Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
A series of novel menthone oxime ethers were synthesized in three steps starting from
(–)-menthol. Analysis of the 13C NMR chemical shift differences between a carbons of
oxime derivatives (O-alkyl oximes) provides a convenient and reliable means of assigning
oxime stereochemistry. It has been found that carbons syn to the oxime are shifted more
upfield than carbons anti to the oxime moiety. Significant E products were obtained.
13
Keywords: C NMR; chemical shifts; menthone oxime ethers; oxime configuration
INTRODUCTION
Menthol and related compounds are widely used in products ranging from
common cold medications to pesticides. The most commercially utilized isomer is
(–)-menthol, which not only has a pleasant minty aroma and taste but also potential
to chemically trigger cold-sensitive TRM8 receptors in the skin to produce a cooling
sensation.[1] In addition, menthol is endowed with analgesic properties[2] and
increases the efficacy of ibuprofen in topical uses via vasodilatation, which decreases
skin barrier function.[3] Based on menthol’s wide range of biological activity, we
decided to prepare a series of O-alkylated menthone oxime derivatives. To the best
of our knowledge, there has been only one example of oxime ether reported (Table 1,
entry 1).
Garner and coworkers studied menthone, isomenthone, and their
tosylhydrazones.[4] In their work, methone was found to adopt a chair conformation
in which both side chains were equatorially oriented, which was proved by x-ray
analysis.[5]
3101
3102 S. FAISAL ET AL.
The 13C NMR data of menthone show approximately the same shifts as its
oxime ether, but there is greater difference in the shifts of carbon-2 (a2) and carbon-6
(a1). Calculation of D syn a1 (Table 2) shows that the greater upfield shift (18–20) of
carbon (a1) is due to additional shielding by the lone pairs of oxygen, which gives
the same effect for all synthesized E-derivatives. Comparison of the 13C NMR of
13
Table 3. C NMR chemical shift (ppm) for (E)-menthone oxime ethers
Entry
1 212.4 161.71 160.8 160.43 161.0 162.33 160.54 160.42 160.50 162.2 161.0 160.43
2 55.9 48.72 48.52 48.47 48.55 48.59 48.57 48.56 48.46 47.44 48.62 48.56
3 27.8 26.78 26.57 26.61 26.64 26.71 26.62 26.52 26.52 26.54 26.73 26.48
4 33.94 32.68 32.01 32.07 32.06 32.33 32.25 31.96 31.96 30.62 32.15 31.93
5 35.47 32.34 31.91 32.03 32.17 32.17 32.06 31.92 31.98 29.63 32.11 31.97
6 50.88 31.72 31.96 32.02 29.72 32.14 32.20 31.92 31.94 33.35 32.26 31.83
7 25.90 26.36 26.43 26.49 26.50 26.47 26.46 26.48 26.47 26.49 26.51 26.52
8 18.70 21.38 19.37 19.38 19.36 19.31 19.28 19.44 19.44 20.84 19.39 19.43
9 22.29 19.1 20.97 21.03 21.08 21.48 21.11 20.96 20.97 22.50 21.07 20.96
10 21.22 21.7 21.53 21.15 21.51 21.07 21.50 21.53 21.54 21.98 21.55 21.52
11 61.0 68.47 74.03 60.66 69.84 73.17 72.90 74.98 73.74 73.19
12 14.82 135.0 77.33 120.87 28.97 28.76 138.5 35.95 29.27
13 16.66 77.22 136.82 28.20 25.34 127.4 139.17 25.96
14 25.86 22.55 33.58 128.2 129.05 29.16
15 18.15 14.07 138.9 127.8 128.24 31.91
16 114.3 126.00 22.61
17 14.09
menthone and its oxime ether proves that O-alkylation gives predominantly the E
isomer. The complete carbon shifts for menthone oxime ethers are given in Table 3.
EXPERIMENTAL
1
H NMR spectra were recorded at 400 MHz in CDCl3 using tetramethylsilane
(TMS) as internal standered. (–)-Menthol was purchased from Sigma Aldrich
Chemicals Limited.
