Letter pubs.acs.org/OrgLett
Regioselective Functionalization of Enamides at the α‑Carbon via Unsymmetrical 2‑Amidoallyl Cations Mirza A. Saputra, Nitin S. Dange, Alexander H. Cleveland,† Joshua A. Malone,† Frank R. Fronczek, and Rendy Kartika* Department of Chemistry, Louisiana State University, 232 Choppin Hall, Baton Rouge, Louisiana 70803, United States S Supporting Information *
ABSTRACT: A new method to functionalize enamides via an intermediacy of unsymmetrical 2-amidoallyl cations is reported. Generated under mild Brønsted acid catalysis, these reactive species were found to undergo addition with various nucleophiles at the less substituted α-carbon to produce highly substituted enamides in high yields with complete control of regioselectivity.
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Scheme 1. Chemistries with 2-Aminoallyl Cations
namines are highly valuable building blocks in organic synthesis. Facilitated by the enhanced reactivity of the αcarbon as a result of π-conjugation from the nitrogen center, enamines are widely known to participate in a variety of C−C bond-forming reactions as a source of carbon nucleophiles.1 Interestingly, enamines could be strategically activated to yield structurally unusual electrophilic species, known as 2-aminoallyl cations.2 This reversal of reactivity, underscored by the distribution of the cationic character over three carbon atoms, has consequently propelled a series of investigations on reactions that largely exploit the predisposition of these intermediates toward cycloaddition processes.3 Inspired by these pioneering works, we became interested in exploring the new reactivity of 2-aminoallyl cations and developing useful synthetic transformations beyond the present technology. Unlike structurally related oxyallyl cations that have been explored extensively as powerful reactive intermediates for the construction of various complex molecular architectures,4 chemistries involving 2-aminoallyl cations have so far received minimal attention. The lack of advancement in this area is perpetuated by various challenges, ranging from arduous synthetic efforts to prepare the requisite substrates and instability of the 2-aminoallyl cations species themselves, which often caused poor reaction efficiencies.3f This manuscript describes our viable contribution to this problem, and herein we report novel examples on the robust generation of 2-aminoallyl cations under mild Brønsted acid catalysis from highly accessible starting materials. Recognizing their presumed electrophilic nature, these 2-aminoallyl cations were successfully implemented as umpoled enamines that could be subjected to functionalization at the α-carbon via intermolecular nucleophilic addition.5 More specifically, we focused our investigations on developing strategies to control regioselectivity in unsymmetrical intermediates and examined their synthetic utility toward complex structural motifs in α,α′-disubstituted enamines that are undoubtedly nontrivial to construct.6 Scheme 1 depicts our hypothesis, in which substituted αhydroxy enamines 3 would be employed as precursors to 2© XXXX American Chemical Society
aminoallyl cations 4. Based on the work of Hsung,3c the design of these substrates would include a deliberate incorporation of an electron-withdrawing group at the nitrogen atom to impede the potentially competitive imino-Nazarov ring fragmentation to the corresponding 3-aminopentadienyl cations (1 → 2). Ionization of compounds 3 will be performed under catalytic Brønsted acid. Despite the general instability of enamines under acidic media, Received: March 30, 2017
