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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Combining Bidentate Lewis Acid Catalysis and Photochemistry: Formal Insertion of o‑Xylene into an Enamine Double Bond Sebastian Ahles,†,‡ Julia Ruhl,†,‡ Marcel A. Strauss,†,‡ and Hermann A. Wegner*,†,‡ †
Institute of Organic Chemistry, Justus Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany Center for Materials Research (LaMa), Justus Liebig University, Heinrich-Buff-Ring 16, 35392 Giessen, Germany
‡
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S Supporting Information *
ABSTRACT: A bidentate Lewis acid catalyzed domino inverse-electron-demand Diels−Alder reaction combined with a photoinduced ring opening formally inserts o-xylene moieties into enamine double bonds. After reduction, phenethylamines were obtained in good yields. The scope of the reaction was determined by variation of all three starting compounds: phthalazines, aldehydes, and amines.
he concept of an ideal synthesis was first expressed numerically by Hendrickson and later condensed into a single number, “ideality”, by Baran.1,2 To come closer to the ultimate practical synthesis, as Wender called it, not only new reactions and reactivities of standard reagents have to be explored but also new starting materials have to be considered and promoted.3,4 In addition, reactions building up several bonds in a single step should be favored. Combining pericyclic reactions into domino sequences proved especially efficient in this regard.5−7 In addition, the inclusion of photochemical reactions, i.e., utilization of electronic isomers, can open up new reaction pathways and selectivity.8−11 We established phthalazines 1 as versatile and robust building blocks in domino inverse-electron-demand Diels− Alder reactions (IEDDA reactions). This was only possible by the use of a boron-based bidentate Lewis acid (BDLA), which lowered the LUMO of the diazine by complexation. The catalyst enabled IEDDA reactions which are usually only possible for aromatics containing a higher number of nitrogen atoms (e.g., 1,2,4-triazines or 1,2,4,5-tetrazines).12−18 In this manner, naphthalenes, dihydronaphthalenes, and highly complex alkaloid-type structures were synthesized in a single step.19−27 The linchpin of all these transformations is the generation of a reactive o-quinodimethane derivative 3 after the initial IEDDA reaction of phthalazines 1 with a suitable dienophile (e.g., enamines 2 or dihydrofurans). The desired product is selectively generated in a domino reaction sequence, depending on the conditions. A convenient one-pot synthesis of phthalazines 1 as well as BDLA allows easy access to these starting materials.19,28 On our quest to harness the potential energy of oquinodimethane derivative 3 and to open up new reaction pathways, we were inspired by the photoinduced ring opening
T
© XXXX American Chemical Society
(PIRO) of 7-dehydrocholesterol in the biosynthesis of vitamin D.29,30 We envisioned that intermediate 3 would react in a similar way, generating the aromatic compound 4 in a 10π conrotatory pericyclic reaction (Scheme 1). Indeed, when a reaction mixture of phthalazine 1, aldehyde 6, amine 7, and a catalytic amount of BDLA in THF was irradiated at 365 nm, the formation of PIRO product 4 was observed by 1H NMR spectroscopy together with other side products. Hence, the Scheme 1. Domino IEDDA Reactions of Phthalazines 1 and Enamines 2 Catalyzed by a Bidentate Lewis Acid
Received: March 22, 2019
A
DOI: 10.1021/acs.orglett.9b01020 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters optimal wavelength for this reaction was determined by qNMR experiments using 1,3,5-trimethoxybenzene (TMB) as the internal standard (Table 1). The product 4 was always
Table 2. Scope of Aldehydes 6a−e in the Domino IEDDA/ PIRO Reactiona
Table 1. Optimization of Irradiation Wavelength for the Domino IEDDA/PIRO Reactiona
