Letter Cite This: Org. Lett. 2018, 20, 7034−7038
pubs.acs.org/OrgLett
An Amine Group Transfer Reaction Driven by Aromaticity Sebastian Ahles,† Silas Götz,‡ Luca Schweighauser,† Mirko Brodsky,† Simon N. Kessler,‡ Andreas H. Heindl,† and Hermann A. Wegner*,† †
Institute of Organic Chemistry, Justus Liebig University Giessen, Heinrich-Buff-Ring 17, 35392 Giessen, Germany Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
‡
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S Supporting Information *
ABSTRACT: A stereoselective domino inverse electrondemand Diels−Alder/amine group transfer reaction catalyzed by a bidentate Lewis acid provides 1-amino-1,2-dihydronaphthalenes, a core structure in many bioactive compounds. A concerted mechanism is proposed based on experimental studies as well as DFT computations demonstrating a new general reactivity scheme. The broad scope of the reaction was evaluated by variation of all three starting compounds, phthalazines, aldehydes, and amines. Scalability was demonstrated by a gram scale reaction without diminished yield.
S
Scheme 1. IEDDA-Domino Reactions of Phthalazines 1 Catalyzed by a Bidentate Lewis Acid
electivity control in chemical transformations demands detailed knowledge of reaction pathways. The smart utilization of concerted mechanisms allows the buildup of chemical bonds in a highly predictive way, controlling constitution and stereochemistry.1,2 Pericyclic reactions are the prime example in this context. While cycloadditions, sigmatropic rearrangements, and electrocyclizations are content of the standard chemical curriculum, concerted group transfer reactions represent a unique feature in reactivity.3,4 Recently, transition metal catalyzed group transfer reactions have gained increased attention.5−7 The incorporation of such transformations within domino processes allows chemists to dramatically increase molecular complexity in one operational step.8−11 In particular, the generation of highly reactive intermediates can enable unusual domino transformations. As an example of the latter we reported an example of a higher order Claisen rearrangement, the first [3,9] sigmatropic rearrangement (Scheme 1).12 Key for the realization of such a transformation was accessing an o-quinodimethane intermediate 3 via an inverse electron demand Diels−Alder reaction (IEDDA reaction) of phthalazine derivatives 1 catalyzed by a bidentate Lewis acid (BDLA) 2.13 Compared to IEDDA reactions with aromatics containing a higher number of nitrogen atoms (e.g., 1,2,4-triazines or 1,2,4,5-tetrazines),14−20 this kind of reaction with phthalazines 1 has only been scarcely exploited, probably due to the harsh conditions normally required.21−24 Besides the [3,9] sigmatropic rearrangement, the intermediary o-quinodimethane 3 not only was involved in the synthesis of substituted naphthalenes by elimination25,26 but also took part in a second Diels−Alder (DA) reaction leading to highly complex alkaloid-type structures (Scheme 1).27 © 2018 American Chemical Society
The high reactivity of o-quinodimethane 328 generated by this reaction also proved to be a disadvantage in some cases. For example, only moderate yields were achieved for a protocol to synthesize substituted naphthalenes from enamines generated in situ from aldehydes and amines.29 During our analysis of various minor side products, we identified the formation of 1-amino-1,2-dihydronaphthalenes 4, a suitable precursor for the synthesis of 1-aminotetralins. Such structures represent a core motif used in various bioactive compounds, especially in antidepressants.30,31 The most utilized strategy to Received: September 17, 2018 Published: October 26, 2018 7034
DOI: 10.1021/acs.orglett.8b02967 Org. Lett. 2018, 20, 7034−7038
Letter
Organic Letters
