaffolds 4 can efficiently be converted into hydrooxindoles over this unique two-step sequence. In conclusion, we serendipitously uncovered a cascade reaction yielding hydroindoles and hydroquinolines. All of the starting materials needed to assemble the heterocycles are abundant: malononitrile, ketones, benzaldehydes, nitromethane, and
First, 6a, prepared by a high-yielding (90%) and diastereoselective (>20:1 dr) NaBH4 reduction of 1a, underwent the cascade reaction diastereoselectively. To reiterate, the cascade reaction with alkylidene-containing substrates 1 is not diastereoselective, whereas the reduced version (6a) yielding 7a is (Table 1 vs Scheme 4). Intrigued by this result, we explored the reaction with bisallylic reagent 2b and found a similar result yielding hydroquinoline 7b as a single diastereomer. Notably, complex hydroquinolines, like hydroindoles, are ubiquitous in C
DOI: 10.1021/acs.orglett.8b00499 Org. Lett. XXXX, XXX, XXX−XXX
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(6) (a) Xue, D.; Chen, Y-Ch.; Wang, Q.-W.; Cun, L. F.; Zhu, J.; Deng, J.-G. Org. Lett. 2005, 7, 5293−5296. (b) Poulsen, T. B.; Bell, M.; Jørgensen, K. A. Org. Biomol. Chem. 2006, 4, 63−70. (c) Jiang, L.; Zheng, H.-T.; Liu, T.-Y.; Yue, L.; Chen, Y.-C. Tetrahedron 2007, 63, 5123. (d) Xue, D.; Li, J.; Zhang, Z.-T.; Deng, J.-G. J. Org. Chem. 2007, 72, 5443. (e) Chen, W.-Y.; Ouyang, L.; Chen, R.-Y.; Li, X.-S. Synth. Commun. 2012, 42, 2585. (7) (a) Nakamura, H.; Iwama, H.; Ito, M.; Yamamoto, Y. J. Am. Chem. Soc. 1999, 121, 10850. (b) Grossman, R. B.; Varner, M. A. J. Org. Chem. 1997, 62, 5235. (c) Vertesaljai, P.; Navaratne, P. V.; Grenning, A. J. Angew. Chem., Int. Ed. 2016, 55, 317. (8) (a) Wade, P. A.; Morrow, S. D.; Hardinger, S. A. J. Org. Chem. 1982, 47, 365. (b) Nemoto, T.; Jin, L.; Nakamura, H.; Hamada, Y. Tetrahedron Lett. 2006, 47, 6577. (c) Gietter-Burch, A. A. S.; Devannah, V.; Watson, D. A. Org. Lett. 2017, 19, 2957. (d) Gildner, P. G.; Gietter, A. A. S.; Cui, D.; Watson, D. A. J. Am. Chem. Soc. 2012, 134, 9942. (9) See the Supporting Information for more specific details. (10) (a) Su, W.; Ding, K.; Chen, Z. Tetrahedron Lett. 2009, 50, 636− 639. (b) Longstreet, A. R.; Campbell, B. S.; Gupton, B. F.; McQuade, D. T. Org. Lett. 2013, 15, 5298. (11) Butts, C. P.; Jones, C. R.; Towers, E. C.; Flynn, J. L.; Appleby, L.; Barron, N. J. Org. Biomol. Chem. 2011, 9, 177. (12) Wallwey, C.; Li, S.-M. Nat. Prod. Rep. 2011, 28, 496. (13) (a) Tanaka, S.; Kohmoto, S.; Yamamoto, M.; Yamada, K. Nippon Kagaku Kaishi 1989, 10, 1742. (b) Yamada, K.; Tanaka, S.; Kohmoto, S.; Yamamoto, M. J. Chem. Soc., Chem. Commun. 1989, 2, 110. (14) (a) Mentel, M.; Breinbauer, R. Curr. Org. Chem. 2007, 11, 159. (b) Yang, Y.; Bai, Y.; Sun, S.; Dai, M. Org. Lett. 2014, 16, 6216. (c) Klare, H. F. T.; Goldberg, A. F. G.; Duquette, D. C.; Stoltz, B. M. Org. Lett. 2017, 19, 988.
buten-1,4-diol derivatives and related bisallylic electrophiles. As such, structural variation can easily be achieved. Though nondiastereoselective in the original protocol (Scheme 3), we uncovered a diastereoselective route when the starting material’s alkylidene is reduced (Scheme 4). Furthermore, the hydroindole scaffolds 4 can be converted into oxindoles by a unique isomerization/oxidation sequence.
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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.8b00499. Experimental procedures, compound characterization data (1H NMR, 13C NMR, and HRMS), and copies of 1H and 13 C NMR spectra (PDF) Stereochemistry elucidation (PDF)
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AUTHOR INFORMATION
Corresponding Author
*grenning@ufl.edu ORCID
Alexander J. Grenning: 0000-0002-8182-9464 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the College of Liberal Arts and Sciences and the Department of Chemistry at the University of Florida for startup funds. We also thank the Mass Spectrometry Research and Education Center and their funding source (NIH S10 OD021758-01A1).
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REFERENCES
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DOI: 10.1021/acs.orglett.8b00499 Org. Lett. XXXX, XXX, XXX−XXX
