O-alkylation of menthone oxime: Synthesis and 13C NMR studies of a series of novel oxime ethers

Article abstract of DOI:10.1080/00397910903370691

A series of novel menthone oxime ethers were synthesized in three steps starting from (-)-menthol. Analysis of the 13C NMR chemical shift differences between 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. Copyright Taylor & Francis Group, LLC.

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O-Alkylation of Menthone Oxime:
Synthesis and 13C NMR Studies of a Series
of Novel Oxime Ethers
Saqib Faisal a , Amina F. Basha b , Hina Siddiqui a & Fatima Z. Basha a
a H. E. J. Research Institute of Chemistry, International Center for
Chemical and Biological Sciences, University of Karachi, Karachi,
Pakistan
b Massachusetts Institute of Technology, Cambridge, Massachusetts,
USA
Published online: 13 Sep 2010.
To cite this article: Saqib Faisal , Amina F. Basha , Hina Siddiqui & Fatima Z. Basha (2010) O-
Alkylation of Menthone Oxime: Synthesis and 13C NMR Studies of a Series of Novel Oxime Ethers,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 40:20, 3101-3108, DOI: 10.1080/00397910903370691
To link to this article: http://dx.doi.org/10.1080/00397910903370691
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Synthetic Communications1, 40: 3101–3108, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903370691
O-ALKYLATION OF MENTHONE OXIME: SYNTHESIS
AND 13C NMR STUDIES OF A SERIES OF
NOVEL OXIME ETHERS
Saqib Faisal,1 Amina F. Basha,2 Hina Siddiqui,1
and Fatima Z. Basha1
1H. E. J. Research Institute of Chemistry, International Center for Chemical
and Biological Sciences, University of Karachi, Karachi, Pakistan
2Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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.
Keywords: 13C 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]
Received August 18, 2009.
Address correspondence to Fatima Z. Basha, H. E. J. Research Institute of Chemistry,
International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270,
Pakistan. E-mail: bashafz@gmail.com
3101

3102
S. FAISAL ET AL.
Table 1. Series of menthone oxime ethers

O-ALKYLATION OF MENTHONE OXIME
3103
RESULTS AND DISCUSSION
Commercially available (–)-menthol 1 was converted to menthone by oxidation
with sodium dichromate in sulfuric acid.[6] Menthone was converted to its oxime 2
in 80–90% yield with hydroxylamine ꢀ HCl in the presence of NaHCO3 in ethanol.[7]
O-Alkylation of the crystalline oxime 2 was accomplished using sodium hydride
as base at room temperature to produce a series of the desired O-alkylated menthone
oxime ethers 3–12 (Scheme 1). The synthesized menthone oxime gave two possible E-
and Z-products in a ratio of 9:1 on the basis of the amount isolated by column chro-
matography. There have been several literature reports on the 13C NMR spectra of
hydrazones,[8,9] indicating a substantial chemical shift difference between the syn and
the anti carbons and therefore suggesting the existence of E- and Z-isomers. However,
no detailed study of oxime O-ethers has been carried out, with the exception of methyl
analogs. In our present study, 13C NMR chemical shifts were used to identify E isomers
of a series of oxime ethers. The separation of the E- and Z-isomers by flash chroma-
tography predominantly gives the faster moving E-product.
1
The O-methyl oxime was identified by its reported H NMR and 13C NMR
shifts.[10] The E- and Z-stereochemical assignments were made with respect to the
isopropyl group according to the method described by Bunnell and Fuchs. The
observations can be qualitatively explained by postulating that the small upfield shift
of the anti-a2-carbons is primarily due to an inductive effect, but the larger upfield
shift of the syn-a1-carbons results from the combination of the inductive effect plus
a steric compression effect, which in turn results in additional shielding.[11]
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
Scheme 1. Synthesis of O-alkylated menthone oxime.

