2.1 Introduction
2.1.1 Organocatalyzed additions to nitroalkenes
100 Berner, Otto M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 2002, 1877.
101 Noland, W. E. Chem. Rev. 1955, 55, 137.
102 Tamura, R.; Kamimura, A.; Ono, N. Synthesis 1991, 1991, 423.
103 Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339.
Asymmetric conjugated additions to nitroalkenes have been broadly studied using chiral auxiliaries104, metal catalysts105, and organocatalysis.100 This section will focus on the development of chiral ligands to affect the addition of various nucleophiles to nitroalkenes. A prominent area of focus has been on the addition of carbonyl-based nucleophiles, with an emphasis on aldehydes, ketones, and 1,3-dicarbonyls. (Figure 50) The predominating mode of activation for aldehyde-based nucleophiles is via enamine catalysis. The Han group developed rigid bicyclic proline-like compounds that catalyze the addition of aldehydes to nitroalkenes.106
L-Proline only furnished the nitroalkane in 25% ee, but this bicyclic catalyst was highly reactive at 5 mol % catalyst loadings and furnished the product in up to 94% ee and high dr. Another approach for proline catalysis was well-illustrated by the Wei, Lin107, and the Paixão108 groups.
Both labs found that derivatizing the acid of L-proline via amide-bond forming reactions enabled them to develop highly selective catalysts. Wei prepared sterically encumbered amides, installing
104 Fernández, R.; Gasch, C.; Lassaletta, J.-M.; Llera, J.-M. Tetrahedron Lett. 1994, 35, 471.
105 Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122, 10716.
106 Yu, H.; Liu, M.; Han, S. Tetrahedron 2014, 70, 8380.
107 Wang, Y.; Li, D.; Lin, J.; Wei, K. RSC Adv. 2015, 5, 5863.
108 de la Torre, A. F.; Rivera, D. G.; Ferreira, M. A. B.; Corrêa, A. G.; Paixão, M. W. J. Org. Chem. 2013, 78, 10221.
Figure 50: Evaluation of organocatalysis employed in asymmetric additions to nitroalkenes.
an N-adamantly group. They observed a clear trend that as the amide substituent increased in size, selectivity improved. The Paixão group ligand development showcased a similar trend, however, small peptide chains were investigated instead of substituted amines. Another common proline catalyst derivative is the Jørgensen-Hayashi catalyst, utilized by Oger and coworkers.109 Some have sought to move beyond proline catalysis, using bifunctional Brønsted acid/base activation. The Gómez-Bengoa110 and Blackmond111 groups both used hydrogen-bond activation to impart facial selectivity. The Gómez-Bengoa utilized a chiral quinidine scaffold to activate the nitroalkene via hydrogen bonding, while the Blackmond group applied a thiourea ligand.
Similar approaches to catalyze the addition of ketones to nitroalkenes were employed, using both enamine112,113,114 and bifunctional catalysis115. Because ketones are less-electrophilic than aldehydes, hydrogen-bonding is a more broadly studied area of catalysis for these substrates.
Additionally, a variety of bifunctional catalysts have been developed for 1,3- dicarbonyls.116,117,118 These additions have served as a method to prepare carbon-carbon bonds in high ee, with both the carbonyl and nitroalkane groups serving as synthetic handles for further modification.
Because there have been a number of successful additions of enols to nitroalkenes to prepare carbon-carbon bonds, many have used these reactions as a template for future work with other strong carbon acids (pKa ~ 10). Nitroalkanes are strong carbon acids, owing to the strong electron-withdrawing effect of the nitro group. For this reason, nitroalkanes may undergo similar addition reactions as carbonyls, while also introducing different functionality. A number of labs have investigated the addition of nitroalkanes to nitroalkenes to prepare 1,3-dinitroalkanes in high ee and dr. (Figure 51) The Wang lab developed a bifunctional amine-thiourea ligand with
109 Candy, M.; Durand, T.; Galano, J.-M.; Oger, C. Eur. J. Org. Chem. 2016, 2016, 5813.
110 Fernandes, T. d. A.; Vizcaíno-Milla, P.; Ravasco, J. M. J. M.; Ortega-Martínez, A.; Sansano, J. M.; Nájera, C.;
Costa, P. R. R.; Fiser, B.; Gómez-Bengoa, E. Tetrahedron: Asymmetry 2016, 27, 118.
111 Ji, Y.; Blackmond, D. G. Catal. Sci. Technol. 2014, 4, 3505.
112 Mahato, C. K.; Kundu, M.; Pramanik, A. Tetrahedron: Asymmetry 2017, 28, 511.
113 Nakashima, K.; Hirashima, S.-i.; Kawada, M.; Koseki, Y.; Tada, N.; Itoh, A.; Miura, T. Tetrahedron Lett. 2014, 55, 2703.