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DOI: 10.1021/acs.orglett.7b00962 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters selective protonation of the α-hydroxyl group would be controlled under kinetically biased conditions, such as through solvent effects. In the presence of external nucleophiles, the emerging unsymmetrical 2-aminoallyl cations 4 would then be captured at the less substituted electrophilic carbon, i.e. the α′position,7 to produce fully substituted enamines 5 that, in principle, should be thermodynamically more favorable than quaternary adduct 6. To demonstrate proof of concept, we initially employed fivemembered α-hydroxy enamide 9, which was decorated with Nmethyl-N-tosyl groups along with a phenyl substituent at the αcarbon.8 As indicated in Scheme 2, synthesis of this model
Our studies then continued with the optimization on the molar equivalents of pyridinium triflate. While we employed 1.0 equiv in the initial screening, the amount of the Brønsted acid was systematically reduced to 0.1 equiv (entries 8−11). As expected, the rate of reaction plummeted with the decreasing loading of the catalyst; however, these modulations did not affect the product yield. In contrast, lowering the molar equivalent of indole reduced the yield to 51%. We ultimately established the optimized conditions to involve the use of 0.3 equiv of pyridinium triflate and 2 equiv of indole (entry 9). The reaction was performed in dichloromethane at room temperature, in which product 11 was isolated in 76% yield as a single regioisomer. We believed that the observed regioselectivity in this methodology was not induced by the conjugate base, i.e. pyridine. As shown in entry 13, activation of 9 with catalytic triflic acid also generated the same product. The structural assignment of enamide adduct 11 and its depicted solid state conformation was unambiguously deduced by X-ray crystallography.10 As hypothesized, indole addition to putative unsymmetrical 2amidoallyl cation 10 had occurred at the less substituted electrophilic α′-carbon in a highly regioselective manner. With the optimized conditions in hand, we then examined the scope of nucleophiles, starting with substituted indoles (Scheme 3). Applications of electron-rich 5-methoxyindole and halogenated 5-bromoindole afforded products 12a and 12b in 74% and 81% yields, respectively. An attempt to perform a gram scale reaction with 5-bromoindole cleanly produced α′-indolyl enamide 12b in 84% yield. We also screened electron-deficient
Scheme 2. Synthesis of Starting Material 9
substrate was readily achieved in just three simple steps from cyclopentane-1,2-dione 7 via a sequence of acid-catalyzed condensation with tosylamide, N-methylation with methyl iodide and potassium carbonate, and an addition of phenylmagnesium bromide to the resulting ketone 8.9 Table 1 describes our reaction optimization, in which we subjected α-hydroxy enamide 9 to a series of ionization Table 1. Reaction Optimization Studies
Scheme 3. Scope of Nucleophilesa
Isolated yield after flash column chromatography. bThe product was contaminated with inseparable byproducts. c1.0 equiv of indole was employed. a
conditions, starting with the screening of various Brønsted acids in the presence of indole (entries 1−4). While strong acids, such as trifluoroacetic acid, rapidly consumed the starting material, these conditions produced the corresponding α′-indolyl enamide 11 that was contaminated with inseparable byproducts. Interestingly, the use of tosic acid or milder Brønsted acids, including pyridinium tosylate and pyridinium triflate, led to much cleaner reactions. In fact, activation of 9 with a stoichiometric amount of pyridinium triflate afforded the intended product 11 in 79% yield. Unsurprisingly, the efficacy of this reaction was found to be sensitive to solvent effects. As indicated in entries 5−7, attempts to execute this pilot reaction in toluene, THF, or acetonitrile led to a significant erosion in product yields.