3104
S. FAISAL ET AL.
Table 2. Comparison of DSyna1 and DAntia2 values of oxime ethers with
menthone
Entry
d a1
D syn a1
d a2
D Anti-a2
3
4
31.96
32.02
29.72
32.14
32.20
31.92
31.94
33.35
32.26
31.83
18.92
18.86
21.16
18.74
18.68
18.96
18.94
17.53
18.62
19.05
48.52
48.47
48.55
48.59
48.57
48.56
48.46
47.44
48.62
48.56
7.38
7.43
7.35
7.31
7.33
7.34
7.44
8.46
7.28
7.34
5
6
7
8
9
10
11
12
Table 3. 13C NMR chemical shift (ppm) for (E)-menthone oxime ethers
Entry
Carbon Menthone E-Oxime
3
4
5
6
7
8
9
10
11
12
1
2
212.4
55.9
27.8
161.71 160.8 160.43 161.0 162.33 160.54 160.42 160.50 162.2 161.0 160.43
48.72 48.52 48.47 48.55 48.59 48.57 48.56 48.46 47.44 48.62 48.56
26.78 26.57 26.61 26.64 26.71 26.62 26.52 26.52 26.54 26.73 26.48
32.68 32.01 32.07 32.06 32.33 32.25 31.96 31.96 30.62 32.15 31.93
32.34 31.91 32.03 32.17 32.17 32.06 31.92 31.98 29.63 32.11 31.97
31.72 31.96 32.02 29.72 32.14 32.20 31.92 31.94 33.35 32.26 31.83
26.36 26.43 26.49 26.50 26.47 26.46 26.48 26.47 26.49 26.51 26.52
21.38 19.37 19.38 19.36 19.31 19.28 19.44 19.44 20.84 19.39 19.43
3
4
33.94
35.47
50.88
25.90
18.70
22.29
21.22
5
6
7
8
9
19.1
21.7
20.97 21.03 21.08 21.48 21.11 20.96 20.97 22.50 21.07 20.96
21.53 21.15 21.51 21.07 21.50 21.53 21.54 21.98 21.55 21.52
61.0 68.47 74.03 60.66 69.84 73.17 72.90 74.98 73.74 73.19
14.82 135.0 77.33 120.87 28.97 28.76 138.5 35.95 29.27
16.66 77.22 136.82 28.20 25.34 127.4 139.17 25.96
25.86 22.55 33.58 128.2 129.05 29.16
10
11
12
13
14
15
16
17
18.15 14.07 138.9 127.8 128.24 31.91
126.00 22.61
14.09
114.3
Note. Solvent: CDCl3.