incomplete conversion (Scheme 2, 4f). We reasoned that the in situ generated conjugated enamine is much less reactive in the initial IEDDA reaction compared to nonconjugated ones. In addition, the elevated temperature led to the formation of the elimination product, the naphthalene. To demonstrate the scalability of this transformation, the reaction of phthalazine (1a) with 3-phenylpropionaldehyde (6c) and pyrrolidine (7a) (Scheme 2, 4c) was carried out on gram scale without diminished yield (2.21 g, 95%). Variation of the amine 7 showed that cyclic ones 7a−c gave the highest yields (Scheme 3). This observation can be
access substituted analogues includes different variations of selective metal catalyzed ring opening of either oxabenzonorbornadiene or azabenzonorbornadienes.32−36 Alternatively, amino-1,2-dihydronaphthalenes can be prepared by metathesis reaction,37 [4 + 2] cycloaddition reaction of isochromenylium tetrafluoroborates,38 via an organocatalytic domino nitroalkane-Michael/aldol condensation reaction, Pt-catalyzed [1,5]-sigmatropic hydrogen shift,39 or via dearomatization.40 In nearly all of these examples, the elaborate starting materials involve a multistep synthesis. Initially observed as a side product we were able to isolate product 4 in high yields when electron-deficient phthalazines 1 were used [e.g., 5,8-difluorophthalazine (1b)]. Increasing the amount of amine 7 led to 1-amino-1,2-dihydronaphthalenes 4 even with electron-neutral phthalazine (1a) (see Supporting Information (SI) for comparison). With the optimized conditions, we explored the use of other Lewis acids. Although BDLA 2 is easily accessible, other strong and commercially available monodentate Lewis acids [BF3, B(C6F5)3] were assayed (see SI).41,42 Similar to our previous studies on the bidentate Lewis acid catalyzed IEDDA reaction of diazines, only BDLA 2 was active and, more importantly, stable enough under the reaction conditions.43,44 To explore the scope of this transformation we started with the screening of various aldehydes 6. Excellent yields were achieved for different alkyl substitution patterns (Scheme 2,
Scheme 3. Scope of Amines in the Domino IEDDA Amine Group Transfer Reactiona
Scheme 2. Scope of Aldehydes in the Domino IEDDA Amine Group Transfer Reactiona
Reaction conditions: Phthalazine (1a) (250 μmol, 1.00 equiv), BDLA 2 (12.8 μmol, 5.1 mol %); amine 7 (500 μmol, 2.00 equiv), 3phenylpropionaldehyde (6c) (375 μmol, 1.50 equiv), THF (1.00 mL, 0.25 M). Isolated as single diastereomers. bIsolated as a mixture of two diastereomers. The ratio was determined by NMR spectroscopy. a
reasoned by steric effects. Still, acylic amine 7d gave the desired product in moderate yield. Amino alkyne 7e and primary amine 7f only generated 1-amino-1,2-dihydronaphthalene 4k/4m, when an electron-deficient phthalazine 1 was used [e.g., 5,8-difluorophthalazine (1b)] (Scheme 3). We attributed this finding to the decreased electron density of the fluorophthalazine compensating for the lower nucleophilicity of primary amines or amino alkynes, respectively. Differently substituted phthalazines 1 gave the desired product in very good yields, even for the more electron-rich methyl substituted one 1e (Scheme 4). Nonsymmetric substituted diazines (1c−e) generated a mixture of constitutional isomers (Scheme 4, 4n−4p). In the case of 6methoxyphthalazine (1f) only one constitutional isomer, 1,2dihydronaphthalene 4q, was isolated in low yield (36%, Scheme 4), even though complete consumption of phthalazine 1f was observed (by 1H NMR spectroscopic analysis of the crude reaction product). Therefore, we assume that only one constitutional isomer of the generated intermediate 3q underwent the final group transfer reaction efficiently, while the other isomer decomposed in an unknown side reaction. The relative configuration of the substituents was correlated to the proximity of the substituents in accordance with the
a Reaction conditions: Phthalazine (1a) (250 μmol, 1.00 equiv), BDLA 2 (12.8 μmol, 5.1 mol %); pyrrolidine (7a) (500 μmol, 2.00 equiv), aldehyde 6 (375 μmol, 1.50 equiv), THF (1.00 mL, 0.25 M). Isolated as single diastereomers. bIsolated as a mixture of two diastereomers and corresponding enantiomers. The ratio was determined by NMR spectroscopy.
