Supplementary Information (I)

Direct multicomponent synthesis of benzocoumarins

Ana Bornadiego, Jesús Díaz*, and Carlos F. Marcos*

Contents

Computational details...............................................................................................................2

References............................................................................................................................... 4

NMR Spectra of Coumarins......................................................................................................5

NMR Spectra of Benzocoumarins..........................................................................................10

Computational calculations

Although the 7-oxabicyclo[2.2.1]heptene intermediate (18) was not isolated, it is pertinent to try to identify whether the [4+2] cycloaddition takes place by and exo or endo attack, as this determines the stereochemistry of the new stereocentres in the Diels-Alder cycloadduct (18). With this aim mechanistic studies were performed using density functional theory (DFT) with Gaussian 16. The geometries of the reactants, transition states (TS) and products were fully optimized in ethanol with the Polarizable Continuum Model (PCM) at the M06-2X/6-31+G** level of theory. The reaction was modelled with 3-methyl-1-(methylamino)-4H-furo[3,4-c]chromen-4-one and N-methylmaleimide in ethanol (Figure S1). According to these calculations, the endo approach is favoured, as TSENDO is 1.8 kcal/mol more stable than TSEXO, resulting in 95.6:4.4 Boltzmann ratio for the endo-exo products. The computational data also reveals an asynchronous mechanism for the [4+2] cycloaddition, which is also coherent with the reaction been favoured in protic solvents.

Quantum chemical computations were carried out with the Gaussian 16 series of programs.1 Full geometry optimizations of stable species were performed in ethanol by employing the hybrid density functional M06-2X2 with the 6-31+G(d,p) basis set.3 The nature of the stationary points was verified by analytical computations of harmonic vibrational frequencies. Solvent effects were considered using the integral equation formalism variant of the polarizable continuum model (IEF-PCM) with the Polarizable Continuum Model (PCM).4

S2

Figure S1. Reaction profile for the Diels-Alder step, calculated at M06-2X level of theory.

Table S1. Energies of the starting materials, transition states and products, calculated at M06-2X level of theory.

Compound E (hartree) H (hartree) S(cal/Kmol) G(hartree)Aminocoumarin -782.16718 0.23406 119.61800 0.17722

N-MethylMaleimide -398.60902 0.10525 84.83600 0.06494TS4+2ENDO -1180.7722 0.33999 150.80100 0.26834TS4+2EXO -1180.7679 0.33997 153.59400 0.26699

BicycloENDO -1180.8100 0.34323 149.91000 0.27200BicycloEXO -1180.8132 0.34384 149.17000 0.27296

Table S2. Calculated energy barriers including the temperature thermodynamic effect.

ΔE (kcal/mol)

ΔH (kcal/mol)

ΔS (kcal/mol)

ΔG (kcal/mol)

ΔΔG (kcal/mol)

Boltzmann ratios

TS4+2ENDO 2.47265 2.89998 -15.99664 18.89708 0.0 95.6TS4+2EXO 5.16008 5.57487 -15.16391 20.73926 1.84218 4.4

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References

1. M. J. T. Frisch, 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-Young, D.; 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.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J., Gaussian 16, Revision B.01, Gaussian, Inc., Wallingford CT2016.

2. Y. Zhao and D. G. Truhlar, Theor. Chem. Acc., 2008, 120, 215-241.3. W. J. Hehre, L. Radom, J. A. Pople and P. v. R. Schleyer, Ab Initio Molecular Orbital Theory,

Wiley, New York1986.4. (a) G. Scalmani and M. J. Frisch, J Chem Phys, 2010, 132, 114110; (b) J. Tomasi, B. Mennucci

and E. Cancès, Journal of Molecular Structure: THEOCHEM, 1999, 464, 211-226; (c) V. Barone, M. Cossi and J. Tomasi, J. Comput. Chem., 1998, 19, 404-417; (d) E. Cancès, B. Mennucci and J. Tomasi, The Journal of Chemical Physics, 1997, 107, 3032-3041; (e) B. Mennucci and J. Tomasi, The Journal of Chemical Physics, 1997, 106, 5151-5158; (f) V. Barone, M. Cossi and J. Tomasi, The Journal of Chemical Physics, 1997, 107, 3210-3221.

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NMR Spectra of Coumarins

3-Benzoyl-2H-chromen-2-one (12a)

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3-Benzoyl-6-bromo-2H-chromen-2-one (12b)

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3-Acetyl-6-bromo-2H-chromen-2-one (12c)

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Ethyl 6-bromo-2-oxo-2H-chromene-3-carboxylate (12d)

S8