O-ALKYLATION OF MENTHONE OXIME
3105
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
1H NMR spectra were recorded at 400 MHz in CDCl3 using tetramethylsilane
(TMS) as internal standered. (–)-Menthol was purchased from Sigma Aldrich
Chemicals Limited.
General Procedure for the Synthesis of Oxime Ethers
Oxidation of menthol. (–)-Menthol (15 g, 96 mmol) was taken in a round-
bottomed flask and dissolved in 30 ml of water at 60 ꢁC treated with sodium dichro-
mate dihydrate (11.65 g, 39 mmol) and 96% sulfuric acid (13.3 g, 135 mmol) in 60 ml
water. The addition of the oxidizing agent requires 40 min, and the temperature was
maintained at 66 to 70 ꢁC. The mixture was cooled and worked up in the usual way.
Oxime formation. Menthone (10 g, 64.9 mmol), hydroxylamine hydrochlor-
ide (4.6 g, 64.9 mmol), and sodium bicarbonate (5.45 g, 64.9 mmol) were taken in a
round-bottomed flask and dissolved in ethanol. The solution was kept overnight,
and products were extracted with ethyl acetate.
O-Alkylation of oxime. Menthone oxime (0.5 g, 2.95 mmol) was dissolved in
8 ml of tetrahydrofuran (THF). Sodium hydride (0.212 g, 8.85 mmol) was added at
0–5 ꢁC with stirring. After 30 min, a stoichiometric amount of alkyl halides was
added at 0–5 ꢁC, and the reaction mixture was kept overnight. The alkylated
products were extracted with dichloromethane.
Spectral Data
(2S,5R)-2-Isopropyl-5-methylcyclohexanone O-methyloxime (3). IR
1
(KBr, cmꢂ1): 2957, 2927, 2857, 1644, 1460, 1054, 873; H 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.
(2S,5R)-2-Isopropyl-5-methylcyclohexanone O-ethyloxime (4). IR (KBr,
1
cmꢂ1): 2955, 2928, 2872, 1635, 1453, 1397, 1053, 940, 874. H NMR (CDCl3, d
ppm): 1.81 (m, 1H), 1.36 (m, 1H), 1.85 (m, 1H), 1.23 (m, 1H), 2.10 (m, 1H), 1.4
(dd, 1H), 2.8 (dd, 2H, J ¼ 9.68 Hz), 1.82 (m, 1H), 0.92 (d, 3H, J ¼ 6.25 Hz), 0.89
(d, 3H, J ¼ 6.7 Hz), 4.04 (q, 2H, J ¼ 7.0 Hz), 1.21 (t, 3H, J ¼ 7.1 Hz). HRMS (EI)
calcd. for C12H23ON: 197.1774; observed: 197.1780.
(2S,5R)-2-Isopropyl-5-methylcyclohexanone O-allyloxime (5). IR (KBr,
1
cmꢂ1): 3081, 2956, 2926, 2868, 1698, 1516, 1458, 1366, 917, 768. H NMR (CDCl3,
d ppm): 1.82 (m, 1H), 1.38 (m, 1H), 1.81 (m, 1H), 1.10 (m, 1H), 1.75 (m, 1H), 1.79
(m, 1H), 2.82 (dd, 2H, J ¼ 9.35 Hz), 2.11 (m, 1H), 4.5 (d, 2H, J ¼ 4.5 Hz), 5.98 (m,
1H), 5.15 (d, 2H, J ¼ 10.41 Hz), 5.25 (d, 2H, J ¼ 17.2 Hz), 0.88 (d, 3H, J ¼ 6.74 Hz),
0.93 (d, 3H, J ¼ 6.21 Hz); HRMS (EI) calcd. for C13H23ON: 209.1779; observed:
209.1768.
(2S,5R)-2-Isopropyl-5-methylcyclohexanone O-(2-propynyl)oxime (6). IR
(KBr, cmꢂ1): 3308, 2955, 2926, 2870, 2123, 1640, 1456, 1357, 1046, 1006. 1H
NMR (CDCl3, d ppm): 18.2 (m, 1H), 1.37 (m, 1H), 1.77 (m, 1H), 1.24 (m, 1H),
1.48 (m, 1H), 2.83 (dd, 2H, J ¼ 9.1 Hz), 1.76 (m, 1H, J ¼ 6.6 Hz), 0.89 (d, 3H,
J ¼ 7.0 Hz), 0.92 (d, 3H, J ¼ 6.3 Hz), 4.59 (s, 2H), 2.40 (s, 1H). HRMS (EI) calcd.
for C13H21ON: 207.1623; observed: 207.1607.
(2S,5R)-2-Isopropyl-5-methylcyclohexanone
O-(3-methyl-2-butenyl)-
oxime (7). IR (KBr, cmꢂ1): 2954, 2925, 2870, 1675, 1635, 1451, 1376, 1011, 918,
1
850. H NMR (CDCl3, d ppm): 1.85 (m, 1H), 1.38 (m), 1.79 (m, 2H), 1.13 (m),
2.82 (dd, 2H, J ¼ 9.01 Hz), 2.10 (m, 1H), 0.92 (d, 3H, J ¼ 6.78 Hz), 0.90 (d, 3H,
J ¼ 6.89 Hz), 4.5 (d, 2H, J ¼ 6.52 Hz), 5.38 (t, 1H, J ¼ 7.54 Hz), 1.73 (s, 3H), 1.68
(s, 3H). HRMS (EI) calcd. for C15H27ON: 237.2093; observed: 237.2067.
(2S,5R)-2-Isopropyl-5-methylcyclohexanone O-pentyloxime (8). IR
1
(KBr, cmꢂ1): 2956, 2931, 2870, 1635, 1456, 1381, 1055, 919, 880. H NMR (CDCl3,
d ppm): 1.82 (m, 1H), 1.32 (m, 1H), 1.79 (m, 1H), 1.23 (m, 1H), 1.36 (m, 1H), 2.77
(dd, 2H, J ¼ 12.52 Hz), 2.11 (m, 1H), 0.89 (d, 3H, J ¼ 8.02 Hz), 0.85 (d, 3H,
J ¼ 6.77 Hz), 3.99 (t, 2H, J ¼ 6.61 Hz), 1.63 (m, 2H), 1.52 (m, 2H); HRMS (EI) calcd.
for C15H29ON: 239.2249; observed: 239.2270.
(2S,5R)-2-Isopropyl-5-methylcyclohexanone O-(5-hexenyl)oxime (9). IR
(KBr, cmꢂ1): 3077, 2931, 2953, 2869, 1695, 1640, 1455, 1377, 1051, 995, 913, 762.
1H NMR (CDCl3, d ppm): 2.05 (m, 1H), 1.42 (m, 1H), 1.78 (m, 1H), 1.2 (m, 1H),
1.83 (m, 1H), 1.80 (m, 1H), 1.39 (dd, 1H), 2.77 (dd, 2H, J ¼ 12.36 Hz), 2.08 (m,
1H), 0.89 (d, J ¼ 8.0 Hz, 3H), 0.85 (d, J ¼ 6.83 Hz, 3H), 3.98 (t, 2H, J ¼ 6.43 Hz),
1.62 (m), 1.64 (m), 5.79 (m), 4.95 (m); HRMS (EI) calcd. for C16H29ON:
251.2213; observed: 251.2249.
(2S,5R)-2-Isopropyl-5-methylcyclohexanone O-benzyloxime (10). IR
1
(KBr, cmꢂ1): 3031, 2957, 2925, 2866, 1631, 1455, 1366, 1045, 914, 913, 698. H
NMR (CDCl3, d ppm): 1.79 (m, 1H), 1.38 (m), 1.13 (m, 1H), 1.84 (m, 1H), 2.09
(m, J ¼ 6.3 Hz), 2.86 (dd, 2H, J ¼ 12.5 Hz), 2.10 (m, 1H), 0.92 (d, 3H, J ¼ 6.2 Hz),
0.87 (d, 3H, J ¼ 4.8 Hz), 0.86 (d, 3H, J ¼ 6.19 Hz), 5.0 (s, 2H), 7.31 (m, 5H); HRMS
(EI) calcd. for C17H27ON: 259.1936; observed: 259.1946.