4a−4c) even in the presence of a tertiary alcohol (Scheme 2, 4d). Silyl ether protected alcohol 4e could only be isolated in a moderate yield (Scheme 2, 4e), probably due to cleavage of the silyl group under Lewis acidic conditions. When phenylacetaldehyde (6f) was used, no formation of product was observed at 60 °C. Even heating the reaction mixture to 100 °C (solvent was changed to 1,4-dioxane) showed only 7035
DOI: 10.1021/acs.orglett.8b02967 Org. Lett. 2018, 20, 7034−7038
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Organic Letters Scheme 4. Scope of Dienes in the Domino IEDDA Amine Group Transfer Reactiona
Scheme 5. Proposed Mechanism for Domino IEDDA Amine Group Transfer Reaction
Reaction conditions: Phthalazine 1 (250 μmol, 1.00 equiv), BDLA 2 (12.8 μmol, 5.1 mol %); pyrrolidine (7a) (500 μmol, 2.00 equiv), 3phenylpropionaldehyde (5) (375 μmol, 1.50 equiv), THF (1.00 mL, 0.25 M). Isolated as single diastereomers. The ratio of constitutional isomers was determined by NMR spectroscopy. a
computed structures by NOESY NMR measurements (see SI for details). The results correspond unambiguously to the trans-configuration in the final product. In accordance to our previous reported domino IEDDA-DA reaction, we concluded that the reactive intermediate 3, generated after nitrogen expulsion, also adopts a trans-configuration.27 As the reaction outcome is positively influenced by an excess of amine, we propose that the generated o-quinodimethane 3 is attacked by a second amine 7. The attack is directed and supported by the amine group within the intermediate 3. Such an attack can occur simultaneously with the expulsion (Scheme 5, pathway A) or in a stepwise manner resulting in the formation of zwitterionic intermediate 9 (Scheme 5, pathway B). In the latter case, a proton transfer from one nitrogen to the other follows, leading to the elimination of the protonated amine and generation of the product 4. The driving force of this reaction is clearly the generation of the aromatic system. To support the mechanistic proposal, structures were optimized at the B3LYP/6-311++G** level of theory and energies were computed at DLPNO-CCSD(T)/def2-TZVPPD using the IEFPCM solvent model for THF. They were carried out on the example of the reaction of phthalazine (1a) with 3methylbutyraldehyde (6a) and pyrrolidine (7a) (Scheme 2).45−50 Starting from the o-quinodimethane intermediate 3a, the remaining reaction path was computed (Figure 1). While the zwitterionic intermediate 9a was clearly established, it converts without barrier to the following transition state TS2a, leading to product 4a. This outcome indicates an “enforced” concerted mechanism (pathway A).51 An alternative higher order N[1,9] sigmatropic shift, in analogy to a N[1,3] sigmatropic shift, reported by Xu and co-worker, and the higher order Claisen rearrangement reported by us can be ruled out.52 The fact that product formation is dependent on amine concentration and a higher activation energy was computed for this pathway precludes it (see SI for details).
Figure 1. Relative Gibbs energy profile for the reaction from intermediate 3a to product 4a.53 Structures were optimized at the B3LYP/6-311++G** level of theory, and energies were computed at DLPNO-CCSD(T)/def2-TZVPPD using the IEFPCM solvent model for THF.