Spectral Data
(2S,5R)-2-Isopropyl-5-methylcyclohexanone O-methyloxime (3). IR
(KBr, cm1): 2957, 2927, 2857, 1644, 1460, 1054, 873; 1H NMR (CDCl3, d ppm):
1.79 (m, 1H), 1.37 (m, 1H), 1.82 (m, 2H), 1.21 (m, 1H), 1.84 (m, 1H), 2.10
(m, 1H), 1.36 (dd, 1H), 2.76 (dd, 2H, J ¼ 8.1 Hz), 0.89 (d, 3H, J ¼ 6.71 Hz), 0.92
(d, 3H, J ¼ 6.42 Hz), 3.79 (s, 3H); HRMS (EI) calcd. for C12H21ON: 183.1623;
observed: 183.1675.
3106 S. FAISAL ET AL.
CONCLUSION
Inspired by the importance of menthol and its derivatives for varied medicinal
importance, the novel oximes ethers were synthesized, and predominantly E-isomers
were obtained. The stereochemical assignments were carried out using 13C NMR. The
NMR chemical shift differences between a-carbons of oxime derivatives provided
a convenient and reliable means of assigning novel O-alkyl oximes’ stereochemistry.
ACKNOWLEDGMENT
The authors are thankful for the financial support from the H. E. J. Research
Institute of Chemistry, International Center for Chemical and Biological Sciences.
Two of us, S. F. and H. S., wish to thank the Umaer Basha Foundation for generous
financial support.
REFERENCES
1. Eccles, R. Menthol and related cooling compounds. J. Pharm. Pharmacol. 1994, 46,
618–630.
2. Galeottia, N.; Mannellia, L. D. C.; Mazzantib, G.; Bartolinia, A.; Ghelardini, C.
Menthol: A natural analgesic compound. Neurosci. Lett. 2002, 322, 145–148.
3. Braina, K. R.; Greena, D. M.; Dykesb, P. J.; Marksb, R.; Bola, T. S. The role of menthol
in skin penetration from topical formulations of ibuprofen 5% in vivo. Skin Pharmacol.
Physiol. 2006, 19, 17–21.
4. Zhukovskaya, N. A.; Dikusar, E. A.; Moiseichuk, K. L.; Vyglazov, O. G. Preparative
synthesis of menthone oxime esters. Russ. J. Appl. Chem. 2006, 79, 634–636.
5. Mullica, D. F.; Garner, C. M.; Prince, M. E.; Mossman, B. C.; Sappenfied, E. L. Structure
analyses of menthone- and isomenthone-tosylhydrazones, C17H26N2O2S. J. Crystallogr.
Spectrosc. Res. 1992, 22, 515–522.
6. Hussey, A. S.; Baker, R. H. Chromic acid oxidation of cyclohexanols to cyclohexanones.
J. Org. Chem. 1960, 25, 1434.
7. Lochynski, S.; Kuldo, J. Stereochemistry of terpene derivatives, part 2: Synthesis of
new chiral amino acids with potential neuroactivity. Tetrahedron: Asymmetry 2000, 11,
1295–1302.
3108 S. FAISAL ET AL.
8. Naulet, N.; Filleux, M. L.; Martin, G. J.; Pronet, J. A Carbon-13 NMR study of
compounds containing C=N or conjugated C-N bonds, iminoethers, imines, amidines,
oximes, phenylhydrazones, semicarbazones. Org. Mangn. Reson. 1975, 7, 326–330.
9. Levy, G. C.; Nelson, G. L. Carbon-13 NMR study of aliphatic amides and oximes:
Spin-lattice relaxation times and fast internal motions. J. Am. Chem. Soc. 1972, 94,
4897–4901.
10. Smith, B. W.; Amezcua, C. A. NMR vs. molecular modeling, part IV: Conformational
analysis of menthone and isomenthone imines. Magn. Reson. Chem. 1999, 37, 110–118.
11. Bunnell, C. A.; Fuchs, P. L. Rapid and unequivocal determination of syn–anti stereo-
chemistry for toluenesulfonylhydrazones and other imine derivatives via carbon-13
nuclear magnetic resonance spectroscopy: A synthetic adjunct. J. Org. Chem. 1977, 42,
2614–2617, and references cited therein.
Copyright of Synthetic Communications is the property of Taylor & Francis Ltd and its content may not be
copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.