Richard N. Butler

Water: Nature’s Reaction Enforcer—Comparative Effects for Organic Synthesis “In-Water” and “On-Water”

3.1.2. Huisgen [3 + 2] Cycloaddition Reaction 6313 3.1.3. Claisen Rearrangement 6315 3.2. Multicomponent Reactions 6316 3.3. Nucleophilic Ring-Opening Reactions 6316 3.4. Wittig Reaction 6318 3.5. Bioorthogonal Reactions 6318 4. Catalyzed Reactions 6319 4.1. Metal-Catalyzed Reactions 6319 4.1.1. Pericyclic Reactions 6320 4.1.2. Arylation Reactions 6321 4.1.3. Olefin Metathesis 6323 4.1.4. Mizoroki-Heck Reaction 6324 4.1.5. Suzuki Reaction 6325 4.1.6. Sonogashira Reaction 6327 4.1.7. Transfer Hydrogenation 6327 4.1.8. Lewis Acid Catalysis 6328 4.2. Organocatalyzed Reactions 6330 4.2.1. Pericyclic Reactions 6330 4.2.2. Michael Reaction 6331 4.2.3. Mannich Reaction 6332 4.2.4. Aldol Reaction 6333 5. Conclusion 6334 6. Supporting Information Available 6335 7. References 6335

Recent Advances in Tetrazole Chemistry

Publisher Summary This chapter discusses the development of tetrazole chemistry from 1965 to 1975. Over the years, it has been noted that the field has grown rapidly, with regard to the industrial interest that the tetrazoles command. Some of the significant areas in this field include the applications of modern physical techniques to tetrazole derivatives and studies of pharmacologically active tetrazoles, particularly, replacement of the carboxylic acid group in known active molecules by its analog—the tetrazole ring. Tetrazole essentially is an aromatic azapyrrole nucleus, which exist in two tautomeric forms. The chapter also describes physicochemical studies. These studies include nuclear magnetic resonance spectroscopy and theoretical calculations, mass fragmentation, tetrazole complexes and crystal structures, and photolysis and tetrazole radicals. Tetrazole can be synthesized by several methods that are also presented in the chapter. In the context of azide-tetrazole isomerism, it is observed that polar solvents tend to favor the tetrazole form and nonpolar solvents the azide form. Another factor that influences this isomerism is the syn-anti isomerism about the C=N moiety.

A Ceric Ammonium Nitrate N-Dearylation of N-p-Anisylazoles Applied to Pyrazole, Triazole, Tetrazole, and Pentazole Rings: Release of Parent Azoles. Generation of Unstable Pentazole, HN5/N5-, in Solution

The reaction of cerium(IV) ammonium nitrate (CAN) with a range of N-(p-anisyl)azoles in acetonitrile or methanol solvents leads to N-dearylation releasing the parent NH-azole and p-benzoquinone in comparable yields. The scope and limitations of the reaction are explored. It was successful with 1-(p-anisyl)pyrazoles, 2-(p-anisyl)-1,2,3-triazoles, 2-(p-anisyl)-2H-tetrazoles, and 1-(p-anisyl)pentazole. The dearylation renders the p-anisyl group as a potentially useful N-protecting group in azole chemistry. The azole released in solution from 1-(p-anisyl)pentazole is unstable HN5, the long-sought parent pentazolic acid. p-Anisylpentazole samples were synthesized with combinations of one, two, and three 15N atoms at all positions of the pentazole ring. The unstable HN5/N5- produced at -40 degrees C did not build up in the solution but degraded to azide ion and nitrogen gas with a short lifetime. The 15N-labeling of the N3- ion obtained from all samples proved unequivocally that it came from the degradation of HN5 (tautomeric forms) and/or its anion N5- in the solution.