In summary, we demonstrate efficient access to 1-amino-1,2dihydronaphthalenes 4 through a diastereoselective domino IEDDA-group transfer reaction in one step. The reaction can be carried out on gram scale and shows a broad substrate scope of secondary amines as well as aldehydes. In the case of the diazine, electron-neutral to electron-poor phthalazines are necessary for good yields. The generality of combining bidentate Lewis acid catalysis for the generation of highly 7036
DOI: 10.1021/acs.orglett.8b02967 Org. Lett. 2018, 20, 7034−7038
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(18) Carboni, R. A.; Lindsey, R. V. J. Am. Chem. Soc. 1959, 81, 4342−4346. (19) Sauer, J.; Heldmann, D. K.; Hetzenegger, J.; Krauthan, J.; Sichert, H.; Schuster, J. Eur. J. Org. Chem. 1998, 1998, 2885−2896. (20) Oakdale, J. S.; Boger, D. L. Org. Lett. 2010, 12, 1132−1134. (21) Bodwell, G. J.; Li, J. Angew. Chem., Int. Ed. 2002, 41, 3261− 3262. (22) Murata, Y.; Kato, N.; Komatsu, K. J. Org. Chem. 2001, 66, 7235−7239. (23) Kato, D.; Sasaki, Y.; Boger, D. L. J. Am. Chem. Soc. 2010, 132, 3685−3687. (24) Sasaki, Y.; Kato, D.; Boger, D. L. J. Am. Chem. Soc. 2010, 132, 13533−13544. (25) Kessler, S. N.; Neuburger, M.; Wegner, H. A. Eur. J. Org. Chem. 2011, 2011, 3238−3245. (26) Kessler, S. N.; Wegner, H. A. Org. Lett. 2012, 14, 3268−3271. (27) Schweighauser, L.; Bodoky, I.; Kessler, S. N.; Häussinger, D.; Donsbach, C.; Wegner, H. A. Org. Lett. 2016, 18, 1330−1333. (28) Segura, J. L.; Martín, N. Chem. Rev. 1999, 99, 3199−3246. (29) Schweighauser, L.; Bodoky, I.; Kessler, S.; Häussinger, D.; Wegner, H. Synthesis 2012, 44, 2195−2199. (30) Sarges, R.; Tretter, J. R.; Tenen, S. S.; Weissman, A. J. Med. Chem. 1973, 16, 1003−1011. (31) Welch, W. M.; Kraska, A. R.; Sarges, R.; Koe, B. K. J. Med. Chem. 1984, 27, 1508−1515. (32) Dockendorff, C.; Jin, S.; Olsen, M.; Lautens, M.; Coupal, M.; Hodzic, L.; Spear, N.; Payza, K.; Walpole, C.; Tomaszewski, M. J. Bioorg. Med. Chem. Lett. 2009, 19, 1228−1232. (33) Gobé, V.; Retailleau, P.; Guinchard, X. Org. Lett. 2014, 16, 5438−5441. (34) Gómez Arrayás, R.; Cabrera, S.; Carretero, J. C. Synthesis 2006, 1205−1219. (35) Grafton, M. W.; Farrugia, L. J.; Sutherland, A. J. Org. Chem. 2013, 78, 7199−7207. (36) Lautens, M.; Rovis, T. Tetrahedron 1999, 55, 8967−8976. (37) Fustero, S.; Lázaro, R.; Herrera, L.; Rodríguez, E.; Mateu, N.; Barrio, P. Org. Lett. 2013, 15, 3770−3773. (38) Hu, Z.-L.; Yang, Z.-Y.; Wang, S.; Yao, Z.-J. Chem. - Eur. J. 2011, 17, 1268−1274. (39) Shu, X.-Z.; Ji, K.-G.; Zhao, S.-C.; Zheng, Z.-J.; Chen, J.; Lu, L.; Liu, X.-Y.; Liang, Y.-M. Chem. - Eur. J. 2008, 14, 10556−10559. (40) Hernandez, L. W.; Klöckner, U.; Pospech, J.; Hauss, L.; Sarlah, D. J. Am. Chem. Soc. 2018, 140, 4503−4507. (41) Ahles, S.; Wegner, H. A. Beilstein TV. www.beilstein.tv/video/ recipe-for-the-preparation-of-a-bidentate-lewis-acid-catalyst/ (accessed April 4th, 2018). (42) Hong, L.; Ahles, S.; Heindl, A. H.; Tiétcha, G.; Petrov, A.; Lu, Z.; Logemann, C.; Wegner, H. A. Beilstein J. Org. Chem. 2018, 14, 618−625. (43) Zhou, Z.; Wakamiya, A.; Kushida, T.; Yamaguchi, S. J. Am. Chem. Soc. 2012, 134, 4529−4532. (44) Kessler, S. N.; Wegner, H. A. Org. Lett. 2010, 12, 4062−4065. (45) Weigend, F.; Ahlrichs, R. Phys. Chem. Chem. Phys. 2005, 7, 3297−3305. (46) Riplinger, C.; Sandhoefer, B.; Hansen, A.; Neese, F. J. Chem. Phys. 2013, 139, 134101. (47) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov, V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
reactive o-quinodimethane intermediates with the driving force of aromaticity promises fruitful application for future reaction design.