114 Liu, F.-L.; Chen, J.-R.; Feng, B.; Hu, X.-Q.; Ye, L.-H.; Lu, L.-Q.; Xiao, W.-J. Org. Biomol. Chem. 2014, 12, 1057.
115 Capitta, F.; Frongia, A.; Ollivier, J.; Aitken, D. J.; Secci, F.; Piras, P. P.; Guillot, R. Synlett 2015, 26, 123.
116 Işık, M.; Unver, M. Y.; Tanyeli, C. J. Org. Chem. 2015, 80, 828.
117 Kastl, R.; Arakawa, Y.; Duschmalé, J.; Wiesner, M.; Wennemers, H. Chimia 2013, 67, 279.
118 Tukhvatshin, R. S.; Kucherenko, A. S.; Nelyubina, Y. V.; Zlotin, S. G. ACS Catalysis 2017, 7, 2981.
multiple hydrogen bond donors.119 These hydrogen bond donors served to activate both -NO2
groups, for activation of both nucleophile and electrophile to control facial selectivity. To verify this, it was observed that if the sulfonamide residue is methylated, no addition product is observed. Notably, to achieve full conversion, a large excess of nitroalkane was used as a solvent. The Tanyeli group published the same reaction using a quinine squaramide chiral ligand.
Similarly, a large excess of nitroalkane was employed. The Johnston lab developed conditions for this reaction using one of their bisamidine ligands.32 This catalyst proved to be highly efficient, necessitating only five equivalents of nitroalkane to achieve full conversion. To illustrate the broad utility of these addition products, the authors prepared anti-β2,3-amino amides in two steps.
The derivation of nitroalkanes via asymmetric Michael additions has primarily focused on carbon-carbon bond forming reactions. Because these transformations are an efficient method to introduce stereochemical complexity, expanding the scope of this work to include the formation of carbon-heteroatoms is an important and underdeveloped area of study. A number of bifunctional organocatalysts have been investigated in the addition of heteroatom-based nucleophiles, as shown below in Figure 52. It can be difficult to influence heteroatom-derived nucleophiles using hydrogen bond catalysts because the basicity of the substrate can deactivate the chiral ligand. To mitigate these potential issues, most nucleophiles are deactivated by an
119 Dong, X.-Q.; Teng, H.-L.; Wang, C.-J. Org. Lett. 2009, 11, 1265.
Figure 51: Evaluation of organocatalyzed nitroalkanes additions to nitroalkenes.
electron-deficient protecting group. As shown in previous examples, thioureas proved to be an effective hydrogen bond donor.120 The Herrera lab carried out an aza-Michael addition to prepare β-nitrohydrazides. This served as an interesting alternative to established methods, such as aza- Henry reactions. They propose that the hyrazide is directed via Brønsted base catalysis, where the trisubstituted amine of the ligand hydrogen bonds with the hydrazide. The Wang group utilized a thiourea ligand derived from cinchonine to direct the addition of phthalimide to nitrolefins.121 The products of this transformation are useful because the phthalimide is a known precursor to amines, making this transformation a useful method to prepare enantioenriched benzylic amines.
The Xiao group illustrated the application of the same thiourea ligand to affect the addition of oximes to nitroalkenes as a method to prepare enantioenriched amino alcohols.114 Both the oxime and the nitroalkane may be selectively deprotected, making selective functionalization of the
120 Alcaine, A.; Marqués-López, E.; Herrera, R. P. RSC Adv. 2014, 4, 9856.
121 Ma, S.; Wu, L.; Liu, M.; Huang, Y.; Wang, Y. Tetrahedron 2013, 69, 2613.
Figure 52: Evaluation of various nucleophiles in nitroalkene additions.
respective heteroatoms relatively straightforward. The Wang group employed a cinchona alkaloid catalyst to direct the addition of triazoles to nitroalkenes.122 A few other heterocycles were investigated in this reaction, though extended reaction times were required for reactivity.
The Yuan group sought to control the addition of thiophenols to trisubstituted nitroalkenes to prepare tertiary thioethers in high ee.114 The products of this reaction may be derivatized to β2,2- amino acids. Similar to the hydrazide chemistry published by the Herrera lab, the thiourea serves to activate the nitroalkene while the trisubstituted amine residue activates the thiophenol via hydrogen bonding.
The preparation of enantioenriched nitroalkanes is an active field since they may be derivatized to a wide variety of small molecule scaffolds. Many groups have studied asymmetric Michael additions to nitroalkenes, though most have focused on the formation of carbon-carbon bond forming reactions. There is much to study in the addition of heteroatoms to nitroalkenes, where only a small number of catalysts and nucleophiles have been studied. The work detailed in this chapter seeks to expand the scope of these reactions to include azide nucleophiles. Additionally, we explored the application of bisamidine catalysis to functionalize nitroalkanes. This work is the first example of BAM catalysis effecting azide additions to nitroalkenes to form chiral carbon-nitrogen bonds using hydrazoic acid.