entry
wavelength (nm)
E/Zb
qNMR yieldc (%)
1 2 3 4 5d
405 425−430 448 470 500
1.00:1.91 1.00:1.22 2.46:1.00 1.31:1.00 ∼1.00:1.00
57 80 81 75 ∼35
Reaction conditions: phthalazine (1a) (375 μmol, 1.00 equiv), BDLA (9.32 μmol, 2.49 mol %), butyraldehyde (6a) (544 μmol, 1.45 equiv), pyrrolidine (7a) (450 μmol, 1.20 equiv), TMB (124 μmol, 0.33 equiv), THF (1.00 mL, 375 mM). bRatio was determined by 1 H NMR. cYield was calculated compared to internal standard TMB, S/N > 640 (except 500 nm: S/N < 90). dYield and ratio could not be determined exactly due to low signal-to-noise. a
detected as a mixture of (E)- and (Z)-configuration of the styrene moiety, with the ratio depending on the wavelength. This observation can be rationalized by photoisomerization after product formation. In regard to the enamine moiety, a (Z)-configuration was initially detected by 1H NMR spectroscopy during the reaction. It completely isomerized to the more stable (E)-configuration under the reaction conditions.31,32 We found that a range of wavelengths, starting from 425 nm up to 470 nm (Table 1, entries 2−4), was suitable for the reactions of phthalazine (1a), butyraldehyde (6a), and pyrrolidine (7a). If the wavelength was increased further, the formation of elimination and amine-transfer product was observed (Table 1, entry 5, and Scheme 1). We noticed that some reactions with different substrates did not proceed to full conversion when irradiated at 425−430 nm. UV/vis spectroscopy of phthalazine−BDLA complex 8a showed broad absorption in this area. We concluded that the complex slowly decomposed under irradiation and confirmed this by 1H NMR studies (see the Supporting Information). Hence, higher wavelengths were chosen for “slower” reactions (Tables 2 and 3). Before the scope could be determined, a purification procedure had to be established. Unfortunately, attempts made by column chromatography, even under basic conditions (silica gel with 5% NEt3 or basic alumina), resulted in partial decompositions. The corresponding aldehyde was not detected in any example. After various attempts, the method of choice for purification was distillation. However, this is only practical for reactions on a larger scale and for products with a suitably low boiling point (see the SI). Therefore, we decided to reduce the enamine 4 to the more stable corresponding phenethylamine 5. This transformation was achieved efficiently by using NaBH(OAc)3 and AcOH in DCM at room temperature.33 Other standard methods were not or only partially successful. Palladium on charcoal under hydrogen atmosphere reduced both the enamine and styrene moiety, platinum on charcoal
Reaction conditions: (a) phthalazine (1a) (750 μmol, 1.00 equiv), BDLA (18.6 μmol, 2.5 mol %), aldehyde 6 (0.98−1.12 mmol, 1.31− 1.49 equiv), pyrrolidine (7a) (900 μmol, 1.20 equiv), THF (2.00 mL, 375 mM); (2) NaBH(OAc)3 (1.50 mmol, 2.00 equiv), AcOH (1.50 mmol, 2.00 equiv), DCM (6.00 mL, 125 mM). bRatio was determined by 1H NMR. cIsolated yield as a mixture of E-/Z-isomers. a
yielded a mixture, and NaBH4 generated amine 5 but also led to decomposition. With a working protocol in hand, different aldehydes 6 were screened first. The isolated yield after reduction was comparable to the one of the corresponding enamine 4 determined by qNMR (Table 1, entry 2, vs Table 2, entry 1). For sterically more demanding β-branched aldehydes 6b,c the yield was only slightly diminished (Table 2, entries 2 and 3). Even in the presence of an acid-sensitive tertiary alcohol moiety the desired product was obtained in 71% yield (Table 2, entry 3). Silyl ether 5d was obtained in moderate yield, probably due to cleavage of the silyl group under Lewis acidic conditions (Table 2, entry 4). The effectiveness of the IEDDA/PIRO reaction could be demonstrated by utilizing the in situ formed enamine containing an additional double B
