2.1 Introduction
2.1.2 Organocatalyzed nucleophilic azidation reactions
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.
The established chemistry to open epoxides with high facial selectivity use chiral Lewis acids, such as chromium124, zirconium125, and zinc126. Similar Lewis acids have been applied to the enantioselective ring opening reaction of meso- or racemic aziridines. Some notable examples being ytterbium127, chromium128, and magnesium129. This work showcased the ability of chiral Lewis acids to impart facial selectivity in nucleophilic ring openings of strained ring systems.
The Antilla lab established that chiral Brønsted acid catalysis is effective in the activation of aziridine rings toward nucleophilic ring opening with selectivity.130 Using a chiral phosphoric acid (CPA) catalyst to activate aziridine rings, they were able to control the addition of TMSN3. Initial mechanistic studies indicated that trimethylsilyl group was critical for facial selectivity, as sodium azide was not reactive in the presence of CPA catalyst. Notably, when the CPA ligand was not employed, sodium azide successfully opened the aziridine ring. Because it is known that basic atoms may activate silane compounds into donating a nucleophile, the Antilla group proposed the transition state shown below in Figure 53. Notably, this mechanism has been disputed by the Della Sala group.131 Because commercially available phosphoric acids contain variable amounts of metallic impurities, Della Sala proposed that trace impurities may play a role in the catalytic cycle. It was observed that when the CPA ligand was washed with acid prior to its use in this ring opening, racemic product was isolated. This work indicates that a chiral Lewis acid may still be required in aziridine addition reactions.
124 Martinez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117, 5897.
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127 Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 6312.
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130 Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 12084.
131 Della Sala, G. Tetrahedron 2013, 69, 50.
The other primary field of study in enantioselective nucleophilic azide additions is the conjugate addition to electron deficient alkenes, such as α,β-unsaturated carbonyl compounds, nitroalkenes, and allenes. Most examples of enantioselective allene functionalization utilize transition-metal catalysis,132,133,134 however, there are a number of organocatalyzed azide additions to other electron deficient olefins. The Miller group investigated β-peptides as organocatalysts to direct the addition of hydrazoic acid to unsaturated imides (Figure 54).135 The mechanism of activation is unclear with these catalysts, however they did not observe any non- linear effects, so they propose that the ligand operates as a monomeric form.136,137 A subsequent investigation into this reaction found that selectivity could be improved by employing a β- substituted His derivative.138 This modification improved ee on their test substrate from 63% ee to 85% ee. Additionally, they were able to improve reactivity at reduced temperatures and expand their substrate scope to include a more diverse library of unsaturated imides.
132 Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959.
133 Zhou, P.; Lin, L.; Chen, L.; Zhong, X.; Liu, X.; Feng, X. J. Am. Chem. Soc. 2017, 139, 13414.
134 Khrakovsky, D. A.; Tao, C.; Johnson, M. W.; Thornbury, R. T.; Shevick, S. L.; Toste, F. D. Angew. Chem. Int.
Ed. 2016, 55, 6079.
135 Horstmann, T. E.; Guerin, D. J.; Miller, S. J. Angew. Chem. Int. Ed. 2000, 39, 3635.
136 Satyanarayana, T.; Abraham, S.; Kagan, H. B. Angew. Chem. Int. Ed. 2009, 48, 456.
137 Guillaneux, D.; Zhao, S.-H.; Samuel, O.; Rainford, D.; Kagan, H. B. J. Am. Chem. Soc. 1994, 116, 9430.
138 Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124, 2134.
Figure 53: Evaluation of enantioselective aziridine opening using TMSN3 nucleophile.
The Alemán group employed a quinine-derived squaramide ligand to direct TMSN3 to enones in high ee.139 Unlike most examples of azide additions in organocatalysis, the authors did not generate hydrazoic acid in situ. This is an interesting deviation from established work, where authors noted that a hydrogen bond acceptor was needed for nucleophilic control. After investigating the role of water as an additive, the authors observed a rate acceleration in the presence of water. Computation studies supported a mechanistic hypothesis wherein water served to activate TMSN3 via hydrolysis, and in further support of this hypothesis, the formation of trimethylsilanol was noted by 1H and 29Si NMR. The work of both Miller and Alemán is a significant addition to the field, despite their limited scope. The Miller group’s conditions were only applied to imides and the Alemán group was limited to aryl ketones. The identification of a chiral ligand, and its development into a catalyst that is both highly selective and widely applicable would greatly increase the utility of this chemistry.
Nitroalkanes are pronucleophiles that have been investigated in the functionalization of electron-poor alkenes. Nitroalkanes are synthetically versatile, and the nitro group is often considered a ‘protected’ form of amine. The enantioselective addition of azide to nitroalkenes
139 Humbrías-Martín, J.; Pérez-Aguilar, M. C.; Mas-Ballesté, R.; Dentoni Litta, A.; Lattanzi, A.; Della Sala, G.;
Fernández-Salas, J. A.; Alemán, J. Adv. Synth. Catal. 2019, 361, 4790.
Figure 54: Evaluation of asymmetric azide additions to enones.
was discovered by the Jørgensen group using a ligand derived from cinchonine.140 While selectivity was modest, their work served as a proof of concept. They investigated the role of acidic additives in this chemistry and observed a profound effect on selectivity. Despite a large investigation, a single acid could not be identified to be applied broadly. Different substrates required different acids for optimal results. Della Sala applied a bifunctional thiourea ligand to direct the addition of hydrazoic acid to nitroalkenes.141 This work was an improvement over previous work, showing moderate selectivity in a variety of substrates. However, neither Della Sala nor Jørgensen found conditions to direct the azide to nitrostyrenes. (Figure 55)
There is a clear need to develop better conditions to catalyze the addition of azides to electron- deficient alkenes. We proposed that BAM catalysis could be adapted to additions of this type, with the overall goal to broaden the scope to include azide nucleophiles and nitroalkene electrophiles with an expanded tolerance while remaining highly selective.