First generation of pentazole (HN5, pentazolic acid), the final azole, and a zinc pentazolate salt in solution: A new N-dearylation of 1-(p-methoxyphenyl) pyrazoles, a 2-(p-methoxyphenyl) tetrazole and application of the methodology to 1-(p-methoxyphenyl) pentazoleElectronic supplementary information (ESI) available: experimental details. See http://www.rsc.org/suppdata/cc/b3/b301491f/

Ceric ammonium nitrate (CAN) in methanol-water gave a new N-dearylation of a series of substituted 1-(p-methoxyphenyl) pyrazoles and a 2-(p-methoxyphenyl)tetrazole producing p-benzoquinone and the parent azole in a mole for mole ratio. Application of this reaction to 1-(p-methoxyphenyl) pentazole at -40 degrees C produced p-benzoquinone. 15N NMR spectra suggest that pentazole, HN5, was also produced and held in solution as N5- with Zn2+ ion. The 15N signal from N5- was -10.0 +/- 2.0 ppm in agreement with calculated values.

Water and Organic Synthesis: A Focus on the In-Water and On-Water Border. Reversal of the In-Water Breslow Hydrophobic Enhancement of the Normal endo-Effect on Crossing to On-Water Conditions for Huisgen Cycloadditions with Increasingly Insoluble Organic Liquid and Solid 2π-Dipolarophiles

Measurements of the endo/exo product ratios for Huisgen cycloadditions with a series of vinyl ketones, alkyl acrylates, and substituted styrenes as dipolarophiles with phthalazinium and pyridazinium dicyanomethanide 1,3-dipoles in acetonitrile and water show that as the reactions change from in-water (large hydrophobic enhancement of endo-products) to on-water, the hydrophobic enhancement of the endo-products is reduced and partially reversed (relative to acetonitrile). An expected increase of the endo-effect with increasing hydrophobic character of the dipolarophile is overcome by decreasing water solubility causing changeover to on-water conditions. On-water reactions do not show increased cycloaddition endo-effects (relative to organic solvents) as do in-water reactions.

Organic synthesis reactions on-water at the organic–liquid water interface

Organic reactions that occur at the water interface for water-insoluble compounds, and reactions in water solution for water soluble compounds, has added a powerful dimension to prospects for organic synthesis under more beneficial economic and environmental conditions. Many organic molecules are partially soluble in water and reactions that appear as heterogeneous mixtures and suspensions may involve on-water and in-water reaction modes occurring simultaneously. The behavior of water molecules and organic molecules at this interface is discussed in the light of reported theoretical and experimental studies. The on-water catalytic effect, relative to neat reactions or organic solvents, ranges from factors of several hundred times to 1-2 times and it depends on the properties of reactant compounds. In some cases when on-water reactions produce quantitative yields of water-insoluble products they can reach ideal synthetic aspirations.

A substituent correlation and medium effects on the annular tautomerism of substituted 5-aryltetrazoles: the nitrogen analogues of benzoic acids. A carbon-13 n.m.r. and dipole moment study

The annular tautomerism of substituted 5-phenyltetrazoles shows a linear correlation of log KT{KT=[N(1)H]/[N(2)H]} with the Hammett σ values of para-substituents. The tautomerism favours the 1H-form but electron-withdrawing substituents displace the equiliblium towards the 2H-form. Solvent dielectric permittivity and temperature effects also influence the annular tautomerism. A change of solvent from dimethyl sulphoxide to dioxane and an increase in temperature had similar effects in orienting the tautomerism towards the 2H-form, but the temperature effect was relatively small. Carbon-13 n.m.r. shifts and dipole moment analyses of the tautomerism gave complementary results.

Understanding “On-Water” Catalysis of Organic Reactions. Effects of H+ and Li+ Ions in the Aqueous Phase and Nonreacting Competitor H-Bond Acceptors in the Organic Phase: On H2O versus on D2O for Huisgen Cycloadditions