DOI: 10.1021/acs.orglett.9b01020 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
ceeded smoothly, and the expected product 5e was obtained in good yield (Table 2, entry 5). Variation of the amine 7 only had an influence on the initial IEDDA reaction temperature (Table 3, entries 1 and 2). A diminished yield was obtained for N,N,N′-trimethylethylenediamine (7d). We suspected that the second nitrogen coordinated to the acidic proton of phthalazine (1a), further decreasing its LUMO, and facilitated the IEDDA reaction (resulting in a lower reaction temperature), but in the same way, it also made the syn-elimination easier, forming the naphthalene product and thereby lowering the yield of PIRO product (Table 3, entry 3).25 For electron-deficient phthalazines 1b−d the temperature had to be tuned. For example, the reaction of 5,8difluorophthalazine (1b) performed at rt yielded only the amine-transfer product. Therefore, the aldehyde 6a was added at −15 to −10 °C, preventing the initial IEDDA reaction. Then, the mixture was slowly warmed under irradiation until gas evolution was observed, at which point it was stirred at that temperature overnight. The amine-transfer product formation was not completely suppressed though, and a slightly lower yield was obtained (Table 3, entries 4−6). For asymmetric substituted phthalazines 1c−f, a mixture of constitutional isomers was obtained (Table 3, entries 5−8). In the case of 5(trifluoromethyl)phthalazine (1c), we were able to separate both isomers (see the SI). Because the regioselectivity is determined by the initial IEDDA reaction, the ratio of C2-/C3isomers is similar to that in previously reported domino IEDDA reactions. For 6-methoxyphthalazine (1f), both constitutional isomers were obtained (Table 3, entry 8). This is in contrast to the amine-transfer reaction, which only yielded the corresponding C2-substituted one.27 In accordance with previous studies, we propose that o‑quinodimethane derivative 3 is formed by the IEDDA reaction of the in situ formed enamine 2 with phthalazine 1 catalyzed by the bidentated Lewis acid BDLA. Irradiation with an appropriate wavelength enables a 10π conrotatory ringopening reaction, generating enamine 4. We reason that gain of aromaticity and change of geometry prevent a back reaction (Scheme 2). Due to the highly reactive nature of o-quinodimethane intermediate 3, we were unable to measure a UV/vis spectrum of this intermediate to determine the best wavelength for the PIRO step. Therefore, we investigated this aspect by TDDFT computations. The results show that substituents had only a marginal influence on the absorption band between 400 and 500 nm, further supporting the key role of intermediate 3 in the proposed mechanism (see the SI). Polymerization was never observed. As previously reported, enamines generated from phenylacetaldehyde derivatives did not react with phthalazines 1 at the chosen conditions.27 In summary, we opened up a new reaction pathway for oquinodimethane derivatives 3 by the irradiation with blue LEDs. In a domino Lewis acid catalyzed IEDDA/PIRO reaction, enamine-substituted o-styrenes 4 were formed. These were reduced to the corresponding phenethylamine 5 in one pot in high yields. The scope and limitations were demonstrated by changing all three starting materials, phthalazine 1, aldehyde 6, and amine 7. The importance of electronic isomers, for the access of new reaction pathways, is clearly demonstrated in this work and offers room for more discoveries.
Table 3. Scope of Amines 7a−d and Phthalazines 1a−f in the Domino IEDDA/PIRO Reactiona
Reaction conditions: (1) phthalazine 1a−f (750 μmol, 1.00 equiv), BDLA (18.6 μmol, 2.5 mol %), butyraldehyde (6a) (1.09 mmol, 1.45 equiv), amine 7a−d (900 μmol, 1.20 equiv), THF (2.00 mL, 375 mM); (2) NaBH(OAc)3 (1.50 mmol, 2.00 equiv), AcOH (1.50 mmol, 2.00 equiv), DCM (6.00 mL, 125 mM). bRatio was determined by 1H NMR. cIsolated yield as a mixture of E-/Zisomers; ratio determined by 1H NMR. dConstitutional isomers were separated (C2-isomer, 24%; C3-isomer, 30%). eIsolated yield as a mixture of C2/C3-constitutional isomers. a
bond. Under these reaction conditions, the formation of the corresponding bridged oligocyclic tetrahydronaphthalene product, resulting from a domino IEDDA/DA reaction, was not observed.26 The domino IEDDA/PIRO reaction proC
DOI: 10.1021/acs.orglett.9b01020 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
(6) Patalag, L. J.; Werz, D. B. Pericyclic Reaections in Domino Processes. In Domino Reactions; John Wiley & Sons, Ltd., 2013; pp 183−218. (7) Chauhan, P.; Mahajan, S.; Enders, D. Acc. Chem. Res. 2017, 50, 2809−2821. (8) Bach, T.; Hehn, J. P. Angew. Chem., Int. Ed. 2011, 50, 1000− 1045. (9) Hoffmann, N. Chem. Rev. 2008, 108, 1052−1103. (10) Quinkert, G. Angew. Chem., Int. Ed. Engl. 1975, 14, 790−800. (11) Bally, T. Chimia 2007, 61, 645−649. (12) Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179−2182. (13) Anderson, E. D.; Boger, D. L. J. Am. Chem. Soc. 2011, 133, 12285−12292. (14) Anderson, E. D.; Boger, D. L. Org. Lett. 2011, 13, 2492−2494. (15) Glinkerman, C. M.; Boger, D. L. Org. Lett. 2018, 20, 2628− 2631. (16) Oakdale, J. S.; Boger, D. L. Org. Lett. 2010, 12, 1132−1134. (17) Sauer, J.; Heldmann, D. K.; Hetzenegger, J.; Krauthan, J.; Sichert, H.; Schuster, J. Eur. J. Org. Chem. 1998, 1998, 2885−2896. (18) Carboni, R. A.; Lindsey, R. V. J. Am. Chem. Soc. 1959, 81, 4342−4346. (19) Kessler, S. N.; Wegner, H. A. Org. Lett. 2012, 14, 3268−3271. (20) Kessler, S. N.; Wegner, H. A. Org. Lett. 2010, 12, 4062−4065. (21) Kessler, S. N.; Neuburger, M.; Wegner, H. A. J. Am. Chem. Soc. 2012, 134, 17885−17888. (22) Schweighauser, L.; Wegner, H. A. Chem. - Eur. J. 2016, 22, 14094−14103. (23) Kessler, S. N.; Neuburger, M.; Wegner, H. A. Eur. J. Org. Chem. 2011, 2011, 3238−3245. (24) Wegner, H. A.; Kessler, S. N. Synlett 2012, 23, 699−705. (25) Schweighauser, L.; Bodoky, I.; Kessler, S. N.; Häussinger, D.; Wegner, H. A. Synthesis 2012, 44, 2195−2199. (26) Schweighauser, L.; Bodoky, I.; Kessler, S. N.; Häussinger, D.; Donsbach, C.; Wegner, H. A. Org. Lett. 2016, 18, 1330−1333. (27) Ahles, S.; Götz, S.; Schweighauser, L.; Brodsky, M.; Kessler, S. N.; Heindl, A. H.; Wegner, H. A. Org. Lett. 2018, 20, 7034−7038. (28) 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. (29) Zhu, G.-D.; Okamura, W. H. Chem. Rev. 1995, 95, 1877−1952. (30) Holick, M. F. Am. J. Clin. Nutr. 1994, 60, 619−630. (31) Sauer, J.; Prahl, H. Tetrahedron Lett. 1966, 7, 2863−2866. (32) Hudrlik, P. F.; Hudrlik, A. M.; Kulkarni, A. K. Tetrahedron Lett. 1985, 26, 139−142. (33) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849−3862.
Scheme 2. Proposed Mechanism for Domino IEDDA/PIRO Reactiona
a
Only one enantiomer is depicted for clarity.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01020. Experimental details, analytical data, NMR and UV/vis spectra, and computational details (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Sebastian Ahles: 0000-0002-3954-5513 Julia Ruhl: 0000-0002-3062-9227 Marcel A. Strauss: 0000-0001-8152-9421 Hermann A. Wegner: 0000-0001-7260-6018 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Heike Hausmann (Justus Liebig University, Giessen) for NMR support and Edgar Reitz (Justus Liebig University, Giessen) for design and construction of the LED devices.
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(1) (2) (3) (4) (5)
REFERENCES Hendrickson, J. B. J. Am. Chem. Soc. 1975, 97, 5784−5800. Gaich, T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657−4673. Wender, P. A. Chem. Rev. 1996, 96, 1−2. Wender, P. A.; Miller, B. L. Nature 2009, 460, 197−201. Tietze, L. F. Chem. Rev. 1996, 96, 115−136. D
DOI: 10.1021/acs.orglett.9b01020 Org. Lett. XXXX, XXX, XXX−XXX
