Diels–Alder Reactions with Ethylene and Superelectrophiles - Organic

Letter Cite This: Org. Lett. 2018, 20, 1849−1852

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Diels−Alder Reactions with Ethylene and Superelectrophiles Hien Vuong,† Barada P. Dash,† Sten O. Nilsson Lill,‡ and Douglas A. Klumpp*,† †

Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, Illinois 60115, United States Early Product Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, S-431 83 Mölndal, Sweden

‡

S Supporting Information *

ABSTRACT: Diels−Alder reactions have been accomplished with ethylene as the dienophile through the use of inverseelectron demand Diels−Alder chemistry. As a key aspect of the chemistry, the dienes are part of tri- or dicationic superelectrophilic systems. Theoretical calculations reveal that the highly charged superelectrophiles possess exceptionally low lying LUMOs, and this facilitates the cycloaddition chemistry with ethylene. The chemistry has been used to prepare a series of tetrahydroquinoline products. This represents the first application of superelectrophilic activation in a cycloaddition reaction, and a new method of utilizing ethylene as a C2 building block.

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the system lowered the activation energy for the pericyclic reaction. It was suggested that the dicationic system benefitted from enhanced π-electron delocalization, and this facilitated the pericyclic reaction. A similar type of electrocyclization was also reported for aza-Nazarov cyclizations.4 At this point, it is not known if highly charged organic cations may enable other types of pericyclic reactions. While numerous examples are known of superelectrophilic reactions forming single C−X and C−C bonds, no such reactions are known to form two bonds in concert. In this Letter, we wish to report an example of a series of cycloaddition reactions involving superelectrophilic intermediates. The high cationic charge densities on superelectrophiles often lead to unusually low energy LUMOs and large orbital coefficients within π-systems.5 Moreover, superelectrophiles have a strong tendency to separate cationic charge during the course of their reactions, providing a potential driving force for pericyclic reactions. These considerations suggest that superelectrophiles may be useful in cycloadditions, such as the Diels−Alder reaction. In order to evaluate the possibility of using superelectrophiles in Diels−Alder reactions, we sought to use aromatic imines/iminium ions and ethylene in the [4 + 2] cycloadditions. Aromatic imines are known to react with electron-rich dienophiles, a transformation known as the Povarov reaction.6 Dienophiles commonly used in the Povarov reaction include ethyl vinyl ether, cyclopentadiene, 3,4-dihydro2H-pyran, indene, ethyl vinyl sulfide, styrene, and allyltrimethylsilane.7 The measured ionization energies for these systems range from 8.14 eV (indene) to 8.98 eV (ethyl vinyl ether).8 The relatively low energies of ionization are consistent with high energy HOMOs, a necessary condition for reverse electron demand Diels−Alder reactions. On the other hand,

he concept of superelectrophilic reactivity was proposed by Olah and co-workers to explain the heightened reactivities of electrophiles in superacidic media.1 Experimental studies revealed astonishing levels of reactivity for di- and tricationic superelectrophiles, including reactions with very weak nucleophiles, such as alkanes and deactivated arenes.2 Despite several decades of work on superelectrophile chemistry, almost no work has been done to examine the chemistry of these highly charged organic structures in pericyclic reactions. A notable exception is the work of Shudo and co-workers who reported the chemistry of a superelectrophilic Nazarov reaction (Scheme 1).3 They found evidence for the involvement of dicationic species in a series of 4π-electrocyclizations. Theoretical calculations showed that increasing the charge on Scheme 1. Superelectrophilic Pericyclic Reactions

Received: January 31, 2018 Published: March 26, 2018 © 2018 American Chemical Society

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DOI: 10.1021/acs.orglett.8b00367 Org. Lett. 2018, 20, 1849−1852

Letter

Organic Letters

were obtained by cyclizations with the phenyl ring, 1-naphthyl ring, and the substituted aryl rings. Although imine 6 has several potential diene or aza-diene sites, cycloaddition was only observed at the Povarov reaction site. The chemistry is amenable to biaryl synthesis, as cycloaddition may be accomplished with subsequent S8 oxidation (Scheme 3). The

ethylene has a measured ionization potential of 10.51 eV, which suggests it should be considerably less reactive as a dienophile in reverse electron demand Diels−Alder reactions.9 Nevertheless with aryl imines as the diene component, utilization of N-heterocyclic groups allow for an increasing charge on the system. We reasoned that increasing charge on the aryl group should lead to lowering of the diene LUMOs and, consequently, increased reactivities in the cycloaddition chemistry. Our initial experimentation involved the reaction of pyridyl imine 1, prepared from 4-fluoroaniline and 2-pyridinecarboxaldehyde (Scheme 2).