O-ALKYLATION OF MENTHONE OXIME
3107
(2S,5R)-2-Isopropyl-5-methylcyclohexanone O-phenethyloxime (11). IR
(KBr, cmꢂ1): 3028, 2954, 2926, 2869, 1635, 1603, 1496, 1453, 1373, 1047, 1026,
1
917, 698. H NMR (CDCl3, d ppm): 1.84 (m, 1H), 1.38 (m), 1.13 (m, 1H), 1.74
(m, 1H), 2.79 (dd, 2H, J ¼ 9.445 Hz), 2.11 (m, 1H), 0.91 (d, 3H, J ¼ 6.71), 4.20 (t,
2H, J ¼ 7.1), 2.94 (t, 2H, J ¼ 6.92 Hz). HRMS (EI) calcd. for C18H27ON:
273.2093; observed: 273.2096.
(2S,5R)-2-Isopropyl-5-methylcyclohexanone O-heptyloxime (12). IR
1
(KBr, cmꢂ1): 2953, 2927, 2864, 1632, 1457, 1376, 1057, 920, 881. H NMR (CDCl3,
d ppm): 1.83 (m, 1H), 1.28 (m, 1H), 1.79 (m, 2H), 1.23 (m), 1.85 (m), 1.43 (dd), 2.77
(dd, 2H, J ¼ 9.05 Hz), 2.10 (m, 1H), 0.88 (m, 3H), 0.91 (m, 3H), 3.99 (t, 2H, J ¼ 6.71).
HRMS (EI) calcd. for C17H33ON: 267.256; observed: 267.254.
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.
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