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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.8b02967.
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Experimental details, analytical data, NMR spectra, relative Gibbs energy profile, energies and Cartesian coordinates of all computed structures are provided (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Andreas H. Heindl: 0000-0002-5403-2177 Hermann A. Wegner: 0000-0001-7260-6018 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Heike Hausmann and Erwin Röcker for NMR- for MS-support, respectively, Urs Gellrich and André K. Eckhardt for advice concerning computations, and Lea E. Schäfer for help with the TOC image.
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REFERENCES
(1) Wender, P. A.; Miller, B. L. Nature 2009, 460, 197−201. (2) Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.; Thomas, A. W.; Wilson, D. M.; Wood, A. Nat. Chem. 2018, 10, 383−394. (3) Sankararaman, S. Pericyclic reactions: A textbook - reactions, applications and theory; Wiley-VCH: Weinheim, 2005. (4) Fernández, I.; Sierra, M. A.; Cossío, F. P. J. Org. Chem. 2007, 72, 1488−1491. (5) Rong, Z.-Q.; Lim, H. N.; Dong, G. Angew. Chem., Int. Ed. 2018, 57, 475−479. (6) Wang, X.; Gensch, T.; Lerchen, A.; Daniliuc, C. G.; Glorius, F. J. Am. Chem. Soc. 2017, 139, 6506−6512. (7) Kumar, R.; Hoshimoto, Y.; Yabuki, H.; Ohashi, M.; Ogoshi, S. J. Am. Chem. Soc. 2015, 137, 11838−11845. (8) Tietze, L. F. Chem. Rev. 1996, 96, 115−136. (9) Chauhan, P.; Mahajan, S.; Enders, D. Acc. Chem. Res. 2017, 50, 2809−2821. (10) Patalag, L. J.; Werz, D. B. Pericyclic Reactions in Domino Processes. In Domino reactions: Concepts for efficient organic synthesis; Tietze, L.-F., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2014; pp 183−218. (11) Lei, C.-H.; Wang, D.-X.; Zhao, L.; Zhu, J.; Wang, M.-X. J. Am. Chem. Soc. 2013, 135, 4708−4711. (12) Kessler, S. N.; Neuburger, M.; Wegner, H. A. J. Am. Chem. Soc. 2012, 134, 17885−17888. (13) Schweighauser, L.; Wegner, H. A. Chem. - Eur. J. 2016, 22, 14094−14103. (14) Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179−2182. (15) Anderson, E. D.; Boger, D. L. Org. Lett. 2011, 13, 2492−2494. (16) Anderson, E. D.; Boger, D. L. J. Am. Chem. Soc. 2011, 133, 12285−12292. (17) Yang, Y.-F.; Yu, P.; Houk, K. N. J. Am. Chem. Soc. 2017, 139, 18213−18221. 7037
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