Isolated yield after flash column chromatography. bThe reaction was performed in 1 g scale. cEnamide 12d was isolated in 25% yield but significantly contaminated with inseparable byproducts. dStarting material 9 was never fully consumed. a
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DOI: 10.1021/acs.orglett.7b00962 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 2. Scope of α-Substituent
indoles. For example, methylindole 5-carboxylate produced coupling adduct 12c in 74% yield. Interestingly, the use of 4cyanoindole led to a complex mixture. Other substitution patterns, such as N-methylindole, 5-methoxy-1H-benzo[g]indole, and 2-phenylindole were found to generate adducts 12e−12g in good yields. The scope of our chemistry also covered pyrrole and acetophenone-derived TMS silylenolate, which furnished 12h and 12i in respectable yields. We similarly investigated the suitability of thiophenol, 3-phenyl-1-propanol, and cyclohexanol. These heteroatom-centered nucleophiles readily produced the corresponding enamides 12j−12l in excellent yields. To examine the substituent effects of the α-position on the formation of 2-amidoallyl cations, we prepared a series of αhydroxy enamides 13 (Table 2). These compounds were readily synthesized by subjecting N-methyl-N-tosyl ketone 8 to various commercially available Grignard reagents.9 As shown in entries 1−4, we initially surveyed other arene groups. Addition of indole to substrates bearing a weakly activating 4-tolyl substituent 13a and deactivating 4-chlorophenyl 13b furnished 14a in 79% and 14b in 83% yields, respectively. Interestingly, incorporation of the 3,5-bis(trifluoromethyl)phenyl group in substrate 13c rendered this compound unionizable under the optimized reaction conditions or even at reflux. This result indirectly supported our hypothesis on the involvement of 2-amidoallyl cations, as formation of such intermediates would be naturally disfavored by strongly deactivated aryl substituents. We also found that aromatic heterocycles at the α-position, such as in 13d, were tolerated, and it readily produced α-thiophene-α′-indole enamide 14d in 58% yield. As exemplified in entries 5−8, aliphatic α-substituents were also found to be compatible in this methodology. For instance, exposure of starting materials that are elaborated with methyl, allyl, n-octyl, and isobutyl groups 13e−13h to catalytic pyridinium triflate and indole furnished the corresponding functionalized enamides 14e−14h in good yields. Interestingly, unsubstituted starting material 13i failed to react, therefore suggesting that functionalities at the α-position played a vital role toward the generation of the putative 2-amidoallyl cations that must be stabilized via either resonance effect by aryl subsitutents, or hyperconjugation and the inductive effect by alkyl subsitutents. Moreover, the lack of reactivity involving substrate 14i also clearly indicated that an SN2′ mechanism was most likely not responsible in this chemistry. As shown in Scheme 4, the suitability of a N-benzyl substituent in this methodology was also examined through the use of αphenyl and α-methyl enamides 15a and 15b. Similarly, we found that the reaction between these substrates with indole under the optimized conditions furnished products 16a and 16b as a single regioisomer in good yields.10,12 In all cases, our reactions successfully produced α′-functionalized enamides 12a−12l and 14a−14i as a single regioisomer.11 Fortuitously, many of these compounds existed as crystalline materials, thus enabling us to unequivocally confirm their chemical structures using X-ray crystallography.10 We observed that these α,α′-disubstituted enamides interestingly exhibit a specific axial conformation in the solid state, in which the newly incorporated nucleophiles at the α′-carbon and the N-methyl group were oriented in the same direction. Nonetheless, the generality of this apparent atropisomerism in solution is unclear.12 In summary, this letter described the development of a convenient and practical strategy toward the generation of novel unsymmetrical 2-amidoallyl cations under mild Brønsted acid
a
Presumed solid-state conformation based on X-ray crystallography data from α-hydroxy enamides 9 and 13c. bIsolated yield after flash column chromatography.
