New optically active pyrazoles: Syntheses and the structural characterization of menthopyrazole analogues

Abstract

New chiral pyrazoles, (4R, 7R)-4-methyl-7-isopropyl-3-phenyl-(3-phenyli s omenthopyrazole; c i s -1) , (4R,7S)-4-methyl-7-isopropyl-(l-menthopyrazole; trans-2), (4R,7R)-4-isopropyl-7-methyl-(isocarvomenthopyrazole, c i s-3) and (4R, 7S) -4 -i s o p r o p y l -7 -m e t h y l -4 , 5 , 6 , 7 -t e t r a h y d r o -1H-indazole (carvomenthopyrazole, trans-3) were prepared. The diastereomeric pairs of these 1-3 were structurally characterized by NMR spectroscopy. The subtle differences of structures of 1-3 should induce the useful effects for a chiral auxiliary or a chiral catalyst. , 7 -t e t r a h y d r o -1H-indazole (3-phenyl-l -m e n t h o p y r azole; trans-1) as a chiral auxiliary [1]. This auxiliary is easily prepared from commercially available l-menthone in good yield with high optical purity, and has unique structure and properties relative to the conventional chiral auxiliaries [2]. The most important characteristics of this auxiliary are that the substrate terminates to nitrogen atom of heteroaromatic pyrazole ring and that the 3-phenyl ring of trans-1 is close to the (4R)-methyl group. Subsequently, the steric repulsion is relaxed by rotation of the phenyl ring, and the substrate is located in the chiral environment. This structural feature causes the diastereofacial attack on the substrate moiety in the reactions with alkyl halides [3], diphenyldisulfide [4], acyl chloride [5], aldehydes [6], and C=N compounds [7]. Moreover, the asymmetric additions of Grignard reagents [8], dienes [9] and 1,3-dipolar compounds [10] on 2-(α , βu n s a t u r a t e d ) a c y l -3 -p h e n y l-l -m e nthopyrazoles have been reported. Otherwise, the extensive use of these optically active pyrazoles was studied as the chiral catalyst for the asymmetric borane reduction of ketones [11,12] and the asymmetric dialkylzinc addition on aldehydes [13].

Stereocontrolled Syntheses of (−)-Cubebol and (−)-10-Epicubebol Involving Intramolecular Cyclopropanation of α-Lithiated Epoxides

“…Formylation of menthone, under now standard alkoxide/formate ester conditions, was originally reported by Claisen, and was also initially examined in the first synthesis of (−)-cubebol by Yoshikoshi, but the approach was abandoned due to the formation of “an inseparable mixture of epimers” . Subsequently, Tolman noted the generation of a 7:93 epimeric mixture during formylation of menthone using NaOMe/HCO 2 Et and, in a key study, Kashima and co-workers found an identical ratio to Tolman with the (currently undesired) cis-isomer predominating, when starting with menthone (or isomenthone) and using NaH/HCO 2 Et . However, Kashima also observed that the use of LDA (−78 °C) followed by HCO 2 Et led to a 75:25 mixture in favor of the trans isomer.…”

“…5b Subsequently, Tolman 19 noted the generation of a 7:93 epimeric mixture during formylation of menthone using NaOMe/ HCO 2 Et and, in a key study, Kashima and co-workers found an identical ratio to Tolman with the (currently undesired) cisisomer predominating, when starting with menthone (or isomenthone) and using NaH/HCO 2 Et. 20 However, Kashima also observed that the use of LDA (-78 °C) followed by HCO 2 Et led to a 75:25 mixture in favor of the trans isomer. The latter result could be improved in our hands to give hydroxymethylenementhone (12) (55%, S:R = 98:2 at C-6, Scheme 3) by using HCO 2 CH 2 CF 3 , which was introduced by Zayia for "kinetic formylation".…”

“…Purification of the residue by column chromatography (20% Et 2 O in light petrol) gave (-)-cubebol (1) (283 mg, 85%, 97:3 mixture 11 ) as a crystalline solid; mp 60-61 °C (lit. 10 (1S,4S,5S,6S,7S,10R)-7-Isopropyl-10-methyltricyclo[4.4.0.0 1,5 ]decan-4-ol (20). Unsaturated terminal epoxide 19 (304 mg, 1.46 mmol) was reacted according to General Procedure 2.…”

“…In our hands, formylation gave mainly hydroxymethyleneisomenthone (28) (83%, 93:7 inseparable mixture with hydroxymethylenementhone (12), Scheme 7), in agreement with the prior observations of Tolman 19 and of Kashima. 20 The origin of the almost complete i-Pr epimerization during the formylation of menthone with alkoxide and a formate ester (also observed during Claisen-Schmidt condensations) 28 is not obvious; indeed, several applications of this chemistry erroneously assume the configuration is unchanged during this process. 17b,23c,29 Subjecting hydroxymethylenementhone (12) to the classical formylation conditions for 3 days returned, as expected, mainly starting material (12:28, 80:20).…”

“…The reaction mixture was extracted with CH 2 Cl 2 (3 Â 50 mL) and the combined organic layers were washed with 10% aq NaHCO 3 (2Â50 mL), dried (MgSO 4 ), and concentrated under reduced pressure to give d-menthone (ent-11) (4.8 g, 97%) as a colorless oil; R f 0.4 (4% ether in petrol); [R] D 25 þ29.4 (c 0.4, CHCl 3 ) (lit. 42 [R] 20 D þ19.0 (c 10.0, EtOH)). Other data as l-menthone 11, see above.…”