For a typical Huisgen cycloaddition, carried out on water, the behavior of water molecules at the oil-water interface depended on the properties of the reactants. With weakly basic reactants, a small quantity of added H(+) (HClO4, 0.0001-0.01 M) present in the aqueous phase had negligible effects, but larger quantities of H(+) (HClO4, 0.1-3.0 M) increased the catalytic effect and caused protons to cross the water-organic interface and affect the products. Added Li(+) ions (LiClO4, 0.1-3.0 M) had no effect for on-water reactions but enhanced the rates and endo products for in-water reactions. For these cycloaddition reactions, the product endo:exo ratios, when compared to those in organic solvents, can be used to distinguish between the on-water and in-water modes. Comparisons of organic reactions on H2O and on D2O indicate that on-water catalysis ranges from weak to strong trans-phase H-bonding for reactants with basic pK(a) < ca. -6 and to interfacial proton transfer for reactants with higher basic pK(a) > ca. 2 (pKa of conjugate acid). Water shows a chameleon-type response to organic molecules at hydrophobic surfaces.

8π-Six-atom rings: 1,3,4,5-oxa- and -thia-triazines and 1,2,3,5-tetrazines from an extended tandem reaction: reactions of 1,2,3-triazolium-1-imides with (E)-cinnamaldehyde, methyl cyanodithioformate, and aryl-N-sulphinylamines: new tetrahydro-oxazolo[4,5-d]-1,2,3-triazoliumides and triazaspiro-[4.4]nonanes. Azolium 1,3-dipoles. Part 4

The reactions of substituted 1,2,3-triazolium-1-imides with (E)-cinnamaldehyde, methyl Cyanodithioformate, and aryl-N-sulphinylamines gave rise to substituted 1,3,4,5-oxatrizines, 1,3,4,5-thiatriazines, and 1,2,3,5-tetrazines, respectively. Each of these is an 87π-six-atom ring. The routes were similar in each case and involved an extended tandem sequence of cycloaddition, rearrangement, fragmentation, and ring expansion. New oxazolo[4,5-d]-1,2,3-triazoles which were formed along the route to the 1,3,4,5-oxatriazines were isolated as stable compounds. The structures and reactivity of the 8π-six-atom rings are discussed. X-Ray crystal structures are reported for 4-(p-bromophenyl)-2,6-diphenyl-4H-1,3,4,5-oxatriazine (6b); 2,4,6-triphenyl-4H-1,3,4,5-thiatriazine (11a); 5-(p-bromophenyl)-2,5-dihydro-2,4,6-triphenyl-1,2,3,5-tetrazine (17b); 2,6-bis(p-bromophenyl)-3a,5,6,6a-tetrahydro-3a,6a-diphenyl-5exo-styryloxazolo[4,5-d]-1,2,3-tri-azol-2-ium-1-ide (4b); and 4-[(5′-methylisoxazol-3′-yl)imino]-2-(p-nitrophenyl)-1,2,3-triazaspiro[4.4]non-1-en-2-ium-3-ide (19b).

Azapropellanes: new fused tetra-azatriazolo[n.3.3.01,x]-dodecenes and tridecenes. Substituted 3,3a,4,5,6,6a-hexahydropyrrolo[2,3-d]-1,2,3-triazoles from a general tandem cycloaddition–rearrangement reaction of 1,2,3-triazolium imides with substituted alkenes: kinetics and mechanism: azolium 1,3-dipoles. Part 3

Reactions of substituted 1,2,3-triazolium-1-imide 1,3-dipoles with a range of substituted alkene and alkyne dipolarophiles gave rise to derivatives of the new ring systems hexahydropyrrolo[2,3-d]-1,2,3-triazoles and the azapropellanes tetra-aza-tricyclo[5.3.3.01,7]tridecenes and -tricyclo[4.3.3.01,6]dodecenes. The reactions, which are regio- and stereo-specific, are shown to be tandem 1,3-dipolar (endo) cycloadditions and sigmatropic rearrangements. X-Ray crystal structures of 6exo-ethoxycarbonyl-2,3a,4,6a-tetraphenyl-3,3a,4,5,6,6a-hexahydropyrrolo[2,3-d]-1,2,3-triazol-2-ium-3-ide (9a) and 12exo-cyano-8,10-diphenyl-7,8,9,10-tetra-azatricyclo[4.3.3.01,6]dodec-7-en-8-ium-9-ide (4a; m= 2) are reported.