Scheme 4. α-Indolylation of N-Benzyl Substrate 15
catalysis. We have demonstrated for the first time that these intermediates could be captured intermolecularly by nucleophiles to give α,α′-disubstituted enamides in high yields with complete regiocontrol. Detailed mechanistic and conformational studies, as well as applications toward complex molecule synthesis, are C
DOI: 10.1021/acs.orglett.7b00962 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
Amination of allenes: (e) Feast, G. C.; Page, L. W.; Robertson, J. Chem. Commun. 2010, 46, 2835. (f) Stoll, A. H.; Blakey, S. B. J. Am. Chem. Soc. 2010, 132, 2108. (g) Stoll, A. H.; Blakey, S. B. Chem. Sci. 2011, 2, 112. (h) Gerstner, N. C.; Adams, C. S.; Tretbar, M.; Schomaker, J. M. Angew. Chem., Int. Ed. 2016, 55, 13240. Fragmentation of vinylaziridine: (i) Prie, G.; Prevost, N.; Twin, H.; Fernandes, S. A.; Hayes, J. F.; Shipman, M. Angew. Chem., Int. Ed. 2004, 43, 6517. (j) Griffin, K.; Montagne, C.; Hoang, C. T.; Clarkson, G. J.; Shipman, M. Org. Biomol. Chem. 2012, 10, 1032. (k) Takahashi, H.; Yasui, S.; Tsunoi, S.; Shibata, I. Org. Lett. 2014, 16, 1192. (4) Review articles on oxayallyl cations: (a) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577. (b) Nakanishi, W.; West, F. G. Curr. Opin. Drug Discovery Dev. 2009, 12, 732. (c) Shimada, N.; Stewart, C.; Tius, M. A. Tetrahedron 2011, 67, 5851. (d) Vaidya, T.; Eisenberg, R.; Frontier, A. J. ChemCatChem 2011, 3, 1531. (e) Lohse, A. G.; Hsung, R. P. Chem. Eur. J. 2011, 17, 3812. (f) Harmata, M. Acc. Chem. Res. 2001, 34, 595. (g) Li, H.; Wu, J. Synthesis 2014, 47, 22. (5) Blakey and Robertson independently reported that 2-amidoallyl cations generated via Rh-catalyzed amination of allenes could be captured by nucleophiles at the central carbon; see ref 3e and 3f. (6) Examples of direct nucleophilic addition to oxyallyl cations: (a) Tang, Q.; Chen, X.; Tiwari, B.; Chi, Y. R. Org. Lett. 2012, 14, 1922. (b) Vander Wal, M. N.; Dilger, A. K.; MacMillan, D. W. C. Chem. Sci. 2013, 4, 3075. (c) Luo, J.; Zhou, H.; Hu, J. W.; Wang, R.; Tang, Q. RSC Adv. 2014, 4, 17370. (d) Luo, J.; Jiang, Q.; Chen, H.; Tang, Q. RSC Adv. 2015, 5, 67901. (e) Liu, C.; Oblak, E. Z.; Vander Wal, M. N.; Dilger, A. K.; Almstead, D. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2016, 138, 2134. (7) Strategies towards controlling regioselectivity in the addition of nucleophiles to unsymmetrical oxyallyl cations: (a) Stepherson, J. R.; Fronczek, F. R.; Kartika, R. Chem. Commun. 2016, 52, 2300. (b) Stepherson, J. R.; Ayala, C. E.; Dange, N. S.; Kartika, R. Synlett 2016, 27, 320. (c) Malone, J. A.; Cleveland, A. H.; Fronczek, F. R.; Kartika, R. Org. Lett. 2016, 18, 4408. (d) Ayala, C. E.; Dange, N. S.; Stepherson, J. R.; Henry, J. L.; Fronczek, F. R.; Kartika, R. Org. Lett. 2016, 18, 1084. (e) Dange, N. S.; Stepherson, J. R.; Ayala, C. E.; Fronczek, F. R.; Kartika, R. Chem. Sci. 2015, 6, 6312. (f) Ayala, C. E.; Dange, N. S.; Fronczek, F. R.; Kartika, R. Angew. Chem., Int. Ed. 2015, 54, 4641. (8) Through screening of various subsitutents at the nitrogen center, we identified the suitability of the N-tosyl group in this methodology. See the Supporting Information (SI). (9) The solid state conformation of 9 and 13c was unambigiously confirmed by X-ray crystallography. From these results, we assumed that 13a−13i and 15a−15b would adopt a similar conformation. See the SI. (10) CCDC 1483737−1483749 and 1507423 contain the supplementary crystallographic data for 9, 11, 12a, 12g, 12i, 12j, 12l, 13c, 14a, 14b, 14d, 14e, 14g, and 16a in sequential order. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre. (11) Six-membered substrates were not ionizable under our conditions, and further studies are currently ongoing. MacMillan et al. also reported similar reactivity involving six-membered oxyallyl cations in their organocatalytic methodology. See ref 6e. (12) We attempted to deduce the conformation of our α,α′disubstituted enamide products in solution using NMR techniques. While results from NOE experiments using representative compounds 11, 12g, 14a, and 14d were ambiguous due to overlapping signals, similar NOE analyses of 12b, 14e, 14f, 14g, 14h, and 16a potentially indicated a population of the two possible conformations as a result of bond rotation along the enamides’ C−N axis. Nonetheless, determination of atropisomerism in 11, 14e, and 16a using variable temperature NMR experiments proved to be inconclusive. While the coalescence temperature for 11 and 14e was not detected between −60 to 90 °C, the bond rotation that led to the coalesced NMR signals in 16a was unclear. Further studies on these interesting conformational behaviors are currently ongoing in our laboratory. See the SI.