Scheme 3. Biaryl Synthesis

cycloaddition reactions are carried out in excess superacid, and therefore, it is likely the reactions involve dicationic and tricationic species. For example, imine 3 should provide dication 19, while the pyrazine and quinoxaline derivatives (9 and 17) are expected to provide the trications 20 and 21 (Figure 1). It is conceivable that other ionizations may occur

Scheme 2. Ethylene Cycloaddition

In no acid or weak acid (CF3CO2H, 52 equiv), little or no cycloaddition product (2) could be obtained. Stronger acids, such as H2SO4 (75 equiv) or CH3SO3H (60 equiv), provided acceptable yields of the tetrahydroquinoline 2, 57% and 50%, respectively. Good yields of product 2 are obtained with inclusion of the Brønsted superacid, CF3SO3H (triflic acid). The optimized conditions utilize 7 equiv of CF3SO3H and 160 psi ethylene to give product 2 in 81% yield (5 h reaction). There was no evidence for ethylene oligomerization or polymerization in the superacid. A series of aryl imines were then prepared and reacted with ethylene in the presence of acid (Table 1). Using the optimized conditions, the imines (3−9) provided the cycloaddition products (10−16) in good yields. The Diels−Alder products

Figure 1. Superelectrophiles generated from heterocyclic imines.

with imine 6 in the superacid, as the azo group possesses good basicity. In the original hypothesis, it was suggested that the more highly ionized dienes would have greater reactivities with ethylene, compared to monocationic or neutral dienes. This was confirmed by the reaction of benzylidene imine 22 with triflic acid and ethylene, as no cycloaddition product is obtained (Scheme 4). Evidently, the monocationic species 23 is not Scheme 4. Attempted Reaction with a Monocationic System

Table 1. Reactants, Products, and Isolated Yields from Cycloaddition Reactions with Ethylene (160 psi) and CF3SO3H (7 equiv) at 25 °C

sufficiently reactive to undergo cycloaddition. As expected for the neutral diene, no cycloaddition products were observed from the same reaction conditions with stilbene. In order to further explore the observed [4 + 2] cycloaddition, density functional theory (DFT) calculations were done (Figure 2). The series of isoelectronic structures (stilbene 24, iminium ion 23, iminium ion 19, and iminium ion 20) were studied. Geometry optimizations were completed at the M06-2X/6-31+G(d,p) level of theory in the gas phase.10 Gibbs’ free energy corrections (ΔG) were calculated, and the structures were verified to be minima or transition states by inspection of the number of imaginary frequencies. In a final step, solvent phase single-point calculations at the same level of theory were performed using a Poisson−Boltzmann solver (v. 4.10), as implemented in Jaguar.11 Solvation effects from the surroundings were calculated using the SCRF method with CF3SO3H as the solvent (dielectric constant = 77.4, probe radius = 2.5985274 Å).12 The free energy correction terms (ΔG) were added to the solution-phase energy to get a final solution free energy value. From the localized transition states, the connecting reactant and product states were determined 1850

DOI: 10.1021/acs.orglett.8b00367 Org. Lett. 2018, 20, 1849−1852

Letter

Organic Letters

the activation energy decreases. Thus, the average bond distance (C2−C3 and C4−C5 bonds) in the monocationic transition state (23ts) is 2.19 Å while the average bond distance in the tricationic transition state (20ts) increases to 2.37 Å. The activation energy is also significantly different between the systems, as it decreases more than 7.0 kcal/mol for the reactions of the dicationic or tricationic iminium ions (19ts and 20ts), compared to the monocationic iminium ion (23ts). The lowered activation energies for the superelectrophilic reactions enable the [4 + 2] cycloadditions to be carried out at ambient conditions. The activation energies for the superelectrophilic systems, 19ts and 20ts, are comparable with other Diels−Alder reactions (ca. 12−30 kcal/mol).13 Cycloaddition with ethylene leads to structures 24b, 23b, 19b, and 20b as reactive intermediates from the reactions. With increasing charge on the system, the conversion is increasingly exergonic. For example, the neutral system 24b is endergonic by 8.4 kcal/mol, while the monocationic system 23b is exergonic by −6.0 kcal/ mol. The superelectrophilic systems are significantly exergonic, −18.2 kcal/mol for dication 19b and −23.1 kcal/mol for trication 20b. Among the charged systems, this trend can be understood to be a consequence of the increasing charge on the aryl group. The cycloaddition leads to charge separation between the iminium ion and the substituent heteroaryl group. Thus, the tricationic system benefits most from the reaction because it provides relief from the electrostatic effects of three neighboring cationic charge centers. Charge−charge repulsive effects are known to be a driving force in the reactions of superelectrophiles.2,14 This also appears to be an important factor in the Diels−Alder reactions of superelectrophiles. A previous DFT study of the Povarov reaction found evidence for highly asynchronous bond formation in the reactions of N-aryl iminium ions with electron-rich dienophiles.6b In some cases, reaction of the iminium ion with an electron-rich olefin gives the cyclization product by a two-step process: the iminium ion reacts with the olefin to give carbocationic or carboxonium ion intermediates, followed by a Friedel−Crafts reaction to provide the new ring. For example, the BF3-catalyzed reaction of imine 22 with methyl vinyl ether is found to have the zwitterionic structure 25 at an energy minimum (Scheme 5). Interestingly, the above superelectro-

