Green protection of pyrazole, thermal isomerization and deprotection of tetrahydropyranylpyrazoles, and high-yield, one-pot synthesis of 3(5)-alkylpyrazoles

Abstract

We report a new synthetic approach that opens up the possibility of large scale, one-pot pyrazole derivatization by a wide variety of functionalities, including alkyl, halogen, hydroxyl, amino, azido, carbonyl, and organo-element (e.g., B, Si, P) groups. The approach is illustrated by the highly efficient synthesis of fourteen 3(5)-alkylpyrazoles, including the novel isopentyl-and n-hexadecyl derivatives, as well as 1,6-bis(pyrazol-3(5)-yl)hexane. The value of the new approach lies in the discovery of a green (solvent-and catalyst-free, quantitative) protection of pyrazole, followed by a high-yield lithiation/ alkylation/deprotection sequence in the same pot. For the first time, the corresponding N-tetrahydropyran-2-yl (THP) intermediates have been isolated and characterized. Thermal isomerization of the 5-alkyl-1-(THP) to the 3-alkyl-1-(THP) isomer is shown to be an advantageous, green alternative to the acid-catalyzed, sequential protecting-group switching methodology in pyrazole chemistry. The X-ray crystal structures of 1,6-bis(pyrazol-3(5)-yl)hexane and 5-n-hexadecyl-1-(tetrahydropyran-2-yl)pyrazole reveal supramolecular architectures that shine light on the remarkable affinity for water and unexpected insolubility in organic solvents of alkylene-bridged bis(pyrazoles).3(5)-Alkylpyrazoles are obtained in high yield from pyrazole by a one-pot procedure. † Electronic supplementary information (ESI) available: 1 H NMR and 13 C NMR spectra of all intermediates and nal products, CIF les for 1,6-bis(pyrazol-3(5)-yl)hexane hydrate and 5-n-hexadecyl-1-(tetrahydropyran-2-yl)pyrazole. CCDC 1040198 and 1040199. For ESI and crystallographic data in CIF or other electronic format see Scheme 1 Current strategies for the synthesis of 3(5)-alkylpyrazoles (R ¼ alkyl group).Scheme 2 Synthesis of 3(5)-alkylpyrazoles by alkylation of pyrazole (DHP ¼ 3,4-dihydro-2H-pyran; R ¼ primary alkyl group; X ¼ I or Br).24082 | RSC Adv., 2015, 5, 24081-24093This journal is

Adjacent Lone Pair (ALP) Effect: A Computational Approach for Its Origin

“…Extensive studies have been conducted on these molecules in order to understand their physical properties and reactivity . In the study of their intrinsic basicities and regioselectivity, however, an interesting phenomenon emerges, that is, the adjacent lone pair (ALP) effect, which states that “a ring‐nitrogen atom bearing an sp 2 lone pair provides a sizable electrostatic obstacle (not Pauli repulsion) to the generation of an sp 2 carbanion at an adjacent ring‐carbon atom” . Notable examples with the ALP effect include the absence of lithiation of 1‐methylpyrazole and 1‐phenylpyrazole at the 3‐position (Scheme ), the higher CH acidity at the 5‐position in a series of N ‐aryl, N ‐methylpyrazoles and N ‐methylimidazole, the lower acidity of the 4‐position of pyrazole demonstrated by both experimental and density function theory studies, and no evidence for any halogen‐metal exchange of imidazole at the 4‐position or of pyrazole at the 3‐position –…”

Development of a Scalable Negishi Cross-Coupling Process for the Preparation of 2-Chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)aniline

“…As we anticipated it could be difficult to purge high levels of these structurally similar side products ( vide infra ) in subsequent steps, we focused efforts on identifying milder conditions to selectively functionalize the 5-position of 2 . In particular, pyrazole 2 is known to undergo selective deprotonation at the 5-position at −78 °C with n -butyllithium ( n -BuLi), followed by trapping with an alkyl electrophile. , We hypothesized that transmetalation of the heteroaryl lithium of 2 to an appropriate zinc salt would generate a heteroaryl zinc reagent in situ that could participate in Negishi cross-coupling with 3 to generate 1 . , Proof-of-concept experiments suggested that this was the case, with 1 formed selectively and no observable overfunctionalization of the aniline ring (Scheme ).…”

Drastic Deprotonation Reactivity Difference of 3- and 5-Alkylpyrazole Isomers, Their I2-Catalyzed Thermal Isomerization, and Telescoping Synthesis of 3,5-Dialkylpyrazoles: The “Adjacent Lone Pair Effect” Demystified

“…Protection of 1H-Pyrazole. THP protection of 1H-pyrazole is accomplished according to our green method previously described 16 by heating 1.200 g (17.62 mmol) of 1H-pyrazole and 2.00 mL (1.85 g, 22.0 mmol) of 3,4-dihydro-2H-pyran for 24 h at 125 °C. After removal of the slight excess of DHP in vacuum, 2.68 g (100%) of pure 1-(tetrahydropyran-2-yl)pyrazole is obtained.…”

“…The liberated protecting group alkylates the next substrate and propagates the reaction. In our case (Figure ), the alkylating agent is presumed to be 2-iodotetrahydropyran, which initially forms from the reaction of 3,4-dihydro-2 H -pyran (formed in trace amounts as a result of partial deprotection of the substrate upon heating) with HI (formed from the reaction of I 2 with the pyrazole ring, leading to 4-iodopyrazole). Alternatively, I 2 can react directly with 3,4-dihydro-2 H -pyran to produce 2,3-diiodotetrahydropyran, which can react similarly to 2-iodotetrahydropyran as the initial alkylating agent.…”

“…Although the isomerization step of 5-alkyl-to 3-alkyl-1-THPpyrazole can be accomplished by simple heating, 16 a catalytic amount of iodine (I 2 ) greatly reduces the reaction time needed to reach equilibrium. This discovery is rooted in our observation that when 5-hexyl-1-THP-pyrazole is prepared from 1-iodohexane, it undergoes isomerization much faster than when it is prepared from 1-bromohexane under the same conditions.…”