currently ongoing in our laboratory. The results will be reported in due course.
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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.7b00962. Crystallographic data for 9 (CIF) Crystallographic data for 11 (CIF) Crystallographic data for 12a (CIF) Crystallographic data for 12g (CIF) Crystallographic data for 12i (CIF) Crystallographic data for 12j (CIF) Crystallographic data for 12l (CIF) Crystallographic data for 13c (CIF) Crystallographic data for 14a (CIF) Crystallographic data for 14b (CIF) Crystallographic data for 14d (CIF) Crystallographic data for 14e (CIF) Crystallographic data for 14g (CIF) Crystallographic data for 16a (CIF) Experimental procedures and spectral data (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Rendy Kartika: 0000-0002-2042-2812 Author Contributions †
A.H.C. and J.A.M. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This material is based upon work supported by the NSF under CHE-1464788. Generous financial support from Louisiana State University is gratefully acknowledged. A.H.C. thanks the Louisiana Board of Regents for the Graduate Fellowship (LEQSF(2015-20)-GF-02). This manuscript is dedicated to Prof. Douglas A. Klumpp at Northern Illinois University on the occasion of his 20th anniversary of professorship.
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REFERENCES
(1) (a) Whitesell, J. K. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991. (b) Enamines: Synthesis, Structure and Reactions, 2nd ed.; Cook, A. G., Ed.; Dekker: New York, 1988. (c) The Chemistry of Enamines, Part I; Rappoport, Z., Ed.; Wiley: New York, 1994; p 523. (2) Formation of 2-aminoallyl cations via ionization of α-haloimines and enamines: (a) Schmid, R.; Schmid, H. Helv. Chim. Acta 1974, 57, 1883. (b) Kim, H.; Zianicherif, C.; Oh, J.; Cha, J. K. J. Org. Chem. 1995, 60, 792. (c) Kende, A. S.; Huang, H. Tetrahedron Lett. 1997, 38, 3353. (d) Dekimpe, N.; Palamareva, M.; Verhe, R.; Debuyck, L.; Schamp, N. J. Chem. Res. 1986, 190. (e) Dekimpe, N.; Stevens, C. Tetrahedron 1990, 46, 6753. (3) Other methods to generate 2-azaallyl cations: imino-Nazarov electrocyclication: (a) Tius, M. A.; Chu, C. C.; Nieves-Colberg, R. Tetrahedron Lett. 2001, 42, 2419. (b) Bow, W. F.; Basak, A. K.; Jolit, A.; Vicic, D. A.; Tius, M. A. Org. Lett. 2010, 12, 440. (c) Ma, Z. X.; He, S. Z.; Song, W. Z.; Hsung, R. P. Org. Lett. 2012, 14, 5736. (d) Bonderoff, S. A.; Grant, T. N.; West, F. G.; Tremblay, M. Org. Lett. 2013, 15, 2888. D
DOI: 10.1021/acs.orglett.7b00962 Org. Lett. XXXX, XXX, XXX−XXX