Figure 2. M06-2X/6-31+G(d,p) calculated structures and reactions energies in solution phase (CF3SO3H).

Scheme 5. Zwitterionic Povarov Reaction using the QRC approach, employing Chemcraft, to visualize the reaction mode. The starting iminium ions (23, 19, and 20) and stilbene (24) and their reactions with ethylene were calculated. Analysis of the gas-phase optimized structures reveals a dramatic lowering of the LUMO, as charge is added to the diene. Thus, stilbene is found to have a LUMO at −0.803 eV, while the dicationic and tricationic imines have LUMOs at −10.648 and −15.319 eV, respectively. In accord with the frontier molecular orbital theory, lowering of the diene LUMO is essential for the reverse electron demand Diels−Alder reaction with ethylene (and its low-lying HOMO). In all cases, an association complex between ethylene and the diene is located as a shallow minimum on the potential energy surface, preceding the transition state (see Supporting Information). Examination of the calculated transition state structures reveals that increasing charge has a significant effect on the structures and energies. With progression from neutral to monocationic to dicationic to tricationic diene, the transition state moves earlier, based on the average new bond lengths, and

philic Povarov reactions do show a delay in forming the C4− C5 bond, compared to the C2−C3 bond. However, bond formation appears to be more concerted with increasing charge on the iminium ion. The tricationic transition state structure (20ts) possesses C2−C3 and C4−C5 bond lengths that differ by only 0.018 Å. This is consistent with the ethylene Povarov reaction exhibiting the characteristics of a Diels−Alder type cycloaddition rather than a stepwise domino process. Finally, it should be noted that ethylene is a desirable C2 building block, and there has been significant recent interest in its use as a dienophile in Diels−Alder reactions.15 Many of these transformations have sought to use biorenewable furan derivatives and other substrates in Diels−Alder reactions with 1851

DOI: 10.1021/acs.orglett.8b00367 Org. Lett. 2018, 20, 1849−1852

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Organic Letters ethylene. These conversions utilize solid acid,15a transition metal,15b or zeolite catalysts15c and require high pressures of ethylene (200 to 6200 psi) and high temperatures (100−300 °C). In general, Diels−Alder reactions with ethylene often require forcing conditions. Exceptions to this are known, however. Diels−Alder reactions with ethylene may be conducted under mild conditions if the diene is destabilized by electronic effects. This usually involves chemistry with reactive species, such as cyclobutadienes, cyclopentadienones, or tetrazines.16−18 In the present study, we show that superelectrophiles may also participate in Diels−Alder reactions with ethylene under mild conditions. In summary, we have found that superelectrophilic iminium ions may undergo [4 + 2] cycloadditions with ethylene. The chemistry provides good yields of heteroaryl-substituted tetrahydroquinolines and, with oxidation, a good yield of a biaryl product. DFT calculations reveal that increasing the charge lowers the LUMO on the diene component and significantly lowers the activation energy for the cycloaddition. Formation of the cycloaddition product also becomes thermodynamically more favorable. To date, the paradigm of Olah’s superelectrophilic chemistry has largely involved single C−X or C−C bond formations by reaction of bonding or lonepair electrons.2 The present study shows that superelectrophilic chemistry also includes pericyclic types of reactions, in which more than one C−X or C−C bond can form during the process.

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Eur. J. Org. Chem. 2012, 2012, 6021. (c) Klumpp, D. A.; Zhang, Y.; O’Connor, M. J.; Esteves, P. M.; de Almeida, L. S. Org. Lett. 2007, 9, 3085. (5) Koltunov, K. Y.; Prakash, G. K. S.; Rasul, G.; Olah, G. A. Heterocycles 2004, 62, 757. (6) (a) Domingo, L. R.; Rios-Gutierrez, M.; Emamian, S. RSC Adv. 2016, 6, 17064. (b) Rios-Gutierrez, M.; Layeb, H.; Domingo, L. R. Tetrahedron 2015, 71, 9339. (7) Kouznetsov, V. V. Tetrahedron 2009, 65, 2721. (8) (a) Morizur, J.-P.; Mercier, J.; Sarraf, M. Org. Mass Spectrom. 1982, 17, 327. (b) Derrick, P. J.; Asbrink, L.; Edqvist, O.; Jonsson, B.O.; Lindholm, E. Int. J. Mass Spectrom. Ion Phys. 1971, 6, 203. (c) Hunter, E. P.; Lias, S. G. J. Phys. Chem. Ref. Data 1998, 27 (3), 413. (d) Dewar, M. J. S.; Haselbach, E.; Worley, S. D. Proc. R. Soc. London, Ser. A 1970, 315, 431. (e) Watanabe, K.; Nakayama, T.; Mottl, J. J. Quant. Spectrosc. Radiat. Transfer 1962, 2, 369. (f) Bock, H.; Seidl, H. J. Organomet. Chem. 1968, 13, 87. (9) Williams, B. A.; Cool, T. A. J. Chem. Phys. 1991, 94, 6358. (10) (a) Zhao, Y.; Truhlar, D. Theor. Chem. Acc. 2008, 120, 215. (b) Jaguar, version 7.7; Schrodinger, LLC: New York, 2010. (11) Marten, B.; Kim, K.; Cortis, C.; Friesner, R. A.; Murphy, R. B.; Ringnalda, M. N.; Sitkoff, D.; Honig, B. J. Phys. Chem. 1996, 100, 11775. (12) (a) Lira, A. L.; Zolotukhin, M.; Fomina, L.; Fomine, S. J. Phys. Chem. A 2007, 111, 13606. (b) Naredla, R. R.; Zheng, C.; Nilsson Lill, S. O.; Klumpp, D. A. J. Am. Chem. Soc. 2011, 133, 13169. (13) Nandi, S.; Monesi, A.; Drgan, V.; Merzel, F.; Novic, M. Chem. Cent. J. 2013, 7, 171. (14) Klumpp, D. A. Chem. - Eur. J. 2008, 14, 2004. (15) (a) Patet, R. E.; Fan, W.; Vlachos, D. G.; Caratzoulas, S. ChemCatChem 2017, 9, 2523. (b) Song, S.; Wu, G.; Dai, W.; Guan, N.; Li, L. J. Mol. Catal. A: Chem. 2016, 420, 134. (c) Chang, C.-C.; Cho, H. J.; Yu, J.; Gorte, R. J.; Gulbinski, J.; Dauenhauer, P.; Fan, W. Green Chem. 2016, 18, 1368. (d) Pacheco, J. J.; Labinger, J. A.; Sessions, A. L.; Davis, M. E. ACS Catal. 2015, 5, 5904. (16) Inagaki, Y.; Nakamoto, M.; Sekiguchi, A. Nat. Commun. 2014, 5, 3018. (17) Szilagyi, S.; Ross, J. A.; Lemal, D. M. J. Am. Chem. Soc. 1975, 97, 5586. (18) Avram, M. Chem. Ber. 1962, 95, 2248.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00367. Experimental procedures, characterization data, and NMR spectra of new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: 1-815-761-3153. ORCID

Barada P. Dash: 0000-0001-8855-0813 Sten O. Nilsson Lill: 0000-0003-4818-8084 Douglas A. Klumpp: 0000-0001-5271-699X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was funded by the U.S. National Science Foundation (Grant No. 1300878), and their support is gratefully acknowledged. This paper is dedicated to the fond memory of Professor George A. Olah (1927−2017).

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REFERENCES

(1) Olah, G. A.; Germain, A.; Lin, H. C.; Forsyth, D. A. J. Am. Chem. Soc. 1975, 97, 2928. (2) Olah, G. A.; Klumpp, D. A. Superelectrophiles and Their Chemistry; Wiley & Sons: New York, 2008. (3) Suzuki, T.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1997, 119, 6774. (4) (a) Karthikeyan, I.; Arunprasath, D.; Sekar, G. Chem. Commun. 2015, 51, 1701. (b) Narayan, R.; Daniliuc, C.-G.; Wuerthwein, E. U. 1852

DOI: 10.1021/acs.orglett.8b00367 Org. Lett. 2018, 